Solvent and structural effects on the UV-Vis absorption spectra of some 4,6-disubstituted-3-cyano-2-pyridones

Article abstract of DOI:10.1007/s10953-012-9897-1

A series of 4,6-disubstituted-3-cyano-2-pyridones was synthesized and their UV-Vis absorption spectra were recorded in the region 200-600 nm in the set of selected solvents. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen-bonding interactions on the spectral shifts were analyzed by means of the linear solvation energy relationship concept of Kamlet and Taft. The influence of solvents as well as substituents on the 2-pyridone/2-hydroxypyridine tautomeric equilibration was evaluated. The absorption band maximum of the 2-hydroxypyridine form is found to appear at a shorter wavelength than that of the 2-pyridone form in all investigated solvents. The replacement of the methyl and phenyl groups at position 6 of the pyridone ring, by a hydroxy group, significantly changes the solvatochromic behavior of the investigated pyridones.

Full text of DOI:10.1007/s10953-012-9897-1

J Solution Chem (2012) 41:1825–1835
DOI 10.1007/s10953-012-9897-1
Solvent and Structural Effects on the UV–Vis Absorption
Spectra of Some 4,6-Disubstituted-3-Cyano-2-Pyridones
•
Adel S. A. Alimmari Bojan Ð. Bozic Aleksandar D. Marinkovic
•
•
ˇ ´
Dusan Z. Mijin Gordana S. Uscumlic
´
ˇ
•
ˇ
ˇ´
´
Received: 18 March 2011 / Accepted: 24 December 2011 / Published online: 11 October 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of 4,6-disubstituted-3-cyano-2-pyridones was synthesized and their
UV–Vis absorption spectra were recorded in the region 200–600 nm in the set of selected
solvents. The effects of solvent dipolarity/polarizability and solvent–solute hydrogen-
bonding interactions on the spectral shifts were analyzed by means of the linear solvation
energy relationship concept of Kamlet and Taft. The influence of solvents as well as
substituents on the 2-pyridone/2-hydroxypyridine tautomeric equilibration was evaluated.
The absorption band maximum of the 2-hydroxypyridine form is found to appear at a
shorter wavelength than that of the 2-pyridone form in all investigated solvents. The
replacement of the methyl and phenyl groups at position 6 of the pyridone ring, by a
hydroxy group, significantly changes the solvatochromic behavior of the investigated
pyridones.
Keywords Pyridone derivatives ꢀ Absorption spectra ꢀ Kamlet-Taft equation ꢀ
Solvent and substituent effects ꢀ Tautomerism
1 Introduction
The derivatives of 4,6-disubstituted-3-cyano-2-pyridones have been used in the manufac-
turing of dyes, pigments, additives for fuels and oils [1–3], stabilizers for polymers [4] and
other important practical materials. However, in the last decade, 2-pyridones have been
widely used in biological screenings, resulting in numerous pharmaceutical applications.
Many of the derivatives exhibit cardiotonic [5], cardiovascular [6], antiviral [7], antihyper-
tensive [8], antianaphylactic [9], inotropic [10], antiallergenic [11], antiinflammatory [12],
antioxidant [13] and antimicrobial [14] activity. Considering the structural characteristics of
Electronic supplementary material The online version of this article (doi:10.1007/s10953-012-9897-1)
contains supplementary material, which is available to authorized users.
ˇ
ˇ ´
´
ˇ´
´
A. S. A. Alimmari ꢀ B. Ð. Bozic ꢀ A. D. Marinkovic ꢀ D. Z. Mijin (&) ꢀ G. S. Uscumlic
Department of Organic Chemistry, Faculty of Technology and Metallurgy, University of Belgrade,
Karnegijeva 4, PO Box 3503, 11120 Belgrade, Serbia
e-mail: kavur@tmf.bg.ac.rs
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J Solution Chem (2012) 41:1825–1835
2-pyridones, existence of pyridone–piridinol tautomerism, with the pyridone being dominant
species in solution, and the group –NH–C(=O) similar to protein amide bond, it was rea-
sonable to expect inherent physiological activity. This mostly depends on the activity of an
amide bond hydrogen which is highly influenced by tautomerism. Determination of
2-pyridone/2-hydroxypyridine tautomerism (Scheme 1) both in the solid state and the
solution phase is quite interesting, both from theoretical and practical standpoints, since the
tautomers have different properties. Several investigations of substituted 2-pyridones have
been performed and reviewed [15, 16]. It was concluded that the equilibrium between the two
tautomers is influenced by the structure of the compounds and solvent used.
In general [17], it is known that 2-hydroxypyridine, in the condensed phase, is in an
oxo-amido form a, and is in the imido aromatic form b in dilute gas phase, as shown in the
equilibrium of Scheme 1. Which of two tautomeric forms is present in solution in greater
amount depends on the polarity of the solvent, because of the existance an energy dif-
ference between those tautomeric forms. Polar solvents lead to a shift of the equilibrium
towards the 2-pyridone form. On the other side, non-polar solvents favor the formation of
2-hidroxypyridine form [18]. However, when particular substituents are bonded to the
pyridone ring, the form a may be the more populated form in the condensed phase [16].
Scheme 1 The equilibrium
between 2-pyridone form (a) and
2-hydroxypyridine form (b) of
4,6-disubstituted-3-cyano-2-
pyridones as well as the
R2
R2
CN
O
CN
OH
canonical structure (c)
R1
N
R1
N
H
a
b
R2
CN
O
R1
N
H
c
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J Solution Chem (2012) 41:1825–1835
1827
In order to collect further information on the influence of substituents bonded to the
pyridone ring and solvent effects on the pyridone–pyridinol tautomerism, in this paper we
report the synthesis of ten 4,6-disubstituted-3-cyano-2-pyridones (Fig. 1) (1, 2 and 3 are
new compounds, which to our knowledge have not been registered in the literature) and
their UV–Vis absorption spectra (200–600 nm) in fifteen solvents of different polarity.
The effect of solvent dipolarity/polarizability and the hydrogen-bonding on the spectral
shifts were interpreted by means of a linear solvatation energy relationship (LSER) using
the Kamlet-Taft equation [19] of the following form:
m ¼ m0 þ sp ꢁ þ bb þ aa
ð1Þ
where p* is an index of the solvent dipolarity/polarizability; b is a measure of the solvent
bond acceptor (HBA) basicity; a is a measure of the solvent hydrogen-bond donor (HBD)
acidity and m0 is the regresion value of this solvent property in cyclohexane as reference
solvent. The regression coefficients s, b and a in Eq. 1 measure the relative susceptibilities
of the absorption frequencies to the different solvent parameters.
The LSER developed by Kamlet and Taft is one of the most ambitious and successful,
quantitative treatments of solvation effects. This treatment assumes attractive interactions
between a solute and its enviroment and allows estimation of the ability of the investigated
compounds to form hydrogen-bonds [20–23].
This paper demonstrates how the linear solvation energy relationship (LSER) can be
used to explain and present multiple interacting effects of the solvent and the influence of
substituents of different nature at the 4 and 6 positions on the pyridone ring, on the
2-pyridone/2-hydroxypyridine tautomerism of 4,6-disubstituted-3-cyano-2-pyridones.
Fig. 1 Structure of the
investigated 4,6-disubstitued-3-
cyano-2-pyridones
R2
CN
O
R1
N
H
No.
R1
R2
1
OH
4-NO2C6H4
2
3
4
5
6
7
OH
OH
OH
OH
CH3
CH3
4-OCH3C6H4
4-ClC6H4
C6H5
CH3
CH3
C6H5
8
9
10
C6H5
C6H5
C6H5
C6H5
4-OCH3C6H4
4-ClC6H4
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J Solution Chem (2012) 41:1825–1835
2 Experimental
2.1 Chemicals and Materials
All the investigated compounds were synthesized following the procedure presented in the
synthetic scheme (Scheme 2). The starting materials were obtained from Aldrich and
Fluka, and were used without further purification. 4-Substituted-6-hydroxy-3-cyano-2-
pyridones were synthesized by the reaction of ethyl 4-substituted benzoylacetate, ethyl
benzoylacetate or ethyl acetoacetate and cyanoacetamide in absolute ethanol in the pres-
ence of potassium hydroxide using a modified literature procedure [24] (Scheme 2a,
compounds 1–5). The new compounds (1–3) have satisfactory elemental analysis. 4,6-
Dimethyl-3-cyano-2-pyridone was obtained from acetylacetone and cyanoacetamide in a
water/ethanol mixture in the presence of a few drops of pyperidine as a catalyst [25]
(Scheme 2b, compound 6). 4-Methyl-6-phenyl-3-cyano-2-pyridone was synthesized from
benzalacetone and cyanoacetamide in a water/ethanol mixture (1:1) in the presence of
potassium hydroxide [26] (Scheme 2c, compound 7). 4,6-Disubstituted-3-cyano-2-pyr-
idones were synthesized by the reaction of ethyl 2-cyano-3-substituted acrylate with
acetophenone and ammonium acetate in ethanol as described in the literature [27]
(Scheme 2d, compounds 8–10). The chemical structure and the purities of the synthesized
compounds were confirmed by their melting points, 1H NMR, FT-IR and UV spectra. Their
full characterization is given in Supplementary Material [ESM].
2.2 Spectral Analysis
1
The H NMR spectra of DMSO-d6 solutions (TMS as internal standard) were measured
with a Varian-Gemini 2000 (200 MHz) spectrometer. IR Spectra were recorded on a
Bomem MB 100 FT-IR spectrophotometer in the form of KBr pellets. The UV–Vis spectra
were measured with a Shimadzu 1700 spectrophotometer. The UV–Vis spectra were taken
in spectrophotometric grade solvents (Aldrich and Fluka) at 5 9 10-5 molꢀdm-3
concentration.
2.3 Regression Analysis
The correlation analysis was carried out using Microsoft Office Excel 2003, which con-
siders the 95 % confidence level. The goodness of fit was discussed using the correlation
coefficient (R), standard error of the estimate (s) and Fischer criterion (F).
3 Results and Discussion
The 4,6-disubstituted-3-cyano-2-pyridones prepared in this work may exist in two tauto-
meric forms (Scheme 1). The infrared spectra for the first five compounds (1–5) shows an
intense OH band in the region 3400–3427 cm-1, weak N–H band in the region
3312–3351 cm-1, weak C=O band in the region 1632–1654 cm-1 and an intense CN band
in the region 2197–2227 cm-1, which suggest that these compounds predominantly exist
in the 2-hydroxypyridine form (Scheme 1, b) in the solid state. The infrared spectra for the
other five compounds (6–10) showed no hydroxyl band, which suggests that these com-
1
pounds exist in the 2-pyridone tautomeric form (Scheme 1, a) in the solid state. The H
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J Solution Chem (2012) 41:1825–1835
1829
R2
R2
CN
O
CN
O
abs ethanol
KOH
(a)
+
O
H2N
HO
N
H
O
C2H5O
R2 = 4-NO2C6H4 (1), 4-OCH3C6H4 (2), 4-ClC6H4 (3), C6H5 (4), CH3 (5)
CH3
H3C
CN
O
CN
O
O
O
water / ethanol
piperidine
(b)
+
H2N
H3C
N
H3C
H
(6)
CN
CN
O
water/ethanol
O
+
(c)
KOH
H2N
O
H3C
N
H3C
H
(7)
R2
R2
CN
O
C6H5
H3C
ethanol
CH3COO-NH4
O
+
+
NC
(d)
O
R1
N
H
C2H5O
R2 = C6H5, R1 = C6H5 (8); R2 = 4-OCH3C6H4, R1 = C6H5 (9);
R2 = 4-ClC6H4, R1 = C6H5 (10)
Scheme 2 Synthetic methods for the preparation of 4,6-disubstituted-3-cyano-2-pyridones
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NMR spectra of the pyridones in DMSO-d6 showed the same results as obtained on the
infrared spectra.
Since the tautomeric equilibria strongly depend on the nature of the media, the behavior
of pyridones in various protic and aprotic solvents was studied. For this purpose, the
absorption spectra of the pyridones (1–10) were measured in fifteen different solvents at a
concentration 5 9 10-5 molꢀdm-3. In the range of concentration values used here, the
possible dimer formation does not influence the spectroscopic data. The experimental data
indicate that the spectra of the investigated compounds comprise mainly two bands in the
UV–Vis region, depending upon the molecular structure and the nature of the solvent. The
absorption band between 230 and 310 nm is assigned to the pyridine ring p–p* electron
transition, while the band between 320 and 390 nm is assigned to a carbonyl n–p* electron
transition. The ultraviolet absorption frequencies of the electronic transition of the
2-pyridone ring (lower energy band) of 4,6-disubstituted-3-cyano-2-pyridones 1–10 in the
set of selected solvents are given in Table 1. It was found that the absorption maxima of
these pyridones are strongly solvent dependent and vary with solvent polarity. By con-
sidering the equilibrium between the 2-pyridone and 2-hydroxypyridine tautomeric forms
[16] in solvents of different polarity, it was reported that increasing solvent polarity shifted
the equilibrium towards the more dipolar pyridone form [18]. This form is more dipolar
then the hydroxy form due to the contribution of the charge-separated mesomeric form
(Scheme 1, canonical structure c). The present results are in agreement with this. Fur-
thermore, the hydrogen-bonding ability of the solvent plays an important role since HBDs
tend to stabilize the oxo form (Scheme 1, a) whereas hydrogen-bond acceptors stabilize the
hydroxy form (Scheme 1, b). The data from Table 1 confirm that the position of the
ultraviolet absorption frequencies depend on the nature of the substituens in positions 4 and
6 of the pyridone ring. The substituent effect mainly acts on the N–H bond and influences
the position of the equilibrium. The absorption band maximum of the 2-hydroxypyridine
form is found to appear at a shorter wavelenght than that of the 2-pyridone form which is,
Table 1 UV-Vis absorption maxima of 2-pyridones (1–10) in different solvents
Solvent/Compound
m 9 10-3/cm-1
1
2
3
4
5
6
7
8
9
10
Methanol
28.47 29.48 29.39 30.40 30.96 30.43 29.17 27.41 28.28 27.25
27.56 29.33 29.26 30.27 30.75 30.40 29.07 27.46 29.38 27.09
27.32 29.31 29.17 30.38 30.66 30.28 28.90 27.47 29.39 27.56
27.69 29.31 29.26 30.07 30.56 30.28 28.89 27.29 29.60 27.25
27.28 29.27 29.07 30.07 30.67 30.19 28.90 27.09 27.17 27.13
28.04 29.29 29.12 30.10 30.27 30.07 29.05 27.25 29.82 27.20
Ethanol
Propan-1-ol
Propan-2-ol
Butan-1-ol
2-Methylpropan-2-ol
1,4-Dioxane
Tetrahydrofuran
Propanone
–
29.52 29.38 30.03 30.64 29.94 28.77 27.07 27.61 26.93
29.67 28.89 29.14 29.14 30.27 29.60 28.49 26.95 26.94 26.71
27.78 28.89 28.82 29.41 29.99 29.90 28.47 27.09 27.16 26.70
Acetonitrile
–
29.07 28.94 29.66 30.34 29.96 28.80 27.07 27.29 26.82
Dimethyl sulfoxide
Ethyl acetate
Methyl acetate
31.33 28.60 28.28 29.45 30.07 29.71 28.06 26.48 26.82 26.04
32.34 29.12 29.39 29.57 30.40 29.82 28.67 26.88 26.97 26.78
26.15 29.14 29.38 29.60 31.00 29.94 28.72 27.00 27.19 26.71
N,N-Dimethylformamide 31.21 29.31 28.18 31.81 30.08 29.62 28.22 26.16 29.98 26.04
N,N-Dimethylacetamide 31.37 28.54 28.00 31.06 30.10 29.60 28.04 26.64 26.88 26.46
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J Solution Chem (2012) 41:1825–1835
1831
Fig. 2 UV–Vis absorption spectra of pyridones (1, 2, 4 and 9) in ethanol
Fig. 3 UV–Vis absorption spectra of pyridones (1, 2, 4 and 9) in dimethyl sulfoxide
except the compounds 1, 2 and 9, dominant in all investigated solvents. The characteristic
absorption spectra of pyridones 1, 2, 4 and 9 in ethanol and dimethyl sulfoxide are shown
in Figs. 2 and 3, respectively.
The effects of solvent dipolarity/polarizability and hydrogen-bonding on the absorption
spectra of 4,6-disubstituted-3-cyano-2-pyridones are interpreted by means of the LSER
concept using Eq. 1. The solvent parameters [19] are given in Table 2. The correlation of
spectroscopic data for the 2-pyridone tautomeric form (lower energy band, Table 1) was
determined by multiple linear regression analysis. The results of the multiple regressions
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Table 2 Solvent parameters
[19]
Solvent
p*
b
a
Methanol
0.60
0.54
0.52
0.48
0.47
0.41
0.55
0.58
0.71
0.75
1.00
0.55
0.60
0.88
0.88
0.62
0.77
0.83
0.95
0.88
0.11
0.37
0.55
0.48
0.31
0.76
0.45
0.42
0.69
0.76
0.93
0.83
0.78
0.76
0.79
0.68
0.00
0.00
0.08
0.19
0.00
0.00
0
Ethanol
Propan-1-ol
Propan-2-ol
Butan-1-ol
2-Methylpropan-2-ol
1,4-Dioxane
Tetrahydrofuran
Propanone
Acetonitrile
Dimethyl sulfoxide
Ethyl acetate
Methyl acetate
N,N-Dimethylformamide
N,N-Dimethylacetamide
0.00
0.00
Table 3 Regression fits to the solvatochromic parameters
Compound
mo
s
b
a
Ra
Sb
Fc
nd
1
2
3
4
5
6
7
8
9
10
a
27.19
30.05
31.48
26.58
30.82
29.89
29.55
27.64
27.90
27.37
5.36 ( 0.96)
-1.05 ( 0.34)
-2.93 ( 0.21)
3.67 ( 0.84)
-1.13 ( 0.52)
-0.70 ( 0.28)
-1.15 ( 0.16)
1.47 ( 0.55)
-1.71 ( 0.47)
0.50 ( 0.17)
0.31 ( 0.09)
0.65 ( 0.31)
0.78 ( 0.04)
0.88 ( 0.09)
0.79 ( 0.07)
0.65 ( 0.11)
1.57 ( 0.45)
0.55 ( 0.09)
0.987
0.921
0.989
0.917
0.997
0.983
0.989
0.968
0.952
0.968
0.33
0.14
0.08
0.26
0.03
0.04
0.06
0.09
0.39
0.08
79
14
10
12
12
12
10
10
12
12
12
11
121
10
-0.15 ( 0.07)
0.24 ( 0.10)
-0.82 ( 0.08)
-0.55 ( 0.10)
-0.95 ( 0.12)
-0.46 ( 0.18)
1.51 ( 0.75)
342
58
-0.83 ( 0.14)
-0.75 ( 0.21)
-2.30 ( 0.91)
-0.80 ( 0.22)
120
40
26
-0.30 ( 0.15)
35
Correlation coefficient
b
c
d
Standard error of the estimate
Fisher0s test
Number of solvents used in the calculations
are presented in Table 3 and coefficients m0, s, b and a (Table 3) of the fit at the 95 %
confidence level. The percentage contributions of the nonspecific (Pp*) and specific solvent
interactions (Pb and Pa) are given in Table 4. The degree of success of Eq. 1 is shown in
Fig. 4 by means of a plot of mmax calculated versus mmax observed in different solvents.
The negative sign of the s and b coefficients (except the coefficient s for compounds 1
and 4 and b for compounds 4 and 9, Table 3) indicate a bathochromic shift with increasing
solvent dipolarity/polarizability and hydrogen-bond acceptor basicity. This suggests sta-
bilisation of the electronic excited state relative to the ground state. The positive sign of the
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J Solution Chem (2012) 41:1825–1835
1833
Table 4 Percentage contribution
of the solvatochromic effects
Compound
Pp*
Pb
Pa
1
65.22
46.81
66.67
67.40
8.38
13.89
30.99
26.13
25.45
46.87
32.86
37.06
24.93
28.03
18.11
20.89
22.20
7.20
2
3
4
11.45
44.75
52.68
30.84
35.04
29.20
33.61
5
6
14.64
32.10
40.03
42.77
48.28
7
8
9
10
Fig. 4 Experimental versus calculated values of m from Eq. 1
a coefficient (except for compound 1) indicates a hypsochromic shift with increasing
solvent HBD acidity. This suggests stabilization of the ground state relative to the elec-
tronic excited state. These results show that the solvent effects on UV–Vis absorption
spectra of 2-pyridones is very complex and strongly dependent on the nature of the sub-
stituents present at the pyridone nucleus and solvent nature. To understand the ground and
excited state electronic properties of 3-cyano-4,6-dimethyl-2-pyridone and 3-cyano-4-
methyl-6-phenyl-2-pyridone, Chen et al. [28] recently reported density functional theory
(DFT) as well as time dependent DFT (TD-DFT) calculations using the GausianÒ 03
program. Ground and excited states were calculated for HOMO (LUMO) and absorption
spectra. From the TD-DFT calculation, Chen et al. showed that n–p* electronic excitation
is dominated by the HOMO–LUMO contribution. This corresponds partially to an
n-electron flow from the carbonyl O atom toward the pyridine ring. The p–p* transition is
mainly dominated by the one-electron excitation from HOMO-2 to the LUMO for 3-cyano-
4,6-dimethyl-2-pyridone. These results are in accordance with our explanation of solvent
effects on the 2-pyridone/2-hydroxypyridine tautomerism equilibration as presented
above by the Kamlet-Taft equation. The percentage contributions of the solvatochromic
interactions (Table 4) for the first four compounds (1–4) show that most of the solvato-
chromism is due to solvent dipolarity/polarizability (non-specific solvent interactions)
rather than solvent basicity and acidity. These results can be explained by the inductive
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electron-withdrawing effect of the ortho hydroxy group (rI/OH = 0.25) [29] at position 6
on the pyridone ring, which stabilizes the dipolar form (Scheme 1, canonical structure c) of
the 2-pyridone tautomer. The replacement of the hydroxy group at position 6 on the
pyridone ring by methyl and phenyl groups significantly changes the solvatochromic
properties of the pyridones. The effect of these substituents is different and the percentage
contribution to the solvatochromic interactions show that the dominant effect on these
pyridones is the specific solvent effect (Pb and Pa). These results can be explained by
the fact that a small inductive electron-donating effect of the ortho methyl group
(rI/CH3 = -0.01) and a small electron-withdrawing effect of the ortho phenyl group
(rI/Ph = 0.10) stabilize the HN–C = O tautomeric form of the 2-pyridone. These results
are in agreement with some literature reports [16, 30] that the electron-donating and
moderate electron-accepting substituents stabilize the 2-pyridone tautomeric form while
strong electron-accepting substituents stabilize the 2-hydroxypyridine form. Additionally,
the 2-pyridones with phenyl, substituted phenyl or methyl groups at the position 4 and 6
absorbed at a higher absorption maxima and showed bathochromic effects in comparison
with analogous pyridones containing hydroxy group at position 6 in the pyridone ring.
4 Conclusion
In summary, ten 4,6-disubstituted-3-cyano-2-pyridones (including three new compounds)
were synthesized by a modified literature procedure. These pyridones exist in 2-pyridone
and 2-hydroxypyridine tautomeric forms. The visible absorption spectra of the pyridones
were found to exhibit a strong solvent and structural dependence. The satisfactory corre-
lation of the ultraviolet absorption frequencies, of the investigated pyridones, with Eq. 1
indicates that the correct model was selected. We have demonstrated that a solvatochromic
equation with three solvatochromic parameters p*, b and a can be used to evaluate the
effects of both types hydrogen-bonding and of the solvent dipolarity/polarizability effect.
The results show that the replacement of methyl and phenyl groups at position 6 on the
pyridone ring, by a hydroxy group, significantly changes solvatochromic behavior of the
investigated pyridones.
Acknowledgments The authors acknowledge the financial support of the Ministry of Science and
Technologic Development of the Republic of Serbia (Project 172 013).
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