Liu Xiuying, Ma Zhiguang, Shen Shigang, Shan Jinhuan, Du Baoan
(College of Chemistry & Environmental Science, Hebei University, Baoding 071002 China)
Abstract Phase transfer catalyst PEG-400 was used in the synthesis of N-benzylphthalimide under microwave irradiation. Several influence factors on the product yield were investigated, such as the proportion of reagents, the irradiation time, the quantity of DMF and PEG-400 used. The experimental conditions were optimized which resulted in a high yield 98.5% within the reaction time of 120s.
The compounds of N-alkylating phthalimides are important intermediates in synthesizing the fatty primary amine and a -amino acid. In the classical method, the N-alkylating phthalimides was synthesized in N,N-dimethylformamide (DMF) by the reaction of halogenated compound with the salt, which was prepared by the reaction of phthalimide and KOH. Afterwards, some methods were reported such as: The phase transfer catalytic effects of polyethylene glycols in N-alkylation; convenient synthesis of N-substituted phthalimide; the reaction of N-alkylation of phthalimide by the inorganic supported reagent[3,4]. However, reaction time of the above reported methods is longer. Take the synthesis of N-benzylphthalimide as an example, generally the reaction time is about 10h, the shortest is 4h and the highest yield is 94%.
N-benzylphthalimide was firstly synthesized catalyzed by the alkaline reagent K2CO3-Al2O3 under microwave irradiation in 2002. In this reaction, a higher yield of 98% was obtained within a shorter time of 420s. However, it took about 6-7h to prepare the catalyst (alkaline reagents K2CO3-Al2O3) and 3h to purify the product after the completion of the reaction. Although the reaction time is only 420s, the work up is far from simplicity. In this respect, the preparatory method was further improved. Synthesis of N-benzylphthalimide with polyethylene glycol-400 as phase transfer catalyst under microwave irradiation was investigated in detail and the better result was obtained.
2.1 Reagents and instruments
Benzyl chloride, N,N-dimethylformamide, potassium carbonate anhydrous are all of analytical grades. phthalimide and polyethylene glycol-400 (PEG-400) are chemical grades. All the reagents are used without further treatment.
Microwave oven (WD750, 750W, 2450Mhz) is from Galanz Electric Limited Company of Shunde, and Infrared spectrophotometer (FTS-40) is from BIO-RAD of America.
Melting point is measured by capillary method.
2.2 Reaction procedure
N-benzylphthalimide was synthesized from phthalimide and benzyl chloride. The reaction was carried out with PEG-400 as phase transfer catalyst and anhydrous K2CO3 as ordinary catalyst in DMF under microwave irradiation. The whole process could be expressed by the following equation:
2.3 Preparation of N-benzylphthalimide
In a 50ml beaker, 1.90g phthalimide (12.5mmol), 2.0g benzyl chloride (15.8mmol), 2.0g anhydrous K2CO3 (13.9mmol), 1.5g PEG-400 and 2.0g DMF were mixed well and then put into the microwave oven. After irradiated continuously for 120s, the mixture was taken out and about 30ml de-ionzed water was added. Immediately, white crystal was formed. Then 5ml 10% aqueous NaOH was added and stirring was continued for 5min to dissolve the rest of phthalimide. The mixture was filtered under the reduced pressure and was washed with de-ionzed water until its pH value was neutral. The white crystal was dried in oven (105ºC) for 2h and the product was obtained. The experiment showed that the average yield attained could be 98.5% and its mp. was 113-114ºC, which was consistent with the reported value. Meanwhile, the infrared spectrum of the product obtained was just the same with that in Sadtler Spectrum Collection.
3 RESULTS AND DISCUSSION
3.1 Influence of the proportion of reagents to yield
The relationship between the proportion of reagents and yield was shown in Table 1. When phthalimide:benzyl chloride =1:1 (molar ratio), the yield was low; when phthalimide:benzyl chloride =1:1.25 (molar ratio), the maximum yield (98.5%) were obtained (entry 4). But when the quantity of benzyl chloride was increased again, the yield was not only decreased, but also some troubles, such as filtering was not easy, excessive benzyl chloride should be treated, were led in the preparationprocess,
Table 1 Relationship between the proportion of reaction reagents and the yield
|No.||phthalimide: benzyl chloride (molar ratio)||average yield (%)|
* 1.5g PEG-400, 2.0g anhydrous K2CO3 and 2.0g DMF were added and irradiated continuously for 120s under microwave oven.
3.2 Influence of the irradiation time to the product yield
The influence of irradiating time, power and temperature on the yield was investigated in this experiment. The results showed when the microwave oven was performed at 900W the reagents were easily coked. When the microwave oven was performed at 750W (the temperature reached 150ºC), and the reagents were irradiated for 60s, the yield was only 68.7% (Table 2, entry 1). Excellent yield was obtained when the irradiation time was 120s (entry 5). It should be noted that the elongation of the reaction time could not increase the yields of the products. On the contrary, yield obtained was decreased (entries 6-7).
Table 2. Relationship between the irradiate time and the yield
|time of irradiation (s)||60||90||100||110||120||150||300|
|average yield (%)||68.7||83.2||91.7||96.1||98.5||95.2||91.2|
* 1.90g phthalimide, 2.0g benzyl chloride, 2.0g K2CO3, 2.0g DMF, 1.5g PEG-400, were added and irradiated continuously under 750W microwave oven.
3.3 Influence of the catalyst and the solvent to the yield
As shown in Table 3 (entries 1-4), K2CO3 played an important role in the reaction. The products were not obtained in the absence of K2CO3 .The yield was low when 1.5g K2CO3 was added. The good yield was obtained when 2.0g K2CO3 was added (entry 3). The yield was not increased with further increasing quantity of K2CO3.
Table 3. Influence of the catalyst and the solvent to the yield
|No.||K2CO3(g)||PEG-400(g)||DMF(g)||time of irradiation (s)||average yield (%)||Color of crystal|
* 1.90g phthalimide and 2.0g benzyl chloride were added and irradiated continuously under 750W microwave oven
The rate of reaction was increased when PEG-400 as phase transfer catalyst was added. It was the process which first combined PEG-400 with Na+, then the pair of ions were formed by Na+ with negative ion of phthalimide. N-benzylphthalimide was synthesized with the pair of ions going into organic phase and combining with benzyl chloride. Right quantity was 1.5g to the synthesis reaction. If the quantity of PEG-400 was not enough, the yield was not high. Excellent yield could not be obtained only in the presence of PEG-400 without DMF, because the reaction-temperature was not controled and the mixture was easily coked (entries 6-13).
The product was synthesized with good yield just in the presence of DMF without the participation of PEG-400. Because the DMF could offer a much greater contact area to the reacting reagents, so DMF added tended to increase the rate of the synthesis reaction. The yield of 98% could be obtained if the reagents were irradiated continuously for 420s in the presence of 2.0g DMF in microwave oven (which was not reported in the literature so far as we know). But the product was light yellow and needed to be purified (entries 14-18), and the reaction time was extended. So it is with the double actions combining of DMF and PEG-400 that the excellent results can be achieved. That is when 2.0g DMF and1.5g PEG-400 were added (entry 3).
In the paper, N-benzylphthalimide was successfully synthesized under microwave irradiation and the optimum conditions were found (phthalimide: benzyl chloride:K2CO3=1:1.25:1.11, with 1.5g PEG-400 as phase transfer catalyst and 2.0g DMF as solvent under continuous irradiation for 120s in 750W microwave oven). The yield attained could be as high as 98.5%, and the reaction time needed was only 120s, which was shorter than the shortest time (420s) reported. All operation cycle took only about 20min. The method was very easy to operate, not only energy used was greatly saved, but also the reagents were reduced, which brought the highest economic value. In addition, pollution could be further reduced.