Polarographic reduction of some potential antineoplastic compounds

Electroanalytical Chemistry and Interfacial Electrochemistry, 54 (1974) 411-416

411

~ Elsevier Sequoia S.A., Lausanne - Printed in The Netherlands

POLAROGRAPHIC REDUCTION PLASTIC C O M P O U N D S

OF

SOME

POTENTIAL ANTINEO-

WAHID U. MALIK, V. K. MAHESH and R. N. GOYAL

Department of Chemistry, University of Roorkee, Roorkee (India) (Received 23rd November 1973; in revised form 26th March 1974)

INTRODUCTION

Polarographic reduction of 1-thiocarbamoyl-4-substituted arylazopyrazoles, well known for their antineoplastic activity x' 2 has not been studied so far. In these compounds represented in (I) the possible reduction sites are N2=C3 or C4=C5 of the ring or the extranuclear - N = N _ Of these, the latter site should be more susceptible to reduction than the other two sites which would require a much higher negative potential for reduction. R N=N--C

C--R

~ll / .I1o R~--C\

1

R1 : C H 3 o r

CGH 5

--N{ C=S NH2 (I)

In this communication .we wish to report our results on the polarography of l-thiocarbamoyl-3,5-dimethyl-4-phenylazopyrazole and l-thiocarbamoyl-3,5-diphenyl-4-phenylazopyrazole and the effect of electron donating substituents on

their E~. Investigations were carried out at different pH except in the case of compounds belonging to the 3,5-diphenyl series; since compounds belonging to the 3,5-diphenyl series were water insoluble the investigations were carried out in a non-aqueous medium without the possibility of determining the effect of pH on their E~. EXPERIMENTAL

The 4-substituted-l-thiocarbamoyl-3,5-dimethyl phenylazopyrazoles having substituents hydrogen, 2-methoxy, 4-methoxy, 2-ethoxy and 4-ethoxy and 4substituted-l-thiocarbamoyl-3,5-diphenyl phenylazopyrazotes having substituents hydrogen, 2-methyl, 2-methoxy, 3-chloro, 3-methyl, 4-chloro, 4-bromo, 4-methoxy, 4-methyl, 2,4-dimethyl, 2,6-dimethyl were synthesized in the laboratory by the method of Garg and Sharma 3.

412

W.U. MAL1K, V. K. MAHESH, R. N. GOYAL

A Cambridge pen recording polarograph was used for recording the polarograms. The capillary characteristic (m~t +) was found to be 3.75 mg ~ s-~. An inert atmosphere was maintained by passing purified nitrogen for about half an hour before recording the polarograms. The solutions of 1-thiocarbamoyl-3,5-dimethyl- and 1-thiocarbamoyl-3,5-diphenyl-4-substituted arylazopyrazoles were prepared in methanol (A.R.) of concentration range 10 -3 to l0 4 M and were kept in well corked pyrex glass measuring flasks. The studies for the compounds of the 3,5-dimethyl series were carried out in the pH range 3.0 to 10.0 using Britton-Robinson buffers. A freshly prepared solution of gelatine was used as maximum suppressor (0.0050/oo). For 1-thiocarbamoyl-3,5-diphenyl-4-substituted arylazopyrazoles the studies were carried out in purified dimethylformamide (A.R.) using 0.5 ml of 1 M KC1, as supporting electrolyte. The value of// was calculated by the millicoulometric method of De Vries and Kroon 4 using a mercury pool. The formula used was //2 ~ //1

\ id;cad / \Aid, sub/

V2¢2

Where id cad is the original diffusion current (corrected for the residual current) for cadmium, V1 its volume, Cl its concentration and Aid.cad is the change in the diffusion current produced by the electrolysis. /d.sub, Aid.sub, V2 and c2 are the corresponding quantities for the solution of the substance, nl and //2 are the number of electrons involved for cadmium ions and substance respectively. As the concentrations and volumes of cadmium ions and substances were the same, the last factor in the equation is unity. RESULTS AND DISCUSSIONS

The polarograms recorded for different 1-thiocarbamoyl-3,5-dimethyl-4substituted arylazopyrazoles in Britton-Robinson buffers of pH 3.0 to 10.0 and for different 1-thiocarbamoyl-3,5-diphenyl-4-substituted arylazopyrazoles in dimethylformamide give well defined cathodic waves. Besides the main reduction wave no other wave was obtained except for the hydrogen reduction wave which appears at -1.60 V vs. SCE. Keeping in view the feasibility of the sites of reduction, it may be inferred that the possible reduction is reduction of N = N - . The diffusion controlled nature of the limiting currents was established from the linearity of id VS. x/h plots, low temperature coefficient (1.6~o)and independence of limiting current of pH. The half-wave potential of the waves was found to shift towards more negative values with the increasing pH for the 3,5-dimethyl series of compounds. The plot of E~ vs. pH shows a linear relationship (Fig. 1). The change in E~ with the increasing concentration of arylazopyrazoles suggests the irreversible nature of the waves. From Fig. 1, it is evident that the o-substituted 3,5-dimethyl arylazopyrazoles viz. 1-thiocarbamoyl-3,5-dimethyl-4-(2-methoxyphenyl)azopyrazole and 1-thiocarbamoyl-3,5-dimethyl-4-(2-ethoxyphenyl)azopyrazoleare reduced at a more positive potential than the corresponding phenylazopyrazole. The similar observation

POLAROGRAPHY OF POTENTIAL ANTINEOPLASTIC COMPOUNDS

413

has also been made for o- and m-substituted 3,5-diphenyl-arylazopyrazoles viz. 1-thiocarbamoyl-3,5-diphenyl-4-(2-methylphenyl)azopyrazole, 1-thiocarbamoyl-3,5diphenyl-4-(2-methoxyphenyl)azopyrazole, 1-thiocarbamoyl-3,5-diphenyl-4-(3-methylphenyl)azopyrazole and 1-thiocarbamoyl-3,5-diphenyl-4-(3-chlorophenyl)-azopyrazole. This can be readily accounted for by considering the effect of the substitution of an electron donating group on the benzene ring. Such a group would facilitate reduction due to increase in electron density at N = N . 1.0 0.9 o

0.8

09 2 R = 2-methoxy 3 ~=4-methoxy 4 R=2-ethoxy

j ~ ~_r At" ~J'~"

/

0.8 0.7

0.6

~_ o6

Q~

l

Q4 Q3

0.2

I

0.2

0.1

0.1 1

.

I

2

I

3

I

4

l

I

5

6

I

I

7

8

pH

I

9

0.3 l

I

10

---

Fig. 1. Plot of - E ½ vs. p H of 1-thiocarbamoyl-3,5-dimethyl-4-substituted arylazopyrazoles.

TABLE 1 VALUES O F E{ AT V A R I O U S C O N C E N T R A T I O N S METHYL-4-SUBSTITUTED ARYLAZOPYRAZOLES Substituent

pH

4-Methoxy 2-Ethoxy 4-Ethoxy

8.0 8.0 8.0 7.0 8.0

1-THIOCARBAMOYL-3,5-DI-

- E { / V at various concentrations, c/mol l 1 1×10

Hydrogen 2-Methoxy

OF

0.54 0.53 0.64 0.52 0.64

5

5×10

0.60 0.57 0.67 0.54 0.67

s

lxlO-4

2x10-4

3x10-4

0.65 0.59 0.68 0.56 0.68

0.68 0.62 0.72 0.60 0.73

0.72 0.64 0.74 0.63 0.76

In the case of p-substituted arylazopyrazoles viz. 1-thiocarbamoyl-3,5dimethyl-4-(4-methoxyphenyl)azopyrazole, 1-thiocarbamoyl-3,5-dimethyl-4-(4ethoxyphenyl)azopyrazole and 1-thiocarbamoyl-3,5-diphenyl-4-(4-methoxyphenyl)azopyrazole the reduction takes place at a more negative potential. Although this behaviour is difficult to explain, one possible explanation which may be put forward is the greater contribution of the transition (III), in the o-substituted than in the p-substituted due to intramolecular attraction between the ethoxial oxygen and the nitrogen of the azo group. Such effect would result in higher electron density at the azo group thereby making reduction easier in the o-substituted arylazopyrazoles.

414

w.u.

MALIK, V. K. MAHESH, R. N. GOYAL

TABLE 2 VALUES O F E~ FOR I-THIOCARBAMOYL-3,5-DIPHENYL-4-SUBSTITUTED AZOPYRAZOLES AT C O N C E N T R A T I O N 1 x 10 _4 M Substituent

--E~/V

AE~/V

Hydrogen

0.720 0.640 0.580 0.600 0.660 0.650 0.715 0.610 0.73 0.620 0.600

-0.080 0.140 0.120 0.060 0.070 0.005 0.110 0.01 0.100 0.120

2-Methyl

2-Methoxy 3-Chloro

3-Methyl 4-Chloro 4- Methyl

4-Bromo 4-Methoxy 2,4-Dimethyl 2,6-Dimethyl

OCH 3

PHENYL-

~O--CH 3

(rr)

(m)

Bachmann and Ferguson 5 have reported such intramolecular changes in the case of tetra-substituted glycols. It is worth mentioning that in the p-substituted arylazopyrazoles such an interaction would not be possible and the electrons are relayed through the conjugated system (I). This situation exists in all the above p-substituted arylazopyrazoles and therefore E~ values are almost the same irrespective of the substituent. It may be pointed out that such behaviour of o-compounds has also been reported by Charton 6 and others 7. A slight shift towards more positive potential in the case of 1-thiocarbamoyl-3,5-diphenyl-4-(4-chlorophenyl)azopyrazole and 1-thiocarbamoyl-3,5-diphenyl-4-(4-bromophenyl)azopyrazole (Table 2) may be attributed to the lower electron donating capacity of halogens in comparison to other groups studied. For compounds having two methyl groups at positions 2 and 4 and at 2 and 6, respectively, the E4 is found to shift towards more positive potential (Table 2). The E~ value of 1-thiocarbamoyl-3,5-diphenyl-4-(2,4-dimethylphenyl)azopyrazole shows reasonable additivity of 2-CH 3 and 4-CH 3 shifts. While the smaller shift H

I

H--C~... / f ///

H ('IV)

POLAROGRAPHY OF POTENTIAL ANTINEOPLASTIC C O M P O U N D S

415

of the order of 0.04 V in 1-thiocarbamoyl-3,5-diphenyl-4-(2,6-dimethylphenyl)azopyrazole may be attributed to steric inhibition of resonance or coplanarity (IV). Zuman s has also put forward a similar explanation for the shifts in the reduction of substituted benzophenones. The following mechanism based on two electron transfer can be proposed for the reduction of these arylazopyrazoles. R

R

--.--/.

R,--c\

vH÷

I

C~-S

I

NH2 R

R

I --N--R'

R

r

H H÷

wher'e R ' : - - C

N--N--R'

C--R1

II

II

RI - C ~

.N

./

I C=S

r

NH2

The above mechanisms also find support by the increase in E~ with increase in pH for all the compounds belonging to 3,5-dimethyl series, since the reduction of these compounds takes place at the expense of H + ion from the medium. Similar reduction steps have been proposed by Zuman and Exner 9 for the polarographic reduction of O- and N-substituted oximes. It has been reported by Nygard 1° and others 11 that azobenzene reduces reversibly at low concentration and at low pH value. Seemingly our compounds represent the reduction at - N = N - except for the fact that we get an irreversible wave. This slight difference in the behaviour can be due to the bulky pyrazole group at one end o f - N = N - . ACKNOWLEDGEMENT

One of the authors (R.N.G.) is very grateful to Dr. Chandra Prakash,

416

W.U. MALIK, V. K. MAHESH, R. N. GOYAL

lately Senior Fellow in the Chemistry Department. University of Roorkee, for the help rendered in the preparation of these compounds. SUMMARY P o l a r o g r a p h i c reduction of 1-thiocarbamoyl-3,5-dimethyl-4-substituted arylazopyrazoles and l-thiocarbamoyl-3,5-diphenyl-4-substituted arylazopyrazoles gives well-defined, irreversible, diffusion-controlled cathodic waves corresponding to two electron transfer. The studies for the former were made in B r i t t o n - R o b i n s o n buffers of p H range 3.0 to 10.0, while for the latter the studies were carried out in dimethylformamide. The value of E~ shifts with increasing concentration of pyrazoles reveals irreversible reduction. Effect of electron donating substituents on E~ for both the series of comp o u n d s is reported. It was observed that the same g r o u p viz. ~ ) C H 3 and -OC2I-I 5 shifts E~ towards m o r e positive value at the ortho position, while E~ is shifted towards more negative value at the para position.

REFERENCES 1 E. J. Modest, H. N. Schlein and G. E. Forby, J. Pharm. Pharmacol., 9 (1957) 68. 2 R. F. Harmon, F. E. Dutton and H. D. Warren, J. Med. Chem., 11 (1968) 627. 3 H. G. Garg and R. A. Sharma, J. Med. Chem., 13 (1970) 579. 4 T. DeVries and J. L. Kroon, J. Amer. Chem. Soc., 75 (1953) 2484. 5 W. E. Bachmann and J. W. Ferguson, J. Amer. Chem. Soc., 56 (1934) 2081. 6 M. Charton and B. I. Charton, J. Or9. Chem., 36 (1971) 260. 7 V. N. Dmitrieva, L. V. Kononenko and V. D. Bezuglyi, Teor. Eksp. Khim., 1 (4) (1965) 456. 8 P. Zuman, Collect. Czech. Chem. Commun., 27 (1962)648. 9 P. Zuman and O. Exner, Collect. Czech. Chem. Commun., 30 (1965) 1832. 10 B. Nygard, Ark. Kemi, 26 (16 17) (1966) 167. 11 C. R. Castor and H. J. Saylor, J. Amer. Chem. Soc., 75 (1953) 1427.