TY - JOUR

T1 - What the Heck?-Automated Regioselectivity Calculations of Palladium-Catalyzed Heck Reactions Using Quantum Chemistry

AU - Ree, Nicolai

AU - Goeller, Andreas H.

AU - Jensen, Jan H.

PY - 2022/12/2

Y1 - 2022/12/2

N2 - We present a quantum chemistry (QM)-based method that computes the relative energies of intermediates in the Heck reaction that relate to the regioselective reaction outcome: branched (alpha), linear (beta), or a mix of the two. The calculations are done for two different reaction pathways (neutral and cationic) and are based on r2SCAN-3c single-point calculations on GFN2-xTB geometries that, in turn, derive from a GFNFF-xTB conformational search. The method is completely automated and is sufficiently efficient to allow for the calculation of thousands of reaction outcomes. The method can mostly reproduce systematic experimental studies where the ratios of regioisomers are carefully determined. For a larger dataset extracted from Reaxys, the results are somewhat worse with accuracies of 63% for beta-selectivity using the neutral pathway and 29% for alpha-selectivity using the cationic pathway. Our analysis of the dataset suggests that only the major or desired regioisomer is reported in the literature in many cases, which makes accurate comparisons difficult. The code is freely available on GitHub under the MIT open-source license: https:// github.com/jensengroup/HeckQM.

AB - We present a quantum chemistry (QM)-based method that computes the relative energies of intermediates in the Heck reaction that relate to the regioselective reaction outcome: branched (alpha), linear (beta), or a mix of the two. The calculations are done for two different reaction pathways (neutral and cationic) and are based on r2SCAN-3c single-point calculations on GFN2-xTB geometries that, in turn, derive from a GFNFF-xTB conformational search. The method is completely automated and is sufficiently efficient to allow for the calculation of thousands of reaction outcomes. The method can mostly reproduce systematic experimental studies where the ratios of regioisomers are carefully determined. For a larger dataset extracted from Reaxys, the results are somewhat worse with accuracies of 63% for beta-selectivity using the neutral pathway and 29% for alpha-selectivity using the cationic pathway. Our analysis of the dataset suggests that only the major or desired regioisomer is reported in the literature in many cases, which makes accurate comparisons difficult. The code is freely available on GitHub under the MIT open-source license: https:// github.com/jensengroup/HeckQM.

KW - ARYLATION

KW - OLEFINS

U2 - 10.1021/acsomega.2c06378

DO - 10.1021/acsomega.2c06378

M3 - Journal article

C2 - 36530278

VL - 7

SP - 45617

EP - 45623

JO - ACS Omega

JF - ACS Omega

SN - 2470-1343

IS - 49

ER -