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

Abstract

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.

Radical Hydrocarboxylation of Unactivated Alkenes via Photocatalytic Formate Activation

“…51−53 Indeed, a similar yield of the hydrocarboxylation product was observed from an analogous deschloro alkene substrate (9). The reaction tolerates diverse protic functional groups, including ureas (10), unprotected alcohols (11,12), carboxylic acids (13), carbamates (13), and amides (4, 7). Of particular note, an α-amino acid derivative was found to be compatible under the reaction conditions and could be transformed into the linear diacid product in high yield (13).…”

“…Of particular note, an α-amino acid derivative was found to be compatible under the reaction conditions and could be transformed into the linear diacid product in high yield (13). Substrates bearing a variety of pendant heterocycles, including oxetanes (12), γ-lactones (14), piperidines (15,16), pyrans (17), and imidazoles (18), each underwent the desired transformation. Hydrocarboxylation proceeds smoothly across a series of sterically hindered substrates (11,12,(14)(15)(16)(17)19), which included fully substituted carbon centers in both cyclic (12) and acyclic systems (19).…”

Molecular Understanding and Practical In Silico Catalyst Design in Computational Organocatalysis and Phase Transfer Catalysis—Challenges and Opportunities

“…Blue Dash line: key bonds in TS. Three-dimensional representations are generated from coordinates given in the cited references: Paton 2018 [ 29 ]; Houk and Xue 2019 [ 30 ]; Goodman 2020 [ 31 ]; Kee and Wong 2020 [ 32 ]; Richmond 2020 [ 33 ]; Wheeler 2020 [ 34 ]; Papai 2020 [ 35 ]; Wong and Yang 2021 [ 36 ]; Sunoj 2022 [ 28 ]; Bistoni 2022 [ 37 ]; Champagne 2022 [ 38 ]; Knowles and Sigman 2022 [ 39 ].…”

A Metastable Ketenyl Radical–Water Complex from UV Photolysis of the Carboxymethyl Radical

“…Moreover, radical–molecule interactions play an increasingly important role beyond atmospheric chemistry. The noncovalent interaction between an N-centered radical and a chiral phosphoric acid is central to the enantioselectivity in an intramolecular hydroamination reaction that was recently developed by Knowles’ group. , …”

“…The noncovalent interaction between an N-centered radical and a chiral phosphoric acid is central to the enantioselectivity in an intramolecular hydroamination reaction that was recently developed by Knowles' group. 33,34 In our work, we accidentally came across the formation of a noncovalent radical−water complex following our interest in the reactions of matrix isolated radicals, 35 where we aimed to produce the carboxymethyl radical 1 through flash vacuum pyrolysis of iodoacetic acid (2, Scheme 1). 36 The carboxymethyl radical is an interesting target by itself because it is assumed to play a role in the interstellar formation of the amino acid glycine 37 and has therefore been prepared by Y. P. Lee's lab in the reaction of hydrogen atoms with acetic acid in a para-H 2 matrix.…”