第四章-缩合反应PPT课件.ppt

Chapter 4Condenation Reaction 第四章第四章第四章第四章 缩合反应缩合反应缩合反应缩合反应 1.第一节第一节 a a-羟烷基、卤烷基、氨烷基羟烷基、卤烷基、氨烷基化反应化反应一、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2.碱催化机理碱催化机理:3.4.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、酮之间的缩合三羟甲基丙烷三羟甲基丙烷5.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6.(b)烯醇硅醚法烯醇硅醚法7.（2）芳醛与芳醛与a a-活性氢的醛、酮的缩合活性氢的醛、酮的缩合8.应用特点应用特点制备反式芳丙醛制备反式芳丙醛9.有机小分子有机小分子脯氨酸脯氨酸催化催化 直接直接 Aldol 反应反应List,B.et al,J.Am.Chem.Soc.2000,122,2395制备手性制备手性b-b-羟基醛羟基醛10.11.（3）分子内的羟醛缩合）分子内的羟醛缩合12.Robinson环化13.14.15.16.17.2.不饱和烃的不饱和烃的a羟烷基化（羟烷基化（Prins反应反应）18.19.Mechanism20.21.22.3.安息香缩合安息香缩合23.24.影响因素影响因素 芳醛结构的影响芳醛结构的影响强吸电子、强供电子对反应都不利；强吸电子、强供电子对反应都不利；自身缩合、交叉缩合自身缩合、交叉缩合25.催化剂的影响催化剂的影响NaCN剧毒，可用噻唑鎓盐、咪唑鎓盐等代剧毒，可用噻唑鎓盐、咪唑鎓盐等代替替26.27.28.Example29.30.4.4.有机金属化合物的有机金属化合物的a a-羟烷基化羟烷基化 (1)(1)Reformatsky反应反应:醛或酮与醛或酮与a a-卤代酸酯在金属锌粉存在下缩卤代酸酯在金属锌粉存在下缩合而得合而得b b-羟基酸酯或脱水得羟基酸酯或脱水得a a、b b-不饱和羧不饱和羧酸酯的反应：酸酯的反应：31.32.metal:Zn,Mg,Cd,Ba,In,Ge,Co,Ni,Ce;metal salt:SmI2,CrCl2,TiCl2,CeX3,Na2Te,R3SnLi,R3Sb/I2,Et2AlCl33.most often ether solvents are used such as diethyl ether,tetrahydrofuran,1,4-dioxane and dimethoxyethane,but mixtures of these solvents with aromatic hydrocarbons and more polar solvents such as acetonitrile,dimethyl formamide,dimethyl sulphoxide,and hexamethylphosphoric triamide are also used;34.35.催化剂催化剂锌粉必须活化，常用锌粉必须活化，常用20%盐酸处理，再用盐酸处理，再用丙酮、乙醚洗涤，真空干燥。丙酮、乙醚洗涤，真空干燥。亦可用亦可用K、Na、Li等还原无水氯化锌，此法等还原无水氯化锌，此法活性较高。活性较高。Mg,Cd,Ba,In,Ge,Co,Ni,Ce等。等。36.例如例如:加入加入(CH(CH3 3O)O)3 3B/THFB/THF可提高收率可提高收率(如上如上)37.（2）Grignard反应反应38.39.40.机理机理:41.42.影响因素影响因素1)the reagents are predominantly prepared by reacting alkyl,aryl,or vinyl halides with magnesium metal in aprotic nucleophilic solvents(e.g.,ethers,tertiary amines);2)the reagents are usually thermodynamically stable but air and moisture sensitive and incompatible with acidic functional groups(e.g.,alcohols,thiols,phenols,carboxylic acids,1,2 amines,terminal alkynes);43.二、a a-卤烷基化反应卤烷基化反应(Blanc(Blanc反应反应)44.3.3.影响因素影响因素也可用也可用ZnClZnCl2 2(干干)等等LewisLewis酸。苯环上供电子基酸。苯环上供电子基,有利于反应进行。吸电子基不利于反应进行。有利于反应进行。吸电子基不利于反应进行。(87%)(87%)45.引入引入-CH-CH2 2ClCl后，可进一步转化成其他官能团后，可进一步转化成其他官能团并增长碳链。并增长碳链。46.三、三、a a-氨烷基化反应氨烷基化反应 MannichMannich反应：有活泼氢的化合物反应：有活泼氢的化合物(醛、酮等醛、酮等)与甲醛、胺进行缩合，与甲醛、胺进行缩合，H H原子被原子被a a-氨甲基氨甲基 取代称为取代称为 a a-氨甲基化反应氨甲基化反应(Mannich(Mannich反应反应)47.反应机理反应机理48.49.如：如：(90%)(90%)抗胆碱药阿托品的中间体抗胆碱药阿托品的中间体50.Introduction51.1.Metal Catalysis 2.Proline Catalysis3.Brnsted Acid-Catalysis4.Protonated Chiral Catalysis 5.ACDC6.H-Bond Catalysis 7.PTC52.Trost,B.M.J.Am.Chem.Soc.2006,128,2778-2779.53.Proline catalysis54.Brnsted acid-catalysis(1)磷原子的四齿结构(2)磷酸的酸性足以诱捕亚胺(3)双功能手性催化剂 55.4.Protonated Chiral Catalysis J.Am.Chem.Soc.2004,126,3418-3419 56.Ishihara,K.J.Am.Chem.Soc 2008,130,1685816860.57.H-Bond Catalysis58.Jacobsen,E.N.Angew.Chem.Int.Ed.2005,44,466468.59.2.Pictet-Spengler reaction60.61.Baldwin环化规则环化规则62.Baldwin环化规则环化规则SP3=tet；SP2=trig；SP=digSP3:5-6-endo 禁阻禁阻SP2:3-5-endo 禁阻禁阻SP:3-4-exo 禁阻禁阻其他允许其他允许63.（3）影响因素）影响因素 only-arylethylamines with electron-donating substituents afford high yields;the reaction is usually carried out with a slight excess of the carbonyl compound(to ensure the complete consumption of the amine)in either protic or aprotic medium;64.3.Strecker反应反应（1）反应通式）反应通式65.（2）反应机理）反应机理66.（3）应用）应用-Corey，199967.第三节第三节 b b-羟烷基、羟烷基、b b-羰烷基羰烷基化反应化反应 一一 b b-羟烷基化反应羟烷基化反应 1.1.反应通式反应通式-F-C-F-C反应反应68.2.反应机理反应机理69.苯环连在取代基多的苯环连在取代基多的C C上上3.应用特点应用特点（1）区域选择性）区域选择性70.（2）立体选择性）立体选择性构型反转构型反转71.（3）制备环内酯）制备环内酯72.二、二、b b-羰烷基化反应羰烷基化反应 MichaelMichael加成反应加成反应73.74.反应机理反应机理:75.76.（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 compounds,etc.as well as by the deprotonation of heteroatoms;77.2)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);78.（4）应用）应用79.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80.81.（2）影响因素）影响因素82.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)remain 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；83.The Wittig reaction has several important variants:HWE Reaction84.the phosphonate carbanions are more nucleophilic than the corresponding phosphorous 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 than from the water-insoluble triphenylphosphine oxide.85.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 substituents86.There are an important modifications of the HWE olefination:in the Still-Gennari 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.87.（4）应用）应用88.89.二二 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）反应通式 90.91.（2）反应机理）反应机理92.93.（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).94.the by-product of the reaction is water and its removal from the reaction mixture by means of azeotropic distillation,the addition of molecular sieves,or other dehydrating agents shifts the equilibrium toward the formation of the product;95.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-elimination step;96.2.Stobbe 反应反应（1）反应通式）反应通式97.（2）反应机理）反应机理98.99.（3）应用）应用制备烯酸制备烯酸100.101.3.Perkin反应反应(1)反应通式反应通式102.（2）反应机理）反应机理103.104.（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105.碘番酸中间体碘番酸中间体106.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107.（4）应用）应用108.109.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,CN,SO2R,CONR2,C(=O),C(=NR);Y=O,NR;110.2.反应机理反应机理111.3.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 derivatives；112.4.应用特点应用特点113.醛、酮同系化醛、酮同系化C+1114.布洛芬的合成布洛芬的合成 115.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116.117.118.Mechanism119.（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120.内向加成原理内向加成原理121.加成定位规则加成定位规则122.Example123.124.二、二、1,3偶极环加成偶极环加成1.Azomethine Ylides125.126.2.Azomethine Imines3.Nitrones127.4.Azides128.5.O3/Carbonyl Oxides129.三、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130.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131.Simmons-Smith cyclopropanation.132.133.134.(1)a 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 steric hindrance;135.(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;136.Example137.138.习题：习题：P164 第一题第一题139.