UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Mechanistic investigations of rhodium-catalyzed alkyne hydrothiolation Wathier, Matthew James


Herein, thorough mechanistic investigations into alkyne hydrothiolation catalyzed by [Tp*RhI(PPh₃)₂] (Tp* = tris(3,5-dimethylpyrazolyl)borate) are reported. The mechanism is shown to proceed through an intermediate [Tp*RhIIIH(SR)] complex (R = alkyl, aryl). Alkyne migratory insertion is shown to occur chemoselectively into the Rh-SR bond, despite the availability of a Rh-H bond, to produce a rhodathiacyclobutene intermediate. The regioselectivity of product formation is revealed to be the result of a competition between 1,2 and 2,1 migratory insertion of the alkyne to produce regioisomeric rhodathiacyclobutene intermediates. Product formation occurs upon reductive elimination, which is associatively induced by coordination of thiol. Putative off-cycle intermediates [Tp*RhH(SR)(PMe₃)] (R = alkyl, aryl) have been successfully synthesized from [Tp*RhH(CH₃)(PMe₃)]. The mechanism of formation of the [Tp*RhH(SR)(PMe₃)] complexes is proposed to involve the reductive elimination of methane, associatively induced by coordination of thiol. This mechanism is analogous to the mechanism proposed for alkyne hydrothiolation catalyzed by [Tp*Rh(PPh₃)₂]. Alkyne hydrothiolation reactions in the presence of [Tp*RhH(SR)(PMe₃)] are shown to produce the same product regioisomer as reactions catalyzed by [Tp*Rh(PPh₃)₂]. The synthesis of the vinyl sulfone-containing drug K777, currently in clinical trials for the treatment of Chagas disease, via alkyne hydrothiolation methodology catalyzed by [RhCl(PPh₃)₃], is reviewed. The methodology proves to be versatile in the synthesis of K777 and related analogues. The analogues are assessed in terms of their reactivity towards Michael addition as a method of predicting pharmacodynamics properties. The methanolic pKAs of a series of para-substituted aryl thiols are reported and correlated to their predicted aqueous pKA values. The Hammett dual parameter correlation to the experimental data reveals that the acidity constants are more dependent on the inductive effects of the para-substituent compared to the resonance effect. The dual parameter correlation also allows for the prediction of the methanolic and aqueous acidity constant of any para-substituted aryl thiol, as long as the substituent’s resonance and induction Hammett constants are known.

Item Citations and Data


Attribution-NonCommercial-NoDerivatives 4.0 International