DOI: 10.1021/jo101819u Published on Web 12/01/2010 J. Org. Chem. 2011, 76, 145–153 145 r 2010 American Chemical Society pubs.acs.org/joc Conformational Analysis of cis-2-Halocyclohexanols; Solvent Effects by NMR and Theoretical Calculations Ernani A. Basso,* Layara A. Abiko, Gisele F. Gauze, and Rodrigo M. Pontes Departamento de Quı´mica, Universidade Estadual de Maring a, Av. Colombo, 5790, 87020-900 Maring a-PR, Brazil eabasso@uem.br Received September 15, 2010 Conformational problems often involve very small energy differences, even low as 0.5 kcal mol -1 . This accuracy can be achieved by theoretical methods in the gas phase with the appropriate accounting of electron correlation. The solution behavior, on the other hand, comprises a much greater challenge. In this study, we conduct and analysis for cis-2-fluoro-, cis-2-chloro-, and cis-2- bromocyclohexanol using low temperature NMR experiments and theoretical calculations (DFT, perturbation theory, and classical molecular dynamics simulations). In the experimental part, the conformers’ populations were measured at 193 K in CD 2 Cl 2 , acetone-d 6 , and methanol-d 4 solutions; the preferred conformer has the hydroxyl group in the equatorial and the halogen in the axial position (ea), and its population stays at about 60-70%, no matter the solvent or the halogen. Theoretical calculations, on the other hand, put the ae conformer at a lower energy in the gas phase (MP2/ 6-311þþG(3df,2p)). Moreover, the theoretical calculations predict a markedly increase in the conformational energy on going from fluorine to bromine, which is not observed experimentally. The solvation models IEF-PCM and C-PCM were tested with two different approaches for defining the atomic radii used to build the molecular cavity, from which it was found that only with explicit consideration of hydrogens can the conformational preference be properly described. Molecular dynamic simulations in combination with ab initio calculations showed that the ea conformer is slightly favored by hydrogen bonding. Introduction Six-membered rings constitute the classical problem in conformational analysis and are closely connected to the birth of modern stereochemistry. 1 The conformational pref- erence is usually rationalized as a delicate compromise among the so-called stereoelectronic effects, which in this context means repulsion between the substituent and the axial hydrogens (1,3-diaxial repulsions) and hyperconjuga- tion. 1,2 These effects are intrinsic to each molecule and have been extensively investigated in the gas phase through theo- retical calculations. 3-6 Often, the energy difference between the possible conformers lies below 1 kcal 3 mol -1 , and it is not rare to find cases in which this conformational energy stays as low as 0.2 kcal 3 mol -1 . 7,8 Attaining such a level of accu- racy in solution is one of the greatest challenges for con- temporary computational chemistry. Much of what we know about conformational analysis came from the study of substituted cyclohexanes. 1,2,9-12 (1) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New York, 1994. (2) Wiberg, K. B.; Hammer, J. D.; Castejon, H.; Bailey, W. F.; DeLeon, E. L.; Jarret, R. M. J. Org. Chem. 1999, 64, 2085–2095. (3) Ribeiro, D. S.; Rittner, R. J. Org. Chem. 2003, 68, 6780–6787. (4) Pophristic, V.; Goodman, L. Nature 2001, 411, 565–568. (5) Goodman, L.; Gu, H.; Pophristic, V. J. Phys. Chem. A 2005, 109, 1223–1229. (6) Basso, E. A.; Oliveira, P. R.; Caetano, J.; Schuquel, I. T. A. J. Braz. Chem. Soc. 2001, 12, 215–222. (7) Freitas, M. P.; Tormena, C. F.; Rittner, R.; Abraham, R. J. J. Phys. Org. Chem. 2003, 16, 27–33. (8) Oliveira, P. R. O.; Rittner, R. Magn. Reson. Chem. 2008, 46, 250–255. (9) Bjornsson, R.; Arnason, I. Phys. Chem. Chem. Phys. 2009, 11, 8689–8697. (10) Jensen, F. R.; Bushweller, C. H.; Beck, B. H. J. Am. Chem. Soc. 1969, 91, 344–351. (11) Schneider, H. J.; Hoppen, V. J. Org. Chem. 1978, 43, 3866–3873. (12) Aliev, A. E.; Harris, K. D. M. J. Am. Chem. Soc. 1993, 115, 6369– 6377.