Search

The tert‐butyl group is a common aliphatic motif extensively employed to implement steric congestion and conformational rigidity in organic and organometallic molecules. Because of the combination of a high bond dissociation energy (~100 kcal mol−1) and limited accessibility, in the absence of directing groups, neither radical nor organometallic approaches are effective for the chemical modification of tert‐butyl C−H bonds. Herein we overcome these limits by employing a highly electrophilic manganese catalyst, [Mn(CF3bpeb)(OTf)2], that operates in the strong hydrogen bond donor solvent nonafluoro‐tert‐butyl alcohol (NFTBA) and catalytically activates hydrogen peroxide to generate a powerful manganese‐oxo species that effectively oxidizes tert‐butyl C−H bonds. Leveraging on the interplay of steric, electronic, medium and torsional effects, site‐selective and product chemoselective hydroxylation of the tert‐butyl group is accomplished with broad reaction scope, delivering primary alcohols as largely dominant products in preparative yields. Late‐stage hydroxylation at tert‐butyl sites is demonstrated on 6 densely functionalized molecules of pharmaceutical interest. This work uncovers a novel disconnection approach, harnessing tert‐butyl as a potential functional group in strategic synthetic planning for complex molecular architectures. [ABSTRACT FROM AUTHOR]

Selective functionalization of unactivated aliphatic C−H bonds represents an important goal of modern synthetic chemistry. Differentiating between such bonds in organic molecules with high levels of selectivity remains a crucial issue, and a profound understanding of even the subtlest reactivity trends is needed. Among the methods that have been developed, those based on hydrogen atom transfer (HAT) have attracted considerable interest. Within this framework, medium effects have proved effective in altering the reactivity and site selectivity in synthetically useful C−H functionalization procedures. In this Review, the mechanistic features behind the available strategies are discussed. It is shown that hydrogen bonding and acid–base interactions can promote C−H bond activation or deactivation toward HAT reagents, thereby providing fine‐control over the site selectivity and product chemoselectivity as well as useful guidelines for future development and applications. In the medium term: Effects of the reaction medium can be used to alter the reactivity and selectivity in synthetically useful procedures for the functionalization of aliphatic C−H bonds. This Review discusses the mechanistic features in terms of hydrogen bonding and acid–base interactions and shows that these effects can promote aliphatic C−H bond (de)activation toward hydrogen atom transfer reagents. [ABSTRACT FROM AUTHOR]

A time-resolved kinetic study on the effect of trifluoroacetic acid (TFA) on the hydrogen atom transfer (HAT) reactions from 1,n-alkanediamines (R2N(CH2)nNR2, R = H, CH3; n = 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)nN+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)nN+R2H. At [substrate] > [TFA], HAT occurs from the α-C-H bonds of R2N(CH2)nNR2, and the mesured kH 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)nN+R2H remote C-H deactivation can be modulated through solvent hydrogen bonding. [ABSTRACT FROM AUTHOR]

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, kH/kD, of 2.0 and 3.1 measured for reaction of this radical with DMSO/DMSO-d6 and HMPA/ HMPA-d18. Very large increases in reactivity were observed on going from CumO* to BnO*, as evidenced by kH(BnO*)/kH(CumO*) ratios of 86,4.8 X 10³, and 1.6 X 104 for the reactions with HMPA, TBPO, and DMSO, respectively. The kH/kd) of 0.91 and 1.0 measured for the reactions of BnO* with DMSO/DMSO-d6 and HMPA/HMPA-d18, together with the kH(BnO*)/kH(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. [ABSTRACT FROM AUTHOR]

A time-resolved kinetic study on the hydrogen abstraction reactions from a series of primary and secondary amines by the cumyloxyl (CumO•) and benzyloxyl (BnO•) radicals was carried out. The results were compared with those obtained previously for the corresponding reactions with tertiary amines. Very different hydrogen abstraction rate constants (kH) and intermolecular selectivities were observed for the reactions of the two radicals. With CumO•, kH was observed to decrease on going from the tertiary to the secondary and primary amines. The lowest kH values were measured for the reactions with 2,2,6,6-tetramethylpiperidine (TMP) and tert-octylamine (TOA), substrates that can only undergo N-H abstraction. The opposite behavior was observed for the reactions of BnO•, where the kH values increased in the order tertiary < secondary < primary. The kH values for the reactions of BnO• were in all cases significantly higher than those measured for the corresponding reactions of CumO•, and no significant difference in reactivity was observed between structurally related substrates that could undergo exclusive α-C-H and N-H abstraction. This different behavior is evidenced by the kH(BnO•)/kH(CumO•) ratios that range from 55-85 and 267-673 for secondary and primary alkylamines up to 1182 and 3388 for TMP and TOA. The reactions of CumO• were described in all cases as direct hydrogen atom abstractions. With BnO• the results were interpreted in terms of the rate-determining formation of a hydrogen-bonded prereaction complex between the radical α-C-H and the amine lone pair wherein hydrogen abstraction occurs. Steric effects and amine HBA ability play a major role, whereas the strength of the substrate α-C-H and N-H bonds involved appears to be relatively unimportant. The implications of these different mechanistic pictures are discussed. [ABSTRACT FROM AUTHOR]

A kinetic study of the hydrogen atom abstraction reactions from propanal (PA) and 2,2-dimethylpropanal (DMPA) by the cumyloxyl radical (CumO•) has been carried out in different solvents (benzene, PhCl, MeCN, t-BuOH, MeOH, and TFE). The corresponding reactions of the benzyloxyl radical (BnO•) have been studied in MeCN. The reaction of CumO• with 1,4-cyclohexadiene (CHD) also has been investigated in TFE solution. With CHD a 3-fold increase in rate constant (kH) has been observed on going from benzene, PhCl, and MeCN to TFE. This represents the first observation of a sizable kinetic solvent effect for hydrogen atom abstraction reactions from hydrocarbons by alkoxyl radicals and indicates that strong HBD solvents influence the hydrogen abstraction reactivity of CumO•. With PA and DMPA a significant decrease in kH has been observed on going from benzene and PhCl to MeOH and TFE, indicative of hydrogen-bond interactions between the carbonyl lone pair and the solvent in the transition state. The similar kH values observed for the reactions of the aldehydes in MeOH and TFE point toward differential hydrogen bond interactions of the latter solvent with the substrate and the radical in the transition state. The small reactivity ratios observed for the reactions of CumO• and BnO• with PA and DMPA (kH(BnO•)/kH(CumO•) = 1.2 and 1.6, respectively) indicate that with these substrates alkoxyl radical sterics play a minor role. [ABSTRACT FROM AUTHOR]

A time-resolved kinetic study on the reactions of the cumyloxyl radical (CumO•) with intramolecularly hydrogen bonded 2-(1-piperidinylmethyl)phenol (1) and 4-methoxy-2-(1-piperidinylmethyl)phenol (2) and with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) has been carried out. In acetonitrile, intramolecular hydrogen bonding protects the phenolic O-H of 1 and 2 from attack by CumO• and hydrogen atom transfer (HAT) exclusively occurs from the C-H bonds that are α to the piperidine nitrogen (α-C-H bonds). With 3 HAT from both the phenolic O-H and the α-C-H bonds is observed. In the presence of TFA or Mg(ClO4)2, protonation or Mg2+ complexation of the piperidine nitrogen removes the intramolecular hydrogen bond in 1 and 2 and strongly deactivates the α-C-H bonds of the three substrates. Under these conditions, HAT to CumO• exclusively occurs from the phenolic O-H group of 1-3. These results clearly show that in these systems the interplay between intramolecular hydrogen bonding and Brønsted and Lewis acid-base interactions can drastically influence both the HAT reactivity and selectivity. The possible implications of these findings are discussed in the framework of the important role played by tyrosyl radicals in biological systems. [ABSTRACT FROM AUTHOR]

A time-resolved kinetic study on the effect of metal ions (Mn+) 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 Mn+ 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 (kH) was observed indicating that interaction between Mn+ 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 kH with increasing Lewis acidity of Mn+ was observed (kH(MeCN) > kH(Li+) > kH(Mg2+)). This behavior was explained in terms of the stronger Lewis acid-base interaction of Mn+ 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 kH was measured after Mg(ClO4)2 addition up to a 1.5:1 amine/Mg(ClO4)2 ratio. At higher amine concentrations, very similar kH 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 Mn+ can dramatically influence kH, 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. [ABSTRACT FROM AUTHOR]