Biocatalysis

Mechanism + Description

The mechanisms of enzymes that convert aryl and heteroaryl halides to phenols are not all fully categorized, but some do seem to catalyse true S_NAr type reactions. These appear to have mechanisms similar to haloalkane dehalogenases (catalytic triad Asp-His-(Asp/Glu)), or are metalloproteases that use water activated by coordination to a metal centre as the nucleophile.

General comments

Whilst not an obvious reaction for bio-catalysis, a number of enzymes have been reported to give S_NAr like conversions with aromatic and heteroaromatic halides. To date, only water has been used as the nucleophile, but rapid developments in evolving enzymes for promiscuous catalysis could facilitate use of other solvents.

Key references

Appl. Environ. Microbiol. April 2009 vol. 75 no. 7 2184-2191 Catalytic Improvement and Evolution of Atrazine Chlorohydrolase

AngewChemInt Ed Engl. 2015, 54(11): 3351–3367. Expanding the Enzyme Universe: Accessing Non-Natural Reactions by Mechanism-Guided Directed Evolution

J. Am. Chem. Soc. 1995 117, 10791 – 10798 Exploration of possible mechanisms for 4-chlorobenzoyl CoA dehalogenase: Evidence for an aryl-enzyme intermediate

Journal of Chemistry Volume 2014 (2014), Article ID 157974 Role of Dehalogenases in Aerobic Bacterial Degradation of Chlorinated Aromatic Compounds

Chemical Reviews (2017), 117(8), 5619-5674. Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

Biochemistry (2016), 55(45), 6304-6313 Active site desolvation and thermostability trade-​offs in the evolution of catalytically diverse triazine hydrolases

Relevant scale up examples

None found.