title: Precise through-space control of an abiotic electrophilic aromatic substitution reaction.
abstract: Nature has evolved selective enzymes for the efficient biosynthesis of complex products. This exceptional ability stems from adapted enzymatic pockets, which geometrically constrain reactants and stabilize specific reactive intermediates by placing electron-donating/accepting residues nearby. Here we perform an abiotic electrophilic aromatic substitution reaction, which is directed precisely through space. Ester arms-positioned above the planes of aromatic rings-enable it to distinguish between nearly identical, neighbouring reactive positions. Quantum mechanical calculations show that, in two competing reaction pathways, both [C-H···O]-hydrogen bonding and electrophile preorganization by coordination to a carbonyl group likely play a role in controlling the reaction. These through-space-directed mechanisms are inspired by dimethylallyl tryptophan synthases, which direct biological electrophilic aromatic substitutions by preorganizing dimethylallyl cations and by stabilizing reactive intermediates with [C-H···N]-hydrogen bonding. Our results demonstrate how the third dimension above and underneath aromatic rings can be exploited to precisely control electrophilic aromatic substitutions.
authors.affiliation: Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Murphy
authors.affiliation: Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Bocanegra
authors.affiliation: Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.
authors.forename: H-Y Katharine
authors.initials: HK
authors.lastname: Chau
authors.affiliation: Department of Materials Science, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.|Department of Mechanical Engineering, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Lee
authors.affiliation: Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.|Department of Materials Science, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.
authors.forename: Jianing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.|Department of Materials Science, The University of Vermont, 82 University Place, Burlington, Vermont 05405, USA.
authors.forename: Severin T
authors.initials: ST
authors.lastname: Schneebeli
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D006860:Hydrogen Bonding; D009566:Nitrates / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy; D011789:Quantum Theory; D014367:Tryptophan Synthase / Q000378:metabolism*
chemical_list: D009566:Nitrates; D019883:Alkyl and Aryl Transferases; C032409:tryptophan dimethylallyltransferase; D014367:Tryptophan Synthase