Theoretical Study of the Coordination of Semicarbazone and Its Methylated Derivatives

Semicarbazone is a molecule with a group RRC=N-NR-C(=O)-NRR. The oxygen atom has two free electron pairs; each nitrogen atom has one free electron pair. These free electron pairs are potential sites of coordination. The simplest molecule in this series is the semicarbazone which the formula is H2C=N-NH-C(=O)NH2. By replacing the oxygen atom by a sulfur atom is obtained a thiosemicarbazone. Some semicarbazones, such as nitrofurazone, and some thiosemicarbazones are known to have many properties: antiviral, antibacterial, antitrypanosomal, anticonvulsant, antitumor, anticancer. They are usually mediated by an association with copper or iron. Indeed transition metal complexes with given chemical structures are useful alternatives in the treatment of certain diseases since coordination of active ingredients deeply modifies both the physiological properties of metals and ligands in the meaning of overall improvement of these properties. The present work focuses on quantum study of the complexation of semicarbazone and its methylated derivatives. The purpose of this study is to determine the most favorable coordination site of each of these ligands. It was found that the oxygen atom appears more favorable to the coordination of semicarbazones. Complexes of these ligands with the Zn (II) were modeled. The calculations were made by the method DFT / B3LYP with the orbital basis 6-31G (d, p).


Introduction
The study at the molecular level of the interaction between metals and bioligands (proteins, nucleic acids, their fragments, and other substances contained in the organism) is topical (Knouniats, 1990) (Williams, 1975) (Yatsimirskiï, 1976) (Kembal, 1975).The bioinorganic chemistry which is currently in full swing is concerned, inter alias, with the coordination of trace elements with organic ligands.The results of these studies find their applications in various fields of science and technology such as medicine, agriculture, environmental protection, catalysis.
Semicarbazones (SCZ) are molecules having a group R 1 R 2 C=N-NR 3 -C(=O)-NR 4 R 5 , thus having donor atoms (N and O) capable of forming bonds with complexing metals.They are of particular interest as ligands.Semicarbazones are derivatives of aldehydes or ketones.They are formed by condensation of these compounds with a semicarbazide as shown by the reaction: H 2 NNHC(=O)NH 2 + RC(=O)R 2 → RR 2 C=NNHC(=O)NH 2 + H 2 O where R 2 is a hydrogen atom (if it is an aldehyde) or an alkyl group (if it is a ketone).The simplest molecule of this series is the semicarbazone of formula H 2 C=N-NH-C(=O)NH 2 .Certain semicarbazones, such as nitrofurazone, and certain thiosemicarbazones are known for their antiviral, antibacterial, antitrypanosomal (antiparasitic), anticonvulsive, anti-tumor, anti-cancer, etc. activities, generally mediated by a binding with copper or iron (Picot, 2008) (Sakirigui et al., 2011) (Kenneth, 1999).-357.924990hartree for E-Ethanalsemicarbazone.The value -357.92hartree which appears under these two isomers is written in the authors' concern to stop at two digits after the decimal point.So there is no question of thinking that the two isomers have the same stability.

Geometric Analysis
The table 1 contains some geometric data of the studied ligands.Analysing SCZs molécules we notice that bond lengths N 1 C 4 and N 6 C 4 are equal to about 1.39Å.This value is intermediate between 1.47 Å (C-N length) and 1.27 Å (C=N length) (Mason, 1961) (Potapov & Tatarintchik, 2008) (Sakurai, Yoshikawa, Yasui, 2008).In other hand we found that C 4 O 5 bonds are about 1.22 Å long, it correspond to a double C=O bond.These observations suggest that the double C=O bond interacts with the free π electronic pairs of N 1 and N 6 nitrogen atoms while a part of electronic pairs clouds off O atom compenses the electronic defect, which issued from this conjugation, at the level of C=O double bond.That's why its length has not varied.The N 6 N 8 , bond length of which about 1.37, is a single bond while the N 8 C 9 bond (1.28 Å) is a double one (Mason, 1961) (Potapov & Tatarintchik, 2008) (Sakurai, Yoshikawa & Yasui, 2008).
The sum of the bond angles arround C 4 atom equals 360° and the dihédral N 1 C 4 O 5 N 6 is about 180° ; this means that the three bonds (and the tree atoms) which are arround C 4 are in the same plane.Consequently the clouds of the π free electronic pairs of N 1 et N 6 and that of π C=O have a same orientation, so it is a confirmation that they forms conjugation bonds N 1 C 4 , N 6 C 4 and C 4 O.This electronic pairs delocalization is not favorable to a coordination trough the N 1 and N 6 nitrogen atoms.Thus we can tell that the bond lengths as CI are not favorable to coordination with a metal ion trough the N 1 and N 6 ; contrarly that indice is favorable to coordination trough O and N 8 because their free electronic pairs are quasi no delocalized (Douglas & Anthony, 1993).

Atomic Charges Analysis
The table 2 corresponds to the atomic charges of the investigated ligands.In these ligands one notice that the atomic charges of N 1 , N 6 et O 5 are about -0,7 a.u.; the N 8 atoms carry rather positive charges (0.086 ; 0.035 ; 0.077 et 0.105 a.u.respectivly for SCZ, Z-EtSCZ, E-EtSCZ, 2-MSCZ and 4-MSCZ).Thus the charge as CI is not favorable to a coordination though N 8 .Although the N 1 and N 6 atoms are negatively charged, the coordination through them is disadvantaged by their rather positive environment; in fact H 2 , H 3 , H 7 et C 11 carry high positive charges (about 0.2 a.u.for hydrogen atoms and 0.3 a.u.for C 11 ) capable of repelling the coordination cation.These reasons assume that the charge is favorable for the coordination of the semicarbazones via the oxygen atom.O and N 6 -

Atomic Indexes of Electropphilic Superdelocalisability (IESD) Analysis
The main IESDs are shown in the table 4. We can notice that all these indexes are negatives.The atomic index of electrophilic superdelocalizability is an magnitude which shows the capacity of given specie to attract a electrophile system.The coordination is thought to be more likely at the level of the atom with the most negative IESD (Gómez-Jeria, 2014).Thus the table 5 revels that oxygen atom.(-0,6eV) is the more favorable coordination site for all studied ligands.It is followed by the trigonal nitrogen atom N 8 (about 0,46eV).

Recapitulative Analysis
In the table 5 you can read, at the intersection of each ligand with each CI, the atom through which coordination can occur during a complexation process.These results should be confirmed by modeling the complexes of these molecules.
The choice in the present study is focused on zinc (II), a trace element that is very present in the treatment of various pathologies.Its electronic structure is 1s22s 2 2p 6 3s 2 3p 6 4s 0 3d 10 4p 0 .Zinc (II) generally gives tetrahedral complexes close to the Td point group.This is understandable when one observes its electronic structure: the orbital s, p x , p y and p z are vacant and are capable of sp 3 hybridization.The sp 3 hybrid orbitals point to the tops of a tetrahedron.The orbital p of atoms recognized as favorable for the coordination of the ligands studied are capable to overlap with these sp 3 orbitals.

Modeling
Semicarbazone complexes ZnCl 2 .Ligand were modeled.They are ZnCl 2 .SCZ, ZnCl 2 .Z-EtSCZ, ZnCl 2 .E-EtSCZ, ZnCl 2 .2MSCZand ZnCl 2 .4MSCZ.Their structures and geometic parameters are shown respectively in the figure 2a and the table 7a.They are some chelates having tetrahedral stucture.The coordination with the complexing atom took place via the oxygen atom (the length of Zn-O equals about 2 Å) and the trigonal nitrogen atom of the ligand (length of Zn-N8 equals about 2 Å) forming a pentagonal ring, which is known to be more stable than if the coordination was established by N 6 instead of N 8 since the cycle tension would be, in this case, higher.These results are consistent with the literature data (Douglas, West & Anthony, 1993) (Alomar., 2012).
Semicarbazone complexes ZnCl 2 .2Ligand(ZnCl 2 .2SCZ,ZnCl 2 .2(Z-EtSCZ), ZnCl 2 .2(E-EtSCZ),ZnCl 2 .2(2MSCZ)et ZnCl 2 .2(4MSCZ))were modeled too.These complexes have tetrahedral structure too.Their structures are shown in figure 2b and, in the table 6b, are recorded some of their geometric data.It is found that the interatomic distances ZnO are of the order 2 Å, length of the Zn-O bond according to the data of the literature (Kuevi, 1992); there is no ZnN link.It can be deduced that the molecules of the semicarbazones that are the subject of the present works, in the proportion Zn / ligand = ½, have entered into coordination via the oxygen atom.
From all the foregoing it emerges that the combination of the analysis of interatomic distances, atomic charges, electrostatic potentials, atomic indices of superdelocalizabilty and the frontier orbitals of the ligands constitute a fairly effective means of studying the coordination of semicarbazones.An energetic study of the complexation processes made it possible to assess the stability of the coordination compounds of these ligands with Zn (II).The negative values of the free enthalpies of coordination show that the coordination of the studied semicarbazones is spontaneous process.The enthalpies are negative, so the process concerning the ligands is exothermic.
From the both conformers of ethanalsemicarbazone one obtains the same chelate; instead the Z-ETSCZ was transformed, during the complexation, into the E-form to avoid congstion with the ZnCl 2 system.The value -1.62 eV obtained in the column of the enthalpies of coordination for the complex Z-ETSCZ would be the sum of the coordination enthalpy of this complex and the reorganization energy of the Z-ETSCZ molecule to E-ETSCZ one.
It should be noted that the introduction of the methyl group in semicarbazone did not involve any significant modification of the properties.

Conclusion
The present works constitute a theoretical study of the coordination of the molecules of some semicarbazones.These were semicarbazone, E-ethanalsemicarbazone, Z-ethanalsemicarbazone, 2-methylsemicarbazone, 4-methylsemicarbazone.This has been possible through the analysis of coordination indicators such as bond lengths, atomic charges, electrostatic atom potentials, boundary orbitals, and atomic electrophilic superdelocalizability indexes.
The results from our calculations showed that these molecules are able to form complexes with metal ions.Zn 2 + is one of those ions.It has been found that the most favorable coordination site is the oxygen atom for these semicarbazones followed by the trigonal nitrogen atom.The methyl group in semicarbazone did not involve any significant modification of the properties.

Table 2 .
Atomic charges (a.u.)The table3shows some energetic values of studied SCZs.One notice that the HOMO et HOMO-1 are respectively of -6,5 eV et -7 eV; these molecular orbitals are dominated respectively by the p z atomic orbital of N 6 and the p x atomic orbital of O.According to this analysis, the frontier orbitals indicate that the coordinating favorable sites of studied SCZs in this investigation work are N 6 nitrogen atom and O.

Table 3 .
Energetic values of the investigated SCZs

Table 5 .
Recapitulative analysis, * BL= Bond lengths, ** AC= Atomic charges It can be seen that all the CIs considered are favorable for the coordination of the studied semicarbazones via the oxygen atom.Coordination through N 8 or N 6 is less likely.No CI is favorable for coordination of semicarbazones, object of the present study, by N 1 .

Table 6a .
Some geometric data of the modelised complexes ZnCl 2 .Ligand

Table 7 .
Some energies of the studied systems