Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms

01 April 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Two limiting mechanisms are possible for oxidative addition of (hetero)aryl (pseudo)halides at Pd(0): a 3-centered concerted and a nucleophilic displacement mechanism. Until now, there has been little understanding about when each mechanism is relevant. Prior investigations to distinguish between these pathways were limited to a few specific combinations of substrate and ligand. Here, we computationally evaluated over 150 transition structures for oxidative addition in order to determine mechanistic trends based on substrate, ligand(s), and coordination number. Natural abundance 13C kinetic isotope effects provide experimental results consistent with computational predictions. Key findings include that (1) differences in HOMO symmetries dictate that, although 12e– PdL is strongly biased toward a 3-centered concerted mechanism, 14e– PdL2 often prefers a nucleophilic displacement mechanism; (2) ligand electronics and sterics, including ligand bite angle, influence the preferred mechanism of reaction at PdL2; (3) phenyl triflate always reacts through a displacement mechanism regardless of catalyst structure due to the stability of a triflate anion and the inability of oxygen to effectively donate electron density to Pd; and (4) the high reactivity of C—X bonds adjacent to nitrogen in pyridine substrates relates to stereoelectronic stabilization of a nucleophilic displacement transition state. This work has implications for controlling rate and selectivity in catalytic couplings, and we demonstrate application of the mechanistic insight toward chemodivergent cross-couplings of bromochloroheteroarenes.

Keywords

cross-coupling
site-selectivity
chemoselectivity
molecular modeling
kinetic isotope effect

Supplementary materials

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Supporting Information
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Experimental and computational details, NMR spectra, and calculated energies
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Cartesian Coordinates
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Cartesian coordinates of minimum-energy calculated structures
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Figure1C
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Animated version of Figure 1C
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