3- Pyridinecarbaldehyde

Most of them are generally classified as poisons. Exceptions to this rule are known. A notable one is 4-dimethyl aminopyridine (DMAP) (24), which is widely used in industry as a superior acylation catalyst (27). Quaternary salts of pyridines are usually toxic, and in particular paraquat (20) exposure can have fatal consequences. Some chloropyridines, especially polychlorinated ones, should be handled with extra care because of their potential mutagenic effects. Vinylpyridines are corrosive to the skin, and can act as a sensitizer for some susceptible individuals. Niacin (27), niacinamide (26), and some pyridinecarbaldehydes can cause skin flushing. 

Pyridinecarbaldehydes. Pialidoxime iodide [51-15-0] (108), a derivative of 2-pyridinecaibaldehyde (109), is used as an antidote against... 

In 1965, Breslow and Chipman discovered that zinc or nickel ion complexes of (E)-2-pyridinecarbaldehyde oxime (5) are remarkably active catalyst for the hydrolysis of 8-acetoxyquinoline 5-sulfonate l2). Some years later, Sigman and Jorgensen showed that the zinc ion complex of N-(2-hydroxyethyl)ethylenediamine (3) is very active in the transesterification from p-nitrophenyl picolinate (7)13). In the latter case, noteworthy is a change of the reaction mode at the aminolysis in the absence of zinc ion to the alcoholysis in the presence of zinc ion. Thus, the zinc ion in the complex greatly enhances the nucleophilic activity of the hydroxy group of 3. In search for more powerful complexes for the release of p-nitrophenol from 7, we examined the activities of the metal ion complexes of ligand 2-72 14,15). 

A subclass of lyases, involved in amino acid metabolism, utilizes pyridoxal 5-phosphate (PLP, 3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4-pyridinecarbaldehyde) as a cofactor for imine/ enamine-type activation. These enzymes are not only an alternative to standard fermentation technology, but also offer a potential entry to nonnatural amino acids. Serine hydroxymethyl-tansferase (SHMT EC 2.1.2.1.) combines glycine as the donor with (tetrahydrofolate activated) formaldehyde to L-serine in an economic yield40, but will also accept a range of other aldehydes to provide /i-hydroxy-a-amino acids with a high degree of both absolute and relative stereochemical control in favor of the L-erythro isomers41. 

Pyridylidenehydantoins such as 139, obtained from pyridinecarbaldehydes by Horner-Wadsworth-Emmons reactions, are cyclized under acidic conditions to tricycles of the type 140 (Scheme 39) <2004TL553>. Similar benzannulated ring systems can be prepared by the reaction of 2-benzimidazolylacetonitriles and, for example, 2-chloronicotinic esters or 2-chloronicotinamides under basic conditions (Equation 32) <1996JHC1147, 1997JHC397>. 

Iron(II) systems based on hexadentate ligands where all the donor functions are imines will generally be low-spin. One well-known example is the Schiff base ligand obtained by condensing tren with 2-pyridinecarbaldehyde (22). 

Pyridinecarbaldehydes, uses for, 22 126 Pyridinecarbonitriles, uses for, 22 123-124 Pyridinecarboxamide, 22 123—124 Pyridinecarboxylic acids, 22 123-124 Pyridine chemicals, 22 124 Pyridine-chromic acid adduct... 

Pd and Cu ion containing zeolites catalyze the vapor phase oxidation of methylpyridines [129]. Thus, on PdCuNa-mordenite, 2-methylpyridine was oxidized to 2-pyridinecarbaldehyde with 40% yield. The reduced reactivity ratio of 2,6-dimethylpyridines to monomethylpyridines on zeolite catalysts compared to oxide catalysts, demonstrates the presence of steric control in these reactions. 

Ozonolysis of alkenylpyridines gives pyridinecarbaldehydes (61JOC4912) and the latter also result from oxidation of 2- and 4-methylpyridines with iodine and dimethyl sulfoxide (70JOC841) or with selenium dioxide, although this last method also gives pyridinecarboxylic acids (69MI20600, 69MI20602). 

The first synthesis of the benzo[6]quinolizinium ion (Scheme 98, Table 9, example 1) was by hydrobromic acid-catalyzed cyclization of the quaternary salt formed between 2-pyridinecarbaldehyde and benzyl bromide. Aromatic cyclodehydration has continued to the present as almost the only method used for the preparation of the acridizinium ion, its derivatives and benzo analogs. Because of its instability, 2-pyridinecarboxaldehyde has been replaced by more efficient derivatives. The first of these was the oxime (example 2) which not only gave a better overall yield, but also made possible the isolation of a crystalline intermediate (181 Z = NOH). The disadvantages are that it is not suitable for high temperature cyclizations involving polyphosphoric acid, and some products (182) (e.g. example 10, Table 10) may tend to form double salts with hydroxylamine hydrobromide. 

The most advantageous 2-pyridinecarbaldehyde derivative proved to be the acetal (example 3, Table 9) although, unlike the oxime, it was not commercially available. The acetal also usually afforded crystalline intermediate salts (181 Z = 0(CH2)20), but in addition made possible for the first time high temperature cyclization in PPA, permitting cyclization to rings deactivated by a nitro (example 25) or sulfo group (example 24). 

The quaternization of 2-pyridinecarbaldehyde with 2,3,6-trimethoxy-9-phenanthryl-methyl bromide (183) yielded a salt (184) which, when cyclized, afforded a dibenz[/i,/]acridizinium derivative (185). Reduction of the quinolizinium ring of (185) afforded ( )-cryptopleurine (57JA3287). 

Acylative cyclization of the readily available 2-pyridinecarbaldehyde with an a,/ -unsaturated carbonyl compound provides a new and convenient route to l-acylcycl[3,2,2]azines [Eq. (7)]. A mechanism for this interesting reaction has been suggested.43... 

Metal complexes of the 1,4-diaza-1,3-butadiene ligands [RN=C(R )C(R")=NR = R-DAB R, R" ] have recently been surveyed by van Koten and Vrieze.111,112 Therefore we will refer extensively to these reviews and to some key references and we will discuss here the main points and new results. The discussion will be restricted to the above ligands, with passing mention of complexes of 2-pyridinecarbaldehyde-JV-imines, which are discussed in Chapter 13.2. 

Calculations indicate that the planar s-trans conformation is 20-28 kJ mol 1 more stable than the s-cis form owing mainly to the interaction of the lone pairs.112 Furthermore, it appears that the rc-acceptor properties of the N=C—C=N skeleton increase in the sequence 2,2 -bipyridine < 2-pyridinecarbaldehyde-iV-methylimine < R-DAB.116... 

Carbonic anhydrase is a zinc(II) metalloenzyme which catalyzes the hydration and dehydration of carbon dioxide, C02+H20 H+ + HC03. 25 As a result there has been considerable interest in the metal ion-promoted hydration of carbonyl substrates as potential model systems for the enzyme. For example, Pocker and Meany519 studied the reversible hydration of 2- and 4-pyridinecarbaldehyde by carbonic anhydrase, zinc(II), cobalt(II), H20 and OH. The catalytic efficiency of bovine carbonic anhydrase is ca. 108 times greater than that of water for hydration of both 2- and 4-pyridinecarbaldehydes. Zinc(II) and cobalt(II) are ca. 107 times more effective than water for the hydration of 2-pyridinecarbaldehyde, but are much less effective with 4-pyridinecarbaldehyde. Presumably in the case of 2-pyridinecarbaldehyde complexes of type (166) are formed in solution. Polarization of the carbonyl group by the metal ion assists nucleophilic attack by water or hydroxide ion. Further studies of this reaction have been made,520,521 but the mechanistic details of the catalysis are unclear. Metal-bound nucleophiles (M—OH or M—OH2) could, for example, be involved in the catalysis. 

The interaction of 2-pyridinecarbaldehyde with Cu(II) has been studied by potentiometric and spectrophotometric methods,522 and formation constants have been determined. The neutral deprotonated complex (167) was characterized in the solid state. 

The NAD+-dependent alcohol dehydrogenase from horse liver contains one catalytically essential zinc ion at each of its two active sites. An essential feature of the enzymic catalysis appears to involve direct coordination of the enzyme-bound zinc by the carbonyl and hydroxyl groups of the aldehyde and alcohol substrates. Polarization of the carbonyl group by the metal ion should assist nucleophilic attack by hydride ion. A number of studies have confirmed this view. Zinc(II) catalyzes the reduction of l,10-phenanthroline-2-carbaldehyde by lV-propyl-l,4-dihy-dronicotinamide in acetonitrile,526 and provides an interesting model reaction for alcohol dehydrogenase (Scheme 45). The model reaction proceeds by direct hydrogen transfer and is absolutely dependent on the presence of zinc(II). The zinc(II) ion also catalyzes the reduction of 2- and 4-pyridinecarbaldehyde by Et4N BH4-.526 The zinc complex of the 2-aldehyde is reduced at least 7 x 105 times faster than the free aldehyde, whereas the zinc complex of the 4-aldehyde is reduced only 102 times faster than the free aldehyde. A direct interaction of zinc(II) with the carbonyl function is clearly required for marked catalytic effects to be observed. 

The effect of charge on the cation is important, and is clearly seen in the hydration of 4-pyridinecarbaldehyde, 3.9. In aqueous solution the free ligand is only partially hydrated, and at equilibrium the ratio of the carbonyl form to the hydrate is about 55 45 (Fig. 3-18). Upon co-ordination of the nitrogen atom of the pyridine to ruthenium(in) in the complex [Ru(NH3)5(3.7)]3+, the ligand is over 90 % hydrated at equilibrium. 

A direct metal involvement in the hydration of an aldehyde is seen in the ruthenium(n) complex of the hydrated form of 2-pyridinecarbaldehyde (3.10). 

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