Role of catalytic nitrile decomposition in tricopper complex mediated direct partial oxidation of methane to methanol

Synthetic homogeneous system known to date performing methane to methanol conversion using O2 as terminal oxidant is unique and based on copper complex with piperazine-based ligand (Cu3L in Fig. 1) in a medium of acetonitrile. Prior work have shown that in order to achieve catalytic turnover, hydrogen peroxide is needed to regenerate the active site. We show in this paper that reaction solvent based on organic nitrile decompose concurrently with methane activation and that in the absence of either acetonitrile, Cu complex or hydrogen peroxide, the catalytic turnover does not happen. We show in this manuscript that the direct methane oxidation to methanol might have been mediated by catalytic Radziszewski oxidation between acetonitrile and H2O2. Additionally we have discovered that in the absence of methane, peroxide mediated acetonitrile decomposition also makes methanol via a background reaction which was hitherto unknown.


Synthetic homogeneous system known to date performing methane to methanol conversion using O 2 as terminal oxidant is unique and based on copper complex with piperazine-based ligand (Cu 3 L in
) in a medium of acetonitrile. Prior work have shown that in order to achieve catalytic turnover, hydrogen peroxide is needed to regenerate the active site. We show in this paper that reaction solvent based on organic nitrile decompose concurrently with methane activation and that in the absence of either acetonitrile, Cu complex or hydrogen peroxide, the catalytic turnover does not happen. We show in this manuscript that the direct methane oxidation to methanol might have been mediated by catalytic Radziszewski oxidation between acetonitrile and H 2 O 2 . Additionally we have discovered that in the absence of methane, peroxide mediated acetonitrile decomposition also makes methanol via a background reaction which was hitherto unknown.
Methane monooxygenase serves as a model to develop biomimetic complexes to turnover methane to methanol under mild conditions. In a remarkable study, Chan et al. introduced the Cu 3 LO 2 complex made after pMMO active site [1][2][3] . Mechanistic differences in the Cu 3 LO 2 complex 3 and Cu-oxo clusters in zeolites are still unresolved 4-6 . Chan et al., showed that in the absence of methane, the use of O 2 and H 2 O 2 as oxidant and reductant could lead to an abortive cycle 7 . The supported version of this catalyst exhibited 171 turnover number when using nearly 200 equivalents of H 2 O 2 in the presence of acetonitrile 8 . Although the supported hybrid organic-inorganic Cu complex showed a high degree of selectivity, the system did not exhibit catalytic turnover using O 2 as terminal oxidant. We had tried H 2 + O 2 , Au-Pd/TiO 2 system 9 for generating hydrogen peroxide in situ along with Cu 3 L complex where we saw almost no methanol formation with water as the solvent. We had also looked at tert-Butyl hydroperoxide (TBHP) which did not succeed as a reducing agent for Cu 3 L regeneration. Given that the Cu 3 L complex does neither turnover with O 2 , nor in aqueous solution we sought to further probe the role of acetonitrile in this catalytic mechanism 3 . The Radziszewski oxidation 10,11 proceeds via nucleophilic addition of hydroperoxide anion to an organic nitrile carbon to afford peroxyimidate which spontaneously undergoes a rearrangement reaction to release singlet oxygen and amide 12 . The evolution of reactive oxygen species from this nitrile decomposition is used for affording selective partial oxidation of a number of functional groups such as sulfoxidation 13,14 , epoxidation 15 , and Bayer-Villiger oxidation 16 . Peroxide and acetonitrile combination in the presence of metals catalyze the partial oxidation of alkanes [17][18][19][20] . Complexes of Cu(II) along with H 2 O 2 result in producing O 2 and OH . radicals via a Cu(II)/Cu(I) redox cycle 21 . Copper catalyzed decomposition of H 2 O 2 is well studied through Fenton like autocatalysis 22 , alkaline solutions 23 , and Cu(I)/Cu(II) and Cu(II)/Cu(III) redox pairs 24 . We probed the rate of Cu(I) incorporation to form the Cu 3 L framework. Ligand structure controls the copper oxygen bonding type 25 and substrate angle by steric effects 3,26 . UV-Vis data indicates counter anions 27 can alter the redox properties as indicated by a shift in the charge transfer bands for bidentate ligands 28 with fewer coordinating anions leading to bis(µ-oxo)dicopper(III) and more strongly coordinating anions leading to peroxodicopper(II). Spectroscopic methods are capable of determining the nature of copper oxygen bonding species 29 . ESI-MS analysis is used to show qualitative purity of Cu 3 L complex species in a solution 30 . There are instances of acetonitrile and hydrogen peroxide environments for C-H bond activation where solvent decomposition and generation of reactive oxygen species through acetonitrile oxidation has not been investigated 31 www.nature.com/scientificreports/ Palomas et al., used multicopper complexes for methane oxidation which was rather selective towards CO 2 39 . In all instances of such complexes showing activity, there was a medium of peroxide and nitriles present 1,3,7,[40][41][42] . Previously the role of acetonitrile as a mediator for oxygen transfer was not known. Here we further elucidate mechanism by independently assessing various organic nitrile decomposition with peroxide.

Results
Ligand 3,3′-(1,4-diazepane-1,4-diyl)bis[1-(4-ethylpiperazine-1-yl)propan-2-ol] (7-N-Etppz) and copper incorporation into this complex is controlled by time and ligand ratio as indicated by the ESI-MS stacked plot (Supplementary Fig. 2-3). Acetonitrile attaches to the complex in nearly all of the tricopper complex species Supplementary Fig. 2-4. More tricopper species are formed with acetate and perchlorate than with tetrafluoroborate, exemplified by Supplementary Table 1. The ligand species is indicated by 441 m/z, and 503 m/z is the monocopper incorporated species. When the ratio of copper to ligand is around 3, the ligand fully incorporates into the complex ( Supplementary Fig. 3). The spectroscopic characteristics are summarized in Supplementary  Table 2. Characterization spectroscopically helps determine copper species as summarized in EPR Table Supplementary Table 3. Addition of hydrogen peroxide led to hyperfine coupling features in EPR hence less interactive Cu II core, while the oxidized Cu 3 LO 2 complex has broad features indicative of closely interacting Cu II core. The complex with BF 4 precursor does not show signal prior to oxidation since all is in Cu I form. UV-Vis characterization of oxidized ( Supplementary Fig. 5) and H 2 O 2 treated (Supplementary Fig. 6) indicates closed complex and integrated clusters with Acetate and ClO 4 counter anions. H 2 O 2 addition reduces the oxide-to-Cu II LMCT. Since nitrile coordinates towards copper site in the complex, it becomes susceptible to nucleophilic attack. Figure 1 and Supplementary Table 4 summarize the Radziszewski acetonitrile partial oxidation. The copper (I) 7-N-Etppz complex and H 2 O 2 are required to produce hydrolysis products of acetonitrile (Supplementary Table 4, entries 1-5). With the copper salt and addition of hydrogen peroxide without the ligand there is some acetonitrile hydrolysis and minimal acetic acid production. Water is incapable of carrying out the hydrolysis. Among copper precursors, BF 4 salt produces the most active complex in hydrolyzing MeCN (Supplementary  Table 4, entry 11). To examine the extent of complex activity towards hydrolyzing acetonitrile, we performed reactions with high H 2 O 2 to acetonitrile ratio which led to significantly higher amounts of acetamide and acetic acid products (Supplementary Table 4, entry 10-11). Figure 2 shows that initially, the rate of acetonitrile to acetamide oxidation is faster than the subsequent amide to acid hydrolysis. At a certain point the acetamide concentration decreases due to hydrolysis to acetic acid. The nitrile decomposition reaction ceases after about two hours due to complex deactivation and hydrogen peroxide degradation ( Supplementary Fig. 10). Nitrile decomposition for a variety of nitrile compounds is illustrated by Table 1.
Substrate scope analysis was performed with high nitrile concentration and limited amounts of hydrogen peroxide. The trichloroacetonitrile and fluoroacetonitrile led to highest turnovers of nitrile to amide ( Table 1, entries 1-2). Due to the presence of electron withdrawing groups, the nitrile group is more vulnerable to nucleophilic approach. The conversions were calculated based on hydrogen peroxide transformation to hydrolysis products since that was the limiting reagent. Electron donating groups such as aryl and vinyl prevent the hydrolysis ( . The further the nitrile groups are apart, the less they affect one another in the case of adiponitrile (Table 1, entry 6). Methanol production is summarized in Table 2. Hydrogen peroxide is better utilized when added slowly due to controlled degradation rate. When urea adduct of hydrogen peroxide was used, higher activity was achieved due to slow dissolution process of H 2 O 2 into the medium ( Table 2, entry 1-2). When added continuously with a rate close to acetonitrile hydrolysis, the complex activity is increased towards methanol production and acetonitrile hydrolysis (

Discussion
ESI-MS results imply the existence of a variety of complex species. A more prevalent presence of di and tricopper species is observed with perchlorate and acetate precursor compared to the tetrafluoroborate salt. This observation implies an interaction between the complex and counter anions 43 . Electronic absorbance spectra exhibits a 265-300 nm peak which is assigned to "oxide"-to-Cu II LMCT 41 . The absorbance is more prominent for ClO 4 and acetate based species where the tricopper species are more abundant. The considerably larger rate of H 2 O 2 decomposition compared to the rate of acetamide production suggests that only about 10% of H 2 O 2 is being utilized in the reaction. We have directionally showed by doing slow addition one can improve the overall TON for methanol. Isotope labeled experiment in presence of 18 Fig. 11). This could be due to the stoichiometric reaction of Cu 3 LO 2 making methanol. Addition of unlabelled H 2 O 2 takes over in the subsequent steps of catalytic turn overs. We determined that produced methanol is at least partly supplied by solvent when acetonitrile was used. Reaction in absence of methane led to some methanol production and 13 C labeled acetonitrile used as the solvent led to 13 C methanol ( Supplementary Fig. 12). We have observed exclusive formation of Cl 3   www.nature.com/scientificreports/ FCH 2 CONH 2 instead of any chlorinated or fluorinated alcohol when trichloroacetonitrile or fluoroacetonitrile were used as solvent. As a part of interrogating the reaction mechanism, we have studied the catalyst decomposition pathway. This aspect of the chemistry was not probed previously, and we recognize this issue as a key problem for this catalytic system. The active life-time of the complex is affected by a Cu leaching mechanism that eventually makes Cu(NH 3 ) x species. We believe ammonia evolution occurs through amide hydrolysis. Evidence of ammonia, water, and acetonitrile coordinated copper is present in the DART-TOF spectra in the range of 80-98 m/z (Supplementary Fig. 13) and ESI-MS ( Supplementary Fig. 14). In the example of trichloroacetonitrile where the TON is high, there was no carboxylic acid detected in the product. This implies that subsequent hydrolysis of amide to acid is correlated with deactivation of the complex. However, due to poor solubility of complex (and possibly methane) into the solvent the TON for methane to methanol conversion is only modestly improved. Overall, we find that acetonitrile is not an innocent solvent in the peroxide mediated catalytic partial oxidation of methane to methanol using the tricopper complex. For the 7-N-Etppz copper complex to form tricopper species, the role of the counter anion needs to be considered since by changing this species, different spectroscopic and activity results are obtained. The extent of nitrile decomposition is controlled by the peroxide amount and the rate of addition as well as electron withdrawing groups attached to the nitrile. At least 90% conversion of peroxide (TON of 25) to amide is achieved in the case of trichloroacetonitrile and a TON of 1.6 was observed for the case of acetonitrile conversion to acetamide and acetic acid. When used as a medium for methane to methanol conversion, chlorinated acetonitrile led to a slightly higher TON of complex activity partly due to faster reactive oxygen species generation but was hindered by the lack of solubility of the complex in the medium.

Methods
Materials. All chemicals were purchased from Sigma-Aldrich unless mentioned otherwise. Solvents (Methanol and Acetonitrile) were first subject to continuous bed drying by solvent dispenser system under argon. They were subject to a freeze pump thaw procedure to remove residual oxygen content and finally were subject to 48 h of static drying by 3 A molecular sieves under argon and subsequent filtration prior to use. The precursors and solvents were stored under argon atmosphere. Copper complex preparations. In a typical run for a 13 mM solution of complex in acetonitrile, 18 mg of 7-N-Etppz ligand and 36 mg of tetrakis(acetonitrile)copper(I) tetrafluoroborate were added to 3 mL of acetonitrile and stirred for desired amount of time prior to use.

7-N-
Acetonitrile to acetic acid and acetamide transformation. In a typical run after the complex preparation within glovebox in a biotage sealed cap vial, up to 0.1 mL of a 35% (w/w) H 2 O 2 solution was added to the solution and left stirring while taking samples at desired time intervals. The reaction is complete within the first 2 h.
Continuous hydrogen peroxide flow for methane to methanol conversion. In a typical run 0.01 mol per min of hydrogen peroxide was added to a 35 mL glass bottle with 3 mL of acetonitrile, catalyst concentration of 13 mM, and methane pressure of slightly above 1 atm. www.nature.com/scientificreports/ Characterizations. 1 H and 13 C NMR were performed with CDCl 3 with a Bruker AVANCE 300 MHz. Electrospray Ionization Mass Spectrometry (ESI-MS) characterization of the complex was done by diluting complex solutions 1000 times from the original 13 mM to reach acceptable limits for use of a triple quadropole Quattro-II (Waters) instrument for low resolution analysis. For high resolution analysis a QStar Elite (AB sciex) instrument was used. Electron Paramagnetic Resonance (EPR) analysis was carried out on a Bruker instrument at 110 K, with a microwave frequency of 9.39 GHz and a modulation amplitude of 10 G. Ultraviolet-visible spectra of samples were obtained with a Shimadzu UV-2450 ultraviolet-visible spectrophotometer. Samples were exposed to air before UV-Vis spectrometer measurements.