Chapter 17 Ketones and Aldehydes II,Aldol Reaction,Reaction at the α- Carbon of Carbonyl Compounds 羰基α–取代反应和缩合反应,General Nucleophilic Additions to the C=O,,,,,Hydrogens of Carbonyl Compounds,1. Keto-Enol Tautomerism?,Enol (an alkene + an alcohol),Reaction at the α- Carbon of Carbonyl Compounds,Some Representative Enol Percents,Enol form of 2,4-pentanedione,103 pm,133 pm,134 pm,141 pm,124 pm,166 pm,H3C,C,C,C,CH3,H,O,O,H,,,,,,,,,,C=C and C=O are conjugated,Intramolecular hydrogen bond,1、 Keto－Enol Tautomerism (互变异构) 酸和碱均可催化这一互变异构平衡的达到 碱性条件下，碱夺取a -H形成烯醇负离子,酸催化条件下，羰基氧首先质子化，吸电子作用进一步增强，然后脱去a –H形成烯醇,1、 Keto－Enol Tautomerism,2、Formation of Enolate 烯醇负离子由于羰基的共轭作用得以稳定 弱碱如NaOH，RONa作用下，反应只能达到一定的平衡 强碱如LDA作用下，可以定量地转化为烯醇负离子,,,,—— low temperature, give kinetic enolate —— high temperature, give thermodynamic enolate,动力学控制产物,热力学控制产物,,,2、Formation of Enolate,强碱有利于形成动力学控制的少取代烯醇负离子。
酸性条件则有利于形成热力学控制的多取代烯醇 弱碱条件下，影响因素会更多，选择性不高2、Formation of Enolate 酸性条件下将形成烯醇，而不是烯醇负离子,,,Examples 预测下列每组化合物，哪一个烯醇负离子是主要的（动力学控制产物）,预测下列每组化合物中，哪一个烯醇结构较稳定，即为热力学控制烯醇？,Racemization,Racemization at an a-carbon is catalyzed by acid,3. The -Carbon Atom and its Hydrogens,羰基C=O的吸电子作用使得a-H具有明显的酸性，在碱性条件下可以离解，生成烯醇负离子，从而成为亲核试剂，进攻羰基碳或卤代烃，发生亲核加成反应、亲核取代反应1,2,3,,——烯醇中的C-C双键接受亲电试剂进攻，发生a –卤代反应；醛酮、羧酸和酰卤可以发生该反应 ——烯醇负离子作为亲核试剂，进攻卤代烃的缺电子碳，则发生亲核取代反应；进攻羰基碳则发生亲核加成反应；,——烯醇负离子作为亲核试剂，发生亲核加成的产物可以脱水缩合形成a, b-不饱和羰基化合物；烯醇负离子还可以与a, b-不饱和羰基化合物反应生成1, 5-二羰基化合物。
1, 5-二羰基化合物进一步发生分子内缩合就形成环状结构烯醇或烯醇负离子具有C=C双键，可以接受亲电试剂进攻，发生亲电取代反应酸碱催化机理有所不同4、a – Halogenation,比较I和II，由于卤素的吸电子作用，II中羰基氧上的电子云密度降低，因此质子化能力降低，反应多停留在一卤代阶段,,,质子化相对容易,Mechanism of Acid-catalyzed：,比较I和II，由于卤素的吸电子作用，II中连卤素碳上氢的酸性增强，更容易形成烯醇负离子，反应难以停留在一卤代阶段，将进一步发生多卤代反应 如果原料是甲基酮，则将发生进一步反应，并断键生成卤仿Mechanism of base-catalyzed：,,,4、a – Halogenation,Acid-catalyzed： —— monosubstituent; —— reactivity:RCOCHR2 RCOCH2R RCOCH3 Base-catalyzed： —— multisubstituent —— reactivity: RCOCH3 RCOCH2R RCOCHR2 —— RCOCH3 and RCH(OH)CH3发生卤仿反应,碘仿反应：用于鉴别甲基酮和能氧化为甲基酮的醇,4、a – Halogenation,羧酸及酰卤 Hell-Volhard-Zelinski reaction (HVZ reaction),4、a – Halogenation,完成下列转化,α-卤代酮在NaOH水溶液中发生重排成为含有相同C数的羧酸，如果是α-环状卤代酮则导致环变小。
法沃斯基重排,,5. Alkylation Reactions,1) From enolate,Lithium Enolates,The extent to which an enolate anion forms depends on the strength of the base used.,One very useful strong base for converting ketones to enolates : Lithium diisopropylamide - (i-C3H7)2N-Li+,Regioselective Formation of Enolate Anions,Lithium Enolates in Directed Aldol Reactions,通过enolate的方法，还会得到二烷基化和氧烷基化的产物,2) From enamine(烯胺),通过enamine的方法，只得到单烷基化的产物，合成上更有用5. Alkylation Reactions,Synthesis Using imine,Alkylation烃基化,6、Aldol加成和Aldol缩合,1) Aldol addition and aldol condensation,Aldol addition Aldol condensation,,,b-hydroxyaldehyde b-hydroxyketone,a, b -unsaturated aldehyde a, b -unsaturated ketone,Aldol additions,Aldol condensation,Aldol products easily dehydrate in acid and sometimes in base.,6、Aldol加成和Aldol缩合,Preparation via Aldol Condensation and reduction!,,6、Aldol加成和Aldol缩合,Intramolecular aldol addition —— to form cyclic b-hydroxyketone or a, b –unsaturatd ketone,6、Aldol加成和Aldol缩合,Dieckmann cyclization.,,,例题与习题 完成下列反应,The mixed aldol addition,如果两个反应物都具有a-H，则将 得到四个产物,6、Aldol加成和Aldol缩合,Crossed Aldol Condensations,Reaction of two different aldehydes: One with an “-hydrogen (donor) Other with no “-hydrogen (acceptor),acceptor,donor,With one excess starting material, one product could be mainly obtained.,How to get the desired product?,采用强碱LDA与一个醛或酮反应，使之定量地转化为烯醇负离子，然后再向该体系中加入另一个醛或酮，则可以得到单一产物。
6、Aldol加成和Aldol缩合,But,Kinetic enolate,Thermodynamic enolate,LiN(i-C3H7)2,Claisen-Schmidt Reactions,When ketons are used as one component, the Crossed Aldol Condensations are called Claisen-Schmidt Reactions,6、Aldol加成和Aldol缩合,Condensations with Nitroalkane,Condensations with Nitriles,6、Aldol加成和Aldol缩合,,-不饱和醛酮加成反应的分类,* 共轭不饱和醛酮的加成,C=C亲电加成,C=O亲核加成,1,4-共轭加成,,1,2-亲核加成,7. Reaction of a, b -unsaturated carbonyl compound,共轭不饱和醛酮的加成,在碱性条件下加成反应的机制,,H+,互变异构,,,H,在酸性条件下加成反应的机制,,,Z-,互变异构,,H,使用强亲核试剂容易发生1，2加成；而使用弱亲核试剂容易发生1，4共轭加成。
—与烯烃的共轭加成对比,,1,2-Addition,observed with strongly basic nucleophiles Grignard reagents LiAlH4 NaBH4 Sodium acetylide strongly basic nucleophiles add irreversibly,1,4-Addition,observed with weakly basic nucleophiles cyanide ion (CN–) thiolate ions (RS–) ammonia and amines azide ion (N3–) weakly basic nucleophiles add reversibly,Copper catalyzed conjugate addition reactions,7. Addition to a, b -unsaturated carbonyl compound,Conjugate Addition of Organocopper regants,Lithium dialkylcuprates add predominantly in the less hindered way.,7. Addition to a, b -unsaturated carbonyl compound,It is the addition of a a, b -unsaturated carbonyl compound with an enolate as a nucleophile ——1, 4 – addition ——to form 1, 5-dicarbonyl compounds,Michael addition,7. Addition to a, b -unsaturated carbonyl compound,The nucleophile can be an enolate generated from compounds other than aldehydes or ketones ——it can be an ester, a nitro-compound, or a nitrile The best nucleophile are: b-diketones, b-diesters, b-keto esters。