Reduconof)Imines)andAmides)toAmines R)Iminesto)amines:The)C=N)double)bondsreactwith)nucleophile)in)a)same)way)asC=O)double)bonds. Therefore,reducing...

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Reduc&on  of  Organic  Compounds METAL  HYDRIDE  REDUCING  AGENTS •Reduc&on  of  Aldehydes  and  Ketones  to  Alcohols •Reduc&on  of  Acids,  Esters  to  Alcohols •Reduc&on  of  Esters,  Amides,  etc.  to  Aldehydes •Reduc&on  of  Imines  and  Amides  to  Amines BORANE •Hydrobora&on  of  alkenes  and  alkynes •Carbonyl  reduc&on HYDROGENATION •Alkene  hydrogena&on •Alkyne  hydrogena&on •Carbonyl  hydrogena&on DISSOLVING  METAL  REDUCTION •Alkyne  reduc&on •Selec&ve  reduc&on  of  alkenes  in  cyclohexenones •Birch  reduc&on LOW  VALENT  METAL  REDUCTIONS •Forma&on  of  Grignard  reagents •N–O,  N–N  bond  reduc&on •Clemmensen  reduc&on  and  Wolff–Kishner  reduc&on NADPH  AND  RELATED  REDUCING  AGENTS

Reduc&on  is  a  process  in  which  a  chemical  species  gains  electron(s). In   most   (but   not   all)   organic   reduc&ons,   two   electrons   are   transferred.   ONen,   the products   contain   one   addi&onal   proton   (from   the   reac&on   workup)   for   each   electron transferred.


The  more  OR  or  R  groups  on  the  metal,  the  lower  the  ac&vity

Reduc&on  of  Aldehydes  and  Ketones  to  Alcohols

Sodium  borohydride  (NaBH4),  lithium  aluminum  hydride  –  LAH  (LiAlH4)  can  reduce  aldehydes  and ketones  to  alcohols.  NaBH4  is  preferred  due  to  its  easy  handling  and  gentle  reac&vity  compared  to the  more  reac&ve  LiAlH4.

Meerwein-­‐Pondorf-­‐Verley  reduc&on  using  Al(Oi-­‐Pr)3  in  isopropanol  (IPA)

Chemoselec&vity  in  reduc&on  of  aldehydes,  ketones  and  enones

Reduc&on  of  Acids,  Esters  to  Alcohols Esters  to  alcohols:  LiAlH4,  LiBH4

-­‐ -­‐ -­‐

Although   the   aldehyde   is   an   intermediate   in   the   reduc&on   of   esters   to   alcohols,   it   is   impossible   to isolate   it   (even   when   using   a   sub-­‐stoichiometric   amount   of   reducing   agent),   as   the   aldehyde   is   much more  reac&ve  than  the  star&ng  ester  and  gets  reduced  immediately. Acids  to  alcohols:  Less  reac&ve  metal  hydrides  as  NaBH4   cannot  reduce  carboxylic  acids  due  to  the forma&on   of   carboxylates   between   carboxylic   acids   and   counter   ions.   In   this   case   only   the   much stronger  LiAlH4  or  borane  can  be  used. LiBH4  :  The  Li+  ca&on  is  a  stronger  Lewis  acid  than  the  Na+  ca&on.  Li+  coordina&on  with  the  carbonyl group   enhances   the   electrophilicity   of   the   carbonyl   carbon,   thereby   facilita&ng   hydride   transfer. Lithium  borohydride  is  a  more  powerful  reducing  agent  than  sodium  borohydride:  it  reduces  esters to  primary  alcohols  but  is  unreac&ve  towards  a  m  ides.

Hydride  consup&on    in  LiAlH4  Reduc&ons

Reduc&on  of  Esters,  Amides,  etc.  to  Aldehydes Diisobutylaluminum  hydride  –  DIBAL  or  DIBAL-­‐H

Unlike   other   metal   hydrides,   DIBAL   acts   as   a   Lewis   acid   that   coordinates   to   Lewis   base   (O   of   C=O) before   it   is   ac&vated   and   transfers   hydride.   Choice   of   solvent   is   crucial   (usually   hexane,   toluene),   as coordina&ng  solvents  like  THF  destabilize  the  tetrahedral  intermediate  and  cause  over-­‐reduc&on.

Reduc&on  of  esters/carboxylic  acids  to  aldehydes  via  Weinreb’s  amide  forma&on

The   formed   tetrahedral   intermediate   is   stabilized   by   chela&ng   the   metal   center   of   the   hydride reducing   agent.   This   prevents   further   reduc&on   un&l   the   aqueous   workup,   in   which   excess   reducing agent  is  decomposed,  and  the  aldehyde  is  revealed.

Reduc&on  of  Imines  and  Amides  to  Amines

-­‐  Imines  to  amines:  The  C=N  double  bonds  react  with  nucleophile  in  a  same  way  as  C=O  double  bonds. Therefore,  reducing  reagents  that  can  reduce  aldehydes  or  ketones  to  alcohols  can  be  used  in  reducing imines  to  amines  such  as  LiAlH4,  NaBH4,  NaCNBH3  in  acidic  condi&ons. -­‐The  advantage  of  NaCNBH3  as  a  selec&ve  reducing  agent  for  imines  is  that  it  tolerates  other  carbonyl groups  which  would  be  also  reduced  by  LiAlH4  or  NaBH4. -­‐  Amides  to  amines:  Again,  LiAlH4  is  a  good  reagent  for  this  transforma&on.  Borane  (BH3)  is  also  a  good alterna&ve  to  LiAlH4  for  reducing  amides  in  the  presence  of  esters  (BH3  does  not  reduce  esters)


Boron   has   three   electrons   in   the   valence   shell,   which   form   three   conven&onal   bonds   with   other atoms   in   a   planar   structure   leaving   a   vacant   2p   orbital.   This   orbital   is   able   to   accept   a   lone   pair from  a  Lewis  base  or  from  a  nucleophile. Borane  exists  as  a  mixture  of  dimer  (B2H6)  and  monomer  (BH3). Diborane,  B2H6,  is  a  gas  and  is  difficult  to  handle.  However,  borane    complexed  with  donors  such as  THF  or  dimethylsulfide  are  commercially  available  and  have  become  valuable  reagents  for  the reduc&on   of   various   func&onal   groups.   BH3·∙   SMe,   is   soluble   in   and   unreac&ve   toward   a   wide variety  of  apro&c  solvents  such  as  THF,  Et2O,  CH2Cl2,and  hydrocarbons.

Hydrobora&on  of  alkenes  and  alkynes

Hydrobora&on   is   regioselec)ve   (an&-­‐Markovnikov)   and   stereoselec)ve   (syn-­‐addi&on   across   the alkenes)

Carbonyl  reduc&on

Unlike  borohydrides,  borane  is  not  an  ion.  It  behaves  as  a  Lewis  acid  and  reacts  best  with  the  most electrophilic   carbonyl   groups.   Consequently,   it   reduces   electron-­‐rich   carbonyl   groups   such   as carboxylic  acid  and  amide  fastest.  Electron-­‐poor  carbonyl  groups  such  as  acyl  chlorides  and  esters  will not  be  affected.

Selec&vity  in  BH3  ·∙  THF  Reduc&ons

HYDROGENATION Cataly&c   hydrogena&on   is   chemoselec&ve   for   the   C=C   double   bonds   over   C=O double  bonds.

Alkene  hydrogena&on

The  mechanism  of  the  hydrogena&on  of  C=C  double  bonds  starts  with  the  coordina&on of  the  double  bonds  on  to  the  catalyst  surface.

Alkyne  hydrogena&on

-­‐  Reduc&on  of  alkynes  to  Z-­‐alkenes:   Lindlar’s  catalyst   (Pd,  CaCO3,  Pb(OAc)2)  is  a palladium   catalyst   (Pd/CaCO3)   poisoned   by   lead.   The   lead   lowers   the   ac&vity   of the   catalyst.   Consequently,   it   will   hydrogenate   alkynes   to   alkenes   rather   than alkenes  to  alkanes. -­‐  Reduc&on  of  alkynes  to  E-­‐alkenes:  Na  in  NH3  (liquid)  (discussed  below)

Carbonyl  hydrogena&on -­‐  Cataly&c  asymmetric  hydrogena&on  (Noyori  –  Nobel  prize  in  Chemistry  2001)

Concept  of  asymmetric  catalysis -­‐  Enan&omeric  ra&o  is  directly  propor&onal  to  the  rela&ve  rate  of  the  enan&omeric  products. -­‐  Enan&omeric  ra&o  is  governed  by  differen&al  ac&va&on  parameters  (∆∆G‡,  ∆∆H‡  and  ∆∆S‡). -­‐  R  and  S  are  chosen  below  arbitrarily.

Some  useful  number  to  think  about  in  enan&oselec&ve  catalysis: -­‐  ∆∆G‡  of  1.38  kcal/mol  is  needed  to  achieve  80%  ee  at  room  temp -­‐  ∆∆G‡  of  ~2.0  kcal/mol  is  needed  to  achieve  90%  ee  at  room  temp -­‐  ∆∆G‡  of  2.60  kcal/mol  is  needed  to  achieve  98%  ee  at  room  temp -­‐  ∆∆G‡  of  2.73  kcal/mol  is  needed  to  achieve  99%  ee  at  room  temp -­‐  ∆∆G‡  of  1.80  kcal/mol  is  needed  to  achieve  98%  ee  at  -­‐78°C


Stereoselec&ve  –  trans  product  is  favored

Selec&ve  reduc&on  of  alkenes  in  cyclohexenones Similar  to  reduc&ons  of  alkynes,  also  stereoselec&ve

Birch  reduc&on

Changing  the  workup  in  a  reduc&on  of  anisole  can  lead  to  cyclohexenones.

Dependent  on  subs&tu&on  of  anisole,  different  substa&on  pamerns  obtained

LOW  VALENT  METAL  REDUCTIONS Forma&on  of  Grignard  reagents Very  basic  and  strong  nucleophile

N–O,  N–N  bond  reduc&on

Reduc&on  of  the  N–O  bond  oNen  proceeds  to  the  free  amine  under  strong  acidic  condi&ons This   is   not   always   the   case   and   the   reac&on   can   be   stopped   at   an   intermediate   stage   by   using neutralcondi&on.

Nitro  compounds  with  α  hydrogen  can  be  reduced  to  the  corresponding  oximes  in  ace&c  acid.

Similarly  N–N  bonds  can  be  reduced.

Clemmensen  reduc&on Does  not  tolerate  acid  sensi&ve  func&onali&es

A  related  reac&on  to  Clemmensen  reduc&on  is  called  the  Wolff–Kishner  reduc&on

NADPH  AND  RELATED  REDUCING  AGENTS Similar  to  hydride  reducing  agents  we  have  covered.  Coupled  with  enzymes,  have  the added  benefit  of  absolute  stereoselec&vity NADH  and  NADPH

FAD Reduc&on  of  molecular  oxygen  reduc&on  leads  to  forma&on  of  epoxides

Ascorbic  acid  as  hydride  donor Mild   reducing   reagent.   Used   biologically   to   protect   against   stray   oxidants   and   reducing important  intermediates  (peroxides  and  Fe3+)

CO2  reduc&on

Biological  CO2  reduc&ons  (CO2  fixa&on)

Conversion   of   CO2   to   small   organic   compounds   is   achieved   in   the   Calvin   cycle,   an   important   step   in photosynthesis.  The  enzyme  RuBisCo  (Ribulose-­‐1,5-­‐bisphosphate  carboxylase  oxygenase)  catalyzes  the CO2  fixa&on.

Industrial/Cataly&c  CO2  fixa&on

Synthesis  of  hydrobenzoic  acid  by  Kolbe-­‐Schmidt  reac&on

Similarly  other  carbon  nucleophiles  can  be  used