Question

(a) Explain why the displacement of \(\mathrm{OH}\) in an alcohol by Br is carried out under acidic conditions. (b) Suggest products at each stage in the following reaction scheme: Why does the OH group need to be protected before the following reaction is carried out? (c) Suggest how you would prepare the following \(^{13}\) C-labelled compound \(\left(\boldsymbol{\theta}=^{13} \mathbf{C}\right)\) starting from the precursor shown below:

Short answer

(a) Acidic conditions help by protonating -OH, making it a good leaving group. (b) Protect -OH during the reaction; suggested method depends on context. (c) Use labeled precursors like C-bromide in a reaction scheme to introduce labeled carbons.

Step-by-step solution

Understanding the Displacement Process

The substitution of the -OH group in alcohol with a bromine atom (Br) is generally performed under acidic conditions. This is because the hydroxyl group (-OH) in alcohols is a poor leaving group. Under acidic conditions, it can be protonated to form water, which is a better leaving group. This facilitates the nucleophilic substitution reaction where bromine substitutes the -OH group.

Identifying Reaction Scheme Products

When dealing with alcohols in a reaction scheme, the -OH group often requires protection to prevent it from reacting with reagents intended for other functional groups. For example, the -OH group can be converted into a more stable ether, such as a tert-butyl ether, to protect it during a reaction sequence. Once the reaction sequence is complete, the protecting group can be removed to regenerate the functional -OH group.

Constructing a Synthetic Pathway for Labelled Compounds

To prepare a compound labeled with carbon-13 (C), you start with a precursor that has the carbon atom you want to label. Using reactions that do not disturb the desired carbon framework, substitute the non-labeled carbon atoms with their labeled counterparts. For example, in a Grignard reaction, one could start with a bromide that is C-labeled and then react it with a carbonyl compound to integrate the labeled carbon into the structure.

Key concepts

Nucleophilic Substitution

Nucleophilic substitution reactions are fundamental in organic chemistry. These reactions involve the replacement of a leaving group by a nucleophile. In the context of alcohols, the hydroxyl group (-OH) tends to be a poor leaving group, making direct substitutions challenging.

To overcome this, acidic conditions are typically employed. Acidic conditions protonate the -OH group, converting it into water, which is a much better leaving group. For instance, when dealing with bromine substitutions, the addition of hydrobromic acid (HBr) can effectively create this transformation. The -OH group is protonated to water, facilitating its departure, and allowing bromide ions to substitute the place previously occupied by -OH.

This principle is essential for various organic synthesis processes, as it helps in effectively replacing functional groups while preserving the rest of the molecular structure. By understanding these mechanisms, chemists can better predict and control the outcomes of synthesis reactions.

Protecting Groups

In organic chemistry, protecting groups are used to temporarily mask reactive sites in a molecule, safeguarding them from unwanted reactions during complex synthesis sequences. A common example involves the protection of the hydroxyl group (-OH).

During synthetic sequences, if the goal is to manipulate other functional groups without impacting -OH, a common strategy is to convert the -OH into an ether, such as a tert-butyl ether. This protects the hydroxyl group during the reaction steps intended for other parts of the molecule.

The use of protecting groups is critical when multiple functional groups are present, each with different reactivity profiles. Once the desired transformations are complete, chemists can easily remove the protecting group, regenerating the original functional group in its intact form, typically under mild conditions to avoid side reactions.

This process of protection and deprotection simplifies complex organic reactions, enhancing selectivity and yield.

Carbon-13 Labeling

Carbon-13 labeling is a valuable technique in organic synthesis and analytical chemistry. It involves incorporating the stable isotope Carbon-13 ( ^{13}C) into a molecule, which can later be used for tracing and analysis.

To achieve this labeling, chemists start with a precursor that already contains the carbon atom to be labeled. By conducting reactions that maintain the integrity of the desired carbon framework, they can substitute a standard carbon atom with Carbon-13. This often involves reactions such as the Grignard reaction, where a ^{13}C-labeled bromide might react with a carbonyl compound, embedding the labeled carbon within the structure.

Carbon-13 labeling is instrumental in studying metabolic pathways, determining molecular structures with NMR spectroscopy, and following the fate of compounds in pharmaceutical studies. Its application aids both fundamental research and practical applications in drug development.