AEROBIC OXIDATION OF R-SUBSTITUTED DERIVATIVES OF ACETYLENE ALCOHOLS WITHOUT A CATALYST

ABSTRACT

In order to study the properties of acetylene alcohols synthesized on the basis of R-substituted benzaldehyde derivatives, the process of their oxidation in open air without the participation of a catalyst and a strong oxidizing agent was carried out for the first time. The most alternative parameters of the oxidation process of acetylene alcohols chosen as the object of study were determined, and the influence of substituents on the target product formation was analyzed. The structure of the synthesized ketones was confirmed by spectroscopic analysis ¹H-NMR, ¹³C-NMR and identified by thin layer chromatography. In addition, the spatial structure, charge distribution and electron density of the synthesized ketones were studied using the ASDFREE12 and Hyper Chem programs, and their biological activity was studied using the PASS Online program.

АННОТАЦИЯ

С целью изучения свойств ацетиленовых спиртов, синтезированных на основе R-замещенных производных бензальдегида, впервые был проведен процесс их окисления на открытом воздухе без участия катализатора и сильного окислителя. Определены наиболее альтернативные параметры процесса окисления ацетиленовых спиртов, выбранных в качестве объекта исследования, проанализировано влияние заместителей на образование целевого продукта. Строение синтезированных кетонов подтверждено методами спектроскопического анализа ¹H-ЯМР, ¹³С-ЯМР и идентифицировано методом тонкослойной хроматографии. Кроме того, с помощью программ ASDFREE12 и Hyper Chem исследовали пространственную структуру, распределение заряда и электронную плотность синтезированных кетонов, а их биологическую активность изучали с помощью программы PASS Online.

Keywords: R-substituted benzaldehyde derivatives, oxidation, ketones, synthesis, acetylene alcohols, biological activity, product yield, chromatography.

Ключевые слова: R-замещенные производные бензальдегида, окисление, кетоны, синтез, ацетиленовые спирты, биологическая активность, выход продукта, хроматография.

Introduction

In organic chemistry, acetylene alcohols synthesized through S-S bond reactions serve as an important basis in the synthesis of fine chemistry and biologically active substances, as well as in the production of pharmaceuticals and natural products. Therefore, in recent years, chemists have become more interested in studying the properties of acetylene alcohols [1, 2]. Studies on replacing stoichiometric oxidations of primary and secondary alcohols with aerobic oxidation are also developing [3, 4]. H. Boran and his research team have reported successful studies for the aerobic oxidation of various activated and non-activated alcohols over a practical Cu catalyst. In their study, they carried out the aerobic oxidation of 1-octanol in the presence of 4 mol% [Cu (CH₃CN)₄]PF₆ and 5 mol% DBED. However, the yield of the reactions carried out was low. In order to increase the efficiency of the reaction, the reactions were carried out in the presence of aromatic amines such as pyridine, NMI and DMAP, and the efficiency was recorded up to 92%, the duration of the reaction was 3 hours [5]. On aerobic oxidation, Z. Yuan and his colleagues found that NaOH serves as a catalyst for oxidation reactions. They reported their results by carefully studying (without any metal catalyst) the reactivity of NaOH with aqueous glycerol, ethylene glycol, 2-propanol, and ethanol and their effect on product distribution. In the course of research, they determined the experimentally measured order of reactivity of various alcohols, the order of molecular mechanisms of oxidation reactions, and the results of calculations based on density functional theory [6]. Yi Xie and co-workers conducted research on a three-component catalytic oxidation system to ensure efficient utilization of O₂ as a terminal oxidant. They activated molecular oxygen as NO equivalent under NaNO₂ acidic conditions and applied this new oxidation pathway to various alcohol substrates and reduced the overall use of environmental pollutants such as 2,4,6-trichlorophenol (TCP) [7]. They also used the NO-mediated oxidation mechanism in methane oxidation. They chose pure benzyl alcohol (0.1 mol scale) as the substrate to provide the best combination of catalyst systems for the new aerobic oxidations, and the performance was recorded at the expected level [8, 9]. The use of water as a solvent for oxidation reactions has received considerable attention and has become an active area of research in green chemistry [10]. Transition-metal-catalyzed aerobic oxidation of alcohols [11] is one typical example. Renhua Liu and his research team have developed a highly efficient catalytic system without transition metals in water for the aerobic oxidation of benzyl alcohols. The newly developed system carried out the process of aerobic oxidation of secondary alcohols in the presence of 1,3-dibromo-5,5-dimethylhydantoin and NaNO₂ in an aqueous environment under optimal conditions. They carried out the reaction at 30 mmol substrate, 0,3 mol% TEMPO, 1,2 mol% DBDMH, 1,2 mol% NaNO₂, 10 mL H₂O, 0,9 MPa air, and 80 °C and reported high yields [12].

In this work, the process of aerobic oxidation of acetylene alcohols, including 1-(4-(tertbutyl) phenyl)-3-phenylpropyn-2-ol-1 (1a) and 1-(3-methoxyphenyl)-3-phenylpropyn-2-ol-1 [13] (2a) selected as the object of research was carried out for the first time without strong oxidizers and catalysts. During the research, 1-(4-(tertbutyl) phenyl)-3-phenylpropyn-2-one-1 (1b) and 1-(3-methoxyphenyl)-3-phenylpropyn-2-one-1 (2b) ketones were synthesized based on the open-air oxidation of acetylene alcohols 1a and 2a.

Research methodology

The oxidation process was carried out according to the following methodology: initially, 37 g (0.015 mol) of 1a with a purity of 98% was placed in a 200 mL wide-mouth Erlenmeyer flask (Duran 200/79/50/131 brand) acetylene alcohol was placed in the open air for oxidation at a temperature of 20 ^oC. The duration of the reaction was set to 144 hours. The oxidized acetylene mixture was then dissolved using 75 mL of dichloromethane. The resulting solution was evaporated for 2 hours using a rotary evaporator (‘Heidolph-VAP Value’ brand). After evaporation, the organic catalyst was first filtered through a small silica gel filter, followed by gradient elution with hexane:dichloromethane. Samples from fractions collected during gradient elution were analyzed by thin layer chromatography. Among the samples, the presence of a ketone formed from the oxidation of acetylene alcohol 1a was detected, and this mixture was first evaporated, then separated into fractions by distillation. As a result, 13,5 g of 1-(4-(tertbutyl)phenyl)-3-phenylpropyn-2-one-1 (1b) was isolated from the oxidation of acetylene alcohol 1a with a yield of 36.7%. Based on the same method, 1-(3-methoxyphenyl)-3-phenylpropyn-2-one-1 (2b) was synthesized with 50,7% yield on the basis of acetylene alcohol 2a, which was selected as the object of research.

Analysis results

In order to study the relevant properties of acetylenic alcohols 1a and 2a, selected as research objects, their oxidation process was carried out in open air without any strong oxidants and catalysts. The reaction scheme of the oxidation of acetylene alcohols selected as the object of research and the structure of the corresponding ketones 1b and 2b synthesized as a result of oxidation are presented in Scheme 1:

Factors affecting the reaction are analyzed to determine optimal conditions for the oxidation process and ensure high productivity of the expected products. First, the temperature factor of the reaction was studied (Graph 1). Reactions were carried out at intervals of -20 ^oС ÷ -60 ^ᵒС. When the reaction temperature was -20 ^ᵒC, the oxidation of acetylene alcohol 1a, which was selected as the research object, was almost not observed. When the reaction temperature was increased, the oxidation of 1a was relatively high and the product yield increased. Judging from this process, the reaction temperature was increased to 60 ^ᵒC, but the degree of oxidation decreased sharply.

Acetylene alcohols selected as the object of research are easily oxidized compared to other organic compounds under the influence of oxygen in the air. The productivity of their aerobic oxidation is low or high mainly depends on how long acetylene alcohols are left in the open air, i.e. the duration of the reaction. Initially, the oxidation process was carried out for 24 hours and the maximum product yield was observed to be 18.7%, almost no oxidation occurred. The reaction was continued again and the reaction time was set to 144 hours. As a result, the productivity of the oxidation reaction of acetylene alcohol increased significantly. Based on the obtained results, the time of the oxidation process was set to 360 hours, but a decrease in the expected product yield was observed (Graph 2).

The nature of the R-substituted substituents in the acetylene alcohol molecule chosen for research work also affects the formation of ketones. Tertiary butyl and methoxy groups in the molecule of acetylene alcohols have different effects on the reaction process. This depends on their mesomeric or inductive effect on the molecule. That is, the carbon in the carbonyl group is stabilized under the influence of the electron-donating group substituents on the benzene ring, and it is destabilized under the influence of the electron-accepting group. As a result, it positively or negatively affects the activation of the hydrogen atom in the acetylene alcohol molecule. If the activity of the hydrogen atom in the acetylene alcohol molecule is high, the productivity of the oxidation process is high, on the contrary, if the activity of the hydrogen atom is relatively low due to the influence of substituents, the productivity of the oxidation process is low.

The structure of synthesized ketones was proved by spectroscopic ¹H- NMR and ¹³C- NMR methods and the following results were recorded:

1-(4-(tertbutyl)phenyl)-3-phenylpropyn-2-one-1 (1b) – R_f (hexane-methylchloride 1:1) = 0.42; (product yield 61%): ¹H- NMR (CDCl₃, 400.1 MHz): δ 8.17-8.15 (m, 2.H), 7.68-7.65 (m, 2Н), 7.54-7.52 (m, 2.35H), 7.48-7.38 (m, 3.14H), 1.345 (d, 10.40H). ¹³C{¹H}- NMR (CDCl₃, 100.6 MHz): δ 177.58, 158.01, 134.47, 132.92, 130.59, 129.47, 128.58, 125.53, 120.20, 92.52, 86.98, 35.18,30.97.

1-(3-methoxyphenyl)-3-phenylpropyn-2-one-1 (2b) – R_f (hexane-methylchloride 1:1) = 0.45; (product yield 50.7%): ¹H- NMR (CDCl₃, 400.1 MHz): δ 7.68-7.84 (m, 1H), 7.70-7.65 (m, 3.02Н), 7.49-7.38 (m, 4.42H), 7.18-7.15 (m, 1.10H), 3.87 (s, 3.05H). ¹³C{¹H}- NMR (CDCl₃, 100.6 MHz): δ 177.70, 159.79, 138.24, 133.02, 130.75, 129.60, 128.65, 122.79, 120.89, 120.08, 112.85, 92.93, 86.93, 55.43.

In order to determine the molecular properties, reactivity and reaction centers of ketones 1b and 2b synthesized during the research work, the spatial structure of molecules, charge distribution and electron density in the atoms of the molecule, 3D structure of molecules and quantum-chemical calculations were studied. Studies were performed using Hyper Chem and ASDFREE12 software (Tables 1 and 2). The 3D structure of the molecule shows that the heterocyclic solution has a planar structure.

Table 1.

Quantum chemical calculations of synthesized ketones

Table 2.

Spatial structure of synthesized ketone molecules, distribution of charges and electron density in molecules

According to the analysis of the values of charge and electron density distribution in the molecule of the compounds, although the hydroxyl group and methyl atoms are in the same position in the molecule, the electron distribution is partially different from each other. Given the diversity of pharmacological properties of ketones formed from the oxidation of acetylene alcohols, we studied the spectrum of biological activity using the PASS online computer program.

In the current pharmaceutical industry, PASS online software is considered as a suitable tool to evaluate the general biological properties and properties of organic molecules and to effectively search for new biologically active compounds. Through this program, it is possible to predict pharmacological effects, mechanisms of action, toxic and side effects depending on the structure of certain compounds [14].

The research results are expressed in the values of Pa and Pi indicators of the program. The Pa value (‘probability of being active’) estimates the probability that the biological activity of the studied compound belongs to a subclass of active compounds based on its structural similarity to the most typical molecules in a certain subset of ‘actives.’ Pi value indicator (‘probability of being active’) evaluates the probability that the studied compound belongs to the ‘active’ subclass of inactive compounds. The results of the conducted research are presented in Tables 3 and 4. The probability of occurrence of ‘activity’ (Pa) and ‘inactivity’ (Pi) in the experiment is ranked according to the decrease of their difference.

Table 3.

Pharmacological properties of synthesized compounds

Table 4.

Toxicological properties of the synthesized compound

Conclusion

In this research work, the process of aerobic oxidation of acetylene alcohols with double aromatic rings and R-substituted substituents in the molecule was studied in the open air without any catalysts and strong oxidants. As a result, a new generation of ketones containing a double aromatic ring and heteroatoms was synthesized. Relevant reaction parameters were studied and optimal conditions were determined. The effect of the nature of the substituents in the molecule of acetylene alcohols and their spatial arrangement on the formation of ketones in the performed reactions was studied and explained. In addition, the spatial structure of synthesized ketone molecules, distribution of charges in atoms, electron density, 3D structure of molecules and quantum-chemical calculations were studied. Based on the molecular structure of the synthesized ketones, their pharmacological and biological properties were studied using special programs.

Acknowledgments and funding

The authors thank to Economics and Pedagogical University for financial and social support. The authors declare that there is no conflict of interest that requires disclosure in this article.

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