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

ABSTRACT: 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 ?* 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.

SUBMITTER: Davis-Gilbert ZW

PROVIDER: S-EPMC6508086 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Davis-Gilbert Zachary W ZW Wen Xuelan X Goodpaster Jason D JD Tonks Ian A IA

Journal of the American Chemical Society 20180531 23

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 Ti<sup>II</sup>/Ti<sup>IV</sup> 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 + ...[more]

PMID: 29763560

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Project description:The rational design of catalysts remains a challenging endeavor within the broader chemical community owing to the myriad variables that can affect key bond-forming events. Designing selective catalysts for any reaction requires an efficient strategy for discovering predictive structure-activity relationships. Herein, we describe the use of iterative supervised principal component analysis (ISPCA) in de novo catalyst design. The regioselective synthesis of 2,5-dimethyl-1,3,4-triphenyl-1H-pyrrole (C) via a Ti-catalyzed formal [2 + 2 +1] cycloaddition of phenylpropyne and azobenzene was targeted as a proof of principle. The initial reaction conditions led to an unselective mixture of all possible pyrrole regioisomers. ISPCA was conducted on a training set of catalysts, and their performance was regressed against the scores from the top three principal components. Component loadings from this PCA space and k-means clustering were used to inform the design of new test catalysts. The selectivity of a prospective test set was predicted in silico using the ISPCA model, and optimal candidates were synthesized and tested experimentally. This data-driven predictive-modeling workflow was iterated, and after only three generations the catalytic selectivity was improved from 0.5 (statistical mixture of products) to over 11 (>90% C) by incorporating 2,6-dimethyl-4-(pyrrolidin-1-yl)pyridine as a ligand. The origin of catalyst selectivity was probed by examining ISPCA variable loadings in combination with DFT modeling, revealing that ligand lability plays an important role in selectivity. A parallel catalyst search using multivariate linear regression (MLR), a popular approach in catalysis informatics, was also conducted in order to compare these strategies in a hypothetical catalyst scouting campaign. ISPCA appears to be more robust and predictive than MLR when sparse training sets are used that are representative of the data available during the early search for an optimal catalyst. The successful development of a highly selective catalyst without resorting to long, stochastic screening processes demonstrates the inherent power of ISPCA in de novo catalyst design and should motivate the general use of ISPCA in reaction development.

Dataset Information

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

Publications

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

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