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An FeV(O) complex has been synthesized from equimolar solutions of (Et4N)2[FeIII(Cl)(biuret-amide)] and mCPBA in CH3CN at room temperature. The FeV(O) complex has been characterized by UV–vis, EPR, Mössbauer, and HRMS and shown to be capable of oxidizing a series of alkanes having C–H bond dissociation energies ranging from 99.3 kcal mol−1 (cyclohexane) to 84.5 kcal mol−1 (cumene). Linearity in the Bell–Evans–Polayni graph and the finding of a large kinetic isotope effect suggest that hydrogen abstraction is engaged the rate-determining step.
High valent iron-oxo intermediates play key roles in enzymatic oxidations.1–5 For example, in the cytochrome P450 enzymes, the high valent FeIV(O)(porphyrin–radical–cation), isoelectronic with FeV(O), has been shown to be the reactive intermediate in the selective hydroxylation of camphor.2,6 In the Rieske dioxygenase enzyme family,1 an FeV(O) active intermediate has been proposed.7,8 Several functional models of both heme9 and nonheme10–13 iron-dependent monooxygenase enzymes have been synthesized15–18 including the TAML system, which has provided fully functional, small molecule replicas of the peroxidase and short-circuited P450 enzymes.12,13 For nonheme iron catalyzed oxidations, FeIV=O active intermediates have been isolated and structurally characterized and their reactivity toward C—H bond hydroxylation has been studied in detail.9,14–16 Synthetic functional models of Rieske dioxygenase family of enzymes have been postulated to engage an FeV(O) reactive species in C—H and C=C bond oxidations.17,18 Several complexes having FeV(O) have been reported, and they are thermally not stable above −40 °C.19,20 Que et al. has described the formation of an FeV(O) complex from [FeIV(O)(TMC)-(MeCN)]2+ at −44 °C (t1/2 = 60 min).21 Recently, Costas et al. has reported formation of a purported FeV(O) at −60 °C (characterized using mass spectroscopy) and studied its reactivity.18 Collins et al. first produced a nonheme FeV(O) complex by oxidation of an FeIII-TAML complex at −60 °C using m-chloroperbenzoic acid (mCPBA); this was thoroughly characterized by UV–vis, ESI–MS, EPR, EXAFS, and Mössbauer spectroscopies.22 The FeV(O) intermediate was shown to be reactive toward sulfoxidation and epoxidation in the −40 to −60 °C range in nitrile solvents.22,23 However, to date it has not been possible to characterize and explore the ambient conditions for the reactivity of an FeV(O) complex because no system has been stable enough to permit this. The availability of an FeV(O) complex that is both stable and reactive at ambient to physiological temperatures would have the potential to advance insight into enzymatic oxidation processes and especially oxidations of the C–H bonds of unactivated alkanes, which are among the most difficult of all oxdiation processes to carry out in a controlled fashion.
We have recently reported the first preparation and initial studies of an FeIII complex of a biuret-amide based macrocyclic ligand, 1,24a a member of the broad suite of catalysts called TAML activators that were invented by Collins in the mid-1990s.24b Complex 1 is the first member of a fifth generation of TAML activators—generation numbers mark the order of preparation of sets of TAML activators with distinctive structural motifs. Activator 1 differs from the prototypical first generation TAML activator by substitution of the CMe2 moiety in the six-membered macrocylic subring25 with an –NMe group (Figure 1). The planar six-membered ring allows electron donation from –NMe group and subsequent delocalization of the electron density throughout the ring.26 This is evident in electrochemical studies where the FeIV/FeIII couple of 1 is 230 mV higher24a than the corresponding Fe-TAML. This in addition to the fact that the –NMe group is situated far away from the Fe center made us to believe that FeV(O) complex (2) should have stability at temperatures higher than −40 °C.22,23 In this article, we report the formation and characterization of the FeV(O) complex 2 from 1. Remarkably, 2 is sufficiently stable that it can be produced quantitatively and its reactivity can be examined at room temperature. We also demonstrate that 2 readily cleaves the unactivated alkane C–H bond of cyclohexane; studies of the kinetics lead to the conclusion that H atom abstraction by FeV(O) is the rate determining step (r.d.s) in the resulting hydroxylation process (Figure 1).
Complex 2 was prepared at 25 °C from the parent TAML activator, (Et4N)2[FeIII(Cl)(biuret-amide)] 1, in CH3CN by adding equimolar amounts of mCPBA.22 Addition of 0.5 equivalent of mCPBA (5 × 10−5 M) to 1 (10−4 M) at RT in CH3CN with exclusion of O2 afforded a violet-colored solution. Addition of a second half equivalent of mCPBA to this violet solution resulted in the formation of a green solution with distinct absorption maxima at 441 nm (ε = 4.35 × 103 M−1 cm−1) and 613 nm (ε = 3.42 × 103 M−1 cm−1) (Figure 2A). The green solution was examined by mass, EPR, and Mössbauer spectroscopies. A sample of the green solution was split and frozen in liquid nitrogen and then analyzed with EPR and Mössbauer spectroscopies. The X-band EPR spectrum at 21 K showed a rhombic S = 1/2 species with g = 1.983, 1.935, 1.726 (Figure 2D). Spin quantification indicated quantitative conversion of the starting FeIII complex (1) to the corresponding FeV(O) (2). The Mössbauer spectrum of 57Fe enriched 2 at 4 K showed a doublet with an isomer shift of Δ = −0.44 mm/s and quadrupole splitting of ΔEq = 4.27 mm/s (Supporting Information Figure SI 1). A paramagnetic pattern is not observed, and the doublet is broad due to intermediate relaxation of the spin system. The intermediate relaxation and broad EPR signal suggest molecular aggregation. The g-values and Mössbauer parameters are close to those of the FeV(O) complex reported previously.22 Both the EPR and Mössbauer spectral analyses suggest quantitative conversion (≥95%) of the starting 1 to 2 (Figure 2 and Supporting Information Figure SI 1). This is in contrast to the FeV(O) prototype TAML, where only 70% of FeV was produced from the starting FeIII complexes at −40 °C (by Mössbauer spectroscopy).22 HRMS examination of 2 in CH3CN revealed one prominent ion at a mass-to-charge ratio of 429.0745 (calculated m/z 429.0730); the isotopic distribution pattern corresponded to that expected for 2 (Figure 2C). HRMS analysis of a solution prepared by introduction of H2 18O (0.5 μL) into the solvent media during the synthesis of 2 showed 70% formation of FeV(18O) (m/z 431.078, Supporting Information Figure SI 2).
Addition of 1 equiv of 1 to 2 also resulted in formation of a violet solution, the UV–vis spectrum (Figure 2A) of which was identical to the solution formed by addition of 0.5 equiv of mCPBA to 1. This common UV–vis spectrum with its conspicuous features at long wavelengths was very similar to the known UV–vis spectra of μ-oxo-(FeIV)2 species of established Fe-TAML complexes.23,27 Moreover, the violet solution was found to be EPR silent. Because they were diamagnetic, their 1H NMR spectra was recorded (Supporting Information Figure SI 3), which again reproduced the behavior of the parent (FeIV)2O TAML complexes.27 The rate of comproportionation between 1 and 2 was determined to be 1.00 × 105 M−1 s−1, twice the rate of the corresponding process for the prototype TAML (NMe replaced by CMe2, Supporting Information Figure SI 4), consistent with the less sterically encumbered nature of the biuret system.23 A detailed study to elucidate the nature of this FeIV is currently underway.
The spontaneous reduction of FeV to FeIV/FeIII was studied using UV–vis spectroscopy by monitoring the decrease characteristic 613 nm band of 2. The initial rate of the decay was found to be first order with respect to 2 and the first order rate constants for the decay (k5/4,3) were determined from the slope of the straight lines at three different temperatures of 25, 10, and 4 °C (Supporting Information Figure SI 5). The k5/4,3 value at 25 °C (4.45 × 10−5 s−1) was similar to the FeV(O) prototype TAML reported at −40 °C,23 showing that the biuret-substituted TAML ligand leads to a much more stable FeV(O) complex. In fact, 2 is the first example of an FeV(O) complex that is stable at room temperature. The stability of the FeIV species (generated by reaction of 1 with 0.5 equivalent of mCPBA) was determined by monitoring the decrease of a characteristic band at 428 nm. Over time, this proposed (FeIV)2O slowly converted to 1.
The unprecedented high stability of 2 has allowed us to examine its room temperature reactivity. Activation of C–H bonds by 2 at room temperature were studied for a range of hydrocarbons with bond dissociation energies (BDE), spanning 85–100 kcal mol−1.28 Excess cyclohexane (1000 equiv) was added to a solution of 2 (10−4 M) in CH3CN at 25 °C with exclusion of O2, and the reaction was monitored by UV–vis spectroscopy. Upon addition of cyclohexane, spectral scans showed the rapid formation of a mixture of FeIV and FeIII species, which then slowly converted to 1 (ESI–MS, UV–vis confirmation, Figure 3). GC and GC–MS analysis indicated cyclohexanol and cyclohexanone as products (Table 1), showing 2 is capable of effective oxygen atom insertion into an unactivated C–H bond. Based on the concentration of 2, the yield of the reaction was determined to be 42% with an alcohol to ketone ratio of 9:1 (Table 1, Supporting Information Figures SI 6 and SI 7). Reactions of 2 with substrates having stronger and weaker C–H bonds than cyclohexane were also studied. Addition of benzene (BDE of C–H ~110 kcal mol−1) to a solution of 2 showed no additional change in the UV–vis spectrum and no product was observed by GC–MS. In contrast, substrates having lower BDE like cumene, ethylbenzene, toluene, and 2,3-dimethylbutane (DMB) reacted more rapidly with 2 than with cyclohexane. In the case of DMB, 2 selectively hydroxylated the tertiary C–H bond (BDE ~96 kcal mol−1, Table 1) in preference to the primary C–H bond (BDE ~99 kcal mol−1), leading exclusively to the formation of 2,3-dimethyl-2-butanol.
To confirm, if part of the product obtained was due to the reaction with the FeIV species, which is initially formed upon addition of substrate to 2, the reactivity of the FeIV species (generated by the reaction of complex 1 with 0.5 equiv of mCPBA) toward C–H activation was also explored. It was found from UV–vis, GC, and GC–MS studies that the reaction of cyclohexane with FeIV species did not lead any product formation on the time scale (≥6 h) of the experiments.
Extensive kinetic studies were performed to ascertain the nature of the hydroxylations by 2 using UV–vis spectroscopy at the isosbestic points for FeIII and FeIV interconversions (353 and 400 nm) under pseudo-first-order conditions. The pseudo-first-order rate constant (kobs) calculated from the absorbance vs time traces at both wavelengths were obtained from nonlinear curve fitting [(At = Aα – (Aα – Ao)e(−kobst)] (Supporting Information Figures SI 8 and 9) and exhibited good agreement in rate constant values within 5% error. The kobs values thus obtained correlated linearly with the substrate concentration to provide the second order rate constant k2 (Supporting Information Figure SI 9), and it was observed that the rate constant decreased with an increase in the BDE of C–H bonds in the substrates. Linearity in Bell–Evans–Polanyi (BEP) relation was found from the plot of log k2′ (k2/the number of equivalent H atoms) vs BDE (Figure 3)28 for all the substrates from cyclohexane to cumene (slope of −0.17). This linearity supports hydrogen abstraction (H•) from a C–H bond by FeV(O) group of 2 in the r.d.s as has been previously reported for [FeIV(O)(N4Py)(CH3CN)] complexes.29 A significant kinetic isotope effect (KIE) of 9 was observed for toluene/toluene-d8 at 25 °C, supporting the conclusion that the r.d.s entails abstraction of an H atom from the C–H bond by the FeV(O) (Figure 3, inset); KIEs of 2.1 and 6.5 have been found for typical porphyrin π-radical cation [(4-TMPyP)•+ FeIV(O)]+ and [(TMP)•+ FeIV(O)(p-CH3–PyO)]+ with xanthene and xanthene-d2, respectively.9,29,30 Oxygen incorporation from FeV(O) into the cyclohexane was followed by using 55% O18 labeled FeV, which resulted 35% O18 enriched product, supporting a rebound mechanism. (Supporting Information Figure SI 7).
Thus, the data supports the conclusion that the mechanism of C–H activation by 2 involves initial abstraction of an H atom from the hydrocarbon substrate by FeV(O) followed by rebound to yield the oxidized product together with the regeneration of the parent FeIII complex 1 (see Figure 3A and Supporting Information Figure SI 10 for pictorial representations of the proposed mechanism). The FeIII complex 1 thus formed undergoes rapid comproportionation (Supporting Information Figure SI 4) with 2 to form the observed μ-oxo-(FeIV)2 product (UV–vis, 1H NMR). Kinetic studies of the comproportionation reaction between 2 and 1 show that the second order rate constant (1.00 × 105 M−1s−1; see Supporting Information Figure SI 4) is at least 105-fold faster than the rate for C–H activation. Because this comproportionation reaction is extremely fast, the direct conversion of 2 to 1 is not observed in initial spectral scans. This is also corroborated by the observation that the product formation in all the reactions is less than 50% for all the substrates. Similar observations have been reported for sulfide oxidation by the parent FeV(O) TAML activator. However, in this system, the likely (FeIV)2O product formed by reacting 2 and 1 undergoes further slow reduction to finally yield 1. The faster self-reduction of our FeIV species is in contrast to the prototype Fe-TAML system, where the μ-oxo-(FeIV)2 is extremely stable and does not undergo reduction. Because the FeIV species is not reactive toward oxidation of alkanes, the formation of the oxidized product in the reaction is solely due to the reaction of alkanes with 2. Preliminary experiments performed in the presence of O2 show high amounts of ketone formation in respect to the corresponding alcohol, indicating that the radical formed after C–H abstraction is capable of reacting with O2, as has been proposed before.30
In conclusion, we have successfully synthesized an FeV(O) complex of a biuret-containing TAML activator at room temperature. EPR and Mössbauer spectroscopic studies show quantitative conversion of FeIII (1) to the FeV(O) complex. This complex displays remarkably higher stability at room temperature than any previously reported FeV-oxo complex. This higher stability has allowed us to study oxidation reactions with alkanes having strong C–H bond, such as that in cyclohexane (BDEC–H = 99.3 kcal mol−1), at room temperature. This is the first report of a well-defined FeV(O) species that has been shown to react with strong C–H bonds. It was observed that 2 oxidizes cyclohexane to cyclohexanol and cyclohexanone with high reaction rates, k2 at 25 °C is (2.26 ± 0.10) × 10−2 M−1 s−1 (Supporting Information Figure SI 9).31 It is possible that the subsequent oxygen atom incorporation may proceed by either rebound mechanism or a dissociative mechanism or a combination of both, as has been recently proposed.32 Studies aimed at further understanding the complete reaction mechanism including efforts to crystallo-graphically characterize 2 are underway.
S.S.G. acknowledges DAE (BRNS; Grant no 2009/37/33/BRNS) for funding. M.G., K.K.S, and C.P. acknowledge CSIR (Delhi) for fellowships. B.B.D. also acknowledges CSIR for a SRA position. S.S.G. and M.G. thank Dr. A. Ryabov for discussion. S.S.G. thanks Dr. Nandini Devi, Dr. Amol Kulkarni and Dr. H. V. Thulasiram for help with UV–vis, GC and GC–MS.