On "pure axial" monosubstituted cyclohexanes: Cyclohexyl nitronate esters adopt O-equatorial conformations

It has been reported recently by Kang and Yin that a complex O-cyclohexyl nitronate and the corresponding O-cyclohexyloxime constitute the "first completely stable axial conformers of monosubstituted cyclohexanes at room temperature." If true, this claim violates a central principle of alicyclic conformational analysis. We have evaluated it by performing ab initio and molecular mechanics calculations to show that energy barriers in the C-O-X=C-C(O)-O-C system (X = N and N+-O-) are low and that the equatorial-axial ratio is 2-3:1. To experimentally verify the predictions, we have synthesized seven analogues of the previously reported O-cyclohexyl nitronate using Mitsunobu chemistry, including genuine O-axial and O-equatorial conformers anchored by a 4-tert-butyl group. Both the H-1 and C-13 NMR spectra of the compounds have been carefully analyzed to be in complete accord with literature precedent. Finally, we have also prepared the compound claimed to be monosubstituted and O-axial. NMR analysis shows the O-cyclohexyl nitronate to be predominately O-equatorial with an estimated eq/ax = 3:1, again in full agreement with previous measurements of O-cyclohexyl A values. Configuration about the C=N bond is tentatively assigned to be E. Both the O-axial conformational proposition and the empirical shift rule of Kang and Yin's study are found to be compromised by the finding that a cyclopentyl derivative was, in fact, confused for the cyclohexyl analogue in the synthetic work and subsequent NMR analysis.