INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 08,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
244
SYNTHESIS OF QUATERNARY AMMONIUM SALTS BASED ON ETHYLENE
CHLOROHYDRIN AND THEIR MODIFICATION WITH CHITOSAN
Iskandar Allaberdiyev
Research Specialist, Uzbekistan GTL LLC
Baxtiyor Bo‘rixonov
Associate Professor (PhD), Department of Inorganic Chemistry, Qarshi State University
Arziqul Panjiyev
Qarshi State Technical University
E-mail:
borixonov90@mail.ru
Abstract:
A quaternary ammonium salt was synthesized based on ethylene chlorohydrin.
Alternative reaction conditions were studied to optimize the synthesis process. The resulting
quaternary ammonium salt was subsequently reacted with chitosan. Given the inherently high
biological activity of chitosan, its conversion into a quaternized, positively charged form was
found to further enhance its bioactivity. The synthesized compounds were analyzed using
physicochemical methods, including IR and ¹H NMR spectroscopy. The obtained data
confirmed the successful formation of the quaternary ammonium chitosan derivative.
Keywords:
Ethylene chlorohydrin, Chitosan, DMF, Ethanol, Choline, Trabectedin, Solifenacin,
Noscapine, Quinapril, IR spectrum, ¹H NMR spectrum
Introduction
N-alkylamines are an important class of chemical compounds widely found in natural products
and pharmaceutical agents. These compounds are commonly used as structural components in a
wide range of drugs, including antidepressants, analgesics, antibiotics, anticancer agents, and
antiviral medications targeting hepatitis C, as well as agrochemicals. [1–2] Among the most
well-known N-alkylamines are morpholine
[3],
piperidine
[4],
pyrrolidine
[5], and
piperazine
[6].
Due to their biological and synthetic relevance, the formation of
C–N bonds
is of great
importance in organic chemistry. One of the most frequently used methods for forming C–N
bonds is the alkylation of amines using organic halides, which is simple and efficient but often
generates large amounts of waste. Alternatively, the catalytic
borrowing hydrogen
methodology using alcohols produces only water as a byproduct, offering a more
environmentally benign pathway. [7]
Cancer remains a major public health concern worldwide, posing significant threats to human
life and well-being. According to the most recent cancer statistics, cancer has become one of
the leading causes of death in China. With a growing and aging population, the cancer burden is
expected to increase even further. [8] Thus, the development of antitumor agents continues to
be of paramount importance.
Tetrahydroisoquinolines
represent a class of nitrogen-containing heterocyclic compounds that
are widely distributed in nature and exhibit various biological activities. These compounds are
found in numerous clinically used drugs, such as:
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 08,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
245
Quinapril
– an antihypertensive agent
–
Noscapine
– a cough suppressant
–
Solifenacin
– used for urological disorders
–
Apomorphine
– an emetic agent
–
Trabectedin
– an anticancer drug. [9]
(
See Figure 1
)
Quaternary ammonium groups
are a class of organic compounds that contain positively
charged ions. Studies have shown that compounds possessing a quaternary ammonium core
structure exhibit significant anticancer activity against tumor cells
(
Figure
2
).
Materials and Methods
Modern physicochemical techniques were employed to analyze the structural and physical
properties of the synthesized compounds. IR spectra were recorded using a Perkin-Elmer
Spectrum 2000 FT-IR spectrophotometer in KBr pellets. The 1H and 13C NMR spectra were
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 08,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
246
obtained using Unity-400+ (400 MHz) and Jeol-600 (600 MHz) spectrometers with deuterated
solvents (CD₃COOD and DMSO-d₆). Tetramethylsilane (TMS) was used as the internal
reference (δ-scale).
Melting points were determined using a MEL-TEMP apparatus (USA). All synthesis
procedures were carried out using thermally and mechanically resistant borosilicate glassware
(Borosilicate 3.3 grade).
3. Results and Discussion
3.1. Reaction of Ethylene Chlorohydrin with Trimethylamine
As outlined above, the aim of our study was to synthesize quaternary ammonium salts via the
reaction of ethylene chlorohydrin with tertiary amines, investigate their molecular structures,
determine their physicochemical properties, and evaluate their potential biological activities.
The first reaction studied was the quaternization of ethylene chlorohydrin with trimethylamine.
ClCH
2
CH
2
OH + (CH
3
)
3
N
[(CH
3
)
3
N
+
CH
2
CH
2
OH] Cl
-
Optimization of Reaction Conditions
To increase product yield and determine optimal reaction parameters, ethylene chlorohydrin
was first distilled at 128–129 °C to obtain a purified, reaction-ready form. It was then reacted
with a 33% solution of trimethylamine in absolute ethanol at a 1:1 molar ratio.
To study the influence of reaction time and temperature on product yield, reactions were
conducted in sealed ampoules at various temperatures for durations of 1 and 2 hours. The
corresponding results are summarized in Table
1- Diagramma
-
Effect of Temperature on the Yield of Hydroxyethyltrimethylammonium Chloride
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 08,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
247
Influence of Reaction Conditions on Product Yield
When the reaction was performed by directly mixing the reagents at room temperature, the
reaction vessel heated up significantly, producing white fumes. Under these conditions, the
yield did not exceed 46%. However, when the same reaction was conducted under ice bath
cooling, the yield increased to 52%, and a colorless, glass-like crystalline product — β-
hydroxyethyltrimethylammonium chloride — was isolated.
To further improve the product yield, the reaction was optimized based on literature data.
Specifically, 1.7 ml of ethylene chlorohydrin was mixed with 4.6 mL of a 33% solution of
trimethylamine in absolute ethanol at 60
°C
in an ice bath. The mixture was then sealed in an
ampoule and heated in a water bath at a constant temperature of 65–70
°C
for 2 hours.
Additional experiments were carried out with varying reagent molar ratios to evaluate their
effect on yield. The results are presented in Figure 2
.
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 08,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
248
The reaction was conducted at a 1:2 molar ratio of ethylene chlorohydrin to trimethylamine at
65–70 °C, taking into account that trimethylamine, although dissolved in absolute ethanol, is a
volatile gas. Therefore, an excess of trimethylamine was used to ensure complete conversion.
After completion of the reaction, the colorless liquid in the ampoule was collected, transferred
to an evaporating dish, and the ethanol was removed by evaporation at room temperature. The
remaining material was placed in a desiccator over CaCl₂ for drying. As a result, needle-like,
colorless crystals of β-hydroxyethyltrimethylammonium chloride were obtained.
To determine product yield, the dried solid was weighed. Under the optimized conditions (1:2
molar ratio, 65–70 °C), the reaction yielded 68% of the desired product.
The results clearly show that increasing the molar ratio of the reagents and maintaining an
elevated reaction temperature positively influenced the product yield.
Modification of Chitosan with the Synthesized Quaternary Ammonium Salt
Following successful synthesis, the obtained quaternary ammonium salt was used to modify
chitosan. The reaction scheme is presented below:
Scheme 1.
Synthesis of Chitosan-Based Quaternary Ammonium Salt via Reaction with β-
Hydroxyethyltrimethylammonium Chloride
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 08,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
249
Optimization of Reaction Conditions Using DMF
To identify the optimal conditions for the synthesis, the reaction was performed in DMF
(dimethylformamide) at various time intervals. Among the tested durations, the highest yield of
the quaternary ammonium salt was obtained after 3 hours of reaction time.
The effect of reaction temperature on product yield was also studied. It was found that reactions
conducted at 40–50 °C provided the highest yields, confirming this temperature range as
optimal for the synthesis of the quaternary ammonium salt.
IR Spectroscopic Analysis of the Synthesized Compounds
The IR spectra of the synthesized compounds were recorded using SPECORD-75IR and Avatar
360 spectrophotometers with KBr pellets
.
Figure 1 displays the IR spectra of chitosan and its quaternary ammonium salt derivative
formed by reaction with the pyridinium-based quaternary ammonium compound.
The broad absorption band in the range of 3200–3500 cm⁻¹ corresponds to the N–H and O–H
stretching vibrations in chitosan. Other characteristic absorption bands observed include:
2878 cm⁻¹ – C–H stretching 1600 cm⁻¹ – Amide bond vibrations 1156 cm⁻¹ and 1078 cm⁻¹ – C–
O–C stretching and secondary hydroxyl C–O vibrations
Out-of-plane deformation vibrations of aromatic C–H groups were detected in the 650–
900 cm⁻¹ region, consistent with aromatic ring substitution.
New peaks observed at 1467 cm⁻¹
,
1464 cm⁻¹
,
and 1471 cm⁻¹ in the modified chitosan spectrum
are assigned to the stretching vibrations of quaternary –N⁺ groups, indicating successful
quaternization. These spectral changes confirm the successful synthesis of chitosan derivatives
containing quaternary ammonium functionality.
¹H NMR Spectral Analysis of Quaternized Chitosan
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 08,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
250
The 1H NMR spectrum of the synthesized quaternary ammonium salt of chitosan was recorded
at 500 MHz in D₂O. The following chemical shifts were observed:
δ 8.68 (s, 1H, He) δ 8.40 (m, 2H, Hc) δ 8.06 (s, 1H, Hb) δ 7.81 (s, 1H, Hd) δ 4.31 (s, 1H, Hn) δ
4.06 (s, 1H, Ha) δ 3.85–3.69 (m, 4H, H3–H6) δ 3.24 (s, 9H, Ho) – typically attributed to
trimethylammonium methyl groups (N⁺(CH₃)₃) δ 2.85 (s, 1H, H2) δ 2.66 (s, 6H, Hm)
Additional characteristic signals supporting structural confirmation:
δ 0.76–1.03 ppm (t, J = 6.8 Hz, 3H) – A triplet corresponding to a terminal methyl group (–CH₃)
adjacent to a methylene group (–CH₂–). δ 2.97–3.20 ppm (s, 6H) – A singlet with six protons,
indicating the presence of two methyl groups attached to nitrogen [e.g., N(CH₃)₂ or N(CH₃)₃]. δ
4.55–4.74 ppm (s, 2H) – A singlet typical for methylene protons adjacent to either oxygen or
quaternary nitrogen (–CH₂–O– or –CH₂–N⁺–).
Conclusion
A quaternary ammonium salt was successfully synthesized by the reaction of ethylene
chlorohydrin with trimethylamine. The resulting compound corresponds to choline
,
which is
widely used in the medical field. This synthesized quaternary ammonium salt was further
reacted with chitosan
,
and the optimal conditions for the modification reaction were
systematically investigated.
The structure of the obtained chitosan derivative was confirmed using IR and ¹H NMR
spectroscopy, and the formation of quaternary ammonium functionalities was clearly evident.
The newly synthesized quaternized chitosan is planned to be further studied for its biological
activity, particularly in relation to its antibacterial and antifungal properties.
Foydalanilgan adabiyotlar ro’yxati:
1. Vo, C.-V. T.; Bode, J. W. Synthesis of Saturated N-Heterocycles.
J. Org. Chem.
2014
,
79
,
2809–2815.
https://doi.org/10.1021/jo5001252
2. Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution
Patterns, and Frequency of Nitrogen Heterocycles Among U.S. FDA Approved
Pharmaceuticals.
J. Med. Chem.
2014
,
57
, 10257–10274.
https://doi.org/10.1021/jm501100b
3. Martins, P.; Jesus, J.; Santos, S.; Raposo, L. R.; Roma-Rodrigues, C.; Baptista, P. V.;
Fernandes, A. R. Heterocyclic Anticancer Compounds: Recent Advances and Paradigm Shift
Towards
Nanomedicine.
Molecules
2015
,
20
,
16852–16891.
https://doi.org/10.3390/molecules200916852
4. Joule, J. A. Natural Products Containing Nitrogen Heterocycles – Some Highlights 1990–
2015.
Adv. Heterocycl. Chem.
2016
,
119
, 81–106.
https://doi.org/10.1016/bs.aihch.2015.10.005
5. Marcatoni, E.; Petrini, M. Recent Developments in the Stereoselective Synthesis of
Nitrogen-Containing Heterocycles Using N-Acylimines.
Adv. Synth. Catal.
2016
,
358
, 3657–
3682.
INTERNATIONAL JOURNAL OF ARTIFICIAL INTELLIGENCE
ISSN: 2692-5206, Impact Factor: 12,23
American Academic publishers, volume 05, issue 08,2025
Journal:
https://www.academicpublishers.org/journals/index.php/ijai
251
6. Taylor, A. P.; Robinson, R. P.; Fobian, Y. M.; Blackemore, D. C.; Jones, L. H.; Fadeyi, O.
Modern Advances in Heterocyclic Chemistry in Drug Discovery.
Org. Biomol. Chem.
2016
,
14
,
6611–6637.
https://doi.org/10.1039/C6OB00936K
7. Lindsey, C. W.; Hopkins, C. R. Return of D4 Dopamine Receptor Antagonists in Drug
Discovery.
J.
Med.
Chem.
2017
,
60
,
7233–7243.
