Sulfur Analogs of the Core Formose Cycle: A Free Energy Map

Using computational methods, we examine if the presence of HS can tame the unruly formose reaction by generating a free energy map of the reaction thermodynamics and kinetics of sulfur analogs within the core cycle. With mercaptoaldehyde as the linchpin C species, and feeding the cycle with CHO, selected aldol additions and enolizations are kinetically more favorable. Thione formation is thermodynamically less favored compared to aldehydes and ketones, but all these species can be connected by enolization reactions. In some sulfur analogs, the retroaldol transformation of a C4 species back into linchpin species is thermodynamically favorable, and we have found one route incorporating where incorporating sulfur selects for a specific pathway over others. However, as CHO diminishes, the aldol addition of larger species is less favorable for the sulfur analogs. Our results also suggest that competing Cannizzaro side reactions are kinetically less favored and thermodynamically disfavored when HS is abundant.