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www.elsevier.nl/locate/ica Inorganica Chimica Acta 305 (2000) 1 ­ 6

Increased catalytic activity of primary amine palladacycles in biomimetic hydrolysis of N -t-BOC -S -methionine p -nitrophenyl ester
Sergey A. Kurzeev a, Gregory M. Kazankov a, Alexander D. Ryabov
a

a,b,

*

Department of Chemistry, M.V. Lomonoso6 Moscow State Uni6ersity, 119899 Moscow, Russia b G.V. Plekhano6 Russian Economic Academy, Stremyanny per. 28, 113054 Moscow, Russia Received 21 October 1999; accepted 28 February 2000

Abstract The kinetics of hydrolysis of N -t-BOC -S -methionine p -nitrophenyl ester (5) promoted by the cyclopalladated complexes of tertiary and primary benzylamines [Pd(C6H4CHR%NR2)Cl(py)], where R = Me (1) and H (3), R% = H (a), S -Me (b) and R -Me (b), has been studied. In buffered solutions complexes 1 and 3 undergo aquation of the chloro ligand to afford species 2 and 4, respectively, and these carry out the hydrolysis according to rate expression kobs = ko + kcat[Pd(II)]t at pH 8 and 25°C. The rate constants for the pathway kcat equal 2.5, 2.1, 2.2, 32, 220 and 260 M - 1 s - 1 for complexes 2a ­ c, 4a ­ c, respectively, demonstrating that the benzylamine (4a) and a-methylbenzylamine (4b,c) complexes are approximately ten and hundred times, respectively, catalytically more active than N,N -dimethylbenzylamine complex 2a. Such a drastic discrimination is observed when the activated ester has a donor center capable of binding with Pd(II). In accord with this is the fact that all complexes studied display similar activity (kcat : 0.8 M - 1 s - 1) in hydrolysis of 2,4-dinitrophenyl acetate. The formation of the catalytically active intermediate between aquated palladacycles derived from either 2 or 4 and 5 is postulated. Different catalytic properties of the primary and tertiary palladacycles with respect to the methionine ester 5 are rationalized in terms of the steric effects in combination with the hydrophobic interactions playing a role in aqueous solution. © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Kinetics; Hydrolysis; Palladium complexes; Cyclometalated complexes

1. Introduction In a series of our previous works it has been demonstrated that cyclometalated complexes of Pd(II) and Pt(II) are functioning mimetics of metallopeptidases [1 ­ 5]. Among the features traditionally ascribed to enzymes, metalacycles display noticeable rate accelerations [2] and stereoselectivity [3]. They manifest the catalytic activity [4] due to facile generation of the aqua/hydroxo ligand trans to the s-bound phenyl ring in aqueous solution [6,7]. The catalyst precursors are usually cyclopalladated or -platinated acetophenone oxime and N,N -dimethylbenzylamine (dmbaH) chloro complexes such as 1, for example, which transform into catalytically active species 2 in aqueous solution. The catalysts derived from dmbaH could obviously suffer
* Corresponding author. Tel.: + 7-095-939 3430; fax: + 7-095-939 5417. E -mail address: ryabov@enz.chem.msu.ru (A.D. Ryabov)

from unfavorable steric hindrance imposed by the N methyl groups which are capable of partial shielding of the reactive center, viz. the coordinated hydroxide. Recently, the cyclopalladated compounds 3 based on primary benzylamines (baH) became readily available [8 ­ 13] and it was tempting to create a catalyst free from the steric hindrance imposed by N -alkylation. Therefore, in this work we report on the catalytic activity of the primary amine complexes 4 (benzylamine, R - and S -a-methylbenzylamines (mbaH)) in hydrolysis of N -t-BOC -S -methionine p -nitrophenyl ester (5), N -t-BOC -S -leucine p -nitrophenyl ester (6), Eq. (1), and 2,4-dinitrophenyl acetate.

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It will be demonstrated that with respect to 5 the catalytic activity increases each time tenfold in the series 2a 4a 4b : 4c, whereas practically identical reactivity of the complexes is observed in the catalyzed hydrolysis of 2,4-dinitrophenyl acetate.

used as received. Sources of other chemicals used in this study were essentially as in the previous work [1].

2.3. Preparation of solutions and kinetic measurements
Stock solutions of palladium(II) complexes (ca. 5 в 10 - 3 M) and esters (ca. 1 в 10 - 3 M) were prepared in MeCN as solvent. A proper volume of the Pd(II) solution was added to 1.8 ml of the phosphate buffer, kept for at least 3 min in the thermostated cell compartment (25°C) and the reaction was initiated by addition of a proper amount of the ester solution. The concentration of MeCN in aqueous solution was always 10%. The reaction progress was monitored at 400 nm due to release of 4-nitro- or 2,4-dinitrophenolate ion. For calculating the pseudo-first-order rate constants kobs, the absorbance versus time data were fitted to the equation A = A + (Ao - A){exp( - kobst )}, where A, A and Ao are absorbances at time t, , and t = 0, respectively. Satisfactory first-order kinetics was observed for more than five half-lives. Each value of kobs reported is a mean value of at least three measurements.

(1)

2. Experimental

2.1. General
H NMR spectra were recorded on Varian UNITY 300 and CXP-200 Bruker spectrometers with a residual solvent signal as internal standard. All J values are in Hz. Spectrophotometric and kinetic measurements were carried on a Shimadzu UV-160A spectrophotometer equipped with a CPS-240A cell positioner/temperature controller or a Hitachi 150-20 instrument with a thermostated by circulating water cell compartment.
1

3. Results

2.2. Materials
Monomeric complexes 3 were synthesized from the parent chloro-bridged dimers [Pd(ba)Cl]2 or [Pd(mba)Cl]2, the preparation of which is descried elsewhere [9,13]. Typical procedure is given below by the example of [Pd(S -mba)Cl(py)] (3b). The dimer S,S [Pd(mba)Cl]2 (0.064 g, 0.244 mmol) was suspended in 4 ml of C6H6 and pyridine (0.021 g, 0.269 mmol) was added on stirring the mixture with a magnetic bar. The yellow suspension cleared up and a white crystalline powder then precipitated. The precipitate was filtered off, washed with C6H6 and dried in the air. Yield 83% (0.069 g). Complexes [Pd(ba)Cl(py)] (3a) and [Pd(R mba)Cl(py)] (3c) were obtained similarly both in a 97% yield. Satisfactory C, H, N analyses were obtained for complexes 3a ­ c. 1H NMR (CDCl3, l ): 3a 4.19 (t, J 6, CH2), 4.50 (bt, J 6, NH2), 6.07 (dd, J 8 and 1, H6), 6.79 (td, J 8 and 1, H5), 6.97 (dd, J 8 and 1, H3), 7.01 (td, J 8 and 1, H4); 7.07 (m, BB% part of AA%BB%C system, Hb, py), 7.65 (m, C part of AA%BB%C system, Hg, py), 8.52 (m, AA% part of AA%BB%C system, Ha, py). 3b and 3c: 1.63 (d, J 6, CCH3), 3.40 and 4.70 (bd, NH2), 4.44 (q, J 6, CH), 6.13 (d, J 8, H6), 6.81 (t, J 8, H5), 6.87 (d, J 8, H3), 7.02 (t, J 8, H4), 7.75 (t, J 7, Hg, py), 8.67 (d, J 7, Ha, py), signal from Hb is obscured by the CDCl3 resonance. The complexes of tertiary amines were synthesized as described previously [6]. N -t-BOC -S -methionine p -nitrophenyl ester (5) and N -t-BOC -S -leucine p -nitrophenyl ester (6) were purchased from Sigma and

3.1. Catalytic acti6ity of complexes 1 and 3 in hydrolysis of the methionene ester
Monomeric chloro complexes of the type [Pd(dmba)Cl(py)] or [Pd(ba)Cl(py)] are known to undergo fast hydrolysis in aqueous solution to afford the corresponding hydroxo species 2 and 4, respectively, at pH \ 6 [6]. Thus, the catalytic activity in hydrolysis of activated esters appears due to the generation of the strong nucleophile at rather acidic pH. As seen in Fig. 1, in which the values of kobs for the hydrolysis of methionine ester 5 are plotted against concentrations of complexes 2 and 4, the usual two-term rate expression holds kobs = ko + kcat[Pd(II)] (2)

where the rate constants ko and kcat refer to the spontaneous and catalytic hydrolysis, respectively. The catalytic activity displayed by 2 and 4 depends crucially on the nature of the cyclopalladated organic ligand. The values of the rate constants for the catalytic pathway kcat are amazing (Table 1). The catalytic activity of all three tertiary amine complexes 2a­c is the lowest and similar within the family. More than a tenfold rate increase is achieved on going from the tertiary (2a) to the primary amine complex 4a. The most striking feature is, however, an additional ten-fold rate increase in the case of 4b,c due to the methyl group at the a-carbon of orthopalladated benzylamine. It should be emphasized that a-methylation


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3

Fig. 1. Pseudo-first-order rate constants for hydrolysis of 5 catalyzed by palladacycles 2, 4 and SS -[Pd(mba)Cl]2 as a function of total Pd(II) concentration (calculated for monomeric form for the dimer). Conditions: pH 8.0 (0.01 M phosphate), 10% MeCN, 25°C. Table 1 Rate constant kcat for the catalytic hydrolysis of 5 in the presence of tertiary and primary palladacycles at pH 8.0 (0.01 M phosphate) and 25°C Catalytic complex 2a 2b 2c 4a 4b 4c Precursor 1a 1b 1c 3a 3b 3c SS -[Pd(mba)Cl] k
cat

(M

-1

s-1)

2

2.5 9 0.4 2.1 9 0.1 2.2 9 0.4 32 9 2 220 9 20 260 9 20 360 9 20

does not affect the reactivity of the tertiary amine complexes and the rate constants kcat for 2b,c are even slightly lower than for complex 2a lacking the a-methyl group. Hence, the overall rate increase achieved on going from complex 2b to 4c is a factor of 126. There is no enantiomeric selectivity (ES) in the catalytic hydrolysis of ester 5 by pairs of enantiomers 2b/c and 4b/c. Correspondingly, the values of kcat are similar within the experimental uncertainty. For comparison, the ES of approximately 5 was observed by us previously for the intermolecular hydrolysis of both enantiomers of N -CBZ-leucine p -nitrophenyl ester catalyzed by complexes 2b/c [3]. Interestingly, even the most promising complexes 4 were found to be practically inactive in hydrolysis of N -t-BOC -leucine p -nitrophenyl ester (6). It should, however, be mentioned that different N -protecting groups affect markedly the susceptibility to hydrolysis of one and the same free amino acid ester, i.e. leucine p -nitrophenyl ester in this case, and the rate of spontaneous hydrolysis of N -CBZ-leucine p -nitrophenyl ester is at least an order of magnitude higher than the rate of its BOC-protected analog at pH 6.2 and 25°C. In principle, the catalysis by the palladacycles could involve the favorable binding between 5 and complexes 2 and 4 presumably via the substitution of pyridine by the methionine sulfur. Therefore, we have tested the catalytic activity of the dimer S,S -[Pd(mba)Cl]2 with respect to 5. The complex exists as a monomer in such media as dimethyl sulfoxide, acetonitrile, alcohols, water [14], and its complexation with 5 should be more facile compared with the pyridine monomers 4. As a result, somewhat higher reactivity of [Pd(mba)Cl]2 compared to 4b,c had to be expected, if the complex S,S -[Pd(mba)Cl]2 is introduced into the aqueous buffered medium from its solution in MeCN. The data also shown in Fig. 1 is consistent with the expectations and kcat for [Pd(mba)Cl]2 is by only a factor 1.6 higher than for 4b (Table 1).

3.2. Catalytic acti6ity of 2 and 4 in hydrolysis of 2,4 -dinitrophenyl acetate
Interestingly, complexes 2 and 4 display similar reactivity toward 2,4-dinitrophenyl acetate. Fig. 2 shows the dependence of kobs on the concentration of 2a, 4a, and 4b. As seen, the hydrolysis follows the rate law 2, the slopes being equal 0.8 9 0.2, 0.7 9 0.4 and 0.8 9 0.1 M - 1 s - 1, respectively. 2,4-Dinitrophenyl acetate has no conceivable binding site for palladium(II) and therefore should be hydrolyzed intermolecularly. Since similar second-order rate constants were measured in this series, whereas kcat are markedly different in hydrolysis of 5 (Table 1), the conclusion was reached that the catalytic discrimination is achieved when the substrate possesses a proper donor center (sulfur in this case).

Fig. 2. Pseudo-first-order rate constants for hydrolysis of 2,4-dinitrophenyl acetate catalyzed by palladacycles 2a (), 4a ( ), and 4b (
) as a function of total Pd(II) concentration. Conditions: pH 8.0 (0.01 M phosphate), 10% MeCN, 25°C.


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3.3. pH profiles for kcat
In order to rationalize the markedly different reactivity of the primary and tertiary amine palladacycles in hydrolysis of 5, we considered a possibility of deprotonation of the coordinated amino group of complexes 4 which could generate a strongly nucleophilic amide moiety responsible for the rate increase (Eq. (3)).

(3) If so, the kcat versus pH profiles should vary appreciably for 2 and 4, since the tertiary amine complexes 2 cannot be deprotonated as shown in Eq. (3). The dependence of kcat on pH was measured for complexes 2a and 4b and the data is in Fig. 3. As seen, the profiles are similarly curved despite a significant difference in reactivity. Therefore, the deprotonated amino group generated via Eq. (3) does not seem to be involved. The nature of the pH-driven rate acceleration should obviously be similar for complexes 2 and 4, and the reactivity series found must be accounted for otherwise. Among the possibilities are steric effects and the hydrophobic interactions, which should be analyzed in terms of the mechanism with the formation of the S -bonded intermediate between the ester and the catalyst.

4. Discussion The results reported here are consistent with a hypothesis that the drastic difference in reactivity of complexes 2 and 4 is realized when an amino ester molecule

possesses a binding donor center for complexation with palladium(II) bearing the coordinated nucleophile. The discrimination disappears in hydrolysis of 2,4-dinitrophenyl acetate, i.e. of the substrate without donor center. This suggests that the catalytic hydrolysis of methionine derivative 5 occurs intramolecularly after the formation of the intermediate between the sulfur atom of 5 and palladium(II) of complexes 2 and 4. Since Eq. (3) plays no role in catalysis, the intramolecular nature of hydrolysis of 5 can account for a tenfold rate increase on going from tertiary to primary amine complexes. In fact, intramolecular reactions are more sensitive to the steric effects compared to their intermolecular counterparts, and a proper adjustment of the intramolecular system makes it possible to vary the reactivity in a very wide range [15,16]. The complexation between the methionine ester and Pd(II) complexes should proceed such as to retain the coordinated nucleophile; otherwise the catalytic activity will not be observed. Since (i) cyclopalladated organic ligands or, alternatively, C,N -chelates are substitutionally inert and (ii) the kcat for 4b,c on one hand, and SS -[Pd(mba)Cl]2, on the other, are close (Table 1), it should be assumed that the one and the same catalytically active species is generated from 4 and SS [Pd(mba)Cl]2. This implies that on reversible complexation with 5 complexes 2 and 4 must part with the pyridine ligand to afford the catalytically active species 7 (Scheme 1). As a result, one arrives at the species which is also generated in aqueous solution from the chloro analog of 7, the latter being independently prepared previously from [Pd(dmba)Cl]2 and 4a in non-aqueous medium, isolated and characterized [2]. Hence, there must be an agreement in reactivity observed in this and in the previous work [2]. This is in fact true and the rate constant of 1.2 в 10 - 3 s - 1 (pH 8, 25°C) reported for hydrolysis of 7 (R = Me, R% = H) falls in the range shown for complexes 2 in Fig. 1. Thus, complexes 7 are conceivable intermediates in reaction 2 and the increased tenfold reactivity on going from tertiary to primary benzylamine is understood in terms of the steric effects. The consequence of the a-methylation looks more puzzling. The presentation of 7 in Scheme 1 makes an impression that R% is located too far away

Fig. 3. The kcat vs. pH profiles for hydrolysis of 5 catalyzed by palladacycles 2a () and 4b (
). Conditions: 0.01 M phosphate, 10% MeCN, 25°C.

Scheme 1.


S.A. Kurzee6 et al. / Inorganica Chimica Acta 305 (2000) 1 ­ 6

5

within the reactive intermediate 7. We have recently observed that the pKa is weakly dependent on the nature of the N -chelate arm in palladacycles [6] and it is not therefore surprising that the pH profiles for complexes 2 and 4 are nearly identical. The pKa shift is plausibly due to the cis effect of the sulfide moiety of 7, which is obviously stronger than that of the pyridine ligand. An alternative rationale could involve the external hydroxide attack, which becomes significant at higher pH.

5. Conclusions This work shows the area in which palladacycles based on primary benzylamines have been successfully applied from the point of view of creating a catalyst superior as compared with the traditional palladacycles derived from secondary and tertiary amines. There were several expectations associated with these complexes but until now no useful applications of complexes such as 3 have been reported. It is also should be pointed out that the primary amine palladacycles provide an unexpected example of the tenfold increase in the catalytic activity due to a-methylation. There is thus a hope that such complexes may find applications as tunable catalysts not in the biomimetic chemistry only.

Fig. 4. The structure of the proposed tetrahedral reactive intermediate derived from 7 after the intramolecular nucleophilic attack of the coordinated hydroxide at the ester carbonyl carbon (key atoms are labeled).

from any catalytically essential part of the catalyst suggesting that it cannot influence the reactivity via electronic effects. The manipulation with the molecular models and simulation of the transition state using a HyperChem 5.01 package1 suggest a tentative rationalization of the a-methyl group effect. Previously, we have emphasized the importance of the hydrophobic and/or stacking interactions, which are very common in biological systems, in the palladacycle-catalyzed stereospecific hydrolysis [3]. Such interactions might play a role here in the catalysis by a-methylbenzylamine derivatives. We have noticed that the formation of the tetrahedral intermediate or transition state, within which the coordinated hydroxyl approaches the target carbonyl carbon, brings the a-methyl group right above the phenyl ring of the leaving 4-nitrophenolate (Fig. 4) suggesting the favorable in aqueous solution hydrophobic interaction which stabilizes the intermediate. The fragment CH2CH2S is flexible and therefore the hydrophobic contact is equally feasible for both enantiomers 4b and 4c. As a result, both display similar reactivity and since the chiral center of the optically active palladacycle is directed oppositely to the asymmetric carbon of the amino acid, it is not surprising that the ES of the hydrolysis is low. The pH dependence in Fig. 3 deserves a comment. In light of the mechanism proposed a pronounced increase in kcat at pH \ 7.5 might indicate that the pKa is shifted to higher values as compared to the parent complex 2a, the pKa of which is around 5 [6]. If so, the rate increase is due to deprotonation of the coordinated aqua ligand
A Polak ­ Ribiere algorithm was used. The transition state molecular mechanics optimization was made assuming the octahedral palladium(II) environment with two hydrides as axial ligands. The torsion angles of the palladacycle were edited manually after the optimization as to make it planar.
1

Acknowledgements The research described in this publication was made possible in part by financial support from the Russian Foundation for Basic Research (98-03-33023a) and INTAS (97-0166). We thank Professor Jose Vicente (University of Murcia) for providing dimeric palladacycles based on primary amines.

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