官能团化学课件

1、第二章 官能团化学：基础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 官能团化学：基础主要内容2.1 有机反应的选择性2.2 烷烃的官能团化2.3 烯烃的官能团化2.4 炔烃的官能团化2.5 芳烃的官能团化2.6 取代苯基衍生物的官能团化2.7 简单杂环化合物的官能团化2.8 官能团的相互转化2.1有机反应的选择性复习：已放在第一章绪论中总结！ 2.1.1区域选择性和区域特异性2.1.2立体化学选择性和立体化学特异性2.2 烷烃的官能团化Example 厄洛替尼(Erlotinib)

3、中间体的合成厄洛替尼，它塞瓦(Tarceva)罗氏、基因技术及OSI制药公司（2007）Iodination ：Text book（2015）：p32Example: 洛索洛芬钠(Sodium Loxoprofen) 中间体的合成2-(4-(bromomethyl)phenyl)propanoic acid2-(4-(chloromethyl)phenyl)propanoic acidExample: 罗非昔布 (Rofecoxib)中间体的合成2-bromo-1-(4-(methylsulfonyl)phenyl)ethanoneAlias：诺菲呋酮 ：型环氧化酶(COX-2)抑制剂，用于缓

4、解骨关节炎症状。万络、Vioxx (162011-90-7)NSAID： MERCK公司Example: 考尼伐坦(Conivaptan)中间体合成新型溴代试剂的应用：pyridinium hydrobromide perbromide 日本安斯泰来制药公司开，精氨酸加压素(AVP)拮抗药，能阻断AVP引起的排尿增多，不丢失电解质(Na+、K+)。2005首次美国上市，商品名为Vaprisol，血容量正常的低钠血症住院患者的治疗。2.3烯烃的官能团化Examples罗格列酮 (Rosiglitazone) 直线式合成最后一步吡格列酮 (Pioglitazone) 直线式合成最后一步Exampl

5、e非典型安定药利培酮(Risperidone)中间体的合成6,7,8,9-tetrahydro-3-(2-hydroxyethyl)-2-methylpyrido1,2-apyrimidin-4-oneJanssen: Risperdal (1993) Example美容药：非那甾胺 (Finasteride)中间体的合成(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)中间体的合成2-bromo-1-(5-ethylpyridin-2-yl)ethanol日本武田公司：名瑞彤、安可拓 (1999) 2.4 炔烃的官能团化Example美容药：他扎罗汀(Tazarotene)的合成Nigishi 偶联反应Allergan: Tazorac (1996)Example非镇静抗组胺药：非索非那定(Tazarotene)中间体的合成Sohogshira 偶联反应Zyrtec: Allegra (1996)特非那定：Seldene 的主要代谢物methyl 3-(4-(4-hydroxybut-1-ynyl)phenyl)-3-methy

7、lbutanoate2.5芳烃的官能团化2.5.1环位取代FC：Example安定药: 利培酮(Risperidone)中间体的合成Janssen: Risperdal (1993) Review：FCA-FCC付克烷基化反应与付克酰化反应反应条件类似，皆是卤代物在强路易斯酸催化条件下与芳环反应。1）付克烷基化反应由于烷基侧链的供电性，反应产物比起原料具有更高亲核性，产物会继续被烷基所取代，导致过烷基化而形成众多副产物。而酰化反应由于羰基的吸电子效应的影响（钝化基团），反应产物（酮）通常不会像烷基化产物一样继续多重酰化。2）如果卤素原子不是处于三级碳原子（叔碳原子）上，有可能发生碳正离子重排反

8、应。付克酰化反应该反应不存在碳正离子重排。 3）？3）FCA-FCC特例选择性B 型单胺氧化酶(MAO-B)抑制剂，用于治疗帕金森病。以N-Fmoc-D-丙氨酸为手性源，经过Friedel-Crafts 酰基化、脱保护和还原反应得(R)-甲基苯乙胺。 司来吉兰(selegiline)中间体的合成Synthesis of chiral selegiline with via resolution from d-tartaric acidSynthesis of selegiline with YeastChiral centerExample抗肿瘤药: 贝沙罗汀(Bexarotene)中间体的合

9、成Ligand：Targretin (2000)Example抗心律失常药: 盐酸决奈达隆中间体的合成(Dronedarone Hydrochloride)2-(bromomethyl)-4-nitrophenol2-bromo(iodo)-4-nitrophenol2.5.2 侧链上的反应苄位对自发氧化敏感，由异丙基苯合成苯酚和丙酮具有商业价值。 苄位卤化一般是自由基历程，常用分子氯或溴！Example-1: 洛索洛芬钠(Sodium Loxoprofen) 的中间体的合成2-(4-(bromomethyl)phenyl)propanoic acid2-(4-(chloromethyl)ph

10、enyl)propanoic acid2.6取代苯衍生物的官能团化表2.1 取代苯亲电取代反应的定位和速率取代基亲电取代的定位相对于苯的取代速率烷基或芳基邻对位快羟基，烷氧基邻对位快氨基，单烷基胺基，二烷基胺基邻对位快卤素邻对位类似 或 慢羰基间位慢氰基间位慢硝基间位慢磺酸基间位慢三氟甲基间位慢Review and focus取代苯亲电取代反应的定位和速率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-邻对位 Faster OH, ORo, p-邻对位 Faster NH2,NHR,NR2o, p-邻对位 FasterHalogeno, p-邻对位 Similar or slower C=Om-间位Slower-C=Nm-间位Slower-NO2m-间位Slower-SO3Hm-间位Slower-CF3m-间位SlowerExample：单取代基的定位上述反应用稀硝酸则发生单硝化，表明苯酚比苯活泼得多。上述反应不需要路易斯酸催化，且不能停留在一元或二

12、元溴代的阶段。 苯环的单溴代单溴代可通过从乙酰苯胺的路径来实施：Example：单取代基的定位降血脂药: 氟伐他汀(Fluvastatin)中间体的合成瑞士诺华公司(Novartis)公司：Lescol (1994)HMG-CoA还原酶抑制剂。阻止胆固醇的生物合成。2-chloro-1-(4-fluorophenyl)ethanone活泼底物更容易发生酰基化反应！Example：单取代基的定位降血脂药: 匹伐他汀(Pitavastatin)中间体的合成Kowa, Nissan chemical和三共：Livalo (1998)HMG-CoA还原酶抑制剂：阻止胆固醇生物合成。(2-aminoph

13、enyl)(4-fluorophenyl)methanoneExample：单取代基的定位组胺H1受体拮抗剂: 非索非那定(Fexofenadine)中间体的合成。德国Hoechest Marion Roussel 公司：Allegra 美国首次上市(1996)季节性过敏性鼻炎和慢性特发性荨麻疹。ethyl 2-(4-(4-chlorobutanoyl)phenyl)-2-methylpropanoate活泼底物更容易发生酰基化反应！Example：双取代基的定位该反应需要更剧烈的条件，因为两个取代基都使硝化难以进行。定位是由邻/对位定位的氯所支配。Example：双取代基的定位抗精神分裂药:

14、 利培酮(Risperidone) 中间体合成比利时Janssen公司：Spiron (1993 Canada)Apexidone, Psychodal利用二氟取代定位效应和F-C反应构建4-二氟苯甲酰基-N-乙酰哌啶基侧链Example：双取代基的定位改变原料合成利培酮中间体，同样还是利用二氟取代定位效应和F-C反应构建替代侧链。Review: Example：双取代基的定位Reverse transcriptase inhibitor efavirenz 抗病毒药: 依法韦恩茨(Efavirenz) (EFV)中间体的合成美国默克(Merk)公司：施贵宝 萨斯迪瓦Sustiva(1998)

15、施多宁 StocrinExample：双取代基的定位抗病毒药: 依法韦恩茨(Efavirenz)中间体的合成1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone酰胺定位邻位金属化反应淬灭三甲基乙酰胺酮原位水解水合物盐酸盐Analytica Chimica Acta 589 (2007) 142149Example：多取代基的定位抗心绞痛药: 伊伐布雷定(Ivabradine)中间体的合成法国施维亚(Servier)公司：Procoralan (2005)2-bromo-4,5-dimethoxybenzaldehyde自由基取代反应的定位在自由基

16、取代反应中，定位效应很不显著，常常预期形成所有的三种异构体。例如：单取因此，药物合成中应该尽量避免利用自由基取代反应的定位效应，进行控制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吡啶的亲电取代吡啶是一个弱碱，具有相当程度

17、的芳香性。例如，它与碘甲烷反应生成季铵盐，加热时，季铵盐重排为碘化2-和4-甲基吡啶。分子轨道计算指出，C-3是电子密度最高的碳原子，但即使是这个位置的电子密度也比苯上的要低得多。因此，亲电取代需要强烈的条件。2.7简单杂环化合物的官能团化吡啶环的亲电取代反应吡啶与哌啶的转化哌啶由吡啶经氢化而制得 (50 Refrerences, 30 Conditions)。From 2-chloro-pyridine to piperidine1) Sodium, ethanol2) SmI2，溶剂：tetrahydrofuran，H2O反应时间：23 min, Yield：92 %, Ambient t

18、emperature 易制毒R=COOH，noExample：取代吡啶的反应抗精神分裂药: 利培酮(Risperidone)中间体1-acetylpiperidine-4-carboxylic acid 的合成比利时Janssen公司：Spiron (1993 Canada)1-acetylpiperidine-4-carboxylic acidIso-nicotinic acid自由基反应自由基型苯基化反应导致生成所有三种单苯基吡啶的混和物。产物复杂，在合成中的应用有限。除非其他位置被占据，则可用。Example：吡啶环氯代、酰氯化反应Braf激酶制剂: 索拉非尼(sorafenib)中间体

19、的合成。德国Bayer 公司：Nexavar、美国FDA批准上市(2005)，中国 (2009).治疗癌症等疾病。Example：吡啶环上的氯代反应Braf激酶制剂: 索拉非尼(sorafenib)中间体的合成。德国Bayer 公司：Nexavar、美国FDA批准上市(2005)，中国 (2009).治疗癌症等疾病。Example：吡啶环外侧链的氯代反应质子泵抑制剂：埃索美拉唑钠 (Esomeprazole sodium)中间体的合成。瑞典AstraZeneca 公司：奥美拉唑光学异构体、FDA批准上市(1999).治疗胃溃疡，十二指肠溃疡，消化性食管炎以及胃炎。吡啶环的亲核取代反应非取代吡啶

20、亲核取代位置主要在2-位。取代吡啶亲核取代反应在特定的位置。Example：吡啶环上的醚化反应Braf激酶制剂: 索拉非尼(sorafenib)中间体的合成。德国Bayer 公司：Nexavar、美国FDA批准上市(2005)，中国 (2009).治疗癌症等疾病。吡啶N-氧化物的反应Example：吡啶N-氧化物的反应凝血酶抑制剂: 达比加群酯(Dabigatran etexilate )中间体的合成。德国Boehringer Ingelheim 公司：Pradaxa德、英国首次上市(2008)阻断凝血瀑布网络的最后步骤及血栓形成。补充：六氢吡啶的N-烷基化组胺H1受体拮抗剂: 非索非那定(F

21、exofenadine)中间体的合成。德国Hoechest Marion Roussel 公司：Allegra 美国首次上市(1996)季节性过敏性鼻炎和慢性特发性荨麻疹。ethyl 2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoate，酯水解之后得终产物。补充：四氢吡啶的N-烷基化抗血小板聚集药：硫酸氢氯比格雷中间体的合成。法国Sanofi-Aventi公司 (1998,美国) 选择性阻断ADP与血小板受体的结合。动脉粥样硬化，极性冠状动脉综合症。补充：嘧啶环的N

22、-烷基化核苷类HIV-1逆转录酶抑制剂: 恩曲他滨(Emtricitabine)中间体的合成。美国Gilead Sciences 公司：FDA上市(2003)与齐多夫定合用治疗HIV-1感染。(5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolan-2-yl)methyl butyrate补充：嘧啶并咪唑环的甲基化新型抗帕金森病药物：Istradefylline 的合成，注册前阶段新药。日本 Kyowa Hakko Kogyo 株式会社。选择性腺苷A2a受体拮抗剂。Istradefylline补充：氨基取代嘧啶的反应新型抗帕金森病

23、药物：Istradefylline的合成，注册前阶段新药。日本 Kyowa Hakko Kogyo 株式会社。选择性腺苷A2a受体拮抗剂。碱性条件下环合后甲基化可得 IstradefyllineOther heterocyclics与吡啶相反，呋喃、吡咯和噻吩是富电子分子，它们与亲电试剂起反应主要在2-和5-位。可是在酸性条件下，呋喃发生聚合，而吡咯发生聚合的程度较低。呋喃、吡咯和噻吩直接卤化通常导致多卤代产物的生成。吡咯的反应总结Example：取代吡咯的甲酰化抗肿瘤药: 舒尼替尼(Sunitinib)中间体的合成美国辉瑞公司(Pfizer)公司：Sutent (2006)多靶点酪氨酸激酶抑

24、制剂。ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylateExample：苯并吡咯的N-甲基化降血脂药: 氟伐他汀(Fluvastatin)中间体的合成瑞士诺华 (Novartis)公司：Lescol (1994)HMG-CoA还原酶抑制剂。阻止胆固醇的生物合成。ethyl 3-(4-fluorophenyl)-1-methyl-1H-indole-2-carboxylateExample：苯并吡咯3-酰基化,N-磺酰化抗抑郁药:盐酸维拉唑酮 (Vilazodone hydrochloride) 中间体的合成。Trovis Pharma LL

25、C 公司：Viibryd， FDA (2011)治疗成年人重度抑郁症。酰基化之后，磺酰化之后，再经硅烷还原成烷基。Example：四氢吡咯的N-甲基化选择性雌激素受体调节剂: 酒石酸拉索昔芬(Lasofoxifene Tartrate)中间体的合成美国辉瑞 (Pfizer)公司：Fablyn (2009欧洲)治疗妇女绝经后骨质疏松症。1-(2-(4-bromophenoxy)ethyl)pyrrolidineExample：哌啶并四氢吡咯N-烷基化喹诺酮类抗菌药: 莫西沙星(Moxifloxacin)中间体的合成。德国拜耳(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采用甲醇钠和DMSO将8-F替换为甲氧基后即为莫西沙星。Example：咪唑环的N-甲基化降压药：氯沙坦 (Losartan)中间体的合成。美国Bristol-Mayers-Squibb公司 (1994,瑞士) 非肽类血管紧张素II受体拮抗剂。Example：苯并咪唑环的N-甲基化抗肿瘤药：帕唑帕尼 (Pazopanib)中间体的合成。英国Glaxo Smith Kline: (

27、2009,10) 。第二代多靶点酪氨酸激酶抑制剂。呋喃的反应总结噻吩的反应总结Example：3-溴噻吩的反应抗血小板聚集药：硫酸氢氯比格雷中间体的合成。法国Sanofi-Aventi公司 (1998,美国) 选择性阻断ADP与血小板受体的结合。动脉粥样硬化，极性冠状动脉综合症。Example： 2-溴噻唑的反应抗肿瘤新药：达沙替尼(Dastinib)中间体的合成。美国百时美施贵宝,别名Sprycel扑瑞赛, (2006,美国FDA)。口服多重酪氨酸激酶抑制剂。2-chloro-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamideExample：

28、2-溴噻唑的反应抗肿瘤新药：达沙替尼(Dastinib)中间体的合成。美国百时美施贵宝,别名Sprycel扑瑞赛, (2006,美国FDA)。口服多重酪氨酸激酶抑制剂。N-(4-methoxybenzyl)-2-(6-chloro-2-methylpyrimidin-4-ylamino) -N-(2-chloro-6-methylphenyl)thiazole-5-carboxamideExample：氨基噻唑的反应抗肿瘤新药：达沙替尼(Dastinib)中间体的合成。美国百时美施贵宝,别名Sprycel扑瑞赛, (2006,美国FDA)。口服多重酪氨酸激酶抑制剂。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羟基的转换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, 亚硫酰氯，制溴代烷 alkyl bromides: Constant boiling hydrobromic acid or phosph

33、orus tribromide, 恒沸氢溴酸或三溴化磷，制碘代烷 alkyl iodides: Iodine with red phosphorus for. 碘和红磷。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：吡啶环外醇羟基的氯代质子泵抑制剂: 埃索美拉唑钠 (Esomeprazole Sodium) 中间体的合成。瑞典Astra Zeneca 公司：Nexium (耐信 )、美国FDA批准上市(1999).治疗胃溃疡、十二指肠溃疡、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)中间

35、体的合成厄洛替尼，它塞瓦(Tarceva)罗氏、基因技术及OSI制药公司（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：醇转化为酯抗血小板凝集药: 盐酸沙格雷酯(Sarpogrelate hydrochloride)中间体的合成。日本三菱化成株式会社：Anplag，日本首次上市(1993).治疗改善慢行动脉闭塞症引起的溃疡、疼痛及冷感等缺血症。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.应用：由Grignard制叔醇，常导致自发脱水。Alcohols to acetals醇除成酯，卤代烷之外可以成缩醛，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：酚转化为双芳醚Braf激酶制剂: 索拉非尼(Sorafenib)中间体的合成。德国Bayer 公司：Nexavar、美国FDA批准上市(2005)，中国 (2009).治疗癌症

42、等疾病。Text book（2015），p43-47 from compound 1-4-7 to 1-4-8Example：酚转化为芳基脂肪醚抗血小板凝集药: 盐酸沙格雷酯(Sarpogrelate hydrochloride)中间体的合成。日本三菱化成株式会社：Anplag，日本首次上市(1993).治疗改善慢行动脉闭塞症引起的溃疡、疼痛及冷感等缺血症。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:磺酰胺含有一个酸性氢，该氢可失去而得到一个强的亲核物

44、种： 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 ? 脂肪胺反应的优化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.较好的离去基团2,4,6-三苯基吡啶被一系列亲核试剂置换优化：脂肪胺的溴代反应优化：脂肪胺的乙酰酯化优化：脂肪胺被其它官能团取代脂肪胺的反应N-亚硝基化合物亚硝酸N, N-

46、二取代肼仲胺芳伯胺与亚硝酸反应形成重氮盐具有重要的意义；可发生各种转换，具有制备的价值。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.对于许多三级卤代烷的反应，仅得到消去产物.How to avoid this?Pharmaceutical application卤代烷用氢氧化钠水解成醇, 强碱、非极性溶剂和高温条件利于消去。碱催化的二级和三级卤代烷的消去反应遵守扎以柴夫规则。卤代烷的金属化反应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与转化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:醛和酮与醇的作用是可逆的.酸性条件半缩酮缩酮半缩醛缩醛羰基转变为亚甲基The analogous dithioketals are used in a conversion of carbonyl groups into methylene groups. The reaction require

56、s a large excess of Raney nickel. 二硫缩酮亚甲基羰基大大过量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采用潮湿氧化银处理重氮酮, 变成多一个亚甲基的羧酸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