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 greaterthan-normal reactivity:
H2
C
H2C
CH2
3
109º 28' (sp ) H2C
CH2
Raney Ni
> 200°
No reaction
C
H2
H2
C
60º (sp3) H2C
H2
C
CH2
Raney Ni
120°
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 shortlived 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
CH3CH2CH3
(CH3)3CH
(CH3)3C
CH3
CH3•
Methane
n-Propane
t-Butane
OH t-Butanol
SH Methanethiol
CH3CH2CH2•
(CH3)3C•
Methyl
n-Propyl
t-Butyl
(CH3)3C
O•
t-Butoxyl
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.
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
to
ca. 130°
O O
O•
2
Di-t-Butyl peroxide
Half-life at 150° ca. 1 h
t-Butoxyl radical
Ph
O
2 Ph
•
O
Benzoyl radical
Ph
O O
60-100°
O
O
Di-Benzoyl peroxide
Half-life at 100° ca. 30 min
NC
N N
CN
60-100°
Azobis(isobutyronitrile)
'AIBN'
Half-life at 100° ca. 5 min
2 NC
Ph• + CO2
Phenyl
radical
• + N N
2-Cyanoprop-2-yl
radical
Photolytic cleavage - compounds with low-energy electronic
absorptions only:
h
Cl-Cl
Ph
Ph
O O
O
h
2 Cl•
2 Ph
O
CH3
O
C
h
CH3
R O N O
R O Cl
O
•
O
O
CH3 C• +
Ph• + CO2
CH3•
h
R O• +
NO•
h
R O• +
Cl•
(2) Redox reactions of non-radical precursors:
Reduction.
_•
+ Na
CH3
O
C
CH3
+
Na
Na+
Naphthalide
radical anion
_
O
Ketyl radical
+
•
C
Na
anion
CH3
CH3
Oxidation:
Ar3N:
+
AgPF6
•
0
+
[Ar3N•] [PF6]- + Ag
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
O O
O
CH3
O
h
Solid Argon
5-10 oK
O
H3C
O
+ CH3
+ CO2
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:
H2 C
H
C
CH2•
•H2C
•CH2
H
C
CH2
CH2
•
etc.
The combination of electronic and steric effects can result in very stable
- and, in suitable circumstances, even isolable - free radicals:
H
O•
O
2,4,6-Tri-t-butylphenoxyl
O•
Galvinoxyl
Characteristic Reaction Pathways of Free Radicals:
(1) Dimerisation:
R• + R•
R R
Leads to non-radical products - termination steps in radical chainreactions.
(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
H3C
H2
C
CH3CH2CH3 + CH3CH=CH2
CH2
CH2
+ H CH
CH3
H3C
H2
C
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:
R
H2
R C CH2
+ CH2=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
+
CH3 C CH
2
CH3
1°
+
C
Very rapid
CH3
CH3
-
H migration
2e in migration
system
3°
H
•
CH3 C CH
2
CH3
1°
•
C
H• migration
CH2H
CH3
CH3
CH2H
3°
3e in migration
system
The transition states for both rearrangements are very similar:
*
H
CH3
CH3
CH2
*
= + or •
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)
(A)
Carbocation - 2e
Favourable T.S.
Rapid rearrangement
(B)
(C)
(A)
Radical - 3e
Unfavourable T.S.
No rearrangement
 -Unsaturated free radicals will undergo rearrangement with
migration of the unsaturated group:

•
CH2
CH2
CH2
 HC
CH
•
CH
C
C
•
CH3
CH
3
CH2
CH2
CH3 C
CH2
CH3
CH3
CH3
1°
3°
Stable intermediate
(6) Fragmentation:
O
Ar
Ar•
C
+
CO2
O•
FREE RADICALS IN ORGANIC SYNTHESIS
(1) Free Radical Substitution of Hydrogen by Other Atoms.
(a) Photochemical halogenation of saturated hydrocarbons
Cl2
h
2 Cl•
CH3CH2CH3 + Cl•
•
CH3CHCH3 + HCl
•
CH3CHCH3 + Cl2
CH3CHClCH3 + Cl•
•
CH3CHCH3 + Cl•
Initiation
Propagation by
chain transfer
Termination