Question

A step in a synthesis of \(\mathrm{PGE}_{1}\) (prostaglandin \(\mathrm{E}_{1}\), alprostadil) is the reaction of a trisubstituted cyclohexene with bromine to form a bromolactone. Propose a mechanism for formation of this bromolactone and account for the observed stereochemistry of each substituent on the cyclohexane ring.

Short answer

Question: Explain the mechanism for the formation of a bromolactone from a trisubstituted cyclohexene, accounting for the stereochemistry involved. Answer: The formation of a bromolactone from a trisubstituted cyclohexene involves the following steps: 1) Electrophilic addition of bromine to the double bond, forming a cyclic bromonium ion. 2) Nucleophilic attack and ring opening by the hydroxyl group, producing a bromohydrin intermediate. 3) Intramolecular nucleophilic substitution, resulting in the bromolactone. The stereochemistry is determined by the anti-fashion addition of bromine atoms and the syn addition of the hydroxyl group during the nucleophilic attack steps.

Step-by-step solution

Identify the trisubstituted cyclohexene and bromine reactants

We are given a trisubstituted cyclohexene with three substituents on the cyclohexane ring reacting with bromine (Br2) to form a bromolactone. Keep in mind the structure of the trisubstituted cyclohexene, and the fact that bromine is a halogen with the ability to participate in electrophilic addition reactions with alkenes.

Reaction of bromine with the trisubstituted cyclohexene

Bromine reacts with the trisubstituted cyclohexene via electrophilic addition. The double bond in the cyclohexene ring acts as a nucleophile and attacks the bromine molecule. One of the bromine atoms forms a bond with one of the carbon atoms that previously formed part of the double bond, resulting in the formation of a cyclic bromonium ion as an intermediate.

Formation of halonium ion intermediate

The cyclic bromonium ion is formed when the sigma bond between the two bromine atoms breaks, with the other bromine atom carrying a positive charge. This creates an electrophilic, highly reactive cyclic bromonium ion.

Nucleophilic attack and ring opening by hydroxyl group

The hydroxyl group in the trisubstituted cyclohexene functions as a nucleophile and attacks the carbon atom of the bromonium ion bearing a positive charge. This causes the ring to open and a new bond to form between the oxygen atom of the hydroxyl group and the carbon atom, giving rise to a bromohydrin intermediate.

Intramolecular nucleophilic substitution to form bromolactone

The negatively charged oxygen atom in the hydroxyl group acts as a nucleophile once again and attacks the other carbon atom bearing the bromine substituent, displacing the bromine atom and forming a new bond between the oxygen and the carbon atom. This results in the formation of a six-membered lactone ring, which is the final bromolactone product.

Account for the stereochemistry of the product

The stereochemistry of the bromolactone is determined by the initial attack of the bromine atom in Step 2 and the orientation of the nucleophilic attack by the hydroxyl group in Steps 4 and 5. Due to the cyclic bromonium ion formation in Step 2, the two bromine atoms add to the double bond in an anti-fashion, forming a trans-product. The nucleophilic attack by the hydroxyl group occurs from the same side as the bromonium ion, leading to a syn addition. This results in the observed stereochemistry of each substituent on the cyclohexane ring of the bromolactone product.

Key concepts

Trisubstituted Cyclohexene

Understanding the chemistry behind trisubstituted cyclohexenes is pivotal when exploring synthetic reactions, such as the creation of bromolactones. A trisubstituted cyclohexene refers to a cyclohexene molecule that has three different substituent groups attached to the ring structure. These substituents influence the molecule's reactivity in significant ways.

For instance, they can dictate the site of electrophilic attack due to alterations in electron density around the cyclic system. Additionally, the physical arrangement of these substituents in space — their stereochemistry — can determine the outcome of a reaction, including its specificity and selectivity. During synthesis, a clear understanding of the cyclohexene's 3D structure is crucial since it impacts the stereochemical course of the ensuing reaction.

Electrophilic Addition Reaction

Electrophilic addition is a fundamental type of chemical reaction in organic chemistry. It's characterized by the addition of an electrophile to a nucleophile. In the context of trisubstituted cyclohexenes, the nucleophile is the double bond of the cyclohexene, rich in electrons and thus attractive to electrophiles like bromine (Br₂).

The reaction begins when the pi electrons of the double bond attack the bromine molecule, causing the formation of a bond with one of the bromine atoms. The 'electrophilic addition reaction' is a cornerstone for many synthesis processes, as it often creates important intermediates which lead to the final desired product through further reaction steps.

Cyclic Bromonium Ion Formation

Following the initial electrophilic attack by bromine, a highly reactive intermediate known as a 'cyclic bromonium ion' is formed. This ion occurs due to the rupture of the bromine-bromine bond and the trapping of the remaining bromine atom by the alkene's double bond, creating a three-membered bromonium ring. This cyclic structure bears a positive charge because of the departure of one bromine atom.

The presence of the cyclic bromonium ion is crucial since it determines the pathway of the rest of the reaction. Its formation opens the door to nucleophilic attack that ultimately leads to bromolactone synthesis. The cyclic nature of the bromonium ion also influences the stereochemistry of the final product.

Stereochemistry in Organic Chemistry

Stereochemistry is the study of the three-dimensional arrangement of atoms within molecules and is a vital aspect of organic chemistry. It addresses how these spatial arrangements affect the physical and chemical properties of compounds.

In our case, the stereochemistry decides the orientation of the electrophilic addition and nucleophilic attacks leading to the final bromolactone. For example, the cyclic bromonium ion intermediate ensures that the resultant bromolactone retains a specific geometric isomerism due to the 'anti' addition of bromine atoms. Subsequent 'syn' addition reactions by nucleophiles, such as a hydroxyl group, lead to the stereochemistry observed in the final bromolactone product. Knowledge of stereochemistry is fundamental for predicting reaction outcomes and is thus integral for synthesizing complex molecules like prostaglandins.