Introduction
Oxidation of various primary amines to nitriles is an important reaction in organic synthesis [1]. There are reports on primary amines oxidation to nitriles in the presence of metal-catalysts [2-7]. Yamazaki [8] reported a simple method for the synthesis of nitriles by metal-free oxidation of primary amines in ethanol. However, the leaching of active metal species or the application of organic solvents in these reaction systems made these methods less benign. Therefore, the research for novel, clean and metal-free oxidation of primary amines to the corresponding nitriles is of particular interest.
According to the principle of “green chemistry”, one of the goals in present organic synthesis is to perform organic reactions in aqueous media because of its environmentally benign nature. Supramolecular reagents should be the perfect media to “dissolve” those substrates into water by forming host-guest complexes, and the substrates could be well converted in water via supramolecular catalysis [9]. Marinescu [10] reported a method on supramolecular oxidation of anilines to the corresponding nitro derivatives catalyzed by ketones, and the mildness, selectivity and reaction rate of this enzymatic catalysis greatly exceeded those of ordinary chemical catalysis. In our efforts to develop biomimetic approaches for chemical reactions involving β-cyclodextrin (abbreviated as β-CD) via supramolecular catalysis, the substrate-selective reactions [11-13] were focused. For example, in comparison with the general methods on the oxidation of various alcohols in NaClO—KBr system reported by Surendra [14], only those substrates with suitable space configuration could be successfully oxidized in our previous report [11]. Accordingly, we report herein an efficient, substrate-selective and practical method for the oxidation of primary amines to nitriles with NaClO as an oxidant catalyzed by β-cyclodextrin in water for the first time.
Experimental section
Chemical reagents
NaClO (Tianjin Chengfu chemical reagent factory, 10%), ethyl acetate (Guangzhou chemical reagent factory, 99%), β-cyclodextrin (Aldrich-Sigma,>95%), H2O2 (Guangzhou Chemical Reagent Factory, 30%), HCl (36%) was purchased from the Guangzhou Chemical Reagent Factory and diluted to HCl (5%), benzyl amine (Fluka,>99%), (2,4-dichlorophenyl)methanamine (Fluka,>99%), naphthalenylmethanamine (Fluka,>98%), 2-phenylethanamine (Fluka,>99%), octan-1-amine (Fluka,>99%), cyclohexylmethanamine (Fluka,>98%). All reagents were of analytical reagent grade. Deionized water was used throughout.
Typical procedure of oxidation of primary amine
Half a millimole of β-cyclodextrin was dissolved in 25 mL deionized water at 50°C and 1 mmol primary amine was added to the above solution while stirring. After the mixture was naturally cooled to room temperature, 5 mL of 10% NaClO was slowly added. The reaction went on for 20 min and stopped. Then, the mixture in the solution was extracted with ethyl acetate (2×30 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuum. The crude product was analyzed by GC (Shimadzu GC-14C). Products were characterized by GC-MS (Shimadzu GCMS-QP2010) and compared with authentic samples.
Large scale oxidation of benzyl amine
The oxidation of benzyl amine was enlarged to ten times amount of the reactant. The crude products were purified via column chromatography (silica gel), using the mixture of petroleum ether and ethyl acetate (V/V= 3∶1) as eluting agent. Then, the solvent was removed by distillation under reduced pressure and the pure benzonitrile (0.962 g, 90% yield) was obtained.
Results and discussion
The oxidation of benzyl amine as a representative sample (Scheme 1) has been performed to optimize the reaction conditions with various oxidants including molecular oxygen, hydrogen peroxide and NaClO, and the result is shown in Table 1.
Tab.1 Effects of different oxidants on oxidation of benzyl aminea) |
| entry | oxidant | time | Conv.b)/% | yieldb)/% (benzonitrile) | yieldb)/% (benzaldehyde) |
|---|---|---|---|---|---|
| 1 | O2 | 4 h | 0 | 0 | 0 |
| 2c) | 30% H2O2 (5 mL) | 4 h | 35 | 5 | 0 |
| 3 | 10% NaClO(5 mL) | 20 min | 100 | 98 | 2 |
| 4d) | 10% NaClO (5 mL) | 30 min | 100 | 92 | 8 |
| 5e) | 10% NaClO (5 mL) | 2 h | 99 | 91 | 8 |
| 6f) | 10% NaClO (5 mL) | 20 min | 92 | 90 | 2 |
| 7g) | 10% NaClO (5 mL) | 20 min | 100 | 98 | 2 |
| 8 | 10% NaClO (5 mL) + 5% HCl(5 mL) | 1 h | 100 | 97 | 3 |
a) Reaction conditions: β-cyclodextrin (0.5 mmol), benzyl amine (1 mmol), H2O (25 mL), r.t; b) Conversions and yields were determined by GC-MS; c) The yield of benzaldehyde oxime was 30%; d) 0.5 mmol β-cyclodextrin was replaced by 5 mL ethanol; e) Blank experiment, without addition of β-cyclodextrin; f) The amount of β-cyclodextrin was 0.4 mmol; g) The amount of β-cyclodextrin was 1 mmol |
The results show that neither weak oxidant O2 nor moderate oxidant H2O2 could be used as an effective oxidant towards benzyl amine oxidation (entries 1,2). However, the strong oxidant NaClO greatly prompted the oxidation, and complete conversion from benzyl amine to benzonitrile could be achieved within 20 min (entry 3). It should be noticed that β-cyclodextrin is crucial and the reaction rate was much lower in the absence of β-cyclodextrin (entry 5). Furthermore, when the amount of β-cyclodextrin was less than 0.5 mmol, the reaction rate was lower (entries 6,7). Though the addition of co-solvent ethanol could also prompt the conversion of benzyl amine (entry 4), the reaction rate as well as the yield of product benzonitrile was lower in comparison with the oxidation catalyzed by β-cyclodextrin. Moreover, the addition of hydrochloric acid could remarkably decrease the oxidation rate of benzyl amine while the yield of benzonitrile was kept unchanged with a longer reaction time (entry 8). Therefore, NaClO as an oxidant and β-cyclodextrin as a catalyst were used in the following oxidation of various primary amines. In order to extend the application of the method, the oxidation of various primary amines has been investigated following the above procedure.
In general, similar with the oxidation of benzyl amine, the addition of co-solvent ethanol could also accelerate the conversion of other primary amines to the corresponding nitriles compared with the oxidation in water. Thus, to explore the difference of primary amines oxidation between β-cyclodextrin and ethanol aqueous media, and to investigate how the catalyst β-cyclodextrin worked in these systems, we also performed these reactions by adding co-solvent ethanol in place of β-cyclodextrin in water. The results are shown in Table 2.
Tab.2 Oxidation of primary amines in presence ofβ-cyclodextrin in watera) |
| entry | substrate | product | conv.b)/% | time | yieldb)/% |
|---|---|---|---|---|---|
| 1 | 100 | 20 min | 98 | ||
| 2c) | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082224.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082223.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | 100 | 30 min | 91 |
| 3 | 100 | 1 h | 95 | ||
| 4c) | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082222.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082221.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | 100 | 1 h | 87 |
| 5 | 100 | 2 h | 98 | ||
| 6c) | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082250.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082249.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | 100 | 1.5 h | 86 |
| 7 | 100 | 1 h | 61 | ||
| 8c) | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082248.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082247.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | 100 | 1 h | 63 |
| 9 | 100 | 1 h | 93 | ||
| 10c) | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082246.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082245.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | 100 | 1.5 h | 82 |
| 11 | 100 | 1.5 h | 78 | ||
| 12c) | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082244.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | <InlineMediaObject OutputMedium="All"><ImageObject FileRef="images\hcm0000082243.tif" Format="TIFF" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject> | 100 | 1 h | 77 |
a) Reaction conditions: β-cyclodextrin (0.5 mmol), substrate (1 mmol), H2O (25 mL), 10% NaClO (5 mL), r.t; b) Conversions and yields were determined by GC-MS; c) 0.5 mmolβ-cyclodextrin was replaced by 5 mL ethanol |
It is known that β-cyclodextrin and substrate can form a host-guest complex in water [15,16]. This complexation depends on the size, shape and hydrophobicity of the guest molecule. Such interaction can enhance the solubility of the substrate in water [17]. In comparison with the oxidation of benzyl amine or cyclohexylmethanamine in β-cyclodextrin aqueous media (entries 1 and 9), the reaction rate was lower in ethanol aqueous media (entries 2 and 10), as did the yield of the corresponding nitriles, indicating that β-cyclodextrin worked not only as a solubilizing agent but also as a catalyst in these reactions [18,19]. In the present system, β-cyclodextrin could activate the substrates by forming hydrogen bonds and break the N—H bond of these, which could accelerate the oxidation and improve the selectivity of the corresponding nitriles. However, when the benzyl amine was modified by introducing Cl groups into the aromatic ring, the obtained (2,4-dichlorophenyl)methanamine presented less promotion in β-cyclodextrin aqueous media compared with in ethanol aqueous media owing to the effect of space configuration (entries 3-4). Similarly, due to the large naphthalen-1-ylmethanamine molecule, the corresponding cyclodextrin-naphthalenylmethanamine complex might be a little difficult to form [11] and the reaction rate also decreased (entries 5, 6). It should be noticed that 2-phenylethanamine could form the stable inclusion complex with β-cyclodextrin, whereas the yield of the product 2-phenylacetonitrile was not improved in β-cyclodextrin aqueous media. β-Cyclodextrin might activate less the b-position of the 2-phenylethanamine because of the space configuration (entries 7, 8). Similar to the deprotection of 2-heptyl-1,3-dioxolane[12] or oxidation of 2-octanol and 1-octanol [11] in water, where the interaction between hydroxyl groups on β-cyclodextrin and the groups to be reacted in the substrates could be hardly performed, the oxidation of octan-1-amine proceeded faster in the ethanol aqueous media than in the β-cyclodextrin aqueous media due to better solubility (entries 11, 12).
As to the oxidation of primary amines in the presence of β-cyclodextrin, the process of benzyl amine oxidation was investigated to monitor the intermediate and products, as shown in Figs. 1 and 2.
From Fig. 1, two final products could be obtained from benzyl amine oxidation, one product was benzaldehyde which was formed by direct cleavage of C-N bond of the substrate, and the other was benzonitrile, which was obtained via further oxidation of reaction intermediate phenylmethanimine. From Fig. 2, the oxidation of benzyl amine in the presence of 0.5 mmol β-cyclodextrin was among the fastest, and the addition of 5 mL hydrochloric acid could decrease the oxidation rate, because the increase of acidity in the reaction system would decrease the interaction of hydrogen bond between β-cyclodextrin and benzyl amine to some extent [20].
Reactions involving cyclodextrin complexes can have complicated mechanisms. Breslow described a detailed treatment of the data about the mechanism involving cyclodextrin [21]. Similarly, β-cyclodextrin and benzyl amine first formed host-guest inclusion complex in water, and the conversion of benzyl amine to phenylmethanimine would be accelerated because the inclusion complex could activate its N-H bonds, so did the second-step conversion from phenylmethanimine to benzonitrile.
Considering the high potential for practical applications of this biomimetic approach, the oxidation of benzyl amine as a model reaction was enlarged to ten times amount of the reactant, as shown in Scheme 2. 90% isolated yield of benzonitrile was obtained, demonstrating the possibility and feasibility for practical applications of this biomimetic approach in the future.
The used β-cyclodextrin could be easily recycled by centrifugation separation after the addition of acetone. The addition amount is important for good recovery. When the volume ratio of acetone to water was 2∶1, 95% β-cyclodextrin could be recycled. The thrice-recycled β-cyclodextrin can still be reused without loss in catalytic activity or selectivity.
Conclusions
We have developed a facile, substrate-selective and transition metal-free oxidation of primary amines catalyzed by β-cyclodextrin with cheap NaClO oxidant in water for the first time. In contrast to the existing methodologies using Lewis acid and transition metal catalysts, the employment of toxic solvents and expensive catalysts is thoroughly avoided by this method. In water, β-cyclodextrin could form the stable complexes with suitable substrates. These complexations depend on the size, shape and hydrophobicity of the guest molecules. Such interactions could enhance the solubility of substrates and activate them by forming hydrogen bonds. However, it was found that β-cyclodextrin could not work if it could not form the stable inclusion complexes with guest molecules. Since β-cyclodextrin could be easily recycled and reused without loss in catalytic activity or selectivity as well as the excellent yields of the nitriles, this biomimetic approach of synthesizing nitriles was highly potential for practical applications.