01有机合成绪论终

1、有机合成有机合成organic synthesis徐indafeng_教材与参考书教材与参考书1、有机合成有机合成黄培强，靳立人，陈安齐黄培强，靳立人，陈安齐 高等教育出版社高等教育出版社2、有机合成设计有机合成设计斯图尔特斯图尔特.沃伦沃伦 著著(英英) 丁新腾丁新腾,林子森林子森 译译绪论（绪论（1）1、有机合成的意义有机合成的意义 人类最基本的需求：人类最基本的需求：生存生存（食品（食品-农药）农药） 人类最高级的渴望：人类最高级的渴望：长寿长寿（疾病（疾病-医药）医药）2、有机合成的艺术性、有机合成的艺术性 有机合成是一门艺术。分子有机合成是一门艺术。分子建筑

2、。风格建筑。风格3、有机合成历史回顾有机合成历史回顾1828年年wohler用典型的无机物合成了尿素。开始了近代有机化学用典型的无机物合成了尿素。开始了近代有机化学发展及有机合成的历史。发展及有机合成的历史。1917年，年，robinson合成了托品酮，开创了系统有机结构理论合成合成了托品酮，开创了系统有机结构理论合成方法反应机制与结构鉴定等的研究并第一次开设了有机合成课程。方法反应机制与结构鉴定等的研究并第一次开设了有机合成课程。三十年代齐格勒发现了定向聚合催化剂；开始了制备与应用高分三十年代齐格勒发现了定向聚合催化剂；开始了制备与应用高分子材料的时代子材料的时代20世纪世纪50年代年代nm

3、r技术开始应用于有机化合物结构测定。技术开始应用于有机化合物结构测定。20世纪世纪50-70年代年代woodword合成了利血平，胆甾醇，维生素合成了利血平，胆甾醇，维生素b12和红霉素（和红霉素（18个手性中心等）将有机合成发展到前所未有的水平。个手性中心等）将有机合成发展到前所未有的水平。 20世纪世纪60年代，年代，merrifiled发展了固相合成技术。发展了固相合成技术。20世纪世纪70年代，年代，corey发明了手性合成理论和方法。发明了手性合成理论和方法。1989年，年，kishi合成了海葵霉素合成了海葵霉素(分子式分子式c129h223n3o54，分子，分子量量2680，64个

4、手性中心，个手性中心，7个骨架内双键），被称为世纪工程。个骨架内双键），被称为世纪工程。20世纪世纪90年代发展了组合化学合成理论和技术。年代发展了组合化学合成理论和技术。当今新的试剂、方法以及手段的开发、应用；标志高选择性、立当今新的试剂、方法以及手段的开发、应用；标志高选择性、立体性的定向合成时代的到来。体性的定向合成时代的到来。 4、合成方法的近期发展趋势、合成方法的近期发展趋势 高选择性有机合成、发展高效合成方法、高选择性有机合成、发展高效合成方法、绿色合成绿色合成已逐步成为战略选择。组合化学。已逐步成为战略选择。组合化学。 为了衡量合成的效率，为了衡量合成的效率，b.m.trost于

5、于1991年提出了原年提出了原子经济性的概念。子经济性的概念。 分析下列两个反应的原子利用率：5、有机合成文献查阅与检索、有机合成文献查阅与检索检索文摘或合成方法用scifinder，web of science，功能最强大的是scifinder。scifinder scholar可检索数据库包括： caplussm（2600万条参考书目记录，每天更新3000条以上，始自1907年）cas registrysm（8600万条物质记录，每天更新约4000条，每种化学物质有唯一对应的cas 注册号，始自1957年） casreact1100万条反应记录，每周更新约700-1300条，始自1974年

6、） chemcats1100万条商业化学物质记录，来自800多家供应商的900多种目录） chmlist24万种化合物的管制品信息，来自19个国家和国际性组织） scifinder scholar（sfs） 数据库数据库 sfs涵盖了化学相关领域涵盖了化学相关领域98以上的文献以上的文献scifinder scholar的检索方式的检索方式主题主题机构名机构名专利号专利号作者名作者名结构，亚结构结构，亚结构俗名俗名分子式分子式官能团官能团相似结构相似结构文献文献反应反应物质物质通过主题检索通过主题检索油田用表面活性剂油田用表面活性剂研究研究“closely associated with on

7、e another”表示在同一个句子当中出现获得初步的检索结果勾勾选选小小方方框框选选择择所所需需文文献献在线在线帮助帮助结果记录数结果记录数结果去重结果去重结果分析结果分析/二次检索二次检索查看相关信息查看相关信息点击显点击显微镜图微镜图标显示标显示书目及书目及文摘信文摘信息；息；点击电点击电脑图标脑图标启动启动chempochemportrt链接链接全文全文；1、获得最新期刊的摘要信息获得最新期刊的摘要信息。通过对前言信息的解读，可以了解研究的热点；2、获得准确完整的引文信息获得准确完整的引文信息。为文献的回溯打好基础。3、得到试剂的理化性质和表征图谱。4、试剂供应商的信息，方便试剂的采购

8、。5、帮助把握课题的发展趋势帮助把握课题的发展趋势。6、进行结构查新进行结构查新.7、通过相似结构化合物的查询功能，为相似结构化合物的合成提通过相似结构化合物的查询功能，为相似结构化合物的合成提 供路线参考供路线参考。scifinder scholar用途用途-preparation of alkane-1. hydrogenation of alkenes2. reduction of alkyl halides3. coupling of alkyl halides with organometalic compounds绪论（绪论（2 2）-preparation of alkane-1

9、. hydrogenation of alkenescnh2nh2 + pt, pd, nicnh2n+2alkenealkane2. reduction of alkyl halides a) hydrolysis of grignard reagent.r-x + mg r-mgxr-hh2oexample:ch3ch2chch3brmgch3ch2chch3mgbrh2och3ch2chch3hsec-butyl bromidesec-butylmagnesium bromiden-butaneb) reduction by metal and acid.r-x + zn + h+ r-

10、h + zn+2 +x-example:ch3ch2chch3brch3ch2chch3hsec-butyl bromiden-butane zn + h+ 3. coupling of alkyl halides with organometalic compounds.r-xr-lilicuxr2-culimay be 1o,2o,3oalkyllithium lithiumdialkylcopperr-xshould be 1or rexample:ch3ch2cllicuich3ch2lich3ch2culich3ch2ch3(ch2)5ch2brethyl chlorideethyl

11、lithium lithiumdialkylcopern-heptyl bromidech3ch2ch2(ch2)5ch3n-nonane-preparation of alkene-1. dehydrohalogenation of alkyl halide2. dehydration of alcohols3. dehalogenation of vicinal dihalides4. reduction of alkynes-preparation of alkene-1. dehydrohalogenation of alkyl halidecchx+ kohalcoholcc+ kx

12、 + h2oease of dehydrohalogenayionof alkyl halides 3o2o1oexamples:ch3ch2ch2ch2clkoh(alcohol)ch3ch2hcch2n-butyl chloride1-butenech3ch2chclch3koh(alcohol)ch3ch2hcch2sec-butyl chloride1-butenech3hc chch32-butene80%20%2. dehydration of alcoholscchohcc+ h2oease of dehydrogenationof alcohols3o2o1oacidexamp

13、les:ch3ch2ch2ch2ohch3ch2hcch2n-butyl alcohol1-butenech3ch2chohch3ch3ch2hcch2sec-butyl alcohol1-butenech3hc chch32-buteneacidch3hc chch32-butenechief productacidchief product3. dehalogenation of vicinal dihalides ccxxcc+ znx2znexamples:ch3chbrchbrch32,3-dibromobutanech3hc chch32-butenezn4. reduction

14、of alkynesr c c rh2lindlar catalystna or li, nh3ccrrhhsynccrhhranti-preparation of alcohol-1. oxymercuration-demercuration2. hydroboration-oxidation3. grignard synthesis4. hydrolysis of alkyl halides5. hydroxylation of alkenes-preparation of alcohol-1. oxymercuration-demercurataionc chg(oac)2h2occoh

15、 hgoacnabh4ccoh hmercuric acetatemarkovnikovaddition2. hydroboration-oxidationc ccchbcchohanti-markovnikovaddition(bh3)2diboraneh2o2, oh -3. grignard synthesisc or mgx+cromgxcrohh2o4. hydrolysis of alkyl halidesrx+oh-(or h2o)roh+ x - (or hx)examples:ch2clnaohh2och2ohbenzyl chloridebenzyl alcoholcch3

16、h3cch3clh2o/h+cch3h3cch3oh5. hydroxylation of alkenesc ckmno4or hio4rco2ohccoh ohocch2o,h+ccohohsyn-hydroxylationanti-hydroxylation6. aldol condensation7. reduction of carbonyl compounds8. reduction of acid and esters-preparation of halide-1. from alcohols2. halogenation of certain hydrocarbons3. ad

17、dition of hydrogen halide to alkenes4. addition of halogen to alkenes and alkynes5. halide exchange-preparation of halide-1. from alcoholsrohrxhx or px3examples:ch3ch2ch2ohcon. hbr ornabr, h2so4 heatch3ch2ch2brn-propyl alcoholn-propyl bromidechch3ohpbr3chch3br1-phenylethanol1-bromo-1-phenylethanech3

18、ch2ohp, i2ch3ch2iethyl alcoholethyl iodide2. halogenation of certain hydrocarbonsrhrxx2examples:ch3br2hvch2brtoluenebenzyl bromidecch3ch3ch3ch3cl2hvcch3ch3ch3ch2clneopentaneneopentyl chloride3. addition of hydrogen halide to alkenesc cc chxhx4. addition of halogen to alkenes and alkynesc cc cxxx2c c

19、c cxxxxx25. halide exchangerxi-riacetone+-preparation of ether-1. williamson synthesis2. alkoxymercuration-demercuration-preparation of ether-1. williamson synthesisrx+ro-na+ oraro-na+rororroaryield from rx:ch31o2o(3o)examples:(ch3)2cho-na+ch3ch2ch2brch3ch2ch2och2(ch2)2ch3sodiumisopropoxiden-propylb

20、romideisopropyl n-propyl etheroh +ch3ch2braq. naohoch2ch3phenolethyl bromideethyl phenyl ether2. alkoxymercuration-demercurationc c+ rohc crohgo2ccf3hg(o2ccf3)2c croh+nabh4alkenemercurictrifluoroacetatemarkovnikovorientation-preparation of alkylbenzene-1. friedel-crafts alkylation2. conversion of si

21、de chain-preparation of alkylbenzene-1. friedel-crafts alkylation+rxlewis acidr+ hxr may rearrangelewis acid: alcl3, bf3, hf, etc.arx cannot be used in place of rxch3chch2ch3clch3ch2ch2ch2clexamples:+alcl3cch3ch2ch3ch2ch2ch2ch3chief product2. conversion of side chainrozn(hg)n, hclor n2h4, basech2rcl

22、emmensen or wolff-kishner reactoinchchrch2ch2rh2 /cat-preparation of phenol-1. hydrolysis of diazonium salts2. alkli fusion of sulfonates-preparation of phenol-1. hydrolysis of diazonium saltsarn2+h2oaroh+n2h+example:n2+ hso4-clcloh+n2h2o, h+, heatm-chlorobenzenediazonium hydrogen sulfatem-chlorophe

23、nol2. alkali fusion of sulfonatesso3nanaoh, h2o300oco-na+dil. h2so4oh sodium2-naphthalenesulfonate sodium2-naphthoxide2-naphthol-preparation of amine-1. reduction of nitro compounds2. reaction of halides with ammonia or amines3. reductive amination4. reduction of nitriles5. hofmann degradation of am

24、ides-preparation of amine-1. reduction of nitro compoundsarno2rno2ormetal,h+or h2, cat.arnh2rnh2or chiefly for aromatic aminenitro compounds1o amineexamples:co2c2h5no2pt, h2co2c2h5nh2ethyl p-nitrobenzoateethyl p-aminobenzoatech3ch2ch2no2ch3ch2ch2nh2fe,hcl1-nitropropanen-propylamine2. reaction of hal

25、ides with ammonia or aminesnh3rxrnh2rxrnhrrxrnrrrxrnrrr xrx must be alkyl or aryl with electron-withdraawing substituentsch3ch2clch3ch2nh2ch3ch2n ch3hnh3ch3clexamples:ethyl chlorideethyl amineethylmethylaminech2clch2nh2ch2nch3ch3nh32ch3ibenzyl chloridebenzyl aminebenzyldimethylaminen(ch3)2n(ch3)3ich

26、3in,n-dimethylanilinephenyltrimethylammonium iodideclno2no2no2no2nhch3ch3nh22,4-dinitrochlorobenzenen-methyl-2,4-dinitroaniline3. reductive aminationc o+ nh3rnh2r2nh2+h2, nior nabh3cnchnh2h2, nior nabh3cnh2, nior nabh3cnchnhrchnhr1o amine2o amine3o amineexamples:c och3ch3+ nh3h2, nichnh2ch3ch3aceton

27、eisopropylamine1o amine(ch3)2chcho+nh2nhch2ch(ch3)2nabh3cnisobutylaldehydeanilinen-isobutylaniline2o aminech3c oh(ch3)2nh+h2, nich3ch2n ch3ch3acetaldehydedimethylaminedimethylethylamine3o amine4. reduction of nitrilesrc n2h2, cat.rch2nh2examples:ch2clnacnch2cnch2ch2nh2h2, ni, 140ocbenzyl chlorideben

28、zylnitrile2-phenylethylamineclch2(ch2)2ch2clnc(ch2)4cnh2nch2(ch2)4ch2nh2nacnh2, ni 1,4-dichlorobutaneadiponitrilehexamethylenediamine(1,6-diaminohexane)5. hofmann degradation of amidesrconh2arconh2obr -rnh2arnh2+ co32_1o amineexamples:ch3(ch2)4conh2kobrch3(ch2)4nh2caproamide(hexanamide)n-pentylamine

29、1o amineconh2brnh2brkobrm-bromobenzamidem-bromoaniline1o amine-reaction of diazonium-1. replacement of nitrogen2. coupling-reaction of diazonium-1. replacement of nitrogenarn2+ z:-arz+n2a) replacement by -cl, -br, -cnarn2+arx +n2cuxexamples:ch3nh2ch3n2+hso4-ch3n2+cl-nano2nano2ch3n2+cl-hclnano2hclh2s

30、o4cuclcubrcucnch3clch3brch3cno-toluidineo-methylanilineo-aminotolueneo-toluenediazonium chlorideo-chlorotolueneo-bromotolueneo-tolunitrileo-cyanotolueneb) replacement by -iarn2+ari +n2kinh2n2+hso4-nano2h2so4kiiexamples:anilineiodobenzenec) replacement by -farn2+bf4-arf +n2heat+bf3examples:nh2n2+cl-n

31、ano2hcln2+bf4-benzenediazonium chloridehbf4fheat+n2+bf3benzenediazonium fluoroboratefluorobenzened) replacement by -oharn2+aroh+n2+h2oh+nh2ch3n2+hso4-ch3nano2h2so4h2o,h+ohch3examples:heato-toluidineo-cresole) replacement by -harn2+aroh+n2+h3po2h2o+h3po3examples:clclnh2hno3h2so4clcln2+hso4-h3po2clcl2

32、,4-dichloroanilinem-dichlorobenzene2. couplingarn2+x-+garn=ngg must be strongly electron-releasinggroup:oh,nr2,nh2,nh2example:n2+cl-+ohn=nohbenzenediazonium chloridep-hydroxyazabenzenep-(phenylazo)phenol-preparation of aldehyde & ketone-1. oxidation of alcohols2. oxidation of methylbenzene3. red

33、uction of acid chloride4. friedel-crafts acylation-preparation of aldehyde & ketone-cr ooocln+h cro3与吡啶生成的络合物与吡啶生成的络合物(sarretty试剂试剂)能迅能迅速将伯醇、仲醇氧化成醛、酮，产率好，而且往往不影响碳碳双键。速将伯醇、仲醇氧化成醛、酮，产率好，而且往往不影响碳碳双键。 ncroooch3(ch2)6ch2ohcro3,1h, 95%ch3(ch2)6chophch=chch2ohcro3,81%phch=chcho吡啶吡啶,rt吡啶吡啶,rtjones试剂（试剂（

34、cro3)溶于溶于h2so4，可使不饱和的仲醇氧化成相应的酮，烯，可使不饱和的仲醇氧化成相应的酮，烯键不受影响。键不受影响。hocro3/ h2so4ch3coch3o新制二氧化锰也是一种选择性氧化剂新制二氧化锰也是一种选择性氧化剂，能氧化与烯丙基或苄基相连的，能氧化与烯丙基或苄基相连的oh生成醛生成醛酮，对酮，对碳上的键无影响碳上的键无影响ch2=chch2ohmno2ch2=chcho ch2oh +mno2石油醚石油醚2. oxidation of methylbenzenearch3cl2, heatcro3/ac2oarchcl2arch(oocch3)2h2oarchoexampl

35、es:cl2,heat, hvbrch3brchcl2h2obrchop-bromotoluenep-bromobenzaldehydech3no2ch(oac)2no2h2ochono2cro3/ac2op-nitrotoluenep-nitrobenzaldehyde3. reduction of acid chloridercocl or ar cocllih(obun)3rcho or archoexample:coclno2lih(obun)3chono2examples:n c5h11cocl+n c5h11coalcl3caproyl chloriden-pentyl pheny

36、l ketone+alcl3cococlbenzoyl chloridebenzophenone(diphenyl ketone)4.-reactions of aldehyde & ketone-1. oxidation2. reduction3. addition of cyanide4. addition derivatives of ammonia5. addition of alcohols6. cannizzaro reaction7. addition of grignard reagent-reactions of aldehyde & ketone-1. ox

37、idationa) aldehydesrchoarchoorag(nh3)2+kmno4k2cr2o7rcooharcoohorused chieflyfor detectionof aldehydeexample:ch3cho+2 ag(nh3)2+ 3oh-ch3coo-2ag + 4nh4 + 2h2o+tollens testfor ketone:co ch3seo269-72%occhooseo260%oobaeyer-villiger reaction (cf3co3h or ch3co3h)o2n coch3co3ho co2no95%b) methyl ketonesrc ch

38、3oarc ch3oox-rc cx3oarc cx3oh2orc o-oarc o-ohaloformreactionexamples:c2h5c ch3o+ 3oi-c2h5c o-o+chi3 + 2 oh-iodoformc=c c ch3och3ch3koclh2so4c=c c ohoch3ch34-methyl-3-penten-2-one3-methyl-2-butenoic acid2. reductiona) reduction to alcoholsc oh2/ ni,pt,pdlialh4 or nabh4, then h+c ohhexamples:oh2, niho

39、hcyclopentanonecyclopentanolc ch3olialh4c ch3ohhacetophenonea-phenylethyl alcoholnote1:lialh4和和nabh4属负氢离子还原剂，主要发生亲核反应，对属负氢离子还原剂，主要发生亲核反应，对c=o，c=n，s=o，n=o等极性双键进行进攻，而对极性较小的等极性双键进行进攻，而对极性较小的c=c则一般不发生反应，因则一般不发生反应，因而具有一定选择还原能力。而具有一定选择还原能力。特点：条件温和，反应速度快，产率高，选择性好。特点：条件温和，反应速度快，产率高，选择性好。lialh4还原能力强，选择性较好。能还

40、原醛酮，羧酸，酯，酰胺，肟，腈，还原能力强，选择性较好。能还原醛酮，羧酸，酯，酰胺，肟，腈，卤代烃，硝基化合物等；在还原卤代烃，硝基化合物等；在还原,-不饱和醛酮时，一般不影响碳碳双键。不饱和醛酮时，一般不影响碳碳双键。nabh4-是一种缓和的还原剂，一般只能使醛、酮、酰氯还原成醇，有时可还是一种缓和的还原剂，一般只能使醛、酮、酰氯还原成醇，有时可还原成酸酐。但不还原羧酸、酯、酰胺、腈及硝基化合物等。如：原成酸酐。但不还原羧酸、酯、酰胺、腈及硝基化合物等。如：ch3coch2ch2ch2no2nabh4ch3oh,h2och3chch2ch2ch2no2oh87%cooch3onabh4ch3

41、oh,h2o hcohoh2ch3+hco2ch3hohb) reduction to hydrocarbonsc oc hhzn(hg), conc. hcln2h4, baseclemmensen reductionfor compounds sensitive to basewolff-kishner reductionfor compounds sensitive to acidexamples:ch3ch2ch2coclalcl3zn(hg), conc. hclcch2ch2ch3och2ch2ch2ch3n-butyrophenonen-butylbenzeneohhcyclop

42、entanonecyclopentanen2h4, basenhch3coch3etoocch3nh2nh2-h2onaoet/etohnhch3ch2ch3etoocch3165170oc wolff-kishner reductionrcro+1h2nnh2rcrnnh21+ h2oohrcrnnhrcr1 hnnrcr1 h + n2rcr1h21 conditionssemicarbazonenaoet or other strong base, 200, sealed tube.naoh or koh, hydrazine hydrate and carbonyl compound,

43、 diethylene glycol, 180200, reflux.hydrazone , kobut , dmso , room temperature c) reduction with borane and dialkylboranesnabh4, a nucleophile, adds to the more positive end of a polarized multiple bond. bh3, a lewis acid, attacks electron-rich centers. reductions of borane do not simply parallel th

44、ose with nabh4. cococochobh2bh4-bh3bh3cloclonabh4bh3chohh+-no reaction+electron-withdrawing effectsimilarly esters are reduced slowly by borane 9-borabicyclo3,3,1nonane (9-bbn) it is highly selective for reduction of ,-unsaturated carbonyl compounds to allylic alcohols. nitro and ester groups react

45、only slowly. bh9-bbnoch3(c5h11)2bhohhch3cisoch3b2h6hohch3transoch3)2bhohhch3cis ,94%of product,optically active example:3. addition of cyanidec o+ cn-cohcncyanohydrinexamples:c ohnacnnahso4c cnhohh2oh2so4c coohhohbenzaldehydemandelonitrilemandelic acidch3c och3nacnnahso4ch3c cnch3ohh2oh2so4ch3c cooh

46、ch3ohch2c coohch3acetonecyanohydrinmethacrylic acid4. addition derivatives of ammoniac o+nh2gc n gused for identificaiton5. addition of alcoholsc o+ 2rohcororh+example:ch3c=oh+ 2 ch3ch2ohh+ch3choch2ch3och2ch3ch2cch3o+ hoch2ch2ohp-ch3c6h4so3hc6h6 ch2cch3oo在有机合成中利用此性质保护羰基在有机合成中利用此性质保护羰基( (官能团的保护官能团的保护

47、) )ch2=ch-choch2chchoohoh实例6. cannizzaro reactionc=oh2strong basecoo-ch2oh+example:h c=oh2+50% naohch3ohhcoo-chocl50% naohcoo-cl+ch2ohclchooch3och3+ch2o50% naohch2ohoch3och3hcoo-7. addition of grignard reactionrmgxc=ohhc=ohrc=orrrc ohhhrc ohhrrc ohrr1o2o3o8. others-reaction of carbanion-1. halogenat

48、ion of ketones2. nucleophilic additon to carbonyl compounds3.claisen and dieckmann condensation reactions1. halogenation of ketonesc coh+x2h+ or oh-c coxx2=cl2, br2, i2ketonea-halo ketoneexamples:oh+ br2h+obrhbr+cyclohexanone2-bromocyclohexanonecch3ch3ch3c ch3oi2, oh-cch3ch3ch3c ci3occh3ch3ch3c coo-

49、ooh-tert-butyl methyl ketonetrimethylacetate iron-reaction of carbanion-2. nucleophilic addition to carbonyl compoundsa) aldol condensationco+c c ohbase or acidcohc c oaldolch2choh-oh-ch2choch2=cho-ch3cohch3ch=ch chooh-, h2o机理机理examples:ch3c=oh+ch2c=ohhh+ch3c ch2c=ohhohnahso4heatch3c=c c=ohhhacetald

50、ehyde3-hydroxybutanal2-butenalch3c=och3+ch2c=och3hh+ch3c ch2c=och3ch3ohnahso4heatch3c=c c=och3hh3cacetone4-hydroxy-4-methyl-2-pentanone4-methyl-3-penten-2-onec=ohch2cch3oh+chchcch3obenzalacetoneclaisen-schmidt condensation reactionsc6h5cho +ch3coch3naohc6h5ch=chcoch3 77%cho+ch2coch3 ch=c coch3b) wittig reactionco+ph3p=c rrc=crrylideph3p=o+oph3p=ch2+ch2+ ph3p=oexamples:methylenecyclohexanemethylenetriphenylphosphoranec)knoevenagel reactiond)benzoin condensation reactione) the mannich reactionthe mannich reactionthe mannich reactionf)darzens reactionclc