Chemistry of Enolates – C vs O Alkylation

Enolates can be very tricky to handle. Upon reaction with a base and in the presence of alkyl halide, the carbonyl compounds with α-hydrogens can undergo a reaction to produce a mixture of c-alkylated product or o-alkylated product. This occurs due to the formation of enolate ion as will be seen ahead in the mechanism.

C-alkylation vs O-alkylation - A continuous challenge in the chemistry of enolates.

C-alkylation vs O-alkylation - A continuous challenge in the chemistry of enolates.

Mechanism

Step 1

In the first step, the base abstracts the alpha-hydrogen of the carbonyl containing compound (in this case a ketone).

Base abstracts alpha-hydrogen of the carbonyl compound.

Base abstracts alpha-hydrogen of the carbonyl compound.

Step 2

In the second step, the carbanion formed can undergo resonance stabilization to form the enolate ion.

the carbanion formed can undergo resonance stabilization to form the enolate ion

the carbanion formed can undergo resonance stabilization to form the enolate ion

Step 3

The enolate ion can now react with the alkyl halide (R-X) to produce either

1. C – Alkylation

Enolate forming C-alkylated product

Enolate forming C-alkylated product

2. O – Alkylation

Enolate forming O-alkylated product

Enolate forming O-alkylated product

Factors determining C vs O alkylation

A number of factors such as negative charge density, solvation, cation coordination, strength of electrophile and product stability affect whether the reaction progresses to C – alkylation or to O – alkylation. Often, in most reactions, a mixture is obtained and the ratios vary from reaction to reaction.

For example3,

A reaction showing both C and O alkylated products

A reaction showing both C and O alkylated products. Image taken from reference 3.

In case when this reaction occurs with methyl iodide – Methyl iodide is a weak electrophile. Also the cation coordination is strong with the O as it has greater negative charge density. Due to these facts the C-alkylated product forms the more thermodynamically stable product.

In case when this reaction occurs with trimethyl silyl chloride – Trimethyl Silyl Chloride is a much stronger electrophile as compared to methyl iodide. The SN2 transition state will resemble the reactants (enolate) more than the products. Also the reaction at the more negative charge density which is the oxygen atom, will be more preferred. Also, since O-Si bond is very stable (25 Kcal more favorable than C-Si bond), the reaction would prefer to go via the o-alkylation thermodynamically as well as kinetically.

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References

  1. Advanced Organic Chemistry: Reactions and synthesis. By Francis A. Carey, Richard J. Sundberg
  2. Organic-Chemistry.org (accessed on February 25, 2011)
  3. http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/aldket2.htm (accessed on February 25, 2011)

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