西安交通大学：《药物化学 Medicinal Chemistry》课程教学资源（PPT课件讲稿）第四章 缩合反应 Condensation Reaction

Chapter 4 Condensation Reaction 第四章缩合反应 本章主要讨论内容 具有活泼氢的化合物与羰基化合物之间的缩合反应 用途:形成新的碳-碳键或碳-杂键

第四章 缩合反应 Chapter 4 Condensation Reaction 本章主要讨论内容： 具有活泼氢的化合物与羰基化合物之间的缩合反应 用途：形成新的碳-碳键或碳-杂键

Definition of Condensation Reaction A condensation reaction is a chemical reaction in which two molecules or moieties(functional groups) combine to form one single molecule, together with the loss of a small molecule When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride, methanol, or acetic acid 两个及两个以上有机化合物分子通过反应,失 去一个小分子,形成一个新的较大分子;或同一分 子发生分子内反应,失去一个小分子,形成新分子 的反应,也称为缩合反应

Definition of Condensation Reaction 两个及两个以上有机化合物分子通过反应，失 去一个小分子，形成一个新的较大分子；或同一分 子发生分子内反应，失去一个小分子，形成新分子 的反应，也称为缩合反应。 A condensation reaction is a chemical reaction in which two molecules or moieties (functional groups) combine to form one single molecule, together with the loss of a small molecule. When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride, methanol, or acetic acid

Intermolecular and intramolecular Intermolecular: When two separate molecules react, the condensation is termed intermolecular a simple exam ple is the condensation of two amino acids to form the peptide bond characteristic of proteins. This reaction example is the opposite of hydrolysis, which splits a chem ical entity into two parts through the action of the polar water molecule, which itself splits into hydroxide and hydrogen ions If the union is between atoms or groups of the same molecule the reaction is termed intramolecular condensation and in many cases leads to ring formation An example is the Dieckmann condensation, in which the two ester groups of a single diester molecule react with each other to lose a small alcohol molecule and form a B ketoester product

Intermolecular and intramolecular • Intermolecular：When two separate molecules react, the condensation is termed intermolecular. – A simple example is the condensation of two amino acids to form the peptide bond characteristic of proteins. This reaction example is the opposite of hydrolysis, which splits a chemical entity into two parts through the action of the polar water molecule, which itself splits into hydroxide and hydrogen ions. • If the union is between atoms or groups of the same molecule, the reaction is termed intramolecular condensation, and in many cases leads to ring formation. – An example is the Dieckmann condensation, in which the two ester groups of a single diester molecule react with each other to lose a small alcohol molecule and form a β- ketoester product

Section la-Functionalized alkylation a羟烷基化反应( a-hydroxyalkylation) Aldol condensation Prins, Benzoin, etc. a卤烷基化反应( a-chloroalky lation) Blanc reaction, a氨烷基化反应(a- aminoalkylation) Mannich, Pictet-Spengler, Strecker, etc

Section Iα-Functionalized alkylation • α-羟烷基化反应 (-hydroxyalkylation) – Aldol condensation, Prins, Benzoin,etc. • α-卤烷基化反应 (-chloroalkylation) – Blanc reaction, • α-氨烷基化反应 (-aminoalkylation) – Mannich, Pictet-Spengler, Strecker,etc

1.1 a-hydroxyalkylation 醇醛(酮)缩合 (Aldol condensation) 不饱和烃的α-羟烷基化反应 Prins reaction) 芳醛的α羟烷基化反应(安息香缩合) (Benzoin condensation) 有机金属化合物的羟烷基化 (a-hydroxyalkylation) Reformatsky reaction

1.1 -hydroxyalkylation • 醇醛(酮)缩合 – (Aldol condensation) • 不饱和烃的-羟烷基化反应 – (Prins reaction) • 芳醛的-羟烷基化反应(安息香缩合) – (Benzoin condensation) • 有机金属化合物的-羟烷基化 – (-hydroxyalkylation): • Reformatsky reaction

1.1.1醇醛缩合反应 (Aldol condensation) Definition: An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a 3 hydroxyaldehyde or B-hydroxyketone, followed by a dehydration to give a conjugated enone. 定义:含有α-H的醛或酮,在稀碱或稀酸(通常为稀碱)的 催化作用下,一分子醛或酮的c氢原子加到另一分子醛 或酮)的氧原子上,其余部分加到羰基碳上,生成⑧羟基 醛或酮)的反应,该增长碳链的反应称为醇(羟)醛(酮)缩 合反应

1.1.1 醇醛缩合反应 (Aldol condensation) Definition: An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β- hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone. 定义：含有α-H的醛或酮，在稀碱或稀酸(通常为稀碱)的 催化作用下，一分子醛(或酮)的-氢原子加到另一分子醛 (或酮)的氧原子上，其余部分加到羰基碳上，生成β-羟基 醛(或酮)的反应，该增长碳链的反应称为醇(羟)醛(酮)缩 合反应

Formation of conjugated enone Aldol condensations are important in organic synthesis, providing a good way to form carbon- carbon bonds It involves the nucleophilic addition of a ketone enolate to an aldehyde to form a B-hydroxy ketone or"aldol(aldehyde alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals. RR RR O H或 H2o RH2C-CC--CR 2 R-CH2-C-R R-C-C-C-C-R OH H Reaction mechanisms

Formation of conjugated enone R CH2 C R' O R H2 C C C C R ' R' R OH O C C CR' R - H2O R' O RH2C 2 OH 或 H H Aldol condensations are important in organic synthesis, providing a good way to form carbon– carbon bonds. It involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or “aldol” (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals. Reaction mechanisms

Mechanism A: Base catalyzed Inorganic Base: NaoH Na, CO3, NaH etc. Organic Base: EtoNa, BuLi, etc. H B R-C—C C-C—R-R—C=C—R 慢 ⊙ O R R RO 快 2 R—C-C+R-8-R÷R-C-C-C-C—R OO H R RO B RR B R-C-C=C-c—R R-C-C-C-C—R -HO OH H 产物不稳定

Inorganic Base: NaOH, Na2CO3, NaH, etc. Organic Base: EtONa, BuLi, etc. Mechanism A：Base catalyzed R H2 C C C C R ' R O R H ' O R H2 C C R' O + R H C C R' O 快 R H2 C C C C R ' R OH R H ' O R H2 C C C C R ' R ' R O B： B： -H2 O 产 物 不 稳 定 R H2 C C R' O R H C C R' O R C H C R' O B： 慢

Mechanism B: Acid catalyzed Acid: H2 SO4 Hcl, TsOH, etc. R-CH2-C-R.H+ R—CH2-C—R R—CH2—C-R O OH HO RR O 2 R一CH3-C—R+R—HC=C—R=~R-C-C-C—C—R HO OH OH R H2O R R-C—C RICH C—R C=C-CR ④OH2 RH2C R

Acid: H2SO4, HCl, TsOH, etc. Mechanism B：Acid catalyzed R H2 C C C H C R ' R ' R OH2 O C C CR' R H - H2 O -H O R' RH2 C R CH2 C R' O R CH2 C R' OH R CH2 C R' HO H + R HC C R' OH R CH3 C R' HO R H2 C C C H C R ' R ' R OH O +

1.1.1.1 Self-Condensation between two same molecules NaoH CH3 CH2 CH2-- -CHO 25°C OH CH2 CH3 2CH3 CH CH2CHO NaoH CH3CH2CH2CH=C一CHO 80°C CH2CH Al(t-BuO) H2PO + OH 般用碱性催化剂

1.1.1.1 Self-Condensation CH3 CH2 CH2 CH OH H C CHO CH2 CH3 CH3CH2CH2CH C CHO CH2 CH3 2CH3CH2CH2CHO NaOH 25℃ NaOH 80℃ OH O O O H3 PO4 O + Al(t-BuO) 4 一般用碱性催化剂 between two same molecules