Synthesis and Theoretical Study of a New Type of Pentacyclic bis-Benzothiazolium Compound

The synthesis of a new type of pentacyclic benzothiazolium compound - 6,13-dihydropyrazino[2,1-b:5,4-b′]bis(1,3-benzothiazole)-7,14-diiumdibromide (2), is reported. Compound 2 was prepared by dimerization of 2-(bromomethyl)benzothiazole. Quantum chemical calculation studies have been carried out on the structures of possible isomers of 2, as well as the products of its deprotonation reactions.


Chemistry
The starting material 2-(bromomethyl)benzothiazole (1) was obtained from commercially available 2-methylbenzothiazole by standard radical bromination in a nonpolar solvent [8]. The target product 2 was prepared by the autoalkylation reaction of compound 1 in dry ethanol (Scheme 1); reaction conditions such as temperature, reaction time and molar ratios of 2-(bromomethyl)benzothiazole to ethanol were optimized and the best conditions found are presented in the Experimental Section. This reaction probably proceeds via the monoalkylated compound 3-(benzothiazol-2-ylmethyl)-2-(bromomethyl)benzothiazolium bromide, which would explain the formation of the insoluble compounds in concentrated polar solutions upon mild warming due to the possibility of an intermolecular reaction of the monoalkylated derivative with another molecule of 2-(bromomethyl)benzothiazole. The solvolysis products 2-(ethoxymethyl)benzothiazole (yield 17 mol%), 2-(ethoxymethyl)-3H-benzothiazoliumbromide (yield 38 mol%) and 2-(bromomethyl)-3Hbenzothiazolium bromide (yield 14 mol%) were also identified and isolated from the reaction mixture.

Theoretical study
To obtain a better understanding of the mechanism of the reaction and the structure of the product, we carried out quantum chemical calculations using the semiempirical AM1 method [9]. The structures of the six isomeric dications 2a-f are presented in Scheme 2. The geometry of all isomers has been fully optimized. The ring nomenclature is shown for isomer 2a. The calculated quantum-chemical data of isomers 2a-f is summarised in Table 1, where HF represents the heat of formation, ∆E is the relative stability calculated as a difference between heats of formation of the corresponding isomer and the most stable isomer 2a, E HOMO is the energy of the highest occupied molecular orbital and E LUMO is the energy of the lowest unoccupied molecular orbital. As it can be seen from the data in Table 1, the most stabilizing structural element is the planar tetravalent nitrogen atom with one double and two single bonds common to two heterocycles which occurs in isomers 2a, 2b and 2d. The remaining structural elements, namely the tetravalent nitrogen with three single N-C bonds and one N-H bond as well as the trivalent sulphur with three S-C bonds, are not planar and destabilize the molecule.
The AM1 calculated optimized geometry of the most stable isomer 2a is shown in Figure 1. This isomer is symmetric with two nitrogen atoms common to two rings and the molecule is nearly planar (the maximum out of plane deformation is about 4 o in the ring C).  The symmetry of the molecule is also evident from the charge densities of the atoms. The sp 3 hybridized carbons in ring C are slightly deformed from a tetrahedral arrangement with an H-C-H angle of 108.5 o and a C-C-N angle of 113.6 o . The preference for structure 2a is further confirmed by the 1 H-NMR spectra, which are consistent with a symmetric structure with four equivalent hydrogens in ring C. As for the remaining data, the minimum frontier orbital energy corresponds to isomer 2c, the maximum E HOMO to 2d and E LUMO to 2e.
As we plan to study the condensation reactions of compound 2a, a theoretical study of the deprotonation of 2a was our next goal. For this purpose we modeled the reaction of 2a with pyridine as a base. To compare the energy of deprotonation, the following isodesmic reactions with pyridine as a model base were considered (Scheme 3). The value of the energy is the relative stability of the system defined as the difference E x -E 2 , where E x is the sum of heats of formation of three molecules in the corresponding system (System 3 or System 1) and E 2 is the sum of heats of formation of molecules in the most stable System 2.

Scheme 3.
The energy data in Scheme 3 show that System 2 is the most stable one, followed by System 3 and then the dication 3a with two pyridine molecules (System 1). This means that the deprotonation of the C ring in 3a by the pyridine molecule ( System 1 → System 2) produces a 65.30 kcal/mol energy decrease. On the contrary, removal of the proton bonded to the sp 3 -carbon in ring C of monocation 3b ( System 2 → System 3) is an endothermic process with a 15.63 kcal/mol increase in energy. This fact is confirmed also by the calculated charge densities: the hydrogen in ring C of dication 3a is more acidic (Q = + 0.176) than the hydrogen bonded to the sp 3 -carbon in ring C of monocation 3b (Q = + 0.132). The optimisation of conditions for the condensation reactions of 3a is currently in progress.

General
Melting points were determined on the Kofler block and are uncorrected. Elemental analyses were determined on a Carlo Erba 1016 instrument. 1 H-NMR spectra were recorded with a 300MHz Varian Gemini 2000 instrument using TMS as an internal standard. Column chromatography was performed using silica gel (40/100 mesh), thin-layer chromatography was performed on silica Silufol UV-254 precoated plates (Kavalier, Czech Republic).

Quantum Chemical Calculation Methods
The molecular orbital calculations were carried out using the AM1 [9] Hamiltonian in the AMPAC [10] molecular orbital calculation framework. All geometries were fully optimized without geometry constraints.
Sample availability: Available from the authors.