藥物合成反應(yīng)第三章?；磻?yīng)

1、Chapter 3,Acylation Reaction,第三章 ?；磻?yīng),概 述,1 定義：有機(jī)物分子中O、N、C原子上導(dǎo)入?；姆磻?yīng),,2 分類： 根據(jù)接受?；拥牟煌煞譃椋?氧酰化、氮?；⑻减；? 意義：藥物本身有?；八幵砗铣墒侄?硝苯地平,常用的?；噭?,,第一節(jié) ?；磻?yīng)機(jī)理,一、電子反應(yīng)機(jī)理1.親電反應(yīng)機(jī)理1）單分子歷程-酰鹵、酸酐,2）雙分子歷

2、程酰化速率與?；瘎┖捅货；餄舛染嘘P(guān)系，為動(dòng)力學(xué)二級(jí)反應(yīng)。,3）酰化劑的強(qiáng)弱順序Z的電負(fù)性越大，離去能力越強(qiáng)，其?；芰υ綇?qiáng)。判斷方法為：HZ的Ka越大或Pka越小，酸性越強(qiáng),4）被?；锏幕钚杂H核能力越強(qiáng)，越容易?；?，可以根據(jù)被?；颮-YH堿性來(lái)衡量RNH2>ROH>RHR的影響：在O，N?；?，R=Ar時(shí)，活性下降，故RNH2>ArNH2及ROH>ArOHR的影響：立體位阻大，酰化困

3、難,2. 親核反應(yīng)機(jī)理極性反轉(zhuǎn)-a氰醇衍生物T,1976,32,1943二、自由基反應(yīng)機(jī)理產(chǎn)物復(fù)雜，應(yīng)用有限,第二節(jié) 氧原子的?；磻?yīng),是一類形成羧酸酯的反應(yīng) 是羧酸的酯化反應(yīng) 是羧酸衍生物的醇解反應(yīng),,一、醇的氧?；?1) 羧酸為酰化劑 提高收率: 加快反應(yīng)速率: (1)提高溫度 (2)催化劑(降低活化能),,(1)增加反應(yīng)

4、物濃度 (2)不斷蒸出反應(yīng)產(chǎn)物之一 (3)添加脫水劑或分子篩除水。,酯化反應(yīng)的機(jī)理,*1 加成－消除機(jī)理,雙分子反應(yīng)一步活化能較高,質(zhì)子轉(zhuǎn)移,加成,消除,四面體正離子,-H2O,-H+,,,,按加成－消除機(jī)制進(jìn)行反應(yīng)，是酰氧鍵斷裂,,,,,* 3oROH按此反應(yīng)機(jī)理進(jìn)行酯化。* 由于R3C+易與堿性較強(qiáng)的水結(jié)合，不易與羧酸結(jié)合， 故逆向反應(yīng)比正向反應(yīng)易進(jìn)行。所以3oROH的酯化 反應(yīng)產(chǎn)率很低。,*2

5、 碳正離子機(jī)理,屬于SN1機(jī)理,該反應(yīng)機(jī)理也從同位素方法中得到了證明,(CH3)3C-OH,H+,(CH3)3COH2,+,-H2O,-H+,,,按SN1機(jī)理進(jìn)行反應(yīng)，是烷氧鍵斷裂,,+ (CH3)3COH,+ H2O,僅有少量空阻大的羧酸按此反應(yīng)機(jī)理進(jìn)行,*3 ?；x子機(jī)理,H2SO4(濃),,,,-H+,屬于SN1機(jī)理,,78%,CH3OH,醇的結(jié)構(gòu)對(duì)酰化反應(yīng)的影響立體影響因素:伯醇＞仲醇＞叔醇、烯丙醇叔碳正離子傾向與水

6、反應(yīng)而逆轉(zhuǎn),,（3）影響因素① 醇結(jié)構(gòu)影響,電子效應(yīng)的影響羥基a位吸電子基團(tuán)通過(guò)誘導(dǎo)效應(yīng)降低O上電子云密度，使親核能力降低芐醇、烯丙醇由于p-p共軛，使活性降低,②羧酸的結(jié)構(gòu)R帶吸電子基團(tuán)-利于進(jìn)行反應(yīng)；R帶給電子不利于反應(yīng)R的體積若龐大，則親核試劑對(duì)羰基的進(jìn)攻有位阻，不利于反應(yīng)進(jìn)行羰基的a位連有不飽和基和芳基，除誘導(dǎo)效應(yīng)外，還有共軛效應(yīng)，使酸性增強(qiáng),③催化劑i提高羧酸反應(yīng)活性(a)質(zhì)子酸催化法: 濃硫酸,氯化氫氣體,

7、磺酸等,,,,,(b)Lewis酸催化法: (AlCl3, SnCl4,FeCl3,等),例,,,,,,,,(c) DCC 二環(huán)己基碳二亞胺,,,,,,,,,,,,,,,例：,,,,,,,,,,ii 用來(lái)提高醇的反應(yīng)活性,偶氮二羧酸酯法（活化醇制備羧酸酯）,,,,,,,,Mitsunobu reaction.,,Mechanism,（4）應(yīng)用特點(diǎn),① 伯醇酯的制備,,,,,,,,,② 仲醇酯的制備,薄荷醇,③ 叔醇酯的制備,2.羧酸

8、酯為?；瘎?1)反應(yīng)通式 R2、R1要求？,（2）反應(yīng)機(jī)理① 酸催化機(jī)理：-增強(qiáng)羧酸酯的活性,,,,,,,,② 堿催化機(jī)理增強(qiáng)醇的活性,（3）影響因素羧酸酯結(jié)構(gòu)的影響如a位有吸電子基團(tuán)，將增強(qiáng)其活性短鏈的羧酸乙酯、甲酯，更常用在RCOOR1中，R1OH酸性越強(qiáng)，酯的?；芰υ綇?qiáng),例：局麻藥丁卡因,,,,,,,,,,,例：抗膽堿藥溴美噴酯（寧胃適）,,,,,,,,,,,例：抗膽堿藥格隆溴胺（胃長(zhǎng)寧）的合成,,,

9、,,,,,,,,,② 活性酯的應(yīng)用 i羧酸硫醇酯,,,,,,,,,,,,,ii羧酸吡啶酯,,,,,,,,,,,,,,iii羧酸三硝基苯酯Cl-TNB,,,,,,,,,,,iv羧酸異丙酯（適用于立體障礙大的羧酸）,,,,,,,,,,,,,V 苯并三唑酯,3 酸酐為?；瘎?）反應(yīng)通式,,,,,,,,,,,,,,,（2）反應(yīng)機(jī)理① H+ 催化② Lewis酸催化,,,,,,,,,,,,,③堿催化: 無(wú)機(jī)堿：（Na2

10、CO3、NaHCO3、 NaOH) 去酸劑；有機(jī)堿：吡啶， Et3N,,,,,,,,,,,,,（3）影響因素催化劑的影響三氟甲磺酸鹽催化Cu(OTf)2、Sc(OTf)3、Yb(OTf)3、Bi(OTf)3等比吡啶類更有效,（4）應(yīng)用特點(diǎn)單一酸酐應(yīng)用有限，一般使用混合酸酐i 羧酸-三氟乙酸混合酸酐（適用于立體位組較大的羧酸的酯化，臨時(shí)制備）,,,,,,,,,,,,,,,ii 羧酸-磺酸混合酸酐 iii羧酸-多取

11、代苯甲酸混合酸酐 Yamaguchi酯化,,,,,,,,,,,,,,,,,,iv 羧酸-磷酸混合酸酐 BOP-Cl DPPA,,其它混合酸酐,,,,,,,,,,,,,,,,,,4. 酰氯為?；瘎?酸酐、酰氯均適于位阻較大的醇) (2)反應(yīng)機(jī)理Lewis酸催化,,,,,,,,,,,,,,,,,,,,堿催化,例,,,,,,,,,,,,,,,,,,,,,（4）應(yīng)用特點(diǎn)①選擇性?；?/p>

12、有機(jī)錫體系實(shí)現(xiàn)選擇性?；?,2-二醇的?；?②叔醇的?；尤階g+、Li+鹽，提高收率,5 酰胺為?；瘎?活性酰胺),,,,,,,,,,,,,,,,,,,,,,（3）應(yīng)用特點(diǎn)① 酰基咪唑?yàn)轷；瘎?,,,,,,,,,,,,,,,,,,,,② PTT為?；瘎┻m用于對(duì)酸、堿均不穩(wěn)定醇的酰化反應(yīng)在中性條件下進(jìn)行,羧酸需要活化10為活性中間體一個(gè)五元雜環(huán)用來(lái)活化,例,活化試劑為CDI優(yōu)點(diǎn)：酸的活化、酰化、硝基還

13、原可在同一溶劑中進(jìn)行-EtOAc,Mechanism,N上無(wú)孤對(duì)電子參與共振，鍵更易斷裂N-H的化學(xué)位移,6.乙烯酮為酰化劑(乙?；? 對(duì)于某些難以?；氖辶u基,酚羥基以及位阻較大的羥基采用本法,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,二 酚的氧酰化,用強(qiáng)?；瘎?酰氯、酸酐、活性酯,,,,,,,,,,,,,,,,,,,,,,,,

14、,,,,,酸酐為酰化劑例,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,選擇性?；?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,相轉(zhuǎn)移條件下，利用酚羥基與堿性催化劑成鹽的性質(zhì)，選擇性?；?縮略語(yǔ)-結(jié)構(gòu)對(duì)照,1. AIBN2. 9-BBN,3. BINOL4. Bn5. Bz6. Boc,7. BOP-Cl8. Cbz9. CDI,,,,10. CSA

15、11. DABCO12. DBN1,5-diazabicyclo[4.3.0]non-5-ene,13. DBU1,8-diazabicyclo[5.4.0]undec-7-ene14. DCC15. DDQ,16. DEAD17. DHP18. DIAD,19. DIBAL20. DIC21. DMAP,22. DMF23. DMP24. EDCI,25. Fmoc

16、26. HMPA/HMPT,27. HOBt28. IBX29. LAH,30. LDA31. m-CPBA32. PMB,33. NBS/NCS34. NMM/NMO35. PCC/PDC,36. PTSA/PPTS37. Red-Al,38. TEA/TFA/TFAA39. TBHP40. TCCA,41. TMEDA/DMEDA42. DPPA,第三

17、節(jié) 氮原子上的?；磻?yīng),比羧酸的反應(yīng)更容易，應(yīng)用更廣,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,一、脂肪氨-N?；?,1.羧酸為酰化劑,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,（1）DCC為催化劑（2）活性磷酸酯為催化劑,2 羧酸酯為?；瘎├?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,例,,,,,,,,,,,,,,,,,,,,,,,,,,,

18、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,3 酸酐為?；瘎?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,如用環(huán)狀酸酐?；瘯r(shí)，在低溫下常生成單?；a(chǎn)物，高溫加熱則可得雙?；瘉啺?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,4 酰氯為酰化劑,,,,,,,,,,,,,,,,

19、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,二、芳胺N-?；?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,第四節(jié) 碳原子上的酰化反應(yīng) 一、芳烴的C-酰化,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,1 Friedel-Crafts (F-C )傅-克?；磻?yīng),(1) 反應(yīng)通式,（

20、2）反應(yīng)機(jī)理,（3）影響因素① 酰化劑的影響I. ?；瘎┑挠绊慳cylating agents besides acyl halides are: aromatic and aliphatic carboxylic acids, anhydrides, ketenes and esters.acyl iodides are usually the most reactive, while acyl fluorides are t

21、he least reactive (I > Br > Cl > F),ii ?；瘎┙Y(jié)構(gòu)的影響,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

22、,,,,,用酸酐作?；瘎?，可制取芳酰脂肪酸，并可進(jìn)一步環(huán)和得芳酮衍生物,② 被?；锏挠绊憇ubstrates that undergo the Friedel-Crafts alkylation are also easily acylated and in most cases electron-rich substrates.no polyacylated products are observed, since, afte

23、r the introduction of the first acyl group, the substrate becomes deactivated;,unprotected Lewis basic functional groups (e.g., amines) are poor substrates, since the acylation will preferentially take place on these fun

24、ctional groups instead of the aromatic ring;,③ 催化劑的影響most often used catalysts are: AlX3, lanthanide triflates, zeolites, protic acids (e.g., H2SO4, H3PO4), FeCl3, ZnCl2, PPA;unlike in the alkylations, Friedel-Crafts a

25、cylations require substantial amounts of catalyst (slightly more than one equivalent), since the acylating agent itself coordinates one equivalent of Lewis acid, and therefore excess is needed to observe catalysis;,One d

26、rawback of the Friedel-Crafts acylation is that the Lewis acid catalyst usually cannot be recovered at the end of the reaction, since it is destroyed in the work-up step.recent studies showed that the use of heterogene

27、ous catalysts (mainly zeolites) makes this important reaction more feasible on an industrial scale.,④溶劑的影響 CCl4, CS2惰性溶劑最好選用.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,2. Hoesch反應(yīng)酚或酚醚在氯化氫和氯化鋅等Lewis酸

28、的存在下，與腈作用，隨后進(jìn)行水解，得到?；踊蝓；用?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,（2）機(jī)理Hoesch-芳酮與Gattermann-芳醛類似，,（3）影響因素：要求電子云密度高，即苯環(huán)上一定要有2個(gè)供電子基（一元酚不反應(yīng)）,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

29、,,,,,,,,,,最終產(chǎn)物為苯甲醛（適用于酚類及酚醚類芳烴）,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,3. Gattermann反應(yīng)(Hoesch反應(yīng)的特例)芳香化合物在三氯化鋁或二氯化鋅存在下與HCN和HCl作用所發(fā)生的芳環(huán)氫被甲?；〈姆磻?yīng)。,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

30、,,,,,,,,,,,,,,,,,,,,,,,,,Gattermann-Koch formylation,(1) at high CO pressure (100-250 atm) the reaction rate increases significantly and even non-activated aromatics (chlorobenzene, benzene) can be formylated;(2) a car

31、rier/activator (Cu2Cl2, TiCl4 or NiCl2) for the catalyst is necessary at atmospheric pressure; however, no activator is needed at high pressure,(3) monosubstituted substrates are formylated almost exclusively at the para

32、 position, but when there is already a para substituent present in the substrate, the formyl group is introduced at the ortho position;(4) the need for high pressures renders this method mainly useful to industrial app

33、lications,(5) The main drawback of the Gattermann formylation was that it called for the use of anhydrous HCN, which is a very toxic compound;(6) R. Adams generated it in situ along with ZnCl2 by reacting Zn(CN)2 with

34、HCl in the presence of the aromatic substrate (Adams modification);,(7) Other modifications used NaCN and CNBr successfully instead of HCN;(8) A serious limitation of both title reactions is that they cannot be used fo

35、r the formylation of aromatic amines due to numerous side reactions.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,4 Vilsmelier反應(yīng)用N-取代甲酰胺作?；瘎妊趿状呋辑h(huán)甲?；姆磻?yīng),,反應(yīng)機(jī)理Vilsmeier-Haack formylation,

36、例,(1) the Vilsmeier reagent is prepared from any N,N-disubstituted formamide by reacting it with an acid chloride (e.g., POCl3, SOCl2, oxalyl chloride);(2) most often the combination of DMF and POCl3 is used and the re

37、sulting Vilsmeier reagent is usually isolated before use;,(3) mostly electron-rich aromatic or heteroaromatic compounds as well as electron-rich alkenes and 1,3-dienes11 are substrates;(4) the transformation is regiose

38、lective favoring the less sterically hindered position.,5 Reimer-Tiemann反應(yīng)芳香族化合物在堿溶液中與氯仿作用，也能發(fā)生芳環(huán)氫被甲?；〈姆磻?yīng)，叫做Reimer-Tiemann反應(yīng)。,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,(1) it is the

39、only electrophilic aromatic substitution reaction that occurs under basic conditions in a protic solvent;(2) phenols, naphthols, alkyl-, alkoxy-, and halogenated phenols, salicylic acid derivatives, heterocyclic phenol

40、s such as hydroxyquinolin es and hydroxypyrimidines, as well as pyrroles and indoles undergo formylation under the reaction conditions;,(3) the regioselectivity is not high, but ortho-formyl products tend to predominate;

41、(4) when the ortho-position is already substituted, para-formyl phenols are obtained(5) when the reaction is conducted in the presence of cyclodextrins, the p-formyl product is formed predominantly.,,,,,,,,,,,,,,,,,,

42、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,二、烯烴的C-?；?,,加成的方向服從馬氏規(guī)則,?；鶅?yōu)先進(jìn)攻氫原子較多的碳原子,機(jī)理,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

43、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,三、羰基α位C-?；?1.活性亞甲基化合物的C-?；?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

44、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,例,2. Claisen反應(yīng)和Dieckmann反應(yīng),機(jī)理,Since the crossed Claisen condensation can potentially give rise to at least four different condensation products, it is a general pract

45、ice to choose one ester with no α-protons (e.g., esters of aromatic acids, formic acid and oxalic acid). The ester with no α-proton reacts exclusively as the acceptor and this way only a single product is formed.,,an est