Noncovalent Stabilization of Radical Intermediates in the Enantioselective Hydroamination of Alkenes with Sulfonamides

Noncovalent
interactions (NCIs) are critical elements
of molecular
recognition in a wide variety of chemical contexts. While NCIs have
been studied extensively for closed-shell molecules and ions, very
little is understood about the structures and properties of NCIs involving
free radical intermediates. In this report, we describe a detailed
mechanistic study of the enantioselective radical hydroamination of
alkenes with sulfonamides and present evidence suggesting that the
basis for asymmetric induction in this process arises from attractive
NCIs between a neutral sulfonamidyl radical intermediate and a chiral
phosphoric acid (CPA). We describe experimental, computational, and
data science-based evidence that identifies the specific radical NCIs
that form the basis for the enantioselectivity. Kinetic studies support
that C–N bond formation determines the enantioselectivity.
Density functional theory investigations revealed the importance of
both strong H-bonding between the CPA and the N-centered
radical and a network of aryl-based NCIs that serve to stabilize the
favored diastereomeric transition state. The contributions of these
specific aryl-based NCIs to the selectivity were further confirmed
through multivariate linear regression analysis by comparing the measured
enantioselectivity to computed descriptors. These results highlight
the power of NCIs to enable high levels of enantioselectivity in reactions
involving uncharged open-shell intermediates and expand our understanding
of radical–molecule interactions.