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Jul 10, 2004 - 31P NMR and UV−vis spectrometric evidence has revealed an unexpected regioselectivity in the reaction of fenitrothion, 1, ...
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Langmuir 2004, 20, 6586-6593

Acceleration of Nucleophilic Attack on an Organophosphorothioate Neurotoxin, Fenitrothion, by Reactive Counterion Cationic Micelles. Regioselectivity as a Probe of Substrate Orientation within the Micelle† Vimal K. Balakrishnan,‡,⊥ Xiumei Han,‡ Gary W. VanLoon,‡ Julian M. Dust,§ Jean Toullec,⊥ and Erwin Buncel*,‡ Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada, Departments of Chemistry and Environmental Science, Sir Wilfred Grenfell College, Corner Brook, Newfoundland A2H 6P9, Canada, and Laboratoire S.I.R.C.O.B., Universite´ de Versailles St-Quentin en Yvelines, Versailles, France Received February 18, 2004. In Final Form: April 6, 2004 31P NMR and UV-vis spectrometric evidence has revealed an unexpected regioselectivity in the reaction of fenitrothion, 1, an organophosphorus pesticide, with the cetyltrimethylammonium (CTA) surfactants CTAOH and CTAMINA, that incorporate the reactive counterions OH- and MINA- (the anti-pyruvaldehyde 1-oximate anion). While both micellar solutions accelerate decomposition of 1 compared to aqueous OHalone, CTAMINA produced the largest rate enhancement (ca. 105) at a pH (8.39) appropriate for environmental applications. In the absence of surfactant, reaction proceeds solely via the SN2(P) pathway. In the presence of surfactant but below the critical micelle concentration (cmc), a competitive SN2(C) pathway was observed in addition to SN2(P). Above the cmc, however, the CTAOH reaction again proceeded solely via the SN2(P) pathway while both pathways were operative with CTAMINA. The changes in reactivity and mechanistic pathway are discussed in terms of premicellar and micellar influences on rates and regioselectivity. A proposal that would account for the observed regioselectivity in the micellar system is that the aromatic ring and aliphatic side-chains of 1 are oriented toward the micellar interior, while the PdS moiety faces the aqueous pseudophase.

Introduction Anthropogenic organophosphorus esters are commonly used as pesticides (e.g., 1, 1a, 1b; see Chart 1) and other bioactive agents,1,2 though additional uses range from flame retardants3,4 and hydraulic fluid additives to plasticizers.2 Due to the biological importance of these esters and their environmental significance, their degradation has been extensively investigated over the past decades.3-8 Nucleophilic attack on phosphorus esters such * Corresponding author. Erwin Buncel: phone, (613)-533-2653; e-mail, [email protected]. † Part 7 in a series on “Mechanisms of abiotic degradation and soil-water interactions of pesticides and other hydrophobic organic compounds”. For the previous paper in this series, see ref 16. ‡ Queen’s University. § Sir Wilfred Grenfell College. | Universite ´ de Versailles St-Quentin en Yvelines. ⊥ Current address: Biotechnology Research Institute, NRCC, 6100 Royalmount Ave., Montreal, QC H4P 2R2, Canada. (1) Carlsson, H.; Nilsson, U.; Ostman, C. Environ. Sci. Technol. 2000, 34, 3885. (2) Lapp, T. W. The Manufacture and Use of Selected Aryl and Alkyl Phosphate Esters; Environmental Protection Agency Report No. 560/ 6-76-008; U.S. Environmental Protection Agency: Washington, DC, 1976. (3) Kirby, A. J.; Warren, S. G. The Organic Chemistry of Phosphorus; Elsevier: Amsterdam, 1967. (4) Cox, J. R.; Ramsay, O. B. Chem. Rev. 1964, 64, 317. (5) Bunton, C. A. J. Chem. Educ. 1968, 45, 21. (6) (a) Bourne, N.; Williams, A. J. Am. Chem. Soc. 1984, 106, 7591. (b) Bourne, N.; Chrystiuk, E.; Davis, A. M.; Williams, A. J. Am. Chem. Soc. 1988, 110, 1890. (c) Ba-Saif, S. A.; Davis, A. M.; Williams, A. J. Org. Chem. 1989, 54, 5483. (d) Williams, A. Adv. Phys. Org. Chem. 1992, 27, 1. (7) (a) Kirby, A. J.; Younas, M. J. Chem. Soc. B 1970, 1165. (b) Kirby, A. J.; Khan, S. A. J. Chem. Soc. B 1970, 1172. (8) (a) Toullec, J.; Moukamim, M. J. Chem. Soc., Chem. Commun. 1996, 221. (b) Couderc, S.; Toullec, J. Langmuir 2001, 17, 3819. (c) Couderc, S. Ph.D. Thesis, Universite´ de Versailles St-Quentin en Yvelines, Versailles, France, 1999.

Chart 1

as 1 results in expulsion of the aryloxide in an SN2(P) displacement reaction. In comparing the reactivity of the insecticides parathion (1a) and paraoxon (1b) that only differ in the nature of the heteroatom Z, nucleophilic attack (alkaline conditions) on 1a at PdS occurs at a rate 5-20 times slower than that for attack on 1b at the corresponding PdO site.9,10 Although pesticides like 1 that incorporate the PdS reactive center would hydrolyze more slowly in the environment than their PdO analogues, the lower mammalian toxicity found for such organophosphorothioates as compared to the organophosphates11 has led to the comparative increase in their use. Our approach to the environmental chemistry of anthropogenic pollutants, including potential practical decontamination methods, has been multipronged. First, (9) Faust, S. D.; Gomaa, H. M. Environ. Lett. 1972, 3, 171. (10) Wolfe, N. L. Chemosphere 1980, 9, 571. (11) Verschueren, K. Handbook of Environmental Data on Organic Chemicals; Van Nostrand Reinhold: New York, 1996.

10.1021/la049572d CCC: $27.50 © 2004 American Chemical Society Published on Web 07/10/2004

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we have sought to understand the abiotic mechanisms of reaction of pesticidal agents including polynitroaniline derivatives,12 organophosphonate esters,13 and organophosphorothioates.14 Second, we have investigated the interactions of some triazine pesticides with soils.15 Altogether these efforts are aimed at the development of practical in or ex situ environmental remediation strategies.16 In this sense, the current study of the reaction of 1 in the presence of aqueous cationic surfactants is part of our ongoing efforts to develop these protocols. Recent research has highlighted the role played by micelles in abiotic degradation processes,8,17 including that of paraoxon, 1b.8a Aqueous cationic surfactant solutions, such as cetyltrimethylammonium bromide, CTABr, at concentrations greater than the critical micelle concentration (cmc) where the surfactant molecules would be present as micelles, are known to accelerate the spontaneous hydrolysis of dinitrophenyl phosphate and acyl phosphate dianions.18,19 More recently, interest has developed in reactive counterion surfactants in which typically inert counterions (e.g., Br- of CTABr) are replaced by nucleophilic counterions such as OH-.8,19 Included among the types of reactive counterions that have been studied recently are those termed “R-nucleophiles”,8 which share the structural feature of the presence of a lone pair of electrons on an atom adjacent to the nucleophilic center.20,21 The ratio of the rate constant for reaction with the R-nucleophile to the rate constant for (12) Annandale, M. T.; vanLoon, G. W.; Buncel, E. Can. J. Chem. 1998, 76, 873. (13) Dust, J. M.; Warren, C. S. Water Qual. Res. J. Can. 2001, 36, 589. (14) (a) Omakor, J. E.; Onyido, I.; vanLoon, G. W.; Buncel, E. J. Chem. Soc., Perkin Trans. 2 2001, 324. (b) Balakrishnan, V. K.; Dust, J. M.; vanLoon, G. W.; Buncel, E. Can. J. Chem. 2001, 79, 157. (c) Onyido, I.; Omakor, J. E.; vanLoon, G. W.; Buncel, E. Arkivoc 2001, 2, 134. (15) Sha’ato, R.; Buncel, E.; Gamble, D. G.; vanLoon, G. W. Can. J. Soil 2000, 80, 301. (16) Shirin, S.; Buncel, E.; vanLoon, G. W. Can. J. Chem. 2002, 81, 42. (17) Brinchi, L.; DiProfio, P.; Germani, R.; Savelli, G.; Tugliani, M.; Bunton, C. A. Langmuir 2000, 16, 10101. (18) Bunton, C. A.; Fendler, E. J.; Sepulveda, L.; Yang, K.-U. J. Am. Chem. Soc. 1968, 90, 5512. (19) (a) Bunton, C. A.; Frankson, J.; Romsted, L. S. J. Phys. Chem. 1980, 84, 2607. (b) Brinchi, L.; DiProfio, P.; Germani, R.; Marte, L.; Savelli, G.; Bunton, C. A. J. Colloid Interface Sci. 2001, 243, 469 and references therein. (20) (a) Buncel, E.; Hoz, S. Isr. J. Chem. 1985, 26, 313. (b) Grekov, A. P.; Veseor, P. Y. Usp. Khim. 1978, 47, 1200. (c) Fina, M. J.; Edwards, J. O. Int. J. Chem. Kinet. 1973, 5, 1. (d) Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84, 16. (21) (a) Tarkka, R. M.; Buncel, E. J. Am. Chem. Soc. 1995, 117, 1503. (b) Um, I. H.; Buncel, E. J. Org. Chem. 2000, 65, 577.

reaction with a reference normal nucleophile (i.e., kR/knormal) defines the “R-effect”20,21 (vide infra). Oximates are a particularly appealing class of R-nucleophiles to examine since many of these have pKa values that fall in the range of 7-10 which makes them ideal candidates for decontamination in the environment or of mucous membranes. Terrier and co-workers have demonstrated that oximates are effective in rapidly degrading phosphate triesters,22 and in cases of organophosphorus poisoning, medical treatment involves injection of oximate nucleophiles into the afflicted individual.23 In our previous kinetic studies of the ethanolysis of 114b,24 using UV-visible spectrophotometry, we found that the maximum absorbance (i.e., Ainf) due to 3-methyl-4-nitrophenoxide, 6 (Scheme 1), the product of nucleophilic attack at phosphorus by ethoxide, at the end of reaction was less than that calculated for complete reaction. It was surmised that other reaction pathways competed with the main SN2(P) route. Product analyses provided firm evidence for the existence of three competitive mechanistic pathways: SN2(P), SN2(C), and SNAr, in order of their relative contribution to the kinetics of ethanolysis (Scheme 1, with the nucleophile Nu ) EtO-).14b,24 Combination of UVvis, gas chromatography-mass spectrometry (GC-MS), and 31P NMR spectroscopy deconvoluted the kinetic data, identified products 2-6, and gave rate constants for these processes. In the present study, we have examined the reaction of 1 in aqueous solution with two nucleophiles, OH- and the R-nucleophile anti-pyruvaldehyde 1-oximate (MINA-, where MINA- is CH3-CO-CHdN-O-), and with cationic cetyltrimethylammonium (CTA+) surfactants whose counterions are the same nucleophiles. The CTAMINA reaction system would combine the anticipated rate enhancement associated with cationic micellar systems with the rate enhancement linked to the R-effect. While in the aqueous system the SN2(P) and SNAr pathways in Scheme 1 become indistinguishable, we assume that the SNAr pathway is very small as it was found to be in the ethanolysis.14b,24 As a result of the utility of 31P NMR spectroscopy in our previous study, the present investigation into the reactivity of 1 in cationic surfactant solutions involves this (22) (a) Terrier, F.; Degorre, F.; Kiffer, D.; Laloi, M. Bull. Soc. Chim. Fr. 1988, 415. (b) Degorre, F.; Kiffer, D.; Terrier, F. J. Med. Chem. 1988, 31, 757. (c) Terrier, F.; MacCormack, P.; Kizilian, E.; Halle´, J.-C.; Demerseman, P.; Guir, F.; Lion, C. J. Chem. Soc., Perkin Trans. 2 1991, 153. (23) For example: Wilson, I. B.; Ginsburg, S. Arch. Biochem. Biophys. 1995, 54, 569. (24) Balakrishnan, V. K. Ph.D. Thesis, Queen’s University, Kingston, Ontario, Canada, 2002.

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technique, as well as kinetic and UV-vis spectroscopic examination. These techniques provide insights into the regioselectivity of nucleophilic attack which, in turn, permit us to infer not just the location but the orientation of the organophosphorus neurotoxin, fenitrothion, in the micelle. Experimental Section Reagents. Fenitrothion (96.7%, 1) used in this study was a gift (Sumitomo Chemicals, Japan) and was purified as previously detailed;14b the purity was ascertained by GC-MS and NMR.24,25 The stock solution of 1 was prepared using this material (20 µL) dissolved in dry dioxane (10 mL) to yield a final concentration of 9.54 × 10-3 M. All other reagents or materials were purchased from commercial sources in the highest purity available. Cetyltrimethylammonium Hydroxide (CTAOH). CTAOH (10 wt %, Aldrich) was standardized by titration against anhydrous KHP (VWR), using phenolphthalein. As CTAOH readily absorbs CO2, care was taken to handle all solutions under argon. Once the concentration of the initial solution was known (0.345 M), the stock solution used in the kinetic experiments (0.0468 M) and in making the CTAMINA solutions was prepared by serial dilution. CTAMINA Solutions. Anti-pyruvaldehyde 1-oxime (monoisonitrosoacetone, MINA, MM ) 87.09 g/mol; Aldrich 98%) was recrystallized from heptane prior to use. A 0.0846 M initial solution was prepared by dissolution of a weighed quantity (0.1843 g, 2.12 × 10-3 mol) of MINA in a 25 mL volumetric using CO2-free distilled water. Subsequent solutions of CTAMINA were prepared by serial dilution of a 0.0206 M stock solution that had been prepared by mixing equal portions (25 mL each) of the initial 0.0846 M MINA solution with the 0.0468 M CTAOH solution. While the CTAMINA solutions were designed to be at the halfequivalence point for MINA, that is, where pH ) pKa ) 8.39,8a the actual pH diverged from this value slightly as has been noted and attributed previously to association of oximate ions with the micelles.8c Kinetic Procedures. Kinetic runs were followed by UV-vis spectrophotometry using either a Varian CARY3 or a HewlettPackard 8452A, each thermostated to 25 °C. All reactions were carried out under pseudo-first-order conditions. All solutions were transferred to cuvettes, under N2, using gastight syringes. Reactions were initiated by injection of the appropriate volume (20 µL) of the stock solution of 1 into the 10 mm path length quartz cuvette such that the total volume in the cell was 2.52 mL with a final concentration of 1 of ca. 7.7 × 10-5 M. Rate constants were determined by standard procedures.14,24 Synthesis of Demethylfenitrothion (2). Demethylfenitrothion, 2, was prepared following the procedure of Chambers and Mathews.26 The identity of the product (MM ) 261.31 g/mol) was verified using 1H, 13C, and 31P NMR spectroscopy (all recorded using a 300 MHz Bruker NMR instrument) and by GC-MS. The peaks are assigned as follows (numbering as in 2, shown in its protonated form).

1H NMR (δ, ppm relative to CHCl , CDCl ; J in Hz): 2.63 (s, 3 3 3H; aryl-CH3), 3.92 (d, 3H; CH3O, 3JP-H ) 14.1), 6.15 (s, 1H; OH), 7.21 (center d, 2H; H-2,6, 3JH5-H6 ) 9), 8.05 (center d, 1H, 3J H6-H5 ) 9).

(25) Fenitrothion: The Effects of its Use on Environmental Quality and its Chemistry; Associate Committee on Scientific Criteria for Environmental Quality; National Research Council Canada Publication 14104; NRCC: Ottawa, Canada, 1977. (26) Chambers, J.; Mathews, W. A. Bull. Environ. Contam. Toxicol. 1977, 18, 326.

Balakrishnan et al. 13C NMR (δ, ppm relative to CHCl , CDCl ; J-modulated): 3 3 21.2 (up, C-7); 55.5 (up, C-8); 119.6, 125.1, 127.1 (up, C-2, 5 and 6); 136.8, 146.2, 153.9 (down, C-1, 3 and 4). 31P NMR (δ, ppm relative to 85% H PO , DMSO-d ): 54.8. 3 4 6 31P NMR Product Analysis. Four experiments were followed by 31P NMR using CTAMINA and CTAOH under conditions that mimic the kinetic runs. (1) Fenitrothion-CTAMINA: Below the cmc. The first experiment involved mixing a CTAMINA solution, whose concentration (7.71 × 10-4 M) was below the cmc of this surfactant, with a solution of 1 (7.72 × 10-5 M) in an NMR tube. The initial spectrum displayed only the signal for the starting material at 67.0 ppm. After a 24 h reaction period, a 31P NMR spectrum was recorded using a 500 MHz Bruker NMR instrument. A sealed capillary tube that contained DMSO-d6 was placed in the NMR tube and served as signal lock; the FID was acquired overnight. In this case, two P-containing products were noted. The first appeared at chemical shift 59.3 ppm that corresponds to the literature value27 of 3 (Scheme 2), while the second appeared at chemical shift 54.9 corresponding to the 31P signal of 2. (2) Fenitrothion-CTAMINA: Above the cmc. Repetition of this experiment using 0.02 M CTAMINA, that is, at a concentration well above the cmc, and 7.72 × 10-5 M 1 resulted in observation of the same peaks: 2 (54.9 ppm) and 3 (59.3 ppm), as the only product signals. (3) Fenitrothion-CTAOH: Below the cmc. The next experiment was performed using CTAOH and 1 under the same reaction conditions as above. At a concentration of 7.71 × 10-4 M CTAOH, two 31P signals were recorded ascribable to 2 and 3 at 54.9 and 59.3 ppm, respectively (Scheme 3). (4) Fenitrothion-CTAOH: Above the cmc. When 0.02 M CTAOH (i.e., at a concentration significantly above the cmc for CTAOH) was mixed with 7.72 × 10-5 M 1, the sole 31P signal evident in the spectrum recorded after 24 h was that of 3 at 59.3 ppm (Scheme 3).

Results Kinetic Treatment. The rate of fenitrothion degradation in the absence and presence of the two cationic surfactants, cetyltrimethylammonium hydroxide (CTAOH) and CTA anti-pyruvaldehyde oximate (CTAMINA), was determined by monitoring the formation of 6 (the product of SN2(P) attack at P; Scheme 1) at its wavelength of maximum absorbance (λmax), 398 nm. The rate constants, kobs(aq) for the aqueous baseline systems (where OH- and MINA- are the nucleophiles used for comparison) and kobs(mic) for the micellar systems, and derived first-order half-lives are listed in Table 1. Values of Ainf ) 1.25 for both MINA and NaOH are characteristic of quantitative production of 6 and indicate that only the SN2(P) pathway was operating in the absence of surfactant. The pseudofirst-order rate constants for OH- (kobs(aq)) are calculated from the reported second-order rate constant, k2 ()2.43 × 10-3 M-1 s-1)14a,28,29 and the OH- concentration at the pH at which the rate constants for the micellar systems were measured. For micellar systems, the concentration of surfactant (ca. 0.02 M) was well above the respective cmc’s (1.8 × 10-3 M for CTAOH and 1.15 × 10-3 M for CTAMINA).8c The observed rate constants (kobs) for the reaction of fenitrothion with aqueous OH- and MINA- and with the same ions when associated with the CTA surfactant are given in Table 1. With both OH- and MINA-, the reaction rates are greater in the presence of surfactant; the rate constants increase with increasing concentration of surfactant but level off above the respective cmc’s in typical saturation-type behavior (Figure 1). The table also gives (27) Tebby, J. C. Handbook of Phosphorus-31 Nuclear Magnetic Resonance Data; CRC Press: Boca Raton, FL, 1991. (28) Vico, R. V.; Buja´nm E. I.; de Rossi, R. H. J. Phys. Org. Chem. 2002, 15, 858. (29) Kamiya, M.; Nakamura, K. Pestic. Sci. 1994, 14, 305.

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Table 1. Kinetic Parameters (25 °C) for the Degradation of Fenitrothion (1) by OH- and MINA- in Aqueous Solution and CTAOH and CTAMINA in Micellar Systems aqueous reaction with the following nucleophile OHconcentration/mol L-1 pH kobs/s-1 t1/2/min

0.020 12.12 3.2 × 10-5 a 360

OH-

MINA-

2.45 × 10-6 8.39 6.0 × 10-9 a 1.9 × 106

0.023 8.39 4.0 × 10-5 290

micellar reaction with the following nucleophile CTAOH

CTAMINA

0.020 12.12 9.6 × 10-4 12

0.020 8.39 8.2 × 10-4 14

Rate Enhancement kobs(CTAOH)/kobs(OH-) ) 30 kobs(CTAMINA)/kobs(MINA-) ) 21 kobs(MINA)/kobs(OH-) ) 6700 kobs(CTAMINA)/kobs(OH-) ) 1.4 × 105 a

micellar effect (OH-) micellar effect (MINA-) MINA- (R-Nu) vs OHmicellar MINA vs aqueous OH-

pH 12.12 pH 8.39 pH 8.39 pH 8.39

Calculated value based on k2 ) 2.43 × 10-3 M-1 s-1 (ref 14a).

Figure 1. The variation of kobs with concentration for CTAOH and CTAMINA. Note the onset of saturation-type behavior when [CTAOH] > cmc.

the ratio of the observed rate constants (i.e., kobs(mic)/ kobs(aq)) for comparison of the micellar systems relative to the standard reaction of 1 with OH- and MINA-. In considering this kinetic behavior, it is important to recall that the rates were determined on the basis of the release of the aryloxide, 6 (Scheme 1). Variation in the Infinity Absorbance (Ainf) Value with Surfactant Concentration. While the calculated value for the absorbance at infinity (Ainf) at 398 nm ([1] ) 7.72 × 10-5 M) is 1.25, the measured Ainf values for reaction systems where surfactant concentration was less than cmc fell below this theoretical Ainf. Plots of Ainf as a function of surfactant concentration (Figure 2), where the concentration of CTANu was gradually increased from 4.0 × 10-4 to 2.0 × 10-2 M, showed an asymptotic increase to a maximum Ainf value which, however, never reached 1.25, the expected value for complete production of 6. The maximum Ainf value in each case was reached at a surfactant concentration that is in reasonable agreement with the reported cmc values. We have shown previously that lower than expected Ainf values indicate the simultaneous operation of the SN2(C) process (Scheme 1).14b This possibility was further explored here via product analyses using 31P NMR spectrometry. 31 P NMR Spectrometric Analysis. The theoretical values of Ainf that were obtained in aqueous systems of both nucleophiles in the absence of surfactant are indica-

Table 2. Products Observed by 31P NMR after Reaction of 7.72 × 10-5 M Fenitrothion for 24 h with CTAOH and CTAMINA concentration (M)

products (pathways) observed

OHMINA-

Aqueous System 0.020 3 (SN2(P)) 0.023 3 (SN2(P))

CTAOH CTAMINA

Below the cmc 7.71 × 10-4 2 (SN2(C)), 3 (SN2(P)) 7.71 × 10-4 2 (SN2(C)), 3 (SN2(P))

CTAOH CTAMINA

0.020 0.020

Above the cmc 3 (SN2(P)) 2 (SN2(C)), 3 (SN2(P))

tive of 6 being the only product. This was verified in separate 31P NMR experiments in the aqueous (surfactantfree) systems where the only P-containing product was found to be 3. To account for the lower than expected production of 6 in the presence of surfactants, 31P NMR spectra were obtained for CTAOH and CTAMINA, both below and above the cmc (Table 2). (1) Fenitrothion-CTANu below the cmc. (a) CTAMINA. The first experiment involved mixing 7.71 × 10-4 M CTAMINA with 7.72 × 10-5 M 1 in the NMR sample tube. Under these conditions, CTAMINA is present in pseudofirst-order excess quantities and the concentration of fenitrothion was chosen to approximate the conditions of

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Figure 2. The variation of Ainf with concentration of CTAOH and CTAMINA. Scheme 2

Scheme 3

Discussion

the UV-vis kinetics. The initial spectrum contained only a single peak for 1. After 24 h of reaction, the 31P NMR spectrum showed the presence of two P-containing products ascribable to 327 and to 2, demethylfenitrothion (Scheme 2). (b) CTAOH. Below the cmc (7.71 × 10-4 M CTAOH), the two signals for 2 and 3 were again recorded (Scheme 3, Table 2). (2) Fenitrothion-CTANu above the cmc. (a) CTAMINA. At a concentration above the cmc for this surfactant, with 7.72 × 10-5 M 1, the 67 ppm signal for 1 is again replaced by the same two peaks assigned to 2 and 3; that is, the same products are identified for CTAMINA both above and below the cmc (Scheme 2, Table 2). (b) CTAOH. Above the cmc at 0.02 M CTAOH, 3 was the sole P-containing species evident in the 31P NMR spectrum; that is, above the cmc only product 3 was found (Scheme 3) in contrast to the result below the cmc where 2 and 3 were both found.

In studying the CTANu-fenitrothion reaction systems, our aim was twofold: (1) to ascertain the degree of acceleration of decomposition of 1 caused by the combination of micellar catalysis8,17-19,30-32 with any enhancement attributable to an R-effect resulting from the use of the oximate R-nucleophile, MINA-,8,20-22 and (2) to determine the effect of surfactants on the regioselectivity of nucleophilic attack on 1.14b,24 Fenitrothion Degradation by OH- and MINA(Absence of Surfactant). It is important to note that in the absence of surfactant reaction of 1 with OH- and MINA- in aqueous solution occurs solely by the SN2(P) pathway. At pH 8.39, the rate of degradation is more facile with MINA- by a factor of 6700 (Table 1). Oximate R-nucleophiles such as MINA- possess exalted reactivity in displacement reactions at different electro(30) (a) Romsted, L. S.; Bunton, C. A.; Yao, J. Curr. Opin. Colloid Interface Sci. 1997, 2, 622. (b) Bunton, C. A.; Nome, F.; Quina, F. H.; Romsted, L. S. Acc. Chem. Res. 1991, 24, 357. (c) Bunton, C. A.; Savelli, G. Adv. Phys. Org. Chem. 1986, 22, 21. (31) (a) Menger, F. M.; Portnoy, C. E. J. Am. Chem. Soc. 1967, 89, 4698. (b) Menger, F. M. Acc. Chem. Res. 1978, 12, 111. (32) Martinek, K.; Yatsimirski, A. K.; Levashov, A. V.; Berezin, I. In Micellization, Solubilization and Microemulsions, Vol. 2; Mittal, K. L., Ed.; Plenum Press: New York, 1977.

Nucleophilic Attack on Fenitrothion

philic centers including phosphorus; they have hence been described as “supernucleophiles”.20 In a strict sense, the R-effect is defined by a different rate constant ratio, that between the R-nucleophile and a normal nucleophile whose conjugate acid has the same pKa as the conjugate acid of the R-nucleophile. Alternatively, the ratio of rate constants for the target reaction with the R-nucleophile as compared to a nucleophile of similar structure (e.g., -OOH versus OH) has been used to quantify the R-effect. In the present system, CH3-CO-CHdNO- (MINA-) is neither structurally similar to hydroxide nor does it have a pKa value comparable to that of hydroxide. In Table 2, the rate constant ratio kobs(MINA-)/kobs(OH-) ) 6700 thus underestimates the R-nucleophile effect noting that the pKa of OH- reference nucleophile is ca. 7 units greater than that of MINA- and so OH- enjoys an advantage as the more basic nucleophile. Acceleration of Fenitrothion Degradation in Surfactant Systems. As is apparent in Figure 1, degradation of 1 is accelerated by the presence of the CTA surfactant in the case of both nucleophiles, OH- and MINA-. The rate constants increase with surfactant concentration, culminating in a maximum above the cmc value. It has been amply demonstrated in a number of studies8b,33 that at concentrations below the cmc, hydrophobic substrates induce the formation of submicellar aggregates where the reaction takes place. One consequence of such aggregation of cationic surfactants is the generally observed rate acceleration of nucleophilic processes in this region. Above the cmc, degradation of 1 is accelerated by a factor of 30 [)kobs(mic)/kobs(aq)] in a micellar solution made up of the reactive counterion cationic surfactant, CTAOH, relative to aqueous NaOH at the same concentration (Table 1). A similar rate enhancement of 20 was observed for the micellar effect in the case of MINA. Clearly, the enhancement is associated with the presence of micelles in the system and may be attributed to the so-called “concentration effect” in the micelle.30-32 The electrostatic attraction of the cationic headgroups of the surfactants at the micelle surface to the nucleophilic anion counterions leads to augmentation of the local concentration of the nucleophile, while incorporation of the substrate in the micelle leads to a higher local concentration of the substrate. This enhanced concentration of the reactants accounts for the higher rate of reaction. Implicit in this explanation is the requirement that the reactive site of fenitrothion be situated in close proximity to the nucleophile, that is, at the micelle-water interface, the Stern layer, where ions are normally taken to be partially associated with one another. Further, the nature of the anions present in the system affects the nucleophile concentration in the Stern layer of cationic micelles, as explained by the pseudophase ion-exchange (PPIE) model of micellar catalysis.30-32 In the case of inert counterion surfactants (e.g., CTABr), anionic nucleophiles in the bulk aqueous phase, such as OH-, compete with non-nucleophilic counterions such as Br- for sites in the Stern layer that lead to reaction. Such competition is diminished or eliminated when the micelles are composed of reactive counterion surfactants such as CTAOH. The result is that these reactive counterion surfactants produce greater rate effects than do inert counterion surfactants.8,19 Further enhancement of the degradation of 1 results from the use of CTAMINA. The kobs(CTAMINA)/kobs(OH-) ratio is now 1.4 × 105 (Table 1), which reflects both the (33) For example: (a) Tee, O. S.; Fedortchenko, A. A. Can. J. Chem. 1997, 75, 1434. (b) Tee, O. S. Can. J. Chem. 2000, 78, 1100. (c) Bunton, C. A.; Fouradian, H. J.; Gillitt, N. D.; Whiddon, C. R. Can. J. Chem. 1998, 76, 946 and references therein.

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effect of micellar catalysis and the exalted nucleophilicity found for R-nucleophiles8,20-22,34 such as MINA-. We previously showed that the R-nucleophilic counterion surfactant, CTAOOH (where hydroperoxide is the R-nucleophile), accelerates the degradation of paraoxon, 1c, a structural analogue of fenitrothion;8 the current work serves to emphasize the potential utility of R-nucleophiles as counterions in surfactants in environmental remediation as well as to expand our understanding of the factors that enhance reaction at P in related compounds.35-38 Among the factors that interact to account for micellar catalysis, there is the requirement that the reactive site of the substrate, 1, be suitably situated in the Stern layer so that it is accessible to the nucleophile. The regioselectivity of attack previously found for 114b,24 provides background into the question of orientation. The rate enhancements that accompany micellization argue for location of 1 in the Stern layer; the observed regioselectivity indicates how 1 is aligned in the Stern layer. Surfactant Influences on Regioselectivity of Nucleophilic Processes. Some remarkable results are revealed in the regioselectivity of the processes investigated in our study. As shown in Table 2, the reaction products, and hence pathways followed, vary depending on whether surfactant is absent or present and in the latter case whether the experiment is run below the cmc or above. These situations will now be discussed in turn. (1) Absence of Surfactant. Only the aryloxide product 6 is obtained in these experiments in quantitative amount, as shown by the equivalence of observed and theoretical Ainf values with both OH- and MINA- as nucleophiles. Now in the case of OH- nucleophile, the product 6 could arise by either SN2(P) or SNAr pathways (Scheme 1); however, we have adduced evidence (vide supra) that the SNAr pathway could be present only to a very small extent, if at all, which leaves the SN2(P) route as the one followed, with both OH- and MINA- (Scheme 1). This accords with numerous studies that have documented the efficacy of the electrophilic phosphorus center for attack by nucleophiles.3-5,9,10 (2) CTAOH and CTAMINA Reactions below the cmc. The results of 31P NMR studies (Table 2) clearly show that below the cmc, both CTAOH and CTAMINA give rise to products 2 and 3 corresponding to SN2(C) and SN2(P) pathways. How then is the advent of the SN2(C) pathway in these systems to be explained? As noted above, the increase in degradation rate in the presence of surfactant, but below the cmc, can be associated with the formation of submicellar aggregates where the reaction takes place However, concurrently, in such an aggregate the ion-paired nucleophilic species, CTA+Nu-, will be subject to a greatly increased steric demand in its approach to the electrophilic phosphorus center as compared to the free ion situation in the absence of surfactant. This in turn permits an alternative pathway, in this case SN2(C), to compete energetically. The SN2(C) pathway at the primary carbon center is obviously not subject to steric encumbrance.39 As well, our previous study14b on the ethanolysis of fenitrothion showed that both SN2(P) and SN2(C) pathways were occurring, so they must both be (34) Neves, M. F. S.; Zanette, D.; Quina, F. H.; Moretti, M. T.; Nome, F. J. Phys. Chem. 1989, 93, 1502. (35) Pregel, M. J.; Dunn, E. J.; Nagelkerke, R.; Thatcher, G. R. J.; Buncel, E. Chem. Soc. Rev. 1995, 24, 449. (36) Nagelkerke, R.; Pregel, H. J.; Dunn, E. J.; Thatcher, G. R. J.; Buncel, E. Org. React. 1995, 29, 11. (37) Buncel, E.; Nagelkerke, R.; Thatcher, G. R. J. Can. J. Chem. 2003, 81, 53. (38) Nagelkerke, R.; Thatcher, G. R. J.; Buncel, E. Org. Biomol. Chem. 2003, 1, 163.

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energetically accessible. In such a situation, it can be expected that one can influence the outcome through modulating the steric circumstance, as we have found. (3) CTAOH and CTAMINA Reactions above the cmc; Orientation of Fenitrothion within the Micelle. As shown by the 31P NMR results in Table 2, above the cmc, CTAOH reacts via the SN2(P) pathway only, while both pathways operate with CTAMINA. In discussing the rate enhancement attendant upon micellization as compared to standard aquatic reactions [i.e., kobs(mic)/kobs(aq), Table 1], a requirement was that the substrate be located in the Stern layer but, more importantly, that the reactive site(s) of 1 be suitably aligned in the micelle. A number of kinetic studies, particularly of nucleophilic attack on carboxylic esters,33,40,41 have been reported, and generally, the enhanced rates found in cationic micellar systems are attributed to the concentration effect30-32 that operates because while the ester tail is more or less buried in the hydrophobic interior of the micelle, the carbonyl group is accessible to the aqueous environment of the Stern layer with its increased concentration of anionic nucleophile.31a,33,40,41 Spectroscopic studies,42 notably that of Fendler and coworkers42d that correlated spectroscopic data with Reichardt’s ET(30) scale of solvent polarity,43 have also suggested that for ketones and carboxylic esters the CdO groups reside in the Stern layer with alkyl groups pointed toward the interior. The accelerated decomposition of 1 in the presence of the CTA micelles in our study agrees with these results and suggests that PdS is lodged in the Stern layer where it is available for nucleophilic attack. In contrast, in a β-cyclodextrin (CD)28 system, the 4-fold decrease in rate constant for alkaline hydrolysis of 1 relative to aqueous NaOH was attributed to the inaccessibility of the P-center; the PdS moiety is embedded in the cavity of the CD and is unavailable not only to OHfrom the bulk medium but also to pendant alkoxyl groups on the rim of the CD.28 Therefore, if 1 is located deep within the hydrophobic core of the micelle in the current systems, inhibition of reaction would be noted rather than the acceleration found. Turning from the observation of micellar catalysis to focus on the regioselectivity observed above the cmc, the decreased contribution of the SN2(C) process in the fenitrothion-CTAMINA reaction, combined with the absence of C-attack for CTAOH (Scheme 3), argues in favor of placement of the methoxyls of 1 toward the micelle interior. That some C-attack is still observed with CTAMINA is a reflection of the R-nucleophilicity of MINAand its higher hydrophobicity as compared to that of OH-; even though the CH3O moieties are relatively inaccessible in the micelle, the more reactive (less selective) MINA(39) (a) Ingold, C. K. Structure and Mechanism in Organic Chemistry, 2nd ed.; Cornell University Press: Ithaca, NY, 1969. (b) Carroll, F. A. Perspectives on Structure and Mechanism in Organic Chemistry; BrooksCole: Pacific Grove, CA, 1998. (c) Jencks, W. P. Catalysis in Chemistry and Enzymology; McGraw-Hill: New York, 1969. (40) For example: (a) Behme, M. T. A.; Fullington, J. G.; Noel, R.; Cordes, E. H. J. Am. Chem. Soc. 1965, 87, 265. (b) Romsted, L. S.; Cordes, E. H. J. Am. Chem. Soc. 1968, 90, 4404. (41) (a) Funaski, N. J. Phys. Chem. 1979, 83, 237. (b) Funaski, N.; Murata, A. Chem. Pharm. Bull. 1980, 28, 805. (42) (a) Suratkar, V.; Mahapatra, S. J. Colloid Interface Sci. 2000, 225, 32. (b) Bunton, C. A.; Ihara, Y. J. J. Org. Chem. 1977, 42, 2865. (c) Bunton, C. A.; Forodian, H. J.; Gillitt, N. D.; Whidden, C. R. Can. J. Chem. 1998, 76, 946. (d) Fendler, J. H.; Fendler, E. J.; Infante, G. A.; Shih, P.-S.; Petterson, L. K. J. Am. Chem. Soc. 1975, 97, 89. (e) Romsted, L. S. In Surfactants in Solution; Mittal, K. L., Lindman, B., Eds.; Plenem Press: New York, 1984. (43) (a) Dimroth, K.; Reichardt, C.; Siepmann, T.; Bohlmann, F. Justus Liebigs Ann. Chem. 1963, 661, 1. (b) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 3rd ed.; Wiley-VCH: New York, 2003.

Balakrishnan et al.

Figure 3. A depiction of fenitrothion orientation within a micelle of CTAMINA for nucleophilic attack at P. For simplicity, only two surfactant molecules located in the spherical micelle are shown.

still reacts at these C-sites, albeit to a significantly lower degree than found below the cmc. The contrasting regioselectivity found here pinpoints the electrophilic CH3O C-centers oriented toward the hydrophobic micellar interior while the PdS moiety is directed outward into the Stern layer with its associated high local concentration of nucleophilic counterions (Figure 3). As a consequence, the major reaction pathway now becomes SN2(P). Below the cmc, the other reaction centers become available and, so, other reaction pathways play a larger role (Schemes 2 and 3). By way of comparison, Sakurai and colleagues44 used regioselectivity in radical combination products from the benzophenone-sensitized photolysis of O-benzoyl-N-(1-naphthoyl)-N-phenylhydroxylamine in CTACl, CTABr, and mixed micelles to assign the location of the less hydrophobic caged radical pairs to the Stern layer and the more hydrophobic to the interior. It is reasonable, then, to locate the aryl ring of 1 even deeper in the micelle core than the methoxyls of this substrate, as shown in Figure 3. Conclusions The salient features of this study illustrate the use of regioselectivity as a probe of substrate orientation within micelles. (1) Reaction of fenitrothion with both NaOH and MINAin aqueous solution (i.e., in the absence of surfactant) yields quantitatively as products 6 (UV/vis) and 3 (31P NMR). (2) In the presence of surfactant but below the cmc, Ainf values for reaction of 1 with CTAOH and CTAMINA were always less than expected for full release of 6. (3) Above the cmc, Ainf values indicate quantitative release of 6 with CTAOH, but with CTAMINA the increase in Ainf agrees with increased though not quantitative formation of the aryloxide, 6. (4) 31P NMR product analysis for CTAOH shows that 2 and 3 form below the cmc, while above the cmc 3 is the sole P-containing product. In contrast, CTAMINA gives 2 and 3, both above and below the cmc, though 2 is a minor product above the cmc. Together these results indicate variable regioselectivity dependent upon (i) the absence or (ii) the presence of micelles. (i) In the absence of surfactant, OH- and MINA- both react solely by the SN2(P) pathway in accord with the high electrophilic nature of the P-center. (ii) In the presence of surfactant, below the cmc, the increased steric demand for CTANu elicited by ion pairing in the submicellar aggregate permits the advent of the SN2(C) pathway in competition with SN2(P). (iii) Above the cmc, reaction occurs solely at PdS for CTAOH and predominantly at PdS for CTAMINA, (44) Kaneko, T.; Tokue, T.; Kubo, K.; Sakurai, T. Bull. Chem. Soc. Jpn. 1999, 72, 2771.

Nucleophilic Attack on Fenitrothion

indicating that while PdS is accessible to attack in the Stern layer of the micelle (as found for CdO systems)31a,40-43 the methoxyl groups (and the aryloxyl group) are oriented toward the hydrophobic interior of the micelle. The minority C-attack product in the case of CTAMINA reflects not only the greater hydrophobicity of MINA- (that would tend to embed it further in the micelle interior, as well) but also its R-nucleophilicity.20-22 Location of PdS in the Stern layer is also in accord with the acceleration in degradation of fenitrothion in the micellar systems as compared to purely aqueous NaOH. While a significant rate enhancement is found for CTAOH (ca. 30), an extraordinary exhancement is found for

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CTAMINA (ca. 105). The latter result illustrates the efficacy of an R-nucleophilic counterion micellar system, whose promise for achieving environmental remediation of 1 is the subject of ongoing investigations in our laboratories. Acknowledgment. Support from the following institutions is gratefully acknowledged: the Natural Sciences and Engineering Research Council of Canada (NSERC) and Queen’s University (E.B. and G.W.v.L.) and the Centre National de la Recherche Scientifique (J.T.). LA049572D