Application of the Darzens Glycidic Ester Synthesis

Darzen Halogenation can be used to produce alkyl halides from alcohols using thionyl chloride or bromide (SOX2) and a tiny amount of a nitrogen base such as tertiary amine or pyridine, or analogous hydrochloride. This procedure cannot be used to make alkyl bromides or iodides because of the unstable nature of the thionyl bromide and the absence of the thionyl iodide. For the production of alkyl chlorides, gaseous SO2 and HCl are desirable byproducts. However, this is not the case with the phosphorus chloride approach, and as a result, it is not employed to make alkyl chlorides.

A ketone or aldehyde reacts with a halo ester and a base to generate an -epoxy ester, also known as a “glycidic ester,” in the Darzens reaction (also known as the Darzens condensation or glycidic ester condensation). In 1904, Auguste Georges Darzens discovered this redox reaction in his laboratory.

Key Details

• The reaction’s broad synthetic scope can be attributed to the reaction’s wide tolerance of functional groups and the numerous reaction conditions that can be used. 

• There are numerous substitutes for simple esters that can be used in the enolate formation process. 

• These changes have assured their continued relevance, with a wide range of solvents and bases providing the necessary conditions. 

• Dihalogen epoxy esters have been used extensively in a wide range of applications.

• The invention of the asymmetric reaction and improved management of stereoisomers are two of the reaction’s most promising recent improvements. 

• Catalytic asymmetric Darzens reactions have a wide range of applications in pharmaceutical chemistry. However, the catalytic asymmetric Darzens reaction does not yet appear to be used in the synthesis of medicinal molecules.

Reaction Mechanics

The reaction step commences when a strong base is employed to produce a carbanion at the halogenated site. This carbanion is a resonance-stabilised enolate because of the ester, making its formation simple. Another carbonyl group is attacked by this nucleophilic structure, resulting in the formation of a new carbon-carbon bond. A base-catalysed aldol reaction is analogous to the first two steps here. The oxygen anion then performs an intramolecular SN2 attack on the halide-bearing site in this aldol-like product to generate an aldehyde. This is a condensation reaction because the two reactant molecules combine and lose HCl in the process.

If additional carbonyl functional groups are available, they can be utilised instead of an ester for this initial deprotonation step. If the starting material is a -halo amide, the end product is an epoxy amide. Any strong base will do for the first deprotonation. The alkoxide with the ester side chain is typically used to avoid problems caused by possible acyl exchange side reactions if the starting material is an ester.

Stereochemistry

• The epoxide can exist in cis or trans-form, depending on the precise structures involved. Cis or trans may be the result of a specific reaction. 

• Many characteristics of the sequence’s intermediary phases influence the stereochemistry of the reaction.

• In this phase, the carbanion first attacks the carbonyl and establishes early stereochemistry of the reaction cycle. 

• At this point, two sp3 (tetrahedral) carbons are formed, allowing the halohydrin intermediate to be diastereomeric in two different ways. 

• Chemical kinetics dictate that the reaction’s primary end product will be the product that is easiest and fastest to generate. 

• The epoxide’s cis or trans-form is determined by the kinetics of an intermediary step in the subsequent SN2 reaction. 

• Since the halohydrin was formed under such basic conditions before the SN2 reaction, it is possible that it will epimerise instead. As a result, the first created diastereomer may transform into another. 

• As this is an equilibrium process, chemical thermodynamics dictates whether the epoxide forms in the cis or trans-form, regardless of the kinetic outcome.

Applications

• It has become possible to synthesise many medications industrially because of the Darzens condensation’s versatility. 

• Since there are so few recent examples, it’s safe to say that this reaction isn’t now considered a primary route for epoxide synthesis. 

• Reactions such as the homologation phases of vitamin A and Ibuprofen have been effectively executed in industrial-scale syntheses using the classical approach. 

• Additionally, a more recent example utilised the Darzens condensation as an alternate synthesis technique for epiasarinin.

Conclusion

One of the most well-known methods for creating -epoxy esters is the Darzens condensation. A halohydrin-type intermediate is formed when a carbonyl molecule reacts with a halo ester along with a base. The glycidic ester is then formed through a further ring closure. The Darzens reaction uses a non-oxidative mechanism to produce epoxides with electron-withdrawing groups. There are several mechanisms for the creation of epoxides.

Darzens condensation permits the carbon-carbon connection and the epoxide ring to be formed in one process, while nucleophilic epoxidation of an unsaturated ester is required for the production of glycidic esters by nucleophilic epoxidation.