Linear free-energy relationships applied to the 13C NMR chemical shifts in 4-substituted N-[1-(pyridine-3- and -4-yl)ethylidene]anilines

Article abstract of DOI:10.1002/jhet.1752

Two series of 4-substituted N-[1-(pyridine-3- and -4-yl)ethylidene]anilines have been synthesized using different methods of conventional and microwave-assisted synthesis, and linear free-energy relationships have been applied to the ¹³C NMR chemical shifts of the carbon atoms of interest. The substituent-induced chemical shifts have been analyzed using single substituent parameter and dual substituent parameter methods. The presented correlations describe satisfactorily the field and resonance substituent effects having similar contributions for C1 and the azomethine carbon, with exception of the carbon atom in para position to the substituent X. In both series, negative ρ values have been found for C1' atom (reverse substituent effect). Quantum chemical calculations of the optimized geometries at MP2/6-31G++(d,p) level, together with ¹³C NMR chemical shifts, give a better insight into the influence of the molecular conformation on the transmission of electronic substituent effects. The comparison of correlation results for different series of imines with phenyl, 4-nitrophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl group attached at the azomethine carbon with the results for 4-substituted N-[1-(pyridine-3- and -4-yl)ethylidene]anilines for the same substituent set (X) indicates that a combination of the influences of electronic effects of the substituent X and the π₁-unit can be described as a sensitive balance of different resonance structures.

Full text of DOI:10.1002/jhet.1752

13
Month 2014
Linear Free-Energy Relationships Applied to the C NMR Chemical
Shifts in 4-Substituted N-[1-(Pyridine-3- and -4-yl)ethylidene]anilines
a
b
c
c
d
b
*
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Milica Rancić , Nemanja Trisović , Milos Milcić , Maja Jovanović , Bratislav Jovanović and Aleksandar Marinković
a
ꢀ
Faculty of Forestry Science, University of Belgrade, Kneza Viseslava 1, 11030 Belgrade, Serbia
bFaculty of Technology and Metallurgy, University of Belgrade, Post Office Box 3503, Karnegijeva 4, 11120 Belgrade, Serbia
cFaculty of Chemistry, University of Belgrade, Studentski trg 3-5, 11000 Belgrade, Serbia
d
ꢀ
Institute for Chemistry, Technology and Metallurgy, University of Belgrade, Njegoseva 12, 11000 Belgrade, Serbia
*
E-mail: marinko@tmf.bg.ac.rs
Additional Supporting Information may be found in the online version of this article.
Received March 5, 2012
DOI 10.1002/jhet.1752
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Two series of 4-substituted N-[1-(pyridine-3- and -4-yl)ethylidene]anilines have been synthesized using
different methods of conventional and microwave-assisted synthesis, and linear free-energy relationships
have been applied to the 13C NMR chemical shifts of the carbon atoms of interest. The substituent-induced
chemical shifts have been analyzed using single substituent parameter and dual substituent parameter
methods. The presented correlations describe satisfactorily the field and resonance substituent effects having
similar contributions for C1 and the azomethine carbon, with exception of the carbon atom in para position
to the substituent X. In both series, negative r values have been found for C10 atom (reverse substituent
effect). Quantum chemical calculations of the optimized geometries at MP2/6-31G++(d,p) level, together
with 13C NMR chemical shifts, give a better insight into the influence of the molecular conformation on
the transmission of electronic substituent effects. The comparison of correlation results for different series
of imines with phenyl, 4-nitrophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl group attached at the azomethine
carbon with the results for 4-substituted N-[1-(pyridine-3- and -4-yl)ethylidene]anilines for the same
substituent set (X) indicates that a combination of the influences of electronic effects of the substituent X
and the p1-unit can be described as a sensitive balance of different resonance structures.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
widely investigated. 4-Substituted N-[1-(pyridine-3- and -4-yl)
ethylidene]anilines are important intermediates in the synthesis
of pharmacologically active triazoles [11], triazolines [12],
and aminoalkylpyridine derivatives that are useful as anticon-
vulsants, excitatory amino acid inhibitors, and N-methyl-D-
aspartate (NMDA) sigma receptor antagonists [13]. The
investigation of the similarities and differences between struc-
turally related aldimines and ketimines may contribute to a bet-
ter understanding of the charge generation at a molecular level
and design of new materials for optical purposes.
The present investigation has been focused on the
study of cross-interaction effects of the benzylidene and
aniline substituents (Fig. 1). Two series of 4-substituted
N-[1-(pyridine-3- and -4-yl)ethylidene]anilines have been
synthesized using different methods of conventional and
microwave-assisted synthesis (Fig. 1), and linear free-
energy relationships (LFERs) have been applied to the
13C NMR chemical shifts of the carbon atom of interest
with the aim to obtain an insight into the factors, which
influence charge distribution in the molecules.
Azomethines have emerged in the past two decades as
promising materials for applications in photonics and
optoelectronics. Low molecular weight compounds and
polymers with the C═N unit are investigated as bent-core
and rod-shaped liquid crystals [1–3], and depending on
the chemical structure, they exhibit one mesophase or
rich polymorphism [4,5]. The favorable properties of
azomethines are mostly governed by extended p-conjugated
system, in which the C═N unit is contained, and are sensitive
even to subtle changes in it. In this context, investigations of
molecular structures of benzylidene anilines have indicated
that changes in substituents in both aniline and benzylidene
rings largely affect the overall electronic distribution and
conformation of the molecules [6–8]. The molecular structures
of N-(phenyl substituted)pyridine-2-, -3-, and -4-aldimines
have been studied in detail [9,10]. On the other side,
ketimines, in which hydrogen atom of the azomethine group
is replaced by an aliphatic or aryl group, have not been
© 2014 HeteroCorporation

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M. Rancić, N. Trisović, M. Milcić, M. Jovanović, B. Jovanović, and A. Marinković
Vol 000
Figure 1. Structures of the 4-substituted N-[1-(pyridine-3-yl)ethylidene]anilines (series 6; X═H, N(CH3)2, OH, OCH3, CH3, Cl, Br, and COCH3) and 4-
substituted N-[1-(pyridine-4-yl)ethylidene]anilines (series 7; X═H, N(CH3)2, OH, OCH3, CH3, F, Cl, Br, COOCH3, and COCH3) with labels of the car-
bon atoms and p-resonance units.
Substituent effects on the 13C NMR shifts of the carbon atoms
of interest in the synthesized compounds have been compared
with the correlation results obtained for different imines: N-ben-
zylideneanilines [14] (series 1), N-[(4-nitrophenyl)-methylene]
anilines (series 2) [14], N-(substituted phenyl)pyridine-2-, -3-,
and -4-aldimines (series 3, 4, and 5, respectively) [9,10].
The 13C NMR chemical shifts are frequently used for the
study of the transmission of electronic effects of substitu-
ents in organic molecules [8–10,14–16]. Analysis of 13C
NMR substituent-induced chemical shifts (SCS) is based
on the principles of LFERs using the single substituent
parameter (SSP) (eq. 1) and dual substituent parameter
(DSP) (eq. 2) equations in the following form:
The transmission of polar and resonance electronic effects
from the substituent X on the aniline ring of both series to the
carbon atoms of interest has been studied by using eqs. 1 and
2. The contributions from both electronic substituent effects
and the other factors determining chemical shifts have
been discussed. MP2/6-31G++(d,p) theoretical calculations
indicated nonplanar E configuration around the C═N bond
in the investigated compounds. The most stable conforma-
tions of N-[1-(pyridine-3-yl)ethylidene]aniline and N-[1-
(pyridine-4-yl)ethylidene]aniline are presented in Figure 2.
RESULTS AND DISCUSSION
s ¼ rs þ h
s ¼ rFF þ rRR þ h
(1)
(2)
The investigation of the effect of the aniline substituent X
on the sensitivity of the polarization of the C═N group to the
benzylidene substituent Y has been the main goal of the
presented study. The contributions of both substituent effects
have been investigated separately. To obtain a better insight
into the transmission of electronic effects of the substituent
X on the aniline ring, an extensive analysis of 13C NMR
chemical shifts of the carbon atoms of interest has been
performed. The chemical shifts of the corresponding carbon
atoms are given in Table 1 in terms of the SCS relative to the
parent compounds.
The general conclusion derived from the data in Table 1
is that all substituents on the aniline ring of the ketimine
molecule influence via their electronic effects (polar/induc-
tive and resonance) the value of the SCS of C1, C7, and
C10 atoms. Electron-donor substituents induce downfield
shifts, whereas electron acceptors induce upfield shifts of
where s is substituent-dependent value SCS, r is the
proportionality constant reflecting the sensitivity of the
13C NMR chemical shifts to the substituent effects, s is
the corresponding substituent constant, and h is the inter-
cept describing unsubstituted member of the series.
Equation 1 attributes the observed substituent effect to an
additive blend of polar and resonance effects given as
corresponding s values. In the DSP (eq. 2), SCS are corre-
lated by a linear combination of field (F) and resonance
scales (R) depending on the electronic demand of the atom
under examination. The calculated values of r, rF, and rR
are relative measures of the transmission of overall, polar
(inductive/field), and resonance effects, respectively, through
the investigated system.
Figure 2. Optimized structures of the N-[1-(pyridine-3-yl)ethylidene]anilines (a) and N-[1-(pyridine-4-yl)ethylidene]anilines (b) obtained by the use of
MP2 method.
Journal of Heterocyclic Chemistry
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Month 2014
Spectra–Structure Correlations of 4-Substituted N-[1-(Pyridine-3-
and -4-yl)ethylidene]anilines
Table 1
SCS values of carbon atoms in substituted N-[1-(pyridine-3-yl)ethylidene]anilines (6) and N-[1-(pyridine-4-yl)ethylidene]anilines (7).
N-[1-(pyridine-3-yl)ethylidene]anilines N-[1-(pyridine-4-yl)ethylidene]anilines
0
134.417
0.874
0.547
0.292
0.310
—
– 0.109
– 0.109
—
0
145.617
0.783
0.601
0.383
0.328
0.005
ꢀ0.163
ꢀ0.163
ꢀ0.362
ꢀ0.398
X
H
SCSaC7
SCSC1
151.059
ꢀ7.411
ꢀ2.512
ꢀ1.256
ꢀ1.274
—
2.622
2.622
—
SCSC1
SCSC7
SCSC1
150.877
ꢀ11.614
ꢀ8.667
ꢀ7.174
4.533
ꢀ3.787
ꢀ1.201
ꢀ1.578
ꢀ0.334
ꢀ0.414
SCSC1
164.005
ꢀ1.475
ꢀ0.655
ꢀ0.447
ꢀ0.054
—
0.933
1.002
—
164.515
ꢀ1.839
ꢀ0.819
ꢀ0.237
ꢀ0.115
0.856
1.056
1.020
2.185
2.185
N(CH3)2
OH
OCH3
CH3
F
Cl
Br
COOCH3
COCH3
1.368
4.941
– 0.315
a13C NMR chemical shifts (in ppm) expressed relative to the unsubstituted compound; downfield shifts are positive.
C1 and C7 atoms. The chemical shift of C10 atom exhibits
the opposite behavior. Among factors contributing to the
differences in SCS values, the molecular geometry might
play an important role, which arises from an out-of-plane
rotation of both pyridyl and phenyl rings for the torsion
angles θC and θN (Fig. 1), respectively, and this task has
been studied on the basis of the results obtained from
theoretical calculation at MP2/6-31G++(d,p) level. The
definite molecular geometry has been defined and discussed
as a consequence of the particular transmission modes of the
substituent electronic effects.
To analyze substituent influence on SCS of the carbon
atoms of interest, the LFER in the form of SSP equation with
the s substituent constant [17] has been applied to ketimines,
and the correlation results are presented in Table 2.
Additionally, results of the correlations for series of
structurally similar imines and the ones for ketimines that
include the following common set of substituents: COOCH3,
Cl, Br, H, CH3, OCH3, and N(CH3)2 are presented in Table 3.
From the observed r values for all carbons, it is obvious
that the chemical shifts of C1, C7, and C10 atoms show
different susceptibility to electronic substituent effects. The
chemical shift of C1 shows increased susceptibility to
substituent effects, and somewhat lower sensitivity of C7
atom is observed. This phenomenon undoubtedly indicates
a considerable contribution of extended resonance interac-
tion of electron-donor substituents from the aniline ring to
C1 atom. Reverse substituent effects are observed for C10
atom in all imines and ketimines studied. The negative sign
of the proportionality constant means reverse behavior, that
is, the SCS values of C10 decrease, although the electron-
accepting ability of the substituent X, given by s, increases.
Although SSP analysis (eq. 1) uses s parameter as an
additive blend of inductive and resonance substituent
effect, it provides a satisfactory description of transmission
of substituent effects. To measure the separate contribu-
tions of polar (inductive/field) and resonance effects of
the substituent X, the regression analysis according to eq.
2, DSP analysis, with the F and R substituent constants
[17], has been performed, and the results of the best fits
for two series of ketimines are presented in Table 4, and
together for common series of substituents for former and
imine series (1–5) are given in Table 5. The correlation
results obtained with various combinations of sI and soR,
sR, sþR, using the equation s = rIsI + rRsR + h, are of lower
statistical values and are not presented. The principal
deficiency of correlations with sR arises from the hybrid
natures of this substituent constant, that is, field is included
Table 2
Correlations of the SCS values for investigated ketimines (6 and 7) with SSP eq. 1.
Series
Atom
r
h
r
F
s
n
6
7
C1
C7
C10
C1
C7
C10
9.29(ꢁ0.40)
2.32(ꢁ0.16)
ꢀ0.95(ꢁ0.06)
9.13(ꢁ0.68)
3.09(ꢁ0.21)
ꢀ0.98(ꢁ0.07)
0.56(ꢁ0.16)
0.30(ꢁ0.06)
0.10(ꢁ0.02)
0.80(ꢁ0.26)
0.44(ꢁ0.09)
0.08(ꢁ0.02)
0.995
0.986
0.988
0.979
0.981
0.980
545
214
244
183
209
216
0.43
0.17
0.07
0.82
0.26
0.08
8
10
r, correlation coefficient; F, Fisher test of significance; s, standard deviation; n, number of data included in the correlation.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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M. Rancić, N. Trisović, M. Milcić, M. Jovanović, B. Jovanović, and A. Marinković
Vol 000
Table 3
Correlations of the SCS values for investigated imines (1–5) and ketimines (6 and 7) with SSP eq. 1.
Series
Atom
r
h
r
F
s
n
Ref.
1
2
3
4
5
6
7
C1
C7
C10
C1
C7
C10
C1
C7
C10
C1
C7
C10
C1
C7
C10
C1
C7
C10
C1
C7
C10
10.77(ꢁ1.41)
4.50(ꢁ0.26)
ꢀ1.13(ꢁ0.11)
10.75(ꢁ1.50)
6.79(ꢁ0.73)
ꢀ1.32(ꢁ0.06)
13.78(ꢁ1.49)
5.35(ꢁ0.41)
ꢀ1.02(ꢁ0.10)
11.74(ꢁ1.42)
5.23(ꢁ0.33)
ꢀ1.01(ꢁ0.09)
13.06(ꢁ1.53)
5.80(ꢁ0.45)
ꢀ1.25(ꢁ0.09)
9.39(ꢁ0.42)
2.30(ꢁ0.18)
ꢀ0.93(ꢁ0.05)
9.598(ꢁ0.71)
2.98(ꢁ0.28)
ꢀ0.97(ꢁ0.09)
2.09(ꢁ068)
0.63(ꢁ0.13)
0.26(ꢁ0.05)
2.31(ꢁ0.73)
0.61(ꢁ0.36)
0.10(ꢁ0.03)
0.64(ꢁ0.63)
0.44(ꢁ0.16)
0.18(ꢁ0.04)
1.81(ꢁ0.56)
0.37(ꢁ0.13)
0.18(ꢁ0.04)
1.93(ꢁ0.62)
0.67(ꢁ0.18)
0.04(ꢁ0.04)
0.52(ꢁ0.17)
0.31(ꢁ0.07)
0.09(ꢁ0.02)
4.33(ꢁ0.30)
0.43(ꢁ0.12)
0.08(ꢁ0.04)
0.960
0.992
0.977
0.954
0.972
0.995
0.972
0.986
0.978
0.965
0.990
0.980
0.968
0.985
0.988
0.995
0.986
0.992
0.986
0.979
0.980
59
293
103
51
86
521
86
166
108
68
246
119
73
163
198
502
128
308
181
114
120
1.80
0.34
0.14
1.93
0.94
0.07
1.55
0.43
0.10
1.47
0.35
0.10
1.62
0.48
0.09
0.44
0.18
0.05
0.77
0.30
0.10
7
[8]
[8]
7
7
7
7
7
7
[10]
[10]
[9]
This work
This work
Table 4
Correlations of the SCS values for investigated ketimines (6 and 7) with DSP eq. 2.
Series
Atom
rF
rR
h
r
F
s
la
6
7
C1
C7
C10
C1
C7
C10
10.56(ꢁ0.80)
2.74(ꢁ0.35)
9.01(ꢁ0.38)
2.24(ꢁ0.17)
ꢀ0.98(ꢁ0.07)
9.16(ꢁ0.80)
2.98(ꢁ0.23)
ꢀ0.99(ꢁ0.08)
0.15(ꢁ0.27)
0.16(ꢁ0.12)
0.06(ꢁ0.05)
4.24(ꢁ0.61)
0.31(ꢁ0.18)
0.07(ꢁ0.06)
0.997
0.992
0.992
0.980
0.987
0.985
370
121
118
80
107
96
0.37
0.16
0.07
0.88
0.26
0.09
0.85
0.82
1.17
1.02
0.83
1.08
ꢀ0.84(ꢁ0.14)
9.02(ꢁ1.75)
3.59(ꢁ0.51)
ꢀ0.928(ꢁ0.17)
al = rR/rF.
in sR value. To obtain resonance values, which present
satisfactory measures of the substituent resonance potential,
pure field contributions may be obtained by the use of
Swain–Lupton constants F and R. From that point of
view, better correlations have been obtained with these
constants, which indicate that pure resonance effect is
included in correlations.
The investigation of SCS values in the benzylidene ring
(side chain group) is of interest, because it may further help
the understanding of polarization effects in compounds
having the C═N bridging group. In general, the introduc-
tion of different groups Y (Fig. 1) at the azomethine carbon
significantly changes contribution of the particular substit-
uent effect, field and resonance, in the investigated
series of imines and ketimines (Table 5), although their
resonance/field ratio might be similar.
The obtained rF and rR values for the C1 atom indicate
a significantly higher contribution of the resonance effect
for series 1 and 2. Significant (series 1) and somewhat
lower (series 3–7) contributions of resonance effect at
C10 indicate that the p-resonance units can effectively
transfer electron density from the substituent to a distant
carbon. Field effects are important at C1 and C7 atoms in
the compounds of series 6 and 7, which is due to the
presence of the methyl group at the azomethine carbon.
Steric repulsion causes a higher deviation of the aniline
ring from the planarity reducing the extent of resonance
interaction. Regarding the particular carbon position in
the molecular structure, the noticeable alternation of rF is
observed. The extent of this alternation bears an evidence
of the transfer of substituent effects by the bond polarization
mechanism. Despite the dependence of the transmission of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Spectra–Structure Correlations of 4-Substituted N-[1-(Pyridine-3-
and -4-yl)ethylidene]anilines
Table 5
Correlation of the SCS values for investigated imines (1–5) and ketimines (6 and 7) with DSP eq. 2.
Series
Atom
rF
rR
h
r
F
s
l
1
C1
C7
C10
C1
C7
C10
C1
C7
C10
C1
C7
C10
C1
C7
C10
C1
C7
C10
C1
C7
C10
2.91(ꢁ2.37)
3.38(ꢁ0.43)
ꢀ0.66(ꢁ0.25)
2.73(ꢁ2.17)
3.26(ꢁ0.50)
ꢀ1.55(ꢁ0.07)
12.62(ꢁ3.75)
3.57(ꢁ0.38)
ꢀ0.90(ꢁ0.24)
6.43(ꢁ2.11)
3.79(ꢁ0.29)
ꢀ0.81(ꢁ0.25)
6.86(ꢁ2.14)
4.02(ꢁ0.34)
ꢀ1.03(ꢁ0.24)
10.48(ꢁ0.89)
2.82(ꢁ0.34)
ꢀ0.88(ꢁ0.13)
9.82(ꢁ2.02)
3.54(ꢁ0.64)
ꢀ0.96(ꢁ0.17)
12.69(ꢁ1.19)
4.95(ꢁ0.22)
ꢀ1.26(ꢁ0.13)
13.23(ꢁ1.01)
6.27(ꢁ0.25)
ꢀ1.20(ꢁ0.03)
14.10(ꢁ1.89)
5.85(ꢁ0.19)
ꢀ1.05(ꢁ0.12)
13.20(ꢁ1.06)
5.63(ꢁ0.15)
– 1.03(ꢁ0.12)
15.12(ꢁ1.07)
6.48(ꢁ0.17)
– 1.34(ꢁ0.12)
9.09(ꢁ0.45)
2.15(ꢁ0.17)
– 0.94(ꢁ0.07)
9.02(ꢁ1.02)
2.77(ꢁ0.32)
ꢀ0.92(ꢁ0.08)
0.11(ꢁ0.79)
0.23(ꢁ0.14)
0.12(ꢁ0.08)
0.16(ꢁ0.72)
0.23(ꢁ0.17)
0.01(ꢁ0.02)
0.27(ꢁ1.25)
0.12(ꢁ0.13)
0.14(ꢁ0.08)
0.13(ꢁ0.70)
0.08(ꢁ0.10)
0.13(ꢁ0.08)
0.23(ꢁ0.71)
0.01(ꢁ0.11)
0.05(ꢁ0.08)
0.17(ꢁ0.30)
0.14(ꢁ0.11)
0.07(ꢁ0.04)
0.85(ꢁ0.67)
0.26(ꢁ0.21)
0.08(ꢁ0.06)
0.983
0.997
0.982
0.987
0.997
0.999
0.973
0.998
0.979
0.988
0.999
0.978
0.990
0.999
0.987
0.997
0.992
0.992
0.981
0.987
0.995
59
304
55
1.08
0.20
0.11
0.99
0.23
0.03
1.70
0.17
0.11
0.96
0.13
0.11
0.97
0.16
0.11
0.40
0.16
0.06
0.92
0.29
0.08
4.36
1.46
1.90
4.85
1.92
0.77
1.12
1.63
1.17
2.05
1.49
1.27
2.20
1.61
1.30
0.87
0.76
1.07
0.92
0.78
0.96
2
3
4
5
6
7
59
342
945
35
537
46
84
856
44
107
798
77
294
118
129
54
57
82
substituent effects on the molecular geometry (Fig. 1), it can
be seen that the p-polarization mechanism is operative within
the distant p3-unit, considering the negative rF for C10. The
negative sign of rF is indicative of the reverse SCS effect,
that is, electron-acceptor substituents cause an upfield shift,
which has been explained to be due to the p-polarization
[18]. Similar effects have been observed in other systems:
N-1-p-substituted phenyl-5-methyl-4-carboxyuracils [19],
3-aryl 2-cyanoacrylamides [20], N-benzylidenanilines [14],
and 2-substituted 5-N0,N0-dimethylaminophenyl-N,N-dimethyl
carbamates [21].
p-Polarization of a distant p-system induced by substitu-
ent dipole is not necessarily transmitted via a conjugated
p-system [18], and theoretical results have confirmed that
a substituent dipole mainly polarizes individual p-units
[22]. This phenomenon is defined as “localized polariza-
tion” (direct p-polarization). On the other side, additional
polarization of the whole p-network can be induced at
terminal atoms of a conjugated p-system, which is
termed as “extended polarization.” The satisfactory DSP
The contributions of polar (inductive/field) and resonance
effects of the substituent X on the SCS of the azomethine
carbon indicate a significant attenuation effect of this group
on the overall transmission of substituent effects. The corre-
lation results for the azomethine carbon demonstrate higher
contribution (series 1–5; Table 5) of p,p-conjugation for
the electron-donor substituted compounds in comparison
with series 6 and 7 and increased n,p-conjugation in the
aniline part of molecule for the electron-acceptor substituted
compounds [9,10]. From this point of view, in the investi-
gated compounds, two opposite effects are operative: the
electron-accepting character of the substituent Y (p1-unit)
and the contribution of n,p-conjugation in the aniline part
depending on the substituent X. When the C═N group and
the aniline ring strive toward coplanarity, the p,p-conjuga-
tion is the prevalent mode of interaction. On the other side,
in the orthogonal orientation, the interaction of the nitrogen
lone pair and the p3-unit is strong. In other words, when
n,p-conjugation in the aniline part is increased, the higher
deviation of this ring influences the transmission mode of
substituent effects.
0
long-range correlation found for SCSC1 indicated signif-
icant contribution of p-polarization to the overall electron
density transmission in series 6 and 7. The decreased
contribution of resonance effects in series of ketimines,
considering l values for C1 and C7 atoms, is undoubtedly
influenced by the nonplanarity of p2- and p3-units, which
indicates that direct p-polarization is of high significance.
Similarly, long-range correlations have been found in
series of insulated systems of N-benzylidenbenzylamines
[23–25] and diaryloxadiazolines [26].
According to previous discussion, the transmission of
substituent electronic effects can be presented by mesomeric
structures (Fig. 3; structures a–e) of the electron-acceptor
substituted derivatives with contribution of p-polarization
(Fig. 3; structure f ).
If X is an electron-acceptor substituent, a dipole on X
(or near the C-X bond) is induced (Fig. 3; structure f ),
and interaction of this dipole through the molecular
structure results in a definite polarization of the individual
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M. Rancić, N. Trisović, M. Milcić, M. Jovanović, B. Jovanović, and A. Marinković
Vol 000
Figure 3. Mesomeric structures of the electron-acceptor substituted ketimines (a–e) with contribution of p-polarization (f).
p-units, as well as polarization of the entire conjugated
system. Resonance interaction in an extended conjugated
system of p2- and p3-units (Fig. 3; structures c and d) has
an opposite effect to the electron-accepting character of
p1-unit, that is, “aza” substituent in series 6 and 7. The
net result of the electron density change at C10 atom is
reflected in a somewhat lower contribution of resonance
effect in comparison with imine series 1 and 3–5; the
lowest contribution is observed for series 2. Resonance
interaction strongly depends on the spatial arrangement
(E configuration around the C═N bond) of the investigated
molecules (Table 6; θC and θN) and can be effectively
transmitted through p2- and p3-units by resonance (Fig. 3;
structures c and d). These effects influence large differ-
ences in the rF values for the carbon atoms within series
6 and 7 and are higher in comparison with the series of
the investigated imines.
In similar systems [8], with imine side chain functional-
ities, it has been discussed that the substituent-sensitive
inherent polarization of the C═N bond can be proposed
as an alternative/competitive explanation of p-polarization.
Conjugative effects in these systems are negligible and can
be explained as the contribution of resonance-induced
polar effect. According to this concept, electron-withdrawing
substituents increase polarization of the C═N bond, increas-
ing contribution of the wave function presented by structure b
in Figure 3. Electron-accepting substituents cause a decrease
of electron density at the azomethine carbon, whereas
electron-donating substituents have the opposite effect.
Electron donors induce the charge separation at the aniline
ring increasing electron density in p3-unit. The increased
electron density on C7 atom (shielding effect caused by
electron donors) is indeed a type of a “push effect” of the
electron-rich aniline ring, which is manifested as higher
Table 6
Elements of optimized geometry of N-[1-(pyridine-3- and -4-yl)ethylidene]anilines obtained by the use of MP2 method.
N-[1-(pyridine-3-yl)ethylidene]anilines
N-[1-(pyridine-4-yl)ethylidene]anilines
Angle
Atomic charge
Angle
Atomic charge
a
b
0
0
X
H
θC
θN
qC
qN
qC1
qC1
0.061
0.032
0.036
0.041
0.048
—
0.063
0.069
—
θC
θN
qC
qN
qC1
qC1
13.9
14.2
14.3
14.4
14.3
—
12.7
12.7
—
57.5
56.8
55.9
55.9
57.4
—
0.176
0.163
0.160
0.160
0.158
—
0.163
0.175
—
ꢀ0.276
ꢀ0.273
ꢀ0.272
ꢀ0.271
ꢀ0.277
—
ꢀ0.282
ꢀ0.285
—
ꢀ0.146
ꢀ0.135
ꢀ0.133
ꢀ0.139
ꢀ0.138
—
ꢀ0.139
ꢀ0.147
—
11.9
12.0
12.5
12.4
12.0
11.8
11.8
11.8
11.5
11.8
57.1
56.3
55.3
55.4
56.5
57.4
57.4
57.6
58.8
58.1
0.140
0.137
0.135
0.133
0.138
0.143
0.149
0.149
0.157
0.152
ꢀ0.269
ꢀ0.265
ꢀ0.262
ꢀ0.261
ꢀ0.267
ꢀ0.266
ꢀ0.271
ꢀ0.272
ꢀ0.278
ꢀ0.276
0.011
0.013
0.014
0.013
0.013
0.009
0.007
0.007
0.005
0.004
0.058
0.028
0.030
0.031
0.044
0.023
0.059
0.065
0.110
0.098
N(CH3)2
OH
OCH3
CH3
F
Cl
Br
COOCH3
COCH3
58
58.2
—
59.5
12.7
0.178
ꢀ0.286
ꢀ0.147
0.100
aThe dihedral angle is defined by the atoms C20-C10-C═N (Fig. 1).
bThe dihedral angle is defined by the atoms C═N-C1-C2.
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Spectra–Structure Correlations of 4-Substituted N-[1-(Pyridine-3-
and -4-yl)ethylidene]anilines
contribution of extended conjugative interaction (Fig. 4;
structure h). A more implicit view in assessing the substitu-
ent effects on the polarization of the C═N group has been
obtained from the calculation of atomic charges (qC, qN,
works [9,10] that electron-donor substituents support
p,p-conjugation and, together with the steric interference of
the methyl group and lower electron-accepting character of
the 3-pyridyl group, cause somewhat higher deviation
of the benzylidene ring in series 6, and thus influence higher
polarization of the C═N bond (Table 6).
0
qC1, and qC1 ) and elements of the optimized geometries
(angles θC and θN) of 4-substituted N-[1-(pyridine-3- and
-4-yl)ethylidene]anilines obtained by the use of MP2 cal-
culation methods (Table 6).
Electron-donor substituents cause an increase of the
+
electronic density at the azomethine carbon via their R
Theoretical calculation showed that E configuration with
respect to the C═N bond of the optimized structure is a far
more stable isomer for both series of ketimines. The opti-
mized conformations are in a very good concordance with
results obtained from NOESY spectra. The established atom
connectivity between H proton of the methyl group at the
azomethine carbon and ortho protons (C20-H and C2-H), in
both series 6 and 7, unambiguously confirms E configuration
of the C═N bond.
effect (Fig. 4; structure g) resulting in the shift of the
corresponding signal toward higher magnetic field. Such
electron density shift causes considerably lower polariza-
tion of the C═N group (Table 6), which in turn causes
somewhat higher deviation of p1-unit with respect to
p2-unit for series 6 of ketimine (Table 6; θC).
A study of the cross-interaction effect of the benzylidene
and aniline substituents on the polarization of the C═N bond
has been additionally performed. DSP model (eq. 3) has been
applied to SCSC7 of the investigated imines and ketimines
with the F and Rꢀ constants of the Y substituents [27].
Because of the pronounced electron-accepting character of
the Y substituent, the Rꢀ constant has been chosen (values
for “aza” substituents are not available in the literature).
As mentioned previously, the major structural character-
istics are reflected in deviation of the aniline ring from the
plane of the C═N group (Table 6; θN). The 3- and 4-pyri-
dyl rings have a tendency to be coplanar with the C═N
bond, whereas the aniline ring behaves oppositely. More-
over, the opposite trend of the changes of the dihedral
angles θN and θC can be observed, which means that a
deviation from planarity of one side of the molecule
produces a small conformational adaptation of the opposite
side. The values of θN vary from 55.9ꢂ (X═OH, OCH3) to
59.5ꢂ (X═COOCH3, COCH3) and are clearly dependent
on substitution on the aniline ring. The dihedral angle θN
increases with increasing electron-accepting character of
the substituent X because of n,p-conjugation of the nitroani-
line type [9,10]. Namely, this conjugation, which involves
the nitrogen lone pair and p-electrons from the aniline
ring (p3-unit), is possible only if the aniline ring takes such
conformational arrangement, that is, it is deflected for a
certain angle θN (Fig. 3; structures c and d). In that way,
the electron density shifts toward the p3-unit causing the
deshielding of the azomethine carbon (Fig. 3; structure d),
and, consequently, the electron density shifts from the benzy-
lidene part of the molecule. Furthermore, the calculated
atomic charges indicate somewhat higher polarization of
the C═N bond, when the electron-accepting character of
the substituent X increases, and generally higher polarization
in series 6 is observed. It has been pointed out in our previous
ꢀ
ꢀ
SCSC7 ¼ rFðYÞF þ rR ðYÞR þ h
(3)
However, correlation results, obtained by eq. 3, are of low
statistical validity (r = 0.48–0.62, F < 5). Because of that, a
three-parameter equation (eq. 4), which includes the steric
parameter (Es(CH3) = ꢀ1.24 for the series of ketimines
[28]), has been applied, and the corresponding rF(Y),
rꢀR(Y), and rEs(Y) values are presented in Table 7.
ꢀ
ꢀ
SCSC7 ¼ rFðYÞF þ rR ðYÞR þ rEsðYÞEs þ h
(4)
The sensitivity of the azomethine carbon to the electron-
accepting character of the benzylidene group Y strongly
depends on the substituent X. The contribution of the steric
effect has been found high for all of the substituents X
(Table 7) and higher for those with larger electron-donating
capabilities. The positive value of the proportionality
constant rF(Y) implies that the field-induced electron density
change at the azomethine carbon increases with increasing
electron-accepting character of the benzylidene substituent
Y, whereas resonance and steric effects act in the opposite
direction. Steric effect has the highest contribution in the
electron-donor substituted series of imines, and in that way,
more planar molecular conformations are achieved. A higher
extent of planarity is induced by the substituent X having
larger +R, and contribution of the wave function h (Fig. 4.)
is increased, as is observed for the series with N(CH3)2
substituent (Table 7). These observations can be explained
in relation to the electron-accepting character of the
substituent Y and the balanced contribution of extended
and localized p-units polarization to the overall transmission
of electronic substituent effect. The higher contribution of
Figure 4. Mesomeric structures of the electron-donor substituted compounds.
Journal of Heterocyclic Chemistry
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M. Rancić, N. Trisović, M. Milcić, M. Jovanović, B. Jovanović, and A. Marinković
Vol 000
Table 7
Correlation of the SCS values for the investigated imines (1–5) and ketimines (6 and 7) with eq. 4.
Substituent (X)
rF(Y)
rRꢀ(Y)
r
Es(Y)
r
F
s
H
3.19
1.93
2.76
2.80
3.18
3.98
ꢀ2.76
ꢀ3.72
ꢀ2.97
ꢀ2.75
ꢀ2.31
ꢀ1.59
ꢀ5.33
ꢀ8.32
ꢀ7.00
ꢀ5.84
ꢀ5.70
ꢀ5.20
0.931
0.959
0.949
0.937
0.935
0.917
59
88
76
65
62
39
1.08
0.45
0.56
0.97
0.85
1.10
N(CH3)2
OCH3
CH3
Cl
COOCH3
extended resonance and p-polarization interaction through
the molecule as a whole, with the electron-donor substituent
X, and higher localized interaction within defined p-units
(Fig. 1) for electron-acceptor substituted molecules can
be supposed.
CONCLUSION
Two series of 4-substituted N-[1-(pyridine-3-and-4-yl)
ethylidene]anilines have been synthesized using two
conventional and one microwave-assisted method. The
developed solvent-free microwave-assisted method has
given higher yields of the products within shorter reaction
time. The applied LFER analysis appears to be a straight-
forward method for correlations of SCS values data of
the investigated molecules with the appropriate substituent
constants. Polar (inductive/field) and resonance effects
have similar contributions at all carbons, except C1 for
imine series 1, 2, and 6, but the actual values of rF and
rR, which correspond to these effects, are significantly
different depending on the carbon position. Considerable
deviation of the aniline and benzylidene rings, with respect
to the C═N group, causes a decrease in the transmission of
both polar and resonance substituent effects. Polar effect is
slightly higher at C1 and C7 carbons in series 6 and 7 of
ketimines and is transmitted mainly by inductive and
p-polarization modes. Reverse polarization is operative
at C10 carbon, regarding contribution of the field effect
of the substituent X, as a consequence of p-polarization
effect. Optimized geometries of the investigated compounds
and transmission of the individual substituent electronic
effects through well-defined p-resonance units indicate that
these units behave both as isolated and as conjugated
fragments, depending on the substituent present in the
corresponding molecules.
The obtained values rF(Y), rꢀR(Y), and rEs(Y) reflect the
sensitivity of the azomethine carbon to the electronic
effects of the benzylidene substituent Y for the appropriate
substituent X. The cross-correlation of the constants rF(Y),
rꢀR(Y), and rEs(Y) versus sp/s+p constants [17] of the
substituent X has been performed according to eq. 1, and
results are presented by eqs. 5–7.
rFðYÞ ¼ 3:12ðꢁ0:08Þ þ 1:47ðꢁ0:18Þsp
(5)
r ¼ 0:981; F ¼ 72; s ¼ 0:18; n ¼ 6
ꢀ
rR ðYÞ ¼ ꢀ2:53ðꢁ0:08Þ þ 1:55ðꢁ0:19Þsp
(6)
r ¼ 0:971; F ¼ 66; s ¼ 0:19; n ¼ 6
rEsðYÞ ¼ ꢀ5:68ðꢁ0:13Þ þ 1:51ðꢁ0:17Þspþ
(7)
r ¼ 0:976; F ¼ 80; s ¼ 0:29; n ¼ 6
Equations 5–7 indicate similar influences of electronic
effects of the substituent X on the sensitivity of the regres-
sion coefficients rF(Y), rꢀR(Y), and rEs(Y). The results of
the cross-correlations of the constants rF(Y), rꢀR(Y), and
rEs(Y) with respect to aniline substituents (X) are mani-
fested in their similar slopes when the electron-accepting
character of the substituent X increases. This leads to a
conclusion that the higher sensitivity is achieved when
two opposite electron-accepting characters of substituents
X and Y operate simultaneously. Although no significant
conformational adaptation has been observed in series
6 and 7 as a consequence of the effect of the substituent
X (Table 6; θN), the high values of torsional angle of the
aniline part of molecules significantly affect the transmission
of electronic substituent effects. The significant and positive
value of the proportionality constant for rEs(Y) (eq. 7)
indicates that the steric hindrance results mainly from the
presence of the methyl group in the ketimine series. Steric
effect increases as electron-donating character of the sub-
stituent X increases, which indicates the importance of
p,p-conjugation on molecular geometry and steric repulsion
on the transmission of the overall substituent effects.
EXPERIMENTAL
Materials, methods, and instrumentation. Two series of the
investigated compounds have been synthesized using different
methods of conventional syntheses according to the literature
procedure. However, these methods still have more limitations
such as long reaction times, moderate yields, use of toxic reagents
or solvents, and demand of extensive purification of the products.
To obtain higher yields and more pure products and to shorten
reaction time, we have developed an additional solvent-free
microwave-assisted method for efficient condensation of
acetylpyridines with anilines. The yields of the investigated
compounds obtained using methods A, B, and C are collected in
Table S1 (Supporting Information).
Journal of Heterocyclic Chemistry
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Month 2014
Spectra–Structure Correlations of 4-Substituted N-[1-(Pyridine-3-
and -4-yl)ethylidene]anilines
minimum that has only real frequencies) and to account for the
zero-point vibrational energy correction. Global minima have
been found for every molecule. The solvent (DMSO) has been
simulated with standard static isodensity surface polarized
continuum model. Theoretical calculations of chemical shifts at
MP2/6-31G++(d,p) level provide good basis for estimation of
experimental data. All calculations have been performed with
Gaussian03 software (Gaussian, Inc., Wallingford, CT) [30].
Fourier-transform infrared spectra have been recorded in
transmission mode using a Bomem (Hartmann & Braun) spec-
trometer (Québec City, Québec, Canada). Elemental analysis
has been performed using a Vario EL III elemental analyzer
(Hanau, Germany).
The 1H and 13C NMR spectral measurements have been
performed on a Varian Gemini 2000 (Palo Alto, California).
The spectra have been recorded at room temperature in DMSO-
d6. The chemical shifts are expressed in parts per million (ppm)
1
Acknowledgments. This work was supported by the Ministry of
Education and Science of the Republic of Serbia (project number
172013).
values referenced to TMS (dH = 0 ppm) in H NMR spectra and
the residual solvent signal (dC = 39.5 ppm) in 13C NMR spectra.
The chemical shifts have been assigned by the complementary
use of DEPT, 2D 1H–13C correlation HETCOR, and by selective
INEPT long-range experiments. All spectra have been recorded
at ambient temperature. 2D NOESY spectra have been recorded
on a Bruker Avance III 500 spectrometer (Rheinstetten,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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M. Rancić, N. Trisović, M. Milcić, M. Jovanović, B. Jovanović, and A. Marinković
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet