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.

Hydrogen atom transfer from 1,2- and 1,3-diols to the cumyloxyl radical. The role of structural effects on metal-ion induced C-H bond deactivation.

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.

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.

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.

Polypodium leucotomos Extract use to prevent and reduce the risk of infectious diseases in high performance athletes.

OBJECTIVE: Many components of the immune system undergo adverse changes during intense physical activity in athletes, leading to a heightened risk of respiratory tract infections. This study evaluated the reduction in infectious processes in athletes due to intensive training with anapsos. METHODS: The study compared athletes who took 480 mg Polypodium leucotomos Extract (Armaya fuerte; Centrum laboratories, Alicante, Spain) twice daily for 3 months (n = 50) with a control group (n = 50) in the evaluation of the onset of infectious processes and relapses during an 8-month period (June 2010 to January 2011). RESULTS: The onset of infectious processes in the Polypodium leucotomos Extract group was lower when compared to the control group (14% versus 56%). Relapse in the Polypodium leucotomos Extract group was seen in just one athlete (14.2%) compared to ten athletes (37.5%) in the control group. CONCLUSION: Polypodium leucotomos Extract has been shown to be useful in the prevention of infectious processes, as well as reducing recurring episodes in athletes.