10.12: Preparation of Alcohols via Substitution Reactions

Overview

Alcohols can be synthesized from alkyl halides via nucleophilic substitution reactions. The highly polar carbon-halogen bond in the substrate makes halide a good leaving group. The hydroxide ion or water can act as a nucleophile to take the place of halide and form an alcohol. The substitution reactions occur via two different reaction pathways, S_N1 or S_N2, depending on the nature of carbon attached to the halide.

Primary alcohols are synthesized from primary alkyl halides, and the reaction proceeds via the S_N2 mechanism. The nucleophile attacks the halogen-bearing carbon from the side opposite to the carbon-halogen bond. However, in the presence of a strong nucleophile, a competing elimination reaction occurs as well.

Figure_1: Parallel reactions of 1-bromobutane into substitution products and elimination products (proton abstraction).

The synthesis of secondary alcohols from secondary alkyl halides via substitution reaction is not favored since a mixture of products is formed from the competing S_N2 and E2 reaction routes.

Figure_2: Parallel reactions of 2-bromo-3-methylbutane into substitution products and elimination products (proton abstraction).

Tertiary alkyl halides undergo S_N1 reaction with a weak base such as water to produce tertiary alcohols along with alkene as a minor product due to a competing E2 elimination reaction.

Figure_3: Parallel reactions of tertiary alkyl halides to elimination and substitution products.

If a strong nucleophile like sodium hydroxide is used, the E1 reaction dominates over S_N1.

The nature of the reactant determines the stereochemistry of the product formed. If the halogen in the alkyl halide is connected to a chiral carbon, the resulting alcohol is a mixture of two enantiomers.

Figure_4: Substitution reaction over an asymmetric carbon to yield a racemic mixture of optically active alcohols as the product

Recall nucleophilic substitution reactions, where a functional group is substituted with another.

These reactions require an sp³-hybridized electrophile with a good leaving group and can be used to synthesize alcohols via an S_N1 or an S_N2 mechanism.

Primary alkyl halides, preferentially, undergo substitution reactions via the S_N2 mechanism with strong nucleophiles like sodium hydroxide to yield primary alcohols. The competing E2 elimination process gives an alkene as the minor product.

The synthesis of secondary alcohols from secondary alkyl halides via substitution is less favorable because competing elimination reactions lead to a mixture of alcohols and alkenes as the final products.

In the synthesis of tertiary alcohols, tertiary alkyl halides undergo substitution reactions via the S_N1 mechanism with weak nucleophiles like water.

However, if water is replaced with a strong nucleophile like sodium hydroxide, the tertiary substrate favors the E2 reaction, producing an alkene.

If the tertiary halide is chiral, then an S_N1 reaction gives a racemic mixture of tertiary alcohols.

The competing elimination reaction can be minimized by applying a relatively low temperature for the synthesis of alcohols in a weak base or neutral medium.