Question

Predict the product of the reaction of valine with the following reagents: (a) \(\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{OH}\), acid (b) Di-tert-butyl dicarbonate (c) \(\mathrm{KOH}, \mathrm{H}_{2} \mathrm{O}\) (d) \(\mathrm{CH}_{3} \mathrm{COCl}\), pyridine; then \(\mathrm{H}_{2} \mathrm{O}\)

Short answer

The product is N-acetyl-valine with a free carboxylic acid group.

Step-by-step solution

Understand the Reaction Type with Valine and Ethanol under Acidic Conditions

When valine reacts with ethanol in the presence of an acid, esterification occurs. The carboxylic acid group of valine (\(-COOH\)) reacts with ethanol to form an ethyl ester (\(-COOCH_2CH_3\)) and water.

Protecting the Amino Group with Di-tert-butyl Dicarbonate

Di-tert-butyl dicarbonate is used to introduce a Boc (tert-butoxycarbonyl) protecting group on the amino group (\(-NH_2\)) of valine. The amino group is transformed into a Boc-protected amine (\(-NH-Boc\)).

Hydrolysis of Ester under Basic Conditions

When the ethyl ester of valine, formed earlier, is treated with \(KOH\) and \(H_2O\), the ester undergoes hydrolysis to regenerate the carboxylic acid group (\(-COOH\)). This process is known as saponification.

Acetylation of the Amino Group Followed by Hydrolysis

In the final step, the reaction with \(CH_3COCl\) in the presence of pyridine converts the free amino group to an amide. This is followed by hydrolysis, which removes any chloride ions or impurities. The amino group is acetylated forming an N-acetyl derivative \(-NH(COCH_3)\).

Key concepts

Esterification

Esterification is a fundamental reaction in organic chemistry. It involves the conversion of a carboxylic acid into an ester, typically in the presence of an alcohol and an acid catalyst. In the context of the exercise, valine, which contains a carboxylic acid group (-COOH), reacts with ethanol. This reaction is acid-catalyzed, meaning an acid speeds up the process by protonating the carboxylic acid, making it more susceptible to nucleophilic attack by the alcohol.

• During this process, the acid group of valine loses a hydrogen ion (H⁺) to become a more reactive carbocation.
• The oxygen of ethanol attacks this carbocation, leading to the formation of an ethyl ester bond (-COOCH₂CH₃).
• A molecule of water is also formed as a byproduct. This is a reversible reaction and can typically be driven to completion by removing the water produced.

This type of reaction is important not only for understanding organic transformations but also for synthesizing fragrances, flavorings, and pharmaceuticals that frequently include ester functionalities.

Amino Group Protection

In organic synthesis, protecting groups are crucial for preventing unwanted reactions during complex multi-step reactions. The amino group (-NH₂) of valine can be easily converted using di-tert-butyl dicarbonate (Boc₂O) to protect it by forming a tert-butoxycarbonyl (Boc) group. This is a standard technique to ensure that the amino group does not participate in any subsequent reactions.

• The Boc group is introduced through a nucleophilic attack by the amino nitrogen on one of the reactive carbonyl carbons in the di-tert-butyl dicarbonate.
• This results in the formation of a Boc-protected amine (-NH-Boc), which is devoid of characteristic reactivity of primary amines under most conditions.
• The Boc group can be later removed under acidic conditions when the desired synthetic transformations are complete.

This protection strategy is widely used in peptide synthesis and other organic syntheses where selective protection and deprotection of sensitive groups are required.

Saponification

Saponification is a chemical reaction that involves the hydrolysis of an ester into a carboxylic acid under basic conditions. This process is especially important for the breakdown of bio-molecules and in industrial applications like soap making. In this context, the ester formed from valine undergoing esterification is transformed back into its corresponding carboxylic acid when treated with a base like potassium hydroxide ( KOH).

• The ester bond is broken by the hydroxide ions, resulting in the formation of a carboxylate ion and an alcohol.
• The carboxylate ion can then pick up a proton (H⁺) from water to regenerate the free carboxylic acid (-COOH) of valine.

Saponification serves as a critical reaction in reversing esterification and is a useful step in the overall synthesis of organic molecules that requires recovery of carboxylic acids from their ester precursors.

N-Acetylation

N-Acetylation is a common modification in both chemical synthesis and biological systems, whereby an acetyl group ( -COCH₃) is transferred to a nitrogen atom. In peptide and protein chemistry, this reaction can provide stability to molecules. During the reaction discussed in the exercise, the free amino group of valine is acetylated using acetyl chloride (CH₃COCl) and a base like pyridine.

• The process starts with the nucleophilic attack of the amine nitrogen on the carbon of the acetyl chloride, forming an intermediate.
• Pyridine serves as a base to neutralize the hydrochloric acid formed during the reaction, thus driving the reaction toward completion.
• The resulting acetylated product (-NH-COCH₃) generally exhibits decreased reactivity compared to its free amino form.

N-Acetylation is highly useful in chemical syntheses where modification of amines is needed to tailor physical or chemical properties of a compound, ensuring compatibility with other functional groups in complex molecular assemblies.