Double Lewis acid activation

Compound 10 has also been used to quantify double Lewis acid activation by two cobalt (HI) ions [37]. In 12, the RNA analogue 2-hydroxypropyl-phenyl phosphate (HPPP) is coordinated to the dinu-clear cobalt site. It is well known that in this substrate the hydroxypropyl group is an efficient intramolecular nucleophile. Release of phenol by intramolecular cyclization is much faster than the reaction by nucleophilic attack of bridging oxide, as observed in 11. At pH >8, transesterification rate is linearly dependent on hydroxide concentration since OH" acts as an intermolecular base for the deprotonation of the hydroxypropyl group. The second order rate constant for the hydroxide-dependent cleavage is 4 x 105 times larger than the second-order rate constant for the hydroxide-dependent spontaneous transesterification of hy-droxypropyl-phenyl phosphate. 

Chin at al. have also demonstrated [52] notable bimetallic cooperativ-ity with the same substrate by the Cu(II) complex 34. The dimer complex is 26 times more active (at pH = 7 and T = 298 K) than the corresponding mononuclear species 35. Based on the crystal structure of the dibenzyl phosphate bridged complex, the authors have proposed double Lewis-acid activation, as in the preceding case. 

Even more efficient bimetallic cooperativity was achieved by the dinuclear complex 36 [53]. It was demonstrated to cleave 2, 3 -cAMP (298 K) and ApA (323 K) with high efficiency at pH 6, which results in 300-500-fold rate increase compared to the mononuclear complex Cu(II)-[9]aneN at pH 7.3. The pH-metric study showed two overlapped deprotonations of the metal-bound water molecules near pH 6. The observed bell-shaped pH-rate profiles indicate that the monohydroxy form is the active species. The proposed mechanism for both 2, 3 -cAMP and ApA hydrolysis consists of a double Lewis-acid activation of the substrates, while the metal-bound hydroxide acts as general base for activating the nucleophilic 2 -OH group in the case of ApA (36a). Based on the 1000-fold higher activity of the dinuclear complex toward 2, 3 -cAMP, the authors suggest nucleophilic catalysis of the Cu(II)-OH unit in 36b. The latter mechanism is comparable to those of protein phosphatase 1 and fructose 1,6-diphosphatase. 

Their activity compared to those of the Cu(II)-terpyridine and Cu(II)-bipyridine complexes indicate notable cooperativity between the metal centers (k mJ2 kmanoaet = 18-26 at pH = 7 and ca. 10 at the pH optimum of the given complex). The pH-rate profile of both complexes shows a bell-shaped structure. Thus, the postulated double general-base catalysis for both complexes is not fully justified. In case of 38 this was explained by possible inhibition by the buffer used. While double Lewis-acid activation is proposed for 37, single Lewis-acid activation is favored for 38. 

Even more interesting is the observed regioselectivity of 37 its reaction with 2, 3 -cCMP and 2, 3 -cUMP resulted in formation of more than 90% of 2 -phosphate (3 -OH) isomer. The postulated mechanisms for 37 consists of a double Lewis-acid activation, while the metal-bound hydroxide and water act as nucleophilic catalyst and general acid, respectively (see 39). The substrate-ligand interaction probably favors only one of the depicted substrate orientations, which may be responsible for the observed regioselectivity. Complex 38 may operate in a similar way but with single Lewis-acid activation, which would explain the lower bimetallic cooperativity and the lack of regioselectivity. Both proposed mechanisms show similarities to that of the native phospho-monoesterases (37 protein phosphatase 1 and fructose 1,6-diphosphatase, 38 purple acid phosphatase). 

Phosphates bridge dinuclear metal centers in the active sites of some phosphoes-terases [1-3]. Dinuclear metal complexes should be able to provide double Lewis acid activation for hydrolyzing phosphates. To quantify double Lewis acid activation for cleaving phosphate diesters, we studied the reaction of 24 (Figure 6.16), which has... 

Figure 6.15 Single and double Lewis acid activation in phosphate hydrolysis.

The fast transesterification of HPNPP in dinuclear complexes 63 was attributed to double Lewis acid activation of the phosphoryl group upon coordination to the... 

A catalysis through a double Lewis acid activation of the scissile phosphate (coordination of two oxygen atoms of the phosphate onto the copper instead of one oxygen atom for a single Lewis acid assistance) was proposed by Chin (334) to account for the higher reactivity of 8 compared to 6. The mechanism proposed by Bashkin et al. for 6 is totally different and is based on the fact that the optimal rate of phosphate trans-esterification is at a pH value close to the value of the metal-bound water molecule (332, 335). Because monoaqua complexes as in 6 do not form stable four-membered ring phosphate coordinates, they may just behave as acid/base coreactants like histidine residues in ribonuclease A (336) or like imidazole buffer (337). 

Fig. 14. Double-Lewis acid activation of phosphate diester proposed for the bis-benz-imidazole binuclear Cu" complex 12. The Cu-Cu distance is 3.7 A. Charges on oxygen atoms and metals have been omitted.

Figure 25 Proposed mechanisms for HPNP transesterification mono Lewis acid activation of the phosphate and the alcohol (a) double Lewis acid activation of the phosphate (b, d, ). (c) Proposed structure of an adduct obtained by double activation of the phosphate, evidencing the steric constraints of the system. ...

The close spatial proximity of the two metal ions in 20 Cu2 allows double Lewis acid activation of the phosphoryl moiety of HPNP and EPNP by the two copper(II) centers. Liberation of p-nitrophenol occurs by nucleophilic attack of the / -hydroxy group in the case of HPNP, and of the metal bound hydroxide ion in the case of EPNP (Fig. 26.5). 

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