定义Definition
酰基亲核取代是亲核试剂进攻羧酸衍生物（酰氯、酸酐、酯、酰胺）的羰基碳，经四面体中间体后离去基团离去、羰基恢复，从而一种羧酸衍生物转化为另一种的反应。
Nucleophilic acyl substitution is the attack of a nucleophile on the carbonyl carbon of a carboxylic acid derivative (acyl chloride, anhydride, ester, amide), forming a tetrahedral intermediate that expels the leaving group and restores the carbonyl — converting one derivative into another.
机理Mechanism
加成–消除两步：亲核试剂加成到 sp² 羰基碳生成四面体（sp³）中间体，随后羰基重新形成并排出离去基团。它不是 SN2 那样的一步背面进攻。酸催化时先质子化羰基氧以提高亲电性（如费歇尔酯化），碱性条件下亲核试剂本身更强（如皂化）。
Two steps — addition then elimination: the nucleophile adds to the sp² carbonyl carbon giving a tetrahedral sp³ intermediate, then the carbonyl reforms and ejects the leaving group; it is not a one-step SN2. Acid catalysis protonates the carbonyl oxygen (Fischer esterification); base supplies a stronger nucleophile (saponification).
反应活性顺序Reactivity order
酰氯 > 酸酐 > 酯 ≈ 羧酸 > 酰胺 > 羧酸根。离去基团碱性越弱（Cl⁻ < RCOO⁻ < RO⁻ < NH₂⁻）、杂原子对羰基的共振给电子越弱，活性越高。一般只能由活泼衍生物转化为较不活泼的衍生物。
Acyl chloride > anhydride > ester ≈ acid > amide > carboxylate. Weaker-base leaving groups (Cl⁻ < RCOO⁻ < RO⁻ < NH₂⁻) and weaker resonance donation to the carbonyl mean higher reactivity; conversions normally run downhill.
生物学意义Biological relevance
蛋白质合成（氨酰-tRNA 酯 → 肽键）、蛋白酶水解肽键、乙酰辅酶 A 的酰基转移都是酰基亲核取代；硫酯在生物体内充当“活化酯”。
Protein synthesis (aminoacyl-tRNA ester → peptide bond), protease hydrolysis and acyl transfer from acetyl-CoA are all nucleophilic acyl substitutions; thioesters serve as biological activated esters.
反应Reactions
视底物和亲核试剂而定（碱、酸或吡啶催化）
Depends on substrate and nucleophile (base, acid or pyridine catalysis)
亲核加成到羰基碳。
Nucleophilic addition to the carbonyl carbon.
形成四面体中间体。
A tetrahedral intermediate forms.
离去基团离去，羰基恢复。
The leaving group departs and the carbonyl reforms.
酰氯醇解成酯。
Alcoholysis of an acyl chloride.
皂化。
Saponification.
反应机理图Mechanism
红色弯箭头表示一对电子的移动方向：从电子来源（孤对电子或化学键）指向电子去向。Red curly arrows show where an electron pair moves: from its source (lone pair or bond) to its destination.
加成：OH⁻ 进攻羰基碳
Addition: OH⁻ attacks the carbonyl carbon
四面体中间体塌缩，赶走 CH₃O⁻（消除）
The tetrahedral intermediate collapses and expels CH₃O⁻ (elimination)
酸碱反应，生成羧酸根（不可逆）
Acid–base step gives the carboxylate (irreversible)
乙酸根 + 甲醇
Acetate + methanol
年表Timeline
- 1895
费歇尔与施派尔报道酸催化酯化
Fischer and Speier report acid-catalysed esterification
- 1951
本德用 ¹⁸O 标记证明四面体中间体
Bender’s ¹⁸O labelling demonstrates the tetrahedral intermediate