Ring inversion substituted cyclohexanes

One much-studied subject is the ring inversion of cyclohexane and polymethylcyclo-hexanes, as shown in Table 8. The subject has been reviewed " but, very generally, compounds with flattened chair conformations due to methyl-methyl 1,3-diaxial interactionshave lowered barriers. Simply substituted compounds where rotation about substituted bonds can take place in the boat-twist manifold of conformations have barriers similar to that of cyclohexane, while more highly substituted compounds, where rotation about substituted bonds must take place on the way to the transition state have markedly higher barriers than in cyclohexane. 

Substitution on a cyclohexane ring does not greatly affect the rate of conformational inversion but does change the equilibrium distribution between alternative chair forms. All substituents that are axial in one chair conformation become equatorial on ring inversion, and vice versa. For methylcyclohexane, AG for the equilibrium... 

Energy differences between conformations of substituted cyclohexanes can be measured by several physical methods, as can the kinetics of the ring inversion processes. NMR spectroscopy has been especially valuable for both thermodynamic and kinetic studies. In NMR terminology, the transformation of an equatorial substituent to axial and vice versa is called a site exchange process. Depending on the rate of the process, the difference between the chemical shifts of the nucleus at the two sites, and the field strength... 

The conformational properties of mono-substituted cyclohexanes, C V, 1111X, in their thiourea inclusion compounds have been studied102. Variable-temperature MAS spectra demonstrate that a chair-chair ring inversion process occurs in the thiourea tunnel, in which the axial and equatorial conformers are interconverted. Predominance of the equatorial conformer is found when X = NH2. 

The Aae criterion was applied to the problem of the piperidine equilibrium (10 11) by examining the H-NMR spectrum of the deutero derivatives 12, 13, and 14 at — 85°C when ring inversion is slow on the NMR time scale.37 The Aae values are recorded in Table I. The preferred conformation for the N-substituted piperidines 13 and 14 was assigned as lone-pair axial because for these compounds Aae values were similar to those in quinolizidine. However, in piperidine (12), where the Aae value is similar to that in cyclohexane, the lone pair was assumed to occupy the equatorial position in the preferred conformation. In support of this contention, protonation of... 

In the first instance, only cyclohexane compounds with hydrogen atoms substituted will be considered, so that there should be no drastic alteration of the ring skeleton. In Table 2 are listed values of barriers to ring inversion in cyclohexyl hahdes where these are known to a reasonable accuracy.35-37) There is no doubt that there is a significant difference between the values for fluorine and chlorine, but bromine occurs between these two values. The barriers to rotation in the series CH3CH2X 38) and in the series (CH3)2CX—C(GH3)3 39) are also quoted in the table, but the trends there are not reflected in the results for ring inversion. 

A barrier of about 12.8 kcal/mol at —15 °C has been determined for a symmetrical 1,2,3,4,5,6-hexachlorocyclohexane 2) while the highest barrier yet found is) for a substituted cyclohexane which retains a skeleton with six carbon atoms is that of the cis form of 1,2,3,4,5,6-hexamethylcyclohexane 10b. The barrier in this instance is 17.0 kcal/mol at 60 C It appears i 8) that the barrier to ring inversion in as-l,2-di- -butylcyclohexane is 16.3 kcal/mol, a high value that can be explained in terms of the f-butyl groups being eclipsed or nearly eclipsed in the transition state. The conformational processes taking place in this molecule are not thoroughly understood. )... 

Energy differences between conformations of substituted cyclohexanes can be measured by several physical methods, as can the kinetics of the ring inversion processes. Nuclear magnetic resonance spectroscopy has been especially valuable... 

Considering then the series a, b, and d in Table 7 the substitution of one hetero-atom lowers the barrier or has little effect which fits with the monosubstitution effect. The series 19 can be extended to 19e X=dimethyl-silyl 79/, X = selenium and 19g, X = tellurium.72) For 19e the barrier to inversion in 5.4 kcal/mol 3) and for 79/ and 19g, it appears to be much lower than in cyclohexane, or in 19a to 19d, since no changes are seen in the nmr spectrum at —100°. It may be in these cases the low barrier reflects the unusual flatness of the six-membered ring, and perhaps particular ease of rotation about carbon-X bonds, both of which may be consequences of these bonds being relatively long. 4)... 

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