Effects of the aldehyde-derived ring substituent on the properties of two new bioinspired trimethoxybenzoylhydrazones: methyl vs nitro groups

Abstract

N-Acylhydrazones are a versatile class of organic compounds with a diversity of potential applications. In this study, two new structure-related 3,4,5-trimethoxybenzoyl-containing N-acylhydrazones were synthesized and fully characterized, both in solution and in the solid state. The compounds differ with respect to the carbonyl precursors, i.e., 3-substituted salicylaldehydes with either a methyl or a nitro group. Single crystals of both compounds were isolated from the respective mother liquors and, in both cases, XRD confirmed the obtention of the (E)-isomer, in an anti-conformation. Computational calculations (gas and water phases) were performed in order to confirm some of the structural and vibrational aspects of the compounds. An important intramolecular H bond involving the phenolic hydroxy group and the azomethine nitrogen was identified in the solid state and seems to be maintained in solution. Moreover, the presence of the electron-withdrawing nitro substituent makes this interaction stronger. However, the contact should probably not subsist for the nitro compound under physiological conditions since the presence of this substituent significantly affects the pK_a of the phenol: an apparent value of 5.68 ± 0.02 was obtained. This also impacts the basicity of the azomethine nitrogen and, as a consequence, increases the hydrazone's susceptibility to hydrolysis. Nevertheless, both compounds are stable at physiological-like conditions, especially the methyl-derived one, which qualifies them for further toxicological and activity studies, such as those involving trivalent metal ions sequestering in the context of neurodegenerative diseases.

Keywords: DFT calculations; N-acylhydrazones; XRD; phenol acidity; ring substituents.

Scheme 1

Structure of (A) 3-methylsalicylaldehyde 3,4,5-trimethoxybenzoyl hydrazone (hdz-CH₃) and (B) 3-nitrosalicylaldehyde 3,4,5-trimethoxybenzoyl hydrazone (hdz-NO₂).

Figure 1

ORTEP representation of the new N-acylhydrazones synthesized in the present work, drawn with thermal ellipsoids at 30% probability. Left: hdz-CH₃ and right: hdz-NO₂.

Figure 2

(A) Superposition of molecular structures and stacked motifs of (B) hdz-CH₃ and (C) hdz-NO₂.

Figure 3

Overlap of the experimental (carbon atoms colored in gray) and theoretical structures (calculated with B3LYP/6-311G(d,p) in gas and water phases colored in yellow and cyan, respectively): hdz-CH₃ seen from (A) above and (B) from the side; hdz-NO₂ seen from (C) above and (D) from the side. The optimized structures of hdz-CH₃ and hdz-NO₂ can be seen in Figure S4 in Supporting Information File 1.

Figure 4

Mid-infrared spectra of the compounds. Experimental conditions: KBr pellets, room temperature. Calculated conditions: gas phase, level of theory B3LYP/6-311G(d,p). (A) Overlapping of the theoretical (black) and experimental (purple) spectra of hdz-CH₃. (B) Overlapping of the theoretical (black) and experimental (yellow) spectra of hdz-NO₂.

Figure 5

¹H NMR (400 MHz) spectra of (A) hdz-CH₃ and (B) hdz-NO₂ in DMSO-d₆ at 25 °C.

Figure 6

Electronic absorption spectra in a selected wavelength region for a solution of hdz-CH₃ in 10% DMSO/HEPES mixture (pH 7.4). Experimental conditions: l = 1.0 cm and T = (25.0 ± 0.1) °C. (A) Gaussian fitting of the bands in the spectrum at t₀, along with the spectra of precursors TMP (dotted gray curve) and MBA (dotted purple). Deconvolution performed with Origin software. (B) Spectra measured at t₀ and after 12, 24, 30, and 48 h. Absorption in pure DMSO (black curve) was added for the sake of comparison.

Figure 7

Electronic absorption spectra of hdz-NO₂ in selected wavelength regions. Experimental conditions: l = 1.0 cm and T = (25.0 ± 0.1) °C. (A) Deprotonation band centered at 440 nm, measured in different 10% DMSO/buffer mixtures (pH ranging from 3.8 to 8.2). Inset: A₄₄₀ versus pH with sigmoidal fitting. Gaussian fitting of the bands in a solution of the hydrazone in (B) 10% DMSO/acetate buffer (pH 3.8) and (C) 10% DMSO/Tris-HCl buffer (pH 8.2). Deconvolution performed with Origin software. Spectra of precursors TMP (dotted gray curve) and NBA (dotted dark yellow) were included to aid in band attribution.

Scheme 2

General scheme for the synthesis of the studied hydrazones.