Question

The BOC-protecting group may be added by treatment of an amino acid with di- tert-butyl dicarbonate as shown in the following reaction sequence. Propose a mechanism to account for formation of these products.

Short answer

Question: Describe the mechanism for the formation of a BOC-protected amino acid when an amino acid is treated with di-tert-butyl dicarbonate. Answer: The mechanism involves a nucleophilic attack of the amine group of the amino acid on the electrophilic carbonyl group of di-tert-butyl dicarbonate. This forms a tetrahedral intermediate which then rearranges, releasing tert-butanol as a leaving group and reforming the carbonyl group, resulting in the formation of the BOC-protected amino acid through a carbamate linkage.

Step-by-step solution

Identify the reaction components

In this reaction, an amino acid is treated with di-tert-butyl dicarbonate (BOC-protecting group) to form a BOC-protected amino acid. The first thing to do is identify the key functional groups involved in the reaction: the amine group of the amino acid and the carbonate group of the di-tert-butyl dicarbonate.

Identify the nucleophile and electrophile

For proposing a mechanism, it is important to determine which reactant is the nucleophile and which one is the electrophile. In this case, the amine group of the amino acid acts as a nucleophile due to the presence of a lone pair on the nitrogen atom, and the di-tert-butyl dicarbonate group acts as an electrophile due to the presence of an electrophilic carbonyl group.

Nucleophilic attack

The reaction mechanism begins with a nucleophilic attack by the amine nitrogen (N) of the amino acid on the carbonyl carbon (C) of the di-tert-butyl dicarbonate. This results in the formation of a tetrahedral intermediate and the migration of a negative charge to the carbonyl oxygen (O).

Rearrangement

Once the tetrahedral intermediate is formed, the negatively charged oxygen atom reclaims the electron pair, breaking the C-O bond, and simultaneously releasing one equivalent of tert-butanol (t-BuOH) as a leaving group.

Formation of the BOC-protected amino acid

Following the release of tert-butanol, the carbonyl group reforms, resulting in the formation of the BOC-protected amino acid. The BOC-protecting group is now bonded to the nitrogen atom of the amino acid through a carbamate linkage. In summary, the proposed mechanism for the formation of the BOC-protected amino acid involves a nucleophilic attack of the amine group of the amino acid on the electrophilic carbonyl group of di-tert-butyl dicarbonate, followed by a rearrangement to release tert-butanol and form the BOC-protected amino acid.

Key concepts

Amino Acids

Amino acids are the basic building blocks of proteins. They contain two key functional groups: an amine group \(-NH_2\) and a carboxyl group \(-COOH\). These groups allow amino acids to participate in various chemical reactions, including forming peptide bonds.
In the context of BOC protection, it's crucial to focus on the amine part of the amino acid. This is because it's the primary target for the protective BOC group. The BOC group ensures that the amino acid remains unaltered during subsequent chemical reactions. This protection is important in peptide synthesis, where multiple reactions occur, and it's vital to shield certain parts of molecules from undesired transformations.
BOC protection temporarily blocks the reactive amine site, making it a key strategy in organic synthesis, particularly when constructing peptides.

Nucleophilic Attack

Nucleophilic attack is a core concept in organic chemistry, referring to the process where a nucleophile (electron-rich species) forms a bond by donating its electron pair to an electrophile (electron-poor species). In the BOC protection reaction, the amine group of the amino acid is the nucleophile.
The nitrogen atom in the amine group possesses a lone pair of electrons, making it a potential electron donor. During the reaction, this lone pair attacks the electrophilic carbon atom in the di-tert-butyl dicarbonate's carbonyl group.

• The nucleophilic attack leads to the formation of a new bond between the nitrogen of the amino acid and the carbon of the BOC group.
• This results in a temporary, unstable structure known as a tetrahedral intermediate.

The strength and direction of this nucleophilic attack play a crucial role in determining the outcome of chemical reactions and product formations.

Reaction Mechanism

Understanding reaction mechanisms is essential for predicting how and why chemical reactions occur. A reaction mechanism provides a step-by-step description of the processes involved in transforming reactants into products.
For the formation of a BOC-protected amino acid, the mechanism begins with the nucleophilic attack, forming the tetrahedral intermediate. This intermediate is a transitional structure that eventually collapses, leading to the formation of stable products.
The rearrangement step is critical here. As the intermediate forms, the negatively charged oxygen reclaims its electron pair. This reformation of the carbonyl group triggers the release of the leaving group, tert-butanol. Such mechanisms highlight how transformations occur subtly within a molecule to facilitate the retention of the desired structure.

Carbamate Linkage

A carbamate linkage is a type of chemical bond involving the attachment of a carbamate group (\[ R-O-(C=O)-N-R’ \]) to a molecule. In the context of BOC protection, this linkage is formed between the amine group of the amino acid and the BOC-protecting group.
This linkage is essential for maintaining the stability and integrity of the protected molecule. By forming a carbamate linkage, the BOC group effectively secures the amine against unwanted reactions. It acts like a shield, preserving the amine's ability to participate in further synthesis steps once the BOC group is removed.
Carbamate linkages are versatile and are employed widely in medicinal chemistry for drug design and peptide synthesis. This linkage is reversible, which means the protective group can be removed when it's no longer needed without damaging the core structure of the amino acid.