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Synthesis of Janus All-Cis Tetrafluorocyclohexanes Carrying 1,4-Diether Motifs
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The Journal of Organic Chemistry

Cite this: J. Org. Chem. 2024, 89, 24, 18445–18451
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https://doi.org/10.1021/acs.joc.4c02345
Published November 27, 2024

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Abstract

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Nucleophilic aromatic substitutions (SNAr) of alkoxides on pentafluoroaryl ethers are explored as a first step in a synthesis sequence to generate all-cis 2,3,5,6-tetrafluorocyclohexyl-1,4-dialkyl ethers 1. The SNAr reaction was explored both experimentally and theoretically to rationalize ortho/para/meta selectivities. tert-Butyl deprotection of products followed by phenol alkylations introduces versatility to the synthesis. The final Rh(CAAC) 3 catalyzed aryl hydrogenation step of intermediate tetrafluoroaryl-1,4-diethers generated cyclohexane products 1. This chemistry introduces a new class of Janus fluorocyclohexane derivatives with ether substituents placed 1,4- to each other.

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Introduction

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There has been a recent discussion regarding the synthesis and properties of “thermodynamically disfavored” cyclohexanes, (1) where there is an ax/eq or eq/ax conformational ambiguity, such as is found in cis-1,2, trans-1,3, and cis-1,4 cyclohexanes, as illustrated in Figure 1. Chemistry to access such substitutions will generally tend toward thermodynamically preferred diequatorial isomers, and thus, specific methods have to be devised to achieve these thermodynamically disfavored cis-configurations. The relatively low representation of such compounds across the large organic molecule demographic runs counter to a wider consensus that molecules with an increased dimensionality offer new prospects for uncovering innovative properties from materials (2) to bioactives. (3)

Figure 1

Figure 1. “Thermodynamically disfavored” cyclohexanes and all-cis-1,2,3,4,5,6-hexafluorocyclohexane 2.

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In this paper, we explore the preparation of cis-1,4 cyclohexyl ethers 1, where the cyclohexane ring also has four fluorine atoms arranged around the ring and with an all-cis configuration. This is an extension of our current interest in facially polarized Janus cyclohexanes. (4) All-cis-1,2,3,4,5,6-hexafluorocyclohexane 2 has attracted some interest due to its high polarity, particularly as it is a cyclohexane, which as a class is generally found to be hydrophobic. (5) In the interconverting chair conformations of this cyclohexane, there are always triaxial C–F bonds pointing in the same direction, which impart a strong molecular dipole. It is the coalignment of the axial C–F bonds, which contribute most significantly to its the molecular polarity. (6)
These systems have been termed Janus cyclohexanes (7) as they have two faces (electropositive-H and electronegative-F face). The first preparation of 2 in our laboratory (5) from inositol was significantly improved by the Glorius laboratory, (8) who developed a direct aryl hydrogenation of hexafluorobenzene. The method involves high pressure hydrogenations (∼50 bar H2) using a Rh catalyst, which was applied to aryl hydrogenations by Zeng et al. (9) The catalyst 3 shown in Figure 2 contains the strongly electron-donating cyclic alkyl amino carbene ligand (CAAC) and reactions are carried out in low polarity solvents. This combination suppressed competing dehydrofluorination reactions, generating a series of Janus cyclohexanes with good efficiency. For the preparation of ethers, Glorius et al. (8c) exemplified the aryl hydrogenation of fluorophenyl silyl (TBS) ethers to the corresponding all-cis pentafluorocyclohexyl ethers, such as 4a. Subsequently, von Delius’s laboratory (10) demonstrated aryl hydrogenation to methyl ether 4b from the pentafluoroanisole precursor. This methyl ether could be converted to alcohol 4c and derivatized to acetate 4c and more elaborate esters, such as 4e, which acted as monomers displaying interesting dynamic behavior due to self-assembly equilibria between the Janus rings. Most recently, (11) von Delius’s laboratory has extended to examples of all-cis 1,3,5-triethers 7a and 7b (via triol 6), which have been prepared by aryl hydrogenations of trifluorotrimethoxybenzene 5 followed by demethylation. The three ether substituents in 7a and 7b adopt a thermodynamically favorable triequatorial conformation, and as a consequence, the three C–F bonds are triaxial. This arrangement is attractive as it offers trisubstituted cyclohexanes with a large dipole due to the oriented C–F bonds.

Figure 2

Figure 2. CAAC catalyst 3 and Janus ether substituted cyclohexanes. (8−10)

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We address here the synthesis of all-cis tetrafluoro disubstituted cyclohexanes 1, where alkyl ether substituents are cis-1,4 to each other. They are a class of Janus cyclohexanes where oxygens replace the 1,4-fluorines; however, there will always be an axial and an equatorial C-OR bond in interconverting chair conformations rendering these “thermodynamically disfavored”. The only example of a 1,4-ether that we are aware of is bis silyl ether 8, which was reported in the original Glorius paper. (8) The new class of Janus 1,4-dialkyl ethers may offer some advantages in that they will have more complex 3D arrangements and will be more dynamic in supramolecular assemblies. The route to these 1,4-cyclohexyl diethers exploits a para selective SNAr reaction on tButO-pentafluorophenol ether 10 and then aryl hydrogenations offer access to molecules of class 1.

Results and Discussion

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A general route to 1,4-disubstituted tetrafluorocyclohexyl ether 1 is outlined in Scheme 1. For SNAr reactions on pentafluoroaryl rings, a regiochemical preference for para over meta attack by nucleophiles is generally observed; although the bias is dependent on the indigenous substituent.

Scheme 1

Scheme 1. Synthesis Routes to All-Cis Tetrafluorocyclohexyl Diethers 1a–1e from tButO Ether 11
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For example, SNAr reactions on C6F5X systems with electron-withdrawing groups (–NO2, –CN) are very highly selective for para products (12) as is a –Ph substituent (13) or even an unsubstituted –H substituent. (14) For pentafluoroaryl ethers such as X = OMe, the para over the meta directing effect is much more modest relative to –H (14) and –Ph, (13) due to the mesomeric donor ability of the methoxyl group. In order to maximize the regiochemical preference in favor of para addition for an alkoxide nucleophile to a pentafluoroaryl ether, an exploration of progressively larger indigenous ether substituents (–OMe 9, –OiPr 10, and –OtBut 11) was conducted and with progressively larger alkoxide nucleophiles to enhance both steric and stereoelectronic factors. Reactions were conducted in THF with 9, 10, and 11 reacting with sodium methoxide (OMe–), iso-propoxide (iPrO–) and tert-butoxide (tButO–) as nucleophiles. The ortho/para/meta product ratios are represented in Table 1. It emerged that the meta/para ratio is the lowest in the reactions conducted on the tButO-aryl ether 11 and with tButO– as a nucleophile.
Table 1. Ortho/Para/Meta Ratios of Products from Reactions of 9–11 with Alkoxide Nucleophilesa
nucleophile9 (MeO)10 (iPrO)11 (tButO)
 orthoparametaorthoparametaorthoparameta
MeONa0.551.271.00.01.81.00.03.71.0
iPrONa0.491.341.00.01.71.00.04.31.0
tButONa0.281.811.00.02.41.00.07.11.0
a

Conditions: 9, 10 or 11 (1.0 equiv), alcohol (0.5 equiv), NaH (0.75 equiv), THF (3 mL), 2.5 h, 50 °C. (Ratios are an averages of triplicates).

It is not clear where the origin of this selectivity arises. In aryl ethers (anisoles), the MeO– substituent tends to adopt a planar orientation with respect to the aromatic ring, maximizing oxygen lone pair conjugation into the ring whereas the tButO– group adopts a perpendicular conformation, which will reduce the donor potential of the oxygen lone pairs. (15) However, the ortho fluorines in 9 also direct the –OMe to a more favored perpendicular conformation, (16) so stereoelectronically the MeO- and tButO-ethers are more equivalent in this perfluorinated series. In order to explore these effects further, reaction profiles with an alkoxide nucleophile were conducted computationally for MeO- ether 9 and tButO-ether 11. In each case, reaction profiles were modeled for para and meta trajectories and with MeO– and tButO– as nucleophiles.
It proved challenging to locate transition states (TSs), but they could be found employing a developing version of Autobench (17) for energy reaction barriers. Considering the methoxyl ether 9 as the substrate and with MeO– as the nucleophile, the energies of the TSs are very similar and only a little (1.3 and 1.6 kcal mol–1) above the ground state energy of 9, as illustrated in Figure 3a. In each case, the reaction is highly exergonic (ΔG0 = −14.9 and −17.8 kcal mol–1) with a high barrier to reversibility and thus the meta/para ratio appears to be determined kinetically with the meta TS a little higher (ΔΔG‡ = 0.8 kcal mol–1) than that of the para TS (Figure 4). When 11 is the substrate and with MeO– again as the nucleophile, the reaction follows a trend similar to that of 9, with a ΔΔG‡ = 0.9 kcal mol–1, but the reaction is very much more exergonic for the meta/para products (ΔG0 = −29.6 and −30.6 kcal mol–1), as illustrated in Figure 3b. On the other hand, when tButO– is the nucleophile combining with tButO ether 11, there is an increase in the reaction energy barriers to ΔΔG‡ = 2.5 kcal mol–1 favoring the para TS, and the reaction is also high exergonic, as illustrated in Figure 3c. In all of these reactions, intermediate Meisenheimer complexes could not be located computationally, and these reactions appear to progress through a concerted SNAr substitution process. Concerted processes have already been proposed for SNAr of perfluoroaromatics, (18,19) and this general mechanism for SNAr reactions was evaluated by Jacobsen (20) and has been discussed more widely. (21)

Figure 3

Figure 3. Reaction profiles for SNAr reactions of (a) 9 with OMe–; (b) 11 with OMe–; and (c) 11 with tButO–; each attacking either at the meta or para positions calculated at the M06-2X/6-311++G** level. The para reaction course is kinetically favored in each case.

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Figure 4

Figure 4. X-ray structures of 1,4-diethers (a) 1a and (b) 1d viewed from two trajectories.

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With the knowledge that the para/meta ratio is most influenced by an incipient tButO ether, 11 emerged as an attractive starting material in order to most effectively influence the para/meta regiochemistry. SNAr reactions generated the tButO ether products 12, predominantly as the para products, with lesser levels of meta isomers (≤15%), as illustrated in Scheme 1. The ethers were then conveniently cleaved to aryl ether phenols 13 by treatment with trifluoroacetic acid. Subsequent alkylation of phenols 13, in this case with 1-bromobutane or methyl iodide-generated diaryl ethers 14.
The resultant ethers 14 were then subject to aryl hydrogenations (H2 50 bar, cat 3) (8) to generate a range of all-cis tetrafluoro-substituted cyclohexyl diethers 1. The approach could reasonably be applied quite widely although the reactions explored here were conducted with well-known liquid crystal motifs as the targets. (22)
In the case of 1b–e, differential scanning calorimetry and polarized optical microscopy analysis showed significant levels of crystalline polymorphism in each case, although no LC phases were observed during both the heating and cooling processes (see Figures S1–S4). In all Janus cis-tetrafluorocyclohexane 1b–e, the alkoxy moieties introduced at the 1,4-positions occupy axial and equatorial positions, forming a bent structure, which appears to prevent LC phase formation.
1,4-Diether products 1a–e were solids and single crystals of 1a and 1d were obtained and submitted for X-ray structure analysis. The resultant structures are illustrated in Figure 4. In each case, the structures adopt the expected chair conformations in the solid state and, consequently, the 1,4-substitution dictates an axial and an equatorial ether bond in each cyclohexane. In both cases, it is the n-butyl ether that adopts the axial orientation. One feature of both structures is that the cyclohexane rings do not stack directly above each other; instead, they rotate such that the C–O bonds eclipse C–F bonds in the ring stacks. Essentially, there is less order in ring stacking relative to compounds where the substituents are all equatorial. (23)
In the solid state, only a single conformer is adopted; however, in solution, 19F-[1H}NMR analysis indicates that these compounds adopt ∼1:1 mixed ratios of presumably the chair conformers, when the ether substituents are nonequivalent and with these nonequivalent substituents switching between axial and equatorial orientations. This is obvious in the representative NMR spectra of 1a, as illustrated in Figure 5.

Figure 5

Figure 5. 19F{1H}-NMR of 1a showing an equilibrium mix of eq/ax 1a and ax/eq 1a in solution.

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The pathway and energy barrier to this interconversion was explored theoretically for the symmetric tetrafluoro dimethyl ether 1f and barriers to interconversion were compared relative to all-cis-hexafluorofluorocyclohexane 2 and to cyclohexane 15 itself to act as points of reference. Calculations were carried out at the M06-2X/6-311++G** theory level. (24,25) The resultant interconversion pathways and energy barriers are illustrated in Figure 6.

Figure 6

Figure 6. (a) Comparative cyclohexyl interconversion energy profiles for dimethoxy ether 1f, all-cis1,2,3,4,5,6-exafluorocyclohexane 2 and cyclohexane 15 showing the relative energies of intermediates. Energy values in kcal mol–1. (b) Schematic of the two interconversion pathways for cyclohexane 1f.

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The values computed here for the TSs and, also the twisted boat intermediates, are similar to those reported in previous studies for both all-cis1,2,3,4,5,6-hexafluorocyclohexane 2 (26) and cyclohexane 15 (27) and, therefore, we assume that the calculated conformational energy profile for 1f is relatively accurate. It is notable that the highest barrier to interconversion for 1f at the “half-chair” structure is close to that for 2 at its “half-chair” intermediate, suggesting a similar level of negative electrostatic interaction between the C–O and C–F bonds in 1f, and C–F and C–F bonds in 2 as the conformational profile progresses through these two intermediates. In fact, the “half-chair” TS in 1f is 0.8 kcal mol–1 lower in energy compared to 2 (15.0 against 15.8 kcal mol–1), which is attributed to the formation of OC–H···F stabilizing contacts formed between methoxy groups and fluorine atoms (Figure S8). These half–chair TSs are ∼4.0 kcal mol–1 above that for cyclohexane 15, where only C–H/C–H bond contacts are present. There are two conformational profiles for 1f, corresponding to two possible symmetrical boat intermediate structures where either two C–O or two C–F bonds occupy the apical positions of the TS structure (see Figure 6b). Ethoxylation at positions 1 and 4 on the fluorinated systems does not significantly affect the ring-flip energy barriers, which are around 15 kcal mol–1 and easily surmountable at room temperature. As a result, it is expected that asymmetric compounds 1a–e, despite showing a single conformer in the solid state, are in a rapid equilibrium between both chair conformers in solution.
In conclusion, we present a synthesis to all-cis 2,3,5,6-tetrafluorocyclohexanes 1 carrying 1,4-diether moieties, as a new class of Janus cyclohexanes. These were prepared by SNAr chemistry with various alkoxide nucleophiles on pentafluoroaryl ether 11. Cleavage of the tButO ethers 12 followed by alkylation of the resultant phenols 13, allowed a range of 1,4 diethers 14 to be prepared, and these were subjected to aryl hydrogenations to generate cyclohexanes of class 1. Low levels of the meta isomers were evident from the SNAr reaction, a reaction that was investigated computationally. This analysis indicated a maximum energy difference (∼2.5 kcal mol–1) between para and meta TSs, for tButO ether 11 and tBuO– as a nucleophile, which is consistent with the experimental outcomes. These “thermodynamically disfavored” compounds form less ordered arrangements in the solid state than previous prepared all-cis-fluorocyclohexanes. (23,28)

Data Availability

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The data underlying this study are available in the published article and its Supporting Information.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c02345.

  • Experimental details and analyses of prepared compounds 1a–1e, copies of 1H, 13C{1H} and 19F{1H} NMR spectra, X-ray data 1a and 1d, details of computation reaction barriers for SNAr reactions on 9 and 11, and interconversion barriers for cyclohexanes 1f, 2, and 15 (PDF)

Accession Codes

Deposition numbers 2384410–2384411 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Centre (CCDC) and Fachinformationszentrum Karlsruhe Access Structures service.

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Author Information

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  • Corresponding Authors
  • Authors
    • Thomas J. Poskin - School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K.
    • Bruno A. Piscelli - Instituto de Química, Departamento de Química Orgânica, Universidade Estadual de Campinas, P.O. Box 6154, Campinas, São Paulo 13083-970, Brazil
    • Aidan P. McKay - School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K.;  Orcidhttps://orcid.org/0000-0002-8578-7054
    • David B. Cordes - School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K.;  Orcidhttps://orcid.org/0000-0002-5366-9168
    • Yuto Eguchi - Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
    • Shigeyuki Yamada - Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan;  Orcidhttps://orcid.org/0000-0002-6379-0447
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank EPSRC (EP/S030506) UK, and FAPESP Brazil are thanked for a Young Researcher Award to R.A.C. (#2018/03910-1) and Scholarships to B.A.P. (#2023/14064-2 and #2022/10156-7). CNPq is acknowledged for a fellowship to R.A.C. (#306912/2023-6) and FAEPEX for research funding. CENAPAD-SP and CESUP computational resources are also gratefully acknowledged.

References

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This article references 28 other publications.

  1. 1
    Li, Y.; Shi, H.; Yin, G. Synthetic techniques for thermodynamically disfavoured substituted six-membered rings. Nat. Rev. Chem 2024, 8, 535– 550,  DOI: 10.1038/s41570-024-00612-3
    Google Scholar
    There is no corresponding record for this reference.
  2. 2
    (a) Chang, J.; Chen, F.; Li, H.; Suo, J.; Zheng, H.; Zhang, J.; Wang, Z.; Valtchev, V.; Qiu, S.; Fang, Q. Three-dimensional covalent organic frameworks with nia nets for efficient separation of benzene/cyclohexane mixtures. Nat. Commun. 2024, 15, 813,  DOI: 10.1038/s41467-024-45005-8
    Google Scholar
    There is no corresponding record for this reference.
    (b) Ma, X.; Scott, T. F. Approaches and challenges in the synthesis of three-dimensional covalent-organic frameworks. Commun. Chem. 2018, 1, 98,  DOI: 10.1038/s42004-018-0098-8
    Google Scholar
    There is no corresponding record for this reference.
  3. 3
    (a) Wang, Z.; Sharma, P. P.; Rathi, B.; Xie, M.; De Clercq, E.; Pannecouque, C.; Kang, D.; Zhan, P.; Liu, X. Escaping from Flatland: Multiparameter Optimization Leads to the Discovery of Novel Tetrahydropyrido[4,3-d]pyrimidine Derivatives as Human Immunodeficiency Virus-1 Non-nucleoside Reverse Transcriptase Inhibitors with Superior Antiviral Activities against Non-nucleoside Reverse Transcriptase Inhibitor-Resistant Variants and Favorable Drug-like Profiles. J. Med. Chem. 2023, 66, 8643– 8665,  DOI: 10.1021/acs.jmedchem.3c00275
    Google Scholar
    There is no corresponding record for this reference.
    (b) Lovering, F. Escape from Flatland 2: Complexity and Promiscuity. MedChemComm 2013, 4, 515– 519,  DOI: 10.1039/c2md20347b
    Google Scholar
    3b
    Escape from Flatland 2: complexity and promiscuity
    Lovering, Frank
    MedChemComm (2013), 4 (3), 515-519CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
    Toxicity plays a major role in attrition in the clinic and promiscuity has been linked to toxicity. A no. of mol. descriptors have been identified that contribute to promiscuity including ionization and logP. In this study we report on the relationship between complexity, as measured by two descriptors [fraction sp3 (Fsp3) where Fsp3 = (no. of sp3 hybridized carbons/total carbon count) and chiral carbon count], and promiscuity as well as Cyp450 inhibition. We find that increasing complexity reduces promiscuity and Cyp450 inhibition. As an understanding of key property descriptors has helped the pharmaceutical industry to address some of the deficiencies of compds. as pertains to bioavailability, awareness of the descriptors that impact promiscuity should allow us to better address toxicity in the clinic.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtFShtL0%253D&md5=c03d3b99da22a684cbbbb00fb1633342
  4. 4
    O’Hagan, D. The Emergence and Properties of Selectively Fluorinated ‘Janus’ Cyclohexanes. Chem. Rec. 2023, 23, e202300027  DOI: 10.1002/tcr.202300027
    Google Scholar
    There is no corresponding record for this reference.
  5. 5
    Keddie, N. S.; Slawin, A. M. Z.; Lebl, T.; Philp, D.; O’Hagan, D. All-cis 1,2,3,4,5,6-Hexafluorocyclohexane is a Facially Polarized Cyclohexane. Nat. Chem. 2015, 7, 483– 488,  DOI: 10.1038/nchem.2232
    Google Scholar
    5
    All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexane
    Keddie, Neil S.; Slawin, Alexandra M. Z.; Lebl, Tomas; Philp, Douglas; O'Hagan, David
    Nature Chemistry (2015), 7 (6), 483-488CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    The highest-energy stereoisomer of 1,2,3,4,5,6-hexafluorocyclohexane, in which all of the fluorines are 'up', is prepd. in a 12-step protocol. The mol. adopts a classic chair conformation with alternate C-F bonds aligned triaxially, clustering three highly electroneg. fluorine atoms in close proximity. This generates a cyclohexane with a high mol. dipole (μ = 6.2 D), unusual in an otherwise aliph. compd. X-ray anal. indicates that the intramol. Fax···Fax distances (∼2.77 Å) are longer than the vicinal Fax···Feq distances (∼2.73 Å) suggesting a tension stabilizing the chair conformation. In the solid state the mols. pack in an orientation consistent with electrostatic ordering. Our synthesis of this highest-energy isomer demonstrates the properties that accompany the placement of axial fluorines on a cyclohexane and the unusual property of a facially polarized ring in org. chem. Derivs. have potential as new motifs for the design of functional org. mols. or for applications in supramol. chem. design.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtleisr8%253D&md5=811e1998f3076508664eebee80d4ecac
  6. 6
    (a) Lecours, M. J.; Marta, R. A.; Steinmetz, V.; Keddie, N. S.; Fillion, E.; O’Hagan, D.; McMahon, T. B.; Hopkins, W. S. Interaction of B12F122- with All-cis 1,2,3,4,5,6 Hexafluorocyclohexane in the Gas Phase. J. Phys. Chem. Lett. 2017, 8, 109– 113,  DOI: 10.1021/acs.jpclett.6b02629
    Google Scholar
    6a
    Interaction of B12F122- with All-cis 1,2,3,4,5,6 Hexafluorocyclohexane in the Gas Phase
    Lecours, Michael J.; Marta, Rick A.; Steinmetz, Vincent; Keddie, Neil; Fillion, Eric; O'Hagan, David; McMahon, Terrance B.; Hopkins, W. Scott
    Journal of Physical Chemistry Letters (2017), 8 (1), 109-113CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
    Clusters of all-cis 1,2,3,4,5,6-hexafluorocyclohexane and the dodecafluorododecaboron dianion, [C6F6H6]n[B12F12]2- (n = 0-4), are investigated in a combined exptl. and computational study. DFT calcns. and IRMPD spectra in the region of 800-2000 cm-1 indicate that C6H6F6 binds to open trigonal faces of B12F122- via a three-point interlocking binding motif. Calcd. binding interactions reveal substantial contributions from C-H···F hydrogen bonding and binding energies that are among the strongest obsd. for a neutral-anion system.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVWms73M&md5=733228a477f57990cef30105331ff8f3
    (b) Ziegler, B. E.; Lecours, M.; Marta, R. A.; Featherstone, J.; Fillion, E.; Hopkins, W. S.; Steinmetz, V.; Keddie, N. S.; O’Hagan, D.; McMahon, T. B. Janus Face Aspect of All-cis 1,2,3,4,5,6-Hexafluorocyclohexane Dictates Remarkable Anion and Cation Interactions In the Gas Phase. J. Am. Chem. Soc. 2016, 138, 7460– 7463,  DOI: 10.1021/jacs.6b02856
    Google Scholar
    6b
    Janus Face Aspect of All-cis 1,2,3,4,5,6-Hexafluorocyclohexane Dictates Remarkable Anion and Cation Interactions In the Gas Phase
    Ziegler, Blake E.; Lecours, Michael; Marta, Rick A.; Featherstone, Joshua; Fillion, Eric; Hopkins, W. Scott; Steinmetz, Vincent; Keddie, Neil S.; O'Hagan, David; McMahon, Terrance B.
    Journal of the American Chemical Society (2016), 138 (24), 7460-7463CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Expts. were carried out in which electrospray ionization was used to generate ionic complexes of all-cis-1,2,3,4,5,6-hexafluorocyclohexane. These complexes were subsequently mass isolated in a quadrupole ion trap mass spectrometer and then irradiated by the tunable IR output of a free electron laser in the 800-1600 cm-1 range. From the frequency dependence of the fragmentation of the complexes, vibrational signatures of the complexes were obtained. Computational work carried out in parallel reveals that the complexes formed are very strongly bound and are among the most strongly bound complexes of Na+ and Cl- ever obsd. with mol. species. The dipole moment calcd. for the heaxafluorocyclohexane is very large (∼7 D), and apparently the bonding in each of the complexes has a significant electrostatic contribution.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntlCmurY%253D&md5=cc190a84a0a188ba31223d86e68ebfdf
  7. 7
    Santschi, N.; Gilmour, R. A Janus Cyclohexane Ring. Nat. Chem. 2015, 7, 467– 468,  DOI: 10.1038/nchem.2240
    Google Scholar
    7
    Organofluorine chemistry A Janus cyclohexane ring
    Santschi, Nico; Gilmour, Ryan
    Nature Chemistry (2015), 7 (6), 467-468CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    The first synthesis of the all-cis isomer of 1,2,3,4,5,6-hexafluorocyclohexane, a mol. with one hydrocarbon face and one fluorocarbon face, is a tour de force of organofluorine chem. and opens up new possibilities for mol. design.
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  8. 8
    (a) Nairoukh, Z.; Wollenburg, M.; Schlepphorst, C.; Bergander, K.; Glorius, F. The Formation of All-cis-(Multi)Fluorinated Piperidines by a Dearomatization-Hydrogenation Process. Nat. Chem. 2019, 11, 264– 270,  DOI: 10.1038/s41557-018-0197-2
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    8a
    The formation of all-cis-(multi)fluorinated piperidines by a dearomatization-hydrogenation process
    Nairoukh, Zackaria; Wollenburg, Marco; Schlepphorst, Christoph; Bergander, Klaus; Glorius, Frank
    Nature Chemistry (2019), 11 (3), 264-270CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
    Piperidines and fluorine substituents are both independently indispensable components in pharmaceuticals, agrochems. and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochem. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalyzed dearomatization-hydrogenation of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete satn. of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine substituents were successfully applied in the prepn. of com. drug analogs. Addnl., fluorinated PipPhos as well as fluorinated ionic liqs. were obtained by this dearomatization-hydrogenation process.
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    (b) Wiesenfeldt, M. P.; Knecht, T.; Schlepphorst, C.; Glorius, F. Silylarene Hydrogenation: A Strategic Approach that Enables Direct Access to Versatile Silylated Saturated Carbo- and Heterocycles. Angew. Chem., Int. Ed. 2018, 57, 8297– 8300,  DOI: 10.1002/anie.201804124
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    8b
    Silylarene Hydrogenation: A Strategic Approach that Enables Direct Access to Versatile Silylated Saturated Carbo- and Heterocycles
    Wiesenfeldt, Mario P.; Knecht, Tobias; Schlepphorst, Christoph; Glorius, Frank
    Angewandte Chemie, International Edition (2018), 57 (27), 8297-8300CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    We report a method to convert readily available silylated arenes into silylated satd. carbo- and heterocycles by arene hydrogenation. The scope includes alkoxy- and halosilyl substituents. Silyl groups can be derivatized into a plethora of functionalities and find application in org. synthesis, materials science, and pharmaceutical, agrochem., and fragrance research. However, silylated satd. (hetero- ) cycles are difficult to access with current technologies. The yield of the hydrogenation depends on the amt. of the silica gel additive. This silica effect also enables a significant improvement of a previously disclosed method for the hydrogenation of highly fluorinated arenes (e.g., to all-cis-C6H6F6).
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    (c) Wiesenfeldt, M. P.; Nairoukh, Z.; Li, W.; Glorius, F. Hydrogenation of Fluoroarenes. Direct Access to All-cis (Multi)Fluorinated Cycloalkanes. Science 2017, 357, 908– 912,  DOI: 10.1126/science.aao0270
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  9. 9
    (a) Zhang, X.; Ling, L.; Luo, M.; Zeng, X. Accessing Difluoromethylated and Trifluoromethylated cis-Cycloalkanes and Saturated Heterocycles: Preferential Hydrogen Addition to the Substitution Sites for Dearomatization. Angew. Chem., Int. Ed. 2019, 58, 16785– 16789,  DOI: 10.1002/anie.201907457
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    9a
    Accessing Difluoromethylated and Trifluoromethylated cis-Cycloalkanes and Saturated Heterocycles: Preferential Hydrogen Addition to the Substitution Sites for Dearomatization
    Zhang, Xue; Ling, Liang; Luo, Meiming; Zeng, Xiaoming
    Angewandte Chemie, International Edition (2019), 58 (47), 16785-16789CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A straightforward process in which a cyclic (alkyl)(amino)carbene/Rh catalyst system facilitates preferential addn. of hydrogen to substitution sites of difluoromethylated and trifluoromethylated arenes and heteroarenes, leading to dearomative redn. was reported. This strategy enabled diastereoselective synthesis of cis-difluoromethylated and cis-trifluoromethylated cycloalkanes such as I [R = 2-COMe, 4-pyrazolyl, 3-OTBS, etc.; R1 = CF2H, CF3] and satd. heterocycles, e.g. II, and even allowed formation of all-cis multi-trifluoromethylated cyclic products with a defined equatorial orientation of the di- and trifluoromethyl groups. Deuterium-labeling studies indicated that hydrogen preferentially attacked substitution sites of planar arenes, resulting in dearomatization, possibly with heterogeneous Rh as reactive species, followed by either reversible or irreversible hydrogen addn. to nonsubstitution sites.
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    (b) Wei, Y.; Rao, B.; Cong, X.; Zeng, X. Highly Selective Hydrogenation of Aromatic Ketones and Phenols Enabled by Cyclic (Amino)(alkyl)carbene Rhodium Complexes. J. Am. Chem. Soc. 2015, 137, 9250– 9253,  DOI: 10.1021/jacs.5b05868
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    9b
    Highly Selective Hydrogenation of Aromatic Ketones and Phenols Enabled by Cyclic (Amino)(alkyl)carbene Rhodium Complexes
    Wei, Yu; Rao, Bin; Cong, Xuefeng; Zeng, Xiaoming
    Journal of the American Chemical Society (2015), 137 (29), 9250-9253CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Air-stable Rh complexes ligated by strongly σ-donating cyclic (amino)(alkyl)carbenes (CAACs) show unique catalytic activity for the selective hydrogenation of arom. ketones and phenols by reducing the aryl groups. The use of CAAC ligands is essential for achieving high selectivity and conversion. This method is characterized by its good compatibility with unsatd. ketones, esters, carboxylic acids, amides, and amino acids and is scalable without detriment to its efficiency.
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  10. 10
    (a) Haridas, S. V.; Shyshov, O.; von Delius, M. Supramolecular Polymerization of All-cis Fluorinated Cyclohexanes: Influence of Side Chains. Org. Mater. 2023, 5, 166– 174,  DOI: 10.1055/s-0043-1761314
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    (b) Shyshov, O.; Haridas, S. V.; Pesce, L.; Qi, H.; Gardin, A.; Bochicchio, D.; Kaiser, U.; Pavan, G. M.; von Delius, M. Living Supramolecular Polymerization of Fluorinated Cyclohexanes. Nat. Commun. 2021, 12, 3134,  DOI: 10.1038/s41467-021-23370-y
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    10b
    Living supramolecular polymerization of fluorinated cyclohexanes
    Shyshov, Oleksandr; Haridas, Shyamkumar Vadakket; Pesce, Luca; Qi, Haoyuan; Gardin, Andrea; Bochicchio, Davide; Kaiser, Ute; Pavan, Giovanni M.; von Delius, Max
    Nature Communications (2021), 12 (1), 3134CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    The development of powerful methods for living covalent polymn. has been a key driver of progress in org. materials science. While there have been remarkable reports on living supramol. polymn. recently, the scope of monomers is still narrow and a simple soln. to the problem is elusive. Here we report a minimalistic mol. platform for living supramol. polymn. that is based on the unique structure of all-cis 1,2,3,4,5,6-hexafluorocyclohexane, the most polar aliph. compd. reported to date. We use this large dipole moment (6.2 Debye) not only to thermodynamically drive the self-assembly of supramol. polymers, but also to generate kinetically trapped monomeric states. Upon addn. of well-defined seeds, we obsd. that the dormant monomers engage in a kinetically controlled supramol. polymn. The obtained nanofibers have an unusual double helical structure and their length can be controlled by the ratio between seeds and monomers. The successful prepn. of supramol. block copolymers demonstrates the versatility of the approach.
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    (c) Shyshov, O.; Siewerth, K. A.; von Delius, M. Evidence for Anion-Binding of All-cis Hexafluorocyclohexane in Solution and Solid State. Chem. Commun. 2018, 54, 4353– 4355,  DOI: 10.1039/C8CC01797B
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    10c
    Evidence for anion-binding of all-cis hexafluorocyclohexane in solution and solid state
    Shyshov, Oleksandr; Siewerth, Kevin Andre; von Delius, Max
    Chemical Communications (Cambridge, United Kingdom) (2018), 54 (34), 4353-4355CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    The authors report a soln. NMR and x-ray crystallog. study on the anion affinity of all-cis 1,2,3,4,5,6-hexafluorocyclohexane, which has only recently become synthetically accessible. The authors' results suggest that the interaction exhibits preferential 1 : 1 stoichiometry, while its strength is only moderate (e.g. Ka = 400 M-1 in acetone for Cl-) and depends mainly on the size of the anion and the dielec. const. of the solvent.
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  11. 11
    Haridas, S. V.; von Delius, M. Synthesis and Supramolecular Properties of All-cis-2,4,6-Trifluorocyclohexane-1,3,5-triol. Chem. Commun. 2024, 60, 606– 609,  DOI: 10.1039/D3CC05510H
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    There is no corresponding record for this reference.
  12. 12
    Burdon, J.; Hollyhead, W. B.; Patrick, C. R.; Wilson, K. V. 1184. Kinetics of nucleophilic substitution in polyfluoro-aromatic compounds. Part I. The reaction of sodium methoxide with some pentafluorophenyl-compounds. J. Chem. Soc. 1965, 6375– 6379,  DOI: 10.1039/jr9650006375
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    There is no corresponding record for this reference.
  13. 13
    Kvíčala, J.; Beneš, M.; Paleta, O.; Král, V. Regiospecific Nucleophilic Substitution in 2,3,4,5,6-Pentafluorobiphenyl as Model Compound for Supramolecular Systems. Theoretical Study of Transition States and Energy Profiles, Evidence for Tetrahedral SN2 Mechanism. J. Fluorine Chem. 2010, 131, 1327– 1337,  DOI: 10.1016/j.jfluchem.2010.09.003
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    13
    Regiospecific nucleophilic substitution in 2,3,4,5,6-pentafluorobiphenyl as model compound for supramolecular systems. Theoretical study of transition states and energy profiles, evidence for tetrahedral SN2 mechanism
    Kvicala, Jaroslav; Benes, Michal; Paleta, Oldrich; Kral, Vladimir
    Journal of Fluorine Chemistry (2010), 131 (12), 1327-1337CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
    2,3,4,5,6-Pentafluorobiphenyl (PFBi) was modified by the nucleophilic substitution of one fluorine using a series of O-, S- and N-nucleophiles, viz. alk. salts of 2,2,2-trifluoro-ethanol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol, 1,2;3,4-di-O-isopropylidenexylitol, allylsulfane, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctane-1-thiol, 3-aminopropan-1-ol (7), and tert-Bu N-(3-aminopropyl)carbamate (8). All the substitutions took place exclusively at the position para to the Ph group. (3-Amino-propyl)amino deriv. of PFBi (15) was further modified at the terminal amino group by acylation or fluoroalkylation. The reaction of 8 was applied to meso-5,10,15,20-tetrakis-(pentafluorophenyl)porphyrin (20) to afford tris- (21) and tetrakis-substituted (22) products with complete para-regioselectivity. Theor. studies of the reaction pathways of PFBi with ammonia, microsolvated lithium fluoride or lithium hydroxide revealed that no Meisenheimer-type intermediates are formed in the course of the simulated reactions: instead, tetrahedral SN2 mechanism was found. Significant regioselectivity of the nucleophilic arom. substitution, leading to 4-substituted products, was predicted based on relative transition state energies in agreement with the obsd. exptl. results.
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  14. 14
    Brooke, G. M.; Burdon, J.; Tatlow, J. C. J. Aromatic Polyfluoro Compounds XII. Orientation Reactions of Pentafluorobenzene. Chem. Soc. 1962, 3253– 3254
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    There is no corresponding record for this reference.
  15. 15
    Tsuzuki, S.; Houjou, H.; Nagawa, Y.; Hiratani, K. High-Level Ab-initio Calculations of Torsional Potential of Phenol, Anisole, and o-Hydroxyanisole: Effects of Intramolecular Hydrogen Bond. J. Phys. Chem. A 2000, 104, 1332– 1336,  DOI: 10.1021/jp993607e
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    15
    High-Level ab Initio Calculations of Torsional Potential of Phenol, Anisole, and o-Hydroxyanisole: Effects of Intramolecular Hydrogen Bond
    Tsuzuki, Seiji; Houjou, Hirohiko; Nagawa, Yoshinobu; Hiratani, Kazuhisa
    Journal of Physical Chemistry A (2000), 104 (6), 1332-1336CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    The internal rotational barrier heights of phenol and anisole were calcd. using several basis sets up to cc-pVQZ with MP2-level electron correlation correction to evaluate the basis set effects. The calcns. showed that the effects of the further improvement of the basis set beyond the cc-pVTZ were very small. Although the electron correlation substantially increased the barrier heights of the two mols., the effects of the electron correlation beyond the MP2 method were not large. The barrier heights calcd. with the CCSD(T) method were close to those with the MP2 method. The internal rotational potentials of methoxy and hydroxyl groups of o-hydroxyanisole were calcd. at the MP2/cc-pVTZ//HF/6-311G** level. The calcd. potentials were compared with those of phenol and anisole. O-Hydroxyanisole preferred planar structure in which the hydroxyl group had an intramol. hydrogen bond with the oxygen atom of the methoxy group. The calcd. torsional potential of the methoxy group had the max. (7.30 kcal/mol) when the methoxy group rotated 180° from the min. energy structure, in which the hydroxyl group did not have the hydrogen bond. The barrier height of the methoxy group of o-hydroxyanisole was considerably larger than that of anisole (2.99 kcal/mol). The large internal rotational barrier height of o-hydroxyanisole showed that the intramol. hydrogen bond greatly stabilized the energy min. structure and that the hydrogen bond strictly restricted the conformational flexibility of the methoxy group.
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  16. 16
    Belyakov, A. V.; Kieninger, M.; Cachau, R. E.; Ventura, O. N.; Oberhammer, H. Molecular Structure and Internal Rotation in 2,3,5,6-Tetrafluoroanisole as Studied by Gas-Phase Electron Diffraction and Quantum Chemical Calculations. J. Phys. Chem. A 2005, 109, 394– 399,  DOI: 10.1021/jp046975d
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    16
    Molecular Structure and Internal Rotation in 2,3,5,6-Tetrafluoroanisole as Studied by Gas-Phase Electron Diffraction and Quantum Chemical Calculations
    Belyakov, Alexander V.; Kieninger, Martina; Cachau, Raul E.; Ventura, Oscar N.; Oberhammer, Heinz
    Journal of Physical Chemistry A (2005), 109 (2), 394-399CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    The geometric structure of 2,3,5,6-tetrafluoroanisole and the potential function for internal rotation around the C(sp2)-O bond were detd. by gas electron diffraction (GED) and quantum chem. calcns. Anal. of the GED intensities with a static model resulted in near-perpendicular orientation of the O-CH3 bond relative to the benzene plane with a torsional angle around the C(sp2)-O bond of τ(C-O) = 67(15)°. With a dynamic model, a wide single-min. potential for internal rotation around the C(sp2)-O bond with perpendicular orientation of the methoxy group [τ(C-O) = 90°] and a barrier of 2.7 ± 1.6 kcal/mol at planar orientation [τ(C-O) = 0°] was derived. Calcd. potential functions depend strongly on the computational method (HF, MP2, or B3LYP) and converge adequately only if large basis sets are used. The electronic energy curves show internal structure, with local min. appearing because of the interplay between electron delocalization, changes in the hybridization around the oxygen atom, and the attraction between the pos. polarized hydrogen atoms in the Me group and the fluorine atom at the ortho position. The internal structure of the electronic energy curves mostly disappears if zero-point energies and thermal corrections are added. The calcd. free energy barrier at 298 K is 2.0 ± 1.0 kcal/mol, in good agreement with the exptl. detn.
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  17. 17
    Cormanich, R. A.; da Silva, G. D. Autobench V1.0: Benchmarking Automation for Electronic Structure Calculations. J. Chem. Inf. Model. 2024, 64, 3322– 3331,  DOI: 10.1021/acs.jcim.4c00250
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    There is no corresponding record for this reference.
  18. 18
    Sadowsky, D.; McNeill, K.; Cramer, C. J. Dehalogenation of Aromatics by Nucleophilic Aromatic Substitution. Environ. Sci. Technol. 2014, 48, 10904– 10911,  DOI: 10.1021/es5028822
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    18
    Dehalogenation of Aromatics by Nucleophilic Aromatic Substitution
    Sadowsky, Daniel; McNeill, Kristopher; Cramer, Christopher J.
    Environmental Science & Technology (2014), 48 (18), 10904-10911CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    Nucleophilic arom. substitution has been implicated as a mechanism for both the biotic and abiotic hydrodehalogenation of aroms. Two mechanisms for the aq. dehalogenation of aroms. involving nucleophilic arom. substitution with hydride as a nucleophile are investigated using a validated d. functional and continuum solvation protocol. For chlorinated and brominated aroms., nucleophilic addn. ortho to carbon-halogen bonds via an anionic intermediate is predicted to be the preferred mechanism in the majority of cases, while concerted substitution is predicted to be preferred for most fluorinated aroms. Nucleophilic arom. substitution reactions with the hydroxide and hydrosulfide anions as nucleophiles are also investigated and compared.
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  19. 19
    Kikushima, K.; Grellier, M.; Ohashi, M.; Ogoshi, S. Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution With a Hydrosilicate. Angew. Chem., Int. Ed. 2017, 56, 16191– 16196,  DOI: 10.1002/anie.201708003
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    19
    Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate
    Kikushima, Kotaro; Grellier, Mary; Ohashi, Masato; Ogoshi, Sensuke
    Angewandte Chemie, International Edition (2017), 56 (51), 16191-16196CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Polyfluorinated arenes underwent regioselective transition metal-free hydrodefluorination with Ph3SiH or Et2SiH2 in the presence of tetrabutylammonium difluorotriphenylsilicate (TBAT) in THF. For example, hexafluorobenzene underwent hydrodefluorination with Et2SiH2 at 60° to yield pentafluorobenzene in 19% yield, 1,2,4,5-tetrafluorobenzene in 70% yield, and 1,2,3,5-tetrafluorobenzene and 1,2,3,4-tetrafluorobenzene in 2% yields. The reaction involves direct hydride transfer from a hydrosilicate as the key intermediate, which is generated from a hydrosilane and a fluoride salt; the eliminated fluoride regenerates the hydrosilicate to complete the catalytic cycle. The mechanism was studied using stoichiometric reactions of silicates and using dispersion-cor. DFT calcns.; hydrodefluorination likely proceeds via concerted nucleophilic arom. substitution.
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  20. 20
    Kwan, E. E.; Zeng, Y.; Besser, H. A.; Jacobsen, E. N. Concerted Nucleophilic Aromatic Substitutions. Nat. Chem. 2018, 10, 917– 923,  DOI: 10.1038/s41557-018-0079-7
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    20
    Concerted nucleophilic aromatic substitutions
    Kwan, Eugene E.; Zeng, Yuwen; Besser, Harrison A.; Jacobsen, Eric N.
    Nature Chemistry (2018), 10 (9), 917-923CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
    Nucleophilic arom. substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chem. research, providing a broadly useful platform for the modification of arom. ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addn.-elimination sequence via a discrete, non-arom. Meisenheimer complex. Here the authors use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C-F bonds.
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  21. 21
    Rohrbach, S.; Smith, A. J.; Pang, J. H.; Poole, D. L.; Tuttle, T.; Chiba, S.; Murphy, J. A. Concerted Nucleophilic Aromatic Substitution Reactions. Angew. Chem., Int. Ed. 2019, 58, 16368– 16388,  DOI: 10.1002/anie.201902216
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    21
    Concerted Nucleophilic Aromatic Substitution Reactions
    Rohrbach, Simon; Smith, Andrew J.; Pang, Jia Hao; Poole, Darren L.; Tuttle, Tell; Chiba, Shunsuke; Murphy, John A.
    Angewandte Chemie, International Edition (2019), 58 (46), 16368-16388CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Recent developments in exptl. and computational chem. have identified a rapidly growing class of nucleophilic arom. substitutions that proceed by concerted (cSNAr) rather than classical, two-step, SNAr mechanisms. Whereas traditional SNAr reactions require substantial activation of the arom. ring by electron-withdrawing substituents, such activating groups are not mandatory in the concerted pathways.
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  22. 22
    Kirsch, P.; Bremer, M. Nematic Liquid Crystals for Active Matrix Displays: Molecular Design and Synthesis. Angew. Chem., Int. Ed. 2000, 39, 4216– 4235,  DOI: 10.1002/1521-3773(20001201)39:23<4216::AID-ANIE4216>3.0.CO;2-K
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    22
    Nematic liquid crystals for active matrix displays: molecular design and synthesis
    Kirsch, Peer; Bremer, Matthias
    Angewandte Chemie, International Edition (2000), 39 (23), 4216-4235CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
    A review, with 122 refs. Substances forming calamitic mesophases have been known for more than 100 yr but only the recent, rapid advance in active matrix liq. crystal display (AM-LCD) technol. helped these materials to achieve the crucial position in flat panel display technol. they hold today. Due to their high contrast, large viewing angle, and rapid switching times, modern AM-LCDs offer a superior picture quality even compared to conventional cathode ray tubes. Their flatness, low wt., and low energy consumption render them the technol. of choice for all kinds of portable devices. Some of the future promises of AM-LCD technol. are centered around the development of liq. cryst. materials for the different subtypes of active matrix applications. This development is aimed, on the one hand, towards improved electrooptical and viscoelastic properties; on the other hand, the increasing performance of LCDs leads to extremely stringent reliability demands on the liq. crystals. Responding to these high stds. of performance and quality, most liq. crystals for contemporary AM-LCD applications are multiply fluorinated compds. with very high purities, as is typical for materials used in the electronics industry. The synthesis of these superfluorinated materials (SFMs) often requires specialized methods, which, in several cases, had to be introduced for the first time into the canon of industrial prodn. The immense market pressure, as well as the rapid advance of AM-LCD technol. on the side of the display manufacturers, urges an increasing pace of the materials development. This demand for new materials can no longer be fulfilled by conventional trial-and-error approaches. As in the pharmaceutical industry, in the search for new, superior liq. crystals, the purely empirical methods are increasingly supported by a rational design based on computational methods.
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  23. 23
    Poskin, T. J.; Piscelli, B. A.; Yoshida, K.; Cordes, D. B.; Slawin, A. M. Z.; Cormanich, R. A.; Yamada, S.; O’Hagan, D. Janus Faced Fluorocyclohexanes for Supramolecular Assembly: Synthesis and Solid-State Structures of Equatorial Mono-Di- and Tri Alkylated Cyclohexanes and With Tri-Axial C-F Bonds to Impart Polarity. Chem. Commun. 2022, 58, 7968– 7971,  DOI: 10.1039/D2CC03010A
    Google Scholar
    There is no corresponding record for this reference.
  24. 24
    Bannwarth, C.; Ehlert, S.; Grimme, S. GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion Contributions. J. Chem. Theory Comput. 2019, 15, 1652– 1671,  DOI: 10.1021/acs.jctc.8b01176
    Google Scholar
    24
    GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion Contributions
    Bannwarth, Christoph; Ehlert, Sebastian; Grimme, Stefan
    Journal of Chemical Theory and Computation (2019), 15 (3), 1652-1671CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    An extended semiempirical tight-binding model is presented, which is primarily designed for the fast calcn. of structures and noncovalent interactions energies for mol. systems with roughly 1000 atoms. The essential novelty in this so-called GFN2-xTB method is the inclusion of anisotropic second order d. fluctuation effects via short-range damped interactions of cumulative at. multipole moments. Without noticeable increase in the computational demands, this results in a less empirical and overall more phys. sound method, which does not require any classical halogen or hydrogen bonding corrections and which relies solely on global and element-specific parameters (available up to radon, Z = 86). Moreover, the at. partial charge dependent D4 London dispersion model is incorporated self-consistently, which can be naturally obtained in a tight-binding picture from second order d. fluctuations. Fully anal. and numerically precise gradients (nuclear forces) are implemented. The accuracy of the method is benchmarked for a wide variety of systems and compared with other semiempirical methods. Along with excellent performance for the "target" properties, we also find lower errors for "off-target" properties such as barrier heights and mol. dipole moments. High computational efficiency along with the improved physics compared to it precursor GFN-xTB makes this method well-suited to explore the conformational space of mol. systems. Significant improvements are furthermore obsd. for various benchmark sets, which are prototypical for biomol. systems in aq. soln.
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  25. 25
    Zhao, Y.; Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 2008, 120, 215– 241,  DOI: 10.1007/s00214-007-0310-x
    Google Scholar
    25
    The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals
    Zhao, Yan; Truhlar, Donald G.
    Theoretical Chemistry Accounts (2008), 120 (1-3), 215-241CODEN: TCACFW; ISSN:1432-881X. (Springer GmbH)
    We present two new hybrid meta exchange-correlation functionals, called M06 and M06-2X. The M06 functional is parametrized including both transition metals and nonmetals, whereas the M06-2X functional is a high-nonlocality functional with double the amt. of nonlocal exchange (2X), and it is parametrized only for nonmetals. The functionals, along with the previously published M06-L local functional and the M06-HF full-Hartree-Fock functionals, constitute the M06 suite of complementary functionals. We assess these four functionals by comparing their performance to that of 12 other functionals and Hartree-Fock theory for 403 energetic data in 29 diverse databases, including ten databases for thermochem., four databases for kinetics, eight databases for noncovalent interactions, three databases for transition metal bonding, one database for metal atom excitation energies, and three databases for mol. excitation energies. We also illustrate the performance of these 17 methods for three databases contg. 40 bond lengths and for databases contg. 38 vibrational frequencies and 15 vibrational zero point energies. We recommend the M06-2X functional for applications involving main-group thermochem., kinetics, noncovalent interactions, and electronic excitation energies to valence and Rydberg states. We recommend the M06 functional for application in organometallic and inorganometallic chem. and for noncovalent interactions.
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  26. 26
    Pratik, S. M.; Nijamudheen, A.; Datta, A. Janus All-cis-1,2,3,4,5,6-Hexafluorocyclohexane: A Molecular Motif for Aggregation-Induced Enhanced Polarization. ChemPhysChem 2016, 17, 2373– 2381,  DOI: 10.1002/cphc.201600262
    Google Scholar
    26
    Janus all-cis-1,2,3,4,5,6-Hexafluorocyclohexane: A Molecular Motif for Aggregation-Induced Enhanced Polarization
    Pratik, Saied Md.; Nijamudheen, Abdulrahiman; Datta, Ayan
    ChemPhysChem (2016), 17 (15), 2373-2381CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Recently synthesized all-cis-1,2,3,4,5,6-hexafluorocyclohexane is the least stable among all possible configurational isomers of 1,2,3,4,5,6-hexafluorocyclohexane. This mol. has a remarkably large dipole moment (6.2 D) as well as high facial polarization. Solid-state, dispersion-cor. DFT (DFT-D3) calcns. are performed on the cryst. phase of all-cis-1,2,3,4,5,6- hexafluorocyclohexane, which reveal that dispersion interactions play a crucial role in its stabilization. A no. of thermodynamically favorable orientations of dimers, trimers and tetramers are demonstrated for this mol. Parallel-stacked aggregates, from dimers to higher-order aggregates, which are absent in the crystal, are found to be thermodynamically most favorable due to the presence of strong short-range C-H···F-C intermol. hydrogen-bonding networks. Because of their cooperative nature, binding energies, dipole moments, and polarizations per mol. increase from monomer to tetramer, whereas the HOMO-LUMO gaps follow the opposite trend. Based on the DFT-D3 calcns., it is proposed that this parallel-stacked arrangement can be further extended to prep. stable a 1D crystal such that a large dipole moment and macroscopic polarizations can arise, which might be useful in designing electronic and nonlinear optical devices. Because the mol. has conformational flexibility, the potential energy surface is investigated for ring flipping and the effects of fluorine substitution are studied by comparing the barrier with respect to cyclohexane and all-cis-1,2,3-trifluorocyclohexane.
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  27. 27
    (a) Anet, F. A. L.; Bourn, A. J. R. Nuclear Magnetic Resonance Line-Shape and Double-Resonance Studies of Ring Inversion in Cyclohexane-d11. J. Am. Chem. Soc. 1967, 89, 760– 768,  DOI: 10.1021/ja00980a006
    Google Scholar
    27a
    Nuclear magnetic resonance line-shape and double-resonance studies of ring inversion in cyclohexane-d11
    Anet, Frank A. L.; Bourn, Anthony J. R.
    Journal of the American Chemical Society (1967), 89 (4), 760-8CODEN: JACSAT; ISSN:0002-7863.
    Kinetic parameters were obtained for ring inversion in cyclohexane-d11 by two different N.M.R. methods: (a) line-shape analysis and (b) double resonance. A field-frequency lock spectrometer operating at 60 Mc./sec. was used for all measurements. Rate consts. were calcd. from -117 to -24° and covered a range of over half a million. The values of ΔF*cb, ΔH*, and and ΔS*cb for the chair-to-boat process were found to be 10.3 and 10.8 kcal./mole and 2.8 entropy units, resp. The results do not agree with the recent spin-echo work of Allerhand, et al. (CA 63, 166c) as far as ΔS*cb is concerned. 26 references.
    >> More from SciFinder ®
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    (b) Hendrickson, J. B. Molecular geometry. VII. Modes of interconversion in the medium rings. J. Am. Chem. Soc. 1967, 89, 7047– 7061,  DOI: 10.1021/ja01002a038
    Google Scholar
    27b
    Molecular geometry. VII. Modes of interconversion in the medium rings
    Hendrickson, James B.
    Journal of the American Chemical Society (1967), 89 (26), 7047-61CODEN: JACSAT; ISSN:0002-7863.
    cf. preceding abstrs. A protocol for examg. sym. ring conformations of six- to ten-membered cycloalkanes without recourse to models is developed and used to order their modes of interconversion and calc. the energy barriers involved, both for sym. modes of transition and for pseudo-rotation. The principles of conformational analysis for substituted rings are also set forth. 24 references.
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  28. 28
    Clark, J. L.; Taylor, A.; Geddis, A.; Neyyappadath, R. M.; Piscelli, B. A.; Yu, C.; Cordes, D. B.; Slawin, A. M. Z.; Cormanich, R. A.; Guldin, S.; O’Hagan, D. Supramolecular packing of alkyl substituted Janus face all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs. Chem. Sci. 2021, 12, 9712– 9719,  DOI: 10.1039/D1SC02130C
    Google Scholar
    There is no corresponding record for this reference.

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  • Abstract

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    Figure 1

    Figure 1. “Thermodynamically disfavored” cyclohexanes and all-cis-1,2,3,4,5,6-hexafluorocyclohexane 2.

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    Figure 2

    Figure 2. CAAC catalyst 3 and Janus ether substituted cyclohexanes. (8−10)

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    Scheme 1

    Scheme 1. Synthesis Routes to All-Cis Tetrafluorocyclohexyl Diethers 1a–1e from tButO Ether 11
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    Figure 3

    Figure 3. Reaction profiles for SNAr reactions of (a) 9 with OMe–; (b) 11 with OMe–; and (c) 11 with tButO–; each attacking either at the meta or para positions calculated at the M06-2X/6-311++G** level. The para reaction course is kinetically favored in each case.

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    Figure 4

    Figure 4. X-ray structures of 1,4-diethers (a) 1a and (b) 1d viewed from two trajectories.

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    Figure 5

    Figure 5. 19F{1H}-NMR of 1a showing an equilibrium mix of eq/ax 1a and ax/eq 1a in solution.

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    Figure 6

    Figure 6. (a) Comparative cyclohexyl interconversion energy profiles for dimethoxy ether 1f, all-cis1,2,3,4,5,6-exafluorocyclohexane 2 and cyclohexane 15 showing the relative energies of intermediates. Energy values in kcal mol–1. (b) Schematic of the two interconversion pathways for cyclohexane 1f.

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  • References

    This article references 28 other publications.

    1. 1
      Li, Y.; Shi, H.; Yin, G. Synthetic techniques for thermodynamically disfavoured substituted six-membered rings. Nat. Rev. Chem 2024, 8, 535– 550,  DOI: 10.1038/s41570-024-00612-3
      There is no corresponding record for this reference.
    2. 2
      (a) Chang, J.; Chen, F.; Li, H.; Suo, J.; Zheng, H.; Zhang, J.; Wang, Z.; Valtchev, V.; Qiu, S.; Fang, Q. Three-dimensional covalent organic frameworks with nia nets for efficient separation of benzene/cyclohexane mixtures. Nat. Commun. 2024, 15, 813,  DOI: 10.1038/s41467-024-45005-8
      There is no corresponding record for this reference.
      (b) Ma, X.; Scott, T. F. Approaches and challenges in the synthesis of three-dimensional covalent-organic frameworks. Commun. Chem. 2018, 1, 98,  DOI: 10.1038/s42004-018-0098-8
      There is no corresponding record for this reference.
    3. 3
      (a) Wang, Z.; Sharma, P. P.; Rathi, B.; Xie, M.; De Clercq, E.; Pannecouque, C.; Kang, D.; Zhan, P.; Liu, X. Escaping from Flatland: Multiparameter Optimization Leads to the Discovery of Novel Tetrahydropyrido[4,3-d]pyrimidine Derivatives as Human Immunodeficiency Virus-1 Non-nucleoside Reverse Transcriptase Inhibitors with Superior Antiviral Activities against Non-nucleoside Reverse Transcriptase Inhibitor-Resistant Variants and Favorable Drug-like Profiles. J. Med. Chem. 2023, 66, 8643– 8665,  DOI: 10.1021/acs.jmedchem.3c00275
      There is no corresponding record for this reference.
      (b) Lovering, F. Escape from Flatland 2: Complexity and Promiscuity. MedChemComm 2013, 4, 515– 519,  DOI: 10.1039/c2md20347b
      3b
      Escape from Flatland 2: complexity and promiscuity
      Lovering, Frank
      MedChemComm (2013), 4 (3), 515-519CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
      Toxicity plays a major role in attrition in the clinic and promiscuity has been linked to toxicity. A no. of mol. descriptors have been identified that contribute to promiscuity including ionization and logP. In this study we report on the relationship between complexity, as measured by two descriptors [fraction sp3 (Fsp3) where Fsp3 = (no. of sp3 hybridized carbons/total carbon count) and chiral carbon count], and promiscuity as well as Cyp450 inhibition. We find that increasing complexity reduces promiscuity and Cyp450 inhibition. As an understanding of key property descriptors has helped the pharmaceutical industry to address some of the deficiencies of compds. as pertains to bioavailability, awareness of the descriptors that impact promiscuity should allow us to better address toxicity in the clinic.
      >> More from SciFinder ®
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    4. 4
      O’Hagan, D. The Emergence and Properties of Selectively Fluorinated ‘Janus’ Cyclohexanes. Chem. Rec. 2023, 23, e202300027  DOI: 10.1002/tcr.202300027
      There is no corresponding record for this reference.
    5. 5
      Keddie, N. S.; Slawin, A. M. Z.; Lebl, T.; Philp, D.; O’Hagan, D. All-cis 1,2,3,4,5,6-Hexafluorocyclohexane is a Facially Polarized Cyclohexane. Nat. Chem. 2015, 7, 483– 488,  DOI: 10.1038/nchem.2232
      5
      All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexane
      Keddie, Neil S.; Slawin, Alexandra M. Z.; Lebl, Tomas; Philp, Douglas; O'Hagan, David
      Nature Chemistry (2015), 7 (6), 483-488CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      The highest-energy stereoisomer of 1,2,3,4,5,6-hexafluorocyclohexane, in which all of the fluorines are 'up', is prepd. in a 12-step protocol. The mol. adopts a classic chair conformation with alternate C-F bonds aligned triaxially, clustering three highly electroneg. fluorine atoms in close proximity. This generates a cyclohexane with a high mol. dipole (μ = 6.2 D), unusual in an otherwise aliph. compd. X-ray anal. indicates that the intramol. Fax···Fax distances (∼2.77 Å) are longer than the vicinal Fax···Feq distances (∼2.73 Å) suggesting a tension stabilizing the chair conformation. In the solid state the mols. pack in an orientation consistent with electrostatic ordering. Our synthesis of this highest-energy isomer demonstrates the properties that accompany the placement of axial fluorines on a cyclohexane and the unusual property of a facially polarized ring in org. chem. Derivs. have potential as new motifs for the design of functional org. mols. or for applications in supramol. chem. design.
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    6. 6
      (a) Lecours, M. J.; Marta, R. A.; Steinmetz, V.; Keddie, N. S.; Fillion, E.; O’Hagan, D.; McMahon, T. B.; Hopkins, W. S. Interaction of B12F122- with All-cis 1,2,3,4,5,6 Hexafluorocyclohexane in the Gas Phase. J. Phys. Chem. Lett. 2017, 8, 109– 113,  DOI: 10.1021/acs.jpclett.6b02629
      6a
      Interaction of B12F122- with All-cis 1,2,3,4,5,6 Hexafluorocyclohexane in the Gas Phase
      Lecours, Michael J.; Marta, Rick A.; Steinmetz, Vincent; Keddie, Neil; Fillion, Eric; O'Hagan, David; McMahon, Terrance B.; Hopkins, W. Scott
      Journal of Physical Chemistry Letters (2017), 8 (1), 109-113CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
      Clusters of all-cis 1,2,3,4,5,6-hexafluorocyclohexane and the dodecafluorododecaboron dianion, [C6F6H6]n[B12F12]2- (n = 0-4), are investigated in a combined exptl. and computational study. DFT calcns. and IRMPD spectra in the region of 800-2000 cm-1 indicate that C6H6F6 binds to open trigonal faces of B12F122- via a three-point interlocking binding motif. Calcd. binding interactions reveal substantial contributions from C-H···F hydrogen bonding and binding energies that are among the strongest obsd. for a neutral-anion system.
      >> More from SciFinder ®
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      (b) Ziegler, B. E.; Lecours, M.; Marta, R. A.; Featherstone, J.; Fillion, E.; Hopkins, W. S.; Steinmetz, V.; Keddie, N. S.; O’Hagan, D.; McMahon, T. B. Janus Face Aspect of All-cis 1,2,3,4,5,6-Hexafluorocyclohexane Dictates Remarkable Anion and Cation Interactions In the Gas Phase. J. Am. Chem. Soc. 2016, 138, 7460– 7463,  DOI: 10.1021/jacs.6b02856
      6b
      Janus Face Aspect of All-cis 1,2,3,4,5,6-Hexafluorocyclohexane Dictates Remarkable Anion and Cation Interactions In the Gas Phase
      Ziegler, Blake E.; Lecours, Michael; Marta, Rick A.; Featherstone, Joshua; Fillion, Eric; Hopkins, W. Scott; Steinmetz, Vincent; Keddie, Neil S.; O'Hagan, David; McMahon, Terrance B.
      Journal of the American Chemical Society (2016), 138 (24), 7460-7463CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Expts. were carried out in which electrospray ionization was used to generate ionic complexes of all-cis-1,2,3,4,5,6-hexafluorocyclohexane. These complexes were subsequently mass isolated in a quadrupole ion trap mass spectrometer and then irradiated by the tunable IR output of a free electron laser in the 800-1600 cm-1 range. From the frequency dependence of the fragmentation of the complexes, vibrational signatures of the complexes were obtained. Computational work carried out in parallel reveals that the complexes formed are very strongly bound and are among the most strongly bound complexes of Na+ and Cl- ever obsd. with mol. species. The dipole moment calcd. for the heaxafluorocyclohexane is very large (∼7 D), and apparently the bonding in each of the complexes has a significant electrostatic contribution.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntlCmurY%253D&md5=cc190a84a0a188ba31223d86e68ebfdf
    7. 7
      Santschi, N.; Gilmour, R. A Janus Cyclohexane Ring. Nat. Chem. 2015, 7, 467– 468,  DOI: 10.1038/nchem.2240
      7
      Organofluorine chemistry A Janus cyclohexane ring
      Santschi, Nico; Gilmour, Ryan
      Nature Chemistry (2015), 7 (6), 467-468CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      The first synthesis of the all-cis isomer of 1,2,3,4,5,6-hexafluorocyclohexane, a mol. with one hydrocarbon face and one fluorocarbon face, is a tour de force of organofluorine chem. and opens up new possibilities for mol. design.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtleju7Y%253D&md5=4f3292bc35d6ed2de2e31175efca9046
    8. 8
      (a) Nairoukh, Z.; Wollenburg, M.; Schlepphorst, C.; Bergander, K.; Glorius, F. The Formation of All-cis-(Multi)Fluorinated Piperidines by a Dearomatization-Hydrogenation Process. Nat. Chem. 2019, 11, 264– 270,  DOI: 10.1038/s41557-018-0197-2
      8a
      The formation of all-cis-(multi)fluorinated piperidines by a dearomatization-hydrogenation process
      Nairoukh, Zackaria; Wollenburg, Marco; Schlepphorst, Christoph; Bergander, Klaus; Glorius, Frank
      Nature Chemistry (2019), 11 (3), 264-270CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
      Piperidines and fluorine substituents are both independently indispensable components in pharmaceuticals, agrochems. and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochem. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalyzed dearomatization-hydrogenation of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete satn. of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine substituents were successfully applied in the prepn. of com. drug analogs. Addnl., fluorinated PipPhos as well as fluorinated ionic liqs. were obtained by this dearomatization-hydrogenation process.
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      (b) Wiesenfeldt, M. P.; Knecht, T.; Schlepphorst, C.; Glorius, F. Silylarene Hydrogenation: A Strategic Approach that Enables Direct Access to Versatile Silylated Saturated Carbo- and Heterocycles. Angew. Chem., Int. Ed. 2018, 57, 8297– 8300,  DOI: 10.1002/anie.201804124
      8b
      Silylarene Hydrogenation: A Strategic Approach that Enables Direct Access to Versatile Silylated Saturated Carbo- and Heterocycles
      Wiesenfeldt, Mario P.; Knecht, Tobias; Schlepphorst, Christoph; Glorius, Frank
      Angewandte Chemie, International Edition (2018), 57 (27), 8297-8300CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We report a method to convert readily available silylated arenes into silylated satd. carbo- and heterocycles by arene hydrogenation. The scope includes alkoxy- and halosilyl substituents. Silyl groups can be derivatized into a plethora of functionalities and find application in org. synthesis, materials science, and pharmaceutical, agrochem., and fragrance research. However, silylated satd. (hetero- ) cycles are difficult to access with current technologies. The yield of the hydrogenation depends on the amt. of the silica gel additive. This silica effect also enables a significant improvement of a previously disclosed method for the hydrogenation of highly fluorinated arenes (e.g., to all-cis-C6H6F6).
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      (c) Wiesenfeldt, M. P.; Nairoukh, Z.; Li, W.; Glorius, F. Hydrogenation of Fluoroarenes. Direct Access to All-cis (Multi)Fluorinated Cycloalkanes. Science 2017, 357, 908– 912,  DOI: 10.1126/science.aao0270
      There is no corresponding record for this reference.
    9. 9
      (a) Zhang, X.; Ling, L.; Luo, M.; Zeng, X. Accessing Difluoromethylated and Trifluoromethylated cis-Cycloalkanes and Saturated Heterocycles: Preferential Hydrogen Addition to the Substitution Sites for Dearomatization. Angew. Chem., Int. Ed. 2019, 58, 16785– 16789,  DOI: 10.1002/anie.201907457
      9a
      Accessing Difluoromethylated and Trifluoromethylated cis-Cycloalkanes and Saturated Heterocycles: Preferential Hydrogen Addition to the Substitution Sites for Dearomatization
      Zhang, Xue; Ling, Liang; Luo, Meiming; Zeng, Xiaoming
      Angewandte Chemie, International Edition (2019), 58 (47), 16785-16789CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A straightforward process in which a cyclic (alkyl)(amino)carbene/Rh catalyst system facilitates preferential addn. of hydrogen to substitution sites of difluoromethylated and trifluoromethylated arenes and heteroarenes, leading to dearomative redn. was reported. This strategy enabled diastereoselective synthesis of cis-difluoromethylated and cis-trifluoromethylated cycloalkanes such as I [R = 2-COMe, 4-pyrazolyl, 3-OTBS, etc.; R1 = CF2H, CF3] and satd. heterocycles, e.g. II, and even allowed formation of all-cis multi-trifluoromethylated cyclic products with a defined equatorial orientation of the di- and trifluoromethyl groups. Deuterium-labeling studies indicated that hydrogen preferentially attacked substitution sites of planar arenes, resulting in dearomatization, possibly with heterogeneous Rh as reactive species, followed by either reversible or irreversible hydrogen addn. to nonsubstitution sites.
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      (b) Wei, Y.; Rao, B.; Cong, X.; Zeng, X. Highly Selective Hydrogenation of Aromatic Ketones and Phenols Enabled by Cyclic (Amino)(alkyl)carbene Rhodium Complexes. J. Am. Chem. Soc. 2015, 137, 9250– 9253,  DOI: 10.1021/jacs.5b05868
      9b
      Highly Selective Hydrogenation of Aromatic Ketones and Phenols Enabled by Cyclic (Amino)(alkyl)carbene Rhodium Complexes
      Wei, Yu; Rao, Bin; Cong, Xuefeng; Zeng, Xiaoming
      Journal of the American Chemical Society (2015), 137 (29), 9250-9253CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Air-stable Rh complexes ligated by strongly σ-donating cyclic (amino)(alkyl)carbenes (CAACs) show unique catalytic activity for the selective hydrogenation of arom. ketones and phenols by reducing the aryl groups. The use of CAAC ligands is essential for achieving high selectivity and conversion. This method is characterized by its good compatibility with unsatd. ketones, esters, carboxylic acids, amides, and amino acids and is scalable without detriment to its efficiency.
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    10. 10
      (a) Haridas, S. V.; Shyshov, O.; von Delius, M. Supramolecular Polymerization of All-cis Fluorinated Cyclohexanes: Influence of Side Chains. Org. Mater. 2023, 5, 166– 174,  DOI: 10.1055/s-0043-1761314
      There is no corresponding record for this reference.
      (b) Shyshov, O.; Haridas, S. V.; Pesce, L.; Qi, H.; Gardin, A.; Bochicchio, D.; Kaiser, U.; Pavan, G. M.; von Delius, M. Living Supramolecular Polymerization of Fluorinated Cyclohexanes. Nat. Commun. 2021, 12, 3134,  DOI: 10.1038/s41467-021-23370-y
      10b
      Living supramolecular polymerization of fluorinated cyclohexanes
      Shyshov, Oleksandr; Haridas, Shyamkumar Vadakket; Pesce, Luca; Qi, Haoyuan; Gardin, Andrea; Bochicchio, Davide; Kaiser, Ute; Pavan, Giovanni M.; von Delius, Max
      Nature Communications (2021), 12 (1), 3134CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      The development of powerful methods for living covalent polymn. has been a key driver of progress in org. materials science. While there have been remarkable reports on living supramol. polymn. recently, the scope of monomers is still narrow and a simple soln. to the problem is elusive. Here we report a minimalistic mol. platform for living supramol. polymn. that is based on the unique structure of all-cis 1,2,3,4,5,6-hexafluorocyclohexane, the most polar aliph. compd. reported to date. We use this large dipole moment (6.2 Debye) not only to thermodynamically drive the self-assembly of supramol. polymers, but also to generate kinetically trapped monomeric states. Upon addn. of well-defined seeds, we obsd. that the dormant monomers engage in a kinetically controlled supramol. polymn. The obtained nanofibers have an unusual double helical structure and their length can be controlled by the ratio between seeds and monomers. The successful prepn. of supramol. block copolymers demonstrates the versatility of the approach.
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      (c) Shyshov, O.; Siewerth, K. A.; von Delius, M. Evidence for Anion-Binding of All-cis Hexafluorocyclohexane in Solution and Solid State. Chem. Commun. 2018, 54, 4353– 4355,  DOI: 10.1039/C8CC01797B
      10c
      Evidence for anion-binding of all-cis hexafluorocyclohexane in solution and solid state
      Shyshov, Oleksandr; Siewerth, Kevin Andre; von Delius, Max
      Chemical Communications (Cambridge, United Kingdom) (2018), 54 (34), 4353-4355CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      The authors report a soln. NMR and x-ray crystallog. study on the anion affinity of all-cis 1,2,3,4,5,6-hexafluorocyclohexane, which has only recently become synthetically accessible. The authors' results suggest that the interaction exhibits preferential 1 : 1 stoichiometry, while its strength is only moderate (e.g. Ka = 400 M-1 in acetone for Cl-) and depends mainly on the size of the anion and the dielec. const. of the solvent.
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    11. 11
      Haridas, S. V.; von Delius, M. Synthesis and Supramolecular Properties of All-cis-2,4,6-Trifluorocyclohexane-1,3,5-triol. Chem. Commun. 2024, 60, 606– 609,  DOI: 10.1039/D3CC05510H
      There is no corresponding record for this reference.
    12. 12
      Burdon, J.; Hollyhead, W. B.; Patrick, C. R.; Wilson, K. V. 1184. Kinetics of nucleophilic substitution in polyfluoro-aromatic compounds. Part I. The reaction of sodium methoxide with some pentafluorophenyl-compounds. J. Chem. Soc. 1965, 6375– 6379,  DOI: 10.1039/jr9650006375
      There is no corresponding record for this reference.
    13. 13
      Kvíčala, J.; Beneš, M.; Paleta, O.; Král, V. Regiospecific Nucleophilic Substitution in 2,3,4,5,6-Pentafluorobiphenyl as Model Compound for Supramolecular Systems. Theoretical Study of Transition States and Energy Profiles, Evidence for Tetrahedral SN2 Mechanism. J. Fluorine Chem. 2010, 131, 1327– 1337,  DOI: 10.1016/j.jfluchem.2010.09.003
      13
      Regiospecific nucleophilic substitution in 2,3,4,5,6-pentafluorobiphenyl as model compound for supramolecular systems. Theoretical study of transition states and energy profiles, evidence for tetrahedral SN2 mechanism
      Kvicala, Jaroslav; Benes, Michal; Paleta, Oldrich; Kral, Vladimir
      Journal of Fluorine Chemistry (2010), 131 (12), 1327-1337CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
      2,3,4,5,6-Pentafluorobiphenyl (PFBi) was modified by the nucleophilic substitution of one fluorine using a series of O-, S- and N-nucleophiles, viz. alk. salts of 2,2,2-trifluoro-ethanol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol, 1,2;3,4-di-O-isopropylidenexylitol, allylsulfane, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctane-1-thiol, 3-aminopropan-1-ol (7), and tert-Bu N-(3-aminopropyl)carbamate (8). All the substitutions took place exclusively at the position para to the Ph group. (3-Amino-propyl)amino deriv. of PFBi (15) was further modified at the terminal amino group by acylation or fluoroalkylation. The reaction of 8 was applied to meso-5,10,15,20-tetrakis-(pentafluorophenyl)porphyrin (20) to afford tris- (21) and tetrakis-substituted (22) products with complete para-regioselectivity. Theor. studies of the reaction pathways of PFBi with ammonia, microsolvated lithium fluoride or lithium hydroxide revealed that no Meisenheimer-type intermediates are formed in the course of the simulated reactions: instead, tetrahedral SN2 mechanism was found. Significant regioselectivity of the nucleophilic arom. substitution, leading to 4-substituted products, was predicted based on relative transition state energies in agreement with the obsd. exptl. results.
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    14. 14
      Brooke, G. M.; Burdon, J.; Tatlow, J. C. J. Aromatic Polyfluoro Compounds XII. Orientation Reactions of Pentafluorobenzene. Chem. Soc. 1962, 3253– 3254
      There is no corresponding record for this reference.
    15. 15
      Tsuzuki, S.; Houjou, H.; Nagawa, Y.; Hiratani, K. High-Level Ab-initio Calculations of Torsional Potential of Phenol, Anisole, and o-Hydroxyanisole: Effects of Intramolecular Hydrogen Bond. J. Phys. Chem. A 2000, 104, 1332– 1336,  DOI: 10.1021/jp993607e
      15
      High-Level ab Initio Calculations of Torsional Potential of Phenol, Anisole, and o-Hydroxyanisole: Effects of Intramolecular Hydrogen Bond
      Tsuzuki, Seiji; Houjou, Hirohiko; Nagawa, Yoshinobu; Hiratani, Kazuhisa
      Journal of Physical Chemistry A (2000), 104 (6), 1332-1336CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
      The internal rotational barrier heights of phenol and anisole were calcd. using several basis sets up to cc-pVQZ with MP2-level electron correlation correction to evaluate the basis set effects. The calcns. showed that the effects of the further improvement of the basis set beyond the cc-pVTZ were very small. Although the electron correlation substantially increased the barrier heights of the two mols., the effects of the electron correlation beyond the MP2 method were not large. The barrier heights calcd. with the CCSD(T) method were close to those with the MP2 method. The internal rotational potentials of methoxy and hydroxyl groups of o-hydroxyanisole were calcd. at the MP2/cc-pVTZ//HF/6-311G** level. The calcd. potentials were compared with those of phenol and anisole. O-Hydroxyanisole preferred planar structure in which the hydroxyl group had an intramol. hydrogen bond with the oxygen atom of the methoxy group. The calcd. torsional potential of the methoxy group had the max. (7.30 kcal/mol) when the methoxy group rotated 180° from the min. energy structure, in which the hydroxyl group did not have the hydrogen bond. The barrier height of the methoxy group of o-hydroxyanisole was considerably larger than that of anisole (2.99 kcal/mol). The large internal rotational barrier height of o-hydroxyanisole showed that the intramol. hydrogen bond greatly stabilized the energy min. structure and that the hydrogen bond strictly restricted the conformational flexibility of the methoxy group.
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    16. 16
      Belyakov, A. V.; Kieninger, M.; Cachau, R. E.; Ventura, O. N.; Oberhammer, H. Molecular Structure and Internal Rotation in 2,3,5,6-Tetrafluoroanisole as Studied by Gas-Phase Electron Diffraction and Quantum Chemical Calculations. J. Phys. Chem. A 2005, 109, 394– 399,  DOI: 10.1021/jp046975d
      16
      Molecular Structure and Internal Rotation in 2,3,5,6-Tetrafluoroanisole as Studied by Gas-Phase Electron Diffraction and Quantum Chemical Calculations
      Belyakov, Alexander V.; Kieninger, Martina; Cachau, Raul E.; Ventura, Oscar N.; Oberhammer, Heinz
      Journal of Physical Chemistry A (2005), 109 (2), 394-399CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
      The geometric structure of 2,3,5,6-tetrafluoroanisole and the potential function for internal rotation around the C(sp2)-O bond were detd. by gas electron diffraction (GED) and quantum chem. calcns. Anal. of the GED intensities with a static model resulted in near-perpendicular orientation of the O-CH3 bond relative to the benzene plane with a torsional angle around the C(sp2)-O bond of τ(C-O) = 67(15)°. With a dynamic model, a wide single-min. potential for internal rotation around the C(sp2)-O bond with perpendicular orientation of the methoxy group [τ(C-O) = 90°] and a barrier of 2.7 ± 1.6 kcal/mol at planar orientation [τ(C-O) = 0°] was derived. Calcd. potential functions depend strongly on the computational method (HF, MP2, or B3LYP) and converge adequately only if large basis sets are used. The electronic energy curves show internal structure, with local min. appearing because of the interplay between electron delocalization, changes in the hybridization around the oxygen atom, and the attraction between the pos. polarized hydrogen atoms in the Me group and the fluorine atom at the ortho position. The internal structure of the electronic energy curves mostly disappears if zero-point energies and thermal corrections are added. The calcd. free energy barrier at 298 K is 2.0 ± 1.0 kcal/mol, in good agreement with the exptl. detn.
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    17. 17
      Cormanich, R. A.; da Silva, G. D. Autobench V1.0: Benchmarking Automation for Electronic Structure Calculations. J. Chem. Inf. Model. 2024, 64, 3322– 3331,  DOI: 10.1021/acs.jcim.4c00250
      There is no corresponding record for this reference.
    18. 18
      Sadowsky, D.; McNeill, K.; Cramer, C. J. Dehalogenation of Aromatics by Nucleophilic Aromatic Substitution. Environ. Sci. Technol. 2014, 48, 10904– 10911,  DOI: 10.1021/es5028822
      18
      Dehalogenation of Aromatics by Nucleophilic Aromatic Substitution
      Sadowsky, Daniel; McNeill, Kristopher; Cramer, Christopher J.
      Environmental Science & Technology (2014), 48 (18), 10904-10911CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      Nucleophilic arom. substitution has been implicated as a mechanism for both the biotic and abiotic hydrodehalogenation of aroms. Two mechanisms for the aq. dehalogenation of aroms. involving nucleophilic arom. substitution with hydride as a nucleophile are investigated using a validated d. functional and continuum solvation protocol. For chlorinated and brominated aroms., nucleophilic addn. ortho to carbon-halogen bonds via an anionic intermediate is predicted to be the preferred mechanism in the majority of cases, while concerted substitution is predicted to be preferred for most fluorinated aroms. Nucleophilic arom. substitution reactions with the hydroxide and hydrosulfide anions as nucleophiles are also investigated and compared.
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    19. 19
      Kikushima, K.; Grellier, M.; Ohashi, M.; Ogoshi, S. Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution With a Hydrosilicate. Angew. Chem., Int. Ed. 2017, 56, 16191– 16196,  DOI: 10.1002/anie.201708003
      19
      Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate
      Kikushima, Kotaro; Grellier, Mary; Ohashi, Masato; Ogoshi, Sensuke
      Angewandte Chemie, International Edition (2017), 56 (51), 16191-16196CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Polyfluorinated arenes underwent regioselective transition metal-free hydrodefluorination with Ph3SiH or Et2SiH2 in the presence of tetrabutylammonium difluorotriphenylsilicate (TBAT) in THF. For example, hexafluorobenzene underwent hydrodefluorination with Et2SiH2 at 60° to yield pentafluorobenzene in 19% yield, 1,2,4,5-tetrafluorobenzene in 70% yield, and 1,2,3,5-tetrafluorobenzene and 1,2,3,4-tetrafluorobenzene in 2% yields. The reaction involves direct hydride transfer from a hydrosilicate as the key intermediate, which is generated from a hydrosilane and a fluoride salt; the eliminated fluoride regenerates the hydrosilicate to complete the catalytic cycle. The mechanism was studied using stoichiometric reactions of silicates and using dispersion-cor. DFT calcns.; hydrodefluorination likely proceeds via concerted nucleophilic arom. substitution.
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    20. 20
      Kwan, E. E.; Zeng, Y.; Besser, H. A.; Jacobsen, E. N. Concerted Nucleophilic Aromatic Substitutions. Nat. Chem. 2018, 10, 917– 923,  DOI: 10.1038/s41557-018-0079-7
      20
      Concerted nucleophilic aromatic substitutions
      Kwan, Eugene E.; Zeng, Yuwen; Besser, Harrison A.; Jacobsen, Eric N.
      Nature Chemistry (2018), 10 (9), 917-923CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
      Nucleophilic arom. substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chem. research, providing a broadly useful platform for the modification of arom. ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addn.-elimination sequence via a discrete, non-arom. Meisenheimer complex. Here the authors use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C-F bonds.
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    21. 21
      Rohrbach, S.; Smith, A. J.; Pang, J. H.; Poole, D. L.; Tuttle, T.; Chiba, S.; Murphy, J. A. Concerted Nucleophilic Aromatic Substitution Reactions. Angew. Chem., Int. Ed. 2019, 58, 16368– 16388,  DOI: 10.1002/anie.201902216
      21
      Concerted Nucleophilic Aromatic Substitution Reactions
      Rohrbach, Simon; Smith, Andrew J.; Pang, Jia Hao; Poole, Darren L.; Tuttle, Tell; Chiba, Shunsuke; Murphy, John A.
      Angewandte Chemie, International Edition (2019), 58 (46), 16368-16388CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Recent developments in exptl. and computational chem. have identified a rapidly growing class of nucleophilic arom. substitutions that proceed by concerted (cSNAr) rather than classical, two-step, SNAr mechanisms. Whereas traditional SNAr reactions require substantial activation of the arom. ring by electron-withdrawing substituents, such activating groups are not mandatory in the concerted pathways.
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    22. 22
      Kirsch, P.; Bremer, M. Nematic Liquid Crystals for Active Matrix Displays: Molecular Design and Synthesis. Angew. Chem., Int. Ed. 2000, 39, 4216– 4235,  DOI: 10.1002/1521-3773(20001201)39:23<4216::AID-ANIE4216>3.0.CO;2-K
      22
      Nematic liquid crystals for active matrix displays: molecular design and synthesis
      Kirsch, Peer; Bremer, Matthias
      Angewandte Chemie, International Edition (2000), 39 (23), 4216-4235CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
      A review, with 122 refs. Substances forming calamitic mesophases have been known for more than 100 yr but only the recent, rapid advance in active matrix liq. crystal display (AM-LCD) technol. helped these materials to achieve the crucial position in flat panel display technol. they hold today. Due to their high contrast, large viewing angle, and rapid switching times, modern AM-LCDs offer a superior picture quality even compared to conventional cathode ray tubes. Their flatness, low wt., and low energy consumption render them the technol. of choice for all kinds of portable devices. Some of the future promises of AM-LCD technol. are centered around the development of liq. cryst. materials for the different subtypes of active matrix applications. This development is aimed, on the one hand, towards improved electrooptical and viscoelastic properties; on the other hand, the increasing performance of LCDs leads to extremely stringent reliability demands on the liq. crystals. Responding to these high stds. of performance and quality, most liq. crystals for contemporary AM-LCD applications are multiply fluorinated compds. with very high purities, as is typical for materials used in the electronics industry. The synthesis of these superfluorinated materials (SFMs) often requires specialized methods, which, in several cases, had to be introduced for the first time into the canon of industrial prodn. The immense market pressure, as well as the rapid advance of AM-LCD technol. on the side of the display manufacturers, urges an increasing pace of the materials development. This demand for new materials can no longer be fulfilled by conventional trial-and-error approaches. As in the pharmaceutical industry, in the search for new, superior liq. crystals, the purely empirical methods are increasingly supported by a rational design based on computational methods.
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    23. 23
      Poskin, T. J.; Piscelli, B. A.; Yoshida, K.; Cordes, D. B.; Slawin, A. M. Z.; Cormanich, R. A.; Yamada, S.; O’Hagan, D. Janus Faced Fluorocyclohexanes for Supramolecular Assembly: Synthesis and Solid-State Structures of Equatorial Mono-Di- and Tri Alkylated Cyclohexanes and With Tri-Axial C-F Bonds to Impart Polarity. Chem. Commun. 2022, 58, 7968– 7971,  DOI: 10.1039/D2CC03010A
      There is no corresponding record for this reference.
    24. 24
      Bannwarth, C.; Ehlert, S.; Grimme, S. GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion Contributions. J. Chem. Theory Comput. 2019, 15, 1652– 1671,  DOI: 10.1021/acs.jctc.8b01176
      24
      GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion Contributions
      Bannwarth, Christoph; Ehlert, Sebastian; Grimme, Stefan
      Journal of Chemical Theory and Computation (2019), 15 (3), 1652-1671CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      An extended semiempirical tight-binding model is presented, which is primarily designed for the fast calcn. of structures and noncovalent interactions energies for mol. systems with roughly 1000 atoms. The essential novelty in this so-called GFN2-xTB method is the inclusion of anisotropic second order d. fluctuation effects via short-range damped interactions of cumulative at. multipole moments. Without noticeable increase in the computational demands, this results in a less empirical and overall more phys. sound method, which does not require any classical halogen or hydrogen bonding corrections and which relies solely on global and element-specific parameters (available up to radon, Z = 86). Moreover, the at. partial charge dependent D4 London dispersion model is incorporated self-consistently, which can be naturally obtained in a tight-binding picture from second order d. fluctuations. Fully anal. and numerically precise gradients (nuclear forces) are implemented. The accuracy of the method is benchmarked for a wide variety of systems and compared with other semiempirical methods. Along with excellent performance for the "target" properties, we also find lower errors for "off-target" properties such as barrier heights and mol. dipole moments. High computational efficiency along with the improved physics compared to it precursor GFN-xTB makes this method well-suited to explore the conformational space of mol. systems. Significant improvements are furthermore obsd. for various benchmark sets, which are prototypical for biomol. systems in aq. soln.
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    25. 25
      Zhao, Y.; Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 2008, 120, 215– 241,  DOI: 10.1007/s00214-007-0310-x
      25
      The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals
      Zhao, Yan; Truhlar, Donald G.
      Theoretical Chemistry Accounts (2008), 120 (1-3), 215-241CODEN: TCACFW; ISSN:1432-881X. (Springer GmbH)
      We present two new hybrid meta exchange-correlation functionals, called M06 and M06-2X. The M06 functional is parametrized including both transition metals and nonmetals, whereas the M06-2X functional is a high-nonlocality functional with double the amt. of nonlocal exchange (2X), and it is parametrized only for nonmetals. The functionals, along with the previously published M06-L local functional and the M06-HF full-Hartree-Fock functionals, constitute the M06 suite of complementary functionals. We assess these four functionals by comparing their performance to that of 12 other functionals and Hartree-Fock theory for 403 energetic data in 29 diverse databases, including ten databases for thermochem., four databases for kinetics, eight databases for noncovalent interactions, three databases for transition metal bonding, one database for metal atom excitation energies, and three databases for mol. excitation energies. We also illustrate the performance of these 17 methods for three databases contg. 40 bond lengths and for databases contg. 38 vibrational frequencies and 15 vibrational zero point energies. We recommend the M06-2X functional for applications involving main-group thermochem., kinetics, noncovalent interactions, and electronic excitation energies to valence and Rydberg states. We recommend the M06 functional for application in organometallic and inorganometallic chem. and for noncovalent interactions.
      >> More from SciFinder ®
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    26. 26
      Pratik, S. M.; Nijamudheen, A.; Datta, A. Janus All-cis-1,2,3,4,5,6-Hexafluorocyclohexane: A Molecular Motif for Aggregation-Induced Enhanced Polarization. ChemPhysChem 2016, 17, 2373– 2381,  DOI: 10.1002/cphc.201600262
      26
      Janus all-cis-1,2,3,4,5,6-Hexafluorocyclohexane: A Molecular Motif for Aggregation-Induced Enhanced Polarization
      Pratik, Saied Md.; Nijamudheen, Abdulrahiman; Datta, Ayan
      ChemPhysChem (2016), 17 (15), 2373-2381CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Recently synthesized all-cis-1,2,3,4,5,6-hexafluorocyclohexane is the least stable among all possible configurational isomers of 1,2,3,4,5,6-hexafluorocyclohexane. This mol. has a remarkably large dipole moment (6.2 D) as well as high facial polarization. Solid-state, dispersion-cor. DFT (DFT-D3) calcns. are performed on the cryst. phase of all-cis-1,2,3,4,5,6- hexafluorocyclohexane, which reveal that dispersion interactions play a crucial role in its stabilization. A no. of thermodynamically favorable orientations of dimers, trimers and tetramers are demonstrated for this mol. Parallel-stacked aggregates, from dimers to higher-order aggregates, which are absent in the crystal, are found to be thermodynamically most favorable due to the presence of strong short-range C-H···F-C intermol. hydrogen-bonding networks. Because of their cooperative nature, binding energies, dipole moments, and polarizations per mol. increase from monomer to tetramer, whereas the HOMO-LUMO gaps follow the opposite trend. Based on the DFT-D3 calcns., it is proposed that this parallel-stacked arrangement can be further extended to prep. stable a 1D crystal such that a large dipole moment and macroscopic polarizations can arise, which might be useful in designing electronic and nonlinear optical devices. Because the mol. has conformational flexibility, the potential energy surface is investigated for ring flipping and the effects of fluorine substitution are studied by comparing the barrier with respect to cyclohexane and all-cis-1,2,3-trifluorocyclohexane.
      >> More from SciFinder ®
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    27. 27
      (a) Anet, F. A. L.; Bourn, A. J. R. Nuclear Magnetic Resonance Line-Shape and Double-Resonance Studies of Ring Inversion in Cyclohexane-d11. J. Am. Chem. Soc. 1967, 89, 760– 768,  DOI: 10.1021/ja00980a006
      27a
      Nuclear magnetic resonance line-shape and double-resonance studies of ring inversion in cyclohexane-d11
      Anet, Frank A. L.; Bourn, Anthony J. R.
      Journal of the American Chemical Society (1967), 89 (4), 760-8CODEN: JACSAT; ISSN:0002-7863.
      Kinetic parameters were obtained for ring inversion in cyclohexane-d11 by two different N.M.R. methods: (a) line-shape analysis and (b) double resonance. A field-frequency lock spectrometer operating at 60 Mc./sec. was used for all measurements. Rate consts. were calcd. from -117 to -24° and covered a range of over half a million. The values of ΔF*cb, ΔH*, and and ΔS*cb for the chair-to-boat process were found to be 10.3 and 10.8 kcal./mole and 2.8 entropy units, resp. The results do not agree with the recent spin-echo work of Allerhand, et al. (CA 63, 166c) as far as ΔS*cb is concerned. 26 references.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXmsV2gtQ%253D%253D&md5=19082447e68d5bf8ac98985b92327691
      (b) Hendrickson, J. B. Molecular geometry. VII. Modes of interconversion in the medium rings. J. Am. Chem. Soc. 1967, 89, 7047– 7061,  DOI: 10.1021/ja01002a038
      27b
      Molecular geometry. VII. Modes of interconversion in the medium rings
      Hendrickson, James B.
      Journal of the American Chemical Society (1967), 89 (26), 7047-61CODEN: JACSAT; ISSN:0002-7863.
      cf. preceding abstrs. A protocol for examg. sym. ring conformations of six- to ten-membered cycloalkanes without recourse to models is developed and used to order their modes of interconversion and calc. the energy barriers involved, both for sym. modes of transition and for pseudo-rotation. The principles of conformational analysis for substituted rings are also set forth. 24 references.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXos1KrtA%253D%253D&md5=112cf8749a4bcf0abe010f52ae2512d9
    28. 28
      Clark, J. L.; Taylor, A.; Geddis, A.; Neyyappadath, R. M.; Piscelli, B. A.; Yu, C.; Cordes, D. B.; Slawin, A. M. Z.; Cormanich, R. A.; Guldin, S.; O’Hagan, D. Supramolecular packing of alkyl substituted Janus face all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs. Chem. Sci. 2021, 12, 9712– 9719,  DOI: 10.1039/D1SC02130C
      There is no corresponding record for this reference.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c02345.

    • Experimental details and analyses of prepared compounds 1a–1e, copies of 1H, 13C{1H} and 19F{1H} NMR spectra, X-ray data 1a and 1d, details of computation reaction barriers for SNAr reactions on 9 and 11, and interconversion barriers for cyclohexanes 1f, 2, and 15 (PDF)

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    Deposition numbers 2384410–2384411 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Centre (CCDC) and Fachinformationszentrum Karlsruhe Access Structures service.


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