Effective methods for the synthesis of hydrazones, quinazolines, and Schiff bases: reaction monitoring using a chemometric approach

Abstract

Synthesis of hydrazones (1a-4a and 1b-4b), quinazolines (3c·MeOH and 3d·MeOH), and hydrazone-Schiff bases (4c and 4d) is achieved by combining suitable aldehydes (2,3- or 2,4-dihydroxybenzaldehyde) with four hydrazides (isonicotinic, nicotinic, and 2- or 4-aminobenzoic acid hydrazide). A suite of approaches for their preparation is described: solution-based synthesis, mechanosynthesis, and solid-state melt reactions. The mechanochemical approach is generally a better choice for the quinazolines, while the solid-state melt reaction is more efficient for derivatives of (iso)nicotinic based hydrazones. Crystalline amine-functionalised hydrazones 4a and 4b undergo post-synthetic modifications in reactions with 3- or 4-pyridinecarbaldehyde vapours to form hydrazone-Schiff bases 4a-3py, 4b-3py, 4a-4py, and 4b-4py. Mechanochemical and vapour-mediated reactions are followed by ex situ powder X-ray diffraction and IR-ATR methods, respectively. The chemometric analysis of these data using principal component analysis provided an insight into the reaction profiles and reaction times. Azines (5a and 5b), achieved from aldehydes and hydrazine, reversibly change colour in response to temperature changes. The structures of all products are ascertained by a combined use of spectroscopic and X-ray diffraction methods. The cytotoxic and antimicrobial activities of all compounds against selected human cancer cell lines and bacterial strains are evaluated.

Fig. 1. Synthetic procedures applied for the preparation of hydrazones, quinazolines, and hydrazine-Schiff bases.

Fig. 2. Hydrazones 1a–4a and 1b–4b. Blue sphere presents N atom in the case of isonicotinic or nicotinic acid hydrazide, or NH₂ group in the case of 2- or 4-aminobenzoic acid hydrazide. Red sphere presents OH group.

Fig. 3. Molecular structures of compounds: (a) 1a·MeOH, (b) 1b·H₂O, (c) 3a, (d) 3b, (e) 4a, and (f) 4b·MeOH. Solvent molecules were excluded because of clarity. Atoms are shown as spheres of arbitrary small radii. The intramolecular hydrogen bonds are indicated as an array of yellow cylinders. In all the structures carbonyl oxygen atom has label O1, neighboring nitrogen atoms N1 and N2 labels (the latter participates in intramolecular hydrogen bond).

Fig. 4. Crystal packing of compound 1b·H₂O. Molecules of 1b are arranged in arrays which are mutually connected with hydrogen bonds (water molecules serve as a bridge) forming sheets. Sheets of molecules are held by stacking interactions and hydrogen bonds.

Fig. 5. Crystal packing of compound 4b·MeOH. Molecules are connected with an extensive network of hydrogen bonds. Methanol molecules serve as a bridge between sheets of hydrazone molecules. The view is projected down the crystallographic c axis.

Fig. 6. PXRD patterns of hydrazones obtained by the solution-based method (blue line) and by the mechanosynthesis (green line).

Fig. 7. Principal component loadings spanned by (a) three and (b) two principal components calculated for a set of PXRD data collected through mechanochemical synthesis of 4a.

Fig. 8. 2,3-Dihydroquinazolinones obtained by the reaction of 2-aminobenzhydrazide and 2,3-dihydroxybenzaldehyde, 3c, and 2,4-dihydroxybenzaldehyde, 3d. Red spheres present OH groups.

Fig. 9. Hydrazone-Schiff bases obtained by the reaction of 4-aminobenzhydrazide and 2,3-dihydroxybenzaldehyde, 4c, and 2,4-dihydroxybenzaldehyde, 4d. Red sphere presents OH group.

Fig. 10. Molecular structures of compounds: (a) 3c·MeOH and (b) 4c. Solvent molecules were excluded because of clarity. Atoms are shown as spheres of arbitrary small radii. The intramolecular hydrogen bonds are indicated as an array of yellow cylinders.

Fig. 11. Time dependence of PC1 scores calculated for a set of IR-ATR data collected through a synthesis of 4a-3py.

Fig. 12. Time dependence of PC1 scores calculated for a set of IR-ATR data collected through a synthesis of 4a-4py.

Fig. 13. Time dependence of PC1 scores calculated for a set of IR-ATR data collected through a synthesis of 4b-3py.

Fig. 14. Time dependence of PC1 scores calculated for a set of IR-ATR data collected through a synthesis of 4b-4py.

Fig. 15. Compounds obtained by the reaction of azine and 2,3-dihydroxybenzaldehyde, 5a, and 2,4-dihydroxybenzaldehyde, 5b. Red sphere presents OH group.

Fig. 16. Molecular structures of compound 5b·H₂O. The solvent molecule was excluded because of clarity. Atoms are shown as spheres of arbitrary small radii. The intramolecular hydrogen bonds are indicated as an array of yellow dotted lines.

Fig. 17. Crystal packing of compound 5b·H₂O. Molecules are connected with an extensive network of hydrogen bonds. Parallel sheets are mutually interconnected via water molecules. The view is projected down the crystallographic c axis.

Fig. 18. The solid-state thermochromic behaviour of 5a. The images of the temperature effects on the appearance of azine 5a were taken when sample was heated in Kugelror oven. The beige colour is recovered after it was cooled to room temperature.