Experimental Demonstration of a Sizeable Nonclassical CH···G

Kyle M. Lambert† , Zachary D. Stempel†, Kenneth B. Wiberg‡ , and William F. Bailey†. † Department of Chemistry, University of Connecticut, 5...
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Experimental Demonstration of a Sizeable Nonclassical CH···G Hydrogen Bond in Cyclohexane Derivatives: Stabilization of an Axial Cyano Group Kyle M. Lambert,† Zachary D. Stempel,† Kenneth B. Wiberg,*,‡ and William F. Bailey*,† †

Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269-3060, United States Department of Chemistry, Yale University, 275 Prospect Street, New Haven, Connecticut 06520-8107, United States

‡

S Supporting Information *

ABSTRACT: Base-catalyzed equilibration of anancomeric cyanocyclohexanes demonstrates that replacement of cis-3,5-dimethyl holding groups with electronwithdrawing CF3 groups dramatically increases the proportion of the axial cyano isomer present at equilibrium. The CF3 groups exert an effect on the conformational energy of the cyano group worth about 0.6 kcal/mol. A nonclassical hydrogen bond between the axial CN group and the syn-axial hydrogens is a major contributor to the axial stability of the group.

T

he literature of the past few decades provides many examples of CH···G Coulombic interactions (nonclassical hydrogen bonds) affecting the conformations of cyclic and acyclic molecules.1 Although the reported experimental and computational results are interesting, and almost surely correct, to our knowledge there has not been any direct assessment of such an interaction in a simple system that also provides information on its magnitude. We recently presented evidence of a stabilizing CH···O interaction in the axial conformation of 5phenyl-1,3-dioxane between an ortho-hydrogen of the phenyl group and an oxygen of the 1,3-dioxane: as a result, the plane of the phenyl ring essentially bisects the dioxane ring.2 The results of this study further demonstrated that the strength of the CH··· O bond was tunable; the interaction is enhanced when remote electron-withdrawing substituents are present on the aromatic ring. We were prompted by these observations to consider a conceptually simple experiment to probe directly a fundamental question: the strength and consequence of such CH···G bonds in a simple cyclohexane derivative. The requisite model systems are illustrated in Figure 1. We reasoned that the conformational energy (−ΔG° or A-value)3 of a group evaluated by direct

equilibration of anancomeric cyclohexanes bearing cis-3,5dimethyl holding groups should be different from that assessed when cis-3,5-bis-trifluoromethyl holding groups are employed. The electron-withdrawing CF3 groups would reasonably be expected to render both C(3) and C(5), as well as the syn-axial hydrogens at these positions, more positive than would be the case in the dimethyl systems. To the extent that a putative CH··· G bond between an axial group at C(1) and the syn-axial hydrogens is of any consequence, there should be a greater proportion of the isomer having an axial substituent in the system bearing the CF3 groups. The approach outlined above requires that the diastereoisomeric systems be easily equilibrated, and it was preferable that the group whose conformational energies were to be evaluated be symmetric. For these reasons, we chose to explore the cyano group whose conformational energy has been determined by various techniques on a number of occasions4 including basecatalyzed equilibration of 4-tert-butylcyclohexyl cyanide.5 The diastereoisomeric cyanides (1−4) were prepared in straightforward fashion as illustrated in Scheme 1 and detailed in the Supporting Information (SI). The only step in the syntheses that deserves comment involves the direct conversion of the cyclohexylmethanols to the cis-nitriles (2 and 4) using hexamethyldisilazane (HMDS) and Bobbitt’s salt (4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate) following our general procedure.6 The isomeric nitriles, 1 and 3, were isolated from the mixtures obtained upon base-catalyzed equilibration of the cis-isomers. Each of the anancomeric pairs of cyanides (1 and 2; 3 and 4) were equilibrated at room temperature (∼23 °C) in sealed ampules under nitrogen as solutions in cyclohexane, Et2O, or THF over dry potassium tert-butoxide. Equilibrium was

Figure 1. Model systems.

Received: October 22, 2017 Published: November 16, 2017 © 2017 American Chemical Society

6408

DOI: 10.1021/acs.orglett.7b03287 Org. Lett. 2017, 19, 6408−6411

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Organic Letters Scheme 1. Preparation of the Substrates

conformational energy of the cyano group. This effect is strikingly dramatic: in the least polar solvents investigated, cyclohexane and Et2O, the cyano group prefers to occupy the axial position. Indeed, the ΔG° value for the CN group in cyclohexane solvent (3 → 4; Table 1, entry 6) is +0.48 kcal/mol, favoring the axial isomer. To our knowledge, this is an unprecedented result.7 Comparison of the ΔG° value in cyclohexane solvent of the CN group evaluated in the 3,5dimethyl system (−0.12 kcal/mol) with that obtained from the 3,5-bis-trifluoromethyl system (+0.48 kcal/mol) demonstrates that the CF3 holding groups exert an effect on the conformational energy worth some 0.60 kcal/mol. The etiology of this effect is most certainly electrostatic. In an effort to achieve further insight into the role of these intramolecular Coulombic interactions, we have examined some substituted cyclohexanes at the MP2/6311+G* level.8 In particular, cyclohexanes bearing F and CN substituents at C(1) with cis-3,5-dimethyl or cis-3,5-bis-trifluoromethyl groups were investigated. The fluoro compounds, we reasoned, should provide a simple model since they involve a single atom as the substituent; the cyano compounds, of course, correspond to molecules 1−4 discussed above. The computed structures of the compounds investigated may be found in the SI; the structures of the four axially substituted compounds, along with some relevant geometrical parameters, are shown in Figure 2. The calculated axial → equatorial energy differences, corrected for differences in zero-point energies and thermal corrections to 25 °C, are summarized in Table 2. With these compounds the computed ΔH° and ΔG° values are fairly close, with the latter

approached independently from samples of each diastereoisomer and, after the solutions were neutralized by shaking with anhydrous ammonium chloride and then filtered, the area ratio of the isomeric mixture was determined by capillary GC analysis providing baseline separation. It was judged that equilibrium had been reached when the same area ratios were obtained from initially pure samples of each isomer. Area ratios for each equilibration, which reflect the equilibrium constant for the process, were taken as the average of 8−12 independent determinations from each side, and the free energy difference for the equilibrium was calculated in the normal way: ΔG° = −RT ln K. The results of these studies are summarized in Table 1. Table 1. Equilibria in Cyanocyclohexanes

entry

R

solvent

K

ΔG° (kcal/mol)a

1 2 3 4 5 6

CH3 (1, 2)

THF Et2O c-C6H12 THF Et2O c-C6H12

1.485 ± 0.003 1.359 ± 0.011 1.223 ± 0.001 1.329 ± 0.004 0.785 ± 0.003 0.422 ± 0.001

−0.23 ± 0.01 −0.18 ± 0.05 −0.12 ± 0.01 −0.17 ± 0.02 +0.26 ± 0.01 +0.48 ± 0.01

CF3 (3, 4)

a

Determined at room temperature. Errors in K are propagated standard deviations; the errors in ΔG° are estimated errors that are larger than the propagated standard deviation to account for an assumed GC response ratio of 1.0 for a given pair of isomers.

The experimental free energy difference (1 → 2; Table 1, entry 1) of −0.23 ± 0.01 kcal/mol in THF at room temperature is in good agreement with the CN group’s A-value of 0.25 kcal/mol determined by Allinger from the equilibration of 4-tertbutylcyclohexyl cyanide with potassium tert-butoxide in THF solvent at 66 °C;5 demonstrating, not unexpectedly, that the entropy contribution to ΔG° is negligible in this system. The equilibration data for the 3,5-dimethyl system (Table 1, entries 1−3) reveals a small solvent effect at play. As might be expected, in the most polar solvent, THF, the molecule with the higher dipole moment (2) is stabilized relative to the axial isomer (1). In the least polar solvent studied, cyclohexane, the free energy difference between 1 and 2 decreases by half to −0.12 kcal/mol. In short, the results gleaned from an examination of the 3,5dimethyl system are unremarkable. Examination of the influence of 3,5-bis-trifluoromethyl holding groups on the conformational energy of the cyano group (3 → 4; Table 1, entries 4−6) vis-à-vis found in the 3,5dimethyl system (1 → 2; Table 1, entries 1−3) demonstrates that the electron-withdrawing nature of the CF3 groups affects the

Figure 2. Computed MP2/6-311+G* structures.8,10 6409

DOI: 10.1021/acs.orglett.7b03287 Org. Lett. 2017, 19, 6408−6411

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Organic Letters

The quantity of immediate interest is the charge at H(3,5), the equivalent axial hydrogens at the carbons bearing the holding groups. It is clear, as expected, that replacement of the methyl holding groups with CF3 groups results in a substantial increase (∼0.02 e) in positive charge at these axial hydrogens, and this would lead to an increased Coulombic interaction with a negatively charged axial substituent at C(1). It should be noted that H(3,5) is rather positive even in the cis-3,5-dimethyl systems, and this will provide some Coulombic stabilization of an axial C(1) group; this likely contributes to the origin of the rather low A-values of F and CN groups in cyclohexane. A rough “back of the envelope” estimate of the Coulombic energy (E = q1q2/r12) associated with the CH···F interaction between a H(3,5) hydrogen and an axial F at C(1) is easily obtained from the Hirshfeld charges (Table 3, entries 1 and 3) and the computed distances from Figure 2 in the di-CH3 and the bis-CF3 systems of 2.65 and 2.60 Å, respectively.13 For the system with di-CH3 holding groups, the Coulombic energy is attractive by 0.67 kcal/mol per hydrogen; for the corresponding bis-CF3 compound, the attractive energy is 0.94 kcal/mol. An analogous but slightly more tedious computation for the CN compounds, involving separate calculations of the Coulombic energy of the interactions of carbon and the nitrogen of the group with a H(3,5) hydrogen, gave the following results: the overall CH··· CN interaction in the di-CH3 molecule (1) is attractive by 0.54 kcal/mol per hydrogen; the corresponding value for the bis-CF3 system is attractive by 0.69 kcal/mol. In this connection we must note, as we have noted elsewhere, that simple summation of Coulombic energies between nonbonded atoms is an approximation, at best, of the actual situation.2 Indeed, as Kirkwood and Westheimer demonstrated some 80 years ago, simple two-center Coulombic energies will be attenuated by the electric fields attendant with the bonds in molecules.14 Nonetheless, this modest exercise provides an order of magnitude estimate of the effect of replacing dimethyl holding groups with bis-trifluoromethyl groups that comports well with both the experimental data for the CN isomers and the computational results for both the CN and F molecules. The MP2/6-311+G* structures (Figure 2) reinforce the conclusion that there is a significant attractive interaction between an axial group at C(1) and the positive 3,5-positions of the bis-CF3 molecules. Cursory inspection of the structures indicates that an axial group is considerably closer to the syn-axial hydrogens in the systems bearing CF3 groups at C(3,5) than in the corresponding CH3 molecules. This is most noticeable in the

Table 2. Energy Differences Calculated Using the MP2/6311+G* Level in kcal/mol

entry

R

G

ΔH°

ΔG°

ΔΔH°a

ΔΔG°a

1 2 3 4

CH3 CF3 CH3 CF3

F F CN CN

0.16 1.61 0.55 1.50

0.12 1.54 0.44 1.35

1.45

1.42

0.95

0.91

(ΔH° or ΔG° in the R = CF3 series) − (ΔH° or ΔG° in the R = CH3 series). a

being a little smaller. This result indicates that the entropy change is quite small, as expected.9 It will be noted that, in each instance, the computed energies show a distinct preference for the axially substituted isomer that is significantly larger than the experimentally determined ΔG° values in cyclohexane solvent (Table 1). This discrepancy is likely due to the large difference in dipole moment between the axial and equatorial forms and the resultant large solvent effect.11 However, the change from axial to equatorial of a C(1) substituent represents a small perturbation, and for this reason, the energy differences between isomers in the 3,5-di-CH3 systems and that in the corresponding 3,5-bis-CF3 systems (ΔΔH° and ΔΔG°) should be more accurate than the total energies. Indeed, a comparison between the computed ΔΔG° = 0.91 kcal/mol for the cyano compounds in each series (Table 2, entry 4) with the experimentally determined ΔΔG° = 0.60 kcal/mol in cyclohexane solution (Table 1) lends some credence to this suggestion. How large are the charge-induced Coulombic interactions that are apparently responsible for the difference in conformational energies of a polar substituent when methyl holding groups are replaced by trifluoromethyl holding groups? For an answer to this seemingly simple question, it is convenient to convert the charge density about a nucleus to an effective atomic charge. We believe that the Hirshfeld charges,12 obtained directly from the charge density, are the most useful for this purpose. We have calculated these charges for all atoms in the molecules depicted in Table 2, and they may be found in the SI. Selected charges, germane to the present question, are summarized in Table 3. Table 3. Calculated Hirshfeld Charges, q (e)

entry

isomer

G

R

H(1)

C(1)

H(3,5)

F

1 2 3 4 5 6 7 8

A B A B A B A B

F F F F CN CN CN CN

CH3 CH3 CF3 CF3 CH3 CH3 CF3 CF3

0.0425 0.0399 0.0534 0.0454 0.0596 0.0561 0.0689 0.0606

0.0585 0.0557 0.0655 0.0618 0.0015 0.0007 0.0078 0.0063

0.0367 0.0338 0.0544 0.0521 0.0364 0.0347 0.0531 0.0528

−0.1460 −0.1522 −0.1348 −0.1356

6410

CN

CN

0.0799 0.0764 0.0807 0.0807

−0.2325 −0.2349 −0.2144 −0.2163

DOI: 10.1021/acs.orglett.7b03287 Org. Lett. 2017, 19, 6408−6411

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110, 6049. (b) Alkorta, I.; Elguero, J. Chem. Soc. Rev. 1998, 27, 163. (c) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond in Structural Chemistry and Biology; Oxford Univ. Press: Oxford, 1999. (2) (a) Bailey, W. F.; Lambert, K. M.; Stempel, Z. D.; Wiberg, K. B.; Mercado, B. Q. J. Org. Chem. 2016, 81, 12116. (b) Wiberg, K. B.; Lambert, K. M.; Bailey, W. F. J. Org. Chem. 2015, 80, 7884. (3) Winstein, S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77, 5562. (4) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New York, 1994; pp 696−697. (5) Allinger, N. L.; Szkrybalo, W. J. Org. Chem. 1962, 27, 4601. (6) Kelly, C. B.; Lambert, K. M.; Mercadante, M. A.; Ovian, J. M.; Bailey, W. F.; Leadbeater, N. E. Angew. Chem., Int. Ed. 2015, 54, 4241. Angew. Chem. 2015, 127, 4315. (7) The only substituents previously known to adopt an axial orientation are HgX moieties as a consequence of their long Hg−X bonds and the polarizable nature of the Hg atom. See ref 4. (8) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2009. (9) Ho̅fner, D.; Lesko, S. A.; Binsch, G. Org. Magn. Reson. 1978, 11, 179. (10) Legault, C. Y. CYLview; Université de Sherbrook, 2009. http:// www.cylview.org. (11) The computed energies refer to the gas phase, and it might be noted that the polarizable continuum model suggests that experimental data obtained in cyclohexane should represent values that are approximately 40% of the maximum effect obtained in the absence of a solvent. (12) (a) Hirshfeld, F. L. Theor. Chim. Acta 1977, 44, 129. (b) Parr, R. G.; Ayers, P. N.; Nalewajski, R. F. J. Phys. Chem. A 2005, 109, 3957. (13) The Coulombic energy, E = q1q2/r12, is conveniently calculated in atomic units (hartrees), using the charge in e, r in Bohr (1 Bohr = 0.529 Å), and the conversion factor 1 H = 627.51 kcal/mol. (14) (a) Kirkwood, J. G.; Westheimer, F. H. J. Chem. Phys. 1938, 6, 506. (b) Kirkwood, J. G.; Westheimer, F. H. J. Chem. Phys. 1938, 6, 513.

smaller C(1)−C(2)−C(3) bond angle and a larger H(1)−G bond angle when 3,5-CF3 groups are present. More subtle is the nonlinear C(1)−C−N angle of 178° in compound 3 in comparison to an almost linear (179.5°) angle in compound 1. In conclusion, direct base-catalyzed equilibration of anancomeric cyanocyclohexanes demonstrates that the conformational energy of the CN group is substantially affected by the nature of the holding groups at the 3,5-positions. When di-CH3 groups are used, the conformational energy is identical to that obtained using a classical 4-t-butyl holding group. However, the conformational energy is considerably reduced when bis-CF3 groups are present. Remarkably, in cyclohexane, the least polar solvent system investigated, the cyano group favors the axial orientation to the extent of almost 0.5 kcal/mol. The computational results described above indicate that the axialstabilizing effect of the electron-withdrawing CF3 groups is plainly electrostatic in origin; a manifestation of a moderately strong, nonclassical CH···CN bond between the syn-axial hydrogens and the CN group worth at least 0.6 kcal/mol. MP2/6-311+G* calculations suggest that the effect of 3,5-bisCF3 groups on the conformational energy of a fluorine is even more dramatic; the attractive CH···F interaction is computed to be worth more than 1 kcal/mol. In the aggregate, the results of the investigation suggest that nonclassical CH···G attractive interactions merit further consideration when evaluating the origin of conformational phenomena in more complex systems involving polar substituents such as the anomeric effect.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03287. Detailed experimental procedures for all synthesized compounds; 1H, 13C, and 19F NMR spectra of all products; 1 H NOESY spectra and analyses; details of the analytical GC data; a summary of the calculations, including computed energies, coordinates, and Hirshfeld charges (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Kyle M. Lambert: 0000-0002-8230-2840 Kenneth B. Wiberg: 0000-0001-8588-9854 William F. Bailey: 0000-0001-9159-0218 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by the facilities and staff of the Yale University Faculty of Arts and Sciences High Performance Computing Center. The work at the University of Connecticut was supported by grants from Procter & Gamble Pharmaceuticals, Mason, OH.

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REFERENCES

(1) For comprehensive reviews of nonclassical CH···G hydrogen bonds, see: (a) Takahashi, O.; Kohno, Y.; Nishio, M. Chem. Rev. 2010, 6411

DOI: 10.1021/acs.orglett.7b03287 Org. Lett. 2017, 19, 6408−6411