第四章-缩合反应PPT课件

.,1,Chapter4,CondenationReaction,第四章缩合反应,.,2,第一节a-羟烷基、卤烷基、氨烷基化反应,一、a-羟烷基化反应1.醇醛缩合反应(Aldol缩合)(1)含有a-活泼氢的醛或酮的自身缩合,.,3,碱催化机理:,.,4,.,5,甲醛与含有a-活泼氢的醛、酮之间的缩合,三羟甲基丙烷,.,6,催化剂的影响以碱催化剂为主，酸催化剂应用较少应用特点定向醇、醛缩合(a)烯醇盐法,.,7,(b)烯醇硅醚法,.,8,（2）芳醛与a-活性氢的醛、酮的缩合,.,9,应用特点制备反式芳丙醛,.,10,有机小分子脯氨酸催化直接Aldol反应,List,B.etal,J.Am.Chem.Soc.2000,122,2395,制备手性b-羟基醛,.,11,.,12,（3）分子内的羟醛缩合,.,13,Robinson环化,.,14,.,15,.,16,.,17,.,18,2.不饱和烃的a羟烷基化（Prins反应）,.,19,.,20,Mechanism,.,21,.,22,.,23,3.安息香缩合,.,24,.,25,影响因素芳醛结构的影响强吸电子、强供电子对反应都不利；自身缩合、交叉缩合,.,26,催化剂的影响NaCN剧毒，可用噻唑鎓盐、咪唑鎓盐等代替,.,27,.,28,.,29,Example,.,30,.,31,4.有机金属化合物的a-羟烷基化,(1)Reformatsky反应:醛或酮与a-卤代酸酯在金属锌粉存在下缩合而得b-羟基酸酯或脱水得a、b-不饱和羧酸酯的反应：,.,32,.,33,metal:Zn,Mg,Cd,Ba,In,Ge,Co,Ni,Ce;metalsalt:SmI2,CrCl2,TiCl2,CeX3,Na2Te,R3SnLi,R3Sb/I2,Et2AlCl,.,34,mostoftenethersolventsareusedsuchasdiethylether,tetrahydrofuran,1,4-dioxaneanddimethoxyethane,butmixturesofthesesolventswitharomatichydrocarbonsandmorepolarsolventssuchasacetonitrile,dimethylformamide,dimethylsulphoxide,andhexamethylphosphorictriamidearealsoused;,.,35,.,36,催化剂,锌粉必须活化，常用20%盐酸处理，再用丙酮、乙醚洗涤，真空干燥。亦可用K、Na、Li等还原无水氯化锌，此法活性较高。Mg,Cd,Ba,In,Ge,Co,Ni,Ce等。,.,37,例如:,加入(CH3O)3B/THF可提高收率(如上),.,38,（2）Grignard反应,.,39,.,40,.,41,机理:,.,42,.,43,影响因素1)thereagentsarepredominantlypreparedbyreactingalkyl,aryl,orvinylhalideswithmagnesiummetalinaproticnucleophilicsolvents(e.g.,ethers,tertiaryamines);2)thereagentsareusuallythermodynamicallystablebutairandmoisturesensitiveandincompatiblewithacidicfunctionalgroups(e.g.,alcohols,thiols,phenols,carboxylicacids,1,2amines,terminalalkynes);,.,44,二、a-卤烷基化反应(Blanc反应),.,45,3.影响因素也可用ZnCl2(干)等Lewis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。,(87%),.,46,引入-CH2Cl后，可进一步转化成其他官能团并增长碳链。,.,47,三、a-氨烷基化反应,Mannich反应：有活泼氢的化合物(醛、酮等)与甲醛、胺进行缩合，H原子被a-氨甲基取代称为a-氨甲基化反应(Mannich反应),.,48,反应机理,.,49,.,50,如：,(90%),抗胆碱药阿托品的中间体,.,51,Introduction,.,52,1.MetalCatalysis2.ProlineCatalysis3.BrnstedAcid-Catalysis4.ProtonatedChiralCatalysis5.ACDC6.H-BondCatalysis7.PTC,.,53,Trost,B.M.J.Am.Chem.Soc.2006,128,2778-2779.,.,54,Prolinecatalysis,.,55,Brnstedacid-catalysis,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,.,56,4.ProtonatedChiralCatalysis,J.Am.Chem.Soc.2004,126,3418-3419,.,57,Ishihara,K.J.Am.Chem.Soc2008,130,1685816860.,.,58,H-BondCatalysis,.,59,Jacobsen,E.N.Angew.Chem.Int.Ed.2005,44,466468.,.,60,2.Pictet-Spenglerreaction,.,61,.,62,Baldwin环化规则,.,63,Baldwin环化规则SP3=tet；SP2=trig；SP=digSP3:5-6-endo禁阻SP2:3-5-endo禁阻SP:3-4-exo禁阻其他允许,.,64,（3）影响因素only-arylethylamineswithelectron-donatingsubstituentsaffordhighyields;thereactionisusuallycarriedoutwithaslightexcessofthecarbonylcompound(toensurethecompleteconsumptionoftheamine)ineitherproticoraproticmedium;,.,65,3.Strecker反应（1）反应通式,.,66,（2）反应机理,.,67,（3）应用-Corey，1999,.,68,第三节b-羟烷基、b-羰烷基化反应,一b-羟烷基化反应1.反应通式-F-C反应,.,69,2.反应机理,.,70,苯环连在取代基多的C上,3.应用特点,（1）区域选择性,.,71,（2）立体选择性构型反转,.,72,（3）制备环内酯,.,73,二、b-羰烷基化反应,Michael加成反应,.,74,.,75,反应机理:,.,76,.,77,（3）影响因素,1)thenucleophile(Michaeldonor)canbederivedbythedeprotonationofCH-activatedcompoundssuchasaldehydes,ketones,nitriles,-dicarbonylcompounds,etc.aswellasbythedeprotonationofheteroatoms;,.,78,2)dependingonthetypeandstrengthoftheelectron-withdrawinggroup(negativechargestabilizinggroup),theuseofevenrelativelyweakbasesispossible(e.g.,NEt3);,.,79,（4）应用,.,80,第四节亚甲基化反应,一羰基烯化反应（1）反应通式及机理,.,81,.,82,（2）影响因素,.,83,theylidesarewateraswellasoxygen-sensitive；thephosphorousylideschemoselectivelyreactwithaldehydes(fast)andketones(slow),othercarbonylgroups(e.g.,esters,amides)remainintactduringthereaction;thestereoselectivity,E-orZ-selectivity,isinfluencedbymanyfactors:typeofylide,typeofcarbonylcompound,natureofsolvent；,.,84,TheWittigreactionhasseveralimportantvariants:HWEReaction,.,85,thephosphonatecarbanionsaremorenucleophilicthanthecorrespondingphosphorousylides,sotheyreadilyreactwithpracticallyallaldehydesandketonesundermilderreactionconditions；theby-productdialkylphosphatesarewater-soluble,soitismucheasiertoseparatethemfromthealkeneproductsthanfromthewater-insolubletriphenylphosphineoxide.,.,86,high(E)-selectivityfordisubstitutedalkenesundermuchmilderconditionsthannormallyusedinWittigreactions；the(E)-selectivityismaximizedbyincreasingthesizeofthealkylgroupoftheR1orR2substituents,.,87,ThereareanimportantmodificationsoftheHWEolefination:intheStill-GennarimodificationR1=OCH2CF3andthereactionaffords(Z)-olefinsexclusively；forbase-sensitivesubstrates,theuseofametalsalt(LiClorNaI)andaweakaminebase(e.g.,DBU)hasproveneffectivetoavoidepimerization.,.,88,（4）应用,.,89,.,90,二羰基a位的亚甲基化反应活性亚甲基的亚甲基化Knoevenagel反应（1）反应通式,.,91,.,92,（2）反应机理,.,93,.,94,（3）影响因素,thenatureofthecatalystisimportant,usuallyprimary,secondary,andtertiaryaminesandtheircorrespondingammoniumsalts,certainLewisacidscombinedwithatertiaryamine(e.g.,TiCl4/Et3N).,.,95,theby-productofthereactioniswateranditsremovalfromthereactionmixturebymeansofazeotropicdistillation,theadditionofmolecularsieves,orotherdehydratingagentsshiftstheequilibriumtowardtheformationoftheproduct;,.,96,thechoiceofsolventiscrucialandtheuseofdipolaraproticsolvents(e.g.,DMF)isadvantageous,sinceproticsolventsinhibitthelast1,2-eliminationstep;,.,97,2.Stobbe反应（1）反应通式,.,98,（2）反应机理,.,99,.,100,（3）应用制备烯酸,.,101,.,102,3.Perkin反应(1)反应通式,.,103,（2）反应机理,.,104,.,105,（3）影响因素芳香醛结构影响吸电子活性增强，给电子相反,.,106,碘番酸中间体,.,107,催化剂的影响相应羧酸的钾盐、钠盐；铯盐效果更好,.,108,（4）应用,.,109,.,110,第五节a、b-环氧烷基化反应(Darzens反应),1.反应通式EWG=CO2R,CN,SO2R,CONR2,C(=O),C(=NR);Y=O,NR;,.,111,2.反应机理,.,112,3.影响因素Aliphaticaldehydesusuallygiveloweryields；-Chloroestersarepreferabletobromooriodoesters,sincetheygivehigheryields；-halosulfones,nitriles,ketones,ketimines,thiolesters,oramides,canalsobeusedtoobtainthecorrespondingderivatives；,.,113,4.应用特点,.,114,醛、酮同系化C+1,.,115,布洛芬的合成,.,116,第六节环加成反应,EDG(electron-donatinggroup)=alkyl,O-alkyl,N-alkyl,etc.EWG(electron-withdrawinggroup)=CN,NO2,CHO,COR,COAr,CO2H,CO2R,COCletc.,一、D-A反应,.,117,.,118,.,119,Mechanism,.,120,（3）影响因素及应用特点共轭二烯双键必需是顺型的顺式原理,.,121,内向加成原理,.,122,加成定位规则,.,123,Example,.,124,.,125,二、1,3偶极环加成1.AzomethineYlides,.,126,.,127,2.AzomethineImines3.Nitrones,.,128,4.Azides,.,129,5.O3/CarbonylOxides,.,130,三、碳烯、氮烯对不饱和键的加成Carbene-电中性二价碳中间体，两电子自选方向相同为三线态，相反为单线态,.,131,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,.,132,Simmons-Smithcyclopropanation.,.