Product Schiff-Base

Product Schiff-Base. Conversion of the substrate Schiff-base to product Schiff-base involves removal of a hydrogen from the a-carbon of the substrate. This chemically-difficult step is achieved in the enzyme by a base catalysed abstraction of a proton and shows interesting stereochemical variation amongst amine oxidases from different sources (Seaman and Palcic, 1992 Coleman et al., 1989, 1991 Shah et al., 1993). When benzylamine is the substrate, it is always the pro-S hydrogen which is removed but when tyramine or dopamine are the substrates, removal of hydrogen from C-1 can be pro-S, pro-R or random depending upon the source of the amine oxidase (see Table 3). 

There is a correlation between this proton abstraction stereochemistry and exchange of the hydrogens at C-2 of tyramine or dopamine substrates. Thus the pro-S specific amine oxidases do not catalyse exchange at C-2 whereas the pro-R speeifie and non-specific amine oxidases catalyse this exchange. 

FIGURE 13. Species identified in the reaction cycle of copper amine oxidases. Oxidised, resting state enzyme (1) reacts with substrate to form a substrate Schiff base (2). Proton abstraction by the active site base (Asp383 in ECAO) leads, via a carbanion intermediate (3) to the product Schiff base (4). Hydrolysis releases the product aldehyde, leaving reduced cofactor in equilibrium between aminoquinol/Cu (S) and semiquinone/Cu (6). The reduced cofactor is reoxidised by molecular oxygen, releasing ammonium ions and hydrogen peroxide. (Modified from Wilmot et al., 1999 with permission). 

Stereochemistry of proton abstraction at C-1 Tyramine and Solvent Exchange Characteristics at C-2 Catalyzed by Semicarbazide-Sensitive and Copper Amine 

Enzyme source C-1 proton abstraction C-2 solvent exchange Ref. 

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TPO (Productive conformation) Substrate Schiff base Product Schiff base Aminoquinol... 

The transition state leads to the product Schiff-base where the TPQ ring has been aromatised. The TPQ ring is effectively mediating proton transfer from substrate. This will be discussed further in the section on the Qxidative Half Cycle below. 

I.3. Reduced Forms of the Enzyme. The hydrolysis of the product Schiff-base to release product and generate the aminoquinol form of the cofactor may involve water which has been retained in the active site. Dooley and co-workers have provided direct evidence for copper reduction during the interaction of amine oxidases with substrate under anaerobic conditions (Dooley et al., 1991). By varying the temperature at which EPR spectra were recorded, it was shown for amine oxidases from several sources that there is a temperature dependent equilibrium between Cu V aminoquinol TPQ and Cu / TPQ semiquinone. The Cu / TPQ semi-quinone form was found to be stabilised in the presence of cyanide. The... 

The crystal stmctures of snbstrate-rednced amine oxidases have been solved, along with site-directed mutants, metal-snbstitnted forms, enzyme complexes with inhibitors, the Oi mimic nitric oxide (NQ) and peroxide. These have been correlated with a wealth of biochemical and spectroscopic data that form the basis for the catalytic mechanism proposed in Scheme 8. A Schiffbase complex species (b) is formed between snbstrate amine and TPQ C-5. Base-catalyzed proton abstraction from substrate a-methylene group, via the conserved active-site aspartate residue, yields the reduced cofactor in a product Schiff-base complex, species (c). Hydrolysis releases product aldehyde, leaving the cofactor in the reduced aminoquinol form, species (d). 

The product Schiff base is cleaved at the completion of the reaction. 

In the first step, the triphenylphosphine reacts with an alkyl azide to form an iminophosphorane with loss of nitrogen Staudinger reaction). In the second step, the nucleophilic nitrogen of the iminophosphorane attacks the carbonyl group to form a four-membered intermediate (oxazaphosphetane) from which the product Schiff base and the byproduct triphenylphosphine oxide are released. 

Obviously, the enantiomeric excess of the product Schiff base is increased if... 

U.S. production 1978 275000 tonnes, anils, A-phenylimides See Schiffs bases. 

The 2-metalated thiazoles react with a variety of electrophilic substrates in a standard way, leading to addition products with aldehydes, ketones, carbon dioxide, epoxides, nitriles, Schiff bases, and to substitution products with alkyl iodides (12, 13, 437, 440). 

Analogously, aldehydes react with ammonia [7664-41-7] or primary amines to form Schiff bases. Subsequent reduction produces a new amine. The addition of hydrogen cyanide [74-90-8] sodium bisulfite [7631-90-5] amines, alcohols, or thiols to the carbonyl group usually requires the presence of a catalyst to assist in reaching the desired equilibrium product. 

Liquid Fabric Softeners. The principal functions of fabric softeners are to minimize the problem of static electricity and to keep fabrics soft (see Antistatic agents). In these laundry additives, the fragrance must reinforce the sense of softness that is the desired result of their use. Most fabric softeners have a pH of about 3.5, which limits the materials that can be used in the fragrances. For example, acetals cannot be used because they break down and cause malodor problems in addition, there is the likelihood of discoloration from Schiff bases, oakmoss extracts, and some specialty chemicals. Testing of fragrance materials in product bases should take place under accelerated aging conditions (eg, 40°C in plastic bottles) to check for odor stabiUty and discoloration. 

Primary aromatic amines react with aldehydes to form Schiff bases. Schiff bases formed from the reaction of lower aUphatic aldehydes, such as formaldehyde and acetaldehyde, with primary aromatic amines are often unstable and polymerize readily. Aniline reacts with formaldehyde in aqueous acid solutions to yield mixtures of a crystalline trimer of the Schiff base, methylenedianilines, and polymers. Reaction of aniline hydrochloride and formaldehyde also yields polymeric products and under certain conditions, the predominant product is 4,4 -methylenedianiline [101 -77-9] (26), an important intermediate for 4,4 -methylenebis(phenyhsocyanate) [101-68-8], or MDI (see Amines, aromatic amines, l thylenedianiline). 

Pomeranz-Fntsch Synthesis, Isoquinolines aie available fiom the cycUzation of benzalamiaoacetals undei acidic conditions (165). The cyclization is preceded by the formation of the Schiff base (33). Although the yields ate modest, polyphosphoric acid produces product in all cases, and is especially useful for 8-substituted isoquinolines (166). 

Benzylarnine, [100-46-9] CgH CH2NH2 (bp, 184°C at 101.3 kPa) produced by reaction of ammonia with benzaldehyde and hydrogenation of the resulting Schiffs base, is used as the raw material for the production of biotin (Vitamin H), as an intermediate for certain photographic materials, and as an intermediate in the manufacture of certain pharmaceutical products. 

Dibenzjiamine, [103-49-17, CgH CH2NHCH2CgH (bp, 300°C at 101.3 kPa) is produced by reaction of benzyl amine with benzaldehyde and hydrogenation of the Schiffs base. It is used in mbber and tire compounding, as a corrosion inhibitor, and as an intermediate in the production of mbber compounds and pharmaceutical products. 

Aldehydes. Alkyleneamines react exothermically with ahphatic aldehydes. The products depend on stoichiometry, reaction conditions, and stmcture of the alkyleneamine. Reactions of aldehydes with ethyleneamines like EDA or DETA give mono- and disubstituted imidazohdines via cyclization of the intermediate Schiff base (20). 

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. 

The parent compound, cyclic diazomethane , was first obtained from formaldehyde, ammonia and chloramine by dichromate oxidation of the initially formed higher molecular diaziridine-formaldehyde condensation product (61TL612). Further syntheses of (44) started from Schiff bases of formaldehyde, which were treated with either difluoramine or dichloramine to give (44) in a one-pot procedure. Dealkylation of nitrogen in the transient diaziridine was involved (65JOC2108). 

Tnfluoromethyl hypofluonte will fluorinate Schiff bases, giving N,a,a-tn-fluoroatmnes and a-fluoroimines [144] and reacts with diazoketones to give adducts in modest yields [145] (equation 6) At-Substituted aziridines give nng opened products by 1,3 addition of fluonne on nitrogen and trifluoromethoxy on carbon [146] (equation 7)... 

Definitive identification of lysine as the modified active-site residue has come from radioisotope-labeling studies. NaBH4 reduction of the aldolase Schiff base intermediate formed from C-labeled dihydroxyacetone-P yields an enzyme covalently labeled with C. Acid hydrolysis of the inactivated enzyme liberates a novel C-labeled amino acid, N -dihydroxypropyl-L-lysine. This is the product anticipated from reduction of the Schiff base formed between a lysine residue and the C-labeled dihydroxy-acetone-P. (The phosphate group is lost during acid hydrolysis of the inactivated enzyme.) The use of C labeling in a case such as this facilitates the separation and identification of the telltale amino acid. 

The transaldolase functions primarily to make a useful glycolytic substrate from the sedoheptulose-7-phosphate produced by the first transketolase reaction. This reaction (Figure 23.35) is quite similar to the aldolase reaction of glycolysis, involving formation of a Schiff base intermediate between the sedohep-tulose-7-phosphate and an active-site lysine residue (Figure 23.36). Elimination of the erythrose-4-phosphate product leaves an enamine of dihydroxyacetone, which remains stable at the active site (without imine hydrolysis) until the other substrate comes into position. Attack of the enamine carbanion at the carbonyl carbon of glyceraldehyde-3-phosphate is followed by hydrolysis of the Schiff base (imine) to yield the product fructose-6-phosphate. 

Elimination of the hydroxyaminomethyl moiety from nitro oxime 15 by treatment with a diazonium salt gave hydrazone 43 (75LA1029) (Scheme 15). The same product was obtained by coupling the diazonium salt with the compound 16. On heating in aniline, oxime 15 was transformed into Schiff base 42. Acylation of the oxime 15 with benzoyl chloride in pyridine led to a mixture of furazan 44 and dinitrile 45. 

The mechanistic pathway of the ordinary Friedlander synthesis is not rigorously known. Two steps are formulated. In a first step a condensation reaction, catalyzed by acid or base, takes place, that can lead to formation of two different types of products (a) an imine (Schiff base) 4, or (b) an o ,/3-unsaturated carbonyl compound 5 ... 

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

A mixture of 1.4 g (10 mmol) of 4-chlorobenzaldehyde and 0.71 g (5 mol %) of the chiral polymer E is stirred in 10 mL of dry toluene for 15 h, under a dry nitrogen atmosphere, to form the Schiff base. After cooling to 0lC, 15 mL (15 mmol) of 1 M diethyl/inc in hexane is added and the mixture is stirred for a further 24 h at O C. 1 N HC1 is then added dropwise at O C, and the chiral polymer is removed by filtration. The polymer is washed several times with 11,0 and Et,0. The aqueous layer is separated and extracted with Et20. The combined organic layer is dried over MgS04 and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, CHC1,) yield 1.61 g (95 %) 99 % ee [a]2,0 —23.9 (r = 4.93, benzene). 

Phthalide enolates 4 add to Schiff bases to produce intermediate adducts 5 which cyclize to mixtures of cis- and Rcws-isoquinolones 6 and 724. The er.y-product predominates consistently by — 2 1 over a series of nonenolizable arylintines. 

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