Facile and straightforward synthesis of Hydrazone derivatives

Institute of Chemical Sciences, Bahuddin Zakariya University, Multan 60800, Pakistan CAS Key Laboratory of Soft Material Chemistry, Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China Departamento de Quimica Organica, Universidad de Cordoba, Campusde Rabanales, Edificio Marie Curie, CtraNnal IV, Km. 396, E-14014 Cordoba, Spain Promising Centre for Sensors and Electronic Devices (PCSED), Advanced Materials and Nano-Research Centre, Najran University, P.O. Box: 1988, Najran 11001, Saudi Arabia Empty Quarter Research Unit, Department of Chemistry, College of Science and Art in Sharurah, Najran University, Sharurah, Najran 11001, Saudi Arabia Department of Electrical Engineering, Faculty of Engineering, Najran University, Najran 11001, Saudi Arabia


Introduction
Hydrazones are special organic compounds derived from the Schiff-base family and comprising of C N N C bonds with additional donor sites. The donor sites make hydrazones more flexible and versatile for their structural and functional properties [1]. For instance, hydrazones are very significant reactants in different reactions such as hydrazone iodination, Shapiro and Bamford-Stevens reaction. On the other hand, hydrazones act as intermediates in Wolff-Kishner reaction. The C and H atoms in hydrazones tend to react with organometallic nucleophiles. Due to its highly acidic nature, the alpha-hydrogen atom of hydrazones is comparatively more nucleophilic than that of ketones [2]. Different studies have reported the biological importance of trigonal hybridized nitrogen atom in azomethine group of hydrazones which is remarkable for having one pair of electrons in its either π or sp 2 orbitals [3,4]. Their hetero atomic nature and specific electronic properties make them very important structural compounds [5]. One of the most promising organic hole transporting materials are aromatic hydrazones. Recently, some researchers have reported the synthesis of polymeric hydrazones with remarkable properties such as high glass transition temperatures, good filmformation and moderate charge transport [6].
The ligation of hydrazones with surface immobilized hydrazines and aldehydes-modified antibodies can be used to anchor captured proteins on oxide coated biosensor substrates [7]. Hydrazones are also being used as inhibitors such as strong poly (ADP-ribose) glycohydrolase (PARG) [8].
Aroyl hydrazones have been reported to use in clinical theranostic applications due to their ferric ion scavenging activities [9]. The role of N, O and S in metal coordination at the active sites of numerous metallobiomolecules is also well known for various industrial, antimicrobial, anticancer and herbicidal applications [10,11]. The chelating ligands get coordinated with metal ions by N, O or S as donor atoms. They have been found to show a wide variety of biological applications and are becoming a hotspot of research [12,13]. The coordination of metal ions with the biologically active compounds can enhance their potential [14]. The polymeric hydrazones and their coordination in polymer drug conjugates is involved in hydrolysis. The rate of hydrolysis is significantly faster at acidic pH as compared to those of carbamates [15]. Hydrazone linkers are stable only in physiological conditions (pH 7.4) but they are prone to get cleaved under acidic conditions such as the intracellular conditions of endosomes and lysosomes protects them by forming micelle around. The hydrophobic drugs are hence gets protected from the host defense system in the body [16]. For instance, the anticancer drug DOX is released at higher rate under acidic conditions due to the nature of linkage between the DOX and micelles [17]. Chromone derivatives have received great attention of researchers for their applications. These compounds show wide spectrum of biological activities such as antimicrobial, antitumor, anti-allergic, antiviral, anti-inflammatory and anticancer activities [18].
Due to the aforementioned applications of hydrazones, herein we have reported the quick, facile, and convenient synthesis of six novel hydrazones containing N, O, or S atoms derived from Chromone. Hopefully, the combination of the chromone moiety with hydrazides may provide more biologically active resulting compounds. The typical synthesis of hydrazones can be described as follows:
The equimolar mixture of 2-amino-3-formylchromone and hydrazine derivative (i.e., 2-hydroxybenzhydrazide, 3hydroxy-2-napthoic acid hydrazide, isonicotinic acid hydrazide, 2-picolinyl hydrazide, thiophene-2-carboxylic hydra-zide, or 2-furoic acid hydrazide) in acetic acid was refluxed for a certain time (Table 1). After reflux, the solution was cooled to room temperature, poured into ice-water and stirred. When the precipitates started to appear, the reaction mixtures were allowed to stand for an hour to afford maximum precipitates. Detail reflux times, colors of the precipitates, and yields of the hydrazones are shown in Table 1. MALDI mass, Fluorescence, FTIR, and 1 HNMR data of the 6 hydrazones are shown in Tables 2-5. UV-Vis and fluorescence spectra of the 6 hydrazones are shown in Figures 1 and  2, respectively.

Results
In this study, different hydrazides were used such as 2hydroxybezhydrazide (CBH), 3-hydroxy-2-napthoic acid hydrazide (CNH), isonicotinic acid hydrazide (CISH), 2picolinyl hydrazide (CPH), thiophene-2-carbhydrazide (CTPH), and 2-fouric acid hydrazide (CFH) for synthesis of hydrzones. The results of the study have revealed that it took only 9 min for CBH to obtain maximum white precipitates of the reaction mixture. On the other hand, the  After reflux, the solutions were cooled at room temperature, poured into ice-water, and stirred. When the precipitates started to appear, the reaction mixtures were allowed to stand for an hour to afford maximum precipitates. The precipitates were then filtered, dried, and characterized. Structures of the precursors and synthesized hydrazones are listed in Table 6.
The results obtained through MALDI mass are well consistent with the molecular weights of these six hydrazones, as shown in Table 2. The λ max and ε max values of these six hydrazones were calculated according to their UV-Vis spectra. Fluorescent properties of the hydrazones were also studied and their excitation and emission wavelengths are mentioned in Table 2. Furthermore, FTIR, 1 H and 13 CNMR spectral data of the hydrazones confirmed the proposed structures of hydrazones.

Discussion
Detailed principle peaks on the FTIR and 1 HNMR spectra are listed in Tables 4 & 5, respectively. The signal at chemical shifts (δ, ppm) of 11.93-12.34 in 1 HNMR spectra are assigned to the -NH group, concomitant with the observation of rapid loss of these signals. Same is the case with -NH 2 groups whose peaks of both protons signals at chemical shifts of 9.28-9.88. The signals at δ of 11.98 ppm and 11.50 ppm are assigned to the aromatic -OH protons of CBH and CNH, respectively. The resonance peaks between 8.91 ppm to 9.08 ppm in the spectra are assigned to the azomethine (-CH=N-) of these hydrazones. Signals at δ 6.70-8.79 are assigned to the aromatic protons. In 13CNMR spectra of these hydrazones, four key resonance signals were  Table 3.      These spectroscopic data confirmed the successful syntheses of the 6 hydrazones mentioned above. The λ max (nm) and εmax values of these six hydrazones were calculated according to their UV-Vis spectra, the λ max , are in the range of 344 to 351 nm and ε max was from 1.50 x 10 4 to 3.26 x 10 4 cm -1 M -1 .

Conclusions
This study highlighted the synthesis and spectroscopic characterization of 6 novel hydrazones. The hydrazones were quickly synthesized through convenient and facile approach. This study reported the synthesis of CBH in 9 min. On the other hand, CNH was synthesized in 1 min only. After the reflux of 25 min, other 4 hydrazones were synthesized. The importance of these hydrazones can be realized in live cell imaging for detection of metal ions. These compounds are quite beneficial for their role as chemo sensors. As a future perspective of this study, these hydrazones containing oxygen, sulfur, and nitrogen atoms may lead biologists for its applications in biomedical fields.

Data Availability
No data were used to support this study.

Conflicts of Interest
There is no conflict of interest.

Funding
This work was supported by the National Natural Science Foundation of China (Grants 21175122 and 91127036), the Fundamental Research Funds for Central Universities (Grant WK2060190018).