CROATICA CHEMICA ACTA CCACAA 59 (4) 917-923 (1986)

CCA-1699YU ISSN 0011-1643

UDC 547.772Original Scientific Paper

Polarographic Behaviour of Some Potential AntineoplasticBenzothiazolylazopyrazolesRajeev Jain and Anju Dixit

Schooi of Studies in Chemistry, Jiwaji University, Gwalior - 474011,India

Recei ved April 24, 1986

The present paper summarises the electrochemical behaviourof 4-benzothiazolylazo-N-thiocarbamoyl-3,5-dimethyl pyrazoles.The reduction of above compounds takes place in a single 2e waveat d.m.e. corresponding to the reduction of azo group. All thecompounds give irreversible waves at pR values pR > 3.0 andreversible waves at pR values pR < 3.0. All waves are diffusioncontrolled and half-wave potentials pR dependent. The effect ofsubstituents has been determined quantitatively by the applicationof Hammett equation. A plausible mechanism has been suggestedfor the electrodeprocess. Furthermore, the effect of ionic-strength,cations, anions and solvent composition has been studied in termsof the changed electrical double layer.

Keeping in mind the great importance of potential antineoplastic 4-benzo-thiazolylazo-N-thiocarbamoyl-3,5-dimethyl pyrazoles (I) from the electroehe-mical point of view, as they have an azo group attached to both sides withheterocyclic rings, polarographic reduction of substituted 4-benzothiazolylazo--N-thiocarbamoyl pyrazoles (having different substituents at the 3 and 5positions of pyrazole ring) I, II and III has been investigated in this paper.Studies were carried out particularly from the point of view of azo groupreduction mechanism and the effect of substituents on the reduction process.

(I) ( II)

( I I 1)"

918 R. .JAIN AND A. DIXIT

EXPERIMENTAL

4-benzothiazolylazo-N-thiocarbamoyl-3,5-dimethyl pyrazoles I, II and III wereprepared by the method developed in this laboratory.'

Apparatus

D. C. polarographic curves were record ed on an ELICO DC CL 25 recordingpolarograph, The capillary characteristics were as follows: m = 1.25 mg S-1 andt = 2.6 s, m2/3t'/6 = 1.360 mg2/3 S'/2 at a zero applied potential vs S.C.E. in 1.0 M KCIsolution at h = 110 cm. The temperature of the solution was maintained at 25 ± 1 =cby keeping the polarographic ccll in a thermostatic bath. The pH metric studieswere made on an ELICO LI-15 expanded scale pH meter fitted with a glasselectrode, and SCE was used as the reference electrode.

Solutions and Procedure

Stock solutions of concentration 1.0 X 10-3 M of all the compounds (Table Iand II) were prepared in purified" N,N-dimethylformamide (Ana1R). Britton-Robin-son buffers" in the pH range 2.0 to 11.0, 0.1 N Na OH, 1.0 M KCl, KBr, KI, KN03,NaCI, LiCI and (CH3)4NBr were prepared indoubly distilled water using Ana1Rgrade chernicals, Solutions for polarographic measurements were prepared bymixing 1.0 ml of the compound, 3.0 ml of D.M.F. (which was necessary to keepthecompound in solution), 1.0 ml of KCl (1.0 M) and 5.0 ml of the appropriateBritton-Robinson buffer. Dissolved oxygen was removed from the solution bypassing the purified nitrogen gas for about 10 minutes and corrections for residualcurrent were made in all the cases, The number of electrons n involved in thereduction process was determined for the parent compound (I) by the method ofDevries and Kroon! using a mercury pool cathode. The temperature coefficient wascalculated by Nejedly's" method.

RESULTS AND DISCUSSION

In the pH range 2.0 to 12.0 all the compounds (Table I and II), exceptthe 6-N02 derivative, were reduced in asingle 2-e process. In the case of6-N02 derivative one more 4-e wave at amore positive potential for thereduction of nitro group was observed. For all the waves the limiting currentwas found to be diffusion controlled, as evident by the linear plots" of idvs. h and the low temperature coefficient (below 1.560/0 K'"). Let the depen-dence of El/2 on pH for the parent compound be represented by the equation:

- El/2 (pH 2.0-8.0) = 0.055 pH + 0.22 V

The dependence of EV2 on pH showed a break at around pH 8.0 (Figure 1).The polarographic characteristics are summarised in Table I and II. A com-parison of limiting currents (id, Table I) indicates that most of the compoundsstudied are reduced by the same number of electrons. The number of electronsinvolved in the electrode process was found to be 2 bycomparison with com-pounds of known 'n' valu es under similar experimental conditions and bythe millicoulometric method suggested by Devries and Kroon.

The half-wave potentials are dependent on pH and shift towards the morenegative potential with an increase in pH. It is deduced from this behaviourthat protonation takes place before the first electro n uptake. The shift of Eli2

toward the more negative potential with increasing concentration of depola-rizer and logarithmic analysis confirmed the irreversible" nature of the elec-trode process. However, below pH 3.0 all the compounds listed in Table Ishow ed a reversible nature of the wave. The number of protons involved per

TABLE

I

Pou

iroqr

aphi

cC

hara

eter

istie

sof

Som

eS

ubst

itute

d4-

Ben

zoth

iazo

lyla

zo-N

-thi

oear

bam

oyl-3

,5-d

imet

hyl

Pur

tizol

esat

pH6.5

RlSc-~

CH3

.IJ-N-N~

,.S

.Ai4

H~r C-S ~H

2

s.NO.

R-E

l/2/

VE3/

r-El/4

idi!.lA

anP

laH

0.56

0.040

0.36

1.26

1.19

lb4-CH

30.57

0.040

0.45

1.26

1.19

le5-CH

30.56

0.040

0.36

1.26

1.19

ld6-CH

30.54

0.040

0.36

1.26

1.19

le4-0CH3

0.59

0.040

0.30

1.26

1.19

If5-0CH3

0.57

0.045

0.33

0.94

1.01

196-Cl

0.52

0.040

0.36

1.26

1.19

Ih6-Br

0.51

0.040

0.36

1.22

1.19

6-0C2H

50.56

Ii0.64"

0.040'·'

0.24"

1.33'·'

0.98*

lj6-N02

1**0.43

0.040

0.57

1.08

1.26

20.58

0.035

0.33

1.35

1.24

1*"

for

the

reduction

ofnitro

group

*at

pH7.9

dEl/2

1Vb:l t<J

I::J.E

l/ 21V

IR

T/a1

1.1V

KOr.h/(cm/s)

ZdpH/pH

N o >'l :I10.055

0.00

0.26

1.917

5.04

X10-4

.... ;J> N0.055

-0.01

0.32

1.917

4.30

X10-4

o t"' ><0.050

0.00

0.26

1.917

2.54

X10.4

r- ;J> N0.055

0.02

0.26

1.917

2.46

X10-4

o '"tJ0.055

-0.03

0.21

1.917

1.79

X10-4

>< !J:I ;J>

0.050

-0.01

0.24

2.169

3.91

X10-.1

N o r-0.055

0.04>

0.26

1.917

1.33

X10-3

t<J tr:

0.050

0.05

0.26

1.917

2.30

X10~4

--

0.045

0.00

0.17"

1.917'·'

2.07

X10-3,.,

0.058

-0.41

1.917

6.27

X10-4

0.057

0.02

0.24

1.674

1.63

X10-.1

eo f-' ~

TA

BL

EII

Pol

arog

raph

icC

hara

cter

istic

sof

Som

eS

ubst

itute

d4-

Ben

zoth

iazo

lyla

zo-N

-thi

ocar

bam

oyl

Pur

azol

esat

pH6.

5

~~-u--{'N

HCflH

4CI

~..->

-N-

N~J..,,/~

H3C

~/ C=S

~H2

S.N

O.

R1R2

-E1i21

Vid

/!J.A

E3i4-

E1i4

/VI

dE1i

21V

RT/a

nalV

KOf,h/(cm/s)

andp

H/p

H

IaCH

sCH

s0.

560.

360.

041.

260

0.26

0.05

51.

917

5.04

X10

-,1

IICH

sN

HC6

H5

0.76

0.48

0.06

0.81

30.

350.

150

2.87

03.

43X

10-4

III

CHs

NH

C6H

4Cl

0.53

0.54

0.02

2.38

00.

390.

045

0.95

68.

26X

JO-3

co t-:l

o ~ > Z »- z tl ?> tl ~ ...• >-3

BENZOTHIAZOLYLAZOPYRAZOLES 921

tt :::

+0·70

}N t 0·50

0·70

0·30

0·50

0'30

0'40

8'0 8'0-------------pH---------.--2'0 4'0 10·0 12'0

Figure 1. Some typical plots of -El/2 vs pH for 4-benzothiazolylazo-N-thiocarba-moyl-3,5-dimethyl pyrazoles in B. R. buffer

molecule of reactant in the rate determining step was calculated by the lite-ratureš-? method and found to be one (Table I).

As the number of electrons involved in the reduction is 2 and the numberof protons involved in the rate determining step is one, the following mecha-nism can be proposed for the reduction of these compounds at d.m.e.

Where

Scheme I

The above mechanism (Scheme 1.) is supported from the increase of E:;lwith pH as proton is consumed first. When the depolarizer solution wastested after controlled potential electrolysis, it did not give the dye test,thereby showing that -N=N- group is reduced to -NH-NH- and furtherreduction of -NH-NH- grouping to amine does not take place. Further-more, UV-Vis. spectra of the solution during electrolysis were record ed at

922 R. JA IN AND A. DIXIT

different time intervals. Amax at 400 nm due to -N=N- grouping showed adecrease in the peak height after each interval of time and finally the wavedisappeared, confirming the above reduction mechanism. Similar results forthe reduction of the azo group have also been described by other workers'"!?at d.m.e.

Structural Effects

In order to express the effect of substituents quantitatively, the half-wavepotentials of the compounds Ia-I] are plotted against the value of the Ham-mett substituent constant (o'). A linear plot was obtained in which, along withmeta and para derivatives, ortho derivatives also fit in the straight line. Thevalue of the specific reaction constant (p) is 0.13 V, which is in good agree-ment with the values reported in the Iiterature-" for similar systems. Thepositive value indicates that the mechanism of the potential determining stepis a nucleophilic one," with an electron being the most probable nucleophilicagent. Thus, any primary electrophilic attack, e. g. protonatian prior to electro ntransfer, has no significant role in the potential determining step. Since theprotonated form is the species believed to undergo electroreduction, the firstproton uptake must be very rapid and, hence, not potential determining.

Similarly, the" values of El/2' aE1/2, El/2 'dEl!2/dpH and 'El!2 • RT/anF wereplotted against Hammett substituent constants. A good linear correlation wasobtained for all the compounds in all the cases except for 5-0CH3 derivativewhich deviate from the regression line. In these cases the valu es of regressioncoefficient (p) were 0.13 V, 0.11 V, 0.14 V and 0.28 V, respectively.

When the methyl group in the pyrazole moiety was replaced by theaminophenyl group, a marked shift in El/2towards negative value was observedin the farmer case (Table II). This shift may be due to the presence of theelectron pair at the nitrogen, resulting in the increased electron density atthe reduction site. However, when the chloro group was introduced in thephenyl ring, a shift in El/2 towards positive patentiaI was observed. This shiftmay be due to the electron withdrawing nature of the chloro group.

Acknowledg~ment. - Authors are very grateful to Dr. R. P. Bhatnagar, Prof.and Head, School of Studies in Chemistry, Jiwaji University, Gwalior for providingfacilities to carry out this work and one of the authors (A. D.)' thanks the ICMR,New Delhi, for the award of a Junior Research Fellowship.

REFERENCES

1. Raj e e v Ja i n and A. Di x i t, J. Indian Chem. Soc. (In Press).2. S. W a w z o nek, E. W. B 1a h a, R. B e r key, and M. E. R u n ner, J.

Electrochem. Soc. 102 (1955) 305. .3. H. T. S. B rit t o n, Hydrogen Ions, Vol. I, D. Van Nostrand, New York, 1956.4. T. De vri e s and J. L. Kr o o n, J. Am. Chem. Soc., 75 (1953) 2484.5. V. Ne jed 1y, Collect. Czech. Chem. Commun. 1 (1929) 319.6. L. Mei t e s, Polarographic Techniques, Interscience, N. Y., 1967.7. B. Jan i k 'and P. J. El v i n g, J. Electrochem. Soc. 116 (1969) 1087.8. M. S h ika t a and r. Ta c h i, Mem. Coll. Agr. Kyoto Univ. 17 (1931) 45.9. W. U. Ma 1i k and R. N. Go y a 1, Talanta 23 (1976) 705.

10. C. R. C a s tor and H. S. Sa y 1o r, J. Am. Chem. Soc. 75 (1953) 1427.11. P. Z uma n, Substituent Effects in Organic Polarography, Plenum Press, N. Y.,

1967.12. H. H. Ja f f e, Chem. Rev. 53 (1953) 191.

BENZOTHIAZOLYLAZOPYRAZOLES 923SAŽETAI{

Polarografsko ponašanje nekih benzotiazolilazopirazola kao potencijalnihantineoplasta

R. J ain i A. Dixit

Istražena je polarografska redukcija nekih supstituiranih derivata 4-benzotia-zolilazo-N-tiokarbamoilpirazola s obzirom na njihov značaj kao potencijalnih anti-neoplasta. Pretpostavljen je mehanizam te redukcije i ispitan je utjecaj supstitue-nata na taj mehanizam u području 2 < pH < 12.