THE CHEMISTRY OF ARYNES
(1) BACKGROUND: THE MECHANISM OF NUCLEOPHILIC
AROMATIC SUBSTITUTION - SNAr
Can aromatic halides undergo SN2-type substitutions with nucleophiles?
Cl
Nu
Nu-
?
+ Cl-
The answer is NO - in an SN2 reaction the nucleophile must approach
the reacting carbon from the rear - and this would require the electronrich nucleophile to penetrate the aromatic -cloud, an extremely
unlikely event. No examples of this kind of reaction are known.
Nucleophilic aromatic substitution, SNAr, CAN take place but it occurs
by an addition-elimination mechanism and requires the presence of at
least one substituent which is strongly electron-withdrawing by
resonance to stabilise the anionic addition intermediate:
Cl
Cl Nu
Nu-
Cl Nu
Nu
_
+ ClNO2
O
N
O
O
N
O
_
NO2
(2) COMMERCIAL
HALOBENZENES:
SYNTHESIS
OF
PHENOLS
FROM
The commercial process is difficult to reconcile with the accepted SNAr
mechanism:
Cl
OH
NaOH
300° C
Cl
OH
OH
NaOH
300° C
+
CH3
CH3
CH3
Suggested explanation - a different mechanism:
Cl
OHH
HO-
Cl
OH
OH
_
_
H2O
Benzyne
intermediate
H
OH
Cl
OH- HCl
OH
OH-
(i)
(ii) H2O
+
CH3
CH3
CH3
CH3
A related reaction which is best explained by proposing a benzyne
intermediate (J.D. Roberts. 1953):
Cl
•
NH2
(i) NaNH 2
(ii) H2O
• = 14C label
H
•
•
NH2 H
+
H
50%
50%
H
The compound C6H4 which we have been referring to as 'benzyne' is
formally derived from benzene by removal of a pair of adjacent H
atoms and the formation of a triple bond. More accurately it should be
called ortho-benzyne since meta- and para- isomers are also known.
The latter, however have quite different structures to the ortho-isomer.
Benzyne is just one of a general class of reactive intermediates known
collectively as 'arynes'. Arynes derived from aromatic species other
than benzene are also known such as:
N
1,2- Naphthalyne
2,3-Pyridyne
S
2,3-Thiophyne
One of the most general syntheses of arynes is -elimination of LiF
from lithiated fluoroarenes:
F
F
RLi
- RH
H
Li
-LiF
Two examples in which aryne intermediates are generated using this
approach and then undergo further reaction are shown below:
F
CO2H
(i) PhLi
(ii) CO2
(iii) H2O
C6H5
C6H5
CO2H
+
+ LiF
F
F
2 Li
- LiBr
Br
O
-LiF
Li
O
DielsAlder
O
For many synthetic applications of arynes it is necessary to generate the
labile intermediate under mild conditions that don't require highly basic
reactive organolithium reagents:
O
N
O
O
h
- 2 CO2
> 40° C
- SO
S O -N 2
2
N
O
O
Phthalic peroxyanhydride
Benzothiadiazole
-S,S-dioxide
NH2
CO2H
N2+
HNO2
H3O+
CO2H
OH-
Mild 
- CO2
- N2
+ N
N
Isolable zwitterion
C O
O-
Properties of benzyne:
Free benzyne is very reactive and rapidly dimerises:
The lifetime of benzyne in the gas phase has been estimated to be at
least 20 nanoseconds (2 x 10-8 seconds) by Mass Spectroscopic
techniques..
Some spectroscopic properties of benzyne have been determined by
Orville Chapman using Matrix Isolation techniques:
O
O
O
O
h
- 2 CO2
Ar
matrix
77° K
(CC) 2085 cm-1
(2100 - 2260 cm-1)
Theoretical calculations suggest that the strained 'bent alkyne' form of
benzyne is lower in energy than the di-radical alternative:
H
C
C
1.422 Å
ca. 1.20 Å
60°
1.298 Å
1.426 Å
H
(A)
(B)
The calculations suggest that the -overlap in the strained  bond is
weaker and that the * component of the bond (i.e. the LUMO) is at
lower energy than normal for a triple bond. Hence arynes behave as
powerful electrophiles.
Aryne reaction patterns:
(1) Addition of nucleophiles to the triple bond.
H
_
Nuc
Nuc-
Nuc
H2O
Nuc = Ph-CC- (30%), [(EtO2C)2CH]- (51%) etc.
H
_
RXH
H
X+
R
XR
RXH = H2O, ROH, RCO2H, RSH, RNH2 etc.
H
H2
C
CH2
X
H
_
H2
C
R
CH2
+
X
R
H
XR
+ CH2=CH2
X = S, NR, PR
H
CH3
X
R
_
CH2
+
X
R
H
_
CH2
X
+ R
(Ylide)
X = S, NR, PR
SUBSTITUENT EFFECTS ON THE ADDITION OF
NUCLEOPHILES TO ARYNES
X
X
sp2

sp2
Note that the  and *molecular orbitals of the reactive 'extra' -bond in
benzyne lie at right angles to the aromatic -cloud and cannot interact
with it. Therefore the 'extra' -bond is insulated from the resonance
effects of substituents because these are transmitted via the -cloud. On
the other hand addition of nucleophiles to the low-energy aryne *
molecular orbital is affected by the inductive effect of neighbouring
substituents:
OCH 3
OCH 3
CH 3
Nu
Nu –
_
Nu –
CH 3
–
Nu
Inductively electron-withdrawing substituents are meta-directing and
inductively electron-releasing substituents are ortho-directing.
(2) Cycloaddition reactions to the aryne triple bond.
Diels-Alder reactions of benzyne with 1,3-dienes in which the aryne
triple bond behaves as dienophile are very common and an example
involving furan as the diene has been described earlier.
The stereochemistry of the product in the following thermally promoted
Diels-Alder reaction with 2,4-hexadiene demonstrates the concerted
nature of the addition.
O
Cl
Cl
O
O
h
+
Cl
Cl
O
•
•
Cl
Cl
Cl
Cl
Cl
Cl
• •
Arynes also undergo formal [2+2] additions to alkenes but many of
these are stepwise rather than concerted processes. The loss of the
alkene trans-stereochemistry in the product of the photochemically
mediated cycloaddition illustrated above suggests that it proceeds via a
photochemically generated diradical excited state of benzyne rather
than by a concerted mechanism.
APPLICATIONS OF ARYNE INTERMEDIATES IN ORGANIC
SYNTHESIS
Arynes have not been exploited in organic synthesis to the same extent
as free radicals or carbenes but there are still many examples of the use
of arenes in natural product synthesis:
Synthesis of an Aporphine alkaloid:
CH3O
CH3O
CH3O
NAc
CH3O
NAc
H
Diels-Alder
OCH3
OCH3
CH3O
CH3O
NAc
Aporphine
alkaloid
1,3- (allylic) hydrogen
shift - aromatisation.
OCH3
Note the unusual incorporation of a benzene double bond as part of the
'diene' component of the Diels-Alder reaction.
3,4-Pyridyne in the synthesis of Ellipticene, an anti-cancer alkaloid:
F
N
F
N
2 Li
- LiBr
N
- LiF
Br
Li
3,4-Pyridyne
CH3
O
N
H
O
N
+
CH3
CH3
O
N
- CO2
N
H
CH3
CH3
N
N
H
CH3
O
Ellipticene
Benzyne in a synthesis of a Lysergic Acid N,N-Diethylamide (i.e. LSD)
precursor:
O
O
CH3O
CH3O
NCH3
NCH3
_
NaNH2, liq. NH3
Br
N
Ac
N
Ac
O
O
CH3O
CH3O
NCH3
H
NCH3
H
NH3
(i) H+
(ii) 1,3-H shift.
H
_
N
Ac
N
Ac
Several steps
O
(CH3CH2)2N
NCH3
H
Lysergic acid N,N-diethylamide
NH