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

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 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 between batches and suppliers, also affect the kinetics. Some reactions are complete in milliseconds, others take hours, and 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 α-C–H of the ketone and the OH of the enol. The overarching mechanism for trifluoromethylation by R3SiCF3, in which pentacoordinate siliconate intermediates 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 reagent effects the most rapid trifluoromethylation, for a specific M+X– initiator.

Solvent‐Promoted Catalyst‐Free Nucleophilic Fluoroalkylation of Aldehydes

“…When a 1:1 mixture of benzaldehyde ( 1 a ) and acetophenone ( 1 i ) was treated with Me 3 Si‐CF 3 ( 2 a , 2.5 equiv) in NMP at 50 °C for 24 h, the adduct 3’i (from acetophenone) was detected in only 5% yield, whereas the adduct 3’a (from benzaldehyde) was formed in 99% NMR yield. In the present solvent‐promoted trifluoromethylation, the high degree of the preference of aldehydes over ketones was observed.…”

Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

“…Thep rocedure is compatible with aw ide array of iminosulfur oxydifluorides,i ncluding aromatic (3a-4j)a nd benzyl (3k, 3l)substrates,while in the case of 4-ethynylbenzeneiminosulfur oxydifluoride,t rimethylsilylation of the terminal alkyne also occurred to give the bis-trifluoromethylated product 3c.D iminished yields were observed with substrates comprising electrophilic groups (e.g.,s tarting materials containing an electrophilic ketone, 3g and 3r)o wing to competing addition reactions (see the Supporting Information). [22] Ac ombination of stopped-flow NMR/IR studies and DFT calculations were employed to discern that the direct transfer of CF 3 from siliconate species to carbonyl electrophiles is kinetically prohibited by the very high barrier of inversion for the À CF 3 anion, which subsequently necessitates the involvement of the "free" À CF 3 anion rather than asiliconate-CF 3 species.The calculations also indicate that reactions with ketones and aldehydes proceed through al ower-barrier process involving attack of the electrophile by a" free" À CF 3 anion arising from rapid and reversible CF 3 dissociation from the siliconate. Aliphatic substrates (3m-3r)w ere also compatible, including compounds with ahigh density of heteroatoms (3o-3q).…”

“…However,s imple functional group protection circumvents this issue,and the corresponding ketal trifluoromethylation product (3h)w as isolated in excellent yield. [22] To date,t he pathways empowering SuFEx catalysis remain am atter of conjecture,a lthough interactions with "H + "o r" R 3 Si + "i nt he SuFEx transition state have been suggested. [20] Until very recently the mechanism of anion-initiated trifluoromethylation had remained unclear, with previous mechanistic proposals suggesting the involvement of both siliconate and carbanion pathways.…”

Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

“…[21] Ac omprehensive mechanistic study by Lloyd-Jones and co-workers on the trifluoromethylation of ketones and aldehydes with TMSCF 3 has resolved the siliconate-carbanion dichotomy. [22] Ac ombination of stopped-flow NMR/IR studies and DFT calculations were employed to discern that the direct transfer of CF 3 from siliconate species to carbonyl electrophiles is kinetically prohibited by the very high barrier of inversion for the À CF 3 anion, which subsequently necessitates the involvement of the "free" À CF 3 anion rather than asiliconate-CF 3 species.The calculations also indicate that reactions with ketones and aldehydes proceed through al ower-barrier process involving attack of the electrophile by a" free" À CF 3 anion arising from rapid and reversible CF 3 dissociation from the siliconate. [22] To date,t he pathways empowering SuFEx catalysis remain am atter of conjecture,a lthough interactions with "H + "o r" R 3 Si + "i nt he SuFEx transition state have been suggested.…”

“…[22] Ac ombination of stopped-flow NMR/IR studies and DFT calculations were employed to discern that the direct transfer of CF 3 from siliconate species to carbonyl electrophiles is kinetically prohibited by the very high barrier of inversion for the À CF 3 anion, which subsequently necessitates the involvement of the "free" À CF 3 anion rather than asiliconate-CF 3 species.The calculations also indicate that reactions with ketones and aldehydes proceed through al ower-barrier process involving attack of the electrophile by a" free" À CF 3 anion arising from rapid and reversible CF 3 dissociation from the siliconate. [22] To date,t he pathways empowering SuFEx catalysis remain am atter of conjecture,a lthough interactions with "H + "o r" R 3 Si + "i nt he SuFEx transition state have been suggested. [3] Here we tentatively propose ab ifluoride-initiated pathway (Scheme 3) on the basis of theoretical calculations.I nitial formation of the siliconate complex 7 occurs through the reaction of bifluoride and TMSCF 3 to release fluoroform (DG = À102 kJ mol À1 ).…”