The Internal Conjugate Base Mechanism

In the original paper, it was pointed out that the ICB mechanism should be applicable to other metal ions, although data were almost non-existent for the reaction of ligands of the type which favour the mechanism with metals other then Ni +. Recently, it has been shown to be operative in the reactions of Co + with two branched poly(amino-alcohol) ligands AAA A -tetrakis-(2-hydroxyethyl)ethylenediamine (TKED) and AAA W -tetrakis-(2-hydroxypropyl)ethylenediamine (THPED). A similar result had previously been obtained with the corresponding Ni + systems. A similar type of acceleration has also been reported in the reaction of Cu + with en. 

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The Internal Conjugate Base Mechanism.—Also in 1966, Rorabacher reported some temperature-jump data involving the monoammine complexes of Co", Ni", and Zn". The rate constants were discussed in terms of the normal mechanism but they were particularly interesting inasmuch as they suggested that the rates which had been reported previously for the reaction of nickel with polyamines e.g. en) had been unusually high. In the 1966 paper, Rorabacher proposed an internal conjugate base mechanism to explain this acceleration, and this is shown in Figure 5. 

The fact that the rate constant for the reaction of FeOH + with Hanta" is 20 times that for reaction with SCN is ascribed to the operation of the internal conjugate-base mechanism of Rorabacher. 

Chloroquine drastically improves the transfection of cells when DNA/polylysine conjugates are used (Zenke et al., 1990 Midoux et al., 1993). So far, the mechanism of action of chloroquine has not been completely elucidated. Chloroquine is supposed to protect the internalized plasmid from intracellular degradation as a result of the neutralization of acidic compartments and the inhibition of endosome fusion with lysosomes. Furthermore, the swelling of vesicles can be induced when the concentration of chloroquine is high enough. However, there is no direct relationship between the neutralization of the acidic cell compartments and the transfection efficiency (Erbacher et al., 1996a). Once taken up by the cells, chloroquine accumulates inside acidic vesicles where it can reach a concentration more than 50 mM, based on the estimated volume of the vesicular compartments. At physiological pH, 82% of chloroquine is protonated and can bind to nucleic acids. Therefore, the interaction of chloroquine with DNA appears to be... 

A very plausible mechanism for this would involve loss of hydrogen chloride from XXII to form the bicyclohexanone (XXXII) this is a cyclopropanone derivation and would certainly react at once with alkali to give XXXI. The problem is to explain how this comes about. One possibility might be a-elimination of HC1 from XXX to form a carbene but this seems unlikely such a carbene would in any case be expected to rearrange to cyclohexenone rather than to XXXII. Another possibility would be an internal displacement of chloride ion from the conjugate base of XXX, as indicated in XXXIII this, however, is sterically improbable since in the grouping —CH2—CH=-CO—CHC1— the... 

A third member of the bimolecular then unimolecular reaction class is a variant of the previous mechanism. In this case, the conjugate base of biotin reacts with bicarbonate to produce an addition intermediate that then reacts with ATP (Scheme 23). It is likely that the phosphorus of the terminal group of ATP would preassociate with an oxygen of bicarbonate. In particular, if the anionic center of bicarbonate associates with a cation, the 7r-electron density of bicarbonate would align with the phosphorus of the terminal phosphate of ATP. The addition of the conjugate base of a urea to a carboxylate is an appropriate model for this mechanism. The intermediate should be very reactive toward ATP based on the observation that the conjugate base of a carbonyl hydrate reacts rapidly with an internal phosphate ester (59). 

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