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DIPEROXYCARBOXYLIC ACIDS N-OXIDATION OF ALKALOIDS IN AQUEOUS MEDIUM: A KINETIC AND MECHANISTIC STUDY

DIPEROXYCARBOXYLIC ACIDS N-OXIDATION OF ALKALOIDS IN AQUEOUS MEDIUM: A KINETIC AND MECHANISTIC STUDY
Николай Блажеевский, профессор, доктор химических наук, профессор

Елена Мозговая, ассистент, кандидат фармацевтических наук

Харьковский национальный фармацевтический университет, Украина

Участник первенства: Национальное первенство по научной аналитике - "Украина";

Открытое Европейско-Азиатское первенство по научной аналитике;

An interaction diperoxy acids with alkaloids is a process of nucleophilic substitution β-peroxide oxygen of peroxyacid with forming of corresponding the N-oxides of alkaloids and is subject to the general laws specific acid-base catalysis.

Keywords: diperoxycarboxylic acids, alkaloids, diperoxysebasic acid

 

Introduction. It is known that alkaloids containing tertiary aliphatic nitrogen, the reaction of the peroxyacids easily attached oxygen, forming the corresponding N-oxides [1]. Published data mainly concerns preparative studies and do not contain enough complete information about the kinetic and mechanism of reactions [2-5].However, transfer of an Oxygen atom from peroxy acids to tertiary aliphatic amines is of considerable interest to both organic and biological chemists. No attempt to determine the second-order rate constant for the reaction of alkaloids with mono- or diperoxy carboxylic acids was made. The study of rate as a function of pH and buffer concentration can permit conclusions about the nature of proton-transfer processes and relationship to the rate-determining step in a reaction.

We have found that N-oxidation by peroxyacids of a large number of biologically active tertiary amines including alkaloids in buffered in aqueous solutions realizes by means of the mechanism of specific acid-base catalysis.

In this paper, the results of the study of the kinetics of the N-oxidation reactions of certain alkaloids containing tertiary amine nitrogen with Diperoxysebasic acid(DPSA) in aqueous buffer solutions are presented.

Experimental part. To prepare test solutions were used as alkaloid salts or free bases pharmacopeia purity. Their concentration controlled by potentiometric titration 0.02 mol L-1 silver nitrate solution using chloride selective electrode OP-08200 (Company "Radelkis", Hungary) or by acid-base titration of acoding to State Pharmacopoeia of Ukraine (SPU) [6].

The Diperoxysebasic acid was prepared by the reaction of excess 50% H2O2 with the corresponding dicarboxylic acid in sulfuric acid as described by Swern [7]. The content of the basic substance in the products of according to iodometric titration was 96-98%.

Peroxyacid (name synonymous) chemical formula: Тmp.С; The active oxygen content (AOC)., % (Theor.), Molarmass, gmol-1Diperoxydecanedioic acid (Diperoxysebasic acid), HO3C(СH2)8CO3H, 96 (dec.) 13.5 (13.7), 234.1).pKH2An=7.68; pKHAn-= 8.35 [8].

Kinetic measurements. All kinetic measurements were conducted at 293±0.2 K. The reactions of alkaloids with DPSA were conducted in oxygen-free buffer solution by observing the decrease in DPSA concentration by iodometric titration under the conditions of [DPSA]>[Alkaloid].

The volume of titrant solution was measured to within ± 0,01 ml using microburette.

pH measurements were made using a pH/mv meter Model «Ionometer I-130» eguipped with a standardized glass electrode EGL-43-07 at 293 K.

Polarographic studies were performed in a glass thermostatted cell with water seal at 293 K on electronic Polarographs PPT-1 (P.M. I., Gomel, Belarus) (Three elektrode cell) and Pa-2 (Czech Republic). The potassium chloride saturated calomel electrode (SCE) comparison and the mercury drop constant capillary microelectrodes m2/3·τ1/6= 2,03 mg2/3·c1/6(Е1/2 = – 1,01 V) was used.

Removal of oxygen from the test solution bubbling high pure argon performed for 15 minutes. The concentration of DPSA found by pre-built calibration curve games ігр- c, mol L-1. Quantitative yield N-oxide alkaloids estimated by polarography method using calibration curve without isolating them from solution[9]. The reaction products were identified by the polarography method without preliminary isolation from the solution: potentials of the half-waves were compared with those values found using N-oxide samples obtained by an independent synthesis method [10].  

The method of polarography shows that the increase of the concentration of the forming N-oxide of the alkaloid during the reaction is directly proportional to the decrease the diperoxy acid concentration in the solution. The values of the initial reaction rate calculated by dependencies c vs. t for dyperoxy acid and N-oxide of alkaloid, were the practically same.

An example of experimental data of reaction kinetics for codeine shown in Fig. 1.

Fig. 1 Semi-logarithmic plots of Ct / [CAm - 2(С0 - Сt)] vs. time N-oxidation of codeine by Diperoxysebasic acid (DPSA) for different pH.  1- 6,3; 2 - 7,4; 3- 8,0; 4 – 8,75; 5 – 9,3. CAm=1·10-3 mol· L-1; CDPSA=1,5·10-3 mol· L-1

 

A plots of log10Ct/ [CAm- 2(С0 - Сt)] on time is kept linear up to 100%conversion, that shown to second kinetic order of reaction and practical absence of influence of the formed products on her velocity.

Dependence of the apparent second-order rate constants on pH has form of curves with maximums, corresponding to the values of pKa salt forms of alkaloids and indicate the ionic nature of the reactions (Fig. 2 a)

Fig. 2 The apparent second-order rate constantsfor the N-oxidation of alkaloids by Diperoxysebasic acidas a function of pH(a) and vs. αAm· (αH2An+ αHAn-)(b): 1 - strychnine; 2 - codeine; 3 - dionin; 4 - atropine; 5 - cocaine; 6 - quinine. CAm = 1·10-3 mol L-1; c(DPSA) = 1,5·10-3 mol L-1. 293 K

Based on the hypothesis that the transitional state of reactions involves a undissociated form of acid (H2An), its monoanion (HAn-) and base form of alkaloid  (tertiary amine) (Am), the kinetic equation that establishes a connection between by the apparent rate constant kobs and the second-order rate constant, Kwas obtained:

kobs= К·αAmH2An + αHAn-),

where, αAm- molar fraction of alkaloid base, (αH2An + αHAn-) – sum of molar fractions of protonated form of diperoxyacid and its mono anion (HAn-) particles.

Molar fractions that correspond to acid-base forms at different concentrations of H+ ions were calculated by known formulas:

αAm= Ka /{(Ka+[H+]}; αH2An = [H+]2 /{[H+]2 + KH2An·[H+] + KH2An· KHAn-};

αHAn-=KH2An·[H+]/ {[H+]2 + KH2An·[H+] + KH2An· KHAn-},

where Ka-  constant of acid dissociation of salt forms of alkaloids;

KH2An- dissociation constant protonated form diperoxycarboxylic acid; KHAn- - constant of acid dissociation of acid salt (of monoanion) diperoxycarboxylic acid.

Obtained plots well agree with the experimental results. kobs was a linear function vs. the product of molar fractions αAmH2An + αHAn-) in the pH range studied (Fig. 2 b), which confirms the adequacy of the proposed above equation experimentally obtained dependence.

We have attempted to establish the dependence of reactivity alkaloids from values pKa them of conjugated acid forms. As shown in Fig. 3, the values of rate constants (K) increases linearly to increasing basicity alkaloids (slope was »0,67), which is typical for nucleophilic substitution reactions (Fig. 3).

Fig. 3 The second-order rate constantsfor the N-oxidation of alkaloids by Diperoxysebasic acid vs. pKa them of conjugated acid forms: 1 - strychnine; 2 - codeine; 3 - dionin; 4 - atropine; 5 - cocaine; 6 - quinine, 7 - papaverin.

The value of K for atropine was somewhat understated, which can be explained by the structural features (steriochemistry) of the atropine molecule.

Conclusion. By kinetic method on example of Diperoxysebasic acid have shown that interaction of diperoxycarboxylic acids with alkaloids in aqueous medium takes place quantitatively by nucleophilic substitution mechanism at β-peroxide atom of peroxy acid oxygen with the formation of corresponding N-oxides, while reaction kinetics agrees with laws of specific acid-base catalysis.

 

References:

  • 1.     PrylezhaevaE.N. ReakcyaPrylezhaeva. Elektrofyl`noe okyslenye. – M. : Nauka, 1974. – 332 s.
  • 2.     Craig J.C. et al. Improved preparation of tertiary amine N-oxides. J. Org. Chem., 1970, 35(5), 1721-1722.
  • 3.     Lu S.-T., Wu Y.-C. and Leou S.-P. The Oxidation of Isoquinoline Alkaloids with m-Chloroperbenzoic Acid. J Chin. Chem. Soc. 1987, 34, 33–42. doi:10.1002/jccs.198700006
  • 4.      BaiY., Desai H.K., Pelletier S.W. J. Nat. Prod., 1995, 58 (6),929-933. doi: 10.1021/np50120a018
  • 5.     Cai I., Sha M., Guo C. and Pan R. M. Synthesis of Tertiary Amine N-Oxides-A Review. Asian Journal of Chemistry. 2012, 24(9), 3781-3784.
  • 6.     Derzhavna Farmakopeya Ukrayiny / Derzhavne pidpry`yemstvo «Naukovo-ekspertny`j farmakopejny`j centr. – 1-e vy`d. Xarkiv : RIREG, 2001. 556 s.
  • 7.     Parker W. E., Witnauer L. P., Swern D. Peroxides IV. Aliphatic Diperacids J. Amer. Chem. Soc. 1957,79,1929-1931.
  • 8.     Blazheyevskiy M.Ye., Riabko D.N. Application of peroxy acids as disinfectants and sterilization agents (monograph). Ed. M.Ye. Blazheyevskiy – Saarbrüchen (Deutshland) : LAP LAMBERT Academic Publishing, 2014. – 129 p.
  • 9.     Blazheyevskiy M.Ye.Polyarografichne vyznachennya tretynnyh aminiv u vyglyadi N-oksydiv, oderzhanyh za poserednycztvom peroksykyslot/ M.Ye. Blazheyevskiy, M.M. Kucher // Aktualni problemy profilaktychnoyi medycyny. Zbirnyk nauk. Pracz. Vyp. 9. Prysvyachenyj 95-richchyu vid Dnya narodzhennya prof. V.P. Kramarenka. – L`viv. – 2011. – S. 48-52.
  • 10.      Bodendorf K., Binder B. Über die Eigenschaften von Aminoxyden. Ach. Pharm. 1954, 287/59(6), 326-328. doi: 10.1002/ardp.19542870608
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Карлов Владимир Анатольевич

Уважаемые авторы! С большим познавательным интересом для себя ознакомился в вашем докладе с поэтапной методикой подготовки раствора для исследований и последовательном во времени анализе изменений его свойств. Спасибо за доклад. Оценка высокая. Благодарю Вас за внимание и отзыв на мою работу. С наилучшими пожеланиями Владимир Карлов.

Блажеевский Николай Евстафьевич

Уважаемый Владимир Анатольевич! Спасибо большое.

Евтухов Владислав Александрович

Шановні Миколо Євстахійовичу та Олено Мозгова! Дякую Вам за пророблені дослідження та детальне вивчення кінетики і механізму реакції N-окиснення алкалоїдів пероксокислотами. Ваша робота дуже цікава у практичному плані! Бажаю Вам успіхів та творчої наснаги у Ваших подальших дослідженнях! З повагою Євтухов Владислав.

Блажеевский Николай Евстафьевич

Дуже дякую, Владислав Олександровичу.

Подлипная Марина Петровна

Вши исследование очень познавательны. Проделанная работа Вами очень впечатлят. Желаю Вам успехов в дальнейших исследованиях. С уважением Подлипная Марина.

Блажеевский Николай Евстафьевич

Большое Вам спасибо, госпожа Марина Петровна.

Симонян Геворг Саркисович

Уважаемие коллеги химики, дорогие Харковчяне отличная кинетическая работа. Полученные результаты доказывают закон скорости реакцииб порядок и механизм реакции. Оценка высокая. С уважением Геворг Саркисович.

Блажеевский Николай Евстафьевич

Большое спасибо уважаемый Геворг Саркисович за внимательное прочтение представленной нами работы и за такую высокую оценку! С уважением авторы
Комментарии: 8

Карлов Владимир Анатольевич

Уважаемые авторы! С большим познавательным интересом для себя ознакомился в вашем докладе с поэтапной методикой подготовки раствора для исследований и последовательном во времени анализе изменений его свойств. Спасибо за доклад. Оценка высокая. Благодарю Вас за внимание и отзыв на мою работу. С наилучшими пожеланиями Владимир Карлов.

Блажеевский Николай Евстафьевич

Уважаемый Владимир Анатольевич! Спасибо большое.

Евтухов Владислав Александрович

Шановні Миколо Євстахійовичу та Олено Мозгова! Дякую Вам за пророблені дослідження та детальне вивчення кінетики і механізму реакції N-окиснення алкалоїдів пероксокислотами. Ваша робота дуже цікава у практичному плані! Бажаю Вам успіхів та творчої наснаги у Ваших подальших дослідженнях! З повагою Євтухов Владислав.

Блажеевский Николай Евстафьевич

Дуже дякую, Владислав Олександровичу.

Подлипная Марина Петровна

Вши исследование очень познавательны. Проделанная работа Вами очень впечатлят. Желаю Вам успехов в дальнейших исследованиях. С уважением Подлипная Марина.

Блажеевский Николай Евстафьевич

Большое Вам спасибо, госпожа Марина Петровна.

Симонян Геворг Саркисович

Уважаемие коллеги химики, дорогие Харковчяне отличная кинетическая работа. Полученные результаты доказывают закон скорости реакцииб порядок и механизм реакции. Оценка высокая. С уважением Геворг Саркисович.

Блажеевский Николай Евстафьевич

Большое спасибо уважаемый Геворг Саркисович за внимательное прочтение представленной нами работы и за такую высокую оценку! С уважением авторы
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