Oximes and hydrazones

The stereoselectivity of the reduction of substituted cyclohexyloximes is poor [ZHl], However, some chiral oximes have been reduced with good stereoselectivity using NaCNBH3-TiCl3 [ZHl]. 

Oximes are reduced to the corresponding hydroxylamines by BHj-THF, BH3 in CF3COOH, amine-boranes [KKl 1], NaBH4, or NaCNBH3 in AcOH in the cold. On warming, NaBH4 in organic acids leads to N-alkylhydroxylamines [GNl, MMl] 

Asymmetric reduction of ketoxime O-alkylethers to chiral primary amines can be carried out with a high enantiomeric excess by borane or better by NaBH4-ZrCl4 in THF in the presence of a chiral amino alcohol [IS2, WM2, ZHl]. 

Moreover, a-oximinoesters can be reduced to a-amino acid esters by NaCNBH3-TiCl4 in aqueous MeOH in buffered conditions. Tartaric acid is the best buffer, although no asymmetric induction is observed [HT3]. 

Usually the presence of a carbonyl group in a sample compound does not give rise to serious difficulties in GC analysis. However, sometimes it can be the reason for instability of the compounds. Owing to its polarity and strong interactions with the support, it can cause peak asymmetry and, in more complex samples, the peaks of carbonyl compounds in the chromatogram can be overlapped by those of interfering components. In these instances the carbonyl group must be converted into an inert derivative. Suitable properties of the derivatives are often utilized also for the preliminary isolation of carbonyl compounds from other components of the sample [98]. 

Direct GC analysis of hydrazones is carried out only with special derivatives, e.g., if the sensitivity of the determination is to be increased. GC retention data have been reported for phenylhydrazones [107], dinitrophenylhydrazones [108], and trichloro-phenylhydrazones [109] of different aldehydes and ketones. Particularly the last two types can be used to advantage in trace analysis using the ECD. 

If two or more functional groups which should be blocked occur in the molecule of the substrate, blocking can be accomplished with a bifunctional reagent producing a cyclic product. 

Dimethyldiacetoxysilane reacts in a similar manner to dimethyldichlorosilane. Pyridine, trimethylamine, etc., can serve as solvents [112,113]. In a similar way acetonid s [114] are prepared from diols prior to GC. 

Oakes and C.E. Willis, Amer. Ass. Clin. Chem. 24th Nat. Meet., August 20- 25, 1972, Abstr. 023, p. 25. 

To increase the stability of compounds containing a carboxyl group, to reduce the asymmetry of their chromatographic zones and, in a number of instances, to solve the problems of functional group analysis, chemical methods are used which result in the production of oximes  

Reactions of carbonyl compounds with hydroxy-, methoxy, and benzyloxyamines are usually conducted in pyridine solution. To speed up the reaction the reaction mixture is heated at 60-100°C. The solvent (pyridine) is removed by evaporation in a flow of nitrogen, the sample is dissolved in ethyl acetate and an aliquot of the solution obtained is analysed by GC. 

In a number of instances (e.g., with steroids and sugars), oximes are formed prior to the silylation reaction [201, 202]. Muriatic o-pentafluorobenzylhydroxylamine has been used successfully to protect ketosteroids and increase the sensitivity of detection [203, 204]. It should be noted that oximes (under certain conditions) are converted quantitatively into the corresponding nitriles in a column [205]. In a number of instances it is expedient to use hydrazones to increase the stability of carbonyl compounds, including that of formaldehyde [206,207] 

Derivatives of this type are formed in order to obtain volatile compounds of sufficient stability for gas chromatographic analysis. Chlorides and fluorides of volatile metals 

Volatile complexes of organic compounds of metals are, however, used more widely in GC analysis [45, 46, 211]. The main adwmti e of the GC analysis of volatile compounds of metals is the possibility of analysing trace amounts of metals with the use of ECDs and microwave emission detectors. When detectors of this type were used, GC methods were compared with such methods as neutron-activation analysis and atomic-absorption spectroscopy. The field of apphcation for this method is indicated in Table 1.5, illustrating the analysis of trace amounts of elements in the form of volatile complexes and compiled from data pubUshed in the literature. 

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Semisynthetic proteins can involve the combination of a synthetic with a biosynthetic portion by either noncovalent or covalent bonds. Among covalent bonds, there are available for use disulfide bonds, peptide bonds, and other, completely unnatural, bonds such as oximes and hydrazones. 

Lanthanide shift reagents have been used to differentiate diastereomeric oximes, dinitrophenyl-hydrazones 304,305, and nitrones 306. A collision complex model to rationalize aromatic solvent induced shifts in the spectra of oximes and hydrazones has been developed305,307. 

Pyran-4-ones and their monobenzo derivatives are easily attacked and degraded by nucleophiles of all kinds. Because of the ease with which such rings are opened, it is often difficult to prepare oximes and hydrazones in the usual way. 

The reaction of N-containing nucleophiles such as hydroxylamine, hydrazine and its derivatives, with pyran-4-ones and their benzo derivatives has been studied intensively. The early workers assumed that oximes and hydrazones were formed in these reactions, but it was later realized that under normal conditions the pyrans rarely yield the expected derivatives because of the susceptibility of the hetero ring to the nucleophile. This is especially true when the pH of the medium is above 7 those reactions which proceed under acidic conditions usually lead to the expected derivative (77T3183). 

Lithium salts of ketone derivatives such as imines, oximes and hydrazones have also been used for directed aldol reactions (Scheme 103).374 375 A recent example involves triple coordination of lithium in a very rigid transition state, to lead to regiospecificity in the product (Scheme 104).376... 

III. COMPOUNDS CONTAINING C=N DOUBLE BONDS A. Imines, Oximes and Hydrazones... 

Heterogeneous hydrogenation of the C=N bond is a very widely used synthetic process with application to small and large-scale reactions. Many of the catalysts described in other sections may also be employed, for example those based on supported rhodium, palladium etc, and Raney Nickel. This area has been reviewed extensively recently192. Hydrogenation of oximes and hydrazones results in formation of amines. Milder conditions can be used for oxime reduction if the ethylaminocarbonyl derivative is prepared in situ prior to reduction276. 

The C=N bonds of imines, oximes and hydrazones can be hydrogenated to form the corresponding amines even under ambient conditions on Pt, Pd, Rh and Raney Ni catalysts in acidic, neutral or basic media (equation 42). The imines, furthermore, are intermediates in the hydrogenation of nitro compounds, nitriles and oximes, and likewise play a key role as intermediates in the reductive amination of carbonyl compounds. 

Pyrans-4-ones and their monobenzo derivatives are easily attacked by nucleophiles via 1,4-conjugate additions which result in subsequent ring opening. Reactivity of this type makes it difficult to convert the carbonyl groups to acetals, oximes, and hydrazones by conventional methods. Since their reactivity toward nucleophiles provides a useful route for the preparation of a variety of rearranged products and new heterocyclic systems, their versatility as reactive intermediates is well documented. 

An exceptionally high influence of the C-substituent at the C=N bond on the cyclization direction has been observed (89KGS927) in a large series of derivatives 80. In the solid state and in solution in several solvents, these compounds exist solely as the isomer 80B. Independently of the mutual disposition of the oxime and hydrazone moieties—i.e., for either X = NCOR, Y = O or for X = O, Y = NCOR and for X = Y = NCOPh—the intramolecular cyclization proceeds only along the path involving nucleophilic XH or YH group addition to the more reactive and less hindered aldoxime or aldohydrazone C=N bond. However, in the gas phase, the presence of small amounts of the isomers 80A and 80B was detected. 

The formation of oximes and hydrazones can be used to modify proteins due to some attractive properties, that is, some stability in aqueous media and compatibility with many functionalities of proteins [134], Their synthesis can be accomplished through the nucleophilic addition-elimination (condensation) of hydrazines and alkoxyamines with aldehydes and ketones, respectively. Typically, it has been used to modify the N-terminus [135-137] of peptides and proteins. For example, oxime formation has been used to modify BSA and diphtheria toxin with Shigella sonnei O-specific oligosaccharides [138],... 

Although there is ample evidence for nucleophilic additions to benzyne la> and some other unstable angle strained cycloalkyne intermediates 15,27,31,205 207), only a few addition reactions to isolable angle strained cycloalkynes are known which can be classified as nucleophilic. Hydroxylamine and hydrazine add to (31) to yield the corresponding oxime and hydrazone, resp. 208). 

As oximes and hydrazones are not good electron acceptors, the mechanism for these reactions most likely involves an intermediate ketyl radical anion, which adds to the C=N double bond. A three-electron-two-orbital interaction involving the nitrogen-centred radical with the lone pair of the adjacent... 

Interestingly, cyclisation of the ketone-nitrone 19 and concurrent N-O bond reduction with excess Sml2 provided exclusively the m-amino alcohol, thereby complementing similar cyclisation reactions with oximes and hydrazones that typically give trans products (Scheme 5.14).33 An alternative mechanism was... 

In the classic carbohydrate chemistry addition reactions of carbonyl groups served as valuable tools for sturctural studies of carbohydrates. For example, hydroxyl amine, hydrazine, and phenyl hydrazine react with carbonyl groups to yield oximes and hydrazones. In the presence of an excess... 

Why are oximes and hydrazones less electrophilic than other imines ... 

Functional groups containing the C = N bond, such as hydrazones, oximes and diazo compounds, can also be used in the synthesis of fluorinated derivatives and these reactions are the subject of this section. The reaction products in these procedures are usually the corresponding g cw-difluoromethylene compounds. Since oximes and hydrazones arc obtained from aldehydes and ketones, these reactions can be considered as an alternative to the direct transformation of a carbonyl group into the difluoromethylene group. As indicated in Section... 

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