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Chapter 16- Chemistry of Benzene: Electrophilic Aromatic ... · 2/1/16 1 Chapter 16- Chemistry of...

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  • 2/1/16  

    1  

    Chapter 16- Chemistry of Benzene: Electrophilic Aromatic Substitution

    Ashley  Piekarski,  Ph.D.  

    Substitution Reactions of Benzene and Its Derivatives

    •  Benzene  is  aroma%c  •  What does aromatic mean?

    •  Reac9ons  of  benzene  lead  to  the  reten9on  of  the  aroma9c  core  

     

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    Why do I care, Dr. P?

    •  In  the  last  chapter,  we  learned  about  the  structure  and  stability  of  aroma9c  compounds  

    •  We  established  a  structure-‐property  rela%onship!  •  This valuable information will help us

    understand the reactions these molecules undergo and the products that are made

    •  Rela9onship  cri9cal  to  understanding  of  how  biological  molecules/pharmaceu9cal  agents  are  synthesizedà  real-‐world  applica%ons!  

    Electrophilic Aromatic Substitution Reactions: Bromination

    •  Benzene’s  π  electrons  par9cipate  as  a  Lewis  base  in  reac9ons  with  Lewis  acids  

    •  The  product  is  formed  by  loss  of  a  proton,  which  is  replaced  by  bromine  

    •  FeBr3  is  added  as  a  catalyst  to  polarize  the  bromine  reagent  

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    Bromination of alkenes

    •  What  was  the  product  of  the  bromina9on  of  propene?  

    •  This  doesn’t  happen  with  benzene…  •  Why do you think that is?

    Addition Intermediate in Bromination

    •  The  addi9on  of  bromine  occurs  in  two  steps  •  In  the  first  step  the  π  electrons  act  as  a  nucleophile  toward  

    Br2  (in  a  complex  with  FeBr3)  •  This  forms  a  ca9onic  addi9on  intermediate  from  benzene  and  

    a  bromine  ca9on  •  The  intermediate  is  not  aroma(c  and  therefore  high  in  energy  

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    Formation of Product from Intermediate

    •  The  ca9onic  addi9on  intermediate  transfers  a  proton  to  FeBr4-‐  (from  Br-‐  and  FeBr3)  

    •  This  restores  aroma%city!  (in  contrast  with  addi9on  in  alkenes)  

    Other Aromatic Substitutions

    •  Chlorine  and  iodine  (but  not  fluorine,  which  is  too  reac9ve)  can  produce  aroma9c  subs9tu9on  with  the  addi9on  of  other  reagents  to  promote  the  reac9on  

    •  Chlorina9on  requires  FeCl3  (acts  as  a  catalyst  to  make  chlorine  a  beXer  electrophile)  

    AKA  Valium  (an9-‐anxiety  drug)  

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    Other Aromatic Substitutions

    •  Chlorine  and  iodine  (but  not  fluorine,  which  is  too  reac9ve)  can  produce  aroma9c  subs9tu9on  with  the  addi9on  of  other  reagents  to  promote  the  reac9on  

    •  Chlorina9on  requires  FeCl3  (acts  as  a  catalyst)  •  Iodine  must  be  oxidized  to  form  a  more  powerful  I+    species  

    (with  Cu+    or  peroxide)  

    Aromatic Nitration

    •  The  combina9on  of  nitric  acid  and  sulfuric  acid  produces  NO2+  (nitronium  ion)  

    •  The  reac9on  with  benzene  produces  nitrobenzene  

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    Aromatic Sulfonation

    •  Subs9tu9on  of  H  by  SO3  (sulfona9on)  •  Reac9on  with  a  mixture  of  sulfuric  acid  and  SO3  •  Reac9ve  species  is  sulfur  trioxide  or  its  conjugate  acid    

    Aromatic Hydroxylation

    •  Not  performed  in  the  laboratory  •  Does  occur  in  biological  pathways!  

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    Alkylation of Aromatic Rings: The Friedel–Crafts Reaction

    •  Alkyla9on  among  most  useful  electrophilic  aroma9c  subs9tu9on  reac9ons!    Very  powerful  rxn.  to  put  in  your  organic  toolbox!  

    •  Aroma9c  subs9tu9on  of  R+  for  H+  

    •  Aluminum  chloride  promotes  the  forma9on  of  the  carboca9on  

    Alkylation of Aromatic Rings: The Friedel–Crafts Reaction

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    Limitations of the Friedel-Crafts Alkylation

    •  Only  alkyl  halides  can  be  used  (F,  Cl,  I,  Br)  •  Aryl  halides  and  vinylic  halides  do  not  react  (their  

    carboca9ons  are  not  stable  enough  to  form)  •  Will  not  work  with  rings  containing  an  amino  group  

    subs9tuent  or  a  strongly  electron-‐withdrawing  group  

    Control Problems

    •  Mul9ple  alkyla9ons  can  occur  because  the  first  alkyla9on  is  ac9va9ng  

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    Carbocation Rearrangements During Alkylation

    •  Similar  to  those  that  occur  during  electrophilic  addi9ons  to  alkenes  

    •  What  are  the  two  types  of  carboca9on  rearrangements  and  why  do  they  occur?  

    Carbocation Rearrangements During Alkylation

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    Learning check

    •  Predict  the  product  and  write  the  complete  stepwise  mechanism  for  the  reac9on  below:  

    CH3CH2Cl

    AlCl3

    AlCl3

    Cl

    Cl

    O

    AlCl3

    CH3SO3

    H2SO4

    a)

    OCH3

    Br2FeBr3

    b)

    NO2

    1. HNO3, H2SO42. H2/Pd

    c)CH3

    O

    Learning check

    •  Predict  the  product  and  write  the  complete  stepwise  mechanism  for  the  reac9on  below:  

    CH3CH2Cl

    AlCl3

    AlCl3

    Cl

    Cl

    O

    AlCl3

    CH3SO3

    H2SO4

    a)

    OCH3

    Br2FeBr3

    b)

    NO2

    1. HNO3, H2SO42. H2/Pd

    c)CH3

    O

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    Acylation of Aromatic Rings

    •  Reac9on  of  an  acid  chloride  (RCOCl)  and  an  aroma9c  ring  in  the  presence  of  AlCl3  introduces  acyl  group,  ⎯COR    •  Benzene with acetyl chloride yields acetophenone

    Mechanism of Friedel-Crafts Acylation

    •  Similar  to  alkyla9on  •  Reac9ve  electrophile:  resonance-‐stabilized  acyl  ca9on    •  An  acyl  ca9on  does  not  rearrange  

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    Learning check

    •  Predict  the  product  and  write  the  complete  stepwise  mechanism  for  the  reac9on  below:  

    CH3CH2Cl

    AlCl3

    AlCl3

    Cl

    Cl

    O

    AlCl3

    CH3SO3

    H2SO4

    a)

    OCH3

    Br2FeBr3

    b)

    NO2

    1. HNO3, H2SO42. H2/Pd

    c)CH3

    O

    Substituent Effects in Aromatic Rings

    •  Subs9tuents  can  cause  a  compound  to  be  more  or  less  reac9ve  than  benzene  

    •  Subs9tuents  affect  the  orienta9on  of  the  reac9on  –  the  posi9onal  rela9onship  is  controlled  •  ortho- and para-directing activators, ortho- and para-

    directing deactivators, and meta-directing deactivators

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    Origins of Substituent Effects

    •  An  interplay  of  induc(ve  effects  and  resonance  effects    

    •  Induc%ve  effect  -‐  withdrawal  or  dona9on  of  electrons  through  a  σ  bond  

    •  Resonance  effect  -‐  withdrawal  or  dona9on  of  electrons  through  a  π  bond  due  to  the  overlap  of  a  p  orbital  on  the  subs9tuent  with  a  p  orbital  on  the  aroma9c  ring    

    •  It  is  cri9cal  you  know  the  difference  between  these  two  defini9ons!  

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    Inductive Effects

    •  Controlled  by  electronega9vity  and  the  polarity  of  bonds  in  func9onal  groups  

    •  Halogens,  C=O,  CN,  and  NO2  withdraw  electrons  through  σ  bond  connected  to  ring  

    •   Alkyl  groups  donate  electrons    

    Resonance Effects – Electron Withdrawal

    •  C=O,  CN,  NO2  subs9tuents  withdraw  electrons  from  the  aroma9c  ring  by  resonance  

    •  π  electrons  flow  from  the  rings  to  the  subs9tuents  

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    Resonance Effects – Electron Donation

    •  Halogen,  OH,  alkoxyl  (OR),  and  amino  subs9tuents  donate  electrons  

    •   π  electrons  flow  from  the  subs9tuents  to  the  ring  •  Effect  is  greatest  at  ortho  and  para  

    An Explanation of Substituent Effects

    •  Ac%va%ng  groups  donate  electrons  to  the  ring,  stabilizing  the  carboca9on  intermediate  

    •  Deac%va%ng  groups  withdraw  electrons  from  the  ring,  destabilizing  the  carboca9on  intermediate  

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    Ortho- and Para-Directing Activators: Alkyl Groups

    •  Alkyl  groups  ac9vate:  direct  further  subs9tu9on  to  posi9ons  ortho  and  para  to  themselves  

    •  Alkyl  group  is  most  effec9ve  in  the  ortho  and  para  posi9ons  because  they  form  the  most  stable  intermediates!  

    Ortho- and Para-Directing Activators: OH and NH2

    •  Alkoxyl,  and  amino  groups  have  a  strong,  electron-‐dona9ng  resonance  effect    

    •  Most  pronounced  at  the  ortho  and  para  posi9ons    

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    Ortho- and Para-Directing Deactivators: Halogens

    •  Electron-‐withdrawing  induc9ve  effect  outweighs  weaker  electron-‐dona9ng  resonance  effect  

    •  Resonance  effect  is  only  at  the  ortho  and  para  posi9ons,  stabilizing  carboca9on  intermediate  

    Meta-Directing Deactivators

    •  Induc9ve  and  resonance  effects  reinforce  each  other  •  Ortho  and  para  intermediates  destabilized  by  deac9va9on  of  

    carboca9on  intermediate  •  Resonance  cannot  produce  stabiliza9on  

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    Summary Table: Effect of Substituents in Aromatic Substitution

    Trisubstituted Benzenes

    •  If  the  direc9ng  effects  of  the  two  groups  are  the  same,  the  result  is  addi9ve  

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    Substituents with Opposite Effects

    •  If  the  direc9ng  effects  of  two  groups  oppose  each  other,  the  more  powerful  ac9va9ng  group  decides  the  principal  outcome  

    •  Usually  gives  mixtures  of  products    

    Meta-Disubstituted Compounds

    •  The  reac9on  site  is  too  hindered  •  To  make  aroma9c  rings  with  three  adjacent  subs9tuents,  it  is  

    best  to  start  with  an  ortho-‐disubs9tuted  compound    

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    Learning check

    •  Predict  the  products  of  the  reac9ons  below:  

    CH3CH2Cl

    AlCl3

    AlCl3

    Cl

    Cl

    O

    AlCl3

    CH3SO3

    H2SO4

    a)

    OCH3

    Br2FeBr3

    b)

    NO2

    1. HNO3, H2SO42. H2/Pd

    c)CH3

    O

    Nucleophilic Aromatic Substitution •  Aryl  halides  with  electron-‐withdrawing  subs9tuents  ortho  and  

    para  react  with  nucleophiles  •  Form  addi9on  intermediate  that  is  stabilized  by  electron-‐

    withdrawal  •  Halide  ion  is  lost  to  give  aroma9c  ring  

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    Benzyne

    •  Phenol  is  prepared  on  an  industrial  scale  by  treatment  of  chlorobenzene  with  dilute  aqueous  NaOH  at  340°C  under  high  pressure  

    •  The  reac9on  involves  an  elimina9on  reac9on  that  gives  a  triple  bond  

    •  The  intermediate  is  called  benzyne  

    Evidence for Benzyne as an Intermediate

    •  Bromobenzene  with  14C  only  at  C1  gives  subs9tu9on  product  with  label  scrambled  between  C1  and  C2  

    •  Reac9on  proceeds  through  a  symmetrical  intermediate  in  which  C1  and  C2  are  equivalent—    must  be  benzyne  

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    Structure of Benzyne

    •  Benzyne  is  a  highly  distorted  alkyne  •  The  triple  bond  uses  sp2-‐hybridized  carbons,  not  the  usual  sp  •  The  triple  bond  has  one  π  bond  formed  by  p–p  overlap  and  

    another  by  weak  sp2–sp2  overlap  

    Oxidation of Aromatic Compounds

    •  Alkyl  side  chains  can  be  oxidized  to  ⎯CO2H  by  strong  reagents  such  as  KMnO4  and  Na2Cr2O7  if  they  have  a  C-‐H  next  to  the  ring  

    •  Converts  an  alkylbenzene  into  a  benzoic  acid,  Ar⎯R  →  Ar⎯CO2H  

    •  Benzene  ring  cannot  be  oxidized!  

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    Bromination of Alkylbenzene Side Chains

    •  Reac9on  of  an  alkylbenzene  with  N-‐bromo-‐succinimide  (NBS)  and  benzoyl  peroxide  (radical  ini9ator)  introduces  Br  into  the  side  chain  

    Mechanism of NBS (Radical) Reaction

    •  Abstrac9on  of  a  benzylic  hydrogen  atom  generates  an  intermediate  benzylic  radical  

    •  Reacts  with  Br2  to  yield  product  •  Br·  radical  cycles  back  into  reac9on  to  carry  chain  •  Br2  produced  from  reac9on  of  HBr  with  NBS    

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    Reduction of Aromatic Compounds

    •  Aroma9c  rings  are  inert  to  cataly9c  hydrogena9on  under  condi9ons  that  reduce  alkene  double  bonds  

    •  Can  selec9vely  reduce  an  alkene  double  bond  in  the  presence  of  an  aroma9c  ring  

    •  Reduc9on  of  an  aroma9c  ring  requires  more  powerful  reducing  condi9ons    (high  pressure  or  rhodium  catalysts)  

    Reduction of Aryl Alkyl Ketones

    •  Aroma9c  ring  ac9vates  neighboring  carbonyl  group  toward  reduc9on  

    •  Ketone  is  converted  into  an  alkylbenzene  by  cataly9c  hydrogena9on  over  Pd  catalyst  

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    Synthesis of Trisubstituted Benzenes

    •  These  syntheses  require  planning  and  considera9on  of  alterna9ve  routes  

    •  Ability  to  plan  a  sequence  of  reac9ons  in  right  order  is  valuable  to  synthesis  of  subs9tuted  aroma9c  rings  

    Learning check

    •  Propose  a  synthesis  for  3-‐bromo-‐2methylbenzenesulfonic  acid.  

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    Learning check

    •  Propose  a  synthesis  for  4-‐chloro-‐1-‐nitro-‐2-‐propylbenzene.  

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2/1/16 1 Chapter 16- Chemistry of Benzene: Electrophilic Aromatic Substitution Ashley Piekarski, Ph.D. Substitution Reactions of Benzene and Its Derivatives Benzene is aroma%c What does aromatic mean? Reac9ons of benzene lead to the reten9on of the aroma9c core
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