We present here a
review of the photochemical and electrochemical
applications of multi-site proton-coupled electron transfer (MS-PCET)
in organic synthesis. MS-PCETs are redox mechanisms in which both
an electron and a proton are exchanged together, often in a concerted
elementary step. As such, MS-PCET can function as a non-classical
mechanism for homolytic bond activation, providing opportunities to
generate synthetically useful free radical intermediates directly
from a wide variety of common organic functional groups. We present
an introduction to MS-PCET and a practitioner’s guide to reaction
design, with an emphasis on the unique energetic and selectivity features
that are characteristic of this reaction class. We then present chapters
on oxidative N–H, O–H, S–H, and C–H bond
homolysis methods, for the generation of the corresponding neutral
radical species. Then, chapters for reductive PCET activations involving
carbonyl, imine, other X=Y π-systems, and heteroarenes,
where neutral ketyl, α-amino, and heteroarene-derived radicals
can be generated. Finally, we present chapters on the applications
of MS-PCET in asymmetric catalysis and in materials and device applications.
Within each chapter, we subdivide by the functional group undergoing
homolysis, and thereafter by the type of transformation being promoted.
Methods published prior to the end of December 2020 are presented.
We
report a new class of catalytic reaction: the thermal substitution
of a secondary and or tertiary alkyl halide with a nitrogen nucleophile.
The alkylation of a nitrogen nucleophile with an alkyl halide is a
classical method for the construction of C–N bonds, but traditional
substitution reactions are challenging to achieve with a secondary
and or tertiary alkyl electrophile due to competing elimination reactions.
A catalytic process could address this limitation, but thermal, catalytic
coupling of alkyl halides with a nitrogen nucleophile and any type
of catalytic coupling of an unactivated tertiary alkyl halide with
a nitrogen nucleophile are unknown. We report the coupling of unactivated
secondary and tertiary alkyl bromides with benzophenone imines to
produce protected primary amines in the presence of palladium ligated
by the hindered trialkylphosphine Cy2t-BuP. Mechanistic studies indicate that this amination of alkyl halides
occurs by a reversible reaction to form a free alkyl radical.
An enantioselective, radical-based method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are proposed to proceed via N-centered radicals formed by proton-coupled electron transfer (PCET) activation of sulfonamide N-H bonds. Non-covalent interactions between the neutral sulfonamidyl radical and a chiral phosphoric acid generated in the PCET event are hypothesized to serve as the basis for asymmetric induction in a subsequent C-N bond forming step, achieving selectivities of up to 98:2 er. These results offer further support for the ability of non-covalent interactions to enforce stereoselectivity in reactions of transient and highly reactive open-shell intermediates. File list (2) download file view on ChemRxiv SUBMIT.pdf (594.12 KiB) download file view on ChemRxiv SI FINAL.pdf (17.32 MiB)
<div><p>An enantioselective, radical-based method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are proposed to proceed <i>via</i> <i>N</i>-centered radicals formed by proton-coupled electron transfer (PCET) activation of sulfonamide N–H bonds. Non-covalent interactions between the neutral sulfonamidyl radical and a chiral phosphoric acid generated in the PCET event are hypothesized to serve as the basis for asymmetric induction in a subsequent C–N bond forming step, achieving selectivities of up to 98:2 er. These results offer further support for the ability of non-covalent interactions to enforce stereoselectivity in reactions of transient and highly reactive open-shell intermediates.</p></div>
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.
<div><p>An enantioselective, radical-based method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are proposed to proceed <i>via</i> <i>N</i>-centered radicals formed by proton-coupled electron transfer (PCET) activation of sulfonamide N–H bonds. Non-covalent interactions between the neutral sulfonamidyl radical and a chiral phosphoric acid generated in the PCET event are hypothesized to serve as the basis for asymmetric induction in a subsequent C–N bond forming step, achieving selectivities of up to 98:2 er. These results offer further support for the ability of non-covalent interactions to enforce stereoselectivity in reactions of transient and highly reactive open-shell intermediates.</p></div>
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