Study On The Non-toxicity Of Cyanide Reagents In Cyanation Of Benzyl Chlorides

The resulting products from cyanation of benzyl chlorides are easily transformed into amines, nitrogen-containing heterocycles, carboxylic acids and carboxylic acid derivatives. So such a kind of reactions plays a crucial role in synthetic organic chemistry, and is widely used in the production of pharmaceutical, spices, dye and pescitide intermediates. Among many methods for synthesizing benzyl cyanides, the method for substituent of benzyl chlorides is one of the most simple and efficient. The cyanide reagents used in such a method are mainly extremely poisonous NaCN,KCN, which seriously restrict their applications in the industry, even pose a potential threat to our environment. Aiming these problems, chemists developed CuCN and TMSCN for the cyanide reagents for cyanation of benzyl chlorides. However, the two compounds have some drawbacks such as high cost and poisonous character.Compared with the above-mentioned cyanide sources, K₄[Fe(CN)₆] has significant advantages. It is non-toxic and even used in food industry, and its price is considerable to NaCN. Moreover, there was no successful example of the reaction between benzyl chlorides and non-toxic K₄[Fe(CN)₆].In this paper, it is analyzed based on character of K₄[Fe(CN)₆] and reaction characteristics of cyanation of benzyl chlorides, a catalyzed method was developed to use poison-free cyanide reagents with K₄[Fe(CN)₆], it realized non-toxic of cyanide reagents, and explored a new and relatively green method for benzyl chlorides transformed into benzene acetonitrile compounds. The main details are as follows:By using PPh₃/Pd(OAc)2 catalyst system, the reaction between benzyl chlorides and non-toxic K₄[Fe(CN)₆] was actualized. It was investigated that effects of reaction conditions, including the orders of the addition of the reagents on the cyanation, reaction temperature, additive, solvent, ligand, amount of catalyst, concentration of water in solvent, on the reactions. The law is as follows:The reaction temperature had a marked effect on the reactions. In the case of higher temperature, benzyl alcohol and 1,2-diphenyl oxide and other by-products were easily obtained, resulting in decreasing the yield of benzyl cyanides(2%). In the case of lower temperature, conversion of benzyl chloride decreased(6%). Experimental results revealed that the reaction temperature of 140℃facilitate the cyanation. The reaction temperatures of 100℃possibly allowed the cyanation to proceed in high yield. But the resulting experimental results were less reproducible, as was true for a reaction time of 1 h which prompted us to perform all the following reactions in 10 h.Effects of water on the reaction were investigated. It has often been required that the solvent is rigorously degassed and the reaction is run in stringent inert conditions, while small amount of water had little effect on the reaction. In the case of more than 5.9 vol% H2O, the cyanation product was dominant. The present of base was a key to completing the reaction. Without base, the cyanation could not proceed. Among the tested base, Na₂CO₃ turned out to be the most effective one. The ratio of PPh₃ to Pd(OAc)2 had also a important effect on reaction. In the case of 3:1 ratio, the highest yield of benzyl cyanide was obtained.Our experimental results revealed that a presence of oxygen badly prevented benzyl chloride from being cyanated. Although Pd(II) catalyst was used, the real catalytically active species is a Pd(0) intermediate rather than the Pd(II) compound. The Pd(0) intermediate easily lost its activity in the presence of oxygen. Thus It has often been required that the solvent is rigorously degassed. The orders of the addition of the reagents had little effect on the reaction. whether the addition of Na₂CO₃ was prior to a coordination of PPh₃ to Pd2+ or not, the cyanation product was obtained in similar yields. Even in the case of the successive addition of Na₂CO₃, PPh₃, K₄[Fe(CN)₆] and benzyl chloride to a solution of Pd(OAc)2 in NMP, the formed catalytically active species could drive the reaction to near completion.The catalytic ability of DPPE/Pd(OAc)2 was investigated. In the such a catalyst system, it was investigated that effects of reaction conditions, including ligand, reaction temperature, additive, concentration of water in solvent, on the reactions. We found a optimized result was obtained when DPPE and Pd(OAc)2 molar ratio is of 1:1, while PPh₃ and Pd(OAc)2 molar ratio of 2:1 proved the optimal experimental result.In conclusion, the reaction between benzyl chlorides and non-toxic K₄[Fe(CN)₆] was actualized by using Pd catalyst system. The presented method allowed a series of benzyl chlorides to be cyanated smoothly. The optimal reaction condition was that: 1 mmol benzyl chloride, 0.3 mmol K₄[Fe(CN)₆], 2 mol% Pd(OAc)2, 3:1 ratio of PPh₃/Pd(OAc)2, 1.5 equ. Na₂CO₃, 0.8 mL NMP as the solvent, a reaction temperature of 140℃, a reaction time of 10 h. Under the optimal reaction condition, benzyl cyanide was obtained in 88% yield.