Titration of Thioethers Claudlo Casalinl, Giulia Cesarano, and Giuseppe Masceliani" Research Laboratories, ALFA Farmaceutici S.p.a., Via Ragazzi del ' 99 n.5, Bologna, Italy
The conditlons for the oxldlmetric titration of alkyl and aryl thioethers and cephalosporlns have been studied. The titration takes place because of catalytic quantities of KBr, which give rise to an intermediatethat can be hydrolyzed to the sulfoxide. The operating conditions are described and a hypothesis is put forward concerning the mechanism of the reaction.
With the aim of investigating the nucleophilic character of thioethers of pharmaceutical interest, and in order to develop rapid and precise methods for the analysis of products and intermediates containing the R-S-R' group, we have continued our study on the possibility of titrating them by potentiometric techniques. Having developed analytical methods for the titration of thioethers as weak bases in nonaqueous media (1, 2 ) , we considered the possibility of oxidizing even compounds such as diphenyl thioether and its analogues for analytical purposes, for which no oxidimetric titration methods yet exist (3), or which require, when existing, special operating conditions (4). The ability of thioethers to take part in addition reactions with halogens, forming derivatives of the type:
is well known. In an aqueous acidic environment these derivatives give rise to the corresponding sulfoxides (5). Bromine (or NBS (6)) readily forms compounds of the type indicated above (better than the other halogens) under ordinary reaction conditions (7). We therefore hypothesized that the addition of catalytic quantities of bromine water to the medium in which the oxidimetric titration of the thioethers is being carried out should render possible, or improve, their titration, with definite analytical advantages. If the hypothesis concerning the possible formation of dihalogen derivatives were valid for all sulfides, then even the most unreactive thioethers should be readily oxidized to sulfoxides with an oxidizing agent of appropriate strength, such as a salt of tetravalent lead for example, provided that traces of bromine were present. Rather than using bromine itself, we should also obtain the same results with KBr, which give rise to bromine in an oxidizing medium. The experimental results have confirmed our hypotheses.
EXPERIMENTAL A Mettler automatic titrator was used, with platinum saturated calomel electrodes. The solution to be titrated contained approximately 2.5 X 10" mol of the thioether and approximately 2.5 X lo4 mol of KBr or 1.2 X mol of bromine in about 70 ml of a 70% solution of acetic acid water. KBr was preferred to bromine water. Lead tetraacetate (0.1 N) was used as the titrant. Standardization of the titrant was carried out with hydroquinone according to Berka's method (8). At the beginning the titrant was added at a rate of 4 mL/min. In the proximity of the potential jump the titrator adjusted automatically the delivery rate of the titrant to the shape 1002
ANALYTICAL CHEMISTRY, VOL. 49, NO. 7, JUNE 1977
of the potentiometric curves. The reaction rate was comparable to that of the usual neutralization reactions. By conventional techniques the compounds undergoing the oxidimetric titration were shown to be of a high degree of purity. The used techniques were GLC (compounds 1, 4, and 6), UV (compounds 4-13), and potentiometric titrations of the amino group (compounds 2 and 3). Compounds 2,3 and its sulfoxide, and 5 were synthesized by V. Borzatta (Synthesis Laboratories, Alfa Farmaceutici). Compounds 11, 13, and the sulfoxide of 13 were prepared by V. Cannata (Alfa Chimica Italiana) (9). Compound 8, was synthesized by methods described elsewhere (IO). The other samples were obtained commercially.
RESULTS AND DISCUSSION The method described above was applied to alkyl thioethers, aryl alkyl thioethers, diphenyl thioether, and the cyclic thioether contained in the cephalosporins. Table I shows the purity and accuracy obtained with the compounds under study. Figures 1-3 show the potentiometric curves for some of the compounds. The influence of bromine in the titrations is clear; in some cases there is a large increase in the potential jump (compare curves 2a and 2c for thioanisole in Figure 2), and in others the titration is only possible in the presence of bromine (e.g., diphenyl thioether Figure 1 and the cephalosporins in Figure 3). As to the titration, the same result is obtained with bromine water, NBS, or potassium bromide. With NBS in some cases of titration of thioethers we have noted, a t least in the first part, sharper potentiometric curves. For practical reasons we used potassium bromide. For a good titration the minimum quantity of the catalyst is 1 mol of potassium bromide to 100 mol of the compound being titrated. Two titration curves for thioanisole are shown in Figure 2, one in the presence of KBr (curve 2c, mole ratio of KBr to compound of 1:lOO) the other in the presence of a large excess of KBr (curve 2d). Two inflections can be seen on curve 2d, the first corresponding to oxidation of the thioether, the second to oxidation of the residual Br- to Brz. The explanation for this phenomenon may be as follows: in the presence of an oxidizing agent the following reaction commences:
ox
2Br- -+ Br, Immediately the following series of reactions is preferred: (3)
S+-Br
1
.Br- HOAc/H,O,
R 'S=O /
+
2HBr
(4)
The hydrobromic acid liberated is continuously oxidized by the oxidizing agent added during the titration and is immediately used up in reaction 3. The redox system is thus complex and is represented by the first section of the potentiometric curve. The system in reaction 2 is only established in solution when all of the thioether has reacted and when an excess of KBr
Table I. Compounds Examineda
!\';:
COYPOUI D S
I.
CH3-CH2-S-CH2-CH3
I
2
4!9 @
PRECISION
__
PURITY f O U N 0 BY OTHER METHODS
x
(01
vi-
97.3
0.557
0.227
97.7
96.6
0.585
0.239
97.1
x
3
~-s-(cH~)~-NH-(cH~)~-cH
99 4
0 228
0.093
99.8
4
@-S-CHJ
99 1
0.640
0.261
97.6
101,9
0.388
0.158
99,3
99 2
0 236
0.086
99.0
7
n
n
H
170.
1063
0 434
98 6
a
n
OCOCH3
H
88.2.
0.621
0.253
110.2
9
@-CH-CO
n
H
17 7
0.895
0.365
98.8
MI
0177
0 358
96 7
"2
IO
cH-cn2-co
ococn3
11
H
H
CH2-CCI3
98 6
0 340
0139
99 2
OCOCHj
Wi
97 7
0 280
0 I14
95 5
H
CH2@N02
991
0 984
0 402
98 8
"2 12
CH-(CH2l3-CO
coon 13
(g-O-CI12-C0
a Compounds 7 and 8 were treated with 5 mL of acetic anhydride and 5 mL of acetic acid. On dissolution (formation of amide), the sample was diluted with 70% acetic acid and titrated as described in the Experimental section.
is used. Thus, in agreement with the redox potentials, the titration curve, representing the completion of reaction 2, can be seen from the graphs only at the end of the oxidation process. Therefore, traces of catalyst-like acting KBr (or some other) are sufficient to bring about the oxidation of thioethers to sulfoxides. When the amount of catalyst is increased there is no substantial benefit as regards the sharpness of the potentiometric curve. In cases in which the titration curve does not permit a clear differentiation between the potential jump associated with oxidation of the thioether and that associated with oxidation of the bromide (e.g., cephalosporins), it is acceptable, for analytical purposes, to carry out a blank titration with the solvent containing the appropriate amount of catalyst and to
subtract the corresponding volume of titrant from the subsequent titration. The nature of the titration products has been confirmed by comparative chromatographic and spectrometric analyses of the oxidation product of compound 3. The latter was oxidized with the stoichiometric quantity of 40% peracetic acid in methanol; the product, isolated and recrystallized from acetonitrile/ethyl acetate, was shown on elemental analysis to correspond to the sulfoxide: ,,,A a t 239 nm in 70% HOAc/H20; Rf0.49 compared to starting compound 3 on TLC; solvent system = isoamyl acetate:methanol:formic acid:water (60:20:5:6). The solution obtained from the oxidimetric titration of compound 3 was shown to behave under UV and on TLC identically with an authentic sample of sulfoxide prepared ANALYTICAL CHEMISTRY, VOL. 49, NO. 7, JUNE 1977
1003
t
t
1
mv
mV
1
2
3
4
5
6
l m l 8
I
*
Figure 1. Potentiometric titration of diphenyl thioether in 70% acetic acid with 0.1 N Pb(CH3C00)4. Curve la (0):in the presence of KBr (mole ratio of KBr to compound of 1:lOO). A small inflection corresponding to the titration of KBr can be seen in the upper part of the curve. Curve l b (0): in the absence of KBr
i
-
i b 6 m l Flgure 3. Potentiometric titration of cephalosporins with 0.1 N Pb(CH3C00)4in 70% acetic acid. Curve 3a (0):cephalexin titrated in the presence of KBr (mole ratio of KBr to compound of 1:lOO). Curve 3 b (W): cephalosporin C sodium salt in the presence of KBr. Curve 3c (0): cephalosporin C sodium salt in the absence of KBr
i
i
as the sulfoxide of compound 13 obtained separately (9). The
R f value for this sulfoxide was 0.7 compared with the phenoxydesacetoxycephalosporin p-nitrobenzyl ester (compound 13). As was to be expected, because of the instability of the complex shown in Equation 1 and the poor reactivity of the components, neither chlorine nor iodine catalyzed the oxidation of the thioethers to sulfoxides. In our experience, in agreement with SuchomelovB et al. (3), the best medium for the titration was 70% aqueous acetic acid. We have extended this method, still in the experimental stage, to the analysis of penicillins. However, the results have not been encouraging: probably the rather vigorous conditions prevailing in the titration medium partially degrade this class of antibiotics, thus casting doubt on the analytical reliability.
1000.
900.
800.
700.
600.
LITERATURE CITED
300
t
i 2 3 4 5 6 7al 0.1N Figure 2. Titration of thioanisole with 0.1 N Pb(CH,C00)4. Curve 2a (0):thioanisole tRrated in 70% acetic acid. Curve 2b (A):thioanisole titrated in 50% acetic acid. Curve 2c (0):thioanisole titrated in 70% acetic acid with the addition of KBr (mole ratio of KBr to compound of 1:lOO). Curve 2d (W): thioanisole titrated in 70% acetic acid with a large excess of KBr separately as described above. Furthermore, by means of TLC with the solvent system described above, it was shown that the compound contained in the titration solution of the cephalosporin 13 was the same
1004
ANALYTICAL CHEMISTRY, VOL. 49, NO. 7,JUNE 1977
(1) G. Mascellani and C. Casalini, Anal. Chem., 47, 2468 (1975). (2) C. Casalini, G. Cesarano, and G. Mascellani, Farmaco Ed. Pr., 31, 447 (1976). (3) L. Suchomeiovl, V. Horlk, and J. Zqka, Microchem. J . , 9, 201 (1965); Chem. Abstr.. 63, 10691d (1965). (4) K. G. Haeusler, R. Geyer, and S. Rennhak, Z.Chem., 14, 483 (1974); Chem. Abstr., 82, 1 0 5 9 9 2 ~(1975). (5) E. Fromm and G. Raiziss, Justus Lieblgs Ann. Chem., 374, 90 (1910). (6) R. Harville and S. F. Reed, Jr., J . Org. Chem., 33, 3976 (1968). (7) K. Fries and W. Vogt, Justus Liebigs Ann. Chem., 381, 340 (1911). (8) A. Berka and J. Zqka, Chem. Listy, 52, 926 (1958); Chem. Abstr., 53, 39731 (1959). (9) Belgian Patents 755256 and 755261. (10) R. Andrisano, G. Guerra, and G. Mascellani, J. Appl. Chem. Bbtechnol., 26, 459 (1976).
RECEIVED for review November 23, 1976. Accepted January 31, 1977.
