Examination of the structure in solid state of amino analogs of 4,4′-[1,5-pentanediylbis(oxy)]bisbenzonitrile by means of X-ray diffraction, 13C CP/MAS NMR, and theoretical calculations

Article abstract of DOI:10.1016/j.molstruc.2007.08.008

A single crystal of X-ray diffraction structures is presented for 4,4′-[1,5-(3-oxapentanediylbis(amino))]bisbenzonitrile 2 and 4,4′-[1,5-(N-methyl-3-azapentane-diylbis(oxy))]bisbenzonitrile 3. The molecular structures of these derivatives differ especially in conformations of the central linker: in 2 this linker adopts a trans/gauche conformation, whereas in 3 - a fully extended conformation. The N atoms in various positions of the aliphatic linker change dramatically the molecular packing mode of both bisnitriles. But in both cases the nitrile groups take part in intermolecular hydrogen bonds: a type of N{single bond}H···N in 2 and of C{single bond}H···N in 3. Various conformations of both molecules were reflected in ¹³C CP/MAS NMR spectra in solid state as single and double resonance patterns for 2 and 3, respectively. A preliminary anticancer assay against 60 cell lines of 3 reveals strong growth inhibition of leukemia, melanoma, and renal cancer cells.

Full text of DOI:10.1016/j.molstruc.2007.08.008

Available online at www.sciencedirect.com
Journal of Molecular Structure 879 (2008) 53–59
www.elsevier.com/locate/molstruc
Examination of the structure in solid state of amino analogs
of 4,40-[1,5-pentanediylbis(oxy)]bisbenzonitrile by means of X-ray
13
diffraction, C CP/MAS NMR, and theoretical calculations
a,
b
a
_
*
´
Dorota Maciejewska , Irena Wolska , Jerzy Zabinski
a
Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Str., 02 097 Warsaw, Poland
Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, 6 Grunwaldzka Str., 60 780 Poznan´, Poland
b
Received 31 May 2007; received in revised form 10 August 2007; accepted 13 August 2007
Available online 23 August 2007
Abstract
A single crystal of X-ray diffraction structures is presented for 4,40-[1,5-(3-oxapentanediylbis(amino))]bisbenzonitrile 2 and 4,40-[1,5-
(N-methyl-3-azapentane-diylbis(oxy))]bisbenzonitrile 3. The molecular structures of these derivatives differ especially in conformations of
the central linker: in 2 this linker adopts a trans/gauche conformation, whereas in 3 – a fully extended conformation. The N atoms in
various positions of the aliphatic linker change dramatically the molecular packing mode of both bisnitriles. But in both cases the nitrile
groups take part in intermolecular hydrogen bonds: a type of NAHÆÆÆN in 2 and of CAHÆÆÆN in 3. Various conformations of both mol-
ecules were reflected in 13C CP/MAS NMR spectra in solid state as single and double resonance patterns for 2 and 3, respectively. A
preliminary anticancer assay against 60 cell lines of 3 reveals strong growth inhibition of leukemia, melanoma, and renal cancer cells.
ꢀ 2007 Elsevier B.V. All rights reserved.
Keywords: 4,40-[1,5-Pentanediylbis(oxy)]bisbenzonitriles; X-ray diffraction analysis; 13C CP/MAS NMR data; DFT theoretical computations; Cytotox-
icity
1. Introduction
sized diamidines with additional amino groups in the ali-
phatic linker, taking it into account that small amines
belong to a growing family of synthetic drugs as well as
several physiological substances. The title bisnitriles are
the key intermediates in our synthetic procedure towards
the diamidines, which could also have some biological
activity [5–7]. These findings stimulated our investigation
into stable conformations in solid state, and the
corresponding intermolecular interactions of 4,40-[1,5-(3-
oxapentanediylbis(amino))]bisbenzonitrile 2 [8] and 4,40-
Pneumocystis carinii pneumonia (PCP) continues to
pose serious public health problem in immunosuppressed
patients. The treatment of PCP is successful, but 4,40-[1,5-
pentanediylbis(oxy)]bisbenzenecarboxyimidamine (pentami-
dine) 1 (Fig. 1), the agent used for prophylaxis and ther-
apy, shows many side effects such as transient
hypoglycemia, pancreatitis, hypotension, and renal
dysfunction [1,2]. Compound 1 belongs to diamidines
interacting with DNA in minor groove in the adenine–
thymine rich region, and significant attempts have been
made to study structural and chemical features that would
allow them to recognize properly the DNA sequences
[3,4]. In the course of our studies we designed and synthe-
[1,5-(N-methyl-3-azapentanediylbis(oxy))]bisbenzonitrile
3
(Fig. 1). The use of single crystal X-ray diffraction studies
in combination with solid state NMR results has proven
to be extremely powerful in structural analyses [9].
However, the process of performing simultaneous analysis
was sometimes delayed due to difficulties in obtaining suf-
ficiently large crystals suitable for X-ray measurements. In
the paper [8], we described the structural analysis
of solid state structure of 2 using 13C CP/MAS NMR
*
Corresponding author. Tel./fax: +48 0225720643.
E-mail address: domac@farm.amwaw.edu.pl (D. Maciejewska).
0022-2860/$ - see front matter ꢀ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2007.08.008

54
D. Maciejewska et al. / Journal of Molecular Structure 879 (2008) 53–59
3'
H
7'
C
2'
1'
N
6
9
8'
N
5
4'
5'
O
N
8
1
9'
7
H
6'
2
C
O
O
4
2
N
3
H2N
H2N
NH2
NH2
C
C
1
6
3
9
9'
6'
pentamidine dication
O
O
5
5'
4'
N
1
8
1'
2'
8'
7
C
CH3
11
7'
2
4
C
N
N
3'
3
Fig. 1. Chemical formulas of 4,40-[1,5-(3-oxapentane)diylbis(amino)]bisbenzonitrile 2 and 4,40-[1,5-(3-aza-N-methylpentane)diylbis(oxy)]bisbenzonitrile 3
with atoms numbering used in the discussion, together with pentamidine dication 1.
spectroscopy, and on this basis we proposed an extended
‘zig-zag’ conformation of amino-ether linker with some
reservations. Our most recent X-ray diffraction measure-
ments of the single crystal of 2 revealed the other confor-
mation of this linker. Besides, in the 13C CP/MAS NMR
spectrum of a new derivative 3 we observed a greater
number of resonances than the number of chemically
equivalent C atoms, but according to X-ray diffraction
measurement of 3, only one molecule was detected in an
independent unit cell. In order to gain a better insight into
the structural aspects responsible for the observed solid
state spectral pattern, we employed theoretical computa-
tions of the 13C shielding constants for X-ray derived
atomic coordinates of 2 and 3. The aim of our analysis
was to find out if simultaneous computation of those
shielding constants for a set of molecules being involved
in intermolecular interactions, in opposition to the com-
putation of only a single isolated molecule, gives more
reliable theoretical values of the shielding constants, as
compared with the values of experimental resonances.
This paper reports the X-ray diffraction analysis for 4,
40-[1,5-(3-oxapentanediylbis(amino))]bisbenzonitrile 2 and
4,40-[1,5-(N-methyl-3-azapentane-diylbis(oxy))]bisbenzonitrile
3, complementary 13C CP/MAS NMR data in solid state
together with theoretical calculations of the shielding
constants at DFT level of theory, a synthesis of new
compound 3 with spectral specification, and cytotoxicity
data for 3.
2.1.1. 4,40-[1,5-(N-Methyl-3-azapentanediylbis(oxy))]bis-
benzonitrile 3
4-Hydroxybenzonitrile (0.60 g, 5 mmol) and mechlor-
ethamine hydrochloride (0.48 g, 2.5 mmol) were added to
15 cm3 of 1-methyl-2-pyrrolidone together with 2.07 g
anh. K2CO3 (15 mmol). The mixture was allowed to stand
at 130 ꢁC for 16 h while stirring. The resulting hot solution
was added to 200 cm3 of cold water. The formed solid was
filtered off and washed with water. The precipitate was
crystallized from ethanol to give 0.66 g (82%) of sandy
1
crystals of 3. Mp. 75.2–75.9 ꢁC; H NMR (400.13 MHz,
CDCl3): 2.510 (s, 3H, 11-NCH3), 3.094 (t, J = 4.8 Hz,
4H, H-9, H-90), 4.169 (t, J = 4.8 Hz, 4H, H-8, H-80),
6.934–6.956 (m, 2-H, 20-H, 6-H, 60-H), 7.566–7.588 (m, 3-
H, 30-H, 5-H, 50-H) ppm. 13C NMR (100.62 MHz, CDCl3):
43.50 (NCH3), 56.56 (C-9, C-90), 66.53 (C-8, C-80), 104.43
(C-4, C-40), 115.42 (C-2, C-20, C-6, C-60), 119.30 (C-7, C-
70), 134.20 (C-3, C-30, C-5, C-50), 162.04 (C-1, C-10) ppm;
ꢀ
IR (KBr): m = 3033, 2951, 2797, 2222 (C„N), 1605,
1508, 1474, 1253 1173, 1015, 833 cmꢀ1
.
2.2. Crystallography
The crystal and molecular structures of 2 and 3 were
determined by X-ray diffraction. The crystals suitable for
X-ray analysis were grown from acetone solution (2) and
ethanol solution (3) by slow evaporation. Diffraction data
were collected on an Oxford Diffraction KM4CCD diffrac-
tometer [10] at 293 K, using graphite-monochromated
MoKa radiation. A total of 699 frames were measured in
four separate runs for 2 and 1072 frames in six separate
runs for 3. The x-scan was used with a step of 0.75ꢁ, two
reference frames were measured after every 50 frames,
and they did not show any systematic changes either in
peaks positions or in their intensities. The unit-cells param-
eters were determined by least-squares treatment of setting
angles of 3191 and 7847 highest-intensity reflections chosen
from the whole experiment for 2 and 3, respectively. Inten-
sity data were corrected for the Lorentz and polarization
effects [11]. The structures were solved by direct methods
with the SHELXS-97 program [12] and refined with full-
matrix least-squares by the SHELXL-97 program [13].
2. Experimental
2.1. Synthesis
All the chemicals were obtained from major chemical
suppliers as high or highest purity grade and were used
without further purification. Melting points were deter-
mined with a Digital Melting Point Apparatus 9001
and are uncorrected. Elemental analyses of C, H, and
N were performed on a Perkin-Elmer 240 analyzer and
satisfactory results within 0.3% of calculated values
were obtained. Notation used in the NMR assignments
is given in Fig. 1.

D. Maciejewska et al. / Journal of Molecular Structure 879 (2008) 53–59
55
P
Table 1
The function
w
w(|Fo|2 ꢀ |Fc|2)2 was minimized with
ꢀ1 = [r2(Fo)2 + (0.0835P)2] for 2 and wꢀ1 = [r2(Fo)2 +
Crystal data, data collection and structure refinement for compounds 2
and 3
(0.0921P)2] for 3, where P = (Fo2 + 2Fc )/3. All non-hydro-
gen atoms were refined anisotropically, the positions of
hydrogen atoms were generated geometrically and refined
as a riding model. Thermal parameters of all hydrogen
atoms were calculated as 1.2 (1.5 for methyl group) times
Ueq of the respective carrier carbon atom.
2
Compound
2
3
Empirical formula
Formula weight
T (K)
Wavelength (A)
Crystal system, space group
C18H18N4O
306.36
293(2)
0.71073
Orthorhombic,
P21212
C19H19N3O2
321.37
293(2)
0.71073
Monoclinic,
P21/c
˚
Unit cell dimensions
2.3. NMR spectra
˚
a (A)
10.1173(9)
15.639(1)
5.1496(5)
13.2623(7)
9.1075(5)
15.6725(8)
112.600(5)
1747.7(2)
4, 1.221
˚
b (A)
1H NMR and 13C NMR 1D and 2D spectra in solution
were recorded with a Bruker Avance DMX 400, as well as
the solid state 13C CP/MAS NMR spectra. Powdered sam-
ples were spun at 10 kHz. Contact time of 2 ms, repetition
time of 8 s, and spectral width of 24 kHz were used for
accumulation of 695 transients. Chemical shifts d (ppm)
were references to TMS. Nonprotonated carbons and
methyl groups were selectively observed by dipolar-dephas-
ing experiment with delay time 50 ls.
˚
c (A)
b (ꢁ)
3
˚
Volume (A )
814.8(1)
2, 1.249
Z, Dx (Mg/m3)
l (mmꢀ1
F(000)
)
0.081
0.081
324
680
h Range for data collection (ꢁ)
hkl Range
3.29–29.99
ꢀ13 6 h 6 8
ꢀ21 6 k 6 21
ꢀ6 6 l 6 7
3.33–29.00
ꢀ17 6 h 6 17
ꢀ12 6 k 6 11
ꢀ20 6 l 6 21
Reflections
Collected
7271
22876
2.4. Molecular modeling details
Unique (Rint
)
2130 (0.025)
1455
2130/0/105
0.971
0.0461
0.1343
4479 (0.035)
2960
4479/0/217
1.043
0.0551
0.1674
Observed (I > 2r(I))
Data/restraints/parameters
Goodness-of-fit on F2
R(F) (I > 2r(I))
Crystallographic atom coordinates of single molecule as
well as the sets of two and three molecules of 2 and 3 were
used for computation of the shielding constants r (ppm) of
13C atoms. The molecules were positioned according to the
crystallographic packing mode. We employed the DFT
method with B3LYP/6-311(d,p) hybrid functional and
the CHF–GIAO approach for the NMR shielding con-
stants computations using Gaussian 03 program [14].
wR(F2) (all data)
3
˚
Max/min Dq (e/A )
0.325/ꢀ0.218
0.161/ꢀ0.199
Table 2
˚
Selected bond lengths (A) and angles (ꢁ) and selected torsional angles (ꢁ)
for compounds 2 and 3
2.5. Cytotoxicity against 60 cell lines
2
3
The in vitro cell line screening utilizing 60 different
human tumor cell lines consisting of leukemia, melanoma,
and cancers of the lung, colon, brain, ovary, breast, pros-
tate, and kidney was carried out in the National Institute
of Health, Bethesda, USA. Additional information details
concerning the NCI’s drug discovery and development pro-
gram are available at web site http://dtp.nci.nih.gov.
C1AN8
C8AN8
C9AO10
C7AN7
1.357(2)
1.445(2)
1.402(2)
1.155(2)
C1AO8
1.363(2)
1.359(2)
1.427(2)
1.430(2)
1.460(2)
1.461(2)
1.141(2)
1.143(2)
C10AO80
C8AO8
C80AO80
C9AN10
C90AN10
C7AN7
C70AN70
C1AN8AC8
122.7(1)
111.5(2)
C1AO8AC8
118.7(1)
117.8(1)
111.1(1)
3. Results and discussion
C9AO10AC90
C10AO80AC80
C9AN10AC90
3.1. Single crystal structure of 2 and 3
C1AN8AC8AC9
N8AC8AC9AO10
C8AC9AO10AC90
173.5(1)
66.4(2)
167.0(2)
C1AO8AC8AC9
178.4(1)
176.2(1)
163.7(1)
173.1(1)
ꢀ172.1(1)
ꢀ165.0(1)
O8AC8AC9AN10
C8AC9AN10AC90
C10AO80AC80AC90
O80AC80AC90AN10
C80AC90AN10AC9
The crystal and molecular structures of 2 and 3 were
determined by single crystal X-ray diffraction. The crystal-
lographic data, together with data collection and structure
refinement details are listed in Table 1. Selected bond
lengths, bond angles and torsion angles are listed in Table
2, and hydrogen bonding parameters – in Table 3. Addi-
tional crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publications No. CCDC 656849 and 656850.
Fig. 2. 4,40-[1,5-(3-Oxapentanediylbis(amino))]bisbenzonit-
rile 2 and 4,40-[1,5-(N-methyl-3-azapentanediylbis(oxy))]-
bisbenzonitrile 3 crystallize in the orthorhombic space
group P21212 and in the monoclinic space group P21/c,
respectively. The molecules of 2 and 3 are new analogs of
pentamidine 1 with strong electron withdrawing nitrile
A perspective view of the molecular conformations,
together with the atom numbering scheme, is shown in

56
D. Maciejewska et al. / Journal of Molecular Structure 879 (2008) 53–59
Table 3
˚
Hydrogen-bonding geometry (A and ꢁ) for compounds 2 and 3
DAHÆÆÆA
d(DAH)
d(HÆÆÆA)
d(DÆÆÆA)
\(DHA)
Compound 2
N8AH8AÆÆÆN7i
0.86
2.41
3.254(2)
167
Compound 3
C20AH20AÆÆÆN7ii
0.93
0.93
2.69
2.62
3.593(2)
3.470(2)
165
152
iii
C50AH50AÆÆÆN70
Symmetry codes: (i) ꢀx + 0.5, y + 0.5, ꢀz + 2; (ii) ꢀx, ꢀy + 1, ꢀz;
(iii) ꢀx ꢀ 2, ꢀy, ꢀz.
groups and some amino-ether linker. All bond angles and
bond lengths within the structures are typical.
Fig. 3. A view showing the interconnections of 2 within a layer. The
In 2, the central O10 atom is located at a twofold crys-
tallographic axis (according to symmetry 1 ꢀ x, 1 ꢀ y, z)
and the asymmetric unit contains one half of the molecule.
The angle between the best planes of the two planar
aromatic rings being 83.81(5)ꢁ, the nitrile groups are
nearly coplanar with these rings. The conformation of the
central linkage is trans for C8AC9AO10AC90 and
C1AN8AC8AC9 and gauche for N8AC8AC9AO10 (the
appropriate torsion angles are listed in Table 2). A similar
conformation is observed for the majority of the related
compounds [15–19]. Such an arrangement represents a
favored less strained conformation although other confor-
mations are also found [8,20]. The crystal structure of 2 is
stabilized by intermolecular NAHÆÆÆN hydrogen bond
between the amino and nitrile groups (Table 3). The mole-
cules are linked by N8AH8AÆÆÆN7 interactions forming
folded layers parallel to (001) plane (Figs. 3 and 4).
The molecular structure of 3 is completely different. The
dihedral angle between the end-to-end phenyl rings is only
4.7(1)ꢁ. The nitrile groups are also found to be coplanar
with these rings. Additionally, the central chain is in an
extended trans conformation (see torsion angles in
Table 2). So, the molecule is nearly coplanar, only the
symmetry code is the same as in Table 3.
Fig. 4. The packing arrangement of 2 indicating folded layers.
CH3 groups resemble antennas (the torsion angle
C8AC9AN10AC11 is ꢀ74.5(2)ꢁ). Such an extended con-
formation is also observed for 4,40-[1,5-pentanediyl-
bis(oxy)]bisbenzonitrile [21]. The crystal structure of 3 is
stabilized by intermolecular CAHÆÆÆN hydrogen bonds
2
3
Fig. 2. A perspective view of the molecular conformations of 2 and 3 together with the atom numbering scheme.

D. Maciejewska et al. / Journal of Molecular Structure 879 (2008) 53–59
57
Fig. 5. The chain of the molecules of 3. The symmetry codes are the same as in Table 3.
between the aromatic ring and the nitrile substituents (see
Table 3). The hydrogen bonding scheme is depicted in
Fig. 5. Nearly linear molecules of 3 are linked via
C50AH50AÆÆÆN70 and C20AH20AÆÆÆN7 interactions to form
infinite chains along the [210] and [2–10] directions. The
chains form the layers parallel to (001) plane (Figs. 6
and 7). The CH3 substituents of the neighboring molecules
from the chains are oriented in opposite directions, accord-
ing to the inversion centers. Thus, the investigated bisnitr-
iles 2 and 3 reveal different conformations of the central
chain. The observed differences could be determined by
the crystal packing of the molecules and intermolecular
interactions and also by the presence of a bulky substituent
CH3 at the central N10 atom of the chain in 3.
The nitrile groups take part in the intermolecular hydro-
gen bonds which can be responsible for efficient interaction
with the biological target.
Fig. 7. The packing arrangement of 3 indicating the layers parallel to
(001) plane.
3.2. NMR spectra in solid state and molecular modeling
The 13C CP/MAS NMR solid state spectrum of 3 is
shown in Fig. 8 together with the most probable assign-
ment of resonances. For comparison, we demonstrated
the 13C CP/MAS NMR spectrum of 2 in the upper right
corner of Fig. 8. Recently, employing the theoretical calcu-
lation of the shielding constants using atomic coordinates
of the stable conformation, corresponding to local minima
of energy, is a routine tool in the search for solid state
structure based on NMR spectra. However, there are some
difficulties for symmetric compounds with a labile linker,
because many energetically close conformations could be
responsible for the spectral pattern. In our case, both
examined molecules are formally halved by central hetero-
atoms (O atom in 2 and N atom in 3). For the chemically
equivalent pairs of atoms from both parts of the molecules
we could expect a different pattern of NMR resonances in
solid state, depending on the kind and the number of stable
conformation and the intermolecular interactions. For
compound 2 we observed a simple, solution-like spectrum.
As it results from X-ray studies, a symmetric butterfly-like
structure with a twofold crystallographic axis (see Fig. 4) is
responsible for this. We computed the shielding constants
for 13C atoms of a single molecule, a dimer and a trimer
isolated from crystallographic arrangement. The best
agreement with the experimental chemical shifts was
obtained for a single molecule of 2. This could be explained
by the fact that intermolecular interactions do not domi-
Fig. 6. The chains of the molecules of 3 within one layer.

58
D. Maciejewska et al. / Journal of Molecular Structure 879 (2008) 53–59
Fig. 8. The 13C CP/MAS NMR spectrum of 4,40-[1,5-(N-methyl-3-azapentanediylbis(oxy))]bisbenzonitrile 3 (for comparison the spectrum of 4,40-[1,5-(3-
oxapentanediylbis(amino))]bisbenzonitrile 2 in the upper right corner).
nate the spectral pattern. For compound 3 we observed
double signals with intensity ratios of 1:1 for the majority
of atoms, merging doublets of the CH2 (8, 80, 9, 90) groups,
and a singlet for NACH3 (11) group. In this case, we
observed a very good correlation between the theoretical
shielding constants and the experimental chemical shifts
for dimer (r2 = 0.998). Computation made for a single mol-
ecule did not show the proper separation of resonances for
the corresponding pairs of atoms from both parts of the
molecule.
(Bethesda, USA). The evaluation against the 60 cell lines
at a single dose of 1 · 10ꢀ5 M revealed that 3 exhibits
significant growth inhibition (GI in %) of cell lines: CCR-
CEM (ꢀ84.41%) and RPMI-8226 (7.02%) both of leuke-
mia, A498 (12.67%) of renal cancer, SK-MEL-5 (6.74%)
of melanoma. Recently, it is examined at five concentration
levels. The mean value of GI is 77.69%.
4. Conclusions
Both carbon atoms ortho to O-alkyl linker in com-
pound 3 are shielded in different ways: resonances of
the pair C2, C20 atoms are shifted to higher field, and
resonances of the pair C6, C60 are shifted in the opposite
direction as compared with averaged signals in the solu-
tion spectrum. The separations of resonances are equal
to 4–8 ppm. The separation of signals of relevant meta
carbons (C5, C50 and C3, C30) is much smaller (1–
2 ppm), indicating that the atoms in the nitrile groups
are not deviated from the linearity.
The procedure of preparation of new 4,40-[1,5-(N-
methyl-3-azapentanediyl-bis(oxy))]bisbenzonitrile
3 was
worked out successfully (yielding 82%). The single crystal
X-ray diffraction measurements revealed a completely
different molecular structure of 2 and 3, with various
dihedral angles between the best planes of both planar
phenyl rings, and different conformations of the linker.
The intermolecular hydrogen bonds NAHÆÆÆN and
CAHÆÆÆN, in 2 and 3, respectively, were found to be
the main driving force which connects molecules into lay-
ers in the crystals. For compound 3 computations based
on crystallographic geometries only a set of molecules
allowed for complete assignment of resonances in solid
state of the 13C CP/MAS NMR spectrum. Compound
3 exhibits growth inhibition of many human tumor lines,
especially of leukemia.
3.3. Cytotoxicity of 4,40-[1,5-(N-methyl-3-azapentanediylbis-
(oxy))]bisbenzonitrile 3
Only compound 3 was accepted to The In Vitro Cell
Line Screening Project of National Cancer Institute

D. Maciejewska et al. / Journal of Molecular Structure 879 (2008) 53–59
59
[13] G.M. Sheldrick, SHELXL97, Program for the Refinement of Crystal
Structures, University of Go¨ttingen, Germany, 1997.
Acknowledgments
[14] Gaussian 03, Revision B.02, M.J. Frisch, G.W. Trucks, H.B.
Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Mont-
gomery, Jr., T. Vreven, K. N. Kudin, J.C. Burant, J.M. Millam,
S.S. Iyengar, J. Tomasi, V. 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, T.
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, V.G. Zakrzewski, 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, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-
Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W.
Gill, B. Johnson, W. Chen, M.W. Wong, C. Gonzalez, J.A. Pople,
Gaussian, Inc., Pittsburgh PA, 2003.
The authors thank Interdisciplinary Center for Mathe-
matical and Computational Modeling (ICM) of Warsaw
University for the computational grant.
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