Organometallic Chemistry

A general reactivity map for predicting outcomes in palladium-catalyzed cross-coupling

Authors

Abstract

Making accurate, quantitative predictions of chemical reactivity based on molecular structure is an unsolved problem in chemical synthesis, particularly for complex molecules. We report a generally applicable and mechanistically based structure-reactivity model for the oxidative addition of (hetero)aryl halides to palladium(0), which is a key step in myriad catalytic processes. This model links simple molecular descriptors – electrostatic potential, steric parameters, and bond strengths – to relative rates of oxidative addition for 71 electrophile substrates. Because oxidative addition often controls the rate and/or selectivity of palladium-catalyzed cross-coupling reactions, this model can be used to make predictions about catalytic reaction outcomes. Demonstrated applications include a quantitative model for the rate of 410 different Sonogashira coupling reactions, and successful site-selectivity predictions for a series of multihalogenated substrates relevant to the synthesis of pharmaceuticals and natural products.

Content

Thumbnail image of Lu-Donnecke-Paci-Leitch-Pd-Reactivity-Map.pdf

Supplementary material

Thumbnail image of Lu-Donnecke-Paci-Leitch-Pd-Reactivity-Map-SI.pdf
A general reactivity map for predicting outcomes in palladium-catalyzed cross-coupling (supporting information)
Supporting information including materials, experimental and computational methods, data, and additional description of analyses and/or experiments that are referred to in the main text.
Thumbnail image of Lu-Donnecke-Paci-Leitch-Pd-Reactivity-Map-Data-Tables.xlsx
A general reactivity map for predicting outcomes in palladium-catalyzed cross-coupling (data tables)
Expanded data tables containing all information used to build regression models, including experimental data and molecular descriptors.
Thumbnail image of Lu-Donnecke-Paci-Leitch-Pd-Reactivity-Map-xyz-Files.zip
A general reactivity map for predicting outcomes in palladium-catalyzed cross-coupling (xyz files)
Zip folder containing all xyz coordinate files for calculated structures, including: 71 oxidative addition substrates; 11 Pd pi-complex intermediates; 6 oxidative addition transition states and the corresponding cis and trans products; 29 Sonogashira substrates; 17 phosphine ligands and their corresponding PdL and PdL2 complexes; and 28 site-selectivity substrates.