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 a 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 self-condensation with the ester. Show how a Reformatsky reaction can be used to synthesize these compounds from an aldehyde or a ketone and an \(\alpha\)-haloester. (a) (b) (c)

Short answer

Answer: The Reformatsky reaction can be used to synthesize two different compounds by reacting an α-haloester with zinc metal to form a zinc enolate intermediate, which then reacts with the aldehyde or ketone to form a β-hydroxyester. Hydrolysis of the resulting organometallic compound in the presence of aqueous acid leads to the formation of the target β-hydroxyester compounds. The specific structures of the aldehyde or ketone and α-haloester will determine the target compounds produced in the reaction.

Step-by-step solution

Step One: Identify the given structures and target compounds

Before starting the reaction process, recognize the structures of the given reactants. An aldehyde and a ketone are carbonyl compounds with general formulas R-CHO and R-CO-R', respectively. An α-haloester is a molecule with α carbon attached to a halogen and an ester group. The target compounds can be identified using the given SMILES notation. (a) The target compound has the structure: \(CO-OHCH(CO)CCC_1CCCC_1\). (b) The target compound has the structure: \(CO-OHCH(CO)Cc_1ccccc_1\).

Step Two: Formation of zinc enolate from α-haloester

The first step in the Reformatsky reaction is to form a zinc salt of an ester enolate anion by reacting the α-haloester with zinc metal. The reaction involves the displacement of the halogen group from the α-haloester by the zinc atom, resulting in the organometallic intermediate. Reaction: \(\ce{RCOOCR'_2X + Zn -> RCOOZnCR'_2}\), where \(\ce{R}\) is the ester group, \(\ce{R'}\) represents the alkyl or aryl group, and \(\ce{X}\) is a halogen (e.g., Cl, Br).

Step Three: Reaction of zinc enolate with aldehyde or ketone

Now, the organometallic intermediate (zinc enolate) reacts with an aldehyde or ketone, forming the final β-hydroxyester product before hydrolysis. Reaction: \(\ce{RCOOZnCR'_2 + R''CHO -> RCOOCR'_2CH(OH)R''}\), where \(\ce{R''}\) is an alkyl or aryl group from the aldehyde or ketone.

Step Four: Hydrolysis to obtain the target compounds

The resulting organometallic compound undergoes hydrolysis in the presence of aqueous acid to form the target β-hydroxyester. Reaction: \(\ce{RCOOCR'_2CH(OH)R'' + H2O -> RCOOHCH(OH)CR'_2R'' + Zn(OH)2}\)

Step Five: Apply the Reformatsky reaction to obtain the target compounds

Now, apply the given reactions to synthesize the target compounds. (a) Synthesize \(COOH(O)CH(CO)CCC_1CCCC_1\) (given SMILES code: COC(=O)C(C)C1(O)CCCC1) using a ketone and α-haloester. Ketone: \(COCH_2C_1CCCC_1\) α-Haloester: \(COClCH_2CO\) Zinc enolate: \(COOZnCH_2CO\) Organometallic intermediate: \(COOCH_2CH(O)C_1CCCC_1\) Target compound: \(COOH(O)CH_2CH(CO)CCC_1CCCC_1\) (b) Synthesize \(COOH(O)CH_2CH(CO)c_1ccccc_1\) (given SMILES code: COC(=O)C(C)C(O)c1ccccc1) using a ketone and α-haloester. Ketone: \(COCH_2c_1ccccc_1\) α-Haloester: \(COClCH_2CO\) Zinc enolate: \(COOZnCH_2CO\) Organometallic intermediate: \(COOCH_2CH(O)c_1ccccc_1\) Target compound: \(COOH(O)CH_2CH(CO)c_1ccccc_1\)

Key concepts

Understanding Organic Chemistry

Organic chemistry is a vibrant and diverse field of chemistry that studies the structure, properties, and reactions of organic compounds, which are defined by the presence of carbon atoms. The study of organic chemistry encompasses a vast array of substances — from simple molecules like methane to complex, high-molecular-weight biopolymers like proteins and DNA.

Understanding the reactions and mechanisms in organic chemistry, such as the Reformatsky reaction, is crucial for synthesizing new molecules and advancing fields like pharmaceuticals, materials science, and biochemistry. For students grappling with reactions, mastering the basics—like functional groups, reaction types, and nomenclature—is a fundamental step to progressing in organic chemistry. Simplifying complex mechanisms into step-by-step processes allows for better comprehension and application of concepts to real-world problems.

The Role of Organometallic Compounds

Organometallic compounds play a pivotal role in organic synthesis. These compounds contain at least one bond between a metal and a carbon atom belonging to an organic molecule. Zinc, magnesium, and lithium are common metals that form stable organometallic compounds, used for various reactions in synthetic chemistry.

The versatility of organometallic compounds comes from their unique reactivity, which allows them to form bonds with a wide range of other atoms and groups. In the Reformatsky reaction, the zinc enolate—a type of organometallic compound—acts as a key intermediate. It is less reactive than Grignard reagents, allowing for controlled reactions with esters and preventing undesired side reactions like self-condensation. For educational content, emphasizing the distinctions between different organometallic reagents and their reactivity profiles helps students predict the outcomes of complex organic reactions.

Synthesis of β-Hydroxyesters

The synthesis of β-hydroxyesters is a fundamental reaction in organic chemistry due to the importance of β-hydroxyesters in various chemical and biological processes. They serve as precursors to numerous other functional groups and are key intermediates for producing a wide array of complex organic compounds, including pharmaceuticals and polymers.

The Reformatsky reaction specifically addresses the synthesis of such compounds efficiently. By transforming an \(\alpha\)-haloester and an aldehyde or ketone into a \(\beta\)-hydroxyester, this reaction offers a guided and elegant strategy for obtaining these valuable products. When teaching the Reformatsky reaction, reinforcing the relationship between the structure of the starting materials and the final hydroxyester can aid students in visualizing how molecules are transformed throughout the reaction. Providing representative examples and comparing them with similar reactions, such as the Grignard reaction, helps students to differentiate and appreciate the unique aspects of this method in synthesizing \(\beta\)-hydroxyesters.