Aldoximes isomers

We will look at three pairs of syn and anti aldoxime isomers, 9A and 9B, corresponding to R = CH3 (acetaldoxime), R = CH2CI (chloroacetaldoxime) and R = CgH5 (benzal-doxime). We will also consider the two isomeric forms lOA and lOB of acetophenone oxime, a ketoxime in which R = CH3 and R" = CeHs. 

FIGURE 2. Structures of the four 2-pyridyl aldoxime isomers in Table 2, shown from top to bottom in order of increasing stability. The black atom in each ring is the nitrogen the small white atoms are hydrogens. (Figure 2 is continued on the next page.)... 

The N resonances of the Z aldoximes 31a-43a (Table 6) differ in being downfield of those for the corresponding E isomers 31b-43b and of formaldoxime 30. The differences between the aldoxime isomer pairs decrease from 4.3 to about 0 ppm as branching increases at the p carbon. In general, N shifts of E isomers are relatively insensitive to the bulk of R and remain approximately the same throughout a series, whereas the shifts of the Z isomers move upheld as the steric interaction between R and the OH group increases as a result of introduction of bulkier R groups. 

OH elimination from ortho substituted aldoximes 179 (X = CH2, NH, O) may be at least partially the result of a hydrogen migration/cyclization/elimination process, whereby the heterocycles 182 are formed72 (46). A metastable peak shape analysis, the investigation of 2H-labelled derivatives and the study of positional isomers indicate that in addition to 182 the protonated isocyanide 183 is formed via a mechanism which is not fully understood. However, it is known that the generation of 183 occurs without any detectable interaction with the XH ortho substituent. 

Then again, many elimination reactions are found to occur much, more readily in that member of a pair of geometrical isomerides in which the atoms or groups to be eliminated are trans to each other than in the isomer in which they are cis (p. 255). As is seen in the relative ease of elimination from and and syn aldoxime acetates to yield the same cyanide ... 

The Ponzio reaction provides a useful route to gem-dinitro compounds and involves treating oximes with a solution of nitrogen dioxide or its dimer in diethyl ether or a chlorinated solvent. The Ponzio reaction works best for aromatic oximes where the synthesis of many substituted aryldinitromethanes have been reported. Compound (56), an isomer of TNT, is formed from the reaction of dinitrogen tetroxide with the oxime of benzaldehyde (55) followed by mononitration of the aromatic ring with mixed acid. Yields are usually much lower for aliphatic aldoximes and ketoximes. " The parent carbonyl compound of the oxime is usually the major by-product in these reactions. 

The restricted rotation around the C=N double bond in oximes (2) gives rise to two possible isomers, 9A and 9B for aldoximes and lOA and lOB for ketoximes. For aldoximes, these are labeled syn (9A) and anti (9B). 

In Table 2 are listed the hydroxylamines, oximes and hydroxamic acids for which we have determined the gas phase structures. We tried to select a representative group in each category. There are two types of oximes, as indicated, aldoximes and ketoximes. Due to restricted rotation around the C=N double bond, these can exist in two isomeric forms (except when R = H for an aldoxime and R = R" for a ketoxime). We have investigated both isomers in nearly every instance. For aldoximes, they are generally labeled syn when the H and OH are on the same side of the double bond and anti when on opposite sides. Note that the ketoximes in Table 2 contain one pair of isomers in which the >C=NOH group is not bonded to two carbons instead one bond is to a chlorine. One of these isomers wiU be of interest in Section B.D in the context of hydrogen bonding vi lone pair—lone pair repulsion. 

The term oxime dates to the 19th century, a combination of the words oxygen and imide. Oximes exist as two stereoisomers syn (Z) and anti (E). Aldoximes, except for aromatic aldoximes, exist for the most part as the syn isomer, while ketoximes are obtained as both syn and anti isomers, which can be separated almost completely. Recently, Kolandaivel and Senthilkumar have studied the molecular structure and conformational stability of anti and syn conformers of some aliphatic aldoximes by employing the ab initio and density funetional theory (DFT) methods. 

The formation of a very electrophilic intermediate 258 from 256 and 257 is proposed (equation 78). The hydroxyl group of the oxime adds to 259, giving a reactive cationic species 260 that rearranges and affords the nitrile 261 (in the case of aldoxime, equation 79), or the amide 262 upon hydrolytic workup (equation 80). The conversion of 260 to the nitrilium ion should occur through a concerted [1,2]-intramolecular shift. This procedure can be applied in the conversion of aldoximes to nitriles. It was observed that the stereochemistry of the ketoximes has little effect on the reaction, this fact being explained by the E-Z isomerization of the oxime isomers under the reaction conditions. 

The discovery of a Bacillus sp. strain capable of degrading aldoximes via their conversion to nitriles prompted the isolation and purification of an enzyme capable of producing the syn geometrical isomer of phenylacetaldoxime from A-hydroxy-L-phenylalanine, suggesting that amino acid-derived aldoximes are biosynthesized and metabolized in microorganisms like in plants ". 

For example, the anti (25) and syn (4-hydroxyphenyl)acetaldoximes, 26, are established intermediates in the biosynthesis of the cyanogenic glucoside of sorghum, dhurrin, 27, and the biochemical pathway for its production in the plant was shown to originate in the A -hydroxylation of tyrosine, in the presence of NADPH/O2, as outlined in equation 15". It was further suggested that the Z (syn) isomer, 26, is utilized preferentially over E(anti )-25 in the subsequent biosynthesis of dhurrin, 27. The same authors provided evidence that the biosynthesis of the aldoxime, 25, proceeds via an aci-nitro containing intermediate, R R C=N(0)0H, that is positioned between Af-hydroxytyrosine and anti-25 in the biosynthetic pathway . 

At that time, however, these reactions were not brought to the level of preparative synthesis of nitriles. The main obstacle seemed to be further transformation of the nitriles to acids. In some cases, upon treating al-doximes with alkalies, it was not at all possible to fix nitriles since they immediately converted to acids. The anti(E)-isomers exhibit an enhanced reactivity in these cases. Thus, when boiled in 2 N NaOH, -aldoximes are slowly converted to a mixture of the corresponding carboxylic acids and sy/i(Z)-aldoximes to evolve ammonia (36JA1227). Under these conditions for 4 hr the - and Z-benzaldoximes undergo 13 and 48% conversion to form benzoic acid in 10 and 38% yield, respectively. Analogously, the -and Z-oximes of furfural, under the same conditions for 1.5 hr, are converted to furan-2-carboxylic acid in 33 and 62% conversion and 18 and 49% yield, respectively. 

Under the same conditions, aldoximes (E- and Z-isomers), along with the formation of diadduct 144, are sometimes dehydrated to nitriles, ethyl acetate being the second reaction product. This is explained (60RTC888) by decomposition of the intermediate O-vinyloxime 145 (Scheme 71) which, however, has never been isolated. 

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. 

To ascertain the structure of the above aldoximes, various substituted pyridazine A-oxides have been treated with amyl nitrite and sodium amide in liquid ammonia. The products were the unstable a- or syn-aldoximes, which are readily isomerized to the stable /3 or anti isomers under the influence of heat or hydrochloric acid. ... 

Reaction with (172) and other aldoximes may require oxime activation, which can be achieved with the addition of 1 equiv. of BF3-OEt2." " Yields in the addition of organometallic reagents to substituted aldoximes are modest and are a function of the isomeric composition of the oxime ethers, as the (Z)-oxime isomers are reported to preferentially react with organolithium reagents (entries 1 and 2, Table 13). ° The reaction has been employed for the preparation of 6-aminoalkyl-substituted pencillins (entry 3, Table 13)."° Cyclic oxime ether additions have also been evaluated (entries 4 and 5, Table 13). ° With the lability of the nitrogen-oxygen bond, addition to S-substituted isoxazolines provides a potential avenue for stereospecific synthesis of substituted 3-aminoalcohols (entry 5, Table 13). 

In conclusion, a MINDO/3 study on the pyridine-2-aldoximes and related derivatives revealed that the syn-2 -pyridinealdoxime is more stable than the corresponding anti isomer. The difference in the isomers is reverted when the corresponding anions are formed. In agreement with the experimental observations, in the case of N-methylated forms, the anti isomer is more stable than the syn form and based on this, it was concluded that the anti-2-PAM is the active form of this well-known drug. It was found that in all of the above oximes, the oxime portion is near perpendicular to the ring of the pyridine except in the anions of the pyridine-2-aldoximes in which a coplanar structure is the most stable. 

It was found that the mechanism of interconversion of these oximes and probably any aldoximes (as also indicated by the case of acetaldoxime), involves "inversion" type mechanism in which the key intermediate is the one in which the carbon, nitrogen and oxygen atoms of the oxime are colinear. The relatively low inversion energy is in good agreement with the observation of the facile interconversion of the less stable form of 2-PAM to the more stable anti isomer. 

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