Cyclic Disulfide Sorting Influenced by Subtle Steric and Electronic Effects

Cyclic disulfides are of interest for their dynamic disulfide linkages in easily assembled large rings that, when paired with strain-based reactivity, can exert great control over macrocycle formation preferences and reactivity. To further understand the fundamental effects related to increasing strain and differing reactivity of monomers in these types of molecules, unsymmetrical dithiols were synthesized and subjected to disulfide formation conditions with Sb(III) or Cu(I) directing agents to give a library of novel self-assembled macrocycles. From these libraries, a slight preference towards narcissistic aryl-aryl and alkyl-alkyl disulfide linkages was observed, when other more stabilizing/destabilizing factors (such as dihedral strain, π-π interactions, etc.) were not in play. This study shows that while this weak electronic preference biases formation of narcissistic disulfide formations at early reaction times, this bias can easily be overcome by steric or electronic stabilizing effects within the assemblies when allowed more time to equilibrate. This leads to significant amplification of one species over others. Further, an interesting preference of Sb(III)-assisted assembly for narcissistic disulfide linkages was observed, which may suggest a more complicated role in antimony-related cascade reactions and pnictogen-thiolate/disulfide interplay that could have relevance in associated disease states and intracellular uptake.