官能團化學課件

1、第二章 官能團化學：基礎Chapter 2 Functional group chemistry：the basics2015-10-18Main Content2.1 Selectivity of organic reactions2.2 Functionalization of alkanes2.3 Functionalization of alkenes2.4 Functionalization of alkynes2.5 Functionalization of aromatic hydrocarbons2.6 Functionalization of benzene derivati

2、ves2.7 Functionalization of simple heterocyclics2.8 Interconversion of functional group第二章 官能團化學：基礎主要內(nèi)容2.1 有機反應的選擇性2.2 烷烴的官能團化2.3 烯烴的官能團化2.4 炔烴的官能團化2.5 芳烴的官能團化2.6 取代苯基衍生物的官能團化2.7 簡單雜環(huán)化合物的官能團化2.8 官能團的相互轉化2.1有機反應的選擇性復習：已放在第一章緒論中總結！ 2.1.1區(qū)域選擇性和區(qū)域特異性2.1.2立體化學選擇性和立體化學特異性2.2 烷烴的官能團化Example 厄洛替尼(Erlotinib)

3、中間體的合成厄洛替尼，它塞瓦(Tarceva)羅氏、基因技術及OSI制藥公司（2007）Iodination ：Text book（2015）：p32Example: 洛索洛芬鈉(Sodium Loxoprofen) 中間體的合成2-(4-(bromomethyl)phenyl)propanoic acid2-(4-(chloromethyl)phenyl)propanoic acidExample: 羅非昔布 (Rofecoxib)中間體的合成2-bromo-1-(4-(methylsulfonyl)phenyl)ethanoneAlias：諾菲呋酮 ：型環(huán)氧化酶(COX-2)抑制劑，用于緩

4、解骨關節(jié)炎癥狀。萬絡、Vioxx (162011-90-7)NSAID： MERCK公司Example: 考尼伐坦(Conivaptan)中間體合成新型溴代試劑的應用：pyridinium hydrobromide perbromide 日本安斯泰來制藥公司開，精氨酸加壓素(AVP)拮抗藥，能阻斷AVP引起的排尿增多，不丟失電解質(Na+、K+)。2005首次美國上市，商品名為Vaprisol，血容量正常的低鈉血癥住院患者的治療。2.3烯烴的官能團化Examples羅格列酮 (Rosiglitazone) 直線式合成最后一步吡格列酮 (Pioglitazone) 直線式合成最后一步Exampl

5、e非典型安定藥利培酮(Risperidone)中間體的合成6,7,8,9-tetrahydro-3-(2-hydroxyethyl)-2-methylpyrido1,2-apyrimidin-4-oneJanssen: Risperdal (1993) Example美容藥：非那甾胺 (Finasteride)中間體的合成(4aR,4bS,6aS,7S,9aS,9bS,11aR)-hexadecahydro-4a,6a-dimethyl-2-oxo-1H-indeno5,4-fquinoline-7-carboxylic acidMerk: Propecia (1997)Example吡格列酮

6、 (Pioglitazone)中間體的合成2-bromo-1-(5-ethylpyridin-2-yl)ethanol日本武田公司：名瑞彤、安可拓 (1999) 2.4 炔烴的官能團化Example美容藥：他扎羅汀(Tazarotene)的合成Nigishi 偶聯(lián)反應Allergan: Tazorac (1996)Example非鎮(zhèn)靜抗組胺藥：非索非那定(Tazarotene)中間體的合成Sohogshira 偶聯(lián)反應Zyrtec: Allegra (1996)特非那定：Seldene 的主要代謝物methyl 3-(4-(4-hydroxybut-1-ynyl)phenyl)-3-methy

7、lbutanoate2.5芳烴的官能團化2.5.1環(huán)位取代FC：Example安定藥: 利培酮(Risperidone)中間體的合成Janssen: Risperdal (1993) Review：FCA-FCC付克烷基化反應與付克?；磻磻獥l件類似，皆是鹵代物在強路易斯酸催化條件下與芳環(huán)反應。1）付克烷基化反應由于烷基側鏈的供電性，反應產(chǎn)物比起原料具有更高親核性，產(chǎn)物會繼續(xù)被烷基所取代，導致過烷基化而形成眾多副產(chǎn)物。而?；磻捎隰驶奈娮有挠绊懀ㄢg化基團），反應產(chǎn)物（酮）通常不會像烷基化產(chǎn)物一樣繼續(xù)多重?；?）如果鹵素原子不是處于三級碳原子（叔碳原子）上，有可能發(fā)生碳正離子重排反

8、應。付克酰化反應該反應不存在碳正離子重排。 3）？3）FCA-FCC特例選擇性B 型單胺氧化酶(MAO-B)抑制劑，用于治療帕金森病。以N-Fmoc-D-丙氨酸為手性源，經(jīng)過Friedel-Crafts ?；?、脫保護和還原反應得(R)-甲基苯乙胺。 司來吉蘭(selegiline)中間體的合成Synthesis of chiral selegiline with via resolution from d-tartaric acidSynthesis of selegiline with YeastChiral centerExample抗腫瘤藥: 貝沙羅汀(Bexarotene)中間體的合

9、成Ligand：Targretin (2000)Example抗心律失常藥: 鹽酸決奈達隆中間體的合成(Dronedarone Hydrochloride)2-(bromomethyl)-4-nitrophenol2-bromo(iodo)-4-nitrophenol2.5.2 側鏈上的反應芐位對自發(fā)氧化敏感，由異丙基苯合成苯酚和丙酮具有商業(yè)價值。 芐位鹵化一般是自由基歷程，常用分子氯或溴！Example-1: 洛索洛芬鈉(Sodium Loxoprofen) 的中間體的合成2-(4-(bromomethyl)phenyl)propanoic acid2-(4-(chloromethyl)ph

10、enyl)propanoic acid2.6取代苯衍生物的官能團化表2.1 取代苯親電取代反應的定位和速率取代基親電取代的定位相對于苯的取代速率烷基或芳基鄰對位快羥基，烷氧基鄰對位快氨基，單烷基胺基，二烷基胺基鄰對位快鹵素鄰對位類似 或 慢羰基間位慢氰基間位慢硝基間位慢磺酸基間位慢三氟甲基間位慢Review and focus取代苯親電取代反應的定位和速率Orientation and rate of electrophilic substitution of substituted benzenesSubstituentOrientation of electrophilic substit

11、utionRate of substitution relative to that of benzeneAlkyl or aryl o, p-鄰對位 Faster OH, ORo, p-鄰對位 Faster NH2,NHR,NR2o, p-鄰對位 FasterHalogeno, p-鄰對位 Similar or slower C=Om-間位Slower-C=Nm-間位Slower-NO2m-間位Slower-SO3Hm-間位Slower-CF3m-間位SlowerExample：單取代基的定位上述反應用稀硝酸則發(fā)生單硝化，表明苯酚比苯活潑得多。上述反應不需要路易斯酸催化，且不能停留在一元或二

12、元溴代的階段。 苯環(huán)的單溴代單溴代可通過從乙酰苯胺的路徑來實施：Example：單取代基的定位降血脂藥: 氟伐他汀(Fluvastatin)中間體的合成瑞士諾華公司(Novartis)公司：Lescol (1994)HMG-CoA還原酶抑制劑。阻止膽固醇的生物合成。2-chloro-1-(4-fluorophenyl)ethanone活潑底物更容易發(fā)生酰基化反應！Example：單取代基的定位降血脂藥: 匹伐他汀(Pitavastatin)中間體的合成Kowa, Nissan chemical和三共：Livalo (1998)HMG-CoA還原酶抑制劑：阻止膽固醇生物合成。(2-aminoph

13、enyl)(4-fluorophenyl)methanoneExample：單取代基的定位組胺H1受體拮抗劑: 非索非那定(Fexofenadine)中間體的合成。德國Hoechest Marion Roussel 公司：Allegra 美國首次上市(1996)季節(jié)性過敏性鼻炎和慢性特發(fā)性蕁麻疹。ethyl 2-(4-(4-chlorobutanoyl)phenyl)-2-methylpropanoate活潑底物更容易發(fā)生?；磻?！Example：雙取代基的定位該反應需要更劇烈的條件，因為兩個取代基都使硝化難以進行。定位是由鄰/對位定位的氯所支配。Example：雙取代基的定位抗精神分裂藥:

14、 利培酮(Risperidone) 中間體合成比利時Janssen公司：Spiron (1993 Canada)Apexidone, Psychodal利用二氟取代定位效應和F-C反應構建4-二氟苯甲?；?N-乙酰哌啶基側鏈Example：雙取代基的定位改變原料合成利培酮中間體，同樣還是利用二氟取代定位效應和F-C反應構建替代側鏈。Review: Example：雙取代基的定位Reverse transcriptase inhibitor efavirenz 抗病毒藥: 依法韋恩茨(Efavirenz) (EFV)中間體的合成美國默克(Merk)公司：施貴寶 薩斯迪瓦Sustiva(1998)

15、施多寧 StocrinExample：雙取代基的定位抗病毒藥: 依法韋恩茨(Efavirenz)中間體的合成1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone酰胺定位鄰位金屬化反應淬滅三甲基乙酰胺酮原位水解水合物鹽酸鹽Analytica Chimica Acta 589 (2007) 142149Example：多取代基的定位抗心絞痛藥: 伊伐布雷定(Ivabradine)中間體的合成法國施維亞(Servier)公司：Procoralan (2005)2-bromo-4,5-dimethoxybenzaldehyde自由基取代反應的定位在自由基

16、取代反應中，定位效應很不顯著，常常預期形成所有的三種異構體。例如：單取因此，藥物合成中應該盡量避免利用自由基取代反應的定位效應，進行控制Nucleophilic substitutionNS is accelerated by electron-withdrawing substituents.Eg. NO2, N-O, etc. However, a leaving group such as halogen is also required.2.7 Functionalization of simple heterocyclic compounds吡啶的親電取代吡啶是一個弱堿，具有相當程度

17、的芳香性。例如，它與碘甲烷反應生成季銨鹽，加熱時，季銨鹽重排為碘化2-和4-甲基吡啶。分子軌道計算指出，C-3是電子密度最高的碳原子，但即使是這個位置的電子密度也比苯上的要低得多。因此，親電取代需要強烈的條件。2.7簡單雜環(huán)化合物的官能團化吡啶環(huán)的親電取代反應吡啶與哌啶的轉化哌啶由吡啶經(jīng)氫化而制得 (50 Refrerences, 30 Conditions)。From 2-chloro-pyridine to piperidine1) Sodium, ethanol2) SmI2，溶劑：tetrahydrofuran，H2O反應時間：23 min, Yield：92 %, Ambient t

18、emperature 易制毒R=COOH，noExample：取代吡啶的反應抗精神分裂藥: 利培酮(Risperidone)中間體1-acetylpiperidine-4-carboxylic acid 的合成比利時Janssen公司：Spiron (1993 Canada)1-acetylpiperidine-4-carboxylic acidIso-nicotinic acid自由基反應自由基型苯基化反應導致生成所有三種單苯基吡啶的混和物。產(chǎn)物復雜，在合成中的應用有限。除非其他位置被占據(jù)，則可用。Example：吡啶環(huán)氯代、酰氯化反應Braf激酶制劑: 索拉非尼(sorafenib)中間體

19、的合成。德國Bayer 公司：Nexavar、美國FDA批準上市(2005)，中國 (2009).治療癌癥等疾病。Example：吡啶環(huán)上的氯代反應Braf激酶制劑: 索拉非尼(sorafenib)中間體的合成。德國Bayer 公司：Nexavar、美國FDA批準上市(2005)，中國 (2009).治療癌癥等疾病。Example：吡啶環(huán)外側鏈的氯代反應質子泵抑制劑：埃索美拉唑鈉 (Esomeprazole sodium)中間體的合成。瑞典AstraZeneca 公司：奧美拉唑光學異構體、FDA批準上市(1999).治療胃潰瘍，十二指腸潰瘍，消化性食管炎以及胃炎。吡啶環(huán)的親核取代反應非取代吡啶

20、親核取代位置主要在2-位。取代吡啶親核取代反應在特定的位置。Example：吡啶環(huán)上的醚化反應Braf激酶制劑: 索拉非尼(sorafenib)中間體的合成。德國Bayer 公司：Nexavar、美國FDA批準上市(2005)，中國 (2009).治療癌癥等疾病。吡啶N-氧化物的反應Example：吡啶N-氧化物的反應凝血酶抑制劑: 達比加群酯(Dabigatran etexilate )中間體的合成。德國Boehringer Ingelheim 公司：Pradaxa德、英國首次上市(2008)阻斷凝血瀑布網(wǎng)絡的最后步驟及血栓形成。補充：六氫吡啶的N-烷基化組胺H1受體拮抗劑: 非索非那定(F

21、exofenadine)中間體的合成。德國Hoechest Marion Roussel 公司：Allegra 美國首次上市(1996)季節(jié)性過敏性鼻炎和慢性特發(fā)性蕁麻疹。ethyl 2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoate，酯水解之后得終產(chǎn)物。補充：四氫吡啶的N-烷基化抗血小板聚集藥：硫酸氫氯比格雷中間體的合成。法國Sanofi-Aventi公司 (1998,美國) 選擇性阻斷ADP與血小板受體的結合。動脈粥樣硬化，極性冠狀動脈綜合癥。補充：嘧啶環(huán)的N

22、-烷基化核苷類HIV-1逆轉錄酶抑制劑: 恩曲他濱(Emtricitabine)中間體的合成。美國Gilead Sciences 公司：FDA上市(2003)與齊多夫定合用治療HIV-1感染。(5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolan-2-yl)methyl butyrate補充：嘧啶并咪唑環(huán)的甲基化新型抗帕金森病藥物：Istradefylline 的合成，注冊前階段新藥。日本 Kyowa Hakko Kogyo 株式會社。選擇性腺苷A2a受體拮抗劑。Istradefylline補充：氨基取代嘧啶的反應新型抗帕金森病

23、藥物：Istradefylline的合成，注冊前階段新藥。日本 Kyowa Hakko Kogyo 株式會社。選擇性腺苷A2a受體拮抗劑。堿性條件下環(huán)合后甲基化可得 IstradefyllineOther heterocyclics與吡啶相反，呋喃、吡咯和噻吩是富電子分子，它們與親電試劑起反應主要在2-和5-位?？墒窃谒嵝詶l件下，呋喃發(fā)生聚合，而吡咯發(fā)生聚合的程度較低。呋喃、吡咯和噻吩直接鹵化通常導致多鹵代產(chǎn)物的生成。吡咯的反應總結Example：取代吡咯的甲酰化抗腫瘤藥: 舒尼替尼(Sunitinib)中間體的合成美國輝瑞公司(Pfizer)公司：Sutent (2006)多靶點酪氨酸激酶抑

24、制劑。ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylateExample：苯并吡咯的N-甲基化降血脂藥: 氟伐他汀(Fluvastatin)中間體的合成瑞士諾華 (Novartis)公司：Lescol (1994)HMG-CoA還原酶抑制劑。阻止膽固醇的生物合成。ethyl 3-(4-fluorophenyl)-1-methyl-1H-indole-2-carboxylateExample：苯并吡咯3-?；?N-磺?；挂钟羲?鹽酸維拉唑酮 (Vilazodone hydrochloride) 中間體的合成。Trovis Pharma LL

25、C 公司：Viibryd， FDA (2011)治療成年人重度抑郁癥。?；螅酋；?，再經(jīng)硅烷還原成烷基。Example：四氫吡咯的N-甲基化選擇性雌激素受體調(diào)節(jié)劑: 酒石酸拉索昔芬(Lasofoxifene Tartrate)中間體的合成美國輝瑞 (Pfizer)公司：Fablyn (2009歐洲)治療婦女絕經(jīng)后骨質疏松癥。1-(2-(4-bromophenoxy)ethyl)pyrrolidineExample：哌啶并四氫吡咯N-烷基化喹諾酮類抗菌藥: 莫西沙星(Moxifloxacin)中間體的合成。德國拜耳(Bayer)公司：德、美上市 (1999)。ethyl 1-cyclo

26、propyl-6,8-difluoro-1,4-dihydro-7-(4aS,7aS)-octa hydropyrrolo 3,4-bpyridin-6-yl)-4-oxoquinoline-3-carboxylate采用甲醇鈉和DMSO將8-F替換為甲氧基后即為莫西沙星。Example：咪唑環(huán)的N-甲基化降壓藥：氯沙坦 (Losartan)中間體的合成。美國Bristol-Mayers-Squibb公司 (1994,瑞士) 非肽類血管緊張素II受體拮抗劑。Example：苯并咪唑環(huán)的N-甲基化抗腫瘤藥：帕唑帕尼 (Pazopanib)中間體的合成。英國Glaxo Smith Kline: (

27、2009,10) 。第二代多靶點酪氨酸激酶抑制劑。呋喃的反應總結噻吩的反應總結Example：3-溴噻吩的反應抗血小板聚集藥：硫酸氫氯比格雷中間體的合成。法國Sanofi-Aventi公司 (1998,美國) 選擇性阻斷ADP與血小板受體的結合。動脈粥樣硬化，極性冠狀動脈綜合癥。Example： 2-溴噻唑的反應抗腫瘤新藥：達沙替尼(Dastinib)中間體的合成。美國百時美施貴寶,別名Sprycel撲瑞賽, (2006,美國FDA)?？诜嘀乩野彼峒っ敢种苿?。2-chloro-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamideExample：

28、2-溴噻唑的反應抗腫瘤新藥：達沙替尼(Dastinib)中間體的合成。美國百時美施貴寶,別名Sprycel撲瑞賽, (2006,美國FDA)?？诜嘀乩野彼峒っ敢种苿-(4-methoxybenzyl)-2-(6-chloro-2-methylpyrimidin-4-ylamino) -N-(2-chloro-6-methylphenyl)thiazole-5-carboxamideExample：氨基噻唑的反應抗腫瘤新藥：達沙替尼(Dastinib)中間體的合成。美國百時美施貴寶,別名Sprycel撲瑞賽, (2006,美國FDA)。口服多重酪氨酸激酶抑制劑。2-(6-chloro-2-

29、methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide2.8 Interconversion of functional groupCertain functional groups are readily introduced in a specific manner whilst others are not.Why?In what kind of manner can we Interconvert functional groups without affecting the remain

30、der of the molecule?Main contents2.8.1 Transformation of hydroxyl group2.8.2 Transformation of amino group2.8.3 Transformation of halogeno compounds2.8.4 Transformation of nitro compounds2.8.5 Transformation of aldehydes and ketones2.8.6 Transformation of acid and its derivatives2.8.1Transformation

31、of hydroxyl group羥基的轉換Alcohols are weak bases, which are capable of reacting as nucleophiles. Reaction of alcohols with acid chlorides or anhydrides results in the formation of ester, which is promoted by a tertiary base.The alkoxide ion is a stronger nucleophile, which can react with alkyl halide,

32、sulfonates (磺酸酯) and sulfates to form ethers.However, elimination competes with substitution in reactions involving secondary and tertiary halides. From Alcohols to Alkyl Halides制氯代烷 alkyl halides : thionyl chloride for chlorides, 亞硫酰氯，制溴代烷 alkyl bromides: Constant boiling hydrobromic acid or phosph

33、orus tribromide, 恒沸氫溴酸或三溴化磷，制碘代烷 alkyl iodides: Iodine with red phosphorus for. 碘和紅磷。Mild conditions must be employed for the preparation of tertiary halides to prevent elimination taking place, e.g. t-butanol shaken with concentrated hydrochloric acid gives t-butyl chloride. Just shaking， OK!Exampl

34、e：吡啶環(huán)外醇羥基的氯代質子泵抑制劑: 埃索美拉唑鈉 (Esomeprazole Sodium) 中間體的合成。瑞典Astra Zeneca 公司：Nexium (耐信 )、美國FDA批準上市(1999).治療胃潰瘍、十二指腸潰瘍、消化性食管炎及胃炎。Contrast with the intermediates structure of Sorafenib. 4-position is occupied by methoxyl group, otherwise the 4-H will be substituted by chloride. Example 厄洛替尼(Erlotinib)中間

35、體的合成厄洛替尼，它塞瓦(Tarceva)羅氏、基因技術及OSI制藥公司（2007）Chlorination：Text book（2015）：p38 from compound 1-3-26 to compound 1-3-27Other similar reagent:POCl3 （ in the same page from compound 1-3-20 to compound 1-3-21 ）PCl5 , SOCl2 （ p34 and 39 from compound 1-3-7 to compound 1-3-8, etc. From alcohols to EsterReacti

36、on of alcohols with acid chlorides or anhydrides results in the formation of ester, which is promoted by a tertiary base.Example：醇轉化為酯抗血小板凝集藥: 鹽酸沙格雷酯(Sarpogrelate hydrochloride)中間體的合成。日本三菱化成株式會社：Anplag，日本首次上市(1993).治療改善慢行動脈閉塞癥引起的潰瘍、疼痛及冷感等缺血癥。Dehydration of alcohols to alkenesDehydration of alkohols

37、to form alkenes can be carried out using a wide variety of Brnsted and Lewis acid.With strong acid, acyclic alcohols appear to be dehydrated largely by El mechanism, perhaps with skeletal rearrangement of the intermediate carbocation. Some reagents, e.g. phosphorus oxychloride 三氯氧磷，are regarded as i

38、nducing dehydrations which are highly stereospecifically trans, consistent with an E2 mechanism. Pharmaceutical ApplicationSince E1 elimination may be less stereospecific than E2, choice of reagent may be an important factor in determining product distribution in dehydrationof alcohols. Notes: Attem

39、pted preparation of tertiary alcohols by, for example, the Grignard reaction often results in spotaneous dehydration to the alkene.應用：由Grignard制叔醇，常導致自發(fā)脫水。Alcohols to acetals醇除成酯，鹵代烷之外可以成縮醛，如：Alcohols add to 2,3-dihydropyran under acidic conditions to give mixed acetals, which are used to protect hy

40、droxyl groups. Other ReactionsThe reactions of alcohols with carbonyl and carbonyl and carboxyl groups are discussed later in 2.8.5 Transformation of aldehydes and ketones2.8.6 Transformation of acid and its derivativesAr-OH ? Transformation of PhenolsPhenols can be alkylated and acylated in ways si

41、milar to those used for alcohols. Aryl methyl ethers are often prepared by reaction of the phenol with diazomethane. 重氮甲烷The preparation of aryl halide from phenols is of little preparative significance. Example：酚轉化為雙芳醚Braf激酶制劑: 索拉非尼(Sorafenib)中間體的合成。德國Bayer 公司：Nexavar、美國FDA批準上市(2005)，中國 (2009).治療癌癥

42、等疾病。Text book（2015），p43-47 from compound 1-4-7 to 1-4-8Example：酚轉化為芳基脂肪醚抗血小板凝集藥: 鹽酸沙格雷酯(Sarpogrelate hydrochloride)中間體的合成。日本三菱化成株式會社：Anplag，日本首次上市(1993).治療改善慢行動脈閉塞癥引起的潰瘍、疼痛及冷感等缺血癥。2.8.2 Transformation of amino groupThe amino group is basic and reacts as a nucleophile with halides, giving rise to sec

43、ondary and tertiary amines and to quanternary ammonium salts. Acid chlorides and anhydride give amides. The sulfonamide derived from reaction of a primary amine with a sulfonyl chloride has an acidic hydrogen, which may be removed to produce a strongly nucleophilic species:磺酰胺含有一個酸性氫，該氫可失去而得到一個強的親核物

44、種： Reaction of aliphatic aminesFor aliphatic amines, reaction of a primary amine with “nitrous acid” is of little preparative significance due to the formation of a complex mixture of products, except in cases where elimination reactions cannot take place. How to ? 脂肪胺反應的優(yōu)化It has been shown that pri

45、mary aliphatic amines can be transformed into a wide variety of products by converting the amino group into a better leaving group such as 2,4,6-triphenylpyridine, which can be displaced by a range of nucleophiles.較好的離去基團2,4,6-三苯基吡啶被一系列親核試劑置換優(yōu)化：脂肪胺的溴代反應優(yōu)化：脂肪胺的乙酰酯化優(yōu)化：脂肪胺被其它官能團取代脂肪胺的反應N-亞硝基化合物亞硝酸N, N-

46、二取代肼仲胺芳伯胺與亞硝酸反應形成重氮鹽具有重要的意義；可發(fā)生各種轉換，具有制備的價值。2.8.3 Transformation of halogeno compoundsA halogen, in addition to providing a good leaving group, withdraws electrons from the adjacent carbon atom. Hence, alkyl halides participate in a wide variety of nucleophilic substitution reactions.Nucleophilic su

47、bstitution reactionsReaction with alcohols and with ammines have already been mentioned; Reaction with many kind of ions are all valuable:Thiolate anions, Cyanide ions, Anions derivative from alk-1-ynes Other carbanions Reaction with OH-:Alkyl halides may be hydrolysed using sodium hydroxide.Problem

48、 still exist, what ? Please think of it? Elimination: competitive reaction1. Elimination reactions may complicate the situation, especially in the case of secondary halides, and for many tertiary halide only elimination products are obtained. 2. In the last case, for most of the secondary and tertia

49、ry halides, elimination is a competitive reaction.對于許多三級鹵代烷的反應，僅得到消去產(chǎn)物.How to avoid this?Pharmaceutical application鹵代烷用氫氧化鈉水解成醇, 強堿、非極性溶劑和高溫條件利于消去。堿催化的二級和三級鹵代烷的消去反應遵守扎以柴夫規(guī)則。鹵代烷的金屬化反應Alkyl halides react with certain metals to form metal alkyls. Of particular synthetic importance are alkyl-lithium der

50、ivatives and Grignard reagents, RMgX.These reagents are both strong bases and good nucleophiles, their synthetic utility will be discussed in chapter 4. Summary for reaction of alkyl halidesSummaryReaction of Aryl halidesAryl halides are less reactive towards nucleophiles than alkyl halides, except

51、in cases where there are efficient electron-withdrawing substituents in positions ortho and/or para to the halogen. Also susceptible to nucleophilic attack are 2- and 4-halogenopyridines. Aryl halides form aryl-lithiums and Grignard reagents.2.8.4 Transformation of nitro compoundsAliphatic nitro com

52、pounds are of lesser synthetic importance than aromatic nitro compounds. However, a stable carbanion can be formed on the carbon adjacent to the nitro group and such carbanions can be used in many of the reactions described in chapter 3 and chapter 5. 硝基芳香化合物的生成與轉化Due to their ease of formation, ary

53、l nitro compounds are of great importance for introducing a nitrogen-containing function to the aromatic ring. Reduction with a wide variety of reagents causes conversion to the amino group.e.g.：Sn/HCl，Raney Ni/H2， Raney Ni/N2H4。Synthetic versatility of amino group has been discussed.Reduction to hy

54、droxylamines, azo compounds and N,N-di-substituted hydranzines is also possible. Summary The product is depending on the reagents chosen.2.8.5 Transformation of aldehydes and ketonesOxidation and reduction of these compounds and their reactions with carbon nucleophiles will be dealt with separately.

55、 Aldehydes and ketones react reversibly under acidic conditions with alcohols to give firstly hemi-acetals and hemi-ketals and then acetals and ketals:醛和酮與醇的作用是可逆的.酸性條件半縮酮縮酮半縮醛縮醛羰基轉變?yōu)閬喖谆鵗he analogous dithioketals are used in a conversion of carbonyl groups into methylene groups. The reaction require

56、s a large excess of Raney nickel. 二硫縮酮亞甲基羰基大大過量2.8.6 Transformation of acids and its derivativesCarboxylic acids are converted by acid catalysed reaction with alcohols into esters. For methyl ester another convenient method involves the use of diazomethane. For more complex esters, reaction of the a

57、lcohol with the acid chloride or with the anhydride may be more satisfactory. Another method involves the reaction of an alkyl halide with the silver salt of the carboxylic acid. Many of the procedures used for amide formation will also serve in esterification. Preparation and transformation of acid

58、 chloridesAcid chlorides are usually prepared by reaction of the acid with thionyl chloride. They converted into anhydrides by reaction with sodium salt of the acid. Reaction of acid chlorides with diazomethane results in the formation of diazoketones, Arndt-Eistert ReactionDiazoketones are converte

59、d by treatment with moist silver oxide into the carboxylic acids containing an additional methylene group. Arndt-Eistert Reaction采用潮濕氧化銀處理重氮酮, 變成多一個亞甲基的羧酸Preparation and transformation of AmidesAmides can be prepared by reaction of ammonia or the appropriate amine with anhydrides, esters or acid chl

60、orides. Alternative methods of amide formation, used widely in peptide syntheses. Primary amides can be dehydrated to nitrile, which can also be prepared by reaction of alkyl halide with potassium cyanide. A useful synthetic reaction of amides is their conversion into amines on treatment with bromin