SYNTHESIS OF N-ALLYL MORPHOLINE AND N-PROPARGYL MORPHOLINE AND THEIR PROPERTIES IN PASS ONLINE

ABSTRACT

This scientific study focuses on the synthesis of N-allyl morpholine and N-propargyl morpholine through the alkylation of morpholine with allyl and propargyl bromides. The primary objective was to obtain novel morpholine derivatives with potential biological activity. The influence of key reaction parameters, including reaction time and molar ratio of reagents, was systematically investigated. The optimal conditions were established to be 2 hours for propargyl bromide and 1 hour for allyl bromide, both with a 1:1 molar ratio, yielding the desired products in 92% and 87%, respectively.

The chemical structures of the synthesized compounds were confirmed through IR spectroscopy and both ¹H and ¹³C NMR spectroscopy. Furthermore, the biological activity of the compounds was predicted using the PASS online tool. The analysis revealed high probability scores (Pa) for activities such as antidepressant, analeptic, and enzyme inhibitory effects, indicating promising pharmacological potential.

This research combines synthetic organic chemistry with computational methods for early-stage biological screening, demonstrating the relevance of morpholine derivatives as valuable scaffolds in medicinal chemistry. The integration of artificial intelligence-based prediction tools enhances the efficiency of drug discovery and underlines the importance of such multidisciplinary approaches in modern pharmaceutical research.

АННОТАЦИЯ

В представленной научной работе описан синтез N-аллилморфолина и N-пропаргилморфолина путем алкилирования морфолина соответствующими алкилгалогенидами — аллилбромидом и пропаргилбромидом. Цель исследования заключалась в получении высокоэффективных производных морфолина, обладающих потенциальной биологической активностью. В ходе экспериментов были проанализированы влияние времени реакции и молярного соотношения реагентов на выход целевых продуктов. Установлено, что оптимальными условиями синтеза являются: для пропаргилбромида — 2 часа, для аллилбромида — 1 час, при мольном соотношении 1:1.

Полученные соединения охарактеризованы с использованием инфракрасной спектроскопии, протонного и углеродного ЯМР, что позволило подтвердить их структуру. Дополнительно, с использованием программы PASS online, была проведена прогнозная оценка биологической активности синтезированных веществ. Согласно результатам, оба соединения проявляют высокие значения вероятности активности (Pa) как аналептики, антидепрессанты, ингибиторы различных ферментов и рецепторов. Это делает их перспективными кандидатами для дальнейших исследований в области медицинской химии.

Таким образом, данное исследование сочетает в себе как синтетические, так и компьютерные методы оценки свойств новых органических соединений и демонстрирует потенциал производных морфолина в фармацевтической науке.

Keywords: Morpholine, alkylation, biological activity, PASS online, NMR, synthesis, spectroscopy, drug design.

Ключевые слова: Морфолин, алкилирование, биологическая активность, PASS online, NMR, синтез, спектроскопия, фармакология.

Introduction

Compounds containing nitrogen in their structure are considered a promising class in organic chemistry. One of the main directions of modern organic chemistry is the synthesis of nitrogen-containing multifunctional compounds involving aliphatic and heterocyclic amines. This is explained by the high reactivity of these amines. Heterocyclic amine morpholine contains nitrogen and oxygen atoms in its structure, and the hydrogen atom in morpholine is reactive and easily replaceable. The reactivity of this atom allows the synthesis of various derivatives of morpholine. This, in turn, enables the synthesis of pharmaceutical drugs with analgesic activity against various viruses [1]. They can also be used as inhibitors of atmospheric and biological corrosion of metals [2]. Morpholine is widely used in organic synthesis. For example, it is present in the antibiotic linezolid [3] and in the cancer drug gefitinib [4]. Morpholine hydrochlorides and quaternary salts of N-alkylmorpholines attract interest as antistatic agents, bactericides, and corrosion inhibitors [5]. Alkylation of amines is carried out by the reaction of the alkylating agent with the amine in the presence of potassium carbonate or a similar base [6]. Additionally, some literature sources describe a simple and convenient method for alkylation using zinc metal as an inexpensive catalyst [7]. Propargylamines are considered an important class of organic chemistry. As intermediates, they play a significant role in the synthesis of multifunctional amino compounds, as well as natural and biologically active compounds. Due to the asymmetric nature of propargylamine, it is involved in the synthesis of various drugs in the pharmaceutical industry [8].

Scheme 1. Synthesis of N-allyl and N-propargyl morpholines

Experimental section

To carry out the reaction of morpholine with alkyl halides, factors such as the reaction time and the initial molar ratio of the reagents were studied for their effect on the yield of the reaction product. The reaction was carried out over various time intervals.

To study the effect of reaction duration on the product yield, reactions were performed at different times. The experiments were conducted over a time range of 1 to 5 hours. The results showed that the reaction of morpholine with propargyl bromide for 2 hours gave a higher product yield. For the reaction of morpholine with allyl bromide, the highest product yield was obtained when the reaction was carried out for 1 hour. (Tables 1–3).

In the reaction of morpholine with haloalkanes, the molar ratios of the reagents were also investigated for their effect on product yield. The results showed that the most efficient results were achieved when the molar ratio of the reagents was 1:1 for both reagents. (Tables 2 and 4).

As a result of the conducted experiments, the alkylation reactions of morpholine with alkyl halides were studied and the results obtained were compared. The results are shown in the table below:

Table 1.

The effect of time on the product yield of the reaction between morpholine and propargyl bromide

Table 2.

The effect of reagent molar ratio on the product yield of the reaction between morpholine and propargyl bromide

Table 3.

The effect of time on the product yield of the reaction between morpholine and allyl bromide

Table 4.

The effect of reagent molar ratio on the product yield of the reaction between morpholine and allyl bromide

In conclusion, the conducted experiments allowed the determination of the optimal conditions for these reactions, resulting in high-yield processes. It was found that the most favorable conditions are a reaction time of 2 hours for experiments with propargyl bromide, 1 hour for experiments with allyl bromide, and a molar ratio of reagents of 1:1. The structures of the synthesized compounds 4 and 5 were confirmed by IR, 1H, and 13C NMR spectroscopic methods.

Discussion of Experimental Results

In the 1H NMR spectrum of N-propargyl morpholine (compound 4), unlike the starting morpholine, a triplet signal characteristic of the terminal alkyne (CH group) protons H-9 was observed at 3.60 ppm (J = 2.6 Hz). Signals for protons H-3 and H-5, which are methylene (CH₂) groups bonded to the nitrogen atom, appeared as a multiplet and doublet of doublets at 3.70 and 4.02 ppm (J = 5.9, 3.9 Hz). The proton H-7, corresponding to the methylene group bonded to the nitrogen atom of the propargyl moiety, appeared at 4.65 ppm. The signals for the methylene protons H-2 and H-6, bonded to the oxygen atom, were detected at 4.85 ppm.  In the ^13C NMR spectrum of compound 4, signals were observed at 50.19 ppm corresponding to the carbon (C-7) bonded to the nitrogen atom in the allyl moiety, 69.69 ppm for the carbon atom C-9, and 82.73 ppm for carbon atom C-8.

In the 1H NMR spectrum of N-allyl morpholine (compound 5), the singlet signal of the methylene protons H-3 and H-5 in the nitrogen-bound ring appeared at 2.40 ppm. Multiplet signals of the methylene protons H-7, bonded to the nitrogen atom in the allyl moiety, were observed between 2.93 and 2.97 ppm. Multiplet signals for the methylene protons H-2 and H-6, bonded to the oxygen atom, appeared at 3.65–3.70 ppm. The multiplet signals for the terminal alkenyl protons H-9 were detected between 5.11 and 5.18 ppm. The multiplet signals for the alkenyl proton H-8 appeared in the range of 5.77 to 5.84 ppm. In the ^13C NMR spectrum of compound 5, the carbon atom C-7 bonded to the nitrogen appeared at 62.22 ppm, C-9 at 118.40 ppm, and C-8 at 134.60 ppm.

Table 5.

Biological activity prediction using PASS online

N-allyl morpholine (5) showed potential activities such as:

Table 6.

N-propargyl morpholine (4) showed potential activities such as:

• The 21st century is the age of information technology, and in the natural sciences—including chemistry—there has been significant growth in the ability to assess and predict the biological activity of various compounds in advance using artificial intelligence (AI) and various online tools. Through online platforms like PASS, it is possible to identify how chemical compounds interact with different receptors and enzymes, enabling the development of targeted and efficient syntheses. This, in turn, significantly accelerates the drug development process and reduces associated costs.

The fact that N-allyl morpholine and N-propargyl morpholine can simultaneously exhibit various biological activities—such as antidepressant, analeptic, and inhibitory functions—represents important information for their potential development as future pharmaceutical agents.

In general, predictive technologies powered by artificial intelligence play a crucial role in driving new innovations in the fields of chemistry and biotechnology.

Synthesis of N-alkyl morpholine derivatives – general procedure:

In a 50 mL round-bottom flask, 4.95 g (0.06 mol) of morpholine was added. After adding 0.6 mol of acetone as a solvent, 0.06 mol of potassium carbonate (K₂CO₃) was added. Then, equimolar amounts (0.06 mol) of alkyl halides (propargyl or allyl bromide) were added. The reaction mixture was stirred magnetically at room temperature under reflux (monitored via TLC). After completion, potassium carbonate was filtered off, and the solvent was evaporated.

N-Propargyl Morpholine (C₇H₁₁NO):

Used: 4.95 g morpholine (0.06 mol), 5.65 mL propargyl bromide (0.06 mol), 8.28 g K₂CO₃ (0.06 mol), 44 mL acetone. Melting point: 186 °C, Rf: 0.57 (solvent system: chloroform: methanol 12:1)

Yield: 92%

¹H-NMR (600 MHz, CD₃OD, d, ppm, J/Hz): 3.60 (1Н, t, J= 2.6, Н-9), 3.70 (2Н, m, Н-3), 4.02 (2Н, dd, J=5.9, 3.9, Н-5), 4.65 (2Н, s, Н-7), 4.85 (4Н, s, Н-2,6).

¹³C NMR (150 МHz, CD₃OD, δ ppm): 50.19 (С-7), 57.11 (С-3,5), 60.03 (С-2,6), 69.69 (С-9), 82.73 (С-8).

IR spectrum (KBr, ν_max, см^-1): 3262, 3200, 2957, 2921, 2129, 1465, 1445, 1370, 1332, 1290, 1270, 1243, 1121, 1080, 1055, 1017, 948, 879, 781-1492, 714.

N-Allyl Morpholine (C₇H₁₃NO):

Used: 4.95 g morpholine (0.06 mol), 5.2 mL allyl bromide (0.06 mol), 8.28 g K₂CO₃ (0.06 mol), 44 mL acetone. At room temperature, it is in a liquid, oily physical state. Rf: 0.66 (solvent system: chloroform: methanol 12:1).

Yield: 87%

¹H-NMR (600 MHz, CDCl₃, d, ppm, J/Hz): 2.40 (4Н, s, Н-3,5), 2.93-2.97 (2Н, m, Н-7), 3.65-3.70 (4Н, m, Н-2,6), 5.11-5.18 (2Н, m, Н-9), 5.77-5.84 (1Н, m, Н-8).

¹³C NMR (150 МHz, CDCl₃, δ ppm): 53.91 (С-3,5), 62.22 (С-7), 67.03 (С-2,6), 118.40 (С-9), 134.60 (С-8).

IR spectrym (KBr, ν_max, см^-1): 2960, 2855, 2802, 1645, 1454, 1422, 1344,1329, 1292, 1115, 1002, 921, 900.

Conclusion

In this study, alkylation reactions of morpholine with propargyl and allyl bromides were investigated. As a result of the experiments, N-allyl morpholine (87%) and N-propargyl morpholine (92%) were synthesized with high yields. The effects of reaction duration and the initial molar ratio of the reagents on product yield were analyzed, and optimal conditions were determined: 2 hours for propargyl bromide, 1 hour for allyl bromide, and a 1:1 molar ratio were found to be the most favorable parameters.

The structures of the synthesized compounds were confirmed by IR, ¹H NMR, and ¹³C NMR spectroscopic methods. According to the results of biological activity prediction using the PASS online tool, the synthesized morpholine derivatives exhibit potential pharmacological properties, such as antidepressant, analeptic, and enzyme inhibitory activities.

These findings suggest that N-alkyl morpholines may serve as promising precursors for the development of new pharmaceutical agents. Moreover, AI-based prediction of biological activity significantly accelerates innovation in pharmaceutical and biotechnological research.

References:

1. V.I. Kozlovsky, M.I. Yakoltsevich, ‘Morpholine derivatives in psychopharmacology,’ Journal of Grodno State Medical University, Vol. 20, No 3, 2022.
2. U.K. Urinov, O.S. Maksumova, ‘Synthesis and properties of heterofunctional compounds,’ Tashkent, 2020.
3. Santiago Grau & Carlos Rubio-Terrés, ‘Pharmacoeconomics of linezolid,’ Expert Opin. Pharmacother, 2008.
4. Plotnikov A., Zehorai E., Procaccia S., Seger R., ‘The MAPK cascades,’ Biochim. Biophys. Acta, 2011.
5. Yu. A. Orlikova, ‘Synthesis and properties of N-butylmorpholinium derivatives,’ Russian Youth Scientific Conference, 2014.
6. Depreux P., Aichaoui H., Lesienr I., Heterocycles, 1993.
7. M.S.R. Murty et al., ‘Zinc Mediated Alkylation of Cyclic Secondary Amines,’ Synthetic Communications, 2003.
8. Sujit Ghosh, Kinkar Biswas, ‘Metal-free multicomponent approach for synthesis of propargylamine,’ Royal Society of Chemistry, 2021.