Proelectrophiles

Lipnick, R.L., Watson, K.R. and Strausz, A.K. (1987) A QSAR study of the acute toxicity of some industrial organic chemicals to goldfish. Narcosis, electrophile and proelectrophile mechanisms. Xenobiotica, 17,... 

In these cases the formation of a n complex was suggested to occur from the protonated aromatic (a complex) and the proelectrophile (P) followed by the formation of the a complex as suggested by Cacace 96... 

With 1-alkoxyallenes as proelectrophiles, the palladium-catalysed asymmetric allylic alkylation proceeds with 1,3-dicarbonyl compounds as pronucleophiles with excellent regioselectivity good enantioselectivity (82-99% ee) was obtained with the Trost lig- and. The pH of the medium proved crucial for the reactivity and selectivity. By using the more acidic Meldrum s acids, the reactions required a co-catalytic amount of a Brpnsted acid, such as CF3CO2H. On the other hand, the less acidic 1,3-diketones failed to react under these conditions but the reaction proved to occur in the presence of the weaker benzoic acid, suggesting the need for general base catalysis. Indeed, a mixture of Et3N and PhCOiH proved to be optimal (93-99% ee). A mechanistic model to rationalize these results has been developed.88... 

There are, however, examples indicating that in ion molecule reactions between a protonated species (AH+) and benzene (B), two isomeric forms of the intermediate complex may exist (AH+)(B) and (A)(BH+) [74,286]. In the cases of water [287] and propene [74], quantum chemical calculations clearly indicate that the former corresponds to a n complex where A-H acts as a hydrogen bond donor towards the centre of the benzene ring, while the latter is a hydrogen bonded complex between the benzenium ion and A. In neither case has a barrier been located, but is probably rather low in both cases. The role of the n complex has still not been clarified, since direct downhill routes from the reactants to the a complex exist. It has been pointed out that n complex formation between a pro electrophile and the substrate may be important in solution and in biological systems for molecular recognition purposes. In such cases the proelectrophile is activated to form the actual electrophile subsequent to n complexation, thereupon giving rise to the a complex. This has been shown by quantum chemistry to provide a reasonable scenario for the reaction between HF and benzene, in which BF3 is ultimately required to promote ion formation of the HF/benzene tt complex [288]. 

R.L. Lipnick (1989b). Narcosis, electrophile, and proelectrophile toxicity mechanisms. Application of SAR and QSAR. Environ. Toxicol. Chem., 8, 1-12... 

G. D. Veith, R.L. Lipnick, and C.L. Russom (1989). The toxicity of acetylenic alcohols to the fathead minnow, Pimephales promelas. Narcosis and proelectrophile SLCtiwation. Xenobiotica, 19(5), 555-565... 

The remarkable stability of ruthenium complexes could, further, be exploited for direct arylations between simple arenes as pronucleophiles and inexpensive, broadly available phenols as proelectrophiles. Notably, this operationally simple dehydrative direct arylation was achieved with a highly chemo- and regioselective ruthenium catalyst, along with a sulfonyl chloride, and proceeded overall through the functionalizations of both C-H as well as C-OH bonds (Scheme 29) [85],... 

The protocol proved generally applicable, and allowed for the functionalization of arenes with different DGs, such as pyridine 27 (Scheme 30), employing both electron-deficient as well as electron-rich phenols as proelectrophile [85],... 

Furthermore, aromatic carboxylic acid MesC02H (88) enabled dehydrative direct arylations with phenols as proelectrophiles to occur in apolar toluene as solvent as well (Scheme 34) [85],... 

Furthermore, tosylates could be generated in situ by employing phenols directly as proelectrophilic reagents. Thus, monoarylations of 2-arylpyridines were accomplished through chemo- and regioselective functionalizations of C—H and C—OH bonds via a formal dehydrative cross-coupling (Scheme 9.24) [61]. 

Narcosis represents the most fundamental mechanism of the toxicity of nonelectrolyte organic compounds, and corresponds to minimum or baseline toxicity. Quantitative structure-activity relationships for chemicals acting by this mechanism for various organisms and routes of exposure provide a valuable probe for determining whether or not a candidate chemical acts via narcosis or by an electrophile, proelectrophile, cyanogenic, or other more specific molecular mechanism. 

Proelectrophile Mechanism. Proelectrophiles, which produce electrophiles by means of metabolic transformation, represent a second class... 

METABOLIC ACTIVATION OF PROELECTROPHILE TO REACTIVE ELECTROPHILE MOLECULAR SPECIES... 

Figure 6. Schematic representation of the physiological and biochemical processes involved in the production of lethality to fish from toxicants acting by narcosis, electrophile, and proelectrophile mechanisms.

For the purposes of this chapter, a cross-dehydrogenative-eoupling (CDC) reaction will be defined as the oxidative coupling of species that are nominally related to electrophiles proelectrophiles) with those nominally associated with being nucleophiles pronucleophiles), see Scheme 11.1. 

We must also deprioritize simple oxidation reactions where there is no added pronucleophile, such as oxidations at mildly activated positions without attendant coupling processes, since a major advantage of CDC reactions is that we can combine pronucleophiles and proelectrophiles clearly some of these studies provide mechanistic information as to the composite steps. While much of the related chemistiy is relevant to Af-demethylation reactions, " oxidative dehalogenations or other processes we do not cover those studies here since they are not aimed at (constructive) synthesis, which is the primary focus of CDC reactions. 

The second experiment we present in this tutorial for classifying compounds according to their mechanism of action involves the classifications of 88 chemicals. The chemicals are either narcotics (nonpolar and polar narcotics) and reactive compounds (respiratory uncouplers, soft electrophiles, and proelectrophiles).The dataset, consisting of 48 narcotic compounds... 

In the first test we used SVM models to discriminate between nonpolar narcotic compounds (chemicals that have baseline toxicity) and other com-potmds having excess toxicity (representing the following MO As polar narcotics, ester narcotics, amine narcotics, weak acid respiratory uncouplers, electrophiles, proelectrophiles, and nucleophiles). From the total set of 337 compotmds, 126 represent the SVM class -Fl (nonpolar narcotic) and 211 represent the SVM class —1 (all other MOA classes). 

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