Potassium hydroxide-water-dioxane system

The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide. 

As the VLB diagram (Fig. 16.28) shows, the water/ dioxane azeotrope is separated easily from both water and from the solvent. However, the laboratory techniques used for drying (molecular sieves, barium oxide, magnesium sulphate and potassium hydroxide) are all rather expensive without a recovery system. Chloroform is an effective azeotropic entrainer and its toxicity is not an automatic disqualification because dioxane itself needs to be handled with very great care. 

A study of the reaction of 2,4-dinitrofluorobenzene and iV-methyl-aniline in ethanol and in 60% dioxane- % water by Bunnett and Randall (80) has resulted in an unequivocal demonstration of catalysis by acetate ion and clearer evidence for catalysis by hydroxide ion. In alcohol the catalyzed rate due to acetate ion is linearly dependent on the acetate ion concentration. When acetic acid, which does not itself catalyze the reaction, is added in amounts equivalent to the potassium acetate, it does not depress the base-catalyzed rate, indicating that the increase in rate is due to the concentration of potassium acetate and not to the concentration of ethoxide ions. Catalysis by hydroxide ion was studied in 60% dioxane-40% water. In this system, too, the high reactivity of hydroxide ion with 2,4-dinitrofluorobenzene is a complication, and the amount of fluoride converted to N-methyl-2,4-dinitrodiphenylamine did not attain 2% in any of the experiments with hydroxide ion added. Nevertheless, the enhancement of the rate of formation of the diphenylamine due to added hydroxide ion is sufficiently lar (almost eightfold at the highest hydroxide ion concentration) to make the fact of catalysis a certainty. The authors concluded further that the catalyzed rate with hydroxide ion was not linearly dependent on the hydroxide ion concentration. This conclusion may be tenuous, since, within experimental error, a plot of the logarithms of the catalyzed rates vs. the logarithms of the hydroxide ion concentrations is linear and has a slope of 1. 

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