有机反应机理第10章2

1、15.4 醇的氧化5.4.1 用二甲亚砜氧化5.4.2 用铬试剂氧化5.4.3 用高价碘化物氧化5.4.4 催化氧化（选讲）25.4.1 用二甲亚砜氧化二甲亚砜可与各种亲电试剂反应生成活性锍盐(sulfonium salt)活性锍盐与醇反应生成烷氧基锍盐烷氧基锍盐发生消除，生成醛或酮3二甲亚砜氧化醇为醛、酮的过程H3CSH3COEH3CSH3COER1R2OHH2CSH3CR1R2OHHBHBH2CSH3CR1R2OHR1R2Oaldehyde or ketoneH3CSCH2H+4解释二甲亚砜氧原子的亲核性前几章是否碰到过二甲亚砜作为亲核试剂的反应5用二甲亚砜氧化的典型反应Pfitzner-

2、Moffatt(普菲茨纳-莫法特)氧化, 1963Albright-Goldman氧化，1965Parikh-Doering（帕瑞克-多林）氧化，1967Swern（斯文）氧化，1978这些氧化反应的区别在哪里？6R1R2OHR1R2OR1R2OHDMSO/DCC/acidsolventPfitzner-Moffatt1963R1R2OHDMSO/Ac2OsolventAlbright & Goldman1965R1R2OHDMSO/TFAA or (COCl)2/NEt3solventSwern, 1976 & 1978DMSO/pyridine-SO3/NEt3/solventParikh

3、 & Doering, 19677Swern氧化DMSO/TFAA or (COCl)2/NEt3solvent1976年，D Swern发现TFAA能在50下活化DMSO氧化醇为醛酮R1R2Oaldehyde or ketoneR1R2OH1o or 2o alcohol1978年又发现草酰氯作为活化剂较TFAA更有效8Swern氧化的机理（TFAA活化）F3COCF3OOCH3SCH3OH3CSOCF3CH3OR1R2OHCF3COOHH3CSOR2CH2HR1HF3COCF3OOCH3SH3CO为什么DMSO不能一步取代三氟乙酸根离子？9Swern氧化的机理（TFAA活化，续）H3CSO

4、R2CH2HR1HNEt3H3CSOR2CH2HR1R1R2Oaldehyde or ketoneH3CSCH2H+讨论中间体内鎓盐结构10中间体的Pummerer重排OCF3OH2CSCH3H2CSOCF3CH3OH-eliminationOCF3OH2CSCH3OCF3O+11Swern氧化的机理（草酰氯活化）ClClOOH3CSOCH3OClOClCH3SCH3Cl+ CO2 + CO ClClOOCH3SCH3OCH3SCH3O12Swern氧化的机理（草酰氯活化，续）CH3SCH3ClR1R2OHH3CSOR2CH2HR1HNEt3H3CSOR2CH2HR1R1R2Oaldehyde

5、 or ketoneH3CSCH2H+13Swern氧化的特点无溶剂易爆炸!常在二氯甲烷中反应低温反应（78）DMSO与草酰氯的起始加成物在60以上不稳定TFAA作活化剂 30以上会发生Pummerer重排14Swern氧化法的改进Xun He and Tak Hang Chan. New non-volatile and odorless organosulfur compounds anchoredon ionic liquids. Recyclable reagents for Swern Oxidation. Tetrahedron, 2006 62 (14): 33893394二甲亚

6、砜，二甲硫醚有恶臭，成本高以下文献提出将亚砜负载在离子液体上，无恶臭，可循环使用15a: n =1b: n=2c: n=516Swern氧化合成vapiprostNHOOOCC6H4C6H5CO2H伐哌前列素：抗血小板凝聚17Daniel Lednicer. Strategies for organic drug synthesis and design, p16, New York:John Wiley & Sons, Inc, 1998参考文献18NHOOOCC6H4C6H5CO2H1. DMSO/TFAA2. DIBAL-HNHOOOCC6H4C6H5CO2H19Swern氧化合成(+)

7、-asteltoxinA mycotoxin，毒枝菌素OOHMeMeHOOHOMeOMeO20Eom, K. D., Raman, J. V., Kim, H., Cha, J. K. Total Synthesis of (+)-Asteltoxin. J. Am. Chem. Soc. 2003, 125(18): 5415-5421.参考文献21OOPMBMeOOHMeTIPSCl80%OOPMBMeOOTIPSMeOsO4/NMO85%OOPMBMeOOTIPSMeMeHOHO1. DMSO/(COCl)2/DCM2. EtMgBrOOPMBMeOOTIPSMeMeHOOH22OOPM

8、BMeOOTIPSMeMeHOOHOOPMBOHMeMeHOOHOOPMBCHOMeMeHOOHDMSO/(COCl)2/DCMsteps23OOPMBCHOMeMeHOOHiPrOPOEtOOiPrO79%OOPMBMeMeHOOHCO2Et1. DIBAL-H, 78%2. DDQ, 80%3. MnO2, 86%OOHMeMeHOOHCHOOPOOMeOMeOOMeMeLiHMDSOOHMeMeHOOHOMeOMeO24Pfitzner-Moffatt氧化DMSO/DCC/acidsolventPfitzner-Moffatt1963反应通式R1R2OH1o or 2o alcoholR

9、1R2Oaldehyde or ketone25Pfitzner-Moffatt氧化反应特点DMSO的活化剂DCC需过量（3倍以上），后处理时加草酸可除去过量的DCC反应必须有中等强度的酸催化，如H3PO4, 二氯乙酸，强酸吡啶盐等，强酸对反应有阻碍作用副产物二环己基脲较难除去，用水溶性的碳二亚胺替代DCC可克服这一问题26Pfitzner-Moffatt氧化机理NCNRRHNCNRRHCH3SCH3ONCNRRHOSCH3CH3DMSO的活化27Pfitzner-Moffatt氧化机理（续）NCNRRHOSCH3CH3R1R2OHHH2CSONRHNROR2H3CR1H3CSOR2CH2HR

10、1RNNROHH+28Pfitzner-Moffatt氧化机理（续）R1R2Oaldehyde or ketoneH3CSCH2H+H3CSOR2CH2HR129Pfitzner-Moffatt氧化反应操作将二环己基碳二亚胺（DCC)溶于DMSO中，然后加入醇和催化酸(磷酸，三氟乙酸，吡啶-磷酸等）进行反应30Pfitzner-Moffatt氧化反应实例ONHNOHOOAcOONHNOOHCOAcODMSO/DCC/H3PO4r.t. 90%315.4.2 用铬试剂氧化典型反应：Jones氧化1946年， E R H Jones发现三氧化铬与稀硫酸的溶液可将伯醇氧化成羧酸，仲醇氧化成酮 32R

11、1R2OHCrO3 or Cr2O72/acidH2O/acetoneR1R2OR1-2 = alkyl, arylketoneJones oxidation, 1946R = alkyl, aryl, alkenylROHCrO3 or Cr2O72/acidH2O/acetoneRHOROHOcarboxylic acidCrO3 or Cr2O72/acidH2O/acetonealdehyde33Jones氧化的机理稀溶液中铬酸以单体H2CrO4存在浓溶液中铬酸以二聚体H2Cr2O7存在反应中醇先与铬酸形成铬酸酯,再脱氢生成产物动力学同位素效应测定表明脱氢是速率控制步骤34CrOHOO

12、OHR1R2OH+HOHCrOHOOOR2R1HR1R2OHCrO3 + HOH2+HOHrds碱促进分子间脱氢机理35CrOHOOOHR1R2OH+HOH无碱促进分子内脱氢机理CrOHOOOR2R1HR1R2OH2CrO3 + 36Jones试剂的制备和氧化操作Jones试剂的制备实例Jones氧化操作将26.7g CrO3溶于23mL浓硫酸中，加水稀释到100mL020oC往醇的丙酮溶液中滴加Jones试剂37Jones试剂氧化仲醇的实例OHOJones oxidation75%38Jones氧化合成石斛碱石斛碱, (-)-dendrobineOOHNH3C39参考文献Sha, C.-K.

13、, Chiu, R.-T., Yang, C.-F., Yao, N.-T., Tseng, W.-H., Liao, F.-L., Wang, S.-L. Total Synthesis of (-)-Dendrobine via -CarbonylRadical Cyclization. J. Am. Chem. Soc. 1997, 119, 4130-4135.40OOHOHN3CrO3/H2SO4/H2Oacetone, r.t., 1.5 h, 94%OOHON31. PPh3/THF, r.t., 12 h2. NaBH3CN/AcOH/MeOH r.t., 12 h Staud

14、inger reaction OOHHN(CH2O)n/HCO2H/H2O120oC, 12 h42% for 3 stepsOOHNH3C41Staudinger反应，1919R1NNN+PR3R1NPR3R1NNNPR3NNNPR3R1N242Staudinger反应产物的转化R1NPR3R1NH2R3PO+H2OR1OHOR3R2NR1R3R2OOR2NR1HR2XOR2XNR143General features of Jones oxidationThe oxidation is usually carried out in acetone, which serves a dual

15、purposeIt reacts with any excess oxidant so it protects the product from overoxidationIt dissolves most organic substrates, and44Primary alcohols are converted to carboxylic acids with the intermediacy of aldehydesAldehydes can be isolated by distillation sometimes if the aldehyde is volatile45Allyl

16、ic and benzylic alcohols are efficiently oxidized to the corresponding aldehydes with little or no over-oxidationIsolated double and triple bonds remain unchangedbut ,-unsaturated aldehyde products may undergo double bond isomerization46For particularly acid sensitive or otherwise delicate substrate

17、s the use of the strongly acidic Jones reagent is clearly not the best method of oxidation47Jones氧化的改进Collins试剂氧化（Sarett and Collins, 19531968)制备CrO3吡啶络合物CrO3(pyridine)2 (Collines试剂）在二氯甲烷中氧化1o or 2oalcoholaldehyde orketoneR1R2OR1R2OHCrO3-pyridineDCM48Collines试剂氧化实例CH3(CH2)5CH2OHCH3(CH2)5CHOCrO3(Py)2

18、/CH2Cl225oCheptan-1-olheptanal7084%可氧化伯醇为醛49PCC和PDC氧化（Corey, 1975 and 1979)R1R2OR1R2OHPCC or PDCDCM1o or 2oalcoholaldehyde orketonePCC：氯铬酸吡啶鎓盐（弱酸性）PDC：重铬酸吡啶鎓盐（中性）50氧化铝负载PCC的制备2.5 g (25 mmol) CrO3溶于5 mL 6 mol/L的盐酸中，0，5 min内加入2.0 g (25 mmol)吡啶。待析出桔黄色PCC结晶后升温至40使结晶溶解，搅拌下加入20.8 g Al2O3，减压除水，100干燥得负载氧化剂P

19、CC/ Al2O3。51PCC氧化苄醇的实例CH2OHBnOBnOBnOPCC/Al2O3/DCM0oC, 2 h, 77%CHOBnOBnOBnO52PFC氧化仲醇的实例HOOC(CH3)2SiMe3OOC(CH3)2SiMe3PFC/CH2Cl2r.t.90%PFC：氟铬酸吡啶鎓盐53Jones试剂与Collines试剂、PCC、PDC的比较对伯醇的氧化Jones氧化：产物往往为羧酸Collines试剂氧化PCC氧化PDC氧化可生成醛54Collines试剂与PCC、PDC的比较Collines试剂：不稳定，易吸潮，难保存，要求无水条件，试剂要过量（5倍量以上）PCC，PDC：不吸潮，易保

20、存，使用广泛55PCC与PDC的比较PCC：呈弱酸性，氧化对酸不稳定的化合物，可加入NaOAc；使用载体可避免生成黑褐色胶状物PDC：可在中性条件下起反应，在DMF或DMSO中氧化能力强，会生成羧酸56不同条件下PCC和PDC氧化伯醇的实例OHcitronellol，香茅醇PCC/CH2Cl2OPCC/CH2Cl2/NaOAcPDC/CH2Cl2CHOPDC/DMFCOOH575.4.3 用高价碘化物氧化(Dess-Martin氧化)1893年，发现IBXIBX几乎不溶于任何有机溶剂，应用受到限制ICOOHKBrO3/H2SO4, orOxone/H2O, 70oC, 3 hIOOOHO2-i

21、odoxybenzoic acid (IBX)Oxone = 2 KHSO5-KHSO4-K2SO4581983年，D B Dess和J C Martin由IBX的酰化合成了能溶于多种有溶剂的DMPIOOOHO2-iodoxybenzoic acid (IBX)Ac2O/TsOH, 80oC, 2 h， orAcOH/Ac2O, 100oCIOAcOOAcOOAcDess-Martin periodinane (DMP)59以DMP为氧化剂的氧化就称作Dess-Martin氧化R1R2OHR1R2NOHorDMPR1R2ODMP可将醇和肟氧化成醛或酮60Dess-Martin氧化的机理IOAc

22、OOAcOOAcIOAcOOAcOAcR1R2OHAcOHIOAcOOAcOOR1R2HAcOHR1R2OIOOAcO+61Dess-Martin氧化的特点 Mild reaction conditions (room temperature, neutral pH)2) High chemoselectivity3) Tolerance of sensitive functional groups on complex substrates4) Long shelf-life and thermal stability (unlike IBX, which has been found to

23、 be explosive)62Dess-Martin氧化合成ustiloxin DUstiloxin: 黑粉菌毒素 ONHHNNHMeHOOHOOONHCO2HEt63Cao B, Park H, Joullie M M. Total Synthesis of Ustiloxin D. J. Am. Chem. Soc. 2002, 124(4): 520-521参考文献64ONHHNNHO2STBSOOHOOOHEtNO21. DMP/DCM2. NaClO23. Gly-OBn/DEPBT iPr2NEt/THF66% for 3 stepsONHHNNHO2STBSOOHOOONHCO

24、2BnEtNO2stepsONHHNNHMeHOOHOOONHCO2HEt65EtOPEtOOOBtOCROHBtOOCROPOEtOEtOHOCROBtHOPOEtOEtODEPBT(BDP)缩合机理66OCROBtNHR1HRNHR1OHOBtHOBtNNNOH=675.4.4 催化氧化化学计量氧化剂氧化存在的主要问题氧化剂消耗大，成本高产生大量副产物，对环境危害大68(2) 钌催化氧化(1) 铜催化氧化(3) 钯催化氧化(4) 无过渡金属催化氧化69(1) 铜催化氧化CuCl/TEMPO体系催化醇的氧化CuCl/Phen/DBADH2/K2CO3体系催化醇氧化 70CuCl/TEMPO体

25、系催化醇的氧化1974年Cella偶然发现TEMPO可将醇氧化为醛酮Cella用间氯过氧苯甲酸(mCPBA)氧化四甲基哌啶醇制氮氧化物，发现羟基被氧化成酮71mCPBA不具备将羟基氧化成酮的活性NHOHMeMeMeMemCPBANOMeMeMeMeO酮是如何生成的？72NHOHMeMeMeMemCPBANOHMeMeMeMeONOMeMeMeMeONOHMeMeMeMeONOHMeMeMeMeOmCPBA73Cella J A，Kelley J A，Kenehan E F. J Chem Soc, Chem. Commun. 1974, 943参考文献74提出TEMPO催化氧化法R1R2OHm

26、CPBA/TEMPO(cat.)DCM, r.t., 1 hR1R2ONMeMeMeMeOTEMPO7576Cella J A, Kelley J A, Kenehan E F. J Org Chem, 1975, 40, 1860Ganem B. J Org Chem. 1975, 40,199877R1R2OHR1R2OO2/TEMPO/CuCl1984年M. F. Semmelhack提出CuCl-TEMPO催化分子氧氧化醇的方法Semmelhack M F, Schmid C R, Corts D A, et al. J Am.Chem. Soc, 1984,106:337478R1R

27、2OHR1R2OO2/TEMPO/CuClbmimPF6, 65oC2002年R Gree等在离子液体中实现了该氧化反应I A. Ansari, R Gree. Org. Lett.J, 2002,4(9):1507NNPF6bmimPF6798081PF6NOMeMeMeMeONONR1R2OHR1R2OO2/TEMPO-IL/CuClbmimPF6, 65oC以离子液体固定化的TEMPO作催化剂，实现了离子液体和催化剂的循环使用TEMPO-IL82离子液体固定化TEMPO催化氧化醇的结果entry alcohol product time/h conversion/%a yield/%b

28、1 OH O 11 99 96 2 OHO2N OO2N 7 92 86 3 OHMeO OMeO 11 99 82 4 OHCl OCl 9 99 90 11 3 - 5 OH O 43 30 - 8312 78 - 6 OH O 44 99 77 7 OH O 16 95 94 8 OOH OO 13 81 52 9 OH O 60 - - 10 n-C11H23-CH2OH n-C11H23-CHO 65 53 - 84离子液体和催化剂循环使用结果run time/h conversion/% yield/% 1 11 99 96 2 11 99 95 3 11 97 96 4 11 9

29、9 96 5 11 99 98 6 11 99 96 O2/TEMPO-IL/CuClbmimPF6, 65oCCH2OHCHO85可能的机理NONOHHR1R2OHHR1R2OR2R1OH2O1/2O2NOHNONOCu (II)Cu (I)Cu (II)86CuCl/Phen/DBADH2/K2CO3体系催化醇氧化1996年，Marko 等在 Science 上报道了 CuCl/Phen/DBADH2/K2CO3 体系，能在温和条件下将伯醇、仲醇、烯丙醇和苄醇氧化成相应的醛、酮，收率高 Phen：1,10-菲咯啉，DBADH2：肼二甲酸二叔丁酯87CuCl/Phen/DBADH2/K2CO

30、3体系催化醇氧化通式R1R2OHCuCl/Phen/DBADH2/O2K2CO3 ( 2 Equiv)/tolueneR1R2OONHNHOOODBADH2NNPhenCuCl/Phen/DBADH2的用量为底物量的5 mol%88Marko I. E.; Giles P. R.; Tsukazaki M.; Brown S. M.; Urch C. J., Copper-catalyzed oxidation of alcohols to aldehydes and ketones: An efficient, aerobic alternative. Science 1996, 274 (

31、5295): 2044-2046 参考文献89Phen + CuCl + ZHNNHZ(Phen)CuNZNHZO2(Phen)CuONZNHZ)2(Phen)CuOHNZNZRCH2OHHOH(Phen)CuOCH2RNZNZ(Phen)CuONZNHZCHRRCHOCuCl/Phen/DBADH2体系催化氧化醇的机理90(2) 钌催化氧化TPAP(Pr4N+RuO4)/NMO体系： Ley氧化Ru(PPh3)3Cl2/TEMPO/O2体系91过钌酸四异丙基铵盐TPAP(Pr4N+RuO4)催化氧化R1R2OHR1R2OTPAP/NMO/solvent/MS4A, r.t.NMO = N-m

32、ethylmorpholine N-oxideLey氧化，198792Ley氧化的条件TPAP用量：5%(相对于被氧化物）共氧化剂：双氧水或N-甲基吗啉氧化物NMO溶剂：CH2Cl2, CH3CN等助催化剂：分子筛93Ley氧化的机理Ru(IV)NMORu(VI)94TPAP的制备 将RuCl4 nH2O加入到过量的溴酸钠(NaBrO3)的1mol/L的碳酸钠水溶液中，氧化成RuO4，接着加入Pr4NOH，即会产生深绿色的TPAP晶体95Ley氧化合成pironetin农用抗生素，作物防倒伏剂 OOHMeOMeMeMeO96参考文献Keck G E, Knutson C E, Wiles S

33、A. Total Synthesis of the Immunosuppressant (-)-Pironetin (PA48153C). Org. Lett. 2001, 3：707-71097OBnOHMe1. MeSnBu3/TiCl42. KH/MeIOBnMeOMeMe9-BBN/H2O2OBnMeOMeMeOHTPAP/NMO/DCM/MS4A0oC to r.t., 25 min, 100%OBnMeOMeMeHOCBr4/PPh3/BuLi/MeIOBnMeOMeMeMe98TPAP/NMO/DCM/MS4A0oC to r.t., 25 min, 100%stepsOOHMeOMeMeMeOOBnMeOMeMeMeLi/NH3OHMeOMeMeMeOMeOMeMeMeH99Ru(PPh3)3Cl2/TEM