Article pubs.acs.org/accounts
Tuning Reactivity and Selectivity in Hydrogen Atom Transfer from Aliphatic C−H Bonds to Alkoxyl Radicals: Role of Structural and Medium Effects Michela Salamone and Massimo Bietti* Dipartimento di Scienze e Tecnologie Chimiche, Università “Tor Vergata”, Via della Ricerca Scientifica, 1, I-00133 Rome, Italy CONSPECTUS: 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.
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INTRODUCTION Hydrogen atom transfer (HAT) represents one of the most fundamental chemical reactions that accordingly has been the subject of intensive experimental and theoretical investigation.1−4 This reaction plays a major role in a variety of important chemical and biological processes. Relevant examples include the mechanism of action of radical scavenging antioxidants,5−7 radical-induced damage to biomolecules and polymers,8,9 enzymatic and biomimetic reactions,10−14 the degradation of volatile organic compounds,15 and a large number of synthetically useful C−H functionalization procedures.16−18 © 2015 American Chemical Society
Among the species involved in these processes, reactive oxygen centered radicals such as alkoxyls have attracted considerable interest. Most attention has been devoted to tertiary alkoxyl radicals, namely tert-butoxyl ((CH3)3CO•, tBuO•) and cumyloxyl (PhC(CH3)2O•, CumO•), because both radicals can be easily generated by UV photolysis of commercially available peroxides (Scheme 1), can tolerate a wide range of experimental conditions, and are characterized by lifetimes in the microsecond time regime.19 Received: July 28, 2015 Published: November 6, 2015 2895
DOI: 10.1021/acs.accounts.5b00348 Acc. Chem. Res. 2015, 48, 2895−2903
Article
Accounts of Chemical Research
to the transition state.4 Alkoxyl radicals display an electrophilic character, and accordingly, the highest kH values have been measured for HAT from the electron-rich α-C−H bonds of tertiary alkylamines (kH = (1−4) × 108 M−1 s−1,22−25 in aprotic solvents). On the other hand, C−H bonds that are α to strong electron withdrawing groups are deactivated toward HAT to alkoxyl radicals (kH ≤ 1 × 104 M−1 s−1).19 An example that highlights the important role of polar effects on C−H bond reactivity is provided by Scheme 3, where the kH and kH(norm) (kH normalized for the number of hydrogen atoms) values for HAT from cyclohexane (CHX),26 MeCN, and acetone27 to CumO• are displayed, together with the pertinent C−H BDEs.28 Despite the weaker C−H bonds of the latter substrates, the C−H bonds of CHX are at least 30 times more reactive. Polar effects were also shown to play an important role in the reaction of CumO• with N-Boc-protected amino acids (Scheme 4).29 With glycine, alanine, and valine HAT occurs from the α-C− H bonds, and the stability of the product radical and steric effects were shown to play a negligible role. A 6.3-fold increase in kH was measured on going from glycine to proline, where preferential HAT from the δ-C−H bonds was observed. This behavior was explained on the basis of the electron withdrawing character of the carboxylic group that deactivates the α-C−H bond directing HAT toward the δ-position (Scheme 5).
Scheme 1
In the absence of hydrogen atom donor substrates (S−H), tBuO• and CumO• mostly undergo C−CH3 β-scission. In the presence of S−H, competition between β-scission and HAT occurs as described in Scheme 2. Compared with tBuO•, CumO• is characterized by an absorption band in the visible region of the spectrum that makes particularly convenient the direct measurement of HAT rate constants by nanosecond laser flash photolysis (LFP).20 Accordingly, the second-order rate constants for HAT from S− H to CumO• (kH) can be derived from the slope of the observed rate constant (kobs) versus S−H concentration plots, where kobs values are measured following the decay of the CumO• visible absorption band at different concentrations of S−H. Within this framework, we have been interested in HAT reactions from aliphatic C−H bonds, with the main objective of obtaining quantitative kinetic information on the role of structural and medium effects on the reactivity and selectivity patterns. These goals have been mostly achieved through timeresolved kinetic studies of the reactions of CumO• with a large variety of substrates that have provided a consistent set of kH values, through which useful guidelines for the description of the factors that govern these reactions have been obtained. The study of medium effects has involved solvent effects as well as the role of added Brønsted and Lewis acids. The main results of our studies will be presented and discussed in this Account.
Stereoelectronic Effects
These effects were shown to play an important role in HAT from amines,22−25,30 ethers,31 and amides32 to tBuO• and CumO•. Scheme 6 displays the kH values for HAT from the αC−H bonds of representative amine substrates to CumO•. Compared with 1-azabicyclo[2.2.2]octane and 1,4diazabicyclo[2.2.2]octane,24 a ≥45- and ≥35-fold increase in kH(norm) was observed for the corresponding reactions of triethylamine (TEA), piperidine, and 1,4-piperazine, for which almost identical kH(norm) values were measured in MeCN.23,30 HAT is most rapid when the α-C−H bond being broken can be eclipsed with the nitrogen lone pair, an overlap that is not possible with the former substrates where these bonds are held with a dihedral angle of ca. 60° and are therefore less labile toward HAT. In the reactions of tertiary acetamides with CumO•,32 where HAT predominantly occurs from the C−H bonds that are α to the nitrogen atom, a ∼2-fold decrease in kH(norm) was observed on going from N,N-dimethylacetamide (DMA) and N,N-diethylacetamide to N,N-diisobutylacetamide. A 29-fold increase in kH(norm) was instead observed on going from the latter substrate to N-acetylpyrrolidine (Scheme 7). In N-acetylpyrrolidine, the α-C−H bonds are held in a conformation where they are optimally aligned with the amide π-system (Scheme 8) providing a kinetic advantage for HAT compared with N,N-diisobutylacetamide, where the bulky N-
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STRUCTURAL EFFECTS The main factor that governs HAT reactivity from C−H bonds is generally represented by bond strengths. Accordingly, the following relative reactivities were obtained for HAT from the aliphatic C−H bonds of hydrocarbons to tBuO•: 1.0, 12.2 and 44, respectively, for primary, secondary, and tertiary sites.21 However, recent time-resolved kinetic studies have pointed out that in solution at room temperature, most HAT reactions from C−H bonds to tBuO• are entropy controlled.22 A decrease in kH with increasing bond strength was observed for substrates characterized by C−H bond dissociation energies (BDEs) >92 kcal/mol, whereas for substrates characterized by C−H BDEs 540-fold decrease in kH was measured on going from isooctane (kH = 7.7 × 106 and 5.4 × 106 M−1 s−1, for DMF and DMA, respectively) to TFE (kH < 1 × 104 M−1 s−1, for both substrates).40 By interacting with the oxygen atom of alkanamides, HBD solvents determine an increase in C(O)−N bond order, a corresponding decrease in CO bond order, and an overall decrease in charge density at nitrogen (Scheme 13, R = H, CH3), that increases the electron deficiency of the C−H bonds of these substrates leading to their deactivation toward HAT to CumO•.40 The significantly larger KSEs observed for alkanamides compared with aldehydes (quantified, for 2,2-DMPA, in a ∼11fold decrease in kH on going from isooctane to TFE,38 see
Scheme 11
Table 1) can be reasonably accounted for on the basis of the stronger HBA ability of the former substrates compared with the latter ones.41 Very interestingly, the analysis of the kH/kD values measured in MeCN and isooctane for the reactions of CumO• with DMF, DMF-d1, DMF-d6, and DMF-d7, clearly shows that changes in solvent polarity can strongly influence the HAT selectivity. In MeCN, kH/kD values of 1.8, 1.7, and 5.2 were obtained for the reactions of DMF-d1, DMF-d6, and DMF-d7, respectively, indicating that HAT occurs from both the formyl C−H and the C−H bonds that are α to nitrogen (Scheme 14, path a).42 In isooctane, kH/kD values of 1.6, 0.95, and 1.8 were instead obtained for the reactions of DMF-d1, DMF-d6, and DMF-d7, indicating that HAT now almost exclusively occurs from the formyl C−H bond (Scheme 14, path b).40 Effect of Acid−Base Interactions
On the basis of the mechanistic picture outlined above, we reasoned that in HAT from the C−H bonds of basic substrates to CumO•, the addition of Brønsted or Lewis acids would lead to similar deactivating effects following protonation or interaction of metal ions with the substrate basic center. Along these lines, we have carried out detailed time-resolved kinetic studies on the effect of acetic (AcOH) and trifluoroacetic acid (TFA) and of alkali and alkaline earth metal ions on the reactions of CumO• with a variety of substrates. Brønsted Acids
The effect of AcOH and TFA on HAT from the C−H bonds of tetrahydropyran (THP) and tertiary alkylamines to CumO• was studied in MeCN.43 The corresponding reactions of 1,nalkanediamines and 1,4-piperazines were studied in MeCN and DMSO in the presence of TFA.44
Scheme 9
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DOI: 10.1021/acs.accounts.5b00348 Acc. Chem. Res. 2015, 48, 2895−2903
Article
Accounts of Chemical Research
Table 1. Second-Order Rate Constants (kH) for HAT From the C−H Bonds of Different Substrates to the Cumyloxyl Radical (CumO•) Measured in Different Solvents at T = 25 °C kH, M−1 s−1 solvent isooctane benzene MeCN t-BuOH MeOH TFE a
2,2-DMPA (1.12 ± 0.01) (5.0 ± 0.3) (2.69 ± 0.05) (3.7 ± 0.2) (1.7 ± 0.1) (1.04 ± 0.02)
a
× × × × × ×
DMF 8
10 107 107 107 107 107
b
THFc
(7.7 ± 0.1) × 10 (3.1 ± 0.1) × 106 (1.24 ± 0.02) × 106 (1.38 ± 0.03) × 106 (9.8 ± 0.2) × 105
