Peptide-metal complexes substitution reactions

Bob s research interests and knowledge across chemistry were great. Throughout his career he retained an interest in biomimetic chemistry, specifically the study of metal ion-promoted reactions and reactions of molecules activated by metal ion coordination. His early interests in carbohydrate chemistry inspired him to study metal ion catalysis of both peptide formation and hydrolysis as well as studies in inorganic reaction mechanisms. He was particularly interested in the mechanisms of base-catalyzed hydrolysis within metal complexes and the development of the so-called dissociative conjugate-base (DCB) mechanism for base-catalyzed substitution reactions at inert d6 metal ions such as Co(III). 

The kinetics and mechanisms of substitution reactions of metal complexes are discussed with emphasis on factors affecting the reactions of chelates and multidentate ligands. Evidence for associative mechanisms is reviewed. The substitution behavior of copper(III) and nickel(III) complexes is presented. Factors affecting the formation and dissociation rates of chelates are considered along with proton-transfer and nucleophilic substitution reactions of metal peptide complexes. The rate constants for the replacement of tripeptides from copper(II) by triethylene-... 

Outside Protonation. When metal-peptide complexes are placed in acidic solutions, the complexes dissociate. Metal ions which are sluggish in their substitution reactions, such as Ni(II) (43), Pd (II) (44), and Co (III) (45), add protons to the peptide oxygens prior to the metal-N (peptide) bond dissociation. The Cun(H 2GGhis)" complex is sufficiently sluggish in its reaction with acid to permit outside protonation to be observed kinetically (12). Protonation constants of 104 2 and... 

Amino acid esters, amides, and peptides can be hydrolyzed in basic solution, and metal ions (Cu(II), Co(II), Ni(II), Mn(II), Ca(II), and Mg(II), and others) speed these reactions. The uncertain mechanism is either through bidentate coordination of the a-amino group and the carbonyl, or only through the amine. The rates of these reactions often exhibit complicated temperature dependence and deduction of the mechanism is difficult. Co(III) complexes promote similar reactions. When four of the six octahedral positions are occupied by amine ligands, and two cis positions are available for ligand substitution, these hydrolysis reactions can be examined in detail. These compounds generally catalyze the hydrolysis of N-terminal amino acids from peptides the amino acid that is removed remains bound to the metal. The reactions apparently proceed by coordination of the free amine to cobalt, followed either by coordination of the carbonyl to cobalt and snbseqnent reaction with OFI or H2O (path 1 in Figure 12.16) or reaction of the carbonyl... 

The use of metal-carbene complexes as an amino-protecting group in peptide synthesis has been reported by Fischer and Weiss (1973). The free amino group of an amino acid ester readily displaces the alkoxy group of an alkoxy-substituted carbene complex. The nitrogen atom of the resulting N-substituted carbene complex is nonbasic and nonnucleophilic because it bears a partial positive charge. The low reactivity of the amino-substituted carbene complex allows a series of reactions to be carried out to construct a peptide chain. Finally, the completed peptide chain can be removed from the carbene complex by treatment with trifluoroacetic acid at 20°. Scheme 16 illustrates the variety of reactions that can be carried out in the presence of the metal-carbene functionality. 

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