Chap. 8 Substitution Reactions by mercy2beans119

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									              Chap. 8 Substitution Reactions

            Y        + R                 X                           R'        Y             +   X
Nucleophilic¡G                                                       not necessarily the same as R

  SN1     (CH3)3CCl                          (CH3)3C+ +     Cl
                                                                                             (CH3)3C +OCH2CH3
                            CH3CH2OH                                  CH3CH2OH

                              − d [(CH 3 )3 CCl ]
                  rate =                          = k[(CH 3 )3 CCl ]                          (CH3)3C OCH2CH3

  SN2      CH3O- + CH3 Br                             H3C   O        CH3 + Br

        nucleophile                      nucleofuge
                             − d [CH 3 Br ]
                  rate =                    = k[CH 3 Br ][CH 3O − ]
      The rxn mechanism encompasses a wide spectrum
       two-dimensional rxn coordinate diagram for SN2

                                                                       L¡G loose transition state
                                                                       T¡G tight transition state
                                                                       P¡G product-like TS (late)
                                                                       R¡G reactant-like TS (early)

                   extreme of                         extreme of
                   loose TS                             tight TS

            an energy minimum
            carbocation interm.
SN1                                                                       carbanion interm       SNAr
                                                                          an energy minimum
Three dimensional rxn coordinate with E as third axis

Effect of moving down (stabilizing) the energy of a corner
¡÷ move the TS away from the corner “along the rxn


Effect of moving down (stabilizing) the energy of a corner (species)
perpendicular to the rxn coordinate, shift the TS toward the corner.
                                                 a better leaving group



     The effect of nucleophile,
     substrate, leaving group,
     solvent on the geometry
     and energy of TS can be
                                     with better leaving group, the
     analyzed based on these
                                     TS shift toward the left.
 SN1 Reaction
                                                   d[R − Y ]
                                          rate =             = k2 [ R + ][Y − ]
               k1                                     dt
  R¡Ð   X                 R+ + X-
               k-1                        s.s.a
  R + + Y-                  R¡Ð   Y       d [ R +]
                                                   = 0 = k1[ R − X ] − k−1[ R + ][ X − ] − k2 [ R + ][Y − ]
                                                       k1[ R − X ]
                                          [ R+] =
                                                   k−1[ X − ] + k2 [Y − ]
                                         k1k2 [ R − X ][Y − ]
                                  Rate =
                                         k−1[ X − ] + k2 [Y − ]

        if [X-] very small (early stage) k-1[X-] << k2[Y-]
                   Rate = k1[R¡Ð X]
        if [X-] increases, rate decreases (common ion effect)
Effect of Structure on SN1 reaction¡G
                          > > >
  rate of solvolysis¡G 3¢X 2¢X 1¢X methyl
                        parallel the stability of carbocation
            size of R1, R2, R3 in R1, R2, R3 C-X
  rate of solvolysis for R(CH3)2CCl, rel.rate 1 for Me
  rate of bridgehead system¡G                     1.67     Et
                                                  1.58     Pr
     rel reactivity

Effect of Solvent¡G
  Grunwald-Winstein eq                                            m¡G sensitivity of the substrate
                                                                      to solvent ionizing power
            log(k/k0) = mY                                        Y¡G ionizing power
        where Y = log(kt-BuCl, solvent, kt-BuCl, methanol)
   Schleyer’s eq
                  rate in a given solvent   NOTs¡G solvent nucleophilicity
        log(k/k0) = l NOTs + mYOTs            l ¡G   sensitivity to solvent
   rate in reference solvent, 80% ethanol   YOTs¡G ionizing power
                                             m ¡G sensitivity to ionizing power

              YOTs = log (k/k0)         for 2-Adamantyl tosylate

                                                     no nucleophilic
                                                     rxn possible

              NOTs = log (k/k0) – 0.3YOTs            for CH3OTs
                                                          both nucleophilic
                                                          rxn and ionizing
                                                          rxn possible
SN1 rxn is first order rxn in substrate
  if sp2-hybridized intermediate is formed
        ¡÷ racemization for chiral S.M.
  Sometimes partial inversion is observed (characteristic of SN2)
     ¡÷ Solvated ions and ion pairs

                                                                       Solvated ion
First order in   H3C

independent of added Cl-
¡÷ no common ion effect
  chloride in B may come from
  the molecule itself
  ¡÷ ion-pair mechanism
              Anchimeric assistance (Neighboring group participation)


                  (¡Ó )-threo                                 ¡Ý

                                          H3C                 CH3
                                                H       H

              if the SN1 rxn has no anchimeric assistance,                                          Br
                                                                                               Br                  B
               the product will contain meso-product in
               addition to the racemic 2,3-dibromobutane


                rate of acetolysis for trans-tosylate¡G cis-tosylate
                                                  103¡G 1
     Evidence of anchimeric assistance                             O

       1. stereochem.                                                      O
       2. rate                                                     OTs                   OTs
                                                                       5            ¡G   1

                                       phenyl group participation through £k
   SN2 reaction
     backside attack with inversion at carbon

          from chiral iodide, the rate of racemization is
          twice the rate of incorporation of radioactive *I

Solvent effect
     depend on solvation energy of reactants and transition state
  1. negative nucleophile + neutral substrate

         rate increases with lower polarity, non-hydroxylic solvent
   2. neutral nucleophile + neutral substrate

         rate increases with increasing polarity
   3. negative nucleophile + positive substrate

         rate increases with lower polarity
   4. neutral nucleophile + positive substrate

         rate increases with lower polarity

Polar solvent can increase solubility of ionic nucleophile, less
polar solvent increase the rate. ¡÷      use crown ether or special
solvent to increase solubility / reactivity of nucleophile
                    CH3I + Cl- ¡÷    CH3Cl + I-

                                              the nucleophilicity can change
32.7                                          dramatically in different solvent
78.4                                protic
                                              in protic solvent
                                                         I- > Br- > Cl-
35.9                                             in aprotic solvent strongly solvate
36.7                                                     Cl- > Br- > I-

                                                        in solvents with polarity
                                                        lower than H2O, the
                                                        activation energy lies
                                                        between that of gas
                                                        phase and H2O

   Substrate Effect
       Steric effect       R-Br + *Br- ¡÷     *Br-R +Br- in acetone

     Electronic effect    R-Cl + *I- ¡÷    R-I +Cl-      in acetone

                                  dual attraction


                              stabilization of TS
                              via £k -system

Nucleophilicity¡G         relate to polarizability


  Nucleophilicity and Basicity are related but not necessarily
Brønsted correlation
                                                         The correlation does not
                  Nucleophilicity ∝ Basicity             hold if the attacking atom
                                                         is different, e.g.


                                                                10 3 mroe basic


                                                                10 4 more nucleophilic
     Swain-Scott equation
                                      n¡G nucleophilicity of a nucleophile
        log(kn/k0) = s n              s¡G sensitivity of substrate to the

     Edward’s equation
                                      H = pka + 1.74     relate to basicity
        log(kn/k0) = £\   Eu + £] H   Eu = E0 + 2.60    relate to oxidization
                                      B¡G basicity (from pK)
        log(kn/k0) = A P + B H        P¡G polarizability (from mole refractivity)

Leaving group Effect¡G
   The more stable the detached leaving group, the more stable
the product system
¡÷   Leaving group ability (Nucleofugality)
      H2O > CH3OH > Br- > NO3- > I- > F- > Cl- > SCN- > (CH3)2S >
      C6H5O- > NH3 > C6H5S- > CH3O- > CN- > > NH2- >>H- >H3C-

     Compare the basicity of the leaving group
       (or the acidity of the conjugate acid)
     Different solvent can change the leaving gp ability
          Electrophilic Aromatic Substitution SEAr
   Basic step

  General Mech.
     1. generation of attacking species
                 +                                       +
           NO2            2 H2SO4 + HNO3            NO2          + 2 HSO4- + H3O+
           Br2 or Br2-MXn     Br2 + MXn             Br2-MXn
                 +                                        +                  -
           R3C               R3CX + MXn             R3C          + [MXn+1]
medium                         O
                         +                                 +              -
           RC        O       R CX + MXn             RC    O + [MXn+1]
 weak      NO
                              HNO2 + H+             N O
                                                             +   + H2O

     2. Formation of encounter complex (£k -complex)

     3. Formation of £m -complex

     4. Loss of proton

  Depending on the electrophile & substrate, rate-determining
   step can be either of these.
  Kinetic evidence for the mechanism
      reaction rate,
      kinetic isotope effect,
                             OCH3            OCH3                        ( not H )
                                    [NO2 ]          substitution of a substituent
  Ipso                                              by another substituent.
                      positive charge is small on the ring
         resemble                     ¡÷        less sensitive to substituent
         reactant                                low £l and low positional

highly reactive

                    positive charge is substantial on the ring

      resemble                             ¡÷     high £l and high positional
      £m -complex                                  selectivity

                                                         relative to £m +
                                                             late transition state

                                                          middle T.S.

                                                             early transition state
                                                      less reactive substrate
                                                      rate depend on substrate conc’n
                                                      as well as electrophile

            r.d.s.                                         more reactive substrate
                                                           rate independent of subst. conc’n

                                                     the deprotonation step is not shown
                                                     if r.d.s. a primary KIE will be observed

Evidence of £m -complex
    CH3                                         CH3
                                                                  salt isolated at low temp.
          + C2H3F + BF3                                BF4-       m.p.(dec.) -70¢X ,
                                8.40        H C2H5                        elem. anal.
    CH3                                    CH3
                         SO2          H          H
          + HF-SbF5                                    SbF6-      NMR temp. dependent
                                      H          H
                      9.38                H H          5.05
                                                 CH3                 CH3           H CH3
                         H H
      For Substituted aromatics, the reaction sites are non-equivalent.
      ¡÷       activating & ortho, para-directing gp¡G alkyl, OCH3, -NR,
 ¡÷            deactivating & meta-directing gp¡G -NO2, -+NR3
      ¡÷       deactivating & ortho, para-directing gp¡G Cl, Br

                   CH3                                   Y

                                   more stabilized                   more stabilized               more
                                   by alkyl group                    by lone pair                  stabilized by
               H       E                             H       E                         H   E
                   CH3                                   Y
                           H                                     H
                               E                                 E                             H
           -            O
                   N                                     Cl

               H       E                             H       E
strongly destabilized

Partial Rate factors

                   k’¡G rate for the rxn of substituted derivative
                   k ¡G rate for the rxn of benzene
               if fZ > 0¡G activating ¡F fZ <0¡G deactivating
                       f oZ , f pZ > f m ¡@
                                               o, p − directing
                           Z       Z     Z
Partial rate factors relate 1. substrate selectivity
                            2. positional selectivity
  high substrate selectivity ¡÷ large differences in rate of rxn
                              ¡÷ low reactivity of electrophile
  low substrate selectivity ¡÷ high reactivity of electrophile
positional selectivity relates to substrate selectivity
In general¡G
 Electrophilie with high substrate selectivity will have
                    low ortho¡G para ratio and negligible meta
 Electrophiles of low substrate selectivity ¡÷    low position selectivity
                                      f P ¡@ for toluene     strongly correlate
  Selectivity factor      S f = log                          with fP
                                      f m ¡@ for toluene
  high substrate selective ¡÷   high positional selective



                                                                      low selective
PMO Theory of directing effect
     if the T.S. is similar to the intermediate £m -complex
H E                                    (late T.S.)
     a pentadienyl cation with 4e-
                   ψ 5 ¡@£\        − 1.7£]                H         E              coefficients of MOψ 3
                   ψ4              −               0.57                  0.57

                   ψ 3 ¡@£\                          0                   0

                   ψ 2 ¡@£\        +£]                        0.57

                   ψ 1¡@£\         + 1.7£]       a substituent will have little effect if at
                                                 meta-position, since it’s a node there

The cation charge is on C1, C3, C5 for a substituent with
positive charge on atom directly bond to the ring, there will
be electrostatic repulsion. ¡÷ meta-directing for      C=O,
C N, ¡Ð NO2

   Nucleophilic Aromatic Substitution SNAr
 First order

                                                          Driving force
 Second orderood leaving gp

1. The site of reaction is the leaving group position, as H is
  not a good leaving group ¡÷ no isomeric mixture formation.
2. a strong e--withdrawing –NO2, -CN at ortho, para-position
  is needed to stabilize the adduct
                                                          N         Br
                                             N                               NO2


                                                                       amino is at the
                                                                       site of leaving gp
                                                                       or one carbon
               OCH3                   OCH3
                           NaNH2                                 the S.M. or product does
                           liq. NH3
                                            NH2                  not isomerize under same
               Br                                                rxn condition
               CF3                    CF3
                      Cl                                       reactivity¡G Br > I > Cl >> F

*C-labeling expt.

                                                                       same intermediate
                                                                       or mechanism for
                                                                       the formation of
   proposed rxn mech.                                                  both product
                                                                            trapping exp.


D-labeling expt.
  D           F                       100% loss of D¡@¡         0% Anilinar formation
            D D
                            F         100% ¡@                   0%
               F D                    100% ¡@ ¡@                0%

                      Cl                13% ¡@            ¡@   28%
Product Distribution in Benzyne Rxns

               relative stability determines the prod. distribution
                                R = CF3,      m-product favored
                                     CH3, ~ equal mixture


                  if R = e--donating group

                    if R = e--withdrawing

         if R = e--donating group   if R = e--withdrawing

                           considered as e-withdrawing since
                           the anion is in sp2, orthogonal to
                           the £k -system

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