Nucleophilicity of sterically hindered enolates

Question

Problem

Answer

C

Question

Here $\ce{KH}$ obviously acts as a base, and forms the enolate from the ketone, which subsequently act as nucleophiles causing an S_N2 reaction on the $\ce{CH3I}$. When this happens twice, we get the compound in option A.
However, after the removal of a third proton from $2,6$-dimethylcyclohexanone, the following enolate is formed -

This enolate will attack through the $\mathrm{C-2}$ atom. This atom is sterically hindered as it is a $3^\circ$ carbon. Hence I reasoned that like tert-butoxide, this enolate wouldn't act as a nucleophile either, so the reaction effectively stops at A.

Since the answer is C, it turns out that the sterically hindered enolate still does react further, and in good yield. Why is my reasoning incorrect? Also, this question is not from a standard textbook, so I would appreciate any reference regarding if and why/why not the enolate will react further.

Answer 1

One thing that will help you understand how this can happen at a position that otherwise looks hindered is to consider the geometry at that position. Carbon 2 is planar in the enolate anion, and the nucleophilic molecular orbital is more $\mathrm{p}$-like than $\mathrm{sp^3}$-like. The picture below highlights this geometry (note that the orbital shown is a simplification of the conjugated HOMO of the enolate anion):

Because the enolate anion is planar at carbon 2, the electrophile approaches from above or below. The methyl group at carbon 2 is not in the way.

Answer 2

Although Ben Norris has given excellent explanation for why the steric hindrence is not playing the role in the reaction of cyclohexanone with excess methyl iodide to give tetramethylated cyclohexanone, there is an enother reason why reaction proceds so smoothly under given condition to give more than 80% yield of 2,2,6,6-tetramethylcyclohexanone. It is the exceptionally high reactivity of $\ce{KH}$ towards ketones compared to that of other strong non-nucleophilic bases such as $\ce{NaNH2}$, and even $\ce{NaH}$ and $\ce{LiH}$ (Ref.1):

As shown in the graph above, methyl tert-butyl ketone (pinacolone) has given 100% metallated enolate within $\pu{5 min}$ in the presence of $\ce{KH}$ at $\pu{20 ^\circ C}$ while it has taken more than $\pu{120 min}$ to give at least 20% metallated enolate with $\ce{NaH}$ under same conditions. For comparition, $\ce{LiH}$ is even less reactive than $\ce{NaH}$ (Ref.1). In a typical reaction ($\pu{25 mmol}$ substrate in $\pu{40 mL}$ of THF in the presence of $\pu{28 mmol}$ of $\ce{KH}$), cyclohexanone is enolated 100% within $\pu{1.5 min}$ and 2-methylcyclohexanone is enolated 100% within $\pu{6 min}$. In the latter case, which can give two enolates, the ratio of isolated enols (as silyl ethers) was found to be $33:67$ less substitured one to more substituted one indicating that reaction is more facile with making more stable enolate even in the presence of steric hindrence.

Thus, it is clear that the question in OP's post is directly related to the reserch done in Ref.2 (which is mentioned by Waylander in his answer. Accordingly, the authors in Ref.2 reported yield of 2,2,6,6-tetramethylcyclohexanone as 96% (GLC analysis) and as 81% (isolated yield by distillation), which is the exact yield given in the question. The procedure was as follows:

To a flask containing $\pu{216 mmol}$ of $\ce{KH}$ in mineral oil $(\pu{40 mL})$, which is in a waterbath maintained at $\pu{25 ^\circ C}$, $\pu{220 mL}$ of THF was added first and then $\pu{5.2 mL}$ of cyclohexanone $(\pu{50 mmol})$ was added dropwise over a $\pu{5 min}$ period. The mixture was stirred for additional $\pu{5 min}$ and $\pu{13.5 mL}$ of $\ce{CH3I}$ $(\pu{216 mmol})$ was added dropwise over a $\pu{15 min}$ period. The reaction mixture was stirred for additional $\pu{15 min}$ before workup with water. The simple distillation of dried organic layer gave $\pu{6.25 g}$ of expected product (81% yield).

---

References:

1. Charles Allan Brown, "Saline hydrides and superbases in organic reactions. III. Facile reaction of potassium hydride with ketones. Rapid, quantitative formation of potassium enolates from ketones via kaliation," J. Org. Chem. 1974, 39(9), 1324–1325 (DOI: https://doi.org/10.1021/jo00923a042).
2. Alan A. Millard and Michael W. Rathke, "Procedure for the permethylation of ketones using potassium hydride and methyl iodide," J. Org. Chem. 1978, 43(9), 1834–1835 (DOI: https://doi.org/10.1021/jo00403a055).

Answer 3

The permethylation of cyclohexanone with KH/MeI is described here JOC paper. The yield quoted is 96% and other ketones are also exemplified.