Related Experiment Video
Updated: Jun 2, 2025
09:16
In Vitro Directed Evolution of a Restriction Endonuclease with More Stringent Specificity
Published on: March 25, 2020
7.2K
Engineered enzymes for enantioselective nucleophilic aromatic substitutions
Thomas M Lister1,2, George W Roberts1,2, Euan J Hossack1,2
1Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK.
Nature
|January 15, 2025
Summary
Researchers developed a biocatalyst, SNAr1.3, for stereoselective nucleophilic aromatic substitution (SNAr) reactions. This engineered enzyme enables efficient and selective C-C and C-X bond formation under mild conditions, advancing green chemistry in pharmaceuticals and agrochemicals.
Area of Science:
- Organic Chemistry
- Biocatalysis
- Green Chemistry
Background:
- Nucleophilic aromatic substitution (SNAr) reactions are crucial for synthesizing pharmaceuticals and agrochemicals.
- Traditional SNAr methods require harsh conditions, limiting selectivity and environmental compatibility.
- Existing catalytic methods for SNAr are scarce and often lack stereocontrol.
Purpose of the Study:
- To develop a biocatalytic approach for stereoselective SNAr reactions.
- To engineer an enzyme capable of efficient and selective SNAr.
- To provide a greener alternative to conventional SNAr synthesis.
Main Methods:
- Directed evolution of a designed enzyme with promiscuous SNAr activity.
- Optimization of catalytic efficiency and stereoselectivity.
- Biochemical, structural, and computational analyses of the engineered enzyme (SNAr1.3).
Main Results:
- An engineered biocatalyst, SNAr1.3, was developed, showing 160-fold improvement over the parent enzyme.
- SNAr1.3 achieved near-perfect stereocontrol (>99% enantiomeric excess) in coupling electron-deficient arenes with carbon nucleophiles.
- The biocatalyst demonstrated high turnover numbers (>4,000) and broad substrate scope, enabling the synthesis of challenging stereocentres.
Conclusions:
- Biocatalysis can be successfully applied to SNAr chemistry, offering high selectivity and efficiency.
- The engineered enzyme SNAr1.3 provides a versatile platform for catalytic SNAr reactions.
- This work expands the scope of biocatalysis for complex molecule synthesis in the pharmaceutical and agrochemical industries.
Related Concept Videos
01:16Electrophilic Aromatic Substitution: Overview
10.6K
In an electrophilic aromatic substitution reaction, an electrophile substitutes for a hydrogen of an aromatic compound.
10.6K
01:30Nucleophilic Aromatic Substitution: Addition–Elimination (SNAr)
3.7K
Nucleophilic substitution in aromatic compounds is feasible in substrates bearing strong electron-withdrawing substituents positioned ortho or para to the leaving group. The reaction proceeds via two steps: the addition of the nucleophile and the elimination of the leaving group.
The reaction begins with an attack of the nucleophile on the carbon that holds the leaving group. This results in the delocalization of the π electrons over the ring carbons. The resonance interaction between...
The reaction begins with an attack of the nucleophile on the carbon that holds the leaving group. This results in the delocalization of the π electrons over the ring carbons. The resonance interaction between...
3.7K
01:11Nucleophilic Aromatic Substitution: Elimination–Addition
4.0K
Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be forced under certain conditions, such as high temperatures or strong bases. The mechanism of substitution under such conditions involves the highly unstable and reactive benzyne intermediate. Benzyne contains equivalent carbon centers at both ends of the triple bond, each of which is equally susceptible to nucleophilic attack. This 50–50 distribution of products is...
4.0K
01:14Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN1
2.1K
Treating arylamines with nitrous acid gives aryldiazonium salts that are effective substrates in nucleophilic aromatic substitution reactions. The diazonio group in these salts can be easily displaced by different nucleophiles, yielding a wide variety of substituted benzenes. The leaving group departs as nitrogen gas, and this easy elimination is the driving force for the substitution reaction.
In the Sandmeyer reaction, for example, the diazonio group is replaced by a chloro, bromo,...
In the Sandmeyer reaction, for example, the diazonio group is replaced by a chloro, bromo,...
2.1K
01:26Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction
3.3K
α-Substituted ketones or aldehydes can be synthesized from enamines by the Stork enamine reaction, named after its pioneer Gilbert Stork. Enamines are useful synthetic intermediates where the lone pair on nitrogen is in conjugation with the C=C bond. They resemble enolate ions, as the resonance forms of both species have a nucleophilic α carbon.
3.3K
02:34Nucleophilic Substitution Reactions
16.0K
Historical perspective
In 1896, the German chemist Paul Walden discovered that he could interconvert pure enantiomeric (+) and (-) malic acids through a series of reactions. This conversion suggested the involvement of optical inversion during the substitution reaction. Further, in 1930, Sir Christopher Ingold described for the first time two different forms of nucleophilic substitution reactions, which are known as SN1 (nucleophilic substitution unimolecular) and SN2 (nucleophilic substitution...
In 1896, the German chemist Paul Walden discovered that he could interconvert pure enantiomeric (+) and (-) malic acids through a series of reactions. This conversion suggested the involvement of optical inversion during the substitution reaction. Further, in 1930, Sir Christopher Ingold described for the first time two different forms of nucleophilic substitution reactions, which are known as SN1 (nucleophilic substitution unimolecular) and SN2 (nucleophilic substitution...
16.0K