The Need for an Alternative to Radicals as the Cause of Fragmentation of a Thiamin‐Derived Breslow Intermediate

Abstract

Mandelylthiamin (1) is a conjugate of benzoylformate and thiamin that loses CO to form the classic Breslow intermediate (2), whose expected fate is formation of the thiamin conjugate of benzaldehyde (3). Surprisingly, it was observed that 2 decomposes to 4 and 5 and rearranges to 6 in competition with the expected protonation to give 3. Recent reports propose that the alternatives to protonation arise from homolysis followed by radical-centered processes. It is now found, instead, that the spectroscopic observations cited in support of the proposed radical pathways are likely to be the result of other events. An alternative explanation is that ionization of the enolic hydroxy group of 2 and resultant electronic reorganization leads to C-C bond cleavage and non-radical intermediates that readily form 4, 5, and 6.

Competing Protonation and Halide Elimination as a Probe of the Character of Thiamin-Derived Reactive Intermediates

“…All reagents were acquired from commercial sources and used without further purification. The hydroxyl group of thiamin was converted to the tert -butyldiphenylsilyl ether (TBDPS) …”

“…The hydroxyl group of thiamin was converted to the tert-butyldiphenylsilyl ether (TBDPS). 42 tert-Butyl p-(bromomethyl)benzoylformate was prepared from 4-(bromomethyl)benzoylformic acid by reaction with liquid isobutylene and sulfuric acid as the catalyst at room temperature. 10 p-(Bromomethyl)benzoylformic acid was prepared by radical bromination of p-methylbenzoylformic acid, 39 which was synthesized from oxidation of p-methylacetophenone with selenium dioxide in pyridine.…”

Charge Dispersion and Its Effects on the Reactivity of Thiamin-Derived Breslow Intermediates

“…Thus, we prepared a series of phenyl-substituted analogues of MTh, accurate comparators for the corresponding enzymic predecarboxylation intermediates derived from ThDP (Scheme , where R = Ph). Our improved synthetic route to MTh serves as the basis for producing phenyl-substituted derivatives of MTh (Scheme , where Z = p -OCH 3 , p -CH 3 , p -F, p -Cl, or m -Br). , The results of kinetic studies with these compounds allow us to make a confident assessment of the charge distribution in the Breslow intermediate and TS that leads to it. We find that the results are consistent with an induced electrostatic environment on the enzyme that maintains a reactive intermediate that minimizes surrounding intrinsic barriers.…”

Can the Radical Channel Contribute to the Catalytic Cycle of N-Heterocyclic Carbene in Benzoin Condensation?

“…As the ratio of the catalyst to benzaldehyde increased to 1:1 and 1:2, the ketone 9 and the spiro-dioxolane 10 were isolated, respectively. − The desired product of benzoin was formed when excess benzaldehyde was added to the 1:1 mixture of NHC and benzaldehyde, where 4 and 9 were two major intermediates . In additional to the known important intermediates mentioned above, unexpected structures were also observed from fragmentation and rearrangement of the Breslow intermediate, yet their formation mechanism is not clear. , …”

“…17 In additional to the known important intermediates mentioned above, unexpected structures were also observed from fragmentation and rearrangement of the Breslow intermediate, yet their formation mechanism is not clear. 18,19 The reactivities of three types of NHCs, in terms of thiazolium, imidazolium, and triazolium, have been systematically studied at the B3LYP/6-311+G(d,p) level in the gas phase: among them, the thiazole ring exhibits a superior ability to stabilize the Breslow intermediate, and its reverse reaction from the Breslow intermediate to the reactant is more facile. 7 The stability of ketone 9 against the enol form 4 has been examined by changing the substituents of NHCs, which indicates that their relative stability was dependent on the nature of NHCs.…”