Nucleophilic pathway

SCHEME 11.3 Postulated mechanisms for the inhibition of serine proteases by coumarin derivatives. NuH nucleophile. Pathway a suicide-type inactivation (suicide substrate). Pathway b transient inactivation by formation of a stable acyl-enzyme (alternate substrate-inhibitor). 

Following the disclosure of the outstanding catalytic ability of imidazole compared to other bases, the catalysis of the POCL reaction by imidazole was studied in more detail [163], and it was concluded that the POCL reaction mechanism included the concurrent catalysis by two imidazole molecules, by what was described as general-base and nucleophilic pathways, respectively. The mechanism for this was suggested to be a base catalysis of imidazole catalysis by imidazole itself as previously reported for imidazole-catalyzed reaction of esters [164, 165], Despite this, it was not until the introduction [151] of 1,1 -oxalyldiimidazole (ODI) as a chemiluminescence reagent, and the postulation of its intermediate appearance in the imidazole-catalysed POCL reaction, that the... 

Finally, we ask, if the reactive triads in Schemes 1 and 19 are common to both electrophilic and charge-transfer nitration, why is the nucleophilic pathway (k 2) apparently not pertinent to the electrophilic activation of toluene and anisole One obvious answer is that the electrophilic nitration of these less reactive [class (ii)] arenes proceeds via a different mechanism, in which N02 is directly transferred from V-nitropyridinium ion in a single step, without the intermediacy of the reactive triad, since such an activation process relates to the more conventional view of electrophilic aromatic substitution. However, the concerted mechanism for toluene, anisole, mesitylene, t-butylbenzene, etc., does not readily accommodate the three unique facets that relate charge-transfer directly to electrophilic nitration, viz., the lutidine syndrome, the added N02 effect, and the TFA neutralization (of Py). Accordingly, let us return to Schemes 10 and 19, and inquire into the nature of thermal (adiabatic) electron transfer in (87) vis-a-vis the (vertical) charge-transfer in (62). 

In this chapter, nucleophilic l,n-additions (n = 4, 6, 8,. ..) to acceptor-substituted dienes, enynes and polyenes are presented2. Addition reactions which obviously proceed via non-nucleophilic pathways (e.g. catalytic reductions, electrophilic or radical additions3), as well as 1,2-additions to the acceptor group, are not covered. 

While electrophilic reactions of alkylidenecycloproparenes are generally rapid, the nucleophilic pathways require more vigorous conditions. The only nucleophilic addition of cycloproparenes known is that of /-butoxide across the bridge bond of 237,240 and 241 which leads to the corresponding heptafulvenes 407. ... 

In addition to OH , other nucleophiles such as BH4 ,318 CN-319,320 and N3-321 also add at the nitrile carbon of cobalt(III)-nitrile complexes at rates which are = 104 times those of the corresponding reactions of the free ligands. Catalysis by C032 in the hydration of [(NH3)5RuNCMe]3+,316 and of the acrylonitrile complex [(NH3)5CoNCCH=CH2]3+,322 has been observed. In the latter complex, a direct nucleophilic pathway results in the incorporation of oxygen from C032 into the amide product with elimination of C02. 

Carrying out the reaction under different reaction conditions (solvent, mercaptide concentration, presence of elemental sulphur) gives rise to variable ratios of reaction products. These results are interpreted in terms of competing 1,7-diradical and 1,5-nucleophilic pathways. The former is reduced in importance relatively to the latter on increasing the mercaptide concentration ... 

NHsIsRuNCMe], and of the ac lonitrile complex [(NH3)sCoNCCH=CH2], has been observed. In the latter complex, a direct nucleophilic pathway results in the incorporation of... 

The additive Pummerer reaction is a reaction in which displacement of the acyloxy group in the initially formed acyloxysulfonium salt by an internal nucleophile occurs to give a new positively charged sulfur species (Scheme 33). A number of pathways are open for the subsequent reaction of intermediate (138), including elimination of the proton a to the sulfur to give a thionium ion (pathway a), displacement of the sulfur from the a -carbon by an external nucleophile (pathway b), elimination of a 3-proton with formation of an alkene and (139) (pathway c) and loss of a proton fimm the carbon atom a to Nu with formation of (140 pathway d). 

In an earlier chapter, we dealt with SN2 reactions in aliphatic compounds. In that chapter it was stated that the normal nucleophilic pathway could not operate at carbon centres that were unsaturated, because of the impossibility of inversion of the configuration of the carbon involved. This does not mean that nucleophilic substitution at a vinyl carbon is impossible if it is to occur, however, then there must be a different pathway by which it must proceed. 

Wu, S., Zhang, C., Xu, D., Guo, H. (2010). Catalysis of carboxypeptidase A promoted-water versus nucleophilic pathways. Journal of... 

The second example in this chapter is the carboxypeptidase A (CPA) [42, 43]. CPA is an exo-peptidase which can hydrolyze the C terminal amino acid from the peptide or ester substrates, whose X-ray structures have been reported for its native form [44, 45] or enzyme-inhibitor complex [46-51]. In addition, an X-ray stmc-mre of enzyme complexed with the proteolysis product was also reported [52]. No matter accumulation of experimental data, its reaction mechanisms still remain incompletely understood [53]. In particular, two major mechanisms, promoted-water pathway and nucleophilic pathway (traditionally it was named as anhydride pathway), using a peptide as the model substrate are depicted in Fig. 9.4. The nucleophilic pathway envisages an acyl-enzyme (AE) intermediate resulting from direct... 

C2a-carbanion or enamine as suggested 35 years ago by Breslow. After considerable research by many groups " , the true structure of the former is still unknown, as its existence is too fleeting for direct detection. Suffice it to say that more recent kinetic studies suggest that it is formed with a pA" near 17-19 and its behavior is consistent with a localized carbanion structure similar to that of cyanide ion. While there were some reports favoring a carbene °, rather than nucleophilic reactivity for the C2-carbanion vis-a-vis electrophiles, more recently there was evidence presented reconfirming that the reactivity of this C2-carbanion is best reflected by nucleophilic pathways, and the mechanistic probes developed provided evidence inconsistent with carbene insertion into C—H single bonds or addition across C=C double bonds ... 

Original references I II and III, IV and V, VI and VII. The kinetically equivalent nucleophilic pathway cf. Figure 3.17) can be rejected on stereoelectronic grounds (the 6-emfo-tet cyclisations violate Baldwin s rules), but nonetheless the methoxyiuethyl ester of salicylic add was synthesised and shown not to be formed in the hydrolysis of 2-methoxymethoxybenzoic acid, but to be stable under the reaction conditions. " ... 

The development of quantitative scales of solvent nucleophilicity based on solvolysis reactions is reviewed. Effects of solvent nucleophilicity are illustrated by product studies, by correlations of kinetic data, and by quantitative estimates of competing nucleophilic pathways, including competing solvent-assisted and anchimerically assisted pathways. The problem of separating quantitatively the nucleophilic and electrophilic solvent contributions to reactivity is discussed. Recent results on the nucleophilicities of aqueous sulfuric acid mixtures are presented. 

Suppression of competing nucleophilic pathways, by changing from normal solvents to fluorinated alcohols, provided evidence for homoallylic participation (40). For solvolyses of cyclohexen-4-yl tosylate (equation 4), the substitution product (IV) is important, but the bicyclic product (V) is formed in significant quantities in HFIP (Table II). The stereochemistry of the substitution product (IV Table II) supports the interpretation that a displacement of solvent with inversion of stereochemistry (ks process) occurs in nucleophilic media, changing to a homoallylic (fcA) process with retention of stereochemistry in HFIP. In acetic acid, the fcA process is just beginning, and in formic acid, the ks and fcA processes occur about equally. 

Any factor that inhibits or disallows coupling of the two odd electrons after the single-electron shift will encourage SET over a polar nucleophilic pathway. This statement forms the basis for understanding the competition between these two routes. The following factors will have a bearing on the polar-SET competition (2). 

An often occurring mechanistic problem is the diagnosis of general base or nucleophilic catalysis which give identical kinetics. Imidazole is a well known catalyst for the hydrolysis of 4-nitrophenyl acetate in water and it is known to involve nucleophilic attack because iV-acetylimidazole has been observed from ultraviolet spectral work [17]. The absence of a solvent deuterium isotope effect confirms the operation of the nucleophilic pathway (Table 7) because a primary isotope effect is expected for the general base mechanism. 

C-0 bond (insertion of the alkene into the Pd-OH bond or nucleophilic attack of water on a Pd-coordinated alkene). The nucleophilic pathway trans attack) is more generally accepted although some discordance still remains [217]. 

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