17.6 Reactions of Alcohols

Reactions of Alcohols

Alcohols are versatile compounds that can be converted to halides, tosylates, alkenes, and esters through different mechanisms. Understanding these reactions is crucial for predicting product formation and stereochemistry in organic synthesis, and they show up constantly in later units on multistep synthesis.

Conversion of Alcohols to Halides

Alcohols don't naturally have good leaving groups ($OH^-$ is a strong base and a terrible leaving group). The trick is to convert the hydroxyl into something that can leave, either by protonation or by forming a sulfonate ester.

Using HX (HCl, HBr, HI):

The mechanism depends on the substrate's substitution pattern.

• Tertiary alcohols react via $S_N1$:

  1. The strong acid protonates the $-OH$ group, converting it to $-OH_2^+$ (water, a good leaving group).
  2. Water departs, forming a tertiary carbocation.
  3. The halide ion ($X^-$) attacks the carbocation to give the alkyl halide.

  Tertiary substrates favor $S_N1$ because the resulting carbocation is stabilized by three alkyl groups through hyperconjugation and induction.

• Primary alcohols react via $S_N2$:

  1. The acid protonates the $-OH$ group.
  2. The halide ion attacks the carbon in a concerted, backside fashion as water departs.

  There's no discrete carbocation intermediate here. Primary carbocations are too unstable to form, so the reaction proceeds through a single concerted step. This means inversion of configuration at the reacting carbon.

• Secondary alcohols can go either way ($S_N1$ or $S_N2$), depending on conditions. Expect mixtures of stereochemical outcomes in some cases.

Reactivity of HX: $HI > HBr > HCl$. This tracks with nucleophilicity and the strength of the acid.

Conversion to Tosylates

Tosylation is a cleaner alternative when you want to install a leaving group without rearrangements or harsh acidic conditions.

1. The alcohol reacts with p-toluenesulfonyl chloride (TsCl) in the presence of a base like pyridine.
2. Pyridine deprotonates the alcohol, generating an alkoxide.
3. The alkoxide attacks the electrophilic sulfur of TsCl, displacing chloride and forming the tosylate ($-OTs$).

The key advantage: this reaction occurs at the oxygen, not at the carbon bearing the $-OH$. That means the stereochemistry at carbon is retained. You now have a substrate with an excellent leaving group ($OTs^-$) ready for $S_N2$ or $E2$ reactions, and you know the configuration going in.

Dehydration of Alcohols to Alkenes

Dehydration is an elimination reaction where the alcohol loses water to form a carbon-carbon double bond.

Acid-Catalyzed Dehydration

Strong acids like $H_2SO_4$ or $H_3PO_4$ with heat drive this reaction.

Tertiary alcohols follow E1:

1. Protonation of the $-OH$ group by the acid.
2. Loss of water to form a carbocation intermediate.
3. A base (often $HSO_4^-$ or solvent) removes a proton from a carbon adjacent to the carbocation, forming the alkene.

Primary alcohols follow E2:

1. Protonation of the $-OH$ group.
2. Simultaneous loss of water and removal of a proton from the adjacent carbon in a single concerted step. (Primary carbocations are too unstable to form as intermediates.)

Secondary alcohols typically follow E1, but E2 is possible depending on conditions.

Zaitsev's rule predicts the major product: the most substituted (most stable) alkene is favored. For example, dehydration of 2-butanol gives primarily 2-butene over 1-butene.

Watch for carbocation rearrangements in E1 pathways. If a hydride or methyl shift can produce a more stable carbocation, it will happen, and you'll get an unexpected product.

Dehydration with $POCl_3$ or $SOCl_2$

These reagents offer milder conditions (often done at 0°C with pyridine as base) compared to the harsh acid/heat setup.

1. The alcohol reacts with $POCl_3$ (or $SOCl_2$) to form an intermediate with a good leaving group.
2. Base-promoted E2 elimination gives the alkene.

Because this proceeds through E2 rather than E1, carbocation rearrangements are avoided. This makes $POCl_3$/pyridine a better choice when you need a clean, predictable product.

Cyclic alcohols undergo dehydration by the same principles, forming cycloalkenes. Ring strain can sometimes influence which product is favored.

Alcohol to Ester Conversion Methods

Fischer Esterification

This is the classic acid-catalyzed method: an alcohol reacts with a carboxylic acid to form an ester and water.

1. The acid catalyst ($H_2SO_4$ or $HCl$) protonates the carbonyl oxygen of the carboxylic acid, making the carbonyl carbon more electrophilic.
2. The alcohol acts as a nucleophile and attacks the activated carbonyl carbon, forming a tetrahedral intermediate.
3. A proton transfer occurs, and water is lost from the tetrahedral intermediate.
4. Deprotonation yields the ester product.

This reaction is an equilibrium, so you need to push it forward. Common strategies: use excess alcohol, remove water (Dean-Stark trap), or use excess acid.

The acid catalyst is regenerated at the end, so it's truly catalytic.

Steglich Esterification

This method uses DCC (dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine) under mild, neutral conditions.

1. DCC activates the carboxylic acid by forming an O-acylisourea intermediate (a much better electrophile than the original acid).
2. The alcohol attacks this intermediate, forming the ester.
3. DCC is converted to dicyclohexylurea (DCU), an insoluble byproduct that's filtered off.

Steglich esterification is preferred for acid-sensitive substrates or when you can't use high temperatures. It's widely used in peptide synthesis and natural product chemistry.

Biological Esterification

In living systems, enzymes called esterases and acyltransferases catalyze ester bond formation and hydrolysis under mild physiological conditions (aqueous, ~37°C, neutral pH).

• Triglycerides (fats and oils) are triesters of glycerol with fatty acids.
• Waxes are esters of long-chain alcohols with long-chain fatty acids.
• Some hormones and pheromones contain ester functional groups.

Esterases also catalyze the reverse reaction (hydrolysis), which is critical for digestion and metabolism of dietary fats.

Reaction Mechanisms and Selectivity

A few overarching principles tie these reactions together:

• Substrate structure determines mechanism. Tertiary alcohols favor $S_N1$/$E1$ pathways; primary alcohols favor $S_N2$/$E2$. Secondary alcohols are the borderline cases where conditions matter most.
• Leaving group quality matters. Converting $-OH$ to $-OH_2^+$, $-OTs$, or a chlorosulfite intermediate is always the first step because hydroxide itself won't leave.
• Zaitsev's rule governs regioselectivity in elimination: the more substituted alkene is the major product.
• Stereochemistry depends on mechanism: $S_N2$ gives inversion, $S_N1$ gives racemization, and E2 requires an anti-periplanar arrangement of the leaving group and the proton being removed.
• Competition between substitution and elimination is always present. Higher temperatures and bulkier bases favor elimination; lower temperatures and good nucleophiles favor substitution.