Labeling reactions electrophilic addition

Detailed investigation of C-14 KIE in simple electrophillic addition reactions has been presented by Kanska and Fry610-612 regarding the mechanism of addition of 2,4-dini-trobenzensulphenyl chloride to substituted styrenes labelled with C-14. Additions of 2,4-dinitrobenzenesulphenyl chlorides to / -substituted a- and -labelled styrenes have been carried out in acetic acid at 30.1 °C (equation 267) ... 

The orientation of electrophilic addition to trifluoropropene was originally thought to be a reflection of the relative stabilities of the intermediate carbocations 4.15A and 4.15B (Figure 4.15), but it was subsequently found that trifluoropropene is dimerised, rather than protonated in highly acidic media [47, 48]. Deuterium labelling studies indicated that the reaction proceeds via initial fluoride ion abstraction to yield an intermediate allyl cation [49] (Figure 4.16). 

Addition of P F]F2 (or CH3C02f F]F) at the double bond of substituted 2,4-dioxypyrimidines (Scheme 16) allows the preparation of the fluorine-18-labelled nucleic acid base 5-[ F]fluorouracil [91-94] and the nucleoside 2 -deoxy-5-[ F]fluorouridine [95-97]. The reaction, usually carried out in acetic acid, demonstrates an excellent regioselectivity, with only the 5-[ F]fluoro derivatives obtained because the C-5 position is the unique activated position for reaction with an electrophile in these systems. The mechanism of this reaction has been studied and the intermediate 5,6-fluoro-acetoxy adduct (or the 5,6-fluoro-hydroxy adduct if the solvent is water) has been isolated and characterised [92]. 

In the preceding section, four diagnostic tests of affinity labeling were listed (inactivation inhibited by substrates, pH dependence of inactivation similar to that of catalysis, labeled inhibitor covalently bound in 1 1 stoichiometry, and saturation kinetics obeyed). The same criteria may be used to diagnose suicide inhibition. In addition, tests must be made to detect any diffusion of the activated intermediate I into solution. For example, the addition of —SH reagents that rapidly react with electrophiles and hence scavenge them should not slow down the rate of reaction. The suicide inhibitor should not, in any case, react with the thiol at an appreciable rate in the absence of enzyme. 

Direct metallation of methylenecyclopropane with butyllithium in THF affords meth-ylenecyclopropyllithium. This reacts with carbonyl electrophiles such as aldehydes, ketones and lactones by ring alkylation to give selectively 2-methylenecyclopropyl carbinols. No products of exo alkylation are isolated. Other bases such as r-BuOK and KH do not deprotonate methylenecyclopropane. Use of diethyl ether as the solvent, instead of THF, significantly reduced the rate of lithiation. Similar reaction of the lithium reagent with ethylene oxide gave 2-(2-methylenecyclopropyl)ethanol (equation 294) In the reaction with C-labeled ethylene oxide the addition of TMEDA to the reaction mixture is recommended. ... 

From the results summarized in Table I, apparently the Brpnsted relationship will hold for all combinations of nucleophiles and electrophiles. Because, as pointed out previously, the Hammett equation is really a special case of the Brpnsted relationship, all the legion of nucleophile-electrophile, rate-equilibrium Hammett correlations that have been studied also fall under the scope of the Brpnsted relationship. For example, nucleophilicities of ArO , ArS , ArC(CN)2 , and the other families listed in footnote c of Table I have generally been correlated by the Hammett equation, where the acidities of benzoic acids in water are used as a model for substituent interactions with the reaction site (a), and the variable parameter p is used to define the sensitivity of the rate constants to these substituent effects. The Brpnsted equation (equation 3) offers a much more precise relationship of the same kind, because this equation does not depend on an arbitrary model and allows rate and equilibrium constants to be measured in the same solvent. Furthermore, the Brpnsted relationship is also applicable to families of aliphatic bases such as carboxylate ions (GCH2C02 ), alkoxide ions (GCH20 ), and amines (GCH2NH2). In addition, other correlations of a kinetic parameter (log fc, AGf, Ea, etc.) can be included with various thermodynamic parameters (pKfl, AG°, Eox, etc.) under the Brpnsted label. 

The various steps in the overall sequence will here be considered individually, but only briefly, and no attempt will be made to indicate the scope of the WEH procedure which, as has already been indicated, has been widely reviewed. The aldol condensation which leads to the ions 154 is considered to be essentially reversible, a feature which has been observed in the reactions between diethyl (prop-2-enyl)phosphonate anion and aromatic aldehy-des Reversibility has also been demonstrated in a variety of other reactions that include crossover experiments, based on the system from benzaldehyde and 153 (Z = CN or COOMe) into which a more electrophilic aldehyde is added this results in the incorporation of the latter into products in such a way that the dissociation of the phospho-nate-benzaldehyde adduct must have occurred The addition of an aldehyde to a deuterium-labelled adduct in the presence of NaOEt-EtOH affords a mixture of labelled and unlabelled alkenes in the ratio of ca 1 1. The product (158) from the interaction of HO (Na2C03 in Et0H-H20) and a dialkyl (a-cyanoethenyl)phosphonate decomposes into the expected alkene, but also dissociates into a carbonyl compound together with a carbanion the latter can then be trapped by the addition of a different aldehyde or ketone (Scheme 30) ... 

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