Role of Fused Ring Size in Organocatalysis by Bicyclic Triazolium Salts

Abstract

Despite many advances in synthetic organocatalysis by N-heterocyclic carbenes (NHCs), it is not understood why product distributions often differ dramatically with catalyst scaffold or with subtle substituent variation within a catalyst family. We herein focused on the kinetic and structural analysis of the origins of the NHC-catalytic behavior.

Overall, sixteen N-aryl substituted bicyclic triazolium satls were attempted, and twelve of them were successfully isolated and purified, and ten crystal structures of them were obtained. During the preparation of these triazolium salts, novel dialkoxy acetal adduct was isolated. We modified the synthetic procedure of triazolium and successfully obtained three pure dialkoxy acetal analogues, and four crystal strucutres of this category. In parallel, three synthetic trials of bis(amino)cyclopropenium salts, precursors of a new class of carbene, were performed.

We used the triazolium salts as carbene precursors to kinetically evaluate the influence of backbone structures towards the catalytic properties. In total, seventeen aryl-substituted aldehydes and fifteen N-aryl bicyclic triazolium salts were used to conduct over one hundred benzoin condensation experiments. The formation and decay of reactants, intermediates, products and by-products were monitored in situ by 1H NMR spectroscopy, and reaction parameters were calculated and fitted by three parallel methonds.

Changing the fused ring size of triazolium salts shows dramatic differences on reaction paraemters of benzoin condensation. Increasing fused ring size from n=1 to n=2 largely decreased the formation rate constant, k1, M-1s-1, of a key intermediate (4.2-7.8 fold), while the formation rate constant with n=2 and n=3 are comparable. The opposite trend can be observed for the dissociation constant, k-1, s-1, of the intermediate, with increased fused ring size decreases the dissociation rate constants. The combined variation of k1 and k-1 lead to the overall equilibrium constant of the intermediate formation, K, M-1, decreases with increased fused ring size of triazolium salts.

We found the electron-withdrawing aryl-substituents of both triazolium salts and aldehydes increases the formation rate constants, k1, of the intermediate. The electron-withdrawing aryl-substituents of triazolium salts also increase the dissociation rate constants, k-1, of the intermediate, while the aryl-subsituents of aldehyde only have small influence on k-1.

We also aimed to find a catalytic route towards the synthesis of d1-deuterated aledehydes. The extent of deuterium incorporation into reactant aldehyde was evaluated under different reaction conditions. We found the best deuterium exchange result at 2.2 hours with 0.02 M of pentafluorophenyl triazolium salt loading and 0.08 M of aldehyde in d4-methanol at 25 C, with 0.16 M NEt3. 73% of aldehyde remained, with 99% of deuterium incorporation, and only 14% of the initial aldehyde formed benzoin product.