Conformational equilibria of trans ‐3‐X‐cyclohexanols (X = Cl, Br, CH₃ and OCH₃). A low temperature NMR study and theoretical calculations

Abstract

The integration of 1H and 13C NMR spectra, at - 90 degrees C in CS2/CD2Cl2 (9:1), for the trans-3-chlorocyclohexanol (1), trans-3-bromocyclohexanol (2), and trans-3-methoxycyclohexanol (4) showed that the equatorial-axial (ea) conformer occurs as ca 63, 63, and 69% in the conformational equilibrium, respectively. This corresponds to the following DeltaG(ea-ae) values (from (1)H spectrum): - 0.32 +/- 0.01, - 0.32 +/- 0.04, - 0.48 +/- 0.05 kcal mol(-1); and to (from 13C spectrum): - 0.31 +/- 0.04, - 0.35 +/- 0.05, and - 0.44 +/- 0.01 kcal mol(-1), respectively, in very good agreement within both series. Thus, although bromine is bulkier than chlorine, the 1,3-diaxial steric effects are similar in these equilibria. However, the integration of (1)H NMR spectrum for the trans-3-methylcyclohexanol (3) gave 90% of the 3ae conformer in the equilibrium, at - 90 degrees C on CS2/CD2Cl2 (9:1), corresponding to a DeltaG(ea-ae) value of 1.31 +/- 0.02 kcal mol(-1). The values obtained through the additivity rule, with data from monosubstituted cyclohexanes (DeltaG(Ad) = DeltaG(X) + DeltaG(OH)), for compounds 1, 2, and 4 (-0.37 +/- 0.15, - 0.34 +/- 0.09, and - 0.46 +/- 0.04 kcal mol(-1), respectively) are in very good agreement with the experimental values, but it is significantly smaller for compound 3 (0.79 +/- 0.02 kcal mol(-1)). Theoretical calculations through different levels of theory (HF/6-311 + g**, B3LYP/6-311 + g**, MP2/6-31 + g**, and CBS-4M) showed that CBS-4M is the best method for the study of conformational equilibria for these systems, since it provides DeltaG(ea-ae) values similar to the experimental values.

Strong hyperconjugative interactions limit solvent and substituent influence on conformational equilibrium: the case of cis-2-halocyclohexylamines

“…A similar axial preference of cyclohexane halo derivatives was observed by Basso and co-workers in cis -2-halocyclohexanols [14], and by de Oliveira and Rittner in trans -3-halocyclohexanols [30]. However, in both studies this preference was not so pronounced as that observed in this work, with a small difference between the populations of the two conformers at equilibrium.…”

Conformational Analysis of cis-2-Halocyclohexanols; Solvent Effects by NMR and Theoretical Calculations

“…Six-membered rings constitute the classical problem in conformational analysis and are closely connected to the birth of modern stereochemistry . The conformational preference 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 hyperconjugation. , These effects are intrinsic to each molecule and have been extensively investigated in the gas phase through theoretical calculations. − Often, the energy difference between the possible conformers lies below 1 kcal·mol −1 , and it is not rare to find cases in which this conformational energy stays as low as 0.2 kcal·mol −1 . , Attaining such a level of accuracy in solution is one of the greatest challenges for contemporary computational chemistry.…”

“…Much of what we know about conformational analysis came from the study of substituted cyclohexanes. ,,− Cyclohexane rings and analogous heterocyclics appear in the structure of innumerous biologically important molecules and, of course, the role played by these molecules depends on how the substituents interact among themselves and with the solvent media. In this respect, several research groups devoted considerably efforts to dissect the solvent effects on conformational equilibria. ,,− …”

“…Abraham et al suggested that an equatorial OH group is solvated differently than an axial one, with direct consequences to the conformational behavior. Oliveira and Rittner investigated the conformational equilibrium of trans -3-X-cyclohexanols, finding that the most stable conformer is the one with the halogen in the axial position, even for a bulky substituent like bromine.…”

“…As mentioned above, trans -2-halocyclohexanols as well as trans -3-halocyclohexanols have been investigated by NMR spectroscopy and theoretical calculations. ,,, In contrast, the cis isomer was left aside over the years, maybe because of the experimental difficulties in preparing some of the halo derivatives as well as by the need of a very refined theoretical approach to correctly reproduce and interpret the experimental data in solution. As we go from fluorine to bromine, it is expected that the ae conformer becomes more stable because it has a much more bulky substituent in the equatorial position.…”