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Notes The Role of Lipophilicity in Oxidation of Mustard Gas Analogues from Micellar Solutions
Scheme 1. Oxidation Products of Yperite
F. Gonzaga, E. Perez, I. Rico-Lattes,* and A. Lattes Laboratoire des IMRCP, UMR CNRS 5623, Universite´ Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex, France
Scheme 2. Structure of MMPP
Received November 24, 1998. In Final Form: May 17, 1999
Introduction Dichloro-2,2′-diethyl sulfide, known as mustard gas or yperite, is a chemical warfare agent first used in World War I. Large amounts of this compound are still stockpiled throughout the world. The compound attacks mucous membranes, skin, eyes, and the respiratory tract and is a lethal alkylating agent at low doses.1 Until the 1980s, yperite was mainly destroyed by incineration. However, incineration of contaminated compounds incurs the additional hazard of transportation to the site of incineration. More biocompatible methods are required for in situ destruction of the compound. Since the corresponding sulfoxide is relatively harmless, we studied here degradation by oxidation (Scheme 1). However, oxidation may also give rise to the sulfone, which is somewhat toxic.2 A method for rapid detoxification is thus required that favors production of the sulfoxide. Various oxidizing agents have been used for this decontamination reaction, including hypochlorites,3 peracids of the oxone type,4 oxaziridines,5 peroxides,6 or magnesium monoperoxyphthalate (MMPP).7 MMPP was employed in the present experiments (Scheme 2). In a recent review of the hydrolysis of toxic organophosphorus compounds,8 we described the interest of organized molecular systems as reaction media. There appear to have been few studies on the use of such media for degradation of sulfur-containing compounds, although they would appear to offer considerable advantages for a rapid and chemoselective reaction. Drago reported the advantages of phase transfer for oxidation of sulfur compounds with sodium hypochlorite,9 while Lion employed MMPP successfully both with and without surfactant.7 Menger employed a microemulsion medium to (1) Somani, S. M. In Chemical Warfare Agents; Somani, S. M., Ed.; San Diego, 1992; Chapter 2, pp 13-50. (2) (a) Davis, F. A.; Jenkins, R. H.; Yocklovich, S. G. Tetrahedron Lett. 1978, 517. (b) Anslow, J. R.; Karnofsky, D. A.; Valjager, B.; Smith, H. W J. Pharmacol. Exptl. Therap. 1948, 93, 1-9. (3) Yang, Y. C.; Baker, J. A.; Ward, J. R. Chem. Rev. 1992, 92, 1729 and cited references. (4) Leblanc, A.; Fosset, L.; Magnaud, G.; Desgranges, M.; SentenacRoumanou, H.; Lion, C.; Charvy, C.; Mohri, A. Phosphorus. Sulfur. Silicon 1993, 79, 141. (5) Yang, Y. C.; Szafraniec, L. L.; Beaudry, W. T. J. Org. Chem. 1990, 55, 3664. (6) Drago, R. S. Coord. Chem. Rev. 1992, 117, 185. (7) Delmas, G.; Desgranges, M.; Lion, C.; Magnaud, M.; SentenacRoumanou, H. French Patent 1991, No. C2676368. (8) Segues, B.; Perez, E.; Rico-Lattes, I.; Riviere, M.; Lattes, A. Bull. Soc. Chim. Fr. 1996, 133, 925-937. (9) Ramsden, J. H.; Drago, R. S.; Riley, R. J. Am. Chem. Soc. 1989, 111, 1, 3958.
Scheme 3. Postulated Equilibrium between MMPP and Formamide
form the sulfoxide of the half-mustard Cl-CH2CH2-SCH2CH3 with sodium hypochlorite.10 These examples point to the interest of organized aqueous media for decontamination of yperite. We studied here the oxidation of sulfur compounds in micellar or mixed micellar media (water + structured polar solvent) as we have shown that such systems are well suited for hydrolysis of toxic organophosphorus compounds.11 Glycerol was employed for the hydrolysis reaction, but for the oxidation reaction we selected formamide, which we have used to produce colloidal media in previous studies.12 In this respect, Reymond has demonstrated the high reactivity of a mixture of hydrogen peroxide and formamide for oxidation of alkenes.13 He postulated the existence of small amounts of performic acid, which is used up as it is formed in situ: HCONH2 + H2O2 a HCO3H + NH3. In a analogous system, we replaced the rather unstable hydrogen peroxide with magnesium monoperoxyphthalate (MMPP). We propose the existence of the equilibrium shown in Scheme 3. We used cetylpyridinium chloride (CPCl) as surfactant, as it promotes localization of both MMPP and formamide (the oxidizing system) at the micellar interface via the (10) Menger, F. M.; Elrington, A. R. J. Am. Chem. Soc. 1991, 113, 9621. (11) Eychenne, P.; Rico-Lattes, I.; Perez, E.; Lattes, A. New J. Chem. 1995, 19, 193. (12) (a) Lattes, A.; Rico-Lattes, I. C. R. Acad. Sci. Paris, Ser. IIb 1997, 324, 575. (b) Rico-Lattes, I. Recent Res. Dev. Org. Chem. 1998, 2, 242 and references herein. (13) Chen, Y.; Reymond, J. L. Tetrahedron Lett. 1995, 23, 4015. (14) Auvray, X.; Perche, T.; Petipas, C.; Anthore, R.; Marti, M. J.; Rico, I.; Lattes, A. Langmuir 1992, 8, 2671-2679.
10.1021/la981638f CCC: $18.00 © 1999 American Chemical Society Published on Web 09/18/1999
Notes
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Table 1. Lipophilicity (log P) of Mustard Gas and of “Half-Mustards” compounds
log P
Cl-CH2-CH2-S-CH2-CH2-Cl C6H5-CH2-CH2-S-CH2-CH2-Cl C6H5-S-CH2-CH2-Cl
1.9 3.2 2.8
following mechanism: for MMPP, by exchange of the counterion Cl- and the perphthalate ion; for formamide, by preferential solvation (with respect to water) of the pyridinium head.14 Results and Discussion Role of Lipophilicity in the Selection of Model Compounds. For considerations of safety, laboratory tests need to be conducted with model compounds such as 2-chloro-2′-phenyldiethyl sulfide C6H5-CH2-CH2-SCH2-CH2-Cl or 2-chloroethyl phenyl sulfide C6H5-SCH2-CH2-Cl. These compounds, referred to as halfmustards, have similar structures to yperite but are considerably less toxic. However, their chemical properties are somewhat different, especially their solubility in aqueous media. This is evaluated from the calculated lipophilicity parameter log P (Table 1). The results obtained for the models can only be transposed to yperite by application of a correction factor for the difference in lipophilicity. To validate the method of decontamination, the model substrate should, therefore, have similar physicochemical parameters to those of yperite. In view of the micellar medium used, the lipophilicity of the substrate as well as that of the corresponding sulfoxide are important as they govern the localization of the different species in the microheterogeneous reaction medium. To our knowledge, this parameter has not been taken into account in previous studies on this problem. We therefore investigated the oxidation of four thioethers as model substrates to examine the role played by localization of the substrate in the medium. The following compounds were selected: similar lipophilicity to yperite, methyl phenyl sulfide (or thioanisole) and p-methoxyphenyl methyl sulfide; much less lipophilic than yperite, tetrahydrothiophene; more lipophilic than yperite, dibenzyl sulfide. The lipophilicities of these substrates and their sulfoxides are listed in Table 2, which also contains details of the two-half-mustards mentioned above, and which have been studied here in comparison with thioethers. Role of Micellar Solutions in the Oxidation Process. The results obtained for the four thioethers and the
two half-mustards in aqueous micellar medium and in the binary system (formamide/water 50:50 v/v) are listed in Table 3. The concentration of CPCl in the two media (0.008 mol L-1) was above the critical micellar concentration (cmc) in pure water (9 × 10-4 mol L-1) and water/ formamide (4.5 × 10-3 mol L-1). It can be seen from the results listed in Table 3 that the yield and selectivity of the reactions differ according to the model substrate. We can distinguish three types of behavior in the oxidation reaction: tetrahydrothiophene (1) (more hydrophilic than yperite); 1-p-methoxyphenyl methyl sulfide (2), thioanisole (3), and half-mustard (5) (comparable lipophilicity to yperite); dibenzyl sulfide (4) and half-mustard (6) (more hydrophobic than yperite). Oxidation of Tetrahydrothiophene 1. For both media, the oxidation yield was almost quantitative with similar sulfoxide/sulfone ratios. This highly hydrophilic substrate (cf. Table 2) is soluble in the continuous phase (without surfactant, the media are homogeneous) and the oxidation reaction was little influenced by the presence of micelles. In the absence of surfactant, the yield and sulfoxide/sulfone ratio were comparable to that obtained in the micellar medium. A proportion of the sulfoxide is in contact with the oxidizing agent in the continuous phase and is thus transformed into the sulfone. With hydrophilic substrates of this kind, the process is not improved by use of a micellar medium. Oxidation of Substrates 2, 3, and 5. The micellar medium had a marked influence with these more lipophilic substrates in two main ways: by enhancing solubility of the hydrophobic substrates (cf. Table 2), in this respect, compounds 2, 3, and 5 are only slightly soluble in the medium in the absence of surfactant; by improving the selectivity, which was most marked in the water/formamide system where selectivities of 11.5 were observed for p-methoxyphenyl methyl sulfide (2), 24 for thiosanisole 3, and 99 for the half-mustard 5. In all cases, the reaction favored the sulfoxide. These results were attributed to the following three processes: the preferential localization at the interface of the oxidizing agent (exchange of Cl- and perphthalate ions) and the formamide (solvating the pyridinium head), this was thought to give rise to performic acid as described by Reymond13 for the action of H2O2 on formamide; the polar substrates may lie in both the core of the micelles and at the interface where the oxidation reaction takes place, the micellar interface thus helps bring the reactants together, the sulfoxide, which is more hydrophilic (cf. Table 2), is then expelled into the continuous phase.
Table 2. Lipophilicities (log P) of the Model Sulfides and of the Related Sulfoxides compounds sulfur mustard 2,2′-dichlorodiethyl sulfoxide tetrahydrothiophen
structures Cl-CH2-CH2-S-CH2-CH2-Cl Cl-CH2-CH2-SO-CH2-CH2-Cl
1.9 0.7 0.8 -0.4
tetrahydrothiophen 1-oxide
p-methoxyphenyl methyl sulfide p-methoxyphenyl methyl sulfoxide thioanisol methyl phenyl sulfoxide 2-chloroethyl phenyl sulfide 2-chloroethyl phenyl sulfoxide 2-chloro-2′-phenyl diethyl sulfide 2-chloro-2′-phe´nyl diethyl sulfoxide benzyl sulfide benzyl sulfoxide
log P
CH3O-C6H4-S-CH3 CH3O-C6H4-SO-CH3 C6H5-S-CH3 C6H5-SO-CH3 C6H5-S-CH2-CH2-Cl C6H5-SO-CH2-CH2-Cl C6H5-CH2-CH2-S-CH2-CH2-Cl C6H5-CH2-CH2-SO-CH2-CH2-Cl C6H5-CH2-S-CH2-C6H5 C6H5-CH2-SO-CH2-C6H5
1.9 0.7 2.1 1.0 2.8 1.7 3.2 2.1 4.0 2.9
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Notes
Table 3. Influence of Medium on the Oxidation of Model Thioethers reactional media
water substrates
CH3O-C6H4-S-CH3 (2) C6H5-S-CH3 (3) (C6H5-CH2)2S (4) C6H5-S-CH2CH2-Cl (5) C6H5-CH2CH2SCH2CH2-Cl (6) a,b
binary system water/formamide (50:50 v/v)
yielda
selectb
98
78/22 (3.5)
96 91 72 97 84
81/15 (5.7) 100 92/8 (11.5) 79/21 (3.8) 100 96/4 (24) 57/43 (1.3) 45 13/87 (0.1) 93/7 (13.3) 100 99/1 (99) 82/18 (3.8) 77 84/16 (5.3)
yield
select
99 81/19 (4.3)
Yields (in %) and selectivity (molar ratio sulfoxide/sulfone).
Conclusion The lipophilicity of the substrate and its corresponding sulfoxide would appear to be key factors for the success of chemical decontamination of yperite in organized media. The reactivity and selectivity of the reaction were found to depend on the localization of the particular substrate in the microheterogeneous medium. p-Methoxyphenyl methyl sulfide, thioanisole, and the half-mustard C6H5S-CH2CH2Cl had similar lipophilicities to that of yperite (cf. Table 2) and appeared to be the most suitable models for study of the degradation of this toxic agent. In contrast, the half-mustard 6 seems not to be a good model for yperite. For these three substrates, a micellar medium consisting of cetylpyridinium chloride and water/formamide (50:50 v/v) gave the highest yields with over 90% sulfoxide production (99% for the half-mustard C6H5-S-CH2CH2-Cl). In contrast, the half-mustard C6H5-CH2-CH2S-CH2-CH2-Cl, too much lipophilic, seems not to be a good model for mustard gas. Therefore these results show the importance of lipophilicity in the choice of mimics of yperite with a limit of 3 for log P of substrates. Materials and Methods
Figure 1. Comparative oxidation of the substrates 1 (a), 2, 3, and 5 (b), and 4 and 6 (c).
Oxidation of Dibenzyl Sulfide 4 and the Half-Mustard 6. These highly hydrophobic substrates (cf. Table 2) are trapped inside the core of the micelles. The reaction is slow (low yield after 1 h) and nonselective. In contrast, in the water/formamide system, preferential localization at the micellar interface led to a marked increase in proportions of sulfone (selectivity ) 0.1) for the most hydrophobic substrate (compound 4). The three modes of oxidation for these model substrates are summarized in Figure 1.
(i) Chemicals. Tetrahydrothiophene (99%), tetramethylene sulfoxide (96%), tetramethylene sulfone (99%), thioanisole (99%), methyl phenyl sulfoxide (97%), dibenzyl sulfide (98%), dibenzyl sulfoxide (98%), dibenzyl sulfone (99%), 2-chloroethyl phenyl sulfide (98%), 1-methoxy-4-(methylthio)benzene (97%), acetophenone (99%), and MMPP (monoperoxyphthalic acid magnesium salt hexahydrate) (80%) were purchased from Aldrich. Cetylpyridinium chloride monohydrate (99%) and formamide (99.5%) were obtained from Acros and benzophenone (99%) from Merck. (ii) Synthesis of Sulfoxides and Sulfones Corresponding to the Model Substrates. Synthesis of the sulfones of the model substrates 2, 5, and 6, typical reaction for 2-chloroethyl phenyl sulfone, 1.600 g (9.3 × 10-3 mol) of 2-chloroethyl phenyl sulfide in 80 mL of ethanol is placed in a 100 cm3 round-bottomed flask. A 7.170 g portion of 80% MMPP (14.5 × 10-3 mol) is then introduced with stirring. The reaction is stirred for 4 h at 50 °C. Residual MMPP is neutralized with excess KHCO3. The reaction mixture is filtered to remove salts, and the filtrate is evaporated under reduced pressure. The residue is taken up in 100 mL of chloroform, which affords the crude product after evaporation under reduced pressure. The sulfone is crystallized from cold pentane/ethyl ether (9/1) and then recrystallized from absolute ethanol (0.891 g; 51%). The product was characterized by nuclear magnetic resonance (NMR) of 1H and 13C. No sulfide or sulfoxide was detected by high-performance liquid chromatography (HPLC) (1 peak). 2-Chloro-2′-phenyl diethyl sulfone and p-methoxyphenyl methyl sulfone were prepared in the same way. Synthesis of sulfoxides corresponding to the model substrates 2, 5, and 6, typical reaction for 2-chloroethyl phenyl sulfoxide, 1.320 g (7.6 × 10-3 mol) of 2-chloroethyl phenyl sulfide in 40 mL of ethanol is placed in a 250 cm3 round-bottomed flask. A 2.366 g (4.8 × 10-3 mol) portion of 80% MMPP in 100 mL of ethanol is added dropwise over a period of 1.5 h while stirring the mixture. The mixture is left to react overnight. Residual MMPP is neutralized with excess KHCO3. The reaction mixture is filtered to remove salts, and the filtrate is evaporated under reduced pressure. The residue is taken up in 100 mL of chloroform, which affords the crude product after evaporation under reduced pressure. The first fraction of crystals (0.187 g; 13%) was characterized by 1H and 13C NMR. A single peak was observed on HPLC. 2-Chloro-2′-phenyl diethyl sulfoxide and p-methoxyphenyl methyl sulfoxide were prepared in the same way. (iii) Calculation of the Lipophilicities (log P). The lipophilicities of the different sulfides and sulfoxides were calculated using TSAR software (Tools for Structure Activity Relationships), developed by Oxford Molecular (2.31 version).
Notes The predicted log P values are calculated by TSAR using the atomic log P values determined by Ghose et al.15 (iv) Critical Micellar Concentrations (cmc) measurements. The cmc measurements by tensiometry were performed with a tensiometer type Tensimat PROLABO no. 3 and a thermostated bath at a temperature of 25 ( 0.1 °C. Surface tensions were measured using a platinum stirrup. We determined the cmc of the solution by plotting variations of surface tension as a function of the logarithm of the concentration of surfactant. (v) Oxidations in Micellar Solutions. A mixture of 5.67 × 10-3 mol of the model substrate and 3.27 × 10-4 mol of surfactant (CPCl) is stirred magnetically in 40.5 mL of water/formamide (50:50 v/v). After 10 min, 3.90 × 10-3 mol of 80% MMPP is introduced rapidly. One hour later, residual MMPP is neutralized with NaHCO3, the mixture is extracted with chloroform (3 × 50 mL), and the solvent is evaporated under reduced pressure. The residue is taken up in 50 mL of chloroform in a graduated flask. One milliliter of this solution is added to a 25 mL graduated flask along with 1 mL of standard stock solution and made up to the mark with chloroform. The resulting solutions were analyzed by GPC for tetrahydrothiophene and HPLC for the substrates 2-6. (vi) Gas Chromatographic Conditions for Oxidation Products. All experiments were performed on a Delsi Nermag DN200 chromatograph: column filled with OV17 (10% chromosorb, 3.5 m, 80-100 mesh, 1/8 in.); vector gas, nitrogen; flow (15) Viswanadhan, V. N.; Ghose, A. K.; Revankar, G. R.; Robins, R. K. J. Chem. Inf. Comput. Sci. 1989, 29, 163-172.
Langmuir, Vol. 15, No. 23, 1999 8331 rate, 1.2 bar; temperatures, injector (305 °C), detector (260 °C), oven (temperature program 170 °C for 3 min, then rise of 20 °C min-1 to 200 °C, then 200 °C for 6 min). The compounds detected were identified from their retention times. The proportions of the two oxides formed in the reaction could then be determined after establishing a calibration curve with standards run under identical conditions. (vii) HPLC Conditions. For each substrate, we determined the amounts of sulfoxide and sulfone produced in the oxidation reaction and the amount of sulfide remaining by HPLC using internal standards for calibration. Benzophenone was employed as internal standard for substrates 2, 3, 4, and 6 and anthracene for substrate 5. The following columns were used: Spherisorb ODS2 (250 × 4.0 mm; 5.0 mm) for substrates 2, 3, 4, and 6; Lichrosorb C18 for substrate 5. The flow rate was controlled by a Waters-Millipore 510 apparatus, and the compounds were detected in a diodearray spectrophotometer (UV 990) controlled by a NEC computer running appropriate data acquisition and processing software. The compounds were identified from their retention times, confirmed by their UV spectra.
Acknowledgment. We would like to thank the DRET for funding this project LA981638F
