The interplay of polar effects in controlling the selectivity of radical reactions

Ruffoni, Alessandro; Mykura, Rory C.; Bietti, Massimo; Leonori, Daniele

doi:10.1038/s44160-022-00108-2

Cited by 84 publications

(46 citation statements)

References 133 publications

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“…Of note, apart from previous mechanistic studies, the activity of a XAT-based manifold under the reported reaction conditions is unlikely due to the highly reducing nature of the PCs and to the presence of a stoichiometric amount of acid. To confirm this finding, we selected a second photoreaction to evaluate the PCs under the ET reaction manifold, namely the photoreduction of trifluoromethylarenes (Figure b), employing 1,3-bistrifluoromethylbenzene 9 ( E red = −2.07 V vs SCE) as a model substrate with olefin 10 (for the reported mechanism see Section G of SI).…”

Section: Resultsmentioning

confidence: 64%

“…These types of photoreactions require an extremely reducing PC excited state. In fact, they classically proceed either under strong UV-light irradiation, or by relying on the photoexcitation of specific radical anions . While in previous reports, PTH 1 was used under UV-light irradiation (<380 nm), we compared the reaction performance of the designed PCs under visible light (427 nm) using both kinetics and final yields (see Section G of the SI, and Figure ).…”

Section: Resultsmentioning

confidence: 99%

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The Rational Design of Reducing Organophotoredox Catalysts Unlocks Proton-Coupled Electron-Transfer and Atom Transfer Radical Polymerization Mechanisms

et al. 2023

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Photocatalysis has become a prominent tool in the arsenal of organic chemists to develop and (re)imagine transformations. However, only a handful of versatile organic photocatalysts (PCs) are available, hampering the discovery of new reactivities. Here, we report the design and complete physicochemical characterization of 9-aryl dihydroacridines (9ADA) and 12-aryl dihydrobenzoacridines (12ADBA) as strong reducing organic PCs. Punctual structural variations modulate their molecular orbital distributions and unlock locally or charge-transfer (CT) excited states. The PCs presenting a locally excited state showed better performances in photoredox defunctionalization processes (yields up to 92%), whereas the PCs featuring a CT excited state produced promising results in atom transfer radical polymerization under visible light (up to 1.21 Đ, and 98% I*). Unlike all the PC classes reported so far, 9ADA and 12ADBA feature a free NH group that enables a catalytic multisite proton-coupled electron transfer (MS-PCET) mechanism. This manifold allows the reduction of redox-inert substrates including aryl, alkyl halides, azides, phosphate and ammonium salts (E red up to −2.83 vs SCE) under single-photon excitation. We anticipate that these new PCs will open new mechanistic manifolds in the field of photocatalysis by allowing access to previously inaccessible radical intermediates under one-photon excitation.

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Section: Resultsmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

The Rational Design of Reducing Organophotoredox Catalysts Unlocks Proton-Coupled Electron-Transfer and Atom Transfer Radical Polymerization Mechanisms

et al. 2023

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“…Intriguingly, the bromine radical (Br·) relevant conditions 28 , 46 – 52 by using NiBr 2 ·DME as a nickel precatalyst (entry 2) or in the presence of an additional bromide (entry 5) led to unselective formation of both the α-amino and benzylic C−H acylation products in significantly lower yields. Chlorine-relevant conditions provided remarkably better reactivity and selectivity, likely benefiting from a thermodynamically facile (BDEs of H−Cl and H−Br: 103 kcal/mol vs 88 kcal/mol) and polarity-matched HAT process 40 . We attributed this regioselective difference to the better polarity matching of an α-amino C−H bond with Cl· than with Br· (local electrophilicity: 3.8 eV vs 3.6 eV) 44 .…”

Section: Resultsmentioning

confidence: 99%

“…To simultaneously achieve efficient site- and enantioselectivity in such a unified catalytic system, we have postulated three design elements to synergistically maximize the interplay of thermodynamic (enthalpic) and kinetic (polar) effects 40 : (i) the chlorine-radical-mediated HAT process should have a significant thermodynamic driving force due to the formation of a H−Cl bond (BDE: 103 kcal/mol) that is stronger than the most sp 3 C−H bonds (α-amino C−H bonds: BDE = 89−94 kcal/mol) 41 ; (ii) by taking advantage of polarity matching effect 42 , 43 , the strong electrophilic character of photoeliminated chlorine radicals (local electrophilicity of Cl·: 3.8 eV) should enable a kinetically selective HAT from the most hydridic C−H bonds in the presence of weaker C−H bonds that are less hydridic or polarity-mismatched 44 ; and (iii) the recognized ability of nickel catalysts to efficiently bind and stabilize alkyl radicals should render the cross-coupling of alkyl radicals with in situ-activated carboxylic acids enantioselective in the presence of an appropriate chiral ligand 45 .…”

Section: Introductionmentioning

confidence: 99%

Site- and enantioselective cross-coupling of saturated N-heterocycles with carboxylic acids by cooperative Ni/photoredox catalysis

et al. 2023

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Site- and enantioselective cross-coupling of saturated N-heterocycles and carboxylic acids—two of the most abundant and versatile functionalities—to form pharmaceutically relevant α-acylated amine derivatives remains a major challenge in organic synthesis. Here, we report a general strategy for the highly site- and enantioselective α-acylation of saturated N-heterocycles with in situ-activated carboxylic acids. This modular approach exploits the hydrogen-atom-transfer reactivity of photocatalytically generated chlorine radicals in combination with asymmetric nickel catalysis to selectively functionalize cyclic α-amino C−H bonds in the presence of benzylic, allylic, acyclic α-amino, and α-oxy methylene groups. The mild and scalable protocol requires no organometallic reagents, displays excellent chemo-, site- and enantioselectivity, and is amenable to late-stage diversification, including a modular synthesis of previously inaccessible Taxol derivatives. Mechanistic studies highlight the exceptional versatility of the chiral nickel catalyst in orchestrating (i) catalytic chlorine elimination, (ii) alkyl radical capture, (iii) cross-coupling, and (iv) asymmetric induction.

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“…Compared to types of organocatalysis (type I and type II in Scheme 1) reversible bonding and non-covalent interactions of redox-active molecules with a substrate are not very well studied and used. The selectivity in organocatalysis by redoxactive molecules is controlled mainly by bond energies, redoxpotentials, polar effects [157,158], and steric effects. Enantioselective transformations are relatively rare.…”

Section: Discussionmentioning

confidence: 99%

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

Lopat’eva¹,

Krylov²,

Lapshin³

et al. 2022

Beilstein J. Org. Chem.

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Organocatalysis is widely recognized as a key synthetic methodology in organic chemistry. It allows chemists to avoid the use of precious and (or) toxic metals by taking advantage of the catalytic activity of small and synthetically available molecules. Today, the term organocatalysis is mainly associated with redox-neutral asymmetric catalysis of C–C bond-forming processes, such as aldol reactions, Michael reactions, cycloaddition reactions, etc. Organophotoredox catalysis has emerged recently as another important catalysis type which has gained much attention and has been quite well-reviewed. At the same time, there are a significant number of other processes, especially oxidative, catalyzed by redox-active organic molecules in the ground state (without light excitation). Unfortunately, many of such processes are not associated in the literature with the organocatalysis field and thus many achievements are not fully consolidated and systematized. The present article is aimed at overviewing the current state-of-art and perspectives of oxidative organocatalysis by redox-active molecules with the emphasis on challenging chemo-, regio- and stereoselective CH-functionalization processes. The catalytic systems based on N-oxyl radicals, amines, thiols, oxaziridines, ketone/peroxide, quinones, and iodine(I/III) compounds are the most developed catalyst types which are covered here.

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The interplay of polar effects in controlling the selectivity of radical reactions

Cited by 84 publications

References 133 publications

The Rational Design of Reducing Organophotoredox Catalysts Unlocks Proton-Coupled Electron-Transfer and Atom Transfer Radical Polymerization Mechanisms

The Rational Design of Reducing Organophotoredox Catalysts Unlocks Proton-Coupled Electron-Transfer and Atom Transfer Radical Polymerization Mechanisms

Site- and enantioselective cross-coupling of saturated N-heterocycles with carboxylic acids by cooperative Ni/photoredox catalysis

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

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