Steric Parameterization Delivers a Reciprocally Predictive Model for Substrate Reactivity and Catalyst Turnover in Rh-Catalyzed Diyne-Alkyne [2 + 2 + 2] Cycloadditions

The Rh-catalyzed [2 + 2 + 2] cycloaddition of diynes
and alkynes
is a synthetically useful transformation that rapidly constructs complex
scaffolds and has been used extensively for >70 years. Despite
this
utility, substrate reactivity issues persist, which are not mechanistically
defined. Here, we provide a general predictive model for reactivity
and turnover for this reaction. Contrary to the proposed electronic
model, this is a predominately sterically driven process where productive
turnover is proportional to alkyne steric parameters. This model allows
for a priori prediction of catalyst loading, turnover, and reaction
yield based on a simple assessment of the steric parameter (e.g.,
A-value) of the alkyne. The relationship is reciprocal, allowing A-values
to be calculated from observed turnover.