Diheteroarylmethanes. 8.1 Mapping charge and electron-withdrawing power of the 1,2,4-triazol-5-yl substituent

Article abstract of DOI:10.1021/jo990687+

Three new triazolyl derivatives, bis(1H-1-phenyl-1,2,4-triazol-5- yl)methane (11), 1H-1-phenyl-5-(β-styryl)-1,2,4-triazole (12), and 1H-5- benzyl-1-phenyl-1,2,4-triazole (13) have been synthesized and the carbanions 11^- and 13^- investigated in DMSO by multinuclear NMR spectroscopy. By applying previously proposed and widely used π-charge/¹³C shift relationships on the spectra of the anions, it is possible to rank the π electron-withdrawing power of the 1,2,4-triazol-5-yl group in terms of charge demand c(X), a quantity that represents the fraction of π negative charge delocalized by the heterocyclic ring. Our results indicate that the charge demand c(X) of this heterocycle is considerably greater than that of other 1,3-azoles (2-imidazolyl, 2-oxazolyl, 2-benzoimidazolyl), being close to that of some mono- and diazinyl substituents. A single set of resonances is presented by both carbanions 11^- and 13^-, thus showing that they exist either as a single geometric isomer species or as a mixture of isomers in a rapid (on the NMR time scale) equilibrium, ¹³C and ¹⁵N shift/π-charge relationships allow accurate π-charge mapping of carbanionic systems. Our results clearly show that, in the case of benzyl carbanion 13^-, all of the three nitrogen atoms are almost equally involved in delocalizing the negative charge. Also, the N-phenyl group contributes to charge delocalization. Anion 11^- is the first of the bis(heteroaryl)methyl carbanions that we have studied, in which all of the negative charge originated by deprotonation of the carbon acid 11 is hosted on the nitrogen atoms without any appreciable involvement of the heteroaromatic carbon frame.

Full text of DOI:10.1021/jo990687+

6756
J . Org. Chem. 1999, 64, 6756-6763
Dih eter oa r ylm eth a n es. 8.1 Ma p p in g Ch a r ge a n d
Electr on -With d r a w in g P ow er of th e 1,2,4-Tr ia zol-5-yl Su bstitu en t
Alessandro Abbotto, Silvia Bradamante, Antonio Facchetti, and Giorgio A. Pagani*
Dipartimento di Scienza dei Materiali dell’Universita` di Milano-Bicocca, via Cozzi 53, I-20125,
Milano, Italy, and Centro CNR Speciali Sistemi Organici, via Golgi 19, I-20133, Milano, Italy
Received April 23, 1999
Three new triazolyl derivatives, bis(1H-1-phenyl-1,2,4-triazol-5-yl)methane (11), 1H-1-phenyl-5-
(â-styryl)-1,2,4-triazole (12), and 1H-5-benzyl-1-phenyl-1,2,4-triazole (13) have been synthesized
and the carbanions 11- and 13- investigated in DMSO by multinuclear NMR spectroscopy. By
applying previously proposed and widely used π-charge/13C shift relationships on the spectra of
the anions, it is possible to rank the π electron-withdrawing power of the 1,2,4-triazol-5-yl group
in terms of charge demand cX, a quantity that represents the fraction of π negative charge delocalized
by the heterocyclic ring. Our results indicate that the charge demand cX of this heterocycle is
considerably greater than that of other 1,3-azoles (2-imidazolyl, 2-oxazolyl, 2-benzoimidazolyl), being
close to that of some mono- and diazinyl substituents. A single set of resonances is presented by
both carbanions 11- and 13-, thus showing that they exist either as a single geometric isomer
species or as a mixture of isomers in a rapid (on the NMR time scale) equilibrium. 13C and 15N
shift/π-charge relationships allow accurate π-charge mapping of carbanionic systems. Our results
clearly show that, in the case of benzyl carbanion 13-, all of the three nitrogen atoms are almost
equally involved in delocalizing the negative charge. Also, the N-phenyl group contributes to charge
delocalization. Anion 11- is the first of the bis(heteroaryl)methyl carbanions that we have studied,
in which all of the negative charge originated by deprotonation of the carbon acid 11 is hosted on
the nitrogen atoms without any appreciable involvement of the heteroaromatic carbon frame.
A number of the properties of heteroaromatic-based
of the extended quantitative scale of the electron-
withdrawing capacity of as many heteroaromatic rings
as possible.
compounds ultimately depend on their geometric and
electronic structure. Among other applications, the hot
field of organic materials for nonlinear optics2 has
stressed the strict dependence of benchmark parameters
(first and second hyperpolarizabilities) on the electronic
nature of the constituting parts.3 In particular, it has
been shown that there is an optimal value of the electron-
withdrawing and electron-donating strength of the end-
cap substituents of push-pull conjugated systems, which
leads to enhanced activities.4 Fine-tuning of the design
and synthesis strategy for achieving highly efficient
heterocycle-based organic materials requires a knowledge
Over the last 10 years, we have proposed 13C (relation-
ships 1 and 2)5,6 and 15N (relationship 3)7-10 shift/π-
charge relationships as a method of choice for experi-
mentally mapping π-charges and ranking the resonance
electron-withdrawing power of primary organic function-
alities6,11,12 and heterocycles, including azines (2- and
4-pyridyl, pyrazinyl, 4-pyrimidyl, 3-pyridazinyl, and 2-
and 4-quinolyl),7,11,13 1,3-azoles (2-oxazolyl, 2-thiazolyl,
2-imidazolyl, and their benzo-fused analogues),14 and
purines (8-purinyl).15
(5) Bradamante, S.; Pagani, G. A. J . Org. Chem. 1984, 49, 2863-
2870.
(1) For part 7, see ref 15. For part 6, see ref 14b. For part 5, see ref
14a.
(2) (a) Chemla, D. S.; Zyss, J . Nonlinear Optical Properties of
Organic Molecules and Crystals; Academic Press: New York, 1987.
(b) Prasad, P. N.; Williams, J . Introduction to Nonlinear Optical Effects
in Molecules and Polymers; Wiley: New York, 1991.
(6) Bradamante S.; Pagani G. A. J . Chem. Soc., Perkin Trans. 2
1986, 1035-1046.
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Soc., Perkin Trans. 2 1991, 481-488.
(8) Abbotto, A.; Bradamante, S.; Pagani, G. A. J . Org. Chem. 1993,
58, 444-448.
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(b) Bredas, J . L. Science 1994, 263, 487-488. (c) Marks, T. J .; Ratner,
M. A. Angew. Chem., Int. Ed. Engl. 1995, 34, 155-173. (d) Dalton, L.
R.; Harper, A. W.; Ghosn, R.; Steier, W. H.; Ziari, M.; Fetterman, H.;
Shi, Y.; Mustacich, R. V.; J en, A. K. Y.; Shea, K. J . Chem. Mater. 1995,
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K.; Persoons, A. J . Mater. Chem. 1997, 7, 2175-2189.
(4) (a) Marder, S. R.; Cheng, L. T.; Tiemann, B. G.; Friedli, A. C.;
Blancharddesce, M.; Perry, J . W.; Skindhoj, J . Science 1994, 263, 511-
514. (b) Wong, K. Y.; J en, A. K. Y.; Rao, V. P.; Drost, K. J . J . Chem.
Phys. 1994, 100, 6818-6825. (c) Blancharddesce, M.; Alain, V.;
Bedworth, P. V.; Marder, S. R.; Fort, A.; Runser, C.; Barzoukas, M.;
Lebus, S.; Wortmann, R. Chem. Eur. J . 1997, 3, 1091-1104. (d)
Marder, S. R.; Kippelen, B.; J en, A. K. Y.; Peyghambarian, N. Nature
1997, 388, 845-851. (d) Cheng, T. R.; Huang, C. H.; Gan, L. B.; Luo,
C. P.; Yu, A. C.; Zhao, X. S. J . Mater. Chem. 1998, 8, 931-935. (e)
Shu, C. F.; Wang, Y. K. J . Mater. Chem. 1998, 8, 833-835.
(9) Abbotto, A.; Bradamante, S.; Pagani, G. A. J . Org. Chem. 1993,
58, 449-455.
(10) Gatti, C.; Ponti, A.; Gamba, A.; Pagani, G. A. J . Am. Chem.
Soc. 1992, 114, 8634-8644.
(11) Bradamante, S.; Pagani, G. A. Pure Appl. Chem. 1989, 61, 709-
716.
(12) Barchiesi, E.; Bradamante, S.; Ferraccioli, R.; Pagani, G. A. J .
Chem. Soc., Perkin Trans. 2 1990, 375-383.
(13) (a) Berlin, A.; Bradamante, S.; Pagani, G. A. J . Chem. Soc.,
Perkin Trans. 2 1988, 1525-1530. (b) Abbotto, A.; Bradamante, S.;
Pagani, G. A.; Rzepa, H.; Stoppa, F. Heterocycles 1995, 40, 757-776.
(14) (a) Abbotto, A.; Bradamante, S.; Pagani, G. A. J . Org. Chem.
1996, 61, 1761-1769. (b) Abbotto, A.; Bradamante, S.; Capri, N.; Rzepa,
H.; Williams, D. J .; White, A. J . Org. Chem. 1996, 61, 1770-1778.
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10.1021/jo990687+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/07/1999

Electron-Withdrawing Power of the 1,2,4-Triazol-5-yl Substituent
J . Org. Chem., Vol. 64, No. 18, 1999 6757
Ta ble 1. Ch a r ge Dem a n d of Va r iou s Su bstitu en ts (X) in
The cPh value represents the charge delocalized onto
the phenyl group in 2- and can be calculated according
to relationship 6 (which is directly related to eq 2), by
adding the local variations of the π-electron densities at
all of the positions of the phenyl ring.
Ca r ba n ion s 1- (cXX) a n d 2- (cPXh
)
a
X
cPXh
cXX
Phb
0.29
0.42
0.40
0.51
0.56
0.28
0.26
0.28
0.26
0.29
b
CONMe2
CO2Meb
COMeb
COPhb
CNb
0.275
0.268
0.325
0.341
0.207
0.233
0.206
0.122
0.318
cPh ) Σ∆qπC-ring ) -Σ∆δ13Cring/160
(6)
SOPhb
In this way, we obtained the two sets of cXX and cXPh
values listed in Table 1 for the various heterocyclic
groups. The first set was obtained by applying multi-
nuclear NMR spectroscopy to the investigation of type
1- diactivated systems (such as the symmetrically sub-
stituted carbanions 3-, 4-, 5-, and 6- originated by depro-
tonation of bis(benzothiazol-2-yl)methane,14a bis(benzox-
azol-2-yl)methane,14a bis(7-methylpurin-8-yl)methane,15
and bis(pyrid-2-yl)methane13b, respectively). The second
set of values was similarly obtained considering type 2-
R-benzyl anions, such as 7-, 8-, 9-, and 10-, which were
obtained from the corresponding benzyl derivatives
2-benzylbenzothiazole,14a 2-benzylbenzoxazole,14a 8-ben-
zyl-7-methylpurine,15 and 4-benzylpyridine,6,8,11,13a re-
spectively.
SO2Phb
b
PO(OEt)2
2-thiazolylc
2-oxazolylc
0.413-0.380
0.346
N-methylimidazol-2-ylc
2-benzothiazolylc
2-benzoxazolylc
N-methylbenzimidazol-2-ylc
2-pyridyld,e
0.283
0.254
0.316
0.288
0.457-0.471
0.424-0.436
0.382
0.411
0.408
0.302
0.299
0.313
4-pyridyld,e
2-quinolyle
3-pyridazinylf
0.417
0.430
0.501
0.446
0.536
2-pyrimidylf
4-pyrimidylf
pyrazinylf
N-methylpurin-8-ylg
0.305
The cXX values are smaller than the cPXh values because of
a
saturation phenomena; the two sets of values are linearly related
b
(refs 8, 11, 12, and 16). References 6 and 12. c Reference 14a.
d
g
Reference 11. e Reference 13b. f Reference 7. Reference 15.
Relationship 1 allows empirical calculation of the
π-electron density qπC 5,6 on a trigonal carbanionic carbon
(systems 1- or 2-) when the chemical shift of the
carbanionic carbon and the NMR shielding contributions
Ai of the various substituents directly bonded to the
anionic site are known.5 Relationships 2 and 3 correlate
the shift variation for each carbon or nitrogen site (which
do not experience rehybridazation upon deprotonation)
of 1- and 2- with that of the π-electron density going from
the neutrals to the anions, thus providing empirical site-
by-site charge mapping of the carbanions.
δ13C ) 122.8 + ΣAi - 160(qπC - 1)
∆δ13C ) -160∆qπC
(1)
(2)
(3)
The ranking of electron-withdrawing capacities allows
a precise prediction of the 13C shift of the carbanionic
carbon in many di- and trisubstituted carbanions.8,9,16 It
is also possible to describe the π-electron density varia-
tion associated with the deprotonation of the neutral to
the conjugated anionic species and then obtain a charge
map of the anion. In addition, we have shown that
carbanions 2- can be present in DMSO as a mixture of
both E and Z isomers because of the partial double bond
between the carbanionic carbon and the Cipso of the
heterocycle or the phenyl ring. The latter has been
observed exclusively in the case of the anion of 2-benzyl-
N-methylimidazole14a and has been rationalized in terms
of charge demands. The charge demand of the 2-imida-
zolyl group is not only the smallest among the hetero-
cycles we have considered but is also quite small in
absolute terms. Consequently, whereas azines and other
1,3-azoles are good competitors of the phenyl ring in
∆δ15N ) -366.34∆qπN
We have defined the charge demand c of a substituent
group X as the fraction of π-charge transferred from a
negatively charged trigonal carbon atom to the adjacent
X group.6,11,12 In particular, the symmetric carbanions 1-
originate the cXX values, whereas the benzyl carbanions
2- originate the cPXh values. The charge demands are
directly related to qπC, the π-electron density on the
(deprotonated) carbanionic carbon atom. Relationships
4 and 5 can be used to obtain the charge demand cXX and
cPXh, respectively.
cXX ) (2 - qπC)/2
(4)
(5)
cPXh ) 2 - cPh - qπC
(16) Barchiesi, E.; Bradamante, S.; Ferraccioli, R.; Pagani, G. A. J .
Chem. Soc., Chem. Commun. 1987, 1548-1549.

6758 J . Org. Chem., Vol. 64, No. 18, 1999
Abbotto et al.
Sch em e 1
delocalizing the negative charge, imidazole is not, thus
demonstrating that the hindered rotation occurs along
different bonds in the two cases. We have recently
reported15 that the 8-purinyl substituent has the highest
charge demand value of the heterocycles we have con-
sidered; in this case, the poor electron-withdrawing
capacity of the imidazolyl ring was improved by an
appropriate fusion with the pyrimidine system, the
charge demand of which was determined to be very
highly ranked.7
In this paper, we show how we increased the charge
demand of the imidazolyl function by introducing a
further azine-like nitrogen atom into the imidazole ring.
We here report the synthesis of bis(1H-1-phenyl-1,2,4-
triazol-5-yl)methane (11) and the results of the 13C NMR
study of the corresponding sodium salt in DMSO, which
was undertaken in order to determine the cXX value. In
analogy with our previous studies, we obtained the
shielding contribution Ai of the 1,2,4-triazol-5-yl sub-
stituent as the difference in the shifts of â-carbons in
styrene and 1H-1-phenyl-5-(â-styryl)-1,2,4-triazole (12).
Finally, we synthesized 1H-5-benzyl-1-phenyl-1,2,4-tria-
zole (13) in order to obtain the cPXh value from the 13C
shifts of the corresponding carbanion.
position using BuLi and reacted with MeI to give 1H-5-
methyl-1-phenyl-1,2,4-triazole (19). Condensation of
the latter with benzaldehyde in DMSO-NaOH afforded
12.
Finally, the benzyl derivative 13 was prepared accord-
ing to Scheme 5, following the same synthetic proce-
dure as that used for 11. The glyoxylate derivative
14 was reacted with phenylacetyl chloride in toluene
to give the triazolylester 20, which was hydrolyzed
under acidic conditions to afford the corresponding
acid 21. Subsequent decarboxylation at 200 °C with
Cu powder gave the pure benzyltriazole 13 in an 18%
overall yield. No attempt was made to optimize this yield
since the obtained amount was sufficient for our pur-
poses.
Resu lts
Syn th esis. To the best of our knowledge, all of the
compounds 11-13 were previously unknown in the
literature. Although 5-substituted triazoles are prepared
by means of well-known procedures starting from differ-
ent precursors,17 we found it difficult to apply one of them
to the preparation of the bis-triazolylmethyl skeleton
present in 11. We attempted various synthetic ap-
proaches involving either preformed triazolyl rings (which
we tried to link by inserting a methylene bridge) or open-
chain systems suitable for ring closure to triazoles
(Scheme 1).
P r ep a r a tion of Ca r ba n ion s. Carbanions 11- and 13-
were prepared in DMSO using dimsylsodium as a base.
We have previously documented elsewhere the reasons
for our choice of DMSO as a solvent.5-11 Given the well-
known properties of DMSO as a highly dissociating
medium and a good coordinating system for the sodium
cation, the sodium salts of our carbanions should have
the form of solvent-separated ion pairs or free ions. Under
these conditions, the effect of the sodium gegenion on
π-electron distribution in the anions should be minimized
or much reduced in comparison with other common
organic solvents. On the other hand, the many merits of
DMSO are somewhat offset by the instability of its
conjugate base above 60 °C, as well as by the fact that
its high melting point prevents low-temperature NMR
studies.
Unfortunately, none of these reactions gave the target
compound 11, which was prepared in three steps follow-
ing the procedure shown in Scheme 2. Ethyl R-amino-R-
(phenylhydrazono)glyoxylate (14) reacted with malonyl
chloride in toluene to give bis(1H-3-ethoxycarbonyl-1-
phenyl-1,2,4-triazol-5-yl)methane (15) in very poor yield
(4%). When acetonitrile was used under the same condi-
tions, although still low, the yield increased to 8%. No
alternative routes to 15 were successful in our hands.
Subsequent acidic hydrolysis using 20% HCl gave bis-
carboxylic acid 16 in very good yields. Decarboxylation
of 16 led to the symmetrically substituted methylene
derivative 11 in lower yields than expected because, in
addition to the desired product, bis-cyanoamide 17 was
obtained (Scheme 3). The side product 17 was isolated
and fully characterized.
NMR Sh ift Assign m en ts. The 13C and 15N shift
assignments in the neutral compounds 11 and 13, and
their corresponding anions 11- and 13-, are shown in
Table 2. We here provide a detailed interpretation of the
NMR data only in relation to those cases in which the
assignment was not straightforward.
(a ) 13C Sh ift s. 1H-1-Methyl-1,2,4-triazole was used
as a model comparative compound.18 The 13C shift as-
signments in the neutral compounds 11 and 13 were
The styryltriazole 12 was obtained according to Scheme
4. 1H-1-Phenyl-1,2,4-triazole (18) was lithiated at the five
(18) (a) Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy;
VCH: Weinheim, 1987; p 282. (b) Kalinowski, H. O.; Berger, S.; Braun,
S. Carbon-13 NMR Spectroscopy; J ohn Wiley & Sons: Chichester, 1988;
p 386.
(17) Temple, C., J r. Triazole 1,2,4. In The Chemistry of Heterocyclic
Compounds; Montgomery, J . A., Ed.; Wiley: New York, 1981; Vol. 37.

Electron-Withdrawing Power of the 1,2,4-Triazol-5-yl Substituent
J . Org. Chem., Vol. 64, No. 18, 1999 6759
Sch em e 2
Sch em e 3
their corresponding atoms in the neutrals. On the basis
of this, it is assumed that the chemical shift order of
the three nitrogen atoms of the neutrals is maintained
in the anions. Consequently, the pyrrolic nitrogen atom
remains at a higher field than the two pyridic nitrogen
atoms.
Geom etr ic Isom er ism in th e An ion s. Unlike all of
the benzylazoles we studied, the 13C NMR spectrum of
the benzyl anion 13- shows a single set of resonance in
DMSO at 27 °C. This result indicates either the presence
of a single species (E or Z geometric isomer) or a rapid
(on the NMR time scale) equilibration between the
interconverting isomers. The presence of geometric iso-
mers is due to the partial π character of the bond linking
the carbanionic carbon and the Cipso of either the hetero-
cycle or the phenyl group. The carbanion of 2-benzyl-N-
methylimidazole was the only one showing hindered
rotation along the bond linking the phenyl group at room
temperature. We explained this result in light of the poor
charge demand of the imidazolyl substituent in compari-
son with that of the phenyl group. In fact, the 13C spectra
of all of the other studied benzylazoles and benzylazines
(in which the heterocycle is a stronger electron-with-
drawing group than the phenyl substituent) provided
evidence of a mixture of both the E and Z isomers along
the other bond. We believe that only the (E)-13- isomer
Sch em e 4
I
Sch em e 5
based on coupling constants and the known hetero-
atom substituent effects operating in the heterocycle.
In the case of ambiguity, the spectrum was analyzed
completely and the discrimination based on the multi-
plicity of patterns and values of the long-range coupling
constants. In compound 13, the two ipso carbon atoms
have a very similar chemical shift value, and their
assignment may be exchanged. However, this uncertainty
does not introduce any significant error in the evaluation
was present in the present case for two reasons. First,
the charge demand of the triazolyl substituent is greater
than that of the benzoimidazolyl and close to those of the
highly ranked 2- and 4-pyridyl and 2-thiazolyl; all of the
corresponding benzyl anions exist as a mixture of the E
and Z isomers. It is therefore likely that the bond
between the carbanionic carbon and the heterocycle in
13- has a double-bond character due to the electron-
withdrawing property (cPXh) of the triazolyl substituent.
Second, the hypothetical planar (Z)-13- isomer would
have a severe steric hindering effect on the two phenyl
groups.
of cPXh
.
(b) 15N Sh ifts. The results of our previous investiga-
tions of aza-heterocycle-based anionic systems7,13,14a,15
have shown that both pyridine- and pyrrole-like nitrogen
atoms undergo high-field displacement when passing
from the neutrals to the anions because of the increase
in the π-electron density on the nitrogen atoms in the
anions. The shift assignments of these three nitrogen
atoms of the triazole ring in compounds 11 and 13 were
based on known nitrogen shielding in the unsubstituted
1H-1-methyl-1,2,4-triazole:19 in anions 11- and 13-, all
of the nitrogen atoms are shielded with respect to
(19) Witanowski, M.; Stefaniak, L.; Webb, G. A. In Annual Reports
on NMR Spectroscopy; Webb, G. A., Ed.; Academic Press: London,
1986; Vol. 18, p 445.

6760 J . Org. Chem., Vol. 64, No. 18, 1999
Abbotto et al.
Ta ble 2. 13Ca a n d 15Nb NMR Sh ifts (p p m ) of Bis(1H-1-p h en yl-1,2,4-tr ia zol-5-yl)m eth a n e (11), Its Con ju ga te Ca r ba n ion
(11-), 1H-5-Ben zyl-1-p h en yl-1,2,4-tr ia zole (13), a n d Its Con ju ga te Ca r ba n ion (13-) in DMSOc
triazole ring positions
compd N(1) N(2) C(3) N(4)
11 221.2 298.9 151.13 254.3 150.79 124.70 129.47 129.06 136.65
11- e 187.9 272.6 150.69 209.4 156.66 123.38 129.26 125.38 140.70
13
220.3 298.9 151.04 254.5 154.09 124.99 129.47 128.99 137.03f 128.46 128.41 126.61 136.17f
13- e 182.8 265.7 150.40 212.7 156.21 121.43 128.65 122.31 142.30 119.99 127.43 111.44 145.21
N-phenyl ring positions
phenyl ring positions
C(5)
ortho meta para ipso
ortho meta para
ipso
CH2/CH- 1J , Hzd
24.64
51.19
31.74
65.29
132.8
154.3
130.0
150.1
a
b
Relative to Me4Si (0.0 ppm). Relative to liquid NH3 (0.0 ppm), 380.23 from neat nitromethane. c 0.50 M solutions at 27 °C, unless
otherwise noted. Relative to the methylene or methine bridge. e 0.10 M. f Values can be exchanged.
d
Ta ble 3. Va r ia tion s of th e Loca l π-Electr on Den sities ∆qπ (m illielectr on s) for Ea ch ith P osition on Goin g fr om th e
Neu tr a l Bis(1H-1-p h en yl-1,2,4-tr ia zol-5-yl)m eth a n e (11) a n d 1H-5-Ben zyl-1-p h en yl-1,2,4-tr ia zole (13) to Th eir Con ju ga te
An ion s 11- a n d 13-, Resp ectivelya ,b
triazole ring positions
N-phenyl ring positions
phenyl ring positions
compd
N(1)
N(2)
C(3)
N(4)
C(5)
ortho
meta
para
ipso
ortho
53
meta
para
ipso
11-
13-
91
102
72
91
3
4
122
114
-37
-13
8
22
1
5
23
42
-25
-33
6
95
-56
a
b
Positive values correspond to an increment of π-electron density. Obtained from ∆qπ ) -(∆δ13C/160) and ∆qπ ) -(∆δ15N/366.34) for
carbon and nitrogen atoms.
Semiempirical calculations using the AM1 and the
PM3 SCF-MO Hamiltonian included in the MOPAC
package20 were made for the two geometric isomers of
anion 13-. The counterion was not included in the
calculation in order to mimic the nature of anionic species
in DMSO, in which they exist as solvent-separated or
free ions. Both the AM1 and PM3 computations pre-
dicted that the E isomer should be the most stable (by
4.6 and 4.5 kcal/mol, respectively). Since the semiem-
pirical approach is usually considered to be sufficiently
accurate in terms of geometry optimization, the computed
planar structure of the (E)-13- isomer (against the
nonplanarity of all of the three rings in the second
isomer) suggests that its predicted higher stability is
justified by its more efficient delocalization along the
entire system.
π-Ch a r ge Ma p p in g of th e An ion s a n d Ch a r ge
Dem a n d s of th e 1H-1,2,4-Tr ia zol-5-yl Su bstitu en t.
The variations in the local π-electron density of the
Like the above benzyl carbanion, the 13C NMR spec-
trum of the anion 11- shows a single set of resonances
in DMSO at 27 °C. However, unlike the benzyl deriva-
trigonal carbon and nitrogen atoms going from the
tive 13-, two strong electron-withdrawing groups
neutrals 11 and 13 to the conjugated anions 11- and 13-
compete equally in delocalizing the negative charge of
are shown in Table 3: these values can be calculated from
relationships 2 and 3, respectively. The π-electron densi-
ties qC of the central carbanionic carbon obtained from
relationship 1, and both of the aromatic rings, qHet and
the adjacent carbanionic center. As a result, the bond
between the carbanionic carbon and the heterocycle
has a lower double-bond character, and thus a lower
rotational barrier, than in 13-. It is therefore not pos-
qPh, in 11- and 13-, are shown in Table 4. Once the
sible to exclude either the hypothesis that one isomer
π-electron densities of the fragments constituting 11- and
predominates in the equilibrium (as in 13-) or that
13- are known, the total π-electron density qtot can be
suggesting the existence of rapid interconversion involv-
calculated by means of relationships 7 and 8 (Table 4).
ing a number of isomers [(E,E)-11-, (E,Z)-11-, and (Z,Z)-
qtot ) qC + 2qHet
(7)
11-].
However, it is reasonable to postulate that the inherent
qtot ) qC + qHet + qPh
(8)
instability of the (Z,Z)-11- isomer would prevent it from
being significantly present in the equilibrium. This
isomer clearly cannot exist as a planar system because
of the presence of the bulky phenyl rings. Both the AM1
and the PM3 calculations in the gas phase indicated a
pseudohelical structure in which none of the four rings
are in the same plane. The computed energy of this
system was found to be 5 kcal/mol larger than those of
isomers (E,E)-11- and (E,Z)-11-, which fall within the
0.5 kcal/mol range.
The excellent agreement of these empirically computed
values with the theoretical number of π-electrons of
systems 11- and 13- once again proves the highly reliable
nature of our approach and validates the computed
values given in Tables 3-5. Finally, Table 5 shows the
charge demands cPXh and cXX of the 1H-1-phenyl-1,2,4-
triazol-5-yl ring, which were calculated by applying
relationships 4 and 5 and using data from Table 4.
Details of the procedure have been previously reported.14
Discu ssion a n d Con clu sion
(20) MOPAC 6.0: Stewart, J . J . P. QCPE 455, 1990. All of the
calculations were made using the keywords AM1 or PM3, EF,
PRECISE, and CHARGE ) -1. The geometries were fully optimized
without any constraint, in the gas phase.
In this study, we prepared a new and interesting series
of 5-substituted triazoles 11-13 previously unknown in

Electron-Withdrawing Power of the 1,2,4-Triazol-5-yl Substituent
J . Org. Chem., Vol. 64, No. 18, 1999 6761
Ta ble 4. Exp er im en ta l π-Electr on Den sities q (electr on s)
for Con ju ga te An ion s 11- a n d 13- of
products arising from ring opening were detected in the
decarboxylation of monoacid 21, we believe that the
formation of the bis-cyanoamide 17 is particularly favored
by the high degree of stability probably provided by the
six-membered chelate arrangement 22.
Bis(1H-1-p h en yl-1,2,4-tr ia zol-5-yl)m eth a n e (11) a n d
1H-5-Ben zyl-1-p h en yl-1,2,4-tr ia zole (13)
a
b
c
d
compd
qHet
qPh
qC
qtot
11-
13-
12.267
12.361
1.429
1.432
25.96e
19.95f
6.157
a
π-Electron density resident on the triazole ring (including
N-phenyl ring): qHet ) 12 + Σ(∆qπ)triazole ring; data are taken from
b
Table 3. π-Electron density resident on the phenyl ring linked
to the carbanionic carbon: qPh ) 6 + Σ(∆qπ)phenyl ring; data are taken
from Table 3. c π-Electron density resident on the carbanionic
carbon, calculated applying relationship 1, using APh ) 13.00 (ref
6), Atriazole ) -1.45 (see Table 5) and chemical shift values reported
The use of our multinuclear NMR approach and charge
demand values provide interesting insights into the
electronic nature of the triazole system.23 First, the
existence of anion 13- as a single geometric isomer is the
consequence of the steric hindrance between the two
phenyl groups and the partial π-character of the bond
linking the carbanionic carbon and C(5) of the triazolyl
ring. Conversely, anion 11- may exist as a mixture of
the E,E and E,Z isomers. In addition, the cPXh value
(0.411) of this substituent is much higher than that of
the imidazolyl moiety, the charge demand of which ranks
low among the heterocycles so far investigated (Table 1).
It is reasonable to imagine that this increase in the
electron-withdrawing capacity of the triazolyl group is
mainly caused by the introduction of the third nitrogen
atom in the para position with respect to the carbanionic
center, a position suitable for delocalizing the charge.
In benzyl anion 13-, the three nitrogen atoms of the
heterocyclic moiety are almost equally involved in the
delocalization process, as each bears about 27% of the
negative charge of the N-phenyltriazolyl group. This
means that almost 80% of the delocalized negative charge
is hosted on the nitrogen atoms, a value that becomes
100% in the case of the symmetrically disubstituted
carbanion 11-. This last represents the first case among
the heterocycles we have studied in which all of the
negative charge delocalized from the carbanionic center
onto the heterocyclic ring is supported by the heteroatoms
without any significant involvement of the aromatic
carbon atoms. The lack of a negative π-charge resident
on the carbon atoms of anion 11- is exactly the average
result of increases and decreases in π-electron density
in comparison with the neutral precursor. It is interesting
to note that the phenyl ring bonded to N(1) of the
heterocycle in benzyl anion 13- participates in delocal-
izing the negative charge even though no resonance
structures can be written in which the negative charge
moves from the carbanionic atom to the phenyl group:
the π-electron density of the N-phenyl group increases
by 63 millielectrons from 13 to 13- (Table 3), which
represents about 20% of the cPXh of the N-phenyltriazolyl
group (Scheme 7).
d
in Table 2. Total π-electron density of the anionic system, to be
compared with the theoretical value of 26 and 20 π-electrons for
11- and 13-, respectively. e Calculated according to relationship
7. f Calculated according to relationship 8.
Ta ble 5. Sh ield in g Con tr ibu tion AX a n d Ch a r ge Dem a n d
of th e 1H-1-P h en yl-1,2,4-tr ia zol-5-yl
Su bstitu en t in Ca r ba n ion s 13- (cXPh) a n d 11- (cXX)
a
b
c
AX
-1.45
cPXh
cXX
0.411
0.286
a
Calculated from the difference between the shifts of â-carbons
in 1H-1-phenyl-5-(â-stiryl)-1,2,4-triazole (12) (111.75 ppm) and
styrene (113.2 ppm; ref 18b, p 161); see text. Calculated applying
b
relationship 5, with cPh ) qPh - 6; data are taken from Table 4.
c Calculated applying relationship 4; data are taken from Table
4.
Sch em e 6
the literature. The styryl and benzyl derivatives 12 and
13 were obtained following classic organic syntheses of
5-substituted triazoles, but no efficient synthetic routes
to the diactivated system 11 were found. It is worth
noting that the final product yields were significantly
different even though the same synthetic procedure was
applied (the condensation of 14 with the appropriate acyl
chloride, hydrolysis, and final decarboxylation).21 Al-
though alternative synthetic approaches to 11 were
explored, they were unfortunately unsuccessful. The
decarboxylation of the symmetrical bis-carboxyclic acid
16 unexpectedly occurred in much lower yields than that
of the corresponding benzyl derivative 21. The low yields
were caused by the preferred competitive ring opening
of the triazole rings of 16. The ring opening in the
pyrazole22 and isoxazole23 series to the corresponding
cyano derivatives under basic conditions are known. It
has also been reported24 that 4-phenyl-1,2,4-triazole
converts to phenylcyanamide when titrated with BuLi.
Since the carboxylic acids of the 1,2,4-triazole series are
known to be readily decarboxylated on heating but
otherwise stable,25 the behavior of the triazolyl ring in
16 seems to be unprecedented, although the cleavage of
16 can be interpreted on the basis of the reaction
mechanism shown in Scheme 6, in which N(4) may act
as a base promoting the reaction. This interpretation is
supported by the experimental observation23a that 3-car-
boxypyrazoles decarboxylate without decomposition when
heated at 250 °C; the presence of a base such as quinoline
is necessary in order to observe ring opening. Since no
This result is due to the high fraction of negative
charge delocalized onto the five-membered heterocycle
from the adjacent carbanionic carbon. The 2p-electron
pair of N(1) is inhibited for delocalization onto the
(21) It is possible that this different behavior is mainly due to the
different acidity of the methylene bridges in phenylacetyl chloride and
malonyl chloride. The primary amino group of 14 may be able to
deprotonate the latter, thus giving rise to a very reactive ketene
intermediate.
(22) Wakefield, B. J .; Wright, D. J . Adv. Heterocycl. Chem. 1979,
125, 147.
(23) (a) Fusco, R.; Rosnati, V.; Pagani, G. Tetrahedron Lett. 1966,
1739-1744. (b) Fusco, R.; Rosnati, V.; Pagani, G. Tetrahedron Lett.
1967, 4541-4544.

6762 J . Org. Chem., Vol. 64, No. 18, 1999
Abbotto et al.
the same solvent (80 mL). The reaction mixture was refluxed
for 3 h, treated with an aqueous solution (700 mL) of stoichio-
metric NaHCO3, and extracted with CH2Cl2 (4 × 400 mL).
After the mixture was washed with H2O and the combined
extracts were dried, the elimination of the solvent left a solid
(7.95 g) that was taken up with ethanol (20 mL) to give the
product as a white solid (0.81 g, 1.81 mmol, 8.4%): mp 158-
159 °C; recrystallization (EtOH) gave an analytical sample
with no increase in mp; 1H NMR (CDCl3) δ 7.47 (10 H, s), 4.44
(4 H, q), 4.39 (2 H, s), 1.38 (6 H, t); 1H NMR (DMSO-d6) δ
7.57-7.52 (6 H, m), 7.51-7.45 (4 H, m), 4.61 (2 H, s), 4.33 (4
H, q), 1.29 (6 H, t); 13C NMR (CDCl3) δ 159.5 (CdO), 154.3
(C-3), 151.4 (C-5), 135.9 (C ipso), 130.1 (C para), 129.6 (C
meta), 125.3 (C ortho), 62.0 (OCH2), 25.1 (bridge CH2), 14.2
(CH3). Anal. Calcd for C23H22N6O4: C, 61.87; H, 4.97; N, 18.82.
Found: C, 61.67; H, 4.93; N, 18.61.
Sch em e 7
heterocyclic ring but available for being pushed toward
the phenyl ring, thus counteracting and relaxing the high
charge strain on the small five-membered heterocycle.
In the bis-activated system 11-, the fraction of the
negative charge delocalized onto the heteroaromatic ring
is smaller. The three nitrogen atoms per ring are thus
capable of hosting the excess negative charge created
upon deprotonation, and no pushing effect from the
electron pair of the nitrogen atom to the N-phenyl ring
is observed.
In short, the 1,2,4-triazol-5-yl group is highly ranked
among the five- and six-membered aza-heterocycles. Its
electron-withdrawing capacity is much greater than that
of the weak 2-imidazolyl substituent because of the
presence of a second pyridine-like nitrogen in an ap-
propriate position. The determined charge demand is
higher than that of oxazole, comparable with that of
thiazole and pyridine, but still lower than that of diaz-
ines. We have shown that the -S- group in thiazolyl
derivatives is electronically and magnetically equivalent
to a -CHdCH- fragment, unlike the N(1) of imidazole,
which strongly donates π-charge to the ring.14a Our
results therefore converge toward the conclusion that the
electron-withdrawing nature of the second pyridine-like
nitrogen atom in 1,2,4-triazole almost exactly compen-
sates the donor property of the pyrrole-like atom, thus
making the triazolyl ring the electronic five-membered
‘equivalent’ of monoazines, such as pyridine.
B i s (1 H -3 -c a r b o x y -1 -p h e n y l -1 ,2 ,4 -t r i a z o l -5 -y l )-
m eth a n e (16). A suspension of 15 (1.26 g, 2.82 mmol) in 20%
HCl (30 mL) was refluxed for 1 h. After the suspension was
cooled to room temperature, half of the solvent was evaporated
under reduced pressure, and then the white precipitate was
collected, washed with water, and dried over CaCl2, overnight
at room temperature and then for a further 30 min at 70 °C,
to afford the product (1.00 g, 2.56 mmol, 90.8%). Recrystalli-
1
zation (H2O) gave an analytical sample: mp 202-203 °C; H
NMR (DMSO-d6) δ 7.49-7.54 (10 H, m), 4.59 (2 H, s). Anal.
Calcd for C19H14N6: C, 58.48; H, 3.61; N, 21.53. Found: C,
58.29; H, 3.88; N, 21.72.
Bis(1H-1-p h en yl-1,2,4-tr ia zol-5-yl)m eth a n e (11). Bis-
(1H-3-carboxy-1-phenyl-1,2,4-triazol-5-yl)methane (16) (0.51 g,
1.31 mmol) was heated in a Kugelrohr apparatus at 200 °C
under vacuum until carbon dioxide evolved. The resulting solid
(0.39 g) was submitted to a flash chromatography (MeOH-
AcOEt 1:9) on silica gel to give 11 as a light oil (81 mg, 0.27
mmol, 21%): 1H NMR (CDCl3) δ 7.96 (2 H, s), 7.40-7.50 (10
H, m), 4.31 (2 H, s); HRMS calcd for C17H14N6 302.1280, found
302.1250.
From the flash chromatography, a white byproduct was
isolated, which was identified as the pure bis-cyanoamide 17
1
(142 mg): mp 188-189 °C; H NMR (CDCl3) δ 7.00-7.50 (10
H, m), 6.50 (1 H, s), 5.52 (1 H, s), 4.90 (2 H, s); MS m/z 302
(M, 100), 77 (40); IR (Nujol) 2232 (CN). Anal. Calcd for
Exp er im en ta l Section
C
17H14N6: C, 67.54; H, 4.66; N, 27.80. Found: C, 67.17; H,
13C and 15N NMR spectra were recorded at 27 °C using a
Bruker AMX-500 spectrometer operating at respectively 125.70
and 50.75 MHz and using 0.50 M solutions in DMSO. The
spectral parameters and calibrations have been previously
reported.7 Anhydrous solvents were prepared by continuous
distillation over sodium sand, in the presence of benzophenone
and under nitrogen or argon, until the blue color of sodium
ketyl was permanent. Extracts were dried over Na2SO4. The
anions were prepared following a previously described proce-
dure.5 Melting points are uncorrected.
Eth yl r-Am in o-r-(p h en ylh yd r a zon o)glyoxyla te (14). A
mixture of concentrated ammonia (ca. 47 mmol, 3 mL) and
dioxane (8 mL) was added dropwise to a solution of ethyl
R-chloro-R-(phenylhydrazono)glyoxylate26 in dioxane (30 mL).
After the mixture was stirred for 8 h at room temperature,
NH4Cl was filtered off and the solution dried. The solvent was
removed under reduced pressure to give the crude product,
which was purified by crystallization with toluene (2.16 g, 10.4
mmol, 69.3%): mp 125 °C (lit.27 mp 128 °C); 1H NMR (CDCl3)
δ 7.23 (2 H, t), 7.09 (2 H, d), 6.88 (2 H, t), 6.64 (1 H, s), 4.51 (2
H, s), 4.34 (2 H, q), 1.38 (3 H, t).
5.01; N, 27.42.
1H-1-p h en yl-5-(â-styr yl)-1,2,4-tr ia zole (12). Aqueous 50%
NaOH (0.8 mL) was added dropwise to a solution of 1H-5-
methyl-1-phenyl-1,2,4-triazole28 (19) (0.50 g, 3.14 mmol) and
benzaldehyde (0.50 g, 4.71 mmol) in DMSO (5 mL). After the
mixture was stirred for 16 h at room temperature, another
aliquot of benzaldehyde (0.17 g) in DMSO (1 mL) was added.
After 40 h, the reaction mixture was poured into water (15
mL) and extracted with diethyl ether (4 × 10 mL); the organic
layer was then washed with water (20 mL). The solvent was
removed from the dried extracts to leave a yellowish oil (0.47
g) that was submitted to flash chromatography (AcOEt-
hexane, 2:1) on silica gel to afford a mixture of the product
and benzylic alcohol. The pure compound 12 (38 mg, 0.15
1
mmol, 5%) was obtained via its stifnate: mp 110-112 °C; H
NMR (CDCl3) δ 8.04 (1 H, s), 7.81 (1 H, d, J R,â ) 16.0), 7.30-
7.60 (10 H, m), 6.89 (1 H, d). Anal. Calcd for C16H13N3: C,
77.71; H, 5.30; N, 16.99. Found: C, 77.87; H, 5.29; N, 17.09.
1H -5-Be n zyl-3-e t h oxyca r b on yl-1-p h e n yl-1,2,4-t r ia z-
ole (20). A solution of phenylacetyl chloride (1.49 g, 9.65 mmol)
in toluene (8 mL) was added dropwise under a nitrogen
atmosphere to a hot solution of 14 (2.00 g, 9.65 mmol) in the
same solvent (32 mL); the immediate formation of a precipitate
was observed. The reaction mixture was refluxed for 4 h, and
then the dark precipitate filtered off. The organic layer was
washed with an aqueous solution of 5% NaOH (2 × 10 mL),
dried, and evaporated under reduced pressure to leave the
crude product as a light brown oil (2.24 g). The product was
Bis(1H -3-et h oxyca r b on yl-1-p h en yl-1,2,4-t r ia zol-5-yl)-
m eth a n e (15). A solution of malonyl chloride (3.06 g, 21.7
mmol) in acetonitrile (20 mL) was added dropwise under a
nitrogen atmosphere to a solution of 14 (9.00 g, 43.4 mmol) in
(24) Olofson, R. A.; Pepe, J . P. Tetrahedron Lett. 1979, 3129-3130.
(25) Polya, J . B. In Comprehensive Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 5.
(26) Fusco R., Romani, R. Gazz. Chim. Ital. 1946, 76, 419-438.
(27) Bowack, D. A.; Lapworth, A. J . Chem. Soc. 1905, 87, 1854-
1869.
(28) Micetich, R. G.; Spevak, P.; Hall, T. W.; Brins, B. K. Heterocycles
1985, 23, 1645-1649.

Electron-Withdrawing Power of the 1,2,4-Triazol-5-yl Substituent
J . Org. Chem., Vol. 64, No. 18, 1999 6763
purified by chromatography on silica gel (CH2Cl2-AcOEt 9:1)
to give 20 as a white solid (1.30 g, 4.23 mmol, 43.8%): mp
85-87 °C; H NMR (CDCl3) δ 7.05-7.50 (10 H, m, aromatic
protons), 4.51 (2 H, q, J ) 7.1), 4.20 (2 H, s,), 1.44 (3 H, t,
CH3). Anal. Calcd for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67.
Found: C, 70.47; H, 5.68; N, 13.45.
The distillation afforded the practically pure 13 (1.12 g, 4.76
mmol, 53.2%) as a white solid: mp ) 52-55 °C; 1H NMR
(CDCl3) δ 8.00 (1 H, s), 7.10-7.45 (10 H, m), 4.16 (2 H, s); 1H
NMR (DMSO-d6) 8.10 (1 H, s), 7.60-7.45 (5 H, m), 7.30-7.15
(3 H, m), 7.12-7.04 (2 H, m), 4.20 (2 H, s); MS (EI) m/z 235
(M•+; 51), 234 (100), 220 (31); HRMS m/z calcd for C15H13N3
235.1109, found 235.1107; calcd for C15H12N3 234.1031, found
234.1029.
1
1H-5-Ben zyl-3-ca r boxy-1-p h en yl-1,2,4-tr ia zole (21). A
suspension of 20 (3.68 g, 11.97 mmol) in H2SO4 (40%, 60 mL)
was refluxed for 2.5 h. After the suspension was cooled to room
temperature, water (30 mL) was added, and the formation of
a precipitate was observed. The white precipitate was collected,
washed with water, and dried over CaCl2, overnight at room
temperature, to afford the product (2.67 g, 9.56 mmol, 79.9%).
Recrystallization (EtOH-H2O) gave an analytical sample: mp
Ack n ow led gm en t. We would like to thank Dr.
Fabio Nicolosi for his help in the preparation of the
anion samples for NMR investigation.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H (CDCl3)
and 13C NMR (DMSO-d6) spectra of compound 11 and copies
of 1H (DMSO-d6) spectra (full and aromatic region) of com-
pound 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
81-82 °C; H NMR (CDCl3) δ 7.54-7.43 (3 H, m), 7.36-7.30
(2 H, m), 7.28-7.20 (3 H, m), 7.12-7.06 (2 H, m), 4.30 (2 H,
s). Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N, 15.04.
Found: C, 68.54; H, 4.50; N, 15.32.
1H-5-Ben zyl-1-p h en yl-1,2,4-tr ia zole (13). A mixture of 21
(2.50 g, 8.95 mmol) and electrolytic copper powder (2.5 g) was
heated in a Kugelrohr apparatus at 175 °C at 0.03 mmHg.
J O990687+