Alkyl  Halides  and  Nucleophilic  Subs5tu5on  Reac5ons      

SN2  and  SN1  Reac,ons  

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Alkyl  Halides  The   electronega5ve   halogen   atom   in   alkyl   halides  creates   a   polar   C—X   bond,  making   the   carbon   atom  electron  deficient.    

                         Electrosta5c  poten5al  maps  of  four  halomethanes  (CH3X)  

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Reac5ons  of  Alkyl  Halides  

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Nucleophilic  Subs5tu5on  Reac5ons  

NaOH

Acetone

cis-1-Chloro-3-methylcyclopentane

H

ClH3C

HOH

HH3C

H

trans-3-Methylcyclohexanol

BrNaOH

Acetone

OH

+ NaCl

+ NaBr

R-2-Bromooctane S-2-Octanol

Br

OHH2O +

OH

2-Bromo-3-methylbutane 2-Methyl-2-butanol 3-Methyl-2-butanol

+ HBr

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Possible  Mechanisms  of  Nucleophilic  Subs5tu5on  Reac5ons  

R-X + Nuclophile R-Nucleophile + X

1st Possibility:

Nucleophile R R-Nucleophile + X

2nd Possibility:R X

X

R + X

Nuclophile

R-Nucleophile

Slow step

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Nucleophilic  Subs5tu5on  Reac5on  

CH3Br OH CH3OH + Br

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Subs5tu5on  Nucleophilic  Bimolecular,  a.k.a.  SN2  Reac5on  

                         Rate  =  k  [Alkyl  halide]*[Nucleophile]  

The  rate  of  an  SN2  reac<on  depends  upon  4  factors:    1.       The  nature  of  the  substrate  (the  alkyl  halide)  2.       The  power  of  the  nucleophile  3.       The  ability  of  the  leaving  group  to  leave  4.       The  nature  of  the  solvent  

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Rela5ve  Rates  of  SN2  Reac5on  for  Several  Alkyl  Bromides  

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•  Me°   >>            1°  >>     2°   >>   3°  

t-­‐butyl  bromide  methyl  bromide   ethyl  bromide   isopropyl  bromide  

Back  side  of  α-­‐C  of  a  methyl  halide  is  unhindered.  

Back  side  of  α-­‐C  of  a    1°  alkyl  halide  is  slightly  

hindered.  

Back  side  of  α-­‐C  of  a    2°  alkyl  halide  is  mostly  

hindered.  

Back  side  of  α-­‐C  of  a    3°  alkyl  halide  is  

completely  blocked.

decreasing  rate  of  SN2  reac)ons  

SPACE  FILLING  MODELS  SHOW  ACTUAL  SHAPES  AND  RELATIVE  SIZES  

Effect  of  Nature  of  Substrate  on  Rate  of  SN2  Reac5ons  

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• The  α-­‐carbon  in  vinyl  and  aryl  halides,  as  in  3°  carboca<ons,  is  completely  hindered  and  these  alkyl  halides  do  not  undergo  SN2  reac<ons.  

Effect  of  the  Nucleophile  on  Rate  of  SN2  Reac5ons  

vinyl  bromide   bromobenzene  

The  overlapping  p-­‐orbitals  that  form  the  π-­‐bonds  in  vinyl  and  aryl  halides  completely  block  the  access  of  a  nucleophile  to  the  back  side  of  the    α-­‐carbon.  

Nu:-­‐   Nu:-­‐  

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Possible  Mechanism  and  Energy  Diagram  for  SN2  Reac5on  

CH3Br OH CH3OH + Br

energy

reaction progress

ΔG

ΔGo

=

H

H H

BrHO

CH3Br

CH3OH

•  Increasing  the  number  of  R  groups  on  the   carbon   with   the   leaving   group  increases   crowding   in   the   transi5on  state,  thereby  decreasing  the  reac5on  rate.  

•  The   SN2   reac5on   is   fastest   with  unhindered  halides.  

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Nucleophiles  in  SN2  Reac5on  

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The  Nucleophile  

•  Bases  are  beeer  nucleophiles  than  their  conjugate  acids.    

             Ex:  OH-­‐  versus  H2O  •  In   going   from   leh   to   right   across   a   period   basicity   and  

nucleophilicity  decreases.  Ex:  NH3  versus  H2O  

•  In   going  down  a   group   in   the  periodic   table,   nucleophilicity  increases  and  basicity  decreases.  Ex:  I-­‐  versus  Cl-­‐    

•  For   two   nucleophiles  with   the   same   nucleophilic   atom,   the  stronger   base   is   the   stronger   nucleophile.   Ex:   CH3O-­‐   versus  CH3CO2

-­‐  

• Nucleophilicity  does  not  parallel  basicity  when  steric  hindrance  becomes  important.  

• Steric  hindrance  decreases  nucleophilicity  but  not  basicity.  13  

Rela5ve  Rates  of  SN2  Reac5ons  for  Several  Living  Groups  

S O

O

O

CH3-LG CH3Cl + LGCl

A  good  leaving  group  reduces  the  barrier  to  a  reac5on.  Stable  anions  that  are  weak  bases  are  usually  excellent  leaving  groups  and  can  delocalize  charge.  

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Rela5ve  Rates  of  SN2  Reac5ons  in  Several  Solvents  

PO

NN

N

Hexamethylphosphoramide (HMPA)

O N S

O

N,N-Dimethylformamide (DMF)

Dimethyl sulfoxide (DMSO)

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SN2  Reac5on  and  Solvent    

• Polar  apro5c  solvents  solvate  ca5ons  by  ion—dipole  interac5ons.  

• Anions  are  not  well  solvated  because  the  solvent.  These  anions  are  said  to  be  “naked”.  

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Examples  of  SN2  Reac5on  

NaOH

Acetone

cis-1-Chloro-3-methylcyclopentane

H

ClH3C

HOH

HH3C

H

trans-3-Methylcyclohexanol

BrNaOH

Acetone

OH

+ NaCl

+ NaBr

R-2-Bromooctane S-2-Octanol

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Subs5tu5on  Nucleophilic  Unimolecular:  SN1  Reac5ons  

R LG R + LG

Nuclophile

R-Nucleophile

Slow step

Rate  =  k  [R-­‐LG]  The  Rate  of  SN1  Reac5on  depends  upon  3  factors:  1. The  nature  of  the  substrate  (alkyl  halide)  2. The  ability  of  the  leaving  group  to  leave  3. The  type  of  solvent    

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SN1  Reac5on  and  The  Substrate  

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SN1 Energy Diagram and Mechanism  

•  Rate-­‐determining  step  is  forma5on  of  carboca5on  

•  rate  =  k[RX]  

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Stereochemistry of SN1 Reaction

•  The  planar  intermediate  leads  to  loss  of  chirality  

– A  free  carboca5on  is  achiral  

•  Product  is  racemic  or  has  some  inversion  

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SN1  Reac5on  Stereochemistry    

•  If  leaving  group  remains  associated,  then  product  has  more  inversion  than  reten5on.  

•  Product  is  only  par5ally  racemic  with  more  inversion  than  reten5on.  

•  Associated  carboca5on  and  leaving  group  is  an  ion  pair.  

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SN1 in Reality •  Carboca5on  is  biased  to  react  on  side  opposite  leaving  group  •  Suggests  reac5on  occurs  with  carboca5on  loosely  associated  with  

leaving  group  during  nucleophilic  addi5on  (Ion  Pair)  •  Alterna5ve  that  SN2  is  also  occurring  is  unlikely  

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Characteristics of the SN1 Reaction Substrate  •  Ter5ary  alkyl  halide  is  most  reac5ve  by  this  mechanism  

–  Controlled  by  stability  of  carboca5on  –  Remember  Hammond  postulate,”Any  factor  that  stabilizes  a  high-­‐energy  

intermediate  stabilizes  transi5on  state  leading  to  that  intermediate”  

•  Allylic  and  benzylic  intermediates  stabilized  by  delocaliza5on  of  charge  –  Primary  allylic  and  benzylic  are  also  more  reac5ve  in  the  SN2  mechanism  

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Nucleophiles in SN1

•  Since  nucleophilic  addi5on  occurs  a-er  forma5on  of  carboca5on,  reac5on  rate  is  not  normally  affected  by  nature  or  concentra5on  of  nucleophile  

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Rela5ve  Rates  of  SN1  Reac5ons  in  Different  Solvents  

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Effect of Leaving Group on SN1  •  Cri5cally  dependent  on  leaving  

group  –  Reac5vity:    the  larger  halides  

ions  are  beeer  leaving  groups  

•  In  acid,  OH  of  an  alcohol  is  protonated  and  leaving  group  is  H2O,  which  is  s5ll  less  reac5ve  than  halide  

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

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Solvent  in  SN1  •  Stabilizing  carboca5on  also  stabilizes  associated  transi5on  state  and  

controls  rate  •  Pro5c  solvents  favoring  the  SN1  reac5on  are  due  largely  to  stabiliza5on  of  the  transi5on  state  •  Pro5c  solvents  disfavor  the  SN2  reac5on  by  stabilizing  the  ground  state  •  Polar,  pro5c  and  unreac5ve  Lewis  base  solvents  facilitate  forma5on  of  R+      

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Examples  of  SN1  Reac5ons  

Br

OHH2O +

OH

2-Bromo-3-methylbutane 2-Methyl-2-butanol 3-Methyl-2-butanol

+ HBr

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Predic5ng  the  Likely  Mechanism  of  a  Subs5tu5on  Reac5on  

• Four   factors  are   relevant   in  predic5ng  whether  a  given  reac5on   is   likely   to  proceed  by  an  SN1  or  an  SN2  reac5on—The  most  important  is  the  iden5ty  of  the  alkyl  halide  

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Predic5ng  the  Likely  Mechanism  of  a  Subs5tu5on  Reac5on  

• The  nature  of  the  nucleophile  is  another  factor.    • Strong   nucleophiles   (which   usually   bear   a   nega5ve   charge)  present  in  high  concentra5ons  favor  SN2  reac5ons.  

• Weak  nucleophiles,  such  as  H2O  and  ROH  favor  SN1  reac5ons  by  decreasing  the  rate  of  any  compe5ng  SN2  reac5on.  

•  Very  Good  Nucleophiles       I-­‐,  HS-­‐,  RS-­‐  

•  Good  Nucleophiles           Br-­‐,  OH-­‐,  RO-­‐,  CN-­‐,  N3-­‐  

•  Fair  Nucleophiles           NH3,  Cl-­‐,  F-­‐,  RCO2

-­‐  

•  Weak  Nucleophiles           H2O,  ROH  •  Very  Weak  Nucleophiles       RCO2H  

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Predic5ng  the  Likely  Mechanism  of  a  Subs5tu5on  Reac5on  

•  A  beeer  leaving  group  increases  the  rate  of  both  SN1  and  SN2  reac5ons.  

• The  nature  of  the  solvent  is  a  fourth  factor.    • Polar   pro5c   solvents   like   H2O   and   ROH   favor   SN1  reac5ons   because   the   ionic   intermediates   (both  ca5ons  and  anions)  are  stabilized  by  solva5on.  

• Polar  apro5c  solvents  favor  SN2  reac5ons  because  nucleophiles  are  not  well  solvated,  and  therefore,  are  more  nucleophilic.  

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Summary  of  SN1  and  SN2  Reac5ons  

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