The free energy profile of the piperidine catalyzed Knoevenagel condensation reaction of acetylacetone with benzaldehyde has been obtained by theoretical calculations. The carbinolamine formation step involves catalysis by methanol solvent, and its decomposition takes place via hydroxide ion elimination without a classical transition state, leading to the iminium ion. Hydroxide ion deprotonates the acetylacetone, forming an enolate that attacks the iminium ion and leads to an addition intermediate. The final step involves elimination of piperidine catalyst. Our analysis suggests the iminium ion formation has the highest barrier and the catalytic effect of piperidine is facilitating the elimination step rather than activation of the benzaldehyde electrophile. Experimental measures of the kinetics lead to an observed free energy barrier of 20.0 kcal mol, in good agreement with the theoretical value of 21.8 kcal mol based on the free energy profile.

A reliable theoretical calculation of the free energy profile of a base-catalyzed Knoevenagel reaction shows that hydroxide ion elimination step is rate determining.

Bench-stable tablets (COtabs) have been developed for the rapid and safe production of carbon monoxide. The tablets can be made in less than 5 min without the use of a glovebox and only require a stock solution of an amine base to liberate a specific quantity of CO in a twochamber system. The COtabs were tested in five different carbonylation reactions and provided similar yields compared to literature procedures. Finally, a gram-scale reaction was conducted, as well as 13 C-isotope labeling of the anticancer drug, olaparib.