Solvatochromic and quantum chemical investigations of newly synthesized succinimides: Substituent effect on intramolecular charge transfer

Article abstract of DOI:10.1007/s00706-013-1052-1

Two series of 1-aryl-3-phenyl- and 1-aryl-3,3-diphenylpyrrolidine-2,5- diones were synthesized and their solvatochromic properties were studied in a set of 15 solvents of different polarity. The effect of specific and non-specific solvent-solute interacti

Full text of DOI:10.1007/s00706-013-1052-1

Monatsh Chem
DOI 10.1007/s00706-013-1052-1
ORIGINAL PAPER
Solvatochromic and quantum chemical investigations of newly
synthesized succinimides: substituent effect on intramolecular
charge transfer
ˇ
Nebojsa Banjac Nemanja Trisovic Zeljko Vitnik Vesna Vitnik
•
•
•
•
ˇ
ˇ
´
Natasa Valentic Gordana Uscumlic Ivan Juranic
•
•
ˇ
´
ˇ´
´
´
Received: 14 February 2013 / Accepted: 5 July 2013
Ó Springer-Verlag Wien 2013
Introduction
Abstract Two series of 1-aryl-3-phenyl- and 1-aryl-3,3-
diphenylpyrrolidine-2,5-diones were synthesized and their
solvatochromic properties were studied in a set of 15 sol-
vents of different polarity. The effect of specific and non-
specific solvent–solute interactions on the position of their
absorption bands was evaluated by using the solvent
parameter sets of Kamlet and Taft. The interpretation of the
effect of different substituent patterns on the solvatochro-
mic properties of the investigated compounds was based on
quantum chemical calculations performed by the density
functional theory (DFT)/CAM-B3LYP method using the
6-311G(d,p) basis set. The theoretical absorption frequen-
cies show very good agreement with the experimental
values. The energy gaps between the HOMO and LUMO
orbitals were also analyzed. It is demonstrated that differ-
ent substituents change the conjugation effect and further
determine the pathways of intramolecular charge transfer.
Succinimides (pyrrolidine-2,5-diones) are commonly used
anticonvulsant drugs in the management of absence (petit
mal) seizures. They suppress the paroxysmal 3 Hz spike-
and-wave activity associated with lapses of consciousness;
thus, the frequency of seizures is reduced and the seizure
threshold increases [1]. The therapeutic action of succini-
mide anticonvulsants results primarily from a decrease in
T-type calcium channel activity [2, 3]. Ethosuximide
(3-ethyl-3-methylpyrrolidine-2,5-dione) is the most commonly
used among these anticonvulsants, whereas methsuximide
(1,3-dimethyl-3-phenylpyrrolidine-2,5-dione) can be espe-
cially useful in conjunction with other anticonvulsants (e.g.,
phenytoin and phenobarbital) in the management of some
cases of partial seizures with complex symptomatology [4].
Phensuximide (1-methyl-3-phenylpyrrolidine-2,5-dione) is
the least toxic, but the least effective of the succinimide
anticonvulsants and its beneficial effects often decrease
during long-term therapy [4]. Because monotherapy with
classical anticonvulsants sometimes fails, patients need
additional drugs or a novel one to suppress seizures.
Experimental evidence indicates that succinimides may be
good candidates for new anticonvulsants, because many of
them are effective in the maximal electroshock (MES)
and subcutaneous pentylenetetrazole (scPTZ) screens that
are established as standards in the early stages of drug
testing [5–7].
Keywords Succinimides ꢀ Absorption spectra ꢀ
Solvent effect ꢀ Quantum chemical calculations
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-013-1052-1) contains supplementary
material, which is available to authorized users.
ˇ
´
´
ˇ´
´
N. Banjac ꢀ N. Trisovic ꢀ N. Valentic ꢀ G. Uscumlic (&)
Faculty of Technology and Metallurgy,
University of Belgrade, Belgrade, Serbia
e-mail: goca@tmf.bg.ac.rs
In the search of new central nervous system (CNS)-
active drug candidates, key features of a molecule which
promote its interaction with a specific receptor have often
been identified through the analysis of the potential of the
interaction of that molecule with other systems in its
vicinity [8]. The computation of the molecular electrostatic
potential energy (MEP) distribution has enabled the
ˇ
Z. Vitnik
Faculty of Chemistry, University of Belgrade,
Belgrade, Serbia
´
V. Vitnik ꢀ I. Juranic
Department of Chemistry, IChTM-Institute of Chemistry,
Technology, and Metallurgy, University of Belgrade,
Belgrade, Serbia
123

N. Banjac et al.
distinction between active and inactive succinimides on the
basis of the difference between minima of the electrostatic
potential in the points close to the carbonyl oxygens of the
succinimide moiety [9, 10]. This difference is positive for
active derivatives and negative for inactive ones. Further-
more, regression analysis has shown a positive quantitative
correlation between the activity of derivatives of 3-phe-
nylpyrrolidin-2,5-dione in the MES test and the
contribution of the substituent in the aromatic fragment to
the total lipophilicity of the compound [11]. Moreover, it
has been demonstrated that the maximum potency of drugs
acting on the CNS is obtained for derivatives with an
optimum lipophilicity (expressed as octanol–water parti-
tion coefficient, log P) close to 2 [12, 13]. Lipophilicity is
directly related to the change in Gibbs energy of solvation
of a molecule between octanol and water; its dipolarity/
polarizability and hydrogen bond basicity, in particular,
favor partitioning into water and thus decrease lipophilic-
ity, whereas molecular size favors octanol [14, 15].
Because of this, the solvational characteristics of succini-
mides need to be taken into account to get at a better
insight into the features responsible for the anticonvulsant
activity and, thereby, to develop some general principles
that might be helpful in the design of new active
compounds.
structural features which are related to the ADMET
(absorption, distribution, metabolism, excretion, and tox-
icity in pharmacokinetics) parameters, obtained by the
established computational medicinal chemistry methods. In
view of the results of this study the investigated succini-
mides meet the pharmacokinetic criteria of preselection of
drug candidates and hence qualify for the pharmacody-
namic phase of drug development. In addition, compounds
1d, 1e, 1i, and 1j appear to possess the best compromise
between human intestinal absorption and plasma protein
binding features. The absorption spectra of 1-aryl-3-phe-
nyl- and 1-aryl-3,3-diphenylpyrrolidine-2,5-diones were
recorded in the range from 200 to 400 nm in the selected
solvents of different polarities. The effects of different
substituents as well as solvent dipolarity/polarizability and
solvent–solute hydrogen bonding interactions on the
absorption maxima shifts were closely examined to eluci-
date the information relevant to the intramolecular charge
transfer (ICT) within the investigated compounds. In this
context, theoretical calculations were performed by the
density functional theory (DFT)/CAM-B3LYP method
using the 6-311G(d,p) basis set.
Results and discussion
The present research is directed towards the synthesis
and characterization of two series of 1-aryl-3-phenyl-
(1a–1j) and 1-aryl-3,3-diphenylpyrrolidine-2,5-diones (2a–2n)
as potentially new anticonvulsant agents (Fig. 1). In our
previous research [16], we established relationships
between their chromatographic data and the selected
1-Aryl-3-phenylpyrrolidine-2,5-diones 1a–1j were pre-
pared from 2-phenylsuccinic acid (3) and the corresponding
anilines 4 under solvent-free conditions (Scheme 1). For the
synthesis of 1-aryl-3,3-diphenylpyrrolidine-2,5-diones
2a–2n, diphenylacetonitrile (5) was alkylated with ethyl
bromoacetate to give the cyano-ester 6. Hydrolysis to
2,2-diphenylsuccinic acid (7) and ring closure provides the
anhydride 8. The subsequent reaction of 8 with anilines 4
gives the corresponding succinimic acids 9, which were
further cyclized to 1-aryl-3,3-diphenylpyrrolidine-2,5-di-
ones 2a–2n in refluxing acetyl chloride (Scheme 2).
The absorption spectra of the investigated succinimides
were recorded in the range from 200 to 400 nm in 15
solvents. The wavelengths corresponding to the most
intense absorption maxima are collected in Table 1 and
characteristic examples are presented in the Electronic
Supplementary Material (Figs. S1–S6). Evidently, the
absorption spectra show similar experimental features, i.e.,
Fig. 1 Chemical structure of the investigated succinimides with the
atoms and torsion angles labeled
123

Solvatochromic and quantum chemical investigations of newly synthesized succinimides
s and a in Eq. (1) measure the relative susceptibilities of
the absorption maxima shift to the indicated solvent
parameters.
The Kamlet–Taft parameters for the solvents used in
correlations are listed in Table 2. The regression values m0,
a, and s fit at the 95 % confidence level are given in
Table 3. With exclusion of diethyl ether, diisopropyl ether,
and tetrahydrofuran, correlation coefficients (R) greater
than 0.98 are obtained, which indicates the high validity of
the multiparameter equations and allows significant con-
clusions to be drawn. The degree of success of the
quantification and interpretation of solvent effects on the
position of the most intense absorption band is illustrated in
Fig. 2 by means of a plot of m measured (mexp) versus m
calculated (mcalc) in different solvents (series 1: R = 0.992,
sd = 0.59, F = 7,922; series 2: R = 0.996, sd = 0.45,
F = 16,197).
The strongest influence on the solvatochromic behavior
of the investigated succinimides is exerted by solvent
hydrogen bond acidity. The positive sign of the coefficient
a (Table 3) is caused by the hydrogen bonding between
HBD solvents and the carbonyl groups, which reduces their
electron density and decreases the ICT character of the
chromophoric system. The investigated succinimides show
positive solvatochromism with regard to the parameter p*
(as shown by the negative s coefficients in Table 3), which
indicates that the electronically excited state has a higher
dipole moment than the ground state and experiences
stronger solvation [18, 19]. The variation in the magnitude
of the s coefficient results from the different pathways of
ICT which is mainly caused by electronic effects of the
substituent X.
there are one or two peaks corresponding to p–p* transi-
tions.1 The UV absorption of the investigated succinimides
is more solvent-dependent than substituent-dependent. A
hypsochromic shift was observed as a function of solvent
polarity and hydrogen bonding ability.
A solvatochromic study allowed us to gain an insight
into the interactions of the investigated molecules with
their surrounding. The effect of solvent dipolarity/polar-
izabilty (non-specific solvent–solute interactions) and
hydrogen bonding (specific solvent–solute interactions) on
the absorption maxima shifts were interpreted by using the
simplified Kamlet–Taft equation [17] of the form
As a result of the resonant interaction with the phenyl
ring, electron-donating substituents cause an increase in
electron density on the oxygen atoms of the pyrrolidine-
2,5-dione system (Table 4), whereby the O(6) is less
electron-rich than that of O(7) owing to the vicinity of the
electronegative phenyl group in position 3. This shift of
electron density towards the oxygen atoms produces a
polarization of the molecules and the oxygen atoms
become preferred sites for the HBD attack. DFT calcula-
tions indicate non-planar conformations of the investigated
succinimides (Table 5). The bond length of the carbonyl
groups gets longer and the deviation from planarity
(expressed in terms of dihedral angle h, Fig. 1) decreases
with increasing electron-donating ability of the substituent
X. When X is an electron-accepting substituent, the
polarization of the molecule results mainly from the elec-
tron-accepting competition between the aryl group in
position 1 and the carbonyl groups of the succinimide
moiety. The bond length of the carbonyl groups is slightly
decreased and the deviation from co-planarity between
these two rings is increased.
m ¼ m0 þ spꢁ þ aa
ð1Þ
where p* is an index of the solvent dipolarity/polarizabilty,
a is a measure of the solvent hydrogen bonding donor
(HBD) acidity, and m0 is the regression value of this solute
property in cyclohexane as reference solvent. The solvent
hydrogen bond basicity parameter b is not significant in
these correlations. The solvent-independent coefficients
1
Optimized structures of our compounds are of C1 symmetry (no
symmetry elements). Therefore, it is hard to identify clear p or r
orbitals, except for local molecular fragments. By visual inspection
most orbitals are of p character on the benzene (phenyl) rings, but for
a molecule as a whole it is impossible to define a p-nodal plane. All
calculated electron transitions involve several electronic transitions
among various pairs of orbitals.
123

N. Banjac et al.
Table 1 Absorption maxima of the investigated succinimides in the selected solvents
Solvent
Compound, m/103 cm-1
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
Methanol
47.53
47.85
47.71
47.48
46.86
46.51
46.08
42.95
39.69
47.52
38.55
39.37
39.87
37.65
37.62
46.25
47.71
47.62
48.08
47.89
47.85
45.62
43.78
40.21
47.91
38.52
39.37
39.87
37.68
37.65
48.17
48.26
48.69
48.88
48.03
47.80
46.77
41.96
39.73
47.72
38.31
39.49
39.59
37.31
36.66
47.44
47.48
47.98
48.40
47.04
46.86
43.74
43.05
39.91
47.17
38.49
39.75
39.71
37.68
37.68
47.48
48.08
48.08
47.98
46.99
46.73
46.13
43.82
39.77
47.73
38.46
39.71
39.65
37.68
37.62
47.48
47.39
47.35
48.03
47.17
47.17
46.51
43.91
37.83
47.87
35.77
38.46
36.42
35.79
35.54
47.89
47.89
47.44
48.31
48.08
47.80
46.95
43.47
39.19
47.43
37.82
38.76
38.82
37.17
37.12
47.66
47.44
47.39
47.98
46.73
46.90
46.43
43.81
39.61
47.52
38.58
39.37
39.56
37.68
37.59
47.13
47.57
47.48
47.48
46.73
47.04
46.21
43.27
39.71
46.79
38.49
39.40
39.56
37.68
37.57
47.08
46.99
46.60
47.21
46.43
46.73
46.25
43.85
39.70
46.37
38.70
39.37
39.71
37.68
37.68
Ethanol
1-Propanol
2-Propanol
1-Butanol
2-Methyl-2-propanol
Diethyl ether
Diisopropyl ether
Dioxan
Tetrahydrofuran
Dimethyl sulfoxide
Methyl acetate
Ethyl acetate
N,N-Dimethylformamide
N,N-Dimethylacetamide
Solvent
Compound, m/103 cm-1
2a 2b 2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Methanol
48.45 48.54 48.50 48.59 48.64 48.64 48.69 48.69 48.59 48.78 48.69 48.45 48.54 48.50
48.69 48.73 48.88 48.78 48.78 48.83 48.83 48.69 48.69 48.78 48.73 48.78 48.69 48.69
47.89 48.03 48.08 47.98 47.85 47.89 48.08 47.94 48.03 47.89 47.98 47.94 47.98 47.85
48.45 48.45 48.54 48.50 48.45 48.40 48.45 48.50 48.54 48.45 48.45 48.50 48.45 48.08
48.54 48.59 48.64 48.56 48.59 48.58 48.59 48.52 48.63 48.45 48.31 48.52 48.55 48.29
47.94 47.98 48.02 47.86 47.96 47.94 47.88 47.79 48.01 47.62 47.33 47.85 47.92 47.15
47.21 47.21 47.44 47.30 47.08 47.13 47.26 47.35 47.35 47.35 47.35 47.35 47.44 47.13
43.33 43.22 43.18 42.37 43.14 42.96 42.30 42.30 43.29 41.02 39.68 42.37 43.03 41.08
39.59 39.59 39.37 39.59 39.59 39.59 39.59 39.22 39.43 39.22 38.91 39.59 39.59 39.59
47.13 46.99 47.21 47.08 47.08 47.13 47.17 47.17 47.13 47.21 47.17 47.17 47.13 47.04
38.37 38.34 38.28 38.28 38.31 38.37 38.37 38.20 38.26 38.14 38.11 38.31 38.37 38.28
39.40 39.46 39.59 39.49 39.43 39.53 39.53 39.49 39.40 39.56 39.43 39.56 39.56 39.59
39.59 39.56 39.56 39.59 39.46 39.56 39.56 39.46 39.49 39.43 39.37 39.59 39.59 39.59
Ethanol
1-Propanol
2-Propanol
1-Butanol
2-Methylpropanol
Diethyl ether
Diisopropyl ether
Dioxan
Tetrahydrofuran
Dimethyl sulfoxide
Methyl acetate
Ethyl acetate
N,N-Dimethylformamide 37.57 37.57 37.54 37.57 37.57 37.57 37.54 37.51 37.48 37.37 37.37 37.37 37.57 37.57
N,N-Dimethylacetamide 35.56 35.56 35.61 35.49 35.56 35.56 35.56 35.59 35.41 35.49 35.49 35.36 35.64 35.54
Furthermore, we have placed emphasis on the sub-
stituent effects on the ICT process, which is relevant to the
excited state properties of the investigated compounds.
According to the DFT calculations, if X is an electron-
donating substituent, the electron density of the HOMO
orbitals is localized on the aryl group in position 1 and the
imide part of the succinimide ring (1c and 2c, Figs. 3 and
4). The electron density of the LUMO orbitals is mainly
localized on the pyrrolidine-2,5-dione and 3-phenyl moie-
ties. When X is a strong electron-accepting substituent, the
situation is reversed (Figs. 3 and 4). The electron density of
HOMO orbital for 1f and 2i is dominantly populated on the
pyrrolidine-2,5-dione and 3-phenyl moieties, whereas the
electron density of the LUMO orbitals is shifted towards
the aryl group in position 1. It should be noted that the
electron density of the HOMO and LUMO orbitals for 2a is
delocalized over the whole molecule which indicates their
weaker ICT character than that of the other investigated
succinimides.
Within the individual series of compounds, the unsub-
stituted compounds (1a and 2a) have a larger energy gap
between the HOMO and LUMO orbitals than that in the
substituted ones. The energy gap of 1a is 8.55 eV, whereas
the energy gaps of 1c and 1f are 7.96 and 7.41 eV,
respectively, and this order is consistent with the com-
pounds of series 2. The introduction of an additional phenyl
123

Solvatochromic and quantum chemical investigations of newly synthesized succinimides
ring into position 3 lowers the LUMO energy of the un-
substituted compound and compounds with electron-
donating substituents and the HOMO energy of the com-
pounds with an electron-accepting substituent. The net
result is that the energy gap between the HOMO and
LUMO orbitals is somewhat smaller for the compounds in
series 2 than for corresponding compounds in series 1 with
the same substituent X. It should be pointed out that the
lowering of the HOMO–LUMO energy gap has a sub-
stantial influence not only on ICT, but also on the
biological activity of compounds.
Finally, the MEP surface maps of compounds 1a and 2a
indicate that the most suitable sites for electrophilic attack
are O(6) and O(7) atoms, whereas the most probable sites,
which can be involved in nucleophilic process, are at C(3)
and C(4) atoms of the pyrrolidine-2,5-dione moiety
(Fig. 5).
Table 2 Kamlet–Taft parameters of the selected solvents [17]
Solvent
p
a
Methanol
0.6
0.93
0.83
0.78
0.76
0.79
0.68
0
Ethanol
0.54
0.52
0.48
0.47
0.41
0.27
0.27
0.55
0.58
1
1-Propanol
2-Propanol
1-Butanol
Conclusions
2-Methyl-2-propanol
Diethyl ether
We have presented the synthesis and characterization of two
series of 1-aryl-3-phenyl- and 1-aryl-3,3-diphenylpyrroli-
dine-2,5-diones. The evaluation of the solvatochromic
properties of these succinimides was carried out by using
the Kamlet–Taft solvent parameter scale. The strongest
influence on the solvatochromic properties was exerted by
specific interactions through hydrogen bonding between
HBD solvents and the carbonyl groups of the succinimide
moiety. With the help of quantum chemical calculations,
Diisopropyl ether
Dioxan
0
0
Tetrahydrofuran
Dimethyl sulfoxide
Ethyl acetate
0
0
0.55
0.6
0
Methyl acetate
N,N-Dimethylformamide
N,N-Dimethylacetamide
0
0.88
0.88
0
0
Table 3 Regression fits to
solvent parameters
Compound
m0/103 cm-1
s/103 cm-1
a/103 cm-1
Ra
sdb
Fc
1a
1b
1c
1d
1e
1f
42.07 ( 1.07)
43.87 ( 1.66)
43.09 ( 1.46)
42.76 ( 1.30)
42.41 ( 1.23)
41.03 ( 1.50)
42.03 ( 1.13)
42.01 ( 1.12)
42.36 ( 1.14)
42.18 ( 1.04)
43.03 ( 1.40)
43.04 ( 1.38)
43.03 ( 1.37)
43.07 ( 1.39)
42.92 ( 1.37)
42.99 ( 1.38)
42.95 ( 1.37)
42.68 ( 1.31)
42.99 ( 1.41)
42.66 ( 1.33)
42.23 ( 1.33)
43.23 ( 1.46)
43.06 ( 1.36)
42.76 ( 1.36)
-4.40 ( 1.34)
-6.60 ( 2.08)
-6.11 ( 1.83)
-5.19 ( 1.63)
-4.81 ( 1.54)
-5.85 ( 1.88)
-5.16 ( 1.41)
-4.37 ( 1.41)
-4.83 ( 1.43)
-4.50 ( 1.31)
-6.27 ( 1.83)
-6.29 ( 1.81)
-6.29 ( 1.80)
-6.34 ( 1.82)
-6.16 ( 1.79)
-6.19 ( 1.82)
-6.16 ( 1.80)
-5.94 ( 1.72)
-6.34 ( 1.85)
-5.98 ( 1.74)
-5.53 ( 1.74)
-6.60 ( 1.92)
-6.25 ( 1.78)
-5.92 ( 1.79)
9.37 ( 0.63)
8.74 ( 0.98)
10.37 ( 0.86)
9.25 ( 0.76)
9.48 ( 0.72)
11.70 ( 0.88)
10.59 ( 0.66)
9.45 ( 0.66)
9.14 ( 0.67)
8.67 ( 0.61)
10.59 ( 0.83)
10.67 ( 0.82)
10.76 ( 0.81)
10.67 ( 0.82)
10.73 ( 0.81)
10.68 ( 0.82)
10.75 ( 0.81)
10.87 ( 0.78)
10.81 ( 0.83)
10.90 ( 0.79)
11.05 ( 0.79)
10.58 ( 0.87)
10.59 ( 0.80)
10.4 5( 0.81)
0.993
0.985
0.991
0.991
0.992
0.992
0.994
0.993
0.992
0.993
0.988
0.989
0.989
0.989
0.989
0.989
0.989
0.990
0.989
0.990
0.990
0.987
0.989
0.989
0.60
0.92
0.81
0.72
0.68
0.83
0.63
0.63
0.63
0.58
0.89
0.88
0.88
0.89
0.87
0.89
0.88
0.84
0.90
0.85
0.85
0.94
0.87
0.87
295
128
211
208
235
240
345
271
259
275
191
198
202
196
203
196
200
222
195
218
218
176
201
193
1g
1h
1i
1j
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
a
Regression coefficient
2m
2n
b
Standard deviation
c
Fisher test
123

N. Banjac et al.
Fig. 2 Relationship between calculated and experimental values of absorption frequencies for the investigated succinimides, according to the
Kamlet–Taft equation (Eq. 1)
Table 4 NBO charge of the
atoms of the succinimide moiety
Compound
C(2)
N(1)
C(5)
O(6)
O(7)
1a
1b
1c
1d
1e
1f
0.758
0.757
0.756
0.758
0.758
0.760
0.759
0.758
0.758
0.759
0.769
0.769
0.768
0.768
0.769
0.770
0.770
0.770
0.772
0.772
0.771
0.770
0.771
0.772
-0.528
-0.527
-0.524
-0.528
-0.528
-0.533
-0.531
-0.528
-0.530
-0.530
-0.525
-0.523
-0.521
-0.521
-0.524
-0.525
-0.525
-0.525
-0.529
-0.529
-0.527
-0.526
-0.526
-0.528
0.743
0.743
0.742
0.744
0.744
0.746
0.744
0.743
0.745
0.744
0.747
0.747
0.746
0.746
0.747
0.748
0.748
0.748
0.749
0.749
0.748
0.747
0.748
0.749
-0.575
-0.576
-0.578
-0.574
-0.574
-0.570
-0.574
-0.576
-0.571
-0.573
-0.587
-0.588
-0.590
-0.589
-0.587
-0.586
-0.586
-0.586
-0.582
-0.583
-0.586
-0.586
-0.586
-0.584
-0.579
-0.580
-0.581
-0.578
-0.578
-0.574
-0.575
-0.579
-0.577
-0.576
-0.576
-0.578
-0.578
-0.580
-0.577
-0.576
-0.576
-0.576
-0.573
-0.574
-0.573
-0.574
-0.574
-0.576
1g
1h
1i
1j
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
the transmission of substituent effects through the molec-
ular skeleton and the nature of the HOMO and LUMO
orbitals were additionally examined. We have demonstrated
that substituents on the phenyl ring in position 1 signifi-
cantly change the conjugation effect and further affect the
ICT character of the investigated succinimides.
Experimental
Commercially available materials were used without fur-
ther purification. The chemical structures and the purities
of the synthesized succinimide derivatives were confirmed
by melting points, elemental analysis, FT-IR, H and 13C
1
This investigation of substituent effects on the solvato-
chromic properties controlled by the ICT character of
succinimides is helpful to understand the interactions with
their environment and may contribute to the design of new
compounds with improved pharmacokinetic properties.
NMR spectra. Elemental analysis was realized using an
Elemental Vario EL III microanalyzer; the results were
found to be in good agreement ( 0.3 %) with the calcu-
lated values. FT-IR spectra were recorded on a Bomem MB
1
100 spectrometer in the form of KBr pellets. H and 13C
123

Solvatochromic and quantum chemical investigations of newly synthesized succinimides
˚
Table 5 Results obtained from the CAM-B3LYP/6-311G(d,p) geometry optimization (bond lengths/A; angles/°) for the investigated
succinimides
Compound
N(1)–C(2)
N(1)–C(5)
C(4)–C(5)
C(3)–C(4)
C(2)–C(3)
N(1)–C(10)
C(2)=O(6)
C(5)=O(7)
h
1a
1.400
1.399
1.398
1.401
1.402
1.405
1.402
1.399
1.402
1.402
1.397
1.396
1.395
1.396
1.397
1.399
1.399
1.399
1.403
1.402
1.400
1.397
1.399
1.401
1.361
1.401
1.400
1.399
1.402
1.402
1.405
1.404
1.401
1.403
1.403
1.401
1.400
1.399
1.399
1.401
1.402
1.402
1.402
1.405
1.404
1.403
1.401
1.402
1.403
1.380
1.513
1.514
1.514
1.513
1.513
1.512
1.513
1.514
1.513
1.513
1.509
1.509
1.509
1.509
1.509
1.508
1.508
1.508
1.507
1.507
1.508
1.509
1.508
1.508
1.513
1.529
1.529
1.529
1.529
1.529
1.529
1.529
1.529
1.529
1.529
1.537
1.537
1.537
1.538
1.537
1.537
1.537
1.537
1.537
1.537
1.537
1.537
1.537
1.538
1.524
1.530
1.530
1.530
1.529
1.529
1.528
1.529
1.530
1.529
1.529
1.541
1.541
1.541
1.541
1.540
1.540
1.540
1.540
1.538
1.539
1.540
1.541
1.540
1.539
1.504
1.429
1.429
1.429
1.427
1.427
1.424
1.426
1.430
1.427
1.427
1.429
1.429
1.429
1.429
1.428
1.427
1.427
1.426
1.423
1.424
1.426
1.429
1.426
1.425
–
1.197
1.198
1.198
1.197
1.197
1.197
1.197
1.198
1.197
1.197
1.199
1.199
1.200
1.200
1.199
1.199
1.199
1.199
1.198
1.198
1.199
1.199
1.199
1.199
1.225
1.199
1.199
1.199
1.199
1.199
1.198
1.198
1.199
1.199
1.198
1.199
1.199
1.199
1.200
1.199
1.199
1.199
1.199
1.198
1.198
1.198
1.198
1.198
1.199
1.212
42.2
42.7
42.8
40.0
39.7
37.5
39.4
43.5
40.2
40.4
1b
1c
1d
1e
1f
1g
1h
1i
1j
2a
137.7
137.8
136.8
137.1
138.5
140.5
140.7
141.2
143.1
141.1
140.9
137.4
140.0
141.1
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Succinimidea
a
Experimental values from X-ray geometry [20]
NMR spectra were recorded on a Varian Gemini 200
spectrometer at 200 MHz for the 1H NMR and 50 MHz for
the 13C NMR spectra. The spectra were recorded at room
temperature in CDCl3 and DMSO-d6. The chemical shifts
are expressed in ppm relative to TMS (d(H) = 0 ppm) in
the 1H NMR and the residual solvent signal (CDCl3:
d(C) = 77 ppm; DMSO-d6: d(C) = 39.5 ppm) in the 13C
NMR spectra. The coupling constants J(H,H) are expressed
in Hz. The UV absorption spectra were measured in
spectroquality solvents (Fluka) at 1 9 10-5 mol dm-3
concentration with a Shimadzu 1700 spectrophotometer.
2-Phenylsuccinic acid (4.1 g, 0.021 mol) and the cor-
responding aniline (0.028 mol) were placed into 100-cm3
flask equipped with a reflux condenser and a magnetic
stirrer. The reaction mixture was heated in an oil bath at
180 °C until it became liquid. The heating was continued
for a further 3 h at 180 °C. The reaction mixture was
allowed to cool to room temperature, during which time it
solidified. Recrystallization of the solid from an ethanol/
water mixture yielded a crystalline product. The melting
1
points, FT-IR, H and 13C NMR spectra of compounds
1a–1e are in agreement with literature data (Table 6) and
undoubtedly corroborate their structures.
General procedure for the preparation of
1-(3- and 4-substituted phenyl)-3-phenylpyrrolidine-
2,5-diones 1a–1j
1-(4-Nitrophenyl)-3-phenylpyrrolidine-2,5-dione
(1f, C16H12N2O4)
Yellow crystalline solid; yield: 37 %; m.p.: 110–113 °C;
IR (KBr): v = 1,779 (C=O), 1,711 (C=O) cm-1; 1H NMR
(200 MHz, CDCl3): d = 8.28 (d, J = 9.6 Hz, 2H, Ar),
7.59 (d, J = 9.0 Hz, 2H, Ar), 7.45–7.25 (m, 5H, Ph), 4.22
(dd, J = 5.1 Hz, 9.5 Hz, 1H, H–C(3)), 3.40 (dd,
All of the investigated 1-aryl-3-phenylpyrrolidine-2,5-di-
ones were synthesized from 2-phenylsuccinic acid (3) and
the corresponding aniline 4 using a modified literature
procedure (Scheme 1) [21].
123

N. Banjac et al.
Fig. 3 Molecular orbitals and
HOMO–LUMO energy gaps for
1a, 1c, and 1f (color figure
online)
Fig. 4 Molecular orbitals and
HOMO–LUMO energy gaps for
2a, 2c, and 2i (color figure
online)
J = 9.8 Hz, 18.8 Hz, 1H, H–C(4)), 3.02 (dd, J = 5.0 Hz,
18.6 Hz, 1H, H–C(4)) ppm; 13C NMR (50 MHz, CDCl3):
d = 175.9 (C(5)), 174.2 (C(2)), 146.8, 137.3, 136.4, 129.3,
128.2, 127.3, 126.8, 124.2, 45.8 (C(3)), 36.9 (C(4)) ppm.
4.20 (dd, J = 5.0 Hz, 9.6 Hz, 1H, H–C(3)), 3.37 (dd,
J = 9.8 Hz, 18.8 Hz, 1H, H–C(4)), 3.00 (dd, J = 5.1 Hz,
18.5 Hz, 1H, H–C(4)), 2.59 (s, 3H, COMe) ppm; 13C NMR
(50 MHz, CDCl3): d = 197.0, 176.2 (C(5)), 174.6 (C(2)),
136.7, 136.6, 135.9, 129.2, 129.0, 128.0, 127.3, 126.3, 45.8
(C(3)), 37.0 (C(4)), 26.5 ppm.
1-(4-Acetylphenyl)-3-phenylpyrrolidine-2,5-dione
(1g, C18H15NO3)
White crystalline solid; yield: 29 %; m.p.: 108–113 °C; IR
1-(3-Methylphenyl)-3-phenylpyrrolidine-2,5-dione
(1h, C17H15NO2)
1
(KBr): v = 1,780 (C=O), 1,708 (C=O) cm-1; H NMR
(200 MHz, CDCl3): d = 8.02 (d, J = 8.4 Hz, 2H, Ar),
7.46 (d, J = 8.4 Hz, 2H, Ph), 7.39–7.27 (m, 5H, Ar ? Ph),
White crystalline solid; yield: 45 %; m.p.: 84–88 °C; IR
1
(KBr): v = 1,781 (C=O), 1,707 (C=O) cm-1; H NMR
123

Solvatochromic and quantum chemical investigations of newly synthesized succinimides
Fig. 5 Molecular electrostatic
potential (MEP) maps of 1a and
2a (color figure online)
Table 6 Synthesis of compounds 1a–1e
General procedure for the preparation of 1-(3- and 4-
substituted phenyl)-3,3-diphenylpyrrolidine-2,5-diones
Compound
Yield/%
M.p./°C
2a–2n
Found
Reported
All of the investigated 1-aryl-3,3-diphenylpyrrolidine-2,5-
diones were synthesized from 2,2-diphenylsuccinic acid
anhydride (8) and the corresponding aniline 4 (Scheme 2)
using a modified literature procedure [23, 24]. 2,2-Diphe-
nylsuccinic acid anhydride (8) was previously synthesized
by the method of Miller and Long [24].
1a
1b
1c
1d
1e
53
40
61
34
34
134–137
145–147
162–164
160–162
156–158
135–138 [22]
145–147 [22]
161–162 [22]
158–162 [22]
155–158 [22]
Acetone (10 cm3), 1.26 g 2,2-diphenylsuccinic acid
anhydride (0.005 mol), and the corresponding aniline
(0.005 mol) were placed into a 50-cm3 flask equipped with a
reflux condenser and a magnetic stirrer. The resulting mixture
was stirred for 4 h atreflux and concentrated to remove excess
acetone. The precipitated crude succinimic acid was taken in
6.5 cm3 of acetyl chloride. The mixture was heated until the
evolution of hydrogen chloride ceased. Acetyl chloride was
evaporated and the crude material was filtered off and re-
crystallized from acetone to yield crystalline product.
(200 MHz, CDCl3): d = 7.42–7.07 (m, 9H, Ar ? Ph), 4.12
(dd, J = 4.6 Hz, 9.6 Hz, 1H, H–C(3)), 3.30 (dd,
J = 9.6 Hz, 18.4 Hz, 1H, H–C(4)), 2.92 (dd, J = 5.0 Hz,
18.6 Hz, 1H, H–C(4)), 2.36 (s, 3H, Me) ppm; 13C NMR
(50 MHz, CDCl3): d = 176.7 (C(5)), 175.3 (C(2)), 139.2,
137.2, 131.7, 129.5, 129.1, 128.9, 127.9, 127.3, 127.0,
123.5, 45.8 (C(3)), 37.1 (C(4)), 21.2 ppm.
1-(3-Chlorophenyl)-3-phenylpyrrolidine-2,5-dione
(1i, C16H12ClNO2)
1,3,3-Triphenylpyrrolidine-2,5-dione (2a, C22H17NO2)
White crystalline solid; yield: 34 %; m.p.: 158–162 °C; IR
White crystalline solid; yield: 39 %; m.p.: 103–107 °C; IR
1
(KBr): v = 1,781 (C=O), 1,706 (C=O) cm-1; H NMR
1
(KBr): v = 1,779 (C=O), 1,713 (C=O) cm-1; H NMR
(200 MHz, CDCl3): d = 7.42–7.19 (m, 9H, Ar ? Ph), 4.13
(dd, J = 5.1 Hz, 9.5 Hz, 1H, H–C(3)), 3.31 (dd,
J = 9.6 Hz, 18.6 Hz, 1H, H–C(4)), 2.93 (dd, J = 5.1 Hz,
18.6 Hz, 1H, H–C(4)) ppm; 13C NMR (50 MHz, CDCl3):
d = 176.2 (C(5)), 174.7 (C(2)), 136.8, 134.6, 132.9, 130.0,
129.2, 128.8, 128.0, 127.3, 126.6, 124.6, 45.8 (C(3)), 36.9
(C(4)) ppm.
(200 MHz, DMSO-d6): d = 7.56–7.28 (m, 15H, Ph), 3.77
(s, 2H, H–C(4)) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 177.7 (C(5)), 174.2 (C(2)), 142.0, 132.4, 129.3, 128.9,
127.7, 127.4, 57.1 (C(3)), 44.5 (C(4)) ppm.
1-(4-Methylphenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2b, C23H19NO2)
White crystalline solid; yield: 31 %; m.p.: 114–116 °C; IR
1-(3-Bromophenyl)-3-phenylpyrrolidine-2,5-dione
(1j, C16H12BrNO2)
1
(KBr): v = 1,779 (C=O), 1,712 (C=O) cm-1; H NMR
(200 MHz, DMSO-d6): d = 7.46–7.28 (m, 12H, Ar ? Ph),
7.17 (d, J = 8.4 Hz, 2H, Ar), 3.75 (s, 2H, H–C(4)), 2.33 (s,
3H, Me) ppm; 13C NMR (50 MHz, DMSO-d6): d = 177.8
(C(5)), 174.3 (C(2)), 142.0, 138.5, 129.8, 129.8, 128.0,
127.7, 127.1, 57.1 (C(3)), 44.4 (C(4)), 20.9 ppm.
White crystalline solid; yield: 37 %; m.p.: 99–104 °C; IR
1
(KBr): v = 1,779 (C=O), 1,707 (C=O) cm-1; H NMR
(200 MHz, CDCl3): d = 7.54–7.24 (m, 9H, Ar ? Ph), 4.14
(dd, J = 5.0 Hz, 9.6 Hz, 1H, H–C(3)), 3.32 (dd,
J = 9.6 Hz, 18.6 Hz, 1H, H–C(4)), 2.95 (dd, J = 5.0 Hz,
18.6 Hz, 1H, H–C(4)) ppm; 13C NMR (50 MHz, CDCl3):
d = 176.2 (C(5)), 174.6 (C(2)), 136.8, 133.0, 131.7, 130.3,
129.4, 129.2, 128.1, 127.3, 125.0, 122.3, 45.8 (C(3)), 37.0
(C(4)) ppm.
1-(4-Methoxyphenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2c, C23H19NO3)
Yellow crystalline solid; yield: 37 %; m.p.: 119–121 °C;
IR (KBr): v = 1,782 (C=O), 1,717 (C=O) cm-1; 1H NMR
123

N. Banjac et al.
(200 MHz, DMSO-d6): d = 7.42–7.28 (m, 10H, Ph), 7.22
(d, J = 9 Hz, 2H, Ar), 7.05 (d, J = 9 Hz, 2H, Ar), 3.78 (s,
3H, OMe), 3.73 (s, 2H, H–C(4)) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 177.9 (C(5)), 174.4 (C(2)), 159.4, 142.1,
128.9, 128.6, 127.7, 125.0, 114.5, 57.0, 55.6 (C(3)), 44.4
(C(4)) ppm.
1-(4-Nitrophenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2i, C22H16N2O4)
White crystalline solid; yield: 29 %; m.p.: 104–106 °C; IR
1
(KBr): v = 1,778 (C=O), 1,715 (C=O) cm-1; H NMR
(200 MHz, DMSO-d6): d = 8.39 (d, J = 9 Hz, 2H, Ar),
7.68 (d, J = 9 Hz, 2H, Ar), 7.44–7.30 (m, 10H, Ph), 3.83
(s, 2H, H–C(4)) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 177.2 (C(5)), 173.6 (C(2)), 147.1, 141.7, 137.9, 129.0,
128.4, 127.8, 127.7, 124.6, 57.2 (C(3)), 44.4 (C(4)) ppm.
1-(4-Hydroxyphenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2d, C22H17NO3)
Dark crystalline solid; yield: 25 %; m.p.: 167–170 °C; IR
1
(KBr): v = 1,761 (C=O), 1,711 (C=O) cm-1; H NMR
1-(4-Cyanophenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2j, C23H16N2O2)
(200 MHz, DMSO-d6): d = 9.80 (s, 1H, OH), 7.42–7.26
(m, 14H, Ar ? Ph), 3.77 (s, 2H, H–C(4)) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 177.7 (C(5)), 174.2 (C(2)),
150.5, 142.0, 129.9, 129.0, 128.8, 128.6, 127.8, 122.9, 57.1
(C(3)), 44.5 (C(4)) ppm.
White crystalline solid; yield: 29 %; m.p.: 129–133 °C; IR
(KBr): v = 1,782 (C=O), 1,714 (C=O) cm-1 1H NMR
;
(200 MHz, DMSO-d6): d = 8.01 (d, J = 8.4 Hz, 2H, Ar),
7.59 (d, J = 8.4 Hz, 2H, Ar), 7.43–7.29 (m, 10H, Ph), 3.81 (s,
2H, H–C(4)) ppm; 13C NMR (50 MHz, DMSO-d6): d =
177.2 (C(5)), 173.7 (C(2)), 141.7, 136.4, 133.4, 129.0, 128.2,
127.8, 127.7, 118.5, 111.5, 57.2 (C(3)), 44.4 (C(4)) ppm.
1-(4-Fluorophenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2e, C22H16FNO2)
White crystalline solid; yield: 27 %; m.p.: 109–111 °C; IR
1
(KBr): v = 1,781 (C=O), 1,714 (C=O) cm-1; H NMR
1-(4-Acetylphenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2k, C24H19NO3)
(200 MHz, DMSO-d6): d = 7.43–7.27 (m, 14H, Ar ? Ph),
3.77 (s, 2H, H–C(4)) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 177.6 (C(5)), 174.2 (C(2)), 164.3, 141.9, 129.7, 129.5,
128.9, 127.7, 116.5, 116.0, 57.1 (C(3)), 44.4 (C(4)) ppm.
White crystalline solid; yield: 34 %; m.p.: 156–158 °C; IR
1
(KBr): v = 1,781 (C=O), 1,713 (C=O) cm-1; H NMR
(200 MHz, DMSO-d6): d = 8.09 (d, J = 8.4 Hz, 2H, Ar),
7.50 (d, J = 8.6 Hz, 2H, Ar), 7.43–7.31 (m, 10H, Ph), 3.80
(s, 2H, H–C(4)), 2.61 (s, 3H, COMe) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 197.5, 177.4 (C(5)), 173.9
(C(2)), 141.8, 136.8, 136.3, 129.2, 129.0, 127.7, 127.4,
57.2 (C(3)), 44.4 (C(4)), 27.0 ppm.
1-(4-Chlorophenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2f, C22H16ClNO2)
White crystalline solid; yield: 23 %; m.p.: 132–135 °C; IR
1
(KBr): v = 1,777 (C=O), 1,711 (C=O) cm-1; H NMR
(200 MHz, DMSO-d6): d = 7.59 (d, J = 8.8 Hz, 2H, Ar),
7.42–7.29 (m, 12H, Ar ? Ph), 3.77 (s, 2H, H–C(4)) ppm;
13C NMR (50 MHz, DMSO-d6): d = 177.5 (C(5)), 174.0
(C(2)), 141.9, 133.4, 131.2, 129.4, 129.2, 129.0, 127.7,
57.1 (C(3)), 44.4 (C(4)) ppm.
1-(3-Hydroxyphenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2l, C22H17NO3)
Dark crystalline solid; yield: 28 %; m.p.: 169–171 °C; IR
1
(KBr): v = 1,778 (C=O), 1,708 (C=O) cm-1; H NMR
(200 MHz, DMSO-d6): d = 9.81 (s, 1H, OH), 7.42–7.25
(m, 11H, Ar ? Ph), 6.86 (d, J = 9.4 Hz, 1H, Ar), 6.73–6.70
(m, 2H, Ar), 3.75 (s, 2H, H–C(4)) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 177.7 (C(5)), 174.2 (C(2)), 158.1, 142.0,
133.4, 130.0, 129.0, 127.8, 117.8, 115.9, 114.3, 57.1 (C(3)),
44.4 (C(4)) ppm.
1-(4-Bromophenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2g, C22H16BrNO2)
White crystalline solid; yield 35 %; m.p.: 150–152 °C; IR
1
(KBr): v = 1,778 (C=O), 1,711 (C=O) cm-1; H NMR
(200 MHz, DMSO-d6): d = 7.73 (d, J = 8.4 Hz, 2H, Ar),
7.42–7.28 (m, 12H, Ar ? Ph), 3.77 (s, 2H, H–C(4)) ppm;
13C NMR (50 MHz, DMSO-d6): d = 177.4 (C(5)), 174.0
(C(2)), 141.9, 132.3, 131.7, 129.5, 129.0, 127.7, 121.9,
57.1 (C(3)), 44.4 (C(4)) ppm.
1-(3-Chlorophenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2m, C22H16ClNO2)
White crystalline solid; yield: 33 %; m.p.: 135–138 °C; IR
1
(KBr): v = 1,783 (C=O), 1,713 (C=O) cm-1; H NMR
1-(4-Iodophenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2h, C22H16INO2)
(200 MHz, DMSO-d6): d = 7.56–7.30 (m, 14H, Ar ? Ph),
3.77 (s, 2H, H–C(4)) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 177.4 (C(5)), 173.9 (C(2)), 141.9, 133.7, 133.4, 131.0,
129.0, 127.8, 127.4, 126.2, 57.1 (C(3)), 44.5 (C(4)) ppm.
White crystalline solid; yield: 25 %; m.p.: 158–160 °C; IR
1
(KBr): v = 1,778 (C=O), 1,712 (C=O) cm-1; H NMR
(200 MHz, DMSO-d6): d = 7.88 (d, J = 8.6 Hz, 2H, Ar),
7.42–7.28 (m, 10H, Ph), 7.14 (d, J = 8.4 Hz, 2H, Ar), 3.76
(s, 2H, H–C(4)) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 177.4 (C(5)), 174.0 (C(2)), 141.9, 138.2, 132.1, 129.5,
129.0, 127.7, 95.0, 57.1 (C(3)), 44.4 (C(4)) ppm.
1-(3-Cyanophenyl)-3,3-diphenylpyrrolidine-2,5-dione
(2n, C23H16N2O2)
White crystalline solid; yield: 33 %; m.p.: 129–133 °C; IR
1
(KBr): v = 1,783 (C=O), 1,711 (C=O) cm-1; H NMR
123

Solvatochromic and quantum chemical investigations of newly synthesized succinimides
2. Coulter DA, Huguenard JR, Prince DA (1989) Ann Neurol
25:582
¨
3. Gomora JC, Daud AN, Weiergraber M, Perez-Reyes E (2001)
Mol Pharmacol 60:1121
4. McEvoy GK (ed) (1995) AHFS Drug Information. American
Society of Health-System Pharmacists, Bethesda
(200 MHz, DMSO-d6): d = 7.95 (s, 1H, Ar), 7.75-7.72 (m,
2H, Ar), 7.42–7.30 (m, 11H, Ar ? Ph), 3.79 (s, 2H, H–
C(4)) ppm; 13C NMR (50 MHz, DMSO-d6): d = 177.3
(C(5)), 173.8 (C(2)), 141.8, 133.2, 132.7, 132.4, 131.0,
130.8, 129.0, 127.8, 118.1, 112.3, 57.1 (C(3)), 44.5 (C(4))
ppm.
´
5. Kaminski K, Obniska J (2008) Bioorg Med Chem 16:4921
6. Obniska J, Byrtus H, Kaminski K, Pawłowski M, Szczesio M,
´
Karolak-Wojciechowska J (2010) Bioorg Med Chem 18:6134
´
Method of calculation
7. Kaminski K, Rzepka S, Obniska J (2011) Bioorg Med Chem Lett
21:5800
8. Murray JS, Abu-Awwad F, Polityer P, Wilson LC, Troupin AS,
Wall RE (1998) Int J Quant Chem 70:1137
9. Kwiatkowski W, Karolak-Wojciechowska J (1993) SAR QSAR
Environ Res 1:233
10. Obniska J, Zajec A, Karolak-Wojciechowska J (1999) Farmaco
54:423
All the calculations were performed using the Gaussian 09
program package [25]. The geometry of the investigated
succinimides was fully optimized with DFT B3LYP/6-
311G(d,p) and CAM-B3LYP/6-311G(d,p) methods without
any constraint on the geometry (for the sake of comparison,
the model compound N-phenylsuccinimde was recalculated
using the MP2 Hamiltonian). The frontier molecular orbital
energies and HOMO–LUMO energy gaps were also cal-
culated with the same methods. The natural bond orbital
(NBO) analysis [26] was performed using NBO 3.1 pro-
gram implemented in the Gaussian 09 program package at
the same level of theory (results obtained from the B3LYP/
6-311G(d,p) calculation are given in the Electronic Sup-
plementary Material). The UV absorption energies of
compounds 1a, 1c, 1f, 2a, 2c, and 2i were calculated by the
time-dependant DFT method in ethanol solvent on the
geometry optimized with the CAM-B3LYP/6-311G(d,p)
method in combination with the conductor-like polarizable
continuum model (CPCM) [27]. Initially, 50 electron tran-
sitions were calculated, but for the purpose of discussion we
only considered (unscaled) electron transitions associated
with wavelengths longer than 170 nm. The convolution of
calculated spectra was done using GaussView 5 [28].
Comparing experimental and calculated spectra, we derived
the regression equation (R2 = 0.993), which gives a scaling
factor 0.847 and shift 51 nm (results for CAM-B3LYP/6-
311G(d,p) and B3LYP/6-311G(d,p) calculations are given
in the Electronic Supplementary Material).
11. Lapszewicz J, Lange J, Rump S, Walczyna K (1978) Eur J Med
Chem 13:465
¨
12. Hansch C, Bjorkrotahn JP, Leo A (1987) J Pharm Sci 76:663
13. Hadjipavlou-Litina D (1998) Med Res Rev 18:91
14. Abraham MH, Lieb WR, Franks NP (1991) J Pharm Sci 80:719
15. Abraham MH (1993) Pure Appl Chem 65:2503
16. Perisic-Janjic N, Kaliszan R, Wiczling P, Milosevic N, Uscumlic
G, Banjac N (2011) Mol Pharm 8:555
17. Kamlet MJ, Abboud JLM, Abraham MH, Taft RW (1983) J Org
Chem 48:2877
18. Hofmann K, Brumm S, Mende C, Nagel K, Seifert A, Roth I,
Schaarschmidt D, Langc H, Spange S (2012) New J Chem
36:1655
19. Riedel F, Spange S (2012) J Phys Org Chem 25:1261
20. Yu M, Huang X, Gao F (2012) Acta Cryst E 68:o2738
21. Sanna A (1927) Gazz Chim Ital 57:761
22. Barman G, Roy M, Ray JK (2008) Tetrahedron Lett 49:1405
23. Katritzky AR, Nair SK, Witek RM, Hutchins SM (2003)
ARKIVOC 5:9
24. Miller CA, Long LM (1951) J Am Chem Soc 73:4895
25. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson
GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF,
Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K,
Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao
O, Nakai H, Vreven T, Montgomery JA, Peralta JE Jr, Ogliaro F,
Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN,
Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A,
Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM,
Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J,
Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R,
Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski
VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels
AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ
(2010) Gaussian 09, revision C.01. Gaussian, Wallingford, CT
26. Glendening ED, Reed AE, Carpenter JE, Weinhold F (1998)
NBO version 3.1, TCI, University of Wisconsin, Madison
27. Cossi M, Rega N, Scalmani G, Barone V (2003) J Comput Chem
24:669
To investigate the reactive sites of the succinimides the
molecular electrostatic potentials were evaluated using the
B3LYP/6-311G(d,p) method and MEP surfaces were
plotted for the isosurfaces of 0.002 a.u. electron density.
Acknowledgments This work was performed within the framework
of the research Projects Nos. ON 172013 and 172035, supported by
the Ministry of Education, Science and Technological Development
of the Republic of Serbia.
28. Dennington R, Keith T, Millam J (2009) GaussView, version
5.0.9. Semichem, Shawnee Mission, KS
References
1. LeDuc B (2008) In: Lemke TL, Williams DA (eds) Foye’s
principles of medicinal chemistry, 6th edn. Lippincott Williams
and Wilkins, Philadelphia
123