Alessandra
Coniglio
,
Carlo
Galli
*,
Patrizia
Gentili
* and
Raffaella
Vadalà
Dipartimento di Chimica, Università‘La Sapienza’, and IMC-CNR Sezione Meccanismi di Reazione, P.le A. Moro 5, 00185, Roma, Italy. E-mail: carlo.galli@uniroma1.it; Fax: +39 06 490421
First published on 7th November 2008
The aminoxyl radical BTNO (benzotriazole-N-oxyl; >N–O˙) is generated from HBT (1-hydroxybenzotriazole; >N–OH) by oxidation with a CeIV salt. BTNO presents a broad absorption band with λmax 474 nm that lends itself to investigate the kinetics of H-abstraction from H-donor substrates by spectrophotometry. Thus, rate constants (kH) of H-abstraction by BTNO from CH2-groups α to the nitrogen atom in X-substituted-(N-acetyl)benzylamines (X-C6H4CH2NHCOCH3) have been determined in MeCN solution at 25 °C. Correlation of the kHX data with the Hammett σ+ parameters gives a small value for ρ (−0.65) that is compatible with a radical H-abstraction step. The sizeable value (kH/kD = 8.8) of the kinetic isotope effect from a suitably deuteriated amide substrate further confirms H-abstraction as rate-determining. Evidence is acquired for the relevance of stereoelectronic effects that speed up the H-abstraction whenever the scissile C–H bond is co-linear with either the nitrogen lone-pair of the amide moiety or an adjacent aromatic group. An assessment of the dissociation energy value of the benzylic C–H bond in ArCH2NHCOMe is accordingly reported.
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Scheme 1 Oxidation of an H-donor substrate (Sub-H) by radical PINO in the presence of dioxygen. |
In principle, aminoxyl radicals can be obtained from the parent hydroxylamines by either H-abstraction or electron-abstraction followed by deprotonation (Scheme 2).1
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Scheme 2 Possible pathways of generation of aminoxyl radicals. |
For example, PINO is generated from HPI by the action of O2 and Co(OAc)2,4,5 or else by oxidation with Pb(OAc)4;6PINO has alternatively been generated electrochemically.7 Kinetic studies of the H-abstraction reaction from substrates having C–H or O–H bonds of appropriate energy have provided information upon the reactivity of PINO towards alkylarenes or phenols.6a,8 The synthetic value of the oxidation reactions induced by PINO has stimulated us to assess the reactivity features of this, as well of other aminoxyl radicals more closely.
We have recently reported on the H-abstraction reactivity of another aminoxyl radical, that is, BTNO (benzotriazoleN-oxyl).9 This radical has been generated from oxidation of HBT (1-hydroxybenzotriazole) with a CeIV salt (Scheme 3) and characterized by UV-Vis and EPR spectra, laser flash photolysis and cyclic voltammetry.9a Rate constants of H-abstraction (kH) from C–H bonds of H-donor substrates, including benzyl alcohols and alkylarenes, have been determined spectroscopically and found to be in the 10−3 to 102M−1 s−1 range at 25 °C in MeCN solution.9b With selected substrates, activation parameters for the H-abstraction step have been measured, and the activation energy successfully correlated to the dissociation energy of the C–H bond undergoing cleavage.9b Whenever comparing BTNOvsPINO, the radical reactivity of PINO has always been found higher than that of BTNO towards similar substrates. The explanation provided is that PINO gives rise to a stronger NO–H bond (in HPI) upon H-abstraction from a substrate, as compared to the weaker NO–H bond in HBT (88 vs. ca. 85 kcal/mol, respectively), this representing a crucial factor for a radical process where bond cleavage and formation dominate the reactivity.1,9b
The present paper deepens our understanding of the reactivity of aminoxyl radicals in the H-abstraction reaction, a topic recently reviewed.1 It also extends this knowledge to the oxidation of amides, a class of substrates never explored kinetically so far. In fact, we report on a kinetic study of the H-abstraction by BTNO from the C–H bond α to the nitrogen atom of amides (Scheme 3), a reaction investigated for synthetic purposes by the use of PINO.10
During our kinetic study, evidence for the important contribution from stereoelectronic effects upon the H-abstraction reactivity has appeared. More specifically, the co-linearity between the α-C–H bond undergoing cleavage and the nitrogen lone-pair of the amide comes out as a key structural requirement.11 Likewise, for substrates similarly bearing a lone-pair, such as alcohols or ethers or amines, the H-abstraction by t-BuO. (or other radicals as well) had been described to be more rapid than H-abstraction from simple hydrocarbons as a result of the specific contribution from stereoelectronic effects.11,12 We report here on our attempt to give quantitative support to these issues. Activation parameters for H-abstraction from the α-C–H bond in two amide substrates have been determined, and enable to assess the contribution from stereoelectronic effects in decreasing the energy value of the scissile C–H bond.
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Fig. 1 UV-Vis spectrum of a 0.5 mM solution of HBT in MeCN: (●) before the addition of CAN; after the addition of CAN (0.5 mM): (▼) 15 ms after the addition, (■) 110 s after the addition. |
The band pertains to the formation of the BTNO species: electron transfer from HBT to CAN is in fact exoergonic and occurs quantitatively (cf. Scheme 3).9 The spectrum of BTNO is not stable but decays according to an almost first-order exponential curve (kdecay = 5.1 × 10−3 s−1 in MeCN at 25 °C), with a half life of 140 s at 0.5 mM.9b The spontaneous decay of BTNO is strongly accelerated in the presence of purposely added H-donor substrates. By following the progress of the reaction at 474 nm through stopped-flow or conventional spectrophotometry, the reactivity of BTNO in the H-abstraction from the CH2-group in α to nitrogen is investigated here for a series of amides (ArCH2NHCOMe, cf. Schemes 3 and 4). Previous synthetic investigations had shown that the radical oxidation performed by either PINO or BTNO in the presence of O2 gives rise to carbonyl end-products (imide + aldehyde) from a common α-amido carbon radical intermediate originating from cleavage of the α-C–H bond of the amide substrate (Scheme 4).10,15
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Scheme 4 Pathways of products formation in the HAT route of oxidation of amides by an aminoxyl radical. |
For kinetic purposes, the solution of the C-H bearing substrate is employed here at initial concentrations higher than the concentration of BTNO, in order to fulfil the pseudo first-order kinetic conditions, and the drop of absorbance at 474 nm is followed. The pseudo-first-order rate constants k′, determined at 25 °C at three-to-four initial concentrations of amide from at least duplicated experiments, are converted into second-order H-abstraction rate constants (kH) by determining the slope of a k′vs. [SubH]° plot, as shown in Fig. 2 for the case of 4-chloro-N-benzylacetamide. Typical uncertainty of the kinetic data ranges from 3 to 6%.
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Fig. 2 Determination of the second order rate constant kH for reaction of BTNO with 4-chloro-N-benzylacetamide in MeCN at 25 °C, from the plot of the pseudo-first-order rate constants k′ at various initial concentration of the substrate. |
The k′ constants are faster than the spontaneous decay of BTNO in all cases investigated, as the linearity of the plot and the minor y-intercept in Fig. 2 demonstrates, and exhibit first-order dependence on the excess substrate concentration. The second-order rate constants (kH) are given in Table 1 for the substrates of this study, which includes the α,α-bisdeuterio-N-benzylacetamide purposely synthesized (vide infra).
Substrate | k H (M−1 s−1) |
---|---|
a Initial conditions: [BTNO] 0.5 mM, [SubH] 5–40 mM. Determinations in triplicate; typical errors 3–6%. | |
PhCH2NHCOMe | 0.49 |
PhCD2NHCOMe | 0.056 |
4-MeO-C6H4CH2NHCOMe | 2.54 |
4-Me-C6H4CH2NHCOMe | 1.17 |
4-Cl-C6H4CH2NHCOMe | 0.43 |
4-CF3-C6H4CH2NHCOMe | 0.26 |
4-NO2-C6H4CH2NHCOMe | 0.33 |
PhCH(Me)NHCOMe | 0.11 |
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|
N-Acetyl-tetrahydroisoquinoline | 26 |
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Fig. 3 Hammett plot for the reaction of 4-X-substituted N-benzylacetamides with BTNO in MeCN at 25 °C. |
Both the ρ and kH/kD data (−0.65 and 8.8) obtained here with the CAN/HBT oxidizing system compare favourably with the corresponding ones (i.e., −0.64 and 6.4, respectively) obtained in the oxidation of X-substituted benzyl alcohols by the copper enzyme laccase as the oxidant in the presence of HBT.19 The close agreement provides clear-cut support to the involvement of the very >N–O˙ radical BTNO as the reactive intermediate in that kind of chemo-enzymatic oxidation, in keeping with the necessary monoelectronic oxidation of mediator HBT by laccase as outlined in Scheme 5.14
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Scheme 5 The aerobic chemo-enzymatic oxidation of an H-donor substrate (Sub-H) by laccase with a >NO-H mediator. |
Therefore, the present kinetic study corroborates our trust in the mechanism of the chemo-enzymatic oxidation by laccase and mediator compounds having the >NO-H functionality.14
What energy value could the benzylic C–H bond of PhCH2NHCOMe have? The kH rate constant determined here (Table 1) for reaction of BTNO with PhCH2NHCOMe is 0.49 M−1 s−1; the kH determined under the same conditions for reaction of BTNO with PhCH2OH is very close in value (i.e., 0.94 M−1 s−1).9b Because we extrapolated a BDE(C-H) of 79 kcal/mol for PhCH2OH,9b the corresponding BDE(C-H) of PhCH2NHCOMe ought to be pretty close in value. Strangely enough, the reactivity of BTNO with the benzylic C–H bond of the amine PhCH2NEt2, despite a reported BDE(C-H) of 89 kcal/mol,20 was too fast to measure (> 100 M−1 s−1) with our kinetic device.9b The BDE(C-H) of the latter compound is 10 kcal/mol larger than the extrapolated BDE(C–H) of PhCH2OH, the kH of which was slow enough to measure.9b Either our extrapolated BDE(C-H) of PhCH2OH is too low, or the literature value of BDE(C-H) for PhCH2NEt2 is too high!
In the attempt to settle this point, we have determined the activation parameters for reaction of BTNO with PhCH2NHCOMe. The rate constants, measured in the temperature range of 12.5 to 49.8 °C according to the experimental procedure described above, are given in Table 2. From use of the Arrhenius equation (lnkH = lnA − Ea/RT),16 an Ea of 4.1 ± 0.2 kcal/mol is obtained. An analogous determination yields an Ea value of 3.1 ± 0.3 kcal/mol for reaction of BTNO with 4-MeO-C6H4CH2NHCOMe (Table 2).
PhCH2NHCOMe | 4-MeO-C6H4-CH2NHCOMe | ||
---|---|---|---|
k H (M−1 s−1) | T (°C) | k H (M−1 s−1) | T (°C) |
0.364 | 12.5 | 0.72 | 12.7 |
0.393 | 18.1 | — | — |
0.490 | 25.0 | 0.80 | 25.5 |
0.680 | 41.3 | 1.13 | 38.5 |
0.832 | 49.8 | — | — |
By entering the newly acquired Ea value (i.e., 4.1 kcal/mol) of PhCH2NHCOMe in the Evans-Polanyi plot already obtained for reaction of BTNO with a few benzylic substrates (Fig. 4),9b a BDE(C-H) of 71 kcal/mol can be extrapolated; analogously, for 4-MeO-C6H4CH2NHCOMe (Ea of 3.1 kcal/mol) a BDE(C–H) of 68 kcal/mol is extrapolated. On averaging these two numbers, one gets 70 (±2) kcal/mol for the dissociation energy of these particular C–H bonds: this certainly represents a small BDE value, particularly when compared to the archetypal benzylic BDE(C-H) of 88.5 kcal/mol of toluene.20 Such a conspicuous drop of C–H bond energy on going from PhCH3 to ArCH2NHCOMe, whatever the precision of our determinations is, is likely to be ascribed to the operation of stereoelectronic effects upon the amide substrate, as we comment on in the next section.
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Fig. 4 Evans-Polanyi plot for reaction of BTNO with benzylic substrates (from ref. 9b), and extrapolation of the BDE(C-H) of PhCH2NHCOMe from the Ea value obtained (see text). |
Actually, the issue could be even more complex than this, as a referee has correctly pointed out. First, we neglet the effect of the solvent when comparing kinetic data vs.BDE data. Hydrogen bonding between our solvent (MeCN) and substrates such as PhCH2NHCOMe or PhCH2OH can certainly affect the rate constants. However, the Evans-Polanyi plot of Fig. 4 shows good linearity for five substrates encompassing alkylarenes and benzylic alcohols, regardless their apolar or polar nature. Therefore, the hydrogen bonding issue provides only a partial explanation for the discrepancy between rate constants and BDE values stressed above. Secondly, we can not exclude that the high rate constant obtained9b for reaction of BTNO with PhCH2NEt2 is rather due to the incursion of a mechanism different from the HAT one. For example, the abstraction of electron (ET) by BTNO from the electron-rich PhCH2NEt2 could be alternatively envisioned. A similar ET route is documented for reaction of the aminoxyl radical PINO (0.92 V/NHE for the PINO/PINO- redox couple) with 4-X-substituted-N,N-dimethylanilines (redox potentials in the 0.5–1.1 V/NHE range), as reported recently.1,21 Benzyl amines are however more difficult to remove an electron from (redox potentials > 1 V/NHE)22 than anilines, and an ET route between BTNO and PhCH2NEt2 could be thought as less favoured. For sure, an ET route between BTNO and the present series of amides can be disregarded in view of redox potential considerations, as the one-electron oxidation of PhNHCOCH3 has a redox potential >1.8 V/NHE.23 Anyhow, we take the ET point as a sound suggestion, and work has already been planned in order to better investigate the boundaries of the ET/HAT dichotomy for reaction of aminoxyl radicals with benzylamines.
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Fig. 5 Stereoelectronic interaction between the lone-pair of an amine and a C–H bond. Reprinted with permission from Griller et al. (ref. 11). Copyright (1981) American Chemical Society. |
This interaction reportedly accounts for a 7–9 kcal/mol weakening of the C–H bond.12 For torsion angles (θ) wider than 30°, the effect drastically fades away.11 Our above finding of a substantial reduction of BDE(C-H) when passing from PhCH3 (88.5 kcal/mol) to PhCH2NHCOMe (71 kcal/mol) is likely due to the stereoelectronic interaction from the nitrogen lone-pair of the amide with the scissile C–H bond.
Additional data obtained from specific substrates enable us to further address the stereoelectronic issue. In a previous synthetic investigation,15 the oxidation of N-acetyl-tetrahydroisoquinoline by BTNO gave evidence for exclusive functionalization at C1, i.e., at the C–H bonds α to nitrogen, to produce an imide compound (cf. Scheme 4 and Fig. 6. Our present kinetic data (Table 1) point out that H-abstraction from N-acetyl-tetrahydroisoquinoline is indeed much faster (ca. 20–40 fold) than from the structurally comparable but acyclic C6H5CH2NHCOMe or 4-Me-C6H4CH2NHCOMe. Simple modelling with Hyperchem shows that in N-acetyl-tetrahydroisoquinoline the benzylic C–H bond of C1 is almost co-linear with both the p-orbitals of the aromatic ring and with the nitrogen lone pair (Fig. 6), being kept in this profitable conformation by steric restrictions caused by the heterocyclic system. This double beneficial effect is likely to weaken that C–H bond, as well as to stabilize the intermediate benzyl radical at C1 (Fig. 6). In the acyclic counterparts, instead, free rotation of the chain partially disrupts a similarly profitable conformation of the corresponding C–H bond, and lessens the extent of stabilisation of the intermediate radical ArCH(˙)NHCOMe.
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Fig. 6 Stabilising interaction from both the π-system and the nitrogen lone-pair to the C1 radical resulting from H-abstraction in N-acetyl-tetrahydroisoquinoline by BTNO. |
As another example, the kH rate constants of PhCH(Me)NHCOMe and PhCH2NHCOMe with BTNO (Table 1), when normalized for the number of equivalent H-atoms, are 0.11 and 0.24 M−1 s−1 respectively (or 0.46:1 in relative terms), thereby indicating an unfavourable contribution from the α-Me-substitution upon reactivity. In principle, H-abstraction from the secondary benzylic C–H bond of PhCH(Me)NHCOMe ought to be easier and faster than for the primary C–H bond of PhCH2NHCOMe. This is consistent with the relative reactivity of H-abstraction from ArCH2CH3 and ArCH3 (normalised for the number of equivalent H-atoms)9b by BTNO, that is 4.2:1 (see also below), as well as with the BDE trend of a secondary vs primary benzylic C–H bond.20 The specific unfavourable effect from α-Me substitution in PhCH(Me)NHCOMe offsets the expected easier cleavage of its secondary C–H bond, and accounts for an overall depression of the H-abstraction rate by ca. 9 fold (i.e., 4.2/0.46). A plausible explanation for this unfavourable effect would be that PhCH(Me)NHCOMe is conformationally more stable (Fig. 7, left structure) whenever the larger groups in α, either Me- or–NHCOMe, are co-linear with the aromatic p-orbitals in order to lessen clash with the aromatic ortho C–H bonds.
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Fig. 7 Limiting conformations of PhCH(Me)NHCOMe and PhCH2NHCOMe. The section of the aromatic ring is represented as a rectangle. |
Consequently, the benzylic C–H bond is preferentially directed in the ring plane, where any incipient α-amido carbon radical resulting from H-abstraction would not experience π-stabilisation. This is going to slow down the oxidation with respect to PhCH2NHCOMe (Fig. 7, right structure), where co-linearity of one α-C–H bond with respect to the plane of the aromatic ring is always feasible.
In order to support this conformational issue, the hydrogen abstraction rate constants by BTNO from a series of benzyl alcohols have been determined in MeCN at 25 °C, and are reported in Scheme 6.
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Scheme 6 Absolute (normalised) and relative rate constants of H-abstraction by BTNO. |
Once again, whereas abstraction of a secondary H-atom is 1.9 fold faster than that of a primary one, in keeping with the corresponding BDE values,20 co-linearity of the t-Bu-group with the aromatic p-orbitals in the tertiary alcohol is preferred because lessens steric hindrance (cf. Fig. 7, left structure), thereby pushing the scissile C–H bond in the ring-plane where no π-stabilization is experienced, and resulting in a depression of reactivity (krel = 0.74).
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