Phenolates- O-alkylation and C-alkylation

Phenolates are formed when phenolic hydroxy groups are exposed to basic conditions.

Formation of Phenolate

Formation of Phenolate

Generally even weak bases are capable of forming the phenolate anion.

This phenolate anion can be reacted with an alkyl halide to yield a possible two products- either the O-alkylated (product 1) or the C-alkylated (product 2).

Reaction of phenolate with alkyl halide yields two possible products

Reaction of phenolate with alkyl halide yields two possible products

The product 1 is formed by the O-alkylation of the phenolate anion, while product 2 is formed via C-alkylation of the phenolate anion. The possibility of product 1 being formed is higher than the probability of formation of product 2. However, under certain conditions, it is possible to form product 2 as well.

NOTE – The O-alkylated product is similar to the reaction seen in Williamson Ether Synthesis

Mechanism

Step 1

In the presence of base the phenol gets converted to the phenolate anion

Formation of Phenolate

Formation of Phenolate

Step 2

This phenolate anion can undergo O-alkylation via the normal SN2 reaction to yield the product 1.

O-alkylation of phenolates leading to formation of ether linkage via SN2 reaction

O-alkylation of phenolates leading to formation of ether linkage via SN2 reaction

Alternatively, the phenolate anion can undergo a resonance transformation and then undergo a C-alkylation with the alkyl halide. The phenol is reformed to restore aromaticity of the phenyl ring yielding product 2.

C-alkylation of phenolate

C-alkylation of phenolate

As aromaticity is disrupted in this mechanism, the energy barrier for the intermediate is higher, and therefore, the probability of product 2 is lower. However if conditions are tweaked such that the oxygen anion is blocked, the possibility of product 2 increases.

Conditions for O-alkylation vs C-alkylation of Phenolates

The solvent selection widely controls what products you get for this reaction.

  1. For O-alkylation: Use DMF, DMSO, t-Butanol
  2. For C-alkylation: Use of protic solvents like water or Trifluoro Ethanol (TFE)

Use of protic solvents pushes the formation of C-alkylated product as the solvent is capable of hydrogen bonding with the phenolate oxygen and therefore shields the oxygen, thus preventing it from attacking the alkyl halide.

For example,

2-Naphthol or β-Naphthol, reacts with benzyl bromide in the presence of base and DMF to give O-alkylated product, while in the presence of trifluoro ethanol (TFE) it yields the C-alkylated product.

Reaction of 2-Naphthol with Benzyl Bromide yielding C-alkylated and O-alkylated products under different solvent conditions.

Reaction of 2-Naphthol with Benzyl Bromide yielding C-alkylated and O-alkylated products under different solvent conditions.

Books on Organic Chemistry

Check out some of the best textbooks for Organic Chemistry

References

  1. Advanced Organic Chemistry: Reactions and synthesis. By Francis A. Carey, Richard J. Sundberg

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