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Lone pair interaction in the Chichibabin reaction
TetrahedronLettersNo.24, pp. 1577-1583,1964. PergamonPress Ltd. Printed in Great Britain.
LONE PAIR INTERACTION IN TEE CHICHIBABIN REACTION H. Lloyd Joneel and
David
L. Bercridge
Department of Chedstry UnlversityofCincinnati Cincinnati 21, Ohio (Received28 February1964; in revisedform 25 April 1964)
The an&nation of pyridine, widely kuown as the Chichibabia reaction: is generally considered a8 a nucleophilic substitutionreaction. Substitution occurs exclusively at a poeition adjacent to the nitrogen atom in the molecule. Several authorm have discussed possible meohanisrs for this reaction in terms of a sigma complex intermediate! However, molecular orbital oalculatione of electron dinsities and localization energies (Fig. 1) indicate the k-position is a more favorable nucleophllic reaction site.
FIG. 1 Electron Densities in Pyridine Parentheseqcontain localization energies after A. Barnes, 2. &. w. E., 8l, 1935 (1959). -
1577
Lone pair interaction in the Chichibabin reaction
1578
To account
for the observed
and steric factors involving
lntemediate?
lining intramolecular Recently,
hydrogen
has been proposed
orbital
intermediate
*
vio-
on the sigma complex the formation
of an aryne intermediate,
in the amination
NHS
as possible
of a stabi-
bond have been invoked.
the formation
NHaDMF
Molecular
such arguments
rule! variations
lation of the non-crossing
pyridine,
phenomena
rto.24
2,3,-dehydro-
of pyridinet
-H-
+
. I
calculationa+
on the electronic
have led us to a possible
structure
explanation
of this
of the exclusive
forelation of 2-aainopyfidiha..
The structure of an aryne intermediate species in which positions.
lp2
two hydrogen
There results
hybrid orbitala,
ato-
a bonding
orthogonal
cule, which has been estimated pure pi-bond! be highly
have been removed
susceptible
from adjacent
between
Interaction
to the pi-electron
the available
system of the mole-
to be about one-fourth
The species is thus very reactive
as strong as a
and has been shown to
to attack by nucleophiles!
A unique situation
occurs in the formation
Here the sp2 carbon orbital6 containing
is that of an aromatic
the nitrogen
of 2,3-dehydropyridine.
are coplanar with the sp2 hybrid orbital
lone pair, and a delocalized
system may be formed by allowing
molecular
the three sp2 orbitals
This leads to a stabilized
reaction
intermediate
+The method of calculation
and parametrization
orbital
to interact.
in which
the lowest
is discussed in Appendix 1.
No.24
Lone pair interactionin the Chichibabinreaction
1579
electron density of the aryne-sp2 system occurs at the position adjaoent to the nitrogen atom (Fig. 2).
Thus, the possibility of a nucleophile
reacting at this position is considerably enhanced.
v
.8!l6
1.024
I
I
1.144
2.000
C
b
a) 2,$-dehydropyridine b) 2,Fdshydropyridine vithlonapairinterw lone pair aeti0n fntsraction =sp2 = 4.48
&sp2
c) 3,kdehydropyridine
G2 =
3.78
= 4.og
TICII2 Electron Densities in variations on Aryno Intermediates Examination of the proposed raaotion
lechaniti ud
products indi-
cates further evidence for significant lone pair interaction in the aryne intermediate. Without loab pair iaterretion, the &nation
of the
aryne intermediate ahoqld give 3-aminopyridiaeas ~011 as 2-a8inopyridine. 9 Nso, in the formation analogous to the corresponding dehydrobonaenc. of the aryne intermediate the more acidic proton in the k-position should be more readily removed then the proton in the 2-position, hence the formation of some 3,4-dehydropyridinewould be indicated. If this wsro the case one would expect as products 4-sminopyrldineand 3-aminolyridineas well as 2- aminopyridine. The yeild of 2-aminopyridineobtained in the 10 Chichibabin reaction is 75-85 per cent and the presence of 3-aminopyridine or k-aminopyridinehas never been reported. A comparison of the relative energies of j,k-dehydropyridineand 2,3-dehydropyridine
1580
with and without
lone pair interaction
oation of 2,3-dchydropyridine im also of interest
in the emination
An analogous li8e.
reaction
The electron
pyridine,
of pyridine
density pattern
indicating
However,
but it is not is more
this intermediate prridine.
likely in the case of quiao-
(Fig. 3) is parallel
that a nucleophile
It
would be
since the j-position
of a j,WJisubstituted echene appears
stabili-
(Fig. 2).
than 2,3-dehydropyridine,
for the hydride ion elimination,
is fea8ible
the increased
to note that the aryne 2,6-dehydropyridine
to form in the a&nation
favorable
indicates
with lone pair interaction
an even more stable intermediate likely
No.24
Lone pair interaction in the Chichibabin reaction
to that of
should favor the 4-position.
.95a
,989 b Ieoquinoline
ginoline ELectron
E+nsities
PIG. 3 in Quinoline
Substitution
occur-clpredominately
the presence
of small amounts
The formation pyridine
of &aminoquinoline
since the localization compounds
zenoid ringa involved The exclusive
but in this case
11 have been reported.
energy at an analogous
generally
decreases
position in a
as the number of ben-
12 increases.
formation
of isoquinoline.
of l-aminoisoquinoline
This is the product
complex aad aryne intermediate likely
at the 2-position,
of the b-amino product is more likely in this case than in
series of aromatic
amination
and Iaoquiaoline
arguments.
to form is 1,3-dehydroisoquinoline,
is observed
expected
in the
from both sigma
The aryne intermediate by the following
most
mechanism:
No.24
Lone pair interactionin the Chichibabinreaction
1581
The charge densities of isoquinolina (Fig. 3) indicate the proton in the l-position is the cost acidic and therefore most likely to be eliminated. The 3-position, having the highest electron density, is then favorable to hydride ion elimination which results in the formation of 1,3-aryne intermediate. The reaction proceodm with the formation of 1-aminoisoquinoline. Thus, a reaction rechsnism for the s&nation of pyridine, quinoline, and isoquinoliao in~olring an aryne interoedlate gives a reasonable account of erporirental observations on these systems. This type of intermediate seems also quita likely in other nualeophilic reactions characteristicof the asa-aroaatic compounds. Acknowledgement. The authors are pleased to acknowledge Dr. Ii.H. Jaff6 and Mr. David L. Webb for their helpful discussions and suggestions concerning this work. Computer facilitieswere provided by the University of Cincinnati Computing Center and financed by NSF Grant 619281.
No.24
Lone pair interaction in the Chichibabin reaction
1582
APPENDIX
All molecular LCAO-HO
orbital
approximation
calculations
diagonal
were performed
elements
in the Eiickel
considerations. of the secular
Follou-
determinant
as aI
where a repremonts
=a
(1)
C + hx&c
the coulomb integral
andh x the eleo troaegativi expressed
CALCULATIONS
with electronegatlvity
ing the usual procedure, were expressed
I:
ty parMeter.
aad $ the resonance Off diagonal
integral
elements were
as (2)
PC-X = kCtX2CnC where k is a proportionality For the pi-electron parameter
constante
systems
considtrod,
the electronegativity
for titrogen vas taken 18 hN = 0.5, and hN
hClc= ‘;;;
(3)
where I! is the number of positione between carbon x and the nitrogen
aton. For the monoero off-diagonal matris elementa, kCIB In the calculations parameter of o+oi
for nitrogen The carbon
the nitrogen
(4)
= kcpC = 1.0
on the aryne-•p2
oyatems,
the electronegativity
was chosen em hB = 1.0, relative
atom coulomb
atom in the molecule
ama (l).- The off-diagonal
integrala
perturbed
were then computed
elemestslwere
to a carbon a
from equations
the valence
the weak overlap integral The relative
energies
14
state ionization
between
(3)
(5)
13
kij = Sij/2.39ev where I represents
of
esbtiatad from the -equation6
= 0.5 (Ii+ Ij) s..
'ij
sP2
by the proximity
(6) potential 13 and S. . in =J
sp2 hybrids on centers i and j.
of the aryne-sp2
systems are defined analogous
to
No.24
Lone pair interactionin the Chichibabinreaction
1583
the relative pi-electron energies in the Eiickeltheory, E,p2 =xn j
a (7) j5 th where n; is the occupation number of the j molecular orbital of emorgy .J
c., the sum being taken over all occupied orbital& J
REFERENCES 1.
Proctor and Gsmblo Company Research Fellow, 1963-1964.
2.
A. E. Chichibabln and 0. A. Seide, J. Russ. M. 1216 (1914).
3.
J Eisch and B. Oilman, chcp. m.1
4. 5.
R. D. Brown and M. L. Heiferman, -_dust J. ChoB.,,lC, 211 (1957). G. Coppens and J. Nasielski, Tetrahedron,l8, 507 (1962).
6.
L. S. Leuitt and B. W. Lewitt, --Chom. Ind. Lond., a,
7.
H. E. Simmons, J. Am. Chee. &.,
8.
R. Huisgen and J. Sauer, Angew. B.,
Ckem. SOf.,
46,
22, 525 (1957).
3,
1621.
1657 (1961).
& 91 )1960). L. A. Carlsmith, and C. W. Vaugksm, 9. J. D. Roberts, H. E. 6immon8, J. h. m. s., 2, 3290 (1953); J. D. Roberts, C. W. Vmaghu, L. A. Carlsmith, and-D. A. Semenov, ibid., g, 611 (1956). 10.
M. T. Leffler, in Organic Reactions, edited by P. Adams, Vo1. 1, Chpt. 4, John Wiley and Sons, Inc., New York (1942).
11.
F. W. Bergstrom, 2. a.
12.
A. Streitwieser,Molecular Orbital Thaor for Or anic Chemists, p. 336, John Wiley and Sons, ----e New York 196x =-
w.,
2, 411 (1937).
84, 540 (1962). 14. R. S. Mulliken, C. A. Rieke, D. Orloff and II.Orloff, J. Chem. w., g, 1248 (1949). 13.
J. Hinze and H. H. Jaffe. -J.&. m.
e.,
LONE PAIR INTERACTION IN TEE CHICHIBABIN REACTION H. Lloyd Joneel and
David
L. Bercridge
Department of Chedstry UnlversityofCincinnati Cincinnati 21, Ohio (Received28 February1964; in revisedform 25 April 1964)
The an&nation of pyridine, widely kuown as the Chichibabia reaction: is generally considered a8 a nucleophilic substitutionreaction. Substitution occurs exclusively at a poeition adjacent to the nitrogen atom in the molecule. Several authorm have discussed possible meohanisrs for this reaction in terms of a sigma complex intermediate! However, molecular orbital oalculatione of electron dinsities and localization energies (Fig. 1) indicate the k-position is a more favorable nucleophllic reaction site.
FIG. 1 Electron Densities in Pyridine Parentheseqcontain localization energies after A. Barnes, 2. &. w. E., 8l, 1935 (1959). -
1577
Lone pair interaction in the Chichibabin reaction
1578
To account
for the observed
and steric factors involving
lntemediate?
lining intramolecular Recently,
hydrogen
has been proposed
orbital
intermediate
*
vio-
on the sigma complex the formation
of an aryne intermediate,
in the amination
NHS
as possible
of a stabi-
bond have been invoked.
the formation
NHaDMF
Molecular
such arguments
rule! variations
lation of the non-crossing
pyridine,
phenomena
rto.24
2,3,-dehydro-
of pyridinet
-H-
+
. I
calculationa+
on the electronic
have led us to a possible
structure
explanation
of this
of the exclusive
forelation of 2-aainopyfidiha..
The structure of an aryne intermediate species in which positions.
lp2
two hydrogen
There results
hybrid orbitala,
ato-
a bonding
orthogonal
cule, which has been estimated pure pi-bond! be highly
have been removed
susceptible
from adjacent
between
Interaction
to the pi-electron
the available
system of the mole-
to be about one-fourth
The species is thus very reactive
as strong as a
and has been shown to
to attack by nucleophiles!
A unique situation
occurs in the formation
Here the sp2 carbon orbital6 containing
is that of an aromatic
the nitrogen
of 2,3-dehydropyridine.
are coplanar with the sp2 hybrid orbital
lone pair, and a delocalized
system may be formed by allowing
molecular
the three sp2 orbitals
This leads to a stabilized
reaction
intermediate
+The method of calculation
and parametrization
orbital
to interact.
in which
the lowest
is discussed in Appendix 1.
No.24
Lone pair interactionin the Chichibabinreaction
1579
electron density of the aryne-sp2 system occurs at the position adjaoent to the nitrogen atom (Fig. 2).
Thus, the possibility of a nucleophile
reacting at this position is considerably enhanced.
v
.8!l6
1.024
I
I
1.144
2.000
C
b
a) 2,$-dehydropyridine b) 2,Fdshydropyridine vithlonapairinterw lone pair aeti0n fntsraction =sp2 = 4.48
&sp2
c) 3,kdehydropyridine
G2 =
3.78
= 4.og
TICII2 Electron Densities in variations on Aryno Intermediates Examination of the proposed raaotion
lechaniti ud
products indi-
cates further evidence for significant lone pair interaction in the aryne intermediate. Without loab pair iaterretion, the &nation
of the
aryne intermediate ahoqld give 3-aminopyridiaeas ~011 as 2-a8inopyridine. 9 Nso, in the formation analogous to the corresponding dehydrobonaenc. of the aryne intermediate the more acidic proton in the k-position should be more readily removed then the proton in the 2-position, hence the formation of some 3,4-dehydropyridinewould be indicated. If this wsro the case one would expect as products 4-sminopyrldineand 3-aminolyridineas well as 2- aminopyridine. The yeild of 2-aminopyridineobtained in the 10 Chichibabin reaction is 75-85 per cent and the presence of 3-aminopyridine or k-aminopyridinehas never been reported. A comparison of the relative energies of j,k-dehydropyridineand 2,3-dehydropyridine
1580
with and without
lone pair interaction
oation of 2,3-dchydropyridine im also of interest
in the emination
An analogous li8e.
reaction
The electron
pyridine,
of pyridine
density pattern
indicating
However,
but it is not is more
this intermediate prridine.
likely in the case of quiao-
(Fig. 3) is parallel
that a nucleophile
It
would be
since the j-position
of a j,WJisubstituted echene appears
stabili-
(Fig. 2).
than 2,3-dehydropyridine,
for the hydride ion elimination,
is fea8ible
the increased
to note that the aryne 2,6-dehydropyridine
to form in the a&nation
favorable
indicates
with lone pair interaction
an even more stable intermediate likely
No.24
Lone pair interaction in the Chichibabin reaction
to that of
should favor the 4-position.
.95a
,989 b Ieoquinoline
ginoline ELectron
E+nsities
PIG. 3 in Quinoline
Substitution
occur-clpredominately
the presence
of small amounts
The formation pyridine
of &aminoquinoline
since the localization compounds
zenoid ringa involved The exclusive
but in this case
11 have been reported.
energy at an analogous
generally
decreases
position in a
as the number of ben-
12 increases.
formation
of isoquinoline.
of l-aminoisoquinoline
This is the product
complex aad aryne intermediate likely
at the 2-position,
of the b-amino product is more likely in this case than in
series of aromatic
amination
and Iaoquiaoline
arguments.
to form is 1,3-dehydroisoquinoline,
is observed
expected
in the
from both sigma
The aryne intermediate by the following
most
mechanism:
No.24
Lone pair interactionin the Chichibabinreaction
1581
The charge densities of isoquinolina (Fig. 3) indicate the proton in the l-position is the cost acidic and therefore most likely to be eliminated. The 3-position, having the highest electron density, is then favorable to hydride ion elimination which results in the formation of 1,3-aryne intermediate. The reaction proceodm with the formation of 1-aminoisoquinoline. Thus, a reaction rechsnism for the s&nation of pyridine, quinoline, and isoquinoliao in~olring an aryne interoedlate gives a reasonable account of erporirental observations on these systems. This type of intermediate seems also quita likely in other nualeophilic reactions characteristicof the asa-aroaatic compounds. Acknowledgement. The authors are pleased to acknowledge Dr. Ii.H. Jaff6 and Mr. David L. Webb for their helpful discussions and suggestions concerning this work. Computer facilitieswere provided by the University of Cincinnati Computing Center and financed by NSF Grant 619281.
No.24
Lone pair interaction in the Chichibabin reaction
1582
APPENDIX
All molecular LCAO-HO
orbital
approximation
calculations
diagonal
were performed
elements
in the Eiickel
considerations. of the secular
Follou-
determinant
as aI
where a repremonts
=a
(1)
C + hx&c
the coulomb integral
andh x the eleo troaegativi expressed
CALCULATIONS
with electronegatlvity
ing the usual procedure, were expressed
I:
ty parMeter.
aad $ the resonance Off diagonal
integral
elements were
as (2)
PC-X = kCtX2CnC where k is a proportionality For the pi-electron parameter
constante
systems
considtrod,
the electronegativity
for titrogen vas taken 18 hN = 0.5, and hN
hClc= ‘;;;
(3)
where I! is the number of positione between carbon x and the nitrogen
aton. For the monoero off-diagonal matris elementa, kCIB In the calculations parameter of o+oi
for nitrogen The carbon
the nitrogen
(4)
= kcpC = 1.0
on the aryne-•p2
oyatems,
the electronegativity
was chosen em hB = 1.0, relative
atom coulomb
atom in the molecule
ama (l).- The off-diagonal
integrala
perturbed
were then computed
elemestslwere
to a carbon a
from equations
the valence
the weak overlap integral The relative
energies
14
state ionization
between
(3)
(5)
13
kij = Sij/2.39ev where I represents
of
esbtiatad from the -equation6
= 0.5 (Ii+ Ij) s..
'ij
sP2
by the proximity
(6) potential 13 and S. . in =J
sp2 hybrids on centers i and j.
of the aryne-sp2
systems are defined analogous
to
No.24
Lone pair interactionin the Chichibabinreaction
1583
the relative pi-electron energies in the Eiickeltheory, E,p2 =xn j
a (7) j5 th where n; is the occupation number of the j molecular orbital of emorgy .J
c., the sum being taken over all occupied orbital& J
REFERENCES 1.
Proctor and Gsmblo Company Research Fellow, 1963-1964.
2.
A. E. Chichibabln and 0. A. Seide, J. Russ. M. 1216 (1914).
3.
J Eisch and B. Oilman, chcp. m.1
4. 5.
R. D. Brown and M. L. Heiferman, -_dust J. ChoB.,,lC, 211 (1957). G. Coppens and J. Nasielski, Tetrahedron,l8, 507 (1962).
6.
L. S. Leuitt and B. W. Lewitt, --Chom. Ind. Lond., a,
7.
H. E. Simmons, J. Am. Chee. &.,
8.
R. Huisgen and J. Sauer, Angew. B.,
Ckem. SOf.,
46,
22, 525 (1957).
3,
1621.
1657 (1961).
& 91 )1960). L. A. Carlsmith, and C. W. Vaugksm, 9. J. D. Roberts, H. E. 6immon8, J. h. m. s., 2, 3290 (1953); J. D. Roberts, C. W. Vmaghu, L. A. Carlsmith, and-D. A. Semenov, ibid., g, 611 (1956). 10.
M. T. Leffler, in Organic Reactions, edited by P. Adams, Vo1. 1, Chpt. 4, John Wiley and Sons, Inc., New York (1942).
11.
F. W. Bergstrom, 2. a.
12.
A. Streitwieser,Molecular Orbital Thaor for Or anic Chemists, p. 336, John Wiley and Sons, ----e New York 196x =-
w.,
2, 411 (1937).
84, 540 (1962). 14. R. S. Mulliken, C. A. Rieke, D. Orloff and II.Orloff, J. Chem. w., g, 1248 (1949). 13.
J. Hinze and H. H. Jaffe. -J.&. m.
e.,