药物合成反应第三章酰化反应.ppt
Chapter 3,Acylation Reaction,第三章 酰化反应,概 述,1 定义：有机物分子中O、N、C原子上导入酰基的反应,2 分类：根据接受酰基原子的不同可分为：氧酰化、氮酰化、碳酰化3 意义：药物本身有酰基前药原理合成手段,硝苯地平,常用的酰化试剂,第一节 酰化反应机理,一、电子反应机理1.亲电反应机理1）单分子历程-酰卤、酸酐,2）双分子历程酰化速率与酰化剂和被酰化物浓度均有关系，为动力学二级反应。,3）酰化剂的强弱顺序Z的电负性越大，离去能力越强，其酰化能力越强。判断方法为：HZ的Ka越大或Pka越小，酸性越强,4）被酰化物的活性亲核能力越强，越容易酰化，可以根据被酰化物R-YH碱性来衡量RNH2ROHRHR的影响：在O，N酰化中，R=Ar时，活性下降，故RNH2ArNH2及ROHArOHR的影响：立体位阻大，酰化困难,2.亲核反应机理极性反转-a氰醇衍生物T,1976,32,1943二、自由基反应机理产物复杂，应用有限,第二节 氧原子的酰化反应,是一类形成羧酸酯的反应 是羧酸的酯化反应 是羧酸衍生物的醇解反应,一、醇的氧酰化,1)羧酸为酰化剂 提高收率:加快反应速率:(1)提高温度(2)催化剂(降低活化能),(1)增加反应物浓度(2)不断蒸出反应产物之一(3)添加脱水剂或分子筛除水。,酯化反应的机理,*1 加成消除机理,双分子反应一步活化能较高,质子转移,加成,消除,四面体正离子,-H2O,-H+,按加成消除机制进行反应，是酰氧键断裂,*3oROH按此反应机理进行酯化。*由于R3C+易与碱性较强的水结合，不易与羧酸结合，故逆向反应比正向反应易进行。所以3oROH的酯化 反应产率很低。,*2 碳正离子机理,属于SN1机理,该反应机理也从同位素方法中得到了证明,(CH3)3C-OH,H+,(CH3)3COH2,+,-H2O,-H+,按SN1机理进行反应，是烷氧键断裂,+(CH3)3COH,+H2O,仅有少量空阻大的羧酸按此反应机理进行,*3 酰基正离子机理,H2SO4(浓),-H+,属于SN1机理,78%,CH3OH,醇的结构对酰化反应的影响立体影响因素:伯醇仲醇叔醇、烯丙醇叔碳正离子倾向与水反应而逆转,（3）影响因素 醇结构影响,电子效应的影响羟基a位吸电子基团通过诱导效应降低O上电子云密度，使亲核能力降低苄醇、烯丙醇由于p-p共轭，使活性降低,羧酸的结构R带吸电子基团-利于进行反应；R带给电子不利于反应R的体积若庞大，则亲核试剂对羰基的进攻有位阻，不利于反应进行羰基的a位连有不饱和基和芳基，除诱导效应外，还有共轭效应，使酸性增强,催化剂i提高羧酸反应活性(a)质子酸催化法:浓硫酸,氯化氢气体,磺酸等,(b)Lewis酸催化法:(AlCl3,SnCl4,FeCl3,等),例,(c)DCC 二环己基碳二亚胺,例：,ii 用来提高醇的反应活性,偶氮二羧酸酯法（活化醇制备羧酸酯）,Mitsunobu reaction.,Mechanism,（4）应用特点,伯醇酯的制备,仲醇酯的制备,薄荷醇,叔醇酯的制备,2.羧酸酯为酰化剂(1)反应通式 R2、R1要求？,（2）反应机理 酸催化机理：-增强羧酸酯的活性,碱催化机理增强醇的活性,（3）影响因素羧酸酯结构的影响如a位有吸电子基团，将增强其活性短链的羧酸乙酯、甲酯，更常用在RCOOR1中，R1OH酸性越强，酯的酰化能力越强,例：局麻药丁卡因,例：抗胆碱药溴美喷酯（宁胃适）,例：抗胆碱药格隆溴胺（胃长宁）的合成,活性酯的应用 i羧酸硫醇酯,ii羧酸吡啶酯,iii羧酸三硝基苯酯Cl-TNB,iv羧酸异丙酯（适用于立体障碍大的羧酸）,V 苯并三唑酯,3 酸酐为酰化剂（1）反应通式,（2）反应机理 H+催化 Lewis酸催化,碱催化:无机碱：（Na2CO3、NaHCO3、NaOH)去酸剂；有机碱：吡啶，Et3N,（3）影响因素催化剂的影响三氟甲磺酸盐催化Cu(OTf)2、Sc(OTf)3、Yb(OTf)3、Bi(OTf)3等比吡啶类更有效,（4）应用特点单一酸酐应用有限，一般使用混合酸酐i 羧酸-三氟乙酸混合酸酐（适用于立体位组较大的羧酸的酯化，临时制备）,ii 羧酸-磺酸混合酸酐 iii羧酸-多取代苯甲酸混合酸酐 Yamaguchi酯化,iv 羧酸-磷酸混合酸酐 BOP-Cl DPPA,其它混合酸酐,4.酰氯为酰化剂(酸酐、酰氯均适于位阻较大的醇)(2)反应机理Lewis酸催化,碱催化,例,（4）应用特点选择性酰化有机锡体系实现选择性酰化非1,2-二醇的酰化,叔醇的酰化加入Ag+、Li+盐，提高收率,5 酰胺为酰化剂(活性酰胺),（3）应用特点 酰基咪唑为酰化剂,PTT为酰化剂适用于对酸、碱均不稳定醇的酰化反应在中性条件下进行,羧酸需要活化10为活性中间体一个五元杂环用来活化,例,活化试剂为CDI优点：酸的活化、酰化、硝基还原可在同一溶剂中进行-EtOAc,Mechanism,N上无孤对电子参与共振，键更易断裂N-H的化学位移,6.乙烯酮为酰化剂(乙酰化)对于某些难以酰化的叔羟基,酚羟基以及位阻较大的羟基采用本法,二 酚的氧酰化,用强酰化剂:酰氯、酸酐、活性酯,酸酐为酰化剂例,选择性酰化例,相转移条件下，利用酚羟基与碱性催化剂成盐的性质，选择性酰化：,缩略语-结构对照,1.AIBN2.9-BBN,3.BINOL4.Bn5.Bz6.Boc,7.BOP-Cl8.Cbz9.CDI,10.CSA11.DABCO12.DBN1,5-diazabicyclo4.3.0non-5-ene,13.DBU1,8-diazabicyclo5.4.0undec-7-ene14.DCC15.DDQ,16.DEAD17.DHP18.DIAD,19.DIBAL20.DIC21.DMAP,22.DMF23.DMP24.EDCI,25.Fmoc26.HMPA/HMPT,27.HOBt28.IBX29.LAH,30.LDA31.m-CPBA32.PMB,33.NBS/NCS34.NMM/NMO35.PCC/PDC,36.PTSA/PPTS37.Red-Al,38.TEA/TFA/TFAA39.TBHP40.TCCA,41.TMEDA/DMEDA42.DPPA,第三节 氮原子上的酰化反应,比羧酸的反应更容易，应用更广,一、脂肪氨-N酰化,1.羧酸为酰化剂,（1）DCC为催化剂（2）活性磷酸酯为催化剂,2 羧酸酯为酰化剂例,例,3 酸酐为酰化剂,如用环状酸酐酰化时，在低温下常生成单酰化产物，高温加热则可得双酰化亚胺,4 酰氯为酰化剂,二、芳胺N-酰化,第四节 碳原子上的酰化反应 一、芳烃的C-酰化,1 Friedel-Crafts(F-C)傅-克酰化反应,(1)反应通式,（2）反应机理,（3）影响因素 酰化剂的影响I.酰化剂的影响acylating agents besides acyl halides are:aromatic and aliphatic carboxylic acids,anhydrides,ketenes and esters.acyl iodides are usually the most reactive,while acyl fluorides are the least reactive(I Br Cl F),ii 酰化剂结构的影响,用酸酐作酰化剂，可制取芳酰脂肪酸，并可进一步环和得芳酮衍生物,被酰化物的影响substrates that undergo the Friedel-Crafts alkylation are also easily acylated and in most cases electron-rich substrates.no polyacylated products are observed,since,after the introduction of the first acyl group,the substrate becomes deactivated;,unprotected Lewis basic functional groups(e.g.,amines)are poor substrates,since the acylation will preferentially take place on these functional groups instead of the aromatic ring;,催化剂的影响most often used catalysts are:AlX3,lanthanide triflates,zeolites,protic acids(e.g.,H2SO4,H3PO4),FeCl3,ZnCl2,PPA;unlike in the alkylations,Friedel-Crafts acylations require substantial amounts of catalyst(slightly more than one equivalent),since the acylating agent itself coordinates one equivalent of Lewis acid,and therefore excess is needed to observe catalysis;,One drawback of the Friedel-Crafts acylation is that the Lewis acid catalyst usually cannot be recovered at the end of the reaction,since it is destroyed in the work-up step.recent studies showed that the use of heterogeneous catalysts(mainly zeolites)makes this important reaction more feasible on an industrial scale.,溶剂的影响 CCl4,CS2惰性溶剂最好选用.,2.Hoesch反应酚或酚醚在氯化氢和氯化锌等Lewis酸的存在下，与腈作用，随后进行水解，得到酰基酚或酰基酚醚,（2）机理Hoesch-芳酮与Gattermann-芳醛类似，,（3）影响因素：要求电子云密度高，即苯环上一定要有2个供电子基（一元酚不反应）,最终产物为苯甲醛（适用于酚类及酚醚类芳烃）,3.Gattermann反应(Hoesch反应的特例)芳香化合物在三氯化铝或二氯化锌存在下与HCN和HCl作用所发生的芳环氢被甲酰基取代的反应。,Gattermann-Koch formylation,(1)at high CO pressure(100-250 atm)the reaction rate increases significantly and even non-activated aromatics(chlorobenzene,benzene)can be formylated;(2)a carrier/activator(Cu2Cl2,TiCl4 or NiCl2)for the catalyst is necessary at atmospheric pressure;however,no activator is needed at high pressure,(3)monosubstituted substrates are formylated almost exclusively at the para position,but when there is already a para substituent present in the substrate,the formyl group is introduced at the ortho position;(4)the need for high pressures renders this method mainly useful to industrial applications,(5)The main drawback of the Gattermann formylation was that it called for the use of anhydrous HCN,which is a very toxic compound;(6)R.Adams generated it in situ along with ZnCl2 by reacting Zn(CN)2 with HCl in the presence of the aromatic substrate(Adams modification);,(7)Other modifications used NaCN and CNBr successfully instead of HCN;(8)A serious limitation of both title reactions is that they cannot be used for the formylation of aromatic amines due to numerous side reactions.,4 Vilsmelier反应用N-取代甲酰胺作酰化剂，三氯氧磷催化芳环甲酰化的反应,反应机理Vilsmeier-Haack formylation,例,(1)the Vilsmeier reagent is prepared from any N,N-disubstituted formamide by reacting it with an acid chloride(e.g.,POCl3,SOCl2,oxalyl chloride);(2)most often the combination of DMF and POCl3 is used and the resulting Vilsmeier reagent is usually isolated before use;,(3)mostly electron-rich aromatic or heteroaromatic compounds as well as electron-rich alkenes and 1,3-dienes11 are substrates;(4)the transformation is regioselective favoring the less sterically hindered position.,5 Reimer-Tiemann反应芳香族化合物在碱溶液中与氯仿作用，也能发生芳环氢被甲酰基取代的反应，叫做Reimer-Tiemann反应。,(1)it is the only electrophilic aromatic substitution reaction that occurs under basic conditions in a protic solvent;(2)phenols,naphthols,alkyl-,alkoxy-,and halogenated phenols,salicylic acid derivatives,heterocyclic phenols such as hydroxyquinolin es and hydroxypyrimidines,as well as pyrroles and indoles undergo formylation under the reaction conditions;,(3)the regioselectivity is not high,but ortho-formyl products tend to predominate;(4)when the ortho-position is already substituted,para-formyl phenols are obtained(5)when the reaction is conducted in the presence of cyclodextrins,the p-formyl product is formed predominantly.,二、烯烃的C-酰化,加成的方向服从马氏规则,酰基优先进攻氢原子较多的碳原子,机理,三、羰基位C-酰化,1.活性亚甲基化合物的C-酰化,例,2.Claisen反应和Dieckmann反应,机理,Since the crossed Claisen condensation can potentially give rise to at least four different condensation products,it is a general practice to choose one ester with no-protons(e.g.,esters of aromatic acids,formic acid and oxalic acid).The ester with no-proton reacts exclusively as the acceptor and this way only a single product is formed.,an ester enolate reacts with a ketone or aldehyde to give an-hydroxyester；a ketone or aldehyde enolate reacts with an ester to give a 1,3-diketone.,3.酮、腈的a位C-酰化,应用二酮的制备分子内酰化,腈的酰化烯胺酰化,习题-写出下列反应机理,
