RESEARCH ARTICLE

AEROBIC OXIDATION 2015 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. Distributed Silver(I) as a widely applicable, homogeneous under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). catalyst for aerobic oxidation of toward 10.1126/sciadv.1500020 carboxylic acids in water—“silver mirror”: From stoichiometric to catalytic

Mingxin Liu, Haining Wang, Huiying Zeng, Chao-Jun Li*

The first example of a homogeneous silver(I)-catalyzed aerobic oxidation of aldehydes in water is reported. More than 50 examples of different aliphatic and aromatic aldehydes, including natural products, were tested, and all of them successfully underwent aerobic oxidation to give the corresponding carboxylic acids in extremely high yields. The reaction conditions are very mild and greener, requiring only a very low silver(I) catalyst loading, using atmospheric as the oxidant and water as the solvent, and allowing gram-scale oxidation with only 2 mg of our catalyst. Chromatography is completely unnecessary for purification in most cases.

Oxidation is a central task for organic chemists to achieve conversion of We began our investigation by introducing various silver(I) salts or different organic compounds. Among them, oxidation of aldehydes to complexes to benzaldehyde as a standard in air at atmospheric pressure give carboxylic acids is one of the most well-known and most frequently without a balloon in a sealed tube (Table 1). We found the efficiency of used methodologies (1, 2), for example, by stoichiometrically using the the transformation to be strongly affected by the presence of inorganic Cr(IV)-based Jones reagent (3, 4), the Ag(I)-based Tollen’s reaction (5), salt (for example, entries 1 and 2). When the reaction was carried out with- the Cu(II)-based Fehling’s reaction (6), and the permanganate reagents out oxygen, a very low yield was obtained (entry 3), reflecting a stoichi- (7). Although it has long been known that aldehydes are very prone to ometricaldehydeoxidation.Theanionsofthesaltwerethentested. oxidation, methods to achieve a highly efficient and clean transfor- Besides formate, only fluoride and tetrafluoroborate provided the ox- mation of aldehydes to carboxylic acids under mild and greener con- idation product (entries 4 to 7). Considering that tetrafluoroborate ditions are still scarce. Even today, most such oxidations still require might undergo hydrolysis to give fluoride in situ, fluoride was thus chosen stoichiometric amounts of hazardous oxidants (8–25)andoftentake as the standard anion to conduct further investigations. Upon examining place in harmful solvents. the cation, surprisingly, it seemedtobetheonlyoneenablingtheox- With its natural abundance and inherent greener characteristics, idation (entries 8 to 11). Sodium fluoride was therefore selected as the water has been a desirable solvent for chemists (26–28). Although bio- salt for optimizing the conditions. We then tested different ligands logical oxidations in water using enzymes or microorganisms are well (entries 12 to 14) and found that the combination of chelating bipyridine − recognized (29–34), it was only in 2000 that Sheldon established an as a ligand and a noncoordinating PF6 as the counter-ion (entry 14) aqueous-phase homogeneous catalytic aerobic oxidation methodology achieved a quantitative yield of the corresponding oxidation. Switching (35, 36). Yet, the method still requires a precious metal (palladium), a from air to oxygen gas under the same atmospheric pressure also led to high pressure (30 bar), and a large amount of additive (TEMPO). In a quantitative isolated yield (entry 15). As a control experiment, only a 2008, Tian et al. reported a heterogeneous catalytic aqueous-phase trace amount of the product was detected in the absence of the silver oxidation of aldehydes using silver(I)/copper(II) oxide (37), but the catalyst. method suffers from a high catalyst loading, a very limited substrate A series of common aldehydes, including both aliphatic and aro- scope, and side reactions. In 2009, Yoshida and co-workers reported a matic examples with different functional groups, was then chosen to con- water-soluble N-heterocyclic carbene (NHC)–catalyzed oxidation of duct the scope investigation with this catalytic system (Table 2). Besides by oxygen (38). However, this method still requires the re- benzaldehyde, which gave a quantitative yield (entry 1, compound 1), action solvent to be a mixture of N,N′-dimethylformamide/H2O in 10:1 aliphatic 1-octanal also gave a quantitative yield of the corresponding acid ratio, which is far from a complete water-phase oxidation. Recently, in (entry 2, compound 38). Hydrocinnamaldehyde and 1-naphthaldehyde 2014, Han and co-workers reported a multifunctional utilization of gave very good yields of 86 and 88% (entries 3 and 4, compounds 49 and silver-NHC complex as catalyst to achieve different oxidation of alco- 4), respectively. With 4-fluorobenzaldehyde, the reaction only gave a hol (39), but the method still relies on organic solvent and anhydrous 34% yield (entry 5, compound 16), whereas 4-chlorobenzaldehyde led to conditions. Here, we wish to report a highly efficient, widely applicable, a 100% recovery of the starting material (entry 6, compound 18). Surpris- homogeneous silver(I)-catalyzed aerobic oxidation of a wide range of ingly, for the unsaturated cinnamaldehyde, even with all the starting ma- aldehydes using only water as solvent, and performed under atmospheric terial consumed, the reaction still did not give any desired product (entry 7, pressurewithoxygengasoroxygenintheairastheoxidantundermild compound 47), whereas the unconjugated 4-allyloxy benzaldehyde led conditions (Fig. 1). to a low conversion of the starting material and no desired product (entry 8, compound 12). p-Anisaldehyde and piperonal, bearing additional oxygen-based functional groups, also led to 100% recovery of the starting Department of Chemistry and FRQNT Centre in Green Chemistry and Catalysis, McGill 6 5 University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada. material (entries 9 and 10, compounds and ). We postulated that *Corresponding author. E-mail: [email protected] those substrates with inferior reactivity might be caused by the competing

Liu et al. Sci. Adv. 2015;1:e1500020 27 March 2015 1of9 RESEARCH ARTICLE

O2 WATER

-Excellent efficiency

-1 atm O2 50°C in water -Extremely low [Ag] cat. load capable of doing gram scale with 2 mg of catalyst (in prolonged time) -Chromatography is unnecessary in almost all cases

Fig. 1. Highlights of our aerobic oxidation. coordination of oxygen, nitrogen, C=C double bond, and so on, to the With the optimized reaction conditions in hand, a much more di- Lewis acidic silver(I) center within the same molecule as the aldehyde car- verse series of aldehydes were selected to examine the substrate scope bonyl. Thus, we rationalized that a stronger coordinating ligand may be (Table 4). To our satisfaction, excellent yields were obtained with all required to release the Ag(I) center from such coordination. aldehydes that we examined. Aromatic aldehydes where the –Rgroupis Using piperonal, unreactive under the above conditions, as the a hydrocarbon (benzaldehyde, p-tolualdehyde, 5-indancarboxaldehyde, model substrate, phosphorus-based and NHC ligands were examined or 1-naphthaldehyde) were all transformed in quantitative or nearly (Table 3). Unless otherwise noted, all experiments were carried out in quantitative yields (compounds 1 to 4). All of the electron-rich aromatic house-light conditions, without light sheltering. With [(CF3)2CHO]3P, a aldehydes that we tested—mono-, di-, and tri-methoxyl–substituted very electron-poor ligand, we only obtained a 21% yield. Furthermore, benzaldehydes—gave quantitative or nearly quantitative yields (com- some decomposition of the piperonal’s formacetal structure was ob- pounds 6 to 9) regardless of the location of the substituent. Please note served (entry 2). The combination of AgPF6 with more electron-rich that piperonal, which was tested in our investigation of the reaction trifurylphosphine gave a good 66% nuclear magnetic resonance yield conditions (compound 5), also gave almost quantitative yield. The (entry 3); however, some decomposition (ca. 15%) of the acetal was still more hydrophobic 4-(pentyloxy)benzaldehyde and 4-(hexyloxy) observed. The catalyst generated from AgPF6 and the NHC ligand IPr benzaldehyde also gave excellent 94 and 90% yields (compounds 10 gave a much lower yield (entry 4). To our surprise, when we switched and 11), respectively. The 4-allyloxy-benzaldehyde gave quantitative AgPF6 to Ag2O, an almost quantitative yieldwasobtained(entry5).Iso- yield as well, with the terminal C=C double bond intact and no ob- lation of the product from the reactionmixturewasveryeasy:Theaqueous servation of the Claisen rearrangement (compound 12), whereas the reaction mixture was simply washed with common non–water-mixable or- 4-benzyloxy-benzaldehyde resulted in a reduced 65% yield, probably ganic solvent and then acidified, followed by extraction using diethyl due to the cleavage of the benzyloxy group (compound 13). . Without needing to perform flash chromatography, the product Other than those electron-rich aldehydes, only slightly reduced with an extremely high purity level was obtained. Meanwhile, a 50% yield yields were obtained with 3-bromo-2,4-dimethoxybenzaldehyde and was achieved when only 0.5 equivalent of the base was added, indicating 5-bromo-1,3-benzodioxole-4-carboxaldehydeinwhichabrominewasalso that the presence of base is necessary to drive the reaction. The con- attached to the aromatic ring (compounds 14 and 15), possibly due to trolled experiment was then conducted to test how the reaction pro- chelation. All other halogenated aromatic aldehydes, including fluorine-, ceeds in the absence of oxygen. Surprisingly, with the reaction conducted chlorine-, bromine-, and the pseudohalogen cyano-substituted ben- with argon at 1 bar and using ordinary distilled water stored in air, the zaldehydes, resulted in quantitative conversions regardless of the location reaction was still capable of giving 66% yield (entry 10), whereas very of the substituent (compounds 16 to 24). With terephthalaldehyde, ex- little product was detected when the system was completely oxygen-free clusive oxidation of only one of the aldehyde groups was obtained in a (entry 11). It should be noted that visible light does not alter the reaction quantitative yield (compound 25). To verify this selectivity, introducing efficiency. 4-formylbenzoic acid to our standard reaction conditions led to a

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Table 1. Investigation of reaction conditions.

O [Ag] 5 mol % O Additive 5 mol % H + O2 OH DIPEA 5 mol % 1 ml water, 50oC, 12 h (0.1 mmol) (Air)*

P PPh2 PPh 2 N N

Cy2PPh BINAP Bipy

Entry [Ag] Additive Starting material conversion NMR yield†

1 AgF/Cy2PPh 0 %0 %

2 AgF/Cy2PPh NaCO2H 19 % 11% ‡ 3 AgF/Cy2PPh NaCO2H 5 %<3 %

4 AgF/Cy2PPh NaF 27%20 %

5 AgF/Cy2PPh NaCl 0 %0 %

6 AgF/Cy2PPh NaBr 0 %0 %

7 AgF/Cy2PPh NaBF4 30 %20%

8 AgF/Cy2PPh LiF 0 %0 %

9 AgF/Cy2PPh KF 0 %0 %

10 AgF/Cy2PPh MgF2 0 %0 %

11 AgF/Cy2PPh AlF3 0 %0 % 12 AgF/BINAP NaF 31 %21% 13 AgF/bipy NaF 30 %22%

14 AgPF6/bipy NaF 100 % > 99 %

15§ AgPF6/bipy NaF 100 % > 99% ¶ 16§ NaF Trace Trace * All reactions were carried out in sealed 10- ml reaction vessels filled with atmospheric air or pure oxygen. † 1H-NMR yield was determined using 1,3,5-mesitylene as an internal standard. ‡ Reaction was carried out under atmospheric argon. § Reactions were carried out under atmospheric pure oxygen. ¶ Isolated yield. quantitative recovery of the starting material. The presence of another nitrogen. Other heterocyclic aromatic aldehydes such as furfural and carbonyl group, other than an acid, in the aldehyde does not affect the 2-thiophenecarboxaldehyde were also subjected to the oxidation, in which oxidation yield: both 4-acetylbenzaldehyde and 4-acetaminobenzaldehyde furfural gave a quantitative yield, whereas 2-thiophenecarboxaldehyde gave quantitative yields (compounds 26 and 27). 4-Hydroxymethyl- gave a reduced 60% yield (compounds 30 and 31), possibly also benzaldehyde also gave a quantitative yield (compound 28). With 4- due to the stronger coordination of the sulfur atom in thiophene. quinolinecarboxaldehyde, a decreased yield (57%) was observed Most electron-poor aromatic aldehydes, represented by nitro- and (compound 29), possibly due to the strong coordination of quinolone trifluoromethyl-substituted benzaldehydes, were highly efficient in

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Table 2. Investigation of substrate scope.

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Table 3. Studies on improving the compatibility of the reaction.

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Table 4. Substrate scope investigation.

Liu et al. Sci. Adv. 2015;1:e1500020 27 March 2015 6of9 RESEARCH ARTICLE this oxidation and gave quantitative yields regardless of the location does interfere with the oxidation slightly. With aryl-substituted con- of the substituent (compounds 32 to 35). jugated cinnamaldehyde and a-methylcinnamaldehyde, the oxidation Various aliphatic aldehydes were also tested: Linear hexanal, hep- proceeded quantitatively (compounds 47 and 48). Hydrocinnamal- tanal, octanal, and even the extremely hydrophobic decanal all gave dehyde and phenylpropionaldehyde also gave quantitative yield quantitative oxidation products (compounds 36 to 39). Similarly, (compounds 49 and 50). The 4-nitro–substituted cinnamaldehyde branched 2-methylbutanal, 2-methylpentanal, 2-ethylbutanal, and gave a slightly reduced 91% yield (compound 51). As a natural prod- 2-ethyl hexanal also gave quantitative yields (compounds 40 to 43). uct and a widely used source of food spice, perillaldehyde also gave a With a C=C double bond being conjugated to the carbonyl, 3-methyl- quantitative yield (compound 52). An even more complex tertiary al- 2-butenal gave a slightly reduced yield of 77% (compound 44). Cit- dehyde, abietadien-18-al, was also successfully oxidized to abietic ronellal gave a moderate 60% yield, whereas citral gave a good 86% acid (compound 53) with an increased reaction temperature and yield (compounds 45 and 46), indicating that the C=C double bond pressure (Fig. 2). Finally, a gram-scale oxidation was conducted with benzaldehyde (Fig. 3). To be practical and economical, we low- ered both the amount of solvent and the amount of catalyst compared to the stan- dard conditions. With only 2 mg of our silver(I) catalyst {equivalent to about 0.036 mol % [360 ppm (parts per million)] catalyst loading}, 560 mg of sodium hy- droxide, and 1.4 ml of benzaldehyde in 10 ml of water at 1 bar of oxygen using an attached balloon, the reaction gave an as- tonishing 82% isolated yield with more Fig. 2. Abietadien-18-al aerobic oxidation. than 1.4 g of analytically pure benzoic acid after 48 hours at 50°C. This indicates that our methodology can be readily scaled up to an industrial level. On the basis of the results of our study, a plausible reaction mechanism that in- volves two catalytic cycles is proposed in Fig. 3: one of the cycles is responsible for extracting the hydride from the aldehyde, whereas the other is responsible for acti- vating the dioxygen molecule in water. Fig. 3. Gram-scale reaction. Each cycle consumes one molecule of

Ag2O + IPr HCl

IPr MeCN H2O O IPr Ag H AgOH O O Ag OH R O OH O IPr-Ag-Cl R H IPr Ag Ag IPr R H O R O OH R O NaOH/H2O R H IPr Ag O O OH Oxygen IPr-Ag-OH Hydride O activation extraction cycle IPr-Ag-H R H cycle OH O IPr 2 O Ag O OH OO R H IPr-Ag-H O O IPr OH O Ag H IPr-Ag-O-OH O R O R OH R OH

R H

A B Fig. 4. Reaction mechanism. (A) Plausible mechanism and (B) ZPE-corrected energies from B3LYP/6-31G(d) and LANL2DZ for Ag. All values are given in kcal/mol and referred to the system AgOH(PMe3) + PhCHO. Gibbs free energy is considered for drawing.

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