Theoretical and Computational Investigation of Novel N-Heterocyclic Carbene Transition Metal Catalysts for Suzuki-Miyaura Cross-Coupling Reactions Relevant to API Synthesis

The Suzuki-Miyaura cross-coupling reaction is among the most widely applied transformations in pharmaceutical synthesis, and the development of improved, more robust, and more selective transition metal catalysts bearing N-heterocyclic carbene ligands represents an active frontier in catalysis research with direct relevance to the local manufacture of active pharmaceutical ingredients in Nigeria. This study conducted a theoretical and computational investigation of novel N-heterocyclic carbene palladium and nickel complexes as catalysts for Suzuki-Miyaura cross-coupling, employing quantum chemical methods to predict catalytic activity and selectivity and guide the synthesis of promising candidates. Density functional theory calculations at the PBE0-D3BJ/def2-TZVP level were used to map the complete catalytic cycle for a library of sixty hypothetical N-heterocyclic carbene-metal complexes, including oxidative addition, transmetallation, and reductive elimination steps. Electronic and steric descriptors of the N-heterocyclic carbene ligands were correlated with computed activation energy barriers to develop a linear scaling relationship enabling rapid catalyst screening. Twelve catalyst candidates with predicted activation barriers at least 15 percent lower than the commercial benchmark catalyst were selected for synthesis. All catalysts were prepared by established N-heterocyclic carbene synthesis methods and fully characterised. Catalytic performance was evaluated for coupling of aryl halides with boronic acids under mild conditions. Computational predictions of relative activity were validated experimentally with 88 percent rank-order agreement. Four novel nickel complexes bearing unsymmetrical N-heterocyclic carbene ligands showed activity comparable to their palladium analogues at one-tenth the cost, an important advantage for API synthesis in resource-limited settings. This work provides an original computational-experimental template for catalyst design.

Keywords: N-heterocyclic carbene, Suzuki-Miyaura coupling, palladium catalysis, density functional theory, active pharmaceutical ingredients