The tautomeric properties of 6-(2-pyrrolyl)pyridazin-3-one and 6-(2-pyrrolyl)pyridazin-3-thione

The pyrrolyl substituent enhances the electron densities on the pyridazine ring and has the effect of shifting the positions of the tautomeric equilibria for 1c , d 2c , d , which exist predominantly as the pyridazin-3-one and -3-thione forms, towards the hydroxyl (thiol) structures, compared with those of those for the parent unsubstituted systems.


Introduction
Protonation of the potentially tautomeric pyridazine systems 1 2 can lead to three monocationic species: a common N-protonated species 5, which would be formed from both tautomers, and two other monocations 4 and 6, which would be produced specifically from 1 and 2, respectively.Thus, the observed pK a values for the conjugated acids of the tautomeric systems 1 2 would be expected to reflect not only the tautomeric equilibrium constants but also the ratio-averaged values for the ionisation of the appropriate monoprotonated conjugate acid pairs 4 5 and 5 6.A third tautomeric (zwitterionic) form 3, which on protonation would give rise to 4 or 6, is also possible, but is excluded from this study on the basis of AM1 MO calculations 1 for the three tautomeric forms, which indicate that 3 would contribute less than 0.1% to the tautomeric equilibria.Subsequent protonation of the each of the monocationic species, 4, 5 and 6, produces only the single dication 7.Not unexpectedly, evidence has been provided indicating that the parent tautomeric systems 1a,b 2a,b exist predominantly as the oxo/thione forms 2 and cursory studies indicating similar tautomeric equilibrium positions for substituted derivatives have also been reported. 3n the course of our studies on the effect of conjugation of π-electron excessive heteroaromatic systems with π-electron deficient hetero-aromatic systems 4 on their semiconducting and non-linear optical properties. 5we synthesised a series of 6-(2pyrrolyl)pyridazines 6 and, in this communication, we report the effect of the 6-pyrrolyl group upon the equilibrium positions for the tautomeric system 1 2.

Results and Discussion
Electronic spectra of 6-(2-pyrrolyl)pyridazine derivatives.Examination of the electronic spectra (Table 1) for the oxygen derivatives shows a close correlation between spectral data for the fixed oxo-form 8c (R' = Et) and the free base of the tautomeric system 1c 2c, both of which differ significantly from that for the O-alkylated derivative 9c (R' = Et).This evidence indicates strongly that the oxo-form 1c is the predominant tautomeric species.

Scheme 2
The similarity between the electronic spectrum of the 3-ethoxy-2-ethyl-6-(2-pyrrolyl)pyridazinium ion 10 and the spectra of the monoprotonated species derived from 1c 2c and from 8c (R' = Et) suggests that the monoprotonation leads preferentially to a single protonated species analogous to 5c (cf.refs.7, 8), although an equilibrium between 5c and 6c cannot be precluded completely.In contrast, the electronic spectrum of the monoprotonated derivative of the 3-ethoxy system 9c (R' = Et) differs significantly from those for monocations of the tautomeric system 1c 2c and of 8c (R' = Et) and suggests that the protonated species analogous to 6c makes an important contribution to the protonation of 9c (R' = Et).These observations are compatible with AM1 MO calculations, 1 which indicate that the electrondonating mesomeric effect of the pyrrole ring enhances the electron density of the pyridazine ring generally and, in particular, at N(1).Not unexpectedly, the spectra for the diprotonated species derived from 1c 2c, 8c (R' = Et), 9c (R' = Et) and 10 are similar with a bathochromic shift of 5 nm for N-alkylated derivative and hypsochromic shift of 5 nm for O-alkylated derivative, relative to the absorption maximum for the diprotonated species derived from tautomeric system 1c 2c.These opposing effects are compensated in the spectrum of the dication of the O,N-diethylpyridazinium derivative 10.Similarly, with the sulphur analogues, there is a closer correlation between the electronic spectra of the tautomeric system 1d 2d and the thione 8d (R' = Et) than there is with the methylthio derivative 9d (R' = Me) indicating the greater contribution of the thione form 1d to the equilibrium mixture.However, in contrast with the oxygen derivatives, the spectra for the monoprotonated species of the three systems 1d 2d, 8d (R' = Et) and 9d (R' = Me) are virtually identical suggesting a predominant protonation of the free bases at N(2) leading to the same mono-cationic species analogous to 5d.As with the oxygen derivatives, bathochromic and hypsochromic shifts respectively are observed in the spectra of the N-and S-alkylated Page 117 © ARKAT USA, Inc.

Basicity measurements of 6-(2-pyrrolyl)pyridazine derivatives.
Previous examination 2 of the tautomeric parent pyridazin-3-one system 1a 2a has indicated the probable simultaneous protonation at both the N(1) and N(2) positions to give the monocations 5a and 6a, but excludes formation of the cation analogous to 4a.The reported pKa 1 measurements 9,10 for the conjugate acids of fixed forms of the parent compounds (Table 2) indicate that the tautomeric compound exists in the oxo form to the extent of ca.10 4.6 :1, while it can be estimated that the pyridazinthione predominates over the thiol structure by a factor of ca.10 5.2 :1. 3 In each case, there is no evidence for any contribution to the tautomeric equilibrium from zwitterionic structures analogous to 3.
The increased basicities of the tautomeric systems 1c,d 2c,d and their fixed forms 8c,d and 9c,d, relative to the parent systems, are consistent with the enhanced electron densities on the six-membered rings upon the introduction of the pyrrolyl group at the 6-position. 1 Significantly, the effect is greater for the protonation of the exocyclic O of 8c than for the protonation of the annular N atoms of 9c, compared with the corresponding sulphur compounds.As the electron-donating effect of the pyrrole group enhances the electron density on N(1) to a greater extent than on N(2), it is possible that the observed differences reflect small, but significantly different ratios in protonation at N(1) and N(2) for the pyrrolyl derivatives compared with the parent compounds, particularly with the pyridazinone systems.Consequently, in contrast with studies of the tautomeric equilibria of systems having only two basic centres, the procedure for the calculation of the equilibrium constants is refined to allow for the possibility of protonation of the three basic centres of the tautomeric systems 1 2. Irrespective of the ratios of the monoprotonated species of the tautomeric systems, it can be shown that the tautomeric equilibrium constant, K T , is related to the ionisation constants for mono-and diprotonation, K 1 and K 2 , of the tautomers 1 and 2: As the values of ionisation constants for the individual tautomers can not be measured, they are replaced by the observed values for mono-and diprotonation of the fixed forms 8 and 9.This close approximation is made on the assumptions that N-and O(S)-alkylation have minimal and equal effects on the ionisation constants of the tautomers and that the sites of protonation are same for the tautomers and their respective fixed forms.The wealth of data in the literature indicates that the first assumption is acceptable and the electronic spectra of the mono-and diprotonated species of 1c,d and 8c,d and of 2c,d and 9c,d (Table 1) indicate that the second assumption is also acceptable.
Thus, the value of K T can be given as: where K 1 and K 2 are the observed ionisation constants, respectively, for the mono-and diprotonated species of the fixed forms 8 and 9.
Thus: pK T = (pK a 1 8 + pK a 2 8 ) -(pK a 1 9 + pK a 2 9 ) From the data given Table 2, the calculated value of K T for the equilibrium 1c 2c indicates that the oxo form 1c is favoured to the extent of ca.2350:1.Similarly, for the equilibrium 1d 2d, the thione structure 1d predominates by ca.6250:1.The difference between the equilibrium positions for the pyridizin-3-one and -3-thione systems is analogous to that observed between those for pyrid-2-one 9 and pyrid-2-thione x and reflects the difference in electronegativities of the O and S atoms and, hence, basicities of the pyridazinone and -thione structures.Additionally, these results, compared with equilibrium constants estimated for 1a,b 2a,b show significant shifts in the equilibrium positions towards the hydroxyl and thiol structures upon the introduction of the 2-pyrrolyl group at the 6-position.The differences in these shifts, which is more significant for the pyridazinone 1c, can be rationalized in terms of the effect of the electron-excessive pyrrole ring upon the electron density at C(3), which has a greater effect on increasing its basicity of the more electronegative exocyclic O atom of 1c, compared with the S atom of 1d, while effectively reducing the acidity of both 2c and 2d.

Experimental Section
General Procedures.Electronic spectra of the neutral species were measured for ca. 4 x 10 -5 M buffered aqueous solutions at pH 7.0 using a Pye Unicam SP8-UV-VIS spectrometer and the spectra of the mono-and di-cationic species were measured in sulphuric acid at H o values indicated in Table 1.The pKa values for the conjugate acids of the tautomeric pyridazinone and thione and their O(S)-and N-alkylated derivatives (Table 2) were determined spectrophotometrically using buffered aqueous phosphate solutions or aqueous sulphuric acid of known H o using standard procedures. 12e syntheses and analytical characterization of the tautomeric systems, 1c,d 2c,d, their fixed form systems 8c,d (R' = Et) and 9c (R' = Et),d (R' = Me), and 3-ethoxy-2-ethyl-6-(2pyrrolyl)pyridazinium tetra-fluoroborate 10 have been described in an earlier publication. 6The structure of 10 was established unequivocally by single crystal X-ray analysis. 13 Scheme 1

Table 1 .
Electronic spectra of the 6-(2-pyrrolyl)pyridazine derivatives and their mono-and dicationic salts a measured at pH 7.00 b measured at H o -2.10 c measured at H o -1.36 d measured at H o -8.77