Ester Cleavage Catalysis in Reversed Micelles by Cu(II) Complexes of

The hydrolytic reactivity of ligands featuring a 6-alkylaminomethylpyridine, 1, or an ... of added water, the w0 (the H2O/AOT ratio) value, and the li...
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Langmuir 2000, 16, 10115-10122

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Ester Cleavage Catalysis in Reversed Micelles by Cu(II) Complexes of Hydroxy-Functionalized Ligands Marika Fanti,† Fabrizio Mancin,† Paolo Tecilla,*,‡ and Umberto Tonellato*,† Department of Organic Chemistry and Centro CNR Meccanismi di Reazioni Organiche, University of Padova, via Marzolo 1, I-35131 Padova, Italy, and Department of Chemical Sciences, University of Trieste, via Giorgeri 1, I-34127 Trieste, Italy Received June 30, 2000. In Final Form: September 12, 2000 The hydrolytic reactivity of ligands featuring a 6-alkylaminomethylpyridine, 1, or an N-alkylethylenediamine, 2, as chelating subunits, in the presence of Cu(II), has been investigated in AOT/H2O/isooctane reversed micelles. The substrates of choice were the p-nitrophenyl esters of picolinic acid (PNPP), of acetic acid (PNPA), and of diphenylphosphoric acid (DPPNPP). In the presence of Cu(II) complexes of hydroxyfunctionalized ligands, such as 1a or 1b, the cleavage of PNPP is a million-fold faster than in the absence of Cu(II) and any ligand, the most effective stoichiometry being 1:1. By converse, the rate effects are rather modest using ligands 1c and 2, devoid of the hydroxy function. The cleavage of PNPA and DPPNPP is only slightly accelerated using all kind of ligands investigated. The high reactivity observed using 1a and 1b and PNPP accords with the mode of action established in aqueous micelles. This involves formation of a ternary complex (ligand/Cu(II)/substrate), pseudointramolecular attack of the (deprotonated) hydroxyl on the ester carbonyl to give a transesterification intermediate, and metal ion promoted hydrolysis of such intermediate. The kinetic response of the reversed micelles is in many ways quite different from that of analogous aqueous aggregates previously investigated. Peculiar features include the apparent insensitivity to relevant variables, such as the pH of added water, the w0 (the H2O/AOT ratio) value, and the lipophilic or hydrophilic character of the ligand. Clean burst kinetics using 1a·Cu(II) and excess PNPP were obtained but indicate a disappointingly low turnover rate. These and other aspects are discussed, also with reference to the behavior of aqueous micelles, and an attempt is made to describe the rather puzzling nature of interface and core of the reversed aggregates.

Introduction Although it has long been known that aqueous micelles can influence chemical rates, in the last years, as the morphology of the wide world of aggregates and the properties of their solutions were better defined, much interest has been devoted to the study of the so-called micellar catalysis.1,2 The main factors at the source of the kinetic effects in aqueous aggregates are now reasonably established. Acting as microscopic pseudophases, micelles as well as other assemblies can concentrate or separate the reactants, thus leading to acceleration or inhibition.1,2 Although a variety of organic reactions has been investigated in the presence of micelles, the hydrolytic cleavage of esters has attracted particular attention. Moreover, to improve the efficacy of the aggregates and to realize truly catalytic systems, aggregates made of designed functionalized surfactants, such as those bearing a nucleophilic function and more recently a chelating subsite for transition metal ions, have been investigated with often remarkable results.2,3 Aggregates formed by or containing complexes of transition metal ions, dubbed metalloaggregates, rank among the most effective catalytic aggregate systems.2b At the source of their efficacy one may envisage, besides the high concentration of the reactants in the small micellar volume, which is a common feature for all the aggregates in water, the ability of the metal ion † ‡

University of Padova. University of Trieste.

(1) Fendler, J. H. Membrane Mimetic Chemistry; Wiley: New York, 1982. (b) Fendler, J. H.; Fendler, J. E. Catalysis in Micellar and Macromolecular Systems; Academic Press: New York, 1975. (2) Bunton, C. A.; Savelli, G. Adv. Phys. Org. Chem. 1986, 22, 213. (b)Tascioglu, S. Tetraedron 1996, 52, 11113. (3) Fornasier, R.; Tonellato, U. J. Chem. Soc., Faraday Trans. 1980, 76, 1301.

to act as Lewis acid and convert the available nucleophilic functions (including water molecules) bound to the ligand to more reactive species by promoting their early deprotonation, i.e. by lowering their apparent pKa value.4 Solubility is a very serious problem for the realization of useful catalytic aggregates.5 The presence of aggregates is of some help insofar as they can coaggregate and hence solubilize hydrophobic substrates in aqueous media, but only up to a point, depending on the (usually limited) concentration of the aggregates and the saturation phenomena, which may also complicate the system in the presence of hydrophobic species other than the substrate. One apparently obvious way to overcome the low solubility and hence the limited supply of substrate to a catalytic aggregate is to resort to reversed micelles or to w/o (water in oil) microemulsions.1,6 Reversed micelles are aggregates residing in organic solvents and made of surfactants (most often AOT, sodium 1,2-bis(2-ethylhexyloxycarbonyl)ethanesulfonate) surrounding a pool of water. They are morphologically much less defined than aqueous micelles, and the main problems are related to the properties of the water pool. When compared to the wealth of studies on the hydrolytic reactivity of or in aqueous aggregates, only a small number of analogous studies have (4) Chin, J. Acc. Chem. Res. 1991, 24, 145. (b) Fife, T. H. In Perspective on Bioinorganic Chemistry; Hay, R. W., Dilworth, J. R., Nolan, K. B., Eds.; JAI Press: London, 1991; Vol. 1, p 43. (c) Koike, T.; Kimura, E. J. Am. Chem. Soc. 1991, 113, 8935. (d) Suh, J. Acc. Chem. Res. 1992, 25, 273. (e) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Phys. Org. Chem. 1992, 5, 619 and references therein. (5) Menger, F. M. J. Am. Chem. Soc. 1991, 113, 9621. (6) See: (a) Ruasse, M.-F.; Blagoeva, I. B.; Ciri, R.; Garcia-Rio, L.; Marques, A.; Mejuto, J.; Monnier, E. Pure Appl. Chem. 1997, 69, 1923. (b) Schwungher, M.-J., Stickdorm, K.; Schoma¨cker, R. Chem. Rev. 1995, 95, 849. (c) Pileni, M. P. J. Phys. Chem. 1993, 97, 6961. (d) Luisi, P. L. Angew. Chem., Int. Ed. Engl. 1985, 24, 439 and references therein.

10.1021/la0009238 CCC: $19.00 © 2000 American Chemical Society Published on Web 12/01/2000

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Langmuir, Vol. 16, No. 26, 2000 Chart 1

been devoted to the reactivity in reversed micelles, and these were mainly focused on reactions occurring inside the aqueous pseudophase without the involvement of functionalized surfactants as reactants.7 The only published study in the specific field of metalloaggregates, remarkable since it is also closely related to the present study, is the work by Tagaki and his group,8 which investigated the reactivity of Zn(II) or Cu(II) complexes of N-alkyl-2-hydroxymethylimidazoles in the esterolytic cleavage of p-nitrophenyl picolinate in AOT/H2O/hexane reversed micelles. Following our rather extensive work in the field of metalloaggregates as catalysts for carboxylic and phosphoric esters hydrolysis9,10 and having realized that solubility is the obstacle for the realization of effective catalysts, we turned our attention to the esterolytic reactivity in reversed metallomicelles. This paper presents a detailed study of the reactivity in AOT/H2O/isooctane of reversed micelles containing ligands 1 and 2 and Cu(II) ions, in the cleavage of the carboxylic [p-nitrophenyl acetate (PNPA) and p-nitrophenyl picolinate (PNPP)] and phosphoric [(diphenyl p-nitrophenyl phosphate (DPPNPP)] esters (see Chart 1). Our previous studies10 on the reactivity in aqueous micellar aggregates of Cu(II) complexes of ligand 1a with a ligand/Cu(II) stoichiometry of 1:1 showed that they are very efficient catalysts of ester hydrolysis, accelerating (7) See for example: (a) Menger, F. M.; Donohue, J. A.; Williams, R. F. J. Am. Chem. Soc. 1973, 95, 286. (b) Kondo, H.; Fujiki, K.; Sunamoto, J. J. Org. Chem., 1978, 43, 3584. (c) Fujii, H.; Kawai, T.; Nishikawa, H. Bull. Chem. Soc. Jpn. 1979, 52, 1978. (d) El Seoud, M. I.; Vieira, R. C.; El Seoud, O. A. J. Org. Chem. 1982, 47, 5137. (e) Athanassakis, V.; Bunton, C. A.; McKenzie, D. C. J. Phys. Chem. 1986, 90, 5858. (f) Del Rosso, F.; Bartoletti, A.; Di Profio, P.; Germani, R.; Savelli, G.; Basko´, A.; Bunton, C. A. J. Chem. Soc., Perkin Trans. 2 1995, 673. (g) Bhattacharya, S.; Snehalatha, K. Langmuir 1997, 13, 378. (8) Fujita, T.; Yoichi, I.; Ogino, K.; Tagaki, W. Bull. Chem. Soc. Jpn. 1988, 61, 1661. (9) Fornasier, R.; Milani, D.; Scrimin, P.; Tonellato, U. Gazz. Chim. Ital. 1986, 116, 55. (b) Fornasier, R.; Scrimin, P.; Tonellato, U.; Zanta, N.; J. Chem. Soc., Chem. Commun. 1988, 717. (c) Tonellato, U. Pure Appl. Chem. 1998, 70, 1961 and references therein. (d) Hampl, F.; Liska, F.; Mancin, F.; Tecilla, F.; Tonellato, U. Langmuir 1999, 15, 405. (e) Mancin, F.; Tecilla, P.; Tonellato, U. Langmuir 2000, 16, 227. (10) Fornasier, R.; Scrimin, P.; Tecilla, P.; Tonellato, U. J. Am. Chem. Soc. 1989, 111, 224. (b) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Org. Chem. 1991, 56, 161. (c) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Org. Chem. 1994, 59, 18.

Fanti et al. Scheme 1

the cleavage of PNPP, PNPA, and DPPNPP, respectively, by 6, 4, and 4 orders of magnitude at pH 6.3. A detailed investigation of the system allowed us to indicate the main mechanistic pattern outlined in Scheme 1. At least in the case of PNPP, it involves formation of a ternary complex (ligand-copper-substrate), pseudointramolecular nucleophilic attack on the substrate by the alcoholate resulting from deprotonation of the alcoholic function of the ligand, and formation of a transacylation product, which is eventually hydrolyzed by a metal-coordinated water molecule to restore the catalyst. A key feature of the complex is the large decrease of the pKa value of the hydroxyl to an apparent value of 7.710c due to its interaction with the metal ion. An analogous mechanism, although producing minor accelerations, is operative in the case of complexes of ligand 1b in water solutions.10c The results here reported confirm that Cu(II) complexes of 1a and 1b are quite effective in promoting the cleavage of selected carboxylic esters also in reversed micelles. This information will be compared to that that we obtained in previous studies employing the same or similar metallocatalysts in aqueous aggregates and discussed. Results The Ligands and Their Cu(II) Complexes. Ligands 1 and 2 have been prepared as previously reported. Ligands 1a, 1b, and 2 are soluble in the AOT/water/ isooctane mixture employed to realize the reversed micellar system here investigated up to a concentration of 2 mM; in the case of ligand 1c, which is much less soluble in reversed aggregates, clean solutions with a hardly sufficient concentration to follow the kinetic measurements could be obtained only in the presence of a large excess of AOT. Copper nitrate can be solubilized in reversed micelles to give the desired complexes only using an acetate buffer of pH lower than 4.9; stable solutions containing copper complexes could be obtained also using higher pH buffers, but only in the presence of a large excess of the ligand. The formation of the complexes is confirmed by the diagnostic changes in the UV-vis spectra of the ligand solutions after the addition of the metal ion. The spectrophotometric analysis allowed us to evaluate the formation constants (Kf) for the complexes of 1a and 1b and Cu(II) under the conditions somehow related to the kinetic experiments described below. The apparent Kf (M-1) for 1a·Cu(II) and 1b·Cu(II) are respectively 8200 and 14 500 in a pH 4.9 aqueous acetate buffer (0.1 M) and larger than 1 × 106 in isooctane containing AOT (2.3 × 10-2 M) and 0.33 M H2O (added as a pH 4.9 acetate buffer). Effect of the Separate Additives to the Reversed Micelles for the PNPP Cleavage. Preliminary kinetic measurements were carried out to test the effect of the many components of the system using the picolinate PNPP as a reference substrate and by following the appearance of p-nitrophenol. The Effect of Cu(II) Only. From experiments carried out in isooctane containing AOT (0.022 M), water (0.33 M) (added as an acetate buffer, 0.1 M, pH 4.9), and

Ester Cleavage Catalysis in Reversed Micelles

Figure 1. Rate constants versus ligand concentration for the cleavage of PNPP in the presence of 1a (b) and 1c (0) at a fixed Cu(II) concentration. Conditions: isooctane, [Cu(II)] ) 1.0 × 10-4 M, [H2O]/[AOT]/[ligand] ) 3000:200:1, H2O added as acetate buffer 0.1 M at pH 4.9, 25 °C.

increasing amounts of Cu(II) as nitrate salt, the observed pseudo-first-order rate constants increase linearly with the ion concentration (vide infra, Figure 3). The rate increases up to 20 000 times at a Cu(II) concentration of 1 × 10-4 M. The Effect of AOT/Water Ratio (the w0 Value). The water/ surfactant molar ratio, usually referred to as w0, is taken as an important parameter in defining, on one hand, the size of the reversed micelles, and, on the other hand, influencing the properties of the water molecules in the water pool, although the nature of these effects are far from being fully defined.1,6a,d The observed rate values, kψ, for the PNPP cleavage as a function of w0 (in the range 5-20) in reversed micelles containing only Cu(II) and 1a‚Cu(II) complexes were found to increase up to a maximum and then decrease. In the case of Cu(II) alone, the effect is quite modest, the observed changes in rate being within a factor of 1.4 and the largest rate value at a w0 value of 7.5. In the presence of 1a‚Cu(II) complexes, the effect is slightly more pronounced: under the conditions used above, the kψ values are within a factor of 3 and the maximum rate is observed at a w0 value of 15. This w0 value has been used in all the following experiments. The Effect of the AOT Concentration. The amount of added surfactant (at a fixed w0 value) is a factor determining the micelles concentration.1a The rate for the PNPP cleavage with increasing AOT concentration, at a w0 ) 15 and at [Cu(II)] ) 1.28 × 10-4 M, increases to a maximum value for [AOT] ) 0.022 M and then decreases as the AOT concentration further increases. The changes are quite small (within a factor of 1.2 on going from [AOT] ) 0.01 to 0.07 M). The “pH” Effect. The effect of pH on the reaction rate was defined by carrying out kinetic measurements using different buffers (0.1 M) of nominal pH values ranging from pH 5 up to pH 8 as added to isooctane with a [ligand]/ [Cu(II)] ratio of 16 (such ratio was needed to ensure stable solutions). Surprisingly, there is virtually no effect of the buffer pH on the reaction rate, the kψ values being within a factor smaller than 1.5 without any appreciable trend. The Effect of the Ligand’s Built-In Hydroxy Function. The rate versus [ligand] profiles, shown in Figure 1, were obtained employing 1a and 1c under the following

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Figure 2. Rate constants versus 1a concentration for the cleavage of PNPP at different fixed Cu(II) concentrations: 2.3 × 10-4 M (0), 1.0 × 10-4 M (b), 4.0 × 10-5 M (×). Conditions: isooctane, [AOT] ) 0.022 M, [H2O] ) 0.33 M added as acetate buffer 0.1 M at pH 4.9, 25 °C.

conditions: [Cu(II)] ) 1.0 × 10-4 M, [H2O]/[AOT]/[ligand] ) 3000/200/1. The two ligands show different behaviors. In the presence of 1a, the reaction rate increases with ligand concentration up to a limiting value; in the presence of 1c, there is a rate decrease by increasing ligand concentration, indicating that 1c·Cu(II) complexes are less reactive than Cu(II) alone. At a ligand concentration of 3 × 10-4 M, 1c·Cu(II) complexes are 240 times less effective than 1a·Cu(II). At any rate, it is worth noticing that in the presence of Cu(II) complexes of 1c the reaction is faster than in their absence by a factor of 1000. The most important indication stemming from these experiments is the role of the built-in hydroxyl, whose activity as a nucleophile is in full display in the case of ligand 1a and fades out when methylated, as in the case of ligand 1c. The Stoichiometry of the Reactive Complex. A series of experiment was specifically addressed to the definition of the ion-ligand stoichiometry of the effective complex (or complexes if more than one of the possible structures are at play). To this aim, we defined the effect of the concentration of ligands 1a and 1b by keeping constant the Cu(II) concentration. As shown in the profiles obtained in the case of 1a (Figure 2) the reaction rate increases sharply to a maximum value and then decreases rapidly as the ligand concentration further increases. Quite similar profiles (not shown) were obtained for 1b. The maximum is observed, under the conditions indicated, for ligand/Cu(II) ratios, respectively, of 8, 4, and 3 for the 1a complexes (Figure 2) and of 6 for 1b complexes in the presence of 4.0 × 10-5 M Cu(II) concentration. A simple (simplistic) analysis of these profiles would indicate rather absurd stoichiometry values, it being unreasonable to assume any type of geometry comprising up to eight ligand molecules around one metal ion. This was a point of much concern, since, as it will be discussed below, a similar behavior was observed by Tagaki and co-workers8 in the case AOT/H2O/hexane reversed micelles employing Cu(II) complexes of a series of N-alkyl-2-hydroxymethylimidazoles (monodentate ligands), so the authors suggested a 4:1 stoichiometry for the active complex at play in their system. We carried out a second set of experiments using a fixed concentration of 1a and increasing the amount of added Cu(II). The results of such an experiment are shown in

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Figure 3. Kinetic profile for the cleavage of PNPP as a function of [Cu(II)] (9) alone and in the presence of [1a] ) 1.0 × 10-4 M (b). Conditions: isooctane, [AOT] ) 0.022 M, [H2O] ) 0.33 M added as acetate buffer 0.1 M at pH 4.9, 25 °C.

Figure 4. Kinetic (b) and UV-vis (0) Job’s plots for 1a·Cu(II) complexes in AOT/water/isooctane reversed micelles. The sum of the concentrations of ligand and metal ions was kept constant at 1.0 × 10-4 M for the kinetic and 5.0 × 10-5 M for the UV-vis plot. The A0 value was taken as the absorbance measured in the presence of the corresponding concentration of free ligand or Cu(II). Conditions: isooctane, [AOT] ) 0.022 M, [H2O] ) 0.33 M added as acetate buffer 0.1 M at pH 4.9, 25 °C.

the profile of Figure 3. The rate of PNPP cleavage rapidly increases with Cu(II) concentration up to a [Cu(II)]/[1a] ratio of 1:1 and then remains constant. This clearly would point to a quite reasonable 1:1 stoichiometry, in sharp contrast with the previous values estimated from the profiles of Figure 2. To confirm the latter conclusion, we determined the stoichiometry of the complexes present in the reaction mixture by means of a Job plot (Figure 4) defined by measuring the UV-vis absorbance of the complex for a series of solutions in which the sum of the concentrations of ligand and metal ion was kept constant while the ratio was varied. The maximum observed for a Cu(II) molar fraction of 0.5 cleanly indicates that a 1:1 complex as the main species present. Furthermore, we defined the kinetic version of the Job plot, also shown in Figure 4. This was

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Figure 5. Kinetic profile for the cleavage of PNPP as a function of added hexadecylamine (b), hexadecanol (O), or CTABr (0) in the presence of 1a·Cu(II). Conditions: isooctane, [1a] ) 1.0 × 10-4 M, [Cu(II)] ) 1.0 × 10-4 M, [AOT] ) 0.022 M, [H2O] ) 0.33 M added as acetate buffer 0.1 M at pH 4.9, 25 °C.

obtained using the apparent first-order rate constants for the cleavage of PNPP instead of the absorbance values; in this case, the shape is somewhat different and rather anomalous: the maximum is here shifted to a lower (0.4) Cu(II) molar fraction, and more intriguing, the reactivity decreases less sharply than expected at the lowest Cu(II) molar fractions (on the left side of the plot). The results reported in Figure 3 and, less unambiguously, in Figure 4 indicate that the reactive species are 1:1 complexes. To gain insight on the source of the apparently anomalous reactivity observed in the presence of excess of ligand 1a, whose lipophilic structure features both an amino (or ammonium) and an alcoholic function, we verified the effect of an added lipophilic amine, alcohol, and an inert cationic surfactant, hexadecyltrimethylammonium bromide (CTABr), on the reaction rate. The results of kinetic experiments carried out for solutions where [AOT] ) 0.022 M, [H2O] ) 0.33 M, [Cu(II)] ) 1 × 10-4 M, [1a] ) 1 × 10-4 M showed (Figure 5) that, whereas the addition of increasing amounts of CTABr or hexadecanol has no effect on the rate, addition of hexadecylamine leads to an increase of the reaction rate, reaching a maximum value for an [amine]/[1a] ratio of 3. Calculating the total additives concentration, [amine + 1a], a [additives]/[Cu(II)] ratio of 4 is obtained, the same observed in Figure 2 under the same conditions. The reactivity ratio between the 1:1 and 4:1 system composition, using the test amine under the conditions employed, is approximately 20. These results clearly indicate that the increased reactivity in the presence of an excess of ligand is not due to the formation of higher order complexes but to the presence of the free amino groups. The Catalytic Turnover: “Burst” Kinetics. As said above, one of the main points of interest of the present study was the assessment of the catalytic properties of the system which, in aqueous solutions, is seriously impaired by the low solubility of the substrates. By contrast, these are quite soluble in isooctane, the bulk solvent of the present study. Thus, we carried out experiments using a large molar excess (20-85 times) of PNPP relative to the complex 1a·Cu(II). The kinetic profiles obtained are reported in Figure 6 and show a typical “burst” behavior.3 p-Nitrophenol is first released

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Figure 6. Time courses for the release of p-nitrophenol via the cleavage of PNPP by 1a‚Cu(II) in the presence of excess of substrate over the catalyst at different [1a‚Cu(II)]: 2.0 × 10-5 M (a), 1.0 × 10-5 M (b), 4.7 × 10-6 M (c). Conditions: isooctane, [PNPP] ) 4.0 × 10-4 M, [AOT] ) 0.022 M, [H2O] ) 0.33 M added as acetate buffer 0.1 M at pH 4.9, 25 °C.

in a fast process (“burst”, first-order) in an amount equal to that of the complex and then in a slower (zeroth-order) process. This behavior accords well with the two-step mechanism (see Scheme 1) operating in water in which the second step (deacylation of the intermediate) is slower than the first and controls the rate of the reaction after reaching stationary conditions (linear portion of the kinetic profile). From the slope of the linear part of the kinetic profiles and the p-nitrophenol  value measured under the working conditions, the turnover rates using the different ratios indicated in the figure are respectively 1.27 × 10-4, 1.19 × 10-4, and 0.48 × 10-4 s-1. Such values still indicate a catalytic behavior, but they are quite low if compared with the rate of the first step and, disappointingly, are much lower than expected. The rather low turnover rate is likely to be due to the inhibitory effect of picolinic acid, a product of the hydrolytic cleavage and a good ligand of Cu(II). In fact, control experiments carried out in the presence of added picolinic acid confirm the inhibitory effect of this compound. Reactivity toward Carboxylic and Phosphoric Esters. The efficacy of the whole system here investigated, that of the reversed metalloaggregates containing the Cu(II) complexes of ligands 1 and 2 in the cleavage of the

carboxylic esters PNPP and PNPA and the phosphoric ester DPPNPP, was defined in a number of experiments hereafter described and taking into account the specific effects described above. Table 1 (runs 1-6) shows the results obtained for the cleavage of PNPP in the presence of Cu(II), 1a, 1b, and 2 under the following conditions: [AOT] ) 0.022 M, [H2O] ) 0.33 M, [Cu(II)] ) 1 × 10-4 M. A scrutiny of reported data shows that the complexes of 1a are very effective in promoting PNPP cleavage, the rate being 6.2 × 106 times (entry 4) greater than that in the absence of ligands and Cu(II) and 300 times larger than that in the presence of only Cu(II). The case of Cu(II) complexes of 1b is surprisingly remarkable (entry 5). The rate acceleration is greater by a factor close to 1 × 106 than that in the absence of ligands and Cu(II), and on the whole the observed rate constants are quite close to those of the lipophilic complex with 1a. The effect of the complexes of 2 is much less important, as already verified because of the absence of hydroxy function bound to the ligand. Table 1 (runs 7-12) also shows the results obtained for the cleavage of PNPA and DPPNPP in the presence of Cu(II) and the ligands 1a and 2 under the following conditions: [AOT] ) 0.044 M, [H2O] ) 0.66 M, [Cu(II)] ) 2.0 × 10-4 M, [ligand] ) 2.1 × 10-3 M. At variance with what was observed in the case of the PNPP, the effect of the metallocomplexes is rather limited. Only in the case of 1a·Cu(II) and PNPA (entry 8) a sizable acceleration is observed. Interestingly, while in the cleavage of PNPA the complex with 1a is more effective than 2, the opposite is verified in the case of DNPNPP. For comparison purposes, we also measured the rate of cleavage of PNPP in water (acetate buffer, pH ) 4.9) containing micelles of the anionic surfactant sodium dodecyl sulfate (SDS). The data were obtained using the Cu(II) complexes of 1a and 1b as catalysts and are reported in Table 1 (runs 13-16). Comparison of the data in aqueous and in reversed micelles shows an outburst in the effectiveness of the Cu(II) complexes with 1a and, particularly, with 1b (compare runs 4-15 and 5-16) in reversed aggregates. Discussion Inspection of Table 1 highlights the main features of the reversed metallomicellar system here investigated. Reversed micelles containing the Cu(II) complexes are quite effective and dramatically selective toward substrates, such as the PNPP, which may bind the complex

Table 1. Pseudo-First-Order Rate Constants for the Cleavage of PNPP, PNPA, and PNPDPP in the Presence of Different Micellar Aggregates at 25 °C and pH 4.9 entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

ligand

substrate

[ligand], M

[Cu(II)], M

kψ, s-1

k/k0

-a

PNPP PNPP PNPP PNPP PNPP PNPP PNPA PNPA PNPA DPPNPP DPPNPP DPPNPP PNPP PNPP PNPP PNPP

1.0 × 10-4 4.1 × 10-4 4.8 × 10-4 1.0 × 10-3 2.1 × 10-3 2.1 × 10-3 2.1 × 10-3 2.1 × 10-3 2.1 × 10-3 2.1 × 10-3 6.0 × 10-4 2.0 × 10-3

1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 2.0 × 10-4 2.0 × 10-4 2.0 × 10-4 2.0 × 10-4 2.0 × 10-4 2.0 × 10-4 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4

4.4 × 10-7 9.0 × 10-3 5.4 × 10-4 2.7 0.32 0.030 6.0 × 10-8 3.2 × 10-5 3.0 × 10-6 4.7 × 10-7 6.7 × 10-6 3.7 × 10-5 5.5 × 10-6 9.7 × 10-4 3.4 × 10-2 5.9 × 10-3

1 20450 1227 6.2 × 106 7.3 × 105 68180 1 533 50 1 14 78 1 176 6180 3

-a 1aa 1aa 1ba 2a -b 1ab 2b -b 1ab 2b -c -c 1ac 1bc

a Isooctane, [AOT] ) 0.022 M, [H O] ) 0.33 M added as acetate buffer 0.1 M. b Isooctane, [AOT] ) 0.044 M, [H O] ) 0.66 M added as 2 2 acetate buffer 0.1 M. c Water, [SDS] ) 0.022 M, acetate buffer 0.1 M.

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due to the presence of a chelating subsite for the metal ion, such as the pyridino nitrogen. Their efficacy depends also on the presence in the ligand, such as in 1a and 1b, of the hydroxy function close to the binding site. Thus, using complexes of 1a and 1b, accelerations (relative to the rate in the absence of the metal ion free or complexed) close to or exceeding a million-fold were observed in the case of the cleavage of PNPP, while the accelerations in the cleavage of carboxylic or phosphoric acid esters, PNPA and DPPNPP, were 4 orders of magnitude lower. On the other hand, using the same substrate, PNPP, the reactivity of complexes of 1c or 2, devoid of a free hydroxy function, was 2 orders of magnitude lower than that of 1a and 1b and close to that of Cu(II) alone. When compared with the reactivity of analogous aqueous micelles or comicelles previously investigated10 in much detail and here only partly reconsidered for comparison (see Table 1), there are also conspicuous differences again related to some structural features of ligand and substrate. In aqueous micelles containing the ligands, the main difference may be noticed in the comparison of 1a and 1b, differing in their hydrophobicity: complexes of 1a are rather effective (accelerations by a factor of 6000) and those of 1b are comparatively inert (Table 1, runs 15 and 16). In the case of reversed aggregates, the two complexes are both very reactive, the accelerations using the two complexes differing only by a factor of 8 over an overall increase in the million range. Moreover, reversed micelles are much more selective (as emphasized above) toward the different substrates than aqueous micelles. Despite these remarkable differences, if one considers that the role of Cu(II) ion is greatly magnified in the case of reversed micelles, there are basic similarities (such as the advantages due to the presence of the hydroxy function in the ligand and the burst kinetics observed for the complexes) that suggest that the modes of action of the ion and its complexes are substantially similar in both types of micellar aggregates. These are indicated in Scheme 2 (with reference to Scheme 1). The effect of Cu(II) alone is much more important than that observed in water solution, the rate accelerations at the same Cu(II) concentration being 2 orders of magnitude larger. The difference can be ascribed to the favorable

Fanti et al.

partition of the metal ion and the substrate in the water pool of the reversed micelles. The mode of action in the absence of ligands quite likely involves the water molecules bound to the metal ion, indicated as path a in Scheme 2.11 Addition of ligands 1 or 2 to reversed micelles loaded with Cu(II) leads to the formation of complexes with different kinetic effects in the cleavage of PNPP, the main ones being the large rate increases in the case of 1a and 1b and the slight rate inhibition in the case of ligands where the hydroxy function is methylated, such as 1c, or absent. When the ligand employed is 1a or 1b, the cleavage occurs mainly by way of the mechanistic path b of Scheme 2 (going to completion as indicated in Scheme 1). The reactivity in the presence of complexes with 1c or 2 indicates that in the absence of a ligand-bound hydroxy function, the copper complexes are still able to increase the rate of cleavage; in this case, the process is likely to occur by nucleophilic attack of a water molecule coordinated to the metal ion, as indicated by path c in Scheme 2. These species can be slightly more (2) or less (1c) active than free Cu(II), depending on the ligand structure. The stoichiometry of the reactive complex has been the object of much attention. As a matter of fact, the results reported in Figure 2 indicate an apparent ligand/metal ion ratio up to 8, much larger than reasonable. As said above, a similar behavior was observed by Tagaki in AOT/ H2O/hexane reversed micelles with Cu(II) and Zn(II) complexes of a series of N-alkyl-2-hydroxymethylimidazoles (monodentate ligands), and in such a case, it was concluded that a complex with a 4:1 stoichiometry was at play.8 In the present system, such a puzzling indication from the data of Figure 2 was found misleading with regard to the stoichiometry of the effective complex in the reversed micelles. On one hand, the Job plot of Figure 4 indicated that a 1:1 complex in the case of 1a and Cu(II) is the main species present. On the other hand, the kinetic version of the Job plot does not match this result, as it shows that the reactivity is still relatively large, even at the lowest Cu(II) molar fraction. Control experiments carried out by adding alcoholic or surfactant additives or free amines showed that only the last additives do increase the rate of cleavage of PNPP. Apparently, at high ligand/Cu(II) ratios, the complex may be modified by the presence of available amino functions that are present in the ligand structure to give rise to a reactive species. These results are difficult to explain, interesting as they appear, in the absence of further evidence that may require complex investigations. At any rate, the active complex of 1a with Cu(II) is here indicated as the 1:1 species shown in Scheme 2, path b. Assuming that the modes of action in aqueous and reversed micelles are similar, many interesting features highlight the peculiarity of the reactivity in reversed micelles. The main factors at play are, on one hand, the partition of the reactants between the bulk solvent, isooctane, and the water pool and, on the other hand, and more important, the nature of the interface and of the water in the pool. Obviously, the organic species mainly reside in isooctane and can move toward the water phase only if drawn into it by a strong attractant present in water. The metal ion in water clearly plays such role in the case of organic species with binding properties. This is the simplest explanation for the transfer of all the ligands, without distinction for their hydrophobicity, and for the very large reactivity difference observed using the coordinating picolinate PNPP and the other substrates PNPA and DPPNPP. When attracted to the pool, where (11) Fife, T. H.; Przystas, T. J. J. Am. Chem. Soc. 1985, 107, 1041.

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reaction proceeds, the picolinic acid accumulates in the pool and the freed ligand may move out. Therefore after the initial burst, the reaction slows down and the turnover rate is smaller than we hoped for.

do the reactants take place? Quite likely at the interface, mixing with the AOT molecules, the polar parts of all the species facing the aqueous pool. The most intriguing problem concerns the actual nature of such an aqueous core. As for its size, reference is here made to the cited work of Tagaki.8 By light scattering measurements of reversed micelles in hexane, [AOT] ) 0.022 M, wo ) 13, it was estimated that a single micelle comprises an average number of 130 molecules of AOT and 1700 molecules of water.8 The water pool reasonably contains the counterions of AOT and all the strongly hydrophilic (ionic) species, from Cu(II) to the buffer molecules. It is no wonder that such an extremely concentrated solution is quite far from ideality, resembling more a brine than an aqueous solution. One may think of quite a number of equilibria not only in the aqueous pool but also between the organic and aqueous phase, so it is virtually impossible to characterize the latter one following standard criteria. The present study on the reactivity of the complexes does not offer any evidence to remove the main doubts, but rather some questions arise mainly related to the insensitivity of the rate to the w0 value and to the pH of added water or, more important, to the actual pH of the pool. Following current hypotheses, the nature of the pool should depend on the w0 value.6,12 When the value is low, the water molecules are tightly bound to the surfactant headgroups and counterions and show particular properties, being more viscous, less polar, and more electrophilic than “normal” water.6a At higher w0 (> 6-10) values, two different kinds of water may be present: a layer of bound water near to the micellar interface and a core of free water in the center of the water pool.12 The insensitivity of the present system to both the w0 value and pH of the added buffer does not accord with a hypothesis of a deep core still resembling the added buffer6d but rather indicates that the actual pH value in the pool is something different. The pH value of an aqueous buffer depends on the molar ratio of acid/base used; in the reversed micelles this ratio may dramatically change due to interphase equilibria. As a matter of fact, the results obtained seem to indicate a self-buffering effect, so the actual pH value or, more precisely, the effective proton availability of the system becomes elusive. This is a matter of concern for the reactivity of the hydroxy-functionalized ligands; the mode of reaction outlined in Schemes 1 and 2 implies the deprotonation of the function assuming, as observed in water and in aqueous aggregates, that the protonated hydroxyl is a very poor nucleophile. Thus, apparently the OH of the surfactant and the water molecules coordinated to the metal ions are in the deprotonated form, whatever the pH value of the added buffer. Either the apparent pKa value in the pool of the hydroxyl group of the complex 1b·Cu(II) is lower than 4.9, so that, also using a pH 4.9 buffer, the functions are in the dissociated form, or the effective pH value at the interface is much higher than that of the buffers employed. Finally, from the “burst” kinetics (see Figure 6) in the case of PNPP and 1a·Cu(II) complexes, the turnover rate of the system was found to be disappointingly low. As said above, it is reasonable to assume, also on the basis of control experiments, that, using a large excess of substrate over the Cu(II) concentration, the picolinic acid released following hydrolysis of PNPP binds to the metal ion and depletes the complexes, which are made increasingly inert as the reaction proceeds. There is a very small chance for any complex to move out to the organic phase, so as the

General Methods and Materials. UV-vis spectra were recorded on a Perkin-Elmer Lambda 16 spectrophotometer equipped with a thermostated cell holder. Cu(NO3)2 was an analytical grade product. Metal ion stock solutions were titrated against EDTA following standard procedures.13 The following buffer components were used as supplied by the manufacturers: acetic acid (Aldrich), 2-morpholinoethanesulfonic acid (MES, Fluka), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES, Sigma), 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPES, Sigma). The sodium 1,2-bis((2-ethyl)hexyloxycarbonyl)ethanesulfonate (AOT) and isooctane were analytical grade Fluka products used as received. The p-nitrophenyl acetate (PNPA) was a Sigma product used as received; p-nitrophenyl

(12) Di Profio, P.; Germani, R.; Onori, G.; Santucci, A.; Savelli, G.; Bunton, C. A. Langmuir 1998, 14, 768 and references therein.

(13) Holzbecher, Z. Handbook of Organic Reagents in Inorganic Analysis; Wiley: Chichester, U.K., 1976.

Conclusions The present study has been mainly performed to verify the possibility to transfer a catalytic system, which has been proved to be very efficient in aqueous aggregate, into reversed aggregates. It was of much interest to verify possible differences in the mode of action of metalloaggregates, made of complexes with Cu(II), in reversed aggregates versus that in aqueous aggregates. The results obtained indicate that high rate accelerations can be achieved also in these systems, reaching, in the case of PNPP, a six-million-fold acceleration. Moreover, the main characteristics of the reaction mechanism are also conserved, and as in normal micellar aggregates, the main source of the kinetic effects observed is the high concentration of the reactants in the aggregate core. However in the case of the reversed metallomicelles the high concentration of organic species in the water pool is determined by the presence of Cu(II) and by the possibility of coordination with the metal ion rather than by their hydrophilic or lipophilic nature. Thus, poor acceleration has been observed in the case of noncoordinating substrates such as PNPA and DPPNPP, and this is at variance with the results reported in the case of aqueous micelles10b and also using enzymes solubilized in reversed micelles.6d A major point of interest in designing the present investigation was the possibility that these systems could overcome some of the major limitations of aqueous aggregates, due to the limited solubility of the substrates, to make effective catalysts with high turnover and open the way to several useful applications. Unfortunately, this goal was not achieved using reversed metallomicelles for quite different reasons. In the case of the picolinate esters PNPP, the turnover is deadlocked, since the very same attracting forces that make the system so reactive for its cleavage are also the source of a self-poisoning effect. Quite likely, the picolinic acid, the product of hydrolysis, is trapped into the water pool somehow bound to Cu(II) and, as the reaction proceeds, it diverts an increasing fraction of the metal ion from its basic role of forming the reactive complexes. Notwithstanding these limitations, reversed metalloaggregates such as those investigated in this study have revealed interesting potentiality, and further optimization of employed ligands and the proper choice of the substrates could lead to the realization of very efficient catalytic systems. Experimental Section

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picolinate (PNPP)14 and diphenyl p-nitrophenyl phosphate (DPPNPP)15 were prepared and purified by literature methods. 6-((n-Dodecylamino)methyl)-2-(hydroxymethyl)pyridine (1a),10b 6-((n-dodecylamino)methyl)-2-((methyloxy)methyl)pyridine (1c),10b 6-((methylamino)methyl)-2-(hydroxymethyl)pyridine (1b),10c and N-(hexadecyl)-N,N′,N′-(trimethyl)-1,2-diaminoethane (2)16 were synthesized as reported. Apparent Formation Constants. The apparent formation constants for the metal complexes of the ligands 1a and 1b were determined at pH 4.9 in water and in the reversed micellar systems. To a buffered (0.1 M) solution of the ligand (5 × 10-5 M) in water or in isooctane/H2O/AOT, small volumes of concentrated metal ion solutions were added and the UV-vis spectra were recorded. From the spectral changes observed upon addition of the metal ion (particularly at 260 and 280 nm), the apparent Kf values were obtained by nonlinear regression analyses of the absorbance (at a selected wavelength) versus metal ion concentration data. (14) Sigman, D. S.; Jorgensen, C. T. J. Am. Chem. Soc. 1972, 94, 1724. (15) Gulick, W. M.; Jr; Geske, D. H. J. Am. Chem. Soc. 1966, 88, 2928. (16) Broxton, T. J.; Cox, R. A. Can. J. Chem. 1993, 71, 670.

Fanti et al. Kinetic Measurements. The slower kinetic traces were recorded on a Perkin-Elmer Lambda 16 spectrophotometer equipped with a thermostated cell holder, and faster reactions were followed on an Applied Photophysics SF.17MV stoppedflow spectrophotometer. Reaction temperature was maintained at 25 ( 1 °C. Reverse micellar solutions were prepared by mixing isooctane solutions containing AOT and other additives with buffered water solutions (eventually containing Cu(NO3)2). The final content of water in the solutions was determined by the Karl Fischer method. The initial concentration of substrate was (1-2) × 10-5 M and the kinetics were in each case first order up to 90% of the reaction. The rate constants were obtained by nonlinear regression analysis of the absorbance versus time data and the fit error on the rate constant was always less than 1%

Acknowledgment. Financial support for this research has been partly provided by the Ministry of the University and Scientific and Technological Research (MURST) under the framework of the “Supramolecular Devices” project. LA0009238