Effect of C Substituents

HOMO of C substituted alkene LUMO of C substituted alkene 

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The reactivity of the individual O—P insecticides is determined by the magnitude of the electrophilic character of the phosphoms atom, the strength of the bond P—X, and the steric effects of the substituents. The electrophilic nature of the central P atom is determined by the relative positions of the shared electron pairs, between atoms bonded to phosphoms, and is a function of the relative electronegativities of the two atoms in each bond (P, 2.1 O, 3.5 S, 2.5 N, 3.0 and C, 2.5). Therefore, it is clear that in phosphate esters (P=0) the phosphoms is much more electrophilic and these are more reactive than phosphorothioate esters (P=S). The latter generally are so stable as to be relatively unreactive with AChE. They owe their biological activity to m vivo oxidation by a microsomal oxidase, a reaction that takes place in insect gut and fat body tissues and in the mammalian Hver. A typical example is the oxidation of parathion (61) to paraoxon [311-45-5] (110). 

Numerous other penicillin sulfones have been reported to be P-lactamase inhibitors, as illustrated in Table 5. The effect of C-6 substituents has been extensively explored starting with 6-APA sulfone (25, R = NH2, R = H, R" = R " = CH ), which has modest activity. Mechanistic considerations led to preparation of sulfones of poor substrates, compounds such as methicillin, cloxaciUin, nafaciUin, and quinaciUin sulfone (25,... 

As discussed in the theoretical section (4.04.1.2.1), electrophilic attack on pyrazoles takes place at C-4 in accordance with localization energies and tt-electron densities. Attack in other positions is extremely rare. This fact, added to the deactivating effect of the substituent introduced in the 4-position, explains why further electrophilic substitution is generally never observed. Indazole reacts at C-3, and reactions taking place on the fused ring will be discussed in Section 4.04.2.3.2(i). Reaction on the phenyl ring of C- and A-phenyl-pyrazoles will be discussed in Sections 4.04.2.3.3(ii) and 4.04.2.3.10(i), respectively. The behaviour of pyrazolones is quite different owing to the existence of a non-aromatic tautomer. 

We will address this issue further in Chapter 10, where the polar effects of the substituents on both the c and n electrons will be considered. For the case of electrophilic aromatic substitution, where the energetics of interaction of an approaching electrophile with the 7t system determines both the rate of reaction and position of substitution, simple resonance arguments are extremely useful. 

The pA of 1,3-dithiane is 36.5 (Cs" ion pair in THF). The value for 2-phenyl-1,3-dithiane is 30.5. There are several factors which can contribute to the anion-stabilizing effect of sulfur substituents. Bond dipole effects contribute but carmot be the dominant factor because oxygen substituents do not have a comparable stabilizing effect. Polarizability of sulfur can also stabilize the carbanion. Delocalization can be described as involving 3d orbitals on sulfur or hyperconjugation with the a orbital of the C—S bond. MO calculations favor the latter interpretation. An experimental study of the rates of deprotonation of phenylthionitromethane indicates that sulfur polarizability is a major factor. Whatever the structural basis is, there is no question that thio substituents enhance... 

A few comments on the polar effects of the substituents reported in Tables IX—XI are now relevant. With the exception of 4-chloro-5-nitroquinoline (see Section IV, C, l,c), they involve only positions not subject to primary steric effects. The relations to the reaction center are of the conjugative cata, amphi) as well as of the non-conjugative class meta, epi, pros) as shown in Chart 3 by structures 45 and 46. 

Nucleophilic substitution of pyridines is discussed in previous sections in relation to the following cyclic transition states (Section II, B, 5), hydrogen bonding and cationization (Section II, C), the leaving group (Section II, D,) and the effect of other substituents (Section II, E) and of the nucleophile (Section II, F). 

This activation is more pronounced on the introduction of stronger electron-donor substituents, but this point is not yet sufficiently studied. The isoxazole ring is unsymmetrical, and the activating effect of the substituent depends on its position. The available evidence shows that a substituent at C-5 activates the nucleus (or rather the 4-position) more strongly than does a substituent at C-3. 

The same conclusion was reached in a kinetic study of solvent effects in reactions of benzenediazonium tetrafluoroborate with substituted phenols. As expected due to the difference in solvation, the effects of para substituents are smaller in protic than in dipolar aprotic solvents. Alkyl substitution of phenol in the 2-position was found to increase the coupling rate, again as would be expected for electron-releasing substituents. However, this rate increase was larger in protic than in dipolar aprotic solvents, since in the former case the anion solvation is much stronger to begin with, and therefore steric hindrance to solvation will have a larger effect (Hashida et al., 1975 c). 

Evidence is provided by this analysis that (a) structural considerations discriminate among at least four practical classes of pi delocalization behavior, each of which has limited generality (b) the blend of polar and pi delocalization effect contributions to the observed effect of a substituent is widely variable among different reaction or data sets (the contributions may be opposite as well as alike in direction), depending upon structural considerations and the nature of the measurement (c) solvent may play an important role in determination of the observed blend of effects (d) it is the first three conditions which lead to the deterioration of the single substituent parameter treatment as a means of general and relatively precise description of observed electronic substituent effects in the benzene series. 

To study the reaction mechanism, the electronic effect of the substituents (p-MeO, p-Me, p-C, m-Cl and H) on the rate of the reaction of phenylmalonic acid was examined. The logarithm of (H) cleanly correlated in a linear fashion... 

Joyeau, R. Felk, A. Guillaume, S. Vergely, I. Doucet, C. Boggetto, N. Reboud-Ravaux, M. Synthesis and inhibition of human leucocyte elastase by functionalized V-aryl azetidin-2-ones effect of different substituents on the aromatic ring. J. Pharm. Pharmacol. 1996, 48, 1218-1230. 

Firstly, the electronic effect of the substituents would be a dominant factor in the determination of the thermal stability of the thiepins. Thermal stability was found to decrease sharply with decreasing substitution. For example, the tri-substituted benzo-[6]thiepin (16 d) extrudes sulfur only when heated while the non-substituted benzo[ >]-thiepin (4) is readily converted into naphthalene and sulfur at 40 °C with a half-life of 80 min 41 >. 

Reinhoudt et al.53) have reported the first synthesis of a monocyclic thiepin stabilized by electronic effects of the substituents. This synthesis utilizes the idea described in Section 2.3.3. 3-Methyl-4-pyrrolidinothiophene (85a) was treated in deuteriochloroform at —30 °C with dimethyl acetylenedicarboxylate. H-NMR monitoring of the reaction indicated that a [2 + 2]cycloaddition proceeded slowly at this temperature giving the 2-thiabicyclo[3.2.0]heptadiene (86a) which rearranged via ring opening of the cyclobutene moiety to the 4-pyrrolydinylthiepin (87a). At the... 

First, one of the strongest piece of evidence in support of the existence of a thianorcaradiene intermediate is the steric effect of the substituents at C-2 and C-7 of a thiepin. Substantial stability gained by 2,7-di-tert-butyl substitution on thiepin implies that these groups force the nonbonding interaction in the thianorcaradiene structure to be large and hence the thiepin structure will be favored (see Section 4-1, 4-3 and 4-4). 

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