有機反應機理PPT課件

1、9.1.1 18電子規(guī)則和中心原子價殼層電子數(shù)的計算過渡金屬絡合物可利用d軌道成鍵，穩(wěn)定結(jié)構(gòu)是價殼層電子數(shù)為18，稱為18電子規(guī)則與八隅體規(guī)則不同的是，許多價殼層電子數(shù)小于18的過渡金屬絡合物也能穩(wěn)定存在價殼層電子數(shù)大于18的過渡金屬絡合物不能穩(wěn)定存在第1頁/共94頁價殼層電子數(shù)N的計算N = Nligand + dn V式中：Nligand為配體提供的電子數(shù)dn為中心原子d電子數(shù)V為絡合物所帶電荷數(shù)第2頁/共94頁常見配體的電子數(shù)單電子配體：R, H, R2N, halogen, etc., 雙電子配體： R2C (carbenes or alkylidene groups), RN(imi

2、do groups), or O(oxide)，以鍵配位的烯烴以及 R3N, RCN, H2O, R3P等Lewis堿多電子配體：烯丙基（3)，丁二烯（4），環(huán)戊二烯基(cp, 5), 苯（6）等第3頁/共94頁計算以下反應中各絡合物的價殼層電子數(shù)18 16 18第4頁/共94頁9.1.2 鍵和 鍵CM鍵：沿鍵軸對稱第5頁/共94頁鍵：沿鍵軸反對稱給予鍵：鍵反饋鍵：鍵第6頁/共94頁配位鍵的表示法第7頁/共94頁9.2 過渡金屬絡合物的基本反應9.2.2 氧化加成和還原消除反應9.2.3 遷移插入和氫消除反應9.2.1 配體的配位和解離9.2.4 轉(zhuǎn)移金屬化反應第8頁/共94頁9.2.1 配體

3、的配位和解離第9頁/共94頁9.2.2 氧化加成和還原消除反應單電子氧化加成和雙電子氧化加成單電子氧化加成雙電子氧化加成LnM + A-BLnMAB2LnM + A-BLnM-A + LnM-B第10頁/共94頁單電子氧化加成和雙電子氧化加成Ph2+ H2Ir(I) d8Ir(III) d6IrPOCPPh2ClPh2IrPHPPh2ClHCO Co(II), d7 Co(III), d62Co(CN)53 + RX RCo(CN)53 + XCo(CN)53Vaska絡合物的各類雙電子氧化加成反應如下 第11頁/共94頁IrClLOCLH2IrHLLHClOCHXIrXLLHClOCArSO

4、2ClIrClLLSO2ArClOCHgCl2IrClLLHgClClOCMeO2CCCCO2MeIrLLClOCCCMeO2CCO2MeCH3IIrClLLCH3IOCO2IrOLLOClOCR3SiHIrHLLSiR3ClOC第12頁/共94頁氧化加成的機理氫的氧化加成：協(xié)同機理LnM + HHLnMHHLnMHH第13頁/共94頁氧化加成的機理（續(xù)）M +MCX-CXCXM鹵代烴的氧化加成：親核機理或自由基機理MCX-X MC第14頁/共94頁親核機理的實驗證據(jù)取代基效應 中心原子上的給電子配體，鹵代烴分子中的吸電子基團對反應有利 R的立體化學 構(gòu)型轉(zhuǎn)化 注意：d0絡合物不能發(fā)生氧化加成

5、反應第15頁/共94頁影響氧化加成的因素氧化加成是中心原子氧化態(tài)升高的過程，任何使中心原子電子云密度升高的因素都會對氧化加成產(chǎn)生有利的影響 對于同系物的同類型氧化加成反應，可根據(jù)以下規(guī)則判別反應的難易 第16頁/共94頁影響氧化加成的因素（續(xù)）中心原子氧化態(tài)越低，越有利于氧化加成 中心原子所在周期數(shù)越高，越有利于氧化加成 中心原子已有配體供電性越強，越有利于氧化加成 第17頁/共94頁影響氧化加成的因素（續(xù)）配位不飽和的絡合物容易發(fā)生氧化加成反應 配位飽和的絡合物發(fā)生氧化加成時，必須先離解出一個配體，生成配位不飽和的中間體，方可反應 第18頁/共94頁氧化加成的逆反應：還原消除 還原消除反應中

6、，中心原子的氧化態(tài)和配位數(shù)均降低。中心原子電子云密度高低對還原消除反應的影響與對氧化加成反應的影響相反 形成CC或CH鍵的還原消除往往是催化過程的最后一步第19頁/共94頁還原消除的機理80 CDMSO不反應PPdPCH3H3CPP= transphos =PP形成CC或CH鍵的還原消除通常為協(xié)同機理PdPCH3CH3PPh2Ph280 CDMSOCH3CH3第20頁/共94頁9.2.3 遷移插入和 氫消除反應+CCLMHCCMHCCMLHCCMH烯氫插入氫消除是烯氫插入的逆反應CCHM第21頁/共94頁烯烷基插入ABMCH2CHRR1MCHR1CH2RH2CCHR1MRMRCH2R1HCMR

7、CHR1H2C遷移基團R構(gòu)型保持對烯烴來說，為同向加成 Markownikoff加成和反Markownikoff加成 第22頁/共94頁羰基插入MCORk1k1CORMCOMRk2+ LMCRLOCOMR第23頁/共94頁9.2.4 轉(zhuǎn)移金屬化反應第24頁/共94頁9.3.1 鹵代烴與不飽和烴的偶聯(lián)鹵代烴與炔烴的偶聯(lián)（Sonogashira偶聯(lián)）鹵代烴與烯烴的偶聯(lián)(Heck反應）9.3 過渡金屬催化反應實例第25頁/共94頁鹵代烴與硼烷的偶聯(lián)(Suzuki偶聯(lián))鹵代烴與格林亞試劑的偶聯(lián)(Kumada偶聯(lián))9.3.2 鹵代烴與金屬有機化合物的偶聯(lián)鹵代烴與有機鋅的偶聯(lián)(Negishi偶聯(lián))鹵代烴與

8、有機錫的偶聯(lián)(Still偶聯(lián))第26頁/共94頁9.3.1 鹵代烴與不飽和烴的偶聯(lián)鹵代烴與烯烴的偶聯(lián), R F Heck, 1970RXR2HR3R1Pd(0)/ligand/basesolvent, heat+R2RR3R1R = aryl, benzyl, alkenyl, alkyl(no hydrogen)第27頁/共94頁Heck反應的特點烯烴中取代基電性對反應影響不大，有吸電基的烯烴收率略高；取代基越多，反應越慢烯丙醇在反應中會發(fā)生重排反應通常在膦配體和堿存在下進行，對水不敏感第28頁/共94頁Heck反應的特點（續(xù)）RX的反應速率按以下順序遞減，氯代烴反應慢I Br OTf Cl

9、對于有 氫的鹵代烴，易發(fā)生 氫消除生成烯烴第29頁/共94頁Heck反應的機理由過渡金屬絡合物的一些基本反應構(gòu)成，包括：氧化加成（oxidative addition)還原消除（reductive elimination)轉(zhuǎn)移金屬化（transmetallation)插入(insertion)和 氫消除( -hydride elimination)第30頁/共94頁LnPd(0)RXoxidative additionLnPd(II)XRR2HR3R1syn insertionR2HR3R1Pd(II)LnXRrotationR2HR3R1Pd(II)LnXRR2RR3R1syn -hydri

10、deeliminationLnPd(II)HXbaseHXreductive elimination第31頁/共94頁Heck反應合成lasiodiplodinA potent anticancer macrocyclic natural productOOOMeMeO第32頁/共94頁Frstner, A., Thiel, O. R., Kindler, N., Bartkowska, B. Total Syntheses of (S)-(-)-Zearalenone and Lasiodiplodin Reveal Superior MetathesisActivity of Ruthen

11、ium Carbene Complexes with Imidazol-2-ylidene Ligands. J. Org. Chem. 2000, 65, 7990-7995參考文獻第33頁/共94頁OOTfOOMeMeOH2CCH2PdCl2(PPh3)2/LiCl/NEt3/DMF90oC, 40 bar, 20 h, 92%OOOMeMeOstepsOOOMeMeO第34頁/共94頁鹵代烴與炔烴的偶聯(lián)Castro-Stephens偶聯(lián)In the early 1960s, R.D. Stephens and C.E. Castro discovered that disubstitut

12、ed acetylenes were produced in good yield upon treatment of aryl iodides with stoichiometric amounts ofcopper(I) acetylides under a nitrogen atmosphere in refluxing pyridine第35頁/共94頁The copper(I) mediated coupling of aryl or vinyl halides with aryl- or alkyl-substituted alkynes is known as the Castr

13、o-Stephens coupling.R1XR2HCu(I)-complex/saltsolvent, base, reflux+R2R1第36頁/共94頁Castro-Stephens偶聯(lián)的機理R1XR2CuLn+R2CuLnR1XThe reaction is believed to proceed via a four-centered transition stateLnCuXR2R1第37頁/共94頁Castro-Stephens偶聯(lián)的缺點Most copper(I) salts are insoluble in organic solvents, so the reactions

14、 are often hetero-geneous and require high reaction temperaturesThe reactions are sensitive to functional groups on the aryl halides, and the yields are often irreproducible第38頁/共94頁Castro-Stephens偶聯(lián)合成tribenzocyclotriyneIOCH3CH3OICH3OOCH3IOCH3CH3O1. CuCl/NH4OH/EtOH2. pyridine, reflux, 24 h 80%OCH3CH

15、3OCH3OOCH3OCH3CH3O第39頁/共94頁Kinder, J. D., Tessier, C. A., Youngs, W. J. Synthesis of a para-methoxy substituted tribenzocyclotriyne. Synlett 1993, 149-150參考文獻第40頁/共94頁Sonogashira偶聯(lián)，1975Catalytic version of the Castro-Stephens couplingR1XR2H+R2R1Pd(0) or Pd(II) (cat.) / ligandCu(I)-salt (cat.) / base

16、 / solvent第41頁/共94頁Pd-catalyst: Pd(PPh3)2Cl2 or Pd(PPh3)4Cu(I)-salt: CuI or CuBrbase: Et2NH, Et3N, (i-Pr)2NEtsolvent: MeCN, THF, EtOAc第42頁/共94頁Sonogashira偶聯(lián)的機理第43頁/共94頁Sonogashira偶聯(lián)的特點The coupling can usually be conducted at or slightly above room temperatureThe handling of the shock-sensitive/explo

17、sive copper acetylides is avoided by the use of a catalytic amounts of copper(I) salt第44頁/共94頁Sonogashira偶聯(lián)的特點（續(xù)）The solvents and the reagents do not need to be rigorously dried. However, a thoroughdeoxygenation is essential to maintain the activity of the Pd-catalystThe order of reactivity for the

18、aryl and vinyl halides is I OTf Br Cl第45頁/共94頁Sonogashira偶聯(lián)合成mappicineNNOOHMappicineCamptothecin，喜樹堿用于治療胃癌、腸癌，慢性粒細胞型和急性白血病等NNOOHOOCamptothecin第46頁/共94頁Toyota, M., Komori, C., Ihara, M. A Concise Formal Total Synthesis of Mappicine and Nothapodytine B via an Intramolecular Hetero Diels-Alder Reaction

19、. J. Org. Chem. 2000, 65, 7110-7113.參考文獻第47頁/共94頁NOHSiMe3stepsNClOHHSiMe3+Pd(PPh3)2/CuI/NEt3DMF, r.t., 1 h, 98%NNOOHMappicine第48頁/共94頁9.3.2 鹵代烴與金屬有機化合物的偶聯(lián)鹵代烴與硼烷的偶聯(lián)，Suzuki偶聯(lián)1979年，A Suzuki和N Miyaura發(fā)現(xiàn)在鈀催化下硼烷可與鹵代烯烴偶聯(lián)，生成E烯烴后來，就把鈀催化下硼烷與有機鹵化物或三氟甲磺酸酯的偶聯(lián)稱作Suzuki偶聯(lián)第49頁/共94頁R1BR2R2X+R1R2X BR2+Pd(0)/Ligand/bas

20、eR = alkyl, OH, O-alkylX = Cl, Br, I, OTf et al 第50頁/共94頁Suzuki偶聯(lián)反應的特點硼烷或硼酸酯毒性小反應有好的立體選擇和區(qū)域選擇性反應條件溫和，水對反應干擾小后處理簡單，無機副產(chǎn)物易除去第51頁/共94頁Suzuki偶聯(lián)反應的缺點鹵代烷和芳香族鹵代烴反應性不好反應需堿催化，可能導致外消旋化等副反應有時可能會生成一些自偶聯(lián)副產(chǎn)物第52頁/共94頁Suzuki偶聯(lián)反應的改進發(fā)展有利于芳烴和鹵代烷烴偶聯(lián)的催化體系第53頁/共94頁Suzuki偶聯(lián)反應的機理由過渡金屬絡合物的一些基本反應構(gòu)成，包括：氧化加成（oxidative addition

21、)還原消除（reductive elimination)轉(zhuǎn)移金屬化（transmetallation)第54頁/共94頁R1BR2+ MORR1BR2ORLnPd(0)R2Xoxidative additionLnPd(II)XR2LnPd(II)ORR2ROBR2ORtransmetallationLnPd(II)R1R2R2R1reductive eliminationMORMXmetathesis第55頁/共94頁芳基硼酸酯與鹵代芳烴偶聯(lián)合成TMC-95AProteasome inhibitorNHONHHONHOONHNHOONH2OOHHOOTMC-95A第56頁/共94頁Lin S

22、, Danishefsky S J. The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: discovery of a new method to generate cis-propenyl amides. Angew Chem Int Ed Engl. 2002, 41(3): 512-515參考文獻第57頁/共94頁OHONH2OH1. MeOH/SOCl22. CbzCl/K2CO33. BnBr/CsCO3/acetone reflux, 88% (3 steps)OMeONHCbzOBnAgSO4/I2/

23、MeOHr.t., 1 h, 99%OMeONHCbzOBnIbis(pinacolato)diboron/PdCl2(dppf)/DCM/KOAc/DMSO, 80oC, 10 h, 91%Miyaura borationBBOOOOOMeONHCbzOBnBOO第58頁/共94頁Miyaura硼酸化反應(1993-1995)BBORORROROArXPdCl2(dppf)/base/solventArBORORBR3R2R1ROORXR3R2R1PdCl2(PPh3)2/PhOK/tolueneFePPh3PPh3dppf第59頁/共94頁Miyaura硼酸化反應機理LnPd(0)R1Xo

24、xidative additiontransmetallationBBORORROROXBOROR(II)BR1LnPdROORreductive eliminationR1BORORXR1LnPd(II)第60頁/共94頁NHOONBocIOMeONHCbzOBnBOO+PdCl2(dppf)2/DCMK2CO3/DME80oC, 2 h, 75%NHOONBocOMeNHCbzOBnOstepsNHONHHONHOONHNHOONH2OOHHOOTMC-95A第61頁/共94頁鹵代烴與格林亞試劑的偶聯(lián)Kumada偶聯(lián), M Kumada 和R J P Corriu, 1972鎳膦絡合物催化

25、下，鹵代烯烴或鹵代芳烴與格林亞試劑的偶聯(lián)R3R1XR2RMgXNiCl2L2solvent/ligandR3R1RR2+Ligand = PPh3; L2 = dppp, dppe, dppb第62頁/共94頁改用鈀膦絡合物催化，可實現(xiàn)鹵代烯烴或鹵代芳烴與有機鋰的偶聯(lián)R3R1XR2RLiPd(0)solvent/ligandR3R1RR2+第63頁/共94頁Kumada偶聯(lián)反應的特點對于鎳催化的偶聯(lián)，配體的種類對活性有影響Ni(dppp)Cl2 Ni(dppe)Cl2 Ni(PR3)2Cl2 Ni(dppb)Cl2Ph3PPPh3dpppPh3PPPh3dppePh3PPPh3dppbFePP

26、h3PPh3dppf第64頁/共94頁Kumada偶聯(lián)反應的特點（續(xù)）有 氫的烷基格林亞試劑不會發(fā)生 氫消除仲烷基格林亞試劑可能異構(gòu)化，生成伯烷基產(chǎn)物dppf為配體可加速 氫消除和還原消除，抑制仲烷基的異構(gòu)化，可用于仲烷基格林亞試劑的偶聯(lián)鹵代烯烴的構(gòu)型保持第65頁/共94頁鎳催化Kumada偶聯(lián)反應的機理L2Ni(II)X22 RMgX2 XMgXtransmetallationL2Ni(II)R2R1XRRoxidative additionreductive eliminationXR1L2Ni(II)第66頁/共94頁XR1L2Ni(II)RMgXXMgXRR1L2Ni(II)R1Xco

27、ordinationRR1L2NiR1X(II)R1Rreductive eliminationoxidative addition第67頁/共94頁鈀催化Kumada偶聯(lián)反應的機理LnPd(0)R1Xoxidative additionXR1LnPd(II)transmetallationRLiLiXR1Rreductive eliminationRR1LnPd(II)第68頁/共94頁Kumada偶聯(lián)反應合成應用實例Synthesis of 18dehydrodesoxyepothlione BSNOOOHOOH第69頁/共94頁參考文獻Alexey R, Jon T N, Kaustav

28、 B, Ting-Chao Chou, and Samuel J D. Total Syntheses of 17- and 18Dehydrodesoxyepothilones B via aConcise Ring-Closing Metathesis-Based Strategy: Correlation of Ring Size with Biological Activity in the Epothilone Series. J Org Chem, 2002, 67(22): 7737-7740第70頁/共94頁SNORIMgBr+PdCl2(dppf)/Et2Or.t., 12

29、h, 75%SNORstepsSNOOOHOOH218dehydrodesoxyepothlione B第71頁/共94頁鹵代烴與有機鋅的偶聯(lián)Negishi偶聯(lián), E Negishi, 1976R1XR2ZnXNiLn or PdLnsolvent/L (ligand)L = PPh3, dppe, et alR1R2+第72頁/共94頁鎳催化Negishi偶聯(lián)機理L2Ni(II)X22 RZnX2 XZnXtransmetallationL2Ni(II)R2R1XRRoxidative additionreductive eliminationXR1L2Ni(II)第73頁/共94頁XR1L

30、2Ni(II)RZnXXZnXRR1L2Ni(II)R1XcoordinationRR1L2NiR1X(II)R1Rreductive eliminationoxidative addition第74頁/共94頁鈀催化Negishi偶聯(lián)機理LnPd(0)R1Xoxidative additiontransmetallationRZnXXZnXRR1LnPd(II)R1Rreductive eliminationXR1LnPd(II)第75頁/共94頁Negishi偶聯(lián)反應的特點Both Ni- and Pd phosphine complexes work well as catalysts.

31、 However, the Pd-catalysts tend to give somewhat higher yields and better stereoselectivity, and their functional group tolerance is better鈀的催化效果較鎳好第76頁/共94頁Negishi偶聯(lián)反應的特點（續(xù)）Of all the various organometals (Al, Zr, B, Sn, Cu, Zn), organozincs are usually the most reactivein Pd-catalyzed cross-coupli

32、ng reactions and do not require the use of additives (e.g., bases as in Suzuki cross couplings) to boost the reactivity有機鋅的鈀催化偶聯(lián)活性高，不需加助催化劑（如Suzuki偶聯(lián)需堿作助催化劑）第77頁/共94頁Negishi偶聯(lián)反應的特點（續(xù)）Greater functional group tolerance in both coupling partners than in the Kumada cross-coupling where more basic organ

33、olithiums and Grignard reagents are utilized as coupling partners有機鋅化合物堿性小于格林亞試劑和有機鋰，官能團容忍度較Kumada偶聯(lián)好第78頁/共94頁Negishi偶聯(lián)反應的特點（續(xù)）Other advantages of the use of organozincs include: high reactivity, high regio-, and stereoselectivity, wide scope and applicability, few side reactions and almost no toxic

34、ity與Still偶聯(lián)比較，有機鋅毒性小于有機錫第79頁/共94頁Negishi偶聯(lián)合成天然抗菌藥(-)-hectochlorinNSOOHOOSNOAcOOOClCl1第80頁/共94頁Jeannie R. P. Cetusic, Frederick R. Green III, Paul R. Graupner, and M. Paige Oliver. Total Synthesis of Hectochlorin. Org. Lett., 2002, 4(8): 13071310參考文獻(見41)第81頁/共94頁NSBrOEtOMgBrZnBr2/THF/(dppf)PdCl289%N

35、egishi couplingNSOEtONSOOHOOSNOAcOOOClCl1steps第82頁/共94頁鹵代烴與有機錫的偶聯(lián)Stille偶聯(lián)，1978，J K stilleRSn(alkyl)3R1XPd(0)/lignadR1R+第83頁/共94頁Stille偶聯(lián)的機理LnPd(0)R1Xoxidative additionXR1LnPd(II)transmetallationRSn(alkyl)3XSn(alkyl)3RR1LnPd(II)R1Rreductive elimination第84頁/共94頁Stille偶聯(lián)反應的特點Organostannanes are not sensitive to moist