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IP屬地：河北 更新時間：2024-07-09 格式：ppt 頁數(shù)：149 大?。?.26MB 人氣指數(shù)：12 舉報 版權(quán)申訴

1、Chapter 3,Acylation Reaction,第三章 ?；磻?概 述,1 定義：有機物分子中O、N、C原子上導入?；姆磻?,2 分類： 根據(jù)接受?；拥牟煌煞譃椋?氧?；?、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) 酰化反應機理,一、電子反應機理1.親電反應機理1）單分子歷程-酰鹵、酸酐,2）雙分子歷

2、程?；俾逝c?；瘎┖捅货；餄舛染嘘P(guān)系，為動力學二級反應。,3）?；瘎┑膹娙蹴樞騔的電負性越大，離去能力越強，其酰化能力越強。判斷方法為：HZ的Ka越大或Pka越小，酸性越強,4）被?；锏幕钚杂H核能力越強，越容易?；梢愿鶕?jù)被?；颮-YH堿性來衡量RNH2>ROH>RHR的影響：在O，N?；?，R=Ar時，活性下降，故RNH2>ArNH2及ROH>ArOHR的影響：立體位阻大，酰化困

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

4、物濃度 (2)不斷蒸出反應產(chǎn)物之一 (3)添加脫水劑或分子篩除水。,酯化反應的機理,*1 加成－消除機理,雙分子反應一步活化能較高,質(zhì)子轉(zhuǎn)移,加成,消除,四面體正離子,-H2O,-H+,,,,按加成－消除機制進行反應，是酰氧鍵斷裂,,,,,* 3oROH按此反應機理進行酯化。* 由于R3C+易與堿性較強的水結(jié)合，不易與羧酸結(jié)合， 故逆向反應比正向反應易進行。所以3oROH的酯化 反應產(chǎn)率很低。,*2

5、 碳正離子機理,屬于SN1機理,該反應機理也從同位素方法中得到了證明,(CH3)3C-OH,H+,(CH3)3COH2,+,-H2O,-H+,,,按SN1機理進行反應，是烷氧鍵斷裂,,+ (CH3)3COH,+ H2O,僅有少量空阻大的羧酸按此反應機理進行,*3 酰基正離子機理,H2SO4(濃),,,,-H+,屬于SN1機理,,78%,CH3OH,醇的結(jié)構(gòu)對?；磻挠绊懥Ⅲw影響因素:伯醇＞仲醇＞叔醇、烯丙醇叔碳正離子傾向與水

6、反應而逆轉(zhuǎn),,（3）影響因素① 醇結(jié)構(gòu)影響,電子效應的影響羥基a位吸電子基團通過誘導效應降低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-利于進行反應；R帶給電子不利于反應R的體積若龐大，則親核試劑對羰基的進攻有位阻，不利于反應進行羰基的a位連有不飽和基和芳基，除誘導效應外，還有共軛效應，使酸性增強,③催化劑i提高羧酸反應活性(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 用來提高醇的反應活性,偶氮二羧酸酯法（活化醇制備羧酸酯）,,,,,,,,Mitsunobu reaction.,,Mechanism,（4）應用特點,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)反應通式 R2、R1要求？,（2）反應機理① 酸催化機理：-增強羧酸酯的活性,,,,,,,,② 堿催化機理增強醇的活性,（3）影響因素羧酸酯結(jié)構(gòu)的影響如a位有吸電子基團，將增強其活性短鏈的羧酸乙酯、甲酯，更常用在RCOOR1中，R1OH酸性越強，酯的酰化能力越強,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（胃長寧）的合成,,,

9、,,,,,,,,,② 活性酯的應用 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?）反應通式,,,,,,,,,,,,,,,（2）反應機理① H+ 催化② Lewis酸催化,,,,,,,,,,,,,③堿催化: 無機堿：（Na2

10、CO3、NaHCO3、 NaOH) 去酸劑；有機堿：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）應用特點單一酸酐應用有限，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)反應機理Lewis酸催化,,,,,,,,,,,,,,,,,,,,堿催化,例,,,,,,,,,,,,,,,,,,,,,（4）應用特點①選擇性?；?/p>

12、有機錫體系實現(xiàn)選擇性酰化非1,2-二醇的?；?②叔醇的?；尤階g+、Li+鹽，提高收率,5 酰胺為酰化劑(活性酰胺),,,,,,,,,,,,,,,,,,,,,,（3）應用特點① ?；溥驗轷；瘎?,,,,,,,,,,,,,,,,,,,,② PTT為?；瘎┻m用于對酸、堿均不穩(wěn)定醇的酰化反應在中性條件下進行,羧酸需要活化10為活性中間體一個五元雜環(huán)用來活化,例,活化試劑為CDI優(yōu)點：酸的活化、?；?、硝基還

13、原可在同一溶劑中進行-EtOAc,Mechanism,N上無孤對電子參與共振，鍵更易斷裂N-H的化學位移,6.乙烯酮為?；瘎?乙?；? 對于某些難以?；氖辶u基,酚羥基以及位阻較大的羥基采用本法,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,二 酚的氧?；?用強酰化劑: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-結(jié)構(gòu)對照,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) 氮原子上的酰化反應,比羧酸的反應更容易，應用更廣,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,一、脂肪氨-N?；?,1.羧酸為?；瘎?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,（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，在低溫下常生成單?；a(chǎn)物，高溫加熱則可得雙酰化亞胺,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,4 酰氯為?；瘎?,,,,,,,,,,,,,,,

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

20、2）反應機理,（3）影響因素① ?；瘎┑挠绊慖. 酰化劑的影響acylating 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，隨后進行水解，得到酰基酚或?；用?,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,（2）機理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個供電子基（一元酚不反應）,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

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(Hoesch反應的特例)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?。,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

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反應用N-取代甲酰胺作?；瘎?，三氯氧磷催化芳環(huán)甲?；姆磻?,反應機理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)氫被甲酰基取代的反應，叫做Reimer-Tiemann反應。,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,(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)先進攻氫原子較多的碳原子,機理,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

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

44、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,例,2. Claisen反應和Dieckmann反應,機理,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