| Darzens reaction | |
|---|---|
| Named after | Auguste Georges Darzens |
| Reaction type | Ring forming reaction |
| Identifiers | |
| Organic Chemistry Portal | darzens-reaction |
| RSC ontology ID | RXNO:0000077 |
TheDarzens reaction (also known as theDarzens condensation orglycidic ester condensation) is thechemical reaction of aketone oraldehyde with anα-haloester in the presence of abase to form an α,β-epoxyester, also called a "glycidic ester".[1][2][3] This reaction was discovered by the organic chemistAuguste Georges Darzens in 1904.[4][5][6]
The reaction process begins with deprotonation at thehalogenated position.[3] Because of the ester substituents, this carbanion is aresonance-stabilizedenolate. Thisnucleophile next attacks thecarbonyl reagent, forming a carbon–carbon bond. These two steps are similar to a base-catalyzedaldol reaction. The oxygen anion in this aldol-like product thenSN2 attacks on the formerly-nucleophilic halide-bearing position, displacing the halide to form an epoxide.[2] This reaction sequence is thus acondensation reaction since there is a net loss of HCl when the two reactant molecules join.[7]
If the starting halide is an α-haloamide, the product is an α,β-epoxy amide.[8] If an α-halo ketone is used, the product is an α,β-epoxy ketone.[2]
Any sufficiently strong base can be used for the initial deprotonation. However, if the starting material is an ester, thealkoxide corresponding to the ester side-chain is commonly chosen in order to prevent complications due to potentialacyl exchangeside reactions.
Depending on the specific structures involved, the epoxide may exist incis andtrans forms. A specific reaction may give onlycis, onlytrans, or a mixture of the two. The specificstereochemical outcome of the reaction is affected by several aspects of the intermediate steps in the sequence.
The initial stereochemistry of the reaction sequence is established in the step where the carbanion attacks the carbonyl. Twosp3 (tetrahedral) carbons are created at this stage, which allows two differentdiastereomeric possibilities of thehalohydrin intermediate. The most likely result is due tochemical kinetics: whichever product is easier and faster to form will be the major product of this reaction. The subsequent SN2 reaction step proceeds with stereochemical inversion, so thecis ortrans form of the epoxide is controlled by the kinetics of an intermediate step. Alternately, the halohydrin can epimerize due to the basic nature of the reaction conditions prior to the SN2 reaction. In this case, the initially formed diastereomer can convert to a different one. This is anequilibrium process, so thecis ortrans form of the epoxide is controlled bychemical thermodynamics—the product resulting from the more stable diastereomer, regardless of which one was the kinetic result.[8]
Glycidic esters can also be obtained vianucleophilic epoxidation of anα,β-unsaturated ester, but that approach requires synthesis of the alkene substrate first whereas the Darzens condensation allows formation of the carbon–carbon connectivity and epoxide ring in a single reaction.
The product of the Darzens reaction can be reacted further to form various types of compounds.Hydrolysis of the ester can lead todecarboxylation, which triggers arearrangement of the epoxide into a carbonyl (4). Alternately, other epoxide rearrangements can be induced to form other structures.
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