1、Chapter 4Condenation Reaction 第一节第一节 a a-羟烷基、卤烷基、氨烷羟烷基、卤烷基、氨烷基化反应基化反应一、一、a a-羟烷基化反应羟烷基化反应1.1.醇醛缩合反应醇醛缩合反应(Aldol缩合缩合)(1)(1)含有含有a a-活泼氢的醛或酮的自身缩合活泼氢的醛或酮的自身缩合 碱催化机理碱催化机理:R+RR+BHCHCRCH2OBCROCHCROR+RRRRRCRCH2OCHCROCRCH2CORCHOBHHOHCRCH2CCORBRR+OHRCRCH2CCOBH(62%)-OHCCHO(CH2)3C3H7CHOH1150CC3H7CHO(90%)OCH2COC
2、H3KOHO甲醛与含有甲醛与含有a a-活泼氢的醛、酮之间的缩合活泼氢的醛、酮之间的缩合NaOH(稀)40-420C+(45%)-HCHOCH3COCH3H2CCHCOCH3H2O14-200C,3h+(90%)CH2CH2K2CO3OH2HCHOCH3CH2CHOCH2CH3CCHOCH2OH(1)H(2)HCHO+NaOHCH3CH2COHCH2OHCH2OHCH2三羟甲基丙烷三羟甲基丙烷 催化剂的影响催化剂的影响 以碱催化剂为主，酸催化剂应用较少以碱催化剂为主，酸催化剂应用较少 应用特点应用特点 定向醇、醛缩合定向醇、醛缩合(a)烯醇盐法烯醇盐法(b)烯醇硅醚法烯醇硅醚法（2）芳醛与芳醛
3、与a a-活性氢的醛、酮的缩合活性氢的醛、酮的缩合 应用特点应用特点 制备反式芳丙醛制备反式芳丙醛脯氨酸脯氨酸直接直接 Aldol 反应反应List,B.et al,J.Am.Chem.Soc.2000,122,2395NHCOOHR=Ar,CH3CHCH2CH2OHCH3CHCH2CH2OH苯环连在取代基多的苯环连在取代基多的C C上上SnCl2/CS2-100C+(40%)C6H5CH3CHCH2OCH3CHCH2CH2OHCH23.应用特点应用特点（1）区域选择性）区域选择性（2）立体选择性）立体选择性 构型反转构型反转（3）制备环内酯）制备环内酯二、二、b b-羰烷基化反应羰烷基化反应
4、 MichaelMichael加成反应加成反应反应机理反应机理:+OHCH3OOCH3HHOOCH3OOCH3COCH2CH+CH2OHCH3OOCH3COCH2CHHCH3OOCH2CH3COCH3-H2OOO+OOCH3OOCH3OCH2CH3OOCH2COCH2HOHH（3）影响因素）影响因素 1)the nucleophile(Michael donor)can be derived by the deprotonation of CH-activated compounds such as aldehydes,ketones,nitriles,-dicarbonyl compound
5、s,etc.as well as by the deprotonation of heteroatoms;2)depending on the type and strength of the electron-withdrawing group(negative charge stabilizing group),the use of even relatively weak bases is possible(e.g.,NEt3);（4）应用）应用 第四节第四节 亚甲基化反应亚甲基化反应 一一 羰基烯化反应羰基烯化反应（1 1）反应通式及机理）反应通式及机理+n-C4H8Li/EtON2,
6、250C(C6H5)3CH3PBrC6H6250C(C6H5)3P CH3BrR+CH2CH2R(C6H5)3P(C6H5)3PCORRR+OCH2HOHC(C6H5)3PCRHOHC(C6H5)3PCRRC(C6H5)3P（2）影响因素）影响因素 the ylides are water as well as oxygen-sensitive；the phosphorous ylides chemoselectively react with aldehydes(fast)and ketones(slow),other carbonyl groups(e.g.,esters,amides)r
7、emain intact during the reaction;the stereoselectivity,E-or Z-selectivity,is influenced by many factors:type of ylide,type of carbonyl compound,nature of solvent；The Wittig reaction has several important variants:HWE Reaction the phosphonate carbanions are more nucleophilic than the corresponding ph
8、osphorous ylides,so they readily react with practically all aldehydes and ketones under milder reaction conditions；the by-product dialkyl phosphates are water-soluble,so it is much easier to separate them from the alkene products t h a n f r o m t h e w a t e r-i n s o l u b l e triphenylphosphine o
9、xide.high(E)-selectivity for disubstituted alkenes under much milder conditions than normally used in Wittig reactions；the(E)-selectivity is maximized by increasing the size of the alkyl group of the R1 or R2 substituents There are an important modifications of the HWE olefination:in the Still-Genna
10、ri modification R1=OCH2CF3 and the reaction affords(Z)-olefins exclusively；for base-sensitive substrates,the use of a metal salt(LiCl or NaI)and a weak amine base(e.g.,DBU)has proven effective to avoid epimerization.（4）应用）应用二二 羰基羰基a a位的亚甲基化反应位的亚甲基化反应1.1.活性亚甲基的亚甲基化活性亚甲基的亚甲基化 Knoevenagel 反应反应（1）反应通式）反
11、应通式 （2）反应机理）反应机理（3）影响因素）影响因素 the nature of the catalyst is important,usually primary,secondary,and tertiary amines and their corresponding ammonium salts,certain Lewis acids combined with a tertiary amine(e.g.,TiCl4/Et3N).the by-product of the reaction is water and its removal from the reaction mixt
12、ure by means of azeotropic distillation,the addition of molecular sieves,or other dehydrating agents shifts the equilibrium toward the formation of the product;the choice of solvent is crucial and the use of dipolar aprotic solvents(e.g.,DMF)is advantageous,since protic solvents inhibit the last 1,2
13、-elimination step;2.Stobbe 反应反应（1）反应通式）反应通式（2）反应机理）反应机理（3）应用）应用 制备烯酸制备烯酸3.Perkin反应反应(1)反应通式反应通式（2）反应机理）反应机理（3）影响因素）影响因素 芳香醛结构影响芳香醛结构影响 吸电子活性增强，给电子相反吸电子活性增强，给电子相反 碘番酸中间体碘番酸中间体 催化剂的影响催化剂的影响 相应羧酸的钾盐、钠盐；铯盐效果更好相应羧酸的钾盐、钠盐；铯盐效果更好（4）应用）应用第五节第五节 a a、b b-环氧烷基化反应环氧烷基化反应(Darzens(Darzens反应反应)1.反应通式反应通式 EWG=CO2R,
14、CN,SO2R,CONR2,C(=O),C(=NR);Y=O,NR;2.反应机理反应机理 3.影响因素影响因素 Aliphatic aldehydes usually give lower yields；-Chloro esters are preferable to bromo or iodo esters,since they give higher yields；-halo sulfones,nitriles,ketones,ketimines,thiol esters,or amides,can also be used to obtain the corresponding deri
15、vatives；4.应用特点应用特点 醛、酮同系化醛、酮同系化C+1布洛芬的合成布洛芬的合成 第六节第六节 环加成反应环加成反应 EDG(electron-donating group)=alkyl,O-alkyl,N-alkyl,etc.EWG(electron-withdrawing group)=CN,NO2,CHO,COR,COAr,CO2H,CO2R,COCl etc.一、一、D-A反应反应Mechanism（3）影响因素及应用特点）影响因素及应用特点 共轭二烯双键必需是顺型的共轭二烯双键必需是顺型的 顺式原理顺式原理 内向加成原理内向加成原理 加成定位规则加成定位规则Example
16、 二、二、1,3偶极环加成偶极环加成 1.Azomethine Ylides 2.Azomethine Imines 3.Nitrones 4.Azides 5.O3/Carbonyl Oxides 三、碳烯、氮烯对不饱和键的加成三、碳烯、氮烯对不饱和键的加成 Carbene-电中性二价碳中间体，两电子自电中性二价碳中间体，两电子自选方向相同为三线态，相反为单线态选方向相同为三线态，相反为单线态 单线态与烯烃的反应有立体定向性单线态与烯烃的反应有立体定向性 三线态与烯烃的反应不具有立体定向性三线态与烯烃的反应不具有立体定向性Simmons-Smith cyclopropanation.(1)a
17、 wide range of alkenes can be used:simple alkenes,-unsaturates ketones and aldehydes,electron rich alkenes;(2)due to the electrophilic nature of the reagent,the rate of cyclopropanation is faster with more electron rich alkenes.However,highly substituted alkenes may react slower due to the increased
18、 steric hindrance;(3)the cyclopropanation is stereospecific,so the stereochemical information in the alkene substrates is translated to the products;(4)when the alkene has functional groups containing heteroatoms(e.g.,OH,OAc,OMe,OBn,NHR),a strong directing effect is observed and the delivery of the alkylidene occurs from the face of the double bond having the closer proximity of the functional group;Example 习题：习题：P164 第一题第一题
