Indian Journal of Chemistry Vol. 40A, May 2001 , pp. 514-518

Kinetic analysis of oxidation of dopamine by sodium N-chlorobenzenesulphonamide in perchloric acid medium: A mechanistic ·

approach

Puttaswamy* & T M Anuradha

Department of Post-Graduate Studies in Chemi stry, Central College, Bangalore Uni versity, Bangalore 560 00 I, Indi a

and

K L Mahadevappa _,

Department of Biochemi stry , Kempe Gowda Institute of Medical Sciences, Bangalore 560 004, India

Receil'ed II Septe111ber 2000; revised 7 Dece111ber 2000

Kinetics of ox idation o f dopamine (DPM ) by sodium N­chlorobenzenesulpho namide (chl oramine-B or CAB) in perchl oric acid medium has been studied at 40°C. The rate shows first order dependence in [CABlo. fraction al order in [DPM]0 , and in verse fractional order in [H+j. The effects o f die lectric constant and solvent isotope have been studied. Michae li s-Menten type of kineti cs have been proposed and activati on parameters for the rate determining step have been computed. A mechanism consistent with the observed kinetics is proposed and di scussed.

The kinetics and mechanism of oxidation by sodium salts of N-ary 1-N-halosulphonamides have attracted the chemists ' attention due to their diverse properties to act as halonium cations, hypohalites and N-anions. The important compound of this group is chloramine­T (CAT) and the mechanistic aspects of many of these reactions have been documented 1• The benzene analogue, chloramine-B (C6H5S02NCINa.J.5H 20; CAB) is becoming important as a mild oxidant. Although the oxidation of organic substrates with CAB has been studied2

, no attention has been focused on reactions of CAB with pharmaceuticaLs, particu­larly with respect to neurotransmitters like catechol­amines. The drug, dopamine (DPM, 3-hydroxy­tyramine) is one of the naturally occuring catechol­amines and the lowered level of this in the brain is known to cause the neurological disorder-Parkinson's disease. Dopamine hydrochloride is widely used in the treatment of shocks and in acute congestive failure. Hence, it was found important and interesting to investigate the oxidative behaviour of CAB towards dopamine. The present report is the first one

discussing the detailed oxidation kinetics of dopamine by CAB in acid medium for elucidating the mecha­nism of oxidation of this drug.

Experimental Chloramine-B was prepared by the method re­

ported in literature3 and its purity checked by ele­mental analysis, iodometric estimation of its active chlorine content, IR and NMR spectral data. Dopa­mine hydrochloride (E. Merck) and other chemicals of analytical grade were used. The ionic strength of the system was maintained at a constant high value (1=0.50 mol dm-3) using a concentrated solution of sodium perchlorate. Solvent isotope studies were made with heavy water (D20, 99.4% isotopic purity, BARC, Mumbai, India). Permittivity of the reaction mixture was altered by the addition of methanol in varying proportions (v/v) and values of permittivity of methanol -water mixtures reported in literature4 were employed. Triply distilled water was used in prepar­ing all aqueous solutions throughout the studies.

Kinetic measurements Kinetic runs were performed under pseudo-first

order conditions with excess of the INH over the oxidant at 40°C. The reaction was carried out in stoppered pyrex boiling glass tubes whose outer surfaces were coated black to eliminate photochemi­cal effects. For each run, requisite amount of solutions of substrate, HCI04, NaCI04 and water (to maintain a constant total volume) were measured and thermally equilibrated at 40°C. A measured amount of the oxidant solution, also equilibrated at the same temperature, was rapidly ad.ded to the mixture in the boiling tube with stirring. The progress of the reaction was monitored by iodometric determination of the unreacted oxidant in measured aliquots of the reaction mixture withdrawn at different intervals of time. The course of the reaction was studied for at least two half-lives. The pseudo - first order rate constants, fl. calculated from the linear plots of log[oxidant] versus time were reproducible within ±3%. Regression analysis of the experimental data was can·ied out on an EC-75 statistical calculator to obtain the regression coefficient, r.

NOTES 515

Table !-Effects of variation of [CAB], [DPM] and [H+] on the rate of reaction

1=0.50 mol dm·3 ; Temp.=313 K

104 [CAB]0 103[DPM]0 102[HCI04] nlk' (mol dm.3) (mol dm-3) (mol dm-3) (s.')

2.0 6.0 4.0 2.96

4.0 6.0 4.0 2.80

6.0 6.0 4.0 2.94

8.0 6.0 4.0 2.90

10.0 6.0 4.0 2.86

12.0 6.0 4.0 2.82

6.0 2.0 4.0 1.65

6.0 6.0 4.0 2.94

6.0 10.0 4.0 3.70

6.0 14.0 4.0 4.25

6.0 18.0 4.0 4.82

6.0 24.0 4.0 5.35

6.0 6.0 1.0 6.02

6.0 6.0 2.0 4.25

6.0 6.0 4.0 2.94

6.0 6.0 6.0 2.38

6.0 6.0 8.0 1.96

6.0 6.0 10.0 1.72

Stoichiometry Varying ratios of oxidant and dopamine, under

conditions([CAB]>>[DPM]) in the presence of 0.04 mol dm-3 HCI04. were kept at 40°C for 24h. The unchanged oxidant in the reaction mixture was determined by iodometric titrations. The analysis showed that one mole of DPM reacted with one mole of oxidant. The observed stoichiometry is shown m Eq. (1):

CsH 11 N02+PhS02NCINa CsH9N0 2+PhS02NH2+Na + +Br"

Product analysis

.. ... (l)

The reduction product of CAB, benzenesulphon­amide (PhS02NH2), was detected5 by thin layer chromatography, using light petroleum-chloroform­butan-1-ol (2:2: I v/v/v) as the solvent and iodine as the detecting agent (Rr=0.88). The reported Rr value is consistent with the literature value5

. The oxidation product of dopamine, 2-(31,41,-benzoquinone) ethyl­amine, an orange red solution was detected by IR and it polymerizes to a brown gel like solid.

Results and discussion The kinetics of oxidation of dopamine by CAB was

investigated at several initial concentrations of the

reactants in acid medium. With the substrate in excess, at constant [HC104], [DPM], and temperature, plots of log[CAB]o versus time were linear (r>0.9936) indicating a first order dependence on [CAB]o. The pseudo-first order rate constants (k) calculated from these plots are given in Table 1. Further the values of J! calculated from these plots are unaltered with variation of [CAB]o confirming the first order dependence on [oxidant]0 • The rate increased with increase in [DPM]o (Table 1 ). A plot of log J! versus log[DPM]o was linear (r=0.9985) with a slope of 0.42, thus indicating a fractional order dependence of the rate on [DPM]0 • Increase in [HCI04] decreased the rate of reaction (Table 1) and a plot of log J! versus log[HCI04] was linear (r=0.9991) with a negati ve slope of 0.56 indicating an inverse fractional order in [H+].

Addition of the reaction product, benzenesu l­phonamide (5 .0x 10-4"4.0x l0-3 mol dm.3) or variation of ionic strength of the medium (0.10-0.80 mol dm.3)

had no significant effect on the rate. Addition of cr or Br" ions (5.0x10·4 - 5.0x10-3 mol dm-3

) in the form of NaCI or NaBr had no effect on the rate. The effect of dieletric constant (D) on the reaction rate was studied by adding various proportions of methanol to the reacting system. It was observed that an increase in methanol composition in the reacting system de­creased the reaction rate and a plot of log J! versus liD was linear (r=0.9901) with a negative slope. Blank experiments showed that the oxidation of methanol by CAB during the experimental duration was negligible (<2%). This was takeri into account in the calculation of net reaction rate constant for the oxidation of DPM each time.

The reaction was studied at different temperatures (298- 323K) and from linear Arrhenius plot of log J! versus 1/T (r=0.9998), values of activation parameters were computed. These values are presented in Table 2. A study of rate in 0 20 medium showed that while J! (H20) is 2.94x l0·4 s· 1

, J! (D20)=2.48xl0-4 s·1,

giving a solvent isotope effect, k(H20)/k(D20)= 1.18.

Alkene monomers such as acrylonitrile and a freshly prepared 10% acrylamide solution, under N2 atmosphere, were added to initiate polymerization in the presence of free radicals. A Jack of polymerization indicated the absence of free radicals in the reaction mixture. Proper control experiments were also run.

Chloramine-B is analogous to chloramine-T and exhibits similar equilibria in aqueous acidic and basic solutions6

·8

. In general, CAB undergoes a two electron

516 INDIAN 1 CHEM. SEC. A, MAY 2001

Table 2-Temperature dependen~e and activation parameters for the oxidation of dopamine by CAB in acid medium

[CAB]0 =6.0xl0-4 mol dm-'; [DPM]0 = 6.0xl0-3 mol dm·3 ;

[HCI04]=4.0 X I o-2 mol dm-3 ; 1=0.50 mol dm-3

Temperature l04k1 s·' Activation Parameters (K) (104k3 s·') Parameter Value

298 1.05(2.38) Ea (kJ mol" 1) 55.3 (59.0)

303 1.42(3.33) t:;.J-11 (kJ mol" 1) 52.7 ± 0.1(56.4 ± 0.2)

308 1.96 ( 4.35) t:;.S' (JK 1 mol" 1) -144.9 ± 0.2(-125.9 ± 0.4)

313 2.94 (6.68) t:;.d (kJ mol" 1) 97.7 ± 0.2(95.5 ± 0.5)

318 4.12 (10.1)

323 5.55 (13 .8)

Values in parenthesis are the decomposition constants and activation parameters for the rate determining step.

change in its reactions. The reduction product of CAB/ PhS02NH2 is pH-dependent and decreases with increase in pH of the medium (values are 1.14V at pH 0.65 and 0.50V at pH 12 for CAT). Depending on the pH of the medium, CAB furnishes different types of reactive species in solution, such as PhS02NHCI, PhS02NCI2, HOC! and H20CI+ in acidic solutions6

·8.

PhS02NCINa

PhS02NCr+W

2PhS02NHCI

PhS02NCb+H20

PhS02NHCI+H20

HOC! ::;;r:~

PhS02NCI-+Na+

PhS02NHCI

PhS02N H2+PhS02NCI2

PhS02NHCI+HOCI

PhS02NH2+HOCI

... (2)

... (3)

. . . (4)

... (5)

... (6)

. .. (7)

... (8)

Therefore, the probable oxidizing species in acid solution of CAB are PhS02NHCI, PhS02NCb, HOC! and H20CI+. The first order dependence of rate on [CAB] and the addition of benzenesulphonamide (PhS02NH2) having no effect on the reaction rate, both indicate that PhS02NCh and HOC! may not be the reactive species [(4) and (6)] and, that these species are present in very low concentrations8 at the experimental conditions employed. The absence of ionic strength effects indicates the involvement of a neutral species in the rate determining step(rds). Hence, the effective oxidizing species in the rate determining step could be the conjugate acid, PhS02NHCI. Further, protonation of monochlora­mines (RNHCI) at pH< 2 according to (9) has been

9 10 reported · .

K

RNHCI+H+ ¢=:::>RNH2CI+ .. . (9)

Here, when R=p-CH3C6H4S02, K=1.02x l 02 at 25°C, while with R=C6H5S02, K= 6 1±5 at 25°C for CAT and CAB respectively. Hence, it is likely that PhS02NHCl is further protonated in acid media. In view of these facts, Scheme I can be proposed to account the observed kinetics for the oxidation of dopamine by CAB in acid medium. A detailed mechanistic interpretation of the reaction is presented (Scheme I) , in which the structures of the complex intermediate species X and X1 are given .

The total effective concentration of the oxidant CAB is [CABL then

[CAB],=[PhS02NH2Cn+[PhS02NHCI]+[X] ... (10)

which leads to the following rate law:

-d[CAB] K 1K2 k3 [CAB], [DPM] Rate = = --'--=---=-----'----

dt [H +] + K1 {I+ K2 [DPM]}

... ( I I )

Rate law (11) is in agreement with the experimental results, wherein a first order dependence of rate on [CAB], a fractional order dependence of rate on [DPM] and an inverse fractional order in [H+] have been noted.

Since, rate=k[CAB]" Eq. (11) can be transformed as:

.. . (1 2)

Based on rate law (12), plots of 1/k' versus 1/[DPM] and llk' versus [H+] were found to be linear

NOTES 517

e PhS02 NHCI + H

HCI + H2N CH2 CH 2 -Q=o 0

[2- (3' 4'- benzoquinone )ethylamine]

Scheme 1

(r > 0.9876) and from the slopes and intercepts of which the values of formation constants K1and K2 and decomposition constant k3 were calculated. They are found to be K1=1.08x l0-3 mol dm-3, K2=4.33x103 dm3

mor' and k3=6.68xl0-4 s-'. Since a fractional order was noticed in [OPM],

Michaelis-Menten kinetics" were adopted and [DPM] was varied at different temperatures (298-323 K). From the linear plots of 111! versus 1/[0PM] at each temperature (r >0.9890) and using Eq. (12), values of decomposition constants k3 were calculated. Activa­tion parameters for the rate determining step were also evaluated using the Arrhenius plot of log k3

versus liT (r=0.9985). These data are reported in Table 2.

Addition of halide ions had no effect on the rate indicating that no interhalogen compound or free chlorine was formed . The reaction product (PhS02NH2) had no influence on the rate showing

that it was not involved in a rate pre-equilibrium. The change in the ionic strength of the medium did not alter the rate indicating that non -ionic species were involved in the rate determining step.

For a reaction involving a fast pre-equilibrium H+ or OR ion transfer, the rate increase in 0 20 medium since 0 30+ and oo-are a stronger acid and a stronger base (-2 to 3 times greater) respectively, than H30 + and OR ions12. The reverse holds for reactions involving retardation by H+ or OR ions. Hence, the proposed mechanism is supported by the decrease in rate in 0 20 medium, indicating retardation by H+. The magnitude, however, is small in the present case (t! (H20)/ 1!(020)=1.18) which can be attributed to the fractional order dependence on [H+].

Several approaches have been put forward to ex­plain quantitatively the effect of the dielectric con­stant of the medium on the rates of reactions in solution. For the limiting case of zero angle of approach between two dipoles Amis 13 has shown that a plot of logk0 versus liD is linear with a negati ve slope, i.e,

. .. ( 13)

where k0 and k~ are the rate constants in media of dielectric constant D and oo, respectively, kB is the Boltzman constant, J..1. 1 and J..1.2 are the permanent moments on the dipoles, r is the distance of approach for the dipole, and T the absolu te temperature. The present experimental observations, i.e, decrease in the rate with decrease in dielectric constant of the medium (by changing the MeOH-H20 composition), are in agreement with dipolar molecule-dipolar molecule interactions and the reaction pathways suggested to explain the kinetic results .

The proposed mechanism is also supported by the moderate values of kinetic and thermodynamic parameters. The low energy of activation and high free energy of activation support the formation of highly solvated transition state. The large negati ve entropy of activation suggests the formation of the compact activated complex with fewer degrees of freedom.

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