The basicities of some pyridazine derivatives

摘要

392 J.C.S. Perkin IIThe Basicities of Some Pyridazine DerivativesBy R. F. Cookson," Nicholas Research Institute, 225 Bath Road, Slough, Bucks.G. W. H. Cheeseman, Chemistry Department, Queen Elizabeth College, Campden Hill, London W8 7AHChanges in the basicity of a number of dimethylaminopyridazines, chloropyridazines, and pyridazones have beencorrelated with substituent constants by use of the Hammett free-energy relationship.LEVISALLES has determined the basicities (expressed aspH at half -neutralisation) of 28 alkylpyridazines andFujisaka et aL2 have reported the pKa's of a variety of3,6-disubstit ut ed p yridazines and several 3-p yridazones.Other pyridazones and pyridazinethiones have beenmeasured by Albert and his co-workers3-5 and byStanovnik and Tisler.6 Although these and otherhave examined a variety of pyridazinederivatives, no attempt has previously been made tocorrelate changes in basicity of pyridazines with sub-stituent constants by use of the Hammett free-energyrelationship (1).PKa = PKO - PO (1)We have determined the basicities of a series ofdimethylaminopyridazines (I), chloropyridazines (111) ,and pyridazones (V).The basicities of the dimethyl-amino-compounds showed a linear correlation with theappropriate meta cr substituent constants and thebasicities of both the chloropyridazines and thepyridazones showed a satisfactory linear correlation withthe corresponding para Q constants. The assumptionthat protonation occurs at the same site within a givenseries of compounds, an essential for meaningful cor-relations, is discussed below.EXPERIMENTALPreparations.-All the known compounds were preparedby published methods (Table 1).3-Amino-Bmethylpyrid-azine, 3-dimethylamino-6-phenylpyridazine, and l-di-methylamino-4-phenylphthalazine were kindly supplied byDr. R. E. Rodway.3-Chloro-6-(p-chloroanilino)pyridazine lo (1 6 g, 0-067 mol) in37 yo alcoholic dimethylamine solution (500 ml) was heatedin an autoclave at 150 "C for 14 h. The solid obtained onevaporation of the mixture was crystallised from alcohol(charcoal) to yield yellow crystals of 3-(p-chZoroaniZino)-6-dimethylaminopyridazine (10 g, 40y0), m.p. 193-195 "C(Found: C, 58.1; H, 5.3; C1, 14.1; N, 22.5. Cl2H1,ClN4requires C, 58.0; H, 5.2; C1, 14.3; N, 22.5).3-BenzyZoxy-6-dinzethyZaminopyridazine.- 3-Chloro-6-di-I J.Levisalles, Bull. Soc. chim. France, 1957, 1009.2 M. Fujisaka, Y. Ueno, H. Shinohara, and E. Imoto, Bull.3 A. Albert and J. N. Phillips, J . Chem. Soc., 1956, 1294.4 A. Albert, R. Goldacre, and J . N. Phillips, J . Chem. SOC.,6 A. Albert and G. B. Barlin, J . Chem. Soc., 1962, 3129.6 B. Stanovnik and M. Tisler, Croat. Chem. Acta, 1964, 36, 81.7 S. F. Mason, J . Chew. Soc., 1959, 1247.8 S. F. Mason, J . Chem. Soc., 1960, 219.9 G. l3. Barlin and W. V. Brown, J . Chem. Soc. ( B ) , 1968,F. Yoneda, Y. Ohtaka, and Y. Nitta, Chem. and Pharm.3- (p-ChZoroaniZino) - 6-dimethyZaminopyridazine .-Chem. SOC. Japan, 1964, 31, 1107.1948, 2240.1435.Bull. Japan, 1963, 11, 740 (Chem.Abs., 1963, 59, 11,4853).methylaminopyridazine l1 (5-2 g, 0.033 mol) was added to asolution of sodium (0.74 g, 0.033 g atom) in benzyl alcohol(50 ml). The stirred mixture was heated a t 180-200 "Cfor 4 h. The excess of benzyl alcohol was distilled off underreduced pressure and the residue treated with water. Theprecipitate was crystallised from light petroleum (b.p.40-60 "C) to give white plates of 3-benzyZoxy-6-dimethyZ-aminopyridazine (6.1 g, SOYo), m.p. 65-67 "C (Found: C,68.2; H, 6.7; N, 18.1. C1,Hl,N30 requires C, 68.1; H,6.6; N, 18.3y0).6-Dimeihylamino-3-pyridazone.- 3-Benzyloxy- 6-di-methylaminopyridazine (22.9 g, 0.1 mol) was heated underreflux in 5~i-hydrochloric acid (150 ml) for 4 h. The cooledmixture was extracted with ether (100 ml) and the aqueouslayer was separated and evaporated to dryness.A solutionof the residual solid in water was basified and the pre-cipitate that formed was collected, washed, and dried.Crystallisation from industrial methylated spirits (1 5 parts)gave pale yellow crystals of 6-dimethylamino-3-pyyridazone(6.0 g, 43y0), m.p. 192-194 "C (Found: C, 51.9; H, 6.5;N, 30.2. C,H,N30 requires C, 51.8; H, 6-5; N, 30.2).Ionisation Constants.-Ionisation constants were deter-mined either spectroscopically or by titration in 50 :/omethylcellosolve. Spectroscopic measurements were per-formed on ca. 1 0 - 4 ~ solutions in 1 cm cells thermostatted at25 "C. A Unicam SP 800 spectrophotometer was used toselect the analytical wavelength and to confirm theexistence of an isosbestic point.Measurements of opticaldensity were made on a Unicam SP 500 spectrometer.The spectroscopic pK, values were calculated by use ofHa l2 for pyridazones whose pK, was less than -0.7 andH , l3 or pH for the 3,6-disubstituted pyridazines and thestronger bases in the pyridazone series. The method ofdetermination was based on that described by Albert andSerjeant l4 except that the optical density of the protonatedspecies (Da) was calculated by the method of Maroni andCalmon,16 thus avoiding the use of exceptionally strong acidwith its concomitant medium effects.laThe titrations in 50 methylcellosolve were performed ina thermostatted bath at 25 "C on ca. 0 . 0 1 ~ solutions of thebases, with standardised ca.N-hydrochloric acid as titrant.Changes in pH were measured with a glass and a calomelelectrode with a Cambridge Bench type pH meter, whichwas calibrated with buffers at pH 4.0 and 9-18 beforetitration. The method of calculation used was thatdescribed by Albert and Serjeant.142131.Chem., 1964, 42, 1957.1963, 85, 878.and Bases,' Methuen, London, 1962.519.90, 6453, and references therein.l1 I. Crossland and H. Kofod, Acta Chem. Scand., 1967, 21,l2 K. Yates, J. B. Stevens, and A. R. Katritzky, Canad. J .l3 M. J . Jorgenson and D. R. Hartter, J . Amer. Chem. Soc.,l4 A. Albert and E. P. Sarjeant, ' Ionisation Constants of Acidsl5 P. Maroni and J . P. Calmon, Bull. Soc. chim. France, 1964,l6 C. C. Greig and C. D. Johnson, J .Amer. Chem. SOC., 19681972TABLE 1393pK, 0 Spread3-Amino-6-methyl- 6-67 1 0.05pyridazine 5.26 0.03Dimethylaminopyridazines (I)R = C1 2.82 0.02R = Ph 4.49 0.02R = H 4.59 0.02R = OCH,Ph 5.12 0.03R = NH*C,H,*Cl-P 6.01 0.03R = NMe, 6.71 h 0.014-phen ylphthalazineChloropyridazines (111)l-Dimethylamino- 4-73 0-02R = C1 -1.50 0.03R = Me 0.89 0.01R = NHPh 2.63 0-02R = Ph -0.06 0.02R = NH*C6H4.C1-P 2.10 0.03Pyridazones (V)R = C02H -2.26 0.06R = C1 -2.01 0.05R = Ph -1.99 0.03R = H -1.40' 0.1R = OH -0.97 1 0.01R = Me -0.81 0.05R = NH*C6H4*C1-~ -0.24 0.05R = NHPh -0.03 0.01R = NMe, 1-36 0.06Methodofdetermin-ationeCeeeeeeekkknn444444kkkMethodofprepar-ationdf! This paperThis paperiiImdP0YSmY2400dThis papera Values obtained a t 25 "C as the average of two separatedeterminations.Cf. 6.32 f 0.05 at 20 "C; ref. 8. Titra-tion in water. d W. G. Overend and L. F. Wiggins, J . Chem.SOC., 1947, 239. 0 Titration in 60 methylcellosolve. f Ref.11. 0 W. N. Haworth and L. F. Wiggins, B.P. 656,228(Ctem. Abs., 1952, 46, 75944. h For the purposes of corre-lation, log 2 must be subtracted from this value to allow forthe symmetry of the molecule. 1 J. Druey, Kd. Meier, andK. Eichenberger, Helv. Chim. Acta, 1054, 37, 121. J H. M.Holava, jun., and R. A. Partyka, J. Medicin. Chem., 1969, 12,555. k Spectroscopic determination in dilute sulphuric aicdby use of H,.P. Coad, R. A. Coad, S. Clough, J. Hyepock,R. Salisbury, and C . Wilkins, J . Org. Chem., 1963, 28, 218.m S. Gabriel and J . Colman, Ber., 1899, 32, 395. fi Spectro-scopic determination in water by use of pH values. 0 Ref. 10.p M. Kumagai, J. Chem. SOC. Japan, 1961, 82, 227 (Chem.Abs., 1962, 56, 10,139). g Spectroscopic determination indilute sulphuric acid by use of HA. R. F. Homer, H.Gregory, W. G. Overend, and L. F. Wiggins, J . Chem. SOC.,1948, 2195. * S. Du Breuil, J . Org. Chem., 1961, 26, 3382.1 Cf. -1.8 f 0.3 for pyridazone and -2.2 f 0.4 for maleichydrazide by use of H , a t 20 OC; ref. 3. R. H. Mizzoni andP. E. Spoerri, J. Amer. Chem. SOC., 1951, 73, 1873.The values given in the Tables are the average of twodeterminations in each of which the spread did not exceed50-06 pH units.DISCUSSIONWe believe that for the dimethylaminopyridazines,protonation occurs meta to the changing substituent togive the mesomeric cation (IIa IIb).It is reason-able to assume that protonation of the chloropyridazineswill occur ortho to the changing substituent, on the ringnitrogen remote from the base-weakening chloro-substituent, to give the cation (IV). The site of proton-ation of the pyridazones (V) appears to be on the exo-cyclic oxygen atom to give the mesomeric cation(VIa VIb) since on protonation a hypsochromicchange in U.V. absorption occurred in all the casesstudied .H+R R RRamp;R *00RYIa) (PI b )I bsol;00An alternative possibility for the pyridazones bearinga nitrogen-containing substituent (VII) is that proton-ation occurs a t a ring nitrogen to give the mesomericamidinium system (VIIIa VIIIb). We considerthis to be unlikely since we would then have expectedprotonation to be accompanied by a bathochromic shiftin U.V.absorption.The pK,'s of the three main sets of pyridazines (I),(111), and (V) were correlated with appropriate Hammettsubstituent constants by least-mean-squares ana1yses.l'The equations obtained are given in Table 2 togetherwith the discrepancies between the observed and thecalculated PKa'S. Of the three equations, agreement isworst for the dimethylamino-compounds. The pre-sumably large contribution to the cation of the canonicalform (IIb) could explain the poor correlation betweenpKa and ameta for these compounds.The equation for the dimethylamino-compounds couldl7 H.H. Jaff6, Chem. Rev., 1953, 53, 191394 J.C.S. Perkin I1be improved by neglecting the 6-benzyloxy-compound.The substituent constant used for the benzyl ether wasthat given la for a variety of meta-alkoxy-groups, as nopublished value is available for the meta-benzoyloxy-group. The equation for the 3-pyridazones takes noaccount of the basicities of the 6-phenyl and 6-hydroxy-compounds. The electronic effect of a para-phenylTABLE 2Theoretical ObservedR 0" PKa PK, ApKaDimethylaminopyridazines (I)pK, = 5.14 - 6.14 0,; Y = 0.947, (p 0.005), 6 points.c1 0-37 2.87 2-82 +0*05Ph 0.06 4.77 4.49 +0*28H 0.0 5.14 4.59 +0.55NMe, -0.21 6.43 d 6.71 +0-02Chloropyridazines (111)pK, = -0.21 - 6.79 up; Y = 0.998, (p 0-OOl), 5 points.OCH,Ph 0.1 b 4.53 5.12 -0.59NH.C6H4.C1(P) - 0.09 5.69 6.01 -0.32(+ 0.3)c1 0.23 -1.77 -1.50 1-0'03Ph -0*01 -0.14 -0.06 -0.08(+ 0.3)Me -0.17 0.94 0.89 +0*05NH.C6H4*Cl(@) - 0.36 ' 2.23 2-10 +0*13Pyridazones (V)pK, = - 1.22 - 2.92 up; r = 0.991, (p 0 - O O l ) , 7 points.CO,H 0.45 -2.53 -2.26 -0.28c1 0.23 -1.89 -2.01 +0*12(Ph -0.01 -1.19 -1.99 +0*80)H 0.0 - 1.22 -1.40 +On18(OH - 0.61 f 0.56 -0.97 +1*53)Me -0.17 -0.72 -0.81 +0*09NH.C,H,*Cl(P) -0.36 -0.17 -0.24 +0.07NHPh -0.40 -0.05 -0.03 -0.02NMe, -0.83 +1.20 +1.36 -0.16NHPh -0.40 2.51 2.63 -0.12(1 From D.H. McDaniel and H. C. Brown, J . Org. Chem., 1958,23, 420, unless otherwise indicated.Values for 3-dimethyl-amino-compounds are urnamp;" and for 3-chloropyridazines and3-pyridazones, upaco is listed. * Estimated from values foralkoxy-groups; ref. 22. Calculated by the method of M.Charton, J . Org. Chem., 1963, 28, 3121. 0.3 pK, unit shouldbe added to this value because of the symmetry in the mole-cule. Not included in correlation. f Ref. 21group is notoriously variable l9 and so it is not surprisingthat the phenylpyridazone deviates from the straightline. 6-Hydroxy-3-pyridazone (maleic hydrazide) isknown to undergo the tautomerism ( 1 X ) m (X) inwhich the hydroxy-form (IX) is preferred.2o From theregression line of 0 on pK,, a B value of -0.09 seemsappropriate for the 6-hydroxy-substituent.This valueis intermediate between the value 21 for a true hydroxy-group (ap = -0.61) and that 22 for a carbonyl group inthis environment (cP = 0.35). This presumably indi-cates that a significant amount of the amide tautomer(X) is present in dilute sulphuric acid. It may be thatthe position of equilibrium of this tautomerism isl8 D. H. McDaniel and H. C. Brown, J . Org. Chem., 1958, 23,E. Berliner and L. H. Liu, J . Amer. Chem. Soc., 1953, 75,*O A. R. Katritzky and J. M. Lagowski, Adv. HeterocyclicA. Gordon, A. R. Katritzky, and S. K. Roy, J . Chem. SOC.420.2417.Chem., 1963, 1, 366.( B ) , 1968, 656.affected by changing acidity and this could account forthe large discrepancy between our value for the basicityof maleic hydrazide and that of Albert and Phillip~.~The earlier workers indicated that maleic hydrazide wasa weaker base than the parent pyridazone, whereas ourwork shows that the reverse is true.Our measurementswere made over a narrow range of acidities, whereasAlbert and Phillips must have used much more concen-trated acid to determine D, (the optical density of theprotonated species). This may explain the markeddifference in the spreads reported here and earlier.The use of HA, where applicable, for the study ofprotonation of pyridazones seems more logical than thepreviously favoured H , as pyridazones may be regardedas cyclic amides and protonation occurs on the oxygenatom.23 I t is noteworthy that 2-pyridones have beenshown to follow HA rather than Ho on pr~tonation.~~Unfortunately our work does not permit us to decidewhether 3-pyridazones do follow HA as our determin-ations of D, assume this to be so.Recalculation of ourresults with Ho rather than HA gave values with muchlarger spreads.The three types of compound studied provide examplesof protonation of pyridazines ortho, meta, and para to aseries of substituents. Thus in the case of the chloro-pyridazines, where the variation of substituent has thegreatest effect (g = 6-79), protonation occurs ortho to thesubstituent. In the dimethylaminopyridazines the siteof protonation is meta to the changing substituent andin the pyridazones protonation occurs on exocyclicoxygen and para to the substituent. As expected, thebasicity of the pyridazones varies least with the changingsubstituent (p = 2.92).It is remarkable that, thebasicities of the chloropyridazines correlate so well withapa,a as the site of protonation is ortho to the changingsubstituent and in general o , , . ~ ~ ~ # B ~ ~ ~ ~ . The cor-relation could not be performed with as severalrequired constants are not available.There is a significant difference between the pK,reported by Mason for 3-amino-6-methylpyridazine,5-32 a t 20 "C, and our result, 5.67 at 25 "C (ca. 5.75 at20 "C) .26 Examination of Levisalles' results,l correctedto 20 "C by Perrin's method, indicates that for 12different pyridazines the introduction of a methyl groupin the 3- or 6-position results in a fairly constant increaseof basicity of 0.64 amp; 0.16 pH units. Comparison of ourresult with that reported for 3-aminopyridazine, 5.19at 20 "C, indicates an increase in basicity due to themethyl group of 0.56 pH unit which is well within therange expected.We thank Dr R. S. Satchel1 for discussion, and theReferees for helpful comments.1/1251 Received, 22nd JuZy. 197112, J . Clark and D. D. Perrin, Quart. Rev., 1964, 18, 296.23 S. F. Mason, J . Chem. Soc., 1959, 1253.24 P. J. Brignell, A. R. Katritzky, and H. 0. Tarhan, J . Chem.SOC. (B), 1968, 1477.M. Charton, J . Amer. Chem. Soc., 1969, 91, 6649.D. D. Perrin, Austral. J . Chem., 1964, 17, 484