Coordination amide carbonyl functions

Zinc may function to promote the nucleophilicity of a bound solvent molecule in both small-molecule and protein systems. The p/Ca of metal-free H2O is 15.7, and the p/Ca of hexaaquo-zinc, Zn (OH2)6. is about 10 (Woolley, 1975) (Table III). In a novel small-molecule complex the coordination of H2O to a four-coordinate zinc ion reduces the to about 7 (Groves and Olson, 1985) (Fig. 2). This example is particularly noteworthy since it has a zinc-bound solvent molecule sterically constrained to attack a nearby amide carbonyl group as such, it provides a model for the carboxypeptidase A mechanism (see Section IV,B). To be sure, the zinc ligands play an important role in modulating the chemical function of the metal ion in biological systems and their mimics. 

Thus, many metal ions catalyze the hydrolysis of esters [7,8], amides [9], and nitriles [10] via electrophilic activation of the C=0 or C=N group. This type of catalysis is characteristic of coordination complexes and is very common in metalloenzyme-mediated processes. Zinc(II), for example, is a key structural component of more than 300 enzymes, in which its primary function is to act as a Lewis acid (see Chapter 4). The mechanism of action of zinc proteases, e.g., thermolysin, involves electrophilic activation of an amide carbonyl group by coordination to zinc(II) in the active site (Figure 4). 

Laser flash photolysis has also been used to study the photophysics and photochemistry of metallocene-containing cryptands and their complexes with rare earth eations [69]. The metallocene moiety was shown to act as an efficient centre for the radiationless deactivation of the lanthanide excited state. Detailed time-resolved studies permitted the characterisation of the coordination chemistry about Dy " within the cryptate and showed, once again, that the functions within the host cryptand primarily responsible for coordination of the guest cation were the amide carbonyl groups. 

A limited number of mechanistic studies of stoichiometric amide hydrolysis reactions promoted by Zn(II) complexes have been reported. Groves and Chambers reported studies of the zinc-mediated hydrolysis of an internal amide substrate wherein amide carbonyl coordination to the zinc center is not possible (Scheme 15).93 Examination of the rate of this reaction as a function of pH (6.5-10.5) yielded a kinetic pKa = 9.16. First-order rate constants at 70 °C (/i = 0.5 (NaC104)) for the Zn-OH2 and Zn-OH-mediated amide hydrolysis reactions differed by a factor of 100 when the data was fit to Equation (1) for the proposed mechanism shown in Scheme 16. The activation parameters determined for this reaction (Ai7 = 22(1) kcal mol-1 and AS = — 18(3) eu) are consistent with an intramolecular hydrolysis process wherein a zinc-bound hydroxide acts as an intramolecular nucleophile to attack the amide carbonyl in the ratedetermining step. 

Enamides are successful substrates on account of their closely defined coordination geometry, since both the olefin and amide carbonyl group are available to bind at c/s-related sites. This must be necessary during the rate-determining stage, for species lacking the amide group (or a closely related functionality similarly sited) react much more slowly and with lower stereoselectivity. 

Obviously, many structural variations are possible in the design of ferrocene oxa-aza cryptands. Some of the oxa-azaferrocene cryptands form alkali metal and lanthanide complexes [90]. FAB mass spectrometry experiments have shown that the cryptands have strong selectivity for the potassium cation compared with Li+, Na, or Cs" " [94], In these complexes the macrocycle functions as a host, but in Mg + complexes the cation is coordinated by the amide carbonyl groups [95]. In the lanthanide complexes the metallocene moiety acts as an efficient center for radiationless deactivation of the lanthanide excited state [96]. 

Bencini and Bianchi have thoughtfully studied the binding behavior of the Zn(II) complex of the phenanthroline-containing macrocycle 40 as a receptor for free amino acids and peptides by NMR and potentiometry. The unsaturated environment of the Zn(II) complex allows for the coordination of the aforementioned substrates. In their zwitterionic form, the binding to Zn(II) occurs through the carboxylate group, whereas in their anionic form, it takes place via the amine functionality, and probably with additional participation of the amide carbonyl of the substrates. It is remarkable that amino acids containing aromatic side chains... 

In general with a peptide not having polar side chains, two pathways are possible for the hydrolysis of the metal-substrate complex. An external water molecule activates the amide carbonyl or the adjacent coordinated OH group acts as a nucleophile on the amide function. This process corresponds to an intramolecular hydrolysis by a metal-ligand. In other words, process A involves a carbonyl coordination intermediate whereas in process B a carbonyl attack by the coordinated hydroxide takes place. These pathways can be followed with 0-enriched water. 

Sargeson and his coworkers have developed an area of cobalt(III) coordination chemistry which has enabled the synthesis of complicated multidentate ligands directly around the metal. The basis for all of this chemistry is the high stability of cobalt(III) ammine complexes towards dissociation. Consequently, a coordinated ammonia molecule can be deprotonated with base to produce a coordinated amine anion (or amide anion) which functions as a powerful nucleophile. Such a species can attack carbonyl groups, either in intramolecular or intermolecular processes. Similar reactions can be performed by coordinated primary or secondary amines after deprotonation. The resulting imines coordinated to cobalt(III) show unusually high stability towards hydrolysis, but are reactive towards carbon nucleophiles. While the cobalt(III) ion produces some iminium character, it occupies the normal site of protonation and is attached to the nitrogen atom by a kinetically inert bond, and thus resists hydrolysis. 

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