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Rationalizing and Adapting Water-Accelerated Reactions for Sustainable Flow Organic Processes
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Rationalizing and Adapting Water-Accelerated Reactions for Sustainable Flow Organic Processes
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  • Katarzyna A. Maltby
    Katarzyna A. Maltby
    Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
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  • Krishna Sharma
    Krishna Sharma
    Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
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  • Marc A. S. Short
    Marc A. S. Short
    Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
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  • Sannia Farooque
    Sannia Farooque
    Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
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  • Rosalie Hamill
    Rosalie Hamill
    Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
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  • A. John Blacker
    A. John Blacker
    Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
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    Orcidhttps://orcid.org/0000-0003-4898-2712
  • Nikil Kapur
    Nikil Kapur
    School of Mechanical Engineering, University of Leeds, Leeds LS2 9JT, U.K.
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    Orcidhttps://orcid.org/0000-0003-1041-8390
  • Charlotte E. Willans
    Charlotte E. Willans
    Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
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    Orcidhttps://orcid.org/0000-0003-0412-8821
  • Bao N. Nguyen*
    Bao N. Nguyen
    Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
    *Email: [email protected]
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ACS Sustainable Chemistry & Engineering

Cite this: ACS Sustainable Chem. Eng. 2023, 11, 23, 8675–8684
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https://doi.org/10.1021/acssuschemeng.3c02164
Published May 30, 2023

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Abstract

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Water-accelerated reactions, wherein at least one organic reactant is not soluble in water, are an important class of organic reactions, with a potentially pivotal impact on sustainability of chemical manufacturing processes. However, mechanistic understanding of the factors controlling the acceleration effect has been limited, due to the complex and varied physical and chemical nature of these processes. In this study, a theoretical framework has been established to calculate the rate acceleration of known water-accelerated reactions, giving computational estimations of the change to ΔG‡ which correlate with experimental data. In-depth study of a Henry reaction between N-methylisatin and nitromethane using our framework led to rationalization of the reaction kinetics, its lack of dependence on mixing, kinetic isotope effect, and different salt effects with NaCl and Na2SO4. Based on these findings, a multiphase flow process which includes continuous phase separation and recycling of the aqueous phase was developed, and its superior green metrics (PMI-reaction = 4 and STY = 0.64 kg L–1 h–1) were demonstrated. These findings form the essential basis for further in silico discovery and development of water-accelerated reactions for sustainable manufacturing.

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A theoretical and practical framework for predicting, rationalizing, and adapting water-accelerated reactions into holistically sustainable flow processes has been demonstrated.

1. Introduction

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Water is the reaction medium used by nature and has been touted as the ultimate sustainable reaction medium for chemical reactions. (1−3) Despite the obvious advantages, organic syntheses often avoid water, and significant research effort has been directed at finding acceptable alternative organic solvents to improve sustainability instead. This curious trend can be attributed to poor solubility of the majority of organic compounds in water, incompatibility of traditional reagents with water, and the challenges in treating organic contaminated waste water. (4) In this context, on-water reactions, i.e., organic reactions which take place as an emulsion in water and exhibit unusual rate acceleration compared to the same reaction in an organic solvent, (5,6) are particularly attractive. Furthermore, improvements in regio- and stereoselectivity have also been reported in some cases in water in comparison to reactions performed in organic solvents. (6−8) The advantages of on-water reactions are as follows: (i) they can be carried out in the water medium, even when the reactants are highly insoluble in water; (ii) rate acceleration under on-water conditions can lead to improved space-time-yield (STY); and (iii) simple and efficient purification of the product in high-yielding reactions.
Since the early discoveries by Breslow and Sharpless, (5,6) the past few decades have seen significant growth in the number of on-water reactions, some of which are synthetically useful. These have been well summarized and discussed in numerous reviews. (9−13) Despite, or perhaps because of, the very wide range of classes of reactions which are known to benefit from the on-water effect, e.g., pericyclic, (14,15) multicomponent, (16) nucleophilic ring-opening, (8,17,18) Mannich, (7) aldol, (19) Henry, (20) Lewis acid-catalyzed, (19) and organocatalytic reactions, (15,21) the mechanistic rationalization of their rate acceleration, which may guide the discovery of new on-water reactions, is still in its infancy. This is further confounded by the limited availability of reliable kinetic data (22−24) and the complex and variable phase behavior of these reactions (Figure 1), which may start off as “in water” and become “on water” as the reaction progresses or vice versa. (25)

Figure 1

Figure 1. Simplified phase complexity scenarios of water-accelerated reactions: (a) all reactants are insoluble in water; (b) one reactant is partially soluble in water; (c) reactants are phase-separated; and (d) one reactant is activated at the aqueous–organic interface.

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The water-acceleration effect has been attributed to the concentration increase in organic droplets, (26) polarity effect, (27,28) and stabilization of the transition state at the water–organic interface. (29) Some of these aspects are established, such as the dependence of the acceleration effect on droplet size/biphasic interfacial area. (30) Others are less well understood, e.g., stabilization of the transition state by hydrogen bonds in early ab initio/statistical and density functional theory (DFT) studies, (31−34) and conflicting salt effects. (6,22,23) In many cases, at least one reactant is partially soluble in water, rendering the strict “on-water reactions” definition invalid and the broader term “water-accelerated reactions”, which will be employed throughout this manuscript, more applicable. These and the lack of a theoretical framework for water-accelerated reactions have been major obstacles in the rational discovery of new and synthetically important reactions and their applications in syntheses.
In this study, we report our comprehensive computational and experimental study of a water-accelerated reaction, leading to a theoretical/practical framework that accounts for both the physical and chemical aspects of this reaction. The results consist of (i) a suitable modern molecular modeling method to study water-accelerated reaction; (ii) the application of such a method for rationalizing conflicting kinetic observations of an example reaction; and (iii) the practical application of mechanistic insights, solubility, and phase behaviors to adapt this example reaction into a multiphase flow process with excellent green metrics by successfully recycling the aqueous phase.

2. Experimental Section

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All experiments were performed at pH 7, verified by measurements with Mettler Toledo SevenExcellence S400.

2.1. Materials

All solvents and reagents were purchased from Sigma-Aldrich UK and used without further purification. Solvents were of HPLC standard.

2.2. Standard Protocol for Henry Reaction

The reactions were heated and stirred (1 cm × 1 cm cross-bar stirrer) on a custom-made heating block with 1 in. offset stirring. Reactions were carried out in 4-dram glass vials (2.1 × 7 cm, 14 mL) sealed with a lid (PTFE septum) unless stated otherwise.
Methylisatin 1 (0.0806 g, 0.5 mmol) was added to a 4-dram vial (2.1 × 7 cm) equipped with a cross-bar stirrer (1 cm × 1 cm) followed by nitromethane (812 μL, 15 mmol). After 5 min, deionized water (3 mL) was added, and the sample tube was sealed with a lid and heated to 70 °C at 700 rpm. After 3 h, the reaction mixture was extracted with ethyl acetate (10 mL) to afford the product 2 as pale-yellow oil (0.1077 g, 97%).

2.3. Reactions in the Presence of Different Salts

The reactions were performed in deionized water, 1 M NaCl, 1 M LiCl, 1 M Na2SO4, and 0.1 M phosphate buffer at pH 7. Reactions were done separately, worked up, and analyzed by 1H NMR for the kinetic data. Methylisatin 1 (0.0806 g, 0.5 mmol) was added to the 4-dram vials (2.1 × 7 cm) separately equipped with cross-bar stirrers (1 × 1 cm) followed by nitromethane (812 μL, 15 mmol). After 5 min, the relevant aqueous additive (3 mL) was added, and the sample tube was sealed with a lid and heated to 70 °C at 700 rpm. The facile reaction on phosphate buffer was done at room temperature to allow kinetic analysis. After a specific time, the reaction mixtures were extracted with ethylacetate and dried (MgSO4), and the solvent was evaporated to afford the product as pale-yellow oil.

2.4. Recycling of the Aqueous Phase in Batch

Methylisatin 1 (51 mg; 0.317 mmol) and nitromethane (0.42 mL; 7.925 mmol) were placed in a reaction vial (OD: 2.1 cm; H: 7 cm) with a PTFE septum lid. When methylisatin dissolved fully in nitromethane, 3 mL of water or 0.1 M phosphate buffer at pH 7 was added, and the reaction vial was placed in a custom-made aluminum heating block with 1 in. offset stirring. The reaction was stirred using a magnetic stirrer (1 cm × 1 cm cross-bar stirrer). Each reaction was left for 3 h to react at 70 °C. Due to issues with phase separation, the sample was left at room temperature with no stirring overnight to reach complete separation; then, the aqueous phase was separated using 1 mL plastic syringe with a stainless-steel needle. A sample of the organic phase was dissolved in CDCl3 and analyzed via 1H NMR using ratios of aromatic signals.

2.5. Flow Experiments

Flow experiments were performed in commercially available continuous stirred tank reactors (CSTRs, fReactors, Asynt) with a membrane phase separator (Zaiput SEP-10) using hydrophobic membrane OB-900-S10 (if syringe pumps used) or OB-2000-S10 (piston recirculation pumps). The setup is shown in Figure 6.
The reactants were delivered to the reactors using syringe/syringe pumps with two streams: (i) N-methylisatin 1 and trimethoxybenzene (internal standard) dissolved in nitromethane and (ii) 0.1 M aqueous phosphate buffer. PTFE tubing was used for all connections (external diameter 1/8″ and internal diameter 1/16″). A cascade of three mini-CSTR fReactors was used, each fReactor was equipped with a 1 cm × 1 cm cross-bar stirrer, and the overall volume was 4.8 mL (excluding tubing between reactors). Temperature was measured with a thermocouple type J and a handheld temperature reader.
The standard experimental conditions are as follows: 0.48 mL/min overall flow rate (0.24 mL/min flow rate of each phase), 10 min residence time, 40 °C, 850 rpm, 0.121 g of methylisatin, and 6 mg of trimethoxybenzene in 1 mL of nitromethane. Samples for analysis were taken from the organic phase of reaction after phase separation (about 2 drops of the organic phase dissolved in about 0.6 mL of CDCl3), and yields/conversions were calculated via 1H NMR.

2.6. Characterization

Nuclear magnetic resonance (NMR) spectra were recorded for 1H at 400 and 500 MHz and 13C at 100 and 125 MHz on a Bruker DPX400 or DRX500 spectrometer. A Bruker DRX 500 spectrometer was equipped with a multinuclear inverse probe for one-dimensional 1H and two-dimensional heteronuclear single-quantum coherence (1H–13C HSQC), heteronuclear multiple bond correlation (1H–13C HMBC), and double quantum filtered correlation (1H–1H COSY). Chemical shifts (δ) are quoted in ppm downfield of tetramethylsilane or residual solvent peaks (7.26 and 77.16 ppm for CDCl3 in 1H and 13C, respectively). The coupling constants (J) are quoted in Hz (multiplicities: s, singlet; bs, broad singlet; d, doublet; t, triplet; and q, quartet, and apparent multiplicities are described as m).
High-resolution mass spectroscopy (HRMS) spectra were recorded on a Dionex Ultimate 3000 spectrometer using electron spray ionization (ESI). All masses quoted are correct to four decimal places. Infrared (IR) spectra were recorded using a PerkinElmer Spectrum One FT-IR spectrophotometer or Bruker Alpha Platinum AR FTIR. Vibrational frequencies are reported in wavenumbers (cm–1).
HPLC was carried out on Agilent 1290 infinity series, equipped with a diode-array detector (DAD), binary pump system connected with online degasser, and Zorbax Eclipse XDB C18, 150 × 4.6 mm, 5 μm, column. The flow rate and the injection volume were 1 mL/min and 10 μL, respectively. The chromatograms were recorded by scanning the absorption at 190–600 nm.

3. Results and Discussion

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Experimental investigations into solvent and salt effects were performed for a previously published Henry reaction (Table 1, Scheme 1, and Figure 2b). (35) This reaction was chosen due to its established water-accelerated nature (35) and its well-understood mechanism in organic solvents. The reaction has a two-step mechanism, partial solubility of one reactant in water, i.e., nitromethane, and a likely enolization step at the organic–water interface [scenario (d) in Figure 1]. Complete consumption of N-methylisatin (1) was observed in 3 h under water-accelerated conditions when 25 equiv of nitromethane was used. No dehydration product was observed by 1H NMR, due to the neutral reaction conditions. The reaction did not proceed in dichloromethane, ethanol, and a mixture of ethanol and water. No reaction was observed when no solvent was added.
Table 1. Influence of Reaction Conditions on Henry Reactiona,b
no.solvent/mediumareaction time (h)yield (%, 1H NMR)
1none80
21,2-dichloroethane180
3EtOH180
4EtOH/H2O 9:1180
5H2O (pH 7)398
a

Typical reaction conditions: N-methylisatin (0.317 mmol), nitromethane (7.925 mmol, 25 equiv), solvent (3 mL), 70 °C, and 800 rpm stirring rate with a BRAND crosshead magnetic stirrer (10 mm span), in sealed 14 mL dram vials (OD 22 mm) and custom aluminum heating blocks (see the Supporting Information).

b

Measured with a pH probe.

Scheme 1

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Figure 2

Figure 2. Dependence of the water-accelerated Henry reaction on reaction conditions: (a) kinetic isotope effect; (b) salt effects by NaCl 1 M, LiCl 1 M, Bu4NCl 1 M, Na2SO4 1 M (70 °C), and phosphate buffer 0.1 M at pH 7 (22 °C), error bars are excluded for clarity; and (c) effect of temperature (color), stirring rate (dot size), excess nitromethane, and amount of 1 on reaction yield at 1 h.

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Kinetic profiling of the reaction with 1H NMR showed zero-order kinetics in [1] with excess nitromethane (Figure 2). When D2O was used instead of water, a kinetic isotope effect of kH2O/kD2O=2.41 was observed (Figure 2a), indicating that a proton transfer is involved in the rate-determining step (RDS). In contrast to the beneficial hydrophobic effect reported by Breslow with the addition of LiCl salt, (6) different effects were observed in this study. When NaCl 1 M, LiCl 1 M, or Bu4NCl 1 M solutions were used as reaction medium, a common and similar decrease in reaction rate was observed (Figure 2b). This effect can be attributed to the salting-out effect, (36) i.e., the decrease in solubility of nitromethane in water due to increased ionic strength, which highlights the need for enolization of nitromethane in the aqueous phase. Measurement of solubility of nitromethane at 70 °C by 1H NMR showed a decrease from 17.1 ± 0.7% w/w in deionized water to 12.9 ± 0.7% w/w in NaCl 1 M. The presence of phosphate buffer 0.1 M at pH 7 led to >20 times acceleration in reaction rate, (37) consistent with well-documented phosphate-catalyzed proton transfers. (38,39) Another salt which showed an unexpected catalytic effect, albeit less pronounced, was Na2SO4. The only related example in the literature is where a change of selectivity was observed between Na2SO4 and NaOTs as salt additives reported by Sela and Vigalok in a Passerini-type multicomponent reaction. (40) Additionally, the solubility of nitromethane in Na2SO4 1 M solution showed an even further decrease to 6.8 ± 0.2% w/w without compromising the acceleration of reaction rate. Thus, the observed acceleration of the reaction in Na2SO4 1 M compared to deionized water cannot be easily explained.
A design of experiments (DoE) was performed to investigate the importance of stirring, temperature, and reactant amount on the reaction yield in 1 h (Figure 2c). Different stirring rates (300–1400 rpm), 1 in. off-center, did not affect the yield of reaction, in contrast with observations by Huck. (41) Temperature was found to have the most significant impact on the reaction yield, suggesting that the RDS is chemical in nature rather than mass transfer at the water–organic interface. Molar equivalents of nitromethane did not affect reaction yield at 50 and 70 °C. Observations at 90 °C can be difficult to interpret close to the nitromethane boiling point (101.2 °C).
This reaction presents a series of unusual behaviors which are not readily explained and is therefore an excellent case study to validate our computational method. These behaviors are (i) the need for water-accelerated conditions; (ii) the low impact of stirring rate; and (iii) the counterintuitive salt effect of Na2SO4.

3.1. Comparison of Computational Methods for Water-Accelerated Reactions

A reliable in silico technique for the discovery of water-accelerated reactions, via decreases in activation energy, is an important enabling technology. While DFT studies showing stabilization of transition states through the inclusion of explicit water molecules in nucleophilic substitution, cyclocondensation, and Claisen rearrangement are known, (42−45) purposeful modeling of water-accelerated reactions is rare. The most recent study was carried out by Jung and Marcus in 2007, using a relatively low-level method and basis set, i.e., B3LYP/6-31+G(d), given the importance of hydrogen-bond-stabilized transition states in these reactions. (31) Thus, we compared several molecular modeling methods for predicting ΔG‡ and the water-induced change in activation energy barriers (via inclusion of explicit water molecules) of three known water-accelerated reactions with experimental data. (5) These methods are PM6-D3H4, B3LYP/6-31+G(d,p), M06-2x/def2-SVP, wB97X-D/def2-TZVP, and wB97X-D/ma-def2-TZVP (Supporting Information, Section S2.5). Attempts at using more accurate DFT and wavefunction methods, e.g., wB97X-V and DLPNO-CCSD(T), were unsuccessful due to the large size and multi-fragment nature of the transition states. The use of very diffuse basis sets (def2-TZVPD and aug-cc-pVTZ) led to basis set near-linear dependencies and failed self-consistent field convergence. (46) In each case, the activation energies are calculated in toluene and toluene with explicit water molecules. The results indicated that only methods M06-2x/def2-SVP, wB97X-D/def2-TZVP, and wB97X-D/ma-def2-TZVP produced the decreases in ΔG‡ which follow the trend observed experimentally in these reactions. However, the calculated value of ΔG‡ for the cycloaddition reaction using wB97X-D/ma-def2-TZVP was too high (35.4 kcal mol–1), given that it only takes 10 min to reach completion at 23 °C. In addition, the CPU time required for M06-2x/def2-SVP optimization of transition states is normally an order of magnitude lower compared to that of wB97X-D/ma-def2-TZVP in potential high-throughput in silico screening. Similar observations have also been reported for calculations of intermolecular interactions. (47) Thus, M06-2x/def2-SVP was taken forward as the method of choice for studying water-accelerated organic reactions.

3.2. Computational Studies of Water-Accelerated Henry Reaction

The M06-2x/def2-SVP method was applied to the reaction between 1 and nitromethane. Due to the reaction conditions with excess nitromethane, a conductor-like polarizable continuum model (CPCM) solvent model of nitromethane was used with explicit water molecules. For a reaction in an organic solvent, the CPCM solvent model of ethanol with explicit ethanol molecules was used to provide the pre-requisite proton for enolization (Table 1, entries 3 and 5). A two-step mechanism was identified, with step 1 being the enolization of nitromethane into its nucleophilic form 3 and step 2 being the nucleophilic attack on 1 (Figure 3a). Under water-accelerated conditions, step 1 is the RDS with ΔG‡ = 30.7 kcal mol–1 (TS1w). Analysis of the HOMO of TS2w showed the expected interaction between the HOMO of the enolized nitromethane and the LUMO of ketone 1 (see Supporting Information, Figure S22) The reaction in ethanol resulted in an increase of 2.7 kcal mol–1 in ΔG‡ (TS2EtOH) and a switch of the RDS to step 2. Both TS1EtOH and TS2EtOH are higher in energy than TS1w and TS2w, as ethanol is a better hydrogen bond acceptor than the donor compared to water, leading to less stabilization of the proton transfer transition states. (48) However, the majority of the increase in activation energy comes from TS2EtOH. While TS2w is stabilized with three H-bonds to the water molecules, only two of those H-bonds are possible with ethanol in TS2EtOH. Close examination of the distances of the forming C–C bond in TS2EtOH (C···C 2.263 Å) and TS2w (C···C 2.252 Å) indicated a later transition state under water-accelerated conditions, which correspond to a lower ΔG‡. These computational results are consistent with our experimental observations, with a significant decrease in activation energy barrier when switching from the ethanol solvent to water-accelerated conditions (Table 1). The identification of step 1 as the RDS under water-accelerated conditions is also in agreement with the zero-order kinetics of the reaction in [1].

Figure 3

Figure 3. Energy profile of Henry reaction under (a) water-accelerated conditions, or in ethanol, and (b) in the presence of HSO4–.

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Importantly, the calculated mechanism under water-accelerated conditions provides rationalization for the observed strong dependence on temperature and the low dependence on stirring rate. An activation energy barrier of 30.7 kcal mol–1 is generally considered high enough to prevent significant conversion at room temperature. Thus, elevated temperature, e.g., 70 or 90 °C, is required. As the reaction is intrinsically limited in rate, increasing mass transfer and organic/aqueous surface area by increasing stirring rate has a limited impact on the reaction rate.
Based on the identification of step 1 as the RDS under water-accelerated conditions and the observed rate acceleration with phosphate buffer 0.1 M at pH 7, it was hypothesized that Na2SO4, which is better than NaCl at salting-out nitromethane from the aqueous phase, (36) may also catalyze step 1 as a proton transfer catalyst. The active catalytic form HSO4– has the pre-requisite proton and is present in very low concentration at pH 7 (pKa = 1.92). (49) Thus, M06-2x/def2-SVP was used to calculate the reaction pathway with HSO4– as the proton transfer catalyst in place of water molecules.
The results of this calculation showed large decreases of 8.9 and 6.7 kcal mol–1 in the activation energy barrier for step 1 and step 2, respectively (Figure 3b, TS2HSO4 still has a small second imaginary frequency of 25.6 cm–1 after exhaustive optimization). Examination of the natural bond orbital (NBO) charges showed a lesser build-up of charges on the enolized form of nitromethane in TS1HSO4 (C −0.246 and N 0.266) compared to those in TS1w (C −0.282 and N 0.274, Figure 4). The same trend was observed for TS2HSO4 (O2N–C −0.001 and C═O −0.248) and TS2w (O2N–C 0.024 and C═O −0.308). These contributed to the lower energies of TS1HSO4 and TS2HSO4. Importantly, when an additional molecule of water was included in step 2 with HSO4–, no transition state was found. Instead, all attempts at finding the transition state optimized directly to the final product. Thus, it is likely that step 2 is barrierless under water-accelerated conditions with Na2SO4 1 M, leaving step 1 as the RDS. The very significant decrease in ΔG‡ of the reaction is partially countered by the low concentration of HSO4– (∼10–5 M at pH 7) and provides a rationale for the observed rate enhancement of the reaction in Na2SO4 1 M. This computational explanation was experimentally verified. A reaction performed in NaHSO4 × 10–5 M was found to reach 94% conversion in 10 min. Increasing the concentration of Na2SO4 from 1 to 2 M also led to an increase in yield from 38 to 93% at 10 min of reaction time. This is the first reported example of Na2SO4 acting as a proton transfer pre-catalyst.

Figure 4

Figure 4. Natural bond orbital (NBO) charge distribution analysis of the transition states TS1w, TS2w, TS1HSO4, and TS2HSO4.

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3.3. Sustainable Flow Process for Water-Accelerated Henry Reaction

To achieve sustainable processes with water-accelerated reaction, recycling of the aqueous phase is essential. Consequently, a continuous process with in-line phase separation and aqueous phase recycling was envisioned. Theoretical calculation suggested a possible decrease in PMI-reaction (process mass intensity of reaction) metrics from 33 in the literature batch protocol (method A, Table 2) to 8 in flow (with 25 equiv of nitromethane), (35) if the aqueous phase can be recycled at least 15 times (see Supporting Information, Section S1.11). Full-process PMI including work-up for flow processes can be highly dependent on scale, and prior studies have sometimes excluded work-up from its calculation. (50,51) Thus, PMI-reaction, which excludes evaporation of nitromethane to isolate the product, will be used in this study for consistency. (52) To circumvent traditional extraction, which suffers from slow phase separation and requires an additional amount of organic solvent, a membrane-enabled continuous phase separation using a Zaiput device was selected. (53)
Table 2. Comparison of Input Materials in Batch and Batch/Flow Protocolsa
method1 (g)MeNO2 (mL)aqueous phase (mL)breaction time (min)PMI/PMI-reaction
A0.0810.113c3033
B0.2252.13c,d180c/10d17c,e/16d,e
C0.0510.420.42d1014
D18.715512d1010
E16.65013d204
a

Method A: literature batch protocol at room temperature; (35) method B: DoE-optimized batch protocol with recycling of the aqueous phase; method C: batch protocol using a 1:1 phase ratio at 40 °C, no recycling; method D: flow protocol using 25 equiv of nitromethane at 40 °C with continuous aqueous phase recycling (13 cycles); and method E: flow protocol using 9 equiv of nitromethane at 40 °C with continuous aqueous phase recycling (4 cycles).

b

Including top-up water/buffer solution.

c

Using water.

d

Using 0.1 M phosphate buffer pH 7.

e

Calculated for batch protocols with recycling of water (at 70 °C) or 0.1 M phosphate buffer (25 °C), 5 cycles.

Initial water recycling studies in batch, based on conditions developed via DoE (method B, Table 2), showed no changes to reaction yield in up to 5 cycles (Figure 5a). The 3 h reaction time in water at 70 °C was considered too long for flow. Thus, a 0.1 M phosphate buffer was used instead of water, and the temperature was kept at 25 °C to give a reaction time of 10 min for up to 100% yield (method B, Table 2). Again, there was no change in reaction yield after recycling the buffer solution 5 times (Figure 5a). However, phase separation post-reaction was slow, taking up to 16 h to fully separate when water was used. When a 1:1 phase ratio was employed (method C), the temperature was increased to 40 °C to maintain a reaction time of 10 min, giving the same yield. A small amount (∼3%) of a new side product, 4 (Figure 7), was detected at this stage, due to contamination of isatin in a new commercial batch of starting material 1. Prolonged exposure of either 1 or 2 to the reaction conditions did not result in any formation of 4, ruling out a demethylation reaction.

Figure 5

Figure 5. (a) Reaction yields with recycling of the aqueous phase in batch, orange bar depicting yield with water as the aqueous phase and green bar depicting yield with 0.1 M phosphate buffer pH 7 as the aqueous phase. Reaction conditions: 51 mg of 1, 0.42 mL of nitromethane, 3 mL of aqueous phase recycled up to 5 times, 850 rpm, 70 °C (water), 25 °C (phosphate buffer), 3 h (water), 10 min (phosphate buffer). (b) Kinetic profile of Henry reaction in batch at a 1:1 phase ratio using 25 equiv (●) or 9 equiv (■) of nitromethane. Reaction conditions: 0.42 mL solution of 1 in nitromethane with 5 mol % trimethoxybenzene as an internal standard [(●) 0.121 g 1/1 mL; (■) 0.331 g 1/1 mL], 0.42 mL of 0.1 M phosphate buffer, 40 °C, 850 rpm, 0–25 min.

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Flow experiments were performed using a cascade of three mini-CSTRs named fRreactors (Figure 6). (54) These fReactors have proven effective at carrying out multiphase reactions with longer reaction times in continuous flow, where reproducible mixing can be important in process control. A phase ratio of 1:1 (v/v) was used to improve the phase separation using the Zaiput membrane separator. These changes also improved the productivity of the process and provided a satisfactory mass balance. When higher aqueous–organic phase ratios were used, a lower yield of product was observed, which was attributed to partial solubility of 1, nitromethane, and product 2 in the aqueous phase.

Figure 6

Figure 6. Flow process diagram including the continuous recycling of the aqueous phase.

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Initial flow experiments employed a residence time of 10 min using 3× fReactors with a total reactor volume of 4.8 mL, at a combined 0.48 mL min–1 flow rate. Multiphase mixing is very poor inside normal 1/8 in. PTFE tubing, and thus, the reaction was considered complete after the CSTRs. Various PTFE hydrophobic and hydrophilic membranes from Zaiput were tested for phase separation. For a lower aqueous to organic phase ratio (1:1), the hydrophobic membrane was required, and the pore size was selected based on the type of pump used. The best results were obtained with OB-900-S10 (for syringe pumps) and OB-2000-S10 (for diaphragm/rotary piston pumps). At higher aqueous to organic phase ratios (up to 7:1), the hydrophilic membrane IL-900-S10 was used with good separation and without breakthrough. The separated aqueous phase, which contains partially dissolved nitromethane, 1, and 2, was recycled through a reservoir, using a recirculation pump (Figure 6).
The output of the flow process was analyzed by 1H NMR, showing a stable composition of 1, 2, and 4, with an average yield of 85.5 ± 1.4% over 11 h, which corresponds to 13 cycles of aqueous phase recycling (12 mL at 0.24 mL min–1 flow rate) and a very high space-time-yield (STY) of 0.47 kg L–1 h–1 (method D, Table 2 and Figure 7a). However, partial solubility of water in nitromethane led to a gradual loss of the aqueous phase (initially 9 mL) over time. Thus, the aqueous phase was topped-up at 4.5 h (2 mL) and 8 h (1 mL). The PMI-reaction value for the process over 11 h was calculated as 10. This is slightly above the optimal theoretical value 8 due to our experiment being stopped at 13 cycles and the need for top-up of the aqueous phase.

Figure 7

Figure 7. Yields and mass balance of flow processes with continuous aqueous phase recycling using (a) 0.121 g of 1 per 1 mL CH3NO2 and (b) 0.3331 g of 1 per 1 mL CH3NO2. (▲) Molar fraction of 1; (■) molar fraction of product 2; (●) molar fraction of side product 3; and (▼) total mass balance.

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To further improve the sustainability of the process, the amount of 1 was increased to reduce the nitromethane/1 ratio from 25 to 9, while maintaining the same aqueous–organic phase ratio of 1:1. The 1:9 molar ratio between 1 and nitromethane is the solubility limit of 1 in nitromethane at room temperature. Furthermore, reducing the amount of hazardous nitromethane is an important consideration for the greenness of the process. This change led to an increased reaction time of 20 min in both batch and the fReactors (Figure 5b), due to the zero-order kinetics of the reaction. The aqueous phase was topped-up at 3.5 h (0.5 mL) and 5.5 h (0.5 mL). The flow process worked well and gave an average yield of 94.4 ± 0.5% (no further purification other than solvent evaporation was required) and an STY of 0.64 kg L–1 h–1 over 7 h (method E, Table 2 and Figure 7b). This consists of 4 cycles (13 mL at 0.12 mL min–1 flow rate), giving an impressive PMI-reaction value of 4. As a comparison, typical organic syntheses in industry have an average PMI value of 10–20 per step, with a significant contribution from organic solvents as reaction and purification media. (55) These can be readily minimized in processes based on water-accelerated reactions.

4. Conclusions

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We report in this manuscript a comprehensive computational and experimental framework for studying, rationalizing, and applying water-accelerated reactions in sustainable processes. These are complex phenomena which are influenced by many factors, e.g., phase behaviors, mass-transfer/mixing, solubility, and water-stabilized transition states, and can display different responses to external stimuli, depending on the complex physical and chemical aspects of the system. For the water-accelerated Henry reaction between N-methylisatin 1 and nitromethane, a combination of phase behaviors, solubility, and modern DFT modeling with explicit water molecules provided an excellent rationalization for (i) the rate acceleration under water-accelerated conditions; (ii) the low impact of stirring rate; (iii) and the unexpected rate acceleration effect of Na2SO4 as the source of a proton transfer catalyst. Importantly, we demonstrated the sustainability of continuous processes employing water-accelerated reactions when optimized for recycling of the aqueous phase, enabled by continuous phase separation. No degradation of yield and purity profile was observed when the aqueous phase was recycled up to 13 times. The use of multiphase flow reactors with excellent mixing led to exceptional sustainability metrics (STY = 0.64 kg L–1 h–1 and PMI-reaction = 4). The experimental and theoretical framework reported here will underpin the future discovery and development of this important class of reactions into sustainable manufacturing processes.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acssuschemeng.3c02164.

  • Experimental procedures and calculations of green metrics and DFT computational details (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Katarzyna A. Maltby - Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
    • Krishna Sharma - Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
    • Marc A. S. Short - Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
    • Sannia Farooque - Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
    • Rosalie Hamill - Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
    • A. John Blacker - Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.;  Orcidhttps://orcid.org/0000-0003-4898-2712
    • Nikil Kapur - School of Mechanical Engineering, University of Leeds, Leeds LS2 9JT, U.K.;  Orcidhttps://orcid.org/0000-0003-1041-8390
    • Charlotte E. Willans - Institute of Process Research & Development, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.;  Orcidhttps://orcid.org/0000-0003-0412-8821
  • Author Contributions

    K. A. M. performed the water recycling and flow experiments and the solubility measurements for nitromethane. S. F. performed initial kinetic studies and DoE experiments. R. H. planned the DoE experiments and processed the collected data. K. S. and M. S. performed the computational studies. B. N. N., A. J. B., C. E. W., and N. K. supervised and provided direction for the project. All authors have given approval to the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was undertaken on ARC3 and ARC4, part of the High-Performance Computing facilities at the University of Leeds, UK. R.H. thanks AstraZeneca and the EPSRC for her CASE studentship. M.S. thanks the CCDC for its support in his studentship. K.S., K.A.M., S.F., A.J.B., N.K., and B.N.N. thank the EPSRC for its support through grant number EP/S013768/1.

Abbreviations

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PMI

process mass intensity

RDS

rate-determining step

DFT

density functional theory

CSTR

continuous stirred tank reactor

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    Catalyst-Free "On-Water" Regio- and Stereospecific Ring-Opening of Spiroaziridine Oxindole: Enantiopure Synthesis of Unsymmetrical 3,3'-Bisindoles
    Hajra, Saumen; Singha Roy, Somnath; Aziz, Sk Mohammad; Das, Dhiraj
    Organic Letters (2017), 19 (15), 4082-4085CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A catalyst-free water-mediated regio- and stereospecific ring-opening reaction of nonracemic spiroaziridine oxindoles and indoles has been developed with retention of configuration. This method provides direct access to enantiopure 3,3'-mixed bisindoles with excellent yield and enantioselectivity (up to 98% ee).
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    Kitanosono, T.; Kobayashi, S. Toward Chemistry-Based Design of the Simplest Metalloenzyme-Like Catalyst That Works Efficiently in Water. Chem.─Asian J. 2015, 10, 133– 138,  DOI: 10.1002/asia.201403004
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    Toward Chemistry-Based Design of the Simplest Metalloenzyme-Like Catalyst That Works Efficiently in Water
    Kitanosono, Taku; Kobayashi, Shu
    Chemistry - An Asian Journal (2015), 10 (1), 133-138CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors describe the design of small mols. that act as the simplest metalloenzyme-like catalysts that can function in water without mimicking enzyme structures. These artificial catalysts, e.g., Sc(OTf)3 and I, efficiently promoted enantioselective direct-type aldol reactions using aq. formaldehyde. The reactions followed Michaelis-Menten kinetics; and heat-resistant asym. environments were constructed in water.
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  20. 20
    Du, Z.-H.; Da, C. S.; Yuan, M.; Tao, B. X.; Ding, T. Y. Efficient Catalyst-Free Henry Reaction between Nitroalkanes and Aldehydes or Trifluoromethyl Ketones Promoted by Tap Water. Synthesis 2022, 54, 5461– 5470,  DOI: 10.1055/a-1933-3709
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    Efficient Catalyst-Free Henry Reaction between Nitroalkanes and Aldehydes or Trifluoromethyl Ketones Promoted by Tap Water
    Du, Zhi-Hong; Yuan, Meng; Tao, Bao-Xiu; Ding, Tie-Ying; Da, Chao-Shan
    Synthesis (2022), 54 (24), 5461-5470CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
    The first examples of highly effective Henry reactions between nitroalkanes and aldehydes or trifluoromethyl ketones that proceed under catalyst-free and additive-free conditions, in a recyclable tap water medium, and at room temp. was reported. This process tolerated a broad range of aldehydes and trifluoromethyl ketones to give a series of β-nitro alc. products in excellent yields. Such products are widely used in the syntheses of pharmaceutical intermediates and natural products. This protocol can be successfully scaled up to a 50-mmol scale without a redn. in yield. Tap water from different locations in China exhibited pH values ranging from 7.5 to 8.1, but the varying pH had no effect on the yield and the processes were successfully reproduced. Finally, the tap water was effectively recovered and reused without any post processing, even when the reaction substrates were different.
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    Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. Organocatalytic Direct Asymmetric Aldol Reactions in Water. J. Am. Chem. Soc. 2006, 37, 734,  DOI: 10.1002/chin.200624079
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    Butler, R. N.; Coyne, A. G. Understanding “On-Water” Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen Cycloadditions. J. Org. Chem. 2015, 80, 1809– 1817,  DOI: 10.1021/jo502732y
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    Understanding "On-Water" Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen Cycloadditions
    Butler, Richard N.; Coyne, Anthony G.
    Journal of Organic Chemistry (2015), 80 (3), 1809-1817CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    For a typical Huisgen cycloaddn., carried out on water, the behavior of water mols. at the oil-water interface depended on the properties of the reactants. With weakly basic reactants, a small quantity of added H+ (HClO4, 0.0001-0.01 M) present in the aq. phase had negligible effects, but larger quantities of H+ (HClO4, 0.1-3.0 M) increased the catalytic effect and caused protons to cross the water-org. interface and affect the products. Added Li+ ions (LiClO4, 0.1-3.0 M) had no effect for on-water reactions but enhanced the rates and endo products for in-water reactions. For these cycloaddn. reactions, the product endo:exo ratios, when compared to those in org. solvents, can be used to distinguish between the on-water and in-water modes. Comparisons of org. reactions on H2O and on D2O indicate that on-water catalysis ranges from weak to strong trans-phase H-bonding for reactants with basic pKa < ca. -6 and to interfacial proton transfer for reactants with higher basic pKa > ca. 2 (pKa of conjugate acid). Water shows a chameleon-type response to org. mols. at hydrophobic surfaces.
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    Tiwari, S.; Kumar, A. Unusual Temperature Dependence of Salt Effects for “on Water” Wittig Reaction: Hydrophobicity at the Interface. Chem. Commun. 2008, 37, 4445– 4447,  DOI: 10.1039/B809127G
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    Bae, H. Y.; Song, C. E. Unprecedented Hydrophobic Amplification in Noncovalent Organocatalysis “on Water”: Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to Nitroalkenes. ACS Catal. 2015, 5, 3613– 3619,  DOI: 10.1021/acscatal.5b00685
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    Unprecedented Hydrophobic Amplification in Noncovalent Organocatalysis "on Water": Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to Nitroalkenes
    Bae, Han Yong; Song, Choong Eui
    ACS Catalysis (2015), 5 (6), 3613-3619CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    In this study, water was demonstrated to be an exceptionally efficient reaction medium for the noncovalent, hydrogen-bonding-promoted enantioselective Michael addn. of malonates to diverse nitroolefins using cinchona-based squaramide catalysts. A significant increase in the reaction rate was obsd. when the reaction was performed "on water" rather than in the conventional org. solvents, because of the hydrophobic hydration effect. This hydrophobic amplification was significantly dependent upon the hydrophobicity of the C3-substituent (vinyl or ethyl) of cinchona-based catalysts. Thus, the use of more hydrophobic catalyst with an Et group at the C3-position, even a highly challenging Michael donor such as di-Me methylmalonate was also smoothly converted to the desired adduct. Furthermore, because of the remarkable rate acceleration under "on water" conditions, the catalyst loading also significantly decreased. Thus, in the case of β-ketoesters, even 0.01 mol % of catalyst loading was enough to complete the reaction at room temp., affording the corresponding Michael adducts with perfect diastereo- and enantioselectivity (up to >99:1 d.r., up to 99% ee). The developed "on water" protocol was successfully applied for the scalable syntheses of an antidepressant (S)-rolipram and an anticonvulsant (S)-pregabalin.
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    Butler, R. N.; Coyne, A. G. Organic Synthesis Reactions On-Water at the Organic-Liquid Water Interface. Org. Biomol. Chem. 2016, 14, 9945– 9960,  DOI: 10.1039/C6OB01724J
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    Organic synthesis reactions on-water at the organic-liquid water interface
    Butler, Richard N.; Coyne, Anthony G.
    Organic & Biomolecular Chemistry (2016), 14 (42), 9945-9960CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    Org. reactions that occur at the water interface for water-insol. compds., and reactions in water soln. for water sol. compds., has added a powerful dimension to prospects for org. synthesis under more beneficial economic and environmental conditions. Many org. mols. are partially sol. in water and reactions that appear as heterogeneous mixts. and suspensions may involve on-water and in-water reaction modes occurring simultaneously. The behavior of water mols. and org. mols. at this interface is discussed in the light of reported theor. and exptl. studies. The on-water catalytic effect, relative to neat reactions or org. solvents, ranges from factors of several hundred times to 1-2 times and it depends on the properties of reactant compds. In some cases when on-water reactions produce quant. yields of water-insol. products they can reach ideal synthetic aspirations.
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    Kleiner, C. M.; Schreiner, P. R. Hydrophobic Amplification of Noncovalent Organocatalysis. Chem. Commun. 2006, 41, 4315– 4317,  DOI: 10.1039/B605850G
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    Gajewski, J. J. A Semitheoretical Multiparameter Approach to Correlate Solvent Effects on Reactions and Equilibria. J. Org. Chem. 1992, 57, 5500– 5506,  DOI: 10.1021/jo00046a036
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    A semitheoretical multiparameter approach to correlate solvent effects on reactions and equilibria
    Gajewski, Joseph J.
    Journal of Organic Chemistry (1992), 57 (20), 5500-6CODEN: JOCEAH; ISSN:0022-3263.
    A solvent rate effect equation which uses four phys. properties of the solvent for parameters has been applied with good success to solvolysis reactions, solvent Et values, Claisen rearrangements, Diels-Alder reactions, endo-exo ratios in Diels-Alder reactions, azo-Cope rearrangements, and enol-ketone equil. of the dimedone and pyridone variety. The coeffs. of the parameters, which are the Kirkwood-Onsager function, the solvent cohesive energy d., the specific solvation of chloride ion, and the specific solvation of potassium ion, lead to differences in dipole moments, in vols. between initial and final states, and in the extent of specific solvation of anionic and cationic sites relative to the solvation of chloride ion and potassium ion, resp.
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    García, J. I.; Martínez-Merino, V.; Mayoral, J. A.; Salvatella, L. Density Functional Theory Study of a Lewis Acid Catalyzed Diels–Alder Reaction. The Butadiene + Acrolein Paradigm. J. Am. Chem. Soc. 1998, 120, 2415– 2420,  DOI: 10.1021/ja9722279
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    Density Functional Theory Study of a Lewis Acid Catalyzed Diels-Alder Reaction. The Butadiene + Acrolein Paradigm
    Garcia, J. I.; Martinez-Merino, V.; Mayoral, J. A.; Salvatella, L.
    Journal of the American Chemical Society (1998), 120 (10), 2415-2420CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The four transition structures (TS's) of the reaction between butadiene and acrolein, both uncatalyzed and catalyzed by BF3, have been theor. studied taking into account electron correlation effects by means of DFT (B3LYP) calcns. In both the uncatalyzed and catalyzed reactions, the endo s-cis is the most stable of the four possible transition structures. In the case of the catalyzed reaction, the inclusion of electron correlation in the search for this transition structure indicates the classical [4+2] reaction path, instead of that corresponding to a [2+4] inverse electron, demands hetero-Diels-Alder reaction, as happens when the Hartree-Fock level of theory is used. The B3LYP/6-31G(d) calcns. lead to activation energy values close to those exptl. found. The origin of the endo/exo selectivity, both in the presence and in the absence of the catalyst, is discussed.
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    Manna, A.; Kumar, A. Why Does Water Accelerate Organic Reactions under Heterogeneous Condition?. J. Phys. Chem. A 2013, 117, 2446– 2454,  DOI: 10.1021/jp4002934
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    Why Does Water Accelerate Organic Reactions under Heterogeneous Condition?
    Manna, Arpan; Kumar, Anil
    Journal of Physical Chemistry A (2013), 117 (12), 2446-2454CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    A kinetic anal. has been carried out to elucidate the role of the oil-water interface in guiding "on water org. reaction" mechanism. The preferential solvation of polarizable ions at the water surface was shown. Exptl. methods were developed to control the mol. structure of oil-water interface in situ. Temp.-dependent analyses allowing one to understand the enthalpic and entropic modifications of the interfacial water mols. during a heterogeneous reaction are given. The kinetic and the thermodn. outcomes established that the hydrogen bond ability of the surface water mols. played a crit. role in the on-water org. reaction mechanism.
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    Guo, D.; Zhu, D.; Zhou, X.; Zheng, B. Accelerating the “On Water” Reaction: By Organic-Water Interface or By Hydrodynamic Effects?. Langmuir 2015, 31, 13759– 13763,  DOI: 10.1021/acs.langmuir.5b04031
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    Accelerating the "On Water" Reaction: By Organic-Water Interface or By Hydrodynamic Effects?
    Guo, Dameng; Zhu, Deyong; Zhou, Xiaohu; Zheng, Bo
    Langmuir (2015), 31 (51), 13759-13763CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    A series of org. reactions proceed dramatically faster in a heterogeneous mixt. of the reactants and water than in a homogeneous mixt. Currently it is unclear whether the rate acceleration is due to the free OH groups at the org.-water interface, or due to the hydrodynamic effects caused by vigorous stirring, vortexing, or ultrasonication. The authors produced static droplets in microfluidic devices to answer this question. A series of org. droplets contg. di-Et azodicarboxylate (DEAD) and quadricyclane surrounded by water were produced, which were transferred to and confined in glass capillaries to minimize the hydrodynamic effects. The cycloaddn. process of DEAD with quadricyclane was recorded by a CCD camera. The results showed the reaction proceeded in three steps, and the org.-water interface alone was catalytically efficient enough to enhance the reaction rate to the same level as in the bulk emulsion reaction, indicating that the hydrodynamic effects were negligible.
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    Jung, Y.; Marcus, R. A. On the Theory of Organic Catalysis “on Water. J. Am. Chem. Soc. 2007, 129, 5492– 5502,  DOI: 10.1021/ja068120f
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    On the Theory of Organic Catalysis "on Water"
    Jung, Yousung; Marcus, R. A.
    Journal of the American Chemical Society (2007), 129 (17), 5492-5502CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A mol. origin of the striking rate increase obsd. in a reaction on water is studied theor. A key aspect of the on-water rate phenomenon is the chem. between water and reactants that occurs at an oil-water phase boundary. In particular, the structure of water at the oil-water interface of an oil emulsion, in which approx. one in every four interfacial water mols. has a free (dangling) OH group that protrudes into the org. phase, plays a key role in catalyzing reactions via the formation of hydrogen bonds. Catalysis is expected when these OH's form stronger hydrogen bonds with the transition state than with the reactants. In expts. more than a 5 orders of magnitude enhancement in rate const. was found in a chosen reaction. The structural arrangement at the oil-water interface is in contrast to the structure of water mols. around a small hydrophobic solute in homogeneous soln., where the water mols. are tangentially oriented. The latter implies that a breaking of an existing hydrogen-bond network in homogeneous soln. is needed to permit a catalytic effect of hydrogen bonds, but not for the on-water reaction. Thereby, the reaction in homogeneous aq. soln. is intrinsically slower than the surface reaction, as obsd. exptl. The proposed mechanism of rate acceleration is discussed in light of other on-water reactions that showed smaller accelerations in rates. To interpret the results in different media, a method is given for comparing the rate consts. of different rate processes, homogeneous, neat and on-water, all of which have different units, by introducing models that reduce them to the same units. The obsd. deuterium kinetic isotope effect is discussed briefly, and some expts. are suggested that can test the present interpretation and increase understanding of the on-water catalysis.
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    Jorgensen, W. L.; Blake, J. F.; Lim, D.; Severance, D. L. Investigation of Solvent Effects on Pericyclic Reactions by Computer Simulations. J. Chem. Soc., Faraday Trans. 1994, 90, 1727– 1732,  DOI: 10.1039/FT9949001727
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    Investigation of solvent effects on pericyclic reactions by computer simulations
    Jorgensen, William L.; Blake, James F.; Lim, Dongchul; Severance, Daniel L.
    Journal of the Chemical Society, Faraday Transactions (1994), 90 (12), 1727-32CODEN: JCFTEV; ISSN:0956-5000.
    A combination of quantum and statistical mechanics is being used to probe the origins of solvent effects on the kinetics of org. reactions. Ab initio MO calcns. provide gas-phase reaction paths and partial charges for the reacting systems. The reaction paths are then followed by Monte Carlo simulations in periodic cells contg. hundreds of solvent mols., and the changes in Gibbs free energies of solvation are obtained. Results are provided for several prototypical pericyclic reactions: Diels-Alder cycloaddns. for Me vinyl ketone with cyclopentadiene and the dimerization of cyclopentadiene, the Claisen rearrangement of allyl vinyl ether, and the electrocyclic ring opening of cyclopropanones to oxyallyls. Detailed insights are obtained on issues such as the acceleration of the Diels-Alder reactions and Claisen rearrangement in water, and the electronic nature of oxyallyls.
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    Blake, J. F.; Jorgensen, W. L. Solvent Effects on a Diels-Alder Reaction from Computer Simulations. J. Am. Chem. Soc. 1991, 113, 7430– 7432,  DOI: 10.1021/ja00019a055
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    Solvent effects on a Diels-Alder reaction from computer simulations
    Blake, James F.; Jorgensen, William L.
    Journal of the American Chemical Society (1991), 113 (19), 7430-2CODEN: JACSAT; ISSN:0002-7863.
    Free energy of solvation profiles for the Diels-Alder reaction of cyclopentadiene and Me vinyl ketone have been obtained from Monte Carlo statistical mechanics simulations in liq. propane, methanol, and water. The gas-phase min.-energy reaction path through the endo-cis transition state was detd. from ab initio MO calcns. and was followed in periodic cells contg. 260-500 solvent mols. Statistical perturbation theory yielded the changes in free energies of solvation along the reaction path. Essentially no solvent effect on the energetics was found in liq. propane. However, in water, the dramatic rate acceleration obsd. by Rideout and Breslow (1980) is mirrored in the computed results. The free energy of solvation of the transition state is computed to be 4.2±0.4 kcal/mol lower relative to the reactants in water than in propane, while the exptl. data show a lowering of the free energy of activation in water by 3.8 kcal/mol relative to an alkane solvent. The corresponding figures for methanol relative to the alkane solvent are 2.4±0.3 kcal/mol from the simulations and 1.5 kcal/mol exptl. Further analyses indicate that the rate acceleration in water results both from a hydrophobic effect and from enhanced H bonding to the carbonyl group in the more polar transition state than in reactants or product.
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    Furlani, T. R.; Gao, J. Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels–Alder Reactions in Aqueous Solution. J. Org. Chem. 1996, 61, 5492– 5497,  DOI: 10.1021/jo9518011
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    Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels-Alder Reactions in Aqueous Solution
    Furlani, Thomas R.; Gao, Jiali
    Journal of Organic Chemistry (1996), 61 (16), 5492-5497CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Using a combined quantum mech. and mol. mech. (QM/MM) potential, we have carried out Monte Carlo simulations to investigate the hydrophobic and hydrogen-bonding effects on Diels-Alder reactions in aq. soln. Two prototypical systems were considered, including the reaction of cyclopentadiene (CP) with Me vinyl ketone (MVK) and the reaction of cyclopentadiene with isoprene. Anal. of the simulation results revealed that the hydrophobic effect is significant in both reactions. Since hydrogen bonding interactions are not involved in the reaction of CP and isoprene, the entire transition-state stabilization (4.6 ± 0.3 kcal/mol) can be attributed to the hydrophobic effect. In the reaction of CP and MVK, enhanced hydrogen-bonding interaction and the hydrophobic effect contribute equally to the transition state stabilization (-3.5 ± 0.4 kcal/mol). These findings are compared with the exptl. results and predictions from previous theor. studies.
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    SaiPrathima, P.; Srinivas, K.; Mohan Rao, M. On Water” Catalysis: An Expeditious Approach for the Synthesis of Quaternary Centered 3-Hydroxy-3-(Nitromethyl)Indolin-2-One Derivatives. Green Chem. 2015, 17, 2339– 2343,  DOI: 10.1039/C4GC02203C
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    "On water" catalysis: an expeditious approach for the synthesis of quaternary centered 3-hydroxy-3-(nitromethyl)indolin-2-one derivatives
    SaiPrathima, Parvathaneni; Srinivas, Keesara; Mohan Rao, Mandapati
    Green Chemistry (2015), 17 (4), 2339-2343CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
    A novel, efficient, eco-friendly "on water" method was developed for the Henry reaction of isatins with nitromethane to afford 3-hydroxy-3-nitromethylindolin-2-ones. An enhancement in reaction rate was obsd. "on water" under mild and catalyst-free conditions. This reaction tolerated a wide range of substrates with good to excellent product yields and is even applicable at large scales. Moreover, this method is environmentally friendly as it reduces the waste generated using toxic solvents.
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    Hyde, A. M.; Zultanski, S. L.; Waldman, J. H.; Zhong, Y.-L.; Shevlin, M.; Peng, F. General Principles and Strategies for Salting-Out Informed by the Hofmeister Series. Org. Process Res. Dev. 2017, 21, 1355– 1370,  DOI: 10.1021/acs.oprd.7b00197
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    General Principles and Strategies for Salting-Out Informed by the Hofmeister Series
    Hyde, Alan M.; Zultanski, Susan L.; Waldman, Jacob H.; Zhong, Yong-Li; Shevlin, Michael; Peng, Feng
    Organic Process Research & Development (2017), 21 (9), 1355-1370CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Overarching principles for salting-out extn. are long-established but poorly disseminated. We highlight the opportunity for more widespread application of this technique using the Hofmeister series as a foundational basis for choosing the right salt. The power of this approach is exemplified by the aq. workup of a highly water-sol. nucleoside in which the use of sodium sulfate allowed for high recoveries without relying on back extn.
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    Bora, P. P.; Bez, G. Henry Reaction in Aqueous Media at Neutral PH. Eur. J. Org. Chem. 2013, 2013, 2922– 2929,  DOI: 10.1002/ejoc.201201682
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    Henry Reaction in Aqueous Media at Neutral pH
    Bora, Pranjal P.; Bez, Ghanashyam
    European Journal of Organic Chemistry (2013), 2013 (14), 2922-2929CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    An efficient method for the synthesis of β-nitro alcs. from nitro alkanes and aldehydes in aq. phosphate buffer under neutral pH conditions at room temp. is reported. In the case of higher nitro alkanes, the reaction showed very good diastereoselectivity to give syn β-nitro alcs. in preference to their anti products.
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    Zhang, L.; Yuan, P.; Chen, J.; Huang, Y. Enantioselective Cooperative Proton-Transfer Catalysis Using Chiral Ammonium Phosphates. Chem. Commun. 2018, 54, 1473– 1476,  DOI: 10.1039/C7CC09549J
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    Chiral phosphorate anions are shown to be highly enantioselective templates for proton-transfer catalysis. A salt generated in situ from a bridgehead amine and a BINOL-derived chiral phosphoric acid serves as an effective proton-shuttle that exhibits remarkable enantioselectivity in a bioinspired, triple co-operative catalysis involving an achiral NHC. Thioesters with a β-chiral center can be prepd. in a single step from substituted cinnamaldehyde derivs., with up to 99% yield and 99% ee. Heteroaryl groups are well tolerated in these reactions, despite the presence of basic sites.
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    Neat liq. H3PO4 has the highest intrinsic proton cond. of any known substance and is a useful model for understanding proton transport in other phosphate-based systems in biol. and clean energy technologies. Here, the authors present an ab initio mol. dynamics study that reveals, for the 1st time, the microscopic mechanism of this high proton cond. Anomalously fast proton transport in H-bonded systems involves a structural diffusion mechanism in which intramol. proton transfer is driven by specific H bond rearrangements in the surrounding environment. Aq. media transport excess charge defects through local H bond rearrangements that drive individual proton transfer reactions. But strong, polarizable H bonds in H3PO4 produce coupled proton motion and a pronounced protic dielec. response of the medium, giving extended, polarized H-bonded chains. The interplay between these chains and a frustrated H-bond network gives rise to the high proton cond.
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    Simple sodium salts completely reversed the product ratios of the Passerini reaction in aq. media. Furthermore, the use of the "salting-in" salt and a small excess of the nucleophile gives significantly higher yields than the use of the satd. soln. of the nucleophile alone. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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    We have demonstrated how biphasic flow can be used to study interfacial reactions on a macroscopic scale. Total flow rate, residence times, and most importantly, the interfacial area between the water and the org. phase can be precisely known and controlled in a (micro)fluidic system, which is not possible in bulk emulsions. We have used this technique to quantify the "on water" effect for the first time. We suggest as a possible mechanism the model based on the stabilization of the transition state by hydrogen bonding proposed by Jung and Marcus. But it is also quite apparent that the magnitude of the "on water" effect can be rather modest and even if the reaction is accelerated initially, the effect becomes less pronounced with longer reaction times. The interfacial nature of the reaction can greatly influence the overall reaction rates as product mols. might become pinned at the interface. These factors strongly counteract the favorable redn. in activation energy. Our method allows for rapid examn. of the key features of "on water" conditions, which could reduce the use of org. solvents.
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    Organic Letters (2013), 15 (9), 2210-2213CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    It was discovered that the presence of water as a cosolvent enables the reaction of activated alkyl fluorides for bimol. nucleophilic substitution reactions. DFT calcns. show that activation proceeds through stabilization of the transition structure by a stronger F···H2O interaction and diminishing C-F bond elongation, and not simple transition state electrostatic stabilization. Overall, the findings put forward a distinct strategy for C-F bond activation through H-bonding.
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    Dhameliya, Tejas M.; Chourasiya, Sumit S.; Mishra, Eshan; Jadhavar, Pradeep S.; Bharatam, Prasad V.; Chakraborti, Asit K.
    Journal of Organic Chemistry (2017), 82 (19), 10077-10091CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as Et glyoxalate and di-Et oxalate in aq. medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. The reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chem. calcns. (d. functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates vs. benzazine-3-ones/benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.
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    An "on water" environment, defined by the absence of water soly. of the reactants, has been reported to provide increased rate accelerations, yields, and specificity for several types of org. reaction classes compared to org. solvents. The arom. Claisen rearrangements of allyl p-R-Ph ethers (R = CH3, Br, and OCH3) and allyl naphthyl ether have been investigated to det. the origin of the on water effect using QM/MM Monte Carlo calcns. and free-energy perturbation theory. The simulations indicate that on water rate enhancements for the rearrangements are derived from the ability of the interfacial waters to stabilize the polar transition state via enhanced hydrogen bonding at the oil/water interface. The position and orientation of the arom. ethers at the interface are crucial factors affecting solvent accessibility during the reaction pathway; computed solute-solvent energy pair distributions and radial distribution functions showed that hydrophobic substituents on the solute provided a more polar solvent environment than hydrophilic substituents by tilting the reacting oxygen toward the water surface. Calcns. in 16 different solvents accurately reproduced the exptl. trend of increased rates correlated to increasing solvent polarity. Hydrophobic effects did not provide a substantial contribution to the lowering of the free energy activation barrier (<0.5 kcal/mol), and solvent polarizability via a polarizable force field was also found to be negligible in the obsd. rate accelerations. New insight into solvent effects for the Claisen rearrangement is presented herein, and a QM/MM approach for computing reactions on a liq. surface is highlighted.
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    The accelerating influence of water as a solvent on the rate of the Claisen rearrangement has been demonstrated on several substrates, thus illustrating the enormous potential it holds for those engaged in the synthesis of natural and unnatural products. Claisen rearrangement products which hitherto were inaccessible due to decompn. at high temps. or elimination can now be realized through the agency of water.
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    A review. In this article, we compare the mol. calcns. reported by Jorge and coworkers with our previous studies.
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    Green Chemistry (2020), 22 (2), 448-454CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
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    Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonist
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    Green Chemistry (2020), 22 (17), 5762-5770CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
    The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the redn. of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clin. trials for the treatment of asthma and chronic obstructive pulmonary disorder. The reaction was investigated within a batch autoclave by using a design of expts. (DoE) approach to identify important parameter effects. The optimized flow process was successfully operated over 6 h with inline benchtop 19F NMR spectroscopy for reaction monitoring. The protocol is shown to be high yielding (98% yield, 3.7 g h-1) with very low catalyst loading (0.065 mol%). The environmental impact of the Ru-catalyzed hydrogenation was assessed and compared to an existing stoichiometric lithium aluminum hydride (LAH) redn. and sodium borohydride (NaBH4) redn. The process mass intensity (PMI) for the Ru-catalyzed hydrogenation (14) compared favorably to a LAH redn. (52) and NaBH4 redn. (133).
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    We describe the development and application of an improved, membrane-based, liq.-liq. separator. Membrane-based sepn. relies on the exploitation of surface forces and the use of a membrane wetted by one of the phases; however, successful sepn. requires accurate control of pressures, making the operation and implementation cumbersome. Here we present an improved separator design that integrates a pressure control element to ensure that adequate operating conditions are always maintained. Addnl., the integrated pressure control decouples the separator from downstream unit operations. A detailed examn. of the controlling phys. equations shows how to design the device to allow operation across a wide range of conditions. Easy to implement, multistage sepns. such as solvent swaps and countercurrent extns. are demonstrated. The presented design significantly simplifies applications ranging from multistep synthesis to complex multistage sepns.
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    Chapman, M. R.; Kwan, M. H. T.; King, G.; Jolley, K. E.; Hussain, M.; Hussain, S.; Salama, I. E.; González Nino, C.; Thompson, L. A.; Bayana, M. E.; Clayton, A. D.; Nguyen, B. N.; Turner, N. J.; Kapur, N.; Blacker, A. J. Simple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence Times. Org. Process Res. Dev. 2017, 21, 1294– 1301,  DOI: 10.1021/acs.oprd.7b00173
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    Simple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence Times
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    Organic Process Research & Development (2017), 21 (9), 1294-1301CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    A universal multi-stage cascade CSTR has been developed which is suitable for a wide range of continuous-flow processes. Coined by authors group the 'Freactor' (free-to-access reactor), the new reactor integrates the efficiency of pipe-flow processing with the advanced mixing of a CSTR, delivering a general 'plug-and-play' reactor platform which is well-suited to multiphasic continuous-flow chem. Importantly, the reactor geometry is easily customized to accommodate reactions requiring long residence times (≥ 3 h tested).
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    Becker, J.; Manske, C.; Randl, S. Green Chemistry and Sustainability Metrics in the Pharmaceutical Manufacturing Sector. Curr. Opin. Green Sustainable Chem. 2022, 33, 100562,  DOI: 10.1016/j.cogsc.2021.100562
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    Green chemistry and sustainability metrics in the pharmaceutical manufacturing sector
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    This review article summarizes recent developments of green chem. and sustainability metrics with a focus on the pharmaceutical industry. We discuss synergies and discrepancies of the green chem. principles with regulatory guidelines in the field of pharmaceutical process development and manufg. under Good Manufg. Practices (GMP). This review captures selected views and publications on green chem. and sustainability metrics. It discusses two recent process development highlights from the pharmaceutical industry which use different approaches to optimize the process mass intensity (PMI) of small-mol. active pharmaceutical ingredient (API) manufg. processes. The first example is the development of green process conditions by switching reaction media from org. solvents to micellar catalysis in water in the Takeda process of the API TAK-954. The second example features process intensifications accomplished by the application of innovative technologies in pharmaceutical processing in the Merck process of the API MK-7264.
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  • Abstract

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    Figure 1

    Figure 1. Simplified phase complexity scenarios of water-accelerated reactions: (a) all reactants are insoluble in water; (b) one reactant is partially soluble in water; (c) reactants are phase-separated; and (d) one reactant is activated at the aqueous–organic interface.

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    Scheme 1

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    Figure 2

    Figure 2. Dependence of the water-accelerated Henry reaction on reaction conditions: (a) kinetic isotope effect; (b) salt effects by NaCl 1 M, LiCl 1 M, Bu4NCl 1 M, Na2SO4 1 M (70 °C), and phosphate buffer 0.1 M at pH 7 (22 °C), error bars are excluded for clarity; and (c) effect of temperature (color), stirring rate (dot size), excess nitromethane, and amount of 1 on reaction yield at 1 h.

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    Figure 3

    Figure 3. Energy profile of Henry reaction under (a) water-accelerated conditions, or in ethanol, and (b) in the presence of HSO4–.

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    Figure 4

    Figure 4. Natural bond orbital (NBO) charge distribution analysis of the transition states TS1w, TS2w, TS1HSO4, and TS2HSO4.

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    Figure 5

    Figure 5. (a) Reaction yields with recycling of the aqueous phase in batch, orange bar depicting yield with water as the aqueous phase and green bar depicting yield with 0.1 M phosphate buffer pH 7 as the aqueous phase. Reaction conditions: 51 mg of 1, 0.42 mL of nitromethane, 3 mL of aqueous phase recycled up to 5 times, 850 rpm, 70 °C (water), 25 °C (phosphate buffer), 3 h (water), 10 min (phosphate buffer). (b) Kinetic profile of Henry reaction in batch at a 1:1 phase ratio using 25 equiv (●) or 9 equiv (■) of nitromethane. Reaction conditions: 0.42 mL solution of 1 in nitromethane with 5 mol % trimethoxybenzene as an internal standard [(●) 0.121 g 1/1 mL; (■) 0.331 g 1/1 mL], 0.42 mL of 0.1 M phosphate buffer, 40 °C, 850 rpm, 0–25 min.

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    Figure 6

    Figure 6. Flow process diagram including the continuous recycling of the aqueous phase.

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    Figure 7

    Figure 7. Yields and mass balance of flow processes with continuous aqueous phase recycling using (a) 0.121 g of 1 per 1 mL CH3NO2 and (b) 0.3331 g of 1 per 1 mL CH3NO2. (▲) Molar fraction of 1; (■) molar fraction of product 2; (●) molar fraction of side product 3; and (▼) total mass balance.

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      Catalyst-Free "On-Water" Regio- and Stereospecific Ring-Opening of Spiroaziridine Oxindole: Enantiopure Synthesis of Unsymmetrical 3,3'-Bisindoles
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      A catalyst-free water-mediated regio- and stereospecific ring-opening reaction of nonracemic spiroaziridine oxindoles and indoles has been developed with retention of configuration. This method provides direct access to enantiopure 3,3'-mixed bisindoles with excellent yield and enantioselectivity (up to 98% ee).
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      Toward Chemistry-Based Design of the Simplest Metalloenzyme-Like Catalyst That Works Efficiently in Water
      Kitanosono, Taku; Kobayashi, Shu
      Chemistry - An Asian Journal (2015), 10 (1), 133-138CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The authors describe the design of small mols. that act as the simplest metalloenzyme-like catalysts that can function in water without mimicking enzyme structures. These artificial catalysts, e.g., Sc(OTf)3 and I, efficiently promoted enantioselective direct-type aldol reactions using aq. formaldehyde. The reactions followed Michaelis-Menten kinetics; and heat-resistant asym. environments were constructed in water.
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      Du, Z.-H.; Da, C. S.; Yuan, M.; Tao, B. X.; Ding, T. Y. Efficient Catalyst-Free Henry Reaction between Nitroalkanes and Aldehydes or Trifluoromethyl Ketones Promoted by Tap Water. Synthesis 2022, 54, 5461– 5470,  DOI: 10.1055/a-1933-3709
      20
      Efficient Catalyst-Free Henry Reaction between Nitroalkanes and Aldehydes or Trifluoromethyl Ketones Promoted by Tap Water
      Du, Zhi-Hong; Yuan, Meng; Tao, Bao-Xiu; Ding, Tie-Ying; Da, Chao-Shan
      Synthesis (2022), 54 (24), 5461-5470CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
      The first examples of highly effective Henry reactions between nitroalkanes and aldehydes or trifluoromethyl ketones that proceed under catalyst-free and additive-free conditions, in a recyclable tap water medium, and at room temp. was reported. This process tolerated a broad range of aldehydes and trifluoromethyl ketones to give a series of β-nitro alc. products in excellent yields. Such products are widely used in the syntheses of pharmaceutical intermediates and natural products. This protocol can be successfully scaled up to a 50-mmol scale without a redn. in yield. Tap water from different locations in China exhibited pH values ranging from 7.5 to 8.1, but the varying pH had no effect on the yield and the processes were successfully reproduced. Finally, the tap water was effectively recovered and reused without any post processing, even when the reaction substrates were different.
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      Butler, R. N.; Coyne, A. G. Understanding “On-Water” Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen Cycloadditions. J. Org. Chem. 2015, 80, 1809– 1817,  DOI: 10.1021/jo502732y
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      Understanding "On-Water" Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen Cycloadditions
      Butler, Richard N.; Coyne, Anthony G.
      Journal of Organic Chemistry (2015), 80 (3), 1809-1817CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      For a typical Huisgen cycloaddn., carried out on water, the behavior of water mols. at the oil-water interface depended on the properties of the reactants. With weakly basic reactants, a small quantity of added H+ (HClO4, 0.0001-0.01 M) present in the aq. phase had negligible effects, but larger quantities of H+ (HClO4, 0.1-3.0 M) increased the catalytic effect and caused protons to cross the water-org. interface and affect the products. Added Li+ ions (LiClO4, 0.1-3.0 M) had no effect for on-water reactions but enhanced the rates and endo products for in-water reactions. For these cycloaddn. reactions, the product endo:exo ratios, when compared to those in org. solvents, can be used to distinguish between the on-water and in-water modes. Comparisons of org. reactions on H2O and on D2O indicate that on-water catalysis ranges from weak to strong trans-phase H-bonding for reactants with basic pKa < ca. -6 and to interfacial proton transfer for reactants with higher basic pKa > ca. 2 (pKa of conjugate acid). Water shows a chameleon-type response to org. mols. at hydrophobic surfaces.
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    23. 23
      Tiwari, S.; Kumar, A. Unusual Temperature Dependence of Salt Effects for “on Water” Wittig Reaction: Hydrophobicity at the Interface. Chem. Commun. 2008, 37, 4445– 4447,  DOI: 10.1039/B809127G
      There is no corresponding record for this reference.
    24. 24
      Bae, H. Y.; Song, C. E. Unprecedented Hydrophobic Amplification in Noncovalent Organocatalysis “on Water”: Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to Nitroalkenes. ACS Catal. 2015, 5, 3613– 3619,  DOI: 10.1021/acscatal.5b00685
      24
      Unprecedented Hydrophobic Amplification in Noncovalent Organocatalysis "on Water": Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to Nitroalkenes
      Bae, Han Yong; Song, Choong Eui
      ACS Catalysis (2015), 5 (6), 3613-3619CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      In this study, water was demonstrated to be an exceptionally efficient reaction medium for the noncovalent, hydrogen-bonding-promoted enantioselective Michael addn. of malonates to diverse nitroolefins using cinchona-based squaramide catalysts. A significant increase in the reaction rate was obsd. when the reaction was performed "on water" rather than in the conventional org. solvents, because of the hydrophobic hydration effect. This hydrophobic amplification was significantly dependent upon the hydrophobicity of the C3-substituent (vinyl or ethyl) of cinchona-based catalysts. Thus, the use of more hydrophobic catalyst with an Et group at the C3-position, even a highly challenging Michael donor such as di-Me methylmalonate was also smoothly converted to the desired adduct. Furthermore, because of the remarkable rate acceleration under "on water" conditions, the catalyst loading also significantly decreased. Thus, in the case of β-ketoesters, even 0.01 mol % of catalyst loading was enough to complete the reaction at room temp., affording the corresponding Michael adducts with perfect diastereo- and enantioselectivity (up to >99:1 d.r., up to 99% ee). The developed "on water" protocol was successfully applied for the scalable syntheses of an antidepressant (S)-rolipram and an anticonvulsant (S)-pregabalin.
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    25. 25
      Butler, R. N.; Coyne, A. G. Organic Synthesis Reactions On-Water at the Organic-Liquid Water Interface. Org. Biomol. Chem. 2016, 14, 9945– 9960,  DOI: 10.1039/C6OB01724J
      25
      Organic synthesis reactions on-water at the organic-liquid water interface
      Butler, Richard N.; Coyne, Anthony G.
      Organic & Biomolecular Chemistry (2016), 14 (42), 9945-9960CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
      Org. reactions that occur at the water interface for water-insol. compds., and reactions in water soln. for water sol. compds., has added a powerful dimension to prospects for org. synthesis under more beneficial economic and environmental conditions. Many org. mols. are partially sol. in water and reactions that appear as heterogeneous mixts. and suspensions may involve on-water and in-water reaction modes occurring simultaneously. The behavior of water mols. and org. mols. at this interface is discussed in the light of reported theor. and exptl. studies. The on-water catalytic effect, relative to neat reactions or org. solvents, ranges from factors of several hundred times to 1-2 times and it depends on the properties of reactant compds. In some cases when on-water reactions produce quant. yields of water-insol. products they can reach ideal synthetic aspirations.
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    26. 26
      Kleiner, C. M.; Schreiner, P. R. Hydrophobic Amplification of Noncovalent Organocatalysis. Chem. Commun. 2006, 41, 4315– 4317,  DOI: 10.1039/B605850G
      There is no corresponding record for this reference.
    27. 27
      Gajewski, J. J. A Semitheoretical Multiparameter Approach to Correlate Solvent Effects on Reactions and Equilibria. J. Org. Chem. 1992, 57, 5500– 5506,  DOI: 10.1021/jo00046a036
      27
      A semitheoretical multiparameter approach to correlate solvent effects on reactions and equilibria
      Gajewski, Joseph J.
      Journal of Organic Chemistry (1992), 57 (20), 5500-6CODEN: JOCEAH; ISSN:0022-3263.
      A solvent rate effect equation which uses four phys. properties of the solvent for parameters has been applied with good success to solvolysis reactions, solvent Et values, Claisen rearrangements, Diels-Alder reactions, endo-exo ratios in Diels-Alder reactions, azo-Cope rearrangements, and enol-ketone equil. of the dimedone and pyridone variety. The coeffs. of the parameters, which are the Kirkwood-Onsager function, the solvent cohesive energy d., the specific solvation of chloride ion, and the specific solvation of potassium ion, lead to differences in dipole moments, in vols. between initial and final states, and in the extent of specific solvation of anionic and cationic sites relative to the solvation of chloride ion and potassium ion, resp.
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    28. 28
      García, J. I.; Martínez-Merino, V.; Mayoral, J. A.; Salvatella, L. Density Functional Theory Study of a Lewis Acid Catalyzed Diels–Alder Reaction. The Butadiene + Acrolein Paradigm. J. Am. Chem. Soc. 1998, 120, 2415– 2420,  DOI: 10.1021/ja9722279
      28
      Density Functional Theory Study of a Lewis Acid Catalyzed Diels-Alder Reaction. The Butadiene + Acrolein Paradigm
      Garcia, J. I.; Martinez-Merino, V.; Mayoral, J. A.; Salvatella, L.
      Journal of the American Chemical Society (1998), 120 (10), 2415-2420CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The four transition structures (TS's) of the reaction between butadiene and acrolein, both uncatalyzed and catalyzed by BF3, have been theor. studied taking into account electron correlation effects by means of DFT (B3LYP) calcns. In both the uncatalyzed and catalyzed reactions, the endo s-cis is the most stable of the four possible transition structures. In the case of the catalyzed reaction, the inclusion of electron correlation in the search for this transition structure indicates the classical [4+2] reaction path, instead of that corresponding to a [2+4] inverse electron, demands hetero-Diels-Alder reaction, as happens when the Hartree-Fock level of theory is used. The B3LYP/6-31G(d) calcns. lead to activation energy values close to those exptl. found. The origin of the endo/exo selectivity, both in the presence and in the absence of the catalyst, is discussed.
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    29. 29
      Manna, A.; Kumar, A. Why Does Water Accelerate Organic Reactions under Heterogeneous Condition?. J. Phys. Chem. A 2013, 117, 2446– 2454,  DOI: 10.1021/jp4002934
      29
      Why Does Water Accelerate Organic Reactions under Heterogeneous Condition?
      Manna, Arpan; Kumar, Anil
      Journal of Physical Chemistry A (2013), 117 (12), 2446-2454CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
      A kinetic anal. has been carried out to elucidate the role of the oil-water interface in guiding "on water org. reaction" mechanism. The preferential solvation of polarizable ions at the water surface was shown. Exptl. methods were developed to control the mol. structure of oil-water interface in situ. Temp.-dependent analyses allowing one to understand the enthalpic and entropic modifications of the interfacial water mols. during a heterogeneous reaction are given. The kinetic and the thermodn. outcomes established that the hydrogen bond ability of the surface water mols. played a crit. role in the on-water org. reaction mechanism.
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    30. 30
      Guo, D.; Zhu, D.; Zhou, X.; Zheng, B. Accelerating the “On Water” Reaction: By Organic-Water Interface or By Hydrodynamic Effects?. Langmuir 2015, 31, 13759– 13763,  DOI: 10.1021/acs.langmuir.5b04031
      30
      Accelerating the "On Water" Reaction: By Organic-Water Interface or By Hydrodynamic Effects?
      Guo, Dameng; Zhu, Deyong; Zhou, Xiaohu; Zheng, Bo
      Langmuir (2015), 31 (51), 13759-13763CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      A series of org. reactions proceed dramatically faster in a heterogeneous mixt. of the reactants and water than in a homogeneous mixt. Currently it is unclear whether the rate acceleration is due to the free OH groups at the org.-water interface, or due to the hydrodynamic effects caused by vigorous stirring, vortexing, or ultrasonication. The authors produced static droplets in microfluidic devices to answer this question. A series of org. droplets contg. di-Et azodicarboxylate (DEAD) and quadricyclane surrounded by water were produced, which were transferred to and confined in glass capillaries to minimize the hydrodynamic effects. The cycloaddn. process of DEAD with quadricyclane was recorded by a CCD camera. The results showed the reaction proceeded in three steps, and the org.-water interface alone was catalytically efficient enough to enhance the reaction rate to the same level as in the bulk emulsion reaction, indicating that the hydrodynamic effects were negligible.
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    31. 31
      Jung, Y.; Marcus, R. A. On the Theory of Organic Catalysis “on Water. J. Am. Chem. Soc. 2007, 129, 5492– 5502,  DOI: 10.1021/ja068120f
      31
      On the Theory of Organic Catalysis "on Water"
      Jung, Yousung; Marcus, R. A.
      Journal of the American Chemical Society (2007), 129 (17), 5492-5502CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A mol. origin of the striking rate increase obsd. in a reaction on water is studied theor. A key aspect of the on-water rate phenomenon is the chem. between water and reactants that occurs at an oil-water phase boundary. In particular, the structure of water at the oil-water interface of an oil emulsion, in which approx. one in every four interfacial water mols. has a free (dangling) OH group that protrudes into the org. phase, plays a key role in catalyzing reactions via the formation of hydrogen bonds. Catalysis is expected when these OH's form stronger hydrogen bonds with the transition state than with the reactants. In expts. more than a 5 orders of magnitude enhancement in rate const. was found in a chosen reaction. The structural arrangement at the oil-water interface is in contrast to the structure of water mols. around a small hydrophobic solute in homogeneous soln., where the water mols. are tangentially oriented. The latter implies that a breaking of an existing hydrogen-bond network in homogeneous soln. is needed to permit a catalytic effect of hydrogen bonds, but not for the on-water reaction. Thereby, the reaction in homogeneous aq. soln. is intrinsically slower than the surface reaction, as obsd. exptl. The proposed mechanism of rate acceleration is discussed in light of other on-water reactions that showed smaller accelerations in rates. To interpret the results in different media, a method is given for comparing the rate consts. of different rate processes, homogeneous, neat and on-water, all of which have different units, by introducing models that reduce them to the same units. The obsd. deuterium kinetic isotope effect is discussed briefly, and some expts. are suggested that can test the present interpretation and increase understanding of the on-water catalysis.
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    32. 32
      Jorgensen, W. L.; Blake, J. F.; Lim, D.; Severance, D. L. Investigation of Solvent Effects on Pericyclic Reactions by Computer Simulations. J. Chem. Soc., Faraday Trans. 1994, 90, 1727– 1732,  DOI: 10.1039/FT9949001727
      32
      Investigation of solvent effects on pericyclic reactions by computer simulations
      Jorgensen, William L.; Blake, James F.; Lim, Dongchul; Severance, Daniel L.
      Journal of the Chemical Society, Faraday Transactions (1994), 90 (12), 1727-32CODEN: JCFTEV; ISSN:0956-5000.
      A combination of quantum and statistical mechanics is being used to probe the origins of solvent effects on the kinetics of org. reactions. Ab initio MO calcns. provide gas-phase reaction paths and partial charges for the reacting systems. The reaction paths are then followed by Monte Carlo simulations in periodic cells contg. hundreds of solvent mols., and the changes in Gibbs free energies of solvation are obtained. Results are provided for several prototypical pericyclic reactions: Diels-Alder cycloaddns. for Me vinyl ketone with cyclopentadiene and the dimerization of cyclopentadiene, the Claisen rearrangement of allyl vinyl ether, and the electrocyclic ring opening of cyclopropanones to oxyallyls. Detailed insights are obtained on issues such as the acceleration of the Diels-Alder reactions and Claisen rearrangement in water, and the electronic nature of oxyallyls.
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    33. 33
      Blake, J. F.; Jorgensen, W. L. Solvent Effects on a Diels-Alder Reaction from Computer Simulations. J. Am. Chem. Soc. 1991, 113, 7430– 7432,  DOI: 10.1021/ja00019a055
      33
      Solvent effects on a Diels-Alder reaction from computer simulations
      Blake, James F.; Jorgensen, William L.
      Journal of the American Chemical Society (1991), 113 (19), 7430-2CODEN: JACSAT; ISSN:0002-7863.
      Free energy of solvation profiles for the Diels-Alder reaction of cyclopentadiene and Me vinyl ketone have been obtained from Monte Carlo statistical mechanics simulations in liq. propane, methanol, and water. The gas-phase min.-energy reaction path through the endo-cis transition state was detd. from ab initio MO calcns. and was followed in periodic cells contg. 260-500 solvent mols. Statistical perturbation theory yielded the changes in free energies of solvation along the reaction path. Essentially no solvent effect on the energetics was found in liq. propane. However, in water, the dramatic rate acceleration obsd. by Rideout and Breslow (1980) is mirrored in the computed results. The free energy of solvation of the transition state is computed to be 4.2±0.4 kcal/mol lower relative to the reactants in water than in propane, while the exptl. data show a lowering of the free energy of activation in water by 3.8 kcal/mol relative to an alkane solvent. The corresponding figures for methanol relative to the alkane solvent are 2.4±0.3 kcal/mol from the simulations and 1.5 kcal/mol exptl. Further analyses indicate that the rate acceleration in water results both from a hydrophobic effect and from enhanced H bonding to the carbonyl group in the more polar transition state than in reactants or product.
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    34. 34
      Furlani, T. R.; Gao, J. Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels–Alder Reactions in Aqueous Solution. J. Org. Chem. 1996, 61, 5492– 5497,  DOI: 10.1021/jo9518011
      34
      Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels-Alder Reactions in Aqueous Solution
      Furlani, Thomas R.; Gao, Jiali
      Journal of Organic Chemistry (1996), 61 (16), 5492-5497CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Using a combined quantum mech. and mol. mech. (QM/MM) potential, we have carried out Monte Carlo simulations to investigate the hydrophobic and hydrogen-bonding effects on Diels-Alder reactions in aq. soln. Two prototypical systems were considered, including the reaction of cyclopentadiene (CP) with Me vinyl ketone (MVK) and the reaction of cyclopentadiene with isoprene. Anal. of the simulation results revealed that the hydrophobic effect is significant in both reactions. Since hydrogen bonding interactions are not involved in the reaction of CP and isoprene, the entire transition-state stabilization (4.6 ± 0.3 kcal/mol) can be attributed to the hydrophobic effect. In the reaction of CP and MVK, enhanced hydrogen-bonding interaction and the hydrophobic effect contribute equally to the transition state stabilization (-3.5 ± 0.4 kcal/mol). These findings are compared with the exptl. results and predictions from previous theor. studies.
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    35. 35
      SaiPrathima, P.; Srinivas, K.; Mohan Rao, M. On Water” Catalysis: An Expeditious Approach for the Synthesis of Quaternary Centered 3-Hydroxy-3-(Nitromethyl)Indolin-2-One Derivatives. Green Chem. 2015, 17, 2339– 2343,  DOI: 10.1039/C4GC02203C
      35
      "On water" catalysis: an expeditious approach for the synthesis of quaternary centered 3-hydroxy-3-(nitromethyl)indolin-2-one derivatives
      SaiPrathima, Parvathaneni; Srinivas, Keesara; Mohan Rao, Mandapati
      Green Chemistry (2015), 17 (4), 2339-2343CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
      A novel, efficient, eco-friendly "on water" method was developed for the Henry reaction of isatins with nitromethane to afford 3-hydroxy-3-nitromethylindolin-2-ones. An enhancement in reaction rate was obsd. "on water" under mild and catalyst-free conditions. This reaction tolerated a wide range of substrates with good to excellent product yields and is even applicable at large scales. Moreover, this method is environmentally friendly as it reduces the waste generated using toxic solvents.
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    36. 36
      Hyde, A. M.; Zultanski, S. L.; Waldman, J. H.; Zhong, Y.-L.; Shevlin, M.; Peng, F. General Principles and Strategies for Salting-Out Informed by the Hofmeister Series. Org. Process Res. Dev. 2017, 21, 1355– 1370,  DOI: 10.1021/acs.oprd.7b00197
      36
      General Principles and Strategies for Salting-Out Informed by the Hofmeister Series
      Hyde, Alan M.; Zultanski, Susan L.; Waldman, Jacob H.; Zhong, Yong-Li; Shevlin, Michael; Peng, Feng
      Organic Process Research & Development (2017), 21 (9), 1355-1370CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      Overarching principles for salting-out extn. are long-established but poorly disseminated. We highlight the opportunity for more widespread application of this technique using the Hofmeister series as a foundational basis for choosing the right salt. The power of this approach is exemplified by the aq. workup of a highly water-sol. nucleoside in which the use of sodium sulfate allowed for high recoveries without relying on back extn.
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    37. 37
      Bora, P. P.; Bez, G. Henry Reaction in Aqueous Media at Neutral PH. Eur. J. Org. Chem. 2013, 2013, 2922– 2929,  DOI: 10.1002/ejoc.201201682
      37
      Henry Reaction in Aqueous Media at Neutral pH
      Bora, Pranjal P.; Bez, Ghanashyam
      European Journal of Organic Chemistry (2013), 2013 (14), 2922-2929CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      An efficient method for the synthesis of β-nitro alcs. from nitro alkanes and aldehydes in aq. phosphate buffer under neutral pH conditions at room temp. is reported. In the case of higher nitro alkanes, the reaction showed very good diastereoselectivity to give syn β-nitro alcs. in preference to their anti products.
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    38. 38
      Zhang, L.; Yuan, P.; Chen, J.; Huang, Y. Enantioselective Cooperative Proton-Transfer Catalysis Using Chiral Ammonium Phosphates. Chem. Commun. 2018, 54, 1473– 1476,  DOI: 10.1039/C7CC09549J
      38
      Enantioselective cooperative proton-transfer catalysis using chiral ammonium phosphates
      Zhang, Linrui; Yuan, Pengfei; Chen, Jiean; Huang, Yong
      Chemical Communications (Cambridge, United Kingdom) (2018), 54 (12), 1473-1476CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Chiral phosphorate anions are shown to be highly enantioselective templates for proton-transfer catalysis. A salt generated in situ from a bridgehead amine and a BINOL-derived chiral phosphoric acid serves as an effective proton-shuttle that exhibits remarkable enantioselectivity in a bioinspired, triple co-operative catalysis involving an achiral NHC. Thioesters with a β-chiral center can be prepd. in a single step from substituted cinnamaldehyde derivs., with up to 99% yield and 99% ee. Heteroaryl groups are well tolerated in these reactions, despite the presence of basic sites.
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    39. 39
      Vilčiauskas, L.; Tuckerman, M. E.; Bester, G.; Paddison, S. J.; Kreuer, K.-D. The Mechanism of Proton Conduction in Phosphoric Acid. Nat. Chem. 2012, 4, 461– 466,  DOI: 10.1038/nchem.1329
      39
      The mechanism of proton conduction in phosphoric acid
      Vilciauskas, Linas; Tuckerman, Mark E.; Bester, Gabriel; Paddison, Stephen J.; Kreuer, Klaus-Dieter
      Nature Chemistry (2012), 4 (6), 461-466CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      Neat liq. H3PO4 has the highest intrinsic proton cond. of any known substance and is a useful model for understanding proton transport in other phosphate-based systems in biol. and clean energy technologies. Here, the authors present an ab initio mol. dynamics study that reveals, for the 1st time, the microscopic mechanism of this high proton cond. Anomalously fast proton transport in H-bonded systems involves a structural diffusion mechanism in which intramol. proton transfer is driven by specific H bond rearrangements in the surrounding environment. Aq. media transport excess charge defects through local H bond rearrangements that drive individual proton transfer reactions. But strong, polarizable H bonds in H3PO4 produce coupled proton motion and a pronounced protic dielec. response of the medium, giving extended, polarized H-bonded chains. The interplay between these chains and a frustrated H-bond network gives rise to the high proton cond.
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    40. 40
      Sela, T.; Vigalok, A. Salt-Controlled Selectivity in “on Water” and “in Water” Passerini-Type Multicomponent Reactions. Adv. Synth. Catal. 2012, 354, 2407– 2411,  DOI: 10.1002/adsc.201200448
      40
      Salt-controlled selectivity in "on water" and "in water" Passerini-type multicomponent reactions
      Sela, Tal; Vigalok, Arkadi
      Advanced Synthesis & Catalysis (2012), 354 (13), 2407-2411, S2407/1-S2407/21CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Simple sodium salts completely reversed the product ratios of the Passerini reaction in aq. media. Furthermore, the use of the "salting-in" salt and a small excess of the nucleophile gives significantly higher yields than the use of the satd. soln. of the nucleophile alone. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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    41. 41
      Mellouli, S.; Bousekkine, L.; Theberge, A. B.; Huck, W. T. S. Investigation of “On Water” Conditions Using a Biphasic Fluidic Platform. Angew. Chem., Int. Ed. 2012, 51, 7981– 7984,  DOI: 10.1002/anie.201200575
      41
      Investigation of "On Water" Conditions Using a Biphasic Fluidic Platform
      Mellouli, Sonia; Bousekkine, Lise; Theberge, Ashleigh B.; Huck, Wilhelm T. S.
      Angewandte Chemie, International Edition (2012), 51 (32), 7981-7984, S7981/1-S7981/8CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We have demonstrated how biphasic flow can be used to study interfacial reactions on a macroscopic scale. Total flow rate, residence times, and most importantly, the interfacial area between the water and the org. phase can be precisely known and controlled in a (micro)fluidic system, which is not possible in bulk emulsions. We have used this technique to quantify the "on water" effect for the first time. We suggest as a possible mechanism the model based on the stabilization of the transition state by hydrogen bonding proposed by Jung and Marcus. But it is also quite apparent that the magnitude of the "on water" effect can be rather modest and even if the reaction is accelerated initially, the effect becomes less pronounced with longer reaction times. The interfacial nature of the reaction can greatly influence the overall reaction rates as product mols. might become pinned at the interface. These factors strongly counteract the favorable redn. in activation energy. Our method allows for rapid examn. of the key features of "on water" conditions, which could reduce the use of org. solvents.
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    42. 42
      Champagne, P. A.; Pomarole, J.; Thérien, M.-È.; Benhassine, Y.; Beaulieu, S.; Legault, C. Y.; Paquin, J.-F. Enabling Nucleophilic Substitution Reactions of Activated Alkyl Fluorides through Hydrogen Bonding. Org. Lett. 2013, 15, 2210– 2213,  DOI: 10.1021/ol400765a
      42
      Enabling Nucleophilic Substitution Reactions of Activated Alkyl Fluorides through Hydrogen Bonding
      Champagne, Pier Alexandre; Pomarole, Julien; Therien, Marie-Eve; Benhassine, Yasmine; Beaulieu, Samuel; Legault, Claude Y.; Paquin, Jean-Francois
      Organic Letters (2013), 15 (9), 2210-2213CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      It was discovered that the presence of water as a cosolvent enables the reaction of activated alkyl fluorides for bimol. nucleophilic substitution reactions. DFT calcns. show that activation proceeds through stabilization of the transition structure by a stronger F···H2O interaction and diminishing C-F bond elongation, and not simple transition state electrostatic stabilization. Overall, the findings put forward a distinct strategy for C-F bond activation through H-bonding.
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    43. 43
      Dhameliya, T. M.; Chourasiya, S. S.; Mishra, E.; Jadhavar, P. S.; Bharatam, P. V.; Chakraborti, A. K. Rationalization of Benzazole-2-Carboxylate versus Benzazine-3-One/Benzazine-2,3-Dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous Medium. J. Org. Chem. 2017, 82, 10077– 10091,  DOI: 10.1021/acs.joc.7b01548
      43
      Rationalization of Benzazole-2-carboxylate versus Benzazine-3-one/Benzazine-2,3-dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous Medium
      Dhameliya, Tejas M.; Chourasiya, Sumit S.; Mishra, Eshan; Jadhavar, Pradeep S.; Bharatam, Prasad V.; Chakraborti, Asit K.
      Journal of Organic Chemistry (2017), 82 (19), 10077-10091CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as Et glyoxalate and di-Et oxalate in aq. medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. The reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chem. calcns. (d. functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates vs. benzazine-3-ones/benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.
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    44. 44
      Acevedo, O.; Armacost, K. Claisen Rearrangements: Insight into Solvent Effects and “on Water” Reactivity from QM/MM Simulations. J. Am. Chem. Soc. 2010, 132, 1966– 1975,  DOI: 10.1021/ja908680c
      44
      Claisen Rearrangements: Insight into Solvent Effects and "on Water" Reactivity from QM/MM Simulations
      Acevedo, Orlando; Armacost, Kira
      Journal of the American Chemical Society (2010), 132 (6), 1966-1975CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An "on water" environment, defined by the absence of water soly. of the reactants, has been reported to provide increased rate accelerations, yields, and specificity for several types of org. reaction classes compared to org. solvents. The arom. Claisen rearrangements of allyl p-R-Ph ethers (R = CH3, Br, and OCH3) and allyl naphthyl ether have been investigated to det. the origin of the on water effect using QM/MM Monte Carlo calcns. and free-energy perturbation theory. The simulations indicate that on water rate enhancements for the rearrangements are derived from the ability of the interfacial waters to stabilize the polar transition state via enhanced hydrogen bonding at the oil/water interface. The position and orientation of the arom. ethers at the interface are crucial factors affecting solvent accessibility during the reaction pathway; computed solute-solvent energy pair distributions and radial distribution functions showed that hydrophobic substituents on the solute provided a more polar solvent environment than hydrophilic substituents by tilting the reacting oxygen toward the water surface. Calcns. in 16 different solvents accurately reproduced the exptl. trend of increased rates correlated to increasing solvent polarity. Hydrophobic effects did not provide a substantial contribution to the lowering of the free energy activation barrier (<0.5 kcal/mol), and solvent polarizability via a polarizable force field was also found to be negligible in the obsd. rate accelerations. New insight into solvent effects for the Claisen rearrangement is presented herein, and a QM/MM approach for computing reactions on a liq. surface is highlighted.
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    45. 45
      Grieco, P. A.; Brandes, E. B.; McCann, S.; Clark, J. D. Water as a Solvent for the Claisen Rearrangement: Practical Implications for Synthetic Organic Chemistry. J. Org. Chem. 1989, 54, 5849– 5851,  DOI: 10.1021/jo00286a010
      45
      Water as a solvent for the Claisen rearrangement: practical implications for synthetic organic chemistry
      Grieco, Paul A.; Brandes, Ellen B.; McCann, Stephen; Clark, Jerry D.
      Journal of Organic Chemistry (1989), 54 (25), 5849-51CODEN: JOCEAH; ISSN:0022-3263.
      The accelerating influence of water as a solvent on the rate of the Claisen rearrangement has been demonstrated on several substrates, thus illustrating the enormous potential it holds for those engaged in the synthesis of natural and unnatural products. Claisen rearrangement products which hitherto were inaccessible due to decompn. at high temps. or elimination can now be realized through the agency of water.
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    46. 46
      Moncrieff, D.; Wilson, S. Computational Linear Dependence in Molecular Electronic Structure Calculations Using Universal Basis Sets. Int. J. Quantum Chem. 2005, 101, 363– 371,  DOI: 10.1002/qua.20275
      46
      Computational linear dependence in molecular electronic structure calculations using universal basis sets
      Moncrieff, D.; Wilson, S.
      International Journal of Quantum Chemistry (2005), 101 (4), 363-371CODEN: IJQCB2; ISSN:0020-7608. (John Wiley & Sons, Inc.)
      A review. In this article, we compare the mol. calcns. reported by Jorge and coworkers with our previous studies.
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    47. 47
      Witte, J.; Neaton, J. B.; Head-Gordon, M. Push It to the Limit: Characterizing the Convergence of Common Sequences of Basis Sets for Intermolecular Interactions as Described by Density Functional Theory. J. Chem. Phys. 2016, 144, 194306,  DOI: 10.1063/1.4949536
      47
      Push it to the limit: Characterizing the convergence of common sequences of basis sets for intermolecular interactions as described by density functional theory
      Witte, Jonathon; Neaton, Jeffrey B.; Head-Gordon, Martin
      Journal of Chemical Physics (2016), 144 (19), 194306/1-194306/12CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      With the aim of systematically characterizing the convergence of common families of basis sets such that general recommendations for basis sets can be made, we have tested a wide variety of basis sets against complete-basis binding energies across the S22 set of intermol. interactions-noncovalent interactions of small and medium-sized mols. consisting of first- and second-row atoms-with three distinct d. functional approxns.: SPW92, a form of local-d. approxn.; B3LYP, a global hybrid generalized gradient approxn.; and B97M-V, a meta-generalized gradient approxn. with nonlocal correlation. We have found that it is remarkably difficult to reach the basis set limit; for the methods and systems examd., the most complete basis is Jensen's pc-4. The Dunning correlation-consistent sequence of basis sets converges slowly relative to the Jensen sequence. The Karlsruhe basis sets are quite cost effective, particularly when a correction for basis set superposition error is applied: counterpoise-cor. def2-SVPD binding energies are better than corresponding energies computed in comparably sized Dunning and Jensen bases, and on par with uncorrected results in basis sets 3-4 times larger. These trends are exhibited regardless of the level of d. functional approxn. employed. A sense of the magnitude of the intrinsic incompleteness error of each basis set not only provides a foundation for guiding basis set choice in future studies but also facilitates quant. comparison of existing studies on similar types of systems. (c) 2016 American Institute of Physics.
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    48. 48
      Finneran, I. A.; Carroll, P. B.; Allodi, M. A.; Blake, G. A. Hydrogen Bonding in the Ethanol–Water Dimer. Phys. Chem. Chem. Phys. 2015, 17, 24210– 24214,  DOI: 10.1039/C5CP03589A
      48
      Hydrogen bonding in the ethanol-water dimer
      Finneran, Ian A.; Carroll, P. Brandon; Allodi, Marco A.; Blake, Geoffrey A.
      Physical Chemistry Chemical Physics (2015), 17 (37), 24210-24214CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      We report the first rotational spectrum of the ground state of the isolated ethanol-water dimer using chirped-pulse Fourier transform microwave spectroscopy between 8-18 GHz. With the aid of isotopic substitutions, and ab initio calcns., we identify the measured conformer as a water-donor/ethanol-acceptor structure. Ethanol is found to be in the gauche conformation, while the monomer distances and orientations likely reflect a cooperation between the strong (O-H···O) and weak (C-H···O) hydrogen bonds that stabilizes the measured conformer. No other conformers were assigned in an argon expansion, confirming that this is the ground-state structure. This result is consistent with previous vibrationally-resolved Raman and IR work, but sheds addnl. light on the structure, due to the specificity of rotational spectroscopy.
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    49. 49
      PubChem Annotation Record for Sulfuric Acid. Hazardous Substances Data Bank (HSDB); National Center for Biotechnology Information, 2021.
      There is no corresponding record for this reference.
    50. 50
      Köckinger, M.; Hanselmann, P.; Roberge, D. M.; Geotti-Bianchini, P.; Kappe, C. O.; Cantillo, D. Sustainable Electrochemical Decarboxylative Acetoxylation of Aminoacids in Batch and Continuous Flow. Green Chem. 2021, 23, 2382– 2390,  DOI: 10.1039/D1GC00201E
      There is no corresponding record for this reference.
    51. 51
      Steiner, A.; Williams, J. D.; de Frutos, O.; Rincón, J. A.; Mateos, C.; Kappe, C. O. Continuous Photochemical Benzylic Bromination Using in Situ Generated Br2: Process Intensification towards Optimal PMI and Throughput. Green Chem. 2020, 22, 448– 454,  DOI: 10.1039/C9GC03662H
      51
      Continuous photochemical benzylic bromination using in situ generated Br2: process intensification towards optimal PMI and throughput
      Steiner, Alexander; Williams, Jason D.; de Frutos, Oscar; Rincon, Juan A.; Mateos, Carlos; Kappe, C. Oliver
      Green Chemistry (2020), 22 (2), 448-454CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
      The detailed development of photochem. benzylic brominations using a NaBrO3/HBr bromine generator in continuous flow mode is reported. Optimization of the bromine generator enables highly efficient mass utilization by HBr recycling, coupled with fast interphase transfer within a microstructured photochem. reactor (405 nm LEDs). Intensification of the reaction system, including complete removal of org. solvent, allowed a redn. in PMI from 13.25 to just 4.33. The photochem. transformation achieved exceptionally high throughput, providing complete conversion in residence times as low as 15 s. The org. solvent-free prepn. of two pharmaceutically relevant building blocks was demonstrated with outstanding mass efficiency, by monobromination (1.17 kg scale in 230 min, PMI = 3.08) or dibromination (15 g scale in 20 min, PMI = 3.64).
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    52. 52
      Prieschl, M.; García-Lacuna, J.; Munday, R.; Leslie, K.; O’Kearney-McMullan, A.; Hone, C. A.; Kappe, C. O. Optimization and Sustainability Assessment of a Continuous Flow Ru-Catalyzed Ester Hydrogenation for an Important Precursor of a Β2-Adrenergic Receptor Agonist. Green Chem. 2020, 22, 5762– 5770,  DOI: 10.1039/D0GC02225J
      52
      Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonist
      Prieschl, Michael; Garcia-Lacuna, Jorge; Munday, Rachel; Leslie, Kevin; O'Kearney-McMullan, Anne; Hone, Christopher A.; Kappe, C. Oliver
      Green Chemistry (2020), 22 (17), 5762-5770CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
      The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the redn. of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clin. trials for the treatment of asthma and chronic obstructive pulmonary disorder. The reaction was investigated within a batch autoclave by using a design of expts. (DoE) approach to identify important parameter effects. The optimized flow process was successfully operated over 6 h with inline benchtop 19F NMR spectroscopy for reaction monitoring. The protocol is shown to be high yielding (98% yield, 3.7 g h-1) with very low catalyst loading (0.065 mol%). The environmental impact of the Ru-catalyzed hydrogenation was assessed and compared to an existing stoichiometric lithium aluminum hydride (LAH) redn. and sodium borohydride (NaBH4) redn. The process mass intensity (PMI) for the Ru-catalyzed hydrogenation (14) compared favorably to a LAH redn. (52) and NaBH4 redn. (133).
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    53. 53
      Adamo, A.; Heider, P. L.; Weeranoppanant, N.; Jensen, K. F. Membrane-Based, Liquid–Liquid Separator with Integrated Pressure Control. Ind. Eng. Chem. Res. 2013, 52, 10802– 10808,  DOI: 10.1021/ie401180t
      53
      Membrane-based, liquid-liquid separator with integrated pressure control
      Adamo, Andrea; Heider, Patrick L.; Weeranoppanant, Nopphon; Jensen, Klavs F.
      Industrial & Engineering Chemistry Research (2013), 52 (31), 10802-10808CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)
      We describe the development and application of an improved, membrane-based, liq.-liq. separator. Membrane-based sepn. relies on the exploitation of surface forces and the use of a membrane wetted by one of the phases; however, successful sepn. requires accurate control of pressures, making the operation and implementation cumbersome. Here we present an improved separator design that integrates a pressure control element to ensure that adequate operating conditions are always maintained. Addnl., the integrated pressure control decouples the separator from downstream unit operations. A detailed examn. of the controlling phys. equations shows how to design the device to allow operation across a wide range of conditions. Easy to implement, multistage sepns. such as solvent swaps and countercurrent extns. are demonstrated. The presented design significantly simplifies applications ranging from multistep synthesis to complex multistage sepns.
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    54. 54
      Chapman, M. R.; Kwan, M. H. T.; King, G.; Jolley, K. E.; Hussain, M.; Hussain, S.; Salama, I. E.; González Nino, C.; Thompson, L. A.; Bayana, M. E.; Clayton, A. D.; Nguyen, B. N.; Turner, N. J.; Kapur, N.; Blacker, A. J. Simple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence Times. Org. Process Res. Dev. 2017, 21, 1294– 1301,  DOI: 10.1021/acs.oprd.7b00173
      54
      Simple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence Times
      Chapman, Michael R.; Kwan, Maria H. T.; King, Georgina; Jolley, Katherine E.; Hussain, Mariam; Hussain, Shahed; Salama, Ibrahim E.; Gonzalez Nino, Carlos; Thompson, Lisa A.; Bayana, Mary E.; Clayton, Adam D.; Nguyen, Bao N.; Turner, Nicholas J.; Kapur, Nikil; Blacker, A. John
      Organic Process Research & Development (2017), 21 (9), 1294-1301CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      A universal multi-stage cascade CSTR has been developed which is suitable for a wide range of continuous-flow processes. Coined by authors group the 'Freactor' (free-to-access reactor), the new reactor integrates the efficiency of pipe-flow processing with the advanced mixing of a CSTR, delivering a general 'plug-and-play' reactor platform which is well-suited to multiphasic continuous-flow chem. Importantly, the reactor geometry is easily customized to accommodate reactions requiring long residence times (≥ 3 h tested).
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    55. 55
      Becker, J.; Manske, C.; Randl, S. Green Chemistry and Sustainability Metrics in the Pharmaceutical Manufacturing Sector. Curr. Opin. Green Sustainable Chem. 2022, 33, 100562,  DOI: 10.1016/j.cogsc.2021.100562
      55
      Green chemistry and sustainability metrics in the pharmaceutical manufacturing sector
      Becker, Jochen; Manske, Carolin; Randl, Stefan
      Current Opinion in Green and Sustainable Chemistry (2022), 33 (), 100562CODEN: COGSC4; ISSN:2452-2236. (Elsevier B.V.)
      This review article summarizes recent developments of green chem. and sustainability metrics with a focus on the pharmaceutical industry. We discuss synergies and discrepancies of the green chem. principles with regulatory guidelines in the field of pharmaceutical process development and manufg. under Good Manufg. Practices (GMP). This review captures selected views and publications on green chem. and sustainability metrics. It discusses two recent process development highlights from the pharmaceutical industry which use different approaches to optimize the process mass intensity (PMI) of small-mol. active pharmaceutical ingredient (API) manufg. processes. The first example is the development of green process conditions by switching reaction media from org. solvents to micellar catalysis in water in the Takeda process of the API TAK-954. The second example features process intensifications accomplished by the application of innovative technologies in pharmaceutical processing in the Merck process of the API MK-7264.
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  • Supporting Information

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