Schiff base formation Chapter

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. 

The Pomeranz-Fritsch synthesis [Eqs. (1) and (2)]1 is the only isoquinoline synthesis involving a simple two-step sequence from common starting materials. Furthermore, it is one of the few methods which can be used to prepare isoquinolines substituted in the 7- and 8-positions. The first step, Schiff base formation [Eq. (1)], takes place readily, but the ring closure [Eq. (2)] is difficult. The yields vary markedly with the concentration of H2S04 and are generally low. Frequently the reaction fails completely. Most of the work described in this chapter was undertaken to circumvent these problems and to realize the potential promise of the synthesis. 

The reaction mechanism consists of Schiff base formation by the keto group of one molecule of ALA with the e-amino group of a lysyl residue of the enzyme, followed by nucleophilic attack by the enzyme-ALA anion on the carbonyl group of a second ALA molecule with elimination of water. Then, a proton is transferred from the amino group of the second ALA molecule to the e-amino group of the lysyl residue with formation of PBG. Lead is a potent inhibitor of ALA dehydratase, presumably by displacement of zinc by lead because the lead-inhibited enzyme can be reactivated by the addition of zinc. ALA dehydratase is inhibited competitively by suc-cinyl acetone (HOOC-CH2-CH2-CO-CH2-CO-CH3), which occurs in urine and blood in hereditary tyrosinemia (Chapter 17). Genetic deficiency of ALA dehydratase is known to occur. 

These peraza-crown syntheses will have increasing applications as methods to remove the metal template are discovered. More practical applications to form the benzoperaza-crowns (peraza-cyclophanes) via Schiff base formation will be discussed in Chapter XL... 

The coloured p-nitro- and 2,4-dinitrophenylhydrazones are ideal derivatives for the separation and characterization of carbonyls by paper, thin-layer and column chromatography. The oximes can easily be revealed on the thin-layer plates by spraying with solutions of copper(Il) chloride or copper(II) acetate (alcoholic) or iron(III) chloride [21,22]. For the visualization of carbonyl compounds by means of fluorogenic labeling by Schiff base formation with reagents such as dansyl-hydrazine, we refer the reader to Chapter 9. 

The approximately 80 known pyrrolidine alkaloids possess a 5-membered nitrogen-containing ring (Massiot and Delaude, 1986 Binder, 1993). Several subgroups of pyrrolidine alkaloids arise by condensation of these units with other molecules, Pyrrolidine bases usually are modified by additional Schiff-base formation, Mannich condensation, and aldol-type processes to yield other alkaloids of tiiis general class. For example, condensation of pyrrolidine derivatives with nicotinic acid is involved in the formation of pyridine alkaloids such as nicotine see Chapter 28). Pyrrolidine units react with acetyl- or malonyl-CoA and condense via a Mannich condensation to form compounds such as hygrine and cuscohygrine and tropane alkaloids see below). 

Indole alkaloids are derived mechanistically in a manner similar to that discussed for ipecacuanha alkaloids in Chapter 32. Schiff-base formation occurs between a carbonyl compound and an amine, but in this case, the amine is tryptamine (1) (instead of 3,4-dihydroxyphenylethyl amine), and the carbonyl-containing terpenoid unit is secologanin (2). The stereochemistry of the condensation products is identical to that of the ipecacuanha alkaloid series. The initial product of the condensation of secologanin (2) and tryptamine (1) in most, if not all, plants that produce monoterpenoid indole alkaloids is strictosidine (3) (Fig. 34.1) (formerly known as isovincoside). 

Complex mixtures are produced by non-enzymatic browning reactions between thermally oxidized lipids and amines, amino acids and proteins (see Chapter 11.B.4). Interactions between aldehydes, epoxides, hydroxy ketones, and dicarbonyls with proteins cause browning that has been related with losses of lysine, histidine, and methionine. Schiff base formation results in polymerization to form brown macromolecules. Interactions between epoxyalkenals formed at elevated temperatures and reactive groups of proteins produce protein pyrroles polymers and volatile heterocyclic compounds. Much of the published research in this complex chemical area was based on model systems. More stmctural information is needed however with real foods subjected to frying conditions. 

One reaction type that merits special consideration is the acylation of amino acids. Other reactions of the amino acids are biologically important. For example, it will be seen later that it is Schiff base formation of the amino function with an aldehyde that provides the basis for all reactions with vitamin (see Chapter 7). However, it is acylation of the amino function of one amino acid with the carboxyl (activated) of another amino acid that leads to formation of the peptide bond and subsequent protein, or polymer formation. It then becomes of interest for the bioorganic chemist to consider and compare the synthesis of the most complex macromolecule in the test tube and the organism. 

Aldehyde-containing macromolecules will react spontaneously with hydrazide compounds to form hydrazone linkages. The hydrazone bond is a form of Schiff base that is more stable than the Schiff base formed from the interaction of an aldehyde and an amine. The hydrazone, however, may be reduced and further stabilized by the same reductants utilized for reductive amination purposes (Chapter 3, Section 4.8). The addition of sodium cyanoborohydride to a hydrazide-aldehyde reaction drives the equilibrium toward formation of a stable covalent complex. Mallia (1992) found that adipic acid dihydrazide derivatization of periodate-oxidized dextran (containing multiple formyl functionalities) proceeds with much greater yield when sodium cyanoborohydride is present. 

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