Imine-enamine mechanism

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

We shall consider the sequence as firstly imine formation (an abbreviated form of this mechanism is shown), followed by imine-enamine tautomerism. This provides a nucleophilic centre and allows a subsequent aldol-type reaction with enamine plus ketone. The pyrrole ring is produced by proton loss and a dehydration. 

Mechanistically it seems that the reactions follow an enamine mechanism, in which the enamine derived from the ketone and proline reacts with the imine formed in situ from the aldehyde and p-anisidine. 

A reaction mechanism involving imine-enamine tautomerism has been proposed. A similar fluorination reaction has been observed for enamines (see Section 1.1.8.8.). 

We have shown that heterogeneous catalysis can be applied to reductive alkylation with success in reactions such as ether synthesis or N-alkylation of amides and anilines. Concerning the mechanism, several pathways are in competition depending on the structure of the substrate and of the alkylating agent. The important point is that both the product of addition (the hemiacetal or hemiaminal) and the product of elimination (imine, enamine or enolether)... 

Figure 14 Structure and reaction mechanism of oxygen-dependent PPO. (a) Crystai structure of tobacco PPO in compiex with the cofactor FAD and a phenyi-pyrazol inhibitor. Each subunit of the dimeric protein consists of three domains, a membrane- (biue), an FAD- (red), and a substrate-binding (green) domain, (b) Proposed reaction mechanism for oxygen-dependent PPO. Ali hydride abstractions occur from C20 after imine-enamine tautomerizations. M = methyi, P = propionate.

The structure of the amine acrylates used in this study after curing is likely to be very complex and this makes it difficult, if not impossible, to evaluate clearly the nature and mechanism of the photooxidation and photoyellowing observed in these systems. The infra-red data clearly indicates the loss of amine alkyl functionality resulting in amine or amide formation. The carbonyl absorption reported previously (14,15) at 1680 cm indicates the latter. The band situated at 1612 cm l, also reported previously (14,15), may be due to imine, enamine, vinyl ether, amine or an, -unsaturated carbonyl species. If it was due to imine or enamine it would be easy to explain its loss due to hydrolysis during irradiation. 

The above-described epimerization system is entirely different from those involved in the biosynthesis of bacterial BLAs. Thus, the prokaryotic IPN epimerase, CefD, catalyzes the reversible epimerization of the L-a-aminoadipoyl side chain in IPN to the D-a-aminoadipoyl side chain in penicillin N in a PLP-dependent manner, probably through a mechanism involving imine/enamine type intermediates, as outlined in Figure 4.35 (B) [176]. The conversion of ACV analogs to cephalosporins using partially purified S. clavuligerus extracts provided evidence that the prokaryotic epimerase may tolerate modifications in the penam nucleus [177]. 

The mechanism begins with the reaction at C(l) to form a phenylhydrazone (p. 793), which consumes the first equivalent of phenylhydrazine. This hydrazone is an imine and imines are in equilibrium with enamines (p. 796), just as ketones are in equilibrium with enols.The imine-enamine equilibrium is shown in Figure 22.32. 

Notice that the mechanisms for imine, enamine, hydrate, and acetal formation are similar. The nucleophile in each reaction has a lone pair on its attacking atom. After the nucleophile has added to the carbonyl carbon, water is eliminated from a protonated tetrahedral intermediate, forming a positively charged species. In imine and hydrate formation, a neutral product is achieved by loss of a proton from a nitrogen and an oxygen, respectively. (In hydrate formation, the neutral product is the original aldehyde or ketone.) In enamine formation, a neutral product is achieved by the loss of a proton from an a-carbon. In acetal formation, a neutral compound is achieved by the addition of a second equivalent of alcohol. 

In this procedure, a hydrazone of an enolizable aldehyde or ketone is heated in strong acid, causing ring closure with simultaneous expulsion of ammonia to furnish the indole nucleus. [Hints The mechanism of the reaction proceeds in three stages (1) an imine-enamine tautomerization (recall... 

What is the mechanism of imine, enamine and acetal formation )... 

This ChemActivity is designed to get you comfortable shuffling protons using curved arrows. In preparation for more complex mechanisms in upcoming ChemActivities, you should sit down with a blank piece of paper and make sure you can come up with a reasonable mechanism for imine, enamine, and acetal formation. 

There are several alternate acceptable mechanisms for imine, enamine, and acetal formation. Different textbooks will show either initial protonation with an acid catalyst or initial reaction of the nucleophile with the carbonyl carbon. TTie former of these two seems energetically more likely and follows the general rule of thumb that an acid catalyst is usually used in the first step of a mechanism. 

As stated in the previous bullet, imine, enamine, and acetal forming reaction mechanisms are open to debate. Another point in these mechanisms where there is room for argument is in the proton transfers. Usually it is proposed that a solvent or other molecule picks up a proton from one atom and delivers it to another atom (as in Steps 3 and 4 in CTQ 21) but you can also accomplish this via a cyclic transition state. Such intramolecular proton transfer steps do not involve any other molecule, and are most favorable for six-member ring transition states. As noted in the activity, four-member cyclic transition states are not favorable. 

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