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Chapter 11- Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

Ashley  Piekarski,  Ph.D.  

Alkyl Halides React with Nucleophiles and Bases

•  Alkyl  halides  are  polarized  at  the  carbon-­‐halide  bond,  making  the  carbon  electrophilic  

•  Nucleophiles  will  replace  the  halide  in  C-­‐X  bonds  of  many  alkyl  halides(reacGon  as  Lewis  base)  

•  Nucleophiles  that  are  Brønsted  bases  produce  eliminaGon  

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Why do I care, Dr. P?

•  Nucleophilic  subsGtuGon,  base  induced  eliminaGon  are  among  most  widely  occurring  and  versaGle  reacGon  types  in  organic  chemistry  

•  ReacGons  will  be  examined  closely  to  see:  -­‐  How  they  occur  -­‐  What  their  characterisGcs  are  -­‐  How  they  can  be  used  

11.1 The Discovery of Nucleophilic Substitution Reactions

•  In  1896,  Walden  showed  that  (-­‐)-­‐malic  acid  could  be  converted  to  (+)-­‐malic  acid  by  a  series  of  chemical  steps  with  achiral  reagents  

•  This  established  that  op#cal  rota#on  was  directly  related  to  chirality  and  that  it  changes  with  chemical  altera#on  •  Reaction of (-)-malic acid with PCl5 gives (+)-

chlorosuccinic acid •  Further reaction with wet silver oxide gives

(+)-malic acid •  The reaction series starting with (+) malic acid

gives (-) acid

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Reactions of the Walden Inversion

What  sort  of  observaGons  can  we  make  about  the  reacGons  

Walden  performed?  

Significance of the Walden Inversion

•  The  reacGons  alter  the  array  at  the  chirality  center  

•  The  reacGons  involve  subsGtuGon  at  that  center  

•  Therefore,  nucleophilic  subsGtuGon  can  invert  the  configuraGon  at  a  chirality  center  

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11.2 The SN2 Reaction

•  ReacGon  is  with  inversion  at  reacGng  center  •  Follows  second  order  reacGon  kineGcs  

•  the rate is linearly dependent on the concentrations of two species

•  Ingold  nomenclature  to  describe  characterisGc  step:  •  S=substitution •  N (subscript) = nucleophilic •  2 = both nucleophile and substrate in

characteristic step (bimolecular)

The SN2 Reaction-Mechanism

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Kinetics of Nucleophilic Substitution

•  Rate  (R)  is  change  in  concentraGon  with  Gme  •  Depends  on  concentraGon(s),  temperature,  inherent  

nature  of  reacGon  (barrier  on  energy  surface)  •  A  rate  law  describes  relaGonship  between  the  

concentraGon  of  reactants  and  conversion  to  products  

•  A  rate  constant  (k)  is  the  proporGonality  factor  between  concentraGon  and  rate  

 

Example:  for  S  converGng  to  P  

R  =  d[S]/dt  =  k  [S]  

Reaction Kinetics

•  The  study  of  rates  of  reacGons  is  called  kine#cs  

•  Rates  decrease  as  concentraGons  decrease  but  the  rate  constant  does  not  

•  Rate  units:  [concentraGon]/Gme  such  as  mol/(L  x  s)  

•  The  rate  law  is  a  result  of  the  mechanism  •  The  order  of  a  reacGon  is  sum  of  the  exponents  of  the  concentraGons  in  the  rate  law  –  the  example  is  second  order  

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SN2 Process

•  The  reacGon  involves  a  transiGon  state  in  which  both  reactants  are  together  

SN2 Transition State

•  The  transiGon  state  of  an  SN2  reacGon  has  a  planar  arrangement  of  the  carbon  atom  and  the  remaining  three  groups  

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11.3 Characteristics of the SN2 Reaction

•  SensiGve  to  steric  effects  •  Why do you think that is?

•  Methyl  halides  are  most  reacGve  •  Primary  are  next  most  reacGve  •  Secondary  might  react  •  TerGary  are  unreacGve  by  this  path  •  No  reacGon  at  C=C  (vinyl  halides)  

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Reactant and Transition State Energy Levels Affect Rate

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Higher  reactant  energy  level  (red  curve)  =  faster  reacGon  (smaller  ΔG‡).  

Higher  transiGon  state  energy  level  (red  curve)  =  slower  reacGon  (larger  ΔG‡).  

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Steric Effects on SN2 Reactions

What  are  the  subsGtuGons  of  these  substrates?  How  would  you  order  the  reacGvity?  

Order of Reactivity in SN2

•  The  more  alkyl  groups  connected  to  the  reacGng  carbon,  the  slower  the  reacGon  

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The Nucleophile

•  Neutral  or  negaGvely  charged  Lewis  base  •  ReacGon  increases  coordinaGon  at  nucleophile  

•  Neutral nucleophile acquires positive charge •  Anionic nucleophile becomes neutral

List of Nucleophiles

What  causes  difference  in  Nucleophilicity?    depends  on  substrate,  solvent,  and  reactant  concentra#ons  

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Relative Reactivity of Nucleophiles

•  More  basic  nucleophiles  react  faster    

•  Beher  nucleophiles  are  lower  in  a  column  of  the  periodic  table  •  Why do you think that is?

•  Anions  are  usually  more  reacGve  than  neutrals  •  These types of reactions are generally ran

under basic conditions

The Leaving Group

•  A  good  leaving  group  reduces  the  barrier  to  a  reacGon  •  Stable  anions  that  are  weak  bases  are  usually  excellent  

leaving  groups  and  can  delocalize  charge  

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The Solvent

•  Solvents  that  can  donate  hydrogen  bonds  (-­‐OH  or  –NH)  slow  SN2  reacGons  by  associaGng  with  reactants  

•  Energy  is  required  to  break  interacGons  between  reactant  and  solvent  

•  Polar  aproGc  solvents  (no  NH,  OH,  SH)  form  weaker  interacGons  with  substrate  and  permit  faster  reacGon  

Summary SN2

•  What  are  good  substrates?  

•  What  are  good  nucleophiles?  

•  What  makes  a  good  leaving  group?  

•  What  is  a  good  solvent?  

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11.4 The SN1 Reaction

•  TerGary  alkyl  halides  react  rapidly  in  proGc  solvents  by  a  mechanism  that  involves  departure  of  the  leaving  group  prior  to  addiGon  of  the  nucleophile  

•  Called  an  SN1  reacGon  –  occurs  in  two  disGnct  steps  while  SN2  occurs  with  both  events  in  same  step  

•  If  nucleophile  is  present  in  reasonable  concentraGon  (or  it  is  the  solvent),  then  ionizaGon  is  the  slowest  step    

The SN1 Reaction-Mechanism

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SN1 Energy Diagram

•  Rate-­‐determining  step  is  formaGon  of  carbocaGon  

R  =  k[RX]  

What  is  missing  from  the  rate  law?  

Rate-Limiting Step

•  The  overall  rate  of  a  reacGon  is  controlled  by  the  rate  of  the  slowest  step  

•  The  rate  depends  on  the  concentraGon  of  the  species  and  the  rate  constant  of  the  step  

•  The  highest  energy  transiGon  state  point  on  the  diagram  is  that  for  the  rate  determining  step  (which  is  not  always  the  highest  barrier)  

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Stereochemistry of SN1 Reaction

•  The  planar  intermediate  leads  to  loss  of  chirality  •  A free carbocation is achiral

•  Product  is  racemic  

SN1 in Reality

•  CarbocaGon  is  biased  to  react  on  side  opposite  leaving  group  

•  Suggests  reacGon  occurs  with  carbocaGon  loosely  associated  with  leaving  group  during  nucleophilic  addiGon  

•  AlternaGve  that  SN2  is  also  occurring  is  unlikely  

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Not completely racemic products

11.5 Characteristics of the SN1 Reaction

Substrate  •  TerGary  alkyl  halide  is  most  reacGve  by  this  mechanism  

•  Controlled by stability of “Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that intermediate”

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Allylic and Benzylic Halides

•  Allylic  and  benzylic  intermediates  stabilized  by  delocalizaGon  of  charge  (Draw  the  resonance  structures  for  the  allyl  carbocaGon  and  the  benzyl  carbocaGon)  •  Primary allylic and benzylic are also more reactive in

the SN2 mechanism

Effect of Leaving Group on SN1

•  CriGcally  dependent  on  leaving  group  •  Reactivity: the larger halides ions are

better leaving groups •  Under  acidic  condiGons,  OH  of  an  alcohol  is  protonated  and  leaving  group  is  H2O,  which  is  sGll  less  reacGve  than  halide  

•  p-­‐Toluenesulfonate  (TosO-­‐)  is  excellent  leaving  group  

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Nucleophiles in SN1

•  Since  nucleophilic  addiGon  occurs  a9er  formaGon  of  carbocaGon,  reacGon  rate  is  not  normally  affected  by  nature  or  concentraGon  of  nucleophile  

Solvent in SN1

•  How  do  you  think  solvent  plays  a  role  in  SN1  reacGons?  •  Stabilizing  carbocaGon  also  stabilizes  associated  transiGon  

state  and  controls  rate  •  Solvent  effects  in  the  SN1  reacGon  are  due  largely  to  

stabilizaGon  or  destabilizaGon  of  the  transiGon  state  

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Polar Solvents Promote Ionization

•  Polar,  proGc  and  unreacGve  Lewis  base  solvents  facilitate  formaGon  of  R+      

•  Solvent  polarity  is  measured  as  dielectric  polariza7on  (P)    •  Nonpolar solvents have low P •  Polar solvents have high P values

Summary SN1

•  What  are  good  substrates?  

•  What  are  good  nucleophiles?  

•  What  makes  a  good  leaving  group?  

•  What  is  a  good  solvent?  

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11.7 Elimination Reactions of Alkyl Halides: Zaitsev’s Rule

•  EliminaGon  is  an  alternaGve  pathway  to  subsGtuGon  •  Opposite  of  addiGon  •  Generates  an  alkene  •  Can  compete  with  subsGtuGon  and  decrease  yield,  

especially  for  SN1  processes  

Zaitsev’s Rule for Elimination Reactions

•  In  the  eliminaGon  of  HX  from  an  alkyl  halide,  the  more  highly  subsGtuted  alkene  product  predominates    

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Mechanisms of Elimination Reactions

•  Ingold  nomenclature:  E  –  “eliminaGon”  •  E1:  X-­‐  leaves  first  to  generate  a  carbocaGon  

•  a base abstracts a proton from the carbocation •  E2:  Concerted  transfer  of  a  proton  to  a  base  and  

departure  of  leaving  group  

E1 Mechanism

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E2 Mechanism

11.8 The E2 Reaction and the Deuterium Isotope Effect

•  What  is  the  rate  law  for  the  E2  reacGon?  

•  How  does  the  rate  of  the  reacGon  change  between  hydrogen  and  deuterium?  

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Geometry of Elimination – E2

•  AnGperiplanar  allows  orbital  overlap  and  minimizes  steric  interacGons  

Periplanar-­‐  all  four  reacGng  atoms  (the  hydrogen,  the  two  carbons,  and  the  leaving  group)  lie  in  the  same  plane  

E2 Stereochemistry

•  Overlap  of  the  developing  sp3  σ  orbital  in  the  transiGon  state  requires  periplanar  geometry,  anG  arrangement  

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Predicting Product

•  E2  is  stereospecific  •  Meso-­‐1,2-­‐dibromo-­‐1,2-­‐diphenylethane  with  base  gives  cis  

1,2-­‐diphenyl  •  RR  or  SS  1,2-­‐dibromo-­‐1,2-­‐diphenylethane  gives  trans  1,2-­‐

diphenyl  

11.9 The E2 Reaction and Cyclohexane Formation

•  Abstracted  proton  and  leaving  group  should  align  trans-­‐diaxial  to  be  anG  periplanar  (app)  in  approaching  transiGon  state    

•  Equatorial  groups  are  not  in  proper  alignment  

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E2 and cyclohexanes

11.10 The E1and E1cB Reactions

•  Competes  with  SN1  and  E2  at  3°  centers  •  V  =  k  [RX],  same  as  SN1  

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E1 Mechanism

shows  no  deuterium  isotope  effect!  

Comparing E1 and E2

•  Strong  base  is  needed  for  E2  but  not  for  E1  •  E2  is  stereospecifc,  E1  is  not  •  E1  gives  Zaitsev  orientaGon  

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11.12 Summary of Reactivity: SN1, SN1, E1,E1cB, E2

• Primary  alkyl  halides:  SN2  subsGtuGon  occurs  if  a  good  nucleophile  is  used,  E2  

eliminaGon  occurs  if  a  strong  base  is  used,  E1cB  eliminaGon  occurs  if  the  leaving  

group  is  two  carbons  away  from  a  carbonyl  group  

• Secondary  alkyl  halides:  SN2  subsGtuGon  occurs  if  a  weakly  basic  nucelophile  is  used  in  a  polar  aproGc  solvent,  E2  eliminaGon  predominates  if  a  strong  base  is  

used,  E1cB  eliminaGon  occurs  if  the  leaving  group  is  two  carbons  away  from  a  

carbonyl  group.    Secondary  allylic  and  benzylic  alkyl  halides  can  also  undergo  SN1  

and  E1  reacGons  if  a  weakly  basic  nucleophile  is  used  in  a  proGc  solvent  

• Ter7ary  alkyl  halides:  E2  eliminaGon  occurs  when  a  base  is  used,  but  SN1  and  E1  

occur  together  under  neutral  condiGons.  ,  E1cB  eliminaGon  occurs  if  the  leaving  

group  is  two  carbons  away  from  a  carbonyl  group