Conformations and Cycloalkanes
Cyclohexane Chair Conformation Stability: Which One Is Lower Energy?
Last updated: December 13th, 2022 |
Finding The Most Stable Conformation Of A Cyclohexane Chair
You’re given a structure with two or more substituents on a cyclohexane ring, and you’re asked to draw the most stable conformation. How do you do that? That’s what this post is about.
Table of Contents
- A-Values Are A Useful Measure of Bulkiness
- A-Values Are Additive
- Example: Determining The Most Stable Conformation Of cis– And trans- 1,2-Dimethylcyclohexane
- To Determine Chair Conformation Stability, Add Up The A-Values For Each Axial Substituent. The Lower The Number, The More Stable It is.
- Summary: Stability of Cyclohexane Conformations
- (Advanced) References and Further Reading
1. A-Values Are A Useful Measure Of Bulkiness
In the last post, we introduced A values and said they were a useful tool for determining which groups are “bulkiest” on a cyclohexane ring. (See post: Ranking the Bulkiness Of Substituents On Cyclohexane Rings With A-Values)
The greater the A-value (bulk), the more favoured the equatorial conformer will be (versus axial). We saw that hydroxyl groups (OH) have a relatively low A-value (0.87), methyl groups are higher (1.70) and the t-butyl group is one of the highest of all (>4.5) .
We also saw that by knowing the A value (which is essentially the energy difference in kcal/mol) we could figure out the % of axial and equatorial conformers in solution using the formula ΔG = –RT ln K
In this post we’re going to extend this concept and see what happens when we have MORE than one group on a cyclohexane ring.
2. A-Values Are Additive
The nice thing about A values is that they are additive. We can make the (safe) assumption that groups on adjacent carbons don’t bump into one another [Note 1] so figuring out the torsional strain of a cyclohexane chair is simply a matter of adding up the A values of the axial groups in any chair conformation.
We can apply this to cyclohexanes with two, three, or even more substituents.
Here are some examples:
3. Example: Determining The Most Stable Conformation Of cis- And trans– 1,2-Dimethylcyclohexane
That’s nice, you might say, but when might we ever want to do that? The key example is when we are examining two chair conformers of the same molecule. A-values are essential in helping us figure out which one is most stable.
Here’s an example of the type of question we might be asked: draw the two chair conformations of cis-1,2-dimethylcyclohexane and trans-1,2-dimethylcyclohexane, and determine which is most stable.
- Here, I’ve started by drawing the conformer of trans-1,2-dimethylcyclohexane where both CH3 groups are axial (remember – it’s trans because one group is up and one group is down).
- The two axial methyl groups give a total of 3.4 kcal/mol of torsional strain.
- A chair flip converts all axial groups to equatorial and vice versa (but all “up” groups remain “up” and all “down” groups remain “down”! ) giving us a conformer where both methyl groups are now equatorial (and therefore do not contribute any strain).
- Therefore the di-equatorial conformer is favoured by 3.4 kcal/mol. [If we wanted to, we could also figure out the equilibrium constant here: K is about 340, giving a ratio 99.6: 1 in favour of the di-equatorial conformer.]
- In the case of cis-1,2-dimethylcyclohexane, I’ve started by drawing an axial CH3 at C-1 and an equatorial CH3 at C-2 (note that my designation of C-1 and C-2 is completely arbitrary). This has a strain energy of 1.70 kcal/mol due to the single axial CH3.
- When we do the chair flip, we convert all axial groups to equatorial and all equatorial to axial, giving us…. a new chair which still has one methyl group equatorial and one axial! The same energy, in other words (1.70 kcal/mol). [The equilibrium constant here is 1, giving a 50:50 ratio]
4. To Determine Chair Conformation Stability, Add Up The A-Values For Each Axial Substituent. The Lower The Number The More Stable It Is
Now that we’ve drawn all four possibilities, we can rank them in order of stability if we want, and then determine that for the two isomers of 1,2-dimethylcylohexane, the di-equatorial conformer of trans-1,2-dimethylcyclohexane is the most stable.
5. Summary: Chair Conformation Stability
In the next post we’re going to talk about fused cyclohexane rings, and ask how we can apply what we’ve already learned to understand more about the stability of the conformers of these molecules.
Note 1. One key exception to the “A values are additive” assumption is 1,2-di-t-butyl cyclohexane, in which the trans form is actually less stable than the cis despite the fact that both groups are equatorial in the trans. That’s because the two t-butyl groups are held together so closely in space that there is significant “1,2” strain (Van der Waals strain). [Note: it turns out in the trans isomer, the diaxial conformation is favored by 6.2 kcal/mol ! see the References section. ]
Another exception is the amino alcohol below. What force might be responsible for the fact that the axial conformer is favoured in equilibrium conditions?
(Advanced) References and Further Reading
This is a topic commonly taught to undergraduates in Organic Chemistry. A-values are empirically derived and denote the thermodynamic preference for a substituent to be in the axial or equatorial position in cyclohexane. A-values can be added, and the total energy thus derived gives the difference in free energy between the all-axial and all-equatorial conformations.
- Neighboring Carbon and Hydrogen. XIX. t-Butylcyclohexyl Derivatives. Quantitative Conformational Analysis
S. Winstein and N. J. Holness
Journal of the American Chemical Society 1955, 77 (21), 5562-5578
An early paper on the determination of A-values (see Table XII) through kinetic (solvolytic) measurements, which is what Prof. Winstein was well known for. The introduction features a nice summary of how A-values are determined, and later on, Prof. Winstein states “The energy quantity by which a t-butyl group favors the equatorial position is sufficiently large to guarantee conformational homogeneity to most 4-t-butylcyclohexyl derivatives”, in agreement with what is commonly taught in organic chemistry classes today.
- Conformational analysis. 32. Conformational energies of methyl sulfide, methyl sulfoxide, and methyl sulfone groups
Ernest L. Eliel and Duraisamy Kandasamy
The Journal of Organic Chemistry 1976, 41 (24), 3899-3904
This paper uses the additivity of A-values to determine the A-values of -SCH3, -SOCH3, and -SO2CH3 (Table IV).
- The gauche interaction in trans-1,2-dimethylcyclohexane
Muthiah Manoharan and Ernest L. Eliel
Tetrahedron Lett. 1983, 24 (5), 453-456
Although this is generally not covered in introductory organic chemistry, one complication with employing A-values is that groups are on adjacent carbons (as in 1,2-dimethylcyclohexane) can undergo steric repulsion through so-called “gauche interactions”. In this paper, the gauche interaction in trans-1,2-dimethylcyclohexane is calculated to be 0.74 kcal/mol.
- Conformational analysis. LVII. The calculation of the conformational structures of hydrocarbons by the Westheimer-Hendrickson-Wiberg method
Norman L. Allinger, Mary Ann Miller, Frederic A. Van Catledge, and Jerry A. Hirsch
Journal of the American Chemical Society 1967, 89 (17), 4345-4357
Tables V-VII in this paper contain conformation energies of disubstituted cyclohexanes, which can be derived from adding the respective A-values.
- Conformational Studies. VII.1 p-Menthane-2,5-diols and the Relative “Size” of the Isopropyl Group
Robert D. Stolow
Journal of the American Chemical Society 1964, 86 (11), 2170-2173
1,2-disubstituted cyclohexanes do not add neatly due to repulsive interactions from the groups being so close to each other.
- Steric Interactions in Organic Chemistry: Spatial Requirements of Substituents
Hans Förster, Prof. Dr. Fritz Vögtle
Angew. Chem. Int. Ed. 1977, 16 (7), 429-441
- Conformational analysis. LXXVIII. The conformation of phenylcyclohexane, and related molecules
L. Allinger and M. T. Tribble
Tet. Lett. 1971, 12 (35), 3259-3262
Oddly enough, in certain phenylcyclohexanes, the phenyl group prefers to be axial, and this paper investigates that using computational methods.
- Janus face all‐cis 1,2,4,5‐tetrakis(trifluoromethyl)‐ and all‐cis 1,2,3,4,5,6‐hexakis(trifluoromethyl)‐ cyclohexanes
David O’Hagan, Cihang Yu, Agnes Kütt, Gerd-Volker Röschenthaler, Tomas Lebl, David B. Cordes, Alexandra M. Z. Slawin, Michael Bűhl
Angew Chem. Int. Ed. 2020, Accepted Article
This recently published paper is on the synthesis of 1,2,3,4,5,6-hexakis(trifluoromethyl)-cyclohexane. Computational analysis shows that it has a barrier to interconversion of approx. 27.1 kcal/mol.
- Conformational Study of cis-1,4-Di-tert-butylcyclohexane by Dynamic NMR Spectroscopy and Computational Methods.
Gurvinder Gill, Diwakar M. Pawar, and Eric A. Noe
J. Org. Chem. 2005, 70, 10726-10731
Although mainly a study of 1,4-Di-t-butylcyclohexane, this paper also presents calculations for comparing the energies of diaxial and diequatorial trans-1,2-Di-t-butylcyclohexane, and finds that the diaxial conformer is more stable than the diequatorial conformer by about 6.2 kcal/mol! Interestingly the twist-boat conformer of this molecule is only slightly lower in energy (0.5 kcal/mol).
28 thoughts on “Cyclohexane Chair Conformation Stability: Which One Is Lower Energy?”
“despite the fact that both groups are equatorial in the cis”. In the trans, actually! but great post, as usual.
shoot! fixed. Thanks for the keen eye, as always.
This was really really helpful to me. I appreciate it. Keep up your good jobs!
I wonder if there is a minor mistake in the diagram of “ranking the four conformers”. The second one should be equatorial+axial.
Thanks for all these amazing materials!
This was very helpful to me. I appreciate this because i am studying organic chemistry right now.
Great, thanks for reading Dominic.
For the ranking one, why is the second the same as the fourth?
Hi James, I realized that two of the conformers in the ranking of the 4 are identical. Can you take a look to see what I’m referring to?
Thanks for pointing that out. Fixed!!
It was really helpful .Also the content was straight to the point .Thanx a lot
OK. Thank you very much Nisarg.
Hey this probably seems dumb, but I’m trying the find the ratio of the two chairs and I can’t find anywhere that actually solves through the delta G of formation equation to solve for K. I know its probably a simple calculation but I don’t understand how to take a single number and turn it into the ratio of products. May be helpful for others in the future. Thanks for the help with the other information though.
That is a great question. Thanks for the suggestion, I should put this in.
If we make a model of the trans-1,2-di-t-butylcyclohexane, we see that the two tertiary butyl groups aren’t bumping onto each other. Rather, they’re pointing away from one another. So, shouldn’t the conformer be more stable than the cis conformer?
Also, it will be really helpful if you could tell whether the net dipole moment of the molecule plays a part in its stability. eg., in case of 1,2-dibromocyclohexane where the Br groups are both in axial positions, the net dipole moment of the molecule is zero but the A value is 0.89 Kcal/mol where as in a case where both Br are in equatorial positions, the molecule has a net dipole moment but zero A value.
I learn a lot from your content.
Yes, with extremely bulky equatorial groups van der Waals strain can arise, which will push the equilibrium toward the diaxial conformer. In the case of trans 1,2-di-butyl cyclohexane, the diaxial conformer was calculated to be 6.2 kcal/mol more stable than the diequatorial conformer. Interestingly, a twist-boat conformation was very close to it in energy. J. Org. Chem. 2005, 70, 10726-10731 . https://pubs.acs.org/doi/pdf/10.1021/jo051654z?rand=0l523xw6
In the case of dipole moments, you could test that by measuring conformational preferences as a function of polarity of the solvent. This can be done in NMR, for example. I am sure it’s been done but I don’t have a literature reference for you at the moment.
thanks to @curiouswavefunction , I found an example of a difluoro compound which strongly favors the diaxial conformer in aqueous solution (95%) but the diaxial ratio drops off as solvent polarity decreases. See here: https://pubs.acs.org/doi/10.1021/ja9934504
I looked into the effects of solvent on A values (i.e. delta G values) for halocycloalkanes. Here’s what Ernest L. Eliel has to say: “The —AG° values are: 0.15 kcal/mol for fluorine, 0.43 kcal/mol for chlorine, and 0.37 kcal/mol for
bromine, and are remarkably independent of solvent. ” . See https://pubs.acs.org/doi/pdf/10.1021/ja01005a024
In case of trans 1,2-di-t-butyl cyclohexane, if we make a model of the compound, we see that the two tertiary butyl groups aren’t bumping at one another. Rather, they are pointing away from each other. So, shouldn’t the cis conformer be more stable?
Thank you for the helpful content.
Thank you so much for the explanation!
I seem to have pondered too much over the molecule as I have another question.
Will there be van der Waals strain in the case of bulky equatorial groups lying distant from one another, say in 1,3 or 1,4 positions? Will the diaxial conformer still be favoured?
What about the effect of different solvents on the stabilization for substituted cyclohexane?
In March’s organic chemistry (7th edition chapter 4) is pointed out that for 1,2-dihalides cyclohexanes there is a preference for the diaxial form. Why not the equatorial?
Hi Andrea! Alluding to your earlier comment, there is likely a solvent effect because of differences in dipole moment. From Eliel’s “Stereochemistry of Organic Compounds”, page 673 I see that the dipole moment of cis 1,2-dichlorocyclopropane is 3.10 and the dipole moment of the trans is 2.63 . This would suggest that in less polar solvents (e.g. pentane, hexane) the trans would be favored so as to minimize the dipole moment.
I seem to recall some discussion of the solvent dependence of A-values from one of Eliels papers but I can’t find it at the moment!
Thank you. Great work with your blog!
The equatorial substituents including methyl group can also have significant gauche interactions with each other. For example, the two equatorial methyl groups in trans-1,2-dimethylcyclohexane (equatorial conformation). The gauhe interaction between these two methyl group is 0.9 kCal/mol instead of zero kCal/mol in this post. Below includes more examples for your reference.
Yes! That is an excellent point. This is addressed in Reference 3. The gauche interaction in trans 1,2-dimethylcyclohexane is 0.74 kcal/mol. https://www.sciencedirect.com/science/article/abs/pii/S0040403900814355
It was really helpful thanks a lot