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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.
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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.
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Herein is delineated a first systematic framework for the definition of structure-antioxidant property relationships in the dihydroxynaphthalene (DHN) series. The results obtained by a combined experimental and theoretical approach revealed that 1,8-DHN is the best performing antioxidant platform, with its unique hydrogen-bonded peri-hydroxylation pattern contributing to a fast H atom transfer process. Moreover, the comparative analysis of the antioxidant properties of DHNs carried out by performing DPPH and FRAP assays and laser flash photolysis experiments, revealed the higher antioxidant power associated with an α-substitution pattern (i. e. in 1,8- and 1,6-DHN) with respect to DHNs exhibiting a ß-substitution pattern (i. e. in 2,6- and 2,7-DHN). DFT calculations and isolation and characterization of the main oligomer intermediates formed during the oxidative polymerization of DHNs supported this evidence by providing unprecedented insight into the generation and fate of the intermediate naphthoxyl radicals, which emerged as the main factor governing the antioxidant activity of DHNs.
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Antioxidantes , Naftalenos , Antioxidantes/química , OxirreduçãoRESUMO
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-CâO π system. In the lactam series, the second-order HAT rate constant (kH) was observed to decrease by a factor of â¼4 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.
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Hidrogênio , Nitrogênio , Hidrogênio/química , Ligação de Hidrogênio , Cinética , Estrutura MolecularRESUMO
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.
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Manganês , Octanos , Álcoois , Catálise , Manganês/química , OxirreduçãoRESUMO
The research was focused on the surveillance of the exposure of buffalo milkers in contact with both animals and potentially contaminated equipment, pointing attention on the diffusion of antibiotic-resistant Staphylococcus spp. The monitoring was performed for 12 months, allowing the collection of 600 raw milk and buffalo udder surface samples, 192 milking lanes, 400 milking clusters, 160 personal protective equipment (PPEs) and electronic devices surface samples in contact with the workers of four milking parlors located in Southern Italy. The analysis of the milk samples evidenced the highest exposure to the bacteria considered (and mainly to S. aureus) from late winter-spring seasons onward. The possible risk arising from buffalo udder, milking clusters, and lines were instead considered rather stable along the entire period of sampling. The PPEs turned out to be a source of contamination for milkers mainly during the spring and summer periods. The analysis for oxacillin/methicillin resistance revealed in all the farms enrolled an overall amount of 37.5% of Staphylococci strains (belonging to S. aureus, S. haemolyticus, S. pseudintermedius, S. chromogenes species) resistant both to methicillin and oxacillin. The investigation demonstrated that the potential transfer of pathogenic bacteria to humans would have a better chance to occur at milk resumption time (since late winter-spring onward) when the number of animals to be milked is greater and the activity in the milking parlor is more challenging. At the same time, the findings seem to point out that the potential risk may be worsened by a significant presence of oxacillin/methicillin-resistant Staphylococci, potentially resulting from irrational use of antibiotics.
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Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Antibacterianos/farmacologia , Búfalos , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Leite/microbiologia , Oxacilina , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/veterinária , Staphylococcus , Staphylococcus aureusRESUMO
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.
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Eletrônica , Hidrogênio , Hidrogênio/química , Ligação de Hidrogênio , Indicadores e ReagentesRESUMO
The applicability of the Evans-Polanyi (EP) relationship to HAT reactions from C(sp3)-H bonds to the cumyloxyl radical (CumOâ¢) has been investigated. A consistent set of rate constants, kH, for HAT from the C-H bonds of 56 substrates to CumOâ¢, 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.
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Teoria da Densidade Funcional , Hidrogênio/química , Radicais Livres/química , Cinética , Estrutura Molecular , Fatores de TempoRESUMO
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.
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Cicloexanos , Ciclopentanos , Ligação de Hidrogênio , Cinética , Estrutura MolecularRESUMO
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.
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Strong C-H bond deactivation toward HAT has been observed in the reactions of the cumyloxyl radical with 1,2- and 1,3-diols, following addition of Li+ and Ca2+. Weaker effects have been observed with Mg2+. The role of the substrate structure and of the metal ion in the formation of Lewis acid-base complexes is discussed.
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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.
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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.
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A kinetic study on the reactions of the cumyloxyl radical (CumOâ¢) 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 CumOâ¢, 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 â¼2-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 CumOâ¢, uncovering moreover ß-C-H deactivation as a relevant contributor in defining site selectivity.
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A kinetic study on the reactions of the cumyloxyl radical (CumOâ¢) with N-Boc-protected amino acids in the presence of the strong organic base DBU has been carried out. CO2H deprotonation increases the electron density at the α-C-H bonds activating these bonds toward HAT to the electrophilic CumO⢠strongly influencing the intramolecular selectivity. The implications of these results are discussed in the framework of HAT-based aliphatic C-H bond functionalization of amino acids and peptides.
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Aminoácidos/química , Hidrogênio , Ligação de Hidrogênio , Cinética , Estrutura Molecular , PrótonsRESUMO
1,8-Naphthalenediol (dihydroxynaphthalene, 1,8-DHN) has been shown to be a potent hydrogen atom transfer (HAT) antioxidant compound because of the strong stabilization of the resulting free radical by intramolecular hydrogen bonding. However, the properties, reactivity, and fate of the 1,8-DHN phenoxyl radical have remained so far uncharted. Herein, we report an integrated experimental and computational characterization of the early intermediates and dimer products that arise by the oxidation of 1,8-DHN. Laser flash photolysis (LFP) studies of HAT from 1,8-DHN to the cumyloxyl and aminoxyl radicals showed the generation of a transient species absorbing at 350, 400, and >600 nm attributable to the 1,8-DHN phenoxyl radical. Peroxidase/H2O2 oxidation of 1,8-DHN was found to proceed via an intense blue intermediate (λmax 654 nm) preceding precipitation of a black melanin-like polymer. By halting the reaction in the early stages, three main dimers featuring 2,2'-, 2,4'-, and 4,4'-bondings could be isolated and characterized in pure form. Density functional theory calculations supported the generation of the 1,8-DHN phenoxyl radical and its subsequent coupling via the 2- and 4-positions giving extended quinone dimers with intense transitions in the visible range, consistent with UV-vis and LFP data. Overall, these results allowed to elucidate the mechanism of oxidative polymerization of 1,8-DHN of possible relevance to melanogenesis in fungi and other processes of environmental and astrochemical relevance.
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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 (CumOâ¢) 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 CumOâ¢, 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.
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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.
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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.
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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 (CumOâ¢) 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 CumOâ¢, 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.