Oximes anions

An artificial metalloenzyme (26) was designed by Breslow et al. 24). It was the first example of a complete artificial enzyme, having a substrate binding cyclodextrin cavity and a Ni2+ ion-chelated nucleophilic group for catalysis. Metalloenzyme (26) behaves a real catalyst, exhibiting turnover, and enhances the rate of hydrolysis of p-nitrophenyl acetate more than 103 fold. The catalytic group of 26 is a -Ni2+ complex which itself is active toward the substrate 1, but not toward such a substrate having no metal ion affinity at a low catalyst concentration. It is appearent that the metal ion in 26 activates the oximate anion by chelation, but not the substrate directly as believed in carboxypeptidase. 

R2=MeC>2C, R3 = d-F CC F ), regioisomeric 4-trifluoromethyl-5-isoxazole-carboxylates, 213 (R1 =Me02C, R2 =CF3, R3 = 4-F3CC6H4) and unexpectedly oximinoyl chloride 214, resulted by 1,4-addition. Product distribution is rationalized in terms of two competing reactions, either 1,4-addition of the oximate anion to the acetylenic ester or formation of the nitrile oxide followed by 1,3-dipolar cycloaddition. Anionic 1,4-addition of the oximinoyl chloride to the acetylenic ester is favoured at low temperatures, while nitrile oxide formation, followed by cycloaddition, occur at temperatures above 0 ° (371). 

Alkylation of oxime anions followed by hydrolysis is another efficient approach toward 0-alkylhydroxylamines. O-Alkylation of oximes of type 24 (equation 15) can also be done through Michael addition with Bayhs-HiUman adducts of type 23 catalyzed by triphenylphosphine . 

O-Substituted oxime derivatives are synthetically useful in a wide variety of transformations. Hoffman and Butani have observed that reaction of a series of aldehydes and ketones with the potassium salt of Af,0-bis(trimethylsilyl)hydroxylamine 4a or 4b (a rapid equilibrium between 4a and its Af,N-bis(silylated) isomer 4b probably exists in solution) gave high yields of the corresponding oximate anion 5, formed via the Peterson-type reaction, together with the silyl ether 6. Anion 5 could be protonated to the oxime 7 or trapped in situ with a variety of electrophiles to give 0-substituted oxime derivatives (Scheme 6). 

AChE and direct the oximate anion toward the P atom, proved to be extremely efficient in terms of rate of displacement of the enzyme-bound phosphoryl group (i.e. reactivation) and, consequently, as an antidote. The pioneering work of Wilson and colleagues in the early 1950s served as the scientific foundation for the synthesis and evaluation of more than 1000 oxime-containing reactivators over the past 50 years, that have been described in hundreds of pubhcations. 2-PAM and several bis-quatemary oximes 39 , 40 and... 

It is accepted that the acmal nucleophile in the reactions of oximes with OPs is the oximate anion, Pyr+-CH=N-0 , and the availability of the unshared electrons on the a-N neighboring atom enhances reactions that involve nucleophilic displacements at tetravalent OP compounds (known also as the a-effect). In view of the fact that the concentration of the oximate ion depends on the oxime s pATa and on the reaction pH, and since the pKs also reflects the affinity of the oximate ion for the electrophile, such as tetra valent OP, the theoretical relationship between the pATa and the nucleophilicity parameter was analyzed by Wilson and Froede . They proposed that for each type of OP, at a given pH, there is an optimum pK value of an oxime nucleophile that will provide a maximal reaction rate. The dissociation constants of potent reactivators, such as 38-43 (with pA a values of 7.0-8.5), are close to this optimum pK, and can be calculated, at pH = 7.4, from pKg = — log[l//3 — 1] -h 7.4, where is the OP electrophile susceptibility factor, known as the Brpnsted coefficient. If the above relationship holds also for the reactivation kinetics of the tetravalent OP-AChE conjugate (see equation 20), it would be important to estimate the magnitude of the effect of changes in oxime pX a on the rate of reactivation, and to address two questions (a) How do changes in the dissociation constants of oximes affect the rate of reactivation (b) What is the impact of the /3 value, that ranges from 0.1 to 0.9 for the various OPs, on the relationship between the pKg, and the rate of reactivation To this end, Table 3 summarizes some theoretical calculations for the pK. ... 

The catalysis may not depend on the configuration of the oxime, since both syn and anti function with similar efficacy138. For this reason a mechanism involving the oxime anion acting as a general base catalyst for solvent attack has been favored. However, the observed large rate enhancement is more in accord with a cyclization mechanism, and, until an anti-syn interconversion prior to hydrolysis can be unequivocally eliminated, the direct attack of the oximate anion on phosphorus remains a strong possibility. 

The yield of l-methyl-2-(2-pyrrolyl)benzimidazole (32) is 58% based on the consumed Z-isomer (Table XVII). Its H-NMR spectrum (DMSO-D6, ppm) shows 3.96 (s, NMe), 6.28 (m, 3H), 6.83 (m, H4), 7.03 (m, H5), 7.23, and 7.56 (benzene protons). The less coplanarZ-oximate anion is likely to encounter less sterical hindrance upon acetylene molecule attack. 

This process, likely based on vinyl chloride, is simple, efficient, safe, and convenient for engineering (it can easily be realized in the simplest conventional reactor at atmospheric pressure), and uses cheap and accessible raw material (dihaloethane and ketoximes). As stated previously, the interaction of ketoximes with dihaloethanes may also lead to N-vinylpyrroles. Occasionally the nucleophilic substitution of halogen by oximate anions, leading to ethyleneglycol diethers of ketoximes, becomes noticeable (see following). 

Detection of the Ovinyloximes 136a,d (Scheme 66) and the 0(2-chloroethyl)oxime 137 (Scheme 67) suggests two possible pathways for the formation of pyrroles from ketoximes and dichloroethane [89KGS901]. First, in a strongly basic medium, dichloroethane may act as an acetylene supplier (Scheme 66). Second, nucleophilic substitution of one chlorine atom in dichloroethane by the oximate-anion may lead to the 0(2-... 

The tridentate nature of the oximate-anion, i.e., its ability to act as O-, N-, and C-nucleophile, complicates analysis of the mechanism of the superbase-catalyzed heterocyclization of ketoximes with acetylene. 

Ambident reactivity was shown by oximate anions normally, Oarylation predominated over N-arylation, with ratios of oxime ethers to nitrones ranging from 9 1 (for the benzophenone oxime anion) to 1.7 1 (for the fluorenone oxime anion) [77]. The arylation of two heterocyclic oximes was performed under mild conditions and led mainly to the corresponding oxime ethers which served as good precursors for the generation of unstable aryl fulminates, ArONC [79,80],... 

We have pursued such ester hydrolysis by artificial enzymes further. With a cyclodextrin dimer related to 25 we have hydrolyzed an ordinary doubly bound ester, not just the more reactive nitrophenyl esters [116], with catalytic turnovers. Also, with a catalyst consisting of a cyclodextrin linked to a metal ligand carrying a Zn2+ and its bound oxime anion, we saw good catalyzed hydrolysis of bound phenyl esters with what is called burst kinetics (fast acylation, slower deacylation), as is seen with many enzymes [117]. 

Predominant P—O Fission. In the absence of Zn2+ ion, the reactions of PPS and PCA were very slow. Therefore, Zn2+ ion is essential for faster reaction. The kinetics described later indicate that the reaction proceeds through the formation of ternary complex (A) as illustrated in Figure 13. The oximate anion in A may either attack phosphorus (Path a) or sulfur (Path b). Inorganic sulfate was obtained quantitatively. This itself is not proof of Path a, because C (prepared separately) was found to be hydrolyzed readily to give sulfate under the same reaction conditions. However, the other isolated major product was B instead of the oxime catalyst that would be regenerated from C. The product B gave methylphenylphosphate when solvolyzed in methanol in the presence of Zn2+ ion. Methylphenylphosphate also was obtained directly from A in the reaction in methanol, whereas the formation of methylsulfate was not detected. Thus, these results all indicate that the Zn2+PCA complex promotes predominant P—O fission. 

These data indicate a very large metal ion effect. Thus, the nucleophilic reactivities of imidazole and oxime anion toward the phos-phoryl group are enhanced by Mg2+ to 41- and more than 746-fold, respectively, in water. The combined effect of metal ion and nucleophile may amount to some 104-106-fold rate enhancement when compared with the water rate (-TO-5 min-1) Such effects would be even larger in the solvents of low water content and they may be very good models of phosphatase activity. However, they do not answer our question for the activation mechanism of S—O fission under neutral conditions. 

The true seccmd-order rate constant A , for the oximate anion (fi = 12) amounts to ca 1000 M" sec. The parent rate constant fca,obs at pH 8 is about one-half of diat of a-microenvironment effects dehydraticm of the oximate group, closeness of the positively charged atom to the active group, and electrmtatic interaction. 

The oxime group (-CH=NOH) in the human body dissociates to the oximate anion (-CH=NO which acts as a nucleophile and cleaves the bond between the enzyme and the phosphorus atom of the inhibitor (Patocka et al, 2005 Heath, 1961). 

An investigation of nitrosobenzene in alkaline solution is complicated by the reaction of nitrosobenzene with hydroxyl ions [163,164]. There is a relatively fast, reversible addition of hydroxyl ion to the nitroso group. Besides that, there is in aqueous solutions at pH > 13 in the absence of dioxygen a relatively slow reaction giving mainly a mixture of azoxybenzene and 4-hydroxynitrosobenzene (p-quinone monoxime) in a reaction suggested as involving a hydride ion transfer from the initially formed 4-hydroxycyclohexa-diene oxime anion to nitrosobenzene hydride ion transfer to nitrosobenzene probably also occurs in alcoholic solutions when an alkoxide is present. In the presence of dioxygen, some nitrobenzene is formed. 

If the reaction path shown is as general as the available evidence suggests, attempts to reduce protonated oximes electrolytically to hydroxylamines are not likely to succeed. Some unprotonated oximes, such as benzaldoxime and benzophenone oxime, are reducible in not too strongly alkaline solution the oxime anion is not reducible. An investigation of the reduction of benzaldoxime in alkaline solution [79] showed that some benzylhy-droxylamine is formed under these conditions. 

Ketoximes are deprotonated by EGB to the oxime anion, which requires a more negative potential for its reduction. Fluorenone oxime gave for n = 1 unchanged oxime, fluorenone (hydrolysis of fluorenone imine), fluorenone imine, and some 0-butylfluorenone oxime, presumably formed by attach of the oxime anion on TBABF4 [62]. 

The application of hydrazone and oxime anions for carbon-carbon bond formation generally offers no advantages to the use of imine anions and, significantly, the hydrolysis of the hydrazone or oxime products to form the product carbonyl group is substantially more difficult than is the cleavage of an imine. The notable exception is in the area of asymmetric induction where powerful direction has been obtained with chiral hydrazone anions. This area has been explored fully by Enders following initial observations of Enders and Corey.2 Enders has recently reviewed these contributions. ... 

Another special case of the MIRC reaction involving a-halocarbanions is the cyclopropanation of hydrazone and oxime anions with methyl a-bromoacrylate to give cyclopropanes 3 and 4, respectively. ... 

Hydroxamic acids react with diaryliodonium salts to afford the O-phenyl derivatives. number of heterocyclic compounds containing A -hydroxyamino groups were selectively arylated on the oxygen atom. 0 (Table 5.4) In the case of oximate anions, ambident behaviour was observed, with predominant 0-arylation. With heterocyclic oximes, the 0-aryl ethers were mainly formed and served as precursors to prepare unstable aryl fulminates, 19 (Table 5.5) In the reaction of quinolone derivatives with diaryliodonium salts, the products of O- or C-arylation were obtained.(Table 5.6)... 

Unsuccessful direct means of detecting the hypothesized intermediates we have been unable to trap the hypothesized oxime anion intermediate with either methyl iodide or chlorotrimethylsilane in the presence of base. We did not observe any characteristic infrared signals using IR probes. 

Generally, the reactivating efficacy of oximes depends on their reactivity and affinity for OPC-inhibited enzyme. Their reactivity is derived from the nucleic activity of oxime anion that is bound on the pyridinium ring (8). Oximes differ from each other by the position of the oxime group on the pyridinium ring only. The reactivity of all available oximes is almost the same because their basic structure is very similar (8). The affinity of oximes for intact enzyme, characterized by dissociation constant of enzyme-reactivator complex (Kdls), and for nerve agent-inhibited enzyme, characterized by dissociation constant of inhibited enzyme-reactivator complex (Kr), is determined by various physicochemical factors such as steric compatibility, electrostatic effects, hydrophobic interactions and by the shape and the size of the whole molecule as well as functional groups (22). 

Acyclic and Cyclic Oxime Anions Stabilized Oxime Anions... 

---