Computational SN2‐Type Mechanism for the Difluoromethylation of Lithium Enolate with Fluoroform through Bimetallic C−F Bond Dual Activation |
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| Authors: | Kazuya Honda Dr Travis V Harris Dr Miho Hatanaka Prof?Dr Keiji Morokuma Prof?Dr Koichi Mikami |
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| Institution: | 1. Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo, Japan;2. Fukui Institute for Fundamental Chemistry, Kyoto University, Kyoto, Japan;3. Department of Chemistry, University of Puget Sound, Tacoma, Washington, USA;4. Department of Chemistry, Faculty of Science and Engineering, Kinki University, Osaka, Japan |
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| Abstract: | The reaction mechanism for difluoromethylation of lithium enolates with fluoroform was analyzed computationally (DFT calculations with the artificial force induced reaction (AFIR) method and solvation model based on density (SMD) solvation model (THF)), showing an SN2‐type carbon–carbon bond formation; the “bimetallic” lithium enolate and lithium trifluoromethyl carbenoid exert the C?F bond “dual” activation, in contrast to the monometallic butterfly‐shaped carbenoid in the Simmons–Smith reaction. Lithium enolates, generated by the reaction of 2 equiv. of lithium hexamethyldisilazide (rather than 1 or 3 equiv.) with the cheap difluoromethylating species fluoroform, are the most useful alkali metal intermediates for the synthesis of pharmaceutically important α‐difluoromethylated carbonyl products. |
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| Keywords: | carbenoids computational chemistry fluorine nucleophilic substitution reaction mechanisms |
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