Synthesis of Alcohols

In this article we will discuss about organic reactions which are commonly used for the Synthesis of Alcohols. 

Alcohols are the important intermediates in Organic Chemistry. They are widely used for synthesis of other functional groups such as alkyl halides, alkenes, ketones, aldehydes, carboxylic acids etc.

Key words: Alcohols, Nucleophilic Substitution, Hydration, Oxymercuration-demercuration, Hydroboration-oxidation, Dihydroxylation, Reduction, Syn addition, Anti addition, Grignard reagents.

1.  Nucleophilic Substitution

Alcohols are synthesized by nucleophilic substitution reaction on a primary alkyl halide. The secondary and tertiary alkyl halides favour elimination reaction (alkene compound) in addition with nucleophilic substitution. In this reaction alkyl halide is treated with alkali hydroxide (KOH / NaOH) to give alcohol product via S_N2 reaction.

Example

1-bromopropane reacts with aqueous potassium hydroxide to form propan-1-ol.

2.  Synthesis of Alcohols from Alkenes

2.1         Hydration of alkene

The alkenes undergo acid catalyzed hydration reaction to form alcohol compounds. In this reaction highly substituted alcohols forms selectively this is known as “Markovnikovs rule”. The hydration reaction follows S_N1 reaction mechanism.  

Example

2-methylbut-2-ene undergoes acid catalyzed hydration reaction to form 2-methylbutan-2-ol. 

2.2         Oxymercuration-demercuration

It is two steps reaction for the synthesis of alcohol from alkene. The first step is oxmercuration where alkene reacts with mercuric diacetate in aqueous solution to produce addition product. Then second step is demercuration which is basically reduction reaction by sodium borohydride (NaBH₄). This two step process gives “Anti addition” of H₂O across the double bond; that means hydrogen (H) and hydroxyl (OH) are opposite to each other. The end product of the reaction is highly substituted alcohol.

Example

2-methylbut-2-ene reacts with mercuric diacetate followed by reduction reaction to produce 2-methylbutan-2-ol. 

2.3         Hydroboration-oxidation

Hydroboration-oxidation is a two step reaction used for synthesis of alcohol from alkene. In the first step alkene reacts with borane to give addition product. Then the second step is hydrolysis of alkyl borane to form alcohol compound. Overall this process follows Anti-Markovnikovs rule and gives less substituted alcohol selectively.    

Example

2-methylprop-1-ene undergoes hydroboration followed by oxidation reaction to give 2-methylpropan-1-ol. In this process H and OH adds from the same side of double bond. This is known as “syn addition”. 

2.4         Dihydroxylation : Syn addition

Dihydroxylation is the oxidation reaction of alkene which produces 1,2-dihydroxy compound. In this reaction alkene reacts with osmium tetroxide (OsO₄) followed by work up with reducing agent like potassium bisulfite (KHSO₃) to produce dihydroxylation compound. Dihydroxylation of alkene is also possible with dilute and cold KMnO₄ / NaOH reaction condition. 

Example

(E)-but-2-ene undergo dihydroxylation by reaction with osmium tetroxide to form butane-2,3-diol. The osmium tetroxide offers “syn addition” of hydroxyl groups across the double bond.

2.5         Dihydroxylation : Anti-addition

The alkenes are known to react with peroxy acid to give epoxide intermediate. The epoxide then hydrolyses to form 1,2-dihydroxy compound with “Anti” geometry.

Example

(E)-but-2-ene reacts with peroxy acid to form dihydroxylation product; butane-2,3-diol. The peroxy acid offers “Anti addition” of hydroxyl groups across the double bond.

3.  Synthesis of Alcohols from Carbonyl Compounds

3.1         Reduction of carbonyl compounds

The carbonyl compounds undergo reduction reaction upon treating with reducing agents such as lithium aluminium hydride (LiAlH₄) or sodiumborohydride (NaBH₄). The carboxylic acids and esters need strong reducing agent like LiAlH₄ to produce alcohol whereas aldehyde and ketones required mild reducing agent like NaBH₄ for the synthesis of alcohol.

Example

Benzaldehyde reacts with sodium borohydride (NaBH₄) to offer benzyl alcohol.

The ester compounds needs more equivalents of reducing agent because after addition of one equivalent of reagent; aldehyde intermediate forms which need one more equivalent of hydride to give complete reduction product. The ethyl benzoate needs strong reducing agent like (LiAlH₄) to give benzyl alcohol as final product via benzaldehyde intermediate.

3.2         Addition of acetylides to carbonyl compounds

The acetylides are nucleophiles which gives nucleophilic addition product when treated with carbonyl compounds.

Example

Prop-1-yen reacts with sodium amide (NaNH₂) to form “acetylide” which then adds on to the benzaldehyde to form alcohol.

3.3         Addition of Grignard reagents to carbonyl compounds

The organomagnesium halides (RMgX) are known as Grignard reagents. The carbonyl compounds tend to react with Grignard reagents to form alcohol compounds. An aldehyde gives secondary alcohol whereas a ketone produces tertiary alcohol upon reaction with a Grignard reagent. Similarly, a Grignard reagent also can react with ester or acyl chloride to form tertiary alcohol. 

Example

The methylmagnesium bromide reacts with benzaldehyde to form 1-phenylethan-1-ol.

In case of ester and acyl chloride; addition of Grignard reagent gives ketone intermediate on which addition of second equivalent of Grignard reagent takes place to form tertiary alcohol.

4.  Synthesis of Alcohols from Epoxides

The epoxides can react with Grignard reagents or organocuprates (Gilman reagent) to form alcohols. 

Example

2-methylcyclopropane reacts with methylmagnesium bromide to produce butan-2-ol. Similarly lithium dimethylcuprate (Gilman reagent) also can be used for this transformation.

To summarize this part; alcohols are very important intermediates in Organic Chemistry. Therefore various methods are available for the synthesis alcohol compounds. We have seen here most commonly used methods for the synthesis of alcohol compounds. 

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