Question

Show the structure of the product you would expect to obtain by \(S_{N}^{2}\) reaction of a cysteine residue with iodoacetic acid.

Short answer

Cysteine reacts with iodoacetic acid to form S-carboxymethylcysteine via an S_{N}^2 mechanism.

Step-by-step solution

Understand the Reactants

Cysteine is an amino acid with a thiol group (-SH). Iodoacetic acid is an alkylating agent that can react with thiol groups to form thioethers. In this reaction, the iodide group acts as a leaving group, allowing the carboxymethyl group of iodoacetic acid to be added to the thiol group of cysteine.

Identify the Reaction Type

The reaction is a nucleophilic substitution, specifically an bimolecular nucleophilic substitution ( S_{N}^2 ) reaction. In this mechanism, the nucleophile (thiolate ion from cysteine) attacks the electrophile (carbon atom attached to the iodine in iodoacetic acid) in a one-step process.

Consider the Reactivity of Cysteine

Cysteine can form a thiolate anion ( S^{-} ) by losing a proton from its thiol group in basic conditions or when close to a stronger base. This thiolate is the nucleophile in the S_{N}^2 reaction, which attacks the electrophilic carbon of iodoacetic acid.

Analyze the Leaving Group

The iodine atom in iodoacetic acid is the leaving group in this reaction. During the S_{N}^2 mechanism, the thiolate anion attacks the carbon, displacing the iodine atom as iodide ( I^{-} ) ion.

Write the Reaction Product

The reaction product is a cysteine residue in which the thiol group is replaced by the thioether linkage formed by the addition of the carboxymethyl group. This means the sulfur atom now connects to a carbon atom that also carries a carboxylic acid group (from iodoacetic acid). The product is S-carboxymethylcysteine.

Key concepts

Nucleophilic Substitution

Nucleophilic substitution is a fundamental type of reaction in organic chemistry, where a nucleophile replaces a leaving group attached to an electrophile. In an SN2 reaction, which stands for bimolecular nucleophilic substitution, the process occurs in one step. This means that the nucleophile attacks the electrophilic center to form a new bond, while the leaving group departs simultaneously. Because both the nucleophile and the electrophile are involved in the rate-determining step, it is called bimolecular.
In the case of the reaction between cysteine and iodoacetic acid, the thiolate ion acts as the nucleophile, poised to attack the electrophilic carbon atom to which iodine is attached. This efficient one-step mechanism results in a high degree of stereochemical inversion at the carbon center in question.

Thiol Group

A thiol group consists of a sulfur atom bonded to a hydrogen atom (\(-SH\)). This functional group is structurally similar to a hydroxyl group (\(-OH\)), replacing oxygen with sulfur. In biology and organic chemistry, thiol groups play a critical role due to their reactivity and ability to form disulfide bonds, stabilizing protein structures.
The thiol group in cysteine is particularly important. It can be deprotonated to form a thiolate anion (\(S^-\)) under basic conditions, making it a strong nucleophile. This nucleophilic property is key to cysteine’s involvement in the nucleophilic substitution reaction with iodoacetic acid, where it attacks an electrophilic site.

Iodoacetic Acid

Iodoacetic acid is an alkylating agent commonly used in biochemical applications to modify proteins, especially by targeting thiol groups. It contains a carboxylic acid group and an iodine atom bound to a methylene group, making it reactive to nucleophiles. The iodine acts as a good leaving group, facilitating various substitution reactions.
In the reaction with cysteine, iodoacetic acid’s methylene group becomes electrophilic due to the electron-withdrawing nature of the iodine. This prepares the ground for a nucleophilic substitution, where the thiolate ion can attack the carbon atom of the methylene group, eventually leading to the formation of a thioether linkage.

Cysteine

Cysteine is a naturally occurring amino acid notable for its thiol group, making it unique among the amino acids. This thiol group can engage in redox reactions and form strong covalent bonds, such as disulfide bridges crucial for protein tertiary structures. In an SN2 reaction, cysteine’s thiol group can act as a nucleophile when transformed into a thiolate anion.
Upon deprotonation, the thiolate form becomes more reactive, making it suitable for attacking electrophilic carbon atoms in iodoacetic acid. Through this process, cysteine can undergo modification, leading to derivatives such as S-carboxymethylcysteine, where the thiol is replaced by a thioether bond.

Thioether

A thioether is a type of functional group characterized by a sulfur atom bonded to two alkyl or aryl groups. It is very stable and resembles ethers, although sulfur replaces the oxygen atom.
In the reaction between cysteine and iodoacetic acid, the thiol group of cysteine is transformed into a thioether linkage. This occurs as the nucleophilic thiolate anion attaches to the carbon atom previously bonded to iodine, thus creating a covalent bond between sulfur and carbon. This transformation is essential in biological systems, often leading to more chemically stable and functional derivatives of cysteine.

Leaving Group

A leaving group is an atom or group of atoms that can depart with an electron pair in a substitution or elimination reaction. The effectiveness of a leaving group is key for reactions to proceed smoothly. Generally, a good leaving group should be able to stabilize the negative charge once it departs and is often weakly basic.
In the SN2 reaction with iodoacetic acid, the iodine atom acts as the leaving group. It is a good leaving group because iodine is large and can accommodate extra electron density comfortably after it is displaced. As the thiolate ion attacks, iodine departs as an iodide ion (\(I^-\)), facilitating the formation of the new covalent bond between the thiolate sulfur and the carbon atom, completing the nucleophilic substitution process.