Document Type : Original Article
University of Babylon, Chemistry Department, Babylon, Iraq
Our interest in this area has been to employ organic synthesis methods to prepare new resorcinol derivatives with high yields. The precursor material has been used to prepare di-substituted molecule pharmaceutical compounds by reacting with acetic acid and zinc dichloride as catalysts at the first step. At second step reaction the product with chloro acetic acid using the sodium hydroxide to converting the carboxyl group in the last product to an acid chloride by SOCl2. The acid chloride was then dissolved in DCM and reacted with four amino drugs (Sulfadiazine, Theophylline, Paracetamol, and 4-amino antipyrine) to produce the new preparative compounds. All the organized compounds have been characterized with the aid of using FT-IR, and 1H-NMR. The physical properties of the synthesized compounds have been additionally decided, and their solubility in distinctive solvents. A theoretical investigation is done to prove the nature of the acylation reaction of resorcinol through the suggestion of three different transition states. Three suggested transition states are examined for the most probable pathway of the acylation reaction. The calculation proves that the acylation reaction is done through the para position of aromatic ring with high yield present than other positions.
In the last years, applications of new drug derivatives have been accelerated to increase the treatment effect towards a wide range of microbial organism that causes disease. One of the famous chemical compounds is resorcinol, a solid organic compound  with less toxic than phenol .
Resorcinol is widely used in industry but is also used as a pharmaceutical agent for topically in dermatological remedies, pimples, associated pores and skin conditions. It can also be utilized in aggregate with the opposite pimples remedy retailers, which include Sulfur [3, 4] and used as a chemical intermediate for manufacturing of m-aminophenol, manufacturing of mild stabilizers for plastics , manufacturing of sunscreen arrangements for the pores and skin, manufacturing of dyes (fluorescein, eosin) , and anti-cancer agents [7, 8].
Resorcinol (Scheme 1) can also be used in many applications as floor coatings, silt, anti-corrosion coatings and adhesives when it interacts with formaldehyde and the formation of resorcinol-formaldehyde (RF) resin as a product of the reaction .
Scheme 1: Chemical structure of resorcinol
In this work, new derivatives of resorcinol will prepare depending on acylation reaction to get on four different derivatives of resorcinol as the primary molecule in all organized compounds (Scheme 2). Spectral analysis methods will be characterized all. these derivatives. In the theoretical investigation, the acylation reaction of resorcinol is carried out using semi-empirical methods (PM3) (Figure 1), where the Geometrical structures are calculated. One-of-a-kind transition states were counseled, and the maximum probable transitions state was investigated, relying upon the energetic and electronic characteristics to indicate the maximum probable pathway of the reaction (Table 2). That Table 3 show the calculations of transition states, energy barrier and Ԑ∆H for the resorcinol derivatives (Scheme 3).
Material and Methods
All the chemical substances used in this study have been Sigma Aldrich and Fluka supported with the very best purity available. Samarra Company for drug manufacturing produced drugs. Gallenkamp MFB-600-Melting factor Stuart apparatus was used to determine organized compounds’ melting factors. The FT-IR spectra changed into measured in a Bruker spectrometer. 1H-NMR decided with the aid of using the use of a Bruker AC four hundred NMR spectrometer set to 500 MHz for 1H-NMR, the chemical shifts (δ) have been expressed in components consistent with million (ppm) relative to tetramethylsilane (TMS) as a default.
Synthesis of resorcinol derivatives
Synthesis of 2,4-dihydroxyacetophenone (TS 2)
Anhydrous ZnCl2 (15 g, 110 mmol) was added to 30 ml of CH3COOH and heated at 140 °C. After all the ZnCl2 has been dissolved, resorcinol (10 g, 90 mmol) has been stirred and heated for 3 hours at 150 °C in an oil bath. The ZnCl2 complex broke down by adding 50% HCI (50 mL). In an ice bath, a bright yellow precipitate formed and cooled, then filtered. A yield was washed with 5% HI and thus recrystallized through hot water, a white solid formed (7.99 g, 80%), m.p. 144-146 °C, molecular formula: C8H8O3, M.wt=152.15 g/mol .
Synthesis of compound (TS3)2-(2-acetyl-5-hydroxyphenoxy) acetic acid
Dissolved 2 g of KOH in 4 mL of water in a 50 mL spherical flask, and 0.5 g of 2,4-dihydroxyacetophenone was delivered to the spherical flask. The aggregate changed into stirred till a homogeneous solution resulted. Fit the flask with a reflux condenser and warmth to a mild boil. Add 6 mL of a 50% aqueous solution (g/mL) of chloro acetic acid dropwise and boil and boil the mixture for 10 min. The aggregate cooled to room temperature and acidified the solution with sensible drop addition of focused HI, revealing the pH with pH paper. The combination turned into cooled in an ice bath and filtered the precipitate through vacuum filtration. The crude strong changed into recrystallized from boiling water to have the funds for compound TS3. The response became observed using the TLC approach of ethyl acetate: acetone (1:1). FT-IR was used to represent TS3. Solid, Color: white, molecular formula:C10H10O5, M.wt=210.19 g/mol .
A general technique for one-pot synthesis of amides (Synthesis of TS5-TS8)
1 mmol of the carboxylic acid is brought to 1 mmol of amine and 3 mmol of triethylamine (Et3N) in dichloromethane, then 1 mmol of SOCl2 is delivered at room temperature. The aggregate is stirred for 5–20 mins at room temperature. The recovery of the mixture into executed by evaporating the solvent under decreased pressure. The ensuing residue is taken up in dichloromethane and washed first with 1 N HCl with 1 N NaOH. The development of reactions becomes monitored through TLC. Solid precipitates had been fashioned, and all products were characterized through FT-IR and 1H-NMR (Scheme 4) .
Antimicrobial susceptibility tests of a few synthesized compounds have been completed consistent with the “nicely diffusion technique ˮ. Synthesized compounds were evaluated on bacterial strains, one gram-notable bacteria (staphylococcus aureus) and one gram-terrible bacteria (Klebsiella pneumonia). Samples have been cultured on Muller Hinton agar medium at a temperature of 37 °C for 24 hours, and the outcomes have been precise for a few compounds .
Scheme 2: Interaction diagram
Scheme 3: Calculation of transition states of acylation reaction
The solution changed from moderate to shielding the check tubes with aluminum foil. DPPH (four mg) has become dissolved in 100 mL of methanol. Some of the produced compounds have been used to make numerous concentrations of 25, 50, and 100 ppm. It was made by dissolving 1 milligram of the chemical in 10 mL of methanol to make one hundred elements in step with million, then diluting it to 50 and 25 components regular with million. The concentrations were made with inside the same way. 1 mL of the diluted or everyday answer (25, 50, 100) ppm modified into delivered to at least one mL of DPPH answer in a test tube. After 30 min of incubation at 37 °C, every answer’s absorbance becomes measured using a spectrophotometer at 517 nm. The following equation has become used to decide the capacity to scavenge DPPH radicals .
The solubility of all synthesized derivatives in different solvents turned into was studied and listed in Table 1.
Results and Discussion
The reaction between resorcinol and drugs produces a bi-molecular compound composed of three drug molecules (TS5-TS8). FT-IR, and 1H-NMR spectrum fixed eyeglass synthesized compounds .
Dark brawn, mp 92-94 °C, yield 97%, FT-IR (KBr) (νmax/ cm-1): 3300 (N-H groups), 1618 (N-H bend), 1770 (C=O ketones), 1680 (CO amide), 3742 (O-H groups), 3049 (C-H aromatic), 2939 (C-H sp3), 1313 and 1253 (C-O), 1437 (O-H), 1157 (S=O). 1H-NMR (500 MHz, DMSO): δ 9.98 (s, O-H, alcohol), 9.96 (s, N-H, amid), 11.3 (s, Nsulfonamide), 6.4-7.6 (d, C-H, aromatic), 4.6 (s, methylene), 2.6 (s, methyl) 7.7-8.4 (d, CH pyrimidine).
Dark green, mp 120-123 °C, yield 89%, FT-IR (KBr) (νmax/ cm-1): 1720 (C=O ketones), 1647 (CO amide), 3674 (O-H alcohol), 3100 (C-H aromatic), 2976 (C-H sp3). 1H-NMR (500 MH, DMSO): δ 9.98 (s, O-H, alcohol), 9.3 (d, imidazol), 6.4 (d, C-H aromatic), 6.5 (s, C-H aromatic), 1.19 (s, methylene), 3.4-3.6 (s, methyl).
Black, mp 108-111 °C, yield 80%, FT-IR (KBr) (νmax/ cm-1): 1678 (C-N), 1739 and 1790 (C=O), 1627 (C=O, amide), 3742 (O-H groups), 3100 (C-H aromatic), 2924 (C-H sp3), 1430 (O-H). 1H-NMR (500 MHz, DMSO): Singlet 2.2 (s, methyl), 2.7 (s, methyl), 4.7 (s, methylene), 6.3 (s, C-H, aromatic), 7.4 (d, C-H, aromatic), 9.9 (s, O-H, alcohol), and 9.5 (s, O-H, alcohol).
Light brawn, mp 146-150 °C, yield 71%, FT-IR (KBr) (νmax/ cm-1): 3394 (N-H groups), 1566 (N-H), 1305.85 (C-N), 1770 (C=O), 1701 (C=O), 3740 (O-H), 2935 (C-H sp3), 1219 (C-O), 1440 (O-H). 1H-NMR (500 MHz, DMSO): 5.3 (s, O-H, alcohol), 8.1 (s, N-H), 6.0 (t, C-H aromatic), 7.8 (d, C-H aromatic), 4.6 (s, methylene), 2.2 (s, methyl), and 2.4 (s, methyl).
Scheme 4: Synthesis of compounds (TS5-TS8)
Figure 1: The geometrical suggested transition state for acylation reaction calculated by PM3-semi empirical method
The findings found that almost all of the compounds examined to have a top antibacterial pastime. These microorganisms have been selected due to their extensive significance in the medical field, as they motive many illnesses further to their various antibiotic and chemical drug resistance. Table 4 exhibits that the produced compounds have an organic pastime towards the microorganism because they'll suppress the microorganism through various quantities of the compounds.
Compounds antiradical operation achieved with the usage of the usual DPPH method.
Table 5 in comparison to the normal (ascorbic acid) hobby (IC50=4.02 mg/mL), the bulk of compounds confirmed mild to the excessive antioxidant hobby. Most hobbies become a consequence of the OH organization in compounds (TS5-TS8) with a sizable hobby. Ascorbic acid, a common medication, with an IC50 of 4.02 M. The forces for the antioxidant hobby of the take a look at materials is with inside the following order whilst in comparison to the reference.
In this study, it is possible to prepare new, developed, and suitable drug derivatives for infection prevention treatment because most prepared derivatives gave good biological activity and antioxidant results. The prepared compounds gave a large proportion of the output and were prepared from simple and available materials. All prepared compounds were stable in various conditions.
Praise is to Allah, Lord of the Worlds, and prayers and peace is upon the Soul of the Prophets and Messengers, who was sent as a mercy to the worlds, and upon his good and pure family. Great thanks and great gratitude to Dr. Saadon Abdulla Aowda and Dr.Abbas A.Drea for their continuous follow-up and accurate observations during the study period. I would like to thank the Deanship of the College of Science for their continuous support of postgraduate students and all the chemistry department professors of the for their efforts and assistance throughout the study period.
No potential conflict of interest was reported by the authors.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
All authors contributed to data analysis, drafting, and revising of the paper and agreed to be responsible for all the aspects of this work.
HOW TO CITE THIS ARTICLE
Tuqa Sattar Abid, Saadon Abdulla Aowda, Abbas A. Drea. New Resorcinol Derivatives: Preparation, Characterization and Theoretical Investigation. J. Med. Chem. Sci., 2023, 6(5) 962-969