I am asked to draw the most stable chair conformation of compound 1.

enter image description here

After doing so I am a little uncertain which of the conformations is the most stable. The most stable conformation is the one where the most bulky group is positioned equatorial. However, do I prioritize Cl over the methyl- and isopropyl-group or are the two groups more prioritized due to them being bonded to Hydrogens which take up more space than a Cl-atom. From what I have read, I would say that the chair conformation on the top is the most stable, prioritizing the methyl- and isopropyl-group. Is that correct?

  • $\begingroup$ Check your hand-drawn structures, I believe them to be wrong. $\endgroup$
    – TAR86
    Feb 8 '18 at 19:04
  • 1
    $\begingroup$ Neither of those structures correspond to compound 1... $\endgroup$
    – Zhe
    Feb 8 '18 at 20:01
  • $\begingroup$ Could you please explain what is wrong with them. Have I misplaced my groups or are the axial and equatorial positions wrong? @Zhe $\endgroup$
    – J.Se
    Feb 11 '18 at 12:30
  • $\begingroup$ Oh, okay I see what I did. So the isopropyl-group should be in axial-down position in the first conformation and equatorial-down position after the ring flip. Correct? But then which is the most stable? @Zhe $\endgroup$
    – J.Se
    Feb 11 '18 at 13:21
  • $\begingroup$ The biggest groups tend to be equatorial. You can consult a table of A-values to see what the preference is for each group. t-Bu is quite large. i-Pr is smaller but still quite large. $\endgroup$
    – Zhe
    Feb 12 '18 at 4:12

The lowest energy conformer for a cyclohexane ring with multiple substituents will be the one in which the largest group occupies an equatorial position.

Steric parameters are tabulated in many organic chemistry textbooks, the most common of which is the A-value. The A-value represents the difference in energy (ΔG) between a group being axial/equatorial on a cyclohexane ring, thus, as a group gets bigger, its A-value increases, reflecting the increasingly high energy needed to flip the ring.

Bulky substituents such as tert-butyl are often said to "lock the conformation", that is, with a tert-butyl group on a ring, the energy to flip is sufficiently high that ring is "locked" in the conformation with the tert-butyl group equatorial.

In your example, building a simple model with a kit will show you that having the iso-propyl group axial isn't terribly favourable (interestingly the iso-propyl group has a similar A-value to ethyl, due to the ability of the group to rotate, avoiding having a methyl group pointing into the ring).

I ran a few simple calculations (molecular mechanics followed by DFT optimisation - gas phase) on the axial and equatorial conformations, which showed that the two conformations are separated by around 3.4 kcal/mol. The minimum energy conformation of your example is shown below: enter image description here


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