Stereoselectivity in the metal-complex catalyzed hydrolysis of amino acid esters—IV rate studies

J. inorg, nucl. Chem., 1973, Vol. 35, pp. 2421-2432. Pergamon Press.

Printed in Great Britain

S T E R E O S E L E C T I V I T Y IN T H E M E T A L - C O M P L E X C A T A L Y Z E D H Y D R O L Y S I S OF A M I N O A C I D E S T E R S - IV RATE STUDIES JOHN R. BLACKBURN and M A R K M. JONES Department of Chemistry, Vanderbilt University Nashville, Tennessee 37203

(Received28 August 1972) A b s t r a c t - T h e study of the stereoselective hydrolysis of enantiomers of histidine methyl ester in the presence of an optically active catalyst has been extended to include lysine, glutamic acid, and glycine incorporated into the catalyst. Hydrolytic studies have also been conducted on methyl esters of methionine, lysine, and aspartic acid in the presence of a variety of optically active [N i(amino acid)] + catalysts. The dependence of the rates of hydrolysis of the amino acid esters on ester structure, catalyst structure, and "effective charge" of the catalyst is discussed. A temperature dependence study of stereoselective effects on the rates of hydrolysis of methyl histidinate has been carried out, that demonstrates the importance of coordination of the ester moiety in producing these effects. The observed kinetic and thermodynamic stereoselectivities are discussed in terms of specific structures for the complexes that give rise to these efforts. INTRODUCTION

PREVIOUSLY it has been shown [1] that the equilibria in mixed complex systems related to those where stereoselective rate differences have been observed, are themselves stereoselective in some cases. The question then remained as to whether the observed rate differences were due to thermodynamic factors primarily or whether there was also a kinetic component dependent upon other factors. For the Ni2+-DL-histidine system, a thermodynamic stereoselective effect was found, while in all other simple bis (amino acid)-Ni 2+ systems such an effect was absent. The present study was carried out to extend information available on mixed amino acid-amino acid ester systems which were in principle capable of exhibiting stereoselective behavior. EXPERIMENTAL The materials used here were largely prepared as described previously. The rate data were also obtained as described previously except for those at temperatures less than 25°C which were obtained under nitrogen to eliminate uptake of CO2 from the air over the longer times they required. The solutions in which the reactions had run to completion were examined to determine [~]~},h . . . . and E,naxto insure the absence of any untoward effects, such as decomposition of the optically active amino acids. RESULTS

Hydrolysis of histidine methyl ester in presence o f Ni(II) The studies of the hydrolysis of histidine methyl ester that were discussed in papers I and II in the series were extended to cover three additional amino acid1. J. R. Blackburn and M. M. Jones, J. inorg, nucl. Chem 35, 1605 ( 1973), (Part 11I). 2421

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J . R . B L A C K B U R N and M, M. JONES

Ni(II) catalysts, employing glycine, lysine, and glutamic acid. Glycine was chosen because the electronic effect of coordination of the 5-membered chelate ring should be very similar to that of other a-amino acids, while very little structural interaction should be noted because of the small size of the molecule. Lysine, like histidine and tryptophan, has a nitrogen atom as its third potential donor site, but lacks the unique structural features of these other basic amino acids; while glutamic acid is structurally quite similar to aspartic acid, but with a slightly larger chelate ring for the third donor site. The rate constants obtained, together with those previously reported, are listed in Table 1. H Y D R O L Y S I S O F L Y S I N E A N D M E T H I O N I N E M E T H Y L E S T E R S IN T H E P R E S E N C E O F Ni(II)

The hydrolysis of amino acid esters other than histidine methyl ester was undertaken to determine the general efficiency of the Ni(AA) +~ catalyst in hydrolyzing the esters of potentially tridentate amino acids. The relative catalytic efficiency could be estimated from the magnitude of the rate enhancement for each amino acid. (The term "catalytic efficiency" will be used to indicate the ratio Table 1. Observed pseudo-first-order rate constants for the hydrolysis of D(-)- and L(+)-histidine methyl ester (DE and LE) in the presence of a Ni(AA) +z catalyst at pH = 8.0 and T = 25°C

Catalyst = Ni(AA) +~ AA zf (H20)~ Glycine D(-)-histidine~t L(÷)-histidine D(--)-tryptophan~ L(+)-tryptophan D(-)ly sine L(÷)-lysine D(-)-aspartic acid~t L(+)-aspartic acid D(-)-glutamic acid L(+) glutamic acid D(--)methionine~ L(+)-methionine

2 1 1 1 1 1 1 0 0 0 0 1 1

ko*bs (× 105) histidine methyl ester DE LE (see -l ) (sec -l ) 9.40 6.26 4.05 5.61 4.26 5.83 6.16 6.10 3"72 3"83 5.67 5-88 5.87 6.10

9.35 6.23 5.60 4.12 5.60 4.12 6.20 6.30 3.61 3.62 6.06 5.90 6.13 5.90

*The quoted constants are the averages of at least 4 determinations for each constant. The maximum standard deviation among the constants was 0.25. tThe value of z is that calculated assuming a charge of -- 1 for the amino acid anion (--2 for aspartic and glutamic acid). Evidence will be presented that indicates that in some cases the ,effective" z varies. ~:Paper 2 in this series, [2]. 2. John R. Blackburn and Mark M. Jones, J. inorg, nucl. Chem. 35, 1597 (1973), (Part I I).

Stereoselectivity of amino acid e s t e r s - IV

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of a given observed catalytic rate constant to that of the uncatalyzed rate constant.) A!ternatively, the catalytic efficiency may be thought of as a measure of the degree of interaction of the ester linkage with the complex catalyst. In addition, by using the same series of amino acids in forming the complex catalyst, the trends noted in the histidine system can be tested for generality, and the general trends and specific differences found can be used to infer structural features of the complexes. Lysine methyl ester was chosen because it, like histidine is a "basic" amino acid derivative, having two donor nitrogens. (The use of tryptophan, which would perhaps have been preferable for the stereoselectivity noted earlier [2], was precluded by the insolubility of the ester in the aqueous system.) Methionine, on the other hand, has only one nitrogen donor (the other potential coordination site being sulfur), but has the same net charge upon coordination that histidine has. The data for these two esters, as expected, was found to adhere to pseudo-first-order kinetics, and the rates obtained are presented in Table 2. As with histidine methyl ester, the notable points of interest are the variations in the rates with charge and amino acid structure. HYDROLYSIS

OF ASPARTIC ACID DIMETHYL PRESENCE OF Ni(ll)

ESTER

IN T H E

The use of aspartic acid dimethyl ester provided another variation in structure in that aspartic acid (as well as glutamic acid) has two carboxylate donor groups and is thus an "acidic" amino acid, as opposed to the "basic" histidine and lysine and "neutral" methionine. The presence of the two carboxylate functional groups Table 2. Observed psuedo-first-order rate constants for the hydrolysis of D ( - ) - and L(+)-lysine methyl ester (DLE and L L E ) and D ( - ) and L(+)-methionine methyl ester (DME and L M E ) in the presence of a N i ( A A ) +z catalyst at p H = 8.0 andT = 25°C

Catalyst = N i ( A A ~ -~ AA

z

(H20)x Glycine D(-)-histidine L(+)-histidine D(--)-lysine L(+)-lysine D(-)aspartic acid L(+)-aspartic acid D(-)-glutamic acid L(+)-glutamic acid D(--)-methionine L(+)-methionine

2 1 1 1 1 1 0 0 0 0 1 1

Kobs (x 10~) for the methyl ester DLE LLE DME LME (sec -1) (sec 1) 6.46 3-34 2.53 2.43 3.55 3.49 2.50 2-45 3-16 3.27 3-74 3.63

6-35 3-20 2.50 2-59 3.54 3.40 2.45 2.34 3.05 3.18 3.57 3.44

8.27t 4-13 2-72 2.77

7.97t 4.15 2.98 2.95

3.22 3.09

3.40 3-50

4.22 4.22

4-35 4-01

* Values reported are for the average of at least three determinations for each constant. The average deviations of the measurements were no greater than 0.25. tThese constants were determined at p H = 7-0 and corrected to 8-0 assuming a p H dependence of I in this range.

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J . R . B L A C K B U R N and M. M. JONES

presented several problems that rendered quantitative analysis of the ester hydrolysis impossible. The first of these problems was that the ester of the amino acid was in fact the dimethyl ester. Attempts to prepare the optically active mono ester were unsuccessful. The possibility of either (or both) a-methyl or/3-methyl ester hydrolysis complicated the interpretation of the data, since the two esters would be expected to hydrolyze at different rates due to the difference in proximity of the a-amino group to the two ester linkages. In addition, it was found that the hydrolytic data fit neither simple first-order nor simple second-order plots with respect to the total ester. Also, the hydrolysis of one equivalent of the diester was found to consume only about one equivalent of base before the reaction came to an effective halt whereas two equivalents would be necessary for complete hydrolysis. (The elemental analysis of the freshly-prepared samples fit the calculated values for the dimethyl esters closely.) The indication was that both the a-methyl and/3-methyl ester linkages underwent catalytic hydrolysis, at competing rates; but that for a given molecule, possibly only one of the two esters was hydrolyzed before the reaction slowed to a negligible rate. The latter observation could alternatively be caused by another source of difficulty, which lay in the very hygroscopic nature of the dimethyl ester hydrochloride. Even though the compounds were kept in stoppered bottles in a desiccator when not in use, they quickly became lumpy and even sticky and had to be dried repeatedly when used. Thus, the possibility that part of the weighed sample was water, so that less ester was introduced into the reaction mixture, or that part of the ester had been hydrolyzed in the bottle by atmospheric moisture could not be overlooked. In fact, the two enantiomers themselves changed purity while they were stored, preliminary to their use, probably due to the difference in the effectiveness of the seal of the bottles. The observed rates of hydrolysis of the D(-)-enantiomer were in all cases approximately 50 per cent faster than those of the L(+)-enantiomer, indicating a higher degree of purity, although when initially prepared, the esters tested equally pure. These difficulties precluded quantitative analysis of the rate data for the enantiomeric dimethyl esters. However, although the absolute rates for mirror image complexes were not the same due to the differences in purities, the relative differences between pairs of non-mirror image complexes should be similar (e.g. data for L A L E / D A L E should be the same as for D A D E / L A D E , where LA and D A are enantiomers of a given acid; and data for (AA)LE/(AA') LE should be the same as for (AA)DE/(AA')DE, where AA and A A ' are different amino acids). Since only qualitative effects could be observed, the dimethyl ester enantiomers were hydrolyzed in the presence of only one "acidic," one "neutral," and one "basic" amino aci6 for comparison of the general trends with those noted for the previously mentioned amino acid esters. The relative initial rates of consumption of base (determined by the amount of time necessary for addition of a given amount of base at the beginning of the reaction) are presented in Table 3. The initial rates of base consumption are relative to the slowest observed r a t e that of the L(+)-histidine-L(+)-aspartic acid dimethyl ester combination. HYDROLYSIS

OF THE AMINO

A C I D E S T E R S IN T H E A B S E N C E

OF Ni(II)

In order to compare the relative catalytic efficiency of the nickel (II) ion for the three esters for which quantitative data could be obtained, it was necessary to

Stereoselectivity of amino acid e s t e r s - IV

2425

Table 3. Relative initial rates* of base consumption for the hydrolysis of aspartic acid dimethyl ester in the presence of Ni(AA) +z catalyst Catalyst

=

Ni(AA)

+z

z

AA D(--)-aspartic acid L(+)-aspartic acid D(--)-histidine L(+)-histidine D(-)-methionine L(÷)-methionine

0 0 1 1 1 1

Aspartic acid dimethy ester LE DE 1-08 1.07 1-05 1.00 1.46 1.09

1.52 1.51 1.46 1.45 1-79 1.59

*Relative to slowest observed initial rate (L(+)-histidineL(+)-aspartic acid dimethyl ester). While absolute rates were not available, the order of magnitude is = 3 × 10-4 since the rate of addition of base was about the same as in the lysine and methionine ester hydrolysis.

obtain the rate constant for the uncatalyzed hydrolysis of the esters at the pH and temperature of the study. When the metal ion is not present in solution, however, a 1 : I correspondence between the ester hydrolyzed and the base consumed is no longer valid, since the protonic equilibria for the ester and for the resulting acid are not the same. For example, methyl histidinate (pK,2 = 7.34 is less than 50 per cent protonated at pH 8.0, while the product of the ester hydrolysis, histidine (pKa3 = 9.20) is almost totally protonated. Thus, as the histidine is formed by hydrolysis, some base is generated by the protonation of the product; and the resulting amount of base required by the overall reaction is lowered. [OH-]~aa~d

= [ O H - ] c o n s u m e d - [OH-]generated-

(l)

The mathematical relationships between the total ester concentration [Ester], and the terms [OH-] consumed and [OH-] generated have been determined elsewhere [3] in terms of the ionization constants of the acid and ester and the pH of the solution, and it has been shown that the amount of base added is directly proportional to the ester hydrolyzed, with the proportionality constant a composite of terms related to the ionization constants and pH. The proportionality [OH-]adae~ = K[Ester]hyOroly,.ed

(2)

constant K is pH dependent, and must be determined at any pH at which hydrolysis is done. The observed pseudo-first-order rate constants can thus be obtained from the ln(a--x) vs time plots. The observed rate constants for the uncatalyzed hydrolysis can be compared with the constants for the nickel(II) catalyzed hydrolysis (from Tables 1-3) to give the relative catalytic efficiency for the complexes containing the different amino acids. The observed values of the 3. J. E. Hix, Jr. and M. M. Jones, J. A m. chem. Soc. 90, 1723 (1968).

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B L A C K B U R N and M. M. J O N E S

various catalyzed and uncatalyzed rates, and the catalytic efficiency, obtained by dividing the catalyzed rate by the uncatalyzed rate, are presented in Table 4. It is evident that although the observed rates of uncatalyzed hydrolysis are fairly close for the three amono acid esters, the efficiency of the nickel(II) ion in catalyzing the hydrolysis of the different esters is quite different, being the greatest for methionine, slightly less for lysine, and good bit less for histidine. Again, these differences will be seen to relate to the structural features of the complexes. Table 4. Catalyzed and uncatalyzed rates of hydrolysis, and catalytic efficiency, for various amino acid and amino acid ester combinations

Ester

Histidine Methionine Lysine

kUU~c

NI(II) kobs

(sec -1)

( s e c -1 )

0.96 x 10-5 1.26 x 10-5 !.50 × 10-5

9 . 4 0 x 10-5 8.12 x 10-4 6.40 x 10-4

k obs NI k obs ......

9.8 64 43

kobs Nl(gly) kobs Ni(asp) kobs

k uncobs

6.6 33 22

3.9 27 16

Temperature dependence of the stereoselective effects of the metal ion catalyzed hydrolysis of histidine methyl ester Although the hydrolysis of histidine methyl ester has been the subject of several studies in recent years, none has dealt with the temperature dependence of the stereoselective effects of the rate noted with an optically active catalyst. Such a study would provide strong evidence either for or against the previously proposed source of these stereoselective effects. Hix ~ concluded from his study that the differences in rate were due to differences in the ability of the ester linkage to coordinate to the metal ion when different enantiomers of the ester were present. In order to have differences in this ester coordination, it was necessary to assume the same structure for the M L A L E and M L A D E complexes. The results of the present study indicate that the source of stereoselectivity arises from a combination of effects, the most notable being differences in the ease of attack by the nucleophile on the coordinated ester linkage, due to differences in the structures of the M L A L E and M L A D E complexes; and that there is little difference in the ease with which the ester linkage can coordinate to the catalyst in the two different structures. A study of the temperature dependence of the stereoselectivity differentiates between the two possibilities for the following reasons. If the ester linkage can coordinate more easily in one structure than in the other, the activation energies for coordination would be expected to differ, and hence the temperature dependencies would not be the same. On the other hand, differences in non-bonded interactions due to differences in structure would not be expected to change appreciably with temperature, hence the temperature dependecies shotdd be very close to each other if the stereoselectivity arises in this manner. Rate studies have been carded out at 5 temperatures ranging from 20 to 36°(2. The results are presented in Table 5. DISCUSSION

Stereoselective effects in the rates of hydrolysis Examination of Tables 1-3 shows that stereoselective effects are evident in only two of the seventeen combinations studied that could theoretically show such

Stereoselectivity of amino acid e s t e r s - IV

2427

Table 5. Observed pseudo-first-order rate constants for the hydrolysis of D(-)and L(+)-histidine methyl ester in the presence of D(-)-histidinato-nickel(II) IDA] and L(+)-histidinato-nickel(I I) [LAI as a function of temperature

Temperature (°C)

Ester configuration

20-4 20-4 22-4 22.4 25.0 25-0 30-1 30.1 36.1 36.1

DE LE DE LE DE LE DE LE DE LE

kobs(× 105) (sec -1) Ni(DA) Ni(LA) 1.84 2.04 2.68 3.40 4.05 5.60 6.97 9.74 11.4 16.1

2-02 1.96 3'42 2.76 5.61 4-12 8-73 6.25 14.9 10.0

kave (× 105) (sec 1) (DD = LL) (DL = LD) 1.90

2'02

2.72

3.41

4.08

5-61

6.61

9-24

10.7

15.5

e f f e c t s - t h e combinations of histidine with histidine methyl ester and tryptophan with histidine methyl ester. This somewhat surprising, and it becomes necessary to look for aspects of these complexes that are unique among those studied. Two features are common to both histidine and tryptophan and absent in the other amino acids. The first is the bulkiness of the parts of the molecule immediately surrounding the third donor site. In the four other molecules, the third potential donor is either in an open ended chain or at the end of such a chain. However, in histidine and tryptophan the third potential donor is fixed in a five-membered ring. The second aspect is this fixed conformation of the third potential donor site in the molecule. In each case, the extra donor site is contained in the almost planar five-membered ring and thus has no freedom of rotation or conformation due to the rigidity of the ring. Stereoselective effects are noted only when both the coordinated acid and the ester have these features. Examination of molecular models of the complexes clarifies the effect of this rigid donor site in the complexes. The six chelate rings formed by the two tridentate ligands produce a very inflexible structure for the complex. While the chelate rings are not particularly strained with regard to bond angles or bond lengths, nevertheless the entire chelate is held very rigidly, with little of the normal "floppiness" of six-membered chelate rings. The chelate rings formed by the other amino acids have various possible conformations and a flexibility of the chain that is not possible in the cases of histidine and tryptophan. The necessity of both chelated molecules having this rigid ring conformation in order to produce stereoselective effects is clearly demonstrated by Table 1, whereby histidine methyl ether shows no stereoselectivity whatsoever with aspartic acid, glutamic acid, methionine, or lysine; and by Tables 2 and 3, whereby the presence of histidine in the complex catalyst causes no stereoselective effects to the hydrolysis of lysine methyl ester, methionine methyl ester or aspartic acid dimethyl ester. It seems very likely that hydrolysis of tryptophan methyl ester in the presence of nickel(II) and histidine would show the same stereoselectivity, but the insolubility of the tryptophan esters prevent the study of this system. The most obvious reason for the difference in

J I N C Vol. 35. No. 7--J

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J . R . B L A C K B U R N and M. M. JONES

rate of hydrolysis of the enantiomers of methyl histidinate when different enantiomers of histidine or tryptophan are present in the catalyst is that the structures of the M D A D E and M L A D E complexes are different, with respect to their respective modes of coordination. Structures which can be used to account for the observed kinetic stereoselectivity are shown in Fig. 1, for the bis(histidinato) nickel(II) complexes. As can be seen, the coordination modes differ in the M D A D E and M L A D E complexes, being cis, cis, trans and cis, cis, cis structures respectively. The coordinated ester linkages can be seen (much more clearly from molecular models than from illustrations) to be protected from nucleophilic attack by the hydroxyl ion from three sides when the ring donors are trans, and protected from only two sides when they are cis. Thus, the presence of the nickel (II) ion catalyzes the hydrolysis, but the presence of the bulky side chain donors of the amino acid and the ester depresses this catalyzed rate somewhat, especially when the bulky groups are trans. At first glance, the observation of stereoselective effects with tryptophan seems at a variance with two prior sets d a t a - t h a t in Paper III [1] of this series where no thermodynamic stereoselective effects of coordination were found for tryptophan, and that from a previously published study, by Williams that indicated that tryptophan was primarily bidentate with nickel(II) [4]. Williams' conclusions were based primarily on the observation of tris-complexes of tryptophan with nickel(II) when the amino acid was present in excess in solution, which he ascribed to the presence of only two strongly chelating sites in the m o l e c u l e the carboxylate and or-amino donors. The indole functional group nitrogen is a much weaker donor group than the other two, thus the presence of three tryptophan chelates on the octahedral nickel(II) center when the ligand is present in excess. The kinetic stereoselectivity noted in Table 1, however, indicates that some interaction between the indole nitrogen and the nickel(II) ion is occurring in solution. The interaction may well be weaker than those of the two other donor

lI I Fig. 1. Probable structures for the Ni(|I) complexes of L(+)-histidine methyl ester and D(--)- and L(+)-histidine. Structure I shows the "optically pure" [(Ni(L+)-histidine) (L(+)-methyl histidinate)] complex, and structure II shows "racemic" [Ni(D(-)histidine(L(+)-methyl histidinate)] complex. 4. D. R. Williams, J. chem. Soc. A, 1551 (1970).

Stereoselectivity of amino acid e s t e r s - IV

2429

groups, but it must be strong enough to keep the indole ring in the vicinity of the nickel(II) ion rather than free to rotate as if no interaction occurred. This weak interaction could explain the lack of thermodynamic stereoselectivity of coordination noted earlier [2] since two strong donor groups are no longer present in cis and trans positions in M(DA)2 and M D A L A bis(tryptophanato)nickel(II) complexes and in the M D A D B and M D A L B histidinatotryptophanatonickel (II) complexes, thus the AHe for the two types of complexes would not be expected to differ appreciably.

The effect of the electronic charge of the catalyst on the rates of hydrolysis of amino acid esters On the basis of their study of the hydrolysis of histidine methyl ester, Conley and Martin [5] proposed that the effect of increasing the charge on the activated complex by one unit created a 40-fold increase in the specific rate constants for the ester hydrolysis. Hix and Jones confirmed the order of magnitude of this effect, finding that the increase was slightly less than 40-fold in the case of the optically pure histidine-methyl histidinate complex and slightly greater for the racemic complex. (It is important to note that this 40-fold increase in the rate constant is relative to the completely factored rate constants, with all contributions other than those specifically from the E and NiAE + molecules subtracted out. The observed differences in rate are a good deal smaller.) Both sets of investigators based these conclusions on the relative rates of the uncatalyzed hydrolysis and the histidinatonickel(II) catalyzed hydrolysis, since coordination of the ester to the histidinatonickel(II) complex is expected to increase the overall charge on the ester by one unit. However, in view of the stereoselective effects discussed in the preceding section it seems likely that the catalyzed rate in this case is somewhat depressed by the bulkiness of the ligands. For this reason, the comparison of the uncatalyzed rate with three catalyzed r a t e s - t h e aquated nickel(II) ion catalyzed rate, the glycinatonickel(II) catalyzed rate, and the aspartatonickel (II) catalyzed r a t e - f o r complexes with net overall charges of 2, 1 and 0 respectively, has been made in Table 4. It can be seen from Table 4 that the catalytic efficiency of the nickel(II) ion is reduced by slightly less than one-half when one equivalent of glycine is present in the solution, presumably coordinated primarily as the NiAE species. Coordination of the glycine reduces the net charge on the metal-ester complex by one unit, from 2 to 0. Upon reducing the net charge from 1 to 0, by replacing the glycine with aspartic acid, the catalytic efficiency is reduced by a much smaller relative amount compared to the drop from 2 to 1. From a purely electrostatic standpoint, the charge of the aspartato(methyl histidinato)nickel(II) complex is the same as that of the free ester, so little effect might be expected on the rates of hydrolysis of the esters. In fact, the catalytic efficiency of the aspartatonickel(II) complex ranges from 4 in the case of histidine methyl ester to almost 30 in the case of methionine methyl ester. This is not at all surprising since, although the charge on the complex may be somewhat dissipated over all the ligands, one would expect the concentration of charge to be greatest at the metal ion. Thus, 5. H. L. Conley, Jr. and R. B. Martin, J. phys. Chem. 69, 2923 (1965).

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J . R . B L A C K B U R N and M. M. J O N E S

even though the overall charge on the complex is zero, the metal ion may be thought to have a slight concentration of positive charge and the balancing negative charge concentrated primarily on the carbonyl oxygens of the aspartic acid. The comparison of the rates observed in the presence of aspartic acid and glutamic acid provides strong support for this concentration of charge concept. Although the net overall charge is apparently the same, the glutamatonickel(II) complex catalyzes the rates of hydrolysis of lysine and histidine methyl esters more effectively than does the aspartato-nickel(II) complex. Comparison of the pK's of the carboxyl groups of aspartic (1.94 and 3.70) and glutamic (2.19 and 4.28) acids leaves little doubt that both groups in each ligand are deprotonated at pH 8.0, hence the complexes do have the same net charge. Unfortunately, the titrimetric data make no distinction between coordinated and uncoordinated - C O O - groups. Several groups of workers have suggested that the/3-carboxyl group of aspartic acid is fully coordinated while the y-carboxyl group of glutamic acid does not coordinate effectively in the intermediate pH ranges. Ritsma et al. draw these conclusions from the comparative stability constants of the bis complexes[6] Gillard and Harrison from isolation of crystalline tris(glutamato) cobalt(II) complexes at moderate pH's [7] and Katzin and Gulyas arrive at the same conclusion from consideration of the optical spectra and circular dichroism curves for the complexes [8]. The three separate methods all point to the fact that the y-carboxyl group is at best weakly coordinating in solution. The concentration of positive charge on the nickel(II) ion would be expected to be smaller when aspartic acid is chelated, rather than glutamic acid, due to the presence of the two anionic donors in close proximity to the nickel(II) ion. When one of these anionic donors is removed from the vicinity of the metal ion, either partially or entirely, the concentration of positive charge at the metal ion would be expected to be slightly higher, with the resulting increase in negative charge centered on the free carboxylate anion. The overall charge on the complex remains the same, but this increase in charge concentration immediately adjacent to ester linkage would enhance the polarizing ability of the metal ion and hence its catalytic efficiency. The effect expected then, would be for the glutamatonickel(II) complex to catalyze the rate of hydrolysis more effectively than the aspartatonickel(II) complex, which is the effect experimentally noted. Within complexes of a given net charge, this effect would be expected to vary as the specific donor groups of the ligands varied, and Tables 1-3 show evidence of this, as the rates vary among the + 1 charged complexes in the manner in which they differed for the +2 charged complexes. In general, among the + 1 charged complexes, the rate can be seen to decrease with increasing size and bulkiness of the ligands, indicating some steric interactions with the attacking O H - nucleophile. The very high (10.53) pKa3 of the E-amino group of lysine indicates strongly that this group may be protonated, and hence uncoordinated in the pH range of the study. The titration curve of L(÷)-lysine dihydrochloride in the presence of nickel(II) shows only two ionizable protons up to pH 8, where three would be expected. A third equivalent of base gives rise to a third inflection point, but at a 6. J. H. Ritsma, G. A. Wiegers and F. Jellinek, Recl. Tray, chim. Pays Bas 88, 411 (1969). 7. R. D. Gillard and P. M. Harfison, J. chem. Soc. (A) 1657 (1967). 8. L. I. Katzin and E. Gulyas, J. Am. chem. Soc. 91, 6940 (1969).

Stereoselectivityof aminoacid esters- IV

2431

pH of - 9.75, confirming the bidentate nature of this ligand. (This effect has been previously noted by Martin [9].) The protonation of the e-amino group would give the complex a net overall charge of +2, but this extra positive charge would be centered on an atom removed by five carbons from the catalytic site, thus causing little change in the electronic charge adjacent to the chelated ester. The lysinatonickel(II) complex is seen to catalyze the ester hydrolysis no more efficiently than the methionine complex, which has a well-defined + 1 charge. The effect of the amino acid ester on the rate of hydrolysis The most obvious variation in rates among the four esters hydrolyzed is that the rate constant for hydrolysis of histidine methyl ester is at least a factor of ten smaller than those for the others, which hydrolyze at comparable rates. This is most likely a result of the rigid nature of the histidine chelate rings discussed earlier. Whereas the other amino acids all have flexible chelate rings, the histidine ester must conform to a particular structure before facile interaction of the ester linkage with the metal ion can be achieved. It is to be expected then, that the catalysis of methyl histidinate hydrolysis by the metal ion would be less efficient than that of the other esters, since the others can interact much more readily with the metal ion. This is an effect due to catalytic rate differences, since the uncatalyzed rates of hydrolysis are very similar for all the amino acid esters. The temperature dependence of the kinetic stereoselectivity The temperature dependence of the histidine-methyl histidinate-nickel(II) system is the strongest evidence for the validity of the structures proposed in Fig. 1. An Arrhenius plot of the data, shown in Fig. 2, illustrates clearly that above about 24°(2, the temperature dependencies of the hydrolysis of the M L A L E and M L A D E complexes are almost identical. Below that temperature, the stereoselectivity rapidly disappears (completely by 19°C) and both rates fall off rapidly. This taken as an indication that the ester linkages in the two complexes 3"75--

-~ 4-5C 47~

~OJ~O0

-

35'0

30.0

250

Temp, °C (plotted os the redprocolof °K) Fig. 2. Temperature dependence of the rates of hydrolysis of L(+)-histidine methyl ester in the presence of L(+)-histidinatonickel(II) complex (circles) and in the presence of

D(--)-histidinatonickel(II)complex(triangles). 9. E. W. Wilson,Jr. and R. B. Martin,lnorg. Chem.9, 528 (1970).

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J . R . B L A C K B U R N and M. M. J O N E S

coordinate equally with the metal ion above 24°C, and that the coordination of the ester linkages of both complexes falls off rapidly with temperature so that it has effectively ceased at about 19°C. The combined effects of the rapid drop off in rate for both complexes and the disappearance of any stereoselective effects is strong evidence that the ester linkage no longer coordinates at 19°C. This is easily explained by noting that at best the ester linkage is a weak donor site, and is at all times in competition with water for the open position on the metal ion: R--O Ni(OHz)+n+

I

C--R.

II

"Ni(ROOCR) +n H20.

(3)

O

At low temperatures, the ester linkage cannot displace the water, thus the catalytic effect noted is purely the electrostatic effect caused by coordination of the other stronger donor sites in the l i g a n d - t h e a-amino and imidazole nitrogens. We can thus estimate the activation energy for the forward step of equilibrium (3) to be -~ 0.6 kcal/mole from the temperature at which stereoselectivity begins. The activation energies for the hydrolysis of the esters can be calculated from the slopes of the Arrhenius plot shown in Fig. 2. The slop is equal to --Ea/R, and for the hydrolysis of the M L A L E and M L A D E complexes, Ea = 7"4 kcal/mol and 7.3kcal/mol respectively. The stereoselectivity has thus been shown to be independent of temperature in the temperature ranges that allow the ester to displace the water and coordinate to the metal ion, and has been shown to disappear completely at temperatures where no interaction of the ester with the metal occurs. CONCLUSIONS

The rates of hydrolysis of coordinated amino acid esters have been shown to depend on the structure of the esters themselves, the structure of the amino acid of the catalyst and the effective charge of the catalyst. Stereoselective effects in the rates have been noted in only two isolated cases, and can be explained by the specific structures of the complexes, i.e. the steric interactions between the bulky ligands of the complex and the attacking nucleophile due to specific coordination modes. Thermodynamic stereoselective effects are evident in only one case, the bis(histidinato) nickel(II) system, and have been determined to arise from AHy differences involving different modes of coordination with the three electronically unique and strongly coordinating donor sites, coordinated cis, cis, trans in the case and cis, cis, cis in the other case. The lack of three strongly coordinating and electronically unique donor sites in any of the other potentially tridentate amino acids studied precludes their manifesting thermodynamic stereoselectivity.