INDIAN J. CHEM., VOL. 16A, MAY 1978

the adduct (K) should therefore be in the orderpivalic > isobutyric> propionic> HOAc. Thevalu?s of !C obtained in the present work (T, ble 2)are In t1115 order suggesting that the mechanismproposed is proba bly correct. Also the ra te cons-tants for the slow step k3 (Table 2) show thr t thera te is highest for pivalic ar.d lowest for <: cetic acid.Incidentally the dEt vrlues are low for pivalic andhigh for" cetic <: cid indica ting tha t these rea ctior.sare enthalpy controlled.

One of the authors (M.A.R.) is indebted to theUGC, New Delhi, for the award of a junior researchfellowship.

References1. SAlPRAKASH,P. K. & SETHURAM,B., Indian]. Chem.,

11 (1973), 246.2. MURTHY, G. S. S., SETHURAM,B. & NAV'ANEETHRAO,

T., Curro su., 43 (1974), 478.3. ANDERSON,J. M. & KOCHl, J. K, J. Am. chem. Soc.,

92 (1970), 2450.4. KOCHl, J. K, BAcHA, J. D. & BETHEA III, T. W., J.

Am. chem. Soc., 89 (1967), 6538.5. SHELDOM,R. A. & KOCHl, J. K, J. Am. chem. Soc., 90

(1968), 6688.6. MAHAMMED,S. S. & SETHURAM,B., Acta chim, hung.,

46 (1965), 115.7. VOGEL, A. 1., A textbook of macro and semimicro qualita-

tive inorganic analysis (Orient Longrnans, London),1967, 326.

8. FElGL, F., Spot tests in organic analysis (Elsevier, London),1966.

9. ADINARAYANA,M., SETHURAM,B. & NAV'ANEETHRAO,T., Curro su.. 44 (1975), 581.

10. INGOLD, C. K., Structure and mechanism in organicchemistry (Cornell University Press, Ithaca), 1953, 734.

Kinetics of Hydrolysis of Chloramphenicol &Its Palmitate under Alkaline Conditions

S. K. DUTTA* & S. K. BxstrDepartment of Pharmacy

Faculty .of Engineering & TechnologyJadavpur University, Calcutta 700032

Received 1 August 1977; accepted 19 November 1977

The hydrolysis of chloramphenicol and its palmitateester in alkaline solution has been studied for a storedstock solution (seven-day old) and a freshly preparedsolution at temperatures between 30° and 50°. Theenergies of activation, Ea, for chloramphenicol and itspalmitate ester are 18·4 and 17·6 (stock solution) and30·2 and 26'8 kcal/rnole (freshly prepared solution)respectively. Overall rate constants at 37°±0·5° ofchloramphenicol and its palmitate ester interpolatedfrom the respective Arrhenius plots are 0·99 and 0·70(stock solution) and 1·11 and 1·17 litre mole? min-1(freshly prepared).

CHLORAMPHENICOL (n-threo-l-p-nitropher.yl-2-dichloroacetamido-l,3-propanediol) is very

stable at room temperature but degradation occursin solution 2 nd beca use of the multiplicity offunctional groups, the degrc1dCltive mechanismbecomes complica ted in solution. E2 rlier kinetic

*To whom correspondence is to be directed.

442

investigation! revealed that the degradation is in-dependent of [H+] in the pH range 2 to 7, but thatbelow pH 2, the H+ ion cutalysed reaction playsa major role in the degradative processcs-. It wasalso reported tha tits degrade tion occurred in neutralsolution. These investigations--" indicated that amidecleavage represented the principal step and oneof the products of metabolism Wi,S the correspondingamine, l-(p-nitrophenyl) -2-amino-1,3-propanediol.The latter compound is also produced by thereaction of chloramphenicol with strong acids andbz ses. This is in conformity with the earlier in-vestigations+, These studies did not, however,elimina te the possibility of other degradative path-ways which might exist. The present investi-gation wr.s, therefore, undertaken to look for otherdegra da tive p ..thwa ys.

The reagents used were chloramphenicol (Dey'sMedical Stores, Calcutta), chloramphenicol palmitate(USP), sodium hydroxide (GRS Merck) and hydro-chloric acid (AR).

Since the antibiotic is insoluble in water 0·02Msolutions of chloramphenicol and palmitate wereprepared in ethanol (90%, v]v, pH 7·15). Theseconstituted the stock solutions. An aliquot of theantibiotic solution W2S withdrawn and equilibratedin a thermostatic bath having a precision of Oo± 0·5°.A measured volume of standard alcoholic solutionof sodium hydroxide] equilibrated at the sametemper, ture was transferred into the alcoholic solu-tion of antibiotic and the time noted immediately.At definite time intervals, 2 ml samples were with-drawn r.nd the excess alkali titrated with standardacid using phenolphth.Jein indicator. For freshlyprepared solutions, a calculated quantity of powderedantibiotic wz.s added to a definite volume of ethanol(to prep:.re 0'02M solution) kept in the thermostaticbath at specified temperature 'and kinetic studywas carried out 2S before. The experimental proce-dure was repea ted using different concentrs tionsof alkalis (0'04M, 0'06M and 0·10M).

If Vo is the volume of the standard acid requiredto neutralize the hydroxide a t the beginning of theexperiment, V, is the volume after t min and V<Xis the equivalent of excess dkali remrinir-g atinfinity (when the rC8ction is 2 ssumed to be complete)we have":

k" = 2·303 log Vt(Vo-V<x) ... (1)t. V<x Vo(V,- V <X)

. Vt(Vo- V<x) .By plotting the value of log Vo(Vt- V<x) against

time a linear plot representing a second orderrer ction w; s obta ined. From the slopes of theplots, kh v: lues were computed. In order toexpress the results in units of litre mole"! mir.",the value of kh thus obtr ined w: s divided by N IV,where V is the volume of the rer ction mixture with,drawn for eech titration and N is the normalityof acid used.

t In the case of chloramphenicol base the ratio of alkalito chloramphenicol in alcohol was 1: 1 but for chloram-phenicol palmitate the ratio of alkali to antibiotic solutionwas 2: 1, the final concentration of antibiotic in the formercase becoming O'OIM and in the latter being 0·0067M.

TABLE 1- DEGRADATION OF CHLORAMPHENICOL ANDCHLORAMPHENICOL PALMITATE IN SODIUM HVDROXIDE

SOLUTION*

Temp.°C

(NaOH cone, = 0·02M)

kh (litre mole! min")

Stock solution Freshly prepared

SUBSTRATE: CHLORAMPHENICOL

36404550

0·80±0·051·21±0·052·07±0'03

2·40±0·056'55±O'02

14'23±0'02

SUBSTRATE: CHLORAMPHENICOL PALMITATE

3035404550

0'36±0'030'50±0'030'95±0'10 1'70±0'02

3'82±0'015·55±0·01

*Densities (glee) at temperatures 30°,35°,41°,45° and 50°are respectively 0'8607, 0'8563, 0'8525, 0·8490 and 0·8455.

TABLE 2 - ApPARENT FIRST ORDER DEGRADATION OFCHLORAMPHENICOL IN SODIUM HVDROXIDE SOLUTION

NaOHt(M)

Robs X 103 (min-l)*t

0·040'060·10

Base Ester~--------- ----------

Stock Freshly Stock Freshlysolution prepared solution prepared

3·33 8·49 1'93 6·955'58 15'42 4·66 17·046·68 53·03 8'67 52'29

*The values are the mean of at least two readings.tkobs from Eq. (1) and kobs = (k. VIJ().tDensities (g/ce) of 0'04, 0·06 and 0·10M NaOH are

respectively 0'8592, 0'8595, 0'8715.

The data on the base catalysed degrcdation ofchloramphenicol and its palmitate ester at elevatedtemperatures both in the crses of (a) stored stocksolution and (b) freshly prepared solution are givenin Table I end the overall rdte cor.stants a t 37°±O·Soof chlorr mphenicol and its palmitate ester inter-pola ted from the respective Arrhenius plots were0·99 and 0·70 litre mole"! min" for stock solutionsand 1·11 and 1·17 litre mole= mirr ' for freshlyprepa red solutions. The energies of activ. tion,Ea, for chlora mphenicol <' nd its pz lmita te ester were18·4 and 17·6 kca l/mole (stock solution) and 30·2r nd 26·8 kcalfmole (freshly prepared solution) res-pectively. The overall ra te constants at 37° wereinterpola ted from the respective Arrhenius plots.For studying the effect of wrying alkali concen-tration (from 0·02 to O·lOM) the kinetic runs wereconducted at 37·So±0·So in order to get c n ideaabout the apparent quantitative degradation ofchloramphenicol and its palmitate ester at bodytemperature. The data obtained <' re summarizedin Table 2. The brge differences in the valuesof E; end kh of (a) stock solutions and (b) freshlyprepared solutions confirm that an 'uncatalysed

NOTES

reaction' pla ys a significa n t role in the degra-dation of the antibiotic, an observation madeearlier by Higuchi et al».

The authors wish to thank Prof. D. K. Roy forhis interest.

References1. HIGUCHI, T., MARCUS, A. D. & BIAS, C. D., J. Am.

Pharm. Assoc. Sci. Ed., 43 (1954), 129. .2. HIGUCHI, T. & MARCUS, A., J. Am. Pharm. Assoc. su.

Ed., 43 (1954), 530.3. HIGUCHI, T. & BIAS, C. D., J. Am. Pharm. Assoc. Sci.

Ed., 42 (1953), 707.4. GLAZKO, A., DILL, "V. A. & REBSTOCK MILDRED, C.,

J. bioi. Chem., 83 (1950), 679. . .5. GLASSTONE, S., Text book oj physica; chemistry (Macmillan,

London), 1949, 1053.

Co(II) & Ni(II) Complexes of Glutaryl & AdipylDiacetone Hydrazones

R. C. AGGARWAL* & BACHCHA SINGH

Department of Chemistry, Banaras Hindu UniversityVaranasi 221005

Received 25 August 1977; accepted 21 December 1977

Co(II) and Ni(lI) complexes of glutaryl diacetonehydrazone (GDAH) and adipyl diacetone hydrazone(ADAH) have been prepared and characterized onthe basis of analytical, magnetic moment, conductanceand electronic and IR spectral data. Two types ofcomplexes, 1: 1 and 1: 2, are formed. Electronicspectral data suggested spin-free octahedral geometryfor 1: 2 Co(lI) complexes and tetrahedral geometryfor 1: 1 Co(lI) complexes. All the Ni(lI) complexesare octahedral.

IN a recent communication, we have reported-the synthesis and structure of certain oxovana-

dium(IV) complexes of diacetone hyd.r2 zon~s. . Inthe present note, the results of our Inves.hgatlOnon Co(II) and Ni(II) complexes of glutaryl diacetone

o 0II II

hydro zone (GDAH) [(CHa)2C=NHN -C(CH2)3C-NHN =C(CH3)2J end adipyl diacetone hydr. zone

o 0II II

(ADAH) [(CH3)2C=NHN -C-(CH2)4-C-NHN=C(CH3)2J are being reported.

All the chemic-Is used were BDH re: gents. GDAHand ADAH were prepared as described earlier",

The complexes MLC12 and ML2C12, where M=Co(II) or Ni(II) and L=GDAH or ADAH, were sy?-thesized by mixing together cold/hot ethanolic,solutions of the metal chloride and ligands in ,....,,1:1and 1:2 mola r ratios respectively. While ML2C12complexes precipitated imrnedia tely, the precipi.ta-tion of MLC12 complexes was effected by the s.dditionof ether to the rer ction mixture. All the complexesthus obtained, were suction filtered, w, shed withethanol, ether and finally dried at room tempera-ture.

----------.*Author to whom all correspondence should be addres sed.

443