![Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F51444.jpg&w=3840&q=50)
Electrochemically driven cross-electrophile coupling of alkyl halides
Wen Zhang1, Lingxiang Lu1, Wendy Zhang2
1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
Nature
|February 21, 2022
Summary
Developing new drugs requires creating carbon-carbon bonds. This study uses electrochemistry for selective cross-electrophile coupling of alkyl halides, improving drug candidate success rates.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Electrochemistry
Background:
- Increasing sp3 carbon content in drug candidates correlates with higher clinical trial success rates.
- Developing selective carbon(sp3)-carbon(sp3) bond formation methods is crucial for modern organic synthesis.
- Cross-electrophile coupling using alkyl halides offers a direct route, avoiding traditional carbon nucleophile preparation issues.
Purpose of the Study:
- To develop a highly selective method for carbon(sp3)-carbon(sp3) bond formation.
- To enable efficient cross-electrophile coupling of diverse alkyl halides.
- To achieve selective coupling without relying on transition metal catalysts.
Main Methods:
- Utilizing electrochemistry for differential activation of alkyl halides based on electronic and steric properties.
- Employing selective cathodic reduction of more substituted alkyl halides to generate carbanions.
- Facilitating bimolecular nucleophilic substitution for coupling with less substituted alkyl halides.
Main Results:
- Demonstrated efficient cross-electrophile coupling of functionalized and unactivated alkyl electrophiles.
- Achieved high chemoselectivity, outperforming existing methods.
- Successfully formed new carbon-carbon bonds without the need for transition metal catalysts.
Conclusions:
- Electrochemical differential activation provides a selective approach to carbon(sp3)-carbon(sp3) bond formation.
- This method enhances the synthesis of complex molecules, particularly relevant for drug discovery.
- The developed protocol offers a greener and more efficient alternative for cross-electrophile coupling.
Related Concept Videos
02:35Electrophilic Addition to Alkynes: Hydrohalogenation
10.4K
Electrophilic addition of hydrogen halides, HX (X = Cl, Br or I) to alkenes forms alkyl halides as per Markovnikov's rule, where the hydrogen gets added to the less substituted carbon of the double bond. Hydrohalogenation of alkynes takes place in a similar manner, with the first addition of HX forming a vinyl halide and the second giving a geminal dihalide.
10.4K
02:38Electrophilic Addition to Alkynes: Halogenation
8.8K
Introduction
Halogenation is another class of electrophilic addition reactions where a halogen molecule gets added across a π bond. In alkynes, the presence of two π bonds allows for the addition of two equivalents of halogens (bromine or chlorine). The addition of the first halogen molecule forms a trans-dihaloalkene as the major product and the cis isomer as the minor product. Subsequent addition of the second equivalent yields the tetrahalide.
Halogenation is another class of electrophilic addition reactions where a halogen molecule gets added across a π bond. In alkynes, the presence of two π bonds allows for the addition of two equivalents of halogens (bromine or chlorine). The addition of the first halogen molecule forms a trans-dihaloalkene as the major product and the cis isomer as the minor product. Subsequent addition of the second equivalent yields the tetrahalide.
8.8K
02:26SN2 Reaction: Transition State
10.3K
An SN2 reaction of an alkyl halide is a single-step process in which bond formation between the nucleophile and the substrate and bond breaking between the substrate and the halide occurs simultaneously through a transition state without forming an intermediate.
When the nucleophile approaches the electrophilic carbon with its lone pairs, the halide acts as a leaving group and moves away with the electron-pair bonded to the carbon. Dotted partial bonds represent the bonds being formed or broken...
When the nucleophile approaches the electrophilic carbon with its lone pairs, the halide acts as a leaving group and moves away with the electron-pair bonded to the carbon. Dotted partial bonds represent the bonds being formed or broken...
10.3K
02:46Halogenation of Alkenes
16.6K
Halogenation is the addition of chlorine or bromine across the double bond in an alkene to yield a vicinal dihalide. The reaction occurs in the presence of inert and non-nucleophilic solvents, such as methylene chloride, chloroform, or carbon tetrachloride.
Consider the bromination of cyclopentene. Molecular bromine is polarized in the proximity of the π electrons of cyclopentene. An electrophilic bromine atom adds across the double bond, forming a cyclic bromonium ion intermediate.
Consider the bromination of cyclopentene. Molecular bromine is polarized in the proximity of the π electrons of cyclopentene. An electrophilic bromine atom adds across the double bond, forming a cyclic bromonium ion intermediate.
16.6K
02:46E1 Reaction: Kinetics and Mechanism
15.9K
Here, in contrast to the E2 reaction mechanism, we delve into the aspects of the E1 reaction mechanism, which has two steps: rate-limiting loss of the leaving group and abstraction of the beta hydrogen by a weak base. Typically, the experimental proof for the E1 mechanism is via kinetic studies or isotope studies. While the former demonstrates the first-order kinetics—the dependence of the reaction solely on substrate concentration—the latter proves the abstraction of hydrogen only...
15.9K
01:14Electrophilic 1,2- and 1,4-Addition of X2 to 1,3-Butadiene
2.9K
Electrophilic addition of halogens to alkenes proceeds via a cyclic halonium ion to form a 1,2-dihalide or a vicinal dihalide.
2.9K