第三章酸催化缩合和重排反应

1、第三章 酸催化缩合和分子重排3.1 酸催化缩合反应3.1.1 Friedel-Crafts反应一、烷基化反应 包括芳烃、烯烃、醛、酮和醇等在催化剂无机酸或lewis酸催化下，生成正离子并与亲核试剂作用，从而生成碳碳或碳氮等键的反应。1、芳烃的烷基化CH2Cl+HClAlCl3+AlCl3H2CCHCH3H+AlCl3H+CH2CH3CH3CH2OH+ H2OCCl3CHO +Cl2H2SO4Cl3CHCCl2+ H2OH2SO4CH3CCH3OOH2+CCH3CH3HOOH+ H2OH2SO4OOCH388%OHH3PO4H2C50%二、酰基化反应1) 合成酮CClO+OAlCl3+AlCl3

2、OOOHOOCO1)Zn-Hg/HCl2) H2SO4,OH2SO4,OOOCH3CH3COOHP2O5OCH3COCH3CH3COOHP2O5OCH3COCH3COCH3NO2CH3COClAlCl3OCH3OCH3COCH3CH3COClAlCl3NO2NO2Br+ (CH3CO)2OAlCl3CS2,BrH3COCOHOHHOZnCl2,HCl(C2H5)2O+CH3CNOHOHHOCNH.HClH3CH2OOHOHHOCOH3CN(CH3)2+CONHC6H5POCl3(H3C)2NCC6H5NC6H5H2OHCl(H3C)2NCC6H5O活泼底物可以用腈或酰胺做酰化试剂烯烃的酰基化：

3、CORCl+ AlCl3COR+AlCl4-COR+RO-H+ROAlCl4-ROCl-HClMe2NH2）合成醛AlCl3CH3+ HCl + COCH3CHOAlCl3-CuCl200HCOOH + ClSO3H+ HCl + COH2SO4 HCl + COHCOClCHOCH3CH3H3CBF3+ FCHOCH3CH3H3CCHOOCH31)HCN,HCl,AlCl32)H2OOCH3CHO氢氰酸剧毒，可用氰化锌代替HCl + HCNAlCl3HNCHClRRHCHNH2ORCHO+ NH3反应历程：1)Zn(CN)2,HCl,AlCl32)H2OOHH3CCH(CH3)2OHH3CC

4、H(CH3)2CHOCH3CH3H3CCH3CH3H3C+Cl2CHOCH3TiCl4CH2Cl2CH3CH3H3CClCHOCH3CH3CH3H3CCHOCH3ClH2OCHO3.1.2 醛、酮及其衍生物的反应无机酸的作用：1、提高羰基对亲核试剂的加成活性； 2、促使羰基化合物的烯醇化。一、自身缩合2CH3CHOH+CH3CHCH2CHOOH-H2OCH3CHCHCHOCH3CHOCH3CHCH2CHOOHCH3CHCHCHOH+CH3CHOHCH3CHOHCH3CHOH+H2CHCHOH-H+CH2CHOHHCCH2OH+CH3CHOHCHCH2CHOHHOCH3-H+CH3CHCH2CH

5、OOHH+CH3CHCH2CHOOH2-H3O+反应历程：COH3CCH32H+CH3CCH3CHCCH3OCOH3CCH3CH3CCH3CHCCHOCCH3CH3二、交叉缩合CHOOH+OH3CHClCHOCHCXArCHO+ CH3NO2HOAc+NHOAcXArCHCHNO2三、酮与酰卤或酸酐的缩合-H+CH3COCH3BF3CH3CCH2OBF3HCH3COCH2BF3OH3CCH3CCOOBF3OH3CCH3CCOOBF3CH3CO+CH3COOBF3-CH3COCH2BF3CH3CO+CH3COCH2COCH3+ BF3CH3COCH2R +(CH3CO)2OBF3CH3COCHC

6、OCH3R不对称酮发生在次甲基上3.1.3 Mannich反应一、Mannich反应 具有烯醇式或潜在烯醇式结构的化合物，与醛（通常为甲醛），在酸催化下，与第一第二胺反应，生成胺甲基化衍生物的反应，叫做Mannich反应。RCOCH3+ HCHO+Et2NH2ClRCOCH2CH2NEt2 Cl+ H2ONaOHRCOCH2CH2NEt2反应历程：HCHO + H+H2COHH2COHMe2NHH2COH+Me2N+HCH2OH-H2OMe2N+=CH2Me2NCH21、酸活化甲醛，催化甲醛和胺的加成2、使含有活泼氢的化合物烯醇化PhCOCH3H+PhCOHCH2H-H+PhCCH2OH3、加

7、成PhCCH2OH+Me2N+=CH2-H+PhCOCH2CH2NMe2PhCOCH=CH2 + Me2NHOH+ HCHO + Me2NHH+OHMe2NH2CCH2NMe2CH2NMe2除了具有活泼氢的醛酮可以反应之外，其他化合物如-二元酸、 -氰基酸、 -酮酸、甚至-甲基吡啶、-萘酚、呋喃、吡咯和他们的衍生物也能反应。CH3CH(COOH)2+ HCHO + Me2NHH+CH3C(COOH)2CH2NMe2NCH3+ HCHO + Me2NHH+NCH2CH2NMe2PhCCH+ HCHO + Me2NHH+PhCCCH2NMe2苯乙炔也可以反应RCOCH3 + ArCHO + ArN

8、H210%NaHCO33）020RCOCH2CH(Ar)NHAr二、在合成中的应用1）制备，-不饱和羰基化合物RCOCH3+ HCHO+Et2NH2ClRCOCH2CH2NEt2 Cl+ H2ORCOCH=CH22)Mannich碱或季铵盐的转换NH+ HCHO + Me2NHH+NHCH2NMe2(CH3)2SO4NHCH2NMe31)CN-2)OH-NHCH2COOHNHCH2NMe3CH3CONHCH(COOEt)2EtO-H+CH3CONHC-(COOEt)2CH3CONHC-(COOEt)2+NHCH2C(COOEt)2NHCOCH31)OH-,2)H+3)NHCH2CHCOOHNH

9、23）合成生物碱H2CH2CCHOCHO+CH3NH2+COH2CH2CCOO-COO-NH3C-OOCCOO-OH3O+NH3CO托品酮托品酮具有镇痛、解毒和解除痉挛等作用。托品酮具有镇痛、解毒和解除痉挛等作用。NH3COZn-HINH3CHOHPhCH(CHO)COOHNH3CHOCOCHPhCHOKBH4CHCl3NH3CHOCOCHPhCH2OH常用于麻醉前给药，眼科中用作扩大瞳孔用药，抢常用于麻醉前给药，眼科中用作扩大瞳孔用药，抢救有机磷中毒用药救有机磷中毒用药H2CH2CCHOCHO+CH3NH2+COH2CH2CCOOCH3COO-NH3CCOOCH3O1)H+2)-CO21)H

10、2)PhCOClNCOOCH3OCOPh古柯碱80%H3C+CH3NH2+COH2CH2CCOO-COO-H2CCH2CH2CHOCHONH3CO1)-2H2O2)-2CO21)H2)PhCOClNH3CONH3COCOPh3.1.4 烯胺一、烯胺的生成NHNHONHONH+p-CH3-C6H4SO3HC6H6,N+ H2OOH3CNH+p-CH3-C6H4SO3HC6H6,NH3CNH3C+85%15%二）烯胺在有机合成中的应用NCH3I,CH3OHNCH3I-OCH3NH3C+H2CCHCNEtOHNH3CCH2CHCNHNH3CCH2CH2CNOH3CCH2CH2CN注意：反应发生在取代

11、基较少的注意：反应发生在取代基较少的- -碳上碳上C2H5CHCHN+H2CCHCOOCH31) CH3CN2) H3O+C2H5CHCHOCH2CH2COOCH3NOCH3(CH2)5COClN(C2H5)3NONOHCO(CH2)5CH3CO(CH2)5CH3OCO(CH2)5CH33.1.5 -皮考啉反应NCH3ZnCl2,PhCHONCHCHPhNCH3ZnCl2,PhCHONCH=CHPh3.1.6 Prins 反应HCHO + H+H2COHCH2OH+CH2OHCCH2OHH2O-H+CCCH2OHOHHCHO-H2OOCH2OCCH2CPhHCCH22HCHO+H+OOPh该反

12、应提供较原来烯烃多一个碳原子醇的合成方法该反应提供较原来烯烃多一个碳原子醇的合成方法氯霉素的合成氯霉素的合成PhHCCH2HOBrCHCH2BrPhOHTsOH,KHSO4-H2OPhHCCHBrHCHOOOPhBrNH3OOPhNH2H+CHOHPhCNH2HCH2OH CHCl2COClCHOHPhCNHCOCHCl2HCH2OHD-(-)-3.2 酸催化分子重排酸催化分子重排3.2.1 频哪醇频哪醇-频哪酮重排频哪酮重排CH3CCH3OHCCH3CH3OH(1) H+(2) -H2OCH3CCH3CCH3CH3OHCH3CCH3CCH3OHCH3-H+CH3CCH3CCH3OCH3CPh

13、CH3OHCHHOHH+H+CPhOCH2CH3CPhCH3CHHOHCHPhCH3CHOHCHPhCH3CHO1）生成稳定碳正离子；）生成稳定碳正离子；2）亲核性更强的原子或基团发生迁移，一般）亲核性更强的原子或基团发生迁移，一般ArRH。CPhPhCCH3CH3OHCPhPhCCH3OCH3CPhPhOHCCH3CH3OHH2SO4ZnCl2CPhPhOHCCH3CH3CPhOCCH3CH3PhLewis酸更容易和甲基连接的碳羟基结合。酸更容易和甲基连接的碳羟基结合。OMg(Hg)OHH3OOOMg2+OHOHH3OH2OZn-Hg/ HClOOHOH2OHO由合成3.2.2 呐咵重排和反

14、呐咵重排呐咵重排和反呐咵重排CH3CCH3OHCCH3CH3NH2HNO2CH3CCH3OHCCH3CH3NN-N2CH3CCH3CCH3CH3OHCH3CCH3CCH3OCH3CH3CCH3CCH3OHCH3-H+呐咵重排呐咵重排:反呐咵重排反呐咵重排:(CH3)3CCH2OHH+(CH3)3CCH2OH2-H2O(CH3)3CCH2(CH3)2CCH2CH3-H+(H3C)2CCHCH3CCCCCCCCCCCC3.2.3 Beckmann重排重排CRNR1OHH+CRNR1OH2-H2OCRNR1CNR1RH2OCNR1RH2O-H+CNR1ROHCNR1HOR和羟基在异侧的烃基重排和羟基

15、在异侧的烃基重排HHNOHHHNHOH+110 C C110 C CH+HNNHHHHHOO利用贝克曼重排，可以合成己内酰胺、取代酰胺和利用贝克曼重排，可以合成己内酰胺、取代酰胺和-氨基酸等重要的合成中间体。氨基酸等重要的合成中间体。ONH2OHrt.NOHBpy BF4/PCl3353K,2hNHOMeMeCO2CH3CHMe268CH3COClAlCl3,C6H5NO2MeMeCO2CH3CHMe2COCH3NH2OH HClMeMeCO2CH3CHMe2CCH3NOH1)HCl-HOAc-Ac2O,25 C C2) H3O+,62%MeMeCO2CH3CHMe2NH2CNOHNO2HCl

16、H+CNOH2+NO2-H2OCNNO2NCNO2H2ONCNO2OH2NCNO2OHHNCNO2OHNCNO2O3.2.4 烯丙基重排烯丙基重排H2CCHCH2OHH2CCHCH2ClH2CCHCH2CH2CHCH21 2 31 2 3H+-H2O-Cl烯丙基正离子的产生烯丙基正离子的产生:-ClCH3CHCHCH2ClCH3CHCHCH2CH3CHCHCH2H2OH2OCH3CHCHCH2OH2-H+CH3CHCHCH2OHCH3CHCHOH2CH2-H+CH3CHCHOHCH2SN1历程：历程：H2CCHCHCH3Cl(C2H5)2NH +CH2CHCHCH3(C2H5)2NCH2CHC

17、HCH3(C2H5)2N(C2H5)2NHClCH2CHCHCH3+SN2SN2SN2和和SN2为竞争反应，当空间位阻较大时发生为竞争反应，当空间位阻较大时发生SN23.2.5 联苯胺重排联苯胺重排 氢化偶氮苯重排为氢化偶氮苯重排为4，4-二氨基联苯的反应称为联二氨基联苯的反应称为联苯胺重排。苯胺重排。NHNHH+H2NNH2NHNH2H+NNHHHHNNHHHHNNHHHHNNHHHHHHNHHNHHHHNHHHNHHH-2H+H2NNH2NHNHH+H2NNH2NHNHCH3H3CH2NNH2H3CCH3H2NNH2H3C(不发生交叉式重排，该重排为分子内重排。不发生交叉式重排，该重排为分

18、子内重排。对半联苯胺对半联苯胺邻半联苯胺邻半联苯胺NHNHH+H3CNHH3CNH2NHNHH3CCH3H+NHH3CCH3H2NNNNNNH2SO3NaNH2SO3NaNNNNNH2SO3NaNH2SO3NaH3CCH3NNNNOHOHNH2NaO3SNH2SO3NaNaO3SSO3NaNHNHH3CCH3H+H2NNH2H3CCH3NaNO2,HClNNH3CCH3NNH2NSO3NaNNNNNH2SO3NaNH2SO3NaH3CCH3如：如：3.2.6 Schimdt 重排重排 在强酸存在下，羧酸、醛酮等与叠氮酸作用，在强酸存在下，羧酸、醛酮等与叠氮酸作用，生成伯胺、酰胺或腈的反应称为施

19、密特重排。生成伯胺、酰胺或腈的反应称为施密特重排。RCOOH + HN3H2SO4C6H6RNH2 + CO2 + N2COROHH2SO4COHROHCOROH2COR+ H2OCORHN3+-H+CORNNN-N2CORNNCORH2ORNH2 + CO2羧酸：羧酸：H2SO4COOHCOOHHN3NH2NH2COOHH2SO4HN3NH2OHH3CH3CCOOHH2SO4HN3OHH3CH3CNH2酮的重排：酮的重排：H2SO4HN3CORRRCONHR + N2CORR1H2SO4HN3RCONHR1R1CONHR+ N2HN3CORR+COHRRNNN-N2COHRRNNCRROHRCONHR历程：历程：重排反应速率：重排反应速率：