Iminium ions nucleophilic hydration

Different rate-determining steps are observed for the acid-catalyzed hydration of vinyl ethers (alkene protonation, ks kp) and hydration of enamines (addition of solvent to an iminium ion intermediate, ks increasing stabilization of a-CH substituted carbocations by 71-electron donation from an adjacent electronegative atom results in a larger decrease in ks for nucleophile addition of solvent than in kp for deprotonation of the carbocation by solvent. 

Peptide aldehydes are fairly reactive and usually exist in solution partially as hydrates Xaa[CH(OH)2] (e.g., 3), which are identified using 13C NMR spectroscopy. 3 3" With amino acids containing nucleophilic side chains, cyclized forms predominate (Scheme 2). Argininal analogues such as Z-Leu-Phe-Arg-H have been shown to exist primarily as the carbinol amine 4 with no spectroscopic evidence for an iminium structure. Lysinal derivatives such as Z-Leu-Phe-Lys-H exist both as a cyclic carbinol amine 5 and as an iminium ion 6 as shown by 3H and 13C NMR spectra. The C-terminal ornithinal analogue Z-Leu-Phe-Orn-H exists primarily as the carbinol amine form 7 and the cyclic iminium form 8 as characterized by the 13C NMR spectra. 3,21 In general, the existence of carbinol and iminium cyclized forms does not preclude the existence of the free or hydrated aldehydes under aqueous conditions. 

A puzzle remains. If equation 16, nucleophilic hydration, is fully rate-controlling, then equations 14 and 15 must be at equilibrium. At the pH values in question, namely pH s 2-7, the dominant form of the enamine in equilibria 14 and 15 should be the iminium ion (30). That is, 30 should not be a steady-state intermediate. In this judgement we are assuming, as before, that the C-basicity of 3 exceeds the A-basicity for the latter, pA H+ = 8.84 (see Table 2). Yet no buildup of iminium ion is reported under hydrolytic... 

The vast majority of enamine hydrolyses which have been investigated from the mechanistic point of view fit comfortably the mechanism given in Scheme 1. The sometimes convoluted pH-rate profiles are caused by changes in rate-controlling step from protonation at Cp, to nucleophilic hydration of the intermediate iminium ion, to breakdown of the carbinolamine addition product, probably via a zwitterion. The pH values at which changes in rate-controlling step occur are determined by a combination of structural features of the enamine and, in some cases, by the concentrations of buffer species which might be present these issues are discussed in the text. 

It is possible that conjugated enamines such as enaminones hydrolyze by the mechanism shown in Scheme 2, a variation of Scheme 1 in which nucleophilic hydration occurs on an O-protonated enamine rather than on the C-protonated (iminium) ion. This mechanism has been proposed for the acidic hydrolysis of compounds 36 and 37. This mechanism cannot be considered established, however, as the experiments that would rule out C-protonation were not done. It is highly pertinent that hydrolyses of other conjugated enamines, 10,11, 25, 26,39 and 40, all obey the expectations of Scheme 1, equation 15, namely they exhibit general-acid catalysis and (for 25, 26, 39 and 40) primary kinetic solvent isotope effects. 

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