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Articles Esterolytic Reactivities of (Dialkylamino)pyridine Amphiphiles Solubilized in Different Pseudo-Three-Component Cationic Microemulsions Santanu Bhattacharya* and Karnam Snehalatha Department of Organic Chemistry, Indian Institue of Science, Bangalore 560012, India Received May 29, 1996X Hydrolysis reactions at pH 8.7 of p-nitrophenyl alkanoates of varying chain lengths mediated by four (dialkylamino)pyridine (DAAP)-functionalized amphiphiles were examined in three different microemulsion (ME) media. All the ME systems studied herein were stabilized by a cationic surfactant, cetyltrimethylammonium bromide (CTABr), and a cosurfactant, 1-butanol. The three MEs could also be described as (a) an oil-in-water, (b) a water-in-oil, and (c) a bicontinuous oil-water ME recipe. The DAAP surfactants employed in this study differ in their electrostatic character at the level of headgroup. In order to examine their esterolytic activities, individual DAAP surfactants were separately doped into each ME and the resulting kinetic data for esterolyses were compared with that of the nonamphilphilic (dimethylamino)pyridine. The ester-cleaving abilities of each DAAP catalyst in three different MEs were also compared. Hydrophilic substrates such as 3-acetoxy-4-nitrobenzoic acid or short chain esters like p-nitrophenyl acetate were found to be especially susceptible to cleavage compared to the alkanoate esters having long alkyl chain residues under these conditions in any of the MEs. Importantly these results are markedly different from what we found in CTABr micelles with the same DAAP catalysts, although the crucial catalytic turnover behavior of the DAAPs was maintained even in MEs.
Introduction Quite often different organic esters and organophosphates which are employed as pesticides or chemical warfare agents are responsible for various modes of environmental contamination.1 These substances are generally insoluble in aqueous media and thus cannot be efficiently hydrolyzed even at high pH. Most of these molecules are also inherently stable under ambient environmental conditions and are hence known as persistent chemicals. Organized assemblies containing nucleophile-attached amphiphiles have been extensively used as potent esterolytic agents toward such substances during the last several years.2,3 Most of these esterolytic processes usually proceed with an attack of the nucleophiles (frequently an anion) on the acyl carbonyl function. Consequently such processes are potentiated by performing the reactions in aggregates such as cationic micelles2 or vesicles3 which assist in bringing together the nucleophilic reagents and the hydrophobic substrates. Aqueous * To whom correspondence should be addressed. Fax: +-91080-334-1683. E-mail:
[email protected]. X Abstract published in Advance ACS Abstracts, December 1, 1996. (1) (a) Ember, L. R. Chem. Eng. News 1994 (Feb. 14 issue), 7. (b) Alternative Technologies for the Destruction of Chemical Agents and Munitions; National Academy Press: Washington, DC, 1993; June. (c) Yang, Y. C.; Baker, J. A.; Ward, J. R. Chem. Rev. 1992, 92, 1729. (d) Chem. Br. 1988, 7, 657. (2) (a) Rosso, F. D.; Bartoletti, A.; Profio, P. D.; Germani, R.; Savelli, G.; Blasko, A.; Bunton, C. A. J. Chem. Soc., Perkin Trans. 2 1995, 673. (b) Moss, R. A.; Zhang, H. M. J. Am. Chem. Soc. 1994, 116, 4471. (c) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Org. Chem. 1994, 59, 18. (d) Davis, F. A.; Ray, J. K.; Kasperowicz, S.; Przeslawski, R. M.; Durst, H. D. J. Org. Chem. 1992, 57, 2594. (e) Hammond, P. S.; Forster, J. S.; Lieske, C. N.; Durst, H. D. J. Am. Chem. Soc. 1989, 111, 7860. (f) Katritzky, A. R.; Duell, B. L.; Durst, H. D.; Knier, B. L. J. Org. Chem. 1988, 53, 3972. (3) (a) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Am. Chem. Soc. 1992, 114, 5086. (b) Moss, R. A.; Hendrickson, T. J. Am. Chem. Soc. 1986, 108, 4471. (c) Kunitake, K.; Ihara, H.; Okahata, Y. J. Am. Chem. Soc. 1983, 105, 6070.
surfactant dispersions such as micelles, vesicles, etc., in addition to their ability to support rate enhancements toward esterolytic reactions, provide means for solubilization of hydrophobic compounds in water-rich media.4 However, the usefulness of micelles and closely related aggregates is seriously compromised due to their limited solubilization capacities.5 Furthermore the dynamic character of the monomer-micelle-substrate interactions and water penetration near reaction sites also result in reduction in any selectivity in such reactions.6 Other systems which have been designed in recent years to act as catalysts toward hydrolytic reactions include nucleophile-bound cyclodextrins, cryptands, and macrocyclic hosts. However, all of these severely lack solubilizing abilities of hydrophobic substances in water-rich medium.7 Large solubilization capacities of microemulsions8 offer a wider scope for their useful exploitation. The above considerations prompted us in the present study to explore the reactivities of some nucleophile-functionalized surfactants when included in a microemulsion (ME) system. 4-(Dialkylamino)pyridine (DAAP, 1) and its derivatives due to their high nucleophilicity have been widely employed as catalytic systems to promote esterolysis (4) (a) Menger, F. M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1086. (b) Bunton, C. A.; Savelli, G. Adv. Phys. Org. Chem. 1986, 22, 213. (c) Fendler, J. H.; Fendler, E. J. Catalysis in Micellar and Macromolecular Systems; Academic Press: New York, 1975. (5) Menger, F. M. J. Am. Chem. Soc. 1991, 113, 9621. (6) Fendler, J. H. Acc. Chem. Res. 1976, 9, 153. (7) Dugas, H.; Penney, C. Bioorganic Chemistry, A Chemical Approach to Enzyme Action; Springer: New York, 1989. (8) (a) Microemulsions. Theory and Practice; Prince, L. M., Ed.; Academic Press: New York, 1977. (b) Langevin, D. Acc. Chem. Res. 1988, 21, 255. (c) Shinoda, K.; Lindman, B. Langmuir 1987, 3, 135. (d) Hoffmann, H.; Platz, G.; Ulbricht, W. Ber. Bunsen-Ges. Phys. Chem. 1986, 90, 877. (e) Cazabat, A. M.; Langevin, D. J. Chem. Phys. 1981, 74, 3148.
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reactions.9 Among the various types of DAAP systems that have been earlier studied include the ones that are polymer-bound.10 However, often despite elaborate synthetic efforts, the reactivities of DAAP polymers were found to be even inferior to the parent (dimethylamino)pyridine 1a.11 Furthermore, while some of the polymer DAAPs were useful, many studies did not adequately address the pertinent details of the process by which the catalysts worked. A desire to understand the functional catalysis with DAAP-based systems and perhaps also to aid in the rational design of potent, catalytic, surfaceactive materials subsequently led to the synthesis of covalently bound DAAP surfactants.12 Due to our continuing interest in the design and examination of new surfactant-based supramolecular systems for various applications,13,14 we recently synthesized14 a new series of DAAP-attached surfactants (1b,c and 2a,b). These amphiphiles had DAAP moieties attached near the ionic headgroup. The flexibility of the DAAP units at the headgroup level rendered them accessible toward substrate molecules when they are arranged in self-assembled aggregates. Thus these systems, 1b,c and 2a,b, when included in cationic comicellar assemblies containing excess cetyltrimethylammonium bromide (CTABr), showed good to impressive rate accelerations in terms of their esterolytic abilities toward p-nitrophenyl alkanoates.14 Although MEs are more practical systems for various applications,15 DAAP-based catalysts despite their good nucleophilic activities have not been examined in this medium so far. Therefore, we have decided to examine the reactivities of these systems separately in water-rich, oil-rich, and water-oil bicontinuous ME states stabilized by CTABr. In this report, we describe the results of the studies of esterolyses of p-nitrophenyl alkanoates promoted by the DAAP amphiphiles 1b,c and 2a,b cosolubilized in different MEs and also present evidence of their turnover behavior when used with excess substrates. Experimental Section General Methods. UV-visible spectra were recorded on a Shimadzu Model 2100 UV-visible recording spectrophotometer. All the reagents and solvents were of highest grade available commercially and used purified, dried, or freshly distilled as required, by literature procedures. Steam-distilled water was used for all kinetic studies. The pH measurements were made with Schott pH meter CG 825. Materials. Cetyltrimethylammonium bromide (Aldrich) was recrystallized several times from methanol. 1-Butanol (SD-fine Chem.) and cyclohexane (Merck) were used fresh after distillation. The aqueous phase was prepared using 0.02 M phosphate buffer prepared by mixing disodium hydrogen phosphate and monosodium hydrogen phosphate with 0.08 M KCl and distilled water. (Dimethylamino)pyridine (Sigma) was recrystallized from EtOAc prior to use. The syntheses of the DAAP-attached amphiphilic compounds 1b,c and 2a,b have already been reported.14 Phase Diagram. The pseudo-three-component phase diagram (Figure 1) was determined by titration at ambient temperature. The phase map shows a continuous region which represents the compositions which are optically clear. Initial compositions of cyclohexane (oil) and 1:1 (weight ratio) CTABr (9) (a) Hofle, G.; Steglich, W.; Vorbrungen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569. (b) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129. (c) Vaidya, R. A.; Mathias, L. J. J. Am. Chem. Soc. 1986, 108, 5514. (d) Rubinsztajn, S.; Zeldin, M.; Fife, W. K. Macromolecules 1990, 23, 4026. (e) Rubinsztajn, S.; Zeldin, M.; Fife, W. K. Macromolecules 1991, 24, 2682. (f) Fife, W. K.; Rubinsztajn, S.; Zeldin, M. J. Am. Chem. Soc. 1991, 113, 8535. (10) (a) Hierl, M. A.; Gamson, E. P.; Klotz, I. M. J. Am. Chem. Soc. 1979, 101, 6020. (b) Delaney, E. J.; Wood, L. E.; Klotz, I. M. J. Am. Chem. Soc. 1982, 104, 799. (11) Frechet, J. M. J.; Darling, G. D.; Hsuno, S.; Lu, P. Z.; de Meftahi Vivas, M.; Rolls, W. A., Jr. Pure Appl. Chem. 1986, 60, 353.
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(surfactant) and cosurfactant (n-butyl alcohol) were titrated with aqueous buffer (water) to determine clear and turbid regions. Preliminary compositions of CTABr, n-butyl alcohol, and aqueous buffer were similarly titrated with aliquots of freshly distilled cyclohexane. The titration point was determined visually by the cloudiness-clarity transition. Addition of small amount of organic (95%), a third aliquot of identical amount of the same substrate was added to the resulting mixture, and the kinetics were followed. After each addition of substrate, the first-order rate constants for ester cleavages were obtained from the three time course segments involving each substrate addition and were identical within experimental error. This indicates that the esterolysis had no effect on the catalyst concentration. The data appear in Table 3, where all the rate constants followed strict first-order kinetics. The rather invariant kψ observed for successive p-nitrophenyl acetate cleavages up to ∼3.0 equiv of substrate suggests that the DAAPs rapidly ‘turn over’ during each cycle and are available at its initial concentration prior to the addition of the next aliquot of substrate.
Influence of Chain Length of p-Nitrophenyl Alkanoates. The esterolytic behavior of several parasubstituted phenyl esters of n-alkanoic acid homologues with varying chain lengths was examined by Jiang and co-workers in different solvent mixtures.19,20 These studies revealed the existence of aggregation and self-coiling of the long hydrophobic segments under the conditions of these experiments. Similar studies in micellar14,21 or polymeric9f environments have also been done. However, there exists little information in literature pertaining to the effect of chain length of substrates on their reactivities in ME media. In view of this, we examined herein the role of gradual variation of hydrophobicity in substrate on the proclivities of nucleophilic DAAPs in ME media.
The three ME recipes, although differing profoundly in terms of their oil or water contents, showed remarkably similar trends in terms of their esterolytic cleavage capacities toward p-nitrophenyl alkanoates as a function of the chain length for a given DAAP catalyst. Thus, p-nitrophenyl alkanoates of shorter chain length showed higher propensity to be esterolyzed and the reactivity decreased monotonously with the increase in the chain length of the substrate in all the MEs. The substrate p-nitrophenyl acetate emerged as apparently the most reactive substrate in all three ME systems irrespective of the DAAP employed. This suggests that the catalysts are presumably located either at the “water-rich” region or at the interfacial region of the droplets where substrates with increasing lipophilic character are decreasingly partitioned. The experimentally determined distribution coefficients (KD) also support this conclusion (see below). In order to further examine the generality of this finding, we employed a different substrate, 4-acetoxy-3-nitrobenzoic acid, which possessed much greater water solubility [KD(P[oil]/P[water]) ) 0.44] and studied its hydrolysis in different ME recipes. As we anticipated this substrate was found to be even more susceptible to esterolysis than any of the other substrates. In the ME-3 system, the kψ for the hydrolysis of 4-acetoxy-3-nitrobenzoic acid promoted by catalyst 1b was found to be ∼3 times faster than that of p-nitrophenyl acetate in the presence of the same catalyst. In the ME-2 system, the rate of esterolysis of 4-acetoxy-3-nitrobenzoic acid is nearly 2 that of pnitrophenyl acetate with the same catalyst. To further confirm this point, the relative distributions of various substrates in cyclohexane and in aqueous medium were examined. At the same time, the Rf values were also (19) Jiang, X. K.; Yong-Zheng, H.; Wei-Qiang, F. J. Am. Chem. Soc. 1984, 106, 3839. (20) Jiang, X. K. Acc. Chem. Res. 1988, 21, 3629. (21) Gitler, C.; Ochoa-Solano, A. J. Am. Chem. Soc. 1968, 90, 5004.
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Table 4. Kinetic and Distribution Parameters for the Cleavages of p-Nitrophenyl Alkanoates by DAAP Catalysts 1a-c and 2,b in the ME-1 Systema 104kψ (s-1)e substrateb 3, n ) 2 n)4 n)6 n)8 n ) 10 n ) 12 n ) 14
c
d
KD
Rf
1a
1b
1c
2a
2b
10.8
0.2 0.5
36.0 20.4 16.4 15.9 16.0 15.8 11.7
10.2 2.7
95.9
20.1 4.0 3.7 3.1 3.0 2.9 1.5
43.2 14.1 10.9 9.6 9.2 9.5 9.5
13.4 5.0 3.2 3.0 2.2 1.1 0.8
205.4
0.6
1.9 1.3
a See text for reaction conditions. b [Substrate] ) 2.5 × 10-5 M. KD ) P[oil]/P[water]; represents the distribution coefficients of the substrate between cyclohexane (oil) and aqueous buffer (water) at 25 °C. d Rf values were determined by thin-layer chromatography on uniformly precoated silica gel plates (Merck) using an eluent composed of 7% EtOAc in petroleum ether (bp 60-80 °C). e For all the reactions, [catalyst] ) 5 × 10-4 M was employed.
c
Figure 3. Variation of catalytic rate constants (kcat, M-1 s-1) for esterolysis as a function of chain lengths of p-nitrophenyl alkanoates 3 (n ) 2-14) in different microemulsion systems. Reaction conditions at pH 8.7, 0.02 M phosphate buffer, µ ) 0.08 (KCl), 25 ( 0.1 °C, [catalyst] ) 5 × 10-4 M, [3] ) 2.5 × 10-5 M: for the ME-1 system 1b (O), 2a (0); for the ME-2 system 1b (4), 2a (2); and for the ME-3 system 1b (9).
determined to indicate relative polarities. The experimentally determined partition coefficients (KD) of a few substrates in water and cyclohexane phases are given in Table 4. The distribution study clearly shows that the partitioning of p-nitrophenyl alkanoate with increasing chain length diminishes profoundly in water. In ME media, the short chain esters such as p-nitrophenyl acetate are likely to be concentrated more in the interface region in contrast to their longer chain counterparts which are probably more likely to be confined at the hydrophobic, oil microdroplet regions of the ME systems. Table 4 also shows the experimentally determined pseudo-first-order rate constants for p-nitrophenyl alkanoate hydrolysis in ME-1 media in the presence of various DAAP catalysts. Figure 3 shows a plot of the second-order “catalytic” rate constants (kcat ) kψ/[catalyst]) as a function of the alkanoate chain length of the substrate. Notably, under the same ME esterolytic conditions, all
the DAAP catalysts showed remarkably greater esterolytic activities toward 3 (n ) 2). This was also found to be true with the nonamphiphilic 1a in ME-1 media. Several important points emerge from the analyses of the kinetic data in Table 4. From an examination of the k2/k14 ratio of the pseudo-first-order rate constants for the esterolysis of 3 (n ) 2) to that of 3 (n ) 14) in the 1a/CTABr ME-1 coaggregates, we find that the hydrolysis rate for 3 (n ) 2) is ∼13.8-fold greater than that for 3 (n ) 14). In contrast, the corresponding rate constant for the esterolysis by the 1b/CTABr ME-1 coaggregates of 3 (n ) 2) is ∼2.3-fold greater than that of 3 (n ) 14) under comparable kinetic conditions. On the other hand, while for 1c/CTABr in ME-1 the k2/k12 ratio is ∼7.8, the corresponding ratio for 2a/CTABr in ME-1 is ∼4.4 and that for 2b/CTABr in ME-1 is ∼16.8. While it is clear that with all DAAPs in CTABr ME-1 media the hydrolysis of the substrate with the shorter chain length is clearly facile relative to their more lipophilic counterparts, the conclusions about the relative substrate preference cannot be based on the order of their catalytic activities. The anionic catalyst 2a and the neutral catalyst 1b showed greater esterolytic reactivity than the cationic 1c and the zwitterionic 2b catalysts. The long chain DAAP catalysts, because of their amphiphilic nature, are likely to be located at the aggregate interface. It is not unreasonable to assume that their polar headgroups might be facing more toward the water phase where substrates of longer chain length will be minimal in concentration. In the case of DMAP (1a), it can partition favorably into water [KD(P[oil]/P[water]) ) 0.06]. In addition due to its neutral but polarizable nature, it may be located near the interface. In W/O ME system, the long chain DAAP catalysts with a charged headgroup might be less available for catalysis relative to 1a because the amphiphilic catalysts being more polar are in the water pool and the substrates being nonpolar are present in the cyclohexane phase. This suggests that location of the catalyst and substrate at favorable sites in the ME system is quite important. Our experiments also suggest that in an oilin-water microemulsion system, the reactivity toward alkanoate esters is reasonable when compared to a waterin-oil system. In the oil-in-water microemulsion system (ME-1) and ME-2 the catalyst may be located more in the interface region. The most reactive DAAP catalysts 1a and 2b are ∼77 and ∼89 times more reactive than the buffered ME-1 alone (devoid of any DAAP) toward p-nitrophenyl acetate. Comparison of Reactivities of DAAP Amphiphiles in Micellar over ME Media. A comparison of the results obtained from the kinetic studies of esterolysis in CTABr ME aggregates with that of the experiments done under CTABr micellar conditions reveals several points worth noting. The rate enhancements induced by various DAAP catalysts in CTABr ME aggregates are considerably less than their corresponding quantities in CTABr comicellar media. This could be due to two possible reasons. In CTABr comicelles, the catalyst to CTABr ratio was 1:10, whereas in CTABr ME aggregates, the corresponding ratio was 1:300. A 30-fold dilution of the DAAPs in noncatalytic CTABr amphiphilic assemblies in a ME aggregate probably makes individual DAAPs less accessible to each substrate molecule. The pronounced partitioning effect of substrates and catalysts on the basis of their polarities in ME aggregates could be the other reason for their lower reactivities in ME aggregates. In contrast in micellar aggregates, catalytic amphiphiles as well as the substrates are brought together near the micellar Stern layer region which in turn facilitates higher reactivity. The catalytic effects of the DAAPs and aggregates
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Figure 4. Comparison of the variation of kψ/k0 for esterolysis as a function of alkanoate chain lengths of p-nitrophenyl alkanoates 3 (n ) 2-14) in micellar and microemulsion media. Reaction conditions: pH 8.7, 0.02 M phosphate buffer, µ ) 0.08 (KCl), 25 ( 0.1 °C, [catalyst] ) 5 × 10-4 M, [3] ) 2.5 × 10-5 M: for the ME-1 system 1b (O), 2a (b); for the micellar system 1b (X), 2a (4).
relative to chain length might have been more clearly demonstrated22 by plotting the substrate chain length vs the ratios of the pseudo-first-order rate constants (kψ) to the noncatalyzed hydrolysis rate constants (k0) in buffer alone. This would compensate for the different inherent hydrolytic reactivities of the substrates and emphasize the effect of the catalytic system in a given aggregate matrix. It appears that the reactivity of DAAP catalysts toward p-nitrophenyl alkanoates in micellar CTABr solution is quite different when compared to their reactivity in the presently described CTABr-stabilized ME media. In micellar medium with the two DAAP amphiphiles (1b and 2a) examined, the hydrolytic activity toward the substrates such as p-nitrophenyl octanoate or p-nitrophenyl decanoate was maximal. Thus, in Figure 4, we see maxima (kψ/k0) corresponding to the esters of these chain lengths. This could be due to the localization of both the DAAP catalyst and the alkanoate esters at the micellar interface region. At lower substrate chain length, the binding to host micelle should be less ‘tighter’. On the other hand, there might be lipophilic coiling19,20 with substrates having longer chain length (n > 10) making the reactive functionality in the substrate less accessible to DAAPs. On the other hand in ME systems, because of the presence of multiple solubilization sites and also due to differential distribution of the catalyst and the substrate, differences in reactivities are seen. Figure 4 also (22) One referee suggested that the examination of reactivity ratios (in aggregate over background buffer) as a function of substrate chain length might emphasize the effect of the individual catalytic formulations. We thank the referee for this suggestion.
Bhattacharya and Snehalatha
shows the dependence of kψ/k0 against substrate chain length in ME media. It appears that under these conditions the reactivities of the substrates first decrease with an increase in the chain length from n ) 2 to n ) 6 and then increase with increase in chain length of the substrate up to n ) 10-12, finally reaching a plateau. It is difficult to figure out the exact reason behind the more complex pattern of reactivity of DAAPs in ME as a function of substrate chain length. Nevertheless it is clear that the reactivities in MEs are quite different from that in micelles. In the presence of excess substrates also notable differences in the kinetic aspects of catalytic reactivities in two aggregate media were seen. In the case of micellar media, the DAAP catalysts 1b and 2a showed catalytic turnover behavior. On the other hand, 2a in micellar CTABr exhibited “burst kinetics” with excess p-nitrophenyl octanoate 3 (n ) 8), but 1b showed fast turnover and no burst kinetics were observed. In ME media with either of the DAAPs, fast turnover and no burst kinetics were seen. Conclusion In summary, the O/W microemulsion (ME-1) offers several practical advantages. This solubilizes hydrophobic substrate molecules into a water-rich medium. The oil droplets provide very large surface area to the aqueous phase where reaction between added substrate molecules and the catalytic sites of DAAP amphiphiles is facilitated. Examination of the results of the present studies in ME media and of the studies that have been reported in the literature shows that DAAP amphiphile-CTABr coaggregate solutions are truly catalytic recipes for esterolysis with significant rate enhancement over background. The truly catalytic character of these ME-based DAAP formulations might be of practical value in the hydrolysis of polar substrates. One possible way to exploit this is to employ substrates with two distinct esterolyzable sites. Selective esterolysis of the substrate segment with less lipophilic residue in the presence of hydrophobic esters could lead to practical control of reaction rates and selectivity. Manipulation of the location of reagents and substrate by careful partitioning in microemulsions might be an important strategy for fine-tuning reactivity at the level of chemo-, regio-, and stereoselective manner. However, such exploitation would require more knowledge of the differential reactivities of a given type of substrate function that differs only in terms of the nature of the substituent or the regio- or stereochemistry. Acknowledgment. This work was generously supported by the Grants-in-Aid Scheme of DRDO, Government of India. K.S. thanks the UGC for a Senior Research Fellowship. LA960526Q
