Structural basis for regioisomerization in the alkali-metal-mediated zincation (AMMZn) of trifluoromethyl benzene by isolation of kinetic and thermodynamic intermediates

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Armstrong, David R. and Blair, Victoria L. and Clegg, William and Dale, Sophie H. and Garcia-Alvarez, Joaquin and Honeyman, Gordon W. and Hevia, Eva and Mulvey, Robert E. and Russo, Luca (2010) Structural basis for regioisomerization in the alkali-metal-mediated zincation (AMMZn) of trifluoromethyl benzene by isolation of kinetic and thermodynamic intermediates. Journal of the American Chemical Society, 132 (27). pp. 9480-9487. ISSN 1520-5126 (https://doi.org/10.1021/ja1038598)

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Abstract

Performed with a desire to advance knowledge of the structures and mechanisms governing alkali-metal-mediated zincation, this study monitors the reaction between the TMP-dialkylzincate reagent RTMEDA)Na(TMP)(Bu-t)Zn(Bu-t)] 1 and trifluoromethyl benzene C6H5CF3 2. A complicated mixture of products is observed at room temperature. X-ray crystallography has identified two of these products as ortho- and meta-regioisomers of heterotrianionic RTMEDA)Na(TMP)(C6H4-CF3)Zn(Bu-t)], 3-ortho and 3-meta, respectively. Multinuclear NMR data of the bulk crystalline product confirm the presence of these two regioisomers as well as a third isomer, 3-para, in a respective ratio of 20:11:1, and an additional product 4, which also exhibits ortho-zincation of the aryl substrate. Repeating the reaction at 0 C gave exclusively 4, which was crystallographically characterized as [{(TMEDA)(2)Na}(+)(Zn(C6H4-CF3)(Bu-t)(2)}(-)}. Mimicking the original room-temperature reaction, this kinetic product was subsequently reacted with TMP(H) to afford a complicated mixture of products, including significantly the three regioisomers of 3. Surprisingly, 4 adopts a solvent-separated ion pair arrangement in contrast to the contacted ion variants of 3-ortho and 3-meta. Aided by DFT calculations on model systems, discussion focuses on the different basicities, amido or alkyl, and steps, exhibited in these reactions, and how the structures and bonding within these isolated key metallic intermediates (prior to any electrophilic interception step), specifically the interactions involving the alkali metal, influence the regioselectivity of the Zn-H exchange process.

ORCID iDs

Armstrong, David R., Blair, Victoria L., Clegg, William, Dale, Sophie H., Garcia-Alvarez, Joaquin, Honeyman, Gordon W., Hevia, Eva ORCID logoORCID: https://orcid.org/0000-0002-3998-7506, Mulvey, Robert E. ORCID logoORCID: https://orcid.org/0000-0002-1015-2564 and Russo, Luca;
CORE (COnnecting REpositories)