Thermodynamic Properties of Tetrazole Derivatives for Synthesis
Development of New Efficient Methods for Synthesis of the Tetrazole Derivatives Possessing Unique Properties on the Basis of Newly Created Methods of Prognostication of the Thermodynamic Properties of Substituted Tetrazoles and Studies of Thermodynamic As
Tech Area / Field
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
- CHE-THE/Physical and Theoretical Chemistry/Chemistry
3 Approved without Funding
Belarussian State University / Institute of Physical Chemical Problems, Belarus, Minsk
- US Department of Commerce / National Institute of Standards and Technology / Thermodynamics Research Center, USA, CO, Boulder\nUniversität Rostock / Fachbereich Chemie, Germany, Rostock\nUniversity of Turin / Department of Chemistry IFM, Italy, Torino
Project summaryThe purpose of the present project is development of new efficient methods for synthesis of a wide variety of tetrazole derivatives; development of methods of prognostication and creation of a data base on thermodynamic properties on the basis of a comprehensive study of thermodynamic properties for a group of key substances: alkyl, phenyl, vinyl and amino substituted tetrazoles in different aggregate states; calculation of chemical equilibria with the participation of tetrazole derivatives; characterization of thermodynamic aspects of their reactivity in various chemical processes; theoretical and experimental studies of regioselective functionalization of tetrazole ring.
Importance of the project.
Tetrazole derivatives possess a complex of unique energetic, chemical and other properties that makes them to be promising objects both for fundamental studies and for wide practical use. Last years substances of this class find new applications in medicine, biochemistry, agriculture, photography and other fields of human activity [Butler R.N. Tetrazoles. – In: Comprehensive Heterocyclic Chemistry II. Pergamon, 1996, Vol. 4, p.621–678. Singh H., Chawla A.S. et al. Progr. Med. Chem. 1980. Vol. 17, p.151–183]. So, a number of highly effective medicines has been prepared on the basis of substituted tetrazoles: cephalosporine antibiotics, hypocholesteric, antihypertensive, antiviral means including HIV ferment inhibitors. Tetrazole derivatives, in particular 5-mercapthtetrazoles and 1-phenyl-5-mercapthtetrazole, already found appreciable application in photography. Prominent herbicidal activity was found for 1-arylsubstituted tatrazol-5-yloxyacetamides and tetrazolylmethylazines. Due to a high content of nitrogen and high energies tetrazole derivatives are unique components of gas generating compositions.
In spite of existence of wide variety of potential applications for tetrazole derivatives, implementation of many of them is retarded by absence of convenient preparative methods of synthesis and reliable information on thermodynamic properties, phase states and equilibrium compositions in different reactions.
The substantial progress in industrial synthesis and conversion of chemical substances is known to determine in significant measure by the level of study of their physico-chemical properties. So, a comprehensive study of thermodynamic properties of oil hydrocarbons carried out in the U.S. under guidance of Prof. F.Rossini became a basis for development of modern technologies of oil processing and petrochemical synthesis [F.D.Rossini. J. Chem. Thermodynamics, 1976, Vol. 8, p.805–834]. Last years thermodynamics methods have been successfully applied to estimate in principle possibilities of implementation of particular projects. These methods allowed to optimize industrial processes due to establishing of relations between different physico-chemical parameters of a system (temperature, pressure, chemical composition, etc.) For example, 22 technological programs of high importance for national safety of the U.S. can be implemented only basing on thermodynamic investigations G.A. Krestov. Zh. Khim. Termodinam. i Termokhim. 1992, Vol.1, p.6–11].
Creation of methods of prognostication of the thermodynamic properties of chemical substances is very important not only for development of chemical technologies and theories concerning relations between structures and properties of substances, but also has a grave economic basis. A comprehensive study of thermodynamic properties for one substance expends about 80,000–100,000 $. That is why less than 0.02% of 10 million known chemical compounds underwent comprehensive thermodynamic studies.
Influence on progress of chemistry of tetrazole derivatives.
The realization of the present project will substantially extend the knowledge of the world scientific community in the scope of organic and physical chemistry of tetrazole derivatives. Creation of methods of prognostication of the thermodynamic properties will allow one to calculate easy and reliably conformational and tautomeric compositions for a wide range of tetrazole derivatives, as well as to estimate quantitative characteristics of thermodynamic aspect of their reactivity in a wide range of temperatures and pressures. That will give a basis for development of energy and resource saving methods and technologies of their synthesis. Hence, implementation of the project will allow one to extend practical use of tetrazole derivatives restricted at the present time by insufficient knowledge of properties of these substances, and by complicacy, non-economy and, as a rule, by increased danger of methods of their preparation.
Highly qualified scientific staff of the Research Institute for Physical Chemical Problems of the Belarussian State University will be involved in the present project, including 2 Doctors of Sciences and 7 Ph. D. which formerly worked for development of rocket materials and technologies as well as powders, gas generating compositions and energetic devices for military purposes in the frame of State Programs of USSR. They have an experience of many years to develop and apply in industry technologies of production of both tetrazole derivatives and many other organic substances. The project participants have published about 400 scientific papers on synthesis and studies of properties of tetrazole derivatives including polymers, studies of thermal transformations of tetrazole derivatives and rocket propellants based on tetrazole polymers, as well as thermodynamics of organic compounds, classical theory of molecular structure, statistical thermodynamics, studies of plastic crystals, thermodynamic analysis of organic synthesis processes. Last years the participants of the present project have developed effective general methods of synthesis of 1-monosubstituted tetrazoles and also methods of synthesis of a series of 2-mono- an 2,5-disubstituted tetrazoles [Gaponik P.N., Karavai V.P., Grigor'ev Yu.V. Khim. Geterozikl.Soed. 1985, # 11, p.1521–1524. Gaponik P.N., Karavai V.P., Davshko, I.E., Bogatikov, A.N., Degtyarik M.M. Khim. Geterozikl.Soed. 1990, # 11, p.1528–1532. Koren A.O., Gaponik P.N., Ivashkevich O.A., Kovalyova T.B. Mendeleev Commun. 1995, # 1, p.41–42. Grigor'ev Yu.V., Maruda I.I., Gaponik P.N. Izv. AN Belarus. Ser. khim. 1997, # 4, p.86–90. Koren A.O., Gaponik P.N., Ostrovskii V.A. Int. J. Chem. Kinet. 1995, Vol. 27, p.919–924. Voitekhovich S.V., Gaponik P.N. Koren A.O. Mendeleev Commun. 1997, # 1, p.41–42]. The methods developed have formed a basis for technological schemes for production of some tetrazoles having a great practical importance. Some of participant of the present project carried out calorimetric determination of enthalpies of formation and vaporization (sublimation) for a series of alkyl- and vinyltetrazoles, quantum chemical calculations of DfH(g; 298.15 K) [Kozyro A.A., Simirsky V.V., Krasulin A.P., Sevruk V.M., Kabo G.J., Frenkel M.L., Gaponik P.N., Grigor'ev Yu.V. Zh. Fiz. Khim. 1990, Vol. 64, p.656–661. Ivashkevich O.A., Gaponik P.N., Koren A.O., Bubel O.N., Fronchek E.V. Int. J. Quantum Chem. 1992, Vol. 43, p.813–826].
Research Institute for Physical Chemical Problems is now one of leading institutes of chemical profile in the Republic of Belarus. Scientific and technical potential of the institute allow one to solve complex problems in different fields of chemistry and chemical technology, to provide a comprehensive scientific and technical support to particular technologies and some branches of industry, e.g., the enterprises of "Belneftekhim" and "Belbiofarm" state concerns, and also activities intended to utilize different industrial by-products and to organize small-volume chemical productions of high science capacity. Workers of the institute have published more than 5,500 scientific papers including 23 monographs, about 3,000 articles, obtained more than 780 author's certificates of USSR and patents for inventions for the period 1978–1999.
Following results will be obtained as a result of realization of the tasks of the project:
Task 1: systematization of published values of and substantiation of methods for prognostication of the thermodynamic properties of tetrazole derivatives (TD) will be made, key substances among TD for experimental studies will be selected, methods of their synthesis and purification will be developed.
Task 2: system of numerical values of thermodynamic properties for the key substances necessary for development of methods for theoretical prediction of properties of TD and for thermodynamic characterization of reactivity will be obtained.
Task 3: calculation of thermodynamic properties of TD in the gas state by the statistical thermodynamics method based on published and own investigations of molecular structures, vibrational spectra, calculations of normal vibration frequencies and moments of inertia of molecules will be carried out.
Task 4: reliable methods of prognostication of the thermodynamic properties of TD in different aggregate states not studied experimentally will be developed and patent claims will be prepared; thermodynamic properties for a wide range of TD will be calculated; software and computer data base on thermodynamic properties of TD will be created.
Task 5: tables on thermodynamic properties of TD (50–100 pages) will be prepared for publication in "TRC Thermodynamics Tables – Non-Hydrocarbons" in cooperation with TRC (Thermodynamics Research Center), a pision of NIST (National Institute of Standards and Technology, United States).
Task 6: semiempirical and ab initio quantum chemical calculations of enthalpies of formation and relative stability of isomers of N-substituted tetrazoles, barriers to internal rotation and conjugation energies in molecules of vinyl-, phenyl- and aminotetrazoles will be made; applicability of different quantum chemical methods for correct and reliable calculations of energetic characteristics of TD will be substantiated.
Task 7: thermodynamic parameters of typical reactions of TD (isomerization, alkylation, polymerization, thermolysis) will be determined, a general approach for selective functionalization of tetrazole ring will be substantiated, thermodynamically substantiated effective technological methods will be developed and patent claims will be prepared for production of some practically important TD (2-alkyl-5-(4-biphenyl)tetrazoles – synthones for preparation for of antihypertensive medicines (Valsartan, Lozartan), 1-tetrazolylacetic acid and its derivatives – intermediate products in synthesis of cephalosporine antibiotics, 1,2-bis(1-tetrazolyl)ethane – a promising reagent for extraction of precious metals from industrial wastes) which can be expanded to a wide range of TD.
Application of results of the project. Results of the studies will be published (also in patents and well known TRC data bases) and will became available for experts in the organic chemistry. The obtained within the framework of the project data will be used for development of methods and technologies of patent value for synthesis of a wide range of both novel and already known TD of practical importance, industrial use of which is now restricted by absence of convenient, safe and profitable methods of production. These data will be of interest for chemical enterprises producing medicines, agricultural chemicals and polymer materials.
Meeting ISTC Goals and Objectives.
Implementation of the project meets ISTC goals and objectives:
– the scientists will take part in the project (more than 60%) which formerly worked for development of rocket materials and technologies as well as powders, gas generating compositions and energetic devices for military purposes in the frame of State Programs of USSR. The project will give them possibilities to re-orient their activities to non-military research;
– contacts will be established during implementation of the project with leading science centers in Europe and U.S. dealing with thermodynamic studies as well as with scientists from those countries, scope of interests of which is tied with synthesis and studies of chemical properties of tetrazole derivatives. Hence the present project will promote integration of scientists to solve scientific and technical problems of international importance;
– results of the planned fundamental studies in chemistry of tetrazole derivatives will form a basis for development of effective methods and technologies for production of both novel and already known practically important tetrazoles promoting involvement of the scientific institution into market economics relations.
Scope of Activities.
Leading institution carrying out this project is Research Institute for Physical Chemical Problems of the Belarussian State University. None other institution takes part. The project is planned to implement for 36 months with total effort of 472 man/months. The work under this project will include following tasks:
– substantiation of selection of substances for experimental studies and their synthesis;
– comprehensive studies of thermodynamic properties of a group of key substances – tetrazole derivatives (TD);
– calculation of thermodynamic properties of the key substances in the ideal gas state in the temperature range 100–1500 K by statistical thermodynamics methods;
– development of methods for prediction of the thermodynamic properties of TD based on the classical theory of molecular structure;
– preparation of tables with thermodynamic properties of TD;
– quantum chemical investigations on TD;
– evaluation of thermodynamic parameters of typical reactions of TD and development of effective technological methods to produce some practically important TD.
Role of Foreign Collaborators.
Following form of participation in the project are approved by foreign collaborators:
– joint investigations;
– information exchange during implementation of the project;
– joint discussion of technical reports;
– joint workshops and consultations;
– testing of results using independent methods and equipment;
– preparation of joint publications.
Technical Approach and Methodology.
The present project includes 7 tasks:
1. A group of key substances for experimental studies will be selected on the basis of a structural theoretical analysis. The key substances should contain structural elements of all possible kinds, that will allow one to determine according contributions of "effective atoms, bonds and groups" to thermodynamic properties that is necessary for later quantitative prediction of properties of tetrazole derivatives not studied experimentally. The key substances will be synthesized and purified according to original authors' of the project methods.
2. Comprehensive measurements of thermodynamic properties of the key substances will be carried out. Main measurements will be performed with calorimeters of different types: adiabatic, bomb, heat conduction, and scanning calorimeters. Some of the calorimeters are calibrated with reference substances: metrological benzoic acid (K-1 trade mark), copper with purity 99.99%, etc. Results of the project authors' measurements obtained with these calorimeters were more than once published and confirmed by independent measurements in other laboratories.
3. Thermodynamic properties of tetrazole derivatives in the gas state will be calculated by the statistical thermodynamics method basing on molecular and spectral data.
4. Basing on the classical theory of molecular structure, methods for prediction of the thermodynamic properties of a wide variety of tetrazole derivatives will be developed and extended calculations for alkyl-, phenyl-, vinyl- and aminotetrazoles will be carried out.
5. 50–100 tables on thermodynamic properties of tetrazole derivatives in the TRC format will be prepared for publication in TRC Thermodynamics Tables – Non-Hydrocarbons.
6. Enthalpies of formation for a wide variety of tetrazole derivatives, energies of internal rotation and conjugation in molecules of vinyl-, phenyl-, and aminotetrazoles, potential energy surfaces for isomerization of N-substituted tetrazoles will be calculated using software for semiempirical calculations (MNDO, AM1, PM3) and non-empirical calculations using 6-31G* and 6-31G** basis sets considering the electron correlation in MP2 approximation. Influence of solvents of different nature on relative stability of N-substituted tetrazoles will be studied using SCRF, SM5 and PCM models. Quantum chemical simulation of thermally stimulated fragmentation of tetrazole derivatives will be carried out. Isomerization processes of N-substituted tetrazoles in different media including acid-controlled and thermally stimulated ones will be investigated experimentally using a set of physico-chemical methods.
7. Basing on analysis of the data obtained in the project, relations between molecular structure and thermodynamic stability of isomeric substituted tetrazoles will be established, constants of chemical equilibria and equilibrium compositions of products of thermal destruction, isomerization, alkylation of tetrazole derivatives will be calculated. Thermodynamic characteristics of isomerization of N-substituted tetrazoles will be evaluated, and thermodynamic parameters of substituted tetrazoles synthesis reactions will be determined. Basing on the compendium of experimental and calculated data, a general approach for selective functionalization of tetrazole ring will be substantiated, general principles and technological recommendations will be proposed for development of convenient selective ways to production of a wide variety of tetrazole derivatives. Effective methods and technological schemes will be developed for synthesis of 2-alkyl-5-(4-biphenyl)tetrazoles – synthones for preparation of antihypertensive medicines (Valsartan, Lozartan), 1-tetrazolylacetic acid and its derivatives – intermediate products in synthesis of cephalosporine antibiotics, 1,2-bis(1-tetrazolyl)ethane – a promising reagent for extraction of precious metals from industrial wastes.
Truth of results will be provided by use of attested experimental methods, reliability of which is confirmed by investigators from other laboratories, by application of quantum chemical software tested on a variety of objects with concurrent checking for accordance with experimental results, and by high qualification of participants of the project having an experience of many years of work in the field of chemistry of tetrazole derivatives and thermodynamics of organic compounds.