Symbiotic Catalysis Relay: Molecular Oxygen Activation Catalyzed by Multiple Small Molecules at Ambient Temperature and its Mechanism

Oxygen is the most abundant element on the Earth and it is also one of the most important participators in the construction of both life and non-life entities. On the other hand, almost all biological processes are closely related to molecular oxygen because of the energy cycle. Generally, the conversion of oxygen in biological systems mainly depends on enzymes,1 for example, the metal-coordinated compound shown in Figure 1 A.2 Many biological processes, which involve molecular oxygen, such as photosynthesis and metabolizations, are usually accomplished cooperatively by using a series of enzymes through complicated procedures to realize the transformation under ambient conditions. Therefore, air or molecular oxygen are ideal oxidants, and it will be of great value, if chemists can use air or molecular oxygen in synthesis under ambient conditions in the same way as enzymes do in nature. To mimic the fantastic transformations achieved by biological processes, many metal complexes have been developed to activate molecular oxygen.3 As one of the most active research fields, organocatalysis has attracted extensive efforts in modern chemistry and has been widely applied in synthetic chemistry during the past decade.1f, 4 However, the application of small organic molecules to mimic the activation of molecular oxygen at ambient temperature is far from practical to date.2, 5

Figure 1. Activation of molecular oxygen. A) Enzymatic oxygenase model for the transfer of an oxygen atom from molecular oxygen to the organic substrate (the picture was taken from Ref. 1). B) Proposed catalysis relay model using small organic molecules for the transfer of oxygen atoms from O₂ to an organic substrate. (SubH₂ is the organic substrate and Sub^ox the oxidized organic product).

Inspired by the activation of molecular oxygen in nature, which uses multiple enzymes cooperatively, we wondered whether multiple small molecules could be used as catalysts to mimic the biological relay processes for the activation of molecular oxygen as shown in Figure 1 B. Considering that molecular-oxygen activation in biological processes is commonly performed below 40 °C, we herein report our efforts in determining, which series of small molecules, common and readily available, could efficiently and cooperatively catalyze the molecular-oxygen activation at ambient temperature, and the corresponding mechanism.

At ambient temperature and atmosphere of molecular oxygen, NO could be rapidly converted into NO₂.6 Therefore, we consider NO₂ as one of the potential catalysts, to which the oxidative power of molecular oxygen in syntheses at ambient temperature can be transferred. In addition, the 2,2,6,6-tetramethylpiperidyl-1-oxy cation (TEMPO⁺) is well known to be able to oxidize alcohol at or even below ambient temperature in the Anelli oxidation.7 As an example, we test the molecular-oxygen activation at ambient temperature through the catalysis relay approach8 to discover a potential combination of multiple catalysts to bridge the oxidative power gap between NO₂ and TEMPO⁺ at room temperature.

Previously, the NO₂/Br⁻/TEMPO system has been proven to be able to oxidize alcohol by using molecular oxygen (0.2 MPa) as the terminal oxidant at 80 °C.9 Moreover, catalytic aqueous HCl has been able to accelerate the aerobic oxidation of active alcohols by means of NO₂/TEMPO⁺ under similar conditions.10 Further research showed that the thermal decomposition of tert-butyl nitrite (TBN) could also be suitable for the aerobic oxidation of active alcohols, although the efficiency was considerably lower compared to the reaction in the presence of H⁺.11 However, a high temperature is necessary in these systems to compensate for the kinetic barrier between NO₂ and TEMPO⁺. Recently, the use of TEMPO as a catalyst to promote the aerobic oxidation of alcohol has been reported.12 The question is, whether a cocatalyst could be introduced to connect with NO₂ and TEMPO⁺ through the catalysis relay approach to oxidize alcohols using molecular oxygen as the terminal oxidant at ambient temperature.

Initial investigations of molecular-oxygen activation at room temperature for the aerobic oxidation were performed by using benzyl alcohol as the model substrate (Table 1).13 Almost no oxidation of benzyl alcohol occurred with either combination of TEMPO/TBN, 2,3-dichloro-5,6-dicyano-quinone (DDQ)/TBN, or TEMPO/DDQ at room temperature (Entries 1–3). Similar results were observed with three-component combinations [TEMPO/TBN/acetic acid (AcOH), Entry 4; DDQ/TBN/AcOH, Entry 5; and TEMPO/DDQ/AcOH, Entry 6]. Although the conversion was obviously improved by using a combination of TEMPO/DDQ/TBN (Entry 7), a breakthrough was achieved when a combination of catalytic amounts of TEMPO, DDQ, and TBN with an excess of AcOH as additive was used and up to 62.9 % of conversion was obtained (Entry 8). Further studies revealed that catalytic amounts of AcOH (15 mol %) or trifluoroacetic acid (TFA, 1 mol %) could also efficiently complete the neat reaction after prolonging the reaction time (Entries 9 and 10). The preliminary experimental results strongly suggested that under ambient condition, four dependent small molecules, TEMPO, DDQ, and TBN, together with AcOH or TFA, could synergistically activate molecular oxygen, and the oxidative power was efficiently transferred by a catalyst relay procedure.

Table 1. Oxygen activation in catalytic aerobic oxidation of benzyl alcohol at room temperature.^[a]

Entry	Concentration [mol %]			Amount	t	Conversion^[b]
	TEMPO	DDQ	TBN	of AcOH	[h]	[%]
[a] The aerobic oxidations were performed by using benzyl alcohol (10 mmol), and ClCH2CH2Cl (10 mL) at 0.2 MPa of oxygen and room temperature. [b] All conversions were determined by using GC analysis and normalized with respect to the area, and selectivity for all reactions was 100 %. [c] The aerobic oxidations were performed by using benzyl alcohol (100 mmol) at 0.2 MPa of oxygen (autoclave connected to oxygen cylinder) and room temperature. [d] The aerobic oxidations were performed by using benzyl alcohol (100 mmol) and trifluoroacetic acid (TFA, 1 mol %) at 0.2 MPa of oxygen (autoclave connected to oxygen cylinder) and room temperature.
1	2	–	5	–	2	1.1
2	–	2	5	–	2	3.2
3	2	2	–	–	2	2.1
4	2	–	5	1 mL	2	2.5
5	-	2	5	1 mL	2	3.0
6	2	2	–	1 mL	2	2.9
7	2	2	5	–	2	14.5
8	2	2	5	1 mL	2	62.9
9	2	2	5	1 mL	12	99.4
10	4	4	5	1 mL	2	98.8
11	4	4	5	0.5 mL	2	99.6
12^[c]	4	4	5	15 mol %	12	99.6
13^[d]	4	4	5	1 mol % TFA	12	99.5

Further optimization showed that the oxidation could be performed in the following conditions: 4 mol % of TEMPO, 4 mol % of DDQ, 5–10 mol % of TBN, 1 mol % of TFA or 15 mol % of AcOH, 0.2 MPa of O₂, 23–26 °C).13, 14 Some selected liquid primary and secondary benzylic and allylic alcohols can be smoothly oxidized to the corresponding aldehydes or ketones in excellent yields under solvent-free conditions (Table 2).

Table 2. Application of the catalysis relay system to the aerobic oxidation of various alcohols.^[a]

Entry	2	Conversion^[b] [%]	Selectivity [%]
[a] The aerobic oxidations were performed by using alcohol (100 mmol) at 0.2 MPa of oxygen (autoclave connected to oxygen cylinder) and room temperature for 12 h. [b] All conversions were determined by using GC analysis and normalized with respect to the area normalization. [c] TBN (10 mol %).
1		99.5	>99
2		100	>99
3		98.3	>99
4		99.8	>99
5^[c]		99.3	>99
6^[c]		100	>99

For the solid alcohol substrates, the oxidation reactions could be performed with the help of some solvents (Table 3, entries 1–3). The oxidation of those inactive alkyl alcohols seemed to be suitable in dichloromethane, however, the conversion and the selectivity were not as good as those of the active substrates (Entries 4–6).

Table 3. Application of the catalysis relay system in the aerobic oxidation of various solid alcohols and alkyl alcohols using a solvent.^[a]

Entry	2	Conversion^[b] [%]	Selectivity [%]
[a] The aerobic oxidations were performed by using alcohol (50 mmol) and a solvent (20 mL) at 0.2 MPa of oxygen (autoclave connected to oxygen cylinder) and room temperature for 12 h (except entry 2, which was performed for 48 h). [b] All conversions and selectivities were determined by using GC analysis and normalized with respect to the area. [c] Toluene as solvent. [d] Isolated yield. [e] CH2Cl2 as solvent. [f] The aerobic oxidations were performed by using alcohol (10 mmol), CH2Cl2 (10 mL), and TEMPO/DDQ/TBN/TFA=5:5:5:0.5. [g] The aerobic oxidations were performed by using alcohol (10 mmol), CH2Cl2 (10 mL), and TEMPO/DDQ/TBN/TFA=4:4:5:0.5.
1^[c]		100	>99
2^[c]		100	>99
3^[c]		100 (99^[d])	>99
4^[e,f]		83.2	91.5
5^[e,f]		66.1	>95.7
6^[e,g]		97.6	>99

According to the experimental data in Table 1, those four catalytic components, TEMPO/DDQ/TBN/(TFA or AcOH), are symbiotic in the activation of molecular oxygen. To evaluate the role of each component and to understand the reaction mechanism, in situ IR spectroscopy was used to investigate the kinetic behavior of the aerobic oxidation reaction by using benzyl alcohol as substrate, and some results are illustrated in Figure 2.

Figure 2. The kinetic profiles for the oxidation of benzyl alcohol. A) Using different stoichiometric amounts of oxidants. Line a: TEMPO/DDQ/AcOH; line b: TEMPO/DDQ; line c: TEMPO/TBN/AcOH; line d: TEMPO/TBN; line e: DDQ/AcOH; line f: DDQ. B) Using stoichiometric amounts of DDQ and TEMPOH. C) Using stoichiometric amounts of DDQ as the oxidant and TEMPO as the catalyst D) Reaction between DDHQ and TBN. E) Oxidation of DDHQ using O₂ as the oxidant and TBN/AcOH as the catalyst. F) Line a: Oxidation of benzyl alcohol using stoichiometric amounts of TBN/AcOH as the oxidant and TEMPO/DDQ as catalyst at 40 °C; line b: Oxidation of benzyl alcohol using O₂ as the oxidant and TEMPO/DDQ/TBN/AcOH as catalyst at 40 °C; line c: Oxidation of benzyl alcohol using O₂ as the oxidant and TEMPO/DDQ/TBN/AcOH as catalyst at 25 °C.

Firstly, the different kinetic behaviors of the oxidation reaction of benzyl alcohol using different stoichiometric oxidants is shown in Figure 2 A. The reaction using stoichiometric amounts of both DDQ and TEMPO showed the fastest reaction rate in the presence of AcOH (Figure 2 A, line a). In the absence of AcOH, the reaction was slightly slower (Figure 2 A, line b). The other oxidant combinations, such as TBN/TEMPO (Figure 2 A, line c), TBN/TEMPO/AcOH (Figure 2 A, line d), DDQ (Figure 2 A, line e), and DDQ/AcOH (Figure 2 A, line f), were not effective in the oxidation of benzyl alcohol. A stoichiometric amount of TEMPO⁺ could oxidize benzyl alcohol to benzaldehyde together with the formation of a by-product, TEMPOH. Thus, in the catalytic reaction, TEMPOH should be a catalytic species in the reaction cycle. It is important to understand which compound turns TEMPOH into TEMPO⁺. Therefore, the kinetic reactions of stoichiometric amounts of TEMPOH with DDQ, O₂, or TBN to oxidize benzyl alcohol were investigated. Shown in Figure 2 B, only the combination of DDQ/TEMPO demonstrated a fast reaction, whereas no benzaldehyde was detected for other combinations. Furthermore, the kinetic oxidation of benzyl alcohol using catalytic amounts of TEMPO in the presence of stoichiometric amounts of DDQ under N₂ was also investigated. The formation of benzaldehyde was detected within 2 h in 96 % yield, for which the kinetic profile is shown in the Figure 2 C. At the same time, a white solid corresponding to DDHQ could be also observed in this reaction.13

These kinetic results revealed that DDQ could convert TEMPOH into TEMPO⁺ (also activate TEMPO to TEMPO⁺) and generate DDHQ and that TEMPO⁺ oxidized the benzyl alcohol at a high kinetic rate at ambient temperature.

Because DDHQ is an air-stable compound,15 is NO₂ able to oxidize DDHQ to regenerate DDQ to bridge the gap between NO₂ and TEMPO⁺? The stoichiometric reaction between TBN (equivalent of NO₂) and DDHQ in the presence of AcOH was investigated. The reaction kinetic profile is shown in Figure 2 D, which clearly indicates that DDQ could be regenerated smoothly. Additional catalytic reactions between DDHQ (suspension in the reaction mixture) with O₂ using catalytic amounts of TBN was also discussed. The kinetic profiles in Figure 2 E of this reaction revealed that catalytic amounts of TBN can bridge the oxidation of DDHQ using O₂ at ambient temperature.

These kinetic results revealed that NO₂ could efficiently bridge the gap between O₂ and DDQ. To verify the proposal of a catalysis relay, a combination of DDQ and TEMPO as catalyst was examined first. By using stoichiometric amounts of TBN, the oxidation of benzyl alcohol in the presence of catalytic amounts of DDQ and TEMPO was feasible, and the kinetic profile is shown in the Figure 2 F, line a. This experiment indicated that two catalytic processes (DDQ/TEMPO⁺) can relay cooperatively.

Furthermore, the catalysis relay process of the combination of TBN/DDQ/TEMPO was again investigated by spectroscopy by using molecular oxygen as terminal oxidant. The kinetic profiles are shown in the Figure 2 F, lines b and c at 40 °C and 25 °C, respectively. Clearly, the oxidation of benzyl alcohol using atmospheric O₂ at ambient temperature proceeded smoothly and efficiently. TEMPO⁺ oxidized alcohol to give the desired oxidation product, and generated TEMPOH. TEMPOH could be converted into TEMPO⁺ by reaction with DDQ, which yielded DDHQ. DDHQ could be converted into DDQ in the presence of NO₂. NO₂ can be efficiently formed by the reaction of NO with the terminal oxidant O₂. Therefore, all of these catalytic cycles are able to smoothly operate at ambient temperature and are symbiotic in nature. It is the oxidative power of molecular oxygen that could be efficiently transferred to the synthetic oxidation process in a symbiotic catalysis relay manner. In other words, molecular oxygen could be activated at ambient temperature through the symbiotic catalysis relay of NO₂/DDQ/TEMPO⁺ (Figure 3).

Figure 3. Illustration of the symbiotic catalysis relay.

In conclusion, molecular oxygen was activated at ambient temperature. Using catalytic amounts of TBN, DDQ, TEMPO, and AcOH (or TFA), O₂ was successfully used as the terminal oxidant to oxidize alcohols to their corresponding carbonyl compounds. Systematic experiments indicated that all of the different catalysts cooperatively worked together similar to a relay approach to catalyze the oxidation of alcohols. Further kinetic studies revealed that the terminal oxidant O₂ oxidizes NO to NO₂; NO₂ oxidizes DDHQ to DDQ and regenerates NO; DDQ oxidizes TEMPOH to TEMPO⁺ and regenerates DDHQ; and finally TEMPO⁺ is the substrate-selective oxidant for the oxidation of alcohols to their corresponding carbonyl products and regenerates TEMPOH. Thus, it is clear that three different catalysis processes are efficiently working together in a symbiotic catalysis relay process to achieve the activation of molecular oxygen (O₂) at ambient temperatures.

Experimental Section

A typical procedure for the aerobic oxidation of benzyl alcohol at ambient temperatures was as follows. Benzyl alcohol (10.8 g, 100 mmol), 2,2,6,6-tetramethylpiperidyl-1-oxy (TEMPO, 0.624 g, 4 mmol), 2,3-dichloro-5,6-dicyano-quinone (DDQ, 0.908 g, 4 mmol), trifluoroacetic acid (TFA, 75 μL, 1 mmol), and tert-butyl nitrite (TBN, 0.515 g, 5 mmol) were filled into a teflon-lined 316 L stainless steel autoclave (300 mL). Then, the autoclave was closed, connected to an oxygen cylinder, and the oxygen pressure was adjusted to 0.2 MPa. The mixture was then stirred at room temperature for 12 h. Then, the oxygen cylinder was disconnected, and the autoclave was carefully depressurized. The sample from the reaction mixture was diluted by using 1,2-dichloroethane, and the conversion and selectivity were detected by using GC without further purification. GC results showed that the reaction was completed with almost quantitative selectivity.

A detailed experimental procedure is described in the Supporting Information.

Acknowledgements

This work was supported by the National Natural Science Foundations of China (20772111, 20876149, 21025206, 20832003, 20972118 and 20772093) and the “973” Project from the MOST of China (2011CB808600). We are also thankful for the support from “the Fundamental Research Funds for the Central Universities”, the Program for New Century Excellent Talents in University (NCET)), and the Academic Award for Excellent Ph.D. Candidates funded by Ministry of Education of China.