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Research ArticleNovember 23, 2020

Origin of Stereoselectivity in FLP-Catalyzed Asymmetric Hydrogenation of Imines
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Andrea Hamza
Andrea Hamza
Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
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http://orcid.org/0000-0002-9614-8522
Kristina Sorochkina
Kristina Sorochkina
Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland
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Bianka Kótai
Bianka Kótai
Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
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Konstantin Chernichenko
Konstantin Chernichenko
Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland
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http://orcid.org/0000-0002-6425-5075
Dénes Berta
Dénes Berta
Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
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http://orcid.org/0000-0002-8299-3784
Michael Bolte
Michael Bolte
Institute of Inorganic Chemistry, Goethe-University, Max-von-Laue-Strasse 7, D-60438 Frankfurt am Main, Germany
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http://orcid.org/0000-0001-5296-6251
Martin Nieger
Martin Nieger
Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland
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http://orcid.org/0000-0003-1677-0109
Timo Repo*
Timo Repo
Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland
*Email: [email protected]
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http://orcid.org/0000-0002-3116-6199
Imre Pápai*
Imre Pápai
Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
*Email: [email protected]
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http://orcid.org/0000-0002-4978-0365

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ACS Catalysis

Cite this: ACS Catal. 2020, 10, 23, 14290–14301

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https://doi.org/10.1021/acscatal.0c04263

Published November 23, 2020

Abstract

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Development of metal-free strategies for stereoselective hydrogenation of unsaturated substrates is of particular interest in asymmetric synthesis. The emerging chemistry of frustrated Lewis pairs offers a promising approach along this line as demonstrated by recent achievements. However, the stereocontrol elements in these reactions are not clearly recognized thus far. Herein, we analyze the origin of stereoinduction in direct hydrogenation of imines catalyzed by a set of chiral boranes. We use the tools of computational chemistry to describe the elementary steps of the catalytic cycle, and we pay special attention to the stereoselectivity-determining hydride transfer process. The enantioselectivities predicted by the applied computational approach are in very good agreement with previous experimental observations. We find that the stereoselectivity is governed by a thermodynamically less favored conformer of the borohydride intermediate and not by the experimentally observed form. The most favored hydride transfer transition states are stabilized by specific aryl–aryl and alkyl–aryl noncovalent interactions, which play an important role in stereoinduction. This computational insight is exploited in proposing additional borane variants to improve the enantioselectivity, which could be demonstrated experimentally

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Introduction

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Chiral amines, particularly those bearing α-stereogenic carbon atoms, are widely used intermediates in the production of pharmaceuticals, agrochemicals, and fine chemicals. Therefore, the development of effective methods for enantioselective synthesis of these compounds is of high interest. (1) Among the available synthetic strategies, the asymmetric hydrogenation of prochiral imines and enamines by the direct use of H₂ as the hydrogen source represents a promising atom-economic approach. (2) A variety of transition metal (TM) complexes comprising chiral organic ligands have been developed, and some of them have proved to be efficient catalysts for direct enantioselective imine hydrogenations. Iridium complexes are known to be particularly powerful hydrogenation catalysts; however, achieving very high enantioselectivities for a wide range of substrates remains challenging. (3)

Metal-free routes to the synthesis of chiral amines via catalytic hydrogenation have also been developed in the past decade. (4) Several successful organocatalytic transfer hydrogenation reactions catalyzed by chiral phosphoric acids as well as hydrosilylations mediated by chiral Lewis bases have been reported, but these transformations require a stoichiometric amount of other hydrogen sources, such as Hantzsch ester or trichlorosilane. (5) The discovery that sterically hindered Lewis acid–base pairs are able to cleave molecular hydrogen reversibly under mild reaction conditions (6) opened a metal-free strategy for direct catalytic hydrogenation of unsaturated molecules. (7) These so-called frustrated Lewis pairs (FLPs) (8) were shown to catalyze various unsaturated organic substrates (9) even under water-tolerant conditions. (10)

The FLP concept has been successfully adopted to design asymmetric catalytic hydrogenation processes as well. (11) Pioneering contributions from Klankermayer et al. (12) provided the first examples of chiral induction by FLPs. Boranes 1–4 (Chart 1) were prepared via hydroboration of chiral olefins with Piers’ borane (C₆F₅)₂BH, (13) and they were employed for the hydrogenation of imines. The (+)-α-pinene derived borane 1 gave only a low enantiomeric excess (ee) in the product amine (13% ee); (12a) however, the asymmetric induction was notably improved (up to 83% ee) using boranes 2–4, which were derived from (1R)-(+)-camphor. (12b)

Chart 1. Selection of Chiral FLP Components Employed in Enantioselective Catalytic Hydrogenations^a

Repo and co-workers developed intramolecular FLPs with chiral amine moieties (e.g., 5); however, they resulted in only moderate enantioselectivities in catalytic hydrogenation of imines and quinolines (up to 37% ee). (14) The same group later introduced chirality via the binaphthyl framework into ansa-aminoboranes, and intramolecular FLP 6 was shown to be an efficient hydrogenation catalyst, particularly for asymmetric hydrogenation of enamines (ee values up to 99%). (15) In 2013, Du proposed a simple and powerful strategy to generate enantiomerically pure bis-boranes 7 in situ by direct hydroboration of binaphthyl-based terminal dienes. (16) Some representatives of this family of chiral boranes, especially those with very bulky Ar substituents on the binaphthyl framework, were demonstrated to be highly effective catalysts in enantioselective hydrogenation of imines, (16) silyl enol ethers, (17) and various heteroarenes (18) as well. Wang and co-workers have recently developed a series of C₂-symmetric bicyclic bis-boranes derived from cis-fused bicyclic dienes by hydroboration. (19) Stereoisomer 8 of this series was found to be exceptionally efficient for imine hydrogenation providing ee’s above 90% for the first time. In subsequent work, spiro-bicyclic bis-boranes 9 were also introduced, (20) exhibiting excellent catalytic activities and stereoselectivities for the hydrogenation of quinolines and 2-vinylpyridines. Attempts to control the stereochemistry of FLP-type hydrogenation by chiral Lewis bases resulted in only modest enantioselectivities, (9b) until a very recent study reported by the Du group, (21) which established this approach as a promising direction for the design of new chiral FLPs. Quite remarkably, chiral oxazolines such as 10, combined with achiral boranes were shown to induce high degree of enantioselectivity in asymmetric hydrogenation of ketones and enones. In addition to direct catalytic hydrogenation, FLP-type asymmetric hydrosilylation has also been successfully applied to reduce various unsaturated substrates with high enantioselectivities. (22)

Despite these impressive advances, our knowledge regarding the stereocontrol elements in FLP-catalyzed asymmetric hydrogenation processes is quite scanty. So far, only a few computational studies have been reported that supplemented the synthetic developments and addressed the issue of stereoselectivity. (15,21,23) Density functional theory (DFT) calculations carried out for the highly selective enamine hydrogenation with catalyst 6 indicated that the energy difference obtained for the hydride transfer transition states leading to the two enantiomeric amine products stems from a combination of repulsive steric and attractive noncovalent interactions. (15) The stereoselectivity determining transition states for asymmetric hydrogenation of ketones catalyzed with the B(p-C₆F₄H)₃/10 pair were also identified computationally. (21) The predicted energy differences were consistent with experimental observations, but the origin of stereoinduction was not examined.

To gain more insight into the nature of molecular interactions responsible for the stereoselectivity of FLP-catalyzed hydrogenation, in our present work we investigated a reaction that is frequently used as a test case in the evaluation of developed catalysts, namely, the direct hydrogenation of imine (E)-N-(1-phenylethylidene)-aniline (im, see Scheme 1). As shown previously, the enantioselectivity of this reaction varies in a fairly broad range (from poor to good) when structurally analogous boranes 1–3 are applied as catalysts; thus, this series of reactions allows us to inspect the effect of a single chiral borane substituent on the stereochemical outcome of the hydrogenation process.

Scheme 1. Reactions Examined Computationally

In this work, we focus primarily on the stereoselectivity-determining hydride transfer step of these reactions; however, for borane 2, we provide a detailed analysis of the H₂ activation process as well. We closely inspect the conformational space of the iminium borodyride species, which is a key intermediate prior to product formation. Accurate prediction of stereoselectivities from quantum chemical calculations is rather challenging. (24) In our present analysis, we attempted to pay respect to the critical issues (e.g., conformational complexity, the choice of the electronic structure method, estimation of entropic contributions, and solvent effects), and computed the enantioselectivity of the examined reactions accordingly (for computational details, see the Supporting Information (SI)). The good agreement obtained between the predicted and observed stereoselectivities allowed us to probe the origin of stereoinduction in these reactions. Based on the new computational insights, structural modifications in borane 2 were proposed, and two of these new chiral boranes were synthesized and tested as catalysts in asymmetric hydrogenation of imines.

Results

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Alternative Catalytic Cycles

As described by Klankermayer et al., (12b) the camphor-derived boranes 2 and 3 could not be isolated in pure stereoisomeric forms; however, kinetically controlled product formation in the reaction of the 2/3 mixture with phosphine P^tBu₃ (P) and H₂ enabled isolation of diastereomerically pure ion pair compounds PH⁺/2H^– and PH⁺/3H^–. These phosphonium/hydroborate FLP salts were then used as catalysts in the hydrogenation of imines. In principle, the catalysis in these reactions can take place via two distinct cycles, as illustrated in Scheme 2.

In cycle 1, the heterolytic H₂ splitting is induced by the P/B pair resulting in the PH⁺/BH^– ion pair. Proton transfer from PH⁺ to im gives the imH⁺/BH^– intermediate, which then undergoes hydride transfer (HT) to yield the chiral amine product am. Alternatively, the imine can serve as a base component of an FLP, so the imH⁺/BH^– intermediate is formed directly via H₂ activation (cycle 2). The HT process represents the stereoselectivity-determining step in both cycles. Our computational analysis suggests that cycle 2 is a more feasible pathway. DFT calculations carried out for the reaction with borane 2 predict a significantly higher barrier for H₂ activation with the P/2 pair as compared to that with im/2 (19.9 versus 15.8 kcal/mol; see Figure 1). (25)

Figure 1. Transition states of H₂ activation by the P/2 and im/2 FLPs. Relative stabilities (in kcal/mol, with respect to the base + B + H₂ reactant states) are given in parentheses. H atoms of the FLPs are omitted for clarity.

Even though P^tBu₃ is certainly more basic than imine im, (26) steric hindrance between the chiral borane substituent and the bulky phosphine destabilizes the transition state of H₂ splitting (TS_HH^P/2) leading to an increased barrier. Furthermore, the protonation of im on the P/2 pathway is computed to have even higher barrier (31.6 kcal/mol) rendering cycle 1 far less favorable. (27) Our calculations thus indicate that although the catalytic process in the hydrogenation of im is initiated by the PH⁺/2H^– ion pair, the catalysis follows the im/2 pathway. The high barrier obtained for the initiation step is consistent with the elevated temperature (T = 65 °C) used in the experimental setup. (12b)

Iminium Borohydride Intermediates for Borane 2

The conformational space of the imH⁺/BH^– intermediate formed upon H₂ activation is rather complex because both ionic components can adopt different structures and their relative positions can vary as well. Conformations of borohydrides BH^– can be classified into three groups that differ in the orientation of the B–H unit with respect to the chiral backbone (Chart 2).

Chart 2. Main Borohydride Conformers as Exemplified by 2H^–

The C₆F₅ borane substituent may also display altered orientations within these classes, resulting in several structural forms. For borohydride 2H^–, DFT calculations predict a c₁-type conformation to be the most stable form, wherein one of the C₆F₅ rings is in stacking arrangement with the phenyl substituent of the chiral unit. (28) This borohydride structure was characterized experimentally via X-ray diffraction analysis of compound PH⁺/2H^–, and it was assumed to play an important role in the catalytic process. (12b) In principle, both E and Z isomers of iminium imH⁺ could be produced in the H₂ activation step, so we have considered this possibility in our computational analysis as well.

For the imH⁺/2H^– ion pair intermediate, we carried out an extensive conformational analysis and identified 14 different isomeric forms all lying within a 5 kcal/mol free energy range. (29) A few representative structures are displayed in Figure 2.

Figure 2. Selected structures of **imH**⁺/2H^– ion pair intermediates. In the labeling, H···H and H···C refer to structures with B–H units pointing to iminium N–H bond or to prochiral C atom; c₁ and c₂ denote two different borohydride conformers. Relative stabilities (in kcal/mol, with respect to the im + 2 + H₂) are given in parentheses. Selected bond distances are in angstroms.

The most stable form of imH⁺/2H^– involves a c₁ borohydride conformer with the B–H bond interacting closely with the iminium N–H group (H···H/c₁ in Figure 2). This imH⁺/2H^– isomer is formed directly after transition state TS_HH^im/2, and it is predicted to be 2.0 kcal/mol above the reactant state (im + 2 + H₂). The dihydrogen bond is apparent from the very short intermolecular H···H distance (1.53 Å), and it provides considerable stabilization for the ion-pair intermediate. (30) Isomer H···H/c₂ features a dihydrogen bonding interaction as well; however, the borohydride anion adopts a c₂-type conformation. This form lies at 2.8 kcal/mol in free energy. Isomeric forms with B–H bonds pointing toward the electrophilic carbon atom of the substrate (H···C/c₁ and H···C/c₂ in Figure 2) are notably less stable as compared to their H···H/c_i analogues; however, these isomers are structurally well prepared for the HT step of the catalytic cycle. Our computational analysis indicates that the H···H and H···C type imH⁺/2H^– isomers can easily interconvert with each other. For instance, the transformation of isomer H···H/c₂ to H···C/c₂ shown in Figure 2 can take place via a barrier of only 5.3 kcal/mol. Computations also suggest that facile transformation between the c₁ and c₂ borohydride conformers is feasible; the free energy barrier estimated for the c₁ → c₂ conversion is only 8.7 kcal/mol. (31) These results imply that the array of conformational isomers identified computationally for the structurally flexible ion-pair intermediate imH⁺/2H^– is likely in fast equilibrium even at room temperature.

Hydride Transfer Transition States for Borane 2

The conformational space of HT transition states leading to the (R)-am and (S)-am enantiomeric products were explored comprehensively, and we identified a set of energetically low-lying conformers on both pathways. The relative stabilities of the most stable structures are summarized in a free energy diagram shown in Figure 3, wherein selected transition-state structures are also depicted.

Figure 3. Hydride transfer transition states identified computationally for hydrogenation of im with borane 2. Each line on the free energy diagram represents a specific isomeric form with the computed relative stability. **TS-2-R**_i and **TS-2-S**_i denote transition states leading to (R)-am and (S)-am products (index i defines the stability order). Full and dotted lines refer to transition state isomers involving c₂ and c₁ borohydride conformers. Selected structures are depicted and marked with arrows; their relative stabilities are given in parentheses (in kcal/mol, with respect to the most stable form). The iminium component is highlighted in blue for clarity. Green and red dotted arrows indicate attractive and repulsive intermolecular contacts. Computed and experimental (in brackets) ee data are shown below the diagram.

The most favored HT transition state corresponds to the formation of product (R)-am (see TS-2-R₁ in Figure 3), and it is predicted to be 14.8 kcal/mol with respect to the reactant state (im + 2 + H₂). In this structure, the borohydride that donates H^– to the iminium has a c₂ conformation, which is somewhat surprising because the c₂ form of 2H^– is predicted to be 4.7 kcal/mol less stable as compared to the c₁ form. (28) Several intermolecular contacts, such as π–π stacking between the iminium phenyl and the borohydride C₆F₅ substituents, or CH···π interaction between the iminium CH₃ and the borohydride phenyl groups, are noticeable in TS-2-R₁. As shown previously for TM-catalyzed hydrogenation reactions, these types of noncovalent interactions can strongly influence the stereochemical outcome; (32,33) therefore, they may provide notable stabilization to transition state TS-2-R₁ as well. Additional HT transition states involving the c₂ form of 2H^– could be identified on the (R) reaction pathway (TS-2-R₂ and TS-2-R₃), but they are computed to be 2–3 kcal/mol less stable than TS-2-R₁. The extent of noncovalent interactions in higher lying transition states is reduced, which corroborates the stabilizing nature of these intermolecular contacts.

Interestingly, the most favored transition state comprising a c₁-type 2H^– conformation (TS-2-R₄) is predicted to be even higher in free energy (at 4.3 kcal/mol). This structure is destabilized by steric repulsion between the chiral borane substituent and the methyl group of iminium imH⁺, which becomes too close as demonstrated by rather short H···H distances measured in the optimized structure (∼2.1 Å). (34)

On the HT reaction pathway that furnishes the minor (S)-am enantiomeric product, iminium imH⁺ approaches 2H^– with the other face. The most stable transition state TS-2-S₁ also involves a c₂-type borohydride; however, the intermolecular contacts are different from those in TS-2-R₁. Although the CH···π interaction between the iminium CH₃ and the borohydride phenyl groups is still present in TS-2-S₁, no close π–π stacking interactions are perceived. The phenyl substituent of the borohydride interacts with the iminium phenyl group, but this aryl–aryl interaction is far from the ideal stacking or T-shaped arrangements. Overall, transition state TS-2-S₁ is found to be 1.5 kcal/mol less stable than TS-2-R₁. Several other close-lying transition states were located on the (S) pathway, of which the next in the stability order (TS-2-S₂) incorporates a c₁-type borohydride. Steric hindrance is also a characteristic feature of this transition state structure (similarly to TS-2-R₄), but due to more favorable π–π stacking interactions, TS-2-S₂ is more stable than TS-2-R₄.

The enantioselectivity of catalytic imine hydrogenation is under kinetic control. (35) The rapid equilibration of various isomers of the imH⁺/2H^– intermediate enables the application of the Curtin–Hammett principle, so the enantiomeric excess (ee) can be estimated from the Boltzmann-weighted relative Gibbs free energies of the identified HT transition states. Using this procedure, the ee of the kinetically favored (R)-am product in the present reaction is computed to be 80.7%, which is in good agreement with the experimental observation (79%). (12b,36)

Reaction with Borane 3

Assuming that the concepts discussed in the previous sections and our conclusions regarding the hydrogenation mechanism can be extended to the analogous reactions with other boranes, we carried out a systematic computational study for the HT process with borane 3 as well. Borane 3 is the diastereomeric pair of 2 having the same bridged bicyclic (R)-camphor derived framework with the altered stereochemical arrangement of the B(C₆F₅)₂ and Ph units (see Chart 1). The free energy diagram illustrating the relative stabilities of HT transition states computed for im hydrogenation with borane 3 is shown in Figure 4 along with the most stable structures identified on the (R) and (S) pathways.

Figure 4. Hydride transfer transition states identified computationally for hydrogenation of im with borane 3. For further relevant information, see the caption of Figure 3.

The most favored transition state TS-3-S₁ can be regarded as a pseudoenantiomeric form of TS-2-R₁ displaying a c₂-type borohydride conformation and the same type of stabilizing intermolecular contacts (π–π stacking and CH₃–π interactions). In this reaction, however, HT transition states involving the c₁ borohydride conformation tend to be energetically more favored as compared to those in the reaction with borane 2, and in fact, the lowest lying transition state on the minor (R) pathway (TS-3-R₁) encompasses a c₁-type borohydride. This latter transition state is computed to be only 0.4 kcal/mol apart from TS-3-S₁. Our structural analysis points to a somewhat reduced steric hindrance between the methyl group of iminium imH⁺ and the chiral bicyclic 3H^– substituent in transition states with c₁ borohydrides, which explains the tendency of having these transition state structures more populated in the reaction with borane 3. (37) As a result of reduced steric repulsion, two transition states (TS-3-R₁ and TS-3-S₂) shift closer to the most favored TS-3-S₁ structure in free energy, which of course influences the enantioselectivity as well. Computations predict ee = 33.7% for this reaction, which is consistent with the measured enantioselectivity (48%). (12b)

Reaction with Borane 1

HT transition state isomers for the reaction with borane 1 were also explored, and we identified a set of structures, some of which were found to have very similar relative stabilities (see Figure 5). (38)

Figure 5. Hydride transfer transition states identified computationally for hydrogenation of im with borane 1. For further relevant information, see the caption of Figure 3. The classification of transition states according to the borohydride conformations is not relevant in this case. The lowest lying energy level in the (S) ensemble (at 0.4 kcal/mol) represents two different structures, **TS-1-S**₁ and **TS-1-S**₂, of which only the former is depicted.

Due to the lack of any bulky substituent on the α-pinene framework in borane 1 (such as Ph in 2 and 3), the chiral environment around the reactive B–H bond of borohydride 1H^– is less defined. For instance, no multiple combinations of stabilizing π–π stacking and CH₃–π contacts are developed between 1H^– and imH⁺; therefore, no structure with particularly enhanced stabilities exists. For the same reason, the most favored transition states on the competing (R) and (S) pathways become less separated in free energy. Indeed, calculations predict five different transition state structures within a 0.5 kcal/mol range, and the most stable diastereomeric forms (TS-1-R₁ and TS-1-S₁) display very similar intermolecular contacts (a single π–π stacking and a CH···π type interaction; see Figure 5). Consequently, a very low enantioselectivity is predicted (ee = 1.5%), which is again in line with experimental observations (13%). (12a)

On the Origin of Stereoselectivity

Several important findings that emerged from our computational analysis are worth highlighting when discussing the origin of enantioselectivity in the examined reactions. First, it appears that for camphor-derived boranes 2 and 3, the stereoselectivity of imine hydrogenation is dictated by thermodynamically less favored borohydride conformers of c₂-type and not by the most stable c₁ form that is observed experimentally. The c₂ conformer of 2H^– is clearly more reactive in hydride transfer to imH⁺ and with its phenyl substituent arranged next to the B–H bond provides a chiral binding site for the approaching protonated substrate. The chiral environment is defined by the three aromatic rings of the borohydride resulting in facial selectivity for the hydride transfer (Figure 6).

Figure 6. Noncovalent interactions (NCI) in hydride transfer transition states **TS-2-R**₁ and **TS-2-S**₁. The borohydride is represented by a gray isodensity surface (ρ = 0.01 au); the iminium is shown in blue. The applied cutoff for reduced density gradient is s = 0.3 au. π–π stacking and CH₃–π interactions are highlighted by green dotted arrows.

The stereoinduction in the present reactions is found to be influenced by multiple stabilizing noncovalent interactions between 2H^– and imH⁺, which are apparent from the NCI plots (39) generated for transition states TS-2-R₁ and TS-2-S₁. The green surface areas on these plots represent weak attractive noncovalent interactions corresponding to π–π stacking, CH₃–π, Ph–Ph, etc. intermolecular contacts. As noted above, and also illustrated in Figure 6, the higher stability of transition state TS-2-R₁ could be associated with more favorable aromatic (C₆F₅···C₆H₅) interactions in this structure as compared to that in TS-2-S₁.

Proposed Modifications in Borane 2

Our computational analysis indicates that the phenyl substituent of camphor derived boranes is an important stereocontrol element in catalytic hydrogenation of im. This is further supported by calculations carried out for a model reaction catalyzed by a borane derived from 2 by omitting the Ph substituent. These calculations predict very low ee (only 5.6%) in this case. (40) We envisioned that additional substitutions implemented on the Ph group of borane 2, or replacing the Ph group by a larger aromatic ring, could alter the enantioselectivity of hydrogenation. The boranes considered for additional computational analysis are shown in Figure 7. (41)

Figure 7. Modified boranes and predicted ee data.

DFT calculations carried out for reactions catalyzed by boranes derived from 2 by adding either electron-withdrawing (F and CF₃) or electron-donating (CH₃ and ^tBu) groups at the meta positions of the Ph ring predicted significantly enhanced enantioselectivities (ee’s above 98%). We find that in these reactions, HT transition state conformers analogous to TS-2-S₁ are notably destabilized with respect to the corresponding R₁ structures. This is due to steric effects induced by the meta substituents on the catalyst Ph group. As discussed above, transition state TS-2-S₁ is displaced only by 1.5 kcal/mol from the most stable TS-2-R₁ structure (Figure 3), but this free energy difference increases to 4–5 kcal/mol with the modified boranes. The strength of the CH₃–π interaction is also altered by introducing the meta substituents, (42) but these interactions are equally present in the most stable diastereomeric transition states (R₁ and S₁; see Figure 6), so they have no considerable influence on the enantioselectivity. For borane 2-ant, calculations predict somewhat lower ee (90.5%). In this borane variant, the c₁-type borohydride conformations attain further stabilization via the extended aromatic stacking interactions, so all HT transition states of c₁-type shift closer in free energy to the most stable form, reducing the enantioselectivity.

Experiments with Borane 2-F

To assess the reliability of DFT predictions, we first synthesized borane 2-F according to the procedure established for the reported camphor-derived boranes 2 and 3 (12) (Scheme 3). Reaction of enantiopure (1R)-(+)-camphor (11) with aryllithium 12, followed by dehydration of resulting tertiary alcohol 13 with thionyl chloride/pyridine gave olefin 14. Hydroboration of 14 with Piers’ borane under solvent-free conditions resulted in a mixture of diastereomeric boranes 2-F and 2-F′ in a 7:1 ratio according to multinuclear NMR. Pure 2-F could be isolated from the crude mixture by recrystallization from pentane at −20°C as a colorless powder in 52% yield, and its structure was confirmed by single-crystal X-ray diffraction analysis (Figure 8).

Scheme 3. Synthesis of Chiral Borane **2-F**

Figure 8. Crystal structure of borane **2-F**. H atoms are omitted for clarity.

Catalytic hydrogenation of imine im with 2-F gave high conversions (above 90%) in 1 h at room temperature, however, no improvement could be obtained for the enantioselectivity as compared to that observed by Klankermayer et al.; the ee measured in our experiments reached 75% at most, depending on the reaction conditions (see Table S6 in the Supporting Information). Noteworthy, hydrogenation of im in the presence of external base 1,2,2,6,6-pentamethylpiperidine (PMP, 5 mol %) gave only 13% conversion. These results support the view emerging from the computational analysis that catalytic hydrogenation takes place via cycle 2 (Scheme 2) even in the presence of an external base.

The reason for the disagreement we see between the computed and measured enantioselectivities is not fully settled. The discrepancy may certainly arise from the inaccuracy of the DFT calculations, although the good match obtained for boranes 1–3 points to other, yet unknown, factors. In an attempt to provide a plausible explanation, we decided to assess the stability of 2-F upon the hydrogenation process. In a thick-wall gas-tight NMR tube, a stoichiometric mixture of 2-F and im in deuterated toluene was pressurized with 10 bar of dihydrogen. After 1 h, the sample was analyzed by ¹H NMR, which revealed appearance of a new set of signals related to camphor scaffold in addition to those of 2-F (44% conversion). Although we could not reliably identify the structure of the newly formed species, a detailed NMR data analysis (¹⁹F, ¹¹B, HH COSY and HH NOESY, see the SI) suggested that it was isomeric to both 2-F and 2-F′. The same species, albeit to a lesser extent (with 18% conversion), was formed when am was probed instead of im under the same reaction condition. On the basis of these observations, it is reasonable to assume that the new borane species produced in the catalytic process may catalyze a parallel low-enantioselective hydrogenation of im, which deteriorates the overall enantioselectivity of this reaction.

Experiments with Borane 2-^tBu

Next, we decided to synthesize and to test borane 2-^tBu, which involves bulkier 3,5-substituents on the phenyl group. Attempt to produce 2-^tBu following the established procedure as for 2-F was unsuccessful due to predominant enolization of 11 upon addition of either 3,5-di-tert-butylphenyllithium or -magnesium bromide. Therefore, we designed an alternative synthetic route outlined in Scheme 4. Camphor 11 was transformed into bromobornene 17 via the Shapiro reaction. The subsequent Suzuki-Miyaura cross-coupling of 17 with 3,5-di-tert-butylphenyl boronic acid 18 gave alkene 19 in 79% yield. The hydroboration of 19 using Piers’ borane under solvent-free conditions gave exclusively diastereomer 2-^tBu in nearly quantitative yield. Recrystallization of 2-^tBu from n-pentane at −20°C provided colorless crystals (83% yield) suitable for X-ray crystallographic analysis (Figure 9).

Scheme 4. Synthesis of Chiral Borane **2-^tBu**

Figure 9. Crystal structure of borane 2-^tBu. H atoms are omitted for clarity.

Hydrogenation of imine im using 5 mol % borane 2-^tBu at room temperature and 50 bar H₂ in toluene gave only moderate conversion (52%) after 1 h, however, the enantioselectivity was high (91% ee; see Table S7 in the Supporting Information). Prolongation of reaction time to 24 h led to quantitative hydrogenation of im with similarly high enantiomeric excess (92%), demonstrating the stability of the catalyst under the applied conditions. Solvent screening showed only a small effect on the stereoselectivity, giving slightly lower ees in etherial solvents (see Table S7 in the Supporting Information). We note that this level of selectivity in FLP-type imine hydrogenation could only be accomplished by recently developed bicyclic borane 8 at significantly lower temperature (−40 °C).

Broadening of substrate scope was not an objective of our present work, but catalyst 2-^tBu was tested for the hydrogenation of a few additional imines as well (Table 1 and also Table S8 in the Supporting Information). Various N-aryl-substituted-imines 20a–20d and imine 20e bearing nonaromatic cyclohexyl substituent at nitrogen could be reduced with high stereoselectivities (91-94% ee). On the other hand, hydrogenation of the benzyl-substituted imine 20f resulted in a dramatically lower enantioselectivity (33%). Quantitative hydrogenation of 2-phenyl quinoline 20g to 2-phenyl-1,2,3,4-tetrahydroquinoline 21g could also be achieved, albeit in 48 h with doubling of catalyst loading, and with a significantly reduced ee (21%). Hydrogenation of selected substrates im and 20c at lower temperature (−15°C) afforded slightly enhanced enantioseletivities: 95% and 96% ee, respectively.

Table 1. Asymmetric Hydrogenations of Imines with 2-^tBu^a

^{^a}

Substrate (0.25 mmol), PhMe (0.5ml), conversion by ¹H NMR spectroscopy, ee by HPLC (Chiralcel OD-H or OJ-H column).

^{^b}

For detailed optimization, see Table S7 in the Supporting Information.

^{^c}

Reaction time 48 h.

^{^d}

10 mol % of 2-^tBu.

These results highlight and confirm the importance of specific aryl–aryl and aryl–alkyl catalyst–substrate interactions in stereoinduction. For the particular borane catalyst 2-^tBu and imines with topology analogous to im (20a–20e) the overall effect of attractive noncovalent and destabilizing steric interactions is highly beneficial; however, this balance is far from optimal for other substrates (20f and 20g).

Summary and Conclusions

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Utilization of chiral FLP catalysts in direct asymmetric hydrogenation of unsaturated compounds is a potential metal-free strategy in stereoselective synthesis. Remarkable developments have been achieved along this line over the past decade; however, the current level of comprehension concerning the stereoselectivity governing factors in these catalytic processes is not sufficient thus far to facilitate new catalyst design. In our present work, we performed a detailed computational analysis for imine hydrogenation reactions reported previously by the Klankermayer group, namely those catalyzed by chiral boranes derived from (+)-α-pinene (borane 1 in Chart 1) and (1R)-(+)-camphor (boranes 2 and 3). Although only a single imine substrate (im) was considered in our computational study, and the selection of borane catalysts is limited as well, yet several interesting findings and conclusions have emerged from our analysis, which considerably improve our understanding.

Computations carried out for imine hydrogenation with borane 2 (the most selective reaction in the series) revealed that catalysis operates preferably via H₂ activation with the im/2 pair even if the borane is introduced in a phosphonium–borohydride form, as in the original experiments. This computational insight could be supported experimentally in our work. The analysis focusing on the hydride transfer step pointed to fast equilibration of various isomers of the imH⁺/2H^– intermediate. We showed that the stereoselectivity is dictated by a thermodynamically unfavored borohydride isomer, and not by the most stable, experimentally observed form. This latter 2H^– isomer is less reactive for steric reasons. In the active form of 2H^–, the phenyl substituent of the camphor framework, along with the two C₆F₅ aromatic rings, define a chiral pocket for the approaching protonated substrate (imH⁺). The most stable hydride transfer transition states are found to be stabilized by specific noncovalent interactions, such as π–π stacking, CH₃–π, and Ph–Ph intermolecular contacts. The enantioselectivity predicted by DFT calculations is in close agreement with experimental observations, and we find similarly good match between computed and measured ee data for the reactions with boranes 1 and 3.

Based on these promising results, we anticipated that alteration of the Ph substituent in borane 2 could be beneficial for stereoinduction, and indeed, calculations for boranes with 3,5-disubstituted Ph groups predicted significantly improved enantioselectivities. Two of these new borane candidates were selected for experimental studies. Boranes 2-F and 2-^tBu were synthesized and probed as catalysts in imine hydrogenation. No improvement in the measured ee could be demonstrated with borane 2-F, but the experiments inferred that catalytic hydrogenation could be performed at room temperature in the absence of an external base. Borane 2-^tBu, however, was shown to be a robust and efficient FLP catalyst in imine hydrogenation, providing ee’s above 90%, which could only be achieved so far at significantly lower temperature.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscatal.0c04263.

Details regarding the computational analysis, total energies and Cartesian coordinates for the considered stationary points, and experimental details (PDF)

cs0c04263_si_001.pdf (7.27 MB)

Terms & Conditions

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Author Information

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Corresponding Authors
- Timo Repo - Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland; http://orcid.org/0000-0002-3116-6199; Email: [email protected]
- Imre Pápai - Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary; http://orcid.org/0000-0002-4978-0365; Email: [email protected]
Authors
- Andrea Hamza - Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary; http://orcid.org/0000-0002-9614-8522
- Kristina Sorochkina - Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland
- Bianka Kótai - Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
- Konstantin Chernichenko - Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland; http://orcid.org/0000-0002-6425-5075
- Dénes Berta - Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary; http://orcid.org/0000-0002-8299-3784
- Michael Bolte - Institute of Inorganic Chemistry, Goethe-University, Max-von-Laue-Strasse 7, D-60438 Frankfurt am Main, Germany; http://orcid.org/0000-0001-5296-6251
- Martin Nieger - Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, 00014 Helsinki, Finland; http://orcid.org/0000-0003-1677-0109
Author Contributions
A.H. and K.S. contributed equally.
Notes
The authors declare no competing financial interest.
CCDC 2007899 (2-F), and 2007900 (2-^tBu) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/.

Acknowledgments

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Financial support for this work was provided by the Hungarian Scientific Research Fund Grant No. K-115660) and from the Academy of Finland (Grant No. 316207). A.H. acknowledges the János Bolyai Scholarship from Hungarian Academy of Sciences. Computer facilities provided by NIIF HPC Hungary (project 85708 kataproc) are also acknowledged. We are grateful to Dr. Tibor András Rokob for insightful discussions and to Dr. Péter Nagy for assisting with benchmark studies.

References

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This article references 42 other publications.

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Frustrated Lewis Pair Chemistry: Development and Perspectives
Stephan, Douglas W.; Erker, Gerhard
Angewandte Chemie, International Edition (2015), 54 (22), 6400-6441CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Frustrated Lewis pairs (FLPs) are combinations of Lewis acids and Lewis bases in soln. that are deterred from strong adduct formation by steric and/or electronic factors. This opens pathways to novel cooperative reactions with added substrates. Small-mol. binding and activation by FLPs has led to the discovery of a variety of new reactions through unprecedented pathways. Hydrogen activation and subsequent manipulation in metal-free catalytic hydrogenations is a frequently obsd. feature of many FLPs. The current state of this young but rapidly expanding field is outlined in this Review and the future directions for its broadening sphere of impact are considered.
(c) Stephan, D. W. Frustrated Lewis Pairs. J. Am. Chem. Soc. 2015, 137, 10018– 10032, DOI: 10.1021/jacs.5b06794
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Frustrated Lewis Pairs
Stephan, Douglas W.
Journal of the American Chemical Society (2015), 137 (32), 10018-10032CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A review. The articulation of the notion of "frustrated Lewis pairs" (FLPs), which emerged from the discovery that H2 can be reversibly activated by combinations of sterically encumbered Lewis acids and bases, has prompted a great deal of recent activity. Perhaps the most remarkable consequence has been the development of FLP catalysts for the hydrogenation of a range of org. substrates. In the past 9 years, the substrate scope has evolved from bulky polar species to include a wide range of unsatd. org. mols. In addn., effective stereoselective metal-free hydrogenation catalysts have begun to emerge. The mechanism of this activation of H2 has been explored, and the nature and range of Lewis acid/base combinations capable of effecting such activation have also expanded to include a variety of non-metal species. The reactivity of FLPs with a variety of other small mols., including olefins, alkynes, and a range of element oxides, has also been developed. Although much of this latter chem. has uncovered unique stoichiometric transformations, metal-free catalytic hydroamination, CO2 redn. chem., and applications in polymn. have also been achieved. The concept is also beginning to find applications in bioinorg. and materials chem. as well as heterogeneous catalysis. This Perspective highlights many of these developments and discusses the relationship between FLPs and established chem. Some of the directions and developments that are likely to emerge from FLP chem. in the future are also presented.
(d) Stephan, D. W. Frustrated Lewis Pairs: From Concept to Catalysis. Acc. Chem. Res. 2015, 48, 306– 316, DOI: 10.1021/ar500375j
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Frustrated Lewis Pairs: From Concept to Catalysis
Stephan, Douglas W.
Accounts of Chemical Research (2015), 48 (2), 306-316CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review. Frustrated Lewis pair (FLP) chem. has emerged in the past decade as a strategy that enables main-group compds. to activate small mols. This concept is based on the notion that combinations of Lewis acids and bases that are sterically prevented from forming classical Lewis acid-base adducts have Lewis acidity and basicity available for interaction with a third mol. This concept has been applied to stoichiometric reactivity and then extended to catalysis. This Account describes three examples of such developments: hydrogenation, hydroamination, and CO2 redn. The most dramatic finding from FLP chem. was the discovery that FLPs can activate H2, thus countering the long-existing dogma that metals are required for such activation. This finding of stoichiometric reactivity was subsequently evolved to employ simple main-group species as catalysts in hydrogenations. While the initial studies focused on imines, subsequent studies uncovered FLP catalysts for a variety of org. substrates, including enamines, silyl enol ethers, olefins, and alkynes. Moreover, FLP redns. of arom. anilines and N-heterocycles have been developed, while very recent extensions have uncovered the utility of FLP catalysts for ketone redns. FLPs have also been shown to undergo stoichiometric reactivity with terminal alkynes. Typically, either deprotonation or FLP addn. reaction products are obsd., depending largely on the basicity of the Lewis base. While a variety of acid/base combinations have been exploited to afford a variety of zwitterionic products, this reactivity can also be extended to catalysis. When secondary aryl amines are employed, hydroamination of alkynes can be performed catalytically, providing a facile, metal-free route to enamines. In a similar fashion, initial studies of FLPs with CO2 demonstrated their ability to capture this greenhouse gas. Again, modification of the constituents of the FLP led to the discovery of reaction systems that demonstrated stoichiometric redn. of CO2 to either methanol or CO. Further modification led to the development of catalytic systems for the redn. of CO2 by hydrosilylation and hydroboration or deoxygenation. As each of these areas of FLP chem. has advanced from the observation of unusual stoichiometric reactions to catalytic processes, it is clear that the concept of FLPs provides a new strategy for the design and application of main-group chem. and the development of new metal-free catalytic processes.
(e) Stephan, D. W. The Broadening Reach of Frustrated Lewis Pair Chemistry. Science 2016, 354, aaf7229– aaf7229, DOI: 10.1126/science.aaf7229
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(f) Jupp, A. R.; Stephan, D. W. New Directions for Frustrated Lewis Pair Chemistry. Trends in Chemistry 2019, 1, 35– 48, DOI: 10.1016/j.trechm.2019.01.006
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New Directions for Frustrated Lewis Pair Chemistry
Jupp, Andrew R.; Stephan, Douglas W.
Trends in Chemistry (2019), 1 (1), 35-48CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)
A review. The concerted action of a Lewis acid and base can activate H2 and other small mols. Such frustrated Lewis pairs (FLPs) have garnered much attention and prompted many investigations into the activation of small mols. and catalysis. Although the nature, mechanism of action, and range of FLP systems continues to expand, this concept has also inspired ever-widening chem. Applications in hydrogenation and polymn. catalysis, as well as in synthetic chem., have provided selective processes and metal-free protocols. Heterogeneous FLP catalysts are emerging, and polymeric FLPs offer avenues to unique materials and strategies for sensing and carbon capture. The prospects for further impact of this remarkably simple reaction paradigm are considered.
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For reviews on FLP-type catalytic hydrogenations, see:
(a) Stephan, D. W.; Erker, G. Frustrated Lewis Pairs: Metal-free Hydrogen Activation and More. Angew. Chem., Int. Ed. 2010, 49, 46– 76, DOI: 10.1002/anie.200903708
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Frustrated Lewis Pairs: Metal-free Hydrogen Activation and More
Stephan, Douglas W.; Erker, Gerhard
Angewandte Chemie, International Edition (2010), 49 (1), 46-76CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Sterically encumbered Lewis acid and Lewis base combinations do not undergo the ubiquitous neutralization reaction to form classical Lewis acid/Lewis base adducts. Rather, both the unquenched Lewis acidity and basicity of such sterically frustrated Lewis pairs (FLPs) is available to carry out unusual reactions. Typical examples of frustrated Lewis pairs are inter- or intramol. combinations of bulky phosphines or amines with strongly electrophilic RB(C6F5)2 components. Many examples of such frustrated Lewis pairs are able to cleave dihydrogen heterolytically. The resulting H+/H- pairs (stabilized for example, as the resp. phosphonium cation/hydridoborate anion salts) serve as active metal-free catalysts for the hydrogenation of, for example, bulky imines, enamines, or enol ethers. Frustrated Lewis pairs also react with alkenes, aldehydes, and a variety of other small mols., including carbon dioxide, in cooperative three-component reactions, offering new strategies for synthetic chem.
(b) Stephan, D. W.; Greenberg, S.; Graham, T. W.; Chase, P.; Hastie, J. J.; Geier, S. J.; Farrell, J. M.; Brown, C. C.; Heiden, Z. M.; Welch, G. C.; Ullrich, M. Metal-Free Catalytic Hydrogenation of Polar Substrates by Frustrated Lewis Pairs. Inorg. Chem. 2011, 50, 12338– 12348, DOI: 10.1021/ic200663v
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Metal-Free Catalytic Hydrogenation of Polar Substrates by Frustrated Lewis Pairs
Stephan, Douglas W.; Greenberg, Sharonna; Graham, Todd W.; Chase, Preston; Hastie, Jeff J.; Geier, Stephen J.; Farrell, Jeffrey M.; Brown, Christopher C.; Heiden, Zachariah M.; Welch, Gregory C.; Ullrich, Matthias
Inorganic Chemistry (2011), 50 (24), 12338-12348CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
In 2006, the first metal-free systems that reversibly activate hydrogen were reported. This finding was extended to the discovery of "frustrated Lewis pair" (FLP) catalysts for hydrogenation. It is this catalysis that is the focal point of this article. The development and applications of such FLP hydrogenation catalysts are reviewed, and some previously unpublished data are reported. The scope of the substrates is expanded to include indoles and diimines. Optimal conditions and functional group tolerance are considered and applied to targets of potential com. significance. Recent developments in asym. FLP hydrogenations are also reviewed. The future of FLP hydrogenation catalysts is considered.
(c) Stephan, D. W.; Erker, G. Frustrated Lewis Pair Mediated Hydrogenations. Topics in Current Chemistry; Springer: Berlin, 2013; pp 85– 110.
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(d) Sumerin, V.; Chernichenko, K.; Schulz, F.; Leskelä, M.; Rieger, B.; Repo, T. Amine-Borane Mediated Metal-Free Hydrogen Activation and Catalytic Hydrogenation. Topics in Current Chemistry; Springer: Berlin, 2012; pp 111– 155.
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(e) Paradies, J. Metal-Free Hydrogenation of Unsaturated Hydrocarbons Employing Molecular Hydrogen. Angew. Chem., Int. Ed. 2014, 53, 3552– 3557, DOI: 10.1002/anie.201309253
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Metal-Free Hydrogenation of Unsaturated Hydrocarbons Employing Molecular Hydrogen
Paradies, Jan
Angewandte Chemie, International Edition (2014), 53 (14), 3552-3557CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The metal-free activation of hydrogen by frustrated Lewis pairs (FLPs) is a valuable method for the hydrogenation of polarized unsatd. mols. ranging from imines, enamines, and silyl enol ethers to heterocycles. However, one of the most important applications of hydrogenation technol. is the conversion of unsatd. hydrocarbons into alkanes. Despite the fast development of the FLP chem., such reactions proved as highly challenging. This minireview provides an overview of the basic concepts of FLP chem., the challenge in the hydrogenation of unsatd. hydrocarbons, and first solns. to this central transformation.
(f) Hounjet, L. J.; Stephan, D. W. Hydrogenation by Frustrated Lewis Pairs: Main Group Alternatives to Transition Metal Catalysts?. Org. Process Res. Dev. 2014, 18, 385– 391, DOI: 10.1021/op400315m
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Hydrogenation by Frustrated Lewis Pairs: Main Group Alternatives to Transition Metal Catalysts?
Hounjet, Lindsay J.; Stephan, Douglas W.
Organic Process Research & Development (2014), 18 (3), 385-391CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
A review. Since the discovery of "frustrated Lewis pairs" in 2006, these metal-free systems have been exploited to activate a variety of small mols., with H2 being perhaps the most significant among them. This finding has since allowed for the development of metal-free strategies to hydrogenation catalysis. In this review, progress toward the development of these new catalysts for redns. of polar org. substrates, olefins, alkynes, and arom. systems, is described.
(g) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Designing Effective ‘Frustrated Lewis Pair’ Hydrogenation Catalysts. Chem. Soc. Rev. 2017, 46, 5689– 5700, DOI: 10.1039/C7CS00154A
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Designing effective 'frustrated Lewis pair' hydrogenation catalysts
Scott, Daniel J.; Fuchter, Matthew J.; Ashley, Andrew E.
Chemical Society Reviews (2017), 46 (19), 5689-5700CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. The past decade has seen the subject of transition metal-free catalytic hydrogenation develop incredibly rapidly, transforming from a largely hypothetical possibility to a well-established field that can be applied to the redn. of a diverse variety of functional groups under mild conditions. This remarkable change is principally attributable to the development of so-called 'frustrated Lewis pairs': unquenched combinations of bulky Lewis acids and bases whose dual reactivity can be exploited for the facile activation of otherwise inert chem. bonds. While a no. of comprehensive reviews into frustrated Lewis pair chem. have been published in recent years, this tutorial review aims to provide a focused guide to the development of efficient FLP hydrogenation catalysts, through identification and consideration of the key factors that govern their effectiveness. Following discussion of these factors, their importance will be illustrated using a case study from our own research, namely the development of FLP protocols for successful hydrogenation of aldehydes and ketones, and for related moisture-tolerant hydrogenation.
(h) Paradies, J. From Structure to Novel Reactivity in Frustrated Lewis Pairs. Coord. Chem. Rev. 2019, 380, 170– 183, DOI: 10.1016/j.ccr.2018.09.014
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From structure to novel reactivity in frustrated Lewis pairs
Paradies, Jan
Coordination Chemistry Reviews (2019), 380 (), 170-183CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
A review. The coexistence of a strong Lewis acid and a Lewis base in soln., the so called frustrated Lewis pair, has led to the discovery of metal-free hydrogen activation. Since then, this observation has inspired numerous chemists to develop more examples. Metal-free hydrogenation is so far the most studied application of frustrated Lewis pairs in chem. and highly efficient methodologies for a no. of substrates have been developed. However, the targeted choice of a FLP-catalyst is yet rather intricate, due to the lack of an in depth understanding of FLP-reactivity. The presented structure-reactivity-relationship for hydrogenation reactions allowed the targeted development and optimization of unprecedented reactions using FLPs as catalysts. This article provides insight into FLP-reactivity by summarizing our mechanistic and synthetic work in this field.
(i) Lam, J.; Szkop, K. M.; Mosaferi, E.; Stephan, D. W. FLP Catalysis: Main Group Hydrogenations of Organic Unsaturated Substrates. Chem. Soc. Rev. 2019, 48, 3592– 3612, DOI: 10.1039/C8CS00277K
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FLP catalysis: main group hydrogenations of organic unsaturated substrates
Lam, Jolie; Szkop, Kevin M.; Mosaferi, Eliar; Stephan, Douglas W.
Chemical Society Reviews (2019), 48 (13), 3592-3612CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. This article is focused on recent developments in main group mediated hydrogenation chem. and catalysis using 'frustrated Lewis pairs' (FLPs). The broading range of substrates and catalyst systems is reviewed and the advances in catalytic redns. and the development of stereoselective, asym. redns. made since 2012 was considered.
(j) Paradies, J. Mechanisms in Frustrated Lewis Pair-Catalyzed Reactions. Eur. J. Org. Chem. 2019, 2019, 283– 294, DOI: 10.1002/ejoc.201800944
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Mechanisms in Frustrated Lewis Pair-Catalyzed Reactions
Paradies, Jan
European Journal of Organic Chemistry (2019), 2019 (2-3), 283-294CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This review summarizes the principle reaction mechanisms of frustrated Lewis pairs (FLP) in hydrogenations and carbon-nitrogen and carbon-carbon bond forming reactions. The fundamental mechanism of hydrogen activation by FLPs is reviewed and the influence of the FLP's nature on hydrogenation reactions is discussed, leading to a structure-reactivity relationship in phosphine/borane or amine/borane derived FLPs. This reactivity concept is validated for a series of FLP-catalyzed reactions. Furthermore, alternative reaction mechanisms e.g. protodeborylations or σ-bond metathesis are discussed.
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For development of water-tolerant FLP catalysts, see:
(a) Mahdi, T.; Stephan, D. W. Enabling Catalytic Ketone Hydrogenation by Frustrated Lewis Pairs. J. Am. Chem. Soc. 2014, 136, 15809– 15812, DOI: 10.1021/ja508829x
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Enabling Catalytic Ketone Hydrogenation by Frustrated Lewis Pairs
Mahdi, Tayseer; Stephan, Douglas W.
Journal of the American Chemical Society (2014), 136 (45), 15809-15812CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Hydrogenation of alkyl and aryl ketones using H2 is catalytically achieved in 18 examples using 5 mol% B(C6F5)3 in an ethereal solvent. In these cases the borane and ether behave as a frustrated Lewis pair to activate H2 and effect the redn.
(b) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Nonmetal Catalyzed Hydrogenation of Carbonyl Compounds. J. Am. Chem. Soc. 2014, 136, 15813– 15816, DOI: 10.1021/ja5088979
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Nonmetal catalyzed hydrogenation of carbonyl compounds
Scott, Daniel J.; Fuchter, Matthew J.; Ashley, Andrew E.
Journal of the American Chemical Society (2014), 136 (45), 15813-15816CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Solns. of the Lewis acid B(C6F5)3 in 1,4-dioxane are found to effectively catalyze the hydrogenation of a variety of ketones and aldehydes. These reactions, the first to allow entirely metal-free catalytic hydrogenation of carbonyl groups under relatively mild reaction conditions, are found to proceed via a "frustrated Lewis pair" mechanism in which the solvent, a weak Bronsted base yet moderately strong donor, plays a pivotal role.
(c) Gyömöre, Á.; Bakos, M.; Földes, T.; Pápai, I.; Domján, A.; Soós, T. Moisture-Tolerant Frustrated Lewis Pair Catalyst for Hydrogenation of Aldehydes and Ketones. ACS Catal. 2015, 5, 5366– 5372, DOI: 10.1021/acscatal.5b01299
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Moisture-Tolerant Frustrated Lewis Pair Catalyst for Hydrogenation of Aldehydes and Ketones
Gyomore, Adam; Bakos, Maria; Foldes, Tamas; Papai, Imre; Domjan, Attila; Soos, Tibor
ACS Catalysis (2015), 5 (9), 5366-5372CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
In this paper, we report on the development of a bench-stable borane for frustrated Lewis pair catalyzed redn. of aldehydes, ketones, and enones. The deliberate fine-tuning of structural and electronic parameters of Lewis acid component and the choice of Lewis base provided for the first time, a moisture-tolerant FLP catalyst. Related NMR and DFT studies underpinned the unique behavior of this FLP catalyst and gave insight into the catalytic activity of the resulting FLP catalyst.
(d) Scott, D. J.; Simmons, T. R.; Lawrence, E. J.; Wildgoose, G. G.; Fuchter, M. J.; Ashley, A. E. Facile Protocol for Water-Tolerant “Frustrated Lewis Pair”-Catalyzed Hydrogenation. ACS Catal. 2015, 5, 5540– 5544, DOI: 10.1021/acscatal.5b01417
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Facile Protocol for Water-Tolerant "Frustrated Lewis Pair"-Catalyzed Hydrogenation
Scott, Daniel J.; Simmons, Trevor R.; Lawrence, Elliot J.; Wildgoose, Gregory G.; Fuchter, Matthew J.; Ashley, Andrew E.
ACS Catalysis (2015), 5 (9), 5540-5544CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
Despite rapid advances in the field of metal-free, "frustrated Lewis pair" (FLP)-catalyzed hydrogenation, the need for strictly anhyd. reaction conditions has hampered wide-scale uptake of this methodol. Herein, we report that, despite the generally perceived moisture sensitivity of FLPs, 1,4-dioxane solns. of B(C6F5)3 actually show appreciable moisture tolerance and can catalyze hydrogenation of a range of weakly basic substrates without the need for rigorously inert conditions. In particular, reactions can be performed directly in com. available nonanhydrous solvents without subsequent drying or use of internal desiccants.
(e) Fasano, V.; Radcliffe, J. E.; Ingleson, M. J. B(C₆F₅)₃-Catalyzed Reductive Amination Using Hydrosilanes. ACS Catal. 2016, 6, 1793– 1798, DOI: 10.1021/acscatal.5b02896
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B(C6F5)3-Catalyzed Reductive Amination using Hydrosilanes
Fasano, Valerio; Radcliffe, James E.; Ingleson, Michael J.
ACS Catalysis (2016), 6 (3), 1793-1798CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
In contrast to the established dogma that B(C6F5)3 is irreversibly poisoned by excess H2O/amine (or imine) bases, B(C6F5)3 is actually a water-tolerant catalyst for the reductive amination of primary and secondary arylamines with aldehydes and ketones in "wet solvents" at raised temps. and using only 1.2 equiv of Me2PhSiH as reductant. Arylamines/N-arylimines do not result in the irreversible deprotonation of H2O-B(C6F5)3, allowing sufficient B(C6F5)3 to be evolved at raised temps. to effect catalytic redns. Stronger Bronsted basic amines such as tBuNH2 (and derived imines) result in irreversible formation of [HO-B(C6F5)3]- from H2O-B(C6F5)3, precluding the formation of B(C6F5)3 at raised temps. and thus preventing any imine redn. A substrate scope exploration using 1 mol % nonpurified B(C6F5)3 and "wet solvents" demonstrates that this is an operationally simple and effective methodol. for the prodn. of secondary and tertiary arylamines in high yield, with imine redn. proceeding in preference to other possible reactions catalyzed by B(C6F5)3, including the dehydrosilylation of H2O and the redn. of carbonyl moieties (e.g., esters).
(f) Scott, D. J.; Phillips, N. A.; Sapsford, J. S.; Deacy, A. C.; Fuchter, M. J.; Ashley, A. E. Versatile Catalytic Hydrogenation Using A Simple Tin(IV) Lewis Acid. Angew. Chem., Int. Ed. 2016, 55, 14738– 14742, DOI: 10.1002/anie.201606639
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Versatile Catalytic Hydrogenation Using A Simple Tin(IV) Lewis Acid
Scott, Daniel J.; Phillips, Nicholas A.; Sapsford, Joshua S.; Deacy, Arron C.; Fuchter, Matthew J.; Ashley, Andrew E.
Angewandte Chemie, International Edition (2016), 55 (47), 14738-14742CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Despite the rapid development of frustrated Lewis pair (FLP) chem. over the last ten years, its application in catalytic hydrogenations remains dependent on a narrow family of structurally similar early main-group Lewis acids (LAs), inevitably placing limitations on reactivity, sensitivity, and substrate scope. Herein, we describe the FLP-mediated H2 activation and catalytic hydrogenation activity of the alternative LA iPr3SnOTf, which acts as a surrogate for the trialkylstannylium ion iPr3Sn+, and is rapidly and easily prepd. from simple, inexpensive starting materials. This highly thermally robust LA is found to be competent in the hydrogenation of a no. of different unsatd. functional groups (which is unique to date for main-group FLP LAs not based on boron), and also displays a remarkable tolerance to moisture.
(g) Dorkó, É.; Szabó, M.; Kótai, B.; Pápai, I.; Domján, A.; Soós, T. Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls. Angew. Chem., Int. Ed. 2017, 56, 9512– 9516, DOI: 10.1002/anie.201703591
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Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls
Dorko, Eva; Szabo, Mark; Kotai, Bianka; Papai, Imre; Domjan, Attila; Soos, Tibor
Angewandte Chemie, International Edition (2017), 56 (32), 9512-9516CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented. As systematic steric tuning of the boron-based Lewis acid (LA) component revealed, the enhanced back-strain makes water binding increasingly reversible in the presence of relatively strong base. This advance allows the limits of FLP's hydrogenation to be expanded, as demonstrated by the FLP reductive amination of carbonyls. This metal-free catalytic variant displays a notably broad chemoselectivity and generality.
(h) Sapsford, J. S.; Scott, D. J.; Allcock, N. J.; Fuchter, M. J.; Tighe, C. J.; Ashley, A. E. Direct Reductive Amination of Carbonyl Compounds Catalyzed by a Moisture Tolerant Tin(IV) Lewis Acid. Adv. Synth. Catal. 2018, 360, 1066– 1071, DOI: 10.1002/adsc.201701418
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Direct Reductive Amination of Carbonyl Compounds Catalyzed by a Moisture Tolerant Tin(IV) Lewis Acid
Sapsford, Joshua S.; Scott, Daniel J.; Allcock, Nathan J.; Fuchter, Matthew J.; Tighe, Christopher J.; Ashley, Andrew E.
Advanced Synthesis & Catalysis (2018), 360 (6), 1066-1071CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
Despite the ever-broadening applications of main-group 'frustrated Lewis pair' (FLP) chem. to both new and established reactions, their typical intolerance of water, esp. at elevated temps. (>100°), represents a key barrier to their mainstream adoption. Herein the authors report that FLPs based on the Lewis acid iPr3SnOTf are moisture tolerant in the presence of moderately strong nitrogenous bases, even under high temp. regimes, allowing them to operate as simple and effective catalysts for the reductive amination of org. carbonyls, including for challenging bulky amine and carbonyl substrate partners.
(i) Hoshimoto, Y.; Kinoshita, T.; Hazra, S.; Ohashi, M.; Ogoshi, S. Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H₂. J. Am. Chem. Soc. 2018, 140, 7292– 7300, DOI: 10.1021/jacs.8b03626
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Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H2
Hoshimoto, Yoichi; Kinoshita, Takuya; Hazra, Sunit; Ohashi, Masato; Ogoshi, Sensuke
Journal of the American Chemical Society (2018), 140 (23), 7292-7300CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Given the growing demand for green and sustainable chem. processes, the catalytic reductive alkylation of amines with main-group catalysts of low toxicity and mol. hydrogen as the reductant would be an ideal method to functionalize amines. However, such a process remains challenging. Herein, a novel reductive alkylation system using H2 is presented, which proceeds via a tandem reaction that involves the B(2,6-Cl2C6H3)(p-HC6F4)2-catalyzed formation of an imine and the subsequent hydrogenation of this imine catalyzed by a frustrated Lewis pair (FLP). This reductive alkylation reaction generates H2O as the sole byproduct and directly functionalizes amines that bear a remarkably wide range of substituents including carboxyl, hydroxyl, addnl. amino, primary amide, and primary sulfonamide groups. The synthesis of isoindolinones and aminophthalic anhydrides has also been achieved by a one-pot process that consists of a combination of the present reductive alkylation with an intramol. amidation and intramol. dehydration reactions, resp. The reaction showed a zeroth-order and a first-order dependence on the concn. of an imine intermediate and B(2,6-Cl2C6H3)(p-HC6F4)2, resp. In addn., the reaction progress was significantly affected by the concn. of H2. These results suggest a possible mechanism in which the heterolysis of H2 is facilitated by the FLP comprising THF and B(2,6-Cl2C6H3)(p-HC6F4)2.
(j) Fasano, V.; LaFortune, J. H. W.; Bayne, J. M.; Ingleson, M. J.; Stephan, D. W. Air- and Water-Stable Lewis Acids: Synthesis and Reactivity of P-Trifluoromethyl Electrophilic Phosphonium Cations. Chem. Commun. 2018, 54, 662– 665, DOI: 10.1039/C7CC09128A
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Air- and water-stable Lewis acids: synthesis and reactivity of P-trifluoromethyl electrophilic phosphonium cations
Fasano, V.; LaFortune, J. H. W.; Bayne, J. M.; Ingleson, M. J.; Stephan, D. W.
Chemical Communications (Cambridge, United Kingdom) (2018), 54 (6), 662-665CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
A new class of electrophilic phosphonium cations (EPCs) contg. a -CF3 group attached to the P(V) center is readily accessible in high yields, via a scalable process. These species are stable to air, H2O, alc. and strong Bronsted acid, even at raised temps. Thus, P-CF3 EPCs are more robust than previously reported EPCs contg. P-X moieties (X = F, Cl, OR), and despite their reduced Lewis acidity they function as Lewis acid catalysts without requiring anhyd. reaction conditions.
(k) Fasano, V.; Ingleson, M. J. Recent Advances in Water-Tolerance in Frustrated Lewis Pair Chemistry. Synthesis 2018, 50, 1783– 1795, DOI: 10.1055/s-0037-1609843
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Recent Advances in Water-Tolerance in Frustrated Lewis Pair Chemistry
Fasano, Valerio; Ingleson, Michael J.
Synthesis (2018), 50 (9), 1783-1795CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
A water-tolerant frustrated Lewis pair (FLP) combines a sterically encumbered Lewis acid and Lewis base that in synergy are able to activate small mols. even in the presence of water. The main challenge introduced by water comes from its reversible coordination to the Lewis acid which causes a marked increase in the Bronsted acidity of water. Indeed, the oxophilic Lewis acids typically used in FLP chem. form water adducts whose acidity can be comparable to that of strong Bronsted acids such as HCl, thus they can protonate the Lewis base component of the FLP. Irreversible proton transfer quenches the reactivity of both the Lewis acid and the Lewis base, precluding small mol. activation. This short review discusses the efforts to overcome water-intolerance in FLP systems, a topic that in less than five years has seen significant progress. (1) Introduction (2) Water-Tolerance (or Alc.-Tolerance) in Carbonyl Redns. (3) Water-Tolerance with Stronger Bases (4) Water-Tolerant Non-Boron-Based Lewis Acids in FLP Chem.( 5) Conclusions.
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For review articles, see:
(a) Chen, D.; Klankermayer, J. Frustrated Lewis Pairs: From Dihydrogen Activation to Asymmetric Catalysis. Top. Curr. Chem. 2013, 334, 1– 26, DOI: 10.1007/128_2012_402
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11a
Frustrated Lewis Pairs: from dihydrogen activation to asymmetric catalysis
Chen Dianjun; Klankermayer Jurgen
Topics in current chemistry (2013), 334 (), 1-26 ISSN:0340-1022.
The non-self-quenched property of Frustrated Lewis Pairs (FLPs) contradicts the classical Lewis acid-base theory, but this peculiarity offers unprecedented possibilities for the activation of small molecules. Among all of their fascinating applications, FLP mediated hydrogen activation and the associated catalytic hydrogenations are currently considered as the most intriguing illustration of their reactivity. The FLPs enabled the catalytic reduction of a wide range of substrates with molecular hydrogen and tuning of the structural properties of the FLP partners allowed broadening of the substrate scope. Based on detailed mechanistic knowledge, FLP based asymmetric hydrogenation of various substrates could be achieved with high enantioselectivities. More importantly, FLP based enantioselective catalysis is not limited to the field of asymmetric hydrogenation, and other exciting catalytic applications have already appeared.
(b) Feng, X.; Du, H. Metal-Free Asymmetric Hydrogenation and Hydrosilylation Catalyzed by Frustrated Lewis Pairs. Tetrahedron Lett. 2014, 55, 6959– 6964, DOI: 10.1016/j.tetlet.2014.10.138
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11b
Metal-free asymmetric hydrogenation and hydrosilylation catalyzed by frustrated Lewis pairs
Feng, Xiangqing; Du, Haifeng
Tetrahedron Letters (2014), 55 (51), 6959-6964CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
A review. This Letter will outline the recent important progress of metal-free catalytic asym. hydrogenation and hydrosilylation using FLP catalysts.
(c) Shi, L.; Zhou, Y.-G. Enantioselective Metal-Free Hydrogenation Catalyzed by Chiral Frustrated Lewis Pairs. ChemCatChem 2015, 7, 54– 56, DOI: 10.1002/cctc.201402838
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11c
Enantioselective Metal-Free Hydrogenation Catalyzed by Chiral Frustrated Lewis Pairs
Shi, Lei; Zhou, Yong-Gui
ChemCatChem (2015), 7 (1), 54-56CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The FLP catalyst for hydrogenation will have a significant impact on this field, which is still dominated by chiral transition-metal catalysts, and could provide an effective metal-free pathway for the synthesis of valuable chiral amines and alcs. However, to achieve better enantioselectivity, reaction activity, and a wider substrate scope further research is required. Theor., a mode IV FLP catalyst would offer several combinations of chiral B moiety and chiral N(P) moiety and would enable rapid screening of catalysts.
(d) Paradies, J. Chiral Borane-Based Lewis Acids for Metal Free Hydrogenations. Topics in Organometallic Chemistry; Springer International Publishing, 2018; pp 193– 216.
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(e) Meng, W.; Feng, X.; Du, H. Frustrated Lewis Pairs Catalyzed Asymmetric Metal-Free Hydrogenations and Hydrosilylations. Acc. Chem. Res. 2018, 51, 191– 201, DOI: 10.1021/acs.accounts.7b00530
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11e
Frustrated Lewis Pairs Catalyzed Asymmetric Metal-Free Hydrogenations and Hydrosilylations
Meng, Wei; Feng, Xiangqing; Du, Haifeng
Accounts of Chemical Research (2018), 51 (1), 191-201CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review. The use of frustrated Lewis pairs is an extremely important approach to metal-free hydrogenations. In contrast to the rapid growth of catalytic reactions, asym. hydrogenations are far less developed due to a severe shortage of readily available chiral frustrated Lewis pair catalysts with high catalytic activities and selectivities. Unlike the stable Lewis base component of frustrated Lewis pairs, the moisture-sensitive boron Lewis acid component is difficult to prep. The development of convenient methods for the quick construction of chiral boron Lewis acids is therefore of great interest. In this Account, we summarize our recent studies on frustrated Lewis pair-catalyzed, asym. metal-free hydrogenations and hydrosilylations. To address the shortage of highly active and selective catalysts, we developed a novel strategy for the in situ prepn. of chiral boron Lewis acids by the hydroboration of chiral dienes or diynes with Piers' borane without further purifn., which allows chiral dienes or diynes to act like ligands. This strategy ensures the construction of a useful toolbox of catalysts for asym. metal-free hydrogenations and hydrosilylations is rapid and operationally simple. Another strategy is using combinations of readily available Lewis acids and bases contg. hydridic and acidic hydrogen atoms, resp., as a novel type of frustrated Lewis pairs. Such systems provide a great opportunity for using simple chiral Lewis bases as the origins of asym. induction. With chiral diene-derived boron Lewis acids as catalysts, a broad range of unsatd. compds., such as imines, silyl enol ethers, 2,3-disubstituted quinoxalines, and polysubstituted quinolines, are all viable substrates for asym. metal-free hydrogenations and give the corresponding products in good yields with high enantioselectivities and/or stereoselectivities. These chiral catalysts are very effective for bulky substrates, and the substrate scope for these metal-free asym. hydrogenations has been dramatically expanded. Chiral alkenylboranes were designed to enhance the rigidity of the framework and modify the Lewis acidity through the resulting double bonds. Frustrated Lewis pairs of chiral alkenylboranes and phosphines are a class of highly effective catalysts for asym. Piers-type hydrosilylations of 1,2-dicarbonyl compds., and they give the desired products in high yields and enantioselectivities. Moreover, asym. transfer hydrogenations of imines and quinoxalines with ammonia borane as the hydrogen source have been achieved with frustrated Lewis pair of Piers' borane and (R)-tert-butylsulfinamide as the catalyst. Mechanistic studies have suggested that the hydrogen transfer occurs via an 8-membered ring transition state, and regeneration of the reactive frustrated Lewis pair with ammonia borane occurs through a concerted 6-membered ring transition state.
(f) Meng, W.; Feng, X.; Du, H. Asymmetric Catalysis with Chiral Frustrated Lewis Pairs. Chin. J. Chem. 2020, 38, 625– 634, DOI: 10.1002/cjoc.202000011
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Asymmetric Catalysis with Chiral Frustrated Lewis Pairs
Meng, Wei; Feng, Xiangqing; Du, Haifeng
Chinese Journal of Chemistry (2020), 38 (6), 625-634CODEN: CJOCEV; ISSN:1001-604X. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This perspective article mainly focuses on the recent advances for the synthesis of chiral Lewis acidic boranes in category of three protocols, (1) hydroboration of chiral internal alkenes with Piers' borane HB(C6F5)2; (2) in situ hydroboration of chiral alkenes or alkynes without any purifn.; (3) and substitution reaction of (C6F5)nBCl3-n with chiral organometallic reagents, as well as their applications in the metal-free asym. hydrogenations and hydrosilylations.
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(a) Chen, D.; Klankermayer, J. Metal-Free Catalytic Hydrogenation of Imines with Tris(Perfluorophenyl)Borane. Chem. Commun. 2008, 2130– 2131, DOI: 10.1039/b801806e
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12a
Metal-free catalytic hydrogenation of imines with tris(perfluorophenyl)borane
Chen, Dianjun; Klankermayer, Juergen
Chemical Communications (Cambridge, United Kingdom) (2008), (18), 2130-2131CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Metal-free homogeneous catalyzed hydrogenation of various imines was accomplished with tris(perfluorophenyl)borane under moderate reaction conditions.
(b) Chen, D.; Wang, Y.; Klankermayer, J. Enantioselective Hydrogenation with Chiral Frustrated Lewis Pairs. Angew. Chem., Int. Ed. 2010, 49, 9475– 9478, DOI: 10.1002/anie.201004525
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12b
Enantioselective Hydrogenation with Chiral Frustrated Lewis Pairs
Chen, Dianjun; Wang, Yutian; Klankermayer, Juergen
Angewandte Chemie, International Edition (2010), 49 (49), 9475-9478, S9475/1-S9475/30CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Frustrated Lewis pairs (FLPs) have been recently introduced as an unprecedented possibility to activate hydrogen. On the basis of this concept the first example of highly enantioselective catalytic hydrogenation of imines using chiral camphor/borane-derived FLPs I and II has been demonstrated.
(c) Ghattas, G.; Chen, D.; Pan, F.; Klankermayer, J. Asymmetric Hydrogenation of Imines with a Recyclable Chiral Frustrated Lewis Pair Catalyst. Dalton Trans. 2012, 41, 9026– 9028, DOI: 10.1039/c2dt30536d
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Asymmetric hydrogenation of imines with a recyclable chiral frustrated Lewis pair catalyst
Ghattas, Ghazi; Chen, Dianjun; Pan, Fangfang; Klankermayer, Juergen
Dalton Transactions (2012), 41 (30), 9026-9028CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
A camphor based chiral phosphonium hydrido borate zwitterion was synthesized and successfully applied in the enantioselective hydrogenation of imines with selectivities up to 76% ee. The high stability of the novel chiral FLP-system enables effective recycling of the metal-free catalyst.
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(a) Parks, D. J.; von H. Spence, R. E.; Piers, W. E. Bis(Pentafluorophenyl)Borane: Synthesis, Properties, and Hydroboration Chemistry of a Highly Electrophilic Borane Reagent. Angew. Chem., Int. Ed. Engl. 1995, 34, 809– 811, DOI: 10.1002/anie.199508091
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13a
Bis(pentafluorophenyl)borane: synthesis, properties, and hydroboration chemistry of a highly electrophilic borane reagent
Parks, Daniel J.; von H. Spence, Rupert E.; Piers, Warren E.
Angewandte Chemie, International Edition in English (1995), 34 (7), 809-11CODEN: ACIEAY; ISSN:0570-0833. (VCH)
Reaction of (C6F5)2BCl with hydride transfer reagent, Me2Si(Cl)H, gave 52% title compd., (C6F5)BH 1. 1 Is a highly active hydroboration reagent towards a range of simple alkenes and alkynes. Addn. of the olefin or alkyne to a suspension of the borane in benzene led to the rapid dissoln. of the solid, and the reaction was complete in 2 min. Thus, hydroboration of Me2C:CMe2 and HC≡CH with 1 gave Me2CHCMe2B(C6F5) and CH:CMeB(C6F5) resp.
(b) Parks, D. J.; Piers, W. E.; Yap, G. P. a. Synthesis, Properties, and Hydroboration Activity of the Highly Electrophilic Borane Bis(Pentafluorophenyl)Borane. Organometallics 1998, 17, 5492– 5503, DOI: 10.1021/om980673e
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13b
Synthesis, Properties, and Hydroboration Activity of the Highly Electrophilic Borane Bis(pentafluorophenyl)borane, HB(C6F5)2
Parks, Daniel J.; Piers, Warren E.; Yap, Glenn P. A.
Organometallics (1998), 17 (25), 5492-5503CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
Two reliable and efficient routes to bis(pentafluorophenyl)borane, 1, are described. A three-step procedure uses the C6F5-transfer agent Me2Sn(C6F5)2 to produce the chloroborane ClB(C6F5)2, which is subsequently converted to 1 by treatment with a silane, and proceeds with an overall yield of 62%. Alternatively, 1 can be made in 69% yield from B(C6F5)3 and Et3SiH by heating the two reagents at 60° for 3 days in benzene. Borane 1 is dimeric in the solid state, as detd. by x-ray crystallog. anal. However, in arom. solvents, detectable amts. of monomeric borane are present (ratio of dimer:monomer 4.5:1). The ease of dimer dissocn. to monomer coupling with the high electrophilicity of the borane makes 1 a very reactive hydroboration reagent in arom. solvents. Hydroborations do not proceed in donor solvents such as THF. A survey of a variety of olefin and alkyne substrates shows that 1 hydroborates with comparable regio- and chemoselectivities to commonly used reagents such as 9-BBN, but at a much faster rate. A 2nd unique feature of the reagent is the facility with which boryl migration takes place in the products of olefin hydroboration. This property can be used to access thermodn. products of hydroboration where other reagents give diastereomeric kinetic products. Alkynes can be selectively monohydroborated; terminal alkyne substrates will react with a 2nd equiv. of 1, while internal alkynes are immune to further hydroboration. Two procedures for the oxidn. of the products of hydroboration were developed. Since the organobis(pentafluorophenyl)boranes are susceptible to protonolysis, oxidn. must be carried out in a two-phase system using highly alk. H2O2 or with a nonaq. procedure using Me3NO as the oxidant. Hydroboration/oxidn. can be carried out rapidly in a 1-pot procedure which gives alc. or carbonyl products in good to excellent yields. E.g., 1-naphthyl-1-cyclohexene was added to a suspension of 1 in benzene followed by addn. of THF and 4.4N H2O2 soln. (30% H2O2/H2O/KOH) to give a 93% yield of 2-(1-naphthyl)cyclohexan-1-ol (1:1 mixt. of diastereomers).
(c) Patrick, E. A.; Piers, W. E. Twenty-Five Years of Bis-Pentafluorophenyl Borane: A Versatile Reagent for Catalyst and Materials Synthesis. Chem. Commun. 2020, 56, 841– 853, DOI: 10.1039/C9CC08338C
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Twenty-five years of bis-pentafluorophenyl borane: a versatile reagent for catalyst and materials synthesis
Patrick, Evan A.; Piers, Warren E.
Chemical Communications (Cambridge, United Kingdom) (2020), 56 (6), 841-853CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
A review. In 1995, the synthesis, properties and remarkable hydroboration activity of bis-pentafluorophenyl borane was first reported. Its reactivity stems from the ready accessibility of the monomeric borane and its high Lewis acidity. In the intervening twenty five years, this reagent has been widely exploited as a means of incorporating Lewis acidic -B(C6F5)2 groups into complex structures for a range of applications. In this "25th Anniversary" Feature article, we highlight the synthetic methods to the borane, its fundamental properties and chem. as well as the diverse array of uses of this borane. These include self-activating olefin polymn. catalysts, frustrated Lewis pair generation, small mol. activation, bond cleavage reactions, Lewis acid catalysis and modification of org. materials.
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Sumerin, V.; Chernichenko, K.; Nieger, M.; Leskelä, M.; Rieger, B.; Repo, T. Highly Active Metal-Free Catalysts for Hydrogenation of Unsaturated Nitrogen-Containing Compounds. Adv. Synth. Catal. 2011, 353, 2093– 2110, DOI: 10.1002/adsc.201100206
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Highly Active Metal-Free Catalysts for Hydrogenation of Unsaturated Nitrogen-Containing Compounds
Sumerin, Victor; Chernichenko, Konstantin; Nieger, Martin; Leskelae, Markku; Rieger, Bernhard; Repo, Timo
Advanced Synthesis & Catalysis (2011), 353 (11-12), 2093-2110CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
New highly active ansa-ammonium borate catalysts I (R1R2N = 3,3,5,5-tetramethyl-1-morpholinyl, 3,3-dimethyl-2-phenyl-2,3-dihydroindol-1-yl, 8-isopropyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-1-yl, etc.) for the direct metal-free hydrogenation of imines were prepd. by tuning of the basicity and steric bulkiness of their amine moieties. The highest catalytic activity among previously reported organocatalytic systems was shown for a wide range of nitrogen-contg. substrates. The first example of asym. imine hydrogenation based on the ansa-ammonium borate concept was demonstrated. Furthermore, effective catalyst recovery by extn. of the acidic soln. with an org. solvent followed by dehydration with TMSBr was elaborated. The initial findings highlight the development of more effective chiral ansa-ammonium borates for enantioselective hydrogenation. Therefore, the progress achieved in the ansa-ammonium borate concept makes it very promising for further elaboration with the aim to obtain industrially applicable catalysts.
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Lindqvist, M.; Borre, K.; Axenov, K.; Kótai, B.; Nieger, M.; Leskela, M.; Pápai, I.; Repo, T. Chiral Molecular Tweezers: Synthesis and Reactivity in Asymmetric Hydrogenation. J. Am. Chem. Soc. 2015, 137, 4038– 4041, DOI: 10.1021/ja512658m
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Chiral molecular tweezers: Synthesis and reactivity in asymmetric hydrogenation
Lindqvist, Markus; Borre, Katja; Axenov, Kirill; Kotai, Bianka; Nieger, Martin; Leskela, Markku; Papai, Imre; Repo, Timo
Journal of the American Chemical Society (2015), 137 (12), 4038-4041CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
We report the synthesis and reactivity of a chiral aminoborane displaying both rapid and reversible H2 activation. The catalyst shows exceptional reactivity in asym. hydrogenation of enamines and unhindered imines with stereoselectivities of up to 99% ee. DFT anal. of the reaction mechanism pointed to the importance of both repulsive steric and stabilizing intermol. non-covalent forces in the stereodetermining hydride transfer step of the catalytic cycle.
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Liu, Y.; Du, H. Chiral Dienes as “Ligands” for Borane-Catalyzed Metal-Free Asymmetric Hydrogenation of Imines. J. Am. Chem. Soc. 2013, 135, 6810– 6813, DOI: 10.1021/ja4025808
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Chiral Dienes as "Ligands" for Borane-Catalyzed Metal-Free Asymmetric Hydrogenation of Imines
Liu, Yongbing; Du, Haifeng
Journal of the American Chemical Society (2013), 135 (18), 6810-6813CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
This paper describes a highly enantioselective metal-free hydrogenation of imines using chiral dienes as "ligands" for the generation of catalysts with HB(C6F5)2 by hydroboration in situ to furnish a variety of chiral amines with up to 89% ee, which provides a practical strategy for the development of novel chiral frustrated Lewis pairs for asym. hydrogenation.
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Wei, S.; Du, H. A Highly Enantioselective Hydrogenation of Silyl Enol Ethers Catalyzed by Chiral Frustrated Lewis Pairs. J. Am. Chem. Soc. 2014, 136, 12261– 12264, DOI: 10.1021/ja507536n
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A Highly Enantioselective Hydrogenation of Silyl Enol Ethers Catalyzed by Chiral Frustrated Lewis Pairs
Wei, Simin; Du, Haifeng
Journal of the American Chemical Society (2014), 136 (35), 12261-12264CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Using a simple combination of tri-tert-butylphosphine and chiral borane generated in situ by the hydroboration of chiral diene with HB(C6F5)2 as a frustrated Lewis pair catalyst, a highly enantioselective metal-free hydrogenation of silyl enol ethers was successfully realized to furnish a variety of optically active secondary alcs. in 93-99% yields with 88->99% ee's.
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(a) Zhang, Z.; Du, H. Cis-Selective and Highly Enantioselective Hydrogenation of 2,3,4-Trisubstituted Quinolines. Org. Lett. 2015, 17, 2816– 2819, DOI: 10.1021/acs.orglett.5b01240
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18a
Cis-Selective and Highly Enantioselective Hydrogenation of 2,3,4-Trisubstituted Quinolines
Zhang, Zhenhua; Du, Haifeng
Organic Letters (2015), 17 (11), 2816-2819CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A highly enantioselective cis-hydrogenation of 2,3,4-trisubstituted quinolines has been realized for the first time using chiral borane catalysts generated in situ from chiral dienes. A variety of tetrahydroquinoline derivs. contg. three contiguous stereogenic centers, e.g., I, were obtained in 76-99% yields with 82-99% ee's.
(b) Zhang, Z.; Du, H. Enantioselective Metal-Free Hydrogenations of Disubstituted Quinolines. Org. Lett. 2015, 17, 6266– 6269, DOI: 10.1021/acs.orglett.5b03307
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18b
Enantioselective Metal-Free Hydrogenations of Disubstituted Quinolines
Zhang, Zhenhua; Du, Haifeng
Organic Letters (2015), 17 (24), 6266-6269CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A metal-free hydrogenation of 2,4-disubstituted quinolines was realized for the first time using chiral diene derived borane catalysts to furnish the corresponding tetrahydroquinolines in 75-98% yields with 95/5-99/1 dr's and 86-98% ee's. This catalytic system was also effective for 2,3-disubstituted quinolines to give moderate to good ee's.
(c) Zhang, Z.; Du, H. A Highly cis-Selective and Enantioselective Metal-Free Hydrogenation of 2,3-Disubstituted Quinoxalines. Angew. Chem., Int. Ed. 2015, 54, 623– 626, DOI: 10.1002/anie.201409471
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A Highly cis-Selective and Enantioselective Metal-Free Hydrogenation of 2,3-Disubstituted Quinoxalines
Zhang, Zhenhua; Du, Haifeng
Angewandte Chemie, International Edition (2015), 54 (2), 623-626CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A wide range of 2,3-disubstituted quinoxalines I (R1 = H, 5-Me, 6-MeO, 7-Cl, 6,7-Me2, etc.; R2 = R3 = Me, Ph; R2 = Et, n-Pr, Ph, 3-BrC6H4, etc., R3 = Me; R2 = Ph, R3 = Et) has been successfully hydrogenated with H2 using borane catalysts to produce the desired tetrahydroquinoxalines II in 80-99% yields with excellent cis-selectivity. Significantly, the asym. reaction employing chiral borane catalysts, generated by the in situ hydroboration of chiral dienes with HB(C6F5)2 under mild reaction conditions, has also been achieved to provide the corresponding cis-1,2,3,4-tetrahydroquinoxalines with up to 96% ee.
(d) Wei, S.; Feng, X.; Du, H. A Metal-Free Hydrogenation of 3-Substituted 2H-1,4-Benzoxazines. Org. Biomol. Chem. 2016, 14, 8026– 8029, DOI: 10.1039/C6OB01556E
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A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines
Wei, Simin; Feng, Xiangqing; Du, Haifeng
Organic & Biomolecular Chemistry (2016), 14 (34), 8026-8029CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines has been successfully realized with 2.5 mol% of B(C6F5)3 as a catalyst to furnish a variety of 3,4-dihydro-2H-1,4-benzoxazines in 93-99% yields. Up to 42% ee was also achieved for the asym. hydrogenation with the use of a chiral diene and HB(C6F5)2.
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Tu, X.; Zeng, N.; Li, R.; Zhao, Y.; Xie, D.; Peng, Q.; Wang, X. C₂-Symmetric Bicyclic Bisborane Catalysts: Kinetic or Thermodynamic Products of a Reversible Hydroboration of Dienes. Angew. Chem., Int. Ed. 2018, 57, 15096– 15100, DOI: 10.1002/anie.201808289
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C2-Symmetric Bicyclic Bisborane Catalysts: Kinetic or Thermodynamic Products of a Reversible Hydroboration of Dienes
Tu, Xian-Shuang; Zeng, Ning-Ning; Li, Ru-Ye; Zhao, Yu-Quan; Xie, De-Zhen; Peng, Qian; Wang, Xiao-Chen
Angewandte Chemie, International Edition (2018), 57 (46), 15096-15100CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
We prepd. a new class of chiral C2-sym. bicyclic bisborane catalysts by addn. reactions of internal dienes with the Piers borane, HB(C6F5)2, and an analog, HB(p-C6F4H)2. The dependence of the addn. pattern on the reaction temp. allowed us to selectively prep. two diastereomeric catalysts from a single diene precursor. The bisboranes prepd. in situ exhibited excellent activity (turnover nos. up to 200 at -40 °C) and enantioselectivity (up to 95 % ee) in imine hydrogenation reactions.
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(a) Li, X.; Tian, J.; Liu, N.; Tu, X.; Zeng, N.; Wang, X. Spiro-Bicyclic Bisborane Catalysts for Metal-Free Chemoselective and Enantioselective Hydrogenation of Quinolines. Angew. Chem., Int. Ed. 2019, 58, 4664– 4668, DOI: 10.1002/anie.201900907
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20a
Spiro-Bicyclic Bisborane Catalysts for Metal-Free Chemoselective and Enantioselective Hydrogenation of Quinolines
Li, Xiang; Tian, Jun-Jie; Liu, Ning; Tu, Xian-Shuang; Zeng, Ning-Ning; Wang, Xiao-Chen
Angewandte Chemie, International Edition (2019), 58 (14), 4664-4668CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A new series of spiro-bicyclic bisborane catalysts I (Ar = Ph, 4-fluorophenyl, 4-phenylphenyl, 3-phenylphenyl) has been prepd. by means of hydroboration reactions of C2-sym. spiro-bicyclic dienes II with HB(C6F5)2 and HB(p-C6F4H)2. When used for hydrogenation of quinolines III (R1 = Me, cyclohexyl, furan-2-yl, 2H-1,3-benzodioxol-5-yl, etc.; R2 = H, Br, tetramethyl-1,3,2-dioxaborolan-2-yl, prop-2-yn-1-yloxy, allyloxy), these catalysts give excellent yields and enantiomeric excesses, and show turnover nos. of up to 460. The most attractive feature of these metal-free hydrogenation reactions was the broad functional-group tolerance, making this method complementary to existing methods for quinoline hydrogenation.
(b) Tian, J.; Yang, Z.; Liang, X.; Liu, N.; Hu, C.; Tu, X.; Li, X.; Wang, X. Borane-Catalyzed Chemoselective and Enantioselective Reduction of 2-Vinyl-Substituted Pyridines. Angew. Chem., Int. Ed. 2020, 59, 18452– 18456, DOI: 10.1002/anie.202007352
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20b
Borane-Catalyzed Chemoselective and Enantioselective Reduction of 2-Vinyl-Substituted Pyridines
Tian, Jun-Jie; Yang, Zhao-Ying; Liang, Xin-Shen; Liu, Ning; Hu, Chen-Yu; Tu, Xian-Shuang; Li, Xiang; Wang, Xiao-Chen
Angewandte Chemie, International Edition (2020), 59 (42), 18452-18456CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Herein, we report that highly chemoselective and enantioselective redn. of 2-vinyl-substituted pyridines has been achieved for the first time. The reaction, which uses chiral spiro-bicyclic bisboranes as catalysts and HBpin and an acidic amide as reducing reagents, proceeds through a cascade process involving 1,4-hydroboration followed by transfer hydrogenation of a dihydropyridine intermediate. The retained double bond in the redn. products permits their conversion to natural products and other useful heterocyclic compds. by simple transformations.
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Gao, B.; Feng, X.; Meng, W.; Du, H. Asymmetric Hydrogenation of Ketones and Enones with Chiral Lewis Base Derived Frustrated Lewis Pairs. Angew. Chem., Int. Ed. 2020, 59, 4498– 4504, DOI: 10.1002/anie.201914568
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Asymmetric Hydrogenation of Ketones and Enones with Chiral Lewis Base Derived Frustrated Lewis Pairs
Gao, Bochao; Feng, Xiangqing; Meng, Wei; Du, Haifeng
Angewandte Chemie, International Edition (2020), 59 (11), 4498-4504CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The concept of frustrated Lewis pairs (FLPs) has been widely applied in various research areas, and metal-free hydrogenation undoubtedly belongs to the most significant and successful ones. In the past decade, great efforts have been devoted to the synthesis of chiral boron Lewis acids. In a sharp contrast, chiral Lewis base derived FLPs have rarely been disclosed for the asym. hydrogenation. In this work, a novel type of chiral FLP was developed by simple combination of chiral oxazoline Lewis bases with achiral boron Lewis acids, thus providing a promising new direction for the development of chiral FLPs in the future. These chiral FLPs proved to be highly effective for the asym. hydrogenation of ketones, enones, and chromones, giving the corresponding products in high yields with up to 95% ee. Mechanistic studies suggest that the hydrogen transfer to simple ketones likely proceeds in a concerted manner.
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For selected contributions, see:
(a) Hermeke, J.; Mewald, M.; Oestreich, M. Experimental Analysis of the Catalytic Cycle of the Borane-Promoted Imine Reduction with Hydrosilanes: Spectroscopic Detection of Unexpected Intermediates and a Refined Mechanism. J. Am. Chem. Soc. 2013, 135, 17537– 17546, DOI: 10.1021/ja409344w
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22a
Experimental Analysis of the Catalytic Cycle of the Borane-Promoted Imine Reduction with Hydrosilanes: Spectroscopic Detection of Unexpected Intermediates and a Refined Mechanism
Hermeke, Julia; Mewald, Marius; Oestreich, Martin
Journal of the American Chemical Society (2013), 135 (46), 17537-17546CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The discovery of intermediates that had not been seen before in imine redn. involving borane-mediated Si-H bond activation provided new insight into the mechanism, eventually leading to a refined catalytic cycle that also bears relevance to asym. variants. The catalysis proceeds through an ion pair composed of a silyliminium ion and a borohydride that subsequently reacts to yield an N-silylated amine and the borane catalyst. The latter step is enantioselectivity-detg. when using a chiral borane. It was now found that there are addnl. intermediates that profoundly influence the outcome of such enantioselective transformations. Significant amts. of the corresponding free amine and N-silylated enamine are present in equimolar ratio during the catalysis. The free amine emerges from a borohydride redn. of an iminium ion (protonated imine) i.e., in turn, generated in the enamine formation step. The unexpected alternative pathway adds another enantioselectivity-detg. hydride transfer to reactions employing chiral boranes. The expts. were done with an axially chiral borane that was introduced by the authors a few years ago, and the refined mechanistic picture helps to understand previously obsd. inconsistencies in the level of enantioinduction in redns. catalyzed by this borane. The findings are general because the archetypical electron-deficient borane B(C6F5)3 shows the same reaction pattern. This must have been overlooked in the past because B(C6F5)3 is substantially more reactive than the chiral borane with just one C6F5 group. Reactions with B(C6F5)3 must be performed at low catalyst loading to allow for detection of these fundamental intermediates by NMR spectroscopy.
(b) Süsse, L.; Hermeke, J.; Oestreich, M. The Asymmetric Piers Hydrosilylation. J. Am. Chem. Soc. 2016, 138, 6940– 6943, DOI: 10.1021/jacs.6b03443
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22b
The Asymmetric Piers Hydrosilylation
Suesse, Lars; Hermeke, Julia; Oestreich, Martin
Journal of the American Chemical Society (2016), 138 (22), 6940-6943CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
An axially chiral, cyclic borane, I, decorated with just one C6F5 group at the boron atom promotes the highly enantioselective hydrosilylation of acetophenone derivs. without assistance of an addnl. Lewis base (up to 99% ee). The reaction is an unprecedented asym. variant of Piers' B(C6F5)3-catalyzed carbonyl hydrosilylation. The steric congestion imparted by the 3,3'-disubstituted binaphthyl backbone of the borane catalyst as well as the use of reactive trihydrosilanes as reducing agents are keys to success.
(c) Mercea, D. M.; Howlett, M. G.; Piascik, A. D.; Scott, D.J.; Steven, A.; Ashley, A. E.; Fuchter, M. J. Enantioselective reduction of N-alkyl ketimines with frustrated Lewis pair catalysis using chiral borenium ions. Chem. Commun. 2019, 55, 7077– 7080, DOI: 10.1039/C9CC02900A
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22c
Enantioselective reduction of N-alkyl ketimines with frustrated Lewis pair catalysis using chiral borenium ions
Mercea, Dan M.; Howlett, Michael G.; Piascik, Adam D.; Scott, Daniel J.; Steven, Alan; Ashley, Andrew E.; Fuchter, Matthew J.
Chemical Communications (Cambridge, United Kingdom) (2019), 55 (49), 7077-7080CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Enantioselective redn. of ketimines was demonstrated using chiral N-heterocyclic carbene (NHC)-stabilized borenium ions in frustrated Lewis pair catalysis. High levels of enantioselectivity were achieved for substrates featuring secondary N-alkyl substituents. Comparative reactivity and mechanistic studies identify key determinants required to achieve useful enantioselectivity and represent a step forward in the further development of enantioselective FLP methodologies.
(d) Liu, X.; Wang, Q.; Han, C.; Feng, X.; Du, H. Chiral Frustrated Lewis Pairs Catalyzed Highly Enantioselective Hydrosilylations of Ketones. Chin. J. Chem. 2019, 37, 663– 666, DOI: 10.1002/cjoc.201900121
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22d
Chiral Frustrated Lewis Pairs Catalyzed Highly Enantioselective Hydrosilylations of Ketones
Liu, Xiaoqin; Wang, Qiaotian; Han, Caifang; Feng, Xiangqing; Du, Haifeng
Chinese Journal of Chemistry (2019), 37 (7), 663-666CODEN: CJOCEV; ISSN:1001-604X. (Wiley-VCH Verlag GmbH & Co. KGaA)
A highly enantioselective Piers-type hydrosilylation of simple ketones was successfully achieved using a chiral frustrated Lewis pair of tri-tert-butylphosphine and chiral diene-derived borane as catalyst. A wide range of optically active secondary alcs. were furnished in 80%-99% yields with 81%-97% ee's under mild reaction conditions.
(e) Lundrigan, T.; Welsh, E. N.; Hynes, T.; Tien, C.; Adams, M. R.; Roy, K. R.; Robertson, K. N.; Speed, A. W. H. Enantioselective Imine Reduction Catalyzed by Phosphenium Ions. J. Am. Chem. Soc. 2019, 141, 14083– 14088, DOI: 10.1021/jacs.9b07293
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22e
Enantioselective Imine Reduction Catalyzed by Phosphenium Ions
Lundrigan, Travis; Welsh, Erin N.; Hynes, Toren; Tien, Chieh-Hung; Adams, Matt R.; Roy, Kayelani R.; Robertson, Katherine N.; Speed, Alexander W. H.
Journal of the American Chemical Society (2019), 141 (36), 14083-14088CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The first use of phosphenium cations in asym. catalysis is reported. A diazaphosphenium triflate, prepd. in two or three steps on a multigram scale from com. available materials, catalyzes the hydroboration or hydrosilylation of cyclic imines with enantiomeric ratios of up to 97:3. Catalyst loadings are as low as 0.2 mol %. Twenty-two aryl/heteroaryl pyrrolidines and piperidines were prepd. using this method. Imines contg. functional groups such as thiophenes or pyridyl rings that can challenge transition-metal catalysts were reduced employing these systems.
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For computational mechanistic studies on FLP-type catalytic hydrogenations (not addressing the issue of stereoselectivity), see:
(a) Rokob, T. A.; Hamza, A.; Stirling, A.; Pápai, I. On the Mechanism of B(C₆F₅)₃-Catalyzed Direct Hydrogenation of Imines: Inherent and Thermally Induced Frustration. J. Am. Chem. Soc. 2009, 131, 2029– 2036, DOI: 10.1021/ja809125r
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23a
On the Mechanism of B(C6F5)3-Catalyzed Direct Hydrogenation of Imines: Inherent and Thermally Induced Frustration
Rokob, Tibor Andras; Hamza, Andrea; Stirling, Andras; Papai, Imre
Journal of the American Chemical Society (2009), 131 (5), 2029-2036CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The reaction mechanism for the transition metal free direct hydrogenation of bulky imines catalyzed by the Lewis acid B(C6F5)3 is investigated in detail by quantum chem. calcns. A recently introduced mechanistic model of heterolytic hydrogen splitting that is based on noncovalent assocn. of bulky Lewis acid-base pairs is shown to account for the reactivity of imine-borane as well as amine-borane systems. Possible catalytic cycles are examd., and the results provide solid support for the imine redn. pathway proposed from exptl. observations. In addn., the feasibility of an autocatalytic route initiated by amine-borane hydrogen cleavage is demonstrated. Conceptual issues regarding the notion of frustration are also discussed. The obsd. reactivity is interpreted in terms of thermally induced frustration, which refers to thermal activation of strained dative adducts of bulky Lewis donor-acceptor pairs to populate their reactive frustrated complex forms.
(b) Nyhlén, J.; Privalov, T. On the Possibility of Catalytic Reduction of Carbonyl Moieties with Tris(Pentafluorophenyl)Borane and H₂: A Computational Study. Dalton Trans. 2009, 29, 5780– 5786, DOI: 10.1039/b905137f
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There is no corresponding record for this reference.
(c) Privalov, T. The Role of Amine-B(C₆F₅)₃ Adducts in the Catalytic Reduction of Imines with H₂: A Computational Study. Eur. J. Inorg. Chem. 2009, 2009, 2229– 2237, DOI: 10.1002/ejic.200900194
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There is no corresponding record for this reference.
(d) Li, H.; Zhao, L.; Lu, G.; Huang, F.; Wang, Z.-X. Catalytic Metal-Free Ketone Hydrogenation: A Computational Experiment. Dalton Trans. 2010, 39, 5519– 5526, DOI: 10.1039/c001399d
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23d
Catalytic metal-free ketone hydrogenation: a computational experiment
Li, Haixia; Zhao, Lili; Lu, Gang; Huang, Fang; Wang, Zhi-Xiang
Dalton Transactions (2010), 39 (23), 5519-5526CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
A computational study has been carried out to examine if the metal-free catalyst I designed for imine hydrogenation is able to hydrogenate ketones, using the cyclohexanone (3) and its derivs. (4-6) as ketone models. The catalytic cycle includes two major steps: hydrogen activation and hydrogen transfer. The concerted pathway in the hydrogen transfer step is preferred over the stepwise pathway. The two sepd. steps for hydrogen activation and hydrogen transfer can benefit the hydrogen addn. to the substrates (e.g., ketones) which do not have strong Lewis base centers, because the substrates need not to be involved in the hydrogen activation. In general, the larger the steric effect of the substrate is, the less severe the side reactions become, and the more difficultly the desired reaction occurs. The energetic results show that the hydrogenations of 3-5 are kinetically and thermodynamically feasible under ambient conditions, but the hydrogenation of 6 is less energetically favorable. Therefore, it is important to establish a proper balance between promoting the desired reaction and meanwhile avoiding the undesired reactions. The issue of the resting state, caused by forming stable alkoxide complexes like in the ketone hydrogenation catalyzed by the metal-ligand bifunctional catalysts, is also discussed.
(e) Zhao, L.; Li, H.; Lu, G.; Huang, F.; Zhang, C.; Wang, Z.-X. Metal-Free Catalysts for Hydrogenation of Both Small and Large Imines: A Computational Experiment. Dalton Trans. 2011, 40, 1929– 1937, DOI: 10.1039/c0dt01297a
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23e
Metal-free catalysts for hydrogenation of both small and large imines: a computational experiment
Zhao, Lili; Li, Haixia; Lu, Gang; Huang, Fang; Zhang, Chenggen; Wang, Zhi-Xiang
Dalton Transactions (2011), 40 (9), 1929-1937CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
This study extends our previous work of using π-FLP strategy to develop metal-free hydrogenation catalysts. Using small MeN:CMe2 imine (i.m.1) as a model, we previously designed cat1 and cat2 catalysts. But it is unclear whether they are capable of catalyzing the hydrogenations of bulky imines. Using tBuN:C(H)Ph (i.m.2) as a representative of large imines, we assessed the energetics of the cat1- and cat2-catalyzed i.m.2 hydrogenations. The predicted energetics indicates that they can still catalyze large imine hydrogenations with exptl. accessible kinetic barriers, although the energetics becomes less favorable. To improve the catalysis, we proposed new catalysts (cat3 and cat4) by tailoring cat1 and cat2. The study indicates that cat3 and cat4 could have better performance for the hydrogenation of the bulky i.m.2 than cat1 and cat2. Remarkably, cat3 and cat4 are also found suitable for small imine (i.m.1) hydrogenation. Examg. the hydrogen transfer substeps in the eight hydrogenations involved in this study, we obsd. that the mechanism for the hydrogen transfer step in the catalytic cycles depends on the steric effect between catalyst and substrate. The mechanism can be switched from stepwise one in the case of large steric effect (e.g.i.m.2/cat2) to the concerted one in the case of small steric effect (e.g.i.m.1/cat3). The new catalysts could be better targets for exptl. realization because of their simpler constructions.
(f) Zhao, L.; Lu, G.; Huang, F.; Wang, Z.-X. A Computational Experiment to Study Hydrogenations of Various Unsaturated Compounds Catalyzed by a Rationally Designed Metal-Free Catalyst. Dalton Trans. 2012, 41, 4674– 4684, DOI: 10.1039/c2dt12152b
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23f
A computational experiment to study hydrogenations of various unsaturated compounds catalyzed by a rationally designed metal-free catalyst
Zhao, Lili; Lu, Gang; Huang, Fang; Wang, Zhi-Xiang
Dalton Transactions (2012), 41 (15), 4674-4684CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
Metal-free hydrogenation has been proposed to be a green alternative to the conventional hydrogenation mediated by precious transition metal complexes. Thanks to the discovery of FLP (frustrated Lewis pair) chem., the field has recently witnessed significant progress. Inspired by the FLP idea of synergically utilizing the catalytic effects of Lewis acid and base, we previously proposed a strategy to construct metal-free active sites for H2 activation and designed a metal-free mol. (1) that shows high reactivity toward H2. Encouraged by the recent exptl. successes in applying the strategy, we have computationally explored if 1 can go further to serve as a catalyst to promote the hydrogenations of various unsatd. compds. examd. by ethylene (CH2:CH2 (4)), silyl enol ether (CH2:C(Me)OSiMe3 (5)), imines (Me2C:NMe (6) and Ph(Me)C:NMe (7)), and ketone (Ph(Me)C:O (9)). The energetic results predicted at the M05-2X(IEFPCM, solvent = THF)/6-311++G** level indicate that these reactions have feasible kinetics and thermodn. for exptl. realization. The hydride transfer step follows the concerted mechanism, although the transfer process has asynchronous character for silyl enol ether (5) and imines (6 and 7). In addn., we have investigated the binding of CO2 to 1 and the 1-mediated hydrogenation of CO2.
(g) Chernichenko, K.; Madarász, Á.; Pápai, I.; Nieger, M.; Leskelä, M.; Repo, T. A Frustrated-Lewis-Pair Approach to Catalytic Reduction of Alkynes to Cis-Alkenes. Nat. Chem. 2013, 5, 718– 723, DOI: 10.1038/nchem.1693
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23g
A frustrated-Lewis-pair approach to catalytic reduction of alkynes to cis-alkenes
Chernichenko, Konstantin; Madarasz, Adam; Papai, Imre; Nieger, Martin; Leskelae, Markku; Repo, Timo
Nature Chemistry (2013), 5 (8), 718-723CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
Frustrated Lewis pairs are compds. contg. both Lewis acidic and Lewis basic moieties, where the formation of an adduct is prevented by steric hindrance. They are therefore highly reactive, and are capable of heterolysis of mol. hydrogen, a property that led to their use in hydrogenation reactions of polarized multiple bonds. Here, the authors describe a general approach to the hydrogenation of alkynes to cis-alkenes under mild conditions using the unique ansa-aminohydroborane as a catalyst. The approach combines several reactions as the elementary steps of the catalytic cycle: hydroboration (substrate binding), heterolytic hydrogen splitting (typical frustrated-Lewis-pair reactivity) and facile intramol. protodeborylation (product release). The mechanism is verified by exptl. and computational studies.
(h) Wang, Z.-X.; Zhao, L.; Lu, G.; Li, H. X.; Huang, F. Computational Design of Metal-Free Molecules for Activation of Small Molecules, Hydrogenation, and Hydroamination. Top. Curr. Chem. 2012, 332, 231– 266, DOI: 10.1007/128_2012_385
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(i) Zhao, J.; Wang, G.; Li, S. Mechanistic Insights into the Full Hydrogenation of 2,6-Substituted Pyridine Catalyzed by the Lewis Acid C₆F₅(CH₂)₂B(C₆F₅)₂. Dalton Trans. 2015, 44, 9200– 9208, DOI: 10.1039/C5DT00978B
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23i
Mechanistic insights into the full hydrogenation of 2,6-substituted pyridine catalyzed by the Lewis acid C6F5(CH2)2B(C6F5)2
Zhao, Jiyang; Wang, Guoqiang; Li, Shuhua
Dalton Transactions (2015), 44 (19), 9200-9208CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
The reaction mechanism for the full hydrogenation of 2-phenyl-6-methylpyridine catalyzed by the Lewis acid C6F5(CH2)2B(C6F5)2 was investigated in detail by d. functional theory calcns. Our calcns. show that a plausible reaction pathway of the hydrogenation of pyridine contains five stages: (1) the generation of a new borane C6F5(CH2)2B(C6F5)2 from the hydroboration of the alkene, which forms a frustrated Lewis pair (FLP) with a pyridine; (2) the activation of H2 by FLP to yield an ion pair intermediate; (3) intramol. hydride transfer from the boron atom to the pyridinium cation in the ion pair intermediate to produce the 1,4-dihydropyridine; (4) hydrogenation of the 1,4-dihydropyridine by the FLP to form the 1,4,5,6-tetrahydropyridine; (5) hydrogenation of the 1,4,5,6-tetrahydropyridine by the FLP to yield the final piperidine. The last two hydrogenation processes follow a similar pathway, which includes four steps: (a) proton transfer from the pyridinium moiety to the substrate; (b) dissocn. of the newly generated pyridine; (c) hydride migration from the hydridoborate moiety to the protonated substrate to produce the hydrogenated product; (d) release of the hydrogenated product to regenerate the free borane. The full hydrogenation of pyridine is calcd. to be exothermic by 16.9 kcal mol-1, relative to the starting reactants. The rate-limiting step is the proton transfer in the second hydrogenation step, with a free energy barrier of 28.2 kcal mol-1 in the gas phase (27.9 kcal mol-1 in toluene) at room temp. and 1.0 atm. Our results can account for the obsd. exptl. facts.
(j) Das, S.; Pati, S. K. On the Mechanism of Frustrated Lewis Pair Catalysed Hydrogenation of Carbonyl Compounds. Chem. - Eur. J. 2017, 23, 1078– 1085, DOI: 10.1002/chem.201602774
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23j
On the Mechanism of Frustrated Lewis Pair Catalysed Hydrogenation of Carbonyl Compounds
Das, Shubhajit; Pati, Swapan K.
Chemistry - A European Journal (2017), 23 (5), 1078-1085CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The authors have explored the reaction mechanism of the metal-free B(C6F5)3-catalyzed hydrogenation of carbonyl compds. to the corresponding secondary alcs. by d. functional theory calcns. Possible reaction routes were studied in detail and the results provide solid support for the mechanism proposed from exptl. observations. The crit. role of the ethereal solvent, as an active participant in the hydrogenation process, is highlighted with the ether-borane Lewis pair shown to be involved in the heterolytic activation of H2. The feasibility of an alternative direct hydrogenation route featuring carbonyl-borane-mediated H2 cleavage also was examd. The authors have also studied the moisture sensitivity of the catalyst and possible decompn. routes. The catalyst shows appreciable water-tolerance and even in the presence of moisture the hydrogenation proceeds through the same mechanism as that followed under anhyd. conditions.
(k) Heshmat, M.; Privalov, T. Carbonyl Activation by Borane Lewis Acid Complexation: Transition States of H₂ Splitting at the Activated Carbonyl Carbon Atom in a Lewis Basic Solvent and the Proton-Transfer Dynamics of the Boroalkoxide Intermediate. Chem. - Eur. J. 2017, 23, 9098– 9113, DOI: 10.1002/chem.201700437
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Carbonyl Activation by Borane Lewis Acid Complexation: Transition States of H2 Splitting at the Activated Carbonyl Carbon Atom in a Lewis Basic Solvent and the Proton-Transfer Dynamics of the Boroalkoxide Intermediate
Heshmat, Mojgan; Privalov, Timofei
Chemistry - A European Journal (2017), 23 (38), 9098-9113CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
By using transition-state (TS) calcns., we examd. how Lewis acid (LA) complexation activates carbonyl compds. in the context of hydrogenation of carbonyl compds. by H2 in Lewis basic (ethereal) solvents contg. borane LAs of the type (C6F5)3B. According to our calcns., LA complexation does not activate a ketone sufficiently enough for the direct addn. of H2 to the O=C unsatd. bond; but, calcns. indicate a possibly facile heterolytic cleavage of H2 at the activated and thus sufficiently Lewis acidic carbonyl carbon atom with the assistance of the Lewis basic solvent (i.e., 1,4-dioxane or THF). For the solvent-assisted H2 splitting at the carbonyl carbon atom of (C6F5)3B adducts with different ketones, a no. of TSs are computed and the obtained results are related to insights from expt. By using the Born-Oppenheimer mol. dynamics with the DFT for electronic structure calcns., the evolution of the (C6F5)3B-alkoxide ionic intermediate and the proton transfer to the alkoxide oxygen atom were investigated. The results indicate a plausible hydrogenation mechanism with a LA, i.e., (C6F5)3B, as a catalyst, namely, (1) the step of H2 cleavage that involves a Lewis basic solvent mol. plus the carbonyl carbon atom of thermodynamically stable and exptl. identifiable (C6F5)3B-ketone adducts in which (C6F5)3B is the "Lewis acid promoter", (2) the transfer of the solvent-bound proton to the oxygen atom of the (C6F5)3B-alkoxide intermediate giving the (C6F5)3B-alc. adduct, and (3) the SN2-style displacement of the alc. by a ketone or a Lewis basic solvent mol.
(l) Mane, M. V.; Vanka, K. Less Frustration, More Activity-Theoretical Insights into Frustrated Lewis Pairs for Hydrogenation Catalysis. ChemCatChem 2017, 9, 3013– 3022, DOI: 10.1002/cctc.201700289
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23l
Less Frustration, More Activity-Theoretical Insights into Frustrated Lewis Pairs for Hydrogenation Catalysis
Mane, Manoj V.; Vanka, Kumar
ChemCatChem (2017), 9 (15), 3013-3022CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
The field of frustrated Lewis pair (FLP) chem. has seen rapid development in only a few years. FLPs have performed most spectacularly in hydrogenation catalysis: a wide variety of FLP-based systems can catalyze the hydrogenation of a range of different substrates, including imines, enamines, ketones, alkynes, and alkenes. However, FLP-based hydrogenation catalysts are yet to match the efficiency of their transition-metal counterparts. The current investigation reveals an important aspect of FLPs that can be exploited to improve their efficiency, i.e., the more sterically hindered the FLP catalyst is, the lower is its turnover frequency. Full quantum chem. calcns. with DFT for a family of different, exptl. known hydrogenation FLP catalysts shows that superior FLP catalysts can be designed by reducing the frustration (by reducing the steric demand and acid/base strength) in the FLP. However, as lowering the steric demand without redn. in the frustration can result in unwanted side reactions, the design of the most efficient FLP catalysts depends on tuning the system so that both the steric demand and the frustration are reduced appropriately.
(m) Heshmat, M.; Privalov, T. Computational Elucidation of a Role That Brønsted Acidification of the Lewis Acid-Bound Water Might Play in the Hydrogenation of Carbonyl Compounds with H₂ in Lewis Basic Solvents. Chem. - Eur. J. 2017, 23, 11489– 11493, DOI: 10.1002/chem.201700937
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23m
Computational Elucidation of a Role That Bronsted Acidification of the Lewis Acid-Bound Water Might Play in the Hydrogenation of Carbonyl Compounds with H2 in Lewis Basic Solvents
Heshmat, Mojgan; Privalov, Timofei
Chemistry - A European Journal (2017), 23 (48), 11489-11493CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Bronsted acidification of water by Lewis acid (LA) complexation is one of the fundamental principles in chem. Using transition-state calcns. (TS), herein we investigate the role that Bronsted acidification of the LA-bound water might play in the mechanism of the hydrogenation of carbonyl compds. in Lewis basic solvents under non-anhyd. conditions. The potential energy scans and TS calcns. were carried out with a series of eight borane LAs as well as the commonly known strong LA AlCl3 in 1,4-dioxane or THF as Lewis basic solvents. Our mol. model consists of the dative LA-water adduct with hydrogen bonds to acetone and a solvent mol. plus one addnl. solvent mol. that participates is the TS structure describing the cleavage of H2 at acetone's carbonyl carbon atom. In all the mol. models applied here, acetone (O=CMe2) is the archetypical carbonyl substrate. We demonstrate that Bronsted acidification of the LA-bound water can indeed lower the barrier height of the solvent-involving H2-cleavage at the acetone's carbonyl carbon atom. This is significant because at present it is believed that the mechanism of the herein considered reaction is described by the same mechanism regardless of whether the reaction conditions are strictly anhyd. or non-anhyd. Our results offer an alternative to this belief that warrants consideration and further study.
(n) Heshmat, M.; Privalov, T. Theory-Based Extension of the Catalyst Scope in the Base-Catalyzed Hydrogenation of Ketones: RCOOH-Catalyzed Hydrogenation of Carbonyl Compounds with H₂ Involving a Proton Shuttle. Chem. - Eur. J. 2017, 23, 18193– 18202, DOI: 10.1002/chem.201702149
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23n
Theory-Based Extension of the Catalyst Scope in the Base-Catalyzed Hydrogenation of Ketones: RCOOH-Catalyzed Hydrogenation of Carbonyl Compounds with H2 Involving a Proton Shuttle
Heshmat, Mojgan; Privalov, Timofei
Chemistry - A European Journal (2017), 23 (72), 18193-18202CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
As an extension of the reaction mechanism describing the base-catalyzed hydrogenation of ketones according to Berkessel et al., we use a std. methodol. for transition-state calcns. in order to check the possibility of heterolytic cleavage of H2 at the ketone's carbonyl carbon atom, yielding one-step hydrogenation path with involvement of carboxylic acid as a catalyst. As an extension of the catalyst scope in the base-catalyzed hydrogenation of ketones, our mechanism involves a mol. with a labile proton and a Lewis basic oxygen atom as a catalyst-for example, R-C(=O)OH carboxylic acids-so that the heterolytic cleavage of H2 could take place between the Lewis basic oxygen atom of a carboxylic acid and the electrophilic (Lewis acidic) carbonyl carbon of a ketone/aldehyde. According to our TS calcns., protonation of a ketone/aldehyde by a proton shuttle (hydrogen bond) facilitates the hydride-type attack on the ketone's carbonyl carbon atom in the process of the heterolytic cleavage of H2. Ketones with electron-rich and electron-withdrawing substituents in combination with a few carboxylic and amino acids-in total, 41 substrate-catalyst couples-have been computationally evaluated in this article and the calcd. reaction barriers are encouragingly moderate for many of the considered substrate-catalyst couples.
(o) Das, S.; Pati, S. K. Unravelling the Mechanism of Tin-Based Frustrated Lewis Pair Catalysed Hydrogenation of Carbonyl Compounds. Catal. Sci. Technol. 2018, 8, 5178– 5189, DOI: 10.1039/C8CY01227J
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Unravelling the mechanism of tin-based frustrated Lewis pair catalysed hydrogenation of carbonyl compounds
Das, Shubhajit; Pati, Swapan K.
Catalysis Science & Technology (2018), 8 (20), 5178-5189CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)
This article presents a comprehensive study on the mechanism of Sn/N frustrated Lewis pair (FLP) catalyzed hydrogenation of carbonyl compds. to corresponding alcs. Possible reaction pathways have been elucidated in detail using d. functional theory computations. The reaction begins with Sn/N FLP-mediated heterolytic cleavage of a H2 mol. to release active hydrogens in soln. Our results reveal that, instead of the usual Bronsted acid activation, the carbonyl substrate is activated by Lewis acid complexation, followed by subsequent hydride and proton delivery to complete the hydrogenation process. Addnl., we have also examd. the feasibility of an autocatalytic pathway. The main feature of this reaction route is Sn/O FLP-mediated H2 cleavage, which has a comparable barrier to H2 splitting by Sn/N FLPs. Overall, our computational mechanistic model is consistent with the exptl. findings and the computed free energy barriers are in good agreement with the obsd. reactivity at exptl. temp. Insights obtained from this study are crucial for the rational development of Sn-based FLP hydrogenation catalysts.
24
For recent reviews on concepts and challenges in computing stereoselectivities, see:
(a) Hopmann, K. H. Quantum Chemical Studies of Asymmetric Reactions: Historical Aspects and Recent Examples. Int. J. Quantum Chem. 2015, 115, 1232– 1249, DOI: 10.1002/qua.24882
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24a
Quantum chemical studies of asymmetric reactions: Historical aspects and recent examples
Hopmann, Kathrin H.
International Journal of Quantum Chemistry (2015), 115 (18), 1232-1249CODEN: IJQCB2; ISSN:0020-7608. (John Wiley & Sons, Inc.)
Asym. catalysis is essential for the synthesis of chiral compds. such as pharmaceuticals, agrochems., fragrances, and flavors. For rational improvement of asym. reactions, detailed mechanistic insights are required. The usefulness of quantum mech. studies for understanding the stereocontrol of asym. reactions was first demonstrated around 40 years ago, with impressive developments since then: from single-point Hartree-Fock/STO-3G calcns. on small org. mols. (1970s), to the first full reaction pathway involving a metal-complex (1980s), to the beginning of the d. functional theory-area, albeit typically involving truncated models (1990s), to current state-of-the-art calcns. reporting free energies of complete organometallic systems, including solvent and dispersion corrections. The combined studies show that the stereocontrol in asym. reactions largely is exerted by nonbonding interactions, including CH/π attraction and repulsive forces. The ability to rationalize exptl. results opens up for the possibility to predict enantioselectivities or to design novel catalysts on basis of in silico results. © 2015 Wiley Periodicals, Inc.
(b) Peng, Q.; Duarte, F.; Paton, R. S. Computing Organic Stereoselectivity-from Concepts to Quantitative Calculations and Predictions. Chem. Soc. Rev. 2016, 45, 6093– 6107, DOI: 10.1039/C6CS00573J
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24b
Computing organic stereoselectivity - from concepts to quantitative calculations and predictions
Peng, Qian; Duarte, Fernanda; Paton, Robert S.
Chemical Society Reviews (2016), 45 (22), 6093-6107CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
Advances in theory and processing power have established computation as a valuable interpretative and predictive tool in the discovery of new asym. catalysts. This tutorial review outlines the theory and practice of modeling stereoselective reactions. Recent examples illustrate how an understanding of the fundamental principles and the application of state-of-the-art computational methods may be used to gain mechanistic insight into org. and organometallic reactions. We highlight the emerging potential of this computational tool-box in providing meaningful predictions for the rational design of asym. catalysts. We present an accessible account of the field to encourage future synergy between computation and expt.
(c) Krenske, E. H. Challenges in Predicting Stereoselectivity. In Applied Theoretical Organic Chemistry; Tantillo, D. J., Ed.; World Scientific: New Jersey, 2018; pp 583– 604.
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There is no corresponding record for this reference.
(d) Gridnev, I. D.; Dub, P. A. Enantioselection in Asymmetric Catalysis; CRC Press: Boca Raton, 2017.
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There is no corresponding record for this reference.
25
For a detailed computational analysis of H₂ activation pathways with the im/2 and P/2 pairs, see the SI (section 2.1).
There is no corresponding record for this reference.
26
Computed proton affinities of P^tBu₃ and im are −277.5 and −231.7 kcal/mol, respectively. These values are obtained as solution phase Gibbs free energies of base → baseH⁺ reactions.
There is no corresponding record for this reference.
27
For a detailed comparison of the energetics of the two catalytic cycles, see the SI (section 2.2).
There is no corresponding record for this reference.
28
For conformational analysis of borohydride 2H^–, see the SI (section 2.3).
There is no corresponding record for this reference.
29
For details of the conformational analysis carried out for the imH⁺/2H^– ion pair intermediate, see the SI (section 2.4).
There is no corresponding record for this reference.
30
For related studies, see, for example:
(a) Rokob, T. A.; Hamza, A.; Pápai, I. Rationalizing the Reactivity of Frustrated Lewis Pairs: Thermodynamics of H₂ Activation and the Role of Acid–Base Properties. J. Am. Chem. Soc. 2009, 131, 10701– 10710, DOI: 10.1021/ja903878z
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30a
Rationalizing the Reactivity of Frustrated Lewis Pairs: Thermodynamics of H2 Activation and the Role of Acid-Base Properties
Rokob, Tibor Andras; Hamza, Andrea; Papai, Imre
Journal of the American Chemical Society (2009), 131 (30), 10701-10710CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The acid-base strengths of recently reported frustrated Lewis pairs and their relation with the thermodn. feasibility of heterolytic H splitting reactions are analyzed in terms of quantum chem. calcns. Reaction free energies of hydrogenation processes are computed, and an energy partitioning scheme is introduced, which involves quant. measures of the acidity and basicity of the reacting Lewis centers. Addnl. terms are also included that account for possible dative bond formation between the active sites and for stabilizing electrostatic interactions occurring in the product species. For intermol. combinations of donor-acceptor components, the calcd. reaction free energies correlate well with the cumulative acid-base strengths. Product stabilization for these systems represents a notable contribution to the overall energetics; however, it generally shows only a slight variation for the studied series. The reactivity of linked donor-acceptor pairs is primarily governed by acid-base properties as well, but the magnitude of stabilizing effects arising from acid-base cooperativity of active sites is also of significant importance in detg. the thermodn. feasibility of the reactions.
(b) Schulz, F.; Sumerin, V.; Heikkinen, S.; Pedersen, B.; Wang, C.; Atsumi, M.; Leskelä, M.; Repo, T.; Pyykkö, P.; Petry, W.; Rieger, B. Molecular Hydrogen Tweezers: Structure and Mechanisms by Neutron Diffraction, NMR, and Deuterium Labeling Studies in Solid and Solution. J. Am. Chem. Soc. 2011, 133, 20245– 20257, DOI: 10.1021/ja206394w
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30b
Molecular hydrogen tweezers: structure and mechanisms by neutron diffraction, NMR, and deuterium labeling studies in solid and solution
Schulz, Felix; Sumerin, Victor; Heikkinen, Sami; Pedersen, Bjoern; Wang, Cong; Atsumi, Michiko; Leskelae, Markku; Repo, Timo; Pyykkoe, Pekka; Petry, Winfried; Rieger, Bernhard
Journal of the American Chemical Society (2011), 133 (50), 20245-20257CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The mechanism of reversible hydrogen activation by ansa-aminoboranes, 1-N-TMPH-CH2-2-[HB(C6F5)2]C6H4 (NHHB), was studied by neutron diffraction and thermogravimetric mass-spectroscopic expts. in the solid state as well as with NMR and FT-IR spectroscopy in soln. The structure of the ansa-ammonium borate NHHB was detd. by neutron scattering, revealing a short N-H···H-B dihydrogen bond of 1.67 Å. Moreover, this intramol. H-H distance was detd. in soln. to be also 1.6-1.8 Å by 1H NMR spectroscopic T1 relaxation and 1D NOE measurements. The x-ray B-H and N-H distances deviated from the neutron and the calcd. values. The dynamic nature of the mol. tweezers in soln. was addnl. studied by multinuclear and variable-temp. NMR spectroscopy. We synthesized stable, individual isotopic isomers NDDB, NHDB, and NDHB. NMR measurements revealed a primary isotope effect in the chem. shift difference pΔ1H(D) = δ(NH) - δ(ND) (0.56 ppm), and hence supported dihydrogen bonding. The NMR studies gave strong evidence that the structure of NHHB in soln. is similar to that in the solid state. This is corroborated by IR studies providing clear evidence for the dynamic nature of the intramol. dihydrogen bonding at room temp. Interestingly, no kinetic isotope effect was detected for the activation of deuterium hydride by the ansa-aminoborane NB. Theor. calcns. attribute this to an "early transition state". Moreover, 2D NOESY NMR measurements support fast intermol. proton exchange in aprotic CD2Cl2 and C6D6.
(c) Zaher, H.; Ashley, A. E.; Irwin, M.; Thompson, A. L.; Gutmann, M. J.; Krämer, T.; O’Hare, D. Structural and Theoretical Studies of Intermolecular Dihydrogen Bonding in [(C₆F₅)₂(C₆Cl₅)B]–H···H–[TMP]. Chem. Commun. 2013, 49, 9755– 9757, DOI: 10.1039/c3cc45889j
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30c
Structural and theoretical studies of intermolecular dihydrogen bonding in [(C6F5)2(C6Cl5)B]-H···H-[TMP]
Zaher, Hasna; Ashley, Andrew E.; Irwin, Mark; Thompson, Amber L.; Gutmann, Matthias J.; Kraemer, Tobias; O'Hare, Dermot
Chemical Communications (Cambridge, United Kingdom) (2013), 49 (84), 9755-9757CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
The product of the intermol. frustrated Lewis pair (FLP) B(C6F5)2(C6Cl5)/2,2,6,6-tetramethylpiperidine and H2 has been studied by single-crystal neutron diffraction. This is the first structurally characterized example of a geometrically unconstrained dihydrogen (H···H) bond within a hydrogenated FLP system.
(d) Zhivonitko, V. V.; Sorochkina, K.; Chernichenko, K.; Kótai, B.; Földes, T.; Pápai, I.; Telkki, V.-V.; Repo, T.; Koptyug, I. Nuclear Spin Hyperpolarization with Ansa-Aminoboranes: A Metal-Free Perspective for Parahydrogen-Induced Polarization. Phys. Chem. Chem. Phys. 2016, 18, 27784– 27795, DOI: 10.1039/C6CP05211H
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30d
Nuclear spin hyperpolarization with ansa-aminoboranes: a metal-free perspective for parahydrogen-induced polarization
Zhivonitko, Vladimir V.; Sorochkina, Kristina; Chernichenko, Konstantin; Kotai, Bianka; Foldes, Tamas; Papai, Imre; Telkki, Ville-Veikko; Repo, Timo; Koptyug, Igor
Physical Chemistry Chemical Physics (2016), 18 (40), 27784-27795CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
The parahydrogen-induced polarization (PHIP) phenomenon, obsd. when parahydrogen is used in H2 addn. processes, provides a means for substantial NMR signal enhancements and mechanistic studies of chem. reactions. Commonly, noble metal complexes are used for parahydrogen activation, whereas metal-free activation is rare. Herein, we report a series of unimol. metal-free frustrated Lewis pairs based on an ansa-aminoborane (AAB) moiety in the context of PHIP. These mols., which have a "mol. tweezers" structure, differ in their substituents at the boryl site (-H, -Ph, -o-iPr-Ph, and -Mes). PHIP effects were obsd. for all the AABs after exposing their solns. to parahydrogen in a wide temp. range, and exptl. measurements of their kinetic and thermodn. parameters were performed. A theor. anal. of their nuclear spin polarization effects is presented, and the roles of chem. exchange, chem. equil. and spin dynamics are discussed in terms of the key dimensionless parameters. The anal. allowed us to formulate the prerequisites for achieving strong polarization effects with AAB mols., which can be applied for further design of efficient metal-free tweezers-like mols. for PHIP. Mechanistic (chem. and phys.) aspects of the obsd. effects are discussed in detail. In addn., we performed quantum chem. calcns., which confirmed that the J-coupling between the parahydrogen-originated protons in AAB-H2 mols. is mediated through dihydrogen bonding.
31
For the estimation of barriers relevant to the interconversion of imH⁺/2H^– isomers, see the SI (section 2.4).
There is no corresponding record for this reference.
32
For computational studies examining the role of stabilizing noncovalent interactions in TM-catalyzed stereoselective hydrogenations, see:
(a) Hopmann, K. H.; Bayer, A. On the Mechanism of Iridium-Catalyzed Asymmetric Hydrogenation of Imines and Alkenes: A Theoretical Study. Organometallics 2011, 30, 2483– 2497, DOI: 10.1021/om1009507
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32a
On the mechanism of iridium-catalyzed asymmetric hydrogenation of imines and alkenes: a theoretical study
Hopmann, Kathrin Helen; Bayer, Annette
Organometallics (2011), 30 (9), 2483-2497CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
Potential energy surfaces for hydrogenation of trans-stilbene, trans-1,2-diphenylpropene and N-Ph acetophenoneketimine, catalyzed by PHOX iridium complex, [4-isopropyl-2-(2-diphenylphosphinophenyl-κP)oxazoline-κN]iridium(1+), were calcd. Phosphine-oxazoline (PHOX)-based iridium complexes have emerged as useful tools for enantioselective hydrogenation of unfunctionalized alkenes and imines. The mechanistic details of the asym. hydrogenation process, however, are poorly understood. Several different mechanisms have been put forward for hydrogenation of unfunctionalized alkenes, but it remains unclear which of these provide an accurate description of the hydrogenation reaction. The mechanistic aspects of Ir-(PHOX)-mediated hydrogenation of imines are little explored, and no detailed mechanism has been formulated to date. Here we provide a comprehensive quantum mech. study of Ir-(PHOX)-mediated hydrogenation of both alkene and imine substrates. Our results support previous findings by Brandt et al., clearly favoring an Ir(III)/Ir(V) reaction cycle for Ir-(PHOX)-mediated hydrogenation of unfunctionalized alkenes. An important aspect of this reaction mechanism is the orientation of the metal-coordinated alkene substrate, which dets. the stereochem. of the resulting product. Our anal. further shows that none of the proposed alkene hydrogenation mechanisms are applicable for imines. For Ir-(PHOX)-mediated imine hydrogenation, we suggest a fundamentally different catalytic cycle involving dissocn. of the imine substrate. The suggested mechanism correctly reproduces the stereoselectivity of imine redn., but indicates that the enantioselectivity should be more sensitive to the reaction conditions and less controllable than the enantioselectivity of alkene hydrogenations.
(b) Václavík, J.; Kuzma, M.; Přech, J.; Kačer, P. Asymmetric Transfer Hydrogenation of Imines and Ketones Using Chiral Ru^IICl(η⁶-p-cymene)[(S,S)-N-TsDPEN] as a Catalyst: A Computational Study. Organometallics 2011, 30, 4822– 4829, DOI: 10.1021/om200263d
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32b
Asymmetric transfer hydrogenation of imines and ketones using chiral RuIICl(η6-p-cymene)[(S,S)-N-TsDPEN] as a catalyst: a computational study
Vaclavik, Jiri; Kuzma, Marek; Prech, Jan; Kacer, Petr
Organometallics (2011), 30 (18), 4822-4829CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
Potential energy surface was calcd. for asym. transfer hydrogenation of an imine, 3,4-dihydro-1-methylisoquinoline and an arom. ketone, PhCOMe, catalyzed by ruthenium chiral (S,S)-1,2-diphenyl-N-tosyl-1,2-ethanediaminato (H2NCHPhCHPhNTs-, TsDPEN) η6-cymene complex, [RuCl(TsDPEN)(η6-cymene)] (1), comprising redn. of the complex 1 by formic acid to the hydride [RuH(TsDPEN)(η6-cymene)] (2), protonation of the imine and hydrogen transfer from ruthenium to carbon of the hydrogen-bonded imine; in the case of acetophenone redn., simultaneous transfer of proton and hydride occurs to oxygen and carbon, resp. D. functional theory (DFT) computational methods were used to investigate the increasingly popular ionic mechanistic concept for the asym. transfer hydrogenation of imines on the chiral catalyst 1. On application of the ionic mechanism, the reaction preferentially affords the (R)-amine product, which is in agreement with the exptl. observations. Calcd. transition state structures for the hydrogenation of protonated 1-methyl-3,4-dihydroisoquinoline are discussed together with their preceding and following energy min. Stabilization of the favorable transition state by a CH/π interaction between the η6-p-cymene ligand and the substrate mol. is explored in depth to show that both C(sp2)H/π is more probable than C(sp3)H/π in this mol. system. Finally, transition state geometries for the asym. transfer hydrogenation of acetophenone are proposed, which take the "std." six-membered cyclic form.
(c) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. Highly Enantioselective Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic Ruthenium Catalysts: Scope, Mechanism, and Origin of Enantioselectivity. J. Am. Chem. Soc. 2011, 133, 9878– 9891, DOI: 10.1021/ja2023042
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32c
Highly Enantioselective Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic Ruthenium Catalysts: Scope, Mechanism, and Origin of Enantioselectivity
Wang, Tianli; Zhuo, Lian-Gang; Li, Zhiwei; Chen, Fei; Ding, Ziyuan; He, Yanmei; Fan, Qing-Hua; Xiang, Junfeng; Yu, Zhi-Xiang; Chan, Albert S. C.
Journal of the American Chemical Society (2011), 133 (25), 9878-9891CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Asym. hydrogenation of quinolines catalyzed by chiral cationic η6-arene-N-tosylethylenediamine-Ru(II) complexes have been investigated. A wide range of quinoline derivs., including 2-alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivs., were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions. This catalytic protocol is applicable to the gram-scale synthesis of some biol. active tetrahydroquinolines, such as (-)-angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the prepn. of the antibacterial agent (S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction, intermediate characterization, and isotope labeling patterns. The evidence obtained from these expts. revealed that quinoline is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addn., isomerization, and 1,2-hydride addn., and hydrogen addn. undergoes a stepwise H+/H- transfer process outside the coordination sphere rather than a concerted mechanism. In addn., DFT calcns. indicate that the enantioselectivity originates from the CH/π attraction between the η6-arene ligand in the Ru-complex and the fused Ph ring of dihydroquinoline via a 10-membered ring transition state with the participation of TfO- anion.
(d) Pablo, Ó.; Guijarro, D.; Kovács, G.; Lledós, A.; Ujaque, G.; Yus, M. A Versatile Ru Catalyst for the Asymmetric Transfer Hydrogenation of Both Aromatic and Aliphatic Sulfinylimines. Chem. - Eur. J. 2012, 18, 1969– 1983, DOI: 10.1002/chem.201102426
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32d
A Versatile Ru Catalyst for the Asymmetric Transfer Hydrogenation of Both Aromatic and Aliphatic Sulfinylimines
Pablo, Oscar; Guijarro, David; Kovacs, Gabor; Lledos, Agusti; Ujaque, Gregori; Yus, Miguel
Chemistry - A European Journal (2012), 18 (7), 1969-1983, S1969/1-S1969/156CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A highly efficient Ru catalyst based on an achiral, very simple, and inexpensive amino alc. ligand (2-amino-2-methylpropan-1-ol) has been developed for the asym. transfer hydrogenation (ATH) of chiral N-(tert-butylsulfinyl)imines. This complex is able to catalyze the ATH of both arom. and the most challenging aliph. sulfinylimines by using iso-Pr alc. as the hydrogen source. The diastereoselective redn. of arom., heteroarom., and aliph. sulfinylketimines, including sterically congested cases, over short reaction times (1-4 h), followed by desulfinylation of the nitrogen atom, affords the corresponding highly enantiomerically enriched (ee up to >99 %) α-branched primary amines in excellent yields. The same ligand was equally effective for the synthesis of both (R)- and (S)-amines by using the appropriate abs. configuration in the iminic substrate. DFT mechanistic studies show that the hydrogen-transfer process is stepwise. Moreover, the origin of the diastereoselectivity has been rationalized.
(e) Hopmann, K. H. Iron/Brønsted Acid Catalyzed Asymmetric Hydrogenation: Mechanism and Selectivity-Determining Interactions. Chem. - Eur. J. 2015, 21, 10020– 10030, DOI: 10.1002/chem.201500602
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32e
Iron-Bronsted Acid-Catalyzed Asymmetric Hydrogenation: Mechanism and Selectivity-Determining Interactions
Hopmann, Kathrin H.
Chemistry - A European Journal (2015), 21 (28), 10020-10030CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Hydrogenation catalysts involving abundant base metals such as cobalt or iron are promising alternatives to precious metal systems. Despite rapid progress in this field, base metal catalysts do not yet achieve the activity and selectivity levels of their precious metal counterparts. Rational improvement of base metal complexes is facilitated by detailed knowledge about their mechanisms and selectivity-detg. factors. The mechanism for asym. imine hydrogenation with Knoelker's iron complex in the presence of chiral phosphoric acids is here studied computationally at the DFT-D level of theory, with models of up to 160 atoms. The resting state of the system is an adduct between the iron complex and the deprotonated acid. Rate-limiting H2 splitting is followed by a stepwise hydrogenation mechanism, in which the phosphoric acid acts as the proton donor. C-H···O interactions between the phosphoric acid and the substrate are involved in the stereocontrol at the final hydride transfer step. Computed enantiomeric ratios show excellent agreement with exptl. values, indicating that DFT-D is able to correctly capture the selectivity-detg. interactions of this system.
(f) Tutkowski, B.; Kerdphon, S.; Limé, E.; Helquist, P.; Andersson, P. G.; Wiest, O.; Norrby, P.-O. Revisiting the Stereodetermining Step in Enantioselective Iridium-Catalyzed Imine Hydrogenation. ACS Catal. 2018, 8, 615– 623, DOI: 10.1021/acscatal.7b02386
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32f
Revisiting the Stereodetermining Step in Enantioselective Iridium-Catalyzed Imine Hydrogenation
Tutkowski, Brandon; Kerdphon, Sutthichat; Lime, Elaine; Helquist, Paul; Andersson, Pher G.; Wiest, Olaf; Norrby, Per-Ola
ACS Catalysis (2018), 8 (1), 615-623CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
The mechanism for the iridium-catalyzed asym. hydrogenation of prochiral imines has been investigated for an exptl. relevant ligand-substrate combination using DFT calcns. The possible stereoisomers of the stereodetermining hydride transfer transition state were considered for four possible hydrogenation mechanisms starting from the recently disclosed active catalyst consisting of iridium phosphine-oxazoline with cyclometalated imine substrate. The hydrogenation was found to proceed via an outer-sphere pathway. The transition state accurately describes the exptl. observations of the active catalyst and provides a structural rationale for the high stereoinduction despite the lack of direct interaction points in the outer-sphere mechanism. The predicted enantioselectivity was consistent with exptl. observations. Exptl. studies support the hypothesis that the iridacycle forms spontaneously and functions as the active catalyst in the hydrogenation.
(g) Salomó, E.; Gallen, A.; Sciortino, G.; Ujaque, G.; Grabulosa, A.; Lledós, A.; Riera, A.; Verdaguer, X. Direct Asymmetric Hydrogenation of N-Methyl and N-Alkyl Imines with an Ir(III)H Catalyst. J. Am. Chem. Soc. 2018, 140, 16967– 16970, DOI: 10.1021/jacs.8b11547
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32g
Direct Asymmetric Hydrogenation of N-Methyl and N-Alkyl Imines with an Ir(III)H Catalyst
Salomo, Ernest; Gallen, Albert; Sciortino, Giuseppe; Ujaque, Gregori; Grabulosa, Arnald; Lledos, Agusti; Riera, Antoni; Verdaguer, Xavier
Journal of the American Chemical Society (2018), 140 (49), 16967-16970CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A novel cationic [IrH(THF)(P,N)(imine)] [BArF] catalyst contg. a P-stereogenic MaxPHOX ligand is described for the direct asym. hydrogenation of N-Me and N-alkyl imines. This is the first catalytic system to attain high enantioselectivity (up to 94% ee) in this type of transformation. The labile THF ligand allows for effective activation and reactivity, even at low temps. D. functional theory calcns. allowed the rationalization of the stereochem. course of the reaction.
(h) Chen, J.; Gridnev, I. D. Size is Important: Artificial Catalyst Mimics Behaviour of Natural Enzymes. iScience 2020, 23, 100960, DOI: 10.1016/j.isci.2020.100960
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32h
Size is Important: Artificial Catalyst Mimics Behavior of Natural Enzymes
Chen, Jianzhong; Gridnev, Ilya D.
iScience (2020), 23 (3), 100960CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)
Heavily substituted (R)-DTBM-SegPHOS is active in the asym. Pd(II)-catalyzed hydrogenation or C-O bond cleavage of α-pivaloyloxy-1-(2-furyl)ethanone, whereas (R)-SegPHOS fails to catalyze either of these transformations. An extensive network of C-H···H-C interactions provided by the heavily substituted Ph rings of (R)-DTBM-SegPHOS leads to increased stabilities of all intermediates and transition states in the corresponding catalytic cycles compared with the unsubstituted analogs. Moreover, formation of the encounter complex and its rearrangement into the reactive species proceeds in a fashion similar to that seen in natural enzymic reactions. Computations demonstrate that this feature is the origin of enantioselection in asym. hydrogenation, since the stable precursor is formed only when the catalyst is approached by one prochiral plane of the substrate.
33
For a selection of related studies on TM-catalyzed stereoselective hydrogenation of other substrates, see:
(a) Hopmann, K. H. Cobalt–Bis(Imino)Pyridine-Catalyzed Asymmetric Hydrogenation: Electronic Structure, Mechanism, and Stereoselectivity. Organometallics 2013, 32, 6388– 6399, DOI: 10.1021/om400755k
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33a
Cobalt-Bis(imino)pyridine-Catalyzed Asymmetric Hydrogenation: Electronic Structure, Mechanism, and Stereoselectivity
Hopmann, Kathrin H.
Organometallics (2013), 32 (21), 6388-6399CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
Academic and industrial efforts aim at replacing precious metal catalysts with cheaper and more environmentally friendly base metal variants. Two Co-bis-(imino)-pyridine (CoBIP) complexes were recently reported as promising candidates for asym. hydrogenation [Monfette, S.; et al. J. Am. Chem. Soc.2012, 134, 4561-4564]. A comprehensive quantum mech. anal. of these complexes is reported here, including electronic structures, preferred conformations, and mechanisms of activation. The full asym. hydrogenation mechanism is analyzed, and the origin of the obsd. enantioselectivities with both CoBIP catalysts is evaluated. A key finding is that CoBIP complexes catalyze a competing alkene isomerization reaction, which can have crucial implications for the yield and the stereochem. outcome of alkene hydrogenation.
(b) Dub, P. a.; Henson, N. J.; Martin, R. L.; Gordon, J. C. Unravelling the Mechanism of the Asymmetric Hydrogenation of Acetophenone by [RuX₂(Diphosphine)(1,2-Diamine)] Catalysts. J. Am. Chem. Soc. 2014, 136, 3505– 3521, DOI: 10.1021/ja411374j
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33b
Unravelling the Mechanism of the Asymmetric Hydrogenation of Acetophenone by [RuX2(diphosphine)(1,2-diamine)] Catalysts
Dub, Pavel A.; Henson, Neil J.; Martin, Richard L.; Gordon, John C.
Journal of the American Chemical Society (2014), 136 (9), 3505-3521CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The mechanism of catalytic hydrogenation of acetophenone by the chiral complex trans-[RuCl2{(S)-binap}{(S,S)-dpen}] and KO-t-C4H9 in propan-2-ol is revised on the basis of DFT computations carried out in dielec. continuum and the most recent exptl. observations. The results of these collective studies suggest that neither a six-membered pericyclic transition state nor any multibond concerted transition states are involved. Instead, a hydride moiety is transferred in an outer-sphere manner to afford an ion-pair, and the corresponding transition state is both enantio- and rate-detg. Heterolytic dihydrogen cleavage proceeds neither by a (two-bond) concerted, four-membered transition state, nor by a (three-bond) concerted, six-membered transition state mediated by a solvent mol. Instead, cleavage of the H-H bond is achieved via deprotonation of the η2-H2 ligand within a cationic Ru complex by the chiral conjugate base of (R)-1-phenylethanol. Thus, protonation of the generated (R)-1-phenylethoxide anion originates from the η2-H2 ligand of the cationic Ru complex and not from NH protons of a neutral Ru trans-dihydride complex, as initially suggested within the framework of a metal-ligand bifunctional mechanism. Detailed computational anal. reveals that the 16e- Ru amido complex [RuH{(S)-binap}{(S,S)-HN(CHPh)2NH2}] and the 18e- Ru alkoxo complex trans-[RuH{OCH(CH3)(R)}{(S)-binap}{(S,S)-dpen}] (R = CH3 or C6H5) are not intermediates within the catalytic cycle, but rather are off-loop species. The accelerative effect of KO-t-C4H9 is explained by the reversible formation of the potassium amidato complexes trans-[RuH2{(S)-binap}{(S,S)-N(K)H(CHPh)2NH2}] or trans-[RuH2{(S)-binap}{(S,S)-N(K)H(CHPh)2NH(K)}]. The three-dimensional (3D) cavity obsd. within these mols. results in a chiral pocket stabilized via several different noncovalent interactions, including neutral and ionic hydrogen bonding, cation-π interactions, and π-π stacking interactions. Cooperatively, these interactions modify the catalyst structure, in turn lowering the relative activation barrier of hydride transfer by ∼1-2 kcal mol-1 and the following H-H bond cleavage by ∼10 kcal mol-1, resp. A combined computational study and anal. of recent exptl. data of the reaction pool results in new mechanistic insight into the catalytic cycle for hydrogenation of acetophenone by Noyori's catalyst, in the presence or absence of KO-t-C4H9.
(c) Nakatsuka, H.; Yamamura, T.; Shuto, Y.; Tanaka, S.; Yoshimura, M.; Kitamura, M. Mechanism of Asymmetric Hydrogenation of Aromatic Ketones Catalyzed by a Combined System of Ru(π-CH₂C(CH₃)CH₂)₂(Cod) and the Chiral Sp²N/Sp³NH Hybrid Linear N4 Ligand Ph-BINAN-H-Py. J. Am. Chem. Soc. 2015, 137, 8138– 8149, DOI: 10.1021/jacs.5b02350
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33c
Mechanism of Asymmetric Hydrogenation of Aromatic Ketones Catalyzed by a Combined System of Ru(π-CH2C(CH3)CH2)2(cod) and the Chiral sp2N/sp3NH Hybrid Linear N4 Ligand Ph-BINAN-H-Py
Nakatsuka, Hiroshi; Yamamura, Tomoya; Shuto, Yoshihiro; Tanaka, Shinji; Yoshimura, Masahiro; Kitamura, Masato
Journal of the American Chemical Society (2015), 137 (25), 8138-8149CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The combination of a Goodwin-Lions-type chiral N4 ligand, (R)-Ph-BINAN-H-Py ((R)-3,3'-diphenyl-N2,N2'-bis((pyridin-2-yl)methyl)-1,1'-binaphthyl-2,2'-diamine; L), with Ru(π-CH2C(CH3)CH2)2(cod) (A) (cod = 1,5-cyclooctadiene) catalyzes the hydrogenation of acetophenone (AP) to (R)-1-phenylethanol (PE) with a high enantiomer ratio (er). Almost no Ru complex forms, with A and L remaining intact throughout the reaction while generating PE quant. according to [PE] = kobst2. An infinitesimal amt. of reactive and unstable RuH2L (B) with C2-Λ-cis-α stereochem. is very slowly and irreversibly generated from A by the action of H2 and L, which rapidly catalyzes the hydrogenation of AP via Noyori's donor-acceptor bifunctional mechanism. A CH-π-stabilized Si-face selective transition state, CSi, gives (R)-PE together with an intermediary Ru amide, D, which is inhibited predominantly by formation of the Ru enolate of AP. The rate-detg. hydrogenolysis of D completes the cycle. The time-squared term relates both to the preliminary step before the cycle and to the cycle itself, with a highly unusual eight-order difference in the generation and turnover frequency of B. This mechanism is fully supported by a series of expts. including a detailed kinetic study, rate law anal., simulation of t/[PE] curves with fitting to the exptl. observations at the initial reaction stage, X-ray crystallog. analyses of B-related octahedral metal complexes, and Hammett plot analyses of electronically different substrates and ligands in their enantioselectivities.
(d) Dub, P. A.; Gordon, J. C. The Mechanism of Enantioselective Ketone Reduction with Noyori and Noyori–Ikariya Bifunctional Catalysts. Dalton Trans. 2016, 45, 6756– 6781, DOI: 10.1039/C6DT00476H
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33d
The mechanism of enantioselective ketone reduction with Noyori and Noyori-Ikariya bifunctional catalysts
Dub, Pavel A.; Gordon, John C.
Dalton Transactions (2016), 45 (16), 6756-6781CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
A review. The catalytic hydrogenation of prochiral ketones with second and third-row transition metal complexes bearing chelating chiral ligands contg. at least one N-H functionality has achieved unparalleled performance, delivering, in the best cases, chiral alcs. with up to 99.9% ee using extremely small catalyst loadings (∼10-5 mol%). Hence the efficacy of this reaction has closely approached that of natural enzymic systems and the reaction itself has become one of the most efficient artificial catalytic reactions developed to date. This article describes the current level of understanding of the mechanism of enantioselective hydrogenation and transfer hydrogenation of arom. ketones with pioneering prototypes of bifunctional catalysts, the Noyori and Noyori-Ikariya complexes. Anal. presented herein expands the concept of "metal-ligand cooperation", redefines the term "cooperative ligand" and introduces "H-/H+ outer-sphere hydrogenation" as a novel paradigm in outer-sphere hydrogenation.
(e) Nakane, S.; Yamamura, T.; Manna, S. K.; Tanaka, S.; Kitamura, M. Mechanistic Study of the Ru-Catalyzed Asymmetric Hydrogenation of Nonchelatable and Chelatable Tert-Alkyl Ketones Using the Linear Tridentate Sp³P/Sp³NH/Sp²N-Combined Ligand PN(H)N: RuNH- and RuNK-Involved Dual Catalytic Cycle. ACS Catal. 2018, 8, 11059– 11075, DOI: 10.1021/acscatal.8b02671
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33e
Mechanistic Study of the Ru-Catalyzed Asymmetric Hydrogenation of Nonchelatable and Chelatable tert-Alkyl Ketones Using the Linear Tridentate sp3P/sp3NH/sp2N-Combined Ligand PN(H)N: RuNH- and RuNK-Involved Dual Catalytic Cycle
Nakane, Satoshi; Yamamura, Tomoya; Manna, Sudipta Kumar; Tanaka, Shinji; Kitamura, Masato
ACS Catalysis (2018), 8 (12), 11059-11075CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
The linear tridentate sp3P/sp3NH/sp2N ligand PN(H)N ((R)-2'-(diphenylphosphino)-N-(pyridin-2-ylmethyl)[1,1'-binaphthalen]-2-amine) exclusively forms fac-[Ru(PN(H)N)(dmso)3](BF4)2 over the mer isomer with the help of the three strongly π-accepting DMSO ligands. The three different ligating atoms exert a divergent effect on the trans-DMSO-Ru bond strengths, enabling the stereoselective generation of fac-RuH(CH3O)(PN(H)N)(dmso) (RuNH). RuNH efficiently hydrogenates both nonchelatable t-Bu Me ketone (BMK) and chelatable t-Bu methoxycarbonylmethyl ketone (BMCK) in the presence of a catalytic amt. of CH3OK. The reaction proceeds at the H-sp3N-Ru-H bifunctional reaction site of fac-RuH2(PN(H)N)(dmso), and high enantioselectivity is attained in a chiral 3D cavity constructed by the sp3N trans DMSO, the conformation of which is fixed by a PyC(6)H-O=S hydrogen bond. We detd. the structures of RuNH, the K amide RuNK, Ru dihydride, and Ru amido species by detailed NMR anal. using 15N-labeled PN(H)N and C(3)-Ph-substituted PN(H)N. The rate of BMK hydrogenation is significantly affected by [CH3OK]0, showing a characteristic curve with a peak followed by a pseudo-minus-first-order decay. The RuNH is easily deprotonated by CH3OK to generate RuNK, which is less reactive but has the same enantioface discrimination ability. Increased contribution of the slow RuNK cycle decreases the rate at higher [CH3OK]0. The RuNH- and RuNK-involved dual catalytic cycle is supported by curve-fitting analyses and K+ trapping expts. In hydrogenation of BMCK, only the RuNH cycle operates because BMCK is preferentially deprotonated over RuNH.
34
For structures of all HT transition states in the reaction with borane 2 and related structural analysis, see the SI (section 2.5).
There is no corresponding record for this reference.
35
The HT step of the catalytic cycle of im hydrogenation is an irreversible process. For the reaction with borane 2, the am + 2 product state is predicted to be 16.1 kcal/mol below the most favored imH⁺/2H.
There is no corresponding record for this reference.
36
The nearly quantitative agreement between computed and observed ee values is no doubt fortuitous and cannot be regarded as a measure of accuracy of the applied computational methodology.
There is no corresponding record for this reference.
37
For structures of all HT transition states in the reaction with borane 3 and related structural analysis, see the SI (section 2.6).
There is no corresponding record for this reference.
38
For structures of all HT transition states in the reaction with borane 1 and related structural analysis, see the SI (section 2.7).
There is no corresponding record for this reference.
39
The RDG data were computed by using the NCIPLOT program:
(a) Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A. J.; Yang, W. Revealing Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132, 6498– 6506, DOI: 10.1021/ja100936w
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39a
Revealing Noncovalent Interactions
Johnson, Erin R.; Keinan, Shahar; Mori-Sanchez, Paula; Contreras-Garcia, Julia; Cohen, Aron J.; Yang, Weitao
Journal of the American Chemical Society (2010), 132 (18), 6498-6506CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Mol. structure does not easily identify the intricate noncovalent interactions that govern many areas of biol. and chem., including design of new materials and drugs. We develop an approach to detect noncovalent interactions in real space, based on the electron d. and its derivs. Our approach reveals the underlying chem. that compliments the covalent structure. It provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small mols., mol. complexes, and solids. Most importantly, the method, requiring only knowledge of the at. coordinates, is efficient and applicable to large systems, such as proteins or DNA. Across these applications, a view of nonbonded interactions emerges as continuous surfaces rather than close contacts between atom pairs, offering rich insight into the design of new and improved ligands.
(b) Contreras-García, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J.-P.; Beratan, D. N.; Yang, W. NCIPLOT: A Program for Plotting Non-Covalent Interaction Regions. J. Chem. Theory Comput. 2011, 7, 625– 632, DOI: 10.1021/ct100641a
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39b
NCIPLOT: A Program for Plotting Noncovalent Interaction Regions
Contreras-Garcia, Julia; Johnson, Erin R.; Keinan, Shahar; Chaudret, Robin; Piquemal, Jean-Philip; Beratan, David N.; Yang, Weitao
Journal of Chemical Theory and Computation (2011), 7 (3), 625-632CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
Noncovalent interactions hold the key to understanding many chem., biol., and technol. problems. Describing these noncovalent interactions accurately, including their positions in real space, constitutes a first step in the process of decoupling the complex balance of forces that define noncovalent interactions. Because of the size of macromols., the most common approach has been to assign van der Waals interactions (vdW), steric clashes (SC), and hydrogen bonds (HBs) based on pairwise distances between atoms according to their vdW radii. We recently developed an alternative perspective, derived from the electronic d.: the non-covalent interactions (NCI) index. This index has the dual advantages of being generally transferable to diverse chem. applications and being very fast to compute, since it can be calcd. from promol. densities. Thus, NCI anal. is applicable to large systems, including proteins and DNA, where anal. of noncovalent interactions is of great potential value. Here, we describe the NCI computational algorithms and their implementation for the anal. and visualization of weak interactions, using both self-consistent fully quantum-mech. as well as promol. densities. A wide range of options for tuning the range of interactions to be plotted is also presented. To demonstrate the capabilities of our approach, several examples are given from org., inorg., solid state, and macromol. chem., including cases where NCI anal. gives insight into unconventional chem. bonding. The NCI code and its manual are available for download at http://www.chem.duke.edu/∼yang/software.htm.
40
For details on the reaction with the simplified borane, see the SI (section 2.8).
There is no corresponding record for this reference.
41
For details on computational analysis for hydrogenation reactions with boranes 2-F, 2-CF₃, 2-CH₃, 2-^tBu, and 2-ant, see the SI (section 2.9).
There is no corresponding record for this reference.
42
For the influence of various substituents on the strength of CH···π interaction, see:
Karthikeyan, S.; Ramanathan, V.; Mishra, B. K. Influence of the Substituents on the CH···π Interaction: Benzene–Methane Complex. J. Phys. Chem. A 2013, 117, 6687– 6694, DOI: 10.1021/jp404972f
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42
Influence of the Substituents on the CH...π Interaction: Benzene-Methane Complex
Karthikeyan, S.; Ramanathan, V.; Mishra, Brijesh Kumar
Journal of Physical Chemistry A (2013), 117 (30), 6687-6694CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
Recently we showed that the binding energy of the benzene...acetylene complex could be tuned up to 5 kcal/mol by substituting the hydrogen atoms of the benzene mol. with multiple electron-donating/electron-withdrawing groups. In continuation, we have here examd. the influence of various substituents on the CH...π interaction present in the benzene...methane complex using the CCSD(T) method at the complete basis set limit. The influence of multiple fluoro substituents on the interaction strength of the benzene...methane complex was found to be insignificant, while the interaction strength linearly increases with successive addn. of Me groups. The influence of other substituents such as CN, NO2, COOH, Cl, and OH was found to be negligible. The NH2 group enhances the binding strength similarly to the Me group. Energy decompn. anal. predicts the dispersion energy component to be on an av. three times larger than the electrostatic energy component. Multidimensional correlation anal. shows that the exchange-repulsion and dispersion terms are correlated very well with the interaction distance (r) and with a combination of the interaction distance (r) and molar refractivity (MR), while the electrostatic component correlates well when the Hammett const. is used in combination with the interaction distance (r). Various recently developed DFT methods were used to assess their ability to predict the binding energy of various substituted benzene...methane complexes, and the M06-2X, B97-D, and B3LYP-D3 methods were found to be the best performers, giving a mean abs. deviation of ∼0.15 kcal/mol.

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Abstract
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Chart 1
Chart 1. Selection of Chiral FLP Components Employed in Enantioselective Catalytic Hydrogenations^a
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^aAr denotes aromatic substituents; Ar^F = C₆F₅ or p-C₆F₄H.
Scheme 1
Scheme 1. Reactions Examined Computationally
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Scheme 2
Scheme 2. Alternative Catalytic Cycles in Imine Reduction^a
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^aNotations: P, im and am are defined in the text, B denotes chiral boranes 2 and 3. HT refers to hydride transfer from BH^– to the prochiral carbon of imH⁺.
Figure 1
Figure 1. Transition states of H₂ activation by the P/2 and im/2 FLPs. Relative stabilities (in kcal/mol, with respect to the base + B + H₂ reactant states) are given in parentheses. H atoms of the FLPs are omitted for clarity.
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Chart 2
Chart 2. Main Borohydride Conformers as Exemplified by 2H^–
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Figure 2
Figure 2. Selected structures of imH⁺/2H^– ion pair intermediates. In the labeling, H···H and H···C refer to structures with B–H units pointing to iminium N–H bond or to prochiral C atom; c₁ and c₂ denote two different borohydride conformers. Relative stabilities (in kcal/mol, with respect to the im + 2 + H₂) are given in parentheses. Selected bond distances are in angstroms.
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Figure 3
Figure 3. Hydride transfer transition states identified computationally for hydrogenation of im with borane 2. Each line on the free energy diagram represents a specific isomeric form with the computed relative stability. TS-2-R_i and TS-2-S_i denote transition states leading to (R)-am and (S)-am products (index i defines the stability order). Full and dotted lines refer to transition state isomers involving c₂ and c₁ borohydride conformers. Selected structures are depicted and marked with arrows; their relative stabilities are given in parentheses (in kcal/mol, with respect to the most stable form). The iminium component is highlighted in blue for clarity. Green and red dotted arrows indicate attractive and repulsive intermolecular contacts. Computed and experimental (in brackets) ee data are shown below the diagram.
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Figure 4
Figure 4. Hydride transfer transition states identified computationally for hydrogenation of im with borane 3. For further relevant information, see the caption of Figure 3.
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Figure 5
Figure 5. Hydride transfer transition states identified computationally for hydrogenation of im with borane 1. For further relevant information, see the caption of Figure 3. The classification of transition states according to the borohydride conformations is not relevant in this case. The lowest lying energy level in the (S) ensemble (at 0.4 kcal/mol) represents two different structures, TS-1-S₁ and TS-1-S₂, of which only the former is depicted.
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Figure 6
Figure 6. Noncovalent interactions (NCI) in hydride transfer transition states TS-2-R₁ and TS-2-S₁. The borohydride is represented by a gray isodensity surface (ρ = 0.01 au); the iminium is shown in blue. The applied cutoff for reduced density gradient is s = 0.3 au. π–π stacking and CH₃–π interactions are highlighted by green dotted arrows.
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Figure 7
Figure 7. Modified boranes and predicted ee data.
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Scheme 3
Scheme 3. Synthesis of Chiral Borane 2-F
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Figure 8
Figure 8. Crystal structure of borane 2-F. H atoms are omitted for clarity.
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Scheme 4
Scheme 4. Synthesis of Chiral Borane 2-^tBu
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Figure 9
Figure 9. Crystal structure of borane 2-^tBu. H atoms are omitted for clarity.
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References
This article references 42 other publications.
1. 1
  (a) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications; Wiley-VCH: Weinheim, 2010.
  There is no corresponding record for this reference.
  (b) Nugent, T. C.; El-Shazly, M. Chiral Amine Synthesis - Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine Reduction. Adv. Synth. Catal. 2010, 352, 753– 819, DOI: 10.1002/adsc.200900719
  1b
  Chiral amine synthesis. Recent developments and trends for enamide reduction, reductive amination, and imine reduction
  Nugent, Thomas C.; El-Shazly, Mohamed
  Advanced Synthesis & Catalysis (2010), 352 (5), 753-819CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The review examd. the chiral amine literature from 2000-2009 (May) concerning enantioselective and diastereoselective methods for N-acylenamide and enamine redn., reductive amination, and imine redn. The reaction steps for each strategy, from ketone to primary chiral amine, are clearly defined, with best methods and yields for starting material prepn. and final deprotection noted. Categories of chiral amines were defined in Section 1 to allow the reader to quickly understand whether their specific target amine falls within a difficult to synthesize, or not, structural class. Amino acids are not considered in this work.
2. 2
  For selected reviews, see:
  (a) Spindler, F.; Blaser, H.-U. Enantioselective Hydrogenation of C=N Functions and Enamines. In Handbook of Homogenous Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007; Vol. 3, pp 1193– 1214.
  There is no corresponding record for this reference.
  (b) Xie, J. H.; Zhu, S. F.; Zhou, Q. L. Transition Metal-Catalyzed Enantioselective Hydrogenation of Enamines and Imines. Chem. Rev. 2011, 111, 1713– 1760, DOI: 10.1021/cr100218m
  2b
  Transition Metal-Catalyzed Enantioselective Hydrogenation of Enamines and Imines
  Xie, Jian-Hua; Zhu, Shou-Fei; Zhou, Qi-Lin
  Chemical Reviews (Washington, DC, United States) (2011), 111 (3), 1713-1760CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  This review is intended to provide an overview of the transition metal-catalyzed enantioselective hydrogenation of enamines and imines for the synthesis of chiral amines. The focus of this review is on the development of chiral metal catalysts for these transformations emphasizing rhodium, ruthenium, iridium, titanium, and palladium catalysts. For the hydrogenation of N-acetyl enamines, the chiral rhodium complexes bearing diphosphine ligands were efficient chiral catalysts. However, in the hydrogenation of N-alkyl/aryl imines, the chiral iridium catalysts contg. phosphine oxazoline ligands exhibit outstanding performance. Furthermore, the highly efficient catalysts for activated imines hydrogenation were dominated by palladium complexes of chiral diphosphine ligands.
  (c) Yu, Z.; Jin, W.; Jiang, Q. Brønsted Acid Activation Strategy in Transition-Metal Catalyzed Asymmetric Hydrogenation of N-Unprotected Imines, Enamines, and N-Heteroaromatic Compounds. Angew. Chem., Int. Ed. 2012, 51, 6060– 6072, DOI: 10.1002/anie.201200963
  2c
  Bronsted Acid Activation Strategy in Transition-Metal Catalyzed Asymmetric Hydrogenation of N-Unprotected Imines, Enamines, and N-Heteroaromatic Compounds
  Yu, Zhengkun; Jin, Weiwei; Jiang, Quanbin
  Angewandte Chemie, International Edition (2012), 51 (25), 6060-6072CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Asym. hydrogenation plays an important role in org. synthesis, but that of the challenging substrates such as N-unprotected imines, enamines, and N-heteroarom. compds. (1H-indoles, 1H-pyrroles, pyridines, quinolines, and quinoxalines) has only received increased attention in the past three years. Considering the interaction modes of a Bronsted acid with a Lewis base, Bronsted acids may be used as the ideal activators of C:N bonds. This minireview summarizes the recent advances in transition metal-catalyzed, Bronsted acid activated asym. hydrogenation of these challenging substrates, thus offering a promising substrate activation strategy for transformations involving C:N bonds.
  (d) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Recent Advances in Transition Metal-Catalyzed Enantioselective Hydrogenation of Unprotected Enamines. Chem. Soc. Rev. 2012, 41, 4126, DOI: 10.1039/c2cs35007f
  2d
  Recent advances in transition metal-catalyzed enantioselective hydrogenation of unprotected enamines
  Xie, Jian-Hua; Zhu, Shou-Fei; Zhou, Qi-Lin
  Chemical Society Reviews (2012), 41 (11), 4126-4139CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  Review. Transition metal-catalyzed enantioselective hydrogenation of enamines is undoubtedly a useful and environmentally friendly method for the prepn. of optically pure chiral amines and amine derivs. Over the last few decades, the use of transition metal catalysts contg. chiral phosphorus or phosphine-oxazoline ligands attracted much attention for the hydrogenation of unprotected enamines. A no. of efficient chiral catalysts were developed, and some of them have shown high potential for the application in the synthesis of optical chiral amines in both lab. and industry. This tutorial review focused on the contributions concerning the transition metal-catalyzed enantioselective hydrogenation of unprotected enamines for the synthesis of chiral amines and amine derivs.
  (e) Stereoselective Formation of Amines; Li, W., Zhang, X., Eds.; Springer-Verlag: New York, 2014; Vol. 343.
  There is no corresponding record for this reference.
  (f) Liu, Y.; Yue, X.; Luo, C.; Zhang, L.; Lei, M. Mechanisms of Ketone/Imine Hydrogenation Catalyzed by Transition-Metal Complexes. Energy Environ. Mater. 2019, 2, 292– 312, DOI: 10.1002/eem2.12050
  2f
  Mechanisms of Ketone/Imine Hydrogenation Catalyzed by Transition-Metal Complexes
  Liu, Yangqiu; Yue, Xin; Luo, Chenguang; Zhang, Lin; Lei, Ming
  Energy & Environmental Materials (2019), 2 (4), 292-312CODEN: EEMNA3; ISSN:2575-0356. (John Wiley & Sons, Inc.)
  A review. Alcs. and amines are important in pharmaceutical, perfume, and agrochem. industries. Catalytic asym. synthesis is one of the major ways to produce chiral alcs./amines from prochiral ketones/imines via hydrogenation. Meanwhile, the alc./amine dehydrogenation with high hydrogen energy d. is paid more and more attention as promising hydrogen-storage media. In this review, we summarize classifications of mechanisms of ketone/imine hydrogenation and alc./amine dehydrogenation catalyzed by transition-metal (TM) complexes, the H2 activation modes, and the nature of asym. ketone/imine hydrogenation (AKH/AIH). This will elaborate our understanding on the nature of the TM-catalyzed ketone/imine hydrogenation and alc./amine dehydrogenation reactions.
3. 3
  For related reviews, see:
  (a) Hopmann, K. H.; Bayer, A. Enantioselective Imine Hydrogenation with Iridium-Catalysts: Reactions, Mechanisms and Stereocontrol. Coord. Chem. Rev. 2014, 268, 59– 82, DOI: 10.1016/j.ccr.2014.01.023
  3a
  Enantioselective imine hydrogenation with iridium-catalysts: Reactions, mechanisms and stereocontrol
  Hopmann, Kathrin Helen; Bayer, Annette
  Coordination Chemistry Reviews (2014), 268 (), 59-82CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
  A review. The current status of knowledge on asym. iridium-catalyzed direct hydrogenations of acyclic and cyclic imines was summarized. An overview of the most interesting catalysts with respect to selectivity, activity and substrate scope was given, including a discussion of the effects of different reaction conditions on the enantioselectivity of imine redn. A detailed anal. of proposed imine hydrogenation mechanisms was presented, revealing that a significant no. of recent proposals suggest outer sphere mechanisms, implying that the substrate does not bind to the metal center during the hydrogenation reaction. Generally, the factors governing the stereocontrol of iridium-catalyzed direct imine hydrogenation were little studied. The mechanistic proposals that had been put forward to explain the enantiodiscrimination of selected complexes were reviewed here, showing that the stereocontrol appears to be governed by weak non-bonding interactions between the substrate and the chiral catalyst complex. These selectivity-detg. interactions might be modified through coordination of solvent, additive, or product mols. to the iridium complex, providing a rationale for the effect of solvent or additives on the enantioselectivity.
  (b) Mwansa, J. M.; Page, M. I. Catalysis, Kinetics and Mechanisms of Organo-Iridium Enantioselective Hydrogenation-Reduction. Catal. Sci. Technol. 2020, 10, 590– 612, DOI: 10.1039/C9CY02147G
  3b
  Catalysis, kinetics and mechanisms of organo-iridium enantioselective hydrogenation-reduction
  Mwansa, Joseph M.; Page, Michael I.
  Catalysis Science & Technology (2020), 10 (3), 590-612CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)
  A review of organo-Ir complexes which have gained a reputation for their great utility in key enantioselective synthetic procedures. Prime examples include the catalytic redn. of carbonyls and imines; Ir-catalyzed allylic substitution and catalyzed enantioselective hydrogenation of unsatd. carboxylic acids. Important aspects in these processes are the reaction conditions such as the catalyst loading, metal-ion ligands, the substrate, solvent and the reaction times-all of which can affect the degree of enantioselectivity. Understanding the mechanisms of these hydrogenation/redn. reactions through kinetic and other related studies makes a vital contribution to improving catalytic efficiency.
  (c) Cui, C.-X.; Chen, H.; Li, S.-J.; Zhang, T.; Qu, L.-B.; Lan, Y. Mechanism of Ir-Catalyzed Hydrogenation: A Theoretical View. Coord. Chem. Rev. 2020, 412, 213251, DOI: 10.1016/j.ccr.2020.213251
  3c
  Mechanism of Ir-catalyzed hydrogenation: A theoretical view
  Cui, Cheng-Xing; Chen, Haohua; Li, Shi-Jun; Zhang, Tao; Qu, Ling-Bo; Lan, Yu
  Coordination Chemistry Reviews (2020), 412 (), 213251CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
  A review. Ir catalysis is widely used in hydrogenation reactions to transform unsatd. mols. to the corresponding satd. mols. Understanding the reaction mechanism is helpful for design of new Ir-catalyzed hydrogenation reactions, as well as for controlling the regio/stereoselectivity. D. functional theory is a powerful tool for mechanistic study of organometallic catalysis, and it has been widely used to reveal the reaction pathways in this research area. With the development of computational methods, much progress has recently been made in mechanistic study of Ir-catalyzed hydrogenation reactions. Herein, we present a review of theor. studies of the mechanism of Ir-catalyzed homogeneous hydrogenation. A redox pathway is commonly proposed for hydrogenation of non-polar unsatd. bonds, which involves oxidative addn. of a hydrogen mol. to afford a high valence Ir hydride complex, insertion of an unsatd. bond into the Ir-H bond, and reductive elimination. Alternatively, the dihydrogen mol. can undergo a heterolysis reaction to provide a formal hydride ion and a proton. Subsequent nucleophilic and electrophilic attack can then also achieve hydrogenation of the polar unsatd. bond. In this review, the studies of the mechanism of Ir-catalyzed hydrogenation are classified according to the type of substrate: olefins, carbonyls, and imines. In each category, the reactions are discussed with respect to the various hydrogen sources. The stereochem. and substituent effect in Ir-catalyzed hydrogenation are also considered.
4. 4
  For a review on metal-free hydrogenation strategies, see:
  Rossi, S.; Benaglia, M.; Massolo, E.; Raimondi, L. Organocatalytic Strategies for Enantioselective Metal-Free Reductions. Catal. Sci. Technol. 2014, 4, 2708– 2723, DOI: 10.1039/C4CY00033A
  4
  Organocatalytic strategies for enantioselective metal-free reductions
  Rossi, Sergio; Benaglia, Maurizio; Massolo, Elisabetta; Raimondi, Laura
  Catalysis Science & Technology (2014), 4 (9), 2708-2723CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)
  A review. One of the most important chem. transformations is the redn. of multiple bonds, carbon-carbon as well as carbon-heteroatom double bonds, since it leads very often to the generation of new stereocenters in the mol. The replacement of metal-based catalysts with equally efficient metal-free counterparts is very appealing in view of possible future applications of non toxic, low cost, and environmentally friendly promoters on an industrial scale. This perspective will focus specially, but not exclusively, on the enantioselective redn. of the carbon nitrogen double bond; despite the historical need for and continued interest in chiral amines, their synthesis remains challenging. Three metal-free catalytic methodologies available for the redn. of carbon-nitrogen double bond will be discussed: (i) binaphthol-derived phosphoric acids catalyzed redns., with dihydropyridine-based compd. as the reducing agent; (ii) trichlorosilane mediated redns., in the presence of catalytic amts. of chiral Lewis bases; (iii) metal-free hydrogenation of imines through FLP (Frustrated Lewis Pair) methodol., that involves the use of a combination of a strong Lewis acid with a variety of sterically encumbered Lewis bases, for examples phosphines or tertiary amines, to activate hydrogen at ambient conditions. Special attention will be devoted to the most recent applications of the last five years.
5. 5
  For a review on organocatalytic transfer hydrogenation and hydrosilation reactions, see:
  Herrera, R. P. Organocatalytic Transfer Hydrogenation and Hydrosilylation Reactions. Top. Curr. Chem. 2016, 374, 29, DOI: 10.1007/s41061-016-0032-4
  5
  Organocatalytic Transfer Hydrogenation and Hydrosilylation Reactions
  Herrera Raquel P
  Topics in current chemistry (Cham) (2016), 374 (3), 29 ISSN:2365-0869.
  The reduction of different carbon-carbon or carbon-heteroatom double bonds is a powerful tool that generates in many cases new stereogenic centers. In the last decade, the organocatalytic version of these transformations has attracted more attention, and remarkable progress has been made in this way. Organocatalysts such as chiral Bronsted acids, thioureas, chiral secondary amines or Lewis bases have been successfully used for this purpose. In this context, this chapter will cover pioneering and seminal examples using Hantzsch dihydropyridines 1 and trichlorosilane 2 as reducing agents. More recent examples will be also cited in order to cover as much as possible the complete research in this field.
6. 6
  Welch, G. C.; Juan, R. R. S.; Masuda, J. D.; Stephan, D. W. Reversible, Metal-Free Hydrogen Activation. Science 2006, 314, 1124– 1126, DOI: 10.1126/science.1134230
  6
  Reversible, Metal-Free Hydrogen Activation
  Welch, Gregory C.; San Juan, Ronan R.; Masuda, Jason D.; Stephan, Douglas W.
  Science (Washington, DC, United States) (2006), 314 (5802), 1124-1126CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Although reversible covalent activation of mol. hydrogen (H2) is a common reaction at transition metal centers, it has proven elusive in compds. of the lighter elements. The compd. (C6H2Me3)2PH(C6F4)BH(C6F5)2 (Me, methyl), which was derived through an unusual reaction involving dimesitylphosphine substitution at a para carbon of tris(pentafluorophenyl)borane, cleanly loses H2 at temps. above 100°. Preliminary kinetic studies reveal this process to be first order. Remarkably, the dehydrogenated product (C6H2Me3)2P(C6F4)B(C6F5)2 is stable and reacts with 1 atm of H2 at 25° to reform the starting complex. Deuteration studies were also carried out to probe the mechanism.
7. 7
  For the first influential works, see:
  (a) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Metal-Free Catalytic Hydrogenation. Angew. Chem., Int. Ed. 2007, 46, 8050– 8053, DOI: 10.1002/anie.200702908
  7a
  Metal-free catalytic hydrogenation
  Chase, Preston A.; Welch, Gregory C.; Jurca, Titel; Stephan, Douglas W.
  Angewandte Chemie, International Edition (2007), 46 (42), 8050-8053CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Phosphonium borates of the form R2PH(C6F4)BH(C6F5)2 (R = 2,4,6-Me3C6H2, tert-Bu) are shown to be metal-free hydrogenation catalysts that effect redn. of sterically hindered imines and aziridines, as well as B(C6F5)3-protected unhindered imines and nitriles, at relatively low H2 pressures and temps.
  (b) Chase, P. A.; Jurca, T.; Stephan, D. W. Lewis Acid-Catalyzed Hydrogenation: B(C₆F₅)₃-Mediated Reduction of Imines and Nitriles with H₂. Chem. Commun. 2008, 14, 1701, DOI: 10.1039/b718598g
  There is no corresponding record for this reference.
  (c) Wang, H.; Fröhlich, R.; Kehr, G.; Erker, G. Heterolytic Dihydrogen Activation with the 1,8-Bis(Diphenylphosphino)Naphthalene/B(C₆F₅)₃ Pair and Its Application for Metal-Free Catalytic Hydrogenation of Silyl Enol Ethers. Chem. Commun. 2008, 45, 5966, DOI: 10.1039/b813286k
  There is no corresponding record for this reference.
  (d) Spies, P.; Schwendemann, S.; Lange, S.; Kehr, G.; Fröhlich, R.; Erker, G. Metal-Free Catalytic Hydrogenation of Enamines, Imines, and Conjugated Phosphinoalkenylboranes. Angew. Chem., Int. Ed. 2008, 47, 7543– 7546, DOI: 10.1002/anie.200801432
  7d
  Metal-free catalytic hydrogenation of enamines, imines, and conjugated phosphinoalkenylboranes
  Spies, Patrick; Schwendemann, Sina; Lange, Stefanie; Kehr, Gerald; Froehlich, Roland; Erker, Gerhard
  Angewandte Chemie, International Edition (2008), 47 (39), 7543-7546CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The metal-free hydrogen activator [2-(dimesitylphosphino)ethyl]bis(pentafluorophenyl)borane (1) catalyzes the unique P/B hydrogenation of the frustrated Lewis pair, e.g. MKeC≡CPBu-t (3), which itself is inactive toward H2 under the applied conditions, to yield the hydrogenation product. System 1/[2-(dimesitylphosphino)ethyl]bis(pentafluorophenyl)hydridoborate (2) (5 mol%) also catalyzes the hydrogenation of a bulky ketimine and of enamines under mild conditions (2.5 bar H2, RT) to yield the resp. amines.
  (e) Sumerin, V.; Schulz, F.; Atsumi, M.; Wang, C.; Nieger, M.; Leskelä, M.; Repo, T.; Pyykkö, P.; Rieger, B. Molecular Tweezers for Hydrogen: Synthesis, Characterization, and Reactivity. J. Am. Chem. Soc. 2008, 130, 14117– 14119, DOI: 10.1021/ja806627s
  7e
  Molecular Tweezers for Hydrogen: Synthesis, Characterization, and Reactivity
  Sumerin, Victor; Schulz, Felix; Atsumi, Michiko; Wang, Cong; Nieger, Martin; Leskelae, Markku; Repo, Timo; Pyykkoe, Pekka; Rieger, Bernhard
  Journal of the American Chemical Society (2008), 130 (43), 14117-14119CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The first ansa-aminoborane N-TMPN-CH2C6H4B(C6F5)2 (where TMPNH is 2,2,6,6-tetramethylpiperidinyl) which is able to reversibly activate H2 through an intramol. mechanism is synthesized. This new substance makes use of the concept of mol. tweezers where the active N and B centers are located close to each other so that one H2 mol. can fit in this void and be activated. Because of the fixed geometry of this ansa-ammonium-borate it forms a short N-H···H-B dihydrogen bond of 1.78 Å as detd. by x-ray anal. Therefore, the bound hydrogen can be released above 100°. In addn., the short H···H contact and the N-H···H (154°) and B-H···H (125°) angles show that the dihydrogen interaction in N-TMPNH-CH2C6H4BH(C6F5)2 is partially covalent in nature. As a basis for discussing the mechanism, quantum chem. calcns. are performed and it is found that the energy needed for splitting H2 can arise from the Coulomb attraction between the resulting ionic fragments, or "Coulomb pays for Heitler-London". The air- and moisture-stable N-TMPNH-CH2C6H4BH(C6F5)2 is employed in the catalytic redn. of nonsterically demanding imines and enamines under mild conditions (110° and 2 atm of H2) to give the corresponding amines in high yields.
8. 8
  For reviews on FLP chemistry, see:
  (a) Topics in Current Chemistry; Erker, G., Stephan, D. W., Eds.; Springer-Verlag, 2013; Vols. 332 and 334.
  There is no corresponding record for this reference.
  (b) Stephan, D. W.; Erker, G. Frustrated Lewis Pair Chemistry : Development and Perspectives. Angew. Chem., Int. Ed. 2015, 54, 6400– 6441, DOI: 10.1002/anie.201409800
  8b
  Frustrated Lewis Pair Chemistry: Development and Perspectives
  Stephan, Douglas W.; Erker, Gerhard
  Angewandte Chemie, International Edition (2015), 54 (22), 6400-6441CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Frustrated Lewis pairs (FLPs) are combinations of Lewis acids and Lewis bases in soln. that are deterred from strong adduct formation by steric and/or electronic factors. This opens pathways to novel cooperative reactions with added substrates. Small-mol. binding and activation by FLPs has led to the discovery of a variety of new reactions through unprecedented pathways. Hydrogen activation and subsequent manipulation in metal-free catalytic hydrogenations is a frequently obsd. feature of many FLPs. The current state of this young but rapidly expanding field is outlined in this Review and the future directions for its broadening sphere of impact are considered.
  (c) Stephan, D. W. Frustrated Lewis Pairs. J. Am. Chem. Soc. 2015, 137, 10018– 10032, DOI: 10.1021/jacs.5b06794
  8c
  Frustrated Lewis Pairs
  Stephan, Douglas W.
  Journal of the American Chemical Society (2015), 137 (32), 10018-10032CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A review. The articulation of the notion of "frustrated Lewis pairs" (FLPs), which emerged from the discovery that H2 can be reversibly activated by combinations of sterically encumbered Lewis acids and bases, has prompted a great deal of recent activity. Perhaps the most remarkable consequence has been the development of FLP catalysts for the hydrogenation of a range of org. substrates. In the past 9 years, the substrate scope has evolved from bulky polar species to include a wide range of unsatd. org. mols. In addn., effective stereoselective metal-free hydrogenation catalysts have begun to emerge. The mechanism of this activation of H2 has been explored, and the nature and range of Lewis acid/base combinations capable of effecting such activation have also expanded to include a variety of non-metal species. The reactivity of FLPs with a variety of other small mols., including olefins, alkynes, and a range of element oxides, has also been developed. Although much of this latter chem. has uncovered unique stoichiometric transformations, metal-free catalytic hydroamination, CO2 redn. chem., and applications in polymn. have also been achieved. The concept is also beginning to find applications in bioinorg. and materials chem. as well as heterogeneous catalysis. This Perspective highlights many of these developments and discusses the relationship between FLPs and established chem. Some of the directions and developments that are likely to emerge from FLP chem. in the future are also presented.
  (d) Stephan, D. W. Frustrated Lewis Pairs: From Concept to Catalysis. Acc. Chem. Res. 2015, 48, 306– 316, DOI: 10.1021/ar500375j
  8d
  Frustrated Lewis Pairs: From Concept to Catalysis
  Stephan, Douglas W.
  Accounts of Chemical Research (2015), 48 (2), 306-316CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review. Frustrated Lewis pair (FLP) chem. has emerged in the past decade as a strategy that enables main-group compds. to activate small mols. This concept is based on the notion that combinations of Lewis acids and bases that are sterically prevented from forming classical Lewis acid-base adducts have Lewis acidity and basicity available for interaction with a third mol. This concept has been applied to stoichiometric reactivity and then extended to catalysis. This Account describes three examples of such developments: hydrogenation, hydroamination, and CO2 redn. The most dramatic finding from FLP chem. was the discovery that FLPs can activate H2, thus countering the long-existing dogma that metals are required for such activation. This finding of stoichiometric reactivity was subsequently evolved to employ simple main-group species as catalysts in hydrogenations. While the initial studies focused on imines, subsequent studies uncovered FLP catalysts for a variety of org. substrates, including enamines, silyl enol ethers, olefins, and alkynes. Moreover, FLP redns. of arom. anilines and N-heterocycles have been developed, while very recent extensions have uncovered the utility of FLP catalysts for ketone redns. FLPs have also been shown to undergo stoichiometric reactivity with terminal alkynes. Typically, either deprotonation or FLP addn. reaction products are obsd., depending largely on the basicity of the Lewis base. While a variety of acid/base combinations have been exploited to afford a variety of zwitterionic products, this reactivity can also be extended to catalysis. When secondary aryl amines are employed, hydroamination of alkynes can be performed catalytically, providing a facile, metal-free route to enamines. In a similar fashion, initial studies of FLPs with CO2 demonstrated their ability to capture this greenhouse gas. Again, modification of the constituents of the FLP led to the discovery of reaction systems that demonstrated stoichiometric redn. of CO2 to either methanol or CO. Further modification led to the development of catalytic systems for the redn. of CO2 by hydrosilylation and hydroboration or deoxygenation. As each of these areas of FLP chem. has advanced from the observation of unusual stoichiometric reactions to catalytic processes, it is clear that the concept of FLPs provides a new strategy for the design and application of main-group chem. and the development of new metal-free catalytic processes.
  (e) Stephan, D. W. The Broadening Reach of Frustrated Lewis Pair Chemistry. Science 2016, 354, aaf7229– aaf7229, DOI: 10.1126/science.aaf7229
  There is no corresponding record for this reference.
  (f) Jupp, A. R.; Stephan, D. W. New Directions for Frustrated Lewis Pair Chemistry. Trends in Chemistry 2019, 1, 35– 48, DOI: 10.1016/j.trechm.2019.01.006
  8f
  New Directions for Frustrated Lewis Pair Chemistry
  Jupp, Andrew R.; Stephan, Douglas W.
  Trends in Chemistry (2019), 1 (1), 35-48CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)
  A review. The concerted action of a Lewis acid and base can activate H2 and other small mols. Such frustrated Lewis pairs (FLPs) have garnered much attention and prompted many investigations into the activation of small mols. and catalysis. Although the nature, mechanism of action, and range of FLP systems continues to expand, this concept has also inspired ever-widening chem. Applications in hydrogenation and polymn. catalysis, as well as in synthetic chem., have provided selective processes and metal-free protocols. Heterogeneous FLP catalysts are emerging, and polymeric FLPs offer avenues to unique materials and strategies for sensing and carbon capture. The prospects for further impact of this remarkably simple reaction paradigm are considered.
9. 9
  For reviews on FLP-type catalytic hydrogenations, see:
  (a) Stephan, D. W.; Erker, G. Frustrated Lewis Pairs: Metal-free Hydrogen Activation and More. Angew. Chem., Int. Ed. 2010, 49, 46– 76, DOI: 10.1002/anie.200903708
  9a
  Frustrated Lewis Pairs: Metal-free Hydrogen Activation and More
  Stephan, Douglas W.; Erker, Gerhard
  Angewandte Chemie, International Edition (2010), 49 (1), 46-76CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Sterically encumbered Lewis acid and Lewis base combinations do not undergo the ubiquitous neutralization reaction to form classical Lewis acid/Lewis base adducts. Rather, both the unquenched Lewis acidity and basicity of such sterically frustrated Lewis pairs (FLPs) is available to carry out unusual reactions. Typical examples of frustrated Lewis pairs are inter- or intramol. combinations of bulky phosphines or amines with strongly electrophilic RB(C6F5)2 components. Many examples of such frustrated Lewis pairs are able to cleave dihydrogen heterolytically. The resulting H+/H- pairs (stabilized for example, as the resp. phosphonium cation/hydridoborate anion salts) serve as active metal-free catalysts for the hydrogenation of, for example, bulky imines, enamines, or enol ethers. Frustrated Lewis pairs also react with alkenes, aldehydes, and a variety of other small mols., including carbon dioxide, in cooperative three-component reactions, offering new strategies for synthetic chem.
  (b) Stephan, D. W.; Greenberg, S.; Graham, T. W.; Chase, P.; Hastie, J. J.; Geier, S. J.; Farrell, J. M.; Brown, C. C.; Heiden, Z. M.; Welch, G. C.; Ullrich, M. Metal-Free Catalytic Hydrogenation of Polar Substrates by Frustrated Lewis Pairs. Inorg. Chem. 2011, 50, 12338– 12348, DOI: 10.1021/ic200663v
  9b
  Metal-Free Catalytic Hydrogenation of Polar Substrates by Frustrated Lewis Pairs
  Stephan, Douglas W.; Greenberg, Sharonna; Graham, Todd W.; Chase, Preston; Hastie, Jeff J.; Geier, Stephen J.; Farrell, Jeffrey M.; Brown, Christopher C.; Heiden, Zachariah M.; Welch, Gregory C.; Ullrich, Matthias
  Inorganic Chemistry (2011), 50 (24), 12338-12348CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
  In 2006, the first metal-free systems that reversibly activate hydrogen were reported. This finding was extended to the discovery of "frustrated Lewis pair" (FLP) catalysts for hydrogenation. It is this catalysis that is the focal point of this article. The development and applications of such FLP hydrogenation catalysts are reviewed, and some previously unpublished data are reported. The scope of the substrates is expanded to include indoles and diimines. Optimal conditions and functional group tolerance are considered and applied to targets of potential com. significance. Recent developments in asym. FLP hydrogenations are also reviewed. The future of FLP hydrogenation catalysts is considered.
  (c) Stephan, D. W.; Erker, G. Frustrated Lewis Pair Mediated Hydrogenations. Topics in Current Chemistry; Springer: Berlin, 2013; pp 85– 110.
  There is no corresponding record for this reference.
  (d) Sumerin, V.; Chernichenko, K.; Schulz, F.; Leskelä, M.; Rieger, B.; Repo, T. Amine-Borane Mediated Metal-Free Hydrogen Activation and Catalytic Hydrogenation. Topics in Current Chemistry; Springer: Berlin, 2012; pp 111– 155.
  There is no corresponding record for this reference.
  (e) Paradies, J. Metal-Free Hydrogenation of Unsaturated Hydrocarbons Employing Molecular Hydrogen. Angew. Chem., Int. Ed. 2014, 53, 3552– 3557, DOI: 10.1002/anie.201309253
  9e
  Metal-Free Hydrogenation of Unsaturated Hydrocarbons Employing Molecular Hydrogen
  Paradies, Jan
  Angewandte Chemie, International Edition (2014), 53 (14), 3552-3557CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The metal-free activation of hydrogen by frustrated Lewis pairs (FLPs) is a valuable method for the hydrogenation of polarized unsatd. mols. ranging from imines, enamines, and silyl enol ethers to heterocycles. However, one of the most important applications of hydrogenation technol. is the conversion of unsatd. hydrocarbons into alkanes. Despite the fast development of the FLP chem., such reactions proved as highly challenging. This minireview provides an overview of the basic concepts of FLP chem., the challenge in the hydrogenation of unsatd. hydrocarbons, and first solns. to this central transformation.
  (f) Hounjet, L. J.; Stephan, D. W. Hydrogenation by Frustrated Lewis Pairs: Main Group Alternatives to Transition Metal Catalysts?. Org. Process Res. Dev. 2014, 18, 385– 391, DOI: 10.1021/op400315m
  9f
  Hydrogenation by Frustrated Lewis Pairs: Main Group Alternatives to Transition Metal Catalysts?
  Hounjet, Lindsay J.; Stephan, Douglas W.
  Organic Process Research & Development (2014), 18 (3), 385-391CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  A review. Since the discovery of "frustrated Lewis pairs" in 2006, these metal-free systems have been exploited to activate a variety of small mols., with H2 being perhaps the most significant among them. This finding has since allowed for the development of metal-free strategies to hydrogenation catalysis. In this review, progress toward the development of these new catalysts for redns. of polar org. substrates, olefins, alkynes, and arom. systems, is described.
  (g) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Designing Effective ‘Frustrated Lewis Pair’ Hydrogenation Catalysts. Chem. Soc. Rev. 2017, 46, 5689– 5700, DOI: 10.1039/C7CS00154A
  9g
  Designing effective 'frustrated Lewis pair' hydrogenation catalysts
  Scott, Daniel J.; Fuchter, Matthew J.; Ashley, Andrew E.
  Chemical Society Reviews (2017), 46 (19), 5689-5700CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. The past decade has seen the subject of transition metal-free catalytic hydrogenation develop incredibly rapidly, transforming from a largely hypothetical possibility to a well-established field that can be applied to the redn. of a diverse variety of functional groups under mild conditions. This remarkable change is principally attributable to the development of so-called 'frustrated Lewis pairs': unquenched combinations of bulky Lewis acids and bases whose dual reactivity can be exploited for the facile activation of otherwise inert chem. bonds. While a no. of comprehensive reviews into frustrated Lewis pair chem. have been published in recent years, this tutorial review aims to provide a focused guide to the development of efficient FLP hydrogenation catalysts, through identification and consideration of the key factors that govern their effectiveness. Following discussion of these factors, their importance will be illustrated using a case study from our own research, namely the development of FLP protocols for successful hydrogenation of aldehydes and ketones, and for related moisture-tolerant hydrogenation.
  (h) Paradies, J. From Structure to Novel Reactivity in Frustrated Lewis Pairs. Coord. Chem. Rev. 2019, 380, 170– 183, DOI: 10.1016/j.ccr.2018.09.014
  9h
  From structure to novel reactivity in frustrated Lewis pairs
  Paradies, Jan
  Coordination Chemistry Reviews (2019), 380 (), 170-183CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
  A review. The coexistence of a strong Lewis acid and a Lewis base in soln., the so called frustrated Lewis pair, has led to the discovery of metal-free hydrogen activation. Since then, this observation has inspired numerous chemists to develop more examples. Metal-free hydrogenation is so far the most studied application of frustrated Lewis pairs in chem. and highly efficient methodologies for a no. of substrates have been developed. However, the targeted choice of a FLP-catalyst is yet rather intricate, due to the lack of an in depth understanding of FLP-reactivity. The presented structure-reactivity-relationship for hydrogenation reactions allowed the targeted development and optimization of unprecedented reactions using FLPs as catalysts. This article provides insight into FLP-reactivity by summarizing our mechanistic and synthetic work in this field.
  (i) Lam, J.; Szkop, K. M.; Mosaferi, E.; Stephan, D. W. FLP Catalysis: Main Group Hydrogenations of Organic Unsaturated Substrates. Chem. Soc. Rev. 2019, 48, 3592– 3612, DOI: 10.1039/C8CS00277K
  9i
  FLP catalysis: main group hydrogenations of organic unsaturated substrates
  Lam, Jolie; Szkop, Kevin M.; Mosaferi, Eliar; Stephan, Douglas W.
  Chemical Society Reviews (2019), 48 (13), 3592-3612CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. This article is focused on recent developments in main group mediated hydrogenation chem. and catalysis using 'frustrated Lewis pairs' (FLPs). The broading range of substrates and catalyst systems is reviewed and the advances in catalytic redns. and the development of stereoselective, asym. redns. made since 2012 was considered.
  (j) Paradies, J. Mechanisms in Frustrated Lewis Pair-Catalyzed Reactions. Eur. J. Org. Chem. 2019, 2019, 283– 294, DOI: 10.1002/ejoc.201800944
  9j
  Mechanisms in Frustrated Lewis Pair-Catalyzed Reactions
  Paradies, Jan
  European Journal of Organic Chemistry (2019), 2019 (2-3), 283-294CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This review summarizes the principle reaction mechanisms of frustrated Lewis pairs (FLP) in hydrogenations and carbon-nitrogen and carbon-carbon bond forming reactions. The fundamental mechanism of hydrogen activation by FLPs is reviewed and the influence of the FLP's nature on hydrogenation reactions is discussed, leading to a structure-reactivity relationship in phosphine/borane or amine/borane derived FLPs. This reactivity concept is validated for a series of FLP-catalyzed reactions. Furthermore, alternative reaction mechanisms e.g. protodeborylations or σ-bond metathesis are discussed.
10. 10
  For development of water-tolerant FLP catalysts, see:
  (a) Mahdi, T.; Stephan, D. W. Enabling Catalytic Ketone Hydrogenation by Frustrated Lewis Pairs. J. Am. Chem. Soc. 2014, 136, 15809– 15812, DOI: 10.1021/ja508829x
  10a
  Enabling Catalytic Ketone Hydrogenation by Frustrated Lewis Pairs
  Mahdi, Tayseer; Stephan, Douglas W.
  Journal of the American Chemical Society (2014), 136 (45), 15809-15812CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Hydrogenation of alkyl and aryl ketones using H2 is catalytically achieved in 18 examples using 5 mol% B(C6F5)3 in an ethereal solvent. In these cases the borane and ether behave as a frustrated Lewis pair to activate H2 and effect the redn.
  (b) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Nonmetal Catalyzed Hydrogenation of Carbonyl Compounds. J. Am. Chem. Soc. 2014, 136, 15813– 15816, DOI: 10.1021/ja5088979
  10b
  Nonmetal catalyzed hydrogenation of carbonyl compounds
  Scott, Daniel J.; Fuchter, Matthew J.; Ashley, Andrew E.
  Journal of the American Chemical Society (2014), 136 (45), 15813-15816CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Solns. of the Lewis acid B(C6F5)3 in 1,4-dioxane are found to effectively catalyze the hydrogenation of a variety of ketones and aldehydes. These reactions, the first to allow entirely metal-free catalytic hydrogenation of carbonyl groups under relatively mild reaction conditions, are found to proceed via a "frustrated Lewis pair" mechanism in which the solvent, a weak Bronsted base yet moderately strong donor, plays a pivotal role.
  (c) Gyömöre, Á.; Bakos, M.; Földes, T.; Pápai, I.; Domján, A.; Soós, T. Moisture-Tolerant Frustrated Lewis Pair Catalyst for Hydrogenation of Aldehydes and Ketones. ACS Catal. 2015, 5, 5366– 5372, DOI: 10.1021/acscatal.5b01299
  10c
  Moisture-Tolerant Frustrated Lewis Pair Catalyst for Hydrogenation of Aldehydes and Ketones
  Gyomore, Adam; Bakos, Maria; Foldes, Tamas; Papai, Imre; Domjan, Attila; Soos, Tibor
  ACS Catalysis (2015), 5 (9), 5366-5372CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  In this paper, we report on the development of a bench-stable borane for frustrated Lewis pair catalyzed redn. of aldehydes, ketones, and enones. The deliberate fine-tuning of structural and electronic parameters of Lewis acid component and the choice of Lewis base provided for the first time, a moisture-tolerant FLP catalyst. Related NMR and DFT studies underpinned the unique behavior of this FLP catalyst and gave insight into the catalytic activity of the resulting FLP catalyst.
  (d) Scott, D. J.; Simmons, T. R.; Lawrence, E. J.; Wildgoose, G. G.; Fuchter, M. J.; Ashley, A. E. Facile Protocol for Water-Tolerant “Frustrated Lewis Pair”-Catalyzed Hydrogenation. ACS Catal. 2015, 5, 5540– 5544, DOI: 10.1021/acscatal.5b01417
  10d
  Facile Protocol for Water-Tolerant "Frustrated Lewis Pair"-Catalyzed Hydrogenation
  Scott, Daniel J.; Simmons, Trevor R.; Lawrence, Elliot J.; Wildgoose, Gregory G.; Fuchter, Matthew J.; Ashley, Andrew E.
  ACS Catalysis (2015), 5 (9), 5540-5544CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  Despite rapid advances in the field of metal-free, "frustrated Lewis pair" (FLP)-catalyzed hydrogenation, the need for strictly anhyd. reaction conditions has hampered wide-scale uptake of this methodol. Herein, we report that, despite the generally perceived moisture sensitivity of FLPs, 1,4-dioxane solns. of B(C6F5)3 actually show appreciable moisture tolerance and can catalyze hydrogenation of a range of weakly basic substrates without the need for rigorously inert conditions. In particular, reactions can be performed directly in com. available nonanhydrous solvents without subsequent drying or use of internal desiccants.
  (e) Fasano, V.; Radcliffe, J. E.; Ingleson, M. J. B(C₆F₅)₃-Catalyzed Reductive Amination Using Hydrosilanes. ACS Catal. 2016, 6, 1793– 1798, DOI: 10.1021/acscatal.5b02896
  10e
  B(C6F5)3-Catalyzed Reductive Amination using Hydrosilanes
  Fasano, Valerio; Radcliffe, James E.; Ingleson, Michael J.
  ACS Catalysis (2016), 6 (3), 1793-1798CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  In contrast to the established dogma that B(C6F5)3 is irreversibly poisoned by excess H2O/amine (or imine) bases, B(C6F5)3 is actually a water-tolerant catalyst for the reductive amination of primary and secondary arylamines with aldehydes and ketones in "wet solvents" at raised temps. and using only 1.2 equiv of Me2PhSiH as reductant. Arylamines/N-arylimines do not result in the irreversible deprotonation of H2O-B(C6F5)3, allowing sufficient B(C6F5)3 to be evolved at raised temps. to effect catalytic redns. Stronger Bronsted basic amines such as tBuNH2 (and derived imines) result in irreversible formation of [HO-B(C6F5)3]- from H2O-B(C6F5)3, precluding the formation of B(C6F5)3 at raised temps. and thus preventing any imine redn. A substrate scope exploration using 1 mol % nonpurified B(C6F5)3 and "wet solvents" demonstrates that this is an operationally simple and effective methodol. for the prodn. of secondary and tertiary arylamines in high yield, with imine redn. proceeding in preference to other possible reactions catalyzed by B(C6F5)3, including the dehydrosilylation of H2O and the redn. of carbonyl moieties (e.g., esters).
  (f) Scott, D. J.; Phillips, N. A.; Sapsford, J. S.; Deacy, A. C.; Fuchter, M. J.; Ashley, A. E. Versatile Catalytic Hydrogenation Using A Simple Tin(IV) Lewis Acid. Angew. Chem., Int. Ed. 2016, 55, 14738– 14742, DOI: 10.1002/anie.201606639
  10f
  Versatile Catalytic Hydrogenation Using A Simple Tin(IV) Lewis Acid
  Scott, Daniel J.; Phillips, Nicholas A.; Sapsford, Joshua S.; Deacy, Arron C.; Fuchter, Matthew J.; Ashley, Andrew E.
  Angewandte Chemie, International Edition (2016), 55 (47), 14738-14742CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Despite the rapid development of frustrated Lewis pair (FLP) chem. over the last ten years, its application in catalytic hydrogenations remains dependent on a narrow family of structurally similar early main-group Lewis acids (LAs), inevitably placing limitations on reactivity, sensitivity, and substrate scope. Herein, we describe the FLP-mediated H2 activation and catalytic hydrogenation activity of the alternative LA iPr3SnOTf, which acts as a surrogate for the trialkylstannylium ion iPr3Sn+, and is rapidly and easily prepd. from simple, inexpensive starting materials. This highly thermally robust LA is found to be competent in the hydrogenation of a no. of different unsatd. functional groups (which is unique to date for main-group FLP LAs not based on boron), and also displays a remarkable tolerance to moisture.
  (g) Dorkó, É.; Szabó, M.; Kótai, B.; Pápai, I.; Domján, A.; Soós, T. Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls. Angew. Chem., Int. Ed. 2017, 56, 9512– 9516, DOI: 10.1002/anie.201703591
  10g
  Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls
  Dorko, Eva; Szabo, Mark; Kotai, Bianka; Papai, Imre; Domjan, Attila; Soos, Tibor
  Angewandte Chemie, International Edition (2017), 56 (32), 9512-9516CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented. As systematic steric tuning of the boron-based Lewis acid (LA) component revealed, the enhanced back-strain makes water binding increasingly reversible in the presence of relatively strong base. This advance allows the limits of FLP's hydrogenation to be expanded, as demonstrated by the FLP reductive amination of carbonyls. This metal-free catalytic variant displays a notably broad chemoselectivity and generality.
  (h) Sapsford, J. S.; Scott, D. J.; Allcock, N. J.; Fuchter, M. J.; Tighe, C. J.; Ashley, A. E. Direct Reductive Amination of Carbonyl Compounds Catalyzed by a Moisture Tolerant Tin(IV) Lewis Acid. Adv. Synth. Catal. 2018, 360, 1066– 1071, DOI: 10.1002/adsc.201701418
  10h
  Direct Reductive Amination of Carbonyl Compounds Catalyzed by a Moisture Tolerant Tin(IV) Lewis Acid
  Sapsford, Joshua S.; Scott, Daniel J.; Allcock, Nathan J.; Fuchter, Matthew J.; Tighe, Christopher J.; Ashley, Andrew E.
  Advanced Synthesis & Catalysis (2018), 360 (6), 1066-1071CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Despite the ever-broadening applications of main-group 'frustrated Lewis pair' (FLP) chem. to both new and established reactions, their typical intolerance of water, esp. at elevated temps. (>100°), represents a key barrier to their mainstream adoption. Herein the authors report that FLPs based on the Lewis acid iPr3SnOTf are moisture tolerant in the presence of moderately strong nitrogenous bases, even under high temp. regimes, allowing them to operate as simple and effective catalysts for the reductive amination of org. carbonyls, including for challenging bulky amine and carbonyl substrate partners.
  (i) Hoshimoto, Y.; Kinoshita, T.; Hazra, S.; Ohashi, M.; Ogoshi, S. Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H₂. J. Am. Chem. Soc. 2018, 140, 7292– 7300, DOI: 10.1021/jacs.8b03626
  10i
  Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H2
  Hoshimoto, Yoichi; Kinoshita, Takuya; Hazra, Sunit; Ohashi, Masato; Ogoshi, Sensuke
  Journal of the American Chemical Society (2018), 140 (23), 7292-7300CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Given the growing demand for green and sustainable chem. processes, the catalytic reductive alkylation of amines with main-group catalysts of low toxicity and mol. hydrogen as the reductant would be an ideal method to functionalize amines. However, such a process remains challenging. Herein, a novel reductive alkylation system using H2 is presented, which proceeds via a tandem reaction that involves the B(2,6-Cl2C6H3)(p-HC6F4)2-catalyzed formation of an imine and the subsequent hydrogenation of this imine catalyzed by a frustrated Lewis pair (FLP). This reductive alkylation reaction generates H2O as the sole byproduct and directly functionalizes amines that bear a remarkably wide range of substituents including carboxyl, hydroxyl, addnl. amino, primary amide, and primary sulfonamide groups. The synthesis of isoindolinones and aminophthalic anhydrides has also been achieved by a one-pot process that consists of a combination of the present reductive alkylation with an intramol. amidation and intramol. dehydration reactions, resp. The reaction showed a zeroth-order and a first-order dependence on the concn. of an imine intermediate and B(2,6-Cl2C6H3)(p-HC6F4)2, resp. In addn., the reaction progress was significantly affected by the concn. of H2. These results suggest a possible mechanism in which the heterolysis of H2 is facilitated by the FLP comprising THF and B(2,6-Cl2C6H3)(p-HC6F4)2.
  (j) Fasano, V.; LaFortune, J. H. W.; Bayne, J. M.; Ingleson, M. J.; Stephan, D. W. Air- and Water-Stable Lewis Acids: Synthesis and Reactivity of P-Trifluoromethyl Electrophilic Phosphonium Cations. Chem. Commun. 2018, 54, 662– 665, DOI: 10.1039/C7CC09128A
  10j
  Air- and water-stable Lewis acids: synthesis and reactivity of P-trifluoromethyl electrophilic phosphonium cations
  Fasano, V.; LaFortune, J. H. W.; Bayne, J. M.; Ingleson, M. J.; Stephan, D. W.
  Chemical Communications (Cambridge, United Kingdom) (2018), 54 (6), 662-665CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  A new class of electrophilic phosphonium cations (EPCs) contg. a -CF3 group attached to the P(V) center is readily accessible in high yields, via a scalable process. These species are stable to air, H2O, alc. and strong Bronsted acid, even at raised temps. Thus, P-CF3 EPCs are more robust than previously reported EPCs contg. P-X moieties (X = F, Cl, OR), and despite their reduced Lewis acidity they function as Lewis acid catalysts without requiring anhyd. reaction conditions.
  (k) Fasano, V.; Ingleson, M. J. Recent Advances in Water-Tolerance in Frustrated Lewis Pair Chemistry. Synthesis 2018, 50, 1783– 1795, DOI: 10.1055/s-0037-1609843
  10k
  Recent Advances in Water-Tolerance in Frustrated Lewis Pair Chemistry
  Fasano, Valerio; Ingleson, Michael J.
  Synthesis (2018), 50 (9), 1783-1795CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
  A water-tolerant frustrated Lewis pair (FLP) combines a sterically encumbered Lewis acid and Lewis base that in synergy are able to activate small mols. even in the presence of water. The main challenge introduced by water comes from its reversible coordination to the Lewis acid which causes a marked increase in the Bronsted acidity of water. Indeed, the oxophilic Lewis acids typically used in FLP chem. form water adducts whose acidity can be comparable to that of strong Bronsted acids such as HCl, thus they can protonate the Lewis base component of the FLP. Irreversible proton transfer quenches the reactivity of both the Lewis acid and the Lewis base, precluding small mol. activation. This short review discusses the efforts to overcome water-intolerance in FLP systems, a topic that in less than five years has seen significant progress. (1) Introduction (2) Water-Tolerance (or Alc.-Tolerance) in Carbonyl Redns. (3) Water-Tolerance with Stronger Bases (4) Water-Tolerant Non-Boron-Based Lewis Acids in FLP Chem.( 5) Conclusions.
11. 11
  For review articles, see:
  (a) Chen, D.; Klankermayer, J. Frustrated Lewis Pairs: From Dihydrogen Activation to Asymmetric Catalysis. Top. Curr. Chem. 2013, 334, 1– 26, DOI: 10.1007/128_2012_402
  11a
  Frustrated Lewis Pairs: from dihydrogen activation to asymmetric catalysis
  Chen Dianjun; Klankermayer Jurgen
  Topics in current chemistry (2013), 334 (), 1-26 ISSN:0340-1022.
  The non-self-quenched property of Frustrated Lewis Pairs (FLPs) contradicts the classical Lewis acid-base theory, but this peculiarity offers unprecedented possibilities for the activation of small molecules. Among all of their fascinating applications, FLP mediated hydrogen activation and the associated catalytic hydrogenations are currently considered as the most intriguing illustration of their reactivity. The FLPs enabled the catalytic reduction of a wide range of substrates with molecular hydrogen and tuning of the structural properties of the FLP partners allowed broadening of the substrate scope. Based on detailed mechanistic knowledge, FLP based asymmetric hydrogenation of various substrates could be achieved with high enantioselectivities. More importantly, FLP based enantioselective catalysis is not limited to the field of asymmetric hydrogenation, and other exciting catalytic applications have already appeared.
  (b) Feng, X.; Du, H. Metal-Free Asymmetric Hydrogenation and Hydrosilylation Catalyzed by Frustrated Lewis Pairs. Tetrahedron Lett. 2014, 55, 6959– 6964, DOI: 10.1016/j.tetlet.2014.10.138
  11b
  Metal-free asymmetric hydrogenation and hydrosilylation catalyzed by frustrated Lewis pairs
  Feng, Xiangqing; Du, Haifeng
  Tetrahedron Letters (2014), 55 (51), 6959-6964CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  A review. This Letter will outline the recent important progress of metal-free catalytic asym. hydrogenation and hydrosilylation using FLP catalysts.
  (c) Shi, L.; Zhou, Y.-G. Enantioselective Metal-Free Hydrogenation Catalyzed by Chiral Frustrated Lewis Pairs. ChemCatChem 2015, 7, 54– 56, DOI: 10.1002/cctc.201402838
  11c
  Enantioselective Metal-Free Hydrogenation Catalyzed by Chiral Frustrated Lewis Pairs
  Shi, Lei; Zhou, Yong-Gui
  ChemCatChem (2015), 7 (1), 54-56CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The FLP catalyst for hydrogenation will have a significant impact on this field, which is still dominated by chiral transition-metal catalysts, and could provide an effective metal-free pathway for the synthesis of valuable chiral amines and alcs. However, to achieve better enantioselectivity, reaction activity, and a wider substrate scope further research is required. Theor., a mode IV FLP catalyst would offer several combinations of chiral B moiety and chiral N(P) moiety and would enable rapid screening of catalysts.
  (d) Paradies, J. Chiral Borane-Based Lewis Acids for Metal Free Hydrogenations. Topics in Organometallic Chemistry; Springer International Publishing, 2018; pp 193– 216.
  There is no corresponding record for this reference.
  (e) Meng, W.; Feng, X.; Du, H. Frustrated Lewis Pairs Catalyzed Asymmetric Metal-Free Hydrogenations and Hydrosilylations. Acc. Chem. Res. 2018, 51, 191– 201, DOI: 10.1021/acs.accounts.7b00530
  11e
  Frustrated Lewis Pairs Catalyzed Asymmetric Metal-Free Hydrogenations and Hydrosilylations
  Meng, Wei; Feng, Xiangqing; Du, Haifeng
  Accounts of Chemical Research (2018), 51 (1), 191-201CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review. The use of frustrated Lewis pairs is an extremely important approach to metal-free hydrogenations. In contrast to the rapid growth of catalytic reactions, asym. hydrogenations are far less developed due to a severe shortage of readily available chiral frustrated Lewis pair catalysts with high catalytic activities and selectivities. Unlike the stable Lewis base component of frustrated Lewis pairs, the moisture-sensitive boron Lewis acid component is difficult to prep. The development of convenient methods for the quick construction of chiral boron Lewis acids is therefore of great interest. In this Account, we summarize our recent studies on frustrated Lewis pair-catalyzed, asym. metal-free hydrogenations and hydrosilylations. To address the shortage of highly active and selective catalysts, we developed a novel strategy for the in situ prepn. of chiral boron Lewis acids by the hydroboration of chiral dienes or diynes with Piers' borane without further purifn., which allows chiral dienes or diynes to act like ligands. This strategy ensures the construction of a useful toolbox of catalysts for asym. metal-free hydrogenations and hydrosilylations is rapid and operationally simple. Another strategy is using combinations of readily available Lewis acids and bases contg. hydridic and acidic hydrogen atoms, resp., as a novel type of frustrated Lewis pairs. Such systems provide a great opportunity for using simple chiral Lewis bases as the origins of asym. induction. With chiral diene-derived boron Lewis acids as catalysts, a broad range of unsatd. compds., such as imines, silyl enol ethers, 2,3-disubstituted quinoxalines, and polysubstituted quinolines, are all viable substrates for asym. metal-free hydrogenations and give the corresponding products in good yields with high enantioselectivities and/or stereoselectivities. These chiral catalysts are very effective for bulky substrates, and the substrate scope for these metal-free asym. hydrogenations has been dramatically expanded. Chiral alkenylboranes were designed to enhance the rigidity of the framework and modify the Lewis acidity through the resulting double bonds. Frustrated Lewis pairs of chiral alkenylboranes and phosphines are a class of highly effective catalysts for asym. Piers-type hydrosilylations of 1,2-dicarbonyl compds., and they give the desired products in high yields and enantioselectivities. Moreover, asym. transfer hydrogenations of imines and quinoxalines with ammonia borane as the hydrogen source have been achieved with frustrated Lewis pair of Piers' borane and (R)-tert-butylsulfinamide as the catalyst. Mechanistic studies have suggested that the hydrogen transfer occurs via an 8-membered ring transition state, and regeneration of the reactive frustrated Lewis pair with ammonia borane occurs through a concerted 6-membered ring transition state.
  (f) Meng, W.; Feng, X.; Du, H. Asymmetric Catalysis with Chiral Frustrated Lewis Pairs. Chin. J. Chem. 2020, 38, 625– 634, DOI: 10.1002/cjoc.202000011
  11f
  Asymmetric Catalysis with Chiral Frustrated Lewis Pairs
  Meng, Wei; Feng, Xiangqing; Du, Haifeng
  Chinese Journal of Chemistry (2020), 38 (6), 625-634CODEN: CJOCEV; ISSN:1001-604X. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This perspective article mainly focuses on the recent advances for the synthesis of chiral Lewis acidic boranes in category of three protocols, (1) hydroboration of chiral internal alkenes with Piers' borane HB(C6F5)2; (2) in situ hydroboration of chiral alkenes or alkynes without any purifn.; (3) and substitution reaction of (C6F5)nBCl3-n with chiral organometallic reagents, as well as their applications in the metal-free asym. hydrogenations and hydrosilylations.
12. 12
  (a) Chen, D.; Klankermayer, J. Metal-Free Catalytic Hydrogenation of Imines with Tris(Perfluorophenyl)Borane. Chem. Commun. 2008, 2130– 2131, DOI: 10.1039/b801806e
  12a
  Metal-free catalytic hydrogenation of imines with tris(perfluorophenyl)borane
  Chen, Dianjun; Klankermayer, Juergen
  Chemical Communications (Cambridge, United Kingdom) (2008), (18), 2130-2131CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Metal-free homogeneous catalyzed hydrogenation of various imines was accomplished with tris(perfluorophenyl)borane under moderate reaction conditions.
  (b) Chen, D.; Wang, Y.; Klankermayer, J. Enantioselective Hydrogenation with Chiral Frustrated Lewis Pairs. Angew. Chem., Int. Ed. 2010, 49, 9475– 9478, DOI: 10.1002/anie.201004525
  12b
  Enantioselective Hydrogenation with Chiral Frustrated Lewis Pairs
  Chen, Dianjun; Wang, Yutian; Klankermayer, Juergen
  Angewandte Chemie, International Edition (2010), 49 (49), 9475-9478, S9475/1-S9475/30CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Frustrated Lewis pairs (FLPs) have been recently introduced as an unprecedented possibility to activate hydrogen. On the basis of this concept the first example of highly enantioselective catalytic hydrogenation of imines using chiral camphor/borane-derived FLPs I and II has been demonstrated.
  (c) Ghattas, G.; Chen, D.; Pan, F.; Klankermayer, J. Asymmetric Hydrogenation of Imines with a Recyclable Chiral Frustrated Lewis Pair Catalyst. Dalton Trans. 2012, 41, 9026– 9028, DOI: 10.1039/c2dt30536d
  12c
  Asymmetric hydrogenation of imines with a recyclable chiral frustrated Lewis pair catalyst
  Ghattas, Ghazi; Chen, Dianjun; Pan, Fangfang; Klankermayer, Juergen
  Dalton Transactions (2012), 41 (30), 9026-9028CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
  A camphor based chiral phosphonium hydrido borate zwitterion was synthesized and successfully applied in the enantioselective hydrogenation of imines with selectivities up to 76% ee. The high stability of the novel chiral FLP-system enables effective recycling of the metal-free catalyst.
13. 13
  (a) Parks, D. J.; von H. Spence, R. E.; Piers, W. E. Bis(Pentafluorophenyl)Borane: Synthesis, Properties, and Hydroboration Chemistry of a Highly Electrophilic Borane Reagent. Angew. Chem., Int. Ed. Engl. 1995, 34, 809– 811, DOI: 10.1002/anie.199508091
  13a
  Bis(pentafluorophenyl)borane: synthesis, properties, and hydroboration chemistry of a highly electrophilic borane reagent
  Parks, Daniel J.; von H. Spence, Rupert E.; Piers, Warren E.
  Angewandte Chemie, International Edition in English (1995), 34 (7), 809-11CODEN: ACIEAY; ISSN:0570-0833. (VCH)
  Reaction of (C6F5)2BCl with hydride transfer reagent, Me2Si(Cl)H, gave 52% title compd., (C6F5)BH 1. 1 Is a highly active hydroboration reagent towards a range of simple alkenes and alkynes. Addn. of the olefin or alkyne to a suspension of the borane in benzene led to the rapid dissoln. of the solid, and the reaction was complete in 2 min. Thus, hydroboration of Me2C:CMe2 and HC≡CH with 1 gave Me2CHCMe2B(C6F5) and CH:CMeB(C6F5) resp.
  (b) Parks, D. J.; Piers, W. E.; Yap, G. P. a. Synthesis, Properties, and Hydroboration Activity of the Highly Electrophilic Borane Bis(Pentafluorophenyl)Borane. Organometallics 1998, 17, 5492– 5503, DOI: 10.1021/om980673e
  13b
  Synthesis, Properties, and Hydroboration Activity of the Highly Electrophilic Borane Bis(pentafluorophenyl)borane, HB(C6F5)2
  Parks, Daniel J.; Piers, Warren E.; Yap, Glenn P. A.
  Organometallics (1998), 17 (25), 5492-5503CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
  Two reliable and efficient routes to bis(pentafluorophenyl)borane, 1, are described. A three-step procedure uses the C6F5-transfer agent Me2Sn(C6F5)2 to produce the chloroborane ClB(C6F5)2, which is subsequently converted to 1 by treatment with a silane, and proceeds with an overall yield of 62%. Alternatively, 1 can be made in 69% yield from B(C6F5)3 and Et3SiH by heating the two reagents at 60° for 3 days in benzene. Borane 1 is dimeric in the solid state, as detd. by x-ray crystallog. anal. However, in arom. solvents, detectable amts. of monomeric borane are present (ratio of dimer:monomer 4.5:1). The ease of dimer dissocn. to monomer coupling with the high electrophilicity of the borane makes 1 a very reactive hydroboration reagent in arom. solvents. Hydroborations do not proceed in donor solvents such as THF. A survey of a variety of olefin and alkyne substrates shows that 1 hydroborates with comparable regio- and chemoselectivities to commonly used reagents such as 9-BBN, but at a much faster rate. A 2nd unique feature of the reagent is the facility with which boryl migration takes place in the products of olefin hydroboration. This property can be used to access thermodn. products of hydroboration where other reagents give diastereomeric kinetic products. Alkynes can be selectively monohydroborated; terminal alkyne substrates will react with a 2nd equiv. of 1, while internal alkynes are immune to further hydroboration. Two procedures for the oxidn. of the products of hydroboration were developed. Since the organobis(pentafluorophenyl)boranes are susceptible to protonolysis, oxidn. must be carried out in a two-phase system using highly alk. H2O2 or with a nonaq. procedure using Me3NO as the oxidant. Hydroboration/oxidn. can be carried out rapidly in a 1-pot procedure which gives alc. or carbonyl products in good to excellent yields. E.g., 1-naphthyl-1-cyclohexene was added to a suspension of 1 in benzene followed by addn. of THF and 4.4N H2O2 soln. (30% H2O2/H2O/KOH) to give a 93% yield of 2-(1-naphthyl)cyclohexan-1-ol (1:1 mixt. of diastereomers).
  (c) Patrick, E. A.; Piers, W. E. Twenty-Five Years of Bis-Pentafluorophenyl Borane: A Versatile Reagent for Catalyst and Materials Synthesis. Chem. Commun. 2020, 56, 841– 853, DOI: 10.1039/C9CC08338C
  13c
  Twenty-five years of bis-pentafluorophenyl borane: a versatile reagent for catalyst and materials synthesis
  Patrick, Evan A.; Piers, Warren E.
  Chemical Communications (Cambridge, United Kingdom) (2020), 56 (6), 841-853CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  A review. In 1995, the synthesis, properties and remarkable hydroboration activity of bis-pentafluorophenyl borane was first reported. Its reactivity stems from the ready accessibility of the monomeric borane and its high Lewis acidity. In the intervening twenty five years, this reagent has been widely exploited as a means of incorporating Lewis acidic -B(C6F5)2 groups into complex structures for a range of applications. In this "25th Anniversary" Feature article, we highlight the synthetic methods to the borane, its fundamental properties and chem. as well as the diverse array of uses of this borane. These include self-activating olefin polymn. catalysts, frustrated Lewis pair generation, small mol. activation, bond cleavage reactions, Lewis acid catalysis and modification of org. materials.
14. 14
  Sumerin, V.; Chernichenko, K.; Nieger, M.; Leskelä, M.; Rieger, B.; Repo, T. Highly Active Metal-Free Catalysts for Hydrogenation of Unsaturated Nitrogen-Containing Compounds. Adv. Synth. Catal. 2011, 353, 2093– 2110, DOI: 10.1002/adsc.201100206
  14
  Highly Active Metal-Free Catalysts for Hydrogenation of Unsaturated Nitrogen-Containing Compounds
  Sumerin, Victor; Chernichenko, Konstantin; Nieger, Martin; Leskelae, Markku; Rieger, Bernhard; Repo, Timo
  Advanced Synthesis & Catalysis (2011), 353 (11-12), 2093-2110CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  New highly active ansa-ammonium borate catalysts I (R1R2N = 3,3,5,5-tetramethyl-1-morpholinyl, 3,3-dimethyl-2-phenyl-2,3-dihydroindol-1-yl, 8-isopropyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-1-yl, etc.) for the direct metal-free hydrogenation of imines were prepd. by tuning of the basicity and steric bulkiness of their amine moieties. The highest catalytic activity among previously reported organocatalytic systems was shown for a wide range of nitrogen-contg. substrates. The first example of asym. imine hydrogenation based on the ansa-ammonium borate concept was demonstrated. Furthermore, effective catalyst recovery by extn. of the acidic soln. with an org. solvent followed by dehydration with TMSBr was elaborated. The initial findings highlight the development of more effective chiral ansa-ammonium borates for enantioselective hydrogenation. Therefore, the progress achieved in the ansa-ammonium borate concept makes it very promising for further elaboration with the aim to obtain industrially applicable catalysts.
15. 15
  Lindqvist, M.; Borre, K.; Axenov, K.; Kótai, B.; Nieger, M.; Leskela, M.; Pápai, I.; Repo, T. Chiral Molecular Tweezers: Synthesis and Reactivity in Asymmetric Hydrogenation. J. Am. Chem. Soc. 2015, 137, 4038– 4041, DOI: 10.1021/ja512658m
  15
  Chiral molecular tweezers: Synthesis and reactivity in asymmetric hydrogenation
  Lindqvist, Markus; Borre, Katja; Axenov, Kirill; Kotai, Bianka; Nieger, Martin; Leskela, Markku; Papai, Imre; Repo, Timo
  Journal of the American Chemical Society (2015), 137 (12), 4038-4041CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  We report the synthesis and reactivity of a chiral aminoborane displaying both rapid and reversible H2 activation. The catalyst shows exceptional reactivity in asym. hydrogenation of enamines and unhindered imines with stereoselectivities of up to 99% ee. DFT anal. of the reaction mechanism pointed to the importance of both repulsive steric and stabilizing intermol. non-covalent forces in the stereodetermining hydride transfer step of the catalytic cycle.
16. 16
  Liu, Y.; Du, H. Chiral Dienes as “Ligands” for Borane-Catalyzed Metal-Free Asymmetric Hydrogenation of Imines. J. Am. Chem. Soc. 2013, 135, 6810– 6813, DOI: 10.1021/ja4025808
  16
  Chiral Dienes as "Ligands" for Borane-Catalyzed Metal-Free Asymmetric Hydrogenation of Imines
  Liu, Yongbing; Du, Haifeng
  Journal of the American Chemical Society (2013), 135 (18), 6810-6813CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  This paper describes a highly enantioselective metal-free hydrogenation of imines using chiral dienes as "ligands" for the generation of catalysts with HB(C6F5)2 by hydroboration in situ to furnish a variety of chiral amines with up to 89% ee, which provides a practical strategy for the development of novel chiral frustrated Lewis pairs for asym. hydrogenation.
17. 17
  Wei, S.; Du, H. A Highly Enantioselective Hydrogenation of Silyl Enol Ethers Catalyzed by Chiral Frustrated Lewis Pairs. J. Am. Chem. Soc. 2014, 136, 12261– 12264, DOI: 10.1021/ja507536n
  17
  A Highly Enantioselective Hydrogenation of Silyl Enol Ethers Catalyzed by Chiral Frustrated Lewis Pairs
  Wei, Simin; Du, Haifeng
  Journal of the American Chemical Society (2014), 136 (35), 12261-12264CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Using a simple combination of tri-tert-butylphosphine and chiral borane generated in situ by the hydroboration of chiral diene with HB(C6F5)2 as a frustrated Lewis pair catalyst, a highly enantioselective metal-free hydrogenation of silyl enol ethers was successfully realized to furnish a variety of optically active secondary alcs. in 93-99% yields with 88->99% ee's.
18. 18
  (a) Zhang, Z.; Du, H. Cis-Selective and Highly Enantioselective Hydrogenation of 2,3,4-Trisubstituted Quinolines. Org. Lett. 2015, 17, 2816– 2819, DOI: 10.1021/acs.orglett.5b01240
  18a
  Cis-Selective and Highly Enantioselective Hydrogenation of 2,3,4-Trisubstituted Quinolines
  Zhang, Zhenhua; Du, Haifeng
  Organic Letters (2015), 17 (11), 2816-2819CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A highly enantioselective cis-hydrogenation of 2,3,4-trisubstituted quinolines has been realized for the first time using chiral borane catalysts generated in situ from chiral dienes. A variety of tetrahydroquinoline derivs. contg. three contiguous stereogenic centers, e.g., I, were obtained in 76-99% yields with 82-99% ee's.
  (b) Zhang, Z.; Du, H. Enantioselective Metal-Free Hydrogenations of Disubstituted Quinolines. Org. Lett. 2015, 17, 6266– 6269, DOI: 10.1021/acs.orglett.5b03307
  18b
  Enantioselective Metal-Free Hydrogenations of Disubstituted Quinolines
  Zhang, Zhenhua; Du, Haifeng
  Organic Letters (2015), 17 (24), 6266-6269CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A metal-free hydrogenation of 2,4-disubstituted quinolines was realized for the first time using chiral diene derived borane catalysts to furnish the corresponding tetrahydroquinolines in 75-98% yields with 95/5-99/1 dr's and 86-98% ee's. This catalytic system was also effective for 2,3-disubstituted quinolines to give moderate to good ee's.
  (c) Zhang, Z.; Du, H. A Highly cis-Selective and Enantioselective Metal-Free Hydrogenation of 2,3-Disubstituted Quinoxalines. Angew. Chem., Int. Ed. 2015, 54, 623– 626, DOI: 10.1002/anie.201409471
  18c
  A Highly cis-Selective and Enantioselective Metal-Free Hydrogenation of 2,3-Disubstituted Quinoxalines
  Zhang, Zhenhua; Du, Haifeng
  Angewandte Chemie, International Edition (2015), 54 (2), 623-626CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A wide range of 2,3-disubstituted quinoxalines I (R1 = H, 5-Me, 6-MeO, 7-Cl, 6,7-Me2, etc.; R2 = R3 = Me, Ph; R2 = Et, n-Pr, Ph, 3-BrC6H4, etc., R3 = Me; R2 = Ph, R3 = Et) has been successfully hydrogenated with H2 using borane catalysts to produce the desired tetrahydroquinoxalines II in 80-99% yields with excellent cis-selectivity. Significantly, the asym. reaction employing chiral borane catalysts, generated by the in situ hydroboration of chiral dienes with HB(C6F5)2 under mild reaction conditions, has also been achieved to provide the corresponding cis-1,2,3,4-tetrahydroquinoxalines with up to 96% ee.
  (d) Wei, S.; Feng, X.; Du, H. A Metal-Free Hydrogenation of 3-Substituted 2H-1,4-Benzoxazines. Org. Biomol. Chem. 2016, 14, 8026– 8029, DOI: 10.1039/C6OB01556E
  18d
  A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines
  Wei, Simin; Feng, Xiangqing; Du, Haifeng
  Organic & Biomolecular Chemistry (2016), 14 (34), 8026-8029CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines has been successfully realized with 2.5 mol% of B(C6F5)3 as a catalyst to furnish a variety of 3,4-dihydro-2H-1,4-benzoxazines in 93-99% yields. Up to 42% ee was also achieved for the asym. hydrogenation with the use of a chiral diene and HB(C6F5)2.
19. 19
  Tu, X.; Zeng, N.; Li, R.; Zhao, Y.; Xie, D.; Peng, Q.; Wang, X. C₂-Symmetric Bicyclic Bisborane Catalysts: Kinetic or Thermodynamic Products of a Reversible Hydroboration of Dienes. Angew. Chem., Int. Ed. 2018, 57, 15096– 15100, DOI: 10.1002/anie.201808289
  19
  C2-Symmetric Bicyclic Bisborane Catalysts: Kinetic or Thermodynamic Products of a Reversible Hydroboration of Dienes
  Tu, Xian-Shuang; Zeng, Ning-Ning; Li, Ru-Ye; Zhao, Yu-Quan; Xie, De-Zhen; Peng, Qian; Wang, Xiao-Chen
  Angewandte Chemie, International Edition (2018), 57 (46), 15096-15100CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  We prepd. a new class of chiral C2-sym. bicyclic bisborane catalysts by addn. reactions of internal dienes with the Piers borane, HB(C6F5)2, and an analog, HB(p-C6F4H)2. The dependence of the addn. pattern on the reaction temp. allowed us to selectively prep. two diastereomeric catalysts from a single diene precursor. The bisboranes prepd. in situ exhibited excellent activity (turnover nos. up to 200 at -40 °C) and enantioselectivity (up to 95 % ee) in imine hydrogenation reactions.
20. 20
  (a) Li, X.; Tian, J.; Liu, N.; Tu, X.; Zeng, N.; Wang, X. Spiro-Bicyclic Bisborane Catalysts for Metal-Free Chemoselective and Enantioselective Hydrogenation of Quinolines. Angew. Chem., Int. Ed. 2019, 58, 4664– 4668, DOI: 10.1002/anie.201900907
  20a
  Spiro-Bicyclic Bisborane Catalysts for Metal-Free Chemoselective and Enantioselective Hydrogenation of Quinolines
  Li, Xiang; Tian, Jun-Jie; Liu, Ning; Tu, Xian-Shuang; Zeng, Ning-Ning; Wang, Xiao-Chen
  Angewandte Chemie, International Edition (2019), 58 (14), 4664-4668CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A new series of spiro-bicyclic bisborane catalysts I (Ar = Ph, 4-fluorophenyl, 4-phenylphenyl, 3-phenylphenyl) has been prepd. by means of hydroboration reactions of C2-sym. spiro-bicyclic dienes II with HB(C6F5)2 and HB(p-C6F4H)2. When used for hydrogenation of quinolines III (R1 = Me, cyclohexyl, furan-2-yl, 2H-1,3-benzodioxol-5-yl, etc.; R2 = H, Br, tetramethyl-1,3,2-dioxaborolan-2-yl, prop-2-yn-1-yloxy, allyloxy), these catalysts give excellent yields and enantiomeric excesses, and show turnover nos. of up to 460. The most attractive feature of these metal-free hydrogenation reactions was the broad functional-group tolerance, making this method complementary to existing methods for quinoline hydrogenation.
  (b) Tian, J.; Yang, Z.; Liang, X.; Liu, N.; Hu, C.; Tu, X.; Li, X.; Wang, X. Borane-Catalyzed Chemoselective and Enantioselective Reduction of 2-Vinyl-Substituted Pyridines. Angew. Chem., Int. Ed. 2020, 59, 18452– 18456, DOI: 10.1002/anie.202007352
  20b
  Borane-Catalyzed Chemoselective and Enantioselective Reduction of 2-Vinyl-Substituted Pyridines
  Tian, Jun-Jie; Yang, Zhao-Ying; Liang, Xin-Shen; Liu, Ning; Hu, Chen-Yu; Tu, Xian-Shuang; Li, Xiang; Wang, Xiao-Chen
  Angewandte Chemie, International Edition (2020), 59 (42), 18452-18456CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Herein, we report that highly chemoselective and enantioselective redn. of 2-vinyl-substituted pyridines has been achieved for the first time. The reaction, which uses chiral spiro-bicyclic bisboranes as catalysts and HBpin and an acidic amide as reducing reagents, proceeds through a cascade process involving 1,4-hydroboration followed by transfer hydrogenation of a dihydropyridine intermediate. The retained double bond in the redn. products permits their conversion to natural products and other useful heterocyclic compds. by simple transformations.
21. 21
  Gao, B.; Feng, X.; Meng, W.; Du, H. Asymmetric Hydrogenation of Ketones and Enones with Chiral Lewis Base Derived Frustrated Lewis Pairs. Angew. Chem., Int. Ed. 2020, 59, 4498– 4504, DOI: 10.1002/anie.201914568
  21
  Asymmetric Hydrogenation of Ketones and Enones with Chiral Lewis Base Derived Frustrated Lewis Pairs
  Gao, Bochao; Feng, Xiangqing; Meng, Wei; Du, Haifeng
  Angewandte Chemie, International Edition (2020), 59 (11), 4498-4504CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The concept of frustrated Lewis pairs (FLPs) has been widely applied in various research areas, and metal-free hydrogenation undoubtedly belongs to the most significant and successful ones. In the past decade, great efforts have been devoted to the synthesis of chiral boron Lewis acids. In a sharp contrast, chiral Lewis base derived FLPs have rarely been disclosed for the asym. hydrogenation. In this work, a novel type of chiral FLP was developed by simple combination of chiral oxazoline Lewis bases with achiral boron Lewis acids, thus providing a promising new direction for the development of chiral FLPs in the future. These chiral FLPs proved to be highly effective for the asym. hydrogenation of ketones, enones, and chromones, giving the corresponding products in high yields with up to 95% ee. Mechanistic studies suggest that the hydrogen transfer to simple ketones likely proceeds in a concerted manner.
22. 22
  For selected contributions, see:
  (a) Hermeke, J.; Mewald, M.; Oestreich, M. Experimental Analysis of the Catalytic Cycle of the Borane-Promoted Imine Reduction with Hydrosilanes: Spectroscopic Detection of Unexpected Intermediates and a Refined Mechanism. J. Am. Chem. Soc. 2013, 135, 17537– 17546, DOI: 10.1021/ja409344w
  22a
  Experimental Analysis of the Catalytic Cycle of the Borane-Promoted Imine Reduction with Hydrosilanes: Spectroscopic Detection of Unexpected Intermediates and a Refined Mechanism
  Hermeke, Julia; Mewald, Marius; Oestreich, Martin
  Journal of the American Chemical Society (2013), 135 (46), 17537-17546CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The discovery of intermediates that had not been seen before in imine redn. involving borane-mediated Si-H bond activation provided new insight into the mechanism, eventually leading to a refined catalytic cycle that also bears relevance to asym. variants. The catalysis proceeds through an ion pair composed of a silyliminium ion and a borohydride that subsequently reacts to yield an N-silylated amine and the borane catalyst. The latter step is enantioselectivity-detg. when using a chiral borane. It was now found that there are addnl. intermediates that profoundly influence the outcome of such enantioselective transformations. Significant amts. of the corresponding free amine and N-silylated enamine are present in equimolar ratio during the catalysis. The free amine emerges from a borohydride redn. of an iminium ion (protonated imine) i.e., in turn, generated in the enamine formation step. The unexpected alternative pathway adds another enantioselectivity-detg. hydride transfer to reactions employing chiral boranes. The expts. were done with an axially chiral borane that was introduced by the authors a few years ago, and the refined mechanistic picture helps to understand previously obsd. inconsistencies in the level of enantioinduction in redns. catalyzed by this borane. The findings are general because the archetypical electron-deficient borane B(C6F5)3 shows the same reaction pattern. This must have been overlooked in the past because B(C6F5)3 is substantially more reactive than the chiral borane with just one C6F5 group. Reactions with B(C6F5)3 must be performed at low catalyst loading to allow for detection of these fundamental intermediates by NMR spectroscopy.
  (b) Süsse, L.; Hermeke, J.; Oestreich, M. The Asymmetric Piers Hydrosilylation. J. Am. Chem. Soc. 2016, 138, 6940– 6943, DOI: 10.1021/jacs.6b03443
  22b
  The Asymmetric Piers Hydrosilylation
  Suesse, Lars; Hermeke, Julia; Oestreich, Martin
  Journal of the American Chemical Society (2016), 138 (22), 6940-6943CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  An axially chiral, cyclic borane, I, decorated with just one C6F5 group at the boron atom promotes the highly enantioselective hydrosilylation of acetophenone derivs. without assistance of an addnl. Lewis base (up to 99% ee). The reaction is an unprecedented asym. variant of Piers' B(C6F5)3-catalyzed carbonyl hydrosilylation. The steric congestion imparted by the 3,3'-disubstituted binaphthyl backbone of the borane catalyst as well as the use of reactive trihydrosilanes as reducing agents are keys to success.
  (c) Mercea, D. M.; Howlett, M. G.; Piascik, A. D.; Scott, D.J.; Steven, A.; Ashley, A. E.; Fuchter, M. J. Enantioselective reduction of N-alkyl ketimines with frustrated Lewis pair catalysis using chiral borenium ions. Chem. Commun. 2019, 55, 7077– 7080, DOI: 10.1039/C9CC02900A
  22c
  Enantioselective reduction of N-alkyl ketimines with frustrated Lewis pair catalysis using chiral borenium ions
  Mercea, Dan M.; Howlett, Michael G.; Piascik, Adam D.; Scott, Daniel J.; Steven, Alan; Ashley, Andrew E.; Fuchter, Matthew J.
  Chemical Communications (Cambridge, United Kingdom) (2019), 55 (49), 7077-7080CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Enantioselective redn. of ketimines was demonstrated using chiral N-heterocyclic carbene (NHC)-stabilized borenium ions in frustrated Lewis pair catalysis. High levels of enantioselectivity were achieved for substrates featuring secondary N-alkyl substituents. Comparative reactivity and mechanistic studies identify key determinants required to achieve useful enantioselectivity and represent a step forward in the further development of enantioselective FLP methodologies.
  (d) Liu, X.; Wang, Q.; Han, C.; Feng, X.; Du, H. Chiral Frustrated Lewis Pairs Catalyzed Highly Enantioselective Hydrosilylations of Ketones. Chin. J. Chem. 2019, 37, 663– 666, DOI: 10.1002/cjoc.201900121
  22d
  Chiral Frustrated Lewis Pairs Catalyzed Highly Enantioselective Hydrosilylations of Ketones
  Liu, Xiaoqin; Wang, Qiaotian; Han, Caifang; Feng, Xiangqing; Du, Haifeng
  Chinese Journal of Chemistry (2019), 37 (7), 663-666CODEN: CJOCEV; ISSN:1001-604X. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A highly enantioselective Piers-type hydrosilylation of simple ketones was successfully achieved using a chiral frustrated Lewis pair of tri-tert-butylphosphine and chiral diene-derived borane as catalyst. A wide range of optically active secondary alcs. were furnished in 80%-99% yields with 81%-97% ee's under mild reaction conditions.
  (e) Lundrigan, T.; Welsh, E. N.; Hynes, T.; Tien, C.; Adams, M. R.; Roy, K. R.; Robertson, K. N.; Speed, A. W. H. Enantioselective Imine Reduction Catalyzed by Phosphenium Ions. J. Am. Chem. Soc. 2019, 141, 14083– 14088, DOI: 10.1021/jacs.9b07293
  22e
  Enantioselective Imine Reduction Catalyzed by Phosphenium Ions
  Lundrigan, Travis; Welsh, Erin N.; Hynes, Toren; Tien, Chieh-Hung; Adams, Matt R.; Roy, Kayelani R.; Robertson, Katherine N.; Speed, Alexander W. H.
  Journal of the American Chemical Society (2019), 141 (36), 14083-14088CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The first use of phosphenium cations in asym. catalysis is reported. A diazaphosphenium triflate, prepd. in two or three steps on a multigram scale from com. available materials, catalyzes the hydroboration or hydrosilylation of cyclic imines with enantiomeric ratios of up to 97:3. Catalyst loadings are as low as 0.2 mol %. Twenty-two aryl/heteroaryl pyrrolidines and piperidines were prepd. using this method. Imines contg. functional groups such as thiophenes or pyridyl rings that can challenge transition-metal catalysts were reduced employing these systems.
23. 23
  For computational mechanistic studies on FLP-type catalytic hydrogenations (not addressing the issue of stereoselectivity), see:
  (a) Rokob, T. A.; Hamza, A.; Stirling, A.; Pápai, I. On the Mechanism of B(C₆F₅)₃-Catalyzed Direct Hydrogenation of Imines: Inherent and Thermally Induced Frustration. J. Am. Chem. Soc. 2009, 131, 2029– 2036, DOI: 10.1021/ja809125r
  23a
  On the Mechanism of B(C6F5)3-Catalyzed Direct Hydrogenation of Imines: Inherent and Thermally Induced Frustration
  Rokob, Tibor Andras; Hamza, Andrea; Stirling, Andras; Papai, Imre
  Journal of the American Chemical Society (2009), 131 (5), 2029-2036CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The reaction mechanism for the transition metal free direct hydrogenation of bulky imines catalyzed by the Lewis acid B(C6F5)3 is investigated in detail by quantum chem. calcns. A recently introduced mechanistic model of heterolytic hydrogen splitting that is based on noncovalent assocn. of bulky Lewis acid-base pairs is shown to account for the reactivity of imine-borane as well as amine-borane systems. Possible catalytic cycles are examd., and the results provide solid support for the imine redn. pathway proposed from exptl. observations. In addn., the feasibility of an autocatalytic route initiated by amine-borane hydrogen cleavage is demonstrated. Conceptual issues regarding the notion of frustration are also discussed. The obsd. reactivity is interpreted in terms of thermally induced frustration, which refers to thermal activation of strained dative adducts of bulky Lewis donor-acceptor pairs to populate their reactive frustrated complex forms.
  (b) Nyhlén, J.; Privalov, T. On the Possibility of Catalytic Reduction of Carbonyl Moieties with Tris(Pentafluorophenyl)Borane and H₂: A Computational Study. Dalton Trans. 2009, 29, 5780– 5786, DOI: 10.1039/b905137f
  There is no corresponding record for this reference.
  (c) Privalov, T. The Role of Amine-B(C₆F₅)₃ Adducts in the Catalytic Reduction of Imines with H₂: A Computational Study. Eur. J. Inorg. Chem. 2009, 2009, 2229– 2237, DOI: 10.1002/ejic.200900194
  There is no corresponding record for this reference.
  (d) Li, H.; Zhao, L.; Lu, G.; Huang, F.; Wang, Z.-X. Catalytic Metal-Free Ketone Hydrogenation: A Computational Experiment. Dalton Trans. 2010, 39, 5519– 5526, DOI: 10.1039/c001399d
  23d
  Catalytic metal-free ketone hydrogenation: a computational experiment
  Li, Haixia; Zhao, Lili; Lu, Gang; Huang, Fang; Wang, Zhi-Xiang
  Dalton Transactions (2010), 39 (23), 5519-5526CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
  A computational study has been carried out to examine if the metal-free catalyst I designed for imine hydrogenation is able to hydrogenate ketones, using the cyclohexanone (3) and its derivs. (4-6) as ketone models. The catalytic cycle includes two major steps: hydrogen activation and hydrogen transfer. The concerted pathway in the hydrogen transfer step is preferred over the stepwise pathway. The two sepd. steps for hydrogen activation and hydrogen transfer can benefit the hydrogen addn. to the substrates (e.g., ketones) which do not have strong Lewis base centers, because the substrates need not to be involved in the hydrogen activation. In general, the larger the steric effect of the substrate is, the less severe the side reactions become, and the more difficultly the desired reaction occurs. The energetic results show that the hydrogenations of 3-5 are kinetically and thermodynamically feasible under ambient conditions, but the hydrogenation of 6 is less energetically favorable. Therefore, it is important to establish a proper balance between promoting the desired reaction and meanwhile avoiding the undesired reactions. The issue of the resting state, caused by forming stable alkoxide complexes like in the ketone hydrogenation catalyzed by the metal-ligand bifunctional catalysts, is also discussed.
  (e) Zhao, L.; Li, H.; Lu, G.; Huang, F.; Zhang, C.; Wang, Z.-X. Metal-Free Catalysts for Hydrogenation of Both Small and Large Imines: A Computational Experiment. Dalton Trans. 2011, 40, 1929– 1937, DOI: 10.1039/c0dt01297a
  23e
  Metal-free catalysts for hydrogenation of both small and large imines: a computational experiment
  Zhao, Lili; Li, Haixia; Lu, Gang; Huang, Fang; Zhang, Chenggen; Wang, Zhi-Xiang
  Dalton Transactions (2011), 40 (9), 1929-1937CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
  This study extends our previous work of using π-FLP strategy to develop metal-free hydrogenation catalysts. Using small MeN:CMe2 imine (i.m.1) as a model, we previously designed cat1 and cat2 catalysts. But it is unclear whether they are capable of catalyzing the hydrogenations of bulky imines. Using tBuN:C(H)Ph (i.m.2) as a representative of large imines, we assessed the energetics of the cat1- and cat2-catalyzed i.m.2 hydrogenations. The predicted energetics indicates that they can still catalyze large imine hydrogenations with exptl. accessible kinetic barriers, although the energetics becomes less favorable. To improve the catalysis, we proposed new catalysts (cat3 and cat4) by tailoring cat1 and cat2. The study indicates that cat3 and cat4 could have better performance for the hydrogenation of the bulky i.m.2 than cat1 and cat2. Remarkably, cat3 and cat4 are also found suitable for small imine (i.m.1) hydrogenation. Examg. the hydrogen transfer substeps in the eight hydrogenations involved in this study, we obsd. that the mechanism for the hydrogen transfer step in the catalytic cycles depends on the steric effect between catalyst and substrate. The mechanism can be switched from stepwise one in the case of large steric effect (e.g.i.m.2/cat2) to the concerted one in the case of small steric effect (e.g.i.m.1/cat3). The new catalysts could be better targets for exptl. realization because of their simpler constructions.
  (f) Zhao, L.; Lu, G.; Huang, F.; Wang, Z.-X. A Computational Experiment to Study Hydrogenations of Various Unsaturated Compounds Catalyzed by a Rationally Designed Metal-Free Catalyst. Dalton Trans. 2012, 41, 4674– 4684, DOI: 10.1039/c2dt12152b
  23f
  A computational experiment to study hydrogenations of various unsaturated compounds catalyzed by a rationally designed metal-free catalyst
  Zhao, Lili; Lu, Gang; Huang, Fang; Wang, Zhi-Xiang
  Dalton Transactions (2012), 41 (15), 4674-4684CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
  Metal-free hydrogenation has been proposed to be a green alternative to the conventional hydrogenation mediated by precious transition metal complexes. Thanks to the discovery of FLP (frustrated Lewis pair) chem., the field has recently witnessed significant progress. Inspired by the FLP idea of synergically utilizing the catalytic effects of Lewis acid and base, we previously proposed a strategy to construct metal-free active sites for H2 activation and designed a metal-free mol. (1) that shows high reactivity toward H2. Encouraged by the recent exptl. successes in applying the strategy, we have computationally explored if 1 can go further to serve as a catalyst to promote the hydrogenations of various unsatd. compds. examd. by ethylene (CH2:CH2 (4)), silyl enol ether (CH2:C(Me)OSiMe3 (5)), imines (Me2C:NMe (6) and Ph(Me)C:NMe (7)), and ketone (Ph(Me)C:O (9)). The energetic results predicted at the M05-2X(IEFPCM, solvent = THF)/6-311++G** level indicate that these reactions have feasible kinetics and thermodn. for exptl. realization. The hydride transfer step follows the concerted mechanism, although the transfer process has asynchronous character for silyl enol ether (5) and imines (6 and 7). In addn., we have investigated the binding of CO2 to 1 and the 1-mediated hydrogenation of CO2.
  (g) Chernichenko, K.; Madarász, Á.; Pápai, I.; Nieger, M.; Leskelä, M.; Repo, T. A Frustrated-Lewis-Pair Approach to Catalytic Reduction of Alkynes to Cis-Alkenes. Nat. Chem. 2013, 5, 718– 723, DOI: 10.1038/nchem.1693
  23g
  A frustrated-Lewis-pair approach to catalytic reduction of alkynes to cis-alkenes
  Chernichenko, Konstantin; Madarasz, Adam; Papai, Imre; Nieger, Martin; Leskelae, Markku; Repo, Timo
  Nature Chemistry (2013), 5 (8), 718-723CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
  Frustrated Lewis pairs are compds. contg. both Lewis acidic and Lewis basic moieties, where the formation of an adduct is prevented by steric hindrance. They are therefore highly reactive, and are capable of heterolysis of mol. hydrogen, a property that led to their use in hydrogenation reactions of polarized multiple bonds. Here, the authors describe a general approach to the hydrogenation of alkynes to cis-alkenes under mild conditions using the unique ansa-aminohydroborane as a catalyst. The approach combines several reactions as the elementary steps of the catalytic cycle: hydroboration (substrate binding), heterolytic hydrogen splitting (typical frustrated-Lewis-pair reactivity) and facile intramol. protodeborylation (product release). The mechanism is verified by exptl. and computational studies.
  (h) Wang, Z.-X.; Zhao, L.; Lu, G.; Li, H. X.; Huang, F. Computational Design of Metal-Free Molecules for Activation of Small Molecules, Hydrogenation, and Hydroamination. Top. Curr. Chem. 2012, 332, 231– 266, DOI: 10.1007/128_2012_385
  There is no corresponding record for this reference.
  (i) Zhao, J.; Wang, G.; Li, S. Mechanistic Insights into the Full Hydrogenation of 2,6-Substituted Pyridine Catalyzed by the Lewis Acid C₆F₅(CH₂)₂B(C₆F₅)₂. Dalton Trans. 2015, 44, 9200– 9208, DOI: 10.1039/C5DT00978B
  23i
  Mechanistic insights into the full hydrogenation of 2,6-substituted pyridine catalyzed by the Lewis acid C6F5(CH2)2B(C6F5)2
  Zhao, Jiyang; Wang, Guoqiang; Li, Shuhua
  Dalton Transactions (2015), 44 (19), 9200-9208CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
  The reaction mechanism for the full hydrogenation of 2-phenyl-6-methylpyridine catalyzed by the Lewis acid C6F5(CH2)2B(C6F5)2 was investigated in detail by d. functional theory calcns. Our calcns. show that a plausible reaction pathway of the hydrogenation of pyridine contains five stages: (1) the generation of a new borane C6F5(CH2)2B(C6F5)2 from the hydroboration of the alkene, which forms a frustrated Lewis pair (FLP) with a pyridine; (2) the activation of H2 by FLP to yield an ion pair intermediate; (3) intramol. hydride transfer from the boron atom to the pyridinium cation in the ion pair intermediate to produce the 1,4-dihydropyridine; (4) hydrogenation of the 1,4-dihydropyridine by the FLP to form the 1,4,5,6-tetrahydropyridine; (5) hydrogenation of the 1,4,5,6-tetrahydropyridine by the FLP to yield the final piperidine. The last two hydrogenation processes follow a similar pathway, which includes four steps: (a) proton transfer from the pyridinium moiety to the substrate; (b) dissocn. of the newly generated pyridine; (c) hydride migration from the hydridoborate moiety to the protonated substrate to produce the hydrogenated product; (d) release of the hydrogenated product to regenerate the free borane. The full hydrogenation of pyridine is calcd. to be exothermic by 16.9 kcal mol-1, relative to the starting reactants. The rate-limiting step is the proton transfer in the second hydrogenation step, with a free energy barrier of 28.2 kcal mol-1 in the gas phase (27.9 kcal mol-1 in toluene) at room temp. and 1.0 atm. Our results can account for the obsd. exptl. facts.
  (j) Das, S.; Pati, S. K. On the Mechanism of Frustrated Lewis Pair Catalysed Hydrogenation of Carbonyl Compounds. Chem. - Eur. J. 2017, 23, 1078– 1085, DOI: 10.1002/chem.201602774
  23j
  On the Mechanism of Frustrated Lewis Pair Catalysed Hydrogenation of Carbonyl Compounds
  Das, Shubhajit; Pati, Swapan K.
  Chemistry - A European Journal (2017), 23 (5), 1078-1085CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The authors have explored the reaction mechanism of the metal-free B(C6F5)3-catalyzed hydrogenation of carbonyl compds. to the corresponding secondary alcs. by d. functional theory calcns. Possible reaction routes were studied in detail and the results provide solid support for the mechanism proposed from exptl. observations. The crit. role of the ethereal solvent, as an active participant in the hydrogenation process, is highlighted with the ether-borane Lewis pair shown to be involved in the heterolytic activation of H2. The feasibility of an alternative direct hydrogenation route featuring carbonyl-borane-mediated H2 cleavage also was examd. The authors have also studied the moisture sensitivity of the catalyst and possible decompn. routes. The catalyst shows appreciable water-tolerance and even in the presence of moisture the hydrogenation proceeds through the same mechanism as that followed under anhyd. conditions.
  (k) Heshmat, M.; Privalov, T. Carbonyl Activation by Borane Lewis Acid Complexation: Transition States of H₂ Splitting at the Activated Carbonyl Carbon Atom in a Lewis Basic Solvent and the Proton-Transfer Dynamics of the Boroalkoxide Intermediate. Chem. - Eur. J. 2017, 23, 9098– 9113, DOI: 10.1002/chem.201700437
  23k
  Carbonyl Activation by Borane Lewis Acid Complexation: Transition States of H2 Splitting at the Activated Carbonyl Carbon Atom in a Lewis Basic Solvent and the Proton-Transfer Dynamics of the Boroalkoxide Intermediate
  Heshmat, Mojgan; Privalov, Timofei
  Chemistry - A European Journal (2017), 23 (38), 9098-9113CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  By using transition-state (TS) calcns., we examd. how Lewis acid (LA) complexation activates carbonyl compds. in the context of hydrogenation of carbonyl compds. by H2 in Lewis basic (ethereal) solvents contg. borane LAs of the type (C6F5)3B. According to our calcns., LA complexation does not activate a ketone sufficiently enough for the direct addn. of H2 to the O=C unsatd. bond; but, calcns. indicate a possibly facile heterolytic cleavage of H2 at the activated and thus sufficiently Lewis acidic carbonyl carbon atom with the assistance of the Lewis basic solvent (i.e., 1,4-dioxane or THF). For the solvent-assisted H2 splitting at the carbonyl carbon atom of (C6F5)3B adducts with different ketones, a no. of TSs are computed and the obtained results are related to insights from expt. By using the Born-Oppenheimer mol. dynamics with the DFT for electronic structure calcns., the evolution of the (C6F5)3B-alkoxide ionic intermediate and the proton transfer to the alkoxide oxygen atom were investigated. The results indicate a plausible hydrogenation mechanism with a LA, i.e., (C6F5)3B, as a catalyst, namely, (1) the step of H2 cleavage that involves a Lewis basic solvent mol. plus the carbonyl carbon atom of thermodynamically stable and exptl. identifiable (C6F5)3B-ketone adducts in which (C6F5)3B is the "Lewis acid promoter", (2) the transfer of the solvent-bound proton to the oxygen atom of the (C6F5)3B-alkoxide intermediate giving the (C6F5)3B-alc. adduct, and (3) the SN2-style displacement of the alc. by a ketone or a Lewis basic solvent mol.
  (l) Mane, M. V.; Vanka, K. Less Frustration, More Activity-Theoretical Insights into Frustrated Lewis Pairs for Hydrogenation Catalysis. ChemCatChem 2017, 9, 3013– 3022, DOI: 10.1002/cctc.201700289
  23l
  Less Frustration, More Activity-Theoretical Insights into Frustrated Lewis Pairs for Hydrogenation Catalysis
  Mane, Manoj V.; Vanka, Kumar
  ChemCatChem (2017), 9 (15), 3013-3022CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The field of frustrated Lewis pair (FLP) chem. has seen rapid development in only a few years. FLPs have performed most spectacularly in hydrogenation catalysis: a wide variety of FLP-based systems can catalyze the hydrogenation of a range of different substrates, including imines, enamines, ketones, alkynes, and alkenes. However, FLP-based hydrogenation catalysts are yet to match the efficiency of their transition-metal counterparts. The current investigation reveals an important aspect of FLPs that can be exploited to improve their efficiency, i.e., the more sterically hindered the FLP catalyst is, the lower is its turnover frequency. Full quantum chem. calcns. with DFT for a family of different, exptl. known hydrogenation FLP catalysts shows that superior FLP catalysts can be designed by reducing the frustration (by reducing the steric demand and acid/base strength) in the FLP. However, as lowering the steric demand without redn. in the frustration can result in unwanted side reactions, the design of the most efficient FLP catalysts depends on tuning the system so that both the steric demand and the frustration are reduced appropriately.
  (m) Heshmat, M.; Privalov, T. Computational Elucidation of a Role That Brønsted Acidification of the Lewis Acid-Bound Water Might Play in the Hydrogenation of Carbonyl Compounds with H₂ in Lewis Basic Solvents. Chem. - Eur. J. 2017, 23, 11489– 11493, DOI: 10.1002/chem.201700937
  23m
  Computational Elucidation of a Role That Bronsted Acidification of the Lewis Acid-Bound Water Might Play in the Hydrogenation of Carbonyl Compounds with H2 in Lewis Basic Solvents
  Heshmat, Mojgan; Privalov, Timofei
  Chemistry - A European Journal (2017), 23 (48), 11489-11493CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Bronsted acidification of water by Lewis acid (LA) complexation is one of the fundamental principles in chem. Using transition-state calcns. (TS), herein we investigate the role that Bronsted acidification of the LA-bound water might play in the mechanism of the hydrogenation of carbonyl compds. in Lewis basic solvents under non-anhyd. conditions. The potential energy scans and TS calcns. were carried out with a series of eight borane LAs as well as the commonly known strong LA AlCl3 in 1,4-dioxane or THF as Lewis basic solvents. Our mol. model consists of the dative LA-water adduct with hydrogen bonds to acetone and a solvent mol. plus one addnl. solvent mol. that participates is the TS structure describing the cleavage of H2 at acetone's carbonyl carbon atom. In all the mol. models applied here, acetone (O=CMe2) is the archetypical carbonyl substrate. We demonstrate that Bronsted acidification of the LA-bound water can indeed lower the barrier height of the solvent-involving H2-cleavage at the acetone's carbonyl carbon atom. This is significant because at present it is believed that the mechanism of the herein considered reaction is described by the same mechanism regardless of whether the reaction conditions are strictly anhyd. or non-anhyd. Our results offer an alternative to this belief that warrants consideration and further study.
  (n) Heshmat, M.; Privalov, T. Theory-Based Extension of the Catalyst Scope in the Base-Catalyzed Hydrogenation of Ketones: RCOOH-Catalyzed Hydrogenation of Carbonyl Compounds with H₂ Involving a Proton Shuttle. Chem. - Eur. J. 2017, 23, 18193– 18202, DOI: 10.1002/chem.201702149
  23n
  Theory-Based Extension of the Catalyst Scope in the Base-Catalyzed Hydrogenation of Ketones: RCOOH-Catalyzed Hydrogenation of Carbonyl Compounds with H2 Involving a Proton Shuttle
  Heshmat, Mojgan; Privalov, Timofei
  Chemistry - A European Journal (2017), 23 (72), 18193-18202CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  As an extension of the reaction mechanism describing the base-catalyzed hydrogenation of ketones according to Berkessel et al., we use a std. methodol. for transition-state calcns. in order to check the possibility of heterolytic cleavage of H2 at the ketone's carbonyl carbon atom, yielding one-step hydrogenation path with involvement of carboxylic acid as a catalyst. As an extension of the catalyst scope in the base-catalyzed hydrogenation of ketones, our mechanism involves a mol. with a labile proton and a Lewis basic oxygen atom as a catalyst-for example, R-C(=O)OH carboxylic acids-so that the heterolytic cleavage of H2 could take place between the Lewis basic oxygen atom of a carboxylic acid and the electrophilic (Lewis acidic) carbonyl carbon of a ketone/aldehyde. According to our TS calcns., protonation of a ketone/aldehyde by a proton shuttle (hydrogen bond) facilitates the hydride-type attack on the ketone's carbonyl carbon atom in the process of the heterolytic cleavage of H2. Ketones with electron-rich and electron-withdrawing substituents in combination with a few carboxylic and amino acids-in total, 41 substrate-catalyst couples-have been computationally evaluated in this article and the calcd. reaction barriers are encouragingly moderate for many of the considered substrate-catalyst couples.
  (o) Das, S.; Pati, S. K. Unravelling the Mechanism of Tin-Based Frustrated Lewis Pair Catalysed Hydrogenation of Carbonyl Compounds. Catal. Sci. Technol. 2018, 8, 5178– 5189, DOI: 10.1039/C8CY01227J
  23o
  Unravelling the mechanism of tin-based frustrated Lewis pair catalysed hydrogenation of carbonyl compounds
  Das, Shubhajit; Pati, Swapan K.
  Catalysis Science & Technology (2018), 8 (20), 5178-5189CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)
  This article presents a comprehensive study on the mechanism of Sn/N frustrated Lewis pair (FLP) catalyzed hydrogenation of carbonyl compds. to corresponding alcs. Possible reaction pathways have been elucidated in detail using d. functional theory computations. The reaction begins with Sn/N FLP-mediated heterolytic cleavage of a H2 mol. to release active hydrogens in soln. Our results reveal that, instead of the usual Bronsted acid activation, the carbonyl substrate is activated by Lewis acid complexation, followed by subsequent hydride and proton delivery to complete the hydrogenation process. Addnl., we have also examd. the feasibility of an autocatalytic pathway. The main feature of this reaction route is Sn/O FLP-mediated H2 cleavage, which has a comparable barrier to H2 splitting by Sn/N FLPs. Overall, our computational mechanistic model is consistent with the exptl. findings and the computed free energy barriers are in good agreement with the obsd. reactivity at exptl. temp. Insights obtained from this study are crucial for the rational development of Sn-based FLP hydrogenation catalysts.
24. 24
  For recent reviews on concepts and challenges in computing stereoselectivities, see:
  (a) Hopmann, K. H. Quantum Chemical Studies of Asymmetric Reactions: Historical Aspects and Recent Examples. Int. J. Quantum Chem. 2015, 115, 1232– 1249, DOI: 10.1002/qua.24882
  24a
  Quantum chemical studies of asymmetric reactions: Historical aspects and recent examples
  Hopmann, Kathrin H.
  International Journal of Quantum Chemistry (2015), 115 (18), 1232-1249CODEN: IJQCB2; ISSN:0020-7608. (John Wiley & Sons, Inc.)
  Asym. catalysis is essential for the synthesis of chiral compds. such as pharmaceuticals, agrochems., fragrances, and flavors. For rational improvement of asym. reactions, detailed mechanistic insights are required. The usefulness of quantum mech. studies for understanding the stereocontrol of asym. reactions was first demonstrated around 40 years ago, with impressive developments since then: from single-point Hartree-Fock/STO-3G calcns. on small org. mols. (1970s), to the first full reaction pathway involving a metal-complex (1980s), to the beginning of the d. functional theory-area, albeit typically involving truncated models (1990s), to current state-of-the-art calcns. reporting free energies of complete organometallic systems, including solvent and dispersion corrections. The combined studies show that the stereocontrol in asym. reactions largely is exerted by nonbonding interactions, including CH/π attraction and repulsive forces. The ability to rationalize exptl. results opens up for the possibility to predict enantioselectivities or to design novel catalysts on basis of in silico results. © 2015 Wiley Periodicals, Inc.
  (b) Peng, Q.; Duarte, F.; Paton, R. S. Computing Organic Stereoselectivity-from Concepts to Quantitative Calculations and Predictions. Chem. Soc. Rev. 2016, 45, 6093– 6107, DOI: 10.1039/C6CS00573J
  24b
  Computing organic stereoselectivity - from concepts to quantitative calculations and predictions
  Peng, Qian; Duarte, Fernanda; Paton, Robert S.
  Chemical Society Reviews (2016), 45 (22), 6093-6107CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  Advances in theory and processing power have established computation as a valuable interpretative and predictive tool in the discovery of new asym. catalysts. This tutorial review outlines the theory and practice of modeling stereoselective reactions. Recent examples illustrate how an understanding of the fundamental principles and the application of state-of-the-art computational methods may be used to gain mechanistic insight into org. and organometallic reactions. We highlight the emerging potential of this computational tool-box in providing meaningful predictions for the rational design of asym. catalysts. We present an accessible account of the field to encourage future synergy between computation and expt.
  (c) Krenske, E. H. Challenges in Predicting Stereoselectivity. In Applied Theoretical Organic Chemistry; Tantillo, D. J., Ed.; World Scientific: New Jersey, 2018; pp 583– 604.
  There is no corresponding record for this reference.
  (d) Gridnev, I. D.; Dub, P. A. Enantioselection in Asymmetric Catalysis; CRC Press: Boca Raton, 2017.
  There is no corresponding record for this reference.
25. 25
  For a detailed computational analysis of H₂ activation pathways with the im/2 and P/2 pairs, see the SI (section 2.1).
  There is no corresponding record for this reference.
26. 26
  Computed proton affinities of P^tBu₃ and im are −277.5 and −231.7 kcal/mol, respectively. These values are obtained as solution phase Gibbs free energies of base → baseH⁺ reactions.
  There is no corresponding record for this reference.
27. 27
  For a detailed comparison of the energetics of the two catalytic cycles, see the SI (section 2.2).
  There is no corresponding record for this reference.
28. 28
  For conformational analysis of borohydride 2H^–, see the SI (section 2.3).
  There is no corresponding record for this reference.
29. 29
  For details of the conformational analysis carried out for the imH⁺/2H^– ion pair intermediate, see the SI (section 2.4).
  There is no corresponding record for this reference.
30. 30
  For related studies, see, for example:
  (a) Rokob, T. A.; Hamza, A.; Pápai, I. Rationalizing the Reactivity of Frustrated Lewis Pairs: Thermodynamics of H₂ Activation and the Role of Acid–Base Properties. J. Am. Chem. Soc. 2009, 131, 10701– 10710, DOI: 10.1021/ja903878z
  30a
  Rationalizing the Reactivity of Frustrated Lewis Pairs: Thermodynamics of H2 Activation and the Role of Acid-Base Properties
  Rokob, Tibor Andras; Hamza, Andrea; Papai, Imre
  Journal of the American Chemical Society (2009), 131 (30), 10701-10710CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The acid-base strengths of recently reported frustrated Lewis pairs and their relation with the thermodn. feasibility of heterolytic H splitting reactions are analyzed in terms of quantum chem. calcns. Reaction free energies of hydrogenation processes are computed, and an energy partitioning scheme is introduced, which involves quant. measures of the acidity and basicity of the reacting Lewis centers. Addnl. terms are also included that account for possible dative bond formation between the active sites and for stabilizing electrostatic interactions occurring in the product species. For intermol. combinations of donor-acceptor components, the calcd. reaction free energies correlate well with the cumulative acid-base strengths. Product stabilization for these systems represents a notable contribution to the overall energetics; however, it generally shows only a slight variation for the studied series. The reactivity of linked donor-acceptor pairs is primarily governed by acid-base properties as well, but the magnitude of stabilizing effects arising from acid-base cooperativity of active sites is also of significant importance in detg. the thermodn. feasibility of the reactions.
  (b) Schulz, F.; Sumerin, V.; Heikkinen, S.; Pedersen, B.; Wang, C.; Atsumi, M.; Leskelä, M.; Repo, T.; Pyykkö, P.; Petry, W.; Rieger, B. Molecular Hydrogen Tweezers: Structure and Mechanisms by Neutron Diffraction, NMR, and Deuterium Labeling Studies in Solid and Solution. J. Am. Chem. Soc. 2011, 133, 20245– 20257, DOI: 10.1021/ja206394w
  30b
  Molecular hydrogen tweezers: structure and mechanisms by neutron diffraction, NMR, and deuterium labeling studies in solid and solution
  Schulz, Felix; Sumerin, Victor; Heikkinen, Sami; Pedersen, Bjoern; Wang, Cong; Atsumi, Michiko; Leskelae, Markku; Repo, Timo; Pyykkoe, Pekka; Petry, Winfried; Rieger, Bernhard
  Journal of the American Chemical Society (2011), 133 (50), 20245-20257CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The mechanism of reversible hydrogen activation by ansa-aminoboranes, 1-N-TMPH-CH2-2-[HB(C6F5)2]C6H4 (NHHB), was studied by neutron diffraction and thermogravimetric mass-spectroscopic expts. in the solid state as well as with NMR and FT-IR spectroscopy in soln. The structure of the ansa-ammonium borate NHHB was detd. by neutron scattering, revealing a short N-H···H-B dihydrogen bond of 1.67 Å. Moreover, this intramol. H-H distance was detd. in soln. to be also 1.6-1.8 Å by 1H NMR spectroscopic T1 relaxation and 1D NOE measurements. The x-ray B-H and N-H distances deviated from the neutron and the calcd. values. The dynamic nature of the mol. tweezers in soln. was addnl. studied by multinuclear and variable-temp. NMR spectroscopy. We synthesized stable, individual isotopic isomers NDDB, NHDB, and NDHB. NMR measurements revealed a primary isotope effect in the chem. shift difference pΔ1H(D) = δ(NH) - δ(ND) (0.56 ppm), and hence supported dihydrogen bonding. The NMR studies gave strong evidence that the structure of NHHB in soln. is similar to that in the solid state. This is corroborated by IR studies providing clear evidence for the dynamic nature of the intramol. dihydrogen bonding at room temp. Interestingly, no kinetic isotope effect was detected for the activation of deuterium hydride by the ansa-aminoborane NB. Theor. calcns. attribute this to an "early transition state". Moreover, 2D NOESY NMR measurements support fast intermol. proton exchange in aprotic CD2Cl2 and C6D6.
  (c) Zaher, H.; Ashley, A. E.; Irwin, M.; Thompson, A. L.; Gutmann, M. J.; Krämer, T.; O’Hare, D. Structural and Theoretical Studies of Intermolecular Dihydrogen Bonding in [(C₆F₅)₂(C₆Cl₅)B]–H···H–[TMP]. Chem. Commun. 2013, 49, 9755– 9757, DOI: 10.1039/c3cc45889j
  30c
  Structural and theoretical studies of intermolecular dihydrogen bonding in [(C6F5)2(C6Cl5)B]-H···H-[TMP]
  Zaher, Hasna; Ashley, Andrew E.; Irwin, Mark; Thompson, Amber L.; Gutmann, Matthias J.; Kraemer, Tobias; O'Hare, Dermot
  Chemical Communications (Cambridge, United Kingdom) (2013), 49 (84), 9755-9757CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  The product of the intermol. frustrated Lewis pair (FLP) B(C6F5)2(C6Cl5)/2,2,6,6-tetramethylpiperidine and H2 has been studied by single-crystal neutron diffraction. This is the first structurally characterized example of a geometrically unconstrained dihydrogen (H···H) bond within a hydrogenated FLP system.
  (d) Zhivonitko, V. V.; Sorochkina, K.; Chernichenko, K.; Kótai, B.; Földes, T.; Pápai, I.; Telkki, V.-V.; Repo, T.; Koptyug, I. Nuclear Spin Hyperpolarization with Ansa-Aminoboranes: A Metal-Free Perspective for Parahydrogen-Induced Polarization. Phys. Chem. Chem. Phys. 2016, 18, 27784– 27795, DOI: 10.1039/C6CP05211H
  30d
  Nuclear spin hyperpolarization with ansa-aminoboranes: a metal-free perspective for parahydrogen-induced polarization
  Zhivonitko, Vladimir V.; Sorochkina, Kristina; Chernichenko, Konstantin; Kotai, Bianka; Foldes, Tamas; Papai, Imre; Telkki, Ville-Veikko; Repo, Timo; Koptyug, Igor
  Physical Chemistry Chemical Physics (2016), 18 (40), 27784-27795CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
  The parahydrogen-induced polarization (PHIP) phenomenon, obsd. when parahydrogen is used in H2 addn. processes, provides a means for substantial NMR signal enhancements and mechanistic studies of chem. reactions. Commonly, noble metal complexes are used for parahydrogen activation, whereas metal-free activation is rare. Herein, we report a series of unimol. metal-free frustrated Lewis pairs based on an ansa-aminoborane (AAB) moiety in the context of PHIP. These mols., which have a "mol. tweezers" structure, differ in their substituents at the boryl site (-H, -Ph, -o-iPr-Ph, and -Mes). PHIP effects were obsd. for all the AABs after exposing their solns. to parahydrogen in a wide temp. range, and exptl. measurements of their kinetic and thermodn. parameters were performed. A theor. anal. of their nuclear spin polarization effects is presented, and the roles of chem. exchange, chem. equil. and spin dynamics are discussed in terms of the key dimensionless parameters. The anal. allowed us to formulate the prerequisites for achieving strong polarization effects with AAB mols., which can be applied for further design of efficient metal-free tweezers-like mols. for PHIP. Mechanistic (chem. and phys.) aspects of the obsd. effects are discussed in detail. In addn., we performed quantum chem. calcns., which confirmed that the J-coupling between the parahydrogen-originated protons in AAB-H2 mols. is mediated through dihydrogen bonding.
31. 31
  For the estimation of barriers relevant to the interconversion of imH⁺/2H^– isomers, see the SI (section 2.4).
  There is no corresponding record for this reference.
32. 32
  For computational studies examining the role of stabilizing noncovalent interactions in TM-catalyzed stereoselective hydrogenations, see:
  (a) Hopmann, K. H.; Bayer, A. On the Mechanism of Iridium-Catalyzed Asymmetric Hydrogenation of Imines and Alkenes: A Theoretical Study. Organometallics 2011, 30, 2483– 2497, DOI: 10.1021/om1009507
  32a
  On the mechanism of iridium-catalyzed asymmetric hydrogenation of imines and alkenes: a theoretical study
  Hopmann, Kathrin Helen; Bayer, Annette
  Organometallics (2011), 30 (9), 2483-2497CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
  Potential energy surfaces for hydrogenation of trans-stilbene, trans-1,2-diphenylpropene and N-Ph acetophenoneketimine, catalyzed by PHOX iridium complex, [4-isopropyl-2-(2-diphenylphosphinophenyl-κP)oxazoline-κN]iridium(1+), were calcd. Phosphine-oxazoline (PHOX)-based iridium complexes have emerged as useful tools for enantioselective hydrogenation of unfunctionalized alkenes and imines. The mechanistic details of the asym. hydrogenation process, however, are poorly understood. Several different mechanisms have been put forward for hydrogenation of unfunctionalized alkenes, but it remains unclear which of these provide an accurate description of the hydrogenation reaction. The mechanistic aspects of Ir-(PHOX)-mediated hydrogenation of imines are little explored, and no detailed mechanism has been formulated to date. Here we provide a comprehensive quantum mech. study of Ir-(PHOX)-mediated hydrogenation of both alkene and imine substrates. Our results support previous findings by Brandt et al., clearly favoring an Ir(III)/Ir(V) reaction cycle for Ir-(PHOX)-mediated hydrogenation of unfunctionalized alkenes. An important aspect of this reaction mechanism is the orientation of the metal-coordinated alkene substrate, which dets. the stereochem. of the resulting product. Our anal. further shows that none of the proposed alkene hydrogenation mechanisms are applicable for imines. For Ir-(PHOX)-mediated imine hydrogenation, we suggest a fundamentally different catalytic cycle involving dissocn. of the imine substrate. The suggested mechanism correctly reproduces the stereoselectivity of imine redn., but indicates that the enantioselectivity should be more sensitive to the reaction conditions and less controllable than the enantioselectivity of alkene hydrogenations.
  (b) Václavík, J.; Kuzma, M.; Přech, J.; Kačer, P. Asymmetric Transfer Hydrogenation of Imines and Ketones Using Chiral Ru^IICl(η⁶-p-cymene)[(S,S)-N-TsDPEN] as a Catalyst: A Computational Study. Organometallics 2011, 30, 4822– 4829, DOI: 10.1021/om200263d
  32b
  Asymmetric transfer hydrogenation of imines and ketones using chiral RuIICl(η6-p-cymene)[(S,S)-N-TsDPEN] as a catalyst: a computational study
  Vaclavik, Jiri; Kuzma, Marek; Prech, Jan; Kacer, Petr
  Organometallics (2011), 30 (18), 4822-4829CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
  Potential energy surface was calcd. for asym. transfer hydrogenation of an imine, 3,4-dihydro-1-methylisoquinoline and an arom. ketone, PhCOMe, catalyzed by ruthenium chiral (S,S)-1,2-diphenyl-N-tosyl-1,2-ethanediaminato (H2NCHPhCHPhNTs-, TsDPEN) η6-cymene complex, [RuCl(TsDPEN)(η6-cymene)] (1), comprising redn. of the complex 1 by formic acid to the hydride [RuH(TsDPEN)(η6-cymene)] (2), protonation of the imine and hydrogen transfer from ruthenium to carbon of the hydrogen-bonded imine; in the case of acetophenone redn., simultaneous transfer of proton and hydride occurs to oxygen and carbon, resp. D. functional theory (DFT) computational methods were used to investigate the increasingly popular ionic mechanistic concept for the asym. transfer hydrogenation of imines on the chiral catalyst 1. On application of the ionic mechanism, the reaction preferentially affords the (R)-amine product, which is in agreement with the exptl. observations. Calcd. transition state structures for the hydrogenation of protonated 1-methyl-3,4-dihydroisoquinoline are discussed together with their preceding and following energy min. Stabilization of the favorable transition state by a CH/π interaction between the η6-p-cymene ligand and the substrate mol. is explored in depth to show that both C(sp2)H/π is more probable than C(sp3)H/π in this mol. system. Finally, transition state geometries for the asym. transfer hydrogenation of acetophenone are proposed, which take the "std." six-membered cyclic form.
  (c) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. Highly Enantioselective Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic Ruthenium Catalysts: Scope, Mechanism, and Origin of Enantioselectivity. J. Am. Chem. Soc. 2011, 133, 9878– 9891, DOI: 10.1021/ja2023042
  32c
  Highly Enantioselective Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic Ruthenium Catalysts: Scope, Mechanism, and Origin of Enantioselectivity
  Wang, Tianli; Zhuo, Lian-Gang; Li, Zhiwei; Chen, Fei; Ding, Ziyuan; He, Yanmei; Fan, Qing-Hua; Xiang, Junfeng; Yu, Zhi-Xiang; Chan, Albert S. C.
  Journal of the American Chemical Society (2011), 133 (25), 9878-9891CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Asym. hydrogenation of quinolines catalyzed by chiral cationic η6-arene-N-tosylethylenediamine-Ru(II) complexes have been investigated. A wide range of quinoline derivs., including 2-alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivs., were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions. This catalytic protocol is applicable to the gram-scale synthesis of some biol. active tetrahydroquinolines, such as (-)-angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the prepn. of the antibacterial agent (S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction, intermediate characterization, and isotope labeling patterns. The evidence obtained from these expts. revealed that quinoline is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addn., isomerization, and 1,2-hydride addn., and hydrogen addn. undergoes a stepwise H+/H- transfer process outside the coordination sphere rather than a concerted mechanism. In addn., DFT calcns. indicate that the enantioselectivity originates from the CH/π attraction between the η6-arene ligand in the Ru-complex and the fused Ph ring of dihydroquinoline via a 10-membered ring transition state with the participation of TfO- anion.
  (d) Pablo, Ó.; Guijarro, D.; Kovács, G.; Lledós, A.; Ujaque, G.; Yus, M. A Versatile Ru Catalyst for the Asymmetric Transfer Hydrogenation of Both Aromatic and Aliphatic Sulfinylimines. Chem. - Eur. J. 2012, 18, 1969– 1983, DOI: 10.1002/chem.201102426
  32d
  A Versatile Ru Catalyst for the Asymmetric Transfer Hydrogenation of Both Aromatic and Aliphatic Sulfinylimines
  Pablo, Oscar; Guijarro, David; Kovacs, Gabor; Lledos, Agusti; Ujaque, Gregori; Yus, Miguel
  Chemistry - A European Journal (2012), 18 (7), 1969-1983, S1969/1-S1969/156CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A highly efficient Ru catalyst based on an achiral, very simple, and inexpensive amino alc. ligand (2-amino-2-methylpropan-1-ol) has been developed for the asym. transfer hydrogenation (ATH) of chiral N-(tert-butylsulfinyl)imines. This complex is able to catalyze the ATH of both arom. and the most challenging aliph. sulfinylimines by using iso-Pr alc. as the hydrogen source. The diastereoselective redn. of arom., heteroarom., and aliph. sulfinylketimines, including sterically congested cases, over short reaction times (1-4 h), followed by desulfinylation of the nitrogen atom, affords the corresponding highly enantiomerically enriched (ee up to >99 %) α-branched primary amines in excellent yields. The same ligand was equally effective for the synthesis of both (R)- and (S)-amines by using the appropriate abs. configuration in the iminic substrate. DFT mechanistic studies show that the hydrogen-transfer process is stepwise. Moreover, the origin of the diastereoselectivity has been rationalized.
  (e) Hopmann, K. H. Iron/Brønsted Acid Catalyzed Asymmetric Hydrogenation: Mechanism and Selectivity-Determining Interactions. Chem. - Eur. J. 2015, 21, 10020– 10030, DOI: 10.1002/chem.201500602
  32e
  Iron-Bronsted Acid-Catalyzed Asymmetric Hydrogenation: Mechanism and Selectivity-Determining Interactions
  Hopmann, Kathrin H.
  Chemistry - A European Journal (2015), 21 (28), 10020-10030CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Hydrogenation catalysts involving abundant base metals such as cobalt or iron are promising alternatives to precious metal systems. Despite rapid progress in this field, base metal catalysts do not yet achieve the activity and selectivity levels of their precious metal counterparts. Rational improvement of base metal complexes is facilitated by detailed knowledge about their mechanisms and selectivity-detg. factors. The mechanism for asym. imine hydrogenation with Knoelker's iron complex in the presence of chiral phosphoric acids is here studied computationally at the DFT-D level of theory, with models of up to 160 atoms. The resting state of the system is an adduct between the iron complex and the deprotonated acid. Rate-limiting H2 splitting is followed by a stepwise hydrogenation mechanism, in which the phosphoric acid acts as the proton donor. C-H···O interactions between the phosphoric acid and the substrate are involved in the stereocontrol at the final hydride transfer step. Computed enantiomeric ratios show excellent agreement with exptl. values, indicating that DFT-D is able to correctly capture the selectivity-detg. interactions of this system.
  (f) Tutkowski, B.; Kerdphon, S.; Limé, E.; Helquist, P.; Andersson, P. G.; Wiest, O.; Norrby, P.-O. Revisiting the Stereodetermining Step in Enantioselective Iridium-Catalyzed Imine Hydrogenation. ACS Catal. 2018, 8, 615– 623, DOI: 10.1021/acscatal.7b02386
  32f
  Revisiting the Stereodetermining Step in Enantioselective Iridium-Catalyzed Imine Hydrogenation
  Tutkowski, Brandon; Kerdphon, Sutthichat; Lime, Elaine; Helquist, Paul; Andersson, Pher G.; Wiest, Olaf; Norrby, Per-Ola
  ACS Catalysis (2018), 8 (1), 615-623CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  The mechanism for the iridium-catalyzed asym. hydrogenation of prochiral imines has been investigated for an exptl. relevant ligand-substrate combination using DFT calcns. The possible stereoisomers of the stereodetermining hydride transfer transition state were considered for four possible hydrogenation mechanisms starting from the recently disclosed active catalyst consisting of iridium phosphine-oxazoline with cyclometalated imine substrate. The hydrogenation was found to proceed via an outer-sphere pathway. The transition state accurately describes the exptl. observations of the active catalyst and provides a structural rationale for the high stereoinduction despite the lack of direct interaction points in the outer-sphere mechanism. The predicted enantioselectivity was consistent with exptl. observations. Exptl. studies support the hypothesis that the iridacycle forms spontaneously and functions as the active catalyst in the hydrogenation.
  (g) Salomó, E.; Gallen, A.; Sciortino, G.; Ujaque, G.; Grabulosa, A.; Lledós, A.; Riera, A.; Verdaguer, X. Direct Asymmetric Hydrogenation of N-Methyl and N-Alkyl Imines with an Ir(III)H Catalyst. J. Am. Chem. Soc. 2018, 140, 16967– 16970, DOI: 10.1021/jacs.8b11547
  32g
  Direct Asymmetric Hydrogenation of N-Methyl and N-Alkyl Imines with an Ir(III)H Catalyst
  Salomo, Ernest; Gallen, Albert; Sciortino, Giuseppe; Ujaque, Gregori; Grabulosa, Arnald; Lledos, Agusti; Riera, Antoni; Verdaguer, Xavier
  Journal of the American Chemical Society (2018), 140 (49), 16967-16970CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A novel cationic [IrH(THF)(P,N)(imine)] [BArF] catalyst contg. a P-stereogenic MaxPHOX ligand is described for the direct asym. hydrogenation of N-Me and N-alkyl imines. This is the first catalytic system to attain high enantioselectivity (up to 94% ee) in this type of transformation. The labile THF ligand allows for effective activation and reactivity, even at low temps. D. functional theory calcns. allowed the rationalization of the stereochem. course of the reaction.
  (h) Chen, J.; Gridnev, I. D. Size is Important: Artificial Catalyst Mimics Behaviour of Natural Enzymes. iScience 2020, 23, 100960, DOI: 10.1016/j.isci.2020.100960
  32h
  Size is Important: Artificial Catalyst Mimics Behavior of Natural Enzymes
  Chen, Jianzhong; Gridnev, Ilya D.
  iScience (2020), 23 (3), 100960CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)
  Heavily substituted (R)-DTBM-SegPHOS is active in the asym. Pd(II)-catalyzed hydrogenation or C-O bond cleavage of α-pivaloyloxy-1-(2-furyl)ethanone, whereas (R)-SegPHOS fails to catalyze either of these transformations. An extensive network of C-H···H-C interactions provided by the heavily substituted Ph rings of (R)-DTBM-SegPHOS leads to increased stabilities of all intermediates and transition states in the corresponding catalytic cycles compared with the unsubstituted analogs. Moreover, formation of the encounter complex and its rearrangement into the reactive species proceeds in a fashion similar to that seen in natural enzymic reactions. Computations demonstrate that this feature is the origin of enantioselection in asym. hydrogenation, since the stable precursor is formed only when the catalyst is approached by one prochiral plane of the substrate.
33. 33
  For a selection of related studies on TM-catalyzed stereoselective hydrogenation of other substrates, see:
  (a) Hopmann, K. H. Cobalt–Bis(Imino)Pyridine-Catalyzed Asymmetric Hydrogenation: Electronic Structure, Mechanism, and Stereoselectivity. Organometallics 2013, 32, 6388– 6399, DOI: 10.1021/om400755k
  33a
  Cobalt-Bis(imino)pyridine-Catalyzed Asymmetric Hydrogenation: Electronic Structure, Mechanism, and Stereoselectivity
  Hopmann, Kathrin H.
  Organometallics (2013), 32 (21), 6388-6399CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
  Academic and industrial efforts aim at replacing precious metal catalysts with cheaper and more environmentally friendly base metal variants. Two Co-bis-(imino)-pyridine (CoBIP) complexes were recently reported as promising candidates for asym. hydrogenation [Monfette, S.; et al. J. Am. Chem. Soc.2012, 134, 4561-4564]. A comprehensive quantum mech. anal. of these complexes is reported here, including electronic structures, preferred conformations, and mechanisms of activation. The full asym. hydrogenation mechanism is analyzed, and the origin of the obsd. enantioselectivities with both CoBIP catalysts is evaluated. A key finding is that CoBIP complexes catalyze a competing alkene isomerization reaction, which can have crucial implications for the yield and the stereochem. outcome of alkene hydrogenation.
  (b) Dub, P. a.; Henson, N. J.; Martin, R. L.; Gordon, J. C. Unravelling the Mechanism of the Asymmetric Hydrogenation of Acetophenone by [RuX₂(Diphosphine)(1,2-Diamine)] Catalysts. J. Am. Chem. Soc. 2014, 136, 3505– 3521, DOI: 10.1021/ja411374j
  33b
  Unravelling the Mechanism of the Asymmetric Hydrogenation of Acetophenone by [RuX2(diphosphine)(1,2-diamine)] Catalysts
  Dub, Pavel A.; Henson, Neil J.; Martin, Richard L.; Gordon, John C.
  Journal of the American Chemical Society (2014), 136 (9), 3505-3521CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The mechanism of catalytic hydrogenation of acetophenone by the chiral complex trans-[RuCl2{(S)-binap}{(S,S)-dpen}] and KO-t-C4H9 in propan-2-ol is revised on the basis of DFT computations carried out in dielec. continuum and the most recent exptl. observations. The results of these collective studies suggest that neither a six-membered pericyclic transition state nor any multibond concerted transition states are involved. Instead, a hydride moiety is transferred in an outer-sphere manner to afford an ion-pair, and the corresponding transition state is both enantio- and rate-detg. Heterolytic dihydrogen cleavage proceeds neither by a (two-bond) concerted, four-membered transition state, nor by a (three-bond) concerted, six-membered transition state mediated by a solvent mol. Instead, cleavage of the H-H bond is achieved via deprotonation of the η2-H2 ligand within a cationic Ru complex by the chiral conjugate base of (R)-1-phenylethanol. Thus, protonation of the generated (R)-1-phenylethoxide anion originates from the η2-H2 ligand of the cationic Ru complex and not from NH protons of a neutral Ru trans-dihydride complex, as initially suggested within the framework of a metal-ligand bifunctional mechanism. Detailed computational anal. reveals that the 16e- Ru amido complex [RuH{(S)-binap}{(S,S)-HN(CHPh)2NH2}] and the 18e- Ru alkoxo complex trans-[RuH{OCH(CH3)(R)}{(S)-binap}{(S,S)-dpen}] (R = CH3 or C6H5) are not intermediates within the catalytic cycle, but rather are off-loop species. The accelerative effect of KO-t-C4H9 is explained by the reversible formation of the potassium amidato complexes trans-[RuH2{(S)-binap}{(S,S)-N(K)H(CHPh)2NH2}] or trans-[RuH2{(S)-binap}{(S,S)-N(K)H(CHPh)2NH(K)}]. The three-dimensional (3D) cavity obsd. within these mols. results in a chiral pocket stabilized via several different noncovalent interactions, including neutral and ionic hydrogen bonding, cation-π interactions, and π-π stacking interactions. Cooperatively, these interactions modify the catalyst structure, in turn lowering the relative activation barrier of hydride transfer by ∼1-2 kcal mol-1 and the following H-H bond cleavage by ∼10 kcal mol-1, resp. A combined computational study and anal. of recent exptl. data of the reaction pool results in new mechanistic insight into the catalytic cycle for hydrogenation of acetophenone by Noyori's catalyst, in the presence or absence of KO-t-C4H9.
  (c) Nakatsuka, H.; Yamamura, T.; Shuto, Y.; Tanaka, S.; Yoshimura, M.; Kitamura, M. Mechanism of Asymmetric Hydrogenation of Aromatic Ketones Catalyzed by a Combined System of Ru(π-CH₂C(CH₃)CH₂)₂(Cod) and the Chiral Sp²N/Sp³NH Hybrid Linear N4 Ligand Ph-BINAN-H-Py. J. Am. Chem. Soc. 2015, 137, 8138– 8149, DOI: 10.1021/jacs.5b02350
  33c
  Mechanism of Asymmetric Hydrogenation of Aromatic Ketones Catalyzed by a Combined System of Ru(π-CH2C(CH3)CH2)2(cod) and the Chiral sp2N/sp3NH Hybrid Linear N4 Ligand Ph-BINAN-H-Py
  Nakatsuka, Hiroshi; Yamamura, Tomoya; Shuto, Yoshihiro; Tanaka, Shinji; Yoshimura, Masahiro; Kitamura, Masato
  Journal of the American Chemical Society (2015), 137 (25), 8138-8149CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The combination of a Goodwin-Lions-type chiral N4 ligand, (R)-Ph-BINAN-H-Py ((R)-3,3'-diphenyl-N2,N2'-bis((pyridin-2-yl)methyl)-1,1'-binaphthyl-2,2'-diamine; L), with Ru(π-CH2C(CH3)CH2)2(cod) (A) (cod = 1,5-cyclooctadiene) catalyzes the hydrogenation of acetophenone (AP) to (R)-1-phenylethanol (PE) with a high enantiomer ratio (er). Almost no Ru complex forms, with A and L remaining intact throughout the reaction while generating PE quant. according to [PE] = kobst2. An infinitesimal amt. of reactive and unstable RuH2L (B) with C2-Λ-cis-α stereochem. is very slowly and irreversibly generated from A by the action of H2 and L, which rapidly catalyzes the hydrogenation of AP via Noyori's donor-acceptor bifunctional mechanism. A CH-π-stabilized Si-face selective transition state, CSi, gives (R)-PE together with an intermediary Ru amide, D, which is inhibited predominantly by formation of the Ru enolate of AP. The rate-detg. hydrogenolysis of D completes the cycle. The time-squared term relates both to the preliminary step before the cycle and to the cycle itself, with a highly unusual eight-order difference in the generation and turnover frequency of B. This mechanism is fully supported by a series of expts. including a detailed kinetic study, rate law anal., simulation of t/[PE] curves with fitting to the exptl. observations at the initial reaction stage, X-ray crystallog. analyses of B-related octahedral metal complexes, and Hammett plot analyses of electronically different substrates and ligands in their enantioselectivities.
  (d) Dub, P. A.; Gordon, J. C. The Mechanism of Enantioselective Ketone Reduction with Noyori and Noyori–Ikariya Bifunctional Catalysts. Dalton Trans. 2016, 45, 6756– 6781, DOI: 10.1039/C6DT00476H
  33d
  The mechanism of enantioselective ketone reduction with Noyori and Noyori-Ikariya bifunctional catalysts
  Dub, Pavel A.; Gordon, John C.
  Dalton Transactions (2016), 45 (16), 6756-6781CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
  A review. The catalytic hydrogenation of prochiral ketones with second and third-row transition metal complexes bearing chelating chiral ligands contg. at least one N-H functionality has achieved unparalleled performance, delivering, in the best cases, chiral alcs. with up to 99.9% ee using extremely small catalyst loadings (∼10-5 mol%). Hence the efficacy of this reaction has closely approached that of natural enzymic systems and the reaction itself has become one of the most efficient artificial catalytic reactions developed to date. This article describes the current level of understanding of the mechanism of enantioselective hydrogenation and transfer hydrogenation of arom. ketones with pioneering prototypes of bifunctional catalysts, the Noyori and Noyori-Ikariya complexes. Anal. presented herein expands the concept of "metal-ligand cooperation", redefines the term "cooperative ligand" and introduces "H-/H+ outer-sphere hydrogenation" as a novel paradigm in outer-sphere hydrogenation.
  (e) Nakane, S.; Yamamura, T.; Manna, S. K.; Tanaka, S.; Kitamura, M. Mechanistic Study of the Ru-Catalyzed Asymmetric Hydrogenation of Nonchelatable and Chelatable Tert-Alkyl Ketones Using the Linear Tridentate Sp³P/Sp³NH/Sp²N-Combined Ligand PN(H)N: RuNH- and RuNK-Involved Dual Catalytic Cycle. ACS Catal. 2018, 8, 11059– 11075, DOI: 10.1021/acscatal.8b02671
  33e
  Mechanistic Study of the Ru-Catalyzed Asymmetric Hydrogenation of Nonchelatable and Chelatable tert-Alkyl Ketones Using the Linear Tridentate sp3P/sp3NH/sp2N-Combined Ligand PN(H)N: RuNH- and RuNK-Involved Dual Catalytic Cycle
  Nakane, Satoshi; Yamamura, Tomoya; Manna, Sudipta Kumar; Tanaka, Shinji; Kitamura, Masato
  ACS Catalysis (2018), 8 (12), 11059-11075CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  The linear tridentate sp3P/sp3NH/sp2N ligand PN(H)N ((R)-2'-(diphenylphosphino)-N-(pyridin-2-ylmethyl)[1,1'-binaphthalen]-2-amine) exclusively forms fac-[Ru(PN(H)N)(dmso)3](BF4)2 over the mer isomer with the help of the three strongly π-accepting DMSO ligands. The three different ligating atoms exert a divergent effect on the trans-DMSO-Ru bond strengths, enabling the stereoselective generation of fac-RuH(CH3O)(PN(H)N)(dmso) (RuNH). RuNH efficiently hydrogenates both nonchelatable t-Bu Me ketone (BMK) and chelatable t-Bu methoxycarbonylmethyl ketone (BMCK) in the presence of a catalytic amt. of CH3OK. The reaction proceeds at the H-sp3N-Ru-H bifunctional reaction site of fac-RuH2(PN(H)N)(dmso), and high enantioselectivity is attained in a chiral 3D cavity constructed by the sp3N trans DMSO, the conformation of which is fixed by a PyC(6)H-O=S hydrogen bond. We detd. the structures of RuNH, the K amide RuNK, Ru dihydride, and Ru amido species by detailed NMR anal. using 15N-labeled PN(H)N and C(3)-Ph-substituted PN(H)N. The rate of BMK hydrogenation is significantly affected by [CH3OK]0, showing a characteristic curve with a peak followed by a pseudo-minus-first-order decay. The RuNH is easily deprotonated by CH3OK to generate RuNK, which is less reactive but has the same enantioface discrimination ability. Increased contribution of the slow RuNK cycle decreases the rate at higher [CH3OK]0. The RuNH- and RuNK-involved dual catalytic cycle is supported by curve-fitting analyses and K+ trapping expts. In hydrogenation of BMCK, only the RuNH cycle operates because BMCK is preferentially deprotonated over RuNH.
34. 34
  For structures of all HT transition states in the reaction with borane 2 and related structural analysis, see the SI (section 2.5).
  There is no corresponding record for this reference.
35. 35
  The HT step of the catalytic cycle of im hydrogenation is an irreversible process. For the reaction with borane 2, the am + 2 product state is predicted to be 16.1 kcal/mol below the most favored imH⁺/2H.
  There is no corresponding record for this reference.
36. 36
  The nearly quantitative agreement between computed and observed ee values is no doubt fortuitous and cannot be regarded as a measure of accuracy of the applied computational methodology.
  There is no corresponding record for this reference.
37. 37
  For structures of all HT transition states in the reaction with borane 3 and related structural analysis, see the SI (section 2.6).
  There is no corresponding record for this reference.
38. 38
  For structures of all HT transition states in the reaction with borane 1 and related structural analysis, see the SI (section 2.7).
  There is no corresponding record for this reference.
39. 39
  The RDG data were computed by using the NCIPLOT program:
  (a) Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A. J.; Yang, W. Revealing Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132, 6498– 6506, DOI: 10.1021/ja100936w
  39a
  Revealing Noncovalent Interactions
  Johnson, Erin R.; Keinan, Shahar; Mori-Sanchez, Paula; Contreras-Garcia, Julia; Cohen, Aron J.; Yang, Weitao
  Journal of the American Chemical Society (2010), 132 (18), 6498-6506CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Mol. structure does not easily identify the intricate noncovalent interactions that govern many areas of biol. and chem., including design of new materials and drugs. We develop an approach to detect noncovalent interactions in real space, based on the electron d. and its derivs. Our approach reveals the underlying chem. that compliments the covalent structure. It provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small mols., mol. complexes, and solids. Most importantly, the method, requiring only knowledge of the at. coordinates, is efficient and applicable to large systems, such as proteins or DNA. Across these applications, a view of nonbonded interactions emerges as continuous surfaces rather than close contacts between atom pairs, offering rich insight into the design of new and improved ligands.
  (b) Contreras-García, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J.-P.; Beratan, D. N.; Yang, W. NCIPLOT: A Program for Plotting Non-Covalent Interaction Regions. J. Chem. Theory Comput. 2011, 7, 625– 632, DOI: 10.1021/ct100641a
  39b
  NCIPLOT: A Program for Plotting Noncovalent Interaction Regions
  Contreras-Garcia, Julia; Johnson, Erin R.; Keinan, Shahar; Chaudret, Robin; Piquemal, Jean-Philip; Beratan, David N.; Yang, Weitao
  Journal of Chemical Theory and Computation (2011), 7 (3), 625-632CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
  Noncovalent interactions hold the key to understanding many chem., biol., and technol. problems. Describing these noncovalent interactions accurately, including their positions in real space, constitutes a first step in the process of decoupling the complex balance of forces that define noncovalent interactions. Because of the size of macromols., the most common approach has been to assign van der Waals interactions (vdW), steric clashes (SC), and hydrogen bonds (HBs) based on pairwise distances between atoms according to their vdW radii. We recently developed an alternative perspective, derived from the electronic d.: the non-covalent interactions (NCI) index. This index has the dual advantages of being generally transferable to diverse chem. applications and being very fast to compute, since it can be calcd. from promol. densities. Thus, NCI anal. is applicable to large systems, including proteins and DNA, where anal. of noncovalent interactions is of great potential value. Here, we describe the NCI computational algorithms and their implementation for the anal. and visualization of weak interactions, using both self-consistent fully quantum-mech. as well as promol. densities. A wide range of options for tuning the range of interactions to be plotted is also presented. To demonstrate the capabilities of our approach, several examples are given from org., inorg., solid state, and macromol. chem., including cases where NCI anal. gives insight into unconventional chem. bonding. The NCI code and its manual are available for download at http://www.chem.duke.edu/∼yang/software.htm.
40. 40
  For details on the reaction with the simplified borane, see the SI (section 2.8).
  There is no corresponding record for this reference.
41. 41
  For details on computational analysis for hydrogenation reactions with boranes 2-F, 2-CF₃, 2-CH₃, 2-^tBu, and 2-ant, see the SI (section 2.9).
  There is no corresponding record for this reference.
42. 42
  For the influence of various substituents on the strength of CH···π interaction, see:
  Karthikeyan, S.; Ramanathan, V.; Mishra, B. K. Influence of the Substituents on the CH···π Interaction: Benzene–Methane Complex. J. Phys. Chem. A 2013, 117, 6687– 6694, DOI: 10.1021/jp404972f
  42
  Influence of the Substituents on the CH...π Interaction: Benzene-Methane Complex
  Karthikeyan, S.; Ramanathan, V.; Mishra, Brijesh Kumar
  Journal of Physical Chemistry A (2013), 117 (30), 6687-6694CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
  Recently we showed that the binding energy of the benzene...acetylene complex could be tuned up to 5 kcal/mol by substituting the hydrogen atoms of the benzene mol. with multiple electron-donating/electron-withdrawing groups. In continuation, we have here examd. the influence of various substituents on the CH...π interaction present in the benzene...methane complex using the CCSD(T) method at the complete basis set limit. The influence of multiple fluoro substituents on the interaction strength of the benzene...methane complex was found to be insignificant, while the interaction strength linearly increases with successive addn. of Me groups. The influence of other substituents such as CN, NO2, COOH, Cl, and OH was found to be negligible. The NH2 group enhances the binding strength similarly to the Me group. Energy decompn. anal. predicts the dispersion energy component to be on an av. three times larger than the electrostatic energy component. Multidimensional correlation anal. shows that the exchange-repulsion and dispersion terms are correlated very well with the interaction distance (r) and with a combination of the interaction distance (r) and molar refractivity (MR), while the electrostatic component correlates well when the Hammett const. is used in combination with the interaction distance (r). Various recently developed DFT methods were used to assess their ability to predict the binding energy of various substituted benzene...methane complexes, and the M06-2X, B97-D, and B3LYP-D3 methods were found to be the best performers, giving a mean abs. deviation of ∼0.15 kcal/mol.
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Origin of Stereoselectivity in FLP-Catalyzed Asymmetric Hydrogenation of IminesClick to copy article linkArticle link copied!

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Abstract

Introduction

Chart 1

Scheme 1

Results

Alternative Catalytic Cycles

Scheme 2

Figure 1

Iminium Borohydride Intermediates for Borane 2

Chart 2

Figure 2

Hydride Transfer Transition States for Borane 2

Figure 3

Reaction with Borane 3

Figure 4

Reaction with Borane 1

Figure 5

On the Origin of Stereoselectivity

Figure 6

Proposed Modifications in Borane 2

Figure 7

Experiments with Borane 2-F

Scheme 3

Figure 8

Experiments with Borane 2-tBu

Scheme 4

Figure 9

Summary and Conclusions

Supporting Information

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Acknowledgments

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Abstract

Chart 1

Scheme 1

Scheme 2

Figure 1

Chart 2

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Scheme 3

Figure 8

Scheme 4

Figure 9

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Origin of Stereoselectivity in FLP-Catalyzed Asymmetric Hydrogenation of Imines
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Experiments with Borane 2-^tBu