Reactions of a Vesicular Functionalized Surfactant with Alkyl 2

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Reactions of a Vesicular Functionalized Surfactant with Alkyl 2-Chloroethyl Sulfides (Mustard Simulants)

tamination of alkyl 2-chloroethyl sulfides 6, simulants that are more reactive than 3 and mustard itself.5

David A. Jaeger* and Alexander K. Zelenin

The synthesis and characterization of surfactant 1 have been reported.3 In a pH 9.0 borate buffer it forms small unilamellar vesicles (SUVs)2 with hydrodynamic diameters of ∼70 nm upon sonication, and giant vesicles (GVs)6 with diameters of ∼25-150 µm upon hydration of a thin film or solid smear. The reactions of simulants 6 with SUVs of 1 (1:1 molar ratio) were performed in the pH 9.0 buffer (D2O) at 25 °C as follows. Simulant 6 was added to the buffer containing

Department of Chemistry, University of Wyoming, Laramie, Wyoming 82071 Received May 26, 2000. In Final Form: August 9, 2000

Introduction Chemical warfare agents such as mustard, a blistering agent, and VX, a nerve agent, continue to represent significant military and terrorist threats. Accordingly,

methods for their chemical decontamination (i.e., conversion into nontoxic compounds) are of practical interest.1 Systems that can simultaneously decontaminate and signal the presence of chemical agents would be valuable additions to currently employed defensive measures.1 The application of such a dual-purpose system based on closed bilayer vesicles2 would involve the following features: (a) vesicles containing an entrapped signaling compound are prepared from a functionalized surfactant; (b) a chemical reaction of the vesicular surfactant with the agent results in its decontamination; and (c) this reaction also effects wounding/destruction of the vesicles and thus triggers the release of the signaling compound to indicate the presence of the chemical agent. We have previously reported studies of the application of vesicular surfactants 1 and 2, which contain reactive functionalized head groups, to the simultaneous decontamination and signaling of mustard simulant 3 and VX simulant 4, respectively.3,4 (Simulants are more benign

model compounds that are used in place of chemical agents themselves.) In the former study, both decontamination and signaling derived from the reaction of vesicular 1 with 3, to give neutral nonsurfactant 5 (eq 1), which cannot support vesicle formation. Herein we report a study that successfully extends the use of vesicular 1 to the decon* Corresponding author. Telephone: 307-766-4335. Fax: 307766-2807. E-mail: [email protected].

Results and Discussion

1’s SUVs, and the resultant mixture was shaken vigorously for ∼30 s to disperse 6, since it was not soluble (0.0099 M 6 if fully dissolved). 31P NMR analysis of the reaction mixture, based on comparison with spectra of authentic compounds, indicated that 1 (δ 111.2) was converted into only 7 (δ ∼ 96) (eq 2) and that the conversion was ∼8090% after 5 min. 1H NMR analysis of the reaction mixture indicated that small amounts of 8-10 were also formed (see eq 3). Reactions of simulants 6 alone in the pH 9.0

buffer (D2O) at 25 °C were also performed. Simulant 6 was added to the buffer (0.0099 M 6 if fully dissolved), and the resultant mixture was shaken vigorously for ∼30 s. 1H NMR analysis of the reaction mixture indicated that 6 was consumed within 5 min to give 8-10 (eq 3), consistent with results reported by Yang and co-workers7 for the reactions of 6a and 6b in H2O. The reaction mixtures of 1 and 6 were lyophilized after 5 min. By 31P NMR analysis of the residues in CDCl3 with (C6H5)3P (δ -4.8) as an internal standard, the average yields of 7a-c in duplicate/triplicate runs were 77, 89, and 90%, respectively. In other runs the isolated yields of 7a-c after column chromatography on silica gel were 60, 71, and 75%, respectively. (1) (a) Yang, Y.-C.; Baker, J. A.; Ward, J. R. Chem. Rev. 1992, 92, 1729. (b) Yang, Y.-C. Chem. Ind. (London) 1995, 334. (c) Yang, Y.-C. Acc. Chem. Res. 1999, 32, 109. (2) Fendler, J. H. Membrane Mimetic Chemistry; Wiley-Interscience: New York, 1982, Chapter 6. (3) Jaeger, D. A.; Schilling, C. L., III.; Zelenin, A. K.; Li, B.; KubiczLoring, E. Langmuir 1999, 15, 7180. (4) Jaeger, D. A.; Li, B. Langmuir 2000, 16, 5. (5) Yang, Y.-C.; Szafraniec, L. L.; Beaudry, W. T.; Davis, F. A. J. Org. Chem. 1990, 55, 3664. (6) For reviews, see: (a) Menger, F. M.; Gabrielson, K. D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2091. (b) Menger, F. M.; Angelova, M. I. Acc. Chem. Res. 1998, 31, 789. (c) Menger, F. M.; Keiper, J. S. Curr. Opin. Chem. Biol. 1998, 2, 726. (7) Yang, Y.-C.; Szafraniec, L. L.; Beaudry, W. T.; Ward, J. R. J. Org. Chem. 1988, 53, 3293.

10.1021/la0007269 CCC: $19.00 © 2000 American Chemical Society Published on Web 10/13/2000

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Langmuir, Vol. 16, No. 24, 2000

In other runs with 6c and 1’s SUVs the reaction mixture was not shaken initially; undissolved droplets of 6c floated at its top. After 10 min there was no formation of 7c by 31 P NMR analysis. Then the reaction mixture was shaken vigorously for ∼30 s and analyzed by 31P NMR after 5 min. The conversion of 1 into 7c was comparable to that in a reaction mixture that was shaken initially. These results clearly indicate that 6c must be efficiently dispersed before it can react within a 5-min period. Attempted reactions of 6c with GVs of 1 (1:1 molar ratio) were followed by phase-contrast optical microscopy. Simulant 6c was added as a freshly prepared THF solution to the pH 9.0 borate buffer containing 1’s GVs without subsequent shaking/stirring, because they are mechanically unstable, as are GVs in general. The resultant concentrations of 6c (if fully dissolved) and THF were 8 × 10-4 M and 0.5 vol %, respectively. After 10 min, there was no change in the apparent number of GVs or in their appearance. In analogous runs in which the concentration of 6c was increased to 0.0098 M (if fully dissolved), close to that used in the SUV runs, there was no apparent change in the GVs up to 30 min after addition of the THF solution of 6c. These results are consistent with those of the SUV runs performed without initial shaking. The lack of an effect of 6c on 1’s GVs is in sharp contrast to 3’s effect on 1’s GVs, which was wounding/destruction.3 This dissimilarity is due to a complex interplay of factors, which probably include 6c and 3’s different reactivities and propensities for sorption by 1’s GVs without shaking. Simulant 6c is reported to be 95 times more reactive than 3 with respect to hydrolysis,5 consistent with our results with 6c (see above) and 3 in the pH 9.0 borate buffer.3 In runs with 3, but not with 6c, 1-5-µm droplets of simulant sorbed onto the GVs. Thus, there was efficient interaction of the GVs with 3 but not with 6c (before the simulant was consumed by hydrolysis), resulting in GV wounding/ destruction only with 3, which was observed during the period from 10 to 17 h after the addition of 3. The reaction of 1’s SUVs with 3 (1:1 molar ratio) was ∼70% complete after 19 h.3 On the basis of the demonstrated intermediacy of 11a in the reaction of 1 and 3,3 the mechanism for the formation of 7 in the reaction of 1 and 6 (eq 2) most likely involves initial ionization of 6 with neighboring group participation by sulfur to give episulfonium ion 12, which is then captured by 1’s nucleophilic, functionalized head group to give 7 (eq 4). Reactions of nucleophiles with mustard simulants and mustard itself generally proceed through episulfonium ions.1,8

Since shaken reaction mixtures of simulants 6 and 1’s SUVs gave 7 accompanied by only small amounts of alcohol 8, 1’s head group is a much better nucleophile than interfacial H2O in capturing episulfonium ion 12. This conclusion is consistent with the competition factor of 2600 M-1 reported9 for the nonsurfactant anion of 13 relative (8) (a) McManus, S. P.; Karaman, R. M.; Sedaghat-Herati, R.; Harris, J. M. J. Org. Chem. 1995, 60, 4764. (b) McManus, S. P.; Karaman, R. M.; Sedaghat-Herati, R.; Hovanes, B. A.; Ding, X.-T.; Harris, J. M. J. Org. Chem. 1993, 58, 6466. (c) Sedaghat-Herati, M. R.; McManus, S. P.; Harris, J. M. J. Org. Chem. 1988, 53, 2539. (9) Ogston, A. G.; Holiday, E. R.; Philpot, J. St L.; Stocken, L. A. Trans. Faraday Soc. 1948, 44, 45.

Notes

to H2O at 25 °C in the capture of 11b, the episulfonium ion derived from mustard.

Decontamination methods for mustard and its simulants include hydrolysis,1,7,8b,10 nucleophilic substitution,1,9 oxidation,1,5,11 and elimination reactions1 in solution, and various reactions on adsorbents.12 In this study, the decontamination of simulants 6 corresponds to their conversion into 7. However, since the anion of surfactant 1 is a potential leaving group, 7 is an alkylating agent, like 6. Thus, the conversion of 1 into 7 does not in principle represent complete decontamination. But 7a and 7b were stable for >11 days in the pH 9.0 borate buffer at 25 °C. In comparison, it is important to note that the conversion of 6 into 8-10 does not correspond to complete decontamination, because 9 and 10 are most likely toxic, as are their analogues derived from mustard.7 The signaling function of the SUV system would correspond to its release of an entrapped signaling compound as the result of vesicle wounding/destruction effected by the reaction of 6 with surfactant 1 to give nonsurfactant 7, which cannot support vesicle formation. A variety of surfactants with nucleophilic, functionalized head groups have been synthesized and applied to the decontamination of simulants for other chemical agents.13 In H2O, 6a, 6b, and 6c are 4.8, 5.9, and 9 times more reactive, respectively, than mustard with respect to hydrolysis.5 Since 1’s SUVs efficiently converted simulants 3 and 6 into 5 and 7, respectively, they should also efficiently react with, and thus decontaminate, mustard itself, which has a reactivity between those of 3 and 6.5 Summary 1’s SUVs reacted with mustard simulants 6 in a pH 9.0 borate buffer at 25 °C to give nonsurfactant 7, with resultant SUV wounding/destruction. The combination of the conversion of 6 into 7 and the potential release of an entrapped signaling compound from the SUVs suggests the application of these systems to simultaneous decontamination and signaling of chemical agents. Experimental Section General Procedures and Materials. 1H (400 MHz) and 13C NMR (100.6 MHz) spectra recorded in CDCl3 employed Me4Si and CDCl3 (center line at δ 77.00 relative to Me4Si) as internal standards, respectively. 1H NMR spectra recorded in the pH 9.0 (10) For examples, see: (a) Yang, Y.-C.; Ward, J. R.; Luteran, T. J. Org. Chem. 1986, 51, 2756. (b) McManus, S. P.; Neamati-Mazaeh, N.; Hovanes, B. A.; Paley, M. S.; Harris, J. M. J. Am. Chem. Soc. 1985, 107, 3393. (c) Bartlett, P. D.; Swain, C. G. J. Am. Chem. Soc. 1949, 71, 1406. (11) For examples, see: (a) Menger, F. M.; Rourk, M. J. Langmuir 1999, 15, 309. (b) Menger, F. M.; Elrington, A. R. J. Am. Chem. Soc. 1991, 113, 9621. (c) Bacaloglu, R.; Blasko, A.; Bunton, C. A.; Foroudian, H. J. J. Phys. Org. Chem. 1992, 5, 171. (12) For examples, see: (a) Mawhinney, D. B.; Rossin, J. A.; Gerhart, K.; Yates, J. T., Jr. Langmuir 1999, 15, 4789. (b) Karwacki, C. J.; Buchanan, J. H.; Mahle, J. J.; Buettner, L. C.; Wagner, G. W. Langmuir 1999, 15, 8645. (c) Wagner, G. W.; MacIver, B. K.; Yang, Y.-C. Langmuir 1995, 11, 1439. (d) Gall, R. D.; Hill, C. L.; Walker, J. E. J. Catal. 1996, 159, 473. (13) For examples, see: (a) Menger, F. M.; Whitesell, L. G. J. Am. Chem. Soc. 1985, 107, 707. (b) Menger, F. M.; Gan, L. H.; Johnson, E.; Durst, D. H. J. Am. Chem. Soc. 1987, 109, 2800. (c) Menger, F. M.; Persichetti, R. A. J. Org. Chem. 1987, 52, 3451. (d) Moss, R. A.; Lukas, T. J.; Nahas, R. C. J. Am. Chem. Soc. 1978, 100, 5920. (e) Moss, R. A.; Kim, K. Y.; Swarup, S. J. Am. Chem. Soc. 1986, 108, 788. (f) Scrimmin, P.; Ghirlanda, G.; Tecilla, P.; Moss, R. A. Langmuir 1996, 12, 6235 and references therein.

Notes borate buffer in D2O employed HOD (δ 4.65 relative to Me4Si) as internal standard. J values are in hertz. 31P NMR (109.4 MHz) spectra were recorded in CDCl3 and the pH 9.0 borate buffer in D2O with 85% H3PO4 as external standard. Simulants 6a and 6b were used as received (Aldrich). The syntheses of surfactant 13 and simulant 6c14 were according to literature procedures. The pH 9.0 borate buffers in H2O and D2O and sonication have been described.3 Extracts were dried over Na2SO4. Elemental analyses were performed by Atlantic Microlab, Inc., Norcross, GA. Reactions of 6 with SUVs of 1 in the pH 9.0 Borate Buffer with Initial Shaking. A mixture of 5.0 mg (0.0099 mmol) of 1 and 1.00 mL of the pH 9.0 borate buffer in D2O was sonicated for 15 min at 55 °C in a 5-mm NMR tube to give a translucent solution. The 31P NMR spectrum of this solution contained one singlet at δ 111.2 for 1. Then 0.0099 mmol of neat 6 was added by a 10-µL syringe, and the tube was hand-shaken vigorously for ∼30 s to give a cloudy mixture that was held at 25 °C and analyzed by 31P NMR, to monitor the formation of 7 (δ ∼ 96) from the reaction of 1 with 6, and by 1H NMR, which was less informative. After 5 min the reaction mixture was lyophilized. Then 1.0 mL of CDCl3 was added to the residue, followed by 4.0 mg (0.015 mmol) of (C6H5)3P as an internal standard. The mixture was analyzed by 31P NMR to give the relative intensities of the singlets for 7 and (C6H5)3P (δ -4.8) and, in turn, the yield of 7. The average yields were 77% of 7a (3 runs), 89% of 7b (2 runs), and 90% of 7c (2 runs). Isolation of 7 from Reactions of 6 with SUVs of 1 the pH 9.0 Borate Buffer. A mixture of 0.20 g (0.39 mmol) of 1 and 20.0 mL of the pH 9.0 borate buffer in H2O was sonicated for 15 min at 55 °C to give a translucent solution. Then 0.40 mmol of 6 was added, and the reaction mixture was stirred for 1 h and then lyophilized to leave a residue that was extracted with 50 mL of CHCl3. After rotary evaporation the residue was chromatographed on silica gel (J. T. Baker 3405) packed in hexane with Et2O-hexane elution to give the product as a colorless oil: 60% of 7a; 71% of 7b; 75% of 7c. For 7a: 1H NMR (CDCl3) δ 4.05 (m, 4 H, 2 CH2O), 3.06 (m, 2 H, CH2S), 2.75 (m, 2 H, CH2S), 2.14 (s, 3 H, CH3S), 1.68 (m, 4 H, 2 CH2CH2O), 1.15-1.41 (m, 36 H, 2 (CH2)9), 0.86 (t, 6 H, 2 CH3); 13C NMR (CDCl3) δ 68.01, 67.94, 34.53, 34.50, 32.91, 32.88, 31.82, 29.93, 29.85, 29.54, 29.48, 29.42, 29.26, 29.07, 25.51, 22.59, 15.28, 14.03; 31P NMR (CDCl3) δ 96.33 (s). Anal. Calcd for C27H57O2PS3: C, 59.95; H, 10.62. Found: C, 60.08; H, 10.64. For 7b: 1H NMR (CDCl3) δ 4.08 (m, 4 H, 2 CH2O), 3.04 (m, 2 H, CH2S), 2.77 (m, 2 H, CH2S), 2.58 (q, J ) 7.4, 2 H, CH3CH2S), 1.68 (m, 4 H, 2 CH2CH2O), 1.18-1.40 (m, 39 H, 2 (CH2)9, CH3CH2S), 0.87 (t, 6 H, 2 CH3); 13C NMR (CDCl3) δ 68.05, 67.98, 33.46, 33.43, 32.11, 32.08, 31.86, 29.97, 29.89, 29.59, 29.52, 29.46, 29.30, 29.11, 25.79, 22.55, 22.63, 14.82, 14.07; 31P NMR (CDCl3) δ 96.39 (s). Anal. Calcd for C28H59O2PS3: C, 60.60; H, 10.72. Found: C, 60.85; H, 10.69. (14) Wragg, R. T. J. Chem. Soc. C 1969, 2087.

Langmuir, Vol. 16, No. 24, 2000 9679 For 7c: 1H NMR (CDCl3) δ 4.05 (m, 4 H, 2 CH2O), 3.04 (m, 2 H, CH2S), 2.77 (m, 2 H, CH2S), 2.57 (t, J ) 7.4, 2 H, CH2CH2CH2S), 1.70 (m, 4 H, 2 CH2CH2O), 1.58 (m, 2 H, CH2CH2CH2S), 1.20-1.43 (m, 38 H, 2 (CH2)9, CH2CH2CH2S), 0.92 (t, 3 H, CH3CH2CH2CH2S), 0.88 (t, 6 H, 2 CH3); 13C NMR (CDCl3) δ 68.04, 67.98, 33.50, 33.47, 32.56, 32.52, 31.87, 31.77, 31.64, 29.98, 29.90, 29.59, 29.53, 29.46, 29.30, 29.12, 25.56, 22.64, 21.89, 14.07, 13.63; 31P NMR (CDCl3) δ 96.26 (s). Anal. Calcd for C30H63O2PS3: C, 61.81; H, 10.89. Found: C, 61.89; H, 10.63. Attempted Reaction of 6c with SUVs of 1 in the pH 9.0 Borate Buffer without Initial Shaking. A solution of 1’s SUVs in the pH 9.0 buffer was prepared as above in a 5-mm NMR tube. Then ∼1.5 mg (0.0098 mmol) of neat 6c was added by a glass pipet to the bottom of the solution at 25 °C. The resultant mixture, which contained oil droplets (6c) at its surface, was analyzed by 31P NMR without spinning of the NMR tube. After 5 min, only 1 was observed. Then the tube was hand-shaken vigorously for ∼30 s to give a cloudy mixture that was analyzed by 31P NMR without spinning. After 5 min, the conversion of 1 into 7c was comparable to that in runs with initial shaking. Attempted Reaction of 6c with GVs of 1 in the pH 9.0 Buffer. GVs were formed by hydration of a thin film of 1 in the pH 9.0 borate buffer in H2O, as described previously.3 To 0.50 mL of a GV sample in a microscope slide well,3 containing ∼0.2 mg (0.0004 mmol) of 1, was added (by a 10-µL syringe) 2.6 µL of freshly prepared 0.15 M 6 (0.0004 mmol) in tetrahydrofuran (THF, distilled from benzophenone Na ketyl). The microscope slide well was covered with a cover slip, and then the reaction mixture was observed by phase-contrast optical microscopy with the instrumentation described previously.3 See the Results and Discussion for observations. The above reaction mixtures contained 8 × 10-4 M each of 1 and 6c and 0.5 vol % THF. Analogous runs were performed with reaction mixtures containing 8 × 10-4 M 1, 0.0098 M 6c, and 0.65 vol % THF with the same results. Reactions of 6 in the pH 9.0 Borate Buffer. To 1.00 mL of the pH 9.0 borate buffer in D2O in a 5-mm NMR tube was added 0.0099 mmol of neat 6 at 25 °C. The resultant mixture was hand-shaken vigorously for ∼30 s and analyzed by 1H NMR. In each case the conversion of 6 to 8-10 was complete within 5 min, with results comparable to those reported by Yang and coworkers7 for 6a and 6b in H2O. See the Supporting Information for the 1H NMR parameters for 6a-c and 8-10a-c in the pH 9.0 borate buffer in D2O.

Acknowledgment is made to the U.S. Army Research Office for the support of this research. Supporting Information Available: Table of 1H NMR parameters for 6a-c and 8-10a-c in the pH 9.0 borate buffer in D2O. This information is available free of charge via the Internet at http://pubs.acs.org. LA0007269