Second-Order Biomimicry: In Situ Oxidative Self-Processing Converts Copper(I)/Diamine Precursor into a Highly Active Aerobic Oxidation Catalyst.

A homogeneous Cu-based catalyst system consisting of [Cu(MeCN)4]PF6, N,N'-di-tert-butylethylenediamine (DBED), and p-(N,N-dimethylamino)pyridine (DMAP) mediates efficient aerobic oxidation of alcohols. Mechanistic study of this reaction shows that the catalyst undergoes an in situ oxidative self-processing step, resulting in conversion of DBED into a nitroxyl that serves as an efficient cocatalyst for aerobic alcohol oxidation. Insights into this behavior are gained from kinetic studies, which reveal an induction period at the beginning of the reaction that correlates with the oxidative self-processing step, EPR spectroscopic analysis of the catalytic reaction mixture, which shows the buildup of the organic nitroxyl species during steady state turnover, and independent synthesis of oxygenated DBED derivatives, which are shown to serve as effective cocatalysts and eliminate the induction period in the reaction. The overall mechanism bears considerable resemblance to enzymatic reactivity. Most notable is the "oxygenase"-type self-processing step that mirrors generation of catalytic cofactors in enzymes via post-translational modification of amino acid side chains. This higher-order function within a synthetic catalyst system presents new opportunities for the discovery and development of biomimetic catalysts.

Introduction

The triplet electronic structure and four-electron redox stoichiometry of molecular oxygen (O2) represent major challenges for the selective aerobic oxidation of organic molecules. Transition-metal catalysts are commonly used to achieve control over the reactivity and selectivity of reactions with O2,[1] and nature is an important source of inspiration for the development of such catalysts. Extensive research efforts have focused on re-creating the coordination environment and reactivity of metalloenzyme active sites with synthetic complexes of iron, copper, or other metal ions, while also mimicking the enzymatic mechanisms of O2-activation and substrate oxidation.[2] For example, copper-containing oxygenases and oxidases mediate transformations ranging from the oxygenation of aromatic and aliphatic C–H bonds to dehydrogenation of amines and alcohols (Figure A),[3,4] and many compelling structural and functional mimics have been developed for the Cu active sites in these enzymes.[5−10]

Figure 1

(A) Representative Cu oxygenases and oxidases, (B) industrial oxidation reactions that employ homogeneous Cu catalysts, and (C) homogeneous Cu/nitroxyl catalysts for aerobic alcohol oxidation.

The results of these biomimetic approaches complement efforts in the chemical industry, where a number of large-scale aerobic oxidation reactions that employ homogeneous Cu catalysts have been developed.[11] Prominent examples include the oxygenation of 2,3,6-trimethylphenol to the corresponding para-quinone en route to synthetic vitamin E,[12,13] and the oxidative polymerization of 2,6-dimethylphenol in the commercial production of poly(para-phenylene oxide) (PPO) resins (Figure B).[14,15] The catalyst for the latter process consists of a Cu salt in combination with a chelating nitrogen ligand. This composition resembles the active sites and synthetic mimics of Cu oxygenases and oxidases, which commonly feature nitrogen-based ligands coordinated to the Cu center(s).[5−10]

Oxidations of alcohols to aldehydes and ketones are among the most common oxidation reactions in organic chemistry, and methods capable of using O2 could find widespread use in both laboratory and industrial applications. Homogeneous copper catalysts for aerobic alcohol oxidation have been studied extensively,[16−18] and nitrogen-ligated Cu complexes with organic nitroxyl cocatalysts, such as those shown in Figure C, are especially effective.[19−22] The steric size of the nitroxyl cocatalyst may be used to control reaction selectivity. For example, TEMPO mediates the chemoselective oxidation of primary alcohols in substrates with both primary and secondary alcohols,[23−25] whereas ABNO is an effective cocatalyst for the dehydrogenation of both primary and secondary alcohols (TEMPO = 2,2,6,6-tetramethyl-1-piperidine N-oxyl; ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl; cf. Figure C).[26−28] The cooperative redox chemistry between the Cu center and the nitroxyl radical resembles galactose oxidase,[29−33] which mediates oxidation of the primary alcohol in galactose at a nitrogen-ligated CuII center bearing a tyrosine-derived phenoxyl-radical ligand (cf. Figure A).

Considerable effort has focused on Cu-catalyzed aerobic alcohol oxidation in the absence a redox-active cocatalyst, but the precedents typically show limited synthetic utility or scope.[34−36] These examples contrast with a recently reported catalyst system that is highly effective without addition of a redox-active cocatalyst (Figure ). The system is composed of a CuI salt, [Cu(MeCN)4]PF6, and the nitrogenous ligands N,N′-di-tert-butylethylenediamine (DBED; the same ligand used for PPO resin production; cf. Figure B) and p-(N,N-dimethylamino)pyridine (DMAP).[37] The excellent reactivity and scope observed with this catalyst system rivals results obtained previously with Cu/nitroxyl catalysts, while also providing complementary chemoselectivity for activated 2° alcohols over 1° alcohols. The system has important practical implications, particularly for large-scale applications, where organic nitroxyls are often the most expensive component of the Cu/nitroxyl catalyst system.[38] In addition, it raises important mechanistic questions concerning the origin of efficient catalysis in the absence of a redox-active cocatalyst.

Figure 2

Rare Cu-only catalyst system that shows excellent reactivity and scope for aerobic oxidation of alcohols.

Here, we present a mechanistic investigation of aerobic alcohol oxidation with this Cu/DBED/DMAP catalyst system. The data reveal that the catalyst undergoes an in situ oxidative self-processing step in which Cu/O2 mediates oxygenation of the DBED diamine ligand to afford a nitroxyl radical that promotes efficient alcohol oxidation in cooperation with Cu.[39] This unexpected catalyst activation step resembles the oxygenation of amines in biological nitrification (e.g., aerobic oxidation of ammonia to hydroxylamine by ammonia monooxygenase; cf. Figure A).[40,41] Moreover, the oxidative catalyst-self-processing step generates the catalytically active organic nitroxyl cocatalyst, which is reminiscent of the oxidation of tyrosine side chains in copper amine oxidases[42,43] and galactose oxidase (GO) that afford the catalytically active quinone and cysteine-modified phenoxyl-radical cofactors (cf. Figure A).[44,45] The in situ self-processing step observed here provides a clear rationale for the efficiency of this catalyst system. Furthermore, these results illuminate prospects for a more profound relationship between synthetic and naturally occurring catalyst systems. Post-translational modification of protein scaffolds is commonly featured in the generation of enzyme active sites.[46] The synthetic catalyst system investigated here manifests similar behavior in that readily accessible precatalyst components undergo in situ modification to afford the active catalyst. This “second-order”[47] biomimetic behavior is not typically considered in the design or development of synthetic catalysts, but doing so could lead to highly effective catalysts derived from simple, low-cost precursors.

Results

Mechanistic studies were initiated by monitoring the reaction time course for Cu/DBED/DMAP-catalyzed aerobic oxidation of 1-octanol to 1-octanal under the previously published conditions (Figure ).[37] The consumption of oxygen gas was probed via gas-uptake measurements within a sealed reaction vessel, while simultaneously monitoring aldehyde formation via in situ ATR-IR spectroscopy. The data in Figure show that the quantity of O2 consumed tracks directly with the amount of aldehyde produced throughout the reaction, with an O2:aldehyde stoichiometry of approximately 1:2. The slight excess of O2 consumed relative to that expected from a 1:2 O2:aldehyde ratio (270 μmol observed versus 250 μmol expected; cf. Figure ) has important implications for the reaction mechanism, as elaborated below. Another noteworthy feature is the significant induction period present at the beginning of the reaction, prior to a nearly linear time course during the steady-state period of the reaction.

Figure 3

In situ IR and O2-uptake time course data for the catalytic oxidation of 1-octanol under standard conditions. Reaction conditions: 0.125 M 1-octanol, 6.25 mM [Cu(MeCN)4]PF6, 6.25 mM DBED, 25 mM DMAP, 100 mg of 4 Å MS, 500 Torr of O2, CH2Cl2 (4 mL), 27 °C.

The excess O2 consumption, together with precedents for Cu-catalyzed dehydrogenation of secondary amines,[48−51] raised the possibility that the DBED ligand could be converted to a mono- or diimine derivative under the reaction conditions. Aliquots of the reaction mixture withdrawn at regular intervals were worked up in a manner that allowed analysis of the DBED ligand (see Figures S2–S4). DBED is steadily consumed throughout the reaction, with kinetics exhibiting the same sigmoidal profile observed for O2 consumption and aldehyde formation (cf. Figure and Figure S2). The bis-diimine–CuI complex 1 and the free diimine 2 were identified in the final reaction mixture in quantities that accounted for 20–30% of the original DBED ligand.[52] However, control experiments employing bis-diimine–CuI complex 1 in place of [Cu(MeCN)4]PF6/DBED, or substitution of DBED with 2 under otherwise identical catalytic conditions, resulted in no catalytic activity.

An important clue into the origin of the induction period prior to the onset of catalysis was obtained from EPR spectroscopic studies, initiated to probe the copper species present during the catalytic reaction. A reference solution of the Cu/DBED/DMAP catalyst system in the absence of substrate under an O2 atmosphere exhibits a nearly axial EPR signal (g = 2.03, g = 2.07, g = 2.26, and A = 535 MHz) (Figure B, black spectrum). EPR spectra of the reaction mixture were obtained by removing aliquots of the solution, rapidly freezing them in liquid nitrogen, and analyzing them by EPR spectroscopy at 115 K. A small CuII signal is evident during the induction period that persists during steady-state turnover (Figure , spectra at t = 7.5, 25, and 45 min.). The spectra also reveal the unexpected presence of an organic radical signal (g = 2.002) with hyperfine coupling to an I = 1 nucleus (A = 85 MHz). This signal, which gains intensity during the steady-state period of the reaction, resembles EPR spectra of the nitroxyl radicals TEMPO[53] and ABNO[54] (see Figure S32) in which the unpaired electron is coupled to the nitrogen I = 1 nucleus. This radical signal disappears after completion of the reaction, together with the growth of a larger CuII signal (Figure , spectrum at t = 120 min).

Figure 4

(A) O2-uptake and (B) EPR spectroscopy time courses for the catalytic oxidation of 1-octanol. Reaction conditions: 0.125 M 1-octanol, 6.25 mM [Cu(MeCN)4]PF6, 6.25 mM DBED, 25 mM DMAP, 100 mg of 4 Å MS, 500 Torr of O2, 27 °C.

The observations in Figure suggest that nitroxyl radicals derived from DBED could be generated under the reaction conditions and that the resulting nitroxyl contributes directly to the catalytic activity. Efforts to prepare the corresponding mono- or bis-nitroxyl species derived from DBED were unsuccessful, most likely reflecting the known instability of nitroxyls bearing C–H bonds adjacent to nitrogen.[55−57] Nitroxyls of this type undergo disproportionation into nitrones and hydroxylamines (eq ). It was possible to prepare the corresponding DBED-derived mono- and bis-hydroxylamines 3 and 4, however, which correspond to the reduced form of the nitroxyl implicated in the catalytic mechanism.[31] Hydroxylamines can undergo in situ oxidation to nitroxyls under catalytic conditions,[31,58] and their use as cocatalyst precursors provides a means to utilize less substituted nitroxyls. The kinetic competence of these hydroxylamine derivatives was demonstrated by replacing DBED with 5 mol % 3 or 4 in combination with 5 mol % [Cu(MeCN)4]PF6 and 20 mol % DMAP. The reactions containing 3 or 4 display no induction period (Figure A), and they exhibit a time course that is nearly identical to a reaction in which DBED is replaced with the stable nitroxyl TEMPO (see Figure S19).

Figure 5

Comparison of catalytic reactions employing 5 mol % [Cu(MeCN)4]PF6 and 20 mol % DMAP, together with 5 mol % DBED, 3, or 4 as organic cocatalysts. (A) Comparison of catalytic turnover rates analyzed by gas-uptake methods. (B) EPR spectra of Cu/DMAP-catalyzed reactions using DBED or 4 as a cocatalyst (inset). (C) Results of competition experiments between primary aliphatic and secondary benzylic alcohol oxidation with different cocatalysts. (D) Kinetic isotope effect data for benzyl alcohol-d1 oxidation with different cocatalysts. aFrom ref (37). bFrom ref (31). See Supporting Information for experimental details.

To complement these observations, EPR spectroscopy was used to analyze the oxidation of 1-octanol using [Cu(MeCN)4]PF6/DMAP and 4. An organic radical was observed with the same spectral parameters as that observed from the catalytic reaction with DBED (Figure B), albeit with a higher concentration that correlates with a higher steady-state rate in the oxidation of 1-octanol (cf. Figure A).

The catalytic relevance of the DBED-derived hydroxylamines 3 or 4 was further probed via substrate–selectivity studies. The relative reactivity of different alcohols in Cu/nitroxyl-catalyzed oxidation reactions has been shown to depend on the steric demands of the nitroxyl cocatalyst. In a competition experiment, the standard Cu/DBED/DMAP catalyst oxidizes 1-phenylethanol in preference to 1-octanol in a 2.9:1 ratio (Figure C).[37] The same competition experiment was performed with Cu/DMAP/hydroxylamine catalysts, in which the hydroxylamine is 3 or 4, and these reactions showed very similar selectivity (1-phenylethanol:1-octanol = 2.6:1 and 3.0:1 with 3 and 4, respectively). These observations may be compared to results with Cu/TEMPO and Cu/ABNO catalyst systems, which exhibit the opposite or somewhat lower selectivity (1-phenylethanol:1-octanol = 1:1.8 and 1.8:1 with TEMPO and ABNO, respectively; cf. Figure C).

Finally, kinetic isotope effect (KIE) studies were used to probe the differences between DBED and hydroxylamines 3 and 4. Different nitroxyls afford different deuterium kinetic isotope effects (KIEs) in the reaction of PhCHDOH, reflecting differences in the transition states for C–H(D) cleavage with the different cocatalysts. For example, Cu/TEMPO and Cu/ABNO catalyst systems exhibit KIEs of 6.1 and 2.7, respectively (Figure D). In contrast, the oxidation of PhCHDOH catalyzed by Cu/DMAP in combination with DBED or one of the DBED-derived hydroxylamines (3 or 4) leads to the same isotope effect in all cases, KIE = 3.3 ± 0.1, consistent with a nearly identical transition state in each of the three reactions.

Discussion

The data presented above show that the high activity of the Cu/DBED/DMAP catalyst system arises from in situ oxygenation of the DBED ligand, which leads to formation of an organic nitroxyl that is an effective cocatalyst for alcohol oxidation. This in situ modification of the diamine ligand distinguishes the Cu/DBED/DMAP system from previous cocatalyst-free systems that employ oxidatively stable aromatic diimine ligands, such as bipyridine or phenanthroline,[34−36] and the generation of a nitroxyl cocatalyst from an alkylamine under the reaction conditions has important implications for future catalyst development. For example, many organic nitroxyls are not readily prepared or isolated, owing to decomposition pathways, such as that noted in eq . In situ generation of the nitroxyl from a stable, readily available amine or hydroxylamine precursor, as demonstrated with DBED, 3, and 4, significantly expands the scope of nitroxyl cocatalysts that may be evaluated for a given transformation. This advantage could contribute to the development of chemoselective alcohol oxidation within complex molecules bearing more than one alcohol. Late-stage functionalization of natural products, biomolecules, or pharmaceuticals is an appealing target for such applications, where intricate protecting group strategies are otherwise required to manipulate a single hydroxyl group.[59−61] The insights from this study also have implications for large-scale applications, where the cost and stability of an optimal nitroxyl are important considerations.

The oxidative self-processing step and catalytic cycle for Cu/DBED/DMAP-catalyzed alcohol oxidation (Scheme ) exhibit a number of biomimetic features. The overall mechanism incorporates both oxygenase- and oxidase-type reactivity. Oxygenation of DBED in the oxidative self-processing step resembles the conversion of ammonia to hydroxylamine by ammonia monooxygenase (cf. Figure A).[40,41,62,63] Synthetic copper–dioxygen adducts with DBED as an ancillary ligand have been studied as active site models for O2 activation and oxygen-atom transfer in Cu-based oxygenases (e.g., tyrosinase; cf. Figure A).[64,65] A similar Cu/O2 adduct is likely responsible for the in situ oxygenation of DBED, as supported by precedents for amine oxygenation with related Cu-oxygenase mimics.[66,67] The oxygenated DBED ligand is then capable of serving as a cocatalyst in an oxidase-type catalytic cycle resembling galactose oxidase, as has been discussed elsewhere for Cu/nitroxyl catalyst systems.[29−32] A related oxygenase/oxidase sequence has been implicated in Cu-catalyzed aerobic oxidative coupling of naphthols.[68] The naphthol substrate was found to undergo in situ oxygenation to afford a quinone or hydroquinone species prior to the onset of steady-state catalytic C–C coupling reactivity.

Scheme 1

Proposed Mechanism for [Cu(MeCN)4]PF6/DBED/DMAP Catalyst System

This biomimetic reactivity embodies higher-order function than typically associated with synthetic models of metalloenzymes. The oxidative processing of the DBED ligand to generate the nitroxyl cocatalyst in situ is reminiscent of metalloenzymes that employ post-translational modification of amino acid side chains in the active site of an enzyme to generate a catalytic cofactor. Noteworthy examples include the oxidative modification of a tyrosine residue in copper amine oxidases to generate a quinone cofactor (“topaquinone”),[42,43] and the oxidative coupling of tyrosine and cysteine en route to the active-site phenoxyl radical ligand in galactose oxidase.[44,45] In the same way that Nature exploits the naturally occurring amino acid side chains to generate reactive cofactors, Cu/DBED/DMAP modifies a simple, readily accessible diamine to access the reactive nitroxyl cocatalyst. This “second-order biomimicry”[47] introduces new opportunities for the field of bioinspired catalysis. Aerobic oxidations are particularly challenging and important targets for future study, and in situ oxygenation of electron-rich organic molecules, such as amines and phenols, can provide the basis for new catalysts for synthetically important transformations.[68−74]

Conclusion

The Cu/DBED/DMAP catalyst system was originally reported as a unique nitroxyl-free Cu-catalyst system for aerobic alcohol oxidation. The present study, however, demonstrates that the catalytic activity arises from oxidative self-processing of the alkylamine ligand to generate a nitroxyl in situ. This pre-steady-state oxygenase reactivity provides the basis for steady-state oxidase reactivity, in which the Cu center and nitroxyl radical serve as cooperative cocatalysts for aerobic alcohol oxidation. Collectively, the results show how a synthetic catalyst system can incorporate higher order function commonly observed in biology, and they set the stage for intentional pursuit of such function in the field of biomimetic chemistry.