Theoretical studies on the structure of [(1-aza-2-benzimidazol-2-ylprop-1-enyl)amino]aminomethane-1-thione

The tautomerisation and acid-base properties of [(1-aza-2-benzimidazol-2-ylprop-1-enyl)amino]aminomethane-1-thione were studied both in the gas and aqueous phase to elucidate the structure of this compound. The computed data, such as bond lengths, bond angles and dihedral angles, were compared with the experimental X-ray results. Excellent correlations for some properties were observed.


Introduction
Since thiosemicarbazones possess large numbers of donor atoms they can act as multifunctional types of ligand.p-Delocalization and configurational flexibility allow them to adopt a wide variety of coordination modes 1 .3][4] It has been believed that the thiosemicarbazones are efficient on certain biological mechanisms because of their abilities to form complexes with metal cations, by bonding through the sulfur and azomethine nitrogen atoms. 5The compounds containing a thiosemicarbazone component have shown a broad spectrum of chemotherapeutic properties, including antimalarial, 6 antitumour, 7 antibacterial, 8 antitrypanosomal, 9 and antiviral 10 activity.The anticonvulsant, 11 antiamoebic 12,13 and antioxidant properties 14 of thiosemicarbazone derivatives should also be mentioned here.Following our work on some other type of ligands, 15- 18 we now report our recent work related to the title compound.
In the presented work we have attempted to determine some physical parameters, which will help to enlighten the structure and ligand properties of the title compound theoretically.The obtained data are depicted in Table .1.

Tautomerisation
To elucidate the structure and reaction mechanism, such as protonation reaction, it is very important to know some thermodynamic and physical parameters of the investigated compound.Therefore before doing further structural calculations we have searched for the possible tautomeric forms of the title compound 1 (Scheme 2) and the obtained results were evaluated as follows; Mole fraction.Both AM1 and PM5 calculated mole fraction values are unity indicating the presence of tautomeric form 1 only.Whereas PM3 method indicate the predominance of tautomeric form 2 with a percentage of 97.44 (Table 1).
Tautomeric equilibrium constants.The AM1 and PM5 calculated K T values (i.e.4.27x10 146 and 6.09x10 89 respectively) supporting the mole fraction method are also indicative of predominance of tautomeric form 1 (Table 2) whereas PM3 calculation results indicate the predominance of form 2.

Relative Stability (RS)
The calculated RS values were collected in Table 3.The AM1 and PM5 results having negative RS values of -4.92 and -7.30 kcalmol -1 respectively indicate the predominance of amino thion form 1 over the amino thion form 2 as K T and mole fraction criteria suggest (Tables 1-2).PM3 results however having positive RS value of 2.24 indicates opposite as in the case of K T and mole fraction approaches.
Similarly, the RS values of -25.72, -27.10 and -28.04 for 3 1 equilibrium indicate the predominance of form 1 over the form 3 supporting the K T and mole fraction criteria with all tree methods.

Acidity constants
The next step to study the structure and reactivity of this biologically active molecule is to evaluate the calculated acidity constants.The possible protonation pathway for the parent compound 1 and its tautomeric forms 2 and 3 are described in Scheme 2. The calculated acidity constants are depicted in Table 4. Since the tautomeric form of 1 was found to be predominant the deprotonation equilibrium of form 1 will be discussed here.
ARKAT USA, Inc.The first NH is placed in the chain (i.e.3NH) and the second NH is in the imidazole ring (i.e.5NH).When one of the protons of the two NH groups is removed the following two mesomeric and a tautomeric form of the anion become feasible; and both ring and chain anions may rearrange into the same form (Scheme 1).The formed minus charge is stabilized better on 6N atom because of the aromaticity of the imidazole ring.Therefore, the closeness of the pK a values for 1 4 and 1 5 deprotonation equilibrium is expected.The PM3 and PM5 calculated pK a values of 20.28 and 19.65 (Table 4) are acceptable results.If we consider the effect of substituent at 2C these results are comparable with experimentally obtained pK a value of 12.75 for deprotonation of benzimidazole 24 .
ARKAT USA, Inc. Protonation pK a values.The protonation acidity constant of benzimidazole molecule was reported as 5.56 25 and none of the calculated pK a value is close to that value.However, if we consider the electronic and steric effect of the big substituted group located at 2C position we can suggest a reaction path for the first protonation of molecule 1.The AM1 calculated pK a values of 1.51 and 1.34 suggest a ring protonation via 1 8 equilibrium.Whereas the PM5 calculated pK a value of 17.30 suggest firstly a transformation into tautomeric form of 2 then deprotonation from the ring proton via 1 8 equilibrium.
Proton affinities (PA).The gas phase calculated proton affinities for molecule 1 were depicted in Table 5.For 5N anion (molecule 4) proton affinities were found to be bigger that that of 3N anion (molecule 5) with all methods.So we can say protonation on 5N anion 4 should be easier that that of 3N anion 5.The reverse argument is applicable for deprotonation.
Similarly proton affinity values for molecule 1 states that the biggest PA values which were calculated with AM1, PM3 and PM5 methods belong to amino group.Therefore, the first protonation should takes place at NH 2 and, as was stated under the other headings, the protonation pattern is 1 6 for molecule 1.

Structure elucidation via correlation
Knowledge of the predominant tautomeric form and some physical parameters will make the elucidation of the structure of the title compound easier.The best way to do this will be searching the correlation between calculated and experimental results.
Bond lengths.The correlation attempt to reveal out the relation between the experimental and computed bond lengths have indicated that the best correlation was observed by PM5 calculations (i.e.R 2 = 0.9871).The slope of the regression line however is a little away from the unity (i.e.m = 1.447) indicating that no one to one correspondence is present.In the bond length calculations for N1-C1, S1-C1 and C2-C4, however, the AM1 method was found to perform better (Table 7).
ARKAT USA, Inc.   ARKAT USA, Inc. Angles.The correlation attempts of experimental and computed bond angles however not successful as bond lengths.The best regression constant R 2 was 0.573 with a slope m of 0.6109 with PM5 method and we can say that it is not a successful attempt so as the other methods (i.e.AM1 and PM3 methods indicate R 2 values of 0.5194 and 0.5002 respectively) (Table 7).
Dihedral angles.The correlation attempts of dihedral angles were revealed that the best correlation was observed by AM1 calculations (i.e.R 2 =0.9871and m=0.9732).The slope is about unity and regression is about unity that means it may safely be used to predict dihedral angles of such a big molecules which contains sulphur and nitrogen heteroatoms (Table 7).PM3 and PM5 methods also produce similar results, which can be used in a predictive manner to eliminate the time and expenditure of elaborate X-ray analysis.

Experimental Section
General Procedures.A slightly modified procedure from the literature was applied to prepare the thiosemicarbazone derivatives. 19To achieve this a mixture of 2-acetylbenzimidazole (5 mmol), thiosemicarbazide (5 mmol) and acetic acid (1 mL) in ethanol (50 mL) was refluxed for six hours.The raw product precipitated in cooled solution was filtered and recrystallised from ethanol: yield: 70-80 %; mp 230-231 °C.The structure elucidation was done by X-ray method and reported elsewere. 20antum chemical calculations were carried out at the Restricted Hartree-Fock level using AM1, PM3, and PM5 semi-empirical SCF-MO methods in the CAChe Work system Pro Version 6.1 program 21 and Restricted Hartree-Fock level using 6-31G** and DFT in B3LYP 6-31G* ab initio methods in the Spartan 22 , implemented on an Intel Pentium Pro.400 MHz computer.Initial estimates for the geometries its structures were obtained by a molecular mechanics program (CS Chemoffice Pro for Windows) 23 , followed by full optimization of all geometrical variables (bond lengths, bond angles and dihedral angles), without any symmetry constraint, using the semiempirical AM1, PM3, and PM5 quantum chemical methods in the CAChe Work system Pro Version 6.1 and Spartan 04 V1.0.3 programs.

Conclusions
It seems that quantum chemical calculation can safely be used in structure elucidation of big molecules such as [(1-aza-2-benzimidazol-2-ylprop-1-enyl)amino]aminomethane-1-thione and this kind of calculations should be performed as a prediction of possible synthesis and the stability of the predictive product.In order words it is an economical predictive approach for elaborate synthesis.

Table 1 .
Semi empiric calculated thermodynamic and physical parameters

Table 6 .
The results with all methods are indicative of biggest nucleophilicity of molecule 1.This results support the greatest basicity of (i.e.greater pK a values) molecule 1 compared to the other tautomers (i.e.molecules 2 and 3) and even than that of anions (i.e.molecules 4 and 5).

Table 7 .
The Gas phase selected bond distances, angles and dihedral angles (T=298 K) in CAChe Work system Pro Version 6.1 program