《药物合成反应第三章酰化反应.ppt》由会员分享，可在线阅读，更多相关《药物合成反应第三章酰化反应.ppt（149页珍藏版）》请在三一办公上搜索。
1、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
2、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
3、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
4、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
5、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,
6、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 DP
7、PA,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
8、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
9、,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
10、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 fluoride
11、s 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,t
12、he 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(
13、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
14、 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
15、 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 pr
16、essure(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
17、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 drawbac
18、k 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 succes
19、sfully 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-disub
20、stituted 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 a
21、lkenes 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
22、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 or
23、tho-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
24、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,
