为什么亚硝酸钠可以促进“氰基”水解为羧基？

昨天群里面的一个问题，做一个解答；

从机理上看， 氰基的酸性水解会经历以下步骤：

第一步氰基到酰胺的反应能垒较低，因为氰基的亲电性强，亲核进攻容易发生，且中间体转化为酰胺的过程无需断裂强化学键，反应在稀酸、稀碱、甚至室温或较低温度都可以快速发生。

但是酰胺的进一步水解会受阻，因为酰胺中氨基的氮原子有孤对电子，可通过p-π 共轭向羰基碳供电子，降低了羰基碳的正电性，使得亲核试剂没有那么容易进攻。

加入亚硝酸钠，其实就是做重氮化反应，既削弱了原有的共轭，又促进酰胺中-NH2的离去。

注：机理只是结果的阐释，主要在于能自圆其说。上图机理中出现双正电位，羰基质子化从开始伴随到结束的原因在于，个人认为羰基碳已经被亲核试剂包围，只不过引而未发！

附1：氰基水解为羧酸的碱性水解机理

附2，氰基水解示例（ 来自国内CRO龙头企业YMKD ）

①酸性水解

A mixture of water (1150mL), commercial sulfuric acid (840 mL) and benzyl cyanide (700 g, 6 mol) was heated under a reflux condenser and stirred for three hours, cooled slightly, and then poured into 2 L of cold water. The mixture should be stirred so that a solid cake was not formed; the phenylacetic acid was then filtered off. The crude material was melted under water and washed by decantation several times with hot water. These washings, on cooling, deposited a small amount of phenylacetic acid which was filtered off and added to the main portion of material. The last of the hot water was poured off from the material while it was still molten, and it was then transferred to a Claisen distilling flask and distilled under reduced pressure. A small amount of water came over first and was rejected; about 20 mL, containing an appreciable amount of benzyl cyanide, then distils. This fraction was used in the next run. The distillate boiling at 176–189°/50 mmHg was collected separately and solidified on standing to give the product (630 g, 77.5%) which melts at 76~76.5°C.

Reference: Organic Syntheses Coll. Vol. 1, 436

②碱性水解

A mixture of 2-phenylpropanenitrile (13.2 g, 0.1 mol) and an aqueous solution of sodium hydroxide (10%, 60 mL) was heated with magnetic stirring in an oil bath at reflux temperature for 4.5 hr. The course of the reaction was monitored by gas-chromatographic analysis. After the solution was cooled to room temperature, it was extracted with diethyl ether to remove nonacidic material (primarily traces of amide). An aqueous solution of hydrochloric acid (15%, 50 mL) was added portionwise. The suspension that formed was poured into a separatory funnel and extracted with diethyl ether (3 × 50 mL). The combined organic extracts were washed with water (60 mL) and dried over sodium sulfate (25 g). After filtration, the solvent was removed by rotary evaporation, and the yellow liquid residue was distilled under reduced pressure to afford 2-phenylpropionic acid (14.3 g, 93%) as a pale-yellow liquid.

Reference: Organic Syntheses Coll. Vol. 10, 640

③亚硝酸钠促进的酸水解

A mixture of compound 1 (6.6 g, 35 mmol), conc. H2SO4 (29 ml), AcOH ( 58 ml) and water (115 ml) was heated at 120°C for 1h, then a solution of NaNO2 (4.0 g), in water (30 ml) was added at 90~100°C. After the mixture had been heated for 1 h, NaCl (40 g) was added to the hot mixture and the whole was cooled in an ice-bath. The precipitate was collected to give the crude free acid (6.2 g, 62%).

Reference: Chem. Pharm. Bull.; EN; 33; 8; 1985; 3336-3348.