1
Effect of the methyl group on intermolecular characteristics of benzodiazepine-2,4-dione
A. El Assyry
(a)*, B. Benali
(a), B. Lakhrissi
(b)(a)Laboratoire d’Optoélectronique et de Physico-chimie des Matériaux (Unité associée au CNRST), Département de Physique,Université Ibn Tofail, B.P. 133, Kénitra, Maroc
(b)Laboratoire d’Agroressources et Génie des Procédés,
Département de Chimie,Université Ibn Tofail, B.P. 133, Kénitra. Maroc
*Corresponding author. E-mail : [email protected] Recieved 13 Dec 2013, Revised 24 Dec 2013, Accepted 24 Dec 2013
Abstract
In this work we determined the effect of the methyl group on intermolecular interactions of benzodiazepine.
The single-crystal structure of benzodiazepine-2,4dione (C9H8N2O2) and 1,5-dimethylbenzodiazepine-2,4-dione (C11H12N2O2) was determined at room temperature. These molecules are mirror symmetrical; their R values respectively are 0.0786 for 322 observed reflections and 0.043 for 781 observed reflections. Quantum chemical calculations using DFT at the B3LYP/6-31G* level of theory was further used to calculate some electronic properties of the molecule in order to ascertain any correlation between the experimental and theoretical results.
Keywords: Benzodiazepine-2,4-dione; 1,5-Dimethylbenzodiazepine-2,4-dione; Intermolecular Interaction – hydrogen bonding; Thermal agitation factors; DFT.
1. Introduction
Benzodiazepine-2,4-dione is a none-planar molecule composed of a phenyl ring linked-with a seven numbered heterocycle (Fig.1). We were interested because of the molecular properties of this compound since several publications recently indicated that some benzodiazepine derivatives have been studied owing to their biological activity as carcinostatic compounds [1,4]. This molecule has a strong interest physico-chemical because of its symmetrical shape and its electrophilic heteroatoms including two nitrogen atoms and two oxygen atoms that cause a large increase in its polarization [5-8]. It is therefore interesting to have detailed information on intermolecular interactions, because this molecule and some of its derivatives have a drawback in that the equilibrium reaction between the ketone and the alcohol in the heptagonal cycle hampers the interpretation of experimental and theoretical results in electron spectroscopy. Exploiting these results can only succeed if we know beforehand the type of molecule involved. This led us to undertake a study by X-ray diffraction on single crystals of the benzodiazepine-2,4-dione (B) and 1,5-dimethylbenzodiazepine-2,4-dione (N,N-DMB).
O H
N O
N H
O CH3
N O
N CH3
Figure 1. Benzodiazepine-2,4-dione and 1,5-Dimethyl-benzodiazepine-2,4-dione chemical diagram.
2
2. Materials and methods
2.1. Experimental section
The compound of benzodiazepine-2,4-dione has been synthesized by Kenitra’s group using a method described elsewhere [9], the synthesis and purification methods of 1,5-dimethylbenzodiazepine-2,4-dione have been described elsewhere [10]. Experimental technique and apparatus are described elsewhere [5].
2.2. Computational chemistry
The quantum calculations were performed using the Gaussian 03 program [11]. The geometry of the studied compound was evaluated using the DFT level of the three-parameter compound functional of Becke (B3LYP) [12]. The 6-31G* basis set was used for all atoms [13-16]. The geometry structure was optimized under no constraint. The following quantum chemical indices were considered: the energy of the highest occupied molecular orbital (EHOMO), the energy of the lowest unoccupied molecular orbital (ELUMO), ΔEgap= EHOMO - ELUMO, the dipole moment (µ) and total energy (TE).
3. Results and Discussions
3.1. Conformational characteristics of the B and N,N-DMB
We performed measurements at room temperature on a single crystal of the benzodiazepine-2,4-dione obtained after crystallization in the mixture n-hexane and ethanol. The crystal obtained was colorless, although small dimensions 0.15 × 0.020 × 0.010 mm3, its crystal structure has been solved by direct methods and refined by the least squares method leading to a final agreement factor of R = 0.0804. The thermal agitation of all atoms except hydrogen atoms was refined anisotropically. The nomenclature adopted for the molecule B is shown in fig.2. Since the molecule is symmetrical with respect to the mirror, the asymmetric unit corresponds only to a part of the molecule located on one side of the mirror (mirror included). The symmetry x, 1/2-y, z is used to generate the coordinates of equivalent atoms. The latter have the same name followed by an a. In fig.2, the thermal ellipsoids of agitation are represented with a probability of 50% of their value.
After crystallization of the 1,5-dimethylbenzodiazepine-2,4-dione in methanol, we obtained a colorless crystal size (mm) 0.25 × 0.10 × 0.10. The crystal structure has been solved by direct methods and refined by the least squares method leading to a final agreement factor of R = 0.0469. The thermal agitation of all atoms except hydrogen atoms was refined anisotropically.
Figure 2. ORTEP plot of benzodiazepine-2,4-dione (B) and 1,5-dimethylbenzodiazepine-2,4-dione (N,N- DMB) with the ellipsoids drawn at the 50% probability level.
3 In Table 1, are presented the anisotropic thermal agitation factors. The atoms C1, O7 and C2 are those with the highest thermal motion. And in Table 2, the atoms C5, C6 and O7 which have the highest thermal agitation.
The N-heterocycle in B is not planar, as revealed by the dihedral angles N4-C5-C6-C5a (-67.3°) and C5-N4- C3-C3a (44.3°). Actually, N atoms are situated practically on the same plane as the phenyl ring; the C6 and C5 atoms are plainly above the phenyl plane. As for lactams the N4-C3 bond distance 1.417(6) Å is higher than the N4-C5 one 1.339(7) Å, which is coherent with the delocalization of the carbonyl double bond.
Table 1. Anisotropic thermal agitation factors of B.
Atoms U11 U22 U33 U23 U13 U12 O7 0.057(3) 0.048(3) 0.084(3) 0.0058(14) 0.002(2) 0.0014(17) N4 0.053(4) 0.047(3) 0.076(3) 0.0061(15) 0.000(2) -0.002(2) C1 0.055(4) 0.073(4) 0.076(4) -0.005(2) -0.001(3) -0.008(2) C2 0.054(4) 0.057(4) 0.076(4) -0.007(2) 0.002(3) -0.002(3) C3 0.049(4) 0.049(3) 0.064(3) -0.0008(19) 0.000(3) 0.001(2) C5 0.049(4) 0.040(3) 0.068(4) -0.007(2) 0.002(2) 0.003(2) C6 0.059(4) 0.048(4) 0.064(4) 0.0000 0.005(3) 0.0000
In a qualitative way, the hydrogen substitution of benzodiazepine molecules by a methyl group on the nitrogen atoms, little effect on the molecule geometry. If the nitrogen atoms N are located on the same plane as the phenyl ring, the C1 and C2 are squarely above and C8 is well below this plane (phenyl ring which is almost parallel to the axis z, the angle value between the link C6-C4 and the axis z is of the order 6.3° [17].
Table 2. Anisotropic thermal agitation factors of N,N-DMB.
Atoms U11 U22 U33 U23 U13 U12 O7 0.0739(9) 0.0427(7) 0.0354(7) 0.0109(5) -0.0035(5) 0.0030(6) N3 0.0425(8) 0.0267(7) 0.0316(7) 0.0026(5) -0.0009(5) -0.0014(5) C1 0.0407(12) 0.0417(12) 0.0346(12) 0.0000 -0.0085(9) 0.0000 C2 0.0436(9) 0.0309(8) 0.0292(8) 0.0023(6) -0.0001(6) 0.0080(6) C4 0.0306(8) 0.0314(8) 0.0275(8) 0.0007(6) -0.0010(5) 0.0007(6) C5 0.0478(10) 0.0350(8) 0.0347(9) -0.0056(6) -0.0017(7) 0.0032(7) C6 0.0480(9) 0.0559(10) 0.0278(8) -0.0081(7) -0.0002(7) 0.0035(8) C8 0.0502(9) 0.0292(8) 0.0479(10) 0.0016(7) 0.0011(7) -0.0049(7)
3.2. Intermolecular characteristics of benzodiazépine-2,4-dione
Fig.3 represents the projections of the B structure respectively along the axes a and c. In this figure, four mesh along the axis a and two mesh along the axis c, were shown to highlight the presence of intermolecular hydrogen bonds.
From Figure 3, it clearly appears that the two cycles of benzodiazepine are not located in the same plane. It is also shown by the value of dihedral angle C5-N4-C3-C2 which is equal to –138.5(4)° (table 3). The flatness of the phenyl ring is demonstrated by the value of dihedral angle C1-C2-C3-C'3 equal to 0.6(6)°. This cycle shows the geometry of a regular hexagon with the binding C-C of standard length 1.39 Å. However, there is a slight decrease in bond length C1-C2 equal to 1.367(7) Å. This geometry characterizes the delocalization of the electrons of aromatic ring. While in the heptagonal ring containing the two nitrogen atoms, only the valence angle C3-N4-C5 (126.0(4)°) is close to that of a regular heptagon (128.57°), all other deviate considerably. The nitrogen atom N4 is nearly in the plane of the phenyl ring as the torsion angle C1-C2-C3-N4 is –176.6(4)°, a value very close to –180°. The structure of non-planar heptagonal cycle is justified by the respective values of
4 torsion angles N4-C5-C6-C'5 (-67.3°) and C5-N4-C3-C'3 (44.3°) (table 3), thereby disadvantaging and partial relocation of the electrons of the carbonyl group throughout the bond C-N; therefore, the reaction equilibrium between form ketone and alcohol in this molecule decreases greatly in the second direction (the ketone form prevails). This hypothesis is supported by the cancellation of the combination at this level, where the valence angle C3-N4-C5 (126.0° is much higher than 108°) which promotes a type structure sp3. Moreover, we note that the carbon C6 is very out of plane phenyl (Figure 3).
Figure 3. Description of the hydrogen bonds arrangement in the crystal of B.
a) Projection showing the zig-zag, b) Projection showing the ribbon
The bond length of N4-C5 (1.339Å) in the benzodiazepine is shorter than that of N4-C3 (1.417Å), the difference between these two values is relatively larger, which indicates a strong intramolecular interaction between the lone doublet of nitrogen atom and the carbonyl group (C=O) [18]. These last two bonds are similar to a single bond, it reinforces the more aromatic than ethylene of C=O (1.239Å) group.
Table 3. Dihedral angles Values of B.
(The symmetry x, 1/2-y, z is used to generate the coordinates of equivalent atoms).
Dihedral angles (°) C3 N4 C5 O7
C5 N4 C3 C2 C5 N4 C3 C3a C3 N4 C5 C6 C1a C1 C2 C3 C1 C2 C2a C1a C1 C2 C3 N4
178.7(4) -138.5(4) 44.3(6) -4.1(6) -0.6(7) 0.0(7) -176.6(4)
C1 C2 C3 C3a N4 C3 C3a N4a C2 C3 C3a N4a C2 C3 C3a C2a N4 C3 C3a C2a N4 C5 C6 C5a O7 C5 C6 C5a
0.6(6) 0.00(6) -177.2(4) 0.00(6) 177.2(4) -67.3(5) 109.9(5)
a)
b)
5
Table 4. Dihedral angles Values of N,N-DMB.
Dihedral angles (°) C8 N3 C4 C5
C2 N3 C4 C4a C4 N3 C2 O7 C8 N3 C2 O7 C4 N3 C2 C1 C8 N3 C2 C1 C2 N3 C4 C5 C8 N3 C4 C4a C2 C1 C2 N3
-37.76 -47.7 -176.36 -3.8 5.9 178.41 134.60 139.92 69.8
C2 C1 C2 O7 C5 C4 C4a N3a N3 C4 C5 C6 C4a C4 C5 C6 N3 C4 C4a N3a C5 C4 C4a C5a C4 C5 C6 C6a C5 C6 C6a C5a
-107.9 177.68 175.16 -2.6 0.0 0.0 2.6 0.0
Intermolecular interaction
The guidelines and the arrangement of benzodiazepine molecules within its crystal structure can be explained by the existence of specific intermolecular interactions [19, 20], ie of non-covalent bonds. Indeed, the molecular association by electrostatic interactions and hydrogen bonding are among the most reliable interactions, more interesting work has shown their important role in crystalline arrangement [21, 22]. The benzodiazepine admits two donors (NH), two acceptors (C=O) hydrogen bond and an aromatic ring, which increases its potential reaction. This is well illustrated by the data in Table 5 which includes the shortest intermolecular distances of B linked with its nearest neighbors. In Table 6, are combined the geometric characteristics of hydrogen bonds (D for the donor atom, A for acceptor).
Table 5. Intermolecular distances of B linked to its nearest neighbors.
The molecules are stacked with two hydrogen bonds (see table 6) between N4-H4 and O7 of a molecule related by the symmetry relation 1-x, 1-y, -z. The N4-H4…O7 bonds form a ribbon parallel to the b direction. It can be noticed that the bond between N1-H1 and O7 of a molecule related by the symmetry relation 1+x, y, 1+z presents a rather short distance (2.552Å) and an angle not to far from 180° (166.3°).
Table 6. Hydrogen bonding geometry of B.
D H A D – H(Å) H…A(Å) D…A(Å) D – H…A(°) N4 H4 O7#1
C1 H1 O7#2
0.8601 2.0271 2.880(6) 170.83 0.9299 2.5525 3.463(7) 166.30
#1 symmetry code : 1-x, 1-y, -z
#2 symmetry code : 1+x, y, 1+z
The molecules are linked by hydrogen bonds N4-H4...O7 forming a zigzag cord in the direction of the axis a (see Fig.3). Each molecule interacts by its two amide groups NH forming a hydrogen bond with the carbonyl. So amide groups are involved invariably in the hydrogen bond network, which hinders the possibility of dimer formation of type NH….
It is well known that the pyridone dimers formed by the bimolecular motif N-H…O are robust [23, 24]. The data in Table 6 are consistent with these results since the distance N-H…O=C is equal to 2.0271Å and the angle intermolecular is 170.83° (close to 180°); These values correspond to a strong hydrogen bond [22, 25].
Atoms involved Distance (Å) Atoms involved Distance (Å)
O7 C6 O7 C2 O7 H6A O7 H2 O7 H4 N4 N4 N4 H6A
3.410(7) 3.356(7) 2.8810 2.7284 2.0271 2.899(6) 2.9312
C5 C6 C1 H6B C3 H6A C5 H4 C5 H6A H2 H4
3.502(8) 3.0883 2.6993 2.9460 2.6985 2.4987
6
Moreover, we note that the bond length C-H…O=C (Table 6) is relatively short (2.5525Å), that is to say smaller than that of an interaction of van der Waals type [26] and the angle C-H…O, equal to 166.3°, has a value close to 180°. However, this interaction is low, the oxygen atom can then be involved in the hydrogen bond N-H…O=C.
Finally, a weaker interaction is also involved in crystal cohesion by the ligands C3…H6A (2.6993Å) and C5...H6A (2.6985Å).
Interactions involving not only features NH and C=O paresseraient play an important role in the construction of the benzodiazepine supramolecule. Indeed, the phenyl ring participates in a relatively weak interaction such as CH…O=C. Additional hydrogen bonding is required by the package geometry between the asymmetric carbon CH2
and aromatic carbon C3 attached to nitrogen.
The necessary condition for the simultaneous formation of these associations is predictably the maintenance of the non planarity of molecules involved. In this model we proposed, the arrangement of benzodiazepine molecules linked by different types of hydrogen bonding in the form of a sheet formed of extended band of zigzag ordered supramolecules.
Onsager Parameter
The parameter ‘’a’’ found in the dipole moment expression, called Onsager radius strongly influences the absolute value of the dipole moment () calculated, because the solvatochromic slope is proportional to 2/a3. For B, non- spherical molecule, we apply the Lippert method [27] where it proposes to take as the value of ‘’a’’, 40 of the long axis length of the molecule.
Figure 4. Ellipsoidal structure of B.
For the benzodiazepine, taking into account the distance separating the two ends of the molecule ie the oxygen O7 of the carbonyl group and hydrogen symmetrical H1 furthest from the aromatic ring (6.5783Å) and van der Waals radius of the two ends (O7: 1.51Å et H1: 1.17Å), we obtain overall a distance of about 8.26Å, which 40% leads to the Onsager radius a=3.3Å. The value thus obtained was used to calculate the dipole moments difference of the ground state and excited state of benzodiazepine [7].
3.3. Intermolecular characteristics of 1,5-dimethyl-benzodiazepine-2,4-dione
Figure 5 represents the projections of the structure of the N,N-DMB respectively along the axes a, b and c.
Contrary to the benzodiazepine, the crystal structure of this molecule is almost parallel in a stack, the phenyl rings overlap perfectly. The major difference with the benzodiazepine is a molecule on two rotates 180 ° about the axis x relative to the center of the phenyl ring. This gives us a parameter a, double the parameter c of the benzodiazepine (table 9). One can also see the effect of steric hindrance created by the substitution of two nitrogen atoms by the methyl group, which prevents the formation of hydrogen bonding between the lone pair of the nitrogen atom and electropositive elements of the neighboring molecule.
7 c
b a
c
(a) (b) (c)
Figure 5. Projection of the structure of the N,N-DMB along the axes a, b and c.
Intermolecular interaction
Table 7. Intermolecular distances of N,N-DMB linked to its nearest neighbors.
Atoms involved Distance (Å) Atoms involved Distance (Å) O7 H6 2.5806 C2 H8A 3.0022 O7 H8A 2.7363 C4 H1A 2.6002 O7 H8C 2.5624 C5 H8B 2.6013 O7 H8B 2.7528 C6 H1A 3.0456 O7 H5 2.6770 C6 H8B 3.0705 O7 H8C 2.6190 C8 H5 2.6609 N3 N3 2.9365(18) H5 H8B 2.3019 N3 H8A 2.9214 H5 H8C 2.4100 C2 H1B 3.0875
Only two rather weak hydrogen bonds are established (see Table 8) between C6-H6 and O7 of a molecule related by the symmetry relation x, y, z-1; the C…O distance is large (3.491 Å), but the C6-H6…O7 angle is 166°.
Table 8. Hydrogen bonding geometry of N,N-DMB.
D H A#2 D – H(Å) H…A#2(Å) D…A#2(Å) D – H…A#2(°) C6 H6 O7 0.9297 2.5806 3.491(2) 166.26
#2 symmetry code : x, y, z-1
We have shown by X-ray diffraction, the existence of a single hydrogen bond in nature C6-H6...O7 in the intermolecular interaction of N,N-DMB with neighboring molecules related by the symmetric x, y, z-1. The distance H6...O7 is relatively high 2.5806Å while the angle C6-H6...O7 is almost linear in the range of 166° that is to say corresponding to a strong hydrogen bond.
Onsager Parameter
For the calculation of the Onsager parameter of N,N-DMB, we applied the second model of Lippert [27]
where the molecular volume of the cavity is considered that of a sphere of radius a.
We estimated the volume of the cavity of the N,N-DMB from the corresponding cell volume containing four molecules. Indeed, taking into account the result of X-ray diffraction, we obtained the value 3.87Å. This value was used in determining the difference of dipole moments of N,N-DMB between the ground state and excited state [28].
b a
8 Effect of substitution
Table 9. Lattice parameters of B and N,N-DMB.
compounds system Space
group
a (Å)
b (Å)
c (Å)
(°)
(°)
(°)
Z d (g.cm-3)
B Monoclinique P21/m 8.5421 11.671 4.037 90 97.58 90 2 1.465
N,N-DMB Orthorhombique Pnma 8.144 13.315 8.996 90 90 90 4 1.391
Analysis of the table above, we found that the substitution of the hydrogen atoms on both nitrogen atoms of B by methyl groups significantly alter the structural characteristics of this molecule.
3.4. Theoretical calculations
Quantum chemical methods have already proven to be very useful in determining the molecular structure as well as elucidating the electronic structure and reactivity [29]. Thus, it has become a common practice to carry out quantum chemical calculations in corrosion inhibition studies. The predicted properties of reasonable accuracy can be obtained from density functional theory (DFT) calculations [30, 31]. Some quantum chemical parameters, which influence the electronic interaction between surface atoms and inhibitor, are the energy of highest occupied molecular orbital (EHOMO), the energy of lowest unoccupied molecular orbital (ELUMO), the energy gap (ΔEgap), dipole moment (μ) and total energy (TE). All quantum chemical properties were obtained after geometric optimization with respect to the all nuclear coordinates using Kohn–Sham approach at DFT level.
The computed quantum chemical properties such as energy of highest occupied molecular orbital (EHOMO), energy of lowest unoccupied molecular orbital (ELUMO), LUMO–HOMO energy gap (ΔEL-H), dipole moment (μ) and total energy (TE) are summarized in the Table 10.
Table 10. Quantum parameters of B and N,N-DMB calculated with B3LYP/6-31G*
Compound TE (eV) EHOMO (eV) ELUMO (eV) ΔEgap (eV) µ (Debye)
B -16439.28 -8.571 -5.088 3.483 3.7766
N,N-DMB -18568.79 -8.136 -5.523 2.613 3.1213
As EHOMO is often associated with the electron donating ability of a molecule, high values of EHOMO are likely to indicate a tendency of the molecule to donate electrons to appropriate acceptor molecules with low-energy, empty molecular orbital. Increasing values of the EHOMO facilitate adsorption (and therefore inhibition) by influencing the transport process through the adsorbed layer. Therefore, the energy of the ELUMO indicates the ability of the molecule to accept electrons; hence these are the acceptor states. The lower the value of ELUMO, the more probable, it is that the molecule would accept electrons [32]. As for the values of ΔE (ELUMO - EHOMO) concern; lower values of the energy difference ΔE will cause higher inhibition efficiency because the energy to remove an electron from the last occupied orbital will be low [33]. For the dipole moment (μ), lower values of μ will favor accumulation of the inhibitor in the surface layer.
As we know, frontier orbital theory is useful in predicting the adsorption centers of the inhibitors responsible for the interaction with surface metal atoms. The HOMO and the LUMO population of B and N,N-DMB were plotted and are shown in Figure 6. Analysis of this figure shows that the density of LUMO is mainly localized on the CH3 substituent, while the density HOMO was distributed around the entire molecule.
9 HOMO LUMO
B
N,N-DMB
Figure 6. The frontier molecule orbital density distributions of B and N,N-DMB
Moreover, the gap between the LUMO and HOMO energy levels of the molecule was another important factor that should be considered. It has been reported that excellent corrosion inhibitors are usually those organic compounds that are not only offer electrons to unoccupied orbital of the metal but also accept free electrons from the metal [34]. It is also well documented in literature that the higher the HOMO energy of the inhibitor, the greater its ability of offering electrons to unoccupied orbital of the metal, and the higher the corrosion inhibition efficiency. It is evident from Table 10 that B has the highest EHOMO in the neutral form. In addition, the lower the LUMO energy, the easier the acceptance of electrons from metal surface, as the LUMO- HOMO energy gap decreased and the efficiency of inhibitor improved. It is clear from Table 10 that the ELUMO
of B exhibits the lowest, making the protonated form the most likely form for the interaction with B molecule.
Low values of the energy gap (ΔE) in N,N-DMB will provide good inhibition efficiencies, because the excitation energy to remove an electron from the last occupied orbital will be low [32]. The total energy of the B is equal to -16439,28 eV but for N,N-DMB is -18568,79 eV. This result indicated that N,N-DMB is favorably adsorbed through the active centers of adsorption. Lower values of dipole moment (μ) will favor accumulation of the inhibitor in the surface layer and therefore higher inhibition efficiency [35].
4. Conclusion
The guidelines and the arrangement of molecules of benzodiazepine-2,4-dione can be explained by the existence of intermolecular interactions.
Unlike the benzodiazepine-2,4-dione, the crystal structure of 1,5-dimethylbenzodiazepine-2,4-dione is parallel in a stack, the phenyl rings overlap perfectly and the steric hindrance created by the methyl groups.
The substitution of the hydrogen atoms carried out by the two nitrogen atoms of the benzodiazepine-2,4- dione by methyl groups significantly alter the structural characteristics of this molecule.
The results obtained from the calculations agree well with experimental values.
Acknowledgements-This work has been supported in part by the Morocco-French (CNRST-CNRS) Convention and the Hassan II Academy of Science and Technology.
10
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