羧酸的合成水解法

经典化学合成反应标准操作羧酸的合成——水解法目录1．前言 (2)2．酰氯的水解 (3)3．酸酐的水解 (4)4．酯的水解 (5)4.1酯的碱水解 (5)4.2酯的酸水解 (5)4.3丙二酸二乙酯合成法 (7)5．酰胺的水解 (8)5.1酰胺的直接酸水解 (9)5.2酰胺的直接碱水解 (9)5.3亚硝酸钠促进的酰胺酸水解法 (9)5.4 酰胺的间接水解法 (9)6．腈的水解 (10)6.1腈的酸水解 (11)6.2腈的碱水解 (11)6.3亚硝酸钠促进的腈的酸水解法 (12)1.前言利用缩水的方法可以将羧酸转变为各种羧酸的衍生物，如酰氯、酸酐、酯、酰胺和腈等，反过来通过水解反应各种羧酸衍生物也可以转变为羧酸，除酰氯和酸酐外，酯、酰胺和腈的水解一般都可以在酸或碱的催化下进行。

羧酸衍生物水解的速度与羰基碳原子的正电性有关，一般来说正电性越大，水解速度越快。

2.酰氯的水解把羧酸制成酰氯，再通过酰氯去进行各种反应是有机合成中常用的方法，较少有用酰氯来制备羧酸的例子，但在有些条件下利用酰氯来制羧酸也是较为有效的。

例如芳环通过佛克反应与草酰氯反应得到相应的酰氯。

一般来讲脂肪酰氯的水解是相当快的，不用加任何催化剂即可反应。

但芳香酰氯的反应要相对慢了很多，有时为了促进其水解需要加入碱和酸。

2.1 酰氯的水解示例n-C5H11(COCl)AlCl3n-C5H11COClHCl n-C5H11Aluminum chloride (160 g, 1.2 mol) was added to a stirred solution of the 4-n-pentylbiphenyl (224 g, 1 mol) in methylene chloride (1000 mL) at approximately -20°C. Then Oxalyl chloride (96 mL) was added to the solution at a temperature below -10°C. After addition, the reaction temperature was allowed to rise to approximately 0°C. Stirring continued at approximately 0°C untill the evolution of hydrogen chloride was ceased. The resulting reaction mixture was poured into ice water forming two nonmiscible fluid layers. The organic layer was seperated from the aqueous layer, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed by distillation to yield a crude 4-n-pentylbiphenyl-4’-carboxy chloride (213 g, 75%) which was used directly in the next step.The 4-n-pentylbiphenyl-4’-carboxy chloride (142 g, 0.5 mol) was reacted with a hot, stirred solution of sodium hydroxide (60 g, 0.75 mol) in water (50 mL) and acetone (500 mL) for about three hours. The cold reaction mixture was then acidified with concentratedhydrochloric acid solution. The acid was filtered and washed with water untill the filtrate was neutralized. The product of the reaction was purified from ethanol to yield 4-n-pentylbiphenyl-4’-carboxylic acid (102.4 g, 80%).Reference: US44243713. 酸酐的水解酸酐也并不常用于制备酸，由于酸酐的活性比酸强，多数情况下直接室温水解就可以转变为羧酸，在有些情况下对反应加加热可以促进反应的进行。

3.1 酸酐的水解示例 O O H OCOOH COOHTo citraconic anhydride (22.4 g, 0.2 mol) was added from a pipet exactly 4 mL (0.22 mole) of distilled water. The mixture was stirred on a hot plate until a homogeneous solution was formed, then covered with a watch glass and allowed to stand for forty-eight hours. At the end of this time the mixture would solidified completely. For further purification it was finely ground in a mortar, washed with 50 mL of cold benzene, dried in the air, and then dried for twenty-four hours in a vacuum desiccator over phosphorus pentoxide to give citraconic acid (24.4 g, 94%) which melts at 92~93°C.Reference: Organic Syntheses. Coll. V ol. 2, 1404. 酯的水解在有机合成中，羧酸和酯可以很方便地相互转换，因此酯化反应是保护羧基的一种常用方法，酯水解也成为水解法制羧酸的重要方法。

4.1 酯的碱水解水解反应是酯化反应的逆反应，酯化反应要在酸性条件下进行的，因此多数情况下酯的水解在碱性条件下进行是有利的。

一般来说非位阻酯的水解主要通过LiOH-MeOH-H 2O 体系于室温下进行反应，正常条件是氢氧化锂的当量为2-5 当量，甲醇与水的比例为5:1~3:1。

如果反应仍不能水解，可适当加热直至回流。

对于有些位阻大、惰性的酯，需要用更强的反应条件，一般可使用NaOH 、KOH 的水溶液或水甲醇的混合溶液进行水解，其中最强烈的条件是用KOH 的水甲醇的混合溶液回流水解，KOH 的浓度越大、溶剂甲醇的比例越高，水解条件越强，很少有在这种条件下水解不了的酯。

对于该类水解反应的后处理一般先浓缩去处醇类溶剂，然后用有机溶剂提取可能未反应完的非酸类副产物，再酸化，许多酸在此时可以析出沉淀，过滤即可得到，若为油则用有机溶剂提取。

有时当一个分子同时存在甲酯和叔丁酯时，用以上条件很难较好的选择性的水解甲酯，有时需要控制碱的当量数和反应温度。

4.1.1 LiOH-MeOH-H 2O 水解体系的标准操作To a solution of ester (10 mmol) in MeOH-H 2O (30 mL, MeOH:H 2O=3:1~5:1, 甲醇浓度越高，水解能力越强) at 0°C was slowly added LiOH.H 2O (800 mg ~ 2 g, 20-50 mmol). The reaction mixture was allowed to warm to room temperature overnight (若水解不完全就加热至反应完全). Methanol was removed in vacuo and the residual aqueous solution was partitioned with Et 2O or AcOEt (~20 mL), then the organic phase was extracted with H 2O (5- 10 mL, two times). The combined aqueous extracts was acidified to pH 2 with 1N HCl. The aqueous phase was extracted with CHCl 3 (three times) (注意若有固体析出则过滤得到相应的酸). The combined organic extract was dried over MgSO 4 and concentrated to afford the desired acid (normal yield >95%).4.1.2 LiOH-MeOH-H 2O 体系的选择性水解甲酯和叔丁酯示例 N NO O OO O N N O HO O O O 12To a solution of compound 1 (14.15 g, 48.1mmol) in MeOH (250 ml) at 0°C was slowly added aqueous LiOH (1M, 48 ml, 48mmol) over 15 min. The reaction mixture was allowed to warm to room temperature overnight with stirring.The organic solvent was removed in vacuo and the residual aqueous solution was partitioned with Et 2O, then the organic phase was extracted with H 2O (two times). The combined aqueous extract was acidified to pH 2 with 1N HCl. The aqueous phase was extracted with CHCl 3 (three times). The combined organic extract was dried over MgSO 4 andconcentrated to afford the desired acid (11.4 g, 85%).Reference: Publ.: US2004/6065 A1 (2004/01/08); Appl.: US2003-465426 (2003/06/19)4.1.3 KOH-H 2O 体系的水解示例 O COOC 2H 5CH 3KOH, heat HCl O COOH CH 3A mixture of ethyl 3-methylcoumarilate (70 g, 0.34mol) and 10% aqueous potassium hydroxide solution (500 mL) was refluxed for 1 hour. The clear yellowish solution was acidified while hot with a slight excess of concentrated hydrochloric acid to precipitate 3-methylcoumarilic acid. The suspension was cooled to room temperature, and the colorless solid was filtered with suction. The filter cake was resuspended in 500 mL of cold water, stirred vigorously for several minutes, and filtered again with suction. The colorless powder The filter cake was dried in a desiccator under reduced pressure to give a colorless powder (54~57 g, 90~95%) which melts at 192~193°C.Reference: Organic Syntheses: Coll. V ol. 4, 5904.2 酯的酸水解某些情况下对于一些特定结构的酯需要在酸性条件下进行水解，例如叔丁酯和一些对碱不稳定的酯。