Modeling reduces nickel needed in catalytic reactions

Nickel catalysts are much less expensive than precious metal catalysts, but the large amounts of nickel catalyst used in many catalytic cross-coupling reactions still discourage industrial adoption. Over roughly the past two years, the vast majority of newly reported nickel-catalyzed cross-coupling reactions required 5 to 20 mole % of nickel catalyst. Neil K. Garg of the University of California, Los Angeles, grad student Nicholas A. Weires, and colleague Daniel D. Caspi of AbbVie have now collaborated to develop a technique that reduces loading (mole percent of catalyst required) in nickel-catalyzed amide esterifications (ACS Catal. 2017, DOI: 10.1021/acscatal.7b01444). They used a kinetic-modeling program, DynoChem, to assess the effect of several variables—ligand-to-metal ratio, reactant stoichiometry, product and by-product generation rate, catalyst temperature-equilibration time, catalyst loading, and reaction concentration—on the rate of benzamide-menthol esterification. They then used the data to develop a kinetic model for the reaction. Use of the model to optimize conditions reduced the 10 mole % nickel catalyst typically required in amide esterifications down to 2 mole %. And using it to tweak a specific benzamide-menthol esterification reduced the reaction’s nickel loading to as little as 0.4 mole %. The researchers hope the approach will help expand industrial use of nickel-catalyzed reactions and the use of kinetic modeling for reaction optimization.