Amide exchange reaction: a simple and efficient CuO catalyst for diacetamide synthesis

Abstract

A highly copper-catalysed amide exchange reaction of hexamethylenediamine (HDA) with CH₃CN and H₂O for the synthesis of hexamethylenebisacetamide (HMBA) without an organic solvent or gas protection was developed. 100% HDA conversion and >99% HMBA selectivity was obtained. X-ray diffraction, scanning emission microscopy, and temperature-programmed reduction of hydrogen were used to characterize the structural properties of the catalyst. The reaction mechanism was also investigated.

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Diacetamide products (DAPs), which are among the simplest imides, model compounds of biochemical relevance, and good co-crystallising agents, have a variety of applications in numerous industrially important processes, as well as in medicine, as pesticides, and in organic synthesis.^1–5 The molecular conformation and basic applications have attracted considerable attention. In recent years, the amide exchange reaction (AER) has been used increasingly to synthesize DAPs by pharmaceutical companies and in research laboratories.^6,7 Among the many different DAPs, hexamethylenebisacetamide (HMBA)^8–10 is a major anti-carcinogen and medical–chemical intermediate used in the synthesis of different organic chemicals,^11–25 including hexamethylenetertamine (HMTA), diethyl hexamethylenedicarbamate (EHDC), and diphenyl hexamethylenedicarbamate (PHDC), (Fig. 1).

Fig. 1 Selected products produced from HMBA.

Given the potential applications of HMBA, considerable work has gone into its production.^26–28 The traditional preparation method of HMBA, however, still utilises a noble metal complex catalyst and an organic solvent under an inert atmosphere and has a low yield. As shown in Scheme 1, RuH₂(PPh₃)₄ was employed in the reaction of HDA, CH₃CN, and H₂O to prepare HMBA using dimethoxyethane (DME) as the solvent under an argon atmosphere, in only 89% yield.^29,30 However, the development of a method using mild conditions and a non-noble metal catalyst for the conversion of diamine to diacetamide is still required. Much effort has gone into identifying alternative non-noble metal catalysts and green ways to produce HMBA. Recently, there has been a lot of focus on different copper-catalysed reaction systems. Copper catalysts have been used as simple and efficient promoters in various reaction systems such as photo-catalytic reactions.^31,32

Scheme 1 Synthesis of HMBA from HDA, CH₃CN and H₂O.

Herein, a simple and efficient copper catalyst was used to replace noble metal catalysts in the reaction of HDA, CH₃CN, and H₂O without an organic solvent or gas protection with an isolated yield of 96%.

The catalytic performance of different metal oxide catalysts was studied (see ESI Table 1†). From the results, it was identified that the CuO catalyst shows better catalytic performance than the others in this reaction, with 100% HDA conversion and >99% HMBA selectivity. However, the use of other copper catalysts, including Cu, Cu₂O, CuCl, CuBr, and CuSO₄, was less successful, leading to poor HMBA selectivity compared to CuO. The CuO catalyst was deemed to be more suitable for the reaction of HDA, CH₃CN, and H₂O (Table 1).

Table 1 Synthesis of HMBA from HDA, CH₃CN, and H₂O with different copper catalysts^a

Entry	Catalyst	Conv. (%)	Sel.^b (%)
a Reaction conditions: 0.01 mol HDA, 0.03 mol CH3CN, 0.06 mol H2O, 0.00625 mol catalyst, 180 °C, 2 h. Conversion and selectivity were determined by gas chromatography.b Selectivity of 1b.
1	CuO	100	>99
2	Cu	98	61
3	Cu2O	98	72
4	CuCl	93	70
5	CuBr	90	84
6	CuSO4	89	60

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Then, we optimised the reaction conditions of the model reaction of HDA, CH₃CN, and H₂O (see ESI, Fig. S1†). Primarily, the influence of the ratio of reagents was investigated. In the presence of 0.00625 moles of catalyst at 180 °C for 2 h, the optimal molar ratio of HDA, CH₃CN, and H₂O was found to be 1 : 3 : 6.

The recyclability of the CuO catalyst was also investigated (Fig. 2). The results show a slight decrease in activity after each run, corresponding to a decrease in HDA conversion from 100% to 98%. This is because CuO recovered only 95% of the charged amount after each run by simply centrifuging, washing, and drying, and it was slightly influenced by water, suggesting that the CuO catalyst could be reused without significant loss of activity. As shown in Fig. 2, HMBA selectivity was also influenced by the slight decrease in activity of the CuO catalyst.

Fig. 2 Cycling tests of CuO. Reaction conditions: 0.01 mol HDA, 0.03 mol CH₃CN, 0.06 mol H₂O, recovered catalyst, 180 °C, 2 h. The selectivity in this figure was assigned to HMBA.

Subsequently, to demonstrate the utility and generality of this approach to the formation of diacetamides, reactions of different diamines, including aliphatic diamines (linear chain and cyclic diamines) and aromatic diamines, with CH₃CN and H₂O were carried out under the optimised conditions, the results are shown in Table 2. Excellent yields of the corresponding diacetamides were obtained with the linear chain and cyclic aliphatic diamines (entries 1–5). On the other hand, lower activities were obtained with aromatic diamines towards the production of the corresponding diacetamides (entry 6–10), which might be due to the weak nucleophilicity of the nitrogen atom and the conjugative effect derived from the benzene ring. 2-Methyl-1H-benzo[d]imidazole was easily formed, detected using an Agilent GC-MS 7890B (see ESI Fig. S4†), from the reaction of o-phenylenediamine and CH₃CN, which proceeded with only 3% selectivity for the diacetylation product. However, high activity was achieved with 1,3-bisaminomethylbenzene (entry 11) with 100% conversion and 83% diacetamide selectivity due to the benzyl group of this aromatic diamine. The CuO catalytic system was applicable to a wide range of aliphatic and aromatic diamines.

Table 2 Synthesis of diacetamides from various diamines^a

Entry	Diamine	Major product	T (h)	Conv. (%)	Sel.^b (%)
a Reaction conditions: 0.01 mol diamine, 0.03 mol CH3CN, 0.06 mol H2O, 0.00625 mol catalyst, 180 °C, 2–8 h. Conversion and selectivity were determined by gas chromatography.b Selectivity of diacetamide.
1			2	100	>99
2			2	100	>99
3			2	100	>99
4			8	100	95
5			8	100	93
6			8	56	20
7			8	45	3
8			8	63	15
9			8	75	25
10			8	35	10
11			2	100	83

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X-ray diffraction (XRD), scanning electron microscopy (SEM), and temperature-programmed reduction of hydrogen (TPR-H₂) were carried out to examine the relationship between the structure of the CuO catalyst and performance of the reaction system. The XRD results of the prepared and used CuO are shown in Fig. 3. The diffraction peaks at 32°, 35°, 38°, 48°, 53°, 58°, 61°, 66°, 68°, 72°, and 75° of the prepared CuO are in good agreement with pure CuO (JCPDS card no. 801916). In addition, the sharp and narrow peaks indicate that the prepared CuO is well crystallised. The peaks at 18°, 33°, 43°, and 50° 2θ in Fig. 3b were assigned to Cu, which was formed by the reaction of by-product NH₃ with CuO, causing a slight decrease in activity of the CuO catalyst.

Fig. 3 Powder XRD patterns of (a) prepared CuO and (b) used CuO.

The CuO catalyst prepared by the hydrothermal method has a nanorod-like morphology with an average diameter of 200 nm, as shown in Fig. 4. For comparison, different morphologies of CuO were also investigated and found to exhibit similar catalytic activities, indicating that the morphology of the CuO catalyst has little influence in this reaction.

Fig. 4 SEM image of the prepared CuO catalyst.

The TPR results of the prepared CuO, commercial CuO, and Cu₂O catalysts are shown in Fig. 5. A broad peak at 305 °C can be observed for the prepared pure CuO catalyst (Fig. 5a). There are two broad peaks at 367 and 534 °C, which are assigned to Cu₂O and CuO, respectively, because Cu₂O is more easily reduced than CuO under the same conditions. In addition, the shift in CuO reduction temperature from 305 to 534 °C indicated some type of interaction between Cu₂O and CuO, which may inhibit the reduction of CuO (Fig. 5b). On the contrary, the introduction of CuO may favour the reduction of Cu₂O, with much lower peaks at 254 and 280 °C observed in Fig. 5c compared to Fig. 5b.

Fig. 5 TPR-H₂ results for (a) prepared CuO, (b) commercial CuO, and (c) commercial Cu₂O.

In order to study the mechanism of the reaction of HDA, CH₃CN, and H₂O catalysed by CuO, reactions of different substrates, including HDA, CH₃CN, H₂O, and CH₃CONH₂, were carried out and traced by gas chromatography-mass spectrometry (GC-MS), (Table 3).

Table 3 Effect of the CuO catalyst on different combinations of reagents, including HDA, CH₃CN, H₂O, and CH₃CONH₂^a

Entry	HDA (mol)	CH3CN (mol)	H2O (mol)	CH3CONH2 (mol)	Conv. (%)	Sel.^b (%)
a Reaction conditions: 180 °C, 2 h, magnetic stirring speed of 960 rpm, 100 mL high pressure reactor. Conversion and selectivity were determined by gas chromatography.b Selectivity of HMBA.c Conversion of HDA.d Conversion of CH3CN.e Without the CuO catalyst.
1	0.01	0.03	0.06	—	100^c	>99
2	0.01	0.03	—	—	—	—
3	0.01	—	—	0.03	82^c	52
4	0.01	—	0.06	—	—	—
5	—	—	0.06	0.01	—	—
6	—	0.03	—	0.01	—	—
7^e	—	0.03	0.06	—	6.5^d	—
8	—	0.03	0.06	—	8^d	—

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Initially, HDA, CH₃CN, and H₂O (molar ratio, 1 : 3 : 6) were added to the reactor, and 100% HDA conversion and >99% HMBA selectivity were obtained (entry 1). The reactions of HDA with CH₃CN, H₂O, and CH₃CONH₂ were investigated. As shown in Table 3 entry 2, no HDA consumption or HMBA was detected in the reaction solution. These results and those of previous reports show that the polymerization reaction of CH₃CN was promoted by a catalytic amount of HDA to form 1,3,5-trimethyl-triazine, which was detected by GC-MS in this experiment. Only 82% HDA conversion and 52% HMBA selectivity were obtained when HDA reacted with CH₃CONH₂ directly (entry 3). There was no reaction between HDA and H₂O, CH₃CONH₂, and H₂O, and CH₃CONH₂ and CH₃CN in the presence of the CuO catalyst under the reaction conditions (entries 4–6). In the end, compared to entry 7, which has 6.5% CH₃CN conversion under no CuO catalyst, the reaction of CH₃CN with H₂O catalyzed by CuO showed 8% CH₃CN conversion to CH₃CONH₂ (entry 8), indicating that CuO has little effect on the reaction of CH₃CN with H₂O.

Based on the reactions discussed above, a feasible reaction pathway for the AER of HDA, CH₃CN, and H₂O catalysed by CuO is proposed, as shown in Scheme 2. The results indicate that HMBA was generated in two consecutive steps. Initially, CH₃CONH₂ was formed by a reaction of CH₃CN and H₂O, followed by the formation of HMBA in the second step via the AER of HDA with CH₃CONH₂, the former reaction was promoted by the latter. It is worth noting that in the second step, CuO plays a significant role in the nucleophilic addition reaction of HDA and CH₃CONH₂. The electrophilicity of the carbonyl carbon atom in CH₃CONH₂ was promoted by the CuO catalyst. The carbonyl was then attacked by nucleophilic HDA.

Scheme 2 Proposed mechanism for the AER of HDA, CH₃CN, and H₂O.

As shown above, the nucleophilic addition of CH₃CONH₂ activated by CuO with HDA occurred to form I, followed by proton transfer to generate II. The elimination of ammonia from II affords intermediate III, which goes on to react with activated CH₃CONH₂ to afford IV. V then forms HMBA via the elimination of ammonia.

Conclusions

We proposed a highly copper-catalysed AER of HDA with CH₃CN and H₂O for the synthesis of HMBA. Under the optimised reaction conditions, good yields of various diacetamides were obtained with different diamines. This optimised catalytic system for the AER of diamines, CH₃CN, and H₂O is preferable for the synthesis of diacetamides via an environmentally benign route. Further development and application of this reaction are currently underway.

Acknowledgements

This study was financially supported by the National Natural Science Foundation of China (No. 21173240).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Details of experimental procedures of preparation and characterization of catalysts and catalytic data, and characterization of the product. See DOI: 10.1039/c6ra05563j

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