title: Accelerating effect of triazolyl and related heteroaryl substituents on SNAr reactions: evidence of hydrogen-bond stabilized transition states.
abstract: The remarkable accelerating effect of 1,2,3-triazolyl substituents on SNAr reactions has been investigated through systematic experiments and density functional theory calculations. The lone pair electrons of an ortho-triazolo substituent play a key role in lowering the activation energy for nucleophilic addition via formation of a preferential hydrogen bond with the amine nucleophile at the transition state for addition. In an extension of this finding, a series of related heteroaryl groups with similar electron pair donor properties have also been found to facilitate SNAr reactions. The experimentally determined solvent effect provides further support for this rationale, which was utilized to achieve an ortho-selective substitution on a difluoroarene substrate.
authors: Department of Medicinal Chemistry and ‡Department of Molecular Structure, Therapeutic Discovery, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors: Wenyuan
authors: W
authors: Qian
authors: Department of Medicinal Chemistry and ‡Department of Molecular Structure, Therapeutic Discovery, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors: Hao
authors: H
authors: Wang
authors: Department of Medicinal Chemistry and ‡Department of Molecular Structure, Therapeutic Discovery, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors: Michael D
authors: MD
authors: Bartberger
mesh_terms: D000588:Amines / Q000737:chemistry*; D004583:Electrons; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D011789:Quantum Theory; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000588:Amines; D014230:Triazoles