Optimizing the Accuracy and Computational Cost in Theoretical Squaramide Catalysis: The Henry Reaction

Abstract

This study represents the first example where the accuracy of different combinations of density functional theory (DFT) methods and basis sets has been compared in squaramide catalysis. After an optimization process of the precision obtained and the computational time required in the computational calculations, highly precise results were achieved compared to the experimental outcomes while using the least amount of time as possible. Here, we have explored computationally and experimentally the mechanism of squaramide-catalyzed Henry reaction. This is a complex reaction of about 100 atoms and a great number of diverse non-covalent interactions. Moreover, this research is one of the scarce examples where the organocatalyst acts in a trifunctional manner and is the first investigation in which a trifunctional squaramide catalyst has been employed. Functional ωB97X-D showed the best results when used with different versions of the 6-311 basis sets, leading to highly accurate calculations of the outcomes of the Henry reaction using nine aldehydes with different structural characteristics. Furthermore, in these relatively large systems, the use of a split-valence triple-zeta basis set saves a large amount of time compared to using larger basis sets that are sometimes employed in organocatalytic studies, such as the TZV and Def2TZV basis set families.

Asymmetric aza-Henry reaction of hydrazones

“…Interestingly, a kinetic isotopic effect of kH/kD = 1.31 was obtained using nitromethane (2a) instead deuterated nitromethane. This KIE value (secondary KIE) differs significantly that those reported in the literature for other aza-Henry transformations [14,15].…”

Asymmetric Organocatalyzed Aza‐Henry Reaction of Hydrazones: Experimental and Computational Studies

“…For the model reaction previously employed, a 2 H KIE ( k H / k D ) of 1.31 (secondary KIE) was observed using CH 3 NO 2 and CD 3 NO 2 (Table , entries 1 and 4). This value is difficult to rationalize based on the previous studies mentioned in Scheme , since the RLS of these studies was proposed to be the nitronate attack to the carbonyl or imine group, which would lead to an inverse secondary 2 H KIE ( k H / k D <1) . Also, if the initial deprotonation of 2 a was the RLS, a primary 2 H KIE ( k H / k D >2) would be expected and, therefore, we can also rule out this possibility …”

“…Assuming that the initial deprotonation of CH 3 NO 2 is a fast process and does not significantly affect the overall 2 H KIE, the calculated 2 H KIE corresponds to that of TS‐I and it is 1.65 for the most stable conformer (Figure S75, Supporting Information), which is similar to the experimental value. This secondary KIE value suggests that the mechanism is concerted, averaging the mismatching KIE effects of the C−C bond formation (associated with secondary inverse KIEs) and the protonation of the imine group (causing a primary KIE). It is worth mentioning that the catalyst plays an important role in the kinetics of the reaction, since it considerably stabilizes the nitronate nucleophile ( 2 a − ) compared to the uncatalyzed 2 a :CH 2 NO 2 H tautomeric equilibrium (Figure A, red versus black lines).…”

Multifunctional chiral aminophosphines for enantiodivergent catalysis in a palladium‐catalyzed allylic alkylation reaction

“…The multifunctional chiral phosphine may act as a ligand to the metal and also organize H‐bonding interactions for synergistic substrate direction. While trifunctional or multifunctional catalysts are seeing wider applications in organocatalytic reactions 49–51 here we demonstrate the application of multifunctional catalysts in metal‐catalyzed processes.…”