1、2021/3/141Chapter 4Condenation Reaction 2021/3/142第一節第一節 a a- -羥烷基、鹵烷基、氨烷羥烷基、鹵烷基、氨烷基化反應基化反應一、一、a a- -羥烷基化反應羥烷基化反應1.1.醇醛縮合反應醇醛縮合反應( (Aldol縮合縮合) )(1)(1)含有含有a a- -活潑氫的醛或酮的自身縮合活潑氫的醛或酮的自身縮合2021/3/143 堿催化機理堿催化機理: : R +RR + BHCHCRCH2OBCROCHCROR+RRRRRCRCH2OCHCROCRCH2CORCHOBHHOHCRCH2CCORBRR+OHRCRCH2CCOBH2021

2、/3/144(62%)-OHCCHO(CH2)3C3H7CHOH1150CC3H7CHO(90%)OCH2COCH3KOHO2021/3/145甲醛與含有甲醛與含有a a- -活潑氫的醛、酮之間的縮合活潑氫的醛、酮之間的縮合NaOH(稀)40-420C+(45%)-HCHOCH3COCH3H2CCHCOCH3H2O14-200C, 3h+(90%)CH2CH2K2CO3OH2HCHOCH3CH2CHOCH2CH3CCHOCH2OH(1) H(2) HCHO+NaOHCH3CH2COHCH2OHCH2OHCH2三羥甲基丙烷三羥甲基丙烷2021/3/146 催化劑的影響催化劑的影響 以堿催化劑為主

3、以堿催化劑為主,酸催化劑應用較少酸催化劑應用較少 應用特點應用特點 定向醇、醛縮合定向醇、醛縮合 (a) 烯醇鹽法烯醇鹽法2021/3/147 (b) 烯醇硅醚法烯醇硅醚法2021/3/148 （2）芳醛與芳醛與a a- -活性氫的醛、酮的縮合活性氫的醛、酮的縮合2021/3/149 應用特點應用特點 制備反式芳丙醛制備反式芳丙醛2021/3/1410脯氨酸脯氨酸直接直接 Aldol 反應反應List, B. et al, J. Am. Chem. Soc. 2000, 122, 2395NHCOOHR = Ar, CH3CHCH2CH2OHCH3CHCH2CH2OH苯環連在取代基多的苯環連在

4、取代基多的C C上上SnCl2 / CS2-100C+(40%)C6H5CH3CHCH2OCH3CHCH2CH2OHCH23.應用特點應用特點 （1）區域選擇性）區域選擇性2021/3/1471 （2）立體選擇性）立體選擇性 構型反轉構型反轉2021/3/1472 （3）制備環內酯）制備環內酯2021/3/1473二、二、 b b- -羰烷基化反應羰烷基化反應 MichaelMichael加成反應加成反應2021/3/14742021/3/1475反應機理反應機理: :+OHCH3OOCH3HHOOCH3OOCH3COCH2CH+CH2OHCH3OOCH3COCH2CHHCH3OOCH2CH3

5、CO2021/3/1476CH3-H2OOO+OOCH3OOCH3OCH2CH3OOCH2COCH2HOHH2021/3/1477（3）影響因素）影響因素 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）應用）應用2021/3/1480 第四節第四節 亞甲基化反應亞甲基化反應 一一 羰基烯化反應羰基烯化反應（1 1）反應通式及機理）反應通式及機理+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）影響因素）影響因素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）應用）應用2021/3/14892021/3/1490二二 羰基羰基a a位的亞甲基化反應位的亞甲基化反應1.1.活性亞甲基的亞甲基化活性亞甲基的亞甲基化 Knoevenagel 反應反應（1）反應通式）反應通式 2021/3/14912021/3/1492 （2）反應機理）反應機理2021/3/14932021/3/1494（3）影響因素）影響因素 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 反應反應 （1）反應通式）反應通式2021/3/1498 （2）反應機理）反應機理2021/3/14992

15、021/3/14100 （3）應用）應用 制備烯酸制備烯酸2021/3/141012021/3/141023. Perkin反應反應(1) 反應通式反應通式2021/3/14103 （2）反應機理）反應機理2021/3/141042021/3/14105 （3）影響因素）影響因素 芳香醛結構影響芳香醛結構影響 吸電子活性增強吸電子活性增強,給電子相反給電子相反2021/3/14106 碘番酸中間碘番酸中間體體2021/3/14107 催化劑的影響催化劑的影響 相應羧酸的鉀鹽、鈉鹽相應羧酸的鉀鹽、鈉鹽;銫鹽效果更好銫鹽效果更好2021/3/14108 （4）應用）應用2021/3/1410920

16、21/3/14110第五節第五節 a a、b b - -環氧烷基化反應環氧烷基化反應(Darzens(Darzens反應反應) ) 1. 反應通式反應通式 EWG = CO2R, CN, SO2R, CONR2, C(=O), C(=NR); Y = O, NR;2021/3/14111 2. 反應機理反應機理2021/3/14112 3. 影響因素影響因素 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. 應用特點應用特點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第六節第六節 環加成反應環加成反應 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反應反應2021/3/141172021/3/141182021/3/14119Mechanism2021/3/14120 （3）影響因素及應用特點）影響因素及應用特點 共軛二烯雙鍵必需是順型的共軛二烯雙鍵必需是順型的 順式原理順式原理2021/3/14121 內向加成原理內向加成原理2021/3/14122 加成定位規則加成定位規則2021/3/14123Example2021/3/141242021/3/

19、14125 二、二、1,3偶極環加成偶極環加成 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、氮烯對不飽和鍵的加成三、碳烯、氮烯對不飽和鍵的加成 Carbene-電中性二價碳中間體電中性二價碳中間體,兩電子自選兩電子自選方向相同為三線態方向相同為三線態,相反為單線態相反為單線態2021/3/14131 單線態與烯烴的反應有立體定向性單線態與烯烴的反應有立體定向性 三線態與烯烴的反應不具有立體定向性三線態與烯烴的反應不具有立體定向性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