第四章-缩合反应课件

1、2021/3/141Chapter 4Condenation Reaction 2021/3/142第一节第一节 a a- -羟烷基、卤烷基、氨烷羟烷基、卤烷基、氨烷基化反应基化反应一、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2021/3/143 碱催化机理碱催化机理: : R +RR + BHCHCRCH2OBCROCHCROR+RRRRRCRCH2OCHCROCRCH2CORCHOBHHOHCRCH2CCORBRR+OHRCRCH2CCOBH2021

2、/3/144(62%)-OHCCHO(CH2)3C3H7CHOH1150CC3H7CHO(90%)OCH2COCH3KOHO2021/3/145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NaOH(稀)40-420C+(45%)-HCHOCH3COCH3H2CCHCOCH3H2O14-200C, 3h+(90%)CH2CH2K2CO3OH2HCHOCH3CH2CHOCH2CH3CCHOCH2OH(1) H(2) HCHO+NaOHCH3CH2COHCH2OHCH2OHCH2三羟甲基丙烷三羟甲基丙烷2021/3/146 催化剂的影响催化剂的影响 以碱催化剂为主

3、以碱催化剂为主,酸催化剂应用较少酸催化剂应用较少 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2021/3/147 (b) 烯醇硅醚法烯醇硅醚法2021/3/148 （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2021/3/149 应用特点应用特点 制备反式芳丙醛制备反式芳丙醛2021/3/1410脯氨酸脯氨酸直接直接 Aldol 反应反应List, B. et al, J. Am. Chem. Soc. 2000, 122, 2395NHCOOHR = Ar, CH3CHCH2CH2OHCH3CHCH2CH2OH苯环连在取代基多的苯环连在

4、取代基多的C C上上SnCl2 / CS2-100C+(40%)C6H5CH3CHCH2OCH3CHCH2CH2OHCH23.应用特点应用特点 （1）区域选择性）区域选择性2021/3/1471 （2）立体选择性）立体选择性 构型反转构型反转2021/3/1472 （3）制备环内酯）制备环内酯2021/3/1473二、二、 b b- -羰烷基化反应羰烷基化反应 MichaelMichael加成反应加成反应2021/3/14742021/3/1475反应机理反应机理: :+OHCH3OOCH3HHOOCH3OOCH3COCH2CH+CH2OHCH3OOCH3COCH2CHHCH3OOCH2CH3

5、CO2021/3/1476CH3-H2OOO+OOCH3OOCH3OCH2CH3OOCH2COCH2HOHH2021/3/1477（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;2021/3/1478

6、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);2021/3/1479 （4）应用）应用2021/3/1480 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+n-C4H8Li / EtON2, 250C(C6H5)3CH3PBrC6H62

7、50C(C6H5)3P CH3BrR+CH2CH2R(C6H5)3P(C6H5)3PCO2021/3/1481RRR +OCH2HOHC(C6H5)3PCRHOHC(C6H5)3PCRRC(C6H5)3P2021/3/1482 （2）影响因素）影响因素2021/3/1483 the ylides are water as well as oxygen-sensitive; the phosphorous ylides chemoselectively react with aldehydes (fast) and ketones (slow), other carbonyl groups (e

8、.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;2021/3/1484 The Wittig reaction has several important variants: HWE Reaction2021/3/1485 the phosphonate carban

9、ions 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 t h a n f r o m

10、 t h e w a t e r - i n s o l u b l e triphenylphosphine oxide.2021/3/1486 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 substituents2021/3/

11、1487 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 epimer

12、ization.2021/3/1488 （4）应用）应用2021/3/14892021/3/1490二二 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 2021/3/14912021/3/1492 （2）反应机理）反应机理2021/3/14932021/3/1494（3）影响因素）影响因素 the nature of the catalyst is important, usually primary, secondary, and tertiary amines and their c

13、orresponding ammonium salts, certain Lewis acids combined with a tertiary amine (e.g., TiCl4/Et3N).2021/3/1495 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 t

14、he equilibrium toward the formation of the product;2021/3/1496 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;2021/3/1497 2. Stobbe 反应反应 （1）反应通式）反应通式2021/3/1498 （2）反应机理）反应机理2021/3/14992

15、021/3/14100 （3）应用）应用 制备烯酸制备烯酸2021/3/141012021/3/141023. Perkin反应反应(1) 反应通式反应通式2021/3/14103 （2）反应机理）反应机理2021/3/141042021/3/14105 （3）影响因素）影响因素 芳香醛结构影响芳香醛结构影响 吸电子活性增强吸电子活性增强,给电子相反给电子相反2021/3/14106 碘番酸中间碘番酸中间体体2021/3/14107 催化剂的影响催化剂的影响 相应羧酸的钾盐、钠盐相应羧酸的钾盐、钠盐;铯盐效果更好铯盐效果更好2021/3/14108 （4）应用）应用2021/3/1410920

16、21/3/14110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;2021/3/14111 2. 反应机理反应机理2021/3/14112 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 h

17、igher yields; -halo sulfones,nitriles,ketones, ketimines, thiol esters,or amides,can also be used to obtain the corresponding derivatives;2021/3/14113 4. 应用特点应用特点2021/3/14114 醛、酮同系化醛、酮同系化C+12021/3/14115布洛芬的合成布洛芬的合成 2021/3/14116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,

18、 etc. EWG (electron-withdrawing group) = CN, NO2, CHO, COR, COAr, CO2H, CO2R, COCl etc.一、一、D-A反应反应2021/3/141172021/3/141182021/3/14119Mechanism2021/3/14120 （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2021/3/14121 内向加成原理内向加成原理2021/3/14122 加成定位规则加成定位规则2021/3/14123Example2021/3/141242021/3/

19、14125 二、二、1,3偶极环加成偶极环加成 1. Azomethine Ylides2021/3/141262021/3/14127 2. Azomethine Imines 3. Nitrones2021/3/14128 4. Azides2021/3/14129 5. O3 / Carbonyl Oxides2021/3/14130 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电中性二价碳中间体,两电子自选两电子自选方向相同为三线态方向相同为三线态,相反为单线态相反为单线态2021/3/14131 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2021/3/14132Simmons-Smith cyclopropanation.2021/3/141332021/3/141342021/3/14135 (1) a wide range of alkenes can be used: simple alkenes, ,-unsaturates ketones and aldehydes, electron rich alkenes ; (2) due to the electro