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。有些氨基酸酯在 1 N 盐酸回流条件下水解（一般回流 1~2 小时即可），蒸干溶剂后可直接以盐的形式进行下面的反应，而无需进一步提纯，此时也可以考虑用酸进行水解。叔丁酯一般比 Boc 难脱，一般要用 50-100%TFA 或 4N HCl/Dioxane （注意：在用 HCl/dioxane 来脱除叔丁酯时，千万不能在溶剂处理时中引入甲醇，乙醇或其他小位阻的醇，否则叔丁酯会转变为相应的酯。

叔丁酸酯的酸水解示例

     1-(4-Methoxycarbonyl-2-methylbutanoyl)-L-proline t-butyl ester (3.4 g, 10.8 mmol) was dissolved in trifluoroacetic acid (25 mL) and the resulting solution was kept at room temperature for one hour. The trifluoroacetic acid was removed in vacuo and the residue was used to the next reaction directly.

对碱不稳定的酯的酸水解示例

      A solution of ethyl α-chlorophenylacetate (119 g, 0.6 mol) in glacial acetic acid (238 mL) and concentrated hydrochloric acid (119 mL) was heated under reflux in a hood for 1.5 hours. At the end of the heating period the solution was concentrated by heating in an oil bath at 100°C at reduced pressure (15~20 mmHg) until no further material was distilled. The residue was allowed to cool to room temperature and poured slowly with stirring into 1 L of ice-cold saturated sodium bicarbonate solution. Solid sodium bicarbonate was added in small portions until the solution became neutral to universal indicator paper. The solution was then extracted with two 200 mL portions of ether. The aqueous phase was acidified cautiously with ice-cold 12N sulfuric acid until the mixture was acid to Congo red paper. The oily suspension was extracted with two 200 mL portions of ether. The ether extracts were washed with two 100mL portions of water and dried over 45 g of anhydrous sodium sulfate. The dried ether extract was concentrated on a steam bath until ether was no longer distilled. To the residue there was added 500 mL of warm (50~60°C) concentrated hydrochloric acid (in a hood) and the suspension was allowed to cool with occasional swirling. Crystallization was completed by chilling in ice and the product was collected on a sintered-glass funnel. After the product was dried as much as possible on the funnel it was dried to constant weight in a vacuum desiccator over solid potassium hydroxide to give the dry acid (82~84 g, 80~82%) which melts at 77.5~79.5°C.