The role of structural and medium effects on hydrogen atom transfer from aliphatic C-H bonds

Selective functionalization of aliphatic C–H bonds represents a topic of increasing interest in modern synthetic organic chemistry, because these reactions can offer advantages both in terms of decreased waste generation and reaction step economy. Methodologies based on Hydrogen Atom Transfer (HAT) to radical and radical-like species have proven to be successful in pursuing this challenging goal. The factors governing reactivity and selectivity in HAT-based aliphatic C−H bond functionalization have been investigated in detail, and include bond strengths, electronic or inductive effects, conjugation, hyperconjugation, steric and stereoelectronic effects, medium effects as well as, with cyclohexane derivatives, torsional effects. My research group has devoted much effort to elucidate and quantitively evaluate these factors by means of time resolved kinetic studies, employing a representative electrophilic HAT reagent, cumyloxyl radical (CumO• ). In keeping with this interest, during the course of my PhD studies I have focused my attention on further investigating the role of substrate structure and of the reaction medium on HAT reactivity and selectivity. In more detail, the experimental work carried out in the framework of my PhD thesis has been developed along the following lines: (a) Due to the electrophilic nature of most of the commonly employed HAT reagents, electronic effects are central in these reactions, and it can be reasonably predicted that, in a molecule containing different reactive sites, HAT will preferentially occur from an electron-rich and thus activated C−H bond rather than from an electron-poor and deactivated one. In order to obtain a deeper understanding of the role of electronic effects on these processes, we have carried out a detailed time-resolved kinetic study on the reactions of an extended series of 1-Z-pentyl, 1-Z-propyl, and Zcyclohexyl derivatives (Z = H, Ph, OH, OAc, NH2, NHAc, NPhth, CO2Me, Cl, Br, CN) with the cumyloxyl radical. (b) Hydroxyl functional groups represent a common structural motif of organic substrates, widely represented in a variety of natural products and biomolecules. Nevertheless, little kinetic information was available on HAT reactions from the aliphatic CH bonds of alcohol and diol substrates. Therefore, we carried out a detailed time-resolved kinetic study on the reactions of CumO• with a series of both linear and cyclic alkanols and alkanediols, along with three methyl glycosides. A quantitative evaluation of the role of α-C-H activation has been provided, also identifying the contribution of β-C-H bond deactivation in defining HAT site-selectivity. With 4-alkylcyclohexanol and cyclohexanediol substrates, torsional effects have been also shown to play a role. (c) Recent studies performed in our laboratory have shown how Lewis acid-base interactions can be used to promote aliphatic C-H bond deactivation of ether, amine and amide substrates towards HAT, through the addition of alkali and alkaline earth metal ion salts. We envisioned that this deactivation strategy could be extended to other class of substrates bearing basic functional groups, such as hydroxyl groups. We thus carried out a time-resolved kinetic study on the effect of Li+, Mg2+ and Ca2+ ions on HAT from the CH bonds 1,2- and 1,3-diols and related disubstituted propane derivatives to the cumyloxyl radical (CumO• ), taking into particular account the role of substrate structure. (d) Torsional effects have been shown to play an important role in defining HAT reactivity and selectivity of monosubstituted cycloalkane derivatives, where in particular tertiary equatorial C−H bond activation and tertiary axial C−H bond deactivation have been observed. In order to provide a quantitative evaluation of the role of torsional effects on HAT from the C−H bonds of cycloalkane derivatives, we have carried out detailed time resolved kinetic study on the reactions of an extended series of monosubstituted cycloalkanes with the cumyloxyl radical. The kinetic data have been accompanied by product studies on the reactions of the same substrates with CumO• and with in situ generated dioxiranes. Taken together, the results thus obtained enable a clear definition of the site-selectivity trends.