教學(xué)課件學(xué)術(shù)資源大全高等有機(jī)化學(xué)lecture 22 radicals

1、Lecture 22: RadicalsC. M. GampeChem 106Reactive Intermediates I: RadicalsChristian M. GampeOctober 26, 2011Key QuestionWhat is the origin of regioselectivity in radical reactions?OOOtBuOH2BNEt3HHOOOagHHScope of LectureStructure and StabilityCascade ReactionsGenerationWhat is the origin of stereosele

2、ctivity in radical reactions?radicalsMeheteroatom- centered radicalsHOC-centered radicalsOHOBnPhOOBnPhOStereoselectivityHReactivityHOBnOBnRegioselectivityd.r. 99:1Helpful References1. Radicals in Organic Synthesis Vol.1 & 2, P. Renaud, M. P. Sibi, Wiley-VCH 2001.2. Marchs Advanced Organic Chemistry:

3、 Reactions, Mechanisms, and Structure, M. B. Smith, J. March, Wiley Interscience 20073. Radical Reactions in Natural Product Synthesis, C. P. Jasperse, D. P. Curran, T. L. Fevig Chem. Rev. 1991, 91, 1237.4. Radical Reactions in Organic Synthesis, S. Zard, Oxford University Press, 2003.5. Molecular O

4、rbitals and Organic Chemical Reactions I. Fleming John Wiley & sons, 2010. and many more textbooks on radicals.What is the mechanism of this reactions?PhPhNNOMe OMe MeOOBu3SnH, AIBNO HMeSMeSMeRHHHRHRH HLecture 22: RadicalsC. M. GampeChem 106DefinitionRadicals are species (atoms, molecules, ions) tha

5、t contain at least one unpaired electron1. HistoryMoses Gomberg (U Michigan) is considered founding father of radical chemistry since he postulated the triphenylmethyl radical in 1900 and broke with the notion that carbon always had to be tetravalent. Here are some more cornerstones of the developme

6、nt of radical chemistry:2. Structure and StabilityWhats the structure of alkyl radicals, planar or pyramidal?f RH HHHRH HRElectron spin resonance spectra as well as IR spectra of the methyl radical suggest that the species is planar, with a very low barrier for out-of-plane bending. However, similar

7、 measure- ments show that CH2F, CHF2, and CF3 are significantly pyrami- dalized with a f of 5, 13, and 18, respectively.How can this finding be explained?s-componentPhPhClM. Gomberg, 1900:JACS 1900, 22, 757PhPhZn dustPh3CPhPh3SnHIn reducing the symmetry from planar to pyramidal Y can mixBrHvan de Ke

8、rk, 1957:Acc Chem Res 1968, 1, 299Ph3SnBr3with Y4, which leads to a stabilization. The efficiency of this stabilization depends on the energy of Y4, which is lower, if the substitutents are electronegative.Hence, electronegative substituents favor a pyramidal geometry.Bu3SnHBarton and McCombie, 1975

9、:J. Chem. Soc. Perkin I, 1975, 1, 1574OSMeHRRSIMeplanarpyramidalH MeMeMeBu3SnHCurran, 1985:Y4MeMeHHHirsuteneJ. Am. Chem. Soc. 1985, 107, 1448Y3Mg-bisoxazolin catalyst Et3B/O2OOOMeYang, 2001:JACS 2001, 123, 8612.OEtCO Et2BrMeY2Y1BrMeMeMeMe92 % eeLecture 22: RadicalsC. M. GampeChem 106p-componentp-Int

10、eractions with the substituents become less stabilizing as the energy gap between the participating orbitals inreases. Further- more, for a given energy gap the interaction becomes less stabili- zing as the overlap increaese. This is a result of being a 2-center- 3-electron interaction as opposed to

11、 a 2-center-2-electron inter- action thats present for instance in carbocation-p-interactions.The same effect is also held responsible for the sigificant and counterintuitive pyramidalization of the tBu-radical:out of plane bending angle: 22H Hbarrier to inversion: 1.2 kcal/mol (Houk, JACS 1981, 103

12、, 5046.and ref. therein.)Me MeHRadicals with resonance are planar, like:planarpyramidalHVinyl radicals can exist either in s- or in p-forms-radicalp-radicalRadicals constrained in cyclic systemsThe following radicals have been determined to be pyramidalized because planarization would result in sign

13、ificantly inreased ring strain.That means there is a sweet spot for electronegative substituents (small energy gap) in a pyramidal geometry (less overlap), which results in maximum stabilization of the system. Pyramidilization seems to occur generally if s-acceptor and p-donor substituents are prese

14、nt (halogens, OH, NH2). For a more detailed discussion, see: Epiotis, JACS 1978, 100, 1352. Bents rule likewise predicts electron withdrawing substituents to prefer binding to an sp3 ratherthan an sp2 carbon, which results in pyramidalization.For this structure, an anomeric effect was determined tha

15、t favors this structure over the epimer by ca. 1.8/1ROMeHROMeDespite low inversion barriers (alkenylalkynyl3 2 1 methyl resonance hyperconjugation captodativeKinetic stability refers to tendency of a radical to form a non- radical species and is mainly governed by steric factors or spin conservation

16、 (singulett vs triplett). Here are some rather stable radicals: (see also persistent radicals below)LUMOSOMOHOMOMeMeMeMeO-ONONOBDE in kcal/molBDE compared to MeH131-26 Further reading:H. Zipse, in Top. Curr. Chem. 2006, 263, 163.111-6H110-5H3. Generation of radicalsBefore we go into detail lets talk

17、 about some general features of radical reations. We can distinguish 3 different elementary radical reactions:H106-1MeH1050iPr99+4HInitiation:IIR XIII XtBuH95+6IRH86+10Propargation:R285+19Group or Atom TransferRR2 XR XPhHPhO H87+18Addition or FragmentationRR2R2NN RNH273+31RearrangementOR2RHLecture 2

18、2: RadicalsC. M. GampeChem 106- Radical reactions can be surprisingly selective, if the selectivity is induced by the substrate. However, the stereochemical outcome is difficult to control by reagents.Termination: Recombination or DisproportionationR2 R2RRRReRRReduction or OxidationCommon ways to ge

19、nerate radicals:eThermolysis. Covalent bonds with BDE of 40 kcal/mol can be homolyzed at T 102/mol sReaction(2,2-Azobis(4-methoxy-2,4-dimethylvaleronitrile) mixture of meso and rac: V-70Me MeMe MeOCNNsolventaddition/H-abstractionSide reactionNNCOMek ca 102/mol st1/2 = 10 h in toluene at 30 Crac: V-7

20、0Lt1/2 = 1 h in toluene at 30 CMeMeMeWhat are the fundamental differences between ionic and radical reactions?2,2-Azobis(2-methylpropionamidine)dihydrochlorideV-50NHMeMeN- Rates of radical reactions are bearly influened by varying solvent effects (meaning polarity; the solvent needs to be inert howe

21、ver.)H2NNMeNH2t1/2 = 10 h in water at 69 CMeNH- Radical reactions are less sensitive to steric factors(since there are no counterions or solvating spheres involved)MeMeN4,4-Azobis(4-cyanopentanoic acid)V-501NMe MeCO2HHO C2- Radical reactions are often surprisingly mild and compatible with OH and NH

22、groups.t= 10 h in water at 69 C1/2Lecture 22: RadicalsC. M. GampeChem 106Redox reactions are another common way to generate radicals. A number of transitions metals are capable to generate radicals by one electron reductions of oxidations.Electrochemical methods are also available.PeroxidesOCO2Diben

23、zoyl peroxidet1/2 = 7 h in CCl4 at 70 COPhPhPhOPhCO2Ooxidative: Ce(IV), Fe(III), Cu(II), Mn(III), anode oxidationreductive: alkali metals, Sm(II), Co(I), Ti(III), cathode reductionODiacetyl peroxide decomposes at 25 C shock, light, heat sensitiveOMeMeOOReviews Sm(II): G. A. Molander, C. R. Harris, C

24、hem. Rev. 1996, 96, 307. D. J. Edmonds, D. Johnston, D. J. Procter, Chem. Rev. 2004, 104, 3371. Mn(III): B. B. Snider, Chem. Rev. 1996, 96, 339.OCO2OMeMetert-Butyl perbenzoatet1/2 = 20 h at 100 COtBuPhPhOMePhotolysis likewise gives access to radicals:Absorption of light transfers the molecule into a

25、n excited state. This often leads to simultanous generation of a vibrationally excited state in E2, which results in bond cleavage in the first vibration. It is also possible that the excited state is completely non-bonding.ODi-t-butyl peroxalatet1/2 = 12 h at 25 COOtButBuOOOOMeMe2 xMeDi-t-butyl per

26、oxidet1/2 = 218 h at 100 COtBu tBuOTrialkylboranesNote that lower temperatures for radical initiation allow the reactions to be more selective. In this respect organoboranes have been shown to excellent radical generators. rown first established that the conjugate addition of Et with Et3B proceeds v

27、ia a radical pathway initiated by O2 (JACS 1970, 92, 710).Notably, whereas trialkylboranes ignite spontaneously in air, they can be handled in aqueous reaction medium. For instance, Et- radicals are generated from Et3B in the presence of traces of O2 at -78 C.energyE3E2E1internuclear distance-78 CWh

28、ich bonds are commonly photolyzed?Et3B + O2Et3B O OEtLecture 22: RadicalsC. M. GampeChem 106BDE for photolysis in kcal/mol:4. Radical reactions4.1 ReductionsRadical reductive defunctionalization using group 14 hydrides is a synthetically highly valuable transformationWith E=hn and n=c/l follows:59Cl

29、Clvisible light:780-380 nm; E=37-75 kcal/mol30-50ROORUV:380-200 nm; E=75-143 kcal/molAIBN, Et3Bor other startersBu3SnHR H35-50RNNRBu3SnRBu3SnBu3SnH40RONOBu3SnXR X48ROClX = I, Br, Cl, NO2, NC, S, SeR2N Cl45rates for reduction of R with Bu3SnH in mol-1s-1R=rates for reduction of RX with Bu3SnH in mol-

30、1s-1RX=For instance, both the diazo and peroxide radical initiators generate radicals upon irradiation with UV-light.Photosensitizers are also commonly employed. These are compounds that easily undergo excitation and inters system crossing to give triplet radicals that initiate the desired reaction.

31、inter system6x108alkyl-IPhMe 1094x108Haryl/vinyl-I alkyl-Br107-108Me9x107cyclopropylR-Xaryl/vinyl-Br a-ester-Cl alkyl-SePhcrossing3S-XRS*Me105-1061x1073x1062x1062x1064x104hn1X-X11SS*1alkyl 2alkyl 3alkyl benzylspin transfer 3X-X1S*alkyl-Cl alkyl-SPh102-104Benzophenone, Rose bengal, or porphyrin dyes

32、are often employed:OHOOR-HhnREt3SiH Ph3SiH (Me3Si)3SiH5x1035x1041x1064x106rates for reduction of 1alkylat 80 C with various reagents in mol-1s-1PhPhPh3OPhPhPhhn23TPP1Otetraphenyl porphyrin (TPP)1TPP+2Ph GeH3(Me3Si)3GeH 2x107More recently Ru(bpy)3Cl2 is used as photoactive redox catalyst.I. a. MacMil

33、lan JACS 2007, 7004; JACS 2008, 398.Bu3SnH Ph3SnH6x1062x107Lecture 22: RadicalsC. M. GampeChem 106Tin-free versions of the Barton-McCombie deoxygenation employ silane or germane reagents. Recenty, Wood described the use of Me3B and H2O. It was shown that Me3B initiates the radical reaction (with tra

34、ce O2) and H2O is the ultimate hydrogen donor (JACS 2005, 127, 12513).Despite their toxicity the highly effective tin reagents are still often employed. Practical tip: 10% KF on SiO2 helps to remove tin residues from the crude product (Chem. Commun 2004, 1968.)A number of functional groups can be re

35、ductively removed under the aforementioned conditions. For deoxygenations Barton and Mc Combie provided a highly efficient protocol (J. Chem. Soc 1975, 1, 1574; Chem. Rev. 1989, 89, 1413) that involves formation of xanthates (I)A realted reaction is the Barton decarboxylation (Proc. Chem. Soc1962, 3

36、09; J. Chem. Soc. Chem. Commun. 1980, 732.)NNaOBu SnH, AIBN3toluene, rfx.OBu SnH, AIBNSOCl , then:OBu3SnNaH, CS2,then MeIS3toluene, rfx. SS2NSMeSMeROR OHROHR OROSIOOBu3SnSRHNNRBu3SnS ROROR HRSMeSMeBu3SnHSSBu3SnROIIOBu Sn3Bu3SnBu3SnBu3SnHSORR ONCO2SNAlso employed:NSBu3SnR OPossible sidereactions are

37、the formation of methyl ethers by reduction of intermediate I or O-to-S migration to give dithio- carbonates.This decarboxylation relies on the formation of a carboxyl radical. These species undergo rapid decarboxylation as was observed previously by Hunsdiecker (Chem. Rev. 1956, 56, 219)These defun

38、ctionalizations can be incorporated into cascade reactions, for instance (Synlett 1992, 987):Bu3SnH,AgBrBrOOOBr2RR BrAgBrROROHROCON2OAIBN,toluene, rfx.OThe fact that tinhydride is a good hydrogen donor has been attributed to the weak Sn-H bond. H-abstraction from carbon is more complicated. Consider

39、 the following:ONOCO Et2CO2EtLecture 22: RadicalsC. M. GampeChem 1064.2 Additions to double bondsOrbital interactions also dominate the selectivity in radical additions to double bonds. That means that nucleophilic radicals react preferrentially with electrophilic double bonds and vice versa.OOOtBuO

40、H2BNEt3HHOOOagHHIt has been shown that the t-butoxy radical shows preferenceXfor abstraction of the g-H whereas a boryl radical abstracts the a-H.X.Coulombic factors barely play a role in radical reactions but the reactivity can be understood on the basis of the frontier orbital theory. The t-butoxy

41、-radical is a electrophilic radical (electro-CO2MeCO2MeX =HMeCl0.01 10CO2MeCN 150350rel rates = 1negativity of O) and hence attacks the more nucleophilic C-H bond.In contrast, this boryl radical is nucleophilic (lone pair interaction with N) and prefers to react with the energetically lower CH-bond.

42、 Remember that substituents influence the nucleo-or electrophilicity of carbon radicals.Ph MeO2CPhMeO CCO Me22XMeO2CCO2Et 1XX =N-morpholineMe 3.5nucleophilic radicalnucleophilic radicalrel rates =23LUMOOn the basis of this data we can also understand why the following copolymerization is selective t

43、o give a carbon chain with alternating substituents:LUMOLUMOSOMOHOMOHOMOHOMOelectrophilic radicalradicalMeO2COAc CO2Meelectrophilic radicalpolymerizationMeO COAc 2CO2MeStereochemical effects likewise dictate, which H will be abstracted:CO2MeCO2MeAngew. Chem. Int. Ed. 1983, 22, 753; Acc. Chem. Res. 1

44、976, 9, 183.OOMetBuOMepreferred 87/13The addition of radicals to double bonds proceeds via a Brgi- Dunitz-like angle and, hence, intramolecular reactions follow Baldwins rules (Tetrahedron 1985, 3925; JOC 1987, 959).For instance, in the following case formation ofthe five-membered ring is kineticall

45、y preferred, although the less stable primary radical is formed. Thus, 5-membered rings will be formed only if the reaction is under kinetic control.OOOOtBuOonly observedOOLecture 22: RadicalsC. M. GampeChem 106These kinetic measurements provided the foundation for the development of radical clocks.

46、 A radical clock is a unimolecular reaction, whos kinetics are known, which is applied to time an- other radical reaction. Since absolute kinetic measurements for radical reactions are sophisticated (half life of a radical ca. 1 ms), these clocks provide facile mechanistic insights in reactions, in

47、which radicals might be involved.The simplest radical clock is based on the ring opening of an a- cyclopropyl radical:k = 6.7 x 107 /s6-endo-trigk = 4 x 1035-exo-trig k = 2 x 105+A classic example of this reactivity is Currans synthesis of hirsutene (JACS 1985, 107, 1488)MeIH MeMeMeBu3SnHMeMeHHHirsuteneThe unexpected 6-endo-trig cyclization product an be preferred if thermodynamic factors dominate. For instance, due to stabilityof the starting radical, 5-exo-trig cyclization is reversible and allows the thermodynamically preferred 6-endo-trig prod