AlBr₃·6H₂O catalyzed oxidation of benzylic alcohols

Abstract

AlBr₃·6H₂O was found to be an efficient catalyst in the field of oxidation of benzylic alcohols. Primary and secondary benzylic alcohols could be transformed into corresponding aldehydes and ketones with almost complete conversion and high selectivity. The non-transition metal related reaction systems have an incomparable advantage over others, such as easy work-up, excellent selectivity as well as commercial availability.

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Selective oxidation of alcohols to carbonyl compounds is one of the most important and challenging transformations in the synthesis of fine chemicals and intermediates.¹ Traditionally, chromate and permanganate reagents are employed for this purpose.² Unfortunately, these oxidations call for the use of at least stoichiometric amounts of oxidants and generate a large quantity of noxious byproducts.³

From an environmental and economic viewpoint, there has been an increasing need for selective oxidation using more green and effective procedures. The transition-metal-catalyzed oxidation of alcohols in the presence of molecular oxygen as the terminal oxidant has received great attention in recent years.⁴ The metal-catalyzed aerobic oxidation of alcohols has recently been reviewed, and these reviews outline significant progress in the elaboration of homogeneous and/or heterogeneous catalysts in general.^3a,5 However, for most cases, the indispensible additives such as N-hydroxyphthalimide,⁶ diethyl azodicarboxylate,⁷ or nitrasonium ions⁸ and some ligands⁹ were required to accomplish the catalytic cycle, as well as the catalyst separation and recycling of homogeneous metal catalysts often made practical and industrial applications very difficult.¹⁰ Mostly, selective methods allowing for oxidation of primary alcohols to aldehydes without overoxidation to carboxylic acids still remain challenging. Particularly, the alternative oxidations in this field are the use of free radical assisted systems, for instance, nitroxyl radical 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)¹¹ and NXS (X = Cl, Br, I),¹² as well as allylbromide based oxidation procedures. They are desirable and efficient catalysts for the aerobic oxidation of a broad range of alcohols under mild reaction conditions. However, for these systems, some limitations are obvious, such as substrates containing acid-sensitive functional groups could not be tolerant in some cases,¹³ the other undesirable auxiliaries, Ru(II),¹⁴ Cu(I),¹⁵ NaNO₂,¹⁶ and Br₂,^16a are absolutely indispensible, and also increased temperature and oxygen pressure are needed. Especially, overoxidation could not be prevented, resulting in carboxylic acid as a major product.¹⁷ As a result, these more complicated systems conduct low atom efficiency, waste disposal, and expensive material cost, as well as great energy should be devoted.

Our previous study explored that a variety of alcohols, including inactive aliphatic alcohols, could be converted into aldehydes and ketones in the presence of H₂O₂ or Oxone® (2KHSO₅·KHSO₄·K₂SO₄) with the catalyst of AlCl₃.¹⁸ Although, these disclosed catalyst systems are efficient, some disadvantages are inevitable, for instance, the high loading amount of catalyst, low oxidant efficiency, and no-tolerance of acid sensitive substituent. In the ongoing research programs, we found that in the presence of air, AlBr₃·6H₂O exhibits excellent catalysis oxidative behavior for alcohols. Notably, for the primary benzyl alcohol, the overoxidation could be suppressed. Subsequently, the optimization of our initial oxidation system led to an improved and highly efficient protocol for the oxidation of primary and secondary benzylic alcohols under mild conditions. We believe that the newly developed simple oxidation system will be an important component in the field of oxidation of alcohols.

Initially, benzyl alcohol was treated with 30 mol% AlBr₃·6H₂O in the commonly used solvents under open air conditions. The results confirmed that the more polar solvent 1,4-dioxane significantly enhanced the reaction rate, while, non-polar hexane, CCl₄, and toluene were found to be poor media. We can also note that significant improvement was achieved by increasing the reaction temperature up to 70 °C, resulting in clean formation of benzaldehyde with relatively high conversion and high selectivity. Furthermore, conducting the above reaction at 100 °C for a longer reaction time furnished benzoic acid as a major product with almost complete conversion. However, the reaction process could not be performed if the temperature is below 60 °C (Fig. 1). We carried out the catalytic oxidation of benzyl alcohol in a batch reactor by following the reaction with time. The plots of reaction products against time are depicted in Fig. 2. These results show that the yield rates of benzaldehyde are almost constant within 250 min. Although, the dehydrogenation of substrate was effective, the transformation occurred after a variable induction period (within 20 to 30 min). Under an argon atmosphere instead of air or O₂, a trace amount of benzaldehyde together with a complicated mixture was observed, and the most amount of substrate could be recovered. This means that the oxygen from air applied as an oxidant was beneficial for both the rate and yield of the product. Herein, the optimum reaction conditions thus far developed employ 1.0 equiv. of substrate, 30 mol% of AlBr₃·6H₂O in dioxane at 70 °C. Here the doubt of the excessive catalytic amount of AlBr₃·6H₂O led us to have a more detailed study on the reaction conditions. However the screened results verified that AlBr₃·6H₂O should be used definitely as we stated 30 mol%, which was possible due to the fact that the solubility of AlBr₃·6H₂O in the organic solvent was poor. After completion of the reaction, a certain amount of AlBr₃·6H₂O always precipitated in the reaction vessel, which seems to be wasted. We considered that these precipitates could offer sufficient concentrations of AlBr₃·6H₂O in the solvent during the reaction, so the amount of AlBr₃·6H₂O used was more than that of some compounds with better solubility in the organic solvents. What should be declared is that these used precipitates of AlBr₃·6H₂O could be reused after the pre-cycle reaction. It was also noted that the rigorous exclusion of moisture is not required in any of these transformations, and comparable results are obtained in the presence and absence of O₂, as well as in freshly distilled commercial solvents. As such, this represents an exceedingly convenient method for oxidation of alcohols to the corresponding carbonyl compounds.

Fig. 1 Study of the AlBr₃·6H₂O catalyst for the aerobic oxidation with different temperatures.

Fig. 2 Typical reaction time course for the oxidation of benzyl alcohol by the AlBr₃·6H₂O system.

Under the reaction conditions mentioned above (0.1 mmol of alcohol, 0.03 mmol of AlBr₃·6H₂O, 2.0 mL of 1,4-dioxane, 70 °C) several primary benzyl alcohols were tested to explore the scope of this method (Scheme 1). Generally, excellent selectivity for the most of transformations to benzaldehydes was demonstrated, while, the oxidation of benzyl alcohol was somewhat less selective, as benzaldehyde and benzoic acid were obtained with 89% and 11% selectivity. Although different substitution patterns on the aryl ring lead to similar GC yields, different reaction times were required according to the electronic contribution of the substituents on the benzene ring. For example, in the cases of 6a and 7a, methyl and methoxyl groups exhibited an accelerating effect on the oxidation reaction, almost complete conversions and >98% selectivity could be obtained. Electron-withdrawing groups are less reactive, and thus longer reaction times and elevated amount of catalyst were needed to reach good conversions. Nitro moieties tolerated these reaction conditions to furnish the corresponding aldehydes and 3b in 100% conversion. Interestingly, compared to p-methyl benzyl alcohol, the m-methyl and o-methyl benzylic alcohols showed low activity under this condition, but with a higher catalyst loading, the complete oxidation could also be achieved. In the presence of 1,4-dioxane and with a higher ratio of AlBr₃·6H₂O (0.05 mmol), 4a and 5a were oxidized into corresponding aldehydes in 98% and 100% conversions, respectively.

Scheme 1 Results of oxidations of various alcohols catalyzed by AlBr₃·6H₂O.

The scope of catalytic oxidation reaction with AlBr₃·6H₂O was also expended to several representative secondary benzyl alcohols. Different diphenylmethanols could successfully be transformed to the corresponding products with excellent conversions (>94%), but with the mixture of benzophenones and brominated derivatives (Table 1). In most cases, benzophenones were afforded as major products; the highest selectivity was nearly up to 80%. Notably, in the optimized reaction conditions, the bromonation process could not be prevented. To have more insight into the parallel transformations of the substrate to the reaction mechanism, modified reaction conditions were exploited, using quinone or MNP (2-methyl-2-nitrosopropane, C₄H₉NO) as a free radicals capture agent. Accordingly, the brominated product was formed predominantly, and accompanying with trace amounts of benzophenone. Similar results also could be verified in the case of performing the reaction in the N₂ atmosphere, or injecting a small amount of water during the reaction. The above results clearly support the proposal that the oxidation reaction system probably resembles that of an N-bromosuccinimide (NBS) mediated process, which carries a bromine radical as the reaction initiator.

Table 1 Selective oxidation of secondary aromatic alcohols^a

Entry	Substrate	Additive	Conv.^b (%)	Sele.^b (%)		Yield^c (%)
				B	C	B	C
a Reaction conditions: alcohol (0.10 mmol), 1,4-dioxane 2 mL, AlBr3·6H2O (0.02 mmol), 70 °C, 4 h. b Conversion and selectivity were determined by GC analysis. c All yields are for pure, isolated products. d N2-balloon protection. e Quinone or MNP as a free radicals capture agent.
1		None	100	47	53	44	50
2^d		N2	93	—	99
3^e		Quinone	95	6	94
4^e		MNP	96	4	96
5		None	>99	60	40	56	35
6		None	94	77	23	73
7			>98	63	37

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In particular, molecular oxygen has received much attention as an ultimate oxidant, since it is photosynthesized by plants, produces little waste, is inexpensive and of larger atom efficiency than that of other oxidants. With this background in mind, in the course of our study, we have found that alcohols were oxidized to the corresponding products under visible light irradiation by a high-pressure xenon lamp and using air as an oxidant. The results clearly demonstrated that excellent yields and selectivity could be obtained in this photocatalyzed oxidation reaction (Scheme 2). More details about the reactions will be reported in our further studies.

Scheme 2 Oxidation of representative alcohols under visible light irradiation by a xenon lamp.

We then studied the aerobic oxidation with the isotope-labeled alcohols, as the substrate has been often used as a mechanistic probe to understand whether the final step of the alcohol oxidation is the dehydrogenation or oxygen transfer from oxidants to yield carbonyl compounds. A GC-MS detector indicated that the abundance of ¹⁶O in product was >97%. We also considered that the oxygen exchange between an isotope-labeled alcohol and AlBr₃·6H₂O occurred during the reaction, then 10 equiv. of H₂¹⁸O was injected, the result demonstrated that the ¹⁶O product was found to be >95%. So what should be concerned is that the oxygen exchange was not accessible. That is, in this oxidation process involving a selective cleavage of the C–O bond of the alcohol with concomitant formation of a new C=O bond, in the product, the oxygen atoms transfer from the oxidant. This interesting finding verified that in the process of alcohol oxidation, the exchange of oxygen atoms between alcohol and oxidant was taken place (Scheme 3).

Scheme 3 The oxidation of isotope-labeled alcohols.

Here, we present in Scheme 4 what we assume is a plausible path of this oxidation. The radical species is thought to be generated by abstraction of a hydrogen radical with a bromine radical, formed by continuous aerobic oxidation of the bromo anion from AlBr₃·6H₂O. The radical species traps molecular oxygen to afford peroxy radical species, which subsequently transforms to benzaldehyde with the selective C–¹⁸O bond cleavage, yielding the no isotope-labeled product.

Scheme 4 Plausible path of the aerobic oxidation of alcohols.^17,19

In summary, we have developed an efficient, inexpensive, clean, free radical initiated oxidation of alcohol protocol, which uses AlBr₃·6H₂O as the catalyst, the inexhaustible air as an oxidant, and dioxane as the solvent, and this method is insensitive to atmospheric moisture, and neither dried solvent is required, which also could provide the reasonable yields under relatively mild conditions. Most importantly, this protocol demonstrated excellent selectivity of the oxidation of primary benzyl alcohols; yielding benzaldehyde as a major product. This issue is regarded as the greatest obstacle for the bromides involved processes. The new form of oxidation reaction is also interesting in keeping with the notion of green chemistry due to non-use of transition metals and halogenated solvents, waste reduction. The scope, further mechanism, and synthetic application of this reaction are under investigation.

Experimental section

General information

AlBr₃·6H₂O was obtained from commercial sources. All solvents used were of analytical grade and were used as received. All of the alcohols used in the reaction were obtained from ABCR GmbH & Co. KG and used as received without further treatment. H₂¹⁸O was obtained from Huayi Isotope Co. All NMR spectra are recorded on MERCURY (400 MHz for ¹H NMR, 100 MHz for ¹³C NMR) spectrometers; chemical shifts are expressed in ppm (δ units) relative to a TMS signal as internal reference in CDCl₃. Gas chromatography (GC) analysis was performed on a Shimadezu GC-2010 equipped with a 15 m × 0.53 mm × 1.5 μm RTX-1 capillary column and a oxyhydrogen flame detector. GC/MS analysis was carried out on a trace HP GC6890/MS5973 equipped with a 25 m × 0.25 mm SE-54 column and a Shimadzu GC-16A gas chromatograph with a 3 m × 3 mm OV-17 column.

General procedure for the oxidation of alcohols with AlBr₃·6H₂O

Method 1. To a 10 mL round flask were added 0.10 mmol alcohol substrate, 2 mL of 1,4-dioxane, and AlBr₃·6H₂O (0.03 mmol, 0.011 g). Then the flask was immersed in a preheated 70 °C oil bath for the desired reaction time. Percentage conversion and reaction selectivity were determined by GC analysis. The yield was obtained when the amount of substrates was increased to 1 mmol. An isolated product is obtained by column chromatography (petroleum ether/ethyl acetate = 1–10 : 1). After the first cycle, the reaction mixture was extracted from the reaction vessel by syringes, the yellow precipitates were washed with petroleum ether several times, then fresh solvent 1,4-dioxane (2 mL) and benzyl alcohol (0.10 mmol) were charged. Under the optimized reaction conditions, the conversion and selectivity were detected as 45% and 98% respectively. After the third cycle, the conversion and selectivity were maintained at 18% and 99%.

Method 2. To a 10 mL round flask were added 0.10 mmol of alcohol substrate, 2 mL of 1,4-dioxane, and AlBr₃·6H₂O (0.03 mmol, 0.011 g). The reaction mixture was irradiated by a xenon lamp (500 W) stirring for the designated time at room temperature. Percentage conversion and reaction selectivity were determined by GC analysis. The yield was obtained when the amount of substrates was increased to 1 mmol. An isolated product is obtained by column chromatography (petroleum ether/ethyl acetate = 1–10 : 1).

The NMR data for representative products

4-Chlorobenzaldehyde (2b). ¹H NMR (CDCl₃, 400 MHz): δ = 10.00 (s, 1H, CHO), 7.85 (d, J = 8 Hz, 2H, Ar–H), 7.54 (d, J = 8 Hz, 2H, Ar–H); ¹³C NMR (100 MHz): δ = 190.84, 140.92, 134.67, 130.88, 129.42.

4-Nitrobenzaldehyde (3b). ¹H NMR (CDCl₃, 400 MHz): δ = 10.17 (s, 1H, CHO), 8.42 (d, J = 8 Hz, 2H, Ar–H), 8.10 (d, J = 8 Hz, 2H, Ar–H); ¹³C NMR (100 MHz): δ = 190.27, 151.10, 140.01, 130.48, 124.31.

Benzil (8b). ¹H NMR (CDCl₃, 400 MHz): δ = 7.99–7.96 (m, 4H, Ar–H), 7.68–7.64 (m, 2H, Ar–H), 7.54–7.26 (m, 4H, Ar–H); ¹³C NMR (100 MHz): δ = 194.56, 134.88, 132.96, 129.89, 129.01.

Benzophenone (9b). ¹H NMR (CDCl₃, 400 MHz): δ = 7.82–7.79 (m, 4H, Ar–H), 7.60–7.58 (m, 2H, Ar–H), 7.56–7.45 (m, 4H, Ar–H); ¹³C NMR (100 MHz): δ = 196.67, 137.49, 132.35, 129.98, and 128.20.

4-Methylbenzophenone (10b). ¹H NMR(CDCl₃, 400 MHz): δ = 7.79 (d, J = 8 Hz, 2H, Ar–H), 7.73 (d, J = 8 Hz, 2H, Ar–H), 7.59–7.55 (t, J = 8 Hz, 1H, Ar–H), 7.49–7.45 (t, J = 8 Hz, 2H, Ar–H), 7.29–7.27 (t, J = 8 Hz, 2H, Ar–H), 2.44 (s, 3H, CH₃); ¹³C NMR (100 MHz): δ = 196.43, 143.19, 137.93, 134.87, 132.11, 130.26, 129.88, 128.94, 128.16, 21.63.

4-Chlorobenzophenone (11b). ¹H NMR (CDCl₃, 400 MHz): δ = 7.79–7.75 (m, 4H, Ar–H), 7.62–7.58 (m, 1H, Ar–H), 7.51–7.46 (m, 4H, Ar–H); ¹³C NMR (100 MHz): δ = 195.51, 138.88, 137.21, 135.83, 132.63, 131.45, 129.92, 128.62, 128.39.

Acknowledgements

This work was financially supported by National Natural Science Foundation of China (No. 20674063 and 20774074), Specialized Research Fund for the Doctoral Program of Higher Education (20050736001) and Young Teacher Research Foundation of Northwest Normal University (NWNU-LKQN-08-8, NWNU-kjcxgc-03-73). We also thank Key Laboratory of Eco-Environment-Related Polymer Materials (Northwest Normal University), Ministry of Education, for financial support.

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Footnote

† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/c1cy00165e

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