L.N. Gumilyov Eurasian National University, a dissertation defense for the degree of Doctor of Philosophy (PhD) by Sadvakassova Madina Zhumabaykyzy on the topic «Analytical control in the synthesis and study of new acyclic urea» by specialty «6D060600 – Chemistry».
The dissertation was carried out at the «Chemistry education department» of L.N. Gumilyov Eurasian National University.
The language of defense is russian
Official reviewers:
Kalugin Sergey Nikolaevich – Doctor of Chemical Sciences, Professor of the Department of Chemistry and Technology of Organic Substances, Natural Compounds and Polymers of the National Joint-Stock Company «Al-Farabi Kazakh National University» (Almaty, Republic of Kazakhstan);
Ten Assel Yuryevna – Candidate of Chemical Sciences, Associate Professor, Leading Researcher at the Laboratory of Synthetic and Natural Medicinal Compounds Chemistry of «A.B. Bekturov Institute of Chemical Sciences» (Almaty, Republic of Kazakhstan).
Temporary members of the Dissertation Council:
Festa Aleksey Alekseevich – Candidate of chemical sciences, Senior Lecturer, Senior Researcher, Patrice Lumumba Peoples' Friendship University of Russia, PhD in Chemistry (Moscow, Russian Federation);
Merkhatuly Nurlan – Doctor of Chemical Sciences, Professor, Department of Inorganic and Technical Chemistry, E. A. Buketov Karaganda National Research University (Karaganda, Republic of Kazakhstan);
Akylbekov Nurgali Ikramovich – Candidate of chemical sciences, PhD, Head of the Laboratory of engineering profile "Methods of physico-chemical analysis" at Korkyt Ata Kyzylorda State University (Kyzylorda, Republic of Kazakhstan).
Scientific advisors:
Erkasov Rakhmetulla Sharapidenovich – Doctor of Chemical Sciences, Professor, Department of Chemistry, L.N. Gumilyov Eurasian National University (Astana, Republic of Kazakhstan);
Bakibaev Abdigali Abdimanapovich – Doctor of Chemical Sciences, Professor, National Research Tomsk State University (Tomsk, Russian Federation).
The defense will take place on April 01, 2026, at 10:00 AM in the Dissertation Council for the training direction «8D053 – Physical and chemical sciences» in the specialty «6D060600 – Химия » of L.N. Gumilyov Eurasian National University. The defense meeting is planned to be held online.
Link: clck.ru/3RjNpd
Address: г. Астана, ул. К. Сатпаева, 2, аудитория 302.
Abstract (English): ABSTRACT on the dissertation of Sadvakassova Madina Zhumabaykyzy on the topic "Analytical control in the synthesis and study of new acyclic urea", submitted for the degree of Doctor of Philosophy (PhD) in the speciality “6D060600 – Chemistry” General description of the work. The work is devoted to the development and application of analytical monitoring in the synthesis and characterization of novel acyclic ureas using 1H and 13C NMR spectroscopy. The dissertation presents a comprehensive analysis of existing physico-chemical methods for studying acyclic ureas and examines the patterns of chemical shift changes in the 1H and 13C NMR spectra of the following series: N-alkyl-N′-arylalkyl ureas, N-arylalkyl-N′-acyl ureas, N,N′-diarylureas, and N-benzydrylureas. The influence of substituents of the same type in the benzydryl fragment on the conformational behavior and electronic structure of selected pharmacologically active benzydrylformamides—precursors of biologically active benzydrylureas—was investigated. Based on the interpretation of experimental NMR data, a model was developed, and an atlas of 1H and 13C NMR spectra of carbamide-containing biologically active compounds was published. The relevance of the work. Among the most well-known physico-chemical methods for analyzing acyclic ureas are titrimetry, electrochemistry, spectroscopy, and various chromatographic techniques—such as gas chromatography, high-performance liquid chromatography (HPLC), and thin-layer chromatography (TLC)—which are used to identify and quantify impurities. Although chromatographic methods are highly selective and, in principle, allow the detection of dozens or even hundreds of individual compounds in a single analysis, there is still no universal chromatographic system for the analysis of acyclic ureas. Furthermore, chromatographic methods require large amounts of expensive solvents, gases, consumables, and reagents; involve time-consuming measurements; demand energy-intensive sample preparation; and generate significant amounts of waste. Neither routine titrimetric methods nor modern chromatographic techniques allow simultaneous quantitative and qualitative assessment of the electronic structure and conformational states of ureas, which are integral characteristics of these compounds. Despite their significant potential and demonstrated efficiency, the use of NMR spectroscopy for quantitative chemical analysis of ureas is not widespread. Currently, NMR spectroscopy is used primarily to determine the structures of ureas and to assess their quality; however, existing techniques often do not allow differentiation of a compound from its homologues with similar properties and applications. Given the considerable potential of NMR spectroscopy for assessing the electronic and conformational states of acyclic ureas, establishing clear patterns between their spectral characteristics and chemical composition represents an urgent and highly relevant area of research. The aim of this work is to perform NMR spectrometric identification and determination of acyclic ureas, as well as to establish the relationship between the chemical shift variations of protons and carbon atoms and the structural features of N-substituted acyclic ureas. To achieve the aim of the research, the following tasks were set: 1. To determine the spectral characteristics of N-alkyl-N′-arylalkylureas, N-arylalkyl-N′-acylureas, N,N′-diarylureas, and N-benzhydrylureas using NMR spectrometric analysis; 2. To identify consistent correlations between the spectral characteristics and structural features of acyclic ureas in the 1H and 13C NMR spectra; 3. To investigate the conformational features of N-benzhydrylformamides—precursors of biologically active N-benzhydrylureas—by 1H and 13C spectroscopy combined with molecular mechanics methods; 4. To interpret the experimental NMR data and develop the basis for publishing an atlas of 1H and 13C NMR spectra of carbamide-containing biologically active compounds. Objects of the research: urea, N-benzhydrylformamides, N-benzhydrylureas, N-alkyl-N′-arylalkylureas, N-arylalkyl-N′-acylureas, and N,N′-diarylureas. The subject of this research is the development of analytical control methods for the synthesis and investigation of the spectral properties of acyclic ureas. Research methods. The paper presents the results obtained using NMR and IR spectroscopy. The initial conformational search of the studied compounds was performed using molecular mechanics with a modified Dreiding force field, implemented in the VConf program of the VeraChem software package (VeraChem LLC, Germantown, MD, USA). Quantum chemical calculations were carried out using the Gaussian 16 program with the DFT method on a server (16 × 2.2 GHz CPU, 16 GB RAM) running an Ubuntu environment. The heights of the energy barriers were calculated based on the characteristics of the corresponding transition states, whose geometries were refined using the OPT=(TS, CALCFC, NOEIGEN) options in Gaussian 16. For all stationary points found on the PES, the frequencies of normal vibrations were analyzed to determine the nature of each stationary point (minimum or transition state). The calculation results were visualized using the GaussView 6.0 program. Scientific novelty of the work. The study contributes to the development of NMR spectrometry and demonstrates its potential in the study of acyclic ureas. It is based on a systematic investigation of the 1H and 13C NMR spectral characteristics of acyclic ureas and their precursors, leading to the following new results: 1. For the first time, an identification analysis of chemical shifts was carried out and the ranges of their variation in the 1H and 13C NMR spectra of new acyclic ureas were established. 2. The relationships between spectral characteristics and structural parameters of N-alkyl-N′-arylalkylureas, N-arylalkyl-N′-acylureas, N,N′-diarylureas, and N-benzhydrylureas were determined. For N,N′-diarylureas, correlations were identified between the electronic characteristics of substituents in the aryl fragment and their spectral behavior in the 1H and 13C NMR spectra. 3. For the first time, the influence of similar substituents in the benzhydryl fragment on the conformational behavior and electronic structure of pharmacologically active N-benzhydrylformamides was investigated. The study revealed that significant rotational barriers exist for the formyl group, resulting in the coexistence of syn- and anti-conformers at normal temperatures. As the conformers may differ in their receptor-binding abilities and biological activities, these findings are valuable for predicting the interactions of formamide derivatives with various biomolecular targets. 4. The concept for publishing an atlas of 1H and 13C NMR spectra of carbamide-containing biologically active compounds was developed, leading to the publication of a monograph on this subject. Theoretical significance of the research. The regions of chemical shifts for the main resonating protons and carbon atoms in the 1H and 13C NMR spectra of N-alkyl-N′-arylalkylureas, N-arylalkyl-N′-acylureas, N,N′-diarylureas, and N-benzhydrylureas have been established, and the ranges of their variation have been determined. The proposed 1H and 13C NMR identification methods for N-substituted ureas have significant potential for application in biochemical and synthetic practice. A comprehensive systematic analysis of NMR and IR spectroscopy data for acyclic ureas has been carried out. The results are of interest to researchers and specialists in analytical and research laboratories, biochemists, as well as students and scholars engaged in the design of biologically active compounds and pharmaceuticals. Practical significance of the research. The developed methods of analytical control for acyclic ureas can be applied in the production of a number of valuable pharmaceuticals and various agrochemical preparations containing the acyclic urea fragment. The practical relevance of the study is confirmed by the fact that a substantial part of the dissertation results was used in the publication of the monograph “Atlas of 1H and 13C NMR Spectra of Carbamide-Containing Biologically Active Compounds and Drugs” This monograph is successfully used as a reference material in the educational process at Tomsk State University and Toraighyrov University, in courses devoted to physico-chemical methods of analysis. The main provisions of the dissertation submitted for defense. 1. The established spectral characteristics and their ranges of variation in the ¹H and ¹³C NMR spectra of N-alkyl-N′-arylalkylureas, N-arylalkyl-N′-acylureas, N,N′-diarylureas, and N-benzhydrylureas ensure reliable signal assignment and unambiguous structural identification of the studied compounds. 2. The conformational features of N-benzhydrylformamides, determined using ¹H and ¹³C NMR spectroscopy in combination with molecular mechanics calculations, demonstrate consistency between experimental data and calculated parameters. 3. The obtained experimental NMR data make it possible to generalize the spectral characteristics of carbamide-containing biologically active compounds in the ¹H and ¹³C NMR spectra. Author’s personal contribution. The author’s personal contribution includes the search and analysis of scientific literature on the research topic, the execution of experimental studies using the developed NMR spectrometric methodologies for acyclic ureas, the acquisition, processing, and interpretation of the experimental data, as well as the preparation of publications and the writing of the dissertation text. The author, together with the scientific supervisor, Doctor of Chemical Sciences, Professor R. Sh. Yerkasov, and the foreign scientific consultant, Doctor of Chemical Sciences, Professor A. A. Bakibaev, formulated the relevance of the research, defined the purpose and objectives of the study, planned the experimental part, and formulated the main conclusions and scientific provisions. The samples for the spectral studies were kindly provided by the staff of the Laboratory of Organic Synthesis at the National Research Tomsk State University. The author took an active part in presenting the key results at scientific conferences. Publications based on the results of the work. Nine scientific papers have been published based on the results of the dissertation, including: 1 article in a journal indexed in Web of Science and Scopus; 4 articles in scientific journals recommended by the Committee for Quality Assurance in Science and Higher Education of the Ministry of Science and Higher Education of the Republic of Kazakhstan; 3 articles published in the proceedings of international conferences; 1 monograph. Sadvakassova M.Zh. took an active role in processing and interpreting the experimental data, preparing the draft manuscript, and editing the text to improve its structure, style, and clarity. The applicant was also responsible for submitting the articles to the journals and maintained communication and correspondence with the editorial offices throughout the review and publication processes. In the article Sadvakassova M.Zh., Khlebnikov A.I., Bakibaev A.A., Kotelnikov O.A., Erkassov R.Sh., Yelubay M.A., Issabayeva M.A. Rotational Barriers in N-Benzhydrylformamides: An NMR and DFT Study. Molecules, 2023, 28(2), 535, the applicant is the first author. At the time of publication, Molecules had an impact factor (IF) of 4.9 and belonged to the Q2 quartile in the categories Chemistry, Multidisciplinary and Biochemistry and Molecular Biology. The journal had a CiteScore of 5.9 in 2021 and a percentile of 73 in Organic Chemistry. Four articles were also published in journals included in the list recommended by the Committee for Quality Assurance in Science and Higher Education of the Republic of Kazakhstan: 1. Bakibaev A.A., Sadvakassova M.Zh., Malkov V.S., Erkassov R.Sh., Sorvanov A.A., Kotelnikov O.A. Study of biologically active acyclic ureas by nuclear magnetic resonance. Bulletin of the Karaganda University. Chemistry Series, 2020, No. 4(100), pp. 60-74. 2. Bakibaev A.A., Sadvakassova M.Zh., Еrkassov R.Sh., Atagulova A.E. Identification and analysis of N-alkyl-N′-arylalkyl ureas by nuclear magnetic resonance. Bulletin of the L.N. Gumilyov ENU, 2020, No. 1(130), pp. 18–22. 3. Bakibaev A.A., Sadvakassova M.Zh., Erkassov R.Sh., Sorvanov A.A., Atagulova A.E. Study of the effect of substituents on the chemical shift displacement of N,N′-diarylureas in nuclear magnetic resonance spectra. Bulletin of the L.N. Gumilyov ENU, 2020, No. 2(131), pp. 18-22. 4. Bakibaev A.A., Sadvakassova M.Zh., Erkassov R.Sh., Atagulova A.E. Identification and analysis of N-arylalkyl-N′-acylureas by nuclear magnetic resonance. Bulletin of the L.N. Gumilyov ENU, 2019, No. 4(129), pp. 8-12. (Order No. 1082 dated 10.07.2012 – (List of publications of the Committee for Control in the Field of Education and Science of the Ministry of Education and Science of the Republic of Kazakhstan (valid until December 31, 2020). The part of the results of the dissertation were presented as reports at the VI International Scientific and Practical Conference “Science and Education in the Modern World: Challenges of the 21st Century”, the International Scientific and Practical Journal “Global Science and Innovation 2020: Central Asia” (Nur-Sultan, 2020), and in the collection of articles from the II International Scientific and Practical Conference “Topical Issues of Modern Science: Theory, Technology, Methodology and Practice” (Ufa, 2020). Structure and scope of the dissertation. The dissertation comprises 105 pages and includes the standard sections: an introduction, three chapters (literature review, experimental part, and discussion of results), a conclusion, and a list of 212 references from domestic and foreign authors.
Conclusion of the Research Ethics Committee
Defense of the dissertation: https://youtu.be/hq0KeU6ubDA?si=JqhIP3CVoIq0Xyq5
