SchifFs base mechanisms

Figure 9.12 Schiff base mechanism utilizing PLP, demonstrated on amino acid transferase.

The formation of adducts through a Schiff base mechanism was the basis to assess the reactivity of the seven model compounds with this new technique. The reactivity index generated with our method was consistent with those reported by Benet et al. [26] and Bolze et al. [27] (Table 10.3), which validated this technique to evaluate AG reactivity. Schiff base adducts of AGs and proteins were obtained from the literature for TOL, ZOM, and DCL... 

The decarboxylation of acetoacetate is acid catalyzed (20). Metals do not catalyze the spontaneous decarboxylation of acetoacetate, presumably because the substrate and the product acetone enol are poor ligands for the metal (27). Primary amines catalyze the decarboxylation of acetoacetate by a Schiff base mechanism (Scheme VII), and this provides the best model for acetoacetate decarboxylase (94). 

Compulsory oxygen-18 exchange from the carbonyl group of the substrate accompanies the enzymic decarboxylation (95). Reaction of the enzyme with acetoacetate in the presence of NaBHa results in inactivation of the enzyme and formation of a product in which a single lysine amino group has been alkylated (96). This and a variety of other lines of evidence indicate that the reaction occurs by means of a Schiff base mechanism analogous to the amine-catalyzed decarboxylation (Scheme VII). Except for the reactive lysine, the identities of other catalytic groups at the active site are not known. 

Like PLP-dependent enzymes, pyruvate-dependent enzymes function by means of a Schiff base mechanism (Scheme XI), with an important difference ... 

Iminium ion formation often precedes decarboxylation and is essential for catalysis in many enzymes. As noted in the introduction, Shostack and Jones proposed a Schiff base mechanism for ODCase that involves iminium formation with an active-site lysine [8]. However, experiments have shown that no exchange between substrate and bulk solvent occurred when the enzymatic reaction was run in H2 0 [10]. 

The mechanism of this reaction involves an activation of the ammonia and hydrogen peroxide because these compounds do not themselves react (118—121). It appears that acetamide functions as an oxygen transfer agent, possibly as the iminoperacetic acid (41) which then oxidizes the transient Schiff base formed between MEK and ammonia (40) to give the oxaziridine (42), with regeneration of acetamide ... 

The mechanism of both syntheses has been studied in detail, and well summarized (44,45). Interesting questions remain for example, in neither of these sequences is it certain whether the carbonyl compound or its Schiff base is undergoing Michael addition. 

Oxaziridines are generally formed by the action of a peracid on a combination of a carbonyl compound and an amine, either as a Schiff base (243) or a simple mixture. Yields are between 65 and 90%. Although oxygenation of Schiff bases is formally analogous to epoxidation of alkenes, the true mechanism is still under discussion. More favored than an epoxidation-type mechanism is formation of a condensation product (244), from which an acyloxy group is displaced with formation of an O—N bond. 

Formation of mixtures of (E)- and (Z)-oxaziridines from sterically defined Schiff bases fits a two step mechanism through (244) (70CC745). 

It is interesting to note that the hydrolysis of certain Schiff bases in weakly acidic solutions shows a similar mechanism (22). N-protonated substituted benzylidene-t-butylamines react with hydroxide ions to amino alcohols in the rate-determining step, and at lower pH the rate is almost entirely determined by attack of water on the protonated Schiff bases as a consequence of the rapidly decreasing concentration of hydroxide ions. 

The mechanism is postulated to involve the initial formation of a Schiff base 17 from the condensation of the anilinic amine 16 with the carbonyl-containing substrate. This is followed by a Claisen condensation between the benzylic carbonyl and the activated a-methylene of the imine. ... 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

In 1983, Yamada et al. developed an efficient method for the racemization of amino acids using a catalytic amount of an aliphatic or an aromatic aldehyde [50]. This method has been used in the D KR of amino acids. Figure 4.25 shows the mechanism of the racemization of a carboxylic acid derivative catalyzed by pyridoxal. Racemization takes place through the formation of Schiff-base intermediates. 

The deamination of primary amines such as phenylethylamine by Escherichia coli (Cooper et al. 1992) and Klebsiella oxytoca (Flacisalihoglu et al. 1997) is carried out by an oxidase. This contains copper and topaquinone (TPQ), which is produced from tyrosine by dioxygenation. TPQ is reduced to an aminoquinol that in the form of a Cu(l) radical reacts with O2 to form H2O2, Cu(ll), and the imine. The mechanism has been elucidated (Wihnot et al. 1999), and involves formation of a Schiff base followed by hydrolysis in reactions that are formally analogous to those involved in pyridoxal-mediated transamination. 

Quite apart from the molecular structure of the channel it must also allow proton movement in only one direction and a pumping mechanism. Stoeckenius 236 has proposed an ingenious means by which the Schiff base linkage of the protein and retinal performs both these functions. 

The NMR spectra have shown the formation of Schiff base as an intermediate product in the synthesis of the fully N-deacetylated oligomers from chitosan.32 The mechanism of the Schiff base reaction leading to chain cleavage and formation of 5-hydroxymethyl-2-furfural has been proposed. 

It was first suggested that the reaction of an alkyl halide with a nickel(I) Schiff base complex yields an alkylnickel(III) intermediate (Equation (56)). Homolytic cleavage of RBr to give an alkyl radical R and a nickel(II) complex (Equation (57)) or, alternatively, one-electron dissociative reduction leading to R (Equation (58)) are possible pathways.254 A mechanism based on the formation of R via dissociative electron transfer of Ni -salen to RX (Equation (59)) has also been proposed.255... 

The synthesis of phthalimidines by dicobalt octacarbonyl-catalyzed carbonylation of Schiff bases was first described by Pritchard78 and the scope of the reaction was evaluated by Murahashi et a/.79 Later Rosenthal et al.80-83 subjected a variety of related compounds to carbonylation, and also achieved a phthalimidine synthesis directly from benzonitrile under the conditions of the oxo process.84 An example illustrating the formation of a phthalimidine is shown in Scheme 49 a comprehensive review of the scope and mechanism of reactions of this type is available.85... 

Schiff base interactions between aldehydes and amines typically are not stable enough to form irreversible linkages. These bonds may be reduced with sodium cyanoborohydride or a number of other suitable reductants (Chapter 2, Section 5) to form permanent secondary amine bonds. However, proteins crosslinked by glutaraldehyde without reduction nevertheless show stabilities unexplainable by simple Schiff base formation. The stability of such unreduced glutaraldehyde conjugates has been postulated to be due to the vinyl addition mechanism, which doesn t depend on the creation of Schiff bases. 

Glutaraldehyde is the most popular b/s-aldchydc homobifunctional crosslinker in use today. Flowever, a glance at glutaraldehyde s structure is not indicative of the complexity of its possible reaction mechanisms. Reactions with proteins and other amine-containing molecules would be expected to proceed through the formation of Schiff bases. Subsequent reduction with sodium cyanoborohydride or another suitable reductant would yield stable secondary amine... 

Certain Schiff bases, i.e. 122, were synthesized as model compounds for Latia luciferin. This compound exhibits strong blue chemiluminescence ( max 385 nm) on oxidation with oxygen in DMSO/potassium t.-butylate, the main products being acetone and 2-formamido pyridine 124. The mechanism suggested by Me Capra and Wrigglesworth includes the concerted bond cleavage of a dioxetane derivative 123. 

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