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  • As the angular structure of

    2019-07-19

    As the angular structure of compound cannot be differentiated from the linear structure by H NMR spectroscopy, a NOESY NMR experiment was performed to unambiguously characterize the regioselectivity of the final compound. In the linear compound , a signature correlation between the proton of the thiazole-fused ring (H) and the H proton is expected. By comparison, there should be no correlation between the proton of the thiazole-fused ring (H) and the H proton in angular compound . Therefore the observed correlation pattern (no correlation between H and H; see ) evidences the formation of angular compound with a 3,4-thiazolonaphthalimide moiety. To unequivocally confirm the regioselectivity of the cyclisation step, the unstable compound was trapped with glycine methyl ester hydrochloride, to afford stable compound in 40% yield. The minor by-product was also isolated in 3% yield (). The two compounds and were fully characterized by H and C NMR and NOESY experiments. NOE patterns similar to those observed for confirm the formation of 3,4-thiazonaphthalimide angular regioisomers. The final proof for this regioselectivity was unambiguously obtained by X-ray crystallography. Indeed, X-ray quality crystals of and were obtained by the slow evaporation of dichloromethane and their crystallographic structures solved by X-ray diffraction (see for details). The solid-state structures confirm the formation of two angular compounds. Compound is the expected angular naphthalimide derivative functionalized by an aminothiazole group with nitrogen in position 3 and sulfur in position 4, whereas the minor compound is a similar derivative with the positions of nitrogen and sulfur atoms inverted, i.e. sulfur in position 3 and nitrogen in position 4 (). The formation of this by-product can be explained by the presence of ∼10% 4-nitro-1,8-naphthalic anhydride in the commercially available 3-nitro-1,8-naphthalic anhydride, as evidenced by the H NMR spectrum of this starting material. The two X-ray structures show intermolecular hydrogen bond networks that result in one dimensional arrangements along the a axis for and the a + b axis for : the protons of the amino groups are H-bonded to one carbonyl ester and one nitrogen JDTic 2HCl to of the thiazole ring for or to one carbonyl ester and one oxygen atom of the naphthalimide for . The aromatic rings are planar with mean deviations of only 0.024 Å for and 0.018 Å for . The shortest distance between the two thiazonaphthalimide rings were found at 3.412 Å for and 3.438 Å for , between two different molecules related by the symmetry center of the space group (2/n for and -1 for ). These distances are short enough to evidence π-stacking interactions in both structures. The literature reports of only 3- and 4-substitution on naphthalic anhydride or naphthalimide may suggest the poor reactivity of position 2 in the aromatic ring due to steric hindrance or electronic effects. This would prevent the reaction of the thiocyanate group at this position and the formation of 2,3-thiazole fused linear compounds. In fact, the reported linear compounds have been characterized by 1D NMR only and therefore lack reliable structural assignment. Notably, the H NMR signals of the aromatic moieties in compounds and are very similar to those previously reported (see ). Therefore, our results based on unambiguous structural proof strongly suggest that the thiazonaphthalimide major compounds previously described by Qian and co-workers are in fact the angular ones, and that their minor product is another angular isomer with reversed positions of the nitrogen and sulfur atoms, formed from an impurity present in the starting material. Thiazonaphthalimide derivatives , and were studied for their photophysical properties and their interactions with ct-DNA. These ester derivatives are preferred over the acids, in order to avoid electrostatic repulsions between the carboxylate group and the negatively charged phosphates of DNA at physiological pH. The comparison of these three derivatives gives valuable information regarding the influence of the nitrogen and sulfur atoms positions in the ring and the substitution of the thiazole group by a hydrogen or an amine group. The fluorescence of each compound was measured after the addition of increasing amounts of ct-DNA (expressed in base pairs (bp)) and excitation at its maximum absorption wavelength at 298 K in a buffered solution. These results show a decrease of the fluorescence of each aromatic compound after the addition of ct-DNA in solution, reflecting an interaction between the aromatic rings and the double-helix of DNA, as shown in A for compound and for compound and , respectively.