Nuclear magnetic resonance and molecular modeling study of exocyclic carbon-carbon double bond polarization in benzylidene barbiturates

Article abstract of DOI:10.1016/j.molstruc.2012.09.021

Benzylidene barbiturates are important materials for the synthesis of heterocyclic compounds with potential for the development of new drugs. The reactivity of benzylidene barbiturates is mainly controlled by their exocyclic carbon-carbon double bond. In this work, the exocyclic double bond polarization was estimated experimentally by NMR and correlated with the Hammett σ values of the aromatic ring substituents and the molecular modeling calculated atomic charge difference. It is demonstrated that carbon chemical shift differences and NBO charge differences can be used to predict their reactivity.

Full text of DOI:10.1016/j.molstruc.2012.09.021

Journal of Molecular Structure 1034 (2013) 310–317
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Nuclear magnetic resonance and molecular modeling study of exocyclic
carbon–carbon double bond polarization in benzylidene barbiturates
⇑
J. Daniel Figueroa-Villar , Andreia A. Vieira
Medicinal Chemistry Group, Department of Chemistry, Military Institute of Engineering, Praça General Tibúrcio 80, 22290-270 Rio de Janeiro, Brazil
h i g h l i g h t s
"
"
"
"
"
Synthesis, NMR analysis and molecular modeling of benzylidene barbiturates.
13C chemical shift difference correlates well with Hammett rp and rm
Solvent interaction and conformation influence calculated NBO atomic charges.
13C chemical shift differences correlates well with NBO charge differences.
Benzylidene barbiturates polarization defines their reactivity.
.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2012
Received in revised form 4 September 2012
Accepted 5 September 2012
Available online 11 October 2012
Benzylidene barbiturates are important materials for the synthesis of heterocyclic compounds with
potential for the development of new drugs. The reactivity of benzylidene barbiturates is mainly con-
trolled by their exocyclic carbon–carbon double bond. In this work, the exocyclic double bond polariza-
tion was estimated experimentally by NMR and correlated with the Hammett
r values of the aromatic
ring substituents and the molecular modeling calculated atomic charge difference. It is demonstrated
that carbon chemical shift differences and NBO charge differences can be used to predict their reactivity.
Ó 2012 Elsevier B.V. All rights reserved.
Keywords:
Benzylidene barbiturates
Double bond polarization
Atomic charge difference
Chemical shift difference
1. Introduction
experimental processes, being confirmed by the bond lengths,
bond dipole moment are and rotational barriers [1–6].
Bond polarization, an important feature for many reactions and
molecular properties [1–8], occurs when the two linked atoms
have different electronegativity, a process that leads to differences
in atomic charge and electronic density. The bond polarization is
~
l, expressed as
One of the important methods for polarization prediction is the
nuclear magnetic resonance, being based on coupling constants,
parameters which are certainly related with the bond length and
its electronic density. The double bond length is certainly related
to its polarization, as well as its rotation capacity, as it was shown
for 2-(tetrahydropyrimidin-2(1H)-ylidene)-N1,N3-diphenylmalo-
namide [2]. Similar results were also found in polymers [7]. Inter-
estingly, one factor that is not usually applied to describe bond
polarization is the chemical shift difference between the two
atoms directly involver on the bond.
One example of molecules with polarized carbon–carbon dou-
ble bond is the benzylidene barbiturates (Fig. 1), of simple prepa-
ration [9–18], and used as important intermediates for the
synthesis of new heterocyclic compounds [10,11,19–25]. The exo-
cyclic carbon–carbon double bond polarization of benzylidene bar-
biturates is promoted by its conjugation with the two carbonyl
groups from the barbituric acid ring and with the benzene aro-
matic ring, which effect certainly can be altered by the electronic
properties and the position of the R2 groups.
observed in terms of the bond dipole moment
~
~
l
¼
D
ed
v
; where
D
e is the atomic charge difference, d is the dis-
~
tance between the two atoms and
with the bond axis.
v
is the unitary vector parallel
The polarization of carbon–carbon double bonds is a very
important defining molecular reactivity factor, being directly in-
volved on the type of mechanism, like reduction, cycloaddition
and Michael addition reactions. The carbon–carbon double bond
polarization depends on the electronic characteristics of the double
bond substituents, which have a stronger influence on the p-bond.
This information has been studied by molecular modeling and
⇑
Corresponding author. Tel.: +55 21 2546 7057; fax: +55 21 2546 7059.
E-mail address: figueroa@ime.eb.br (J.D. Figueroa-Villar).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.09.021

J.D. Figueroa-Villar, A.A. Vieira / Journal of Molecular Structure 1034 (2013) 310–317
311
2. Results and discussion
Benzylidene barbiturates of this work were prepared by con-
densation of benzaldehydes (1–24) with barbituric acid (25) in
95% ethanol and reflux for 30 min (Fig. 3 and Table 1) [10]. When
these reactions were carried out under reflux with salicylaldehyde
(8), 5-hydroxysalicyladehyde (18) and 5-chlorosalicylaldehyde
(20), the obtained products were the respective 5-(2,4-dioxo-
2,3,4,5-tetrahydro-1H-chromeno[2,3-d]pyrimidin-5-yl)pyrimidine-
2,4,6(1H,3H,5H)-triones 33a, 43a and 45a [18]. In order to prepare
their respective benzylidene barbiturates 33, 43 and 45, the
reaction was carried out at 25 °C, leading to the orange cationic
intermediates 33b, 43b and 45b, which were converted to the
respective benzylidene barbiturates by dissolution in polar sol-
vents like EtOH, MeOH and DMSO (Fig. 4) [18]. Due to the strong
electron withdrawing effect of the nitro group, the 5-nitrosalicylal-
dehyde (21) was able to react with barbituric acid under reflux to
afford the respective benzylidene barbiturate (46) without the for-
mation of the respective orange cationic intermediate. All products
(26–49) were purified by recrystallization in ethanol, leading to
yields from 50% to 99%.
Fig. 1. Benzylidene barbiturates and their polarization.
The main reactivity of benzylidene barbiturates occurs at the
C7–C5 double bond conjugated with two carbonyl groups of the
barbituric acid ring, which mainly leads to Michael or cycloaddi-
tion reactions, as shown in Fig. 2 [10,11,19–25].
The electrophilicity parameters of the benzylidene barbiturates
have been shown to be correlated with their reactivity as Michael
acceptors and were used to predict other reactions [21]. Recently,
the electrophilicity effect of the aromatic ring substituents on
N,N-dimethylbenzylidene barbiturates was correlated with 1H
and 13C NMR chemical shift differences of the N-methyl protons
and between the C4 and C6 carbonyl signals of the barbituric ring,
which also displayed correlation with the calculated substituents
electrophilic constants rx [26].
In our previous works with benzylidene barbiturates we
observed that their reactivity is related to the polarization of
their C7–C5 double bond [10,18,19,23,25], and considered that
this polarization depends on the electronic properties and posi-
tion of the aromatic ring substitutents. Because carbon–carbon
double bond polarization must be related to the involved atoms
charge difference, in this work we investigated and proved the
possibility of using the experimental difference of 13C NMR
Since most of these benzylidene barbiturates were previously
reported [9–18], in this work their structures were completely
characterized by 1H and 13C NMR spectroscopy. The 13C NMR spec-
tra were used to obtain the C7–C5 difference in chemical shift
(DdC7–C5) (Table 1), a parameter that we considered directly corre-
lated with the exocyclic double bond polarization of the benzyli-
dene barbiturates. In order to confirm these assignments, all
compounds were submitted to APT and GATED decoupled 13C
NMR spectroscopy (GATED), which display the multiplicity and
the short and long range couplings for each carbon atom. In all
GATED spectra, the signal of C5 appears as single doublet with
2JCH from 3.0 to 4.5 Hz, while C7 is displayed as doublet of broad
C7–C5 chemical shift (
Bond Orbital) atomic charges
substitution constants (rp and
D
dC7–C5), the calculated NBO (Natural
eC7–C5 and the Hammett
m) to describe the polarization
(
D
)
r
of benzylidene barbiturates.
Fig. 2. Michael-type reactions with benzylidene barbiturates.

312
J.D. Figueroa-Villar, A.A. Vieira / Journal of Molecular Structure 1034 (2013) 310–317
Fig. 3. Synthesis of benzylidene barbiturates (the R groups are identified in Table 1).
Table 1
Type and position of R groups, Hammett sigma values, chemical shifts (ppm) of C5, C7 and their chemical shift difference
DdC7–C5 for all the prepared benzylidene barbiturates.
Compound
R
rp or rm
dC5
dC7
DdC7–C5
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
11-OH
11-OMe
11-Me
H
11-Cl
11-Br
11-NO2
9-OH
9-OMe
9-OEt
9-Br
9-Cl
9-NO2
9-F
10-OMe
10-Br
10-NO2
9,12-diOH
9,10-diOMe
9-OH-12-Cl
9-OH-12-NO2
9-Cl-12-NO2
9-Br-11,12-OCH2O–
9-OEt-10,12-diNO2
ꢁ0.37
114.1
115.5
117.7
119.0
119.7
119.8
122.3
117.2
118.5
111.8
121.5
121.8
120.5
121.4
119.2
120.5
121.9
116.5
116.4
118.7
120.0
123.8
119.3
123.8
155.5
154.9
155.3
154.8
152.9
153.0
151.3
150.4
150.0
150.0
152.0
149.8
152.4
145.8
154.7
152.5
148.7
148.7
150.2
148.3
147.2
146.9
151.0
144.4
41.4
39.4
37.6
35.8
33.2
33.2
29.0
33.2
31.5
38.2
30.5
28.0
31.9
24.4
35.5
32.0
26.8
32.2
33.8
23.6
27.2
23.1
31.7
20.6
ꢁ0.27
ꢁ0.17
0.00
0.2
0.23
0.78
–
–
–
–
–
–
–
0.12
0.39
0.71
–
–
–
–
–
–
–
multiplets (dbm), doublet of triplets (dt), double doublet of dou-
blets (ddd) or doublet of doublets (dd), depending on the presence
of substituents at the ortho position. In all benzylidene barbiturates
each carbon. In Table 2 only the NBO charges are shown because
these are the only atomic charge difference values that correlate
well with chemical shifts.
1
the initial doublet of C7 corresponds to JCH from 150 to 160 Hz.
The initial correlation of the chemical shift difference (
DdC7–C5)
The correlation of the chemical shift difference C7–C5 with the
rp and rm constants is shown in Fig. 5, displaying a r2 value of
0.9632. The r2 values, which refer to the fraction of variance ex-
plained by the used model, indicates the quality of correlation of
the tested data. When r2 closer to 1.0, especially when superior
to 0.9 the correlation is of good quality. However, for more com-
plex cases, r2 values above 0.7 are also good results. As expected,
for the para- and meta-substituted benzylidene barbiturates (16–
21 and 40–41), the C7–C5 double bond polarization is controlled
by the R groups’ properties, confirming that the chemical shift dif-
ference is a predictive polarization parameter. As expected, this re-
sult confirms that polarization of the C7–C5 double bond is
controlled by the R groups electronic properties.
with the NBO atomic charge difference ( eC7–C5) was carried out
D
with the p-substituted benzylidene barbiturates, leading to
r2 = 0.8833 (0.0038x + 0.1172). Interestingly, the elimination of
p-hydroxybenzylidene barbiturate (26) from the graphic lead to
r2 = 0.9427, indicating that the calculated
D
eC7–C5 of compound
26 was affecting the correlation with
DdC7–C5 because 26 was the
only hydroxylated para-substituted benzylidene barbiturate. The
OH group contributes to formation of hydrogen bonds as H-donor
and H-acceptor, but in this case, because all NMR spectra were
determined in DMSO-d6 solution, we considered the participation
of the OH group only as H-donor. Because the NBO charges were
calculated in vacuum, it was clear that the interaction of
compound 26 with the solvent would change the NBO atomic
charges of C7 and C5. Accordingly, the atomic charges of 26
were re-calculated with formation of H-bond with DMSO (26-
The other parameter that is related to bond polarization is the
atomic charge difference. The charges of C5 and C7 were calculated
in vacuum by molecular modeling using the B3LYP method and the
6-311++Gꢀꢀ basis set using the Spartan 04 program [27], which
afforded the electrostatic, Mulliken and natural charges (NBO) for
DMSO), leading to
DdC7–C5–D
eC7–C5 correlation with r2 = 0.9632
(y = 0.0047x + 0.0889). The reason for this type of calculation was
based on the effect of the hydrogen bonding of the OH group with

J.D. Figueroa-Villar, A.A. Vieira / Journal of Molecular Structure 1034 (2013) 310–317
313
Fig. 4. Preparation of ortho-hydroxybenzylidene barbiturates.
solvents, indicating that solvent–molecule interactions, depending
on their nature, can be included in the molecular modeling calcu-
lations. The other R groups were not involved in important solvent
interaction, for example, the atomic charge calculation including
electrostatic interaction of DMSO the nitro group of 32 did not lead
to important improvement of r2.
In order to correlate the calculated atomic charge differences
with
DdC7–C5 the second analysis was conducted with the p- and
m-substituted benzylidene barbiturates (compounds 26–32 and
40–42), using only the NBO results, which confirmed a good corre-
lation with chemical shift differences, as shown in Fig.
8
(r2 = 0.9244, y = 0.004x + 0.1158).
Fig. 5. Linear correlation of the C7–C5 chemical shift difference (
Hammett substitution constants of R in para- and meta-substituted benzylidene
barbiturates (rp and m) (26–32 and 40–42).
DdC7–C5) with the
As expected from Figs. 5 and 7, there is a good correlation be-
tween the natural charge difference
(DeC7–C5) and rp + rm
r
(r2 = 0.9558, y = ꢁ20.359x + 5.2944), as shown in Fig. 8. These re-
sults indicate that for m- and p-benzylidene barbiturates any one
of the three parameters rp, DeC7–C5 and DdC7–C5 can be used to esti-
DMSO on the electronic properties of the hydroxyl group, a process
that is confirmed on the data of Table 2, line 3, showing a 0.016 e
mate and compare their polarization. As mentioned before, the cal-
culated Mulliken and electrostatic charges do not correlate well
with the chemical shift differences, displaying r2 values lower than
0.5 (graphics not shown).
The Hammett constants can be applied to substitution groups
located at the para and meta position of aromatic rings, and could
not be used with benzylidene barbiturates with R groups at the
ortho position, like 33–39 and 43–49, simply because the ortho
difference between the
DeC7–C5 of both conditions. It is clear that
the p-OH group is involved on intermolecular interactions, mainly
by the formation of a hydrogen bond between the OH group of 26
and the oxygen of DMSO, which is only an H-acceptor, as shown in
Fig. 6. This process affects the electronic properties of the OH group
and effects the C7–C5 double bond polarization. This result
confirms that electronic properties of R groups can be affected by
Table 2
Calculated NBO atomic charges of C5, C7 and the charge differences for all the benzylidene barbiturates.
Compound
NC5
NC7
D
eC7–C5
Compound
NC5
NC7
0.007
DeC7–C5
26
ꢁ0.276
ꢁ0.290
ꢁ0.278
ꢁ0.270
ꢁ0.264
ꢁ0.261
ꢁ0.260
ꢁ0.240
ꢁ0.263
ꢁ0.265
ꢁ0.268
ꢁ0.270
ꢁ0.251
ꢁ0.253
ꢁ0.009
ꢁ0.007
ꢁ0.009
ꢁ0.007
ꢁ0.007
ꢁ0.012
ꢁ0.012
ꢁ0.021
ꢁ0.027
ꢁ0.017
ꢁ0.015
ꢁ0.014
ꢁ0.023
ꢁ0.010
0.267
0.283
0.269
0.263
0.257
0.249
0.248
0.219
0.236
0.248
0.253
0.256
0.228
0.243
38
39
40
41
ꢁ0.259
ꢁ0.254
ꢁ0.263
ꢁ0.255
ꢁ0.247
ꢁ0.266
ꢁ0.267
ꢁ0.266
ꢁ0.257
ꢁ0.245
ꢁ0.237
ꢁ0.263
ꢁ0.239
0.266
0.232
0.259
0.244
0.230
0.245
0.250
0.253
0.235
0.216
0.217
0.236
0.206
26 + DMSO
27
28
29
30
31
32
33-syn
33-anti
34
35
36
ꢁ0.022
ꢁ0.004
ꢁ0.011
ꢁ0.017
ꢁ0.021
ꢁ0.017
ꢁ0.013
ꢁ0.022
ꢁ0.029
ꢁ0.020
ꢁ0.027
ꢁ0.033
42
43-syn
43-anti
44
45
46
47
48
49
37

314
J.D. Figueroa-Villar, A.A. Vieira / Journal of Molecular Structure 1034 (2013) 310–317
benzylidene barbiturates there are compounds with OH groups
at the ortho position, which different conformations (syn and anti,
Fig. 9) atomic charges were studied by molecular modeling. Fig. 9
shows the conformations syn and anti for compounds 33 and 43.
On the syn conformation the O–H bond is oriented towards the
barbituric acid ring, a condition that leads to strong repulsion of
OH with H7, while the anti conformations have the O–H bond at
the opposite position, with a lower repulsion with H10.
Interestingly, this conformational variation leads to
ferences of 0.012 and 0.005 for compounds 33 and 43, respectively,
and in all cases, the best correlations between eC7–C5 and dC7–C5
or rp rm are better with the 33-anti and 43-anti, which display
r2 = 0.7664 (y = 0.0031 + 0.1474) (Fig. 10).
DeC7–C5 dif-
Fig. 6. Hydrogen bonding of the OH group of 26 with DMSO.
D
D
+
The analysis of Fig. 10 results indicate that the major differences
with the average correlation occur for the ortho-substituted com-
pounds, suggesting that these differences are due to their confor-
mational difference as compared with the m- and p-benzylidene
barbiturates. For example, in the case of compound 38 the ortho
position of the nitro group clearly leads to a non-planar conforma-
tion (Fig. 11a) with a dihedral angle H7–C7–C8–C9 of 63°, different
from the planar conformation of the isomer with the nitro group at
the para position (32), which is completely planar (Fig. 11b) (dihe-
dral angle 0°). These conformational differences, confirmed by the
molecular modeling, explain the out of line behavior of compounds
like 38, because the loss of planarity decreases the conjugation of
the aromatic ring with the C5–C7 double bond. A similar case
was only observed with the o-chlorinated benzylidene barbiturate
(36), which possesses a H7–C7–C8–C9 dihedral angle of 32°, much
greater than that of the o-brominated analogue (35), in which pos-
sess a 0° dihedral angle. Despite Br is much bulkier than Cl, molec-
ular modeling shows that the o-brominated compound is perfectly
plane, because the C–Br bond distance (1.920 Å) is 9% longer than
the C–Cl bond distance (1.788 Å). All the other o-substituted ben-
zylidene barbiturates (33–36) display H7–C7–C8–C9 dihedral an-
gles from 1° to 0° due to conjugation with the C7–C5 double
bond and the barbituric ring.
Fig. 7. Correlation of the natural charge difference C7–C5 (electrons) (
DeC7–C5) with
the chemical shift difference C5–C7 ( dC7–C5) for the para-substituted, compounds
D
26–32, and the meta-substituted compounds, 40–42.
Fig. 8. Correlation of the natural charge difference C7–C5 (electrons) with the R
Hammett substitution constants of the meta- and para-benzylidene barbiturates
(rp + rp) for compounds 26–32 and 40–43.
position of substituents, which include steric effects, are not appro-
priate for the Hammett approach [28]. Therefore, to expand the
description of the C7–C5 bond polarization it was tested the corre-
lation of the calculated natural charges and the chemical shift dif-
ferences with all the studied benzylidene barbiturates. Even using
the different conformations of all the benzylidene barbiturates,
there is a clear correlation between the charge difference (
DeC7–C5)
Fig. 10. Correlation of the natural charge difference C7–C5 (
for all the benzylidene barbiturates (33–49).
DeC7–C5) versus DdC7–C5
and the chemical shift difference ( dC7–C5). Among the studied
D
Fig. 9. Different conformations of the benzylidene barbiturates 33 and 43.

J.D. Figueroa-Villar, A.A. Vieira / Journal of Molecular Structure 1034 (2013) 310–317
315
Fig. 11. Conformations for compounds 32 and 38 calculated by molecular modeling.
Fig. 12. Mechanistic scheme of the reaction of isocyanides with N,N0-dimethylbenzylidene barbiturates.
These results confirm that it is possible to estimate the C7–C5
bond polarization with dC7–C5 for any benzylidene barbiturate
because there is a reasonable correlation between eC5–C7 and
dC5–C7 for all the tested compounds (r2 0.7664). This information
is important since the polarization of the benzylidene barbiturates
controls their reactivity. For example, it has been shown that
N,N0-dimethylated benzylidene barbiturates can react with isocya-
nides by Michael-type addition reactions, as well as by [1 + 4]
cycloaddition processes [19,24], as shown in Fig. 12.
If the C5–C7 double bond polarization of benzylidene barbitu-
rate is high, the Michael-type addition reaction is favored. On the
other hand, if the bond polarization is lower, the [2 + 4] cycloaddi-
tion should be expected.
NMR spectra were obtained with 2048 transients using a 45° pulse
and a delay time (d1) of 5.0 s. All samples were also analyzed using
the GATED 13C NMR (d1 of 20.0 s and 8192 transients) in order to
confirm the carbons multiplicity and HETCOR to confirm the H–C
correlation.
D
D
D
3.2. General synthetic procedure
In a 200 mL round bottom flask, 1.54 g (12 mmol) of barbituric
acid (25) were dissolved in 50 mL of hot distilled water. To this
solution it was added a solution of the aldehyde (1–24) (12 mmol)
in 10 mL of 95% ethanol. The mixture was kept under reflux and
agitation for 30 min with the formation of a precipitate. The solid
was separated by filtration and recrystallized in methanol to obtain
the pure form of the respective benzylidene barbiturate, in yields
from 90% to 99%. The data for the synthesis of the benzylidene bar-
biturates 26–49 is shown in Table 3, and the specific synthetic pro-
cedure data for the four new compounds is described below.
3. Experimental
3.1. NMR analysis
The 1H and 13C NMH spectra were obtained in a Varian UNITY-
300 spectrometer, using DMSO-d6 as solvent. The DMSO-d5 resid-
ual protons (d 2.49) and the deuterated carbon signal (d 39.5) were
used as relative chemical shift references. All samples were pre-
pared in 5 mm NMR tubes with 20 mg of the respective benzyli-
dene barbiturate dissolved in 0.6 mL of DMSO-d6. All spectra
were recorded as 20.0 0.1 °C. For the 1H NMR spectra, there were
used 16 transients, a 30° pulse and a delay (d1) of 0.5 s. The 13C
3.2.1. Synthesis of 5-(2,5-dihydroxybenzylidene)pyrimidine-
2.4.6(1H.3H.5H)-trione (43)
There were used 1.66 g of 2,5-dihydroxybenzaldehyde (18) and
stirring at 20–22 °C, leading to 1.79 g of compound 43 as a gray so-
lid. M.p. 390 °C (decomposition); 60% yield. Using a 30 °C reaction
temperature, it was obtained the cationic intermediate 43b as a
violet solid in 50% yield, which was completely converted to

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J.D. Figueroa-Villar, A.A. Vieira / Journal of Molecular Structure 1034 (2013) 310–317
Table 3
3.2.5. Molecular modeling
Experimental data of benzylidene barbiturates synthesis.
All the benzylidene barbiturates had their structures minimized
using the B3LYP system, with the 6-311++Gꢀꢀ basis set with the
Spartan 04 program [27]. The calculations were prepared to pro-
vide the electrostatic, Mulliken and NBO (natural charge) atomic
charges of all the atoms, as well as the simulated 13C NMR spectra
of each molecule.
The interaction of compound 26 with the solvent (DMSO) was
established before the calculation, and the different conformations
of the ortho-substituted benzylidene barbiturates were also previ-
ously prepared to the energy minimization process, and these con-
formations were maintained to the final results.
Reagent
No.
Product
No.
Yield (%)
MP (°C)
Amount (g)
Amount (g)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1.46
1.63
1.44
1.27
1.68
2.22
1.81
3.55
1.63
1.80
2.22
1.68
1.81
1.47
1.63
2.22
1.81
1.38
1.61
0.39
2.00
2.23
2.74
2.70
26
27
28
29
30
31
32
33a
34
35
36
37
38
39
40
41
42
43a
44
45
46
47
48
49
2.65
2.77
2.54
2.60
2.95
3.34
3.10
4.63
2.71
2.90
3.20
2.90
2.91
2.81
2.77
3.20
3.00
2.12
2.58
0.44
3.16
3.37
3.90
4.08
95
95
92
99
98
94
99
90
92
93
90
97
93
96
94
90
95
98
88
84
95
95
96
90
234 (dec.)
265–268
281–283
274–276
287–289
252–254
282–284
283 (dec.)
266–268
260–262
265–267
242–243
290–292
270–272
262–264
278–279
270–273
390 (dec.)
206–207
281–282
258–260
390–393
260 (dec.)
232–233
4. Conclusion
The 13C NMR chemical shift difference between the two carbon
atoms of the exocyclic double bond of benzylidene barbiturates
(DdC7–C5) is an experimental parameter directly correlated with
the bond polarization. This information is confirmed by the corre-
lation between the chemical shift differences with the para and
meta Hammett sigma values of the aromatic ring substituents (rp
and
r
m) (r2 0.96), as well as the
D
dC7–C5 correlation with the NBO
charge difference between the two carbon atoms (
D
eC7–C5), which
is also very appropriate for the para- and meta-substituted com-
pounds (r2 0.92). The correlation of Mulliken and electrostatic
compound 43 by solution in polar solvents (EtOH or MeOH); 1H
NMR (DMSO-d6) d 11.27 (1H,s), 11.13 (1H,s), 9.98 (1H,s), 8.61
(1H,s), 7.72 (1H,s), 6.87 (1H,d), 6.78 (1H,d); 13C NMR (DMSO-d6)
d 163.9 (s), 161.8 (s), 152.7 (s), 150.4 (s), 150.3 (s), 148.7 (d),
123.3 (d), 120.0 (d), 117.7 (d), 116.5 (s), 116.1 (s). Elemental
analysis: calcd. for C11H8N2O5: C 53.23, H 3.25, N 11.29; found: C
53.63, H 3.45, N 10.97.
charge differences with
DdC7–C5 or rp and rm indicate that they
are not efficient to estimate bond polarization. It was also shown
that substitution groups with stronger electron donating capacity
lead to greater bond polarization, a condition that promotes
Michael-type addition reactions, while electron withdrawing
groups lead to lower polarization and must facilitate [1 + 4] and
[2 + 4] cycloadditions.
It was shown that conformational changes and intermolecular
interaction process modify the atomic charge differences on the
C7–C5 carbon–carbon double bond, this being a process that must
be monitored in order to establish better correlations between
3.2.2. Synthesis of 5-(2-hydroxy-5-nitrobenzylidene)pyrimidine-
2.4.6(1H.3H.5H)-trione (46)
There were used 2.00 g (12 mmol) of 2-hydroxy-5-nitrobenzal-
dehyde (21), leading to 3.16 g of compound 46 as a yellow solid.
M.p. 258–260 °C; 95% yield; 1H NMR (DMSO-d6) d 12.2 (1H,s),
11.44 (1H,s), 11.31 (1H,s), 9.08 (1H,d), 8.44 (1H,s), 8.25 (1H,dd),
7.11 (1H,d); 13C NMR (DMSO-d6) d 163.7 (s), 163.0 (s), 161.6 (s),
150.1 (s), 147.2 (d), 138.7 (s), 128.8 (d), 128.6 (d), 125.3 (s),
120.0 (s), 116.0 (d). Elemental analysis: calcd. for C11H7N3O6: C
47.66, H 2.55, N 15.16; found: C 46.81, H 2.72, N 14.86.
atomic charge differences and the tested parameters (rp and
as well as ( dC7–C5).
rm),
D
The benzylidene barbiturates with substituents at the ortho po-
sition display a less planar conformation when compared with the
meta- and para-substituted compounds. Because meta- and para-
substituted benzylidene barbiturates display planar structures,
there exists a better conjugation between the aromatic ring and
the exocyclic double bond of the barbituric acid ring. Therefore,
it is also clear that ortho-substitution leads to lower double bond
polarization, a condition that should be better for [1 + 4] cycloaddi-
tion reactions.
3.2.3. Synthesis of 5-(2-chloro-5-nitrobenzylidene)pyrimidine-
2.4.6(1H.3H.5H)-trione (47)
There were used 2.23 g (12 mmol) of 2-chloro-5-nitrobenzalde-
hyde (22), leading to 3.37 g of compound 47 as a crème solid. M.p.
390–393 °C; 95% yield; 1H NMR (DMSO-d6) d 11.57 (1H,s), 11.38
(1H,s), 8.57 (1H,s), 8.26 (1H,d), 8.19 (1H,s), 7.83 (1H,d); 13C
NMR (DMSO-d6) d 162.3 (s), 161.2 (s), 150.3 (s), 146.9 (d), 145.6
(s), 139.5 (s), 134.4 (s), 130.5 (d), 126.6 (d), 125.8 (d), 123.8 (s). Ele-
mental analysis: calcd. for C11H6N3O5Cl: C 44.69, H 2.04, N 14.21;
found: C 45.23, H 2.21, N 14.44.
Despite the differences in conformations and planarity, the cor-
relation of
DdC7–C5 with DeC7–C5 to estimate the exocyclic double
bond polarization for the diverse type of tested compounds gives
reasonable results (r2 = 0.7664), indicating that both, chemical shift
differences (DdC5–C7) and calculated charge differences (DeC7–C5),
are appropriate to estimate the relative polarization of all types
of benzylidene barbiturates.
Acknowledgments
3.2.4. Synthesis of 5-(2-ethoxy-3,5-dinitrobenzylidene)pyrimidine-
2.4.6(1H.3H.5H)-trione (49)
We thank the financial support provided by CNPq, CAPES/Pró-
defesa, FAPERJ and INBEB.
There were used 2.70 g of 2-ethoxy-3,5-dinitrobenzaldehyde
(24), leading to 4.08 g of product 49 as a white solid. M.p. 232–
233 °C; 90% yield; 1H NMR (DMSO-d6) d 11.60 (1H,s), 11.44
(1H,s), 8.90 (2H,s), 8.36 (1H,s), 4.15 (2H,q), 1.28 (3H,t); 13C NMR
(DMSO-d6) d 162.0 (s), 161.0 (s), 155.5 (s), 150.0 (s), 144.4 (d),
142.8 (s), 141.0 (s), 131.0 (s), 130.0 (d), 123.8 (s), 121.5 (d). Ele-
mental analysis: calcd. for C13H9N4O8: C 44.71, H 2.60, N 16.04;
found: C 43.89, H 2.67, N 15.89.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2012.
09.021.

J.D. Figueroa-Villar, A.A. Vieira / Journal of Molecular Structure 1034 (2013) 310–317
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