Hydrogen Atom Transfer from 1,<i>n</i>‑Alkanediamines to the Cumyloxyl Radical. Modulating C–H Deactivation Through Acid–Base Interactions and Solvent Effects

A time-resolved kinetic study on the effect of trifluoroacetic acid (TFA) on the hydrogen atom transfer (HAT) reactions from 1,<i>n</i>-alkanediamines (R₂N­(CH₂)_<i>n</i>NR₂, R = H, CH₃; <i>n</i> = 1–4), piperazine, and 1,4-dimethylpiperazine to the cumyloxyl radical (CumO^•), has been carried out in MeCN and DMSO. Very strong deactivation of the α-C–H bonds has been observed following nitrogen protonation and the results obtained have been explained in terms of substrate basicity, of the distance between the two basic centers and of the solvent hydrogen bond acceptor ability. At [substrate] ≤ 1/2 [TFA] the substrates exist in the doubly protonated form HR₂N⁺(CH₂)_<i>n</i>N⁺R₂H, and no reaction with CumO^• is observed. At 1/2 [TFA] < [substrate] ≤ [TFA], HAT occurs from the C–H bonds that are α to the nonprotonated nitrogen in R₂N­(CH₂)_<i>n</i>N⁺R₂H. At [substrate] > [TFA], HAT occurs from the α-C–H bonds of R₂N­(CH₂)_<i>n</i>NR₂, and the mesured <i>k</i>_H values are very close to those obtained in the absence of TFA. Comparison between MeCN and DMSO clearly shows that in the monoprotonated diamines R₂N­(CH₂)_<i>n</i>N⁺R₂H remote C–H deactivation can be modulated through solvent hydrogen bonding

Fine Control over Site and Substrate Selectivity in Hydrogen Atom Transfer-Based Functionalization of Aliphatic C–H Bonds

The selective functionalization of unactivated aliphatic C–H bonds over intrinsically more reactive ones represents an ongoing challenge of synthetic chemistry. Here we show that in hydrogen atom transfer (HAT) from the aliphatic C–H bonds of alkane, ether, alcohol, amide, and amine substrates to the cumyloxyl radical (CumO^•) fine control over site and substrate selectivity is achieved by means of acid–base interactions. Protonation of the amines and metal ion binding to amines and amides strongly deactivates the C–H bonds of these substrates toward HAT to CumO^•, providing a powerful method for selective functionalization of unactivated or intrinsically less reactive C–H bonds. With 5-amino-1-pentanol, site-selectivity has been drastically changed through protonation of the strongly activating NH₂ group, with HAT that shifts to the C–H bonds that are adjacent to the OH group. In the intermolecular selectivity studies, trifluoroacetic acid, Mg­(ClO₄)₂, and LiClO₄ have been employed in a orthogonal fashion for selective functionalization of alkane, ether, alcohol, and amide (or amine) substrates in the presence of an amine (or amide) one. Ca­(ClO₄)₂, that promotes deactivation of amines and amides by Ca²⁺ binding, offers, moreover, the opportunity to selectively functionalize the C–H bonds of alkane, ether, and alcohol substrates in the presence of both amines and amides

Kinetic Solvent Effects on the Reactions of the Cumyloxyl Radical with Tertiary Amides. Control over the Hydrogen Atom Transfer Reactivity and Selectivity through Solvent Polarity and Hydrogen Bonding

A laser flash photolysis study on the role of solvent effects on hydrogen atom transfer (HAT) from the C–H bonds of <i>N</i>,<i>N</i>-dimethylformamide (DMF), <i>N</i>,<i>N</i>-dimethylacetamide (DMA), <i>N</i>-formylpyrrolidine (FPRD), and <i>N</i>-acetylpyrrolidine (APRD) to the cumyloxyl radical (CumO^•) was carried out. From large to very large increases in the HAT rate constant (<i>k</i>_H) were measured on going from MeOH and TFE to isooctane (<i>k</i>_H(isooctane)/<i>k</i>_H(MeOH) = 5–12; <i>k</i>_H(isooctane)/<i>k</i>_H(TFE) > 80). This behavior was explained in terms of the increase in the extent of charge separation in the amides determined by polar solvents through solvent–amide dipole–dipole interactions and hydrogen bonding, where the latter interactions appear to play a major role with strong HBD solvents such as TFE. These interactions increase the electron deficiency of the amide C–H bonds, deactivating these bonds toward HAT to an electrophilic radical such as CumO^•, indicating that changes in solvent polarity and hydrogen bonding can provide a convenient method for deactivation of the C–H bond of amides toward HAT. With DMF, a solvent-induced change in HAT selectivity was observed, suggesting that solvent effects can be successfully employed to control the reaction selectivity in HAT-based procedures for the functionalization of C–H bonds

Hydrogen Abstraction from Cyclic Amines by the Cumyloxyl and Benzyloxyl Radicals. The Role of Stereoelectronic Effects and of Substrate/Radical Hydrogen Bonding

A kinetic study on the hydrogen abstraction reactions from cyclic amines and diamines (pyrrolidines, piperidines, morpholines, and piperazines) by the cumyloxyl (CumO^•) and benzyloxyl (BnO^•) radicals was carried out. The reactions with CumO^• were described in all cases as <i>direct</i> hydrogen abstractions. The differences in the hydrogen abstraction rate constant (<i>k</i>_H) were explained in terms of the different number of abstractable hydrogen atoms, the operation of stereoelectronic effects, and, with the morpholines, on the basis of polar effects. Significantly higher <i>k</i>_H values were measured for the reactions of the amines with BnO^•. This behavior was explained on the basis of a mechanism that proceeds through the rate-determining formation of a hydrogen bonded pre-reaction complex between the radical α-C–H and the nitrogen lone pair followed by hydrogen abstraction within the complex. A decrease in <i>k</i>_H was observed going from secondary to tertiary amines and, with tertiary amines, on increasing steric hindrance at nitrogen, pointing toward the important role of steric and electronic effects on pre-reaction complex formation. These results expand previous findings contributing to a detailed mechanistic description of the reactions of alkoxyl radicals with amines, showing that structural effects in both the substrate and the radical can play a dramatic role and providing new information on the role of substrate/radical interactions on these processes

Reactions of the Cumyloxyl and Benzyloxyl Radicals with Strong Hydrogen Bond Acceptors. Large Enhancements in Hydrogen Abstraction Reactivity Determined by Substrate/Radical Hydrogen Bonding

A kinetic study on hydrogen abstraction from strong hydrogen bond acceptors such as DMSO, HMPA, and tributylphosphine oxide (TBPO) by the cumyloxyl (CumO^•) and benzyloxyl (BnO^•) radicals was carried out in acetonitrile. The reactions with CumO^• were described in terms of a direct hydrogen abstraction mechanism, in line with the kinetic deuterium isotope effects, <i>k</i>_H/<i>k</i>_D, of 2.0 and 3.1 measured for reaction of this radical with DMSO/DMSO-<i>d</i>₆ and HMPA/HMPA-<i>d</i>₁₈. Very large increases in reactivity were observed on going from CumO^• to BnO^•, as evidenced by <i>k</i>_H(BnO^•)/<i>k</i>_H(CumO^•) ratios of 86, 4.8 × 10³, and 1.6 × 10⁴ for the reactions with HMPA, TBPO, and DMSO, respectively. The <i>k</i>_H/<i>k</i>_D of 0.91 and 1.0 measured for the reactions of BnO^• with DMSO/DMSO-<i>d</i>₆ and HMPA/HMPA-<i>d</i>₁₈, together with the <i>k</i>_H(BnO^•)/<i>k</i>_H(CumO^•) ratios, were explained on the basis of the formation of a hydrogen-bonded prereaction complex between the benzyloxyl α-C–H and the oxygen atom of the substrates followed by hydrogen abstraction. This is supported by theoretical calculations that show the formation of relatively strong prereaction complexes. These observations confirm that in alkoxyl radical reactions specific hydrogen bond interactions can dramatically influence the hydrogen abstraction reactivity, pointing toward the important role played by structural and electronic effects

Reactions of the Cumyloxyl and Benzyloxyl Radicals with Tertiary Amides. Hydrogen Abstraction Selectivity and the Role of Specific Substrate-Radical Hydrogen Bonding

A time-resolved kinetic study in acetonitrile and a theoretical investigation of hydrogen abstraction reactions from <i>N</i>,<i>N</i>-dimethylformamide (DMF) and <i>N</i>,<i>N</i>-dimethylacetamide (DMA) by the cumyloxyl (CumO^•) and benzyloxyl (BnO^•) radicals was carried out. CumO^• reacts with both substrates by <i>direct</i> hydrogen abstraction. With DMF, abstraction occurs from the formyl and <i>N</i>-methyl C–H bonds, with the formyl being the preferred abstraction site, as indicated by the measured <i>k</i>_H/<i>k</i>_D ratios and by theory. With DMA, abstraction preferentially occurs from the <i>N</i>-methyl groups, whereas abstraction from the acetyl group represents a minor pathway, in line with the computed C–H BDEs and the <i>k</i>_H/<i>k</i>_D ratios. The reactions of BnO^• with both substrates were best described by the rate-limiting formation of hydrogen-bonded prereaction complexes between the BnO^• α-C–H and the amide oxygen, followed by intramolecular hydrogen abstraction. This mechanism is consistent with the very large increases in reactivity measured on going from CumO^• to BnO^• and with the observation of <i>k</i>_H/<i>k</i>_D ratios close to unity in the reactions of BnO^•. Our modeling supports the different mechanisms proposed for the reactions of CumO^• and BnO^• and the importance of specific substrate/radical hydrogen bond interactions, moreover providing information on the hydrogen abstraction selectivity

Binding to Redox-Inactive Alkali and Alkaline Earth Metal Ions Strongly Deactivates the C–H Bonds of Tertiary Amides toward Hydrogen Atom Transfer to Reactive Oxygen Centered Radicals

The effect of alkali and alkaline earth metal ions on the reactions of the cumyloxyl radical (CumO^•) with <i>N</i>,<i>N</i>-dimethylformamide (DMF) and <i>N</i>,<i>N</i>-dimethylacetamide (DMA) was studied by laser flash photolysis. In acetonitrile, a >2 order of magnitude decrease in the rate constant for hydrogen atom transfer (HAT) from the C–H bonds of these substrates (<i>k</i>_H) was measured after addition of Li⁺. This behavior was explained in terms of a strong interaction between Li⁺ and the oxygen atom of both DMF and DMA that increases the extent of positive charge on the amide, leading to C–H bond deactivation toward HAT to the electrophilic radical CumO^•. Similar effects were observed after addition of Ca²⁺, which was shown to strongly bind up to four equivalents of the amide substrates. With Mg²⁺, weak C–H deactivation was observed for the first two substrate equivalents followed by stronger deactivation for two additional equivalents. No C–H deactivation was observed in DMSO after addition of Li⁺ and Mg²⁺. These results point toward the important role played by metal ion Lewis acidity and solvent Lewis basicity, indicating that C–H deactivation can be modulated by varying the nature of the metal cation and solvent and allowing for careful control over the HAT reactivity of amide substrates

Effect of Metal Ions on the Reactions of the Cumyloxyl Radical with Hydrogen Atom Donors. Fine Control on Hydrogen Abstraction Reactivity Determined by Lewis Acid–Base Interactions

A time-resolved kinetic study on the effect of metal ions (M^<i>n</i>+) on hydrogen abstraction reactions from C–H donor substrates by the cumyloxyl radical (CumO^•) was carried out in acetonitrile. Metal salt addition was observed to increase the CumO^• β-scission rate constant in the order Li⁺ > Mg²⁺ > Na⁺. These effects were explained in terms of the stabilization of the β-scission transition state determined by Lewis acid–base interactions between M^<i>n</i>+ and the radical. When hydrogen abstraction from 1,4-cyclohexadiene was studied in the presence of LiClO₄ and Mg­(ClO₄)₂, a slight increase in rate constant (<i>k</i>_H) was observed indicating that interaction between M^<i>n</i>+ and CumO^• can also influence, although to a limited extent, the hydrogen abstraction reactivity of alkoxyl radicals. With Lewis basic C–H donors such as THF and tertiary amines, a decrease in <i>k</i>_H with increasing Lewis acidity of M^<i>n</i>+ was observed (<i>k</i>_H(MeCN) > <i>k</i>_H(Li⁺) > <i>k</i>_H(Mg²⁺)). This behavior was explained in terms of the stronger Lewis acid–base interaction of M^<i>n</i>+ with the substrate as compared to the radical. This interaction reduces the degree of overlap between the α-C–H σ* orbital and a heteroatom lone-pair, increasing the C–H BDE and destabilizing the carbon centered radical formed after abstraction. With tertiary amines, a >2-order of magnitude decrease in <i>k</i>_H was measured after Mg­(ClO₄)₂ addition up to a 1.5:1 amine/Mg­(ClO₄)₂ ratio. At higher amine concentrations, very similar <i>k</i>_H values were measured with and without Mg­(ClO₄)₂. These results clearly show that with strong Lewis basic substrates variations in the nature and concentration of M^<i>n</i>+ can dramatically influence <i>k</i>_H, allowing for a fine control of the substrate hydrogen atom donor ability, thus providing a convenient method for C–H deactivation. The implications and generality of these findings are discussed

Tuning Selectivity in Aliphatic C–H Bond Oxidation of <i>N</i>‑Alkylamides and Phthalimides Catalyzed by Manganese Complexes

Site selective C–H oxidation of <i>N</i>-alkylamides and phthalimides with aqueous hydrogen peroxide catalyzed by manganese complexes is described. These catalysts are shown to exhibit substantially improved performance in product yields and substrate scope in comparison with their iron counterparts. The nature of the amide and imide group and of the <i>N</i>-alkyl moiety are shown to be effective tools in order to finely tune site selectivity between proximal (adjacent to the nitrogen) and remote C–H bonds on the basis of steric, electronic, and stereoelectronic effects. Moreover, formation of the α-hydroxyalkyl product in good yield and with excellent product chemoselectivity was observed in the reactions of the pivalamide and acetamide derivatives bearing an α-CH₂ group, pointing again toward an important role played by stereoelectronic effects and supporting the hypothesis that these oxidations proceed via hydrogen atom transfer (HAT) to a high-valent manganese–oxo species. Good product yields and mass balances are obtained in short reaction times and under mild experimental conditions when relatively low loadings of an electron-rich manganese catalyst are used. The potential utility of these reactions for preparative purposes is highlighted in the site-selective oxidation of the pivalamide and phthalimide derivatives of substrates of pharmaceutical interest

Electronic and Torsional Effects on Hydrogen Atom Transfer from Aliphatic C–H Bonds: A Kinetic Evaluation via Reaction with the Cumyloxyl Radical

A kinetic study on the hydrogen atom transfer (HAT) reactions from the aliphatic C–H bonds of a series of 1-Z-pentyl, 1-Z-propyl, and Z-cyclohexyl derivatives and of a series of <i>N</i>-alkylamides and <i>N</i>-alkylphthalimides to the electrophilic cumyloxyl radical (CumO^•) has been carried out. With 1-pentyl and 1-propyl derivatives, α-CH₂ activation toward CumO^• is observed for Z = Ph, OH, NH₂, and NHAc, as evidenced by an increase in <i>k</i>_H as compared to the unsubstituted alkane substrate. A decrease in <i>k</i>_H has been instead measured for Z = OAc, NPhth, CO₂Me, Cl, Br, and CN, indicative of α-CH₂ deactivation with HAT that predominantly occurs from the most remote methylenic site. With cyclohexyl derivatives, α-CH activation is only observed for Z = OH and NH₂, indicative of torsional effects as an important contributor in governing the functionalization selectivity of monosubstituted cyclohexanes. In the reactions of <i>N</i>-alkylamides and <i>N</i>-alkylphthalimides with CumO^•, the reactivity and selectivity patterns parallel those observed in the oxidation of the same substrates with H₂O₂ catalyzed by manganese complexes, supporting the hypothesis that both reactions proceed through a common HAT mechanism. The implications of these findings and the potential of electronic, stereoelectronic, and torsional effects as tools to implement selectivity in C–H oxidation reactions are briefly discussed