Tautomeric forms of N-(5-nitrosalicylidene)-2-butylamine: Experimental and theoretical DFT study

Article abstract of DOI:10.1016/j.molstruc.2009.03.007

Tautomeric forms of N-(5-nitrosalicylidene)-2-butylamine in various solvents were studied with the IR and NMR (¹H, ¹³C) spectroscopy. Also computational studies of keto-amine (O···HN) and enol-imine (OH···N) tautomers of N-(5-nitrosa

Full text of DOI:10.1016/j.molstruc.2009.03.007

Journal of Molecular Structure 928 (2009) 25–31
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Tautomeric forms of N-(5-nitrosalicylidene)-2-butylamine: Experimental
and theoretical DFT study
a
b,
c
c
*
´
B. Kukawska-Tarnawska , A. Les , T. Dziembowska , Z.J. Rozwadowski
a Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
b Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
c Institute of Chemistry and Environmental Protection, Szczecin University of Technology, Aleja Piastów 42, 71-0 65 Szczecin, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Tautomeric forms of N-(5-nitrosalicylidene)-2-butylamine in various solvents were studied with the IR
and NMR (1H, 13C) spectroscopy. Also computational studies of keto-amine (OꢀꢀꢀHN) and enol-imine
(OHꢀꢀꢀN) tautomers of N-(5-nitrosalicylidene)-2-butylamine molecule in the ground state were carried
out with the DFT and SCRF theory at B3LYP/6-31G(d,p) level. Experimental data show that the solvent
can invert the keto-amino: enol-imine equilibrium. The enol-imine tautomer prevails in non polar CCl4
and weakly polar CDCl3 or CD2Cl2 solvents, while in polar CD3CN solvent the keto-amine form dominates.
Theoretical results agree qualitatively with the experimental findings and suggest also that predomi-
nance of particular tautomers can be influenced by the aliphatic chain geometry. Theoretical enol-imine
model structure corresponding to the vacuum or non polar environment e.g.CCl4 is more stable than the
keto-amino counterpart. On the contrary, the keto-amino form is predicted to be more stable than the
enol-imine form in aqueous or in CH3CN polar environments. A satisfactory correlation between theoret-
ical 1H and 13C shielding constants and experimental 1H and 13C chemical shifts becomes an additional
argument that the three-dimension structures predicted theoretically should appear in the experimental
conditions.
Received 27 February 2009
Accepted 1 March 2009
Available online 12 March 2009
Keywords:
Schiff bases
Tautomerism
Intramolecular hydrogen bond
IR and 1H and 13C spectroscopy
B3LYP calculations
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
stituents to the imine (N) atom [8,10]. The role of solvent polarity
and specific intermolecular interactions on the shift of tautomeric
Schiff bases belong to the class of molecules of general interest
in physical and biochemical sciences. They play a crucial role in a
myriad of enzymatic reaction [1,2]. Some of the Schiff bases have
been used as pharmaceutics for cancer targeting [3–5]. Protonated
Schiff base of retinal is the chromophore group of rhodopsin, the
protein classified to the visual pigments in humans, as so the
light-driven trans-membrane proton pump in bacteriorhodopsin
(bR) [6]. The ortho-hydroxy Schiff bases are the group of chemical
compounds where tautomerism is driven by the intramolecular
proton transfer. These bases received considerable attention in re-
spect to the biological activity [1,2] and possible applications as a
new organic materials in the nanotechnology [7]. The main struc-
tural feature of N-(5-nitrosalicylidene)-2-butylamine, the ortho-
hydroxy Schiff base, is the presence of the proton donor OH group
in ortho-position in aromatic ring and the proton acceptor C@N
equilibrium towards the enol-imine or keto-amino forms was
studied by a variety of computational chemistry methods, as so
15
13
1
experimental methods, using IR, UV,
N NMR,
C NMR,
H
NMR, and X-ray crystallography techniques [8–12]. It was shown
that the potential barrier and the energy difference between the
minima of the tautomers in the double-well potential may be low-
ered by an increase of the acidity of the phenol OH group and the
basicity of the proton acceptor N atom, an extension of the p-elec-
tron delocalization over the whole molecule, and the kind of the
solvent used in the experimental unit [2,8,11].
The aim of the present work is to report the results of the exper-
imental and theoretical investigations of the tautomeric forms of
the ortho-hydroxy Schiff base N-(5-nitrosalicylidene)-2-butyl-
amine, Fig. 1. A flexible non-symmetric alkyl substituent (CH3–
CH(ꢁ)–C2H5) of the central nitrogen atom was considered. Such
a conformational flexibly results from the presence of three C–C
single bond and one C–N single bond. Formally, this substituent
can be labelled as R or R*(or S and S*) due to the not symmetrical
substitution at the carbon atom attached to nitrogen atom, accord-
ing to the Cahn, Ingold and Prelog nomenclature. It seems
interesting because of its unknown conformation that can affect
the stability of entire molecule, in particular its tautomeric
group linked together by the planar
p-electron system [8,9]. This
type of molecular arrangement influences on the properties of
the Schiff bases. The formation of (OHꢀꢀꢀN) and (OꢀꢀꢀHN) hydrogen
bonds depends on the aldehyde used in the synthesis and the sub-
* Corresponding author. Tel./fax: +48 22 822 23 09.
E-mail address: ales@tiger.chem.uw.edu.pl (A. Les´).
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.03.007

26
B. Kukawska-Tarnawska et al. / Journal of Molecular Structure 928 (2009) 25–31
0.5 deg, respectively. To ensure that obtained geometry of the con-
sidered molecules converged correctly, except the default conver-
gence criteria, the option tight cutoffs on forces and step size
were forced. The harmonic frequencies and IR intensities were cal-
culated with the DFT method and the analytical second derivatives
[16]. The approximated tautomeric constant has been calculated
based on the statistical thermodynamics formula of Eq. (1):
DG=RT
K ¼ eꢁ
ð1Þ
In Eq. (1), the
D
G denotes the difference of Gibbs free energy calcu-
lated for the individual tautomers within approaches implemented
in the Gaussian 03 suite of the programs [18,19]. The obtained elec-
tron density reorganization during the proton transfer reaction was
examined with Natural Atomic Orbital and Natural Bond Orbital
Analysis version 3.1 also implemented in the G03 program [20].
Estimation of N-(5-nitrosalicylidene)-2-butylamine interaction
with different solvents was modeled using the SCRF and Oniom
methods [16,21,22].
The theoretical IR spectra of N-(5-nitrosalicylidene)-2-butyl-
amine in enol-imine and keto-amine forms were obtained within
the harmonic oscillations theory by the B3LYP/6-31G (d,p) method.
The values of 1H and 13C nuclear isotropic shieldings were calcu-
lated by the SCF GIAO method at the B3LYP/6-31G(d,p) level imple-
mented in G03 suite of programs [16] and references therein.
Fig. 1. Structure of the N-(5-nitrosalicylidene)-2-butylamine with: (a) numbering
of carbon atoms (b) two different conformers of the aliphatic chain substituted to
the Schiff moiety.
3D-structure. As a consequence one can expect the different bio-
chemical activity depended on the spatial configuration [13,14].
We have undertaken the theoretical study on the molecular struc-
ture, total energy and free energy G (Gibbs energy) of the
enol-imine (OHꢀꢀꢀN) and keto-amine (OꢀꢀꢀHN) tautomers of two
geometric isomers (R* or S) of the N-(5-nitrosalicylidene)-2-butyl-
amine with the Density Functional Theory (DFT) at the B3LYP/6-
31G(d,p) level of the theory. The solvent effect of the water, CH3CN,
and CCl4 on the tautomeric appearance was carried out using the
SCRF model at the same level of the theory as the calculations
for the isolated molecules in the ground state. Theoretical results
were compared to the experimental data.
3. Result and discussion
3.1. Tautomeric and stereoisomeric forms of N-(5-nitrosalicylidene)-2-
butylamine
Four basic stereoisomers were studied as the models of N-(5-
nitrosalicylidene)-2-butylamine structure, Fig. 1a,b and Table 1.
Each tautomer, e.g. keto-amino and enol-imine form have the ali-
phatic chain with the R* or S configured carbon atom C20. The nat-
urally occurring enantiomer S and its R mirror image possess all
geometrical parameters the same, as well as the electronic, and
molecular properties. In our modeling study, going from the S iso-
mer, we generated computationally two stereoisomers denoted as
R and R* differing of the conformation of the sec-butyl group, see
Fig. 1b. Keto-amino and enol-imine tautomers of the stereoisomer
2. Experimental
N-(5-nitrosalicylidene)-2-butylamine was obtained by conden-
sation of the sec-butylamine and 5-nitro-2-hydroxybenzaldehyde
in ethanol solution [15]. The IR spectra were recorded on the Bru-
ker spectrometer in CCl4, CH2Cl2, CHCl3 and CH3CN solution and in
KBr solid state. The solvents were purified by standard methods. 1H
13
and
C NMR spectra and COSY experiments were measured on
Table 1
the Bruker DPX-400 Advance instrument in 0.1 M in CCl4, CDCl3,
CD2Cl2 and CD3CN solutions. The chemical shifts were measured
relative to internal TMS, the chemical shifts in CCl4 related to
DSS in external lock (D2O).
Selected structural B3LYP/6-31G(d,p) data for N-(5-nitrosalicylidene)-2-butylamine.
Parameters
of structure
R* stereoisomer
enol-imine
Keto-
amine
S,R stereoisomers
enol-imine
Keto-
amine
tautomer
tautomer
tautomer
tautomer
Methyl and ethyl substituents at the C20 carbon atom of N-(5-
nitrosalicylidene)-2-butylamine can occupy non-equivalent
positions in the 3D-space and, therefore, one gets two geometrical
stereoisomers (denoted as R* or S according to Prelog’s rule). In
case of N-(5-nitrosalicylidene)-2-butylamine we considered two
starting conformers of 2-butyl chain, S and R*, Fig. 1b. Moreover,
due to the presence of intramolecular hydrogen bond forming qua-
si-cyclic ring structure for each tautomers, one can expect that the
additional inter-fragment interaction can, in principle, hinder the
rotation around the central N–C20 bond. Full optimization of the
geometry of keto-amino and enol-imine tautomers for each stereo
isomeric form in the ground state, the rotation around the N–C20
bond, as so the rotation of the CH3 substituent was performed at
the DFT B3LYP level with the 6-31G(d,p) basis set.
Bond length (Å)
C1C2
C1C7
C2O
OH
OHꢀꢀꢀN
OꢀꢀꢀHN
OꢀꢀꢀN
C7 N
C7H
1.428
1.461
1.329
1.010
1.665
–
1.469
1.412
1.263
–
1.428
1.461
1.330
1.012
1.654
–
1.469
1.414
1.264
–
–
–
1.658
2.567
1.648
2.566
2.587
2.579
1.283
1.096
–
1.470
1.535
1.543
1.535
1.313
1.091
1.051
1.465
1.534
1.545
1.533
1.283
1.095
–
1.465
1.532
1.546
1.531
1.313
1.088
1.051
1.469
1.528
1.544
1.532
NH
NC20
C20C10
C20C30
C30C40
Selected bond angles in (deg)
All calculations were carried out using the Gaussian 03 suite of
programs [16] and analytical gradient techniques [17]. Optimized
geometry was specified by the largest component of the energy
gradient. It was smaller than a threshold of 10ꢁ6 a.u., yielding bond
lengths and angles converged to better than within 0.005 Å and
O–C2–C1
C1–C7–N
C2–C1–C7
H–O–C2
H–N–C7
121.4
121.2
120.7
106.6
–
121.8
122.3
119.3
–
121.4
121.0
120.6
106.5
–
121.8
122.0
119.6
–
111.1
110.6

B. Kukawska-Tarnawska et al. / Journal of Molecular Structure 928 (2009) 25–31
27
R* were obtained from the respective forms S by exchange of the
methyl and ethyl groups assignment to the asymmetric atom car-
bon C20 according to the compact rule of Cahn, Ingold and Prelog.
Enantiomeric R-enol-imine and R keto-amino tautomers were ob-
tained by reflection of the respective forms of S tautomers accord-
ing to the Z-plane. The optimized geometries and the
corresponding calculated, relative values of electronic energies,
and Gibbs energies are reported in Tables 1 and 2. Results indicate
that in vacuum or in non polar solvents, where the interactions be-
tween considered species can be neglected, the S-enol-imine tau-
tomer should be the dominant form. Additionally the calculated
B3LYP/6-31G(d,p) temperature-dependence keto-amino and enol-
imine tautomeric equilibrium constants K is shown on the Fig. 2.
The theoretical results reflect keto-amino and enol-imino propor-
tion could change in vacuum or weakly polar environment with
growing temperature from 270 to 330 K. Tautomeric equilibrium
constant for the S-stereoisomer increases slightly with rising tem-
perature from about 0.050 to 0.089 over the temperature range. A
similar relation is obtained for the deuterated S isomer. Interest-
ingly, for the R* isomer and its deuterated analog the opposite rela-
tion, i.e. lowering the K values with temperature, was found. The
comparison of the electronic energies with the ZPE correction
suggests that the S (R) enol-imine tautomer (ꢁ762.47026 a.u.) is
more stable than keto-amine form (ꢁ762.46758 a.u.) by 7.04 kJ/
mol. Astonishing result was obtained for the second isomer,
R* (S*)-N-(5-nitrosalicylidene)2-butylamine. The keto-amine form
(ꢁ762.46852 a.u.) appeared to be energetically preferred compar-
ing to the enol-imine form (ꢁ762.46726 a.u.) by 3.31 kJ/mol. The
spontaneously interconvert. This last effect was predicted when
we compared the forms denoted as R vs. R*. It is reasonable to ex-
pect that the experimentally observed tautomeric equilibrium re-
sults from a statistical averaging of various conformations of the
N-(5-nitrosalicylidene)-2-butylamine molecule in a given solvent
and at a fixed temperature. The geometrical parameters of the all
investigated structures are characterized by planar geometry of
the ring fragment with a small deviation in 3D of about 0.1 degree
for the torsion angles in respect to the C7NC20 fragment of the mol-
ecule. A small differences 0.005 deg were noticed only for the
some bond angles and dihedral angles. The aliphatic chain is
slightly pushed under the plane of the ring about 2 degrees in all
cases of the S(R)-tautomers, and the R*-enol-imine but about the
5 degrees for the R*-keto-amine tautomer. A formal replacement
substituent’s at the asymmetric carbon C20 in the N-(5-nitrosalicy-
lidene)-2-butylamine leading to the R*-stereoisomer, and optimi-
zation of the resulting structure, can lead to modification of the
intramolecular contacts between the non-bonded atoms. The dif-
ferences in the structural parameters, in particular the NꢀꢀꢀO intra-
molecular distances, were visualized in Table 1. Transfer of the
proton shows the way of the typical changes e.g. shortening of
the C–O and C1–C7 bond distances and a lengthening of the C7–
N bond distances. Such alternations of bond distances were also
found for other Schiff bases [8,23]. For the rest geometrical param-
eters no principal modifications were predicted. All geometrical
parameters are available upon request from the Authors in the
Appendix A.
D
G, free energy difference of enol-imine R* and S conformers of
3.1.1. Supplementary models of the aliphatic substituent
the same tautomer, but with different 3D geometry of aliphatic
chain is estimated to be 6.9 kJ/mol, i.e. a value that is comparable
Furthermore, B3LYP/6-31G(d,p)//B3LYP/6-31G(d,p) calculations
for the isopropyl (dimethyl) and isopentyl (diethyl) tautomeric
pairs of the N-(5-nitrosalicylidene)-2-butylamine analogs were
performed to better identify with a possible influence of aliphatic
substituent structure on the tautomeric equilibrium. Isopropyl (di-
methyl) substitution on C20 carbon atom of the N-(5-nitrosalicylid-
ene)-2-butylamine have lead up to conclusion that in the vacuum
the enol-imine tautomers should win through the keto-amine
forms. The results of calculations for the diethyl-substituted ana-
logs are more difficult for analysis due to strong influence of simul-
taneous rotation of both the methylene –CH2– and the terminal
–CH3 groups on the relative energy of keto-amine and enol-imine
forms. The corresponding data are presented in the Table 2. It
can be seen that for the diethyl-substituted compound the keto-
amino tautomer corresponding to the R*(S*)-form of the ethyl-
to the
forms. Similarly,
3.3 kJ/mol and nearly equal to the value
D
G = 6.7 kJ/mol of S-keto-amine and enol-imine tautomeric
G for keto-amine S and R* is predicted to be
G = 3.5 kJ/mol between
D
D
R*-enol-imine and keto-amine tautomers. The present results
clearly show that the tautomeric equilibrium of the keto-amino:
enol-imino forms in N-(5-nitrosalicylidene)-2-butylamine can be
influenced by not only two known factors i.e. the solvent and the
temperature but also by the molecular rearrangement of the flex-
ible alkyl residue attached to the central nitrogen atom. The reason
is a relatively small difference in energy of both tautomeric forms
that can be easily modified by contributions from intermolecular
interactions with the solvent and as a result of geometry changes
of the alkyl residue adopting various conformations which do not
Table 2
Electronic, relative electronic and Gibbs energies between keto-amine and enol-imine tautomers calculated with DFT B3LYP/6-31G(d,p) and combined with the Onsager model of
solvent for T = 298.15 K and p = 1 atm.
Compound
Keto-amine tautomer
Electronic energy (a.u)
ꢁ762.710940
Enol-imine tautomer
Electronic energy (a.u)
ꢁ762.713270
D
E (kJ/mol)
6.117
D
G (kJ/mol)
+6.7
S(R)-N-(5-nitrosalicylidene)-2-butylamine isolated molecule
In CCl4
In CH3CN
In H2O
ꢁ762.714451
ꢁ762.720607
ꢁ762.720947
ꢁ723.394140
ꢁ802.025938
ꢁ802.025667
ꢁ802.028064
ꢁ762.711641
ꢁ762.714765
ꢁ762.717133
ꢁ762.717255
ꢁ723.397341
ꢁ802.027547
ꢁ802.027726
ꢁ802.025744
ꢁ762.710196
+0.824
+2.0
ꢁ9.121
ꢁ9.694
+8.404
+4.223
+5.406
ꢁ6.090
ꢁ3.794
ꢁ7.5
ꢁ8.1
7.8
5.5
5.6
Dimethyl analog of S-form isolated system
Diethyl1 analog of S-form isolated system
Diethyl2 analog of S-form isolated system
Diethyl3 analog of S-form isolated system
R*-N-(5-nitrosalicylidene)-2-butylamine isolated molecule
ꢁ6.8
ꢁ3.5
In CCl4
In CH3CN
In H2O
ꢁ762.715082
ꢁ762.721198
ꢁ762.721539
ꢁ723.396263
ꢁ802.023668
ꢁ802.027126
ꢁ802.028064
ꢁ762.711844
ꢁ762.714549
ꢁ762.714691
ꢁ723.397341
ꢁ802.022173
ꢁ802.025610
ꢁ802.025744
ꢁ8.501
ꢁ17.457
ꢁ17.979
+2.830
ꢁ3.925
ꢁ3.981
ꢁ6.091
ꢁ8.4
ꢁ17.4
ꢁ18.0
0.8
ꢁ4.3
ꢁ4.0
ꢁ6.7
Dimethyl analog of R*-form isolated system
Diethyl1 analog of R*-form isolated system
Diethyl2 analog of R*-form isolated system
Diethyl3 analog of R*-form isolated system

28
B. Kukawska-Tarnawska et al. / Journal of Molecular Structure 928 (2009) 25–31
Table 3
Experimental equilibrium constants K and
DG (kJ/mol) for N-(5-nitrosalicylidene)-2-
butylamine and for N-(5-nitrosalicylidene)-iso-propylenoamine *, N-(5-nitrosalicy-
lidene)-benzyloamine ** published by Rozwadowski [25].
Solvent
Dielectric constant
T (K)
K
DG
CCl4
CDCl3
2.228
4.81
295
295
230
295
295
295
270
250
230
295
270
250
230
0.04
0.46
1.69
0.49
1.42
0.51
0.78
1.18
2.07
0.14
0.19
0.26
0.38
+7.9
+1.9
ꢁ1.3
+1.8
ꢁ0.9
1.7
CD2Cl2
CD3CN
CDClꢂ3
8.93
35.94
4.81
0.6
ꢁ0.3
ꢁ1.4
4.8
3.7
2.8
CDClꢂ3ꢂ
4.81
1.9
in aqueous solution be converted into a general tendency observed
for Schiff bases [8,11].
Additionally we performed preliminary studies of the chiral sol-
vent effect (2-chlorobutane) on the N-(5-nitrosalicylidene)-2-
butylamine molecule in order to obtain an extra information about
the chemical behavior of the mirror conformers using the Oniom
(QM:MM) method [22]. Our calculations show that there can be
a small differences in electronic energy of the two enantiomeric
forms and equal to about 5.3 kJ/mol.
3.3. Electronic charge distribution
The NBO analysis for the atoms in molecules of the enol-imine
and keto-amine tautomers was done at the B3LYP/6-31G(d,p) level
of the theory. Selected partial electronic charges (Mulliken analy-
sis) and the occupancy of the valence orbital in molecule are
shown in Table 4. The C7 and N atoms became more positive for
R*-N-(5-nitrosalicylidene)-2-butylamine than in S(R)-N-(5-nitro-
salicylidene)-2-butylamine. The transfer of proton leads to the
negative charge of the oxygen atom and to the reversed effect on
the N atom in the chelate moiety. Two basis set e.g. 6-31G(d,p)
and 6-31++G(d,p) with the full optimization of the geometry were
Fig. 2. B3LYP/6-31G(d,p) keto-amino: enol-imino tautomeric equilibrium constants
K versus temperature T (K) for the R*,S pair and their deuterated (R*D, SD) analogs.
methyl reference structure should be energetically favored over
the enol-imino form.
3.2. Solvent effects on the tautomeric equilibrium
The calculations were performed in such a way that the
complexity of the solvent models increases and the theoretical
modeling of the interactions of the respective tautomeric form of
the N-(5-nitrosalicylidene)-2-butylamine with CCl4, CH3CN and
H2O solvents was made. One of the simplest models, i.e. Onsanger’s
reaction field theory of the electrostatic solute–solvent interaction
was taken into account using the SCRF B3LYP/6-31G(d,p) method
[16,21]. The SCRF calculations reported here were carried out using
the values of the dielectric constants equal to 2.228, 36.64 and
78.39 for of CCl4, CH3CN and H2O, respectively. The cavity radius
(a0) was calculated from the molecular volume, defined as the vol-
ume inside a contour of 0.001 e/bohr3 electron density [16], indi-
vidually for each solute molecule. The influence of the solvent on
the calculated thermodynamical parameters is presented in the
used in calculations of the corresponding dipole moments
l. The
enol-imine tautomer of all stereo isomers has the dipole moment
equals to 5.8 D in the B3LYP/6-31G(d,p) calculations and to 6.1 D
in the B3LYP/6-31++G(d,p). The same analysis was done for the cal-
culations of the dipole moment for the keto-amine tautomer. The
R*-N-(5-nitrosalicylidene)-2-butylamine in the keto-amine form
posses the dipole moment equals 8.2 D for the calculations in the
first basis set and 8.8 D for the second basis set. The S N-(5-nitro-
salicylidene)2-butylamine in the same form has the dipole mo-
ment equals 8.3 D and 8.9 D, respectively. It recommends that
the keto-amine tautomer has slightly polar properties than the
enol-imine compound.
3.4. Experimental spectroscopic studies
Table 2. The calculated
DG value for the N-(5-nitrosalicylidene)-
2-butylamine in CCl4 as well as for the isolated molecule repro-
duced the experimental values only qualitatively, see Table 3. Both
the theoretical and experimental techniques show the predomi-
nance of the enol-imino form in the carbon tetrachloride solution.
One should add that it is very difficult to obtain quantitative agree-
ment between the theoretical and experimental values of the ther-
modynamical parameters most probably due to the complicated
intermolecular interactions not involved in the theoretical model-
ing as, for example, formation of complex associates [11,12]. It is
worth notice that predominance of the keto-amino stereoisomer
The IR frequencies of N-(5-nitrosalicylidene)-2-butylamine reg-
istered in series of the solvent of increasing polarity and in the so-
lid state. The respective data are presented in Table 5 and
compared with calculated values for enol-imine and keto-amine
forms of N-(5-nitrosalicylidene)-2-butylamine. The collection of
very large and also weak absorptions in the region at 2800–
2600 cmꢁ1 is typical for
indicates the presence of the medium strength hydrogen bond
[9,24]. The calculated OH and NH harmonic frequencies are over-
estimated with respect to the experimental values. This may result
mOH/NH vibration in the Schiff bases and
m
m

B. Kukawska-Tarnawska et al. / Journal of Molecular Structure 928 (2009) 25–31
29
Table 4
NBO analysis.
Atom
C1
S,R enol-imine tautomer
S,R keto-amine tautomer
R* enol-imine tautomer
R* keto-amine tautomer
0.0287
ꢁ0.1856
0.3322
0.4070
ꢁ0.5644
ꢁ0.6817
0.3706
0.5193
ꢁ0.5291
ꢁ0.5095
0.1969
0.1114
1.976*
ꢁ0.0200
ꢁ0.2343
0.4107
0.0272
ꢁ0.1862
0.3339
0.4079
ꢁ0.5584
ꢁ0.6797
0.3579
0.5193
ꢁ0.5287
ꢁ0.5097
0.2010
0.1141
1.976*
ꢁ0.0210
ꢁ0.2364
0.4109
0.4572
ꢁ0.6164
ꢁ0.6574
0.3451
0.4709
ꢁ0.4678
ꢁ0.5424
0.1639
0.1588
1.975
C2
0.4561
ꢁ0.6175
ꢁ0.6592
0.3489
0.4728
ꢁ0.4975
ꢁ0.5400
0.1710
O
H,taking
part in the proton transfer
N
C7
0.1523
1.974
C1C2
1.545
1.546
C1C7
C6C1
C2O
1.974
1.970
1.994
1.977
1.971
1.995*
1.969
1.974
1.970
1.994
1.976
1.971
1.995*
1.969
OH
C7 N
1.971
1.989*
1.949
1.971
1.989*
1.948
1.988*
1.960
1.977
1.985
1.988*
1.961
1.977
1.985
NH
NC2’
1.982
1.988
Mulliken atomic (upper row) and natural atomic (lower row) charges, occupancy of the selected valence bond (* denotes double bond).
Table 5
Experimental and theoretical B3LYP/6-31G (d, p)//B3LYP/6-31G(d,p) vibration frequencies (cmꢁ1)of the N-(5-nitrosalicylidene)-2-butylamine; vw, very weak; br, broad.
Theoretical frequencies
Enol-imine
Experimental frequencies
Keto-amine
CCl4
CH2Cl2
3052
CHCl3
CH3CN
KBr
3087
3076
3118
3081
3062
2971
2932
2877
2700–2400
1637
1625
1582
1530
2972
2934
2878
vw, br
1639
1623
1582
1543
2973
2934
2878
vw, br
1639
1617
1582
1547
Solv
Solv
Solv
Solv.
1642
1616
–
2970
2926
2878
2750–2500
1650
1609
–
1550
2916
1640
1628
2952
1633
1611
1547
1523
1566
1529
1551
1537
1488
1463, 1402
1489
1462
1488
1462
1490
Solv
1481
1458, 1443
1404
1465
1403
1380
1366
1348
1294
1264
1237
1454
1412
1382
1357
1338
1270
1263
1216
1379
1368.2
1343
1296
1265
1235
1215
1198
1151
1381
1381
Solv
1364
1340
1299
1341
1299
1326
–
1326
–
1232
1217
1199
1150
1128
Solv
Solv
1196
1150
1129
1234
–
1200
1161, 1151
1129
1234
–
1181
1162
1132
1185
1159
1131
1131
1189
1160
1134
1134
1133, 1124
1093
1028
1006
973, 943
924
1093
1029
1006
974, 943
923
1093
1006
1092
Solv
1094
1035
1006
978, 943
910
1020
1006
1050
1022
974, 943
922
943
–
906
906
905
–
–
847
844
838
838
838
841
843
from inaccuracy of the theoretical approach, in particular from
anharmonicity of the vibrations, not considered in the present cal-
culations. The most sensitive to the proton transfer in the Schiff
bases is the region of the imine and aromatic ring vibration at
1640–1500 cmꢁ1 [9,23–24]. Comparison of the absorption in this
range in the series solvents and in the solid state suggests that
N-(5-nitrosalicylidene)-2-butylamine should exist in solutions in
tautomeric equilibrium, that shifts towards the keto-imino form
with increasing polarity of the solvent. Additional information
concerning the proton transfer equilibrium was obtained from
standard NMR studies. The 1H and 13C NMR NMR data for N-(5-
nitrosalicylidene)-2-butylamine in series of the same solvents are

30
B. Kukawska-Tarnawska et al. / Journal of Molecular Structure 928 (2009) 25–31
presented in Table 6. Tautomeric equilibrium in N-(5-nitrosalicy-
lidene)-2-butylamine was studied on the basis of the 13C NMR
chemical shifts. The proton transfer equilibrium constants KT were
estimated adopting the method applied previously for series of 2-
((alkyl)iminomethyl)-4-nitrophenols [25], that gave the results
consistent with those obtained by UV spectroscopy [26]. The KT
Table 6
1H and 13C d chemical shifts assignments of the N-(5-nitrosalicylidene)-2-butylamine, ov – overlapped.
Solvent
d(C/H)
Position of the investigated atom
1
2
3
4
5
6
7
10
20
30
40
CDCl3
295 K
13C
1H
115.9
–
113.7
–
116.0
–
116.5
–
171.5
15.01
176.0
15.10
175.4
15.06
171.7
15.05
167.5
14.45
120.0
128.9
138.1
–
135.7
–
137.5
–
138.4
–
128.5
162.2
8.33
21.5
64.3
30.3
10.5
6.93
119.0
6.86
ov.
6.77
120.0
6.89
118.4
7.14
8.18
129.5
8.20
129.7
8.10
8.25
130.7
8.32
131.4
8.31
129.2
8.24
127.9
8.37
1.37
21.3
1.46
21.1
1.34
21.6
1.35
22.6
1.55
3.46
62.5
3.59
63.0
3.57
64.7
3.44
66.8
3.53
1.71
29.9
1.76
30.7
1.70
30.7
1.70
31.2
1.89
0.95
10.7
0.98
10.7
0.93
10.7
0.93
11.3
1.14
13C
1H
163.1
ꢃ8.31
165.3
8.48
162.8
8.34
230 K
CD3CN
13C
1H
CD2Cl2
CCl4
13C
1H
128.6
8.13
127.8
8.35
13Ca
1Hb
117.8
–
140.1
–
162.1
8.61
a
Chemical shifts related to CCl4 (98.7).
Chemical shifts related to DSS in external lock D2O.
b
Chloroform
1H calculated averaged chemical shielding
(ppm)
32
30
28
26
24
22
20
18
0
2
4
6
8
10
12
14
16
1H chemical shift (ppm)
13C calculated averaged chemical shielding
(ppm)
200
180
160
140
120
100
80
60
40
20
0
0
20
40
60
80
100
120
140
160
180
13C chemical shift (ppm)
Fig. 3. Plot of the chemical shifts (d) versus isotropic nuclear shielding (
0.991 and R2 for 13C 0.994.The values of the R2 in CCl4 are 1H 0.988 13C 0.999, in CH2Cl2 1H 0.993 13C 0.991 and in CH3CN 1H 0.996 13C 0.993.
r
) calculated by SCF GIAO B3LYP/6-31G(d,p) for the mixture of tautomers in CHCl3 with R2 for 1H

B. Kukawska-Tarnawska et al. / Journal of Molecular Structure 928 (2009) 25–31
31
values were estimated considering the C-2 chemical shift values
(dC-2), Table 6, from the Eq. (2):
Calculating Project No. G20-9. Also we thank Michele Pavanello
for reading and commenting on the text.
K ¼ ½dðC ꢁ 2Þ ꢁ dðC ꢁ 2ÞEnolꢄ=d½ðC ꢁ 2ÞKeto ꢁ dðC ꢁ 2Þꢄ
ð2Þ
Appendix A. Supplementary data
The values for the corresponding pure tautomeric form d(C-2)Enol
(166.89 ppm) and d(C-2)Keto (181.4 ppm) were estimated from the
correlation d(C-2) = 1.081. 3J(NH,H) + 166.89 Fig. 2 in [25]. We
adopted the 3J(NH,H) values equal 0 Hz for enol-imine form and
13.4 Hz [15] for keto-amine one. The results are given in Table 6.
The predicted equilibrium constants KT increase with the relative
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2009.03.007.
References
permittivity of the solvents (e
) (R2 = 0.95). The 1H and 13C values
[1] J. M Berg, J.L. Tymoczko, L. Stryer, Biochemistry, Freeman W.H. Comp., NY and
Basingstoke, 2002.
[2] C.M. Metzler, A. Cahill, D.E. Metzler, J. Am. Ch. Soc. 102 (1980) 6075.
[3] A. Das, M.D. Trousdale, S. Ren, E.J. Lien, Antiviral Res. 44 (1999) 201.
[4] S. Ren, Z.A. Tokes, C. Osipke, B. Zhou, Y. Yen, E.J. Lien, Anticancer Res. 21 (2001)
3445.
[5] S. Ren, R. Wang, K. Komatsu, P. Bonaz-Krause, Y. Zyrianow, C.E. McKenna, C.
Osipke, Z.A. Tokes, E.J. Lien, J. Med. Chem. 45 (2002) 410.
[6] L. Song, M.A. El-Sayed, J.K. Lanyi, Science 261 (1993) 891;
D. Oesterhelt, W. Stoeckenius, in: S. Freischer, L. Packer (Eds.), Methods of
Enzymology, Biomembranes Part A, vol. 31, Academic Press, New York, 1974,
pp. 667–678;
of nuclear shielding calculated by SCF GIAO method at B3LYP/6-
31G(d,p) level were compared with the averaged of the 1H and
13C chemical shifts taking into account experimentally estimated
percentage of keto-amine forms in series of the solvents. The agree-
ment between theoretical averaged values and 13C experimental
data is excellent (r2 in the 0.989–0.999 range). The sample plots
for the mixture of tautomers in CHCl3 is given in Fig. 3.
R.H. Lozier, R.A. Bogomolni, W. Stoeckenius, Biophys. J. 15 (1975) 955.
[7] E. Hadjoudis, Mol. Eng. 5 (1995) 301;
4. Conclusions
E. Hadjoudis, I.M. Mavridis, Chem. Soc. Rev. 33 (2004) 579;
E. Hadjoudis, M. Vittorakis, I. Moustakali-Mavridis, Tetrahedron 43 (1987)
1345.
The molecule of N-(5-nitrosalicylidene)-2-butylamine contain-
ing asymmetric carbon atom C20 was investigated in the form of
the S or R enantiomers, each appearing in the keto-amino and
enol-imine tautomeric form. For the comparison, two other con-
formers named S*, and R* originating as a result of the interchang-
ing of the CH3 and the C2H5 groups were studied. The calculated
[8] T. Dziembowska, Pol. J. Chem. 72 (1998) 193.
[9] A. Filarowski, A. Koll, A. Karpfen, P. Wolschann, Chem. Phys. 297 (2004) 323.
[10] M. Gavranic, B. Kaitner, E. Mestrovis, J. Chem. Crystallogr. 26 (1996) 1071.
[11] W.M.F. Fabian, L. Antonov, D. Nedeltcheva, F.S. Kamonuah, I.P.J. Taylor, J. Phys.
Chem. A 108 (2004) 7603.
[12] P.I. Nagy, W.M.F. Fabian, J. Phys. Chem. B 110 (2006) 25026.
[13] A. Giardini Guidoni, S. Piccirillo, D. Scuderi, M. Satta, T.M. Di Palma, M.
Speranza, A. Filippi, A. Paladini, Int. J. Photenergy 3 (2001) 223.
[14] Ajith D. Gunatilleka, Colin F. Poole, Analyst 125 (2000) 127.
[15] Z. Rozwadowski, Magn. Reson. 45 (2007) 605.
[16] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman,
V.G. Zakrzewski, J.A. Montgomery Jr., T. Vreven, K.N. Kudin, J.C. Burant, S.S.
Milliam, J. Iyengar, J. Tomasi, B. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, E. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li,
J.E. Knox, H.P. Hratchian, J.B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R.E.
Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y.
Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D.
Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B.
Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov,
G. Liu, A. Liashenko, P. Piskorz, L. Komaromi, R.L. Martin, D.J. Fox, T. Keith, A.M.
Al-Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B.G.
Johnson, W. Chen, M.W. Wong, C. Gonzales, J.A. Pople, Gaussian 03, Revision
A.1. Gaussian, Inc., Pittsburgh, PA, 2003.;
K. Wolin
´ ski, J.F. Hilton, P. Pulay, J. Am. Chem. Soc. 112 (1990) 8251. and
references therein.
[17] J.B. Foresman, M. Head-Gordon, J.A. Pople, M.J. Frisch, J. Phys. Chem. 96 (1992)
135.
[18] Z. Slanina, Contemporary theory of chemical isomerism, ACADEMIA (1986) 159.
[19] D.A. McQuarrie, Statistical Thermodynamics, Harper and Row, New York, 1973.
[20] A.D. Reed, L.A. Curtiss, F. Weinhold, Chem. Rev. 88 (1988) 899.
[21] M.W. Wong, J. Frisch, K.B. Wiberg, J. Am. Chem. Soc. 113 (1991) 4776;
M.W. Wong, K.B. Wiberg, M.J. Frisch, J. Am. Chem. Soc. 114 (1992) 523.
[22] M. Svensson, S. Humbel, R.D.J. Froese, T. Matsubara, S. Sieber, K. Morokuma, J.
Phys. Chem. 100 (1996) 19357.
[23] T. Dziembowska, K. Ambroziak, I. Majerz, J. Mol. Struct. 738 (2005) 15.
[24] I. Majerz, A. Pawlukojc´, L. Sobczyk, T. Dziembowska, E. Grech, A. Szady-
Chełmieniecka, J. Mol. Struct. 552 (2000) 243.
Gibbs free energies e.g.
in the weakly interacting environment indicate the balance of the
enol-imine and keto-amino forms. G are small and it is easy to
notice that they can be sensitive to the influence of the polar envi-
ronment. The comparison of the calculated G for the S-keto-ami-
no and S-enol-imine of the N-(5-nitrosalicylidene)-2-butylamine
and the G for the R*-keto-amino and R*-enol-imine has showed
DG for the reaction of the tautomerization
D
D
D
much more dissimilarity. The electronic and Gibbs energies for
the investigated compounds calculated with DFT B3LYP/6-
31G(d,p) and combined with the Onsager model of solvent for
T = 298.15 K and p = 1 atm suggest the dominance of the R* keto-
amine tautomer independently on the solvents’ polarity. Such a
solvent effect was detected in the experimental IR and NMR spec-
trum. The detailed analysis of the free energy of the both dimethyl
analogs e.g. S and R* molecules suggest that the presence of the
nearby CH3 group should favorites on the enol-imine form than
the keto-amine. All these results have predicted that apart from
solvent and temperature effects also the intramolecular flexible
geometry of the alkyl residue of the N-(5-nitrosalicylidene)-2-
butylamine can be a significant factor influencing the tautomeric
equilibrium of the keto-amino:enol-imino forms.
Acknowledgements
The calculations were performed on the Cluster of IBM eServ-
er325 of the computer at the Interdisplinary Centre of Mathemat-
ical and Computational Modelling Warsaw University (ICM). We
acknowledge for computer time on these installations within the
[25] Z. Rozwadowski, T. Dziembowska, Magn. Reson. Chem. 37 (1999) 274 (p. 277,
reference to Fig. 1; The values of
D
C-2(OD) increase linearly with 3J(NH,H)).
[26] I. Król-Starzomska, M. Rospenk, Z. Rozwadowski, T. Dziembowska, Polish. J.
Chem. 74 (2000) 1441.