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Methyl group steric effects on the kinetics of the copper(II)-tripeptide reactions with triethylenetetramine

Rates of reaction of triethylenetetramine (trien) with doubly deprotonated (tripeptido)cuprate(II) complexes are measured as a function of the number and position of methyl groups in the amino acid residues. Twelve tripeptides that consist of glycyl (G), L-alanyl (A), and α-aminoisobutyryl (Aib) residues are compared. The Cu(H-2Aib3)- complex reacts 8 orders of magnitude more slowly with trien than does the Cu(H-2G3)- complex. Methyl groups on the α-carbon of the second and third amino acid residues (from the amino terminus) decrease the rate of the trien substitution reaction to a much greater extent than methyl groups on the first residue. An empirical correlation between the second-order rate constant (Ktrien, M-1 s-1 at 25.0°C, pH ? 11) and the number and position of the methyl groups is found: log ktrien = 6.7 - 0.2C1 - 2.2C2 - 1.6C3, where Ci denotes the number of methyl groups in the ith amino acid residue. The enormous changes in reactivity are attributed primarily to steric effects in these ligand-ligand exchange reactions.

Effect of hydroxide ion on the kinetics of triethylenetetramine displacement of tripeptides from copper(II) complexes

Triethylenetetramine (trien) reacts rapidly with doubly deprotonated (tripeptido)cuprate(II) complexes, Cu(H-2L)-, to give Cu(trien)2+ and the free tripeptide, where L = GAG, GGA, GAibG, and Aib3 (G, glycyl; A, L-alanyl; Aib, α-aminoisobutyryl). The reactions are first order in each reactant, and the second-order rate constants (M-1 s-1, 25.0°C, μ = 1.0 M) decrease greatly with the number of methyl groups in the second and third residues: 8.4 × 104 (GAG), 7.9 × 104 (GGA), 43 (GAibG), and 0.13 (Aib3). When L is GAG, GGA, and GAibG, the values of the second-order rate constants (for [trien]T and [Cu(H-2L)-]T) increase above p[H+] 9 and reach maximum values at p[H+] 10.7 ± 0.7. The increase occurs because trien and Htrien+ are more reactive than H2trien2+. The rate constants decrease in higher base due to the formation of Cu(H-2L)(OH)2-, which is less reactive than Cu(H-2L)- with trien. Values for the stability constants of the hydroxide adduct, KOH (M-1, 25.0°C, μ = 1.0 M), are 41, 10, and 4 for L = GAG, GAibG, and GGA, respectively. A hydroxide adduct is not observed for the Aib3 complex (KOH -1). The Cu(H-2Aib3)- complex behaves differently because the reaction with trien is more sterically hindered. An acid-assisted H2trien2+ path contributes to the observed rate below p[H+] 10, and the rate begins to increase below p[H+] 9.5. However, a proton-transfer step between H3O+ and Cu(H-2Aib3)- (kH = 2.5 × 106 M-1 s-1) can limit the reaction so that it no longer depends on the [trien]T concentration. Above p[H+] 10, the reaction is first order in both [trien]T and [Cu(H-2Aib3)-], and the rate increases to a plateau at p[H+] 12. At higher p[H+] levels the rate is assisted by OH-, in contrast to the inhibition found for the other tripeptides. A third-order rate constant (0.41 M-2 s-1) is found for the path due to [trien][OH-][Cu(H-2Aib3)-].