Question

In 1887 , the Russian chemist Sergei Reformatsky at the University of Kiev discovered that treatment of an \(\alpha\)-haloester with zinc metal in the presence of an aldehyde or ketone followed by hydrolysis in aqueous acid results in formation of a \(\beta\)-hydroxyester. This reaction is similar to a Grignard reaction in that a key intermediate is an organometallic compound, in this case a zinc salt of an ester enolate anion. Grignard reagents, however, are so reactive that they undergo selfcondensation with the ester. Show how a Reformatsky reaction can be used to synthesize these compounds from an aldehyde or ketone and an \(\alpha\)-haloester.

Short answer

Question: Explain the mechanism of the Reformatsky reaction in synthesizing a β-hydroxyester from an aldehyde or ketone and an α-haloester. Answer: The Reformatsky reaction mechanism involves four steps: 1. Activation of the α-haloester by treating it with zinc metal to form an organozinc compound. 2. Formation of the key intermediate - a zinc salt of an ester enolate anion - through the rearrangement of bonds within the organozinc compound. 3. Nucleophilic attack of the zinc-stabilized ester enolate on the carbonyl carbon of the aldehyde or ketone, resulting in a tetrahedral alkoxide intermediate. 4. Hydrolysis of the intermediate under acidic conditions to yield the desired β-hydroxyester product.

Step-by-step solution

Preparation of the organozinc reagent

The Reformatsky reaction begins with the activation of the \(\alpha\)-haloester by treating it with zinc metal. The zinc replaces the halogen (X) to form an organozinc compound, which is a nucleophilic species. The general equation for this step is: $$\ce{R-CO-CH2-X + Zn -> R-CO-CH2-ZnX}$$

Formation of a zinc salt of an ester enolate anion

The next step involves the formation of the key intermediate, a zinc salt of an ester enolate anion. The lone pair of electrons on the oxygen atom of the carbonyl group forms a double bond with the adjacent carbon atom, while the \(\alpha\)-carbon forms a bond with the zinc ion. Simultaneously, one of the oxygen-zinc bonds breaks, as the zinc ion transitions to a new coordination site. The resulting structure is the ester enolate anion stabilized by zinc ion coordination. $$\ce{R-CO-CH2-ZnX <=> R-C(O^-)-CH=ZnX}$$

Nucleophilic attack on the carbonyl group of the aldehyde or ketone

The zinc-stabilized ester enolate serves as a nucleophile, and it attacks the electrophilic carbonyl carbon of the aldehyde or ketone. This process forms a new carbon-carbon bond and generates a tetrahedral alkoxide intermediate. $$\ce{R-C(O^-)-CH=ZnX + R'-CHO -> RCOCH(-O^-)-R' + ZnX}$$

Hydrolysis in the presence of aqueous acid

Finally, the reaction is quenched with aqueous acid to hydrolyze the intermediate, followed by protonation of the alkoxide oxygen atom to give the desired \(\beta\)-hydroxyester product. The general equation for this step is: $$\ce{RCOCH(-O^-)-R' + H3O+ -> RCOCH(OH)-R' + H2O}$$ In summary, the Reformatsky reaction can be used to synthesize a \(\beta\)-hydroxyester from an aldehyde or ketone and an \(\alpha\)-haloester through a four-step process involving the formation of an organozinc compound, generation of a zinc salt of an ester enolate anion, nucleophilic attack on the carbonyl group of the aldehyde or ketone, and finally hydrolysis under acidic conditions.

Key concepts

Organometallic Compounds

Organometallic compounds are fascinating chemicals where metals form direct bonds with carbon atoms. They play a crucial role in organic synthesis due to their ability to act as nucleophiles, attacking electrophilic centers in various substrates. In the context of the Reformatsky reaction, zinc metal reacts with an \(\alpha\)-haloester to replace the halogen and create an organozinc compound. This species is considerably less reactive than its Grignard counterparts, allowing for more controlled reactivity.
Organometallic compounds have been pivotal in developing new synthetic methodologies, including coupling reactions such as the Nobel Prize-winning Suzuki and Heck reactions.

Synthesis of Beta-hydroxyesters

Synthesis of \(\beta\)-hydroxyesters is a significant transformation in organic chemistry because these compounds are valuable intermediates in the manufacture of pharmaceuticals, fragrances, and polymers. The Reformatsky reaction synthesizes \(\beta\)-hydroxyesters by joining an \(\alpha\)-haloester and a carbonyl compound (aldehyde or ketone).
This process elegantly constructs a carbon-carbon bond while introducing a hydroxyl group (\

Nucleophilic Attack on Carbonyl Group

The carbonyl group is an essential functional group in organic chemistry, characterized by a carbon atom double-bonded to an oxygen atom. It is highly reactive toward nucleophiles due to its polarization—oxygen is more electronegative, drawing electron density away from carbon, making the carbon electrophilic. In the Reformatsky reaction, the organozinc enolate serves as the nucleophile, attacking the electrophilic carbon of the carbonyl group in the aldehyde or ketone. This step is fundamental for C-C bond formation and the development of complex molecules.

Ester Enolate Anion Formation

The formation of the ester enolate anion is a central step in the Reformatsky reaction. After the initial nucleophilic substitution where the zinc replaces the halogen, the resulting organozinc compound undergoes internal rearrangement. A bond forms between the alpha-carbon and zinc, simultaneously leaving oxygen more negatively charged, creating the ester enolate anion. This critical intermediate is stabilized by the zinc ion and is ready for the subsequent nucleophilic attack.
Understanding how enolates form and how they can be stabilized by different metals is significant for students because it underpins a vast amount of organic synthesis involving esters and other carbonyl derivatives.