The frequently overlooked importance of solvent in free radical syntheses

Litwinienko, Grzegorz; Beckwith, A. L. J.; Ingold, K. U.

doi:10.1039/c1cs15007c

Cited by 81 publications

(64 citation statements)

References 52 publications

(98 reference statements)

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“…Minisci observed that the ratio of C2:C4 substitution of protonated pyridines showed a distinct solvent effect, 11, 30 and it is known that many other radical reactions exhibit large solvent effects. 31 Calculations have also shown that the nucleophilicity and chemical hardness of a radical can vary depending on solvent, either of which could impact the balance between innate and conjugate reactivity. 32 …”

Section: Resultsmentioning

confidence: 99%

Radical-Based Regioselective C–H Functionalization of Electron-Deficient Heteroarenes: Scope, Tunability, and Predictability

2013

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Radical addition processes can be ideally suited for the direct functionalization of heteroaromatic bases, yet these processes are only sparsely used due to the perception of poor or unreliable control of regiochemistry. A systematic investigation of factors affecting the regiochemistry of radical functionalization of heterocycles using alkylsulfinate salts revealed that certain types of substituents exert consistent and additive effects on the regioselectivity of substitution. This allowed us to establish guidelines for predicting regioselectivity on complex π-deficient heteroarenes, including pyridines, pyrimidines, pyridazines and pyrazines. Since the relative contribution from opposing directing factors was dependent on solvent and pH, it was sometimes possible to tune the regiochemistry to a desired result by modifying reaction conditions. This methodology was applied to the direct, regioselective introduction of isopropyl groups into complex, biologically active molecules, such as diflufenican (44) and nevirapine (45).

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Section: Resultsmentioning

confidence: 99%

Radical-Based Regioselective C–H Functionalization of Electron-Deficient Heteroarenes: Scope, Tunability, and Predictability

2013

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“…This may, for example, include the water‐mediated isomerization of the benzyloxyl radical ( 4 ) to the hydroxybenzyl radical through a formal 1,2‐hydrogen shift (not shown) . The relevance of this pathway will, among other things, depend on the polarity of the surrounding solvent and its ability to engage in hydrogen‐bonding interactions with the radical 4 . For the sake of completeness, it should also be mentioned that the toluene shown in Figure as an active reaction partner can potentially also “solvate” the hydroperoxide 3 while it undergoes O−O bond homolysis and then react with the generated HO .…”

Section: Resultsmentioning

confidence: 99%

Radical‐Pair Formation in Hydrocarbon (Aut)Oxidation

Sandhiya

Zipse

2019

Chemistry A European J

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The reaction profiles for the uni‐ and bimolecular decomposition of benzyl hydroperoxide have been studied in the context of initiation reactions for the (aut)oxidation of hydrocarbons. The unimolecular dissociation of benzyl hydroperoxide was found to proceed through the formation of a hydrogen‐bonded radical‐pair minimum located +181 kJ mol−1 above the hydroperoxide substrate and around 15 kJ mol−1 below the separated radical products. The reaction of toluene with benzyl hydroperoxide proceeds such that O−O bond homolysis is coupled with a C−H bond abstraction event in a single kinetic step. The enthalpic barrier of this molecule‐induced radical formation (MIRF) process is significantly lower than that of the unimolecular O−O bond cleavage. The same type of reaction is also possible in the self‐reaction between two benzyl hydroperoxide molecules forming benzyloxyl and hydroxyl radical pairs along with benzaldehyde and water as co‐products. In the product complexes formed in these MIRF reactions, both radicals connect to a centrally placed water molecule through hydrogen‐bonding interactions.

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“…A detailed knowledge of these effects is needed to understand radical-mediated oxidation in biological systems and to optimize the yield of radical synthesis [70]. The examples reported clearly show that non-covalent interactions play a major role in directing the reactivity of alkoxyl radicals with specific functional groups.…”

Section: Intermolecular Non-covalent Interactions Of the Substrate Wimentioning

confidence: 99%