In Situ Studies of Arylboronic Acids/Esters and R₃SiCF₃ Reagents: Kinetics, Speciation, and Dysfunction at the Carbanion–Ate Interface

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Reagent instability reduces the efficiency of chemical processes, and while much effort is devoted to reaction optimization, less attention is paid to the mechanistic causes of reagent decomposition. Indeed, the response is often to simply use an excess of the reagent. Two reaction classes with ubiquitous examples of this are the Suzuki−Miyaura cross-coupling of boronic acids/esters and the transfer of CF 3 or CF 2 from the Ruppert−Prakash reagent, TMSCF 3 . This Account describes some of the overarching features of our mechanistic investigations into their decomposition. In the first section we summarize how specific examples of (hetero)arylboronic acids can decompose via aqueous protodeboronation processes: Ar−B(OH) 2 + H 2 O → ArH + B(OH) 3 . Key to the analysis was the development of a kinetic model in which pH controls boron speciation and heterocycle protonation states. This method revealed six different protodeboronation pathways, including self-catalysis when the pH is close to the pK a of the boronic acid, and protodeboronation via a transient aryl anionoid pathway for highly electron-deficient arenes. The degree of "protection" of boronic acids by diol-esterification is shown to be very dependent on the diol identity, with sixmembered ring esters resulting in faster protodeboronation than the parent boronic acid. In the second section of the Account we describe 19 F NMR spectroscopic analysis of the kinetics of the reaction of TMSCF 3 with ketones, fluoroarenes, and alkenes. Processes initiated by substoichiometric "TBAT" ([Ph 3 SiF 2 ][Bu 4 N]) involve anionic chain reactions in which low concentrations of [CF 3 ] − are rapidly and reversibly liberated from a siliconate reservoir, [TMS(CF 3 ) 2 ][Bu 4 N]. Increased TMSCF 3 concentrations reduce the [CF 3 ] − concentration and thus inhibit the rates of CF 3 transfer. Computation and kinetics reveal that the TMSCF 3 intermolecularly abstracts fluoride from [CF 3 ] − to generate the CF 2 , in what would otherwise be an endergonic α-fluoride elimination. Starting from [CF 3 ] − and CF 2 , a cascade involving perfluoroalkene homologation results in the generation of a hindered perfluorocarbanion, [C 11 F 23 ] − , and inhibition. The generation of CF 2 from TMSCF 3 is much more efficiently mediated by NaI, and in contrast to TBAT, the process undergoes autoacceleration. The process involves NaI-mediated α-fluoride elimination from [CF 3 ][Na] to generate CF 2 and a [NaI•NaF] chain carrier. Chain-branching, by [(CF 2 ) 3 I][Na] generated in situ (CF 2 + TFE + NaI), causes autoacceleration.Alkenes that efficiently capture CF 2 attenuate the chain-branching, suppress autoacceleration, and lead to less rapid difluorocyclopropanation. The Account also highlights how a collaborative approach to experiment and computation enables mechanistic insight for control of processes.

TMSCF3-Mediated Conversion of Salicylates into α,α-Difluoro-3-coumaranones: Chain Kinetics, Anion-Speciation, and Mechanism

“…The above features inform tests to probe and distinguish the two general pathways of [CF 3 ] − addition (A) versus CF 2 addition (B), Scheme . The presence of [ 5 ] − , and by implication [CF 3 ] − , was confirmed by the appearance of a broad signal at δ F ≈ −64.2 ppm 3 during stage II of the in situ 19 F NMR analysis of the conversion of silyl ether 2a TMS to ketal 3a TMS on cooling the sample to 275 K, see Section S1.4 in the Supporting Information. Moreover, on using TESCF 3 , the rate of generation of ketals 3c,d,e TES is strongly suppressed compared to identical conditions when employing TMSCF 3 ( 1 ), see Section S1.3 in the Supporting Information.…”

“…The pentacoordinate siliconate [ 5 ] − , Scheme , is a key indicator for trace concentrations of the carbanion­(oid), [CF 3 ] − [Bu 4 N] + , in a medium containing TMSCF 3 ( 1 ). ,, The siliconate does not react directly with electrophiles but instead acts as a dynamic and dominant anion reservoir ( K 2 ) to a metastable ( k F and k C ) system . The rates of reactions of carbonyl species with TMSCF 3 ( 1 ) [ are powerfully attenuated by this equilibrium and thus accelerate with conversion when there is a substoichiometric TMSCF 3 reagent: [ 1 ] 0 /[carbonyl] 0 < 1 .…”

“…However, both processes ( K 2 and k F ) are sensitive to the steric hindrance of the silyl reagent. For example, using TESCF 3 leads to higher [CF 3 ] − concentrations ( K 2 TMS / K 2 TES ≈ 20) and overall faster CF 3 -addition to carbonyl species, but slower generation of CF 2 …”

“…Kinetic modeling, see Section , shows that 3a–e TMS do not need to be better fluoride ( k SF ) acceptors than TMSCF 3 ( k F ) for there to be substantial acceleration in TMSF generation in stage III, provided that 3a–e TMS do not exergonically complex [CF 3 ] − to generate a siliconate (Scheme ). ,, …”

“…Since its introduction in 1984, TMSCF 3 ( 1 ) has been a reagent of choice for the addition of CF 3 to electrophiles. , Over the past decade, the scope of application of 1 has expanded considerably and now includes, for example, the transfer of CF 2 and C–H silylation. − The majority of the reactions of TMSCF 3 ( 1 ) require the addition of a silaphilic anion, and a growing body of evidence indicates that this liberates a transient trifluoromethylcarbanion­(oid) “[CF 3 ] − ” from the TMS group. , Through kinetic and NMR spectroscopic studies, we recently established that reactions of TMSCF 3 initiated by [Ph 3 SiF 2 ] − [Bu 4 N] + (“TBAT”), a readily handled surrogate for “[F] − ”, proceed via anionic chain reactions, Scheme …”