Reactions of Alcohols

Alcohols are ubiquitous in nature and can be formed and augmented in many different ways. This atom discusses their synthesis and reactions.

Alcohol Synthesis

Nucleophilic Substitution

Nucleophilic substitution is a common example, with S_N2 conditions working best for primary alcohol synthesis and S_N1 conditions affording secondary and especially tertiary alcohols.

A common primary alcohol synthesis via S_N2 is:

R-CH₂Br + OH^- → R-CH₂OH + Br^-

A common tertiary alcohol synthesis via S_N1 is:

R₃CBr + H₂O → R₃COH + Br^-

Reduction

Reduction of ketones and aldehydes affords secondary and primary alcohols, respectively. Hydride-containing reducing agents like NaBH₄ and LiAlH₄ (with acid workup) produce alcohols. For example, consider the reduction of the aldehyde:

RCHO + NaBH₄ → RCH₂OH

Under stronger conditions, carboxylic acids, esters, acid anhydrides, and acyl halides can also be reduced to primary acids. LiAlH₄ can perform the reduction.

Hydration

Alkenes can be hydrated in acidic conditions, in which case the elements of water are added across a double bond that is broken. The mechanism includes three steps: 1) protonation; 2) nucleophilic addition of water to the resulting carbocation to form a protonated alcohol; 3) deprotonation of the protonated alcohol. Stepwise, the general reaction is:

R-CH=CH₂ + H₂SO₄ + H₂O RCH⁺-CH₃ + H₂O RCHOH₂⁺CH₃

Deprotonation from the solvent yields: RCHOHCH₃

The product of acid-catalyzed hydration is called a "Markownikoff" product: because the carbocation must be on the most substituted carbon (where it is most stable), this is where the hydroxyl adds. To produce an anti-Markownikoff product, in which the alcohol is formed on the less substituted end, hydroboration, followed by oxidation, can be used.

Reacting an alkene with BH₃ will add a hydride onto the more substituted carbon, and BH₂ onto the less substituted carbon. The resulting organoborane can be oxidized by H₂O₂ in basic conditions to remove the -BH₂, and replace it with -OH:

R-CH=CH₂ + BH₃ R-CH₂-CH₂BH₂

R-CH₂-CH₂BH₂ +H₂O₂ + OH^- R-CH₂-CH₂OH

Reactions of Alcohols

Alkoxide formation

Alcohols can be deprotonated in the presence of bases to form alkoxide salts:

ROH + NaH RO^- Na⁺ + H₂

Williamson ether synthesis

Alkoxides can be used to form ethers by reacting with leaving group-containing alkanes. The Williamson ether synthesis involves an alkoxide nucleophile reacting with an electrophilic alkyl halide to produce an ether. For example:

RO^- Na⁺ + R'Cl ROR' + Na⁺Cl^-

Elimination

Alcohols can undergo elimination, but only by E1. In basic conditions, which are required for E2, alcohols are deprotonated (see alkoxide formation) before they can be eliminated.

The classic example of alcohol elimination is an exact reversal of hydration. In the presence of acid, the alcohol is first protonated, then dissociates, leaving a carbocation. A weak base (typically a solvent) then deprotonates the most-substituted vicinal carbon, affording an e-isomer product. The reaction can be modeled as:

RCHOHCH₃ + H₂SO₄ RCHOH₂⁺CH₃ RCH⁺CH₃

From here, the water produced can deprotonate the carbocation to form a double bond:

RCH⁺CH₃ + H₂O R-CH=CH₂ + H3O⁺

Alkyl halide formation

SN1 and SN2 Synthesis of Alkyl Halides From Alcohols

On the left, a tertiary alcohol undergoes an SN1 reaction. On the right, a primary alcohol undergoes an SN2 reaction. Both afford alkyl halides.

Alcohols can be converted to alkyl halides by S_N1 and S_N2 modes of nucleophilic substitution. Both modes can occur using similar conditions. In the case of halogenating a primary alcohol, S_N2 can be achieved by using a hydrohalic acid. The acid protonates the alcohol to make it a good leaving group, then the halide displaces the alcohol with nucleophilic attack on the electrophilic carbon. An example of such a reaction is:

ROH + HCl ROH₂⁺ + Cl^- RCl + H₂O

A similar reaction can be performed using PBr₃ or SOCl₂ (for bromination and chlorination, respectively) as agents to make the hydroxyl more labile.

Secondary and tertiary alcohols can undergo S_N1 nucleophilic substitution when exposed to hydrohalic acids. The acid first protonates the alcohol before the reaction continues with a classic S_N1 mechanism.

Esterification

Alcohols can react with carboxylic acids, acid anhydrides, and acyl halides to form esters. The classic esterification is the Fischer esterification, which is the acid-catalyzed reaction of a carboxylic acid and alcohol and has the general form:

ROH + R'CO₂H + H⁺ (cat.) RCO₂C' + H₂O

Oxidation

Alcohols can be oxidized to ketones, aldehydes, and carboxylic acids depending on their substitution and reaction conditions. Although tertiary alcohols cannot be oxidized, secondary alcohols can be converted to ketones using an oxidizing agent. KMnO₄ and K₂Cr₂O₇ can, in acid, oxidize secondary alcohols to ketones, as can CrO₃ in the presence of peracetic acid.

Primary alcohols can be oxidized to aldehydes or carboxylic acids. MnO₂, pyridinium chlorochromate and the Sarett-Collins reagent will afford the aldehyde, while acidic solutions of KMnO₄ or K₂Cr₂O₇ beget the carboxylic acid.