Synthesis, Catalytic GPx-like Activity, and SET Reactions of Conformationally Constrained 2,7-Dialkoxy-Substituted Naphthalene-1,8- peri- diselenides

Abstract

Several 2,7-dialkoxy-substituted naphthalene-1,8-peri-diselenides were prepared and tested for catalytic antioxidant activity in an NMR-based assay employing the reduction of hydrogen peroxide with stoichiometric amounts of benzyl thiol. Acidic conditions enhanced their catalytic activity, whereas basic conditions suppressed it. The highest activity was observed with a 2,7-bis(triethyleneglycol) derivative. These compounds serve as mimetics of the antioxidant selenoenzyme glutathione peroxidase. Studies based on NMR peak-broadening effects and EPR spectroscopy indicated that a thiol-dependent SET reaction occurs under the conditions of the assay, which can be reversed by the addition of triethylamine. In contrast, peak broadening induced by proton-catalyzed electron transfer during the treatment of naphthalene-1,8-peri-diselenides with trifluoroacetic acid can be suppressed by the addition of excess thiol. These observations provide new insights into the redox mechanisms of these processes.

Figure 1

C–Se–Se–C dihedral angles of diselenides.

Scheme 1. Synthesis of Naphthalene peri-Diselenides

Figure 2

¹H NMR assay of diselenide catalyst 1b in the oxidation of benzyl thiol with hydrogen peroxide. The ¹H NMR spectra were recorded at 400 MHz in CDCl₃-CD₃OD (95:5).

Figure 3

(a–f) Kinetic plots for assays of diselenide catalysts: (a) 1b, (b) 1c, (c) 1d, (d) 1e, (e) 1f, (f) 1g. Reactions were performed at 18 °C in CDCl₃–CD₃OD (95:5). Initial concentrations were as follows: benzyl thiol, 0.031 M; H₂O₂, 0.035 M; catalyst, 0.0031 M; and DMT, 0.0155 M. The formation of dibenzyl disulfide was monitored by ¹H NMR spectroscopy via integration of the disulfide methylene signal at 3.57 ppm vs the aromatic signal of DMT at 8.06 ppm. The plots are averages of either three or four runs.

Figure 4

Possible O···Se coordination in naphthalene peri-diselenides 1e–1g.

Scheme 2. Catalytic Cycle for the Reduction of Hydrogen Peroxide with Naphthalene peri-Diselenides and Benzyl Thiol

Scheme 3. PCET Reaction of Naphthalene peri-Diselenide 1b

Figure 5

¹H NMR spectrum of 1:1 mixture of diselenide 1b and selenolseleninate 8b. The ¹H NMR spectrum was obtained in CDCl₃-CD₃OD (95:5) at 400 MHz by treating 1b with 50 mol % of H₂O₂ for 4 h.

Scheme 4. SET Reaction of Diselenide 1b after Treatment with Benzyl Thiol

Figure 6

EPR spectrum of diselenide 1b in the presence of benzyl thiol and hydrogen peroxide under the usual conditions of the antioxidant assay.

Figure 7

¹H NMR peak broadening during the reaction of diselenide 1b and selenolseleninate 8b with benzyl thiol and triethylamine. (a) Spectrum of diselenide 1b (0.05 mmol) and selenolseleninate 8b (0.05 mmol); (b) after addition of 0.01 mmol of benzyl thiol; and (c) after addition of 0.036 mmol of triethylamine. ¹H NMR spectra were obtained at 400 MHz in CDCl₃-CD₃OD (95:5). The complete spectra showing integration and chemical shifts are provided in the Supporting Information.

Scheme 5. Reaction of Postulated Intermediate 9b with Triethylamine

Figure 8

Effect of benzyl thiol and TFA on peak broadening of catalyst 1c. (a) 1c: 15.5 mg, 0.034 mmol. (b) TFA: 1.3 μL, 1.9 mg, 0.017 mmol. (c) Benzyl thiol (1st portion): 2.0 μL, 2.1 mg, 0.017 mmol. (d) Benzyl thiol (2nd portion): 2.0 μL, 2.1 mg, 0.017 mmol. (e) Benzyl thiol (3rd portion): 36 μL, 38 mg, 0.306 mmol. The ¹H NMR spectra were taken at 400 MHz. The spectra were recorded in 1.0 mL of CDCl₃.