Tuning Reactivity and Selectivity in Hydrogen Atom Transfer from Aliphatic C–H Bonds to Alkoxyl Radicals: Role of Structural and Medium Effects

Abstract

Hydrogen atom transfer (HAT) is a fundamental reaction that takes part in a wide variety of chemical and biological processes, with relevant examples that include the action of antioxidants, damage to biomolecules and polymers, and enzymatic and biomimetic reactions. Moreover, great attention is currently devoted to the selective functionalization of unactivated aliphatic C-H bonds, where HAT based procedures have been shown to play an important role. In this Account, we describe the results of our recent studies on the role of structural and medium effects on HAT from aliphatic C-H bonds to the cumyloxyl radical (CumO(•)). Quantitative information on the reactivity and selectivity patterns observed in these reactions has been obtained by time-resolved kinetic studies, providing a deeper understanding of the factors that govern HAT from carbon and leading to the definition of useful guidelines for the activation or deactivation of aliphatic C-H bonds toward HAT. In keeping with the electrophilic character of alkoxyl radicals, polar effects can play an important role in the reactions of CumO(•). Electron-rich C-H bonds are activated whereas those that are α to electron withdrawing groups are deactivated toward HAT, with these effects being able to override the thermodynamic preference for HAT from the weakest C-H bond. Stereoelectronic effects can also influence the reactivity of the C-H bonds of ethers, amines, and amides. HAT is most rapid when these bonds can be eclipsed with a lone pair on an adjacent heteroatom or with the π-system of an amide functionality, thus allowing for optimal orbital overlap. In HAT from cyclohexane derivatives, tertiary axial C-H bond deactivation and tertiary equatorial C-H bond activation have been observed. These effects have been explained on the basis of an increase in torsional strain or a release in 1,3-diaxial strain in the HAT transition states, with kH(eq)/kH(ax) ratios that have been shown to exceed one order of magnitude. Medium effects on HAT from aliphatic C-H bonds to CumO(•) have been also investigated. With basic substrates, from large to very large decreases in kH have been measured with increasing solvent hydrogen bond donor (HBD) ability or after addition of protic acids or alkali and alkaline earth metal ions, with kinetic effects that exceed 2 orders of magnitude in the reactions of tertiary alkylamines and alkanamides. Solvent hydrogen bonding, protonation, and metal ion binding increase the electron deficiency and the strength of the C-H bonds of these substrates deactivating these bonds toward HAT, with the extent of this deactivation being modulated by varying the nature of the substrate, solvent, protic acid, and metal ion. These results indicate that through these interactions careful control over the HAT reactivity of basic substrates toward CumO(•) and other electrophilic radicals can be achieved, suggesting moreover that these effects can be exploited in an orthogonal fashion for selective C-H bond functionalization of substrates bearing different basic...

Proton-Coupled Electron Transfer in Organic Synthesis: Fundamentals, Applications, and Opportunities

“…Selectivity in HAT processes is generally a function of bond strength differential, with the weakest bonds in the substrate being oxidized most rapidly [33]. In fact, such relationships are often presented as evidence for radical-based mechanisms of bond cleavage.…”

Activation and Deactivation Strategies Promoted by Medium Effects for Selective Aliphatic C−H Bond Functionalization

“…[1] Within this approach, CÀHbonds are regarded as functional groups,and points of potential diversification of al ead structure can be achieved without resorting to de novo synthesis,afeature that makes this strategy particularly useful when applied to drug molecules,natural products,a nd biomolecules. [3][4][5][6] These include bond strengths, electronic or polar effects,c onjugation, hyperconjugation, steric and stereoelectronic effects,torsional effects,aswell as medium effects. [3][4][5][6] These include bond strengths, electronic or polar effects,c onjugation, hyperconjugation, steric and stereoelectronic effects,torsional effects,aswell as medium effects.…”

“…[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ther eagents that are typically involved in these processes include heteroatomcentered radicals and radical ions,p hotoexcited species and photocatalysts (carbonyl compounds,polyoxometalates), biocatalysts (cytochrome P450 and oxygenases) and bioinspired catalysts,a swell as closed-shell species such as dioxiranes. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ther eagents that are typically involved in these processes include heteroatomcentered radicals and radical ions,p hotoexcited species and photocatalysts (carbonyl compounds,polyoxometalates), biocatalysts (cytochrome P450 and oxygenases) and bioinspired catalysts,a swell as closed-shell species such as dioxiranes.…”

Effect of Brønsted acids on the thiophenol-mediated radical addition–translocation–cyclization process for the preparation of pyrrolidine derivatives

“…Their mildness and functional group tolerance make them particularly attractive for the synthesis of highly functionalized compounds and their reactivity has permitted some unusual transformations. Among all radical reactions, the activation of aliphatic C-H bonds via hydrogen atom transfer (HAT) is a truly unique synthetic tool [3][4][5][6][7]. The preparation of five-membered ring via radical translocationcyclization (RTC) processes involving transient alkenyl radicals proved to be a particularly efficient process [8].…”

“…Interestingly, Bietti et al have recently demonstrated that the rate of hydrogen atom abstraction from the a-position of tertiary alkylamines by the cumyloxyl radical can be lowered by protonation of the amine (Scheme 3) [5,29]. The authors showed that the rate constant for hydrogen atom abstraction from the a-C-H bonds decreased drastically upon protonation of the nitrogen.…”