Substituent electrophilicities in the NMR spectra of barbituric derivatives

Article abstract of DOI:10.1002/mrc.2858

Comparison of the ¹H and ¹³ C NMR spectra of a series of substituted 5-benzylidene-N,N′-dimethylbarbituric acids (1) revealed chemical-shift variations of different centers that correlated with the theoretical electrophilicities or with the substituent electrophilic constant σ_ω, in an example of the usefulness of these DFT-based indices. Copyright

Full text of DOI:10.1002/mrc.2858

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Research Article
Received: 13 September 2011
Revised: 21 October 2011
Accepted: 25 October 2011
Published online in Wiley Online Library: 14 March 2012
(wileyonlinelibrary.com) DOI 10.1002/mrc.2858
Substituent electrophilicities in the NMR
spectra of barbituric derivatives
Marcos Caroli Rezendea* and Iriux Almodovara
1
Comparison of the H and 13 C NMR spectra of a series of substituted 5-benzylidene-N,N’-dimethylbarbituric acids (1) revealed
chemical-shift variations of different centers that correlated with the theoretical electrophilicities or with the substituent
electrophilic constant sv , in an example of the usefulness of these DFT-based indices. Copyright © 2012 John Wiley & Sons, Ltd.
Keywords: electrophilicity index; electrophilicity substituent constants; substituted 5-benzylidene-N,N’-dimethylbarbituric acids
Following Hammett’s approach, we postulated that constants so
Introduction
should provide an adequate measure of the electrophilic contribu-
tion of these substituents to other systems besides benzoic acids.[7]
Theoretical parameters derived from the density functional and
the hard-soft acid base theory have been increasingly employed
in the prediction and interpretation of a variety of chemical
processes. Among them, the concept of electrophilicity, originally
defined in a quantitative way by Parr et al.[1] has proved a valuable
tool for bridging a gap between theory and empirical data.[2–7]
Reports of correlations of theoretical electrophilicities with rates
and reactivities, and applications to the analysis of spectroscopic
data are found in the literature.[8–10]
In the present communication, we investigated the existence
of correlations of these DFT-based indices with NMR data from
a system, in which substituent electrophilicities are expected to
play an important role.
In the present communication, we decided to extend their use to
the analysis of the NMR data of substituted derivatives 1, showing
that this approach also applies to data from spectroscopic
measurements. The present report thus adds to the variety of
chemical processes for which theoretical electrophilic constants
so adequately describe the electronic contribution of substituents.
It also probes the limitations of this theoretical parameter. Like
Hammett’s original s constant, despite its applications to a
potentially unlimited number of processes, it may fail to describe
contributions where through-conjugation is present.
Experimental
Substituted5-benzylidene-1,3-dimethylbarbituricacids(1)(Scheme1)
constitute an interesting family of compounds, in which various
features of their NMR spectra should depend on the electrophilicity
of the X substituent. As an example, we had previously reported on
the equivalence of the N-methyl singlets in their 1H-NMR spectra,
which depended on the nature of substituent X.[11]
This long-range effect, observed previously for two derivatives
with substituents of widely different electrophilicities (p-NO2 and
p-NMe2),[7] should vary systematically with the electrophilicity of
X. Other features that also seemed to vary with the nature of X
were the 13 C chemical-shifts of the carbonyl groups at C-4 and
C-6, and the 13 C chemical-shift of C-5.
To investigate these variations in a systematic way, we prepared
a series of substituted N,N’-dimethylbarbituric derivatives 1 and
compared their 1H and 13 C NMR spectra, in search of correlations
between the spectral data and global or group electrophilicities,
obtained from theoretical calculations.
Preparation and spectral characterization of compounds 1
Melting points were recorded with an Electrothermal apparatus
and were not corrected. H and 13 C NMR spectra were recorded
1
on a Bruker Avance DRX-300 spectrometer, operating at 300.13
(1H) and 75.47 (13 C) MHz and employing 5-mm tubes, with average
concentrations of 30 mg.ml–1. CDCl3 was used as solvent, with
tetramethylsilane as internal reference. Typical running conditions
1
employed a spectral width of 4496.27 Hz for H and 19607.25 Hz
for 13 C, with 32768 (1H and 13 C) data points.
Compounds 1 were prepared by a standard Knoevenagel
condensation of equimolar amounts of N,N’-dimethylbarbituric
acid (Aldrich) and the corresponding substituted benzaldehyde.[7]
After refluxing the reagents in acetic acid for 2 h, product 1
crystallized out of the cooled solution, being washed with ether
and recrystallized with ethanol.
Substituent electrophilicities were calculated theoretically by
means of their electrophilic constants so, recently derived by us
from the Hammett-like Eqn (1), based on the global electrophilici-
ties oΒꢀX of substituted benzoic acids. By analogy with the classical
Hammett approach, Eqn (1) allowed the definition of electrophilic
substituent constants so for the X substituents, by arbitrarily
making ro = 1.[7]
In this way, the following 5-benzylidene-N,N’-dimethylbarbituric
derivatives were prepared: 5-(4-nitrobenzylidene)-N,N’-dimethyl-
barbituric acid (1a), m.p. 192–194 ꢂC, lit.[7], 193–195 ꢂC; 5-(3-
nitrobenzylidene)-N,N’-dimethylbarbituric acid (1b), m.p. 150–152 ꢂC;
*
Correspondence to: Marcos Caroli Rezende, Facultad de Química y Biología,
Universidad de Santiago, Casilla 40, Correo 33, Santiago, Chile. E-mail:
marcos.caroli@usach.cl
log oB-X=oBꢀH ¼ roꢁso
(1)
a Facultad de Química y Biología, Universidad de Santiago, Santiago, Chile
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Substituent electrophilicities
O
Theoretical calculations
All theoretical calculations employed the Gaussian03 package.[12]
Optimizations were performed with the hybrid B3LYP/6-31 G(d)
method. The chemical potential m and hardness ꢀ of each molecule
were calculated from Eqns (3) and (4), where EHOMO and ELUMO
are the HOMO and LUMO energies, respectively, employing
Koopmann’s approximation.[2]
Me
O
Me
O
2
5
N
N
1
3
4
6
m ¼ ðEHOMO þ ELUMOÞ=2
ꢀ ¼ ELUMO ꢀ EHOMO
(2)
(3)
X
The global electrophilicity of each molecule was calculated with
the aid of Eqn (4)[1]
1
Scheme 1. Structure of substituted 5-benzylidene-N,N’-dimethylbarbituric
derivatives 1, with the numbering of the barbituric ring atoms.
o ¼ m2=2ꢀ
(4)
5-(4-bromobenzylidene)-N,N’-dimethylbarbituric acid (1c), m.p.
172–175 ꢂC; 5-benzylidene-N,N’-dimethylbarbituric acid (1 d),
m.p. 156 ꢂC, lit.[7], 157–159 ꢂC; 5-(3-methoxybenzylidene)-N,N’-
dimethylbarbituric acid (1e), m.p. 135-136 ꢂC; 5-(4-methylthio-
benzylidene)-N,N’-dimethylbarbituric acid (1f), m.p. 156–159 ꢂC;
5-(4-methoxybenzylidene)-N,N’-dimethylbarbituric acid (1 g), m.p.
144–145 ꢂC, lit.[7], 143–145 ꢂC; 5-(4-dimethylaminobenzylidene)-N,
N’-dimethylbarbituric acid (1 h), m.p. 223–225 ꢂC, lit.[7], m.p.
224–226 ꢂC. 1H and 13 C NMR data, in CDCl3, of all derivatives
are given in Table 1.
Results and Discussion
1
The H and 13 C NMR spectra of compounds 1a–1 h are given in
Table 1.
In all proton spectra, the N-CH3 signals appeared as two
conspicuous singlets in the range d = 3.30–3.50 ppm. The 13 C
carbonyl signals of all barbituric derivatives appeared in the
range d = 151–152 (C-2) and d = 159–165 ppm (C-4 and C-6).
Assignments were based on the proximity of the benzylidene
group to the center under consideration. The benzylidene group
Table 1. 1H- and 13 C-NMR spectra of compounds 1a–1 h in CDCl3
Cpd (X)
1H-NMR/d
13 C-NMR/d
1a (4-NO2)
3.36 (s, 3 H, 3-NCH3); 3.45 (s, 3 H, 1-NCH3); 7.95 (d, 2 H,
J = 8.5 Hz, ArH meta to NO2); 8.29 (d, 2 H,
28.67(3-NCH3); 29.34 (1-NCH3); 120.87(C-5); 123.26 (2ArCH);
132.30(2ArCH); 139.21 (ArC); 149.05 (ArC-NO2); 150.99
(NCON); 155.45(CH-olef); 159.84 (C-4); 161.54 (C-6)
28.71(3-NCH3); 29.34 (1-NCH3); 120.27 (C-5); 126.33 (ArCH);
126.90 (ArCH); 129.26 (ArCH); 134.34(ArC); 137.81(ArCH);
147.98 (ArC-NO2); 151.03 (NCON); 155.47(CH-olef);
160.02 (C-4); 161.70 (C-6)
J = 8.5 Hz, ArH ortho to NO2); 8.58 (s, 1 H, C = CH)
3.37 (s, 3H, 3-NCH3); 3.44 (s, 3H, 1-NCH3); 7.64
(t, 1H, J = 8.0 Hz, ArH meta to NO2); 8.17 (m, 1H, ArH
ortho to NO2); 8.34 (m, 1H, ArH para to NO2); 8.56
(s, 1H, CH = C); 8.83 (m, 1H, ArH ortho to NO2)
3.36 (s, 3H, 3-NCH3); 3.41 (s, 3H, 1-NCH3); 7.59
(d, 2H, J = 10 Hz, ArH ortho to Br); 7.93
1b (3-NO2)
1c (4-Br)
1 d (H)
28.58 (3-NCH3); 29.24 (1-NCH3); 118.04 (C-5); 128.12 (ArC);
131.52 (ArC); 131.70 (2ArCH); 134.91 (2ArCH); 151.21
(NCON); 157.62 (CH olef); 160.42 (C-4); 162.36 (C-6).
28.56 (3-NCH3); 29.22 (1-NCH3); 117.66 (C-5); 128.36
(2ArCH); 132.79(ArC); 133.04 (ArCH); 133.54 (2ArCH);
151.38(NCON); 159.44(CH-olef); 160.46 (C-4); 162.61 (C-6)
28.61(3-NCH3); 29.25 (1-NCH3); 55.56 (OCH3); 117.76 (ArCH)
and (C-5); 119.53 (ArCH); 126.73 (ArCH); 129.31 (ArCH);
133.92 (ArC); 151.37 (NCON); 159.29 (ArC-OCH3) and
(CH-olef); 160.43 (C-4); 162.66 (C-6)
(d, 2H, J = 10 Hz, ArH meta to Br); 8.47 (s, 1H, CH = C)
3.35 (s, 3 H, 3-NCH3); 3.39 (s, 3 H, 1-NCH3); 7.44
(t, 1H, J = 7.5 Hz, ArH); 7.50 (q, 2H, J = 7.5 Hz, ArH);
8.03 (d, 2H, J = 7.5 Hz); 8.54 (s, 1H, C = CH)
1e (3-OMe)
3.37 (s, 3H, 3-NCH3); 3.42 (s, 3H, 1-NCH3); 3.86 (s, 3H, OCH3);
7.08 (m, 1H, ArH ortho to OCH3); 7.37 (t, 1H, J = 7.9 Hz,
ArH meta to OCH3); 7.57 (m, 1H, ArH para to OCH3);
7.56 (m, 1H, ArH ortho to OCH3); 8.17 (s, 1H, CH = C)
2.54 (s, 3H, SCH3); 3.38 (s, 3H, 3-NCH3); 3.41 (s, 3H, 1-NCH3);
7.27 (d, 2H, J = 8.7 Hz, ArH ortho to SCH3); 8.15
(d, 2H, J = 8.5 Hz, ArH meta to SCH3); 8.49 (s, 1H, CH = C)
3.39 (s, 3 H, 3-NCH3); 3.41 (s, 3H, 1-NCH3); 3.91 (s, 3H, OCH3),
6.98 (d, 2H, J = 8 Hz, ArH ortho to OMe); 8.32 (d, 2H,
J = 8 Hz, ArH meta to OMe); 8.52 (s, 1H, C = CH)
1f (4-SMe)
14.71 (SCH3); 28.55(3-NCH3); 29.22 (1-NCH3); 115.85 (C-5); 124.61
(2ArCH); 128.83(C-Ar); 135.08 (2 ArCH); 147.78 (ArC-S);
151.44 (NCON); 158.67 (CH-olef); 160.88 (C-4); 162.98 (C-6).
28.50(3-NCH3); 29.18 (1-NCH3); 55.75 (OCH3); 114.10 (2 ArCH);
114.42(C-5); 125.26(ArC); 138.08 (2ArCH); 151.55 (NCON);
159.02(CH-olef); 161.11 (C-4); 163.26 (C-6); 164.43 (ArC-OCH3)
1 g (4-OMe)
1 h (4-NMe2)
3.13 (s, 6H, N(CH3)2); 3.37 (s, 3H, 3-NCH3); 3.38 (s, 3H, 1-NCH3); 28.33(3-NCH3); 29.00 (1-NCH3); 40.18 (N(CH3)2); 109.76(C-5); 111.14
6.68 (d, 2H, J = 8 Hz, ArH ortho to NMe2); 8.39 (d, 2H,
J = 8 Hz, ArH meta to NMe2); 8.41 (s, 1H, C = CH)
(2ArCH); 121.18(C-Ar); 139.64 (2ArCH); 151.94(NCON);
154.52 (ArC-NMe2); 158.87(CH-olef); 161.74 (C-4); 164.13 (C-6)
Magn. Reson. Chem. 2012, 50, 266–270
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M. C. Rezende and I. Almodovar
tended to deshield the centers closer to it, and its field effect also
was dependent on its distance from the center, decreasing with
this distance. Thus, the effect of the benzylidene substituent on
the carbonyl signals decreased in the order C-2 < C-4 < C-6. In
the same way, its effect on the N-CH3 singlets was larger for
the more deshielded 1-NCH3 than for the 3-NCH3.
over the neighboring carbonyl groups at C-2, C-4 and C-6. Elec-
tron-donors, or nucleophilic substituents, should favor structure I,
whereas electron-acceptors, or electrophilic substituents, should
favor structure II. In the former, electron delocalization takes place
on two independent moieties of the molecule, as shown in
Scheme 2-I so that the upper part of the barbituric ring is ‘switched
off’ from the lower part and the benzylidene group. In structure II,
the benzylidene group no longer interacts with the barbituric ring,
and the latter system is ‘switched off’ from the benzylidene group.
Thus, the electrophilicity of the X substituent determines the
degree of ‘coupling’ between the benzylidene and the barbituric
fragments.
Table 2 lists the chemical-shift differences, in Hz, between the
1
N-methyl singlets (ΔdN-Me) in the H NMR spectra and between
the C-4 and C-6 carbonyl signals (ΔdC = O) in the 13 C NMR spectra
of compounds 1a–1 h. It also includes the 13 C chemical-shifts
of the C-5 atom in these derivatives. As can be seen, these data
vary with the substituent X. The table also includes the global
electrophilicities of these compounds (o), calculated with the
aid of Eqn 4. A final set of theoretical values included in the table
is the electrophilicity constant so for each substituent, derived
from the Hammett-like Eqn (1), applied to substituted benzoic
acids.[7]
These considerations are reflected in some trends of the 1H NMR
spectra of derivatives 1, highlighted in Table 2. As a consequence of
the ‘uncoupling’ of the two moieties by nucleophilic substituents in
structure I, the N-methyl protons become increasingly equivalent
with the increased nucleophilicity of X, as part of a symmetric
H3CN-CO-NCH3 fragment. This symmetry is reduced in structure II
because of delocalization with the C-4 and C-6 carbonyl groups,
which are not equivalent.
The dependence of ΔdN-Me and of ΔdC=O on X may be
understood with the aid of structures I and II that contribute to
the resonance hybrid of 1 (Scheme 2).
Structure I depicts the delocalization of the electrons of the X
substituent over the benzylidene fragment and the carbonyl
groups at C-4 and C-6 of the barbituric ring. Structure II depicts
the delocalization of the nitrogen electrons at N-1 and N-3
A similar argument applies to the variation of the ΔdC=O values
in the 13 C NMR spectra of 1. Nucleophilic substituents favor a less
symmetric moiety involving the C-4 and C-6 carbonyl groups in
structure I and, accordingly, greater ΔdC=O values. When the
benzylidene group is ‘switched off’ from the barbituric ring, by
the effect of electrophilic substituents in structure II, the carbonyl
groups at C-4 and C-6 become more equivalent because of the
greater symmetry of the barbituric moiety.
The above interpretations may be summarized by invoking the
interaction between N-1/N-3 and C-4/C-6. The former, as part of a
symmetric fragment, tend to be equivalent, if no perturbation by
the rest of the molecule takes place. The latter, being closer to
the benzylidene group, tend to be unequivalent, if ‘switched
off’ from the symmetric H3CN-CO-NCH3 fragment. Both situations
correspond to structure I. When the two groups interact, as in
structure II, N-1/N-3 become less equivalent, by the influence of
C-4/C-6, and C-4/C-6 become more equivalent, by the influence
of N-1/N-3.
Table 2. Chemical-shift differences between the N-Me singlets
(ΔdN-Me) and between the C-4 and C-6 carbonyl signals (ΔdC = O) of
substituted derivatives 1
X
ΔdN-Me/Hz ΔdC=O/Hz
d
C-5/ppm oa/kcal.mol-1
sob
p-NO2 (a)
m-NO2 (b)
p-Br (c)
36
28
20
16
20
12
8
128
126
146
161
167
157
161
179
120.87
120.27
118.04
117.66
117.76
115.85
114.42
109.76
84.90
74.23
66.6
0.29
0.25
0.07
H (d)
61.62
60.31
60.47
55.68
49.30
0.00
m-OMe (e)
p-SMe (f)
p-OMe (g)
p-NMe2 (h)
- 0.07
0.08
- 0.11
- 0.28
The hypothesis that the chemical-shift difference ΔdN-Me
should depend on the molecular electrophilicity was tested by
plotting ΔdN-Me against the global electrophilicity o of molecules
1a–1 h (Fig. 1).
4
aGlobal electrophilicities of compounds 1a–1 h b Values of substituent
electrophilicity constants taken from reference [7]
.
δ−
δ−
O
O
CH3
CH3
δ+
N
δ+
CH3
CH3
δ+
N
δ+
N
N
δ−
δ−
δ−
δ−
O
O
O
O
δ−
δ+
X
X
I
II
Scheme 2. Structures that contribute to the resonance hybrid of 1, with an indication of how the X substituent affects conjugation and electron-
delocalization between different fragments of the molecule.
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Substituent electrophilicities
40
The observed linear relationship (R = 0.96) yielded a value of
r = 0.37, indicating that the substituent contribution to the
global electrophilicity of compounds 1 is less significant than its
contribution to the electrophilicity of substituted benzoic acids.
The general applicability of the electrophilic substituent
constants so is verified in a plot of the 13 C chemical-shift
differences ΔdC=O of Table 2 against so (Fig. 3).
4-NO2
35
30
3-NO2
25
3-OMe
20
4-Br
The shift difference ΔdC=O varied with the substituent constant
H
15
10
5
s
o according to relationship (7),
4-SMe
ΔdC¼O ¼ 155:8 ꢀ 95:9 so ð N ¼ 8; R ¼ 0:96; SD ¼ 5:9Þ (7)
4-OMe
4-NMe2
50 55
thus showing that this theoretical parameter correlates reasonably
well with the experimental spectral variations. In agreement
with the above discussion based on the canonical structures of
Scheme 2, ΔdC=O decreases with an increased value of the electro-
philic constant so,, which reflects an increased contribution of
canonical structure II to the resonance hybrid.
0
45
60
65
70
75
80
85
90
ω / kcal.mol-1
Figure 1. Variation of the chemical-shift differences ΔdN-Me with the
electrophilicity o of compounds 1. Correlation coefficient R = 0.97.
The above examples thus add to the list of data from
chemical processes, which present good correlations with global
or substituent electrophilicities, calculated from purely theoretical
considerations. The Hammett-like approach defined by Eqn (1)[7]
also is validated by the spectral trends exhibited by system 1.
The general applicability of the theoretical so constants,
confirmed by the particular plots of Figs 2 and 3, should not
be a surprise, in view of the good correlations observed be-
tween so and Hammett’s s constants.[7] This observation also
anticipates poorer performances of the theoretical so constant,
when applied to experimental data that correlate poorly with
Hammett’s s values. Kinetic data related with compounds 1
provide examples of this. Rate and equilibrium constants for the
addition of amines to substituted 5-benzylidene barbituric acids
have been measured in different solvents.[13,14] The obtained
kinetic constants were found to correlate with s+ constants,
showing that the reactivity of the electrophilic double-bond of
compounds 1 depended more strongly on the nucleophilicity of
the X substituent than might be expected from their s values. This
is a result of the well-known exalted through-resonance between
para-substituents X and a conjugated double bond (Scheme 3)
and should be observed in a comparison of the chemical shifts of
the olefinic carbon atoms of substituted derivatives 1.
The chemical-shift difference between the N-Me singlets of 1
thus correlates with the global electrophilicity of the molecule
o by means of Eqn (5).
ΔdNꢀMe ¼ ꢀ40:7 þ 0:91o ðN ¼ 8; R ¼ 0:97; SD ¼ 2:7Þ (5)
As expected from the above analysis, the difference ΔdN-Me
increases with the molecular electrophilicity, which increasingly
favors contribution by the canonical structure II to the resonance
hybrid.
The postulated validity of the electrophilic substituent constants
so to a system different from substituted benzoic acids was tested
next. According to this theoretical Hammett-like approach, a linear
relationship of the form of (1) should exist between the global
electrophilicities oX of substituted derivatives 1 and the previously
determined set of electrophilic constants so. This is expressed by
Eqn (6),
log oX=oH ¼ rꢁsw
(6)
where the subscripts refer to the X substituent of 1 and r is a
proportionality constant, which measures how the substituent
electrophilicities affect the global molecular electrophilicity of the
barbituric derivatives. Figure 2 is a plot of log oX against so.
Figure 4 is a plot of the C-5 chemical shifts of derivatives 1 listed
in Table 2, against the electrophilic substituent constants so.
1.95
1.90
1.85
1.80
1.75
1.70
1.65
4-NO2
180
4-NMe2
3-OMe
170
160
150
140
130
120
3-NO2
H
4-Br
4-SMe
4-OMe
H
3-OMe
4-SMe
4-Br
4-OMe
4-NO2
3-NO2
4-NMe2
-0.2
-0.3
-0.1
0.0
0.1
0.2
0.3
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
σω
σω
Figure 2. Linear relationship between the logarithm of the electrophilicity
oX of compounds 1 and the electrophilic substituent constants so.
Correlation coefficient R = 0.96.
Figure 3. Variation of the 13 C chemical shift differences ΔdC = O with the
electrophilic substituent constants so of compounds 1. Correlation
coefficient R = 0.96.
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