Mechanism of Ti-Catalyzed Oxidative Nitrene Transfer in [2 + 2 + 1] Pyrrole Synthesis from Alkynes and Azobenzene

Zachary W. Davis-Gilbert, Xuelan Wen, Jason D. Goodpaster, Ian A. Tonks

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A combined computational and experimental study on the mechanism of Ti-catalyzed formal [2 + 2 + 1] pyrrole synthesis from alkynes and aryl diazenes is reported. This reaction proceeds through a formally TiII/TiIV redox catalytic cycle as determined by natural bond orbital (NBO) and intrinsic bond orbital (IBO) analysis. Kinetic analysis of the reaction of internal alkynes with azobenzene reveals a complex equilibrium involving Ti=NPh monomer/dimer equilibrium and Ti=NPh + alkyne [2 + 2] cycloaddition equilibrium along with azobenzene and pyridine inhibition equilibria prior to rate-determining second alkyne insertion. Computations support this kinetic analysis, provide insights into the structure of the active species in catalysis and the roles of solvent, and provide a new mechanism for regeneration of the Ti imido catalyst via disproportionation. Reductive elimination from a 6-membered azatitanacyclohexadiene species to generate pyrrole-bound TiII is surprisingly facile and occurs through a unique electrocyclic reductive elimination pathway similar to a Nazarov cyclization. The resulting TiII species are stabilized through backbonding into the π∗ of the pyrrole framework, although solvent effects also significantly stabilize free TiII species that are required for pyrrole loss and catalytic turnover. Further computational and kinetic analysis reveals that in complex reactions with unysmmetric alkynes the resulting pyrrole regioselectivity is driven primarily by steric effects for terminal alkynes and inductive effects for internal alkynes.

Original languageEnglish (US)
Pages (from-to)7267-7281
Number of pages15
JournalJournal of the American Chemical Society
Issue number23
StatePublished - Jun 13 2018

Bibliographical note

Funding Information:
Financial support was provided by the University of Minnesota (start-up funds, Doctoral Dissertation Fellowship to Z.W.D.-G.), the National Institutes of Health (1R35GM119457), and the Alfred P. Sloan Foundation (I.A.T. is a 2017 Sloan Fellow). Equipment for the Chemistry Department NMR facility was supported through a grant from the National Institutes of Health (S10OD011952) with matching funds from the University of Minnesota. We acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota and the National Energy Research Scientific Computing Center (NERSC) a DOE Office of Science User Facility supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231 for providing resources that contributed to the results reported within this paper.

Publisher Copyright:
© 2018 American Chemical Society.

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