Highly Selective C(sp3)-H Bond Oxygenation at Remote Methylenic Sites Enabled by Polarity Enhancement.

A detailed study on the C(sp3)-H bond oxygenation reactions with H2O2 catalyzed by the [Mn(OTf)2(TIPSmcp)] complex at methylenic sites of cycloalkyl and 1-alkyl substrates bearing 19 different electron-withdrawing functional groups (EW FGs) was carried out. Oxidations in MeCN were compared to the corresponding ones in the strong hydrogen bond donating (HBD) solvents 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and nonafluoro tert-butyl alcohol (NFTBA). Formation of the products deriving from oxygenation at the most remote methylenic sites was observed, with yields, product ratios (PR) for oxygenation at the most remote over the next methylenic sites, and associated site-selectivities that significantly increased going from MeCN to HFIP and NFTBA. Unprecedented site-selectivities were obtained in the oxidation of cyclohexyl, cycloheptyl, cyclooctyl, 1-pentyl, 1-hexyl, and 1-heptyl substrates, approaching >99%, >99%, 90%, >99%, 93%, and 88% (PR >99, >99, 9.4, >99, 14, and 7.5) with cyclohexyl-2-pyridinecarboxylate, cycloheptyl-2-pyridinecarboxylate, cyclooctyl-4-nitrobenzenesulfonamide, 1-pentyl-3,5-dinitrobenzoate, 1-hexyl-3,5-dinitrobenzoate, and 1-heptyl-3,5-dinitrobenzoate, respectively. The results are rationalized on the basis of a polarity enhancement effect via synergistic electronic deactivation of proximal methylenic sites imparted by the EWG coupled to solvent HB. Compared to previous procedures, polarity enhancement provides the opportunity to tune site-selectivity among multiple methylenes in different substrate classes, extending the strong electronic deactivation determined by native EWGs by two carbon atoms. This study uncovers a simple procedure for predictable, high-yielding, and highly site-selective oxidation at remote methylenes of cycloalkyl and 1-alkyl substrates that occurs under mild conditions, with a large substrate scope, providing an extremely powerful tool to be implemented in synthetically useful procedures.

Radical and Cationic Pathways in C(sp3)-H Bond Oxygenation by Dioxiranes of Bicyclic and Spirocyclic Hydrocarbons Bearing Cyclopropane Moieties.

A product and DFT computational study on the reactions of 3-ethyl-3-(trifluoromethyl)dioxirane (ETFDO) with bicyclic and spirocyclic hydrocarbons bearing cyclopropyl groups was carried out. With bicyclo[n.1.0]alkanes (n = 3-6), diastereoselective formation of the alcohol product derived from C2-H bond hydroxylation was observed, accompanied by smaller amounts of products derived from oxygenation at other sites. With 1-methylbicyclo[4.1.0]heptane, rearranged products were also observed in addition to the unrearranged products deriving from oxygenation at the most activated C2-H and C5-H bonds. With spiro[2.5]octane and 6-tert-butylspiro[2.5]octane, reaction with ETFDO occurred predominantly or exclusively at the axial C4-H to give unrearranged oxygenation products, accompanied by smaller amounts of rearranged bicyclo[4.2.0]octan-1-ols. The good to outstanding site-selectivities and diastereoselectivities are paralleled by the calculated activation free energies for the corresponding reaction pathways. Computations show that the σ* orbitals of the bicyclo[n.1.0]alkane cis or trans C2-H bonds and spiro[2.5]octanes axial C4-H bond hyperconjugatively interact with the Walsh orbitals of the cyclopropane ring, activating these bonds toward HAT to ETFDO. The detection of rearranged oxygenation products in the oxidation of 1-methylbicyclo[4.1.0]heptane, spiro[2.5]octane, and 6-tert-butylspiro[2.5]octane provides unambiguous evidence for the involvement of cationic intermediates in these reactions, representing the first examples on the operation of ET pathways in dioxirane-mediated C(sp3)-H bond oxygenations. Computations support these findings, showing that formation of cationic intermediates is associated with specific stabilizing hyperconjugative interactions between the incipient carbon radical and the cyclopropane C-C bonding orbitals that trigger ET to the incipient dioxirane derived 1,1,1-trifluoro-2-hydroxy-2-butoxyl radical.

Electronic control over site-selectivity in hydrogen atom transfer (HAT) based C(sp3)-H functionalization promoted by electrophilic reagents.

The direct functionalization of C(sp3)-H bonds represents one of the most investigated approaches to develop new synthetic methodology. Among the available strategies for intermolecular C-H bond functionalization, increasing attention has been devoted to hydrogen atom transfer (HAT) based procedures promoted by radical or radical-like reagents, that offer the opportunity to introduce a large variety of atoms and groups in place of hydrogen under mild conditions. Because of the large number of aliphatic C-H bonds displayed by organic molecules, in these processes control over site-selectivity represents a crucial issue, and the associated factors have been discussed. In this review article, attention will be devoted to the role of electronic effects on C(sp3)-H bond functionalization site-selectivity. Through an analysis of the recent literature, a detailed description of the HAT reagents employed in these processes, the associated mechanistic features and the selectivity patterns observed in the functionalization of substrates of increasing structural complexity will be provided.

Resolving Oxygenation Pathways in Manganese-Catalyzed C(sp3)-H Functionalization via Radical and Cationic Intermediates.

The C(sp3)-H bond oxygenation of the cyclopropane-containing mechanistic probes 6-tert-butylspiro[2.5]octane and spiro[2.5]octane with hydrogen peroxide catalyzed by manganese complexes bearing aminopyridine tetradentate ligands has been studied. Mixtures of unrearranged and rearranged oxygenation products (alcohols, ketones, and esters) are obtained, suggesting the involvement of cationic intermediates and the contribution of different pathways following the initial hydrogen atom transfer-based C-H bond cleavage step. Despite such a complex mechanistic scenario, a judicious choice of the catalyst structure and reaction conditions (solvent, temperature, and carboxylic acid) could be employed to resolve these oxygenation pathways, leading, with the former substrate, to conditions where a single unrearranged or rearranged product is obtained in good isolated yield. Taken together, the work demonstrates an unprecedented ability to precisely direct the chemoselectivity of the C-H oxidation reaction, discriminating among multiple pathways. In addition, these results conclusively demonstrate that stereospecific C(sp3)-H oxidation can take place via a cationic intermediate and that this path can become exclusive in governing product formation, expanding the available toolbox of aliphatic C-H bond oxygenations. The implications of these findings are discussed in the framework of the development of synthetically useful C-H functionalization procedures and the associated mechanistic features.

Factors Governing Reactivity and Selectivity in Hydrogen Atom Transfer from C(sp3)-H Bonds of Nitrogen-Containing Heterocycles to the Cumyloxyl Radical.

A kinetic study of the hydrogen atom transfer (HAT) reactions from nitrogen-containing heterocycles (secondary and tertiary lactams, 2-imidazolidinones, 2-oxazolidinones, and succinimides) to the cumyloxyl radical has been carried out employing laser flash photolysis with ns time resolution. HAT occurs from the C-H bonds that are α to nitrogen, activated by hyperconjugative overlap with the N-C═O π system. In the lactam series, the second-order HAT rate constant (kH) was observed to decrease by a factor of ∼4 going from the five- and six-membered ring derivatives to the eight-membered ones, a behavior that was rationalized on the basis of a reduced extent of hyperconjugative activation associated to the greater flexibility of the larger rings compared to the smaller ones. In the five-membered-ring substrate series, the kH values were observed to increase by >3 orders of magnitude on going from succinimide to 2-imidazolidinones, a behavior that was explained in terms of the divergent contribution of hyperconjugative activation and deactivating electronic effects determined by ring functionalities. The results are discussed in the framework of the development of HAT-based C-H bond functionalization procedures.

Bimodal Evans-Polanyi Relationships in Hydrogen Atom Transfer from C(sp3)-H Bonds to the Cumyloxyl Radical. A Combined Time-Resolved Kinetic and Computational Study.

The applicability of the Evans-Polanyi (EP) relationship to HAT reactions from C(sp3)-H bonds to the cumyloxyl radical (CumO•) has been investigated. A consistent set of rate constants, kH, for HAT from the C-H bonds of 56 substrates to CumO•, spanning a range of more than 4 orders of magnitude, has been measured under identical experimental conditions. A corresponding set of consistent gas-phase C-H bond dissociation enthalpies (BDEs) spanning 27 kcal mol-1 has been calculated using the (RO)CBS-QB3 method. The log kH' vs C-H BDE plot shows two distinct EP relationships, one for substrates bearing benzylic and allylic C-H bonds (unsaturated group) and the other one, with a steeper slope, for saturated hydrocarbons, alcohols, ethers, diols, amines, and carbamates (saturated group), in line with the bimodal behavior observed previously in theoretical studies of reactions promoted by other HAT reagents. The parallel use of BDFEs instead of BDEs allows the transformation of this correlation into a linear free energy relationship, analyzed within the framework of the Marcus theory. The ΔG⧧HAT vs ΔG°HAT plot shows again distinct behaviors for the two groups. A good fit to the Marcus equation is observed only for the saturated group, with λ = 58 kcal mol-1, indicating that with the unsaturated group λ must increase with increasing driving force. Taken together these results provide a qualitative connection between Bernasconi's principle of nonperfect synchronization and Marcus theory and suggest that the observed bimodal behavior is a general feature in the reactions of oxygen-based HAT reagents with C(sp3)-H donors.

Deciphering Reactivity and Selectivity Patterns in Aliphatic C-H Bond Oxygenation of Cyclopentane and Cyclohexane Derivatives.

A kinetic, product, and computational study on the reactions of the cumyloxyl radical with monosubstituted cyclopentanes and cyclohexanes has been carried out. HAT rates, site-selectivities for C-H bond oxidation, and DFT computations provide quantitative information and theoretical models to explain the observed patterns. Cyclopentanes functionalize predominantly at C-1, and tertiary C-H bond activation barriers decrease on going from methyl- and tert-butylcyclopentane to phenylcyclopentane, in line with the computed C-H BDEs. With cyclohexanes, the relative importance of HAT from C-1 decreases on going from methyl- and phenylcyclohexane to ethyl-, isopropyl-, and tert-butylcyclohexane. Deactivation is also observed at C-2 with site-selectivity that progressively shifts to C-3 and C-4 with increasing substituent steric bulk. The site-selectivities observed in the corresponding oxidations promoted by ethyl(trifluoromethyl)dioxirane support this mechanistic picture. Comparison of these results with those obtained previously for C-H bond azidation and functionalizations promoted by the PINO radical of phenyl and tert-butylcyclohexane, together with new calculations, provides a mechanistic framework for understanding C-H bond functionalization of cycloalkanes. The nature of the HAT reagent, C-H bond strengths, and torsional effects are important determinants of site-selectivity, with the latter effects that play a major role in the reactions of oxygen-centered HAT reagents with monosubstituted cyclohexanes.

Practical and Selective sp3 C-H Bond Chlorination via Aminium Radicals.

The introduction of chlorine atoms into organic molecules is fundamental to the manufacture of industrial chemicals, the elaboration of advanced synthetic intermediates and also the fine-tuning of physicochemical and biological properties of drugs, agrochemicals and polymers. We report here a general and practical photochemical strategy enabling the site-selective chlorination of sp3 C-H bonds. This process exploits the ability of protonated N-chloroamines to serve as aminium radical precursors and also radical chlorinating agents. Upon photochemical initiation, an efficient radical-chain propagation is established allowing the functionalization of a broad range of substrates due to the large number of compatible functionalities. The ability to synergistically maximize both polar and steric effects in the H-atom transfer transition state through appropriate selection of the aminium radical has provided the highest known selectivity in radical sp3 C-H chlorination.

The Quest for Selectivity in Hydrogen Atom Transfer Based Aliphatic C-H Bond Oxygenation.

Aliphatic C-H bond functionalization is at the frontline of research because it can provide straightforward access to simplified and cost-effective synthetic procedures. A number of these methodologies are based on hydrogen atom transfer (HAT), which, as a consequence of the inert character of C-H bonds, often represents the most challenging step of the overall process. Because the majority of organic molecules contain multiple nonequivalent C-H bonds that display similar chemical properties, differentiating between these bonds with high levels of selectivity represents one of the most challenging issues. Clarification of the factors that govern the relative reactivity of C-H bonds toward HAT reagents is thus of primary importance in order to develop selective functionalization procedures. In this Account we describe, through the combination of kinetic studies employing a genuine HAT reagent such as the cumyloxyl radical, along with oxidations performed with H2O2 and iron or manganese catalysts, our contribution toward the development of selective C-H functionalization methodologies. Despite the different nature of these reagents, an oxygen-centered radical and a metal-oxo species, congruent reactivity and selectivity patterns have emerged, providing strong evidence that both reactions proceed via HAT. Consequently, selectivity in this class of metal catalyzed C-H oxidations can be reasonably predicted and synthetically exploited. Amides have been identified as preferential functional groups for governing selectivity on the basis of electronic, steric, and stereoelectronic effects. Torsional effects have proven moreover to be particularly important C-H directing factors in the oxidation of cyclohexane scaffolds where a delicate balance of these effects, in synergistic combination with catalyst design, enables highly chemoselective and enantioselective oxidations. Medium effects have been also shown to govern the relative HAT reactivity of C-H bonds in proximity to polar, hydrogen bond acceptor (HBA) functional groups. By engaging in hydrogen bonding with these groups, fluorinated alcohols strongly deactivate proximal C-H bonds toward HAT-based oxidation. As a result, alcohols, ethers, amines, and amides, which are electron rich and effective proximal C-H activating groups toward HAT reagents in conventional solvents, become oxidatively robust deactivating functionalities that direct C-H oxidation toward remote positions. These deactivating effects enable moreover the accomplishment of product chemoselective methylenic hydroxylations. Overall, clarification of the factors that govern HAT-based reactions has served to provide unique examples of catalytic methodologies for chemoselective and enantioselective oxidation of nonactivated aliphatic C-H bonds of potential utility in organic synthesis.

Evaluation of Polar Effects in Hydrogen Atom Transfer Reactions from Activated Phenols.

Evaluation of polar effects in hydrogen atom transfer (HAT) processes is made difficult by the fact that in most cases substrates characterized by lower bond dissociation energies (BDEs), activated from an enthalpic point of view, are also more activated by polar effects. In search of an exception to this general rule, we found that the introduction of a methoxy substituent in the 3-position of 2,6-dimethylphenol results in a small increase in the O-H BDE and a decrease of the ionization potential of the phenol. These findings suggest that the enthalpic effect associated with the addition of the m-methoxy group to 2,6-dimethylphenol will decrease reaction rates, while the polar effects will increase reaction rates. Our model analysis of polar effects has been experimentally validated by comparing the reactivity of 2,6-dimethylphenol with that of 2,6-dimethyl-3-methoxyphenol in HAT promoted by a series of radicals (cumyloxyl, galvinoxyl, 2,2-diphenylpycrylhydrazyl, phthalimide- N-oxyl, and benzotriazole- N-oxyl radicals). In line with our predictions, the ratio of HAT rate constants ( kH mOMe/ kHH) is larger in cases where there is a greater contribution of polar effects in the HAT reaction, i.e., in HAT promoted by N-oxyl radicals containing electron-withdrawing groups or when more polar solvents are employed.

Hydrogen Atom Transfer from Alkanols and Alkanediols to the Cumyloxyl Radical: Kinetic Evaluation of the Contribution of α-C-H Activation and ß-C-H Deactivation.

A kinetic study on the reactions of the cumyloxyl radical (CumO•) with a series of alkanols and alkanediols has been carried out. Predominant hydrogen atom transfer (HAT) from the α-C-H bonds of these substrates, activated by the presence of the OH group, is observed. The comparable kH values measured for ethanol and 1-propanol and the increase in kH measured upon going from 1,2-diols to structurally related 1,3- and 1,4-diols is indicative of ß-C-H deactivation toward HAT to the electrophilic CumO•, determined by the electron-withdrawing character of the OH group. No analogous deactivation is observed for the corresponding diamines, in agreement with the weaker electron-withdrawing character of the NH2 group. The significantly lower kH values measured for reaction of CumO• with densely oxygenated methyl pyranosides as compared to cyclohexanol derivatives highlights the role of ß-C-H deactivation. The contribution of torsional effects on reactivity is evidenced by the ∼2-fold increase in kH observed upon going from the trans isomers of 4- tert-butylcyclohexanol and 1,2- and 1,4-cyclohexanediol to the corresponding cis isomers. These results provide an evaluation of the role of electronic and torsional effects on HAT reactions from alcohols and diols to CumO•, uncovering moreover ß-C-H deactivation as a relevant contributor in defining site selectivity.

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 N-alkylamides and N-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 kH as compared to the unsubstituted alkane substrate. A decrease in kH 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 N-alkylamides and N-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.

Aerobic Oxidation of 4-Alkyl-N,N-dimethylbenzylamines Catalyzed by N-Hydroxyphthalimide: Protonation-Driven Control over Regioselectivity.

A change in regioselectivity has been observed in the hydrogen atom transfer (HAT) reactions from 4-alkyl-N,N-dimethylbenzylamines (alkyl = ethyl, isopropyl, and benzyl) to the phthalimide N-oxyl radical (PINO) by effect of protonation. This result can be rationalized on the basis of an acid-induced deactivation of the C-H bonds α to nitrogen toward HAT to PINO as evidenced by the 104-107-fold decrease in the HAT rate constants in acetonitrile following addition of 0.1 M HClO4. This acid-induced change in regioselectivity has been successfully applied for selective functionalization of the less activated benzylic C-H bonds para to the CH2N(CH3)2 group in the aerobic oxidation of 4-alkyl-N,N-dimethylbenzylamines catalyzed by N-hydroxyphthalimide in acetic acid.

Tuning reactivity and selectivity in hydrogen atom transfer from aliphatic C-H bonds to alkoxyl radicals: role of structural and medium effects.

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 functionalities.

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 Study of the Reaction of the Phthalimide-N-oxyl Radical with Amides: Structural and Medium Effects on the Hydrogen Atom Transfer Reactivity and Selectivity.

A kinetic study of the hydrogen atom transfer (HAT) reactions from a series of secondary N-(4-X-benzyl)acetamides and tertiary amides to the phthalimide-N-oxyl radical (PINO) has been carried out. The results indicate that HAT is strongly influenced by structural and medium effects; in particular, the addition of Brønsted and Lewis acids determines a significant deactivation of C-H bonds α to the amide nitrogen of these substrates. Thus, by changing the reaction medium, it is possible to carefully control the regioselectivity of the aerobic oxidation of amides catalyzed by N-hydroxyphthalimide, widening the synthetic versatility of this process.

Oxidation of Aryl Diphenylmethyl Sulfides Promoted by a Nonheme Iron(IV)-Oxo Complex: Evidence for an Electron Transfer-Oxygen Transfer Mechanism.

The oxidation of a series of aryl diphenylmethyl sulfides (4-X-C6H4SCH(C6H5)2, where X = OCH3 (1), X = CH3 (2), X = H (3), and X = CF3 (4)) promoted by the nonheme iron(IV)-oxo complex [(N4Py)Fe(IV)═O](2+) occurs by an electron transfer-oxygen transfer (ET-OT) mechanism as supported by the observation of products (diphenylmethanol, benzophenone, and diaryl disulfides) deriving from α-C-S and α-C-H fragmentation of radical cations 1(+•)-4(+•), formed besides the S-oxidation products (aryl diphenylmethyl sulfoxides). The fragmentation/S-oxidation product ratios regularly increase through a decrease in the electron-donating power of the aryl substituents, that is, by increasing the fragmentation rate constants of the radical cations as indicated by a laser flash photolysis (LFP) study of the photochemical oxidation of 1-4 carried out in the presence of N-methoxyphenanthridinium hexafluorophosphate (MeOP(+)PF6(-)).

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 N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-formylpyrrolidine (FPRD), and N-acetylpyrrolidine (APRD) to the cumyloxyl radical (CumO(•)) was carried out. From large to very large increases in the HAT rate constant (kH) were measured on going from MeOH and TFE to isooctane (kH(isooctane)/kH(MeOH) = 5-12; kH(isooctane)/kH(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.

Reactivity and selectivity patterns in hydrogen atom transfer from amino acid C-H bonds to the cumyloxyl radical: polar effects as a rationale for the preferential reaction at proline residues.

Absolute rate constants for hydrogen atom transfer (HAT) from the C-H bonds of N-Boc-protected amino acids to the cumyloxyl radical (CumO(•)) were measured by laser flash photolysis. With glycine, alanine, valine, norvaline, and tert-leucine, HAT occurs from the α-C-H bonds, and the stability of the α-carbon radical product plays a negligible role. With leucine, HAT from the α- and γ-C-H bonds was observed. The higher kH value measured for proline was explained in terms of polar effects, with HAT that predominantly occurs from the δ-C-H bonds, providing a rationale for the previous observation that proline residues represent favored HAT sites in the reactions of peptides and proteins with (•)OH. Preferential HAT from proline was also observed in the reactions of CumO(•) with the dipeptides N-BocProGlyOH and N-BocGlyGlyOH. The rate constants measured for CumO(•) were compared with the relative rates obtained previously for the corresponding reactions of different hydrogen-abstracting species. The behavior of CumO(•) falls between those observed for the highly reactive radicals Cl(•) and (•)OH and the significantly more stable Br(•). Taken together, these results provide a general framework for the description of the factors that govern reactivity and selectivity patterns in HAT reactions from amino acid C-H bonds.

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 N,N-dimethylformamide (DMF) and N,N-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 (kH) 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 Ca(2+), which was shown to strongly bind up to four equivalents of the amide substrates. With Mg(2+), 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 Mg(2+). 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.