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When the cyclohexane ring is connected to two or more substituents, establishing a more stable chair conformation becomes increasingly challenging. To determine the stable chair conformation, the steric effects of each substituent and any extra steric interactions must be examined for both chair conformations.
Two principles are used to study the effect of conformations on the relative stability of disubstituted cyclohexanes:
Substitutes prefer equatorial rather than axial locations to decrease steric strain induced by 1,3-diaxial interactions.
In the more stable conformation, the larger substituent will be in the equatorial position.
Define Disubstituted Cyclohexanes
When a cyclohexane ring has only one substituent, it prefers to adopt an equatorial orientation to reduce 1,3-diaxial steric repulsions (cf. methylcyclohexane). The substitution pattern determines the conformational preference of disubstituted systems. The all-equatorial isomers are the more stable of the two pairs for X = Y, because the lower energy arrangement places the larger of the two groups in an equatorial position.
Disubstituted Cyclohexanes
Cis and Trans Substituted System
On conformationally limited systems, the labels cis/trans describe the relative orientations of substituents. When two substituents are oriented on the same side of a planar ring, they are called cis, and when they are on opposing sides, they are called trans. Note that the designations cis/trans and axial/equatorial refer to different features of cyclohexane skeleton substituents.
Consider 1-chloro-2-methylcyclohexane, a common disubstituted cyclohexane. One stereoisomer of this molecule has both the chloro and methyl groups at equatorial locations.
With a conformational diastereomer in which both the chloro and methyl groups are oriented axially, this chemical quickly achieves conformational equilibrium.
Trans-1-chloro-2-methylcyclohexane refers to either conformation (or a mixture of both).
When two substituents have an up–down relationship in cyclic compounds, the name “trans” is employed.
The chloro and methyl groups occupy neighbouring equatorial and axial locations in a distinct stereoisomer of 1-chloro-2-methylcyclohexane.
Cis-1-chloro-2-methylcyclohexane is a conformational diastereomer combination that quickly equilibrates. In a cis-disubstituted cycloalkane, the substituents are connected up–up or down–down.
The chair interconversion has no effect on the cis connection. The same cis and trans substitution definitions apply to substituent groups in additional cyclohexane ring positions. The terms cis and trans define the relative stereochemical configurations of the two asymmetric carbons when the substituents in a disubstituted cyclohexane are on asymmetric carbons. Still, they say nothing about the absolute configurations of these carbons. As a result, cis-1-chloro-2-methylcyclohexane has two enantiomers.
Conformational Analysis
Conformational analysis can be performed on disubstituted cyclohexanes, much like monosubstituted cyclohexanes. The 1,3-diaxial interactions (or gauche-butane interactions) in each conformation are compared to assess the relative stability of the two chair conformations.
When two groups on substituted cyclohexane disagree over the equatorial position, the preferable conformation can typically be inferred from the groups’ relative conformational preferences. Take the chair interconversion of cis1-tert-butyl-4-methylcyclohexane, for example.
The van der Waals repulsions of the tert-butyl group are so strong that they regulate the conformational equilibrium. As a result, the tert-butyl group that adopts the equatorial position in the chair conformation is overwhelmingly preferred. Based on this, the methyl group is forced to take up an axial position.
Chemists may remark that the conformational equilibrium is “locked” since there is so little conformation with an axial tert-butyl group. This statement is somewhat deceptive because it indicates that the two conformations are not in balance. The equilibrium does occur quickly, but contains only a small amount of the axial tert-butyl group configuration.
Conclusion
When a cyclohexane ring has only one substituent, it prefers to adopt an equatorial orientation to reduce 1,3-diaxial steric repulsions (cf. methylcyclohexane). The substitution pattern determines the conformational preference of disubstituted systems.
The all-equatorial isomers are the more stable of the two pairs for X = Y, because the lower energy arrangement places the larger of the two groups in an equatorial position.
In 1,2- and 1,4-disubstituted cyclohexanes, a cis configuration provides one axial and one equatorial group. In such species, chair flipping becomes a problem. The significant steric strain of 1,2- and 1,4-disubstituted cyclohexane in a trans configuration successfully inhibits the diaxial conformation.
For 1,3-disubstituted cyclohexanes, the cis form is diequatorial, and the flipped conformation has more steric contact between the two axial groups. Trans-1,3-disubstituted cyclohexanes, like cis-1,2- and cis-1,4-substituted cyclohexanes, can flip between the two axial/equatorial forms.
