Indian Journal of ChemistryVol. 27 A, December 1988, pp. 1028-1030

Kinetics of Halogenation of Sulphacetamide & Sulphanilamide byTrichloroisocyanuric Acid

P S RADHAKRISHNAMURTI* & N K RATHDepartment of Chemistry, Berhampur University, Berhampur 760 007

andM YEDUKONDALU

College of Pharmaceutical Sciences, Berhampur 760002Received 25 September 1987; revised 19 November 1987; accepted 25 January 1988

rlalogenation of sulphacetamide and sulphanilamide by trichloroisocyanuric acid (TCICA) in aqueous aceticacid-perchloric acid medium is pseudo-first order in [TCICAj and fractional order in [H + J. The reaction is first or-der in [sulphanilarnide] and fractional order in [sulphacetamide]. Change of dielectric constant of the medium hasa marginal effect on the reaction rate. However, addition of NaCI enhances the rate in both the cases. A plausiblemechanism has been suggested to account for the observed kinetics.

The kinetics of halogenation of substituted ben-ZOIC acids using a variety of halogenating agentslikc N-iodosuccinimidc (NIS), chloramine-T(CAT) and trichloroisocyanuric acid (TCICA)have been studied in our laboratory I..,. In thepresent paper we report the results of investig-ations on the kinetics of chlorination of sulphaeet-amide and sulphanilamide by TCICA. To ourknowledge this is the first systematic kinetic re-port on the use of TCICA as a chlorinating agentfor sulpha drugs.

Materials and MethodsSulphacetamide and sulphanilamide (Riedel)

were recrystalised before use. TCICA (Fluka) wasused as such. All other reagents used were of AR(BDH) grade, redistilled or recrystallised beforeuse.

In the kinetic runs, disappearance of TCICAwas followed iodometrically in acid medium. Therate constants computed were reproducible within±5%.

Stoichiometric runs employing [TCICAj > [S]o(e.g. [TCICAj=2xlO-3 to 4XIO-2 mol dm-3,[S]o=2xlO-4 to 5xlO-4 mol dm-3 at[HCl04]=O.5 mol dm v') did not give meaningfulresults as the self-decomposition of TCICA underthese conditions appreciably large.

Sulphacetamide gave 3-chlorosulphacetamide asthe product and sulphanilamide gave 3-chlorosul-phanilamide.

Results and DiscussionThe salient features of the kinetic results are as

follows:

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(i) The reaction exhibits perfect pseudo-first or-der kinetics for more than four half-lives of TCI-CA disappearance as seen from the good linearplots of log [TCICAj, versus time.

(ii) The pseudo-first order rate constant (kobJincreases with increase in [S]o and [H+]. The de-pendence of kobs on [sulphacetamide] and [H +1 isfractional each in the range studied; plots of(kobJ - I versus [st I or (kobs - I versus [H +]- I arelinear with finite intercept on the (kobJ- I-axis.However, the order in [sulphanilamide] is unity,probably due to the low equilibrium constant ofthe complex.

(iii) Increase in the percentage of acetic acid inthe reaction medium (i.e. decreasing dielectricconstant of the medium) has a marginal effect onthe reaction rate at [Cl-laq = O. In the presence ofCl- , kilns increases significantly.

(iv) Increase in pH decreases the kobs value incase of sulphanilamide. However, the reactionwith sulphacetamide becomes very sluggish withincrease in pH.

Structure and reactivityStructural differences are responsible for the

higher rate observed with sulphanilamide as com-pared to that with sulphacetamide (Tables 1 and2). The pKa values of sulphanilamide and sulpha-cetamide are 10.4 and 5.4 respectively and thisclearly brings out the reasons for the higher reac-tivity of sulphanilamide. Application of Kendalls'treatment using the relation log B= Ho - pKa + logBo for these two substrates also shows higherreactivity for sulphanilamide. The relative acid in-dependent rate constants computed are of the or-

RADHAKRISHNAMURTI et al: KINETICS OF HALOGENATION OF SULPHACETAMIDE & SULPHANILAMIDE

Table 1-Effect of Varying [TCICA], [HCl04], [S], Sol-vent, [NaCl] and Temperature on the Reaction Rate

Variations k, x 10' (min-')

Sulphacetamide Sulphanilamide

[TCICAjx W(mol dm t')

1.25 2.77 8.752.50 2.49 7.635.00 2.12 7.60

[Substrate] x 10'(mol dm r']

0.5 2.49 7.631.0 3.71 13.862.0 5.71 26.194.ll 7.13

[HClO.] x 10'(moldm -')

1.0 2.49 7.632.0 3.67 10.395.0 6.59 14.4210.0 9.89 18.6750.0 16.32 54.80IQO.O 18.80 87.23

HOAc(v/v)40 2.99 9.2950 2.49 7.6360 2.44 7.9670 3.77 7.046

Temperature(0C)35 2.49 7.6340 3.90 9.1945 5.00 14.70

[NaCljx 104

(mol dm=')0.0 2.49 7.636.0 3.18.0 3.0610.0 3.67 111.2320.0 4.60 14.13

Table 2 - Arrhenius Activation Parameters at 308°KE." I1H" log",A I1S"

(kJmol-') (kJmol-') (JK-'mol-')

Sulphacetamide 99.0 96.5 12.18 4.89Sulphanilamide 99.6 97.0 13.77 - 2.45

der of 109 and 105 for sulphanilamide and sulpha-cetamide respectively.

Rate law and mechanismThe important steps in the present reactions are

shown in Scheme 1.Concentrations of monochloroisocyanuric acid

(MCICA) and isocyanuric acid (ICA) would benegligible in acid medium as (K\K2KJ) and (K\K2)

are negligible as compared to K\ (ref. 4). In thepredominantly aqueous solution [HOCl],[CI +] (ref.

TtitA + Hfl _ DeICA + HOCI (~1 - 1.7 lC10"'" mol dm-l,

DtICA' ~o _ IoItltA + HOtl (~-106 lCIrmol dm-ll

-,<ltA • H~ _ itA • HOtl (!I, -I.' lC Ur4 mol dnrl,

HOCI • H+ ~ H"lotl"

H20t(" • cr' ..b. "2' HTl

1/+ H+. + t+fJ

~H. ~[~~"J A

tl2 -.!!1.($rtl

A' R' A'

e S I (CTt)• H+te

( II and R' _ substituents I

scheme 1

5) and [CIOOCCH,] (ref. 6) would be negligible.If as a first approximation it is assumed that theTCICA species itself has a negligible contributiontowards the overall halogenation rate and that theeffective halogenating species are H~OCl + in theabsence of added cr and (H,OCl + + Cl,) in the- -presence of added Cl-, then the rate laws (I) and(2), respectively can be derived from Scheme 1.

d (TClCA]

dl • Ro~

... ( I I

t,a~c215,~ (5)(H" ](TCICA]

( (OClCA] .• ~I· ~1K",(H") ) ( I • KC2 (5] )

.• ~lC]~]KI'4~ (S)(H"][CC}[TCICA]

( (OCICA) • ~I • ~l~ISs(H+][C1-) 111 • Kc:J r5] )

For the observed pseudo-first order disappear-ance of [TCICAj in the employed concentrationrange, if [DCICAj term in the denominator issmall and negligible in comparison to other terms,Eqs (3) and (4) follow from Eqs (1) and (2) re-spectively.

.- - (21

!!obS t et ]cC ) ad • 0) • ~H20Cl'

kx2~e2~ [S) [Ho} ... (])

~Xl~Cl~lSs [Sl[H'](C\- J(I' ~4~5(H·rCI-})( I. KeltS) ) (4)

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INDIAN 1. CHEM., VOL. 27A, DECEMBER 1988

In Eqs )3) and (4) ~,OCI + and kC), representthe pseudo-first order 'rate constants due toHzOCI + and Cl, respectively.

Although the mechanistic implications of ob-served kinetics of chlorination reaction using TCI-CA have been most plausibly explained, certainother factors need mention.

(a) Scheme l' envisages the equilibrium interac-tion of (unprotonated) substrate(s) with the mosteffective chlorinating species in the medium, i.e.H20CI + in the absence of added CI- and(HzOCI + + Cl2) in the presence of added Cl ", toform a charge transfer (CT) complex which de-composes in a slow step to form the products.The formation of CT complexes of aromatic sub-strates with various electrophilic reagents in gen-eral, and with halogens in particular, is well docu-mented".

(b) The amino derivatives might be significantlypresent in the protonated form in the [H +1 rangeused. If the protonated form of the substrate(SH' ) were reactive the rate law (2) would havecontained another [H + 1 term in the numeratorand also the predominant product would havebeen a meta-chloro compound, but these are notobserved experimentally. On the other hand ifScheme 2 (in which an N-chloro intermediate isformed" from SH + and the effective chlorinatingspecies with the loss of H ", as rapidly as it rear-ranges to a CT-complex) is considered as a repre-sentative sequence for the reaction of the aminoderivative, rate law (5) could be derived by writ-ing [S]=[S]oKj[H+] where K; is the proton disso-ciation .constant of the conjugate acid (SH +) ofthe amino derivative",

Scheme 2 leads to rate law (5)."2~drKa~ [H"lr'lg

'Obi • • ••( S I •. /I, ~(tf)J( ,.(H') , IIaKrC'l, ~a~~l'll

+C;' ~2-+ CIOHi~r-

R'(NC.I

~"+ "R'

Scheme 2

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Making an approximation that ([H +]+KaKr[S]) < < KaKrK~2[S] < < 1, (Kr is a very smallquantity in the [H+] and [S]o employed) Eq. (5)approximates to Eq. (3).

It is implied that these reactions pass throughan activated state of CT complex arising essential-ly and effectively from the deprotonated SH + andthe chlorinating species under consideration.

It is known that N-chloroanilines undergo rapidrearrangement!", the N-chloro group attacking thenucleus leading to nuclear halogenated deriva-tives. Further the N-chloro intermediates wouldbe very reactive under the conditions of the pres-ent study and would not have any built-in concen-tration, for Eq. (6) would operate otherwise,R'C6H4NH(Cl) + 21- +H+-+

R'C6H4NH2 +12+ CI- ... (6)

and the smooth kinetics could not have been fol-lowed by iodometry.

(d) The reactivity order for chlorination ofthese substrates is Cl2 > H20CI + > > HOCI,which is more or less the general order observedfor chlorination of aromatic substrates in aqueousacid media. The non-participation of CI + (the un-hydrated species) in chlorination reactions carriedout in aqueous acid solutions has been discussedearlier".

References1 Radhakrishnamuni P S & Panda B K, Indian J Chern,

llA(1983) 770.2 Radhakrishnamurti P S & Rath N K, Indian J Chern, 16A

(1987) 407-411.3 Radhakrishnamurti P S & Mishra S A, Ph.D. Thesis

(1983 )Berhampur University.4 Osaka Pharmaceutical Assoc. Osaka-Fu-Yaku Zasshi, 30

(1979) 39; Chern Abstr, 91 (1979) 157695g.5 Swain C G & Crist D R, J Am chem Soc, 94 (1972)

3195.6 Comprehensive inorganic chemistry, Vol 2, edited by J C

Bailar, H J Emeleus, R Nyholm & AFT Dickenson(Pergamon, New York) 1973 Chap. 26.

7 Latimer W M, Oxidation potentials (Prentice Hall, NewJersey) (1961), p. 54.

8 Neale R S, Scheper R G & Walsh M R, J org Chern, 29(1964) 3390; Haberfield P & Daxis Paul, J Am chemSoc, 87 (1965) 5502.

9 Meites L, Hand book of analytical chemistry (McGraw-Hill, London) 1963, Sec. 1, pp. 8, 20.

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