定义Definition
诺文纳格尔缩合是醛或酮与活泼亚甲基化合物（如丙二酸二乙酯、氰乙酸酯、丙二腈）在弱碱（哌啶、吡啶等）催化下缩合并脱水，生成 α,β-不饱和化合物的反应。
The Knoevenagel condensation joins an aldehyde or ketone with an active methylene compound (diethyl malonate, cyanoacetate, malononitrile) under weak-base catalysis (piperidine, pyridine) and dehydrates to an α,β-unsaturated product.
机理Mechanism
活泼亚甲基两侧都有吸电子基，pKa 约 9–13，弱碱即可生成碳负离子；它加成到羰基得 β-羟基中间体，随即脱水得到共轭烯烃。胺催化时也可能先生成亚胺正离子（更亲电），再被碳负离子进攻。
The active methylene, flanked by two acceptors (pKa ≈ 9–13), is deprotonated by weak base; the carbanion adds to the carbonyl and the β-hydroxy intermediate dehydrates to the conjugated alkene. With amine catalysts an iminium ion may form first as the electrophile.
多布纳改良Doebner modification
以丙二酸为原料、吡啶为溶剂并加少量哌啶，缩合后同时脱羧，直接得到肉桂酸等 α,β-不饱和羧酸。
With malonic acid in pyridine plus a little piperidine, condensation is followed by decarboxylation to give α,β-unsaturated acids such as cinnamic acid directly.
由来与应用Origin and uses
德国化学家埃米尔·诺文纳格尔于 1890 年代报道。用于合成香豆素衍生物、药物中间体、染料以及共轭有机材料，也是汉奇吡啶合成等多组分反应的一步。
Reported by Emil Knoevenagel in the 1890s; used for coumarins, drug intermediates, dyes and conjugated materials, and as a step in multicomponent reactions such as the Hantzsch synthesis.
反应Reactions
催化量哌啶或吡啶，乙醇或苯中回流（分水）
Catalytic piperidine or pyridine in ethanol or benzene at reflux (water removal)
弱碱使活泼亚甲基去质子化。
Weak base deprotonates the active methylene.
碳负离子加成到醛羰基。
The carbanion adds to the aldehyde.
脱水生成共轭烯烃。
Dehydration gives the conjugated alkene.
多布纳改良合成肉桂酸。
Doebner synthesis of cinnamic acid.
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.
哌啶夺取丙二酸酯的活泼 H，碳负离子进攻醛羰基
Piperidine deprotonates the malonate; the carbanion attacks the aldehyde
质子化后再脱水（E1cB）
After protonation, dehydration (E1cB)
亚苄基丙二酸二甲酯
Dimethyl benzylidenemalonate
年表Timeline
- 1890s
诺文纳格尔报道胺催化缩合
Knoevenagel reports amine-catalysed condensations
- 1900
多布纳改良法
Doebner modification