One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2CR2) across a carbon–carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.

A general catalytic methodology for 1,2-RF/Y-difunctionalization of conjugated alkenes is reported. Diverse functionalized carbon radicals (RF•), which are generated through copper­(I)-initiated selective halogen atom abstraction via a tert-butyl hydroperoxide-induced α-amino radical process, undergo regiocontrolled addition to carbon–carbon double bonds. The newly formed carbon radicals combine with Y = CN, N3, or NCS from TMSY in a copper­(I)-promoted process to form a broad spectrum of α-cyano-, α-azido-, and α-thiocyano-β-substituted products with additional functionalities in RF in high yields. Conversion of the reaction products to functionalized cyclopropane, amide, amine, triazole, thiol, and tetrazole highlights the potential utility of this method.

Oxidative cleavage reactions of arylalkenes by tert-butyl hydroperoxide that occur by free radical processes provide access to carboxylic acid or ketone products. However, the pathway to these cleavage products is complex, initiated by regioselective oxygen radical addition to the carbon–carbon double bond. Subsequent reactions of the initially formed benzyl radical lead eventually to carbon–carbon cleavage. Thorough investigations of these reactions have identified numerous reaction intermediates that are on the pathways to final product formation, and they have identified a new synthetic methodology for the synthesis of peroxy radical addition-induced hydroperoxide formation.

Heteroaromatic stacking interactions are important in drug binding, supramolecular chemistry, and materials science, making protein–ligand model systems of these interactions of considerable interest. Here we studied 30 congeneric ligands that each present a distinct heteroarene for stacking between tyrosine residues at the dimer interface of procaspase-6. Complex X-ray crystal structures of 10 analogs showed that stacking geometries were well conserved, while high-accuracy computations showed that heteroarene stacking energy was well correlated with predicted overall ligand binding energies. Empirically determined K D values in this system thus provide a useful measure of heteroarene stacking with tyrosine. Stacking energies are discussed in the context of torsional strain, the number and positioning of heteroatoms, tautomeric state, and coaxial orientation of heteroarene in the stack. Overall, this study provides an extensive data set of empirical and high-level computed binding energies in a versatile new protein–ligand system amenable to studies of other intermolecular interactions.

Heteroaromatic stacking interactions help stabilize protein tertiary structure and are important in drug binding, supramolecu-lar chemistry, and materials science. Although diverse computational and experimental approaches have been utilized to study these interactions, a broadly useful protein–ligand model system has yet to emerge, despite laudable efforts by Diederich and co-workers in this vein. Here we studied thirty synthetic ligands that present diverse heteroarene probes for stacking between symmetry-related tyrosine residues at the dimer interface of procaspase-6. We demonstrate crystallograph-ically that stacking geometries are highly conserved across the ligand test set and show with high-accuracy computations that differences in ligand binding free energies are primarily attributable to the relative strength of the stacking interactions. The empirical results are discussed in light of recent computational studies of these interactions, including the effects of torsional strain, heteroarene tautomeric state, and co-axial orientation of stacking groups. Overall, this study provides an extensive dataset of empirical and high-level computed binding energies in a versatile new protein–ligand system highly amenable to studies of other intermolecular interactions.