symmetrical and the maximum occurs a t the same potential as obtained with zero uncompensated resistance. The height of the derivative wave is, of course, still less than that of the zero resistance wave becaust: of the decrease in true scan rate when R ( d i / d t ) is non-zero. -1s a result, the half peak width is increasrd over the zero-resistance value o f ‘!)6 niv. I n terms of Equation 27 for t h e half-peak width, this correction of t h c voltage axis eliminates the first two terms and leaves only the log term. which includes the t ieoretiral value of !)O.O - nii-, plus a correction factor \vhich TL inc,rea;tls the peak-width because of the tlecrtme in true scan rate during the wave. I n gciirral, the peak-height results are more ?:4tisfactory tklan the half-peak width rleterminationa. A number of fnrtors. in addition to the lag, con-triliutr to this result. First. the mt~asrirenientof the xidth at half-peak height requires that d i l d t be e v a l u a t ~ l indepriidently of di,,’dt. This can be done only approximately if uncompensated resistance i:, involved because o f thc depression of the residual current tlerivative curve during the n-ave E q u a t i o n 12). Second. at high resistzinccs the derivative n a v e is srverely
d r a n n out and the trailing edge is often very noisy. The measurement of the width becomes some\\-hat arbitrary in this case. Finally, aside from the experimental difficulties involved, the theoretical Equation 27 is very troublesome to evaluate; however, as a n alternative, the empirical Equation 29 could be used much more conveniently. Thus, though the equations appear to represent peak widths quite n ell, the complications inherent in their application limit their usefulness. Equation 19 and its rearranged form, Equation 28, \vhich relate derivative peak-height, residual current, and uncompensated resistance, have been found to be very useful in detecting and evaluating uncompensated resistance betneen the D.1I.E. and the reference electrode probe in truly high-resistance solutions-Le., in nonaqueous solutions of high specific resistance. .inother very useful feature of Equation 28 is that the value of n can be obtained from the intercept e\pression. The results of some nonaqueous studies nil1 he prew i t e d in a subsequent paper. LITERATURE CITED
Lloyd, S . A., ( 1 Arthur, P., Lewis, P. 4., Vanderkam, R . K., A 4 s a ~CHEM. . 33, 458 (1961).
(2) e t h u r , P., Vanderkam, R. H., I b i d . p. 165. (3) Brdicka, R., Collection Czech. C h e m Conmun. 8, 419 (1936). (4) Cooke, W.D., Kelley, N. T., Fisher, D. J., ANAL.CHEM.33,1209 (1961). (5) Devay, J., Acta Chini. Hung. TOIMLS. 35,265 (1963). (6) Ilkovic, D., Collection Czech. Chem. Comnaun. 8, 13 (1936). ( 7 ) Jackson, W., Jr., Elving, P. J., .ISAL. CHEM.28, 375 (1956). (8) Kaspar, C., Trans. Electroche:u. SOC. 77,357 (1940); 78,131 (1940). (9) Kelley, M. T., Jones, H. C., Fisher, D. J., ANAL.CHEJI. 31, 1475 (I{I59). (10) Kelley, 31. T., Fisher, D. J., Jones, H. C., Ibid., 32, 1262 (1960). ( 11) Kelley, M. T., Fisher, D. J., Jones, H. C., “Advances in Polarography,” I. S. Longmuir, ed., Vol. I, p. 15% Pergamon Press, 1959. (12) Kolthoff, I. M., nlarshall, J. C., GuDta. S. I,.. J . Electroanal. Cheni. 3. 20s’ (1962). (13) Lingane, J. J., Williams, R., J . . L n e . Chem. SOC.74, 790 (1952). (14) Xicholson, M. &I., ANAL CHEV. 27, 1364 (1955). RECEIVEDfor review July li, 1963. Accepted October 28, 1963. Presented in part at Division of Analytical Chemistrv, 142nd and 145th Meetings, ACS. -4tlantic City U.J., September 1962, and New York, ;Vi September 1963. Work supported by a grant from the E. S. Atomic Energy Commission, Contract S o . AT(11-1)-256. Taken in part from the Ph.1). thesis of Peter 8. RIcKinney. Contribution 30,1160 from the L3epartnient of Chemistry, Indiana University.
.
Deter min(It io n of p -ChIo roa ceta niIide in Phenacetin: A Polarographic Method RICHARD JONES anti BRIAN C. PAGE Pharmacy Departmeni, University of Sydney, Sydney, Australia
b A polarographic method for the determination of p-chloroacetanilide in a large excess of phenacetin (p-ethoxyacetanilide) has been developed. A series of commercial samples of phenacetin has been analyzed for p-chloroucetanilide, and the results obtained b y the polarographic method have been compared with ihose from a volumetric determination. The estimation described in this icommunication i s simple and accurate. The polarographic wave given b y p-chloroacetanilide i s shown to represent the addition of two electrons, and logarithmic analysis demonstrates that the overall reaction i s irreversible.
I
N THE 1\IAKVFACTURC OF P H E S A C C T I S ,
p-cliloroacetanilide is a n intermediate and is therefore usually present as a n impurity in pharm,iceutical prellarations containing phmacetin. It has l hy Gad and his cobeen ~ v e l established
n-orkers ( 5 ) that p-chloroacetanilide causes methaemoglobinemia. Indeed, Hald observed cyanosis in patients ivho had taken significant quantities of phenacetin, which was subsequently shoirn to contain 18% of the chloroderivative (1 I ) . This led Hald to advocate a limit of 0.15y0 for p-chloroacetanilide in phenacetin ( 9 ) , and before long several countries imposed limits of this order of magnitude. The only mcthod available for the determination of p-chloroacetanilide in phenacetin vas developed by Hald ( I O ) , and involves the hydrogenolysis of the C-Cl bond with Raney nickel follon-ed by titration of the chloride in the usual manner. This method is rather time consuming. especially when the estimation has to he carried out on mistures of aspirin, phenacetin, and caffeine (A.P.C. preparations.) I n addition, the end point of the titration is difficult to detect, and the results obtained are not always reproducihle.
This communication describes a polarogra1)hic method for the estimation of p-chloroacetanilide in phenacetin, n hich affords good reproducibility, and has the advantage of being speedy and sim1)le. No mention of the polarographic reduction of p-chloroacetanilide could be found in the literature. Gergely and Iredale (6) demonstrated that iodobenzene is reduced a t -1.616 volts z’s. the S.C.E., and some iodonaphthalents have been studied by Ranianathan and Subrahmanya (81) in aqueous miltures of ethanol, acetone. and dioxan. Serera1 groups (15, 20, 23) tried unsuccessfully to detect a reduction step for the more difficultly reducible chlorobenzene. However, comparatively recently, Lambert (I 7 ) shon ed that by employing dimethylformamide (D.M.F.) as solvent \T ith tetraethylammonium iodide (Et4T\’I) as supporting electrolyte, it is possible to study reductions a t very negative potentials. Subsequently VOL 36, NO, 1, JANUARY 1964
35
IO
Current
P,
a.
5
log
-0.5v
0
-I.OV Voltogc
VI
-1.5v Hg pool.
-2.ov
+- 1.0 -
Vol 1 s
-.dd Vi
b. fl
I
-0.5v
-I.OV Voltage
-1.5v vS
Hg
Log-plot of reduction step shown in Figure 1
II
I] 0
Figure 2.
Y
-2.ov pool.
Figure 1 . Polarographic steps due to p-chloroacetanilide in D.M.F. and Et4NI (0.1M) a.
b.
Normal C / V plot Derivative plot
Lambert and Iiobayashi (19) reported that chlorobenzene reduced at - 2.58 volts us. S.C.E. The advantages of D.iI1.F. as a polarographic solvent have been realized by other workers. S o t only is it a very po\verful solvent, but it is aprotic in nature, a property which frequently stabilizes radical ions thus enabling the reaction mechanism at the electrode to be interpreted more readily. To cite a single example, Wawzonek et al. studied a great number of olefinic and aromatic hydrocarbons in D.M.F. (as). General aspects regarding the use of organic solvents in polarography are well summarized by Given and Peover in a recent review article ( 7 ) . The present authors have found that p-chloroacetanilide gives a clearly discernible wave in D.M.F., whereas phenacetin is not reduced before the electrolyte. This situation is the basis for the method described herein. EXPERIMENTAL
A Tinsley pen-recording polarograph and electrode assembly were used to obtain the polarograms. All determinations were carried out in D.31.F. with 0.1JI E 4 S I as electrolyte, at 30' C. i0.5' C. Solutions were deoxygenated by passing oxygen-free nitrogen through them for at least 15 minutes as advocated by Arthur and Lyons ( 1 ) . Direct and derivative curves were recorded at sensitivities chosen t o produce a convenient step height. These were usually 20 and 10 for the direct, and 2 and 5 for the derivative polarograms (the 36
ANALYTICAL CHEMISTRY
quently the phenacetin was recovered by filtration and dried. The national origin of these samples is given in Table I.
sensitivity figures represent the number of microamperes required for a full scale deflection). D.M.F. of commercial quality was purified by the first of four methods described by Thomas and Rochow (24), after which deoxygenated solvent and electrolyte sho\ved no reduction steps a t the greatest sensitivity used. EtdNI was recrystallized from ethanol and dried for 2 hours under vacuum at 60' C. Phenacetin free from p-chloroacetanilide was synthesized from p-aminophenol as described by Vogel (65). The phenacetin obtained was recrystallized twice from ethanol to give white flakes, m.p. 136' C. Relative viscosity measurements were made by timing a knoa-n volume of liquid flowing through a capillary. Of the four samples analyzed, three were bulk phenacetin and one was extracted from a commercial A.P.C. preparation by digesting the mixture in aqueous sodium bicarbonate solution. Under these conditions, only the phenacetin was insoluble, providing that the volume of solvent was sufficiently large to keep the caffeine in solution. Conse-
RESULTS A N D DISCUSSION
Polarography of p-Chloroacetanilide. Both chlorobenzene and p chloroacetanilide gave characteristic reduction waves with half wave potentials -2.01 and -2.06 volts zs. the mercury pool, respectively. Direct and derivative polarograms for p-chloroacetanilide are shonn in Figure 1. It has been established (8) that the mercury pool constitutes a stable reference electrode in the presence of halide ions, therefore all voltages are referred to the mercury pool. Since no external reference electrode in1 olving salt bridges was used, correction for iR drop in the electrode circuit was unnecessary. The mercury pool anode \\as usually a t a potential of -0.5 volts relative to the S.C.E , and El values is. the mercury pool were convertpd t o values us. the S.C.E. by adding the appropiiate measurement. The present authors did not determine this, but bv using the value of -0.50 volts recorded by Given, Peover and Schoen (a), the E L value for chlorobenzene given above is in good agreement with that quoted I -2.58 2s S.C.E.) in the literature ( 1 31. The electrode characteristics of the capillary used over the range 0.0 olt to 2.0 T olt. n ere determined. U71irn a 110-
Table I. Estimation of p-Chloroacetanilide in Commercial Samples of Phenacetin, by Polarographic and Volumetric Methods
Sample of phenacetin Bulk sample 1 (U.K.) Bulk sample 2 (China) Bulk sample 3 (U.S.S.R.) A.P.C. sample (U.K.)
p-Chloroacetanilide content, ___ (;c~PolaroeraDhic 1-olumetric method method 0.114 0.101 0.371 0.290 0,380 0.335 0.101 0.132
tential of -2.06 volts was applied to the cell, the value of r n z 4 1 f 6is 1.411 mg 2'3 second1'6, where rn is the weight of mercury delivered by the capillary in one second and t is the dr ~p time in seconds. From this the diffusicn current constant (I= id/Crn2/3t1f6) for ,u-chloroacetanilide in D.M.F. was found to be 3.49. The diffusion current (ste 3 height) in microamperes is i d and C is, the concentration of the reducible speciw in millimoles per liter. -4 reversible elect "ode reaction will obey the general Heyrovskg-Ilkovic relationship (16) s h o m in Equation 1, where E is the applied E = Em
+ 2 303RT nF
.
id
=
Figure 3. A. 6.
Calibration curve
No phenacetin present 10% w./v. phenacetin present
-i
log10 7(1)
potential which prodices a current i, R is the universal gas constant, T is the absolute temperature n is the number of electrons involved in the reduction step and F is the Faraday A graph of loglo (id-i)/ivs. E will give a straight line with slope 2.303RTlizF (60.1 millivolts for n = 1 a t 30" C.) for a reversible reaction. By measuring the slope of the log-plot, the value of n can be determined (logarithmic analysis). The logplot of the reducticn step shown in Figure 1 is given in Figure 2. The curve is linear between - 1.95 and - 2.20 volts, and on either side of these values deviation from linez rity is apparent, though this could well be due to the difficulty encountered in determining the values of i a t the beginning and end of the wave where eriors are magnified. The slope of the lintkar portion of the curve is 130 millivolts which gives n a value 0.462. This :onclusion is unacceptable and can only lead to the assumption that the reaction is irreversible. The number of electrons involved in the reaction cannot therefore be determined from the log-plot but it can be found from the Ilkovic equation, Equation 2 (13). Id
W I of ~ ~ c h l o ~ o ~ c c l o n Mg ~l~dr
605nFCD'1~in~1~t~
(2)
I n Equation 2 the only symbol not previously described is D which is the diffusion coefficient. ProTTided that an estimate of the value of 1)is possible, n can be determined. This is usually accomplished by using a calue of D for a similar species in a similar solvent. Jones and Spotswood (14) reported the value of I (which is a function of D) for the single electron acidition to anthraquinone in D.M.F. as 1.60. Comparing this with the value of I for p-chloroacetanilide (3.49) in rhe present work, shows that n is most likely 2. The reduction mechinism for aliphatic halides a t the dropp ng mercury electrode has been discusfed (4, 12, I S , 82). It is probable that th; reaction mechanism for aromatic halides is similar. The indications that the reduction process is irreversible (front the log-plot) and
caused by the presence of phenacetin. Of the parameters upon which i d depends, only D would be expected to alter when phenacetin is added. It seems therefore that the explanation for the increase in step height lies here. The diffusion coefficient is related to the mobility of the species in question, and this in turn to the viscosity of the solution according to the Stokes-Einstein law (3) shov-n in Equation 3, where K is the Avogadro Number, r is the radius of the molecule and 9 is the viscosity.
that the v a v e represents a two electron addition (from the wave height) is in keeping with this. Quantitative Determination of pChloroacetanilide by the Polarographic Method. T'arying weights of p-chloroacetanilide in 5 ml. of solution gave diffusion currents shown graphically in Figure 3. The half-wave potential v-as independent of concentration, and the results show t h a t the diffusion current varies linearly with the concentration of p-chloroacetanilide (see curve A , Figure 3). Derivative polarograms gave distinct peaks whose heights showed a similar linear relationship. mhile the derivative curve allowed the half-wave potential to be observed with greater precision, the higher sensitivity setting of the instrument required for these determinations rendered their precision less reliable. Estimation of the p-chloroacetanilide in the commercial samples of phenacetin, by the volumetric method (IO), showed the presence of amounts of impurity varying between 0.1 and 3.40/,. It mas therefore necessary that 500 mg. of phenacetin should be present in 5 ml. of solution, in order that sufficient chloroderivative will be included for estimation. Phenacetin is readily soluble in D.1I.F. t o this extent. The diffusion currents obtained for varying weights of p-chloroacetanilide in 5 ml. of solution containing 500 mg. of phenacetin were measured and it can be seen that these values do not lie on curve A as might be anticipated. Instead a different calibration graph, curve B, is obtained (Figure 3) when phenacetin is present, yet a linear relation again is evident, with the slope of curve B greater than that of curve A . Dilution studies have shown that the slope of curve B reverts to that for curve A as the concentration of phenacetin is decreased; this observation, together with the fact that curve B also passes through the origin, demonstrates that it is the phenacetin, rather than merely some impurity, which is causing the increase in diffusion current. I t is difficult to explain this increase in diffusion current of the order of 10%
Therefore if the relative viscosity of D.M.F. containing 1Oy0 phenacetin is 3oQ/, less than that of D.hl.F. alone, the increase in diffusion current would be satisfactorily accounted for. HOWever, viscosity measurements showed that in fact the pure D.M.F. was slightly less viscous than the solution of phenacetin in D.M.F. On the other hand it must be remembered that the speed of diffusion is probably determined by interactions a t the molecular level rather than by the macroscopically measured viscosity. =Inother factor which could alter the apparent diffusion current is the determination of step height. It is evident frompigure 1 that the shape of the curve after -2.23 volts is mere conjecture since the electrolyte decomposes at this point. It is possible that the apparent increase in id rvhen phenacetin is added, is due to a change in the shape of the curve after -2.23 volts, and that if the whole plot \$-ere available for analysis, different values of idwould be measured. However, provided that a linear calibration curve can be readily obtained, the method is still sound from an analytical point of view. The analyses of several commercial samples of phenacetin by the volumetric and polarographic niethodsarecompared in Table I. The polarographic method gives results which although they are the same order of magnitude differ significantly from those obtained by the chemical method. I t is evident that in most cases the volumetric method gives higher values, and we feel that the most likely source of error lies in the detection of the end point of the titration. It is probable that the polarographic method is more reliable because it was found that results rvere wadily reproducible by this method and a linear calibration curve passing through the origin was obtained. The volumetric method did not give results with such good reproducibility. Two out of four of the commercial samples contained amounts of p-chloroacetanilide which exceed the limit of impurity (0.1696%) given in the British Pharmacopoeia ( 2 ) . It is hoped to extend this method to VOL. 36, NO. 1, JANUARY 1964
37
the direct determination of A.P.C. preparations so t h a t the need t o extract the phenacetin will be obviated. ACKNOWLEDGMENT
Sincere thanks are extended to several members of this department, in particular S. E. Wright and -4.J. Ryan for their help and advice. Also, rve are grateful to H. H. Bauer of the Department of Agriculture, Sydney University, for discussions concerning the theoretical aspects of this work. LITERATURE CITED
(1) Arthur, P., Lyons, H., Asar,. CHEY. 24, 1422 (1952). (2) British Pharmacopoeia, p. 476, Pharmaceutical Press, London, 1958. (3) Einstein, A., Ann. Physik. 17, 549 (1905); Z. Electrochem. 14, 235 (1908). (4) Elving, P. J., Record Chem. Proyr. Kresye-Hooker Sci. Lib. 14, 99 (1953). (5) Gad, I., Jacobsen, E., Madsen, P.,
Schmith, K., Ugeskrijt Laeger 112, 1405 (1950). (6) Gergely, E., Iredale, T., J . Chem. SOC. 1951, 13. (7) Given, P. H., Peover, M. E. , Proc. 2nd Intern. Polaroq. Conar.. Cambridae 3, 948 (1961). (8) Given, P. H., Peover, >I. E., Schoen, J. M., J . Chem. SOC.1958, 2680. (9) Hald, J., Acta Pharm. Intern. 2, 27 (1951). (10) Ibad., p. 87. (11) Hald, J., Dansk Tidsskr. Farm. 24, 183 (1950). (12) Hush, N. P., 2. Electrochem. 61, 734 I
,
I
.
IlRo7i.
(13)-1lkbvic, D., Coollection Czech. Chena. Commun. 6 , 498 (1934). (14) Jones, R., Spotswood, T. hIcL., Australian J . Chenz. 15, 492 (1962). (15) Keller. H., Hochweber. M., von Halban. H.. h e l c : Chim. l c t a 29.761 (1946). (1:) Kolthoff, I.,, I. M.,Lingane, ‘J. J:, Polarography,” p. 168, Interscience, Polarography, NPW New Vork York, 1048 1948. (17) (1jj-iLambert, F. L., . 4 s a ~ .CHEX 30, 1018 (1958). (18) Lambert, F. L., Kobayashi, IC, J . Am. Chem. SOC.82, 5324 (1960).
(19) Lambert, F. L., Kobayashi, K., J . Org. Chem. 23, 773 (1958). (20) Levin, E. S., Fodiman, Z. I., Zh. Fiz. Khinz. 28. 601 (1954). (21) Ramanathk, C. S., Subrahmanya, R. S., Proc. Indian Acad. Sci. 48A, 62 (1958). (22) Rosenthal, I., Albright, C. H., Elving, P. J., J. Electrochem. SOC.99, 227 (1952). (23) Stackelberg, M. von, Stracke, K., 2. Electrochem. 53, 118 (1949). (24) Thomas, A. B., Rochow, E. G., J . Am. Chem. SOC.79, 1843 (!957). (25) Vogel, A. I., “Practical Organic Chemistry,” 3rd ed., p. 996, Longmans, Green and Go., London, 1961. (26) Wawzonek, S., Blaha, E. W., Berkey, R., Runner, hl. E., J . Electrochem. SOC. 102, 235 (1955).
~
RECEIVED for review May 13, 1963. Accepted October 3, 1963. This work was carried out with financial support from Grant EF-258, Sational Institute of Health, U.S. Public Health Service.
Chronopotentiometry of the Bromide-Bromine Couple at Platinum and Carbon Paste Electrodes D. G. DAVIS and M. E. EVERHART Department o f Chemistry, Louisiana State University in New Orleans, New Orleans 22, l a .
b The bromide-bromine couple has been studied at both platinum and carbon paste electrodes b y chronopotentiometry. This couple behaves irreversibly at carbon paste electrodes. Bromide ion can b e determined using both electrodes but accurate results for bromine are found only with platinum electrodes. Bromine i s absorbed on the carbon paste electrodes as shown by current reversal chronopotentiometry.
platinum electrodes due to an interesting absorption phenomena. The electrochemi3try of the bromidebromine couple a t noble metal electrodes has recently been reviewed by Vetter ( I S ) and a mechanism proposed for the electrode reaction through an impedance study (1). No nork with bromide ion on carbon pa.te electrodes has been reported, although the oxidation of iodide ion ha3 been studied (S).
I
The apparatus used to supply a constant electrolysis current and to record chronopotentiograms was the same as previously reported ( 3 ) . The cell used was similar to that described by Bard (1) and incorporated a working electrode of either the shielded platinum type ( 1 ) or carbon paste (8). The other features of the cell and the experimental procedures for taking chronopotentiograms have also been reported (4). Transition times were taken at the points where the potential time curve became linear. Currents were varied to give transition times in the range of 2 to 60 seconds. Carbon paste electrodes Ivere prepared by the procedures of Olson and Adams (8)using both Xujol and bromonaphthalene as pasting liquids. The electrode used for the majority of the work was composed of 7 grams of
EXPERIMENTAL
to make use of carbon paste electrodes ( 8 ) in these laboratoriej met with many difficulties, including irreversible behavior, much more pronounced than is usually found at platinum electrodes. For instance, ferric ion in dilute sulfuric acid was not reduced until 0 volts us. SCE at carbon paqte and hydroxylamine was not oxidized a t all ( 2 ) . Some other systems appear to behave essentially reversibly (8). Further study indicated that a comparison of the electrochemistry of the bromide-bromine couple a t carbon pasta and platinum electrodes would be of interest and that the analysis of bromide solutions at both of the electrodes could be accomplished. The determination of bromine. however. iq only practical at 38
N I ~ I A L ATTEMPTS
ANALYTICAL CHEMISTRY
powdered spectroscopic graphite (Sational Carbon Go. SP-2) mixed with about 4 ml. of Nujol. S u j o l was preferred because of its slightly greater anodic range (8). Bromonaphthalene electrodes proved to be very similar in properties to those using Nujol, but the latter has the added advantage that i t is odorless and nonvolatile. A few runs were made in which oxygen from the air was removed with purified nitrogen. I n most cases this nas not done since no reduction nave for oxygen was found at carbon paste electrodes for the current densities and potential ranges used. Reagent grade chemicals were used throughout this work. Solutions of bromine were standardized by controlled potential coulometric analysis using a n Analytical Instruments potentiostat and current integrator. RESULTS A N D DISCUSSION
I The Constancy of i ~ l ’ ~ / C Table . shows values of i ~ l ’ ~ /(TI Chere 7 i4 the tranqition time in Ceconds, C is the concentration in moles per cm.3and i is the current in ampere.) for the oxidation of bromide ion at various concentrations. Good analytical rebults are obtained as long as the concentration iz above about 2mX. At lower concentrations , ’ C off and, the average value of ~ T ~ ’ ~ fall> a t 1Pa.t on carbon paste electrode-. 1- no
