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Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of the Siliconate-Carbanion Dichotomy by Stopped-Flow NMR/IR.

Johnston, C, West, T, Dooley, R, Reid, M, Jones, AB, King, E, Leach, AG and Lloyd-Jones, GC (2018) Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of the Siliconate-Carbanion Dichotomy by Stopped-Flow NMR/IR. Journal of the American Chemical Society. ISSN 0002-7863

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Abstract

The mechanism of CF3 transfer from R3SiCF3 (R = Me, Et, iPr) to ketones and aldehydes, initiated by M+X- (<0.004 to 10 mol%) has been investigated by analysis of kinetics (variable-ratio stopped-flow NMR and IR), 13C/2H KIEs, LFER, addition of ligands (18-c-6, crypt-222), and density functional theory (DFT) calculations. The kinetics, reaction orders, and selectivity vary substantially with reagent (R3SiCF3) and initiator (M+X-). Traces of exogenous inhibitors present in the R3SiCF3 reagents, which vary substantially in proportion and identity be-tween batches and suppliers, also affect the kinetics. Some reactions are complete in milliseconds, others take hours, others stall before completion. Despite these differences, a general mechanism has been elucidated in which the product alkoxide and CF3- anion act as chain carriers in an anionic chain reaction. Silyl enol ether generation competes with 1,2-addition and involves protonation of CF3- by the -C-H of the ketone, and the OH of the enol. The overarching mechanism for trifluoromethylation by 1, in which pentacoordinate siliconate in-termediates are unable to directly transfer CF3- as a nucleophile or base, rationalizes why the turnover rate (per M+X- initiator) depends on the initial concentration (but not identity) of X-, the identity (but not concentration) of M+, the identity of the R3SiCF3 reagent, and the carbonyl / R3SiCF3 ratio. It also rationalizes which R3SiCF3 rea-gent effects the most rapid trifluoromethylation, for a specific M+X- initiator.

Item Type: Article
Uncontrolled Keywords: 03 Chemical Sciences
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: American Chemical Society
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Date Deposited: 22 Aug 2018 10:35
Last Modified: 15 Sep 2018 05:07
DOI or Identification number: 10.1021/jacs.8b06777
URI: http://researchonline.ljmu.ac.uk/id/eprint/9114

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