Kinetics and mechanism of PPh₃ oxygenation with ³O₂ catalyzed by a 1,3,2-oxazaphosphole as flavin mimic

Abstract

A 1,3,2-oxazaphosphole picks up triplet dioxygen in 1 : 1 stoichiometry similar to flavin organic co-factors. 1,3,2-Oxazaphosphole catalyzes the oxygenation of triphenylphosphine to triphenylphosphine oxide. The reaction obeys an overall third order rate equation. In a radical pathway, organic hydroperoxide is formed from the catalyst and ³O₂, which oxygenates PPh₃, similar to flavin cofactors.

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The oxygenation/oxidation of organic substrates, with triplet dioxygen as a primary oxidant, is a desirable method for economical and environmental¹ reasons. However, spin restriction² and thermodynamic³ burden hamper its reactivity. In order to circumvent these problems, transition metal complexes⁴ and energy-rich organic compounds⁵ (co-factors such as pterins⁶ and flavins⁷ in biology) are necessary to activate dioxygen for these reactions.

Previously, we found that 1,3,2-oxazaphospholes can easily be prepared through a reaction of quinone monoimines with triphenylphosphine in a [4 + 1] electrocyclic reaction, or quinones with triphenylphosphine in the presence of ammonia in a sealed tube in good yield.⁸ Later, to our surprise, we observed that 1,3,2-oxazaphospholes react with triplet dioxygen in a stoichiometry of 1 : 1 (Fig. S1†). In different solvents, the same amount of O₂ was taken up with various velocities (Fig. S2†). The peroxide formed is not stable at room temperature. Iodometric titration of the oxygenated solutions of 3 resulted in a peroxide content of 10–30%, immediately after titration. This O₂-uptake is very similar to flavin models in which N,N,N,-3,5,10-trialkylated flavins (1) were used, and it was demonstrated that, in their reaction with ³O₂, flavin hydroperoxides (2) can be generated.⁹ We assumed that, in a similar manner, 2,2-dihydro-2,2,2-triphenylphenanthro[9,10d]1,3,2λ⁵-oxazaphospholes (3) give alkylhydroperoxides (4) (Scheme 1), which can oxygenate/oxidase various singlet organic compounds.

Scheme 1 Similarities in flavin models (1) and 2,2-dihydro-2,2,2-triphenylphenanthro[9.10d]1,3,2λ⁵-oxazaphosphole (3) reactions with ³O₂ to give hydroperoxides 2 and the hypothetical hydroperoxide 4.

Kinetic studies resulted in an overall third order rate equation, reaction rate = k_obs[catalyst][PPh₃][O₂] with a k_obs value of 39.10 ± 0.82 × 10⁻² M⁻² s⁻¹. The time course of the reaction is shown in Fig. 1, which was measured by UV-Vis spectroscopy¹⁰ at 260 nm (Fig. S3†). The dependence on the triphenylphosphine and dioxygen concentrations was also shown to be first order using reaction rate vs. initial concentrations of PPh₃, catalyst (3) and O₂ plots (Fig. S4–S6†).

Fig. 1 Time course of the oxygenation of PPh₃ catalyzed by 3. Temperature 80 °C and 1 bar O₂ pressure, [PPh₃]_o = 0.5 M, [3] = 2.5 × 10⁻³ M, 20 mL DMF. TON = 160, TOF = 5.7 h⁻¹.

Labeling experiments using ¹⁸O₂ clearly demonstrated that the O-atom of triphenyphosphine oxide originates from O₂. The ν(P=O) frequencies being 1190 and 1153 cm⁻¹ for ¹⁶OPPh₃ and ¹⁸OPPh₃, respectively (Fig. S7†).¹¹ The activation parameters E_a = 31.6 ± 2.9 kJ mol⁻¹, ΔH^‡ = 28.7 ± 2.9 kJ mol⁻¹ and ΔS^‡ = −174 ± 8 J mol⁻¹ K⁻¹ of the catalytic reaction suggest that the transition state is very crowded, and the small value for the activation energy indicates the easiness of the reaction.

In order to clarify some points of the reaction mechanism, we measured possible radicals formed during the catalytic reaction. Fig. 2 shows that a well-resolved spectrum of the organic radical 7 could be found. This red-colored, persistent radical could also be generated from the reaction of the 1,3,2-oxazaphosphole (3) and TEMPO [(2,2,6,6-tetramethylpyperidin-1-yl)oxyl]. It is non-reactive against dioxygen at room temperature for days. However, it reacts rapidly with KO₂ with diminishing red color, resulting in a green-colored solution (Fig. S8†). On the other hand, the addition of triethylamine accelerated the reaction rate (Fig. S9†), which suggests that deprotonation accelerates the reaction. According to these kinetic data and spectroscopic findings, we propose a mechanism as shown in Scheme 2. According to this mechanism, 1,3,2-oxazaphosphole (3) is in equilibrium with the iminophosphorane tautomer 5. Then, this is deprotonated either by triphenylphosphine or added triethylamine, resulting in the deprotonated iminophosphorane (6). Triethylamine, added in a 1 : 1 molar ratio to the catalyst, makes the reaction faster within the margin of error as rapidly as a 5 : 1 triethylamine : catalyst ratio. This means that, in a 1 : 1 ratio, the iminophosphorane is almost completely deprotonated. The phenolate anion, which has a high energy HOMO orbital and is very energy-rich,¹³ easily donates an electron in a SET (Single Electron Transfer) reaction to the dioxygen, resulting in the radical 7 and superoxide anion. Unfortunately, production of the superoxide anion could not be proven with any spin traps¹⁴ due to its consecutive reactions, the short life time of the adduct and superposition in the EPR spectra. However, NBT (nitroblue tetrazolium chloride)¹⁵ tests were positive. Production of the organic radical 7 was proven by EPR (Fig. 2) and it reacts with superoxide anion (KO₂) to 9 (Fig. S8†). The red color changes to greenish indicating the reaction of the radical to the hydroperoxide (4) and to its decomposition products. Similarly, hydroperoxide has been prepared and characterized by X-ray measurement from 3,4,6-triisopropylcatechol with di-tert-butylperoxide and dioxygen.¹⁶ The formation of the unstable hydroperoxide 4 is the rate-determining step (k_obs), which also involves the various pre-equilibria and fast protonation of 9. The course of the catalytic reaction of the hydroperoxide 4 with the substrate PPh₃ (Scheme 3) may take two pathways: oxygenating the bound phosphorus as part of the iminophosphorane (4), a part of the catalyst (pathway a), or that of added PPh₃ being oxygenated to the oxide (pathway b).

Fig. 2 The EPR spectrum of 7. Blue = measured, red = simulated, g = 2.0032, a_P = 6.90, a_N = 1.10, a_H1–7 = 2.35, 2.26, 2.11, 0.85, 0.79, 0.73, 0.67 G.¹²

Scheme 2 Proposed mechanism of hydroperoxide (4) formation.

Scheme 3 Pathways a and b for the oxygenation of PPh₃ by the hydroperoxide 4.

In reaction path a where the iminophosphorane is oxygenated, 9-nitroso-10-hydroxyphenanthrene (10) is formed, which is the tautomeric form of 9,10-phenanthrenequinon oxime.¹⁷ This is also able to transfer an O-atom to PPh₃ resulting in 9,10-phenanthrenequinone monoimine (Fig. S10†) and with additional triphenylphosphine, the iminophosphorane (5) is reformed. Pathway b starts with the classical oxygenation of PPh₃ and 11 is formed. Thereafter, triphenylphosphine abstracts an O-atom from 11, which results in triphenylphosphine oxide and iminophosphorane (5) is formed at the conclusion of the catalytic cycle.

Conclusions

Although triplet dioxygen does not react with ground state but primarily with singlet organic molecules, its activation beside transition metal complexes can be done with some organic molecules, such as flavin mimics. It has been disclosed that 2,2-dihydro-2,2,2-triphenylphenanthro[9.10d]1,3,2λ⁵-oxazaphosphole reacts with ³O₂ under ambient conditions and catalyzes the oxygenation of triphenylphosphine to its oxide. Labeling experiments indicated that the source of oxygen in triphenylphosphine oxide originates from dioxygen. On the basis of kinetic and spectroscopic data, a possible radical mechanism is proposed. The O-transfer to triphenylphosphine from the hydroperoxide differs from the usual H₂O₂ (ref. 18) or hydroperoxide¹⁹ oxygenation since, in the present case, both O-atoms of the hydroperoxide are transferred to the triphenylphosphine. However, the scope of the catalytic oxidations/oxygenations remains to be elaborated.

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Footnote

† Electronic supplementary information (ESI) available: Method of kinetics, kinetic data, UV-Vis spectra, infrared spectra, and activation parameters of the reaction. See DOI: 10.1039/c4ra01320d

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