Tetrazolo[l,5-b]pyridazines exist in solution exclusively in the
tetrazolo form. In solutions of strong acids an equilibrium of both
forms, azido and tetrazolo, is established. The equilibrium constants
in concentrated sulfuric acid or in trifluoromethanesulfonic acid
were determined

B. Stanovnik

M. Tišler

V. Pirc

English

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CROATICA CHEMICA ACTA CCACAA 45 (4) 547-550 (1973) CCA-798 YU ISSN 0011-1643 Pyridazines. LXII. Tetrazolo-Azido Equilibria of Tetrazolo[l,5-b ]pyridazines V. Pirc, B. Stanovnik, and M. Tisler 547.852.9 Note Department of Chemistry, University of Ljubljana, 61001 Ljubljana, Slovenia, Yugoslavia Received September 10, 1973 Tetrazolo[l,5-b]pyridazines exist in solution exclusively in the tetrazolo form. In solutions of strong acids an equilibrium of both forms, azido and tetrazolo, is established. The equilibrium constants in concentrated sulfuric acid or in trifluoromethanesulfonic acid were determined. Azido-tetrazolo isomerization of tetrazoloazines has been subject of many investigations.1 The general conclusions that can be drawn from studies in the tetrazolo[l,5-b]pyridazine series are as follows. Tetrazolo[l,5-b]pyridazines exist in solid state or in solution exclusively in the tetrazolo form. However, it was reported that an examination of the IR spectrum of 6-pyrrolidinotetra-zolo[l,5-b]pyridaz~ne in the presence of trifluoroacetic acid revealed the pre-sence of some azido form. 2 Destabilization of the tetrazolo form is further observed in the case of 6-azidotetrazolo[l,5-b ]pyridazines or other 6-azidoazolopyridazines3- 8 and 7--azidoazinopyridazines.9·10 Similarly, N-oxidation of tetrazolo[l ,5-b]pyridazine generates the azido form to give 3-azidopyridazine 1-oxide.4•9 Moreover, for some methyl substituted 6-azidotetrazolo[l ,5-b ]pyridazines and azidopyridotetra-zo1o[l,5-b ]pyridazines equilibria of the isomeric forms were established.3•11 On the ground of these results one can anticipate that other reactions which would involve N5 of the tetrazolo[l,5-b]pyridazine ring should follow the same pattern and give the corresponding azidopyridazines. We have therefore studied the behaviour of several tetrazolo[l,5-b]pyridazines in con-centrated sulfuric and/or trifluoromethanesulfonic acid in order to determine the equilibrium between the tetrazolo and azido form. Indeed, it was possible on the ground of NMR measurements to determine the rate constants and equilibrium constants for several compounds. The results are presented in Table I. For example, the characteristic pattern of signals for tetrazolo[l,5-blpyri-dazine in CDC18 is H6 (i: = 1.05) < H8 (i: = 1.25) < H 7 (i: = 2.18). In trifluoro-methanesulfonic acid this order is changed to H 6 < H 0 < H4 (Hr; corresponds to H 6 of tetrazolo[l,5-b]pyridazine, H, to H 7 and H, to H 8 ) which is consistent w,ith 3-azidopyridazine in its protonated form. Similar behaviour was observed also with other compounds under investigation. The determined enthalpy changes, D.H, for these isomerizations in acid solution are somewhat lower as observed for 7-(or 8)-methyl-6-azidotetrazolo--[1,5-b]pyridazine3 in dimethylsulfoxide. With increased temperature the pro-TABLE I Azido-tetrazolo isomerization of tetrazolo [1,5-b]pyridazines cc=s 1 N2 7 II 6 4 N3 5 Compound Acid 304K Tetrazolo[l,5-b]pyridazine B 0.86 7-Methyltetrazolo [1,5-b ]-pyridazine B 0.75 I 6-Chloro-7-methyltetrazolo-[1,5-b ]pyridazine A 0.056 8-Methyltetrazolo[l,5-b]-pyridazine B 3.9b) 6-Chloro-3-methyltetrazolo-[1,5-b ]pyridazine A 0.0175°) 7,8-Dimethyltetrazolo[l,5-b]-pyridazine A 1.36 6-Chloro-7,8-dimethy1 tetrazolo--[1,5-b ]pyridazine B 0.13 A = H2SO,, B = trifluoromethanesulfonic acid a protonated azidopyridazine/tetrazolo[l,5-b)pyridazine b at 298.5 K c at 301 K d at 383 K I I +H+ ~ -H+ 323 K 1.3 1.2 0.08 5.4 - 1.6 0.21 I 4 50. 3...,.N3 6 12 ,.....,.N H1 K •> T 343K 363 K J /J. H/kcal mo1-1 J Ea/kcal moP 1.77 2.1 -3.4 I 19. 1.6 2.2 -4.4 I 18.7 0.13 0.17 -4.4 19.4 6.5 8.7 -2c7 13.4 I 0.099 0.17 -4.9 21.7 0.23d) 1.9 2.25 -2.2 19.0 0.34 0.49 I -5.1 17.5 <:.11 ~ co ~ '1J ...... !:cl () t>:I .., :i:. r:-' PYRIDAZINES. LXII. 549 tonated azidopyridazines become the predominant isomer, except for all substituted 6-chlorotetrazolo[l ,5-b]py ridazines where the tetrazole form still prevails. These e~periments show that in a solution of very strong acid tetra-zolo[l,5-b]pyridazines are also capable of azido-tetrazolo isomerization. In the case of 6-azidotetrazolo[l ,5-b]pyridazine and its methyl analogs, 6-acetony lthio-, 6-methoxy-, 6-amino- or 6-hidrazinotetrazolo[l,5-b ]pyridazine no ring opening of the fused tetrazole ring could be observed when these compounds were dissolved in strong acid at room temperature. At elevated temperatures, however, chemical reactions, ·other than protonation occured. EXPERIMENTAL Melting points were determined on a Kofler micro hot stage. NMR measurements made on a JEOL JNM-C-60HL spectrometer (TMS as internal standaTd). The synthesis of the following compounds was reported previously: tetrazolo [1,5-b]pyridazine,'2 (NMR spectrum: DMSO-d6 : -r: = 1.05 (dd, H6), 2.18 (dd, H7) 1.25 (dd, Hs) J 6 ,7 = 4.5, J 7,s = 9.5, J 6,s = 1.5 Hz), 6-chloro-8-methyltetrazolo[l,5-b]-pyrida-zine13 (NMR spectrum: CDCla : -r: = 2.75 (q, H 1). 7.20 (d, 8-CHa), h .s- Me = 1.5 Hz), 8--methyl tetrazolo[l,5-b ]pyridazine14 and 6-chloro-7-methyltetrazolo{l,5-b ]pyridazine13 (NMR spectrum: CDCla: -r: = 1.80 (q, Hs), 7.35 (d, 7-CHa), J s,7-Me = 1.5 Hz. 6-Chloro-7 ,8-dimethy ltetrazo lo[l ,5-b ]pyridazi ne To an ice cooled suspension of 6-chloro-4,5-dimethyl-3-hydrazinopyridazine15 (0.86 g) (prepared from the 3,6-dich1oro analog 16) in water (10 ml) and hydrochloric acid (2 ml, cone.) a solution of sodium nitrite in water (0.4 g in 2 ml) was added. After 30 min the product was filtered off and crystallized from ethanol (0.72 g, 760/o), m. p . 77-78 °c. NMR spectrum: DMSO-dG: -r: = 7.25 (d, 8-CH3), 7.50 (d, 7-CHa), J 1 - Me, s - Mc = 1.0 Hz. Anal. CGH6ClN5 (183.60) calc'd.: C 39.26; H 3.29 ; N 38.15°/~ found: C 39.09; H 3.44 ; N 38.330/o 7,8-Dimethyltetrazolo[l,5-b]pyridazine was prepared in a similar manner from 4,5-dimethyl-3-hydrazinopyridazine hy-drochloride in 900/o yield, m. p. 130-131 °c. NMR spectrum : CDC13 : -r: = 1.70 (s, HG), 7.29 (d, 8-CH3), 7.51 (d, 7-CHa), J 7 _Mc. s -Mc = 0.9 Hz. Anal. C0H7N5 (149.16) calc'd.: C 48.31; H 4.73; N 46.960/o found: C 48.31: H 4.82; N 47.310/o 7-M ethyltetrazolo[l ,5-b]pyridazine To a solution of 6-chloro-7-methyltetrazolo[l,5-b]pyridaziine13 (1.06 g) in me-thanol (30 ml) palladized charcoal (0.3 g of 5°/o) and ammonia (1 ml of 250/o) were added and the reaction mixture was stirred in an atmosphere of hydrogen. After consumption of the necessary amount of hydrogen, the mixture was extracted with chloroform. The extracts were m ixed with fivefold amount of ice cold petroleum ether and the separated product was collected and crystallized from a mixture of chloroform and petroleum ether. Yield 0.7 g (830/o), m. p. 132 °c. NMR spectrum: CDCl3: -r: = 1.50 (d, HG), 1.90 (dq, Hs), 7.37 (d, 7-CHs), Jo,s = 1.8, J s.1 - Mc = 1.2 Hz. Anal. C5H5N5 (135.13) calc'd.: C 44.44; H 3.73; N 51.830/o found: C 44.24; H 3.76; N 51.280/o Kinetic measurements A sample of about 30 mg of the corresponding compound was dissolved in 0.5 ml of cone. sulfuric or trifluoromethanesulfonic acid and the solution was left at room temperature for several days to allow equilibration. The r a te of equilibrium for-mation and the equilibrium constants were measured at 304, 323, 343, and 363 K 550 V. PIRC ET AL. (in some cases also at 298.5, 301, and 383 K). The equilibrium constants as well as values of l'l H and E" are presented in Table I and were calculated as described previously.3 Temperature measurements are accurate to ± 0.5 K at the sample and the measurements of l'lv are accurate to ± 0.5 Hz. We assign a maximum error of ± 0.6 kcal/mol to D..H and E" values. REFERENCES 1. M. Tis 1 er, Synthesis (1973) 123. 2. N. B. Sm i r nova, I. J. Posto vs k ii, N. N. Veres ca gin a , I. B. Lu n-d in a, and I. I. Mud rec ova, Khim. Geterotsikl. Soedin. (1968) 167. 3. B. St an o v n i k and M. Ti s 1 er, Tetrahedron 25 (1969) 3313. 4. T. It a i and S. Kamiya, Chem. Pharm. Bull. 11 (1963) 348 ; Chem. Abstr. 59 (1963) 8734. 5. T. S a s a k i, K. Ka n em at s u , and M. Mura ta, J. Org. Chem. 36 (1971) 446. 6. W. D . Guither, D. G. Clark, and R. N. Castle, J. Heterocycl. Chem. 2 (1965) 67. 7. I. B. Lundin a, J. N. Shein k er, and I. J. Posto vs k ii, I zv. Akad. Nauk SSSR Ser. Khim. (1967) 66. 8. S. Po 1 an c, B. Ver c e k, B. St a no v n i k, and M. Tis 1 er, Tetrahedron Lett. (1973) 1677. 9. B. S ta no v n i k, M. Ti s 1 er, M. C e g 1 a r, and V. B ah, J. Org. Chem. 35 (1970) 1138. 10. B. S tan o v n i k and M. Tis 1 er, Synthesis (1970) 180. 11. B. St an o v n i k, M. T iS 1 er, and B. Stefano v, J. Org. Chem. 36 (1971) 3812. 12. N. Tak ah a ya sh i, J . Pharm. Soc. Jap. 76 (1965) 765; Chem. Abstr. 51 (1957) 1192. 13. S. Linh o 1 t er and R. R o sen o er n , Acta Chem. Scand. 16 (1962) 2389. 14. V. Pirc, B. St an o v n i k , M. Tis 1 er, J. Marse 1, and W. W. Pa u d-1 er, J. Heterocycl. Chem. 7 (1970) 639. 15. M. Jape 1 j , B. St an o v n i k, and M. Tis 1 er, Monatsh. Chem. 100 (1969) 671. 16. US Pat. 2.858.311 ; Chem. Abst r. 53 (1959) 6270. IZVLECEK Piridazini. LXII. Tetrazolo-azido ravnotezja pri tetrazolo[l,5-b]piridazinih V. Pi rc, B. Stanovnik in M. Tisler Tetrazolo[l,5-b]piridazini obstajajo v raztopini izkljucno v tetrazolski obliki. V raztopinah jakih kislin pa se vzpostavi ravnotezje med obema oblikama, azidno in tetrazolsko. Dolocili smo ravnotezne konstante v koncentrirani zvepleni kislini in v trifluormetansulfonski kislini. ODDELEK ZA KEMIJO FAKULTETA ZA NARAVOSLOVJE IN TEHNOLOGIJO Sprejeto 10. septembra 1973. 61001 LJUBLJANA 

Pyridazines. LXII. Tetrazolo-Azido Equilibria of Tetrazolo[1,5-b ]pyridazines

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