Amides are ubiquitous in biologically active natural products and commercial drugs. The most common strategy for introducing this functional group is the coupling of a carboxylic acid with an amine, which requires the use of a coupling reagent to facilitate elimination of water. However, the optimal reaction conditions often appear rather arbitrary to the specific reaction. Herein, we report the development of statistical models correlating measured rates to physical organic descriptors to enable the prediction of reaction rates for untested carboxylic acid/amine pairs. The key to the success of this endeavor was the development of an end-to-end data science–based workflow to select a set of coupling partners that are appropriately distributed in chemical space to facilitate statistical model development. By using a parameterization, dimensionality reduction, and clustering protocol, a training set was identified. Reaction rates for a range of carboxylic acid and primary alkyl amine couplings utilizing carbonyldiimidazole (CDI) as the coupling reagent were measured. The collected rates span five orders of magnitude, confirming that the designed training set encompasses a wide range of chemical space necessary for effective model development. Regressing these rates with high-level density functional theory (DFT) descriptors allowed for identification of a statistical model wherein the molecular features of the carboxylic acid are primarily responsible for the observed rates. Finally, out-of-sample amide couplings are used to determine the limitations and effectiveness of the model.

From the preparation of pharmaceuticals to enzymatic construction of natural products, carbocations are central to molecular synthesis. Although these reactive intermediates are engaged in stereoselective processes in nature, exerting enantiocontrol over carbocations with synthetic catalysts remains challenging. Many resonance-stabilized tricoordinated carbocations, such as iminium and oxocarbenium ions, have been applied in catalytic enantioselective reactions. However, their dicoordinated counterparts (aryl and vinyl carbocations) have not, despite their emerging utility in chemical synthesis. We report the discovery of a highly enantioselective vinyl carbocation carbon-hydrogen (C-H) insertion reaction enabled by imidodiphosphorimidate organocatalysts. Active site confinement featured in this catalyst class not only enables effective enantiocontrol but also expands the scope of vinyl cation C-H insertion chemistry, which broadens the utility of this transition metal-free C(sp³)-H functionalization platform.