Effects of salts on the stability of the cationic radical of phenothiazine derivatives

0039-9140/91 33.00 + 0.00

Tabto, Vol. 38, No. 11, pp. 13094313, 1991 Printed in Great Britain. All rights reserved

Copyright 0 1991 Pergmlon Fkss plc

EFFECTS OF SALTS ON THE STABILITY OF THE CATIONIC RADICAL OF PHENOTHIAZINE DERIVATIVES I. JEL~EK, I. Ni%mov,4 and P. RYCHLOVSK+ Department of Analytical Chemistry, Charles University, Albertov 2030,128 40 Prague 2, Czechoslovakia (Received 11 February 1991. Accepted 6 March 1991) Sammar-Effects of cations and anions of various salts on the stability of the diethazine cation radical were studied in various mineral acids. It was found that stability is enhanced in the presence of salts that contain the same anion as that contained in the cation radical salt. Other anions decrease the stability. The influence of salt cations is negligible.

Many derivatives of phenothiazine (I) are used in analytical chemistry, especially those substituted in positions 3 and 7 (dyes of the methylene blue group) as well as those substituted in position 10 alone and positions 2 and 10. The latter substances are also utilized in medicine as antipsychotic pharmaceuticals.

Analytical use of phenothiazine derivatives with substituents in position 10 (A) is usually based on their reversible oxidation to intensely coloured cationic radicals (A’+), which makes it possible to employ them as redox indicators or spectrophotometric reagents.’ However, this application is complicated by limited stability of these cationic radicals, the rate of their degradation being strongly dependent on the composition of the reaction mixture. The stability of the cationic radical is also considered as an important factor in pharmacological use, as these radicals are often assumed to be the actual pharmacologically active component. It follows from published studies’-’ that cationic radicals of most phenothiazine derivatives decompose to yield an approximately equimolar mixture of the original derivative (A) and its sulphoxide (AO), according to the overall equation

It has been demonstrated that the stability, or the rate of degradation, of cationic radicals strongly depends on the following factors: (a) type and position of substituents on the phenothiazine skeleton.2-5 (b) acidity of the reaction medium3-the stability of the cationic radical A’+ increases with increasing acidity, given by the H30+ ion activity rather than its concentration (as correlation with the Hammett acidity function); i.e., the H30+ ion exerts a thermodynamic stabilizing effect rather than a kinetic effect. (c) in media with low acidities (pH 2-7) the rate of cationic radical decomposition depends on the type and concentration of buffer usedm5-’ From the kinetics of decomposition of cationic radicals which are second-order with respect to A’+, the following reaction mechanisms have been proposed: _ A’++B-7 _KI [AB]’ [AB]’ + A *+&[AB]+ k-z

+ A

[AB]+ + H20- k3 AO+HB+H+ (For anions B- that do not contain hydrogen, e.g., acetate, CH3COO-) A’+ + HB- &[AB]‘-

acidic

+ H+

[AB]‘- + A *+&[AB]*+A k-z

2A’++H20-+A+AO+2H+ However, the decomposition is more complex in some cases and products have not yet been unambiguously identified.

[AB]’ + H,&AO

+ HB- + H+

(For anions HB- that contain acidic hydrogen, e.g., dihydrogenphosphate, H2PO:-)

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I. JEL~NEK et al.

Both reactions are specifically base catalysed, i.e., the catalytic effect of a base depends on the

chemical structure of the base. The above kinetic studies employed buffered media (acetate, phosphate, citrate, glycine, etc.) and a constant ionic strength obtained with sodium chloride; however, the effect of sodium chloride on the reaction has not been studied. The effect of neutral salts on rate of decomposition of the cationic radical, A*+, is also very important from the point of view of practical application (especially in view of the observed specific catalysis of the decomposition) and thus this paper deals with this problem. Diethazine (lo-diethylaminoethylphenothiazine) was selected for the study; this substance is also used in clinical practice as an antiparkinson drug.

EXPERIMENTAL

Chemicals

Diethazine hydrochloride, used for the preparation of the diethazine radical cation, was obtained from I&ivae (Modiany, Czechoslovakia) and its purity was checked by TLC with a methanol-chloroform (1: 1) mobile phase. The diperchlorate salt of the diethazine cationic radical, DE’+ClO;- HClO., (M, = 498.4), was prepared by oxidation of diethazine hydrochloride with hydrogen peroxide in perchloric acid, according to Levy et aL3 A stock solution of 1 x lo-*M DE’+ClO;-HClO, was prepared by dissolving this substance in concentrated perchloric acid. This solution, stored in the dark, is stable for several weeks. The dichloride salt of the diethazine cationic radical, DE’+Cl’-HCl (i&f,= 370.4), was prepared by electrochemical oxidation of 1 x 10e3M diethazine chloride in concentrated hydrochloric acid. The oxidation was performed coulometrically at a potential of 750 mV vs. SCE, the potential was found from an experimental voltammetric curve and the end of the generation was determined from the measured electric charge. Ultra-violet absorption spectra indicated that the oxidation of DE to DE’+ was quantitative. Bands corresponding to DE hydrochloride and to the higher oxidation state, i.e., the DE sulphoxide, were absent. Salt solutions were prepared by dissolving these salts, of analytical-grade purity, in distilled water.

Apparatus

Spectrophotometric measurements were performed with a PU 8800 instrument (Pye Unicam, Cambridge, England) in l.OO-cm cuvettes. Solutions were kept at 25 + 0.5”. Procedure

Absorbance was recorded against time at a wavelength of 5 12 nm corresponding to the absorption maximum of the radical cation, over an interval of 60 min starting from the moment the compounds were mixed. Degradation halftimes were found from these curves and these variables were linearized (assuming a secondorder reaction, the equation ll/c = k,t + lr/co is valid). Values of the rate constant, k,, were obtained from the slope of a plot of l/c vs. t. The cs12value for DE’+, which was used to calculate concentration from the measured absorbance, was found from the absorbance of 2 x 10T4M DE’+ in concentrated (1 l.OM) perchloric acid where DE’+ is stable. RESULTS

AND DISCUSSION

Initial time dependent changes of the diethazine cationic radical, DE’+ were obtained from its W and visible absorption spectra. It can be seen in Fig. 1 that the absorption maxima of the diethazine cationic radicals (A = 212, 265 and 272 nm) decrease with time while maxima of diethazine’ (A = 205, 250 and 299 nm) and its sulphoxide9 (2 = 2332.5, 268 and 292.5 nm) increase indicating that the latter substances are the final products of DE*+, decomposition. The effect of the non-oxidized diethazine hydrochloride on the rate constant of the DE’+ decomposition was studied first. As assumed, an addition of diethazine hydrochloride leads to a decrease in the k, value for decomposition of the diethazine cationic radical (measurements were performed in perchloric acid medium). Dependence of the rate constant on the diethazine hydrochloride concentration is linear. Measurements were performed up to a diethazine hydrochloride concentration of 1 x 10-‘&f; at higher concentrations the solution becomes turbid. In the study of the influence of ions on the rate of DE’+ decomposition, phosphoric acid was first selected as the reaction medium, as it is often used in spectrophotometric determinations of metals with phenothiazine derivatives and its effect on the stability of the cationic radicals of phenothiazine derivatives has

1311

Stability of the cationic radical of phenothiazine derivatives

. ./ ./

3

/ ;**,*

*e’@

,&P

*

#* /a )-O-O

A

-*-o-M. 1-

0.2

0.4

1

C0nc.M

Fig. 2. Dependence on salt concentration of the rate of decay of the perchlorate salt of the diethazine radical cation. Concentration of DE’+ClOr . HClO, = 2 x lo-‘M; medium, 3M H,PO, I

200

1

260

300 A, nm

Fig. 1. Time changes in the absorption spectrum of the diethazine radical cation in the UV region. Concentration of DE’+ClO;-HClO, = 5 x lO-JM. Concentration of HClO, = 0.23M. Curves 1 to 4 were obtained at times of 1, 30, 60 and 180 min. respectively after mixing.

already been studied. lo In order to interpret the results obtained, the behaviour of DE’+ perchlorate in perchloric acid and DE’+ chloride in hydrochloric acid had to be studied. Stability of the per-chlorate of the diethazine radical cation Phosphoric acid media. The effect of the concentration of the sodium salts of ClO;, Cl-, SO:- and NO; on the rate constant of DE’+ degradation was studied. The DE’+ species was prepared as the perchlorate salt and dissolved in 3M phosphoric acid. It can be seen from Fig. 2 that the presence of the perchlorate anion increases the DE’+ stability; the rate constant is seen to decrease. On the other hand, Cl- and Sti4- decrease the DE’+ stability. The degradation of DE’+ is greatly enhanced in the presence of nitrate; the effect of nitrate is apparently described by a more complex mechanism, as demonstrated by the time dependences of DE’+ degradation that do not correspond to a second-order reaction. The effect of the salt cations on the resultant k, value was also studied [LiCl, NaCl, KC1 and NH,Cl, curves 2(a)-(d)]. The cation exerts only a small influence on the resultant rate constant. The ratio increases in the order, TAL M/I I-”

Curve 1 Curve 2(a) (b) (c) (d) Curve 3

NaClO, LiCi NaCl KC1 NH&l NazSO,

Li+ < Na+ < K+ < NH:, i.e., with decreasing value of the mean activity coefficient for these salts (y f values for OSM solutions of these salts are 0.73, 0.68, 0.65 and 0.62, respectively). Moreover, hydrolysis of ammonium chloride probably also plays a role. It follows from the above results that only sodium perchlorate, i.e., a salt with the same anion as that of the diethazine cation radical, causes a decrease in the rate of the cation radical degradation. Therefore, a further study of the behaviour of the DE’+ perchlorate was conducted in a medium containing only the ClO; anions. Perchloric acid media. The effect of perchloric acid concentration, i.e., the influence of H+ and ClO; ions, on the rate constant of the DE’+ perchlorate decomposition was studied first, from a maximal (1 l.OM) to a minimal (0.23M) perchloric acid concentration, obtained by dilution of the stock solution. The dependence of the rate constant on the perchloric acid concentration is given in Fig. 3 (values are averages of five experimental values). It can be seen that the rate constant decreases with increasing perchloric acid concentration. There is a variance on the dependence around 4.OM perchloric acid. The decomposition of the

I. JEL~NEK et al.

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Fig. 3. Dependence of the HClO, concentration of the rate of decay of the perchlorate salt of the diethazine radical cation. Concentration of DE’+Cl’-HCIOd = 2 x lo-‘A4.

diethazine radical cation probably obeys a more complex mechanism at perchloric acid concentrations higher than 4.Oil4, as the U/c US. t dependences do not correspond to 2nd order kinetics. The DE’+ perchlorate is stable at a perchloric acid concentration of 6M or higher. To verify the hypothesis that the perchlorate anion decelerates the decomposition of the perchlorate of the diethazine cationic radical, the effect of sodium perchlorate was studied over the concentration range 0.05-l.OM. The dependence of the rate constant on the sodium perchlorate concentration is given in Fig. 4, curve 1. The reaction rate is constant up to a

IJ

0

1

I

0.4

1

0.0

Corm, M Fig. 4. Dependence on salt concentration of the rate of decay of the perchlorate salt of the diethazine radical cation. Concentration of DE’+Cl’-HClO, = 2 x 10e4A4; medium, OX4 HClO, for curve 1 and 2.OM HClO, for curve 2, 3. Curve 1 NaClO, Curve 2 NaCl Curve 3 HCl

Cone, M Fig. 5. Dependence on salt concentration of the rate of decay of the hydrochloride salt of the diethazine radical cation. Concentration of DE’+ Cl’- HCl = 2 x lo-‘M; medium, 2M HCl Curve l(a) (b) (c) (d) Curve 2 Curve 3

LiCl NaCl KC1 IQ-W1 Na,SO, NaClO,

sodium perchlorate concentration of 0.2M and then decreases at higher concentrations. The effect of chloride anion (sodium chloride) was also followed in a perchlorate medium (curve 2). It can be seen that sodium chloride increases the rate of the DE’+ decomposition, especially at lower concentrations. To verify this finding, the effect of hydrochloric acid was also studied (curve 3). The decomposition rate increases from O.Ol-2.OM hydrochloric acid, i.e., the effect of Cl- predominates over the stabilizing effect of, H+. Sodium nitrate affects the DE’+ disproportionation in perchloric acid medium according to a mechanism that is more complex than a 2nd order reaction. Stability of the chloride of the diethazine radical cation As above, the effect of selected anions (Clot, SOi- and Cl-) was studied by following the rate of degradation of the diethazine radical cation

Stability of the cationic radical of phenothiazine derivatives

prepared by electrochemical oxidation of the hydrochloride salt. Dependences are given in Fig. 5. It is evident that chloride causes the rate constant for the decomposition of the DE’+ radical cation to decrease, i.e., increases the stability of the radical cation. In contrast, sulphate and perchlorate cause an increase in the rate constant; sulphate a slight increase and perchlorate a large one. The effects of Li+, Na+, K+ and NH: on the resultant rate constant were also followed [curves l(a)-(d)]. Here, the rate constant of DE’+ disproportionation decreases, i.e., the DE’+ stability increases as follows: NH: < K+ < Na+ c Li+. It follows from the above results that the kind of salt present in solution significantly affects the stability of the cationic radicals of phenothiazine derivatives. The stability is strongly enhanced in the presence of salts with the same anion as that contained in the salt of the cation radical, while other salts decrease the stability. This finding can be utilized in analytical deter-

1313

minations based on the formation of coloured cationic radicals of these substances. Acknowledgement-The authors are grateful to Dr J. Vohlidal for valuable discussions. REFERENCES I. Nkncovb, N. ZimovC&dcov~ and I. Nsmec, Chem. Li.sry, 1982, 76, 142. 2. T. N. Tozer and L. D. Tuck, J. Pharm. Sci., 1965,54, 1169. 3. L. Levy, T. N. Tozer, L. D. Tuck and D. B. Loveland, J. Med. Chem., 1972, 15, 898. 4. A. Ortiz, T. Poyato and J. I. FemBndez-Alonso, J. Pharm. Sci., 1983, 72, 50. 5. P. H. Sackett and R. L. McCreery, J. Med. Chem., 1979, 22, 1447. 6. H.-Y. Cheng, P. H. Sackett and R. L. McCreery, J. Am. Chem. Sot., 1978, 100, 962. I. Idem, J. Med. Chem., 1978, 21, 948. 8. A. Ortiz, H. Pardo and J. I. FenGndez-Alonso, J. Pharm. Sci., 1980, 69, 378. 9. A. De Leenheer, J. Assoc. Off: Anal. Chem., 1973, 56, 105. 110. I. Nemcovb, J. Novotnjr and V. Horsk& Microchem. J., 1986, 34, 180.