Nucleophilic Substitution Reactions These reactions are polar and by mercy2beans121

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									Nucleophilic   Substitution   Reactions

These reactions are polar and usually involve negatively charged nucleophiles.


                  Br                      X                  Br
X:

The organic substrates for such reactions are usualy alcohols of alkyl halides.




Electrophilic centers exist by virtue of the electronegativity difference between
carbon and leaving group bond.
The Leaving Group

Generally, good leaving groups are WEAK BASES.



                      Br                          X               Br
     X:

All of the halides are good leaving groups except fluoride.


Hydroxide is very basic, and a woeful leaving group.



     X:              OH                       X           OH




One solution…


                           O       O                                   O
                                                              O
                               S              N                       S
                                                                               CH3
          OH          Cl               CH 3                   O

                    Mesyl Ch lo r id e
                                                          A su lfo n at e est er .
                                                          "Mesyla te - OMs"


                       O
                O                                                          O
                                                                  O
                      S                               X
                               CH 3                                       S
X:              O                                                               CH 3
                                                                  O
Other sulfonates…



                                O                                                              O
                    O                                                                     O
            H                                                                                  S
       H                    S                                                                       CF3
                                    CF3         Tr iflat e              OTf
                    O                                                                     O



                            O
                    O
            H
       H                    S
                                                 CH 3        p -To lu en esu lfo n at e       OTs
                    O                                        o r To sy lat e


                                O
                        O
                H
            H                   S
                                                               Br osy lat e                   OBs
                                                    Br
                        O



Neutral molecules are spiffy leaving groups…



       X:                           OH                             X                      OH




                                                                                  H
                                            H      Br
                                    OH                                        O
                                                                                  H


                                        H                                                           H

  Br                                O                              Br                          O
                                        H                                                           H
The Nucleophile…

Good nucleophiles are usually basic, or polarizable.

Rules to Remember…

1) A negatively charged species is usually more nucleophilic than its conjugate base.




2) For a given atom and charge, nucleophilicity parallels basicity.

                                                                O
 H 3 CH 2 C      O             H   O                  O             C   O
                                                            H3 C




3) Within a group of the periodic table, bigger is better in terms of nucleophilic
   character of the attacking atom.




4) Steric effects can effect nucleophilicity…

                                          H3 C
                                       H3 C
              H 3 CH 2 C   O                  C   O
                                                                N
                                        H3 C
Classify your substrate!
Structural features determine whether certain reactions will take place which
mechanism operates.


                                                          H       Br                       CH 3
CH 3 CH3 CH2 OH          CH 3 CH 3 CH 2 Cl
                                                                               H3 C
                                                                                           C
                                             H 3 CH 2 C            CH 3                            OH
                                                                                H3 C



             CH2 Cl                 CH2 OH                                                        CH 3
                                                              H2 C        Br        H3 C
                                                                                               C     OH
                                                  H2 C        C
                                                                               H2 C        C
                                                                  H
                                                                                               H

      H3 C       H

             C                           CH 2 CH 2 Cl                          Br                        Br
                 OH                                                                    H2 C         C

                                                                                                         H




Alkyl halides        (and many alcohols)          undergo          substitution        by t w o
mechanisms:
                            Sn 1 and Sn 2 .

The Sn 1 mechanism involves the formation of a carbocation intermediate in the rate-
determining step.

3°, benzylic and allylic substrates undergo Sn 1 reaction because they form relatively
stable carbocations.

1° substrates undergo Sn2 reaction because they are sterically uncluttered.

2° substrates undergo both reaction types, but sluggishly.
The Sn 1 Reaction

       H3 C                                   H3 C
                             H2 O
          C        Br                             C        OH   + HBr
   H3 C                                     H3 C
      H3 C                                     H3 C
Rea ct ion s in wh ich t h e solv en t p a r tici p at es as a n u celo p h ile ar e called
solv oly sis r ea ct io n s.

The Mechanism…

   H3 C                                   CH3                             H3 C            H
        C     Br                        C             Br                     C       O
H3 C                           H3 C                                   H3 C
   H3 C                                     CH3                                           H
                                                                         H3 C                   Br

                                H     O

                                        H
                                                                          H3 C

                                                                                 C   OH       + HBr
                                                                       H3 C
                                                                          H3 C

The reaction profile…
Since the SN1 reaction involves carbocations that are formed in the RDS, then only
those substrates that form relatively stable carbocations will undergo this reaction.

What makes for a stabilized                            carbocation?


                H2
                C                                 CH 2
                        Cl


               H 2C          Br                           CH 2
 H 2C          C                       H 2C        C
                    H                                     H
H3 C               H2                 H3 C
                   C                                      CH 2
        O                                     O
                         Cl

Alkyl carbocations                    are stabilized                 by hyperconjugation             to adjacent   C-H
bonds.

 1°                                     3°
           H                                                                     H
                                  H
               C        C                     H
        H                     H                                              C
            H                                                                     H
                                                      C              C           H H
                                             H                                   C
                                                  H
                                                                                         H
                                                                                 H

Vinyl (and aryl) carbocations cannot be stabilized by resonance.

  H                 Cl                  H
       C        C                                                            H
                                              C        C         H       =           C       C   H
                                                                             H
  H                 H                   H

So, the order of stability of carbocations is:

Benzyl = allyl > 3° > 2° > 1° > CH3 + > vinyl, aryl
  The Hammond Postulate – a useful and oft used tool to rationalize                                          the
  relative rates of reactions.

  “The structure of a transition state tends to resemble that species to which it is closer
  in energy.”

  For endothermic processes…                                   For exothermic processes…




    the TS is closer in energy to the p r o d u c t s        the TS is closer in energy to the reactants a n d
    and therefore said to be "product-like" i n              therefore said to be "reactant-like" in s t r u c t u r e .
    structure. As a result, we can i n f e r                 As a result, we can infer something about t h e
    something about the energy of t h e                      energy of the transition state from the stability
    transition state from the stability of t h e             of the r e a c t a n t .
    product.



   H 3C                         CH 3           H3 C                 H 3C                        CH 3         H3C

          C   Br            C           Br         C    Nu                 C   Br           C          Br        C   Nu
H3 C                H 3C                     H3 C                   H                 H                      H
   H 3C                          CH 3           H3 C                    H                        H               H

                     Nu :                                                            Nu :




  Therefore, when comparing reactions that involve carbocation intermediates, the one
  involving the more stable carbocation intermediate will be…
Reactions Involving Carbocations
Substitution

                                                                          H3 C
                          CH3
                                                                                 C     Nu
                      C                  Nu
                                                                 H3 C
           H3 C                                                     H3 C
                           CH3


Elimination
                                                           OH2                              CH3
                                         CH 3
                  H3 C           C                H                                        C
                                                                                 H3C
                                             C                                                      CH 2
                                                  H
                                            H

Addition
                                                      CH 3
                    CH 3                                                     H3 C                           CH3
                                     H2 C        C                                             H2
                                                                                               C      C
                  C                                                                    C
         H3 C                                        CH3                    H3 C
                      CH 3                                                                                 CH 3
                                                                                       CH 3


Rearrangement

               H3 C                                                       H3 C
            H3 C                       CH3                                                  CH3
                   C             C                                           C         C
                                                                                               CH 3
                                                                 H3 C
                H3 C                 H                      H
Carbocation rearrangments are often promoted by the presence of Lewis Acids. In
this case, the intermediates are said to be “carbocation-like” if not carbocations.

                                                                                                                  Cl       AlCl 3
    H3 C                                           H3 C                                         H3 C
 H3 C                 Cl         AlCl 3                          Cl        AlCl 3                                      H
                                                H3 C
        C       C                                      C     C        H                                C          C        H
                          H
     H                H                                          H                          H3 C
                                                      H                                                                H
Carbocation Rearrangements are always possible when group migration can lead to a
more stable carbocation. Generally, this is a pain…

      H3 C            CH3      H 2 O,                 H3 C
   H3 C                                                                CH3                H3 C            CH3
                        I      CH3 OH, ∆           H3 C                                H3 C
          C       C                                                      OH                                 H
                                                          C        C                          C     C
     H3 C             H                             H3 C               H                  HO              CH3


   H3 C           CH3                    H3 C                                      H3 C
H3 C                                                       CH 3                                    CH 3
                    I                 H3 C
       C      C                              C       C                                  C      C
                                                                                                    CH3
 H3 C             H                                                             H3 C
                                       H3 C              H                                     H



                                          H3 C             CH3                     H3 C            CH3
                                       H3 C                                     H3 C
                                                             OH                                      H
                                              C       C                                C       C
                                           H3 C            H                       HO              CH3


Another case…


                                                               H    H                                H

                          Cl   H 2 O,
                               CH3 OH, ∆




Yet another example…
                                H3 C                               H3 C
              CH 3                            CH3
                                       C                                   CH     CH2 Cl                    CH 3
                      CH 3                    Cl
              C                H3 C                                                                                CH 3
                                                                   H3 C     AlCl3                           C
                      CH 3             Al Cl 3
                                                                                                                   CH 3
Stereochemistry         of the SN 1 reaction


         Br

         C                       NaI
                                                               CH2 CH3
                CH2 CH 3                       H3 C        C
  H3 C        Ph               Acet o n e
                                                                   Ph




                                      I                                                I
                                      C                                               C
                       H 3 CH 2 C                                                             CH2 CH 3
                                 Ph         CH 3                              H3 C          Ph


Reactions in which the configuration of an asymmetric center is scrambled are said to
occur with

Sometimes (depending on conditions), reactions occur with only partial
racemization…


                  Br                                           Br -

                  C                        NaI
                                                                        CH2 CH3
                         CH2 CH 3                       H3 C   C
         H3 C          Ph                 Ac et o n e
                                                                         Ph




                                                I                                            I
                                               C                                             C
                              H 3 CH 2 C                                                           CH2 CH 3
                                        Ph          CH 3                             H3 C        Ph
The SN 2 Reaction
     Best for 1° subtrates. And methyl, of course.



        I            H3 C       Br               I         CH 3          Br


The mechanism involves a single elementary process that is bimolecular.




Stereochemistry     of the SN 2 Reaction

      The collision in this reaction must occur such that the nucleophile attacks the
back side of the C-LG bond.

                           H                                    H
                       H                                            H
            I               C        Br              I      C                 Br
                        H                               H
In chiral substrates, this means that the reaction occurs exclusively              with
                          H3 C                                           CH3
                  H 3 CH2 C                                                CH2 CH3
                              C           Br                        S   C                 Br
H3 C    S                                                H3 C
                            H                                            H
inversion of the absolute stereochemistry.     This is an example of a stereospecific
reaction.
Stereospecific:          A reaction in which the mechanism dictates that different
stereoisomeric          reactants give different stereoisomeric products.




Why?

                              H                                          H
                        H                                                    H

        I                         C      Br                    I     C           Br

                         H                                               H




Substrate         structure       and SN 2

    Su b st r at e      Relat iv e r at e
                        o f r eac tion
       CH3 Br                 100
       CH3 CH 2 Br            1 .3 1
       CH3 CH 2 CH 2 Br       0 .8 1
       H3 C
                CHBr              0 .0 1 5
       H3 C
            CH3

H3 C        C      Br             0 .0 0 4

            CH3

So, the order of reactivity for SN 2 is:

                                         CH 3 > 1° > 2° >>3° > vinyl, aryl
The effect of branching              next to the 1° carbon…


  CH3 Br                          100
  CH3 CH 2 Br                     1 .3 1
  CH3 CH 2 CH 2 Br                0 .8 1
  CH3 CH 2 CH 2 CH 2 Br           0 .5 2


                   Br             0 .0 52




                   Br            0 .0 00 0 1



Neopentyl    substrates          are prone to rearrangement…



                            H2
            H3 C            C                                                  H2
                                               CH 3 OH/ H2 O
                        C         OTs                              H3 C        C
            H3 C                                                           C        CH 3
                        CH 3
                                                                    H3 C   OH



                                                       H2
                                      H3 C             C
                                                C           CH 3

                                                CH 3
Solvent dependence       of SN 1 and SN 2 reactions…

SN 1 reactions are facilitated by using polar, protic solvents – solvents that are capable
of stabilizing ionic intermediates.

Examples:




SN 2 reactions are facilitated by using polar, aprotic solvents – solvents that will not
mask the nucleophile with a large solvation sphere.

Examples:




Making alkyl iodides – the Finkelstein Reaction


                                     Aceton e
                     R     Br                       R     I
                                       NaI
Pitfalls in the synthesis of amines…


                  :NH 3          CH3 CH 2 Br                     CH3 CH 2 NH 3 Br

        CH3 CH 2 NH 3 Br                :NH 3                  CH3 CH 2 NH 2            NH 4 Br

                                                                               Br
       CH3 CH 2 NH 2             CH3 CH 2 Br                        CH3 CH 2 NH 2 CH 2 CH 3



OK for preparing 3° amines from 2° amines…



                                                                                                      Cl
             NH     +         HO
                                                  Cl                                N

                                                                                           70 %
and quaternary ammonium compounds.

                                 CH 3                                                    CH 3
                                         CH 3 I
                          N                                                         N

                          CH 3                                                 H3 C CH 3

Preparing alkyl halides from alcohols – SN 1 or SN 2.

3° alcohols react via SN1…

      H 3C                H        Br               H3 C
     H3 C                                         H 3C              H
             C      OH                                                                                     CH 3
                                                           C    O                       H3 C      C
                                                                                                           CH 3
      H3 C                                        H3 C              H
                                                                                                            O
                                                                                                                  H
                                                                                                      H
                                                                 H3 C
                                                               H3 C
                                                                        C      Br

                                                               H3 C
1° alcohols by SN 2

                                           H 2 SO 4 , NaBr
              CH3 CH 2 CH 2 CH 2 OH                            CH3 CH 2 CH 2 CH 2 Br




sometimes facilitated by Lewis acids

                                        Zn Cl 2 , HCl
           CH 3 CH2 CH2 CH2 OH                               CH 3 CH2 CH2 CH2 Cl




                                       H
             H3 CH2 CH 2 CH 2 C   O
                                       Zn Cl 2


Some other reagents…



                                      PBr 3
                           OH                                    Br        60%



                                      SOCl2
                           OH                                               Cl     78%
Both these reactions operate on the principal of converting OH into a better leaving
group…

                                                                             Br
                                        Br
                                        P                                    P
                 OH                                                 O                 Br
                                  Br         Br

                                                                H




                          OR                                            Br

                          P                                             P
                 O                OR                            O                Br

                              H        Br



                      OR                                                     OR

                      P                                                      P
                O             OR                           Br       O                 OR
                      H                                                          H




                                             SOCl 2
                               OH                                                O             Cl
                                                                                           S

                                                                                       O



                                                      Cl
Ethers in substitution             reactions:
Making them…

The Williamson ether synthesis

        O                                     O
            H                                                              O
                                                           Br
              NaH, DMF



This is just an SN 2 reaction, so the substrate dependence for SN 2 applies.




and breaking    them…

                                                HI
                           O                                          I

                               H     I




                                                                           I
                       O
                                                                O
                       H
                                                                H

TMSI, Trimethylsilyl Iodide

                           I
             Me 3 Si                                       I
 H3 C                              H3 C           SiMe 3            CH 3
        O                                 O                                    SiMe 3
                                                                           O
Epoxides are good substrates                    for substitution          reactions

With good nucleophiles and neutral conditions, it is an SN 2 reaction, and occurs w i t h
inversion at the reaction center…

                                                                               O
                                    O

                                                          Nu
                     Nu :


                     H                                            N3                        H
                             NaN 3 , Et OH, H 2 O                     H                         OH
                     O
                                                                      OH                        H
                     H                                                                      N3
                                                                  H


                                                                  N
 N    N     N                                                N
                                                      N
                         H
                                                          H

                         O

                                                          O
                         H                                                H     OH
                                                      H

In SN 2 ring-opening of epoxides, the nucleophile tends to attack the least hindered
end of the epoxide.


                         O                                   HO
                                  Ph SH, Ph S                                        89 %
          H3 C                                        H3 C
                 H                                           H                SPh
Under acidic conditions, the nucleophile adds to the most substituted end. This is a
little complicated. This resembles, but is not, an SN 1 process.



                     O                                    H3 C             OH
                               CH3 OH, H3 O+           H3 C
          H3 C
            H3 C                                       H 3 CO

The intermediate – carbocation, or not


                           H                           H                                       H
                     O                           O                                       O

                     CH2                         CH2           =                         CH2
        H3 C                     H3 C                                    H3 C
         H3 C                     H3 C                                    H3 C

                 H                         H                                         H

             O                         O                                         O
                                                           =
                   CH2                         CH2                                    CH2
     H3 C                      H3 C                                    H3 C
      H3 C                      H3 C                                    H3 C

Attack occurs at that carbon that is best able to stabilize positive charge
development.

                                    H
                                O
                                                -H+               H3 C           OH
                                CH 2                           H3 C
                 H3 C
                  H3 C
                                                               H3 CO
                                O
                           H           CH 3
A Comparison     of SN 1 and SN 2

                                          SN 1                          SN 2
Mechanism                    2 or more steps involving a 1 step bimolecular process
                             carbocation intermediate
Kinetics                     first order in substrate    second order over all, first
                             only                        order in substrate and
                                                         nucleophile
Substrate    dependence      Those substrates capable    Those substrates that are
                             of forming stabilized       sterically unhindered at
                             carbocations                the substitution site.



Stereochemistry              Occurs with racemization       Occurs exclusively with
                             or partial racemization at     inversion at the reaction
                             the reaction center            center

Importance o f               Not involved in RDS, but       Involved in RDS therefore
nucleophile                  better if less basic form of   reactivity is important
                             nucleophile is employed
Importance    of leaving     Leaves in RDS therefore it     Leaves in RDS therefore it
group                        is important                   is important
Solvent                      Polar protic solvents are      Polar aprotic solvents are
                             best.                          best.

								
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