Substituted Cyclohexanes

When a cyclohexane ring bears at least one substituent, the two chairs in equilibrium may no longer have the same energy. In general, the chair form with the bulkiest substituent(s) equatorial is the most stable one, as shown by the following experimental data.

Animated space-filling model of the conformational equilibrium of a substituted cyclohexane

Video: Substituted cyclohexanes: axial substituent (less than 0.1%) versus equatorial (more than 99.9%)

If we set the chair-to-chair equilibrium as shown, a shift upwards, towards the equatorial conformer, implies a positive change in free energy, as displayed by the equations:

R	ΔG° (kcal/mol)	R	ΔG° (kcal/mol)
H	0.0	F	0.3
CH₃	1.8	Cl	0.5
CH₃CH₂	1.8	Br	0.6
(CH₃)₂CH	2.2	I	0.5
(CH₃)₃C	>5.0	OH	0.9
CO₂H	1.4	CH₃O	0.8
CO₂CH₃	1.3	NH₂	1.4

Equilibrium between the chairs with R axial and R equatorial: K = [axial]/[equatorial] and ΔG° = −RT ln K

Can we understand why the methyl group has an experimental conformational energy of 1.8 kcal/mol? Recall that the gauche interaction between two methyl groups in butane had an energy cost of 0.9 kcal/mol.

Anti and gauche conformations of butane in Newman projection: ΔG° = 0.9 kcal/mol

The axial methyl group of methylcyclohexane has two gauche interactions (0.9 + 0.9 = 1.8 kcal/mol)

That's why an axial methyl group is less stable than an equatorial one by twice 0.9, that is 1.8 kcal/mol. In general, substituents are less stable in the axial position because of their interaction with the CH₂ groups at positions 3 and 5. Depending on the size of the substituent, this interaction will be more or less severe and its conformational energy larger or smaller.

Chair equilibrium of a 1,1-disubstituted isomer

Chair equilibria of the cis and trans 1,3-disubstituted isomers

Chair equilibria of the cis and trans 1,2-disubstituted isomers

Chair equilibria of the cis and trans 1,4-disubstituted isomers

In disubstituted cyclohexanes, the conformational equilibrium will be shifted towards the chair with fewer axial substituents and/or the chair with the substituent of highest conformational energy in the equatorial position.