REACTIVE INTERMEDIATES IN SYNTHETIC ORGANIC CHEMISTRY by azaaaaa5

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									  REACTIVE INTERMEDIATES IN SYNTHETIC ORGANIC
                         CHEMISTRY
Carbon atoms in stable - hence relatively unreactive - carbon
compounds have the following characteristics:
(1) Closed (i.e. octet) valence shells - 8 electrons in the carbon valence
shell - 4 covalent bonds - hence no vacant or singly-filled low energy
orbital to allow attack by electron-donors.
(2) Neutral, i.e. no overall charge - hence no very strong electrostatic
driving force for attack by nucleophiles or electrophiles.
(3) Bond angles appropriate for the hybridisation involved - i.e. ca.
109° 28' for sp3, ca. 120° for sp2 and 180° for sp - hence no serious
bond-strain.
Moderate deviations from these criteria lead to compounds with greater-
than-normal reactivity:
                          H2
                          C
                   H2C         CH2     Raney Ni
                                                      No reaction
               3
   109º 28' (sp ) H2C          CH2      > 200°
                          C
                          H2
                          H2                                H2
                          C                                 C
                                       Raney Ni
                                        120°
        60º (sp3) H2C          CH2                 H3C           CH3
Species with large deviations from these criteria - such as carbanions,
R–, or carbocations, R+, are usually too unstable to allow isolation -
but may show synthetically useful reactivity when generated as short-
lived reactive intermediates in chemical reactions.
The three reactive intermediates studied in this course are:
                         Free radicals
                         Carbenes and
                         Arynes.

ORGANIC FREE RADICALS:
Organic Free Radicals: organic compounds which contain at least one
unpaired electron. In the simplest cases an atom in the compound has
only seven electrons in its valence shell and the unpaired electron is
localised on either a carbon atom or on a heteroatom. Note the
characteristic 'yl' termination of the systematic names for free radicals
and the representation of the unpaired electron by a dot at the
appropriate atom:
            CH4     Methane                        CH3•   Methyl

  CH3CH2CH3         n-Propane            CH3CH2CH2•       n-Propyl


      (CH3)3CH      t-Butane                (CH3)3C•      t-Butyl

  (CH3)3C     OH t-Butanol               (CH3)3C    O•    t-Butoxyl

      CH3     SH Methanethiol               CH3      S•   Methanethiy
                                                          l


    Optimum geometry - planar - sp2 hybridised:                C
        The norbornyl radical has considerably
        increased reactivity because ring-strain
        prevents the bridge-head carbon attaining       •
        the optimum planar geometry:


                    Preparation of Free Radicals:

(1) Homolytic cleavage of weak single covalent bonds.

                             or h
            R E E R                      R E• + •E R


                       E = N, O, S, Halogen, etc.

Note the use of 'fish-hook' single-headed curved arrows, i.e.   to
indicate the movement of a single electron.

Thermal cleavage:

         N-N, O-O, S-S, Cl-Cl, Br-Br, C-N, N-Cl, O-Cl, O-Br
                       ca. 130°
       O O                            2          O•
Di-t-Butyl peroxide                   t-Butoxyl radical
Half-life at 150° ca. 1 h


Ph               Ph                           O
                       60-100°
        O O                           2 Ph     •           Ph• + CO2
O                O                            O
Di-Benzoyl peroxide                   Benzoyl radical      Phenyl
Half-life at 100° ca. 30 min                               radical


                            60-100°
NC        N N         CN                  2 NC        • + N N

 Azobis(isobutyronitrile)         2-Cyanoprop-2-yl
          'AIBN'                  radical
Half-life at 100° ca. 5 min


     Photolytic cleavage - compounds with low-energy electronic
                           absorptions only:
                                    h
                       Cl-Cl                  2 Cl•


   Ph                  Ph                          O
                               h
          O O                             2 Ph     •           Ph• + CO2
    O                  O                           O

                   O                           O
                               h
                   C                      CH3 C• +        CH3•
             CH3       CH3

                                h
             R O N O                         R O• +     NO•


                                h
                R O Cl                       R O• +     Cl•

(2) Redox reactions of non-radical precursors:

Reduction.
                                                           •
                                                           _
                                                               Naphthalide
                   + Na              Na +                      radical anion

        O                                          _
                                                 O
                                                        Ketyl radical
        C          +    Na               Na+     C•        anion
  CH3        CH3                             CH3    CH3

Oxidation:
                                                       •
        Ar3N:      +   AgPF6                  [Ar3N•]  + [PF6]- + Ag0
                                             Amminium
                                            radical cation
Detection of Free Radicals:

(1) Electron Spin Resonance (ESR) Spectroscopy.

The degeneracy of spin of an unpaired electron is lifted in a strong
magnetic field. E corresponds to microwave radiation. Hyperfine
splitting due to electron-proton spin coupling aids structural
interpretation.


       CH3•        Quartet resonance



        •
        _          Septet resonance


                              •

               •                              etc. Octet resonance




(2) Matrix Isolation:

Free radicals generated and trapped in a radiation-transparent solid
argon matrix at very low temperature may be studied spectroscopically:

 CH3               CH3    h                  O
         O O                           H3C         + CH3      + CO2
   O               O     Solid Argon           O
                         5-10 oK
Stability of Free Radicals:

           allylic ≈ benzylic > 3° alkyl > 2° alkyl > 1° alkyl

Substitution effect - radical centres are electron-deficient, hence
stabilised by attached electron releasing alkyl groups.

Resonance effect:

                       H                           H
                       C                           C
                H 2C       CH2•             •H2C       CH2


                 •CH2                      CH2

                                   •
                                                         etc.



The combination of electronic and steric effects can result in very stable
- and, in suitable circumstances, even isolable - free radicals:


                O•                                   H



                                       O                         O•



    2,4,6-Tri-t-butylphenoxyl                    Galvinoxyl
Characteristic Reaction Pathways of Free Radicals:
(1) Dimerisation:
                        R•   +   R•            R R
Leads to non-radical products - termination steps in radical chain-
reactions.
(2) Radical abstraction:


        R•          E C                     R—E +           •C

                    Ease of abstraction = I ≈ Br > H > Cl
This can be a chain transfer process in radical mechanisms.

(3) Disproportionation - one radical is oxidised by another:
     2 CH3CH2CH2                         CH3CH2CH3 + CH3CH=CH2




        H2                                                  H2
        C                         CH2
 H 3C        CH2      + H CH                                C
                                                     H3C           CH3
                                 CH3
                                                            +
                                                                   CH2
                                                       H       C
                                                                   CH3
Hydrogen abstraction from one n-propyl radical by the other results in
the radical accepting hydrogen being reduced to an alkane. The radical
losing hydrogen is simultaneously oxidised to an alkene.
This leads to non-radical products - i.e. is a termination step in radical
chain-reactions.

(4) Radical addition to unsaturated structures:

                                                  H2
             R         + CH2=CH2                R C CH2


This is a chain propagation step in radical chain-reactions.

(5) Rearrangement:

Despite what we might expect, simple free radicals do not normally
undergo rearrangement:

                   H                                    +
                                 Very rapid
               +                                        C
         CH3 C CH                  -
                                 H migration
                                                    CH3      CH2H
           CH3    2                                   CH3
                              2e in migration
                 1°                                     3°
                                   system
                   H
                                                        •
               •                                        C
         CH3 C CH                                 CH3        CH2H
           CH3    2                                 CH3
                              H• migration
                 1°                                     3°
                             3e in migration
                                  system

The transition states for both rearrangements are very similar:


                             H         *
                   CH3           CH2            *   = + or •
                    CH3
Consider the orbitals involved in the transition state: H 1s and 2 C 2p.

                                         1s




                              2p              2p



Combination of the H 1s and 2 C 2p atomic orbitals gives three
molecular orbitals:



                                                         

          (A)              (B)                                     (C)
(A) is bonding for the hydrogen atom and both carbon atoms.
(B) is bonding for the two C atoms but antibonding for the C2-H
interaction.
(C) is antibonding for the two C atoms. In addition there is no net
interaction between the hydrogen atom and the two carbon atoms.
(A) is the lowest energy orbital while (B) and (C) are approximately
equivalent in energy.

                (B)                (C)             (B)              (C)


                        (A)                                  (A)

         Carbocation - 2e                       Radical - 3e
          Favourable T.S.                     Unfavourable T.S.
        Rapid rearrangement                   No rearrangement
-Unsaturated free radicals will undergo rearrangement with migration
of the unsaturated group:
                                    •
            CH2                     CH2
      HC                           CH                          CH2
                                                         •
         C •                                             C      CH
  CH3       CH2           CH3 C        CH2         CH3       CH2
     CH3                                              CH3
                            CH3
        1°                                              3°
                           Stable intermediate
(6) Fragmentation:

                          O
               Ar   C                         Ar•   +   CO2
                          O•



FREE RADICALS IN ORGANIC SYNTHESIS

(1) Free Radical Substitution of Hydrogen by Other Atoms.

  (a) Photochemical halogenation of saturated hydrocarbons


                               h                         Initiation
                    Cl2               2 Cl•
                                       •
 CH3CH2CH3 + Cl•                    CH3CHCH 3 + HCl
                                                          Propagation by
    •                                                     chain transfer
 CH3CHCH 3 + Cl 2                   CH3CHClCH 3 + Cl•
         •
      CH3CHCH 3 + Cl•                                     Termination

								
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