Cyclohexanone, conformational analysis

The principles involved in the conformational analysis of six-membered rings containing one or two trigonal atoms, for example, cyclohexanone and cyclohexene are similar. The barrier to interconversion in cyclohexane has been calculated to be 8.4-12.1 kcal mol . Cyclohexanone derivatives also assume a chair conformation. Substituents at C2 can assume an axial or equatorial position depending on steric and electronic influences. The proportion of the conformation with an axial X group is shown in Table 4.4 for a variety of substituents (X) in 2-substituted cyclohexanones. 

The principles involved in the conformational analysis of six-membered rings containing one or two trigonal atoms, e.g., cyclohexanone and cyclohexene, are similar.242... 

Workers at DuPont used a pharmacophore model and database search to develop the first type III mimetic inhibitor of HIV protease, DuP450 (87)(Fig. 15.38). This evolved from a 3D pharnacophorethat retained two key interactions replacement of the flap-bound water and a hydroxyl transition-state isostere (155). Molecular modeling led to a cyclohexanone as a better spacer between these groups, and finally the seven-membered cyclic urea (87) was created (Fig. 15.38). The development of these inhibitors illustrates the importance of conformational analysis in the design of constrained analogs. 

An analysis of the solvent dependence of the A>c and /hh couplings combined with an analysis of the changes in the IR first overtone carbonyl bond intensities and theoretical calculations allowed Abraham and co-workers to determine directly the conformational equilibria in 2-bromocyclo-hexanone, a model compound, by the use of which the authors illustrated an improved method of conformational analysis of substituted cyclohexanones. 

Devlin FJ, Stephens PJ. Conformational analysis using ab initio vibrational spectroscopy 3-methyl-cyclohexanone. J Am Chem Soc 1999 121 7413-7414. 

This reaction, known as the Bouveauft-BJanc reduction, used to be used to reduce carbonyl compounds to alcohols, but now aluminium hydrides and borohydrides are usually more convenient. You met an example of ttie Bouveault-Blanc reduction in Chapter 33 (conformational analysis-reduction of cyclohexanones). oy raii ... 

The results reported in this paper agree with previous data (1, 3) and are consistent with the mechanism of the hydrogenation in that the reaction proceeds via an enol which is in equilibrium with the cyclohexanone. The enol can react with hydrogen to give the trans-isomer and the cyclohexanone gives the cis-isomer as shown by conformational analysis of the enol and ketone intermediates shown in Figure 4, where the preferred direction of addition of the hydrogen to the C=C and C=0 bonds is illustrated. 

Yoshinaga, R, Tormena, C. R, Freitas, M. R, Rittner, R., Abraham, R. J. (2002). Conformational analysis of 2-halo-cyclohexanones an NMR, theoretical and solvation study. Journal of the Chemical Society, Perkin Transactions 2,... 

Kleinpeter, E., Heydenreich, M., Koch, A., Linker, T. (2012). Synthesis and NMR spectroscopic conformational analysis of esters of 4-hydroxy-cyclohexanone-the more polar the molecule the more stable the axial eonformer. Tetrahedron, 68(10), 2363-2373. 

Because of the number of conformations that need to be considered for acyclic systems, cyclohexanones are somewhat simpler for analysis. However, even for these systems the situation is not easily amenable to isolating specific components of selectivity. Several explanations have been proposed over the years to account for the preference of axial attack of cyclohexanones by sterically unhindered nucleophiles (L1A1H4, NaBH4, AIH3) [9]. Equatorial attack is favoured for sterically hindered cyclohexanones or reducing agents (Fig. 6-7). 

It is reasonable to assume that the simple concepts introduced for monocyclic rings such as cyclopentane, cyclohexane, cyclohexene, and cyclohexanone can be applied, with little change, to complex molecules containing those units. Throughout this book the analysis of simple rings will be used to understand the conformational bias and reactivity of larger and more difficult synthetic targets. 

In 1953, Corey reported that conformational equiUbrium in a-chloro and bromo-substituted cyclohexanones strongly favors (>97%, 2.3kcal/mol) the axial conformer. IR-analysis of the carbonyl stretching frequencies indicated that this conformational effect is accompanied by a red-shift in the carbonyl absorption, indicative of the C = O bond weakening due to the Jt interaction. 

Turning to non-transition-metal catalysis, transition-state structures for the reduction of 2-methyl- and 2-isopropyl-cyclohexanone by LAH have been identified by DFT, and LUMO maps and NBO analysis have been used to examine the uneven distribution of the molecular orbital about the carbonyl r-plane, in order to explain the product ratio " substituent effects, the conformational ratio in the reactant, and... 

With the axial-aryl chair conformation clearly established for all cases of alkaloids in the mesembrine subgroup previously studied, it was surprising to find that the hydrochloride of (—)-mesembrine exists in the solid state with the cyclohexanone ring in a twist-boat conformation, as indicated in 17 (24). A study of the CD of mesembrine hydrochloride in H2O was undertaken in an attempt to seek a possible correlation between the conformation of the hydrochloride in the solid state revealed by the X-ray structure analysis and the solution conformation. Unfortunately, the CD spectrum of mesranbrine hydrochloride in H2O shows the absence of an n ni transition associated... 

A set of Vhh couplings have been reported by Montalvo-Gonzalez " for five exocyclic alkenes and fifteen different ketimines obtained from cyclohexanone and its derivatives. An analysis of the coupling values allowed them to establish relative stereochemical and preferential conformations in the studied compounds. 

Conformational effects on mesomorphism and twisting ability of chiral cyclohexanones in mesophases have been studied by Kutulya et al by the use of the semiempirical AMI and PM3 methods and by analysis of proton-proton couplings. 

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