Образование 3, 4-дихлор-1, 2, 5-оксадиазол-2-оксида при нитрозировании дихлорметана

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UDC 543. 51:544. 45
Вестник СПбГУ. Сер. 4. Т. 3 (61). 2016. Вып. 1
T. A. Kornilova, A. I. Ukolov, R. R. Kostikov, I. G. Zenkevich
St. Petersburg State University, 7−9, Universitetskaya nab., St. Petersburg, 199 034, Russian Federation
GC-MS identification of minor constituents formed as the result of diazotation using dichloromethane as the solvent shows one of the product is 3,4-dichloro-1,2,5-oxadiazol-2-oxide (3,4-dichlorofuroxane). This compound forms as the result of nitrosation of dichloromethane giving dichloroformoxime (phosgene oxime), followed by its dehydrochlorination and dimeriza-tion. Compounds of this class are characterized by unique regularities of mass spectrometric fragmentation that allows their identification without isolation from reaction mixtures or comparing their analytical parameters with reference samples. Gas chromatographic retention index of 3,4-dichlorofuroxane on standard non-polar stationary phase (935 ± 2) is determined. Refs 11. Figs 1.
Keywords: dichloromethane, nitrosation, 3,4-dichloro-1,2,5-oxadiazol-2-oxide, GC-MS, mass spectrum, GC retention index.
Т. А. Корнилова, А. И. Уколов, Р. Р. Костиков, И. Г. Зенкевич
Санкт-Петербургский государственный университет,
Российская Федерация, 199 034, Санкт-Петербург, Университетская наб., 7−9
Хромато-масс-спектрометрическая идентификация минорных компонентов, образующихся в результате реакции диазотирования в таком растворителе, как дихлорметан, показала, что одним из продуктов реакции является 3,4-дихлор-1,2,5-оксадиазол-2-оксид (3,4-дихлор-фуроксан). Это соединение образуется в результате нитрозирования дихлорметана c образованием дихлорформоксима (фосгеноксида) с последующим его дегидрохлорированием и димеризацией. Соединения этого класса характеризуются уникальными закономерностями масс-спектрометрической фрагментации, что позволяет идентифицировать их без препаративного выделения или сопоставления аналитических параметров с данными для образцов сравнения. Определён газохроматографический индекс удерживания 3,4-дихлорфуразана на стандартной неполярной фазе RTX-5, равный 935 ± 2. Библиогр. 11 назв. Ил. 1.
Ключевые слова: дихлорметан, нитрозирование, 3,4-дихлор-1,2,5-оксадиазол-2-оксид, хромато-масс-спектрометрический анализ, масс-спектр, газохроматографический индекс удерживания.
Introduction. Determination and identification of minor constituents (impurities) of reaction mixtures and various substances is an important analytical problem. Most of organic compounds contain the rests of reagents and/or solvents used during their syntheses. As a consequence of this general statement, the quality control of medicinal preparations implies not only the content of so-called residual solvents used at the final stages of their syntheses, but at the previous stages [1]. Even the similar preparations available from different producers contain different sets of impurities- it was illustrated on the example of such well-known medicines as & quot-Paracetamol"-™ and & quot-Panadol"-TM [2]. These differences can determine the features of their pharmacological activity. The sets of impurities in synthetic drugs allow revealing not only the schemes of their syntheses, but even the concrete producers [3].
© Санкт-Петербургский государственный университет, 2016
In accordance with this concept, the detailed GC-MS analysis of reaction mixtures obtained at the synthesis of alkyl esters of diazoacetic acid, N2CH-CO2R (R = CH3-C4H9), indicated the presence of previously unknown constituents as alkyl chloroacetates, ClCH2CO2R, and esters, formed by esters of glycolic acid and nitrous and nitric acids, ONOCH2CO2R and O2NOCH2CO2R [4, 5]. However, the listed examples do not restrict the number of constituents of these reaction mixtures and their lists can be expanded.
The paper is devoted to the identification of one of rather unusual products of the reaction of nitrosation conducted in dichloromethane used as the solvent.
Reaction conditions. 10−15 mL of dichloromethane was added to water solution of hydrochloride of alkyl ester (R = CH3-C4H9) of aminoacetic acid (20−40mM), followed by cooling this mixture up to — 5 °C. Water solution of NaNO2 (molar excess «1. 2) was added (dropped under stirring at argon atmosphere). The mixture was cooled up to -9-10C, 5% solution of sulfuric acid was added, and stirring was continued 10−15 minutes. Organic layer was separated, washed with saturated solution of NaHCO3 and dried over anhydrous Na2SO4.
GC-MS analysis of reaction mixtures was carried out after their dilution with the same solvent (CH2Cl2) in ratio approximately 1: 100. Injected amounts were 1L, split ratio 1: 200, injector temperature in all regimes was not exceeding 100C.
Regime A. Chromato-mass-spectrometer Shimadzu QP 2010 equipped with fused quartz WCOT column with stationary phase HP-5 MS (polydimethyl siloxane with 5% phenyl groups), length L = 25 m, internal diameter 0. 20 mm (film thickness 0. 33 ^m) in temperature programming regime from 45C (initial isotherm, 1 min) up to 280C (final isotherm, 2 min), ramp 5 grad/min. Linear velocity of carrier gas (helium) 40 cm/s.
Regime B. Gas chromatograph Agilent 5975 with mass spectrometric detector Agilent 7000 B equipped with fused quartz WCOT column with stationary phase HP Ultra-1 (100% polydimethyl siloxane), length L = 17 m, internal diameter 0. 20 mm (film thickness 0. 11 ^m) in temperature programming regime from 40 up to 200C (final isotherm 2 min), ramp 2 grad/min. Linear velocity of carrier gas (helium) 48 cm/s.
Mass spectrum (EI, 70 eV) of 3,4-dichloro-1,2,5-oxadiazol-2-oxide in numerical form, m/z (Irel, %): 158(6), 156(45), 154(66) M, 140(3), 138(2), 128(10), 126(65), 125(3), 124(100) [M-NO], 123(2), 119(2), 110(2), 108(4), 107(2), 97(3), 96(33), 95(2), 94(51) [M-2NO], 91(3), 89(10), 84(12), 79(2), 77(2), 75(5), 73(15), 68(3), 61(7), 60(25) [N2O2], 59(11), 52(22), 49(12), 47(41) [CCl].
Reference n-alkanes C8-Ci2 were used for determining the retention index of target compound. All calculations were conducted using QBasic program.
Results and discussion. The interaction of nitrous acid with primary amines can be conducted both in aqueous solution [6], and organic solvents such as diethyl ether or dichloromethane [7]. In the last case the reaction mixtures contain the variable amounts of the component with gas chromatographic retention index RI = 935 ± 2 (stationary phase RTX-5, Regime A). Mass spectrum of this component looks rather unusual- hence it should be presented in the graphical form (see Figure).
Peaks with m/z = 154, 156 and 158 most probably belong to the molecular ions. Their rather high intensity (WM is ca. 20% of total ion current) allows proposing, at least, the presence of conjugation system in the molecule. The ratio of intensities of isotopic peaks («9: 6:1) indicate the existence of two chlorine atoms. Another rather unusual feature is the similar ratio of isotopic peaks of fragment ions with m/z = 124, 126 and 128, as well as those for ions with m/z = 94, 96 and 98. Thus, the principal way of fragmentation of
Mass spectrum (EI, 70 eV) of the component with retention index RI = 935 ± 2
& lt-D
js §
CD ^
this product implies not the losses of chlorine atoms, but two particles (consequently) with masses 30 Da. The signal with m/z = 60 corresponds to both these fragments, 60 = 2×30, while the presence of chlorine atoms in the molecule is confirmed additionally by the peaks with m/z = 47 and 49 (ratio of intensities 3: 1).
Such unusual combination of mass spectrometric features seems to be typical for rather & quot-exotic"- class of compounds. Consecutive losing of two particles NO with masses 30 Da is typical for members of 1,2,5-oxadiazol-2-oxides (furoxanes) [8, p. 527]. The library search using mass spectra database NIST 2014 [9] indicates the signals of the series M^[M-30]^[M-2×30] are observed in mass spectra of 4-methyl-5-phenoxyfuroxane (m/z = 192 ^ 162 ^ 132), 4-nitro-5-phenylfuroxane (207 ^ 177 ^ 147), 4,5-diphenyl-furoxane (238 ^ 208 ^ 178), and others.
The component with mass spectrum presented at Figure was revealed in reaction mixtures prepared using dichloromethane as a solvent only- it is the source of two chlorine atoms in the molecule. Hence, the first stage of the formation of this product seems to be nitrosation of dichloromethane with formation of unstable intermediate [Cl2CH-NO], which isomerizes into dichloroformoxime (trivial name phosgene oxime), [Cl2C=NOH]. Its following dehydrochlorination (sometimes classified as disproportionation [10]) and dimerization gives the product with molecular formula C2N2O2Cl2 — 3,4-dichlorofuroxane (I).
Thus, the scheme of process can be written as follows:
Cl Cl
CH C12 Cl. CHNO -& gt- CLC=NOH ClCNO -^Vn N+
2 2 2 2 -HCl ^O^ O-
The key stage of this scheme is the formation of 3,4-dichlorofuroxane in the results of the decomposition of phosgene oxime. Thermal, hydrolytic, and catalytic (at the presence of active metals) instability of this oxime is well known [11], but the formation of 3,4-dichlo-rofuroxane is indicated only in the monograph [10, S. 207].
Thus, if the nitrosation is carried out in the dichloromethane solutions, one of unusual products of this reaction is 3,4-dichlorofuroxane formed in the result of solvent nitrosation.
Acknowledgments. This work is fulfilled using the equipment of the Resource Center & quot-Chemistry"- at the Institute for Chemistry of St. Petersburg State University. The authors thank the staff of this Center for assistance.
1. CPMP/QWP/450/03 Rev. 1. European Medicinal Agency. Committee for medicinal products for human use. 2013. 6 p.
2. Zenkevich I. G., Kazankov S.P., Kuz'-minikh K. S., Kosman V. M., Tsibul'-skaya I. A., Litvinova L. S. Comparative characterization of organic impurities in preparations Panadol™ and Paracetamol™ tablets. Medical News, 1997, no 1, pp. 51−53.
3. Zenkevich I. G., Kuz'-minikh K. S., Kazankov S. P. Interpretation of gas chromatographic retention parameters of some phenethylamines and their impurities. Abstr. Conf. & quot-Theory and application of maintenance, prevention, disclosure and investigation of drug crimes& quot-. St. Petersburg, 2000, pp. 184−187.
4. Kornilova T. A., Ukolov A. I., Kostikov R. R., Zenkevich I. G. Stability of diazocarbonyl compounds at the conditions of gas chromatographic and chromato-mass spectrometric analysis. Rus. J. General Chem., 2012, vol. 82, no 10, pp. 1675−1685.
5. Kornilova T. A., Ukolov A. I., Kostikov R. R., Zenkevich I. G. A simple criterion for gas chromatog-raphymass spectrometric analysis of thermally unstable compounds, and reassessment of the by-products of alkyl diazoacetate synthesis. Rapid Commun. Mass Spectrom., 2013, vol. 27, no 3, pp. 461−466.
6. Organisch-chemisches Grundpraktikum. Berlin: Veb Deutscher Verlag der Wissenschaften, 1976. Bd. 2.
7. Weigand-Hilgetag. Methods of Experiment in Organic Chemistry (Russian Transl.). Moscow, Khimia Publ., 1968.
8. Porter Q. N., Baldas J. Mass spectrometry of heterocyclic compounds. New York, Wiley-Intersci., 1971. 564 p.
9. The NIST 14 Mass Spectral Library (NIST14/2014/EPA/NIH). Software/Data Version (NIST14) — NIST Standard Reference Database, N 69, 2014. National Institute of Standards and Technology, Gaithers-burg, MD 20 899- Available at: http: //webbook. nist. gov (accessed: 02. 10. 2015).
10. Franke S. Lehrbuch der Militarchemie. Berlin, Deutscher Militarverlag, 1967. Bd. 1.
11. Aleksandrov V.N. Poisonous substances. Moscow, Military Publ., 1969.
Стaтья пoступилa в pедaкцию 5 октября 2015 г.
Контактная информация
Kornilova Tatiana Alekseevna — PhD- e-mail: takorn@yandex. ru Ukolov Anton Igorevich — PhD- e-mail: antonukolov@gmail. com
Kostikov Rafael Ravilovich — Dr. of Chemistry, Professor- e-mail: rakostikov@yandex. ru Zenkevich Igor Georgievich — Dr. of Chemistry, Professor- e-mail: izenkevich@mail15. com
Корнилова Татьяна Алексеевна — кандидат химических наук- e-mail: takorn@yandex. ru Уколов Антон Игоревич — кандидат химических наук- e-mail: antonukolov@gmail. com Костиков Рафаэль Равилович — доктор химических наук, профессор- e-mail: rakostikov@yandex. ru Зенкевич Игорь Георгиевич — доктор химических наук, профессор- e-mail: izenkevich@mail15. com

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