Reduccion y oxidacion Universidad de Granada -SPAIN-

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Reduccion y oxidacion Universidad de Granada -SPAIN-

  1. 1. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   1  
  2. 2. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   2  Obje>vos  • Conocer  los  procesos  que  permiten  variar  (incrementar/disminuir)  el  nº  de  oxidación  medio  de  los    C  de  un  compuesto  orgánico  • Conocer  los  reac>vos  que  permiten  llevar  a  cabo  la  oxidación/reducción  de  un  compuesto  orgánico  • Conocer  los  mecanismos  de  las  reacciones  de  oxidación/reducción  según  el  reac>vo  usado  • Conocer  la  quimioselec>vidad  de  los  reac>vos  y  procesos  de  oxidación/reducción  
  3. 3. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   3  Generalidades  Números  de  oxidación  en  compuestos  Orgánicos  El  número  de  oxidación  es  un  número  entero  que  representa  el  número  de  electrones  que  un  átomo  pone  en  juego  cuando  forma  un  compuesto  determinado.  A-­‐B  Χ  A  <  Χ  B    A BA BA BA+B-A2+B2-A3+B3-A-­‐A  Χ  A  =  Χ  A    A AA AA A A···A···A·A·A··A··Numero  de  oxidación  de  un  átomo    =  Carga  formal  del  atomo    Moléculas  neutras:  Suma  de  nº  oxidación  =  0  Iones:  Suma  de  nº  oxidación    =  carga  del  ion  14 Oxidations and ReductionsFigure 14.1 shows how the oxidation numbers of the atoms in H2O are obtained inthis way. According to the foregoing rules, the bonding electrons of both O¬H bondsare assigned to the more electronegative oxygen, not to the hydrogens. The O atomthus possesses oxidation number Ϫ2, and both H atoms have oxidation number ϩ1.nrsH O H1. Step: Set oxidation number = + 12. Step: Set oxidation number = – 2nrs CH41. Step: Set oxidation number = + 12. Step: Set oxidation number = – 4For the assignment of the oxidation numbers in hydrogen peroxide (Figure 14.3),The same procedure is used in Figure 14.2 to determine the oxidation numbers inmethane, the simplest organic molecule. Since carbon has a higher electronegativitythan hydrogen, the two bonding electrons of each C¬H bond are assigned to carbon.Hence, the oxidation number of carbon is Ϫ4 and that of all H atoms is ϩ1.580] 5/23/01 11:48 AM Page 54614 Oxidations and Reductions546Figure 14.1 shows how the oxidation numbers of the atoms in H2O are obtained inthis way. According to the foregoing rules, the bonding electrons of both O¬H bondsare assigned to the more electronegative oxygen, not to the hydrogens. The O atomthus possesses oxidation number Ϫ2, and both H atoms have oxidation number ϩ1.Fig. 14.1. Determinationof the oxidation numbersin H2O.H O H1. Step: Set oxidation number = + 12. Step: Set oxidation number = – 2Fig. 14.2. Determinationof the oxidation numbersin CH4.CH41. Step: Set oxidation number = + 12. Step: Set oxidation number = – 4Fig. 14.3. Determinationof the oxidation numbersin H2O2.For the assignment of the oxidation numbers in hydrogen peroxide (Figure 14.3),the two electrons of each O¬H bond count only for the O atoms, and the two bond-ing electrons of the O¬O bond count 50% to each O atom. In this way, one finds theoxidation numbers in ϩ1 for both H atoms and Ϫ1 for both O atoms.Applying the analogous approach to ethane (Figure 14.4) results in the oxidationH O O H1. Step: Set oxidation number = + 12. Step: Set oxidation number = – 1The same procedure is used in Figure 14.2 to determine the oxidation numbers inmethane, the simplest organic molecule. Since carbon has a higher electronegativitythan hydrogen, the two bonding electrons of each C¬H bond are assigned to carbon.Hence, the oxidation number of carbon is Ϫ4 and that of all H atoms is ϩ1.thus possesses oxidation number Ϫ2, and both H atoms have oxidation number ϩ1.sH O H1. Step: Set oxidation number = + 12. Step: Set oxidation number = – 2s CH41. Step: Set oxidation number = + 12. Step: Set oxidation number = – 4ss H3C CH31. Step: Set oxidation number = + 12. Step: Set oxidation number = – 3For the assignment of the oxidation numbers in hydrogen peroxide (Figure 14.3),the two electrons of each O¬H bond count only for the O atoms, and the two bond-ing electrons of the O¬O bond count 50% to each O atom. In this way, one finds theoxidation numbers in ϩ1 for both H atoms and Ϫ1 for both O atoms.Applying the analogous approach to ethane (Figure 14.4) results in the oxidationnumber of ϩ1 for each H atom and Ϫ3 for each C atom.H O O H1. Step: Set oxidation number = + 12. Step: Set oxidation number = – 1The same procedure is used in Figure 14.2 to determine the oxidation numbers inmethane, the simplest organic molecule. Since carbon has a higher electronegativitythan hydrogen, the two bonding electrons of each C¬H bond are assigned to carbon.Hence, the oxidation number of carbon is Ϫ4 and that of all H atoms is ϩ1.Fig. 14.2. Determinationof the oxidation numbersin CH4.CH41. Step: Set oxidation number = + 12. Step: Set oxidation number = – 4Fig. 14.3. Determinationof the oxidation numbersin H2O2.Fig. 14.4. Determinationof the oxidation numbersin C2H6.H3C CH31. Step: Set oxidation number = + 12. Step: Set oxidation number = – 3For the assignment of the oxidation numbers in hydrogen peroxide (Figure 14.3),the two electrons of each O¬H bond count only for the O atoms, and the two bond-ing electrons of the O¬O bond count 50% to each O atom. In this way, one finds theoxidation numbers in ϩ1 for both H atoms and Ϫ1 for both O atoms.Applying the analogous approach to ethane (Figure 14.4) results in the oxidationnumber of ϩ1 for each H atom and Ϫ3 for each C atom.Figure 14.5 reminds us that the oxidation numbers of the atoms in ions and mole-cules are determined in the same way as in inorganic chemistry. In the ammonium ion,the four H atoms again possess the oxidation number ϩ1, and the N atom has the ox-idation number Ϫ3.H O O H1. Step: Set oxidation number = + 12. Step: Set oxidation number = – 1methane, the simplest organic molecule. Since carbon has a higher electronegativitythan hydrogen, the two bonding electrons of each C¬H bond are assigned to carbon.Hence, the oxidation number of carbon is Ϫ4 and that of all H atoms is ϩ1.14.1 Oxidation Numbers in Organic Chemical Compounds and Redox Reactions 547The simplest organic analog of the ammonium ion is the methylammonium ion(Figure 14.6). If one assigns the bonding electrons of the C¬H bonds to carbon andthose of the N¬H and C¬N bonds to nitrogen, one obtains oxidation numbers of ϩ1Fig. 14.5. Determinationof the oxidation numbersin NH4ϩ.H N41. Step: Set oxidation number = + 12. Step: Set oxidation number = – 3Bruckner Ch14 [545-580] 5/23/01 11:48 AM Page 54714.1 Oxidation Numbers in Organic Chemical Compounds and Redox ReactionsThe simplest organic analog of the ammonium ion is the methylammonium ion(Figure 14.6). If one assigns the bonding electrons of the C¬H bonds to carbon andthose of the N¬H and C¬N bonds to nitrogen, one obtains oxidation numbers of ϩ1for each of the H atoms, Ϫ3 for the N atom, and Ϫ2 for the C atom.FoinH3C NH31. Step: Set oxidation number = + 12. Step: Set oxidation number = – 33. Step: Set oxidation number = – 2The procedure exemplified for ethane (Figure 14.4) can be employed to assignoxidation numbers to the C and H atoms of all hydrocarbons. The oxidation numberof every H atom is ϩ1. However, the oxidation numbers in the C atoms depend onFoinH N41. Step: Set oxidation number = + 12. Step: Set oxidation number = – 33003T Bruckner Ch14 [545-580] 5/23/01 11:48 AM Page 547Moléculas  con  Enlace  covalente  
  4. 4. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   4  Generalidades  Números  de  oxidación  en  compuestos  Orgánicos  Fig. 14.7. Oxinumbers of Cselected hydrosubstructures.C CH3C CH2 C, C CH2C CH C,CC C,CCCCCCC C C,C CC ,H C, C CHC C COxidation number = –3 for the C printed in bold in:Oxidation number = –2 for the C printed in bold in:Oxidation number = –1 for the C printed in bold in:Oxidation number = 0 for the C printed in bold in:Fig. 14.8. Oxinumbers of th1- and 2-butenH3C CH2 CH CH2 H3C CH CH CH3–3 –3 –3–2 –2–1 –1 –1of every H atom is ϩ1. However, the oxidation numbers in the C atoms depend onthe structure, and they are summarized in Figure 14.7. The C atom of a methylgroup always possesses the oxidation number Ϫ3 in any hydrocarbon. The C atom ofa methylene group always possesses the oxidation number Ϫ2 in any hydrocarbon,the C atom of a methyne group always possesses Ϫ1, and every quaternary C atompossesses the oxidation number 0.With the data in Figure 14.7, oxidation numbers can be assigned to the C atoms ofthe two isomeric butenes of Figure 14.8. Hence, 1-butene possesses the oxidation num-ber Ϫ3 at one C atom, the oxidation number Ϫ2 at two C atoms, and the oxidationnumber Ϫ1 at one C atom. On the other hand, 2-butene consists of two sets of two Catoms with oxidation numbers Ϫ3 and Ϫ1, respectively.Fig. 14.7. Oxidationnumbers of C atomsselected hydrocarbosubstructures.C CH3C CH2 C, C CH2C CH C,CC C,CCCCCCC C C,C CC ,H C, C CHC C COxidation number = –3 for the C printed in bold in:Oxidation number = –2 for the C printed in bold in:Oxidation number = –1 for the C printed in bold in:Oxidation number = 0 for the C printed in bold in:Fig. 14.8. Oxidationnumbers of the C at1- and 2-butene.H3C CH2 CH CH2 H3C CH CH CH3–3 –3 –3–2 –2–1 –1 –1With the data in Figure 14.7, oxidation numbers can be assigned to the C atoms ofthe two isomeric butenes of Figure 14.8. Hence, 1-butene possesses the oxidation num-ber Ϫ3 at one C atom, the oxidation number Ϫ2 at two C atoms, and the oxidationnumber Ϫ1 at one C atom. On the other hand, 2-butene consists of two sets of two Catoms with oxidation numbers Ϫ3 and Ϫ1, respectively.El  nº  de  oxidación  del  C  depende  de  la  estructura  Dos  compuestos  orgánicos  poseen  el  mismo  estado  de  oxidación  si  la  media  de  los  estados  de  oxidación  de  sus  átomos  de  C  es  idénFca  y  si  el  estado  de  oxidación  de  los  heteroátomos  presentes  es  el  usual  (  Li,  +1;  Mg,  +2;  B,  +3;  N  and  P,  -­‐3;  O  y  S,  -­‐2;  and  -­‐1  para  los  halogenos).    Isomerización  del  buteno  La  media  de  los  nº  de  oxidación  en  los  isomeros  es  la  misma  No  se  trata  de  un  proceso  redox  H3C C CH H2C C CHH22HC CHCH3C C CH2BrH3C C CH3OCH CH2H3CO–3–3 –3 –3–3000–1–1–1 –1+1–2–2–2–2 +2ection ofh the sameon numberery atom:er of the OationBr atoms,14 Oxidations and ReductionsThis difference has one irritating consequence: the isomerization of 1-butene to2-butene would change the oxidation numbers of two atoms. This isomerization thuswould constitute a redox reaction or, more specifically, a redox disproportionation.That result, however, is not compatible with “good common sense.”What causes this problem? The assignment of oxidation numbers in organic chem-istry should not be overly burdened by questions of whether the procedure reallymakes sense. The important feature of the butenes of Figure 14.8 lies with the factthat the C atoms in the butenes on average possess the same oxidation number. Theaverage oxidation numbers are (Ϫ3 Ϫ 2 Ϫ 1 Ϫ 2)ր4 ϭ Ϫ2 for 1-butene and (Ϫ3 Ϫ 1Ϫ 1 Ϫ 3)ր4 ϭ Ϫ2 for 2-butene. The isomerization 1-butene → 2-butene leaves theaverage oxidation numbers of the atoms invariant, and the isomerization of butenerightly no longer needs to be viewed as a redox reaction. It is best to remember thefollowing:The six C3 skeletons shown in Figure 14.9 all have an average oxidation number ofϪ1 1ր3 of their C atoms. Accordingly, all these compounds are representatives of thesame oxidation state.Two organic chemical compounds possess the same oxidation state if the averageoxidation numbers of their C atoms are the same and if any heteroatoms that mightbe present possess their usual oxidation numbers (Li, ϩ1; Mg, ϩ2; B, ϩ3; N and P,Ϫ3; O and S, Ϫ2; and Ϫ1 for halogen atoms).H3C C CH H2C C CHH22HC CHCH3C C CH2BrH3C C CH3OCH CH2H3CO–3–3 –3 –3–3000–1–1–1 –1+1–2–2–2–2 +2Fig. 14.9. A selection ofcompounds with the sameaverage oxidation numberof Ϫ1 1/3 at every atom:oxidation number of the Oatoms, Ϫ2; oxidationnumber of the Br atoms,Ϫ1.That result, however, is not compatible with “good common sense.”What causes this problem? The assignment of oxidation numbers in organic chemistry should not be overly burdened by questions of whether the procedure reallmakes sense. The important feature of the butenes of Figure 14.8 lies with the facthat the C atoms in the butenes on average possess the same oxidation number. Thaverage oxidation numbers are (Ϫ3 Ϫ 2 Ϫ 1 Ϫ 2)ր4 ϭ Ϫ2 for 1-butene and (Ϫ3 ϪϪ 1 Ϫ 3)ր4 ϭ Ϫ2 for 2-butene. The isomerization 1-butene → 2-butene leaves thaverage oxidation numbers of the atoms invariant, and the isomerization of butenrightly no longer needs to be viewed as a redox reaction. It is best to remember thfollowing:The six C3 skeletons shown in Figure 14.9 all have an average oxidation number oϪ1 1ր3 of their C atoms. Accordingly, all these compounds are representatives of thsame oxidation state.Two organic chemical compounds possess the same oxidation state if the averageoxidation numbers of their C atoms are the same and if any heteroatoms that mightbe present possess their usual oxidation numbers (Li, ϩ1; Mg, ϩ2; B, ϩ3; N and P,Ϫ3; O and S, Ϫ2; and Ϫ1 for halogen atoms).Based on the preceding rule, one can state the following definition:Nº  de  oxidación    medio  =-­‐1  1/3  Todos  estos  compuestos  son  representaFvos  del  mismo  estado  de  oxidación  
  5. 5. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   5  Generalidades  Reacciones  Redox  en  Q.  Orgánica  Reacciones  que  incrementan  el  nº  de  oxidación  medio  de  los  C  o  de  uno  de  los  heteroatomos  presentes  14.1 Oxidation Numbers in Organic Chemical Compounds and Redox Reactions 549R HR metalR NR OR SR HalR C HOC CR C CHal OR CCCCll34R C R′OR C HetOR C(OR′)2R C(SR′)2C COH OHOC CR C COPhSeO C HetHet1 C Het2Ooxidationreduction*Selenium is considered to be more electronegative in organic compounds than carbon, eventhough the Pauling electronegativities are about the same.Table 14.1. Organic Chemical Redox Reactions I: Change of the Average Oxidation Numbers ofC Atoms*Table 14.2. Organic Chemical Redox Reactions II: Change of the Average Oxidation Numbersof N Atoms3003T Bruckner Ch14 [545-580] 5/23/01 11:48 AM Page 549R HR metalR NR OR SR HalR C HOC CR C CHal OR CCCCll34R C R′OR C HetOR C(OR′)2R C(SR′)2C COH OHOC CR C COPhSeO C HetHet1 C Het2Oreduction*Selenium is considered to be more electronegative in organic compounds than carbon, eventhough the Pauling electronegativities are about the same.Table 14.2. Organic Chemical Redox Reactions II: Change of the Average Oxidation Numbersof N AtomsN NON OHN NC N OHC N OHC N NC N N CC NOOC N NC N NoxidationreductionReacciones  que  decrecen  el  nº  de  oxidación  medio  de  los  C  o  de  uno  de  los  heteroatomos  presentes  OXIDACIÓN  REDUCCIÓN   Proceso  en  los  que  un  substrato  capta  e-­‐  Proceso  en  los  que  un  substrato  cede  e-­‐  
  6. 6. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   6  REDUCCIONES  Donores  de  e-­‐  Agentes    de  reducción  H2  Hidrogenolisis  Hidrogenaciones  catalí>cas  Reac>vos  de  transferencia  de  átomos  de  H  Reac>vos  de  transferencia  de  H  nucleofilico  Hidruros  de  complejos  metálicos  iónicos  solubles  Hidruros  metálicos    covalentes  neutros  Compuestos  organometálicos    con  un  H  en  β Bu3SnH,  (Me3Si)3SiH  BH3,  DIBAL,  Et3SiH  Derivados  tetravalentes  de  B  y  Al  M  (Li,  Na,  K,  Mg,,  Zn)  disueltos  H·∙  H-­‐  Ø     Ø     Ø     Ø     Donor  de  H+  LiAlH4,  Red-­‐Al  NaBH4  LiBHEt3    
  7. 7. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   7  REDCCIONES  REDUCCIONES  1º  Rsp3-­‐X  →  Rsp3-­‐H  ó  Rsp3-­‐X  →  Rsp3-­‐M    2º  Compuestos  C=O  y  esteres  por  transferencia  de  un  e-­‐.  Acoplamiento  reduc>vo    3º  Derivados  de  Acidos  Carboxílicos  a  Alcoholes  o  Aminas  4º  Derivados  de  Acidos  Carboxílicos  a  Aldehidos  5º  Compuestos  Carbonilicos  a  Hidrocarburos  6º  Hidrogenación  de  alquenos  7º  Reducciones  de  Compuestos  Aromá>cos  y  Alquinos  REDUCCIONES  
  8. 8. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   8  REDUCCIONES  1.  Reducciones  de  Rsp3-­‐X  →  Rsp3-­‐H  ó  Rsp3-­‐X  →  Rsp3-­‐M    Rsp3-­‐X     Bromuros,  ioduros  y  sulfonatos  de  alquilo  primarios  y  secundarios  lent aluminum; and• organometallic compounds that contain a b H-atom that can be transferred onto anorganic substrate.14.4.1 Reductions Rsp3¬X → Rsp3¬H or Rsp3¬X → Rsp3¬MPrimary and secondary alkyl bromides, iodides, and sulfonates can be reduced to thecorresponding alkanes with LiBHEt3 (superhydride) or with LiAlH4. If such a reac-tion occurs at a stereocenter, the reaction proceeds with substantial or often even com-plete stereoselectivity via backside attack by the hydride transfer reagent. The reduc-tion of alkyl chlorides to alkanes is much easier with superhydride than with LiAlH4.The same is true for sterically hindered halides and sulfonates:Bu CC H3MeMeBu CC H2MeMeOTsLiBHEt3Several options can be considered when it comes to the mechanisms of these re-ductions and of other reductions with complex metal hydrides. It is convenient to imag-ine that a hydrogen atom with hydride character is detached from the reducing agentin the transition state. However, LiAlH4 seemingly is also capable of effecting a sin-gle electron transfer onto organic substrates.B14.4 Reductions 577The same reducing agents LiBHEt3 and LiAlH4 also react with epoxides in SN2-type reactions converting them into alcohols (Figure 14.35).The sterically less hinderedPhOHOPh Ph OHOOHOH“H ”“H ”H O3H O3LiAlH ;4LiBHEt ;3 withoutwithoutFig. 14.35. Reduction ofepoxides. The sterically lesshindered C¬O bond isattacked regioselectively.3003T Bruckner Ch14 [545-580] 5/25/01 18:21 Page 57714.4 Reductions 577The same reducing agents LiBHEt3 and LiAlH4 also react with epoxides in SN2-type reactions converting them into alcohols (Figure 14.35).The sterically less hinderedPhOHOPh Ph OHOOHOH“H ”“H ”H O3H O3LiAlH ;4LiBHEt ;3 withoutwithoutFig. 14.35. Reduction ofepoxides. The sterically lesshindered C¬O bond isattacked regioselectively.3003T Bruckner Ch14 [545-580] 5/25/01 18:21 Page 577X  =  Br,  I,  SO3R    LiBHEt3    LiAlH4    Rsp3-­‐X     Epóxidos  X  =  -­‐O-­‐  LiBHEt3    LiAlH4    Control  regioselecCvo  por  ataque  SN2  al  O  menos  impedido  Rsp3-­‐H  ROH  EstereoselecCvidad:  Procesos  SN2  con  inversión  Lithium  trie>llborohidruro  –  Superhidruro  •  Mas  enérgico  que  LIAlH4  y  NaBH4  •  Mas  seguro  que  LIAlH4  
  9. 9. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   9  REDUCCIONES  1.  Reducciones  de  Rsp3-­‐X  →  Rsp3-­‐XH  ó  Rsp3-­‐X  →  Rsp3-­‐M    Rsp3-­‐X     Epóxidos  X  =  -­‐O-­‐  Red-Al [NaAlH2(OCH2CH2 OCH3)2] or DIBAL, respectively.Red-Al first generates one equivalent of hydrogen gas from such epoxy alcohols A(Figure 14.36).An O¬Al bond forms in the resulting trialkoxyaluminate D. The epoxyfragment in D then is reduced via an intramolecular reaction. The transfer of a hy-dride ion from aluminum leads selectively to the formation of a 1,3-diol, since the ap-proach path that would lead to the 1,2-diol cannot be collinear to the C¬O bond whichwould have to be broken (cf. Section 2.4.3).The treatment of epoxy alcohols A with DIBAL also first liberates one equivalentof H2 (Figure 14.36, right). An O¬Al bond is formed, which in the resulting interme-ROHOROHOHROHOHOAlOOMeMeOHOOOAlOHR HiiBuBuRHHRed-AlA (pure enantiomer)DIBALRed-AlDIBAL99.3 : 0.77 : 93®B CD E“H ”Fig. 14.36. Regioselectivereduction ofenantiomerically pureepoxy alcohols toenantiomerically purediols. 1,3-Diols are formedwith Red-Al and 1,2-diolsare formed with DIBAL.DIBAL    Red-­‐Al    Control  regioselecCvo  por  adecuada    selección  del  agente  reductor  Proceso  intramolecular   Proceso  intermolecular  1,2-­‐diol  ó  1,3-­‐diol  bis(2-­‐methoxyethoxy)aluminumhydride  Soluble  en  disolvs  aromáFcos  (tolueno)  Mas  estable  a  aire,  humedad  y  Tpta  que  LIAlH4  
  10. 10. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   10  REDUCCIONES  1.  Reducciones  de  Rsp3-­‐X  →  Rsp3-­‐XH  ó  Rsp3-­‐X  →  Rsp3-­‐M    Rsp3-­‐X     Bromuros,  ioduros  de  alquilo  1º,  2º  y  3º  X  =  Br,  I  Bu3SnH  1.9 Defunctionalizations via Radical Substitution Reactions 35Both in radical defunctionalizations effected with Bu3SnH and in those carried outwith (Me3Si)3SiH, the radical formation is initiated by the radical initiator AIBN (Fig-ure 1.31). The initiation sequence begins with the decomposition of AIBN, which istriggered by heating or by irradiation with light, into the cyanated isopropyl radical.In the second step of the initiation sequence, the cyanated isopropyl radical producesthe respective initiating radical;that is,it converts Bu3SnH into Bu3Sn.and (Me3Si)3SiHinto (Me3Si)3Si.. The initiating radical gets the actual reaction chain going, which ineach case comprises two propagation steps.Both Bu3SnH and (Me3Si)3SiH are able to defunctionalize alkyl iodides or bromidesbut not alcohols. On the other hand, in the so-called Barton–McCombie reaction theycan defunctionalize certain alcohol derivatives, namely, ones that contain a C“S dou-Fig. 1.30. Dehalogenationsthrough radicalsubstitution reactions.IOO OOOBrOOOBu SnH,3AIBN (cat.)AIBN (cat.)(Me Si) SiH,3 3ckner Ch01 [1-42] 5/25/01 17:02 Page 351.9 Defunctionalizations via Radical Substitution Reactions 35Both in radical defunctionalizations effected with Bu3SnH and in those carried outwith (Me3Si)3SiH, the radical formation is initiated by the radical initiator AIBN (Fig-ure 1.31). The initiation sequence begins with the decomposition of AIBN, which istriggered by heating or by irradiation with light, into the cyanated isopropyl radical.In the second step of the initiation sequence, the cyanated isopropyl radical producesthe respective initiating radical;that is,it converts Bu3SnH into Bu3Sn.and (Me3Si)3SiHinto (Me3Si)3Si.. The initiating radical gets the actual reaction chain going, which ineach case comprises two propagation steps.Fig. 1.30. Dehalogenationsthrough radicalsubstitution reactions.IOO OOOBrOOOBu SnH,3AIBN (cat.)AIBN (cat.)(Me Si) SiH,3 3ner Ch01 [1-42] 5/25/01 17:02 Page 35with (Me3Si)3SiH, the radical formation is initiated by the radical initiator AIBN (Fig-ure 1.31). The initiation sequence begins with the decomposition of AIBN, which istriggered by heating or by irradiation with light, into the cyanated isopropyl radical.In the second step of the initiation sequence, the cyanated isopropyl radical producesthe respective initiating radical;that is,it converts Bu3SnH into Bu3Sn.and (Me3Si)3SiHinto (Me3Si)3Si.. The initiating radical gets the actual reaction chain going, which ineach case comprises two propagation steps.Both Bu3SnH and (Me3Si)3SiH are able to defunctionalize alkyl iodides or bromidesbut not alcohols. On the other hand, in the so-called Barton–McCombie reaction theycan defunctionalize certain alcohol derivatives, namely, ones that contain a C“S dou-ble bond (e.g., thiocarboxylic esters or thiocarbonic esters). Figure 1.32 shows howthe OH group of cholesterol can be removed by means of a Barton–McCombie reac-tion. The C“S-containing alcohol derivative used there is a xanthate (for the mecha-nism of the formation reaction of xanthates, see Figure 7.4).Si(SiMe )3 3 Si(SiMe )3 3N N CNNC N N+NNNNNCCCCCInitiation step:∆HHHHHSnBu3 SnBu3ML3 ML3ML3ML3ML3ML3≡≡HalHHalPropagation steps: RRHRR++++++++2orFig. 1.31. Mechof the radicaldehalogenation1.30.(Me3Si)3SiH  Reacciones  radicalaria  AIBN  Xantogenatos  1º,  2º  y  3º   Rsp3-­‐H  TTMS,  Tris(>me>lsilil)silano  Hidruro  de  tribu>lestaño  Tóxico  Energías  de  enlace:  Bu3Sn-­‐H  74  kcal/mol,  Et3Si-­‐H  90  kcal/mol,  TMS3Si-­‐H  79  kcal/mol  
  11. 11. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   11  REDUCCIONES  1.  Reducciones  de  Rsp3-­‐X  →  Rsp3-­‐H  ó  Rsp3-­‐X  →  Rsp3-­‐M    Rsp3-­‐X     Haluros  de  alquilo  1º,  2º  y  3º  X  =  Halogeno  14.4 Reductionsdropwise to this reducing reagent. The mechanism of reduction corresponds step bystep to the one outlined in Figure 14.37 except that the dissolved radical anion is thesource of the electrons, which are transferred as opposed to a metal surface. Further-more, a C 3¬S bond breaks instead of a C 3¬I bond. In the reductive lithiation ofIIIMMMeeeIMgMeMgMgMgMgMg MgMgMgMgMgMgMgMgMgMg~ e~ e+++ +1+1+20Fig. 14.37. Mechanism of the formation of a Grignard compound; ϳeϪindicates electronmigration. The reaction is initiated by an electron transfer from the metal to the substrate. Theextra electron occupies the s*(C¬I) orbital, whereby the C¬I bond is weakened and breaks.This cleavage leads to the formation of a methyl radical and an iodide ion on the metalsurface. In the third step of the reaction, the valence electron septet of the methyl radical isconverted into an octet by formation of a covalent bond between the methyl radical and ametal radical. The Grignard reagent is thus formed.3003T Bruckner Ch14 [545-580] 5/23/01 11:48 AM Page 579Mecanismo  de  la  formación  de  un  reacCvo  de  Grignard  M  =  Mg,  Li,  Zn  Compuesto  organometálico  Disolventes  apró>cos:  THF,  hexano,  eter  M  con  superficie  libre  de  óxidos:  •  Procedimientos  mecánicos  •  Procedimientos  químicos  •  Preparación  in  situ  this reducing reagent. The mechanism of reduction corresponds step byne outlined in Figure 14.37 except that the dissolved radical anion is theelectrons, which are transferred as opposed to a metal surface. Further-¬S bond breaks instead of a Csp3¬I bond. In the reductive lithiation ofes (Screttas–Yus process), the radical anion is generated in situ and onlymounts, starting with a stoichiometric amount of Li powder and a few mole--tert-butylbiphenyl (possibility for preparation: Section 5.2.5). The contin-ated lithium di-tert-butylbiphenylide reduces the alkyl chloride. This reac-reductive lithiation of alkyl phenyl sulfides follow the same mechanism.-tert-butylbiphenylide in homogeneous solution is a very strong reducingreagent allows for easy metallations in cases that are more difficult withum and would be impossible to accomplish with magnesium. The reduc-MeIMgMeMg MgMgMg MgMg Mg~ e++ +1+2chanism of the formation of a Grignard compound; ϳeϪindicates electronreaction is initiated by an electron transfer from the metal to the substrate. Theoccupies the s*(C¬I) orbital, whereby the C¬I bond is weakened and breaks.leads to the formation of a methyl radical and an iodide ion on the metalthird step of the reaction, the valence electron septet of the methyl radical isan octet by formation of a covalent bond between the methyl radical and aThe Grignard reagent is thus formed.Br LiCl ClMgRieke-Mg2 Li– LiBr( -BuLi)secFig. 14.38. Heterogeneousreduction of alkyl halidesto Grignard compounds,organolithium compounds,and—possiblyfunctionalized—organozinccompounds; Zn* refers todropwise to this reducing reagent. The mechanism of reduction corresponds step bystep to the one outlined in Figure 14.37 except that the dissolved radical anion is thesource of the electrons, which are transferred as opposed to a metal surface. Further-more, a Csp3¬S bond breaks instead of a Csp3¬I bond. In the reductive lithiation ofalkyl chlorides (Screttas–Yus process), the radical anion is generated in situ and onlyin catalytic amounts, starting with a stoichiometric amount of Li powder and a few mole-percent of di-tert-butylbiphenyl (possibility for preparation: Section 5.2.5). The contin-uously generated lithium di-tert-butylbiphenylide reduces the alkyl chloride. This reac-tion and the reductive lithiation of alkyl phenyl sulfides follow the same mechanism.Lithium di-tert-butylbiphenylide in homogeneous solution is a very strong reducingreagent. This reagent allows for easy metallations in cases that are more difficult withmetallic lithium and would be impossible to accomplish with magnesium. The reduc-Fig. 14.37. Mechanism of the formation of a Grignard compound; ϳeϪindicates electronmigration. The reaction is initiated by an electron transfer from the metal to the substrate. Theextra electron occupies the s*(C¬I) orbital, whereby the C¬I bond is weakened and breaks.This cleavage leads to the formation of a methyl radical and an iodide ion on the metalsurface. In the third step of the reaction, the valence electron septet of the methyl radical isconverted into an octet by formation of a covalent bond between the methyl radical and ametal radical. The Grignard reagent is thus formed.Br LiMeO2CIMeO2CZnICl ClMgRieke-Mg2 Li– LiBrZn*( -BuLi)secFig. 14.38. Heterogeneousreduction of alkyl halidesto Grignard compounds,organolithium compounds,and—possiblyfunctionalized—organozinccompounds; Zn* refers tosurface-activated metalliczinc.dropwise to this reducing reagent. The mechanism of reduction corresponds ststep to the one outlined in Figure 14.37 except that the dissolved radical anionsource of the electrons, which are transferred as opposed to a metal surface. Fumore, a Csp3¬S bond breaks instead of a Csp3¬I bond. In the reductive lithiatialkyl chlorides (Screttas–Yus process), the radical anion is generated in situ andin catalytic amounts, starting with a stoichiometric amount of Li powder and a fewpercent of di-tert-butylbiphenyl (possibility for preparation: Section 5.2.5). The couously generated lithium di-tert-butylbiphenylide reduces the alkyl chloride. Thistion and the reductive lithiation of alkyl phenyl sulfides follow the same mechaLithium di-tert-butylbiphenylide in homogeneous solution is a very strong redreagent. This reagent allows for easy metallations in cases that are more difficulmetallic lithium and would be impossible to accomplish with magnesium. The rThis cleavage leads to the formation of a methyl radical and an iodide ion on the metalsurface. In the third step of the reaction, the valence electron septet of the methyl radicalconverted into an octet by formation of a covalent bond between the methyl radical andmetal radical. The Grignard reagent is thus formed.Br LiMeO2CIMeO2CZnICl ClMgRieke-Mg2 Li– LiBrZn*( -BuLi)secM  =  Mg  Reacción  Heterogénea  Disolventes  pró>cos:  HOAc,  ROH  Rsp3-­‐H  Protonación  del  Comp.    Organometálico  
  12. 12. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   12  REDUCCIONES  1.  Reducciones  de  Rsp3-­‐X  →  Rsp3-­‐H  ó  Rsp3-­‐X  →  Rsp3-­‐M    Rsp3-­‐X     Fenilsulfuros  de  alquilo  y  cloruros  de  alquilo  X  =  SPh,  Cl  M  =  Li  Compuesto  organometálico  14 Oxidations and Reductions580tion of chloride A in Figure 14.39 provides a good example. A is a rather weatron acceptor because it is an alkoxide, that is, an anion.The reducing power of lithium di-tert-butylbiphenylide is so high that it icapable of the reductive lithiation of a Csp2¬Cl bond (Figure 14.40; Csp2¬Clare stronger than Csp3¬Cl bonds according to Section 1.2). In the example glithium (dialkylamino)carbonyl compound A is formed that is not accessibleother way. If one generates the organolithium compound A in this way and in thence of a carbonyl compound, the former adds immediately to the C“O doublof the latter. For example, A reacts in situ with benzaldehyde to give alcoholgeneration of organometallic compounds from halides in the presence of a cacompound followed by an in situ reaction of these species with each other is reSPh LiClHOClOtert-Butert-BuOLi+ Li SPh+ Li ClLi LiLi(2 equivalents)n-BuLi(1 equivalent)Li (> 2 equivalents),A BFig. 14.39. Reductivelithiation of an alkyl arylsulfide (Cohen process)and an alkyl chloride(Screttas–Yus process).3003T Bruckner Ch14 [545-580] 5/23/01 11:48 AM Page 580Li>acion  reduc>va   Reacción  Homogénea  14 Oxidations and Reductions580tion of chloride A in Figure 14.39 provides a good example. A is a rather weak elec-tron acceptor because it is an alkoxide, that is, an anion.The reducing power of lithium di-tert-butylbiphenylide is so high that it is evencapable of the reductive lithiation of a Csp2¬Cl bond (Figure 14.40; Csp2¬Cl bondsare stronger than Csp3¬Cl bonds according to Section 1.2). In the example given, alithium (dialkylamino)carbonyl compound A is formed that is not accessible in anyother way. If one generates the organolithium compound A in this way and in the pres-SPh LiClHOClOtert-Butert-BuOLi+ Li SPh+ Li ClLi LiLi(2 equivalents)n-BuLi(1 equivalent)Li (> 2 equivalents),A BFig. 14.39. Reductivelithiation of an alkyl arylsulfide (Cohen process)and an alkyl chloride(Screttas–Yus process).3003T Bruckner Ch14 [545-580] 5/23/01 11:48 AM Page 580Reacción  de  Cohen  Reacción  de  Screnas-­‐Yus  X  =  SPh  X  =  Cl  Agente  reductor:  Sal  soluble  de  liFo  de  un  radical  aniónico  de  un  derivado  de  naealeno  (liFum  naealenide)  o  bisfenilo  LDBB    que  es  la  fuente  de  e-­‐  LDBB  Agente  reductor  muy  fuerte  
  13. 13. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   13  REDUCCIONES  1.  Reducciones  de  Rsp3-­‐X  →  Rsp3-­‐H  ó  Rsp3-­‐X  →  Rsp3-­‐M    Rsp2-­‐X     Compuestos  carbonilicos  X  =  Cl  M  =  Li  R-­‐OH  Reacción  Homogénea  Reacción  de  Barbier  tion of chloride A in Figure 14.39 provides a good example. A is a rather weak elec-tron acceptor because it is an alkoxide, that is, an anion.The reducing power of lithium di-tert-butylbiphenylide is so high that it is evencapable of the reductive lithiation of a Csp2¬Cl bond (Figure 14.40; Csp2¬Cl bondsare stronger than Csp3¬Cl bonds according to Section 1.2). In the example given, alithium (dialkylamino)carbonyl compound A is formed that is not accessible in anyother way. If one generates the organolithium compound A in this way and in the pres-ence of a carbonyl compound, the former adds immediately to the C“O double bondof the latter. For example, A reacts in situ with benzaldehyde to give alcohol B. Thegeneration of organometallic compounds from halides in the presence of a carbonylcompound followed by an in situ reaction of these species with each other is referredto as the Barbier reaction.Fig. 14.39. Reductivelithiation of an alkyl arylsulfide (Cohen process)and an alkyl chloride(Screttas–Yus process).iPr2N ClOiPr2NOLi iPr2NOPhOHPhCH O;tert-Butert-BuLi (> 2 equivalents),(cat.)A BHFig. 14.40. Reductivelithiation of a carbamoylchloride to the(dialkylamino)carbonyllithium compound A andits immediately followingreaction with a carbonylcompound (Barbierreaction) leading toalcohol B.In some cases, a metal reduces a Csp3¬heteroatom bond faster to a Csp3-M bondthan it reduces the hydrogen of an OH group to H2 and, in these cases, protic solventscan be used. Instead of the organometallic compound, one then obtains the productresulting from its protonation. This kind of reduction is used, for example,• in the defunctionalization of alkyl phenyl sulfones with sodium amalgam in MeOH.(Figure 14.41; another reaction of the intermediate formed, an organo-sodium com-pound, occurs in the Julia–Lythgoe olefination because there is a leaving group inthe b-position relative to the metallated center (cf. Figure 4.37)];• in the dehalogenation of 2,2-dichlorocyclobutanones (Figure 14.42, top) withZn/HOAc;LDBB  Reacción  entre  un  halo  derivado  y  un  c.  carbonílico  análoga  para  la  obtención  de  R-­‐O.  Análoga  a  la  reacción    con  reacFvos  de  Grignard  pero  en  una  etapa  Otros  ejemplos  de  la  reacción  de  Barbier  
  14. 14. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   14  REDUCCIONES  1.  Reducciones  de  Rsp3-­‐X  →  Rsp3-­‐H  ó  Rsp3-­‐X  →  Rsp3-­‐M    Rsp3-­‐X     R=  Ph  :  Benzil  eteres,  esteres  y  carbamatos  X  =  O  M  =  Li,  Na  en  NH3  liq.  R-­‐H  Reacción  Homogénea  • and in the deoxygenation of acyloin to ketones (Figure 14.42, bottom) with Zn/HCl.OClClHHH OHHHOOHOZn,HOAcHOAcZn, HCl,AB~ e~ eMeO LiMeO OLiMM MMee eeOO OOO OLi Litert-BuOH,– tert-BuO Liaddition ofliquid NH3;+ tert-BuOH, + Li– Li O2Fig. 14.42. Reductions ofa-heterosubstitutedketones to a-unsubstitutedketones. SeeFigures 12.32 and 14.51 forthe preparation ofcompounds A and B,respectively.Fig. 14.43. One-potsynthesis of an alkyl-substituted aromaticcompound that involves adissolving lithiumreduction of a benzylalkoxide.The Csp3¬O bonds of benzyl alcohols, benzyl ethers, benzyl esters, and benzyl car-bamates also can be reduced to a C¬H bond (Figures 14.43 and 14.44). Lithium or14 Oxidations and Reductions582sodium in liquid ammonia are good reducing agents for this purpose. One usually addsan alcohol, such as tert-BuOH, as a weak proton source. Lithium and sodium dissolveOONON CO2tert-BuOtert-BuPhHHHHOONON CO2tert-BuOtert-BuPhHHHHNON CO2tert-BuOtert-BuPhHOCOH2, cat. Pd/C, NEt3spontaneously(Preparation: Fig. 6.26)++Fig. 14.44. The O-benzylcarbamate →toluene reduction for theremoval of a protectinggroup.3003T Bruckner Ch14-2[581-612] 5/23/01 11:50 AM Page 582Desprotección  de  grupos  protectores  conteniendo  bencilos  El  M  (Na  o  LI)  se  disuelve  en  NH3  liquido:  Disolución  de  M+  y  e-­‐  solvatados  Alcóxido  bencilico  Fuente  de  H+  
  15. 15. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   15  ROZZ = H AldehidosZ = R CetonasZ = OR EsteresROZM+ROHZ- M+HO-+ H2OREDUCCIONES  2.  Reducciones  de  Compuestos  C=O  y  esteres  por  transferencia  de  un  e-­‐.  Acoplamiento  reduc>vo    M  =  Na,  K  CeCl  sium in the presence of the indicator benzophenone. Potassium and benzophenone re-act to give the deep-blue potassium ketyl radical anion A (Figure 14.45). Water thenprotonates ketyl A to the hydroxylated radical B as long as traces of water remain.Further potassium reduces B via another electron transfer to the hydroxysubstitutedorganopotassium compound C. C immediately tautomerizes to the potassium alkox-ide D. Once all the water has been consumed, no newly formed ketyl A can be pro-tonated so that its blue color indicates that drying is complete.In the drying of THF or ether (Figure 14.45), the sequence ketone → ketyl → hy-droxylated radical → hydroxylated organometallic compound → alkoxide is of coursenot intended to convert all the ketone into “product.” The reaction depicted in Figure14.46 features the same sequence of steps as Figure 14.45 (and there is thus no need todiscuss their mechanism again). In the reaction of Figure 14.46, however, the reactionis intended to run to completion until all of the ketone has been consumed. The reasonfor this is that it is the purpose of this reaction to reduce the ketone to the alcohol. TheFig. 14.45. Chemistrthe drying of THF owith potassium andbenzophenone featuthe ketone → ketylreduction and the trreaction of the ketyresidual water.OO OOO HH OH+ Kfive otherresonancestructuresK KKK+ H O– K OH2~ HAB C Dcauses blue color inthe absence of watercauses colorlessness inthe presence of waterSecado  de  Disolventes  (THF  y  eter)  con  M  en  presencia  de  Benzofenona  como  indicador  CeCl  Radical  Hidroxilado  Radical  Hidroxilado  Compuesto  Organometálico  Alcoxido  ROHZCompuestos  CO  impedidos  M  =  Na  isopropanol  
  16. 16. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   16  REDUCCIONES  M  =  Na,  K  14 Oxidations and Reductionssubstrate in Figure 14.46 is a conformationally fixed cyclohexanone and the reducingagent is sodium, which dissolves in isopropanol. Playing a dual role, this solvent alsoacts as a proton source. Since the supply of this proton source is unlimited in this case,all of the ketone is converted into alkoxide.Interestingly, the reduction shown in Figure 14.46 is highly diastereoselective. Only.46.reoselectiveion of aexanone withing sodium.O OHO~ Htert-Butert-Butert-Butert-Butert-Butert-BuOHOOHHNaNaNain PrOHiNa, PrOHi+ PrOH,i– Na OiPrNavia Naequatorially oriented substituentA Br Ch14-2[581-612] 5/25/01 18:25 Page 584Reducción  diasteroselec>va  de  una  ciclohexanona  Compuestos  CO  con  libertad  conformacional  limitada  Este  nivel  de  estereoselecFvidad  no  se  puede  conseguir  con  agentes  de  transferencia  de  H-­‐  2.  Reducciones  de  Compuestos  C=O  y  esteres  por  transferencia  de  un  e-­‐.  Acoplamiento  reduc>vo    
  17. 17. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   17  REDUCCIONES  M  =  Mg  Acoplamiento  pinacolinico  de  cetonas  the hydroxylated radical A is reduced to the hydroxylated organosodium compoundB. For steric reasons, the OH group assumes a pseudo-equatorial position in the triva-lent and moderately pyramidalized C atom of the radical center of the cyclohexyl ringof intermediate A. Consequently, the unpaired electron at that C atom occupies apseudo–axially oriented AO. This preferred geometry is fostered and settled once andfor all with the second electron transfer. It gives rise to the organosodium compoundB. B isomerizes immediately to afford the equatorial sodium alkoxide.In reactions of carbonyl compounds other than the ones shown in Figures 14.45 and14.46 with nonprecious metals, initially, ketyls are formed as well. However, the Mgketyl of acetone (Figure 14.47) is sterically much less hindered than the K ketyl of ben-zophenone (Figure 14.45). The former therefore dimerizes while the latter does not.4.47. Reductiveization of acetonecol coupling).HO OHO OOOO O OMg (+ cat. or stoich. HgCl ); H O2 2– Mg(OH)2H O2via MgMgMgMg 22Compuestos  CO  no  impedidos  Dimerización  2.  Reducciones  de  Compuestos  C=O  y  esteres  por  transferencia  de  un  e-­‐.  Acoplamiento  reduc>vo    
  18. 18. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   18  REDUCCIONES  M  =  Ti  (0  a  +2)   Reacción  de  McMurry  Compuestos  Dicarbonilicos:  Dialdehidos  astereoisomers. The coupling shown in Figure 14.48, for example, yields the cis- andtrans-dihydroxylated 14-membered rings in a 30 : 70 ratio.At higher temperatures, the same carbonyl compounds and the same “low-valent ti-tanium” yield alkenes instead of glycols. Dicarbonyl compounds cyclize under theseconditions giving cycloalkenes (e.g., Figure 14.48, bottom). This type of reductive cou-pling is called a McMurry reaction. As with the Ti-mediated glycol formation, this re-action generally is not diastereoselective. The 14-membered cycloalkenes of Figure14.48, for example, are formed in a 10 : 90 cis : trans ratio.The diastereoselectivities for the Ti-mediated glycol vs alkene formations from thedialdehyde of Figure 14.48 are rather different. Yet, the Ti glycolate intermediates of thefirst coupling mode are converted into the alkenes of the second coupling mode uponheating. That nonetheless this discrepancy of diastereoselectivities is observed is inOHOHOHOHOO14 14141414+++70 : 3010 : 90lower temperatureshigher temperaturesTiCl (prereducedby Zn/Cu couple)3ciscistranstransFig. 14.48. Reductivecoupling of a dicarbonylcompound to afforddiastereomeric glycols ordiastereomeric alkenes(McMurry reaction).double bond of the resulting alkene. The rotation about the C¬C(O) bond in the in-termediate C is essentially free. This explains why the alkene, the McMurry product,is not formed as a pure stereoisomer and why its double bond configuration is inde-pendent of the stereostructure of the initially present titanium glycolates.Even C“O groups of esters (Figure 14.50, top) and amides (Figure 14.50, bottom)can undergo intramolecular McMurry reactions with ketone carbonyl groups if theyare exposed to “low-valent titanium” prepared in a slightly different way. The mecha-nism of these reactions corresponds by and large to the mechanism of the alde-hyde/aldehyde coupling (Figures 14.48 and 14.49).The McMurry cyclizations shown in Figure 14.50 are quite interesting from a syn-thetic point of view. The cyclization product B of ketoester A is a 10-membered enolOTiLnOOTiLOO TiLnOn70 : 3010 : 90“ TiO ”2A BC+ +Fig. 14.49. Mechanism of the McMurry reaction. The heterocyclic monotitanium glycolates Aand B or analogous dititanium glycolates decompose at higher temperatures via heterolyticcleavage of one of their C¬O bonds and form the radical intermediate C. The alkene isformed by cleavage of the second C¬O bond. This alkene is not obtained as a singlestereoisomer because of the free rotation about the C¬C(O) bond in the radical intermediateC. Note that the alkene is formed with a cis,trans-selectivity that is independent of theconfiguration of the titanium glycolate precursor(s).Acoplamiento    pinacolinico  intramolecular  Formación  De  olefinas  Ventajas   Inconvenientes  •  Altos  rendimientos  •  Formación  de  ciclos  de  3-­‐20  atomos  •  Ausencia  de  diasteroselecFvidad  2.  Reducciones  de  Compuestos  C=O  y  esteres  por  transferencia  de  un  e-­‐.  Acoplamiento  reduc>vo    
  19. 19. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   19  REDUCCIONES  M  =  Ti  (0  a  +2)   Reacción  de  McMurry  cruzadas  Compuestos  Dicarbonilicos  mixtos  14.4 Reductions 587ether. It can be hydrolyzed by acid to give ketone C, which itself cannot be the prod-uct of a McMurry reaction. The cyclization of ketoamide D illustrates one of the mostversatile syntheses of 2,3-disubstituted indoles (Fürstner indole synthesis).Carboxylic esters also can be reduced with dissolving sodium (Figure 14.51). Verydifferent products are obtained depending on whether the reduction is carried out inethanol or xylene. The reaction of esters with sodium in ethanol is referred to as theBouveault–Blanc reaction. Prior to the discovery of complex metal hydrides, this re-action was the only method for the reduction of esters to alcohols. The diester shownin Figure 14.51 produces a diol in this way.BMMeeOOR1R2OOOOONNR1HHR2TiCl (prereducedwith LiAlH34) workup withH O /3 ∆TiCl (cat.),Zn (stoich.),3Me SiCl (stoich.)3A B CDFig. 14.50. CrossedMcMurry reactions:ketone/ester coupling (top)and ketone/amide coupling(bottom).3003T Bruckner Ch14-2[581-612] 5/23/01 11:50 AM Page 587Cetona  -­‐  Ester  Cetona-­‐  Amida  Síntesis  de  indoles  de  Fürstner  Síntesis  de  cetonas  2.  Reducciones  de  Compuestos  C=O  y  esteres  por  transferencia  de  un  e-­‐.  Acoplamiento  reduc>vo    
  20. 20. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   20  14 Oxidations and Reductions588acyloin—E. The acyloin condensation is of special value because this method allowsOHOHR O R OHEtOR OHEtOEtOEtOOOEtOEtOOOEtOEtOOOHOOHEtOEtOOOEtOEtOOOOHOHOOOOOO– NaOEt– NaOEtNaNaNaNaNaNaNaNa~ HNaNaNa NaNa+ EtOH,viaNa inXylol;H O3+ H O310 1010 10 10 10– 2 Na OEtNa inEtOHacyloincondensationBouveault–BlancreductionA BC DE F GH I JtautomerizationFig. 14.51. Reduction of acarboxylic ester withdissolving sodium.Branching ofthe reduction paths inthe presence(Bouveault–Blancreduction) and absence(acyloin condensation) ofprotons.3003T Bruckner Ch14-2[581-612] 5/25/01 18:26 Page 588REDUCCIONES  M  =  Na    (EtOH)  Reacción  de    Bouveault-­‐Blanc  Esteres   Diesteres  Condensación  Acilóinica  M  =  Na    (xileno)  Ventajas  Síntesis  de  macrociclos  sin  necesidad  de  técnicas  de  dilución  Anión  hemiacetálico  2.  Reducciones  de  Compuestos  C=O  y  esteres  por  transferencia  de  un  e-­‐.  Acoplamiento  reduc>vo     Aciloina:  α-­‐hidroxi-­‐cetona  
  21. 21. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   21  REDUCCIONES  3.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Alcoholes  o  Aminas  14.4 Reductions 589A decomposes, faster than it is formed, into an aldehyde and a lithium alkoxide. TheR1X R1 OHR1R1OOR OONH2R1 ONHR2R1 ONR2R3RNH2R1NHR2R1NR2 3RR1R1 NNH21)4)for X = OR: LiAlH ; DIBAL in THF or Et Ofor X = OH: BH ; LiAlH42)233)4for X = Cl: NaBH ; LiAlH(O -Bu)for X = NMe OMe: LiAlH ; DIBALfor X = NMePh: add / LiAlHfor X = OR: 1 DIBAL in toluene orhexane or CH Cl4 3414 42 2tertLiAlH ; DIBAL4LiAlH ; H , NH , Pd/C4 2 3Typically used reagent(s)Reduction1 DIBAL in toluene or hexane or CH Cl2 2Table 14.6. Survey of Reductions of Carboxylic Acid Derivatives to Alcohols, Amines, orAldehydes1Bouveault–Blanc reduction, not commonly used nowadays except for the chemoselective re-duction of X ϭ OR in the presence of X ϭ OH.2Preferred reagent for the reduction of a,b-unsaturated esters to allyl alcohols.3Can be employed only if the substrate does not contain C“C or C‚C bonds; reduces carboxylicacids (X ϭ OH) chemoselectively in the presence of carboxylic acid esters (X ϭ OR).4Only a few special tertiary amides can be reduced to alcohols, e.g., with superhydride.LiAlH4    DIBAL  
  22. 22. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   22  REDUCCIONES  3.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Alcoholes  o  Aminas  LiAlH4     R1OOR2 R1OH14 Oxidations and ReductionsIn polar solvents, however, the tetrahedral intermediate A of Figure 14.53 decom-poses faster than it is generated, with formation of an aldehyde and ROAl(iBu)2. Thissolvent effect is explained in Figure 14.53, using THF as an example. The tetrahedralintermediate A contains a trivalent Al and forms a Lewis acid–Lewis base complexwith the solvent. The intermediate A is thus converted into the aluminate complex B,which contains tetravalent Al. The Al atom in A is bonded to only one O atom, whichR1C OHHR1 C OR O2R1 C OR O2HAAAA BlllR1 C OR O2HAAllAlHR1 C OHR1 C OHHLiLiLiLiLiR O Li +2+++slowfastfaster thanformation of A14.52. Mechanism ofLiAlH4 reduction ofoxylic esters tohols via aldehydes.kner Ch14-2[581-612] 5/23/01 11:50 AM Page 590Electrofilia:  Aldehído  >  Ester  En  estas  condiciones  no  es  posible  aislar  el  aldehido  
  23. 23. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   23  REDUCCIONES  3.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Alcoholes  o  Aminas  DIBAL  In polar solvents, however, the tetrahedral intermediate A of Figure 14.53 decom-poses faster than it is generated, with formation of an aldehyde and ROAl(iBu)2. Thissolvent effect is explained in Figure 14.53, using THF as an example. The tetrahedralintermediate A contains a trivalent Al and forms a Lewis acid–Lewis base complexwith the solvent. The intermediate A is thus converted into the aluminate complex B,which contains tetravalent Al. The Al atom in A is bonded to only one O atom, whichR1C OHHAl AlR1 C OHHLiLi +fastR1 C OR2OR1 C OR2OHR1 C OR2OHOHR1 C OHR2R2OOOOOR1 C OHHslowfastslower thanformation of Afaster thanformation of A/BAl Bui 2Al Bui 2Al Bui 2Al Bui 2Al Bui 2Al Bui 2Al Bui 2R O +2–A B+Fig. 14.53. Mechanism of the DIBAL reduction of carboxylic esters to aldehydes and furtherto alcohols. In nonpolar solvents the reaction stops with the formation of the tetrahedralintermediate A. During aqueous workup, A is converted into the aldehyde via the hemiacetal.In polar solvents, however, the tetrahedral intermediate A quickly decomposes forming thealdehyde via complex B. In the latter situation the aldehyde successfully competes withDisolventes  no-­‐polares  Aldehido  Disolventes  polares  Alcohol  Durante  procesado  acuoso  Electrofilia:  Aldehído  >  Ester  Aluminato  tetraédrico  Debilitación  del  C-­‐O  R1OOR2R1OHR1OHó
  24. 24. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   24  REDUCCIONES  3.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Alcoholes  o  Aminas  DIBAL  Solv  polares  R1OOR2 R1OHthe same O atom, but it also binds weakly to a THF molecule. The bond between Aland the O atom that originated from the ester is stronger in A than in B because ofthe additional contact with THF in the latter. The Al¬O bond thus breaks relativelyeasily in B and gives rise to a situation in which the aldehyde is formed faster from Bthan the tetrahedral intermediate A is formed from DIBAL and the ester.The alreadyformed aldehyde and the still unconsumed ester therefore compete for the remainingDIBAL, and the aldehyde wins because of its higher electrophilicity.Therefore, DIBALreductions of carboxylic esters in polar solvents go “all the way” to the alcohol.There is one type of ester → alcohol reduction for which one always employs DIBAL(in a polar solvent) rather than LiAlH4 (in ether of THF). This reduction is the re-duction of a,b-unsaturated esters to allyl alcohols (example in Figure 14.54). The re-action of this kind of substrate with LiAlH4 sometimes results in a partial reductionof the C“C double bond to a C¬C single bond in addition to the desired transfor-mation ¬C(“O)OR → ¬CH2OH.Fig. 14.54. DIBALreduction of an a,b-unsaturated ester to anallylic alcohol. (See Figure9.11 for a preparation ofthe substrate.)OOOMeOOOOHDIBAL (2 equivalents),Et O2Products of theReduction of Nitrileswith LiAlH4 andDIBALThe two reducing agents considered so far in this section—LiAlH4 and DIBAL—also are the reagents of choice for the reduction of nitriles (Figure 14.55). The mech-anistic details of these reactions can be gathered from the figure, and the result can besummarized as follows.LiAlH4 or DIBAL reduces carboxylic amides at low temperatures only to such anextent that aldehydes are obtained after aqueous workup (Figure 14.56). This worksmost reliably, according to Figure 6.33, if the amides are Weinreb amides. At highertemperatures, the treatment of carboxylic amides with either LiAlH4 or DIBAL re-sults in amines. Accordingly, N,N-disubstituted amides give tertiary amines, mono-• The reduction of nitriles with LiAlH4 leads to iminoalanate B via iminoalanateA. The hydrolytic workup affords an amine.• The reduction of nitriles with DIBAL can be stopped at this stage of the imi-noalane C. The hydrolysis of this iminoalane gives the aldehyde. The iminoalaneC also can be reacted—more slowly—with another equivalent of DIBAL to theaminoalane D. The latter yields the amine upon addition of water.Esteres  α,β-­‐insaturados  LiAlH4  produce  la  reducción  del  doble  enlace      DIBAL  reacciona  lentamente  con  compuestos  electron-­‐deficientes  y  mas  rápido  con  electrón-­‐ricos.    DIBAL  es  un  agente  reductor  electrofilico  .  LiAlH4  es  un  agente  reductor  nucleofilico  
  25. 25. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   25  REDUCCIONES  3.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Alcoholes  o  Aminas  DIBAL  14 Oxidations and Reductions592Fig. 14.55. Mechanism ofthe LiAlH4 reduction (top)and the DIBAL reduction(bottom) of nitriles.R C NHR C NHAlHHHR C NHAlHHHH AlH3R C N R C OHR CH2 NH2HHR C NHR C NHHLiLiLiLiAlH3H O ; OH3H O3H O ; OH3reduction;hydrolysisoreither++++Al Bui 2Al Bui 2Al Bui 2Al Bui 2Al Bui 2A BC Dreductions with LiAlH4 and DIBAL, respectively. Their decomposition in principlecould affect the C¬O bond (→ → → amine) or the C¬N bond (→ → → alcohol).There are two factors that provide an advantage for the C¬O bond cleavage:T Bruckner Ch14-2[581-612] 5/25/01 18:26 Page 592LiAlH4    ROHRNH2RCNóMol  extra  DIBAL  Lenta  Iminoalanato  Iminoalanato  Iminoalanano  
  26. 26. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   26  REDUCCIONES  DIBAL  LiAlH4     R1ONR2R3 R1NR2R3HHR C NHR C NHHH O ; OH3H O3+Al Bui 2Al Bui 2Al Bui 2Al Bui 2Al Bui 2C DR1C OHNNNR2R2R2R3R3R3R1 C OHNAlR2R3O AlAlR1 C ONR2R3R1CH2NR2R3R1 CNHR2R3R1 C OHR1 C OHNAAlliiBBuu22R2R3O AliBuiBuLiAlHor4DIBALDIBALoverallreactionLiAlH4LiLiLiLiA BCDFig. 14.56.Chemoselectivity of thereduction of amines.reductions with LiAlH4 and DIBAL, respectively. Their decomposition in principlecould affect the C¬O bond (→ → → amine) or the C¬N bond (→ → → alcohol).There are two factors that provide an advantage for the C¬O bond cleavage:Ion  Iminio  R2    =  R3  =  H  è Amina  primaria  R2    ó  R3  =  H  è Amina  secundaria  R2    =  R3  ≠  H  è Amina  terciaria    3.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Alcoholes  o  Aminas  
  27. 27. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   27  REDUCCIONES  4.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Aldehidos  DIBAL  R1OZ R1OH6 Nucleophilic Substitution Reactions on the Carboxyl CarbonWeinreb amides can be reduced to aldehydes not only with DIBAL but also withLiAlH4. In general this is not true for other amides.tert-Hexylmonobromoborane reduces free carboxylic acids selectively to the alde-R C N OMMMMeeeeOR C N OMeOAliBu2HRR RCC CHOH ClOO OH2N OMe ClH2MeN OMe Cl /iBu Al2 HClCO Bu/NEt2 3ipyridineH O3workupAB(see Figure 6.14);] 5/23/01 11:40 AM Page 264R1ONMeOMeAmidas  Weinreb  Estabilización  del  Intermedio  tetraédricos  por  coordinación  6 Nucleophilic Substitution Reactions on the Carboxyl Carbon228substitution product. Instead, the decrease in the concentration of the starting mate-rial serves as a measure of the reactivity.OC XOC XNuCONuC XNuOHCNuOHtetrahedralintermediate+ Nukadd+ H– H+ Xwith orwithout acidcatalysisnot untilthe workup:MM– X– HX orFig. 6.4. Mechanism of SNreactions at the carboxylcarbon via a stabletetrahedral intermediate.3003T Bruckner Ch06 [221-270] 5/25/01 17:10 Page 228LiAlH4    
  28. 28. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   28  REDUCCIONES  THMBB  A.  carboxilicos  R1OOH2gle-bonded O atom to supplement its electron sextet. Thus the C“O double bond ofthe acyloxyborane A lacks any resonance stabilization whatsoever. Consequently, thiscompound contains an extremely electrophilic C“O double bond. A second equiva-lent of the borane adds to it in the second reaction step. The tetrahedral intermediateB, which resembles an acetal, is produced. Unlike a real acetal, compound B is stableunder the reaction conditions, because B cannot heterolyze to give a carboxonium ion:If its C¬O bonds were broken, an acceptor-substituted carbenium ion and not a car-boxonium ion would be produced.Accordingly, this carbenium ion would bear an oxy-Fig. 6.34. Chemoselectivereduction of freecarboxylic acids toaldehydes. Intermediate Byields, upon hydrolysis,initially an aldehydehydrate, which dehydratesto the aldehydespontaneously(mechanism: Section 7.2.1).R C OHOR CHOHOHR C HOBOOR C O BOBrR C O BOBrBBr2 HOCHR OBBBrBr– HH4 OH–2 Br–H2O+ABtert-­‐Hexylmonobromoborane  Aumento  de  la  electrofilia  4.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Aldehidos  aciloxiborano  “acetal”  analógo  hidrolisis  acetal  
  29. 29. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   29  REDUCCIONES  Cloruros  de  ácidos  DIBAL and esters give alcohols through an overreaction with the aldehydes that arenow rapidly formed in situ (details: Figure 14.53). The reaction of LiAlH4 and esters(Figure 14.52) always proceeds to alcohols through such an overreaction.Following “strategy 2” from Figure 6.32, chemoselective SN reactions of hydride-donors with carboxylic acid derivatives also succeed starting from carboxylic chlorides.For the reasons mentioned further above, weakly nucleophilic hydride donors are usedfor this purpose preferentially and should be added dropwise to the acylating agent inorder to achieve success:R C ClOR C HONa B , low temperatureorCu(PPh ) B3 2HH44orLi Al (O -Bu) , low temperaturetert 3H6.5.3 Acylation of Organometallic Compoundsand Heteroatom-Stabilized “Carbanions”:Synthesis of KetonesTertiary amides in general and Weinreb amides in particular react according to “strat-egy 1” of Figure 6.32 not only with hydride-donors to give stable tetrahedral interme-diates (Figure 6.33), but also with organolithium and Grignard compounds (reactionsleading to A or to B, Figure 6.35). The aqueous workup of these intermediates A orB leads to pure acylation products. In this way, DMF or the Weinreb amide of formicacid and organometallic compounds give aldehydes. In the same way, tertiary amidesor Weinreb amides of all higher monocarboxylic acids and organometallic compoundsform ketones.The same reaction mechanism—again corresponding to “strategy 1” of Figure 6.32—explains why carboxylic acids and two equivalents of an organolithium compound re-act selectively to form ketones (Figure 6.36). The first equivalent of the reagent de-R1OClbonded. Consequently, the structural prerequisite for the occurrence of a substitutionreaction is absent.Regarding question (c): the addition of a nucleophile to the C“O double bond ofcarboxylic or carbonic acid derivatives would give products of type C or D (Figure 6.1).However, these compounds are without exception thermodynamically less stable thanthe corresponding substitution products A or B. The reason for this is that the threebonds in the substructure Csp3(¬O¬H)¬Het of the addition products C and D aretogether less stable than the double bond in the substructure Csp2(“O) of the substi-tution products A and B plus the highlighted single bond in the by-product H¬Het. Infact, ordinarily (Section 6.2), substitution reactions on the carboxyl carbon leading ul-timately to compounds of type A or B take place via neutral addition products of typesC or D as intermediates (Figure 6.1). These addition products may be produced eithercontinuously through attack of the nucleophile (cf. Figures 6.2, 6.5) or not until an aque-ous workup has been carried out subsequent to the completion of the nucleophile’s at-tack (cf. Figure 6.4). In both cases, once the neutral addition products C and D haveformed, they decompose exergonically to furnish the substitution products A or B viarapid E1 eliminations, respectively.C XOC XONuC XNuOHCNuOCNuOHtetrahedralintermediate+ Nukaddkretrokelim+ H – HKeqk′elim+ X+ XFig. 6.2. Mechanism of SNreactions of goodnucleophiles at thecarboxyl carbon: kadd is therate constant of theaddition of thenucleophile, kretro is therate constant of the back-reaction, and kelim is therate constant of theelimination of the leavinggroup; Keq is theequilibrium constant forthe protonation of thetetrahedral intermediate atthe negatively chargedoxygen atom.Donores  de  H-­‐  débiles  4.  Reducciones  de  Derivados  de  Acidos  Carboxílicos  a  Aldehidos  Precauciones  Bajas  temperaturas  Adición  gota  a  gota  del  reductor  
  30. 30. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   30  REDUCCIONES  5.  Reducciones  de  Compuestos  Carbonilicos  a  Hidrocarburos  Reducción  de  Wolff-­‐Kishner  R1OR2R1 R2Deoxigenación  de  aldehídos  y  cetonas  via  hidrazonas  o  semicarbazonas  en  medio  básico    in a high boiling solvent (~180-200 °C) so that the use of a sealed tube can be avoided;7,8,172) for base-sensitivesubstrates better yields are achieved when the hydrazone is preformed and the base is added to the substrates atlower temperatures (e.g., 25 °C) followed by refluxing the reaction mixture; 3) esters, lactones, amides, and lactamsare hydrolyzed under the reaction conditions; 4) sterically hindered carbonyl compounds are deoxygenated moreslowly than unhindered ones, so higher reaction temperatures are required (Barton modification);11,145) the use ofDMSO instead of glycols as the reaction medium containing KOt-Bu, followed by the slow addition of preformedhydrazones, allows the reduction to take place at room temperature (Cram modification). However, on small scalethis method is inconvenient, and good results are very substrate dependent;126) preformed hydrazones can also bemixed with KOt-Bu and refluxed in toluene (~110 °C) to effect the reduction (Henbest modification);137) for α,β-unsaturated carbonyl compounds, the use of preformed semicarbazones is advised (hydrazine tends to givepyrazolines with these substrates), which undergo reduction under the original or most of the modified reactionconditions;3and 8) certain aromatic carbonyl compounds (e.g., benzophenone, benzaldehyde) do not require the useof a strong base for reduction, they are reduced when heated with excess hydrazine hydrate.3A powerful alternativeof the W-K reduction is the treatment of tosylhydrazones with hydride reagents to obtain the corresponding alkanes(Caglioti reaction).22A few side reactions have been observed: 1) formation of azines; 2) reduction of ketonesubstrates to alcohols when the reaction is unsuccessful; 3) isomerization of double bonds especially in the case ofα,β-unsaturated carbonyl compounds ; 4) elimination of the α-heteroatom substituent to afford alkenes (Kishner-Leonard elimination);23,24and 5) cleavage or rearrangement of strained rings adjacent to the carbonyl group.Mechanism: 25-32The rate-determining step is the proton capture at the carbon terminal. This process takes place in a concertedfashion with the solvent-induced proton abstraction at the nitrogen terminus to form a diimide that undergoes a loss ofN .R1R2H HR1R2NNH2R1R2NHNketone oraldehydehydrazoneONH2R1R2NNH2hydrazone- N2semicarbazonesealed tubeAlkaneHuang-Minlon modification (1946):R1R2OEtOH/NaOEt180 °Cplatinized porous plateKOH / heat / - N285% NH2NH2·H2O / KOHR1R2H HAlkaneR1R2NNH2hydrazoneR1R2NNH2hydrazone1. distill off the excessreagent and water2. 180-200 °C / - N2ethylene glycol / heatDMSOKOt-Bu/t-BuOHroom temperatureCram modification (1962):R1-2= H, alkyl, aryl, alkenylKishner (1911) Wolff (1912)
  31. 31. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   31  REDUCCIONES  5.  Reducciones  de  Compuestos  Carbonilicos  a  Hidrocarburos  Modificación  de  Huang-­‐Minlon  De  la  Reducción  de  Wolff-­‐Kishner  NH2-­‐NH2·∙H2O,  KOH    E>lenglicol,  200ºC  R1OR2R1 R2the azo compound C, (3) E2 elimination with the liberation of nitrogen and formationof the benzylpotassium D, and (4) protonation of D in the benzylic position, leadingto the formation of the carboxylate F. The carboxylic acid E is formed by protonationof this carboxylate during acidic workup of the reaction mixture.Starting from previously isolated hydrazones, it turns out that they can be reducedto the corresponding hydrocarbons by treatment with base in an aprotic solventat temperatures significantly below the 200ЊC of the Huang–Minlon modifica-tion of the Wolff–Kishner reduction. However, hydrazones cannot be preparedin a one-step reaction between a ketone and hydrazine, since usually azinesBBrrOOOOBrOOHHO O OH,OBrOOHBrOONNH2BrOONNHviabase-catalyzedtautomerization– N , – H O2 2+ ROH,– K ORH O3N H · H O,solid KOH2 4 2200°C; H O3 KKO HA BCDE FOverallreactionAFig. 14.58. Wolff–Kishnerreduction of a ketone. Theexample shows the secondstep of the five-stepHaworth synthesis ofnaphthalene.HIdrazona  Diimida  (Azo  compuesto)  E2  Procesado:  H3O+  Descomposicion  reductora    de  Hidrazonas  R1NR2NH2
  32. 32. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   32  REDUCCIONES  R1OR2R1 R2Alterna>va  I  Reducción  de  Wolff-­‐Kishner  NH2NHCONH2·∙HCl,  KtBuO    Tolueno,  100ºC  Procesado:  H3O+  Descomposición  reductora    de  Semicarbazonas  zone formation—here the semicarbazone formation as a special case of a hydrazone for-mation—and a tautomerization to an azo compound C (the position of the C“C doublebond in C is not known). The tert-butoxide adds to the C“O double bond of the car-bonic acid moiety of the azo compound C and forms the tetrahedral intermediate F (theposition of the C“C double bond remains unknown). The fragmentation of F yields acarbamate, N2, and the allylpotassium compound E. The protonation of F—presumablyunder kinetic control—occurs in a regioselective fashion and results in the alkene D.Tosylhydrazones can be reduced to the corresponding alkanes under milder condi-tions compared to the reduction of carbonyl compounds by the Wolff–Kishner method.This is illustrated in Figure 14.60 by the reduction of the aldhydrazone A (for a pos-sible preparation, see Table 7.2) to the alkane C. The reduction is carried out withNaBH4 in MeOH. The effective reducing agent, formed in situ, is NaBH(OMe)3. Thisreductant delivers a hydride ion for addition to the C“N double bond of the tosyl-hydrazone A. Thereby the hydrazide anion B is formed. Much as in the second stepNNONH2NN NH2O Otert-BuH2N NH C NH2OO NH2OOtert-Butert-BuO NNONH2HKKK+ H– K ba· HClKO -Bu,toluene100°Ctert– N ,2–viabase-catalyzedtautomerizationA BCD E FOverallreactionFig. 14.59. Alternativethe Wolff–Kishnerreduction: reductivedecomposition of asemicarbazone.R1NR2HN NH2OSemicarbazona  Azo  compuesto  Nota:  La  presencia  de  un  doble  enlace  conjugado  no  es  requisito  5.  Reducciones  de  Compuestos  Carbonilicos  a  Hidrocarburos  Intermedio  tetrahedrico  
  33. 33. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   33  REDUCCIONES  5.  Reducciones  de  Compuestos  Carbonilicos  a  Hidrocarburos  R1OR2R1 R2Alterna>va  II  Reducción  de  Wolff-­‐Kishner  NaBH4,  MeOH,  reflujo  Descomposición  reductora    de  Tosilhidrazonas  Formación  in  situ  14 Oxidations and Reductions596of an E1cb elimination, the anion B eliminates a para-tolylsulfinate and a diazo com-pound D is generated. The conversion of the diazo compound D into the hydrocarbonproduct C requires the same structural changes as the conversion of the diazo com-pound C of the Wolff–Kishner reduction (Figure 14.58) into the reduction product.These two transformations could therefore be mechanistically analogous.Conjugated tosylhydrazones also can be reduced to hydrocarbons with themethod depicted in Figure 14.60, that is, with NaBH(OMe)3. The C“C double bondis retained but it is shifted. Figure 14.61 exemplifies this situation for tosylhydra-zone A. The sequence of initial steps A → B → D resembles the one shown in Fig-Non NNTsH HNon NNTsHH HNonH HH Non NNHHH B(OMe)3Na Na– B(OMe)3Details unknown: – N2NaBH ,MeOH,4∆A BC D+ Ts NaOverallreactionFig. 14.60. Alternative IIto the Wolff–Kishnerreduction: reduction of atosylhydrazone; “Non”refers to a nonyl group.3003T Bruckner Ch14-2[581-612] 5/25/01 18:27 Page 596R1NR2HNTsNaBH(OMe)3    Diazo  compuesto  Nota:  Non  =  nonilo  Transferencia  de  H-­‐  Anion  hidrazida  Eliminación  
  34. 34. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   34  REDUCCIONES  5.  Reducciones  de  Compuestos  Carbonilicos  a  Hidrocarburos  R1OR2R1 R2Alterna>va  II  Reducción  de  Wolff-­‐Kishner  NaBH4,  MeOH,  reflujo  Descomposición  reductora    de  Tosilhidrazonas  conjugadas  Formación  in  situ  R1NR2HNTsNaBH(OMe)3    product C requires the same structural changes as the conversion of the diazo com-pound C of the Wolff–Kishner reduction (Figure 14.58) into the reduction product.These two transformations could therefore be mechanistically analogous.Conjugated tosylhydrazones also can be reduced to hydrocarbons with themethod depicted in Figure 14.60, that is, with NaBH(OMe)3. The C“C double bondis retained but it is shifted. Figure 14.61 exemplifies this situation for tosylhydra-zone A. The sequence of initial steps A → B → D resembles the one shown in Fig-ure 14.60. However, the diazo compound D undergoes a different reaction, namely,a retro-ene reaction. A retro-ene reaction is a one-step fragmentation reaction ofH B(OMe)3Na– B(OMe)3NaBH ,MeOH,4∆HHHOtert-BuHNHHHOtert-BuNTs HNNHHTsNNHHNa– Na Ts* *ABCD– N2OverallreactionFig. 14.61. Reduction of aconjugated tosylhydrazone.14.4 Reductions 597an unsaturated compound of type A or B, which affords two unsaturated compoundsaccording to the following pattern:Habcdec cb ba aH HdeHabcde deorA B+ +The retro-ene reaction of Figure 14.61 directly leads to the reaction product C.Aromatic aldehydes and aromatic ketones also can be reduced to hydrocarbons3003T Bruckner Ch14-2[581-612] 5/25/01 18:28 Page 597Diazo  compuesto  Reacción  retro-­‐eno  Isomerización  del  C=C  
  35. 35. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   35  REDUCCIONES  5.  Reducciones  de  Compuestos  Carbonilicos  a  Hidrocarburos  R1OR2R1 R2Tandem    hidrogenación-­‐hidrogenolisis    polar  (iónica)  The retro-ene reaction of Figure 14.61 directly leads to the reaction product C.Aromatic aldehydes and aromatic ketones also can be reduced to hydrocarbonsin a completely different manner, namely via the so-called ionic hydrogenation fol-lowed by an ionic hydrogenolysis. This kind of reduction is possible only if it can pro-ceed via resonance-stabilized cationic intermediates. This resonance stabilization isreadily achieved in a benzylic position, and it is therefore advantageous to employ aro-matic carbonyl compounds in this kind of reduction. The carboxonium ion A, formedONO2HONO2HONO2OHONO2EEtt33SSiiONO2Et3SiHNN OO 22F3CCO2 S Si iE Et t3 3HFFF333CCCCCCOOO222SSSSiiiiEEEEtttt3333HHHF CCO H3 2F CCO3 2F CCO3 2– F CCO H3 2F CCO H3 2Et SiH3+ +Et SiOSiEt +3 3++++ +++viaABOverallreactionFig. 14.62. Polarhydrogenation/hydrogenolysis of anaromatic ketone (meta-nitroacetophenone).CF3COOH causes areversible protonation ofthe ketone to thecarboxonium ion A. Thereducing agenttriethylsilane thentransfers a hydride iononto A to form a benzylicalcohol. This alcoholpresumably is silylated,protonated, and convertedinto the benzyl cation B. Asecond hydride transferyields the final product.R1OR2R1 = Arilo; R2 = HR1 = Arilo; R2 = AlquiloIntermedio  ca>ónico  (benzílico)  estabilizado  por  resonancia  F3CCO2H,  Et3SiH  (2  equivalentes)    Protonación  Transferencia  de  H-­‐  Alcohol  benzilico  Sililación  Protonación  Transferencia  de  H-­‐  
  36. 36. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   36  REDUCCIONES  5.  Reducciones  de  Compuestos  Carbonílicos  a  Hidrocarburos  Li,  EtNH2,  tert-­‐BuOH    Fosoforilación  de  un  enolato  cetonico  reduction of meta-nitroacetophenone (Figure 14.62). Cation A abstracts a hydride ionfrom the first equivalent of the reducing agent, triethylsilane. A benzyl alcohol is thusobtained as a transient intermediate. It is presumably silylated, protonated, and even-tually converted into the benzyl cation B. The latter abstracts another hydride ion fromthe second equivalent of the triethylsilane, which leads to the final product.The reduction of a ketone to an alkene is feasible not only for unsaturated ke-tones (Figures 14.59 and 14.61) but for saturated ketones as well. To this end thelatter must be converted into enol phosphonoamidates or enol dialkylphosphonatesvia suitable lithium enolates. One substrate of each type is shown in Figure 14.63(A and B). Lithium dissolved in EtNH2/tert-BuOH mixtures is a suitable reducingagent for both these compounds. Their Csp2¬O bond is cleaved by a sequence ofthree elementary steps with which you are familiar from the formation of methyl-magnesium iodide (Figure 14.37): (1) electron transfer, (2) dissociation of the rad-ical anion obtained to a vinyl radical and a negatively charged phosphoric acid de-rivative, and (3) electron transfer onto the vinyl radical and formation of analkenyllithium compound. In the final and unavoidable fourth reaction step, thealkenyllithium compound is protonated by tert-BuOH to furnish the alkene prod-uct. The C“C double bond remains in the same position as in the precursors A andB, respectively (Figure 14.63). This means that two different alkenes are formed,since the double bonds were in different positions in compounds A and B.HHHO OO Otert-Bu tert-Butert-Bu tert-BuHOP(NMe)2OHHHHHHXHHHHOP(OEt)2OH HXLi, EtNH , -BuOH2 tert Li, EtNH , -BuOH2 tertX = Li (primary product) (primary product)X = LiD: X = H+ -BuOH,tert + -BuOH,tert– Li O -ButertC: X = HA B– Li O -ButertFig. 14.63. Ketone →alkane reduction via enolphosphonoamidates (forone way to prepare A, seeFigure 10.21) and enoldialkylphosphates (oneway to prepare B is to usea combination of themethods depicted inFigures 10.17 and 10.22).The cleavage of theCsp2¬O bond of thesubstrates occurs inanalogy to the electrontransfers in the formationof methylmagnesiumiodide (Figure 14.37). Thealkenyllithiumintermediates areprotonated in theterminating step to affordthe target alkenes.R1OR2R1R2R1 R2OP(X)2OX= NR fosfonamidatosX= OR dialquilfosfato10.1 Basic Considerations 389OHHHHOtert-BuOHHHHOtert-Bu(Me2N)2POOHHHHOtert-Bu(Me2N)2P ClO– LiClLDALi12Rprim OMeO ORprim OMeO O(EtO)2PO(EtO)2POCl(EtO)2POClRprimOO OMe(EtO)2PORprimOO OMeRprim OMeO ONaHNEt3– HNEt Cl3– NaClNaH in THFNEt3Fig. 10.21. O-Phosphorylation of aketone enolate to affordan enol phosphonamide.(See Figure 10.10, bottomrow, regarding theregioselectivity of theenolate formation.)Fig. 10.22. O-Phosphorylation of aketone enolate to affordan enol phosphate. (SeeFigure 10.4 regarding thestereochemistry of theenolate formation.)OO OSO2 CF3N PhSO2 CF3SO2NPhSO2 CF3CF312LiLDA– LiFig. 10.20. O-Sulfonylationof a ketone enolate to givean enol triflate. (SeeFigure 10.9 regarding theregioselectivity of theenolate formation.)Rotura  Csp2-­‐O:  Mecanismo  de  formación  de  R.  De  Grignard  LDA  
  37. 37. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   37  REDUCCIONES  6.  Hidrogenación  de  alquenos  Estereoselec>vidad:  Adición  cis  altamente  estereoselec>va  R2R1R4R3R2R1R4R3H2Hidrogenación  catalí>ca  heterogénea  Pd,  Pt,  Ru,  Rh,  Ni  Raney   El  níquel  Raney  se  produce  tratando  un  bloque  de  aleación  Ni-­‐Al  con  una  solución  concentrada  de  NaOH  C. What follows is a kind of cis-selective hydropalladation of the alkene. A Pd atombinds to one end of a C“C bond and an H atom that was bonded to a proximate Pdadds to the other end of the C“C bond. The hydropalladation product is describedby stereostructure E. Compound E can react further only if an H atom migrates to aPd atom that is right next to the Pd atom that was involved in the hydropalladation.This migration (of an H atom that is already bonded elsewhere on the surface) occursby way of surface diffusion. The intermediate D is then formed. It releases alkane A,the product of a stereoselective cis-hydrogenation.Part II of Figure 14.65 shows the side reactions that occur when the Pd-catalyzedhydrogenation is not completely cis-selective. The start is the formation of the p-complex F from the hydropalladation product E by a b-hydride elimination of sorts(see Figures 13.8, 13.9, 13.26). In a way, this reaction is the reverse of the reaction typethat formed E from the other p-complex C (part I of Figure 14.65). In an equilibriumreaction, the isomerized p-complex F subsequently releases the alkene iso-B, which isa double bond isomer of the substrate alkene B.Subsequently, the new alkene iso-B is hydrogenated. In principle it may add hydro-gen from either of its diastereotopic faces. However even if the addition were 100%Me MeMHMeHMe eHMeHH ,2Pt/C,EtOHat 25°C 70 : 3084 : 16+at 0°CFig. 14.64. Examples ofheterogeneous catalytichydrogenations of C“Cdouble bonds that occurwith incomplete cis-selectivity.AQuimioselec>vidad:  Dependiente  del  M  Pd:  C=C  sobre  CO    Pt:  CO  sobre  C=C  Rh:  Anillos  aromá>cos  
  38. 38. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   38  REDUCCIONES  6.  Hidrogenación  de  alquenos  R2R1R4R3R2R1R4R3H2Hidrogenación  catalí>ca  heterogénea  14 Oxidations and Reductions600cis-selective, a mixture of alkane A and iso-A could be formed, as shown by the struc-H HR4R2R1 R3R2R2R2R2R4R4R4R4R3R3R3R3R1R1R1R1PdPdPdPdPdPdPdPdPdPdPdPdPdPdPdHHHHHHHHH(dissolved)2A BD EC~ HFig. 14.65, Part IMechanism of the cis-selective heterogeneousPd-catalyzedhydrogenation of C“Cdouble bonds.Complejo  π  reversible  Hidropaladacion  cis  selec>va  Migración  de  H  Mecanismo  de  la  hidrogenación  selec>va  
  39. 39. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   39  REDUCCIONES  6.  Hidrogenación  de  alquenos  R2R1R4R3R2R1R4R3H2Hidrogenación  cataliwca  heterogénea  Mecanismo  de  la  hidrogenación  no-­‐  selec>va  14.4 Reductions 601Figures 5.50 and 5.37. BINAP-containing precious metal complexes catalyze—amongothers—the following hydrogenations:R5R5R5R2R5R5R5R4R4 R4R4R4R4R4R1R1R1R3R3 R3R3R3R3R3R6R6R6R1R6R6R6R1R1R1PdPdPdPdPdPdPdPdPdPdPdHH HHHHHHHHH HHHHHHHFEfor R = CHR R , this is the same as2 5 6may occur undercertain conditionsselectivity-destroying step+ H2≡≡ Aiso-Biso-AFig. 14.65, Part IIMechanism of the stereo-unselective heterogeneousPd-catalyzedhydrogenation of C“Cdouble bonds.Eliminación  β de  H-­‐  Caras  diasterotópicas  Caras  diasterotópicas  
  40. 40. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   40  REDUCCIONES  6.  Hidrogenación  de  alquenos  R2R1R4R3R2R1R4R3H2Hidrogenación  catalí>ca  homogénea  Catalizador  de  Wilkinson  Coordinacion  del  substrato  al  M:    enlaces  π  o  pares  de  e-­‐  Catalizador  de  Vaska  
  41. 41. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   41  REDUCCIONES  6.  Hidrogenación  de  alquenos  R2R1R4R3R2R1R4R3H2Ø  Inmovilización    de  catalizadores  homogéneo  asimétrico  en  un  soporte  heterogéneo    Hidrogenación  catalí>ca  asimétrica  heterogénea  Ø  Modificación  quiral  de  la  superficie  de  un  M:  Pd  –  Fibroina  de  la  seda,  Pd/C/S-­‐meFonina  Cinconidina  Hidrogenación  catalí>ca  asimétrica  homogénea  Estereoselec>vidad:    Cat  quirales  por  uso  De  ligandos  quirales  Complejos  de  M  solubles  M  del  grupo  del  Pt  M  Rh  Ø  Presencia  de  un  grupo  coordinaFvo  en  las  proximidades  del  C=C  -­‐  Knowles  Ru  Ir  Ø  Hidrogenación  asimétrica  de  Noyori  Fe  Ligandos  Fosfinas  P,N  y  P,O  Carbenos    N-­‐heterocíclicos  
  42. 42. Oxidaciones  y  Reducciones  Química  Orgánica  Avanzada  Fernando  Hernández  Mateo   42  REDUCCIONES  6.  Hidrogenación  de  alquenos  R2R1R4R3R2R1R4R3H2Hidrogenación  catalí>ca  asimétrica  homogénea  Mecanismo  general  de  catalizadores  de  Rh  Síntesis  de  L-­‐DOPA  Interacciones  estéricas  desfavorables    Entre  el  ligando  y  el  sustrato  proquiral  Complejo  con  estereoquimica  bien  definida  dependiente  de  quiralidad  del  catalizador  

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