STUDY OF SOME FLUOREN-9-ONE THIOSEMICARBAZONES: SYNTHESIS, CATALYTIC EFFECTS AND SPECTRAL CHARACTERIZATION  

Bienvenu GLINMA1,2*image, Bénédicta KPADONOU1image, Hyacinthe AGNIMONHAN1image, 

Sèdami MEDEGAN1,2image, Salomé KPOVIESSI1image, Coco KAPANDA3image, Fernand GBAGUIDI1,2image

1Chemistry Department, Physical Organic Chemistry and Synthesis Laboratory, Faculty of Science and Technology, University of Abomey-Calavi, Calavi, Benin.

2Medicinal and Organic Chemistry Laboratory, School of Pharmacy, Faculty of Health Sciences, University of Abomey-Calavi, Campus du Champ de Foire, Cotonou, Benin.

3Louvain Drug Research Institute (LDRI), School of Pharmacy, Université Catholique de Louvain, Brussels, Belgium.

 

Abstract

Aim and objective: Nowadays, Schiff bases have shown a remarkable importance in medicinal chemistry research. Semicarbazones, thiosemicarbazones and their derivatives are important Schiff base ligands with biological properties. Fluorenones are important organic compounds used in many different fields. Here, we reported the synthesis of fluoren-9-one thiosemicarbazones (F1-F4).  

Methods: For their synthesis, we first carried out a theoretical study based on the physical properties (reasonable pharmacokinetics and drug availability) of the compounds using Lipinski's rules. We also varied the reaction conditions using several reagents (HCl, 1N; H2SO4 conc. and GAA) and ethanol in order to optimize reaction yields. Structure of each molecule was characterized by spectrometrical analysis (MS and IR, and especially NMR 1H and 13C).

Results: During the course of the study, we observed an increase in reaction yields in the presence of the less aqueous acids, particularly with GAA, which gave the best yields (89, 77, 91 and 96%) for molecules F1, F2, F3 and F4 respectively. 

Conclusion: We noted that compounds presented essential properties to exhibit pharmaceutical activities. They could have a variety of pharmaceutical activities on pathogens resistant to existing treatments.

Keywords: Catalyst, fluoren-9-one, pharmaceutical properties, synthesis.

INTRODUCTION

 

Fluoren-9-one is a versatile compound with a range of properties. It widely used for preparing dye material and modifying resin and other materials1,2. A fluorene derivative, this compound is used in antimalarial drugs synthesis. It is used in polymers and dyes too. Fluorenone is used in organic electronic material synthesis. Some examples: (i) blue and green phosphorescent organic LED host synthesis; (ii) synthesising fluorene-based molecular motors; (iii) synthesis of chichibabin hydrocarbons for organic spintronics; (vi) it is also involved in the formation of picenes through the photosensitisation reactions of 1,2-di(1-naphthyl)ethane3. Fluorenone is used to manufacture pharmaceuticals, particularly antimalarial drugs. Fluorenone substitutes act as antibiotics, cancer treatments, antivirals and nerve agents4. Some substituted  'azafluorenones are biologically active, such as the naturally occurring antimicrobial compound onychine (1-methyl-4-azafluorenone)5. 1,8-Diazafluoren-9-one is used for fingerprint detection. Thiosemicarbazones are nitrogen- and sulphur-containing compounds used in synthesis. They are sulfur-based derivatives of semicarbazones6. They derivative molecules are organic molecules that are of great biological importance6-9. Their structure allows for flexible bonds10.

They have a wide range of applications in materials science. The chemistry of thiosemicarbazones has been researched for 20 years, and fluorescent derivatives have been reported11,12. Many studies have been conducted on the structure-activity relationship of thiosemicarbazones. Changes in the amino substituents or N-heterocyclic ring affect biological activity. Changes in the aldehyde or ketone structure also affect antibacterial and anticancer activity13,14. With all its beneficial properties cited in the literature, and with the aim of bringing added value to the synthesis, we initiated the synthesis and study of catalysts on the yield of reactions between fluoren-9-one and thiosemicarbazides used to have new organic molecules of pharmacological interest.

 

MATERIALS AND METHODS

 

In current work, reactants were directly used without any further purification. Obtained from chemical companies including Sigma-Aldrich, Acros Organic, Janssen Chimica, Supelco and Riedel-de Haen, they are fluoren-9-one (98%), hydrochloric acid HCl (37%, 1N), sulfuric acid H2SO4 (95-97%), and glacial acetic acid GAA (≥ 99%), technical ethanol (EtOH, 96°), thiosemicarbazide and derivatives 2-methyl-, 4-methyl- and 4-phenyl-3-thiosemicarbazide (99.5%). Products obtained from the synthesis were characterised by elemental analyses such as: (i) Proton and carbon-13 NMR spectra (on a Bruker Avance 400 UltraSheild apparatus with DMSO-D6 or CDCl3 as solvent) were recorded when the instrument was calibrated to frequencies of 400.130 MHz and 100.612 MHz for proton and 13C respectively. Chemical shifts (δ) are expressed in ppm relative to the reference tetramethylsilane. The multiplicity of 1H NMR signals has been classified: singlet (s), doublet (d), triplet (t), multiplet or massif (m) etc. (ii) Mass spectra were recorded in positive mode and by atmospheric pressure chemical ionization (APCI), and masses are given in m/z ([MH+]). The melting points (p.m.) of each product has not been determined with our “Köfler bench” apparatus.

To synthesize the different molecules (thiosemi-carbazones, F1-F4), we explored the methods described in the previous work (Figure 1), varying the reaction catalysts15,16, and then they have been characterized by spectrometrical analysis methods.

General method: In an Erlenmeyer, prepare in a solution of 0.01 mole of fluoren-9-one dissolved in 10-20 mL of ethanol with 1 mL of HCl (1N) or a few drops (maximum 3-4) of concentrated H2SO4 or 1 mL of glacial acetic acid (GAA). In a flask, prepare a solution (0.01 mole) of thiosemicarbazide or derivatives in 10 mL of ethanol, and then make the mixture by adding fluoren-9-one solution to thiosemicarbazide solution slowly. This mixture was refluxed for 2 to 4 hours with magnetic stirring. After cooling the reaction mixture, the precipitate obtained was filtered and washed with fresh distilled water until 

neutrality. The crude product was dried and recrystallised in ethanol to yield the purified molecule.

 

RESULTS AND DISCUSSION

 

Four products have been synthesized: fluoren-9-one thiosemicarbazone (F1), fluoren-9-one 2-methyl-3-thiosemicarbazone (F2), fluoren-9-one 4-methyl-3-thiosemicarbazone (F3) et fluoren-9-one 4-phenyl-3-thiosemicarbazone (F4). We checked the chemical structure of the predefined molecules to obtain the correct structural information.17 

The scaffold is low molecular weight, reasonably lipophilic (Log P or C log P), capable of forming hydrogen bonds (Figure 2, Table 1) and can be synthesized economically17,18,19.

The more data available for modelling, the more reliable the results17. Analyzing the results of a few physical parameters according to QSAR study, we note that all the compounds met the criteria of bioavailability and pharmacokinetics, essential properties for presenting pharmaceutical activities. In addition, all our compounds have good lipophilicity, Log P<5, which is an important feature in pharmacological studies. This term reflects a substance's ability to enter cells through lipid membranes, indicating toxicant uptake and baseline toxicity17.

During the work, studies (from Chem3D Ultra 8.0) on solubility and stability in subcritical water were reported (Table 2). Green solvent data on solubility and degradation of organic compounds is needed for environmental remediation, chemistry, chemical engineering, medicine and more. The solubility of organic compounds increases with water temperature20.

The lipophilicity agree well with the surface areas and exchange volumes obtained from theoretical calculations. The more lipophilic F4 liquid product has the widest distribution of available surface area and volume, and therefore the greatest solubility. Find it in the literature, studies showed that a molecular dot surface is a smooth envelope of points on the molecular surface. Organic compound solubilities affect process equipment design and operation. The free volume and distribution of the compound will affect the penetrants transport properties. Low-polarity organics are insoluble in water at ambient conditions, but at higher temperatures, they become soluble21.

In the course of our study we investigated the effect of catalysts. Results have been shown in Table 3. Among the compounds, 4-phenyl-3-thiosemicarbazone (F4) gave the highest yields. Overall, it was observed that the F2 product gave the lowest yield each time with the variation of catalysts. This could be due to steric effects brought about by methyl on the nitrogen atom (N2). We noticed that the stronger and less aqueous the acid used, the higher the yield. As the synthesis is a condensation reaction leading to an imine function, the stronger the nucleophile of the acid used, the more it could still react on the product obtained. Hydrochloric acid being aqueous, the reaction is slow and leads to low yields, while concentrated sulfuric acid and GAA (both less aqueous) improved the reaction yield. This result confirmed one of our previous studies in which less aqueous reaction media favoured the yield of products obtained22.

Structural characterization of synthesized compounds

Fluoren-9-one thiosemicarbazone (F1).

Yield: 76-89%. 

1H NMR with DMSO-d6 as solvent and δ expressed in ppm: from 6.04 to 6.45 (broad s, 2H); 7.30-7.62 (m, 8H-Ar); 8.04 (s, 1H, N2-H). 

13C NMR with DMSO-d6 as solvent and δ expressed in ppm: 185.17 C=S, 157.36 C=N, 144.21, 132.17, 130.31, 130.07, 129.55, 128.63. 

Mass by LC-MS (MH+): 254.34. Theoretical formula: C14H11N3S.

Fluoren-9-one 2-methyl-3-thiosemicarbazone (F2). Yield: 65-77%. 

1H NMR with CDCl3 as solvent and δ expressed in ppm: 6.57 (s, 2H, -NH2); 7.33-7.73 (m, 8H-Ar); 3.16 (s, 3H). 

13C NMR with CDCl3 and as solvent and δ expressed in ppm: 176.31 C=S, 156.65 C=N, 144.21, 133.15, 130.31, 130.17, 129.47, 128.77 (C-Ar fluorenyl), 44.27 (2N-CH3). 

Mass by LC-MS (MH+): 268.35. Theoretical formula: C15H13N3S.

Fluoren-9-one 4-methyl-3-thiosemicarbazone (F3). Yield: 71-91%.

1H NMR with DMSO-d6 as solvent and δ expressed in ppm: 7.33-7.73 (m, 8H-Ar); 2.96 (s, 3H); 7.85 (s, 1H, N4-H); 8.97 (s, 1H, N2-H). 

13C NMR with DMSO-d6 as solvent and δ expressed in ppm: 183.21 C=S, 159.23 C=N, 143.51, 132.16, 131.05, 130.23, 129.57, 128.67 (C-Ar fluorenyl), 33.35 (4N-CH3). 

Mass by LC-MS (MH+): 268.33. Theoretical formula: C15H13N3S.

Fluoren-9-one 4-phenyl-3-thiosemicarbazone (F4). Yield: 77-96%. 

1H NMR with DMSO-d6 as solvent and δ expressed in ppm: 7.39-7.67 (m, 8H-Ar); 6.51-7.23 (m, 5H-Ar); 8.35 (s, 1H, N4-H); 9.27 (s, 1H, N2-H).

13C NMR with DMSO-d6 as solvent and δ expressed in ppm: 187.35 C=S, 154.74 C=N, 143.51, 132.16, 131.05, 130.23, 129.57, 128.67 (C-Ar fluorenyl); 137.54, 129.21, 126.72, 125.23 (C-Ar phenyl). 

Mass by LC-MS (MH+): 330.43. Theoretical formula: C20H15N3S.

For structural analysis of the compounds, we used their LC/MS spectra and, above all, proton and carbon-13 NMR. From these spectra, we obtained the molar mass, signals and peaks characteristic of the different products obtained. The 1H and 13C NMR spectra showed signals and peaks characteristic of protons and carbons present in the structure of each molecule, such as fluorenone aromatic proton groups (chemical shift d in ppm) ranging from 7.30 to 7.73 (8HAr); -NH2 protons at around “broad” 6.04-6.45 ppm (F1) and 6.57 ppm (F2) because the two Hs have different chemical environments; -N2H- protons at 8.04, 8.97 and 9.27 ppm for F1, F3 and F4 respectively. This observed difference is due to the chemical environment and electronic effects within each structure. We also noted the presence of characteristic signals at 7.85 and 8.35 respectively from -N4H- for products F4 and F5. Signals from the N-substituted methyl protons of compounds F2 and F3 were also obtained at somewhat weaker fields than classical methyl, as they were located on nitrogen atoms at various electronic effects (3.16 and 2.96 ppm respectively).

F4 showed signals corresponding to N4-substituted phenyl. In 13C NMR, we focused more on the peak of the imine carbon C=N, the main function characterizing the product of the condensation reaction. Chemical shift peaks between 154.74 and 159.23 ppm correspond to C=N in our products. We observed the disappearance of the carbonyl peak (C=O) previously present in the fluorenone structure, at a chemical shift of 201 ppm. The other structural elements of each molecule remain virtually identical to their respective base spectra (C=S, CAr, -CH3, C-phenyl). LC/MS spectra, obtained in positive mode, gave us the molecular weights of each compound [MH+]. These analyses revealed the purity of our synthesized products. This work in agreement with those reported8,10,16,22-26.

Limitations of the study

During the course of current study, there was problems with the cold dissolution of the reactants. There was need to heat the mixture at 60°C to obtain a clear solution.

 

CONCLUSIONS

 

The synthesis of four organic molecules with the catalyst effects has been reported The scaffold has advantageous properties. In the catalyst study, it showed that the stronger and less aqueous the acid used, the higher the yield. All the compounds met the criteria of bioavailability and pharmacokinetics, their solubility was significantly enhanced with increasing water temperature, essential properties for presenting pharmaceutical activities.

 

ACKNOWLEDGEMENTS 

 

We would like to thank Prof. Jacques POUPAERT and Prof. Didier LAMBERT for their contribution to the recording of spectra in their research unit, School of Pharmacy at the LDRI Institute in Belgium.

 

AUTHOR’S CONTRIBUTION

 

Glinma B: design, methodology, synthesis, review. Kpadonou B: writing original draft of article and comments, . Agnimonhan F: spectral data processing and comments, co-writer of the original draft. Medegan S and Kpoviessi S: review and editing. Kapanda C: recording of product spectra. Ggaguidi F: research supervisor. Final article was checked and approved by all authors. 

 

DATA AVAILABILITY

 

The accompanying author can provide the empirical data that were utilized to support the study's conclusions upon request.

 

CONFLICT OF INTEREST  

 

None to declare.

 

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