Nucleophiles factors contributing

IV-acyloxy-iV-alkoxyamides, biological activity, 97-115 anticancer activity of, 115 mutagenicity of, in Ames Salmonella/ microsome assay, 97-115 IV-acyloxy-iV-alkoxyamides, chemical reactivity, 59-96 factors contributing, 59-60 nucleophilic substitution reactions, see Nucleophilic substitution reactions solvolysis studies, see Solvolysis... 

L in Scheme 11.3) departs. Nucleophilic addition to the intermediate benzyne (step D) is readily explained by perturbative MO arguments. The extra and orbitals of benzyne are compared to those of ethylene in Figure 11.7. The aromatic n system is not involved in the special properties of benzyne. The third benzyne n bond is due to the overlap in fashion of the two sp2 hybrid orbitals which lie in the nodal plane of the intact 6 electron system. Two factors contribute to a very low LUMO for benzyne. First, the sp2 hybrid orbitals are lower in energy than the 2p orbitals from which the ethylene orbitals are constructed. Second, the intrinsic interaction between the two sp2 orbitals is less than the normal / cc since the orbitals have less p character and are tipped away from each other. The low LUMO of benzyne makes the molecule a strong Lewis acid, susceptible to attack by bases, and a reactive dienophile in Diels-Alder reactions, as we shall see later. 

This means that the nucleophile is pushed away more strongly in the alkene case than in the carbonyl case. At the same time, the attractive in phase overlap between Nu and Q is smaller with n cc than with 7t co, which tends to maintain Nu nearer to the vertical position in the carbonyl case. Both factors contribute to give a larger angle for the reaction with alkenes or alkynes. 

Perfluorocarbons are essentially inert to hydrolysis unless heated to very high temperatures, although it has been calculated that the free energy of hydrolysis of carbon tetrafluoride is exothermic by 304kJmoP [12], and the inertness therefore stems from a high activation barrier. The carbon backbone in a perfluorocarbon is shielded towards attack by nucleophiles by the non-bonding electron pairs associated with the many adjacent fluorine atoms, and this is undoubtedly a major factor contributing to the relative inertness of fluorocarbons. 

Nucleophilic strength for a given substituent can be measured in terms of the rate of the Sn2 reaction or in reactions with carbonyl derivatives. The relative rates of several nucleophiles were determined by reaction with iodomethane and are shown in Table 2.13. As mentioned previously, several factors contribute to nucleophilic strength. Electronic effects are important, as illustrated by the electron releasing methyl group, which should make methoxide more nucleophilic than hydroxide. The rate of the Sn2 reaction of sodium hydroxide with iodomethane is 1.3 x lO" M s whereas the rate with sodium methoxide with iodomethane is 2.51 x 1Q2 M- s-1.98... 

In a homogeneous system, a particular electrophile at low concentration would react randomly with nucleophiles at rates determined by stereochemical factors and by the nucleophilic strength of each nucleophile. The contributions of these factors can be measured and it is, therefore, possible to utilise measurements of the rate of reaction at a particular nucleophilic centre to calculate the rate of reaction with another nucleophile. Although an electrophile absorbed by, or formed within an animal would tend to react at random with cellular nucleophiles, many of these nucleophiles are organised in a highly ordered manner within cells, tissues and organs. 

Sn2 reactions of allylic halides with good nucleophiles (Section 6-8) are faster than those of the corresponding saturated haloalkanes. Two factors contribute to this acceleration. One is that the allylic carbon is attached to a relatively electron-withdrawing sp hybridized carbon (as opposed to sp Section 13-2), making it more electrophilic. The second is that overlap between the double bond and the p orbital in the transition state of the Sn2 displacement (see Figure 6-4) is stabilizing, resulting in a relatively low activation barrier. 

The above SnI reaction is facilitated by the presence of the para methoxy substituent, which allows for extra stabilization of the positive charge. In the absence of this substituent, Sn2 processes may dominate. Thus, the parent phenylmethyl (benzyl) halides and sulfonates undergo preferential and unusually rapid Sn2 displacements, even under solvolytic conditions, and particularly in the presence of good nucleophiles. As in allylic Sn2 reactions (Section 14-3), two factors contribute to this acceleration. One is that the benzylic carbon is made relatively more electrophilic by the neighboring sp -hybridized phenyl carbon... 

Another factor contributing to the living NVC polymerization may be the rapid initiation reaction between iodine and this highly nucleophilic monomer. 

Regioselective addition to a,p-unsaturated carbonyl compounds is an age-old pursuit, and reactions selective for either 1,2- or 1,4-addition are ubiquitous in modern organic synthesis. Nucleophile character (hard versus soft) and solvent polarity (contact versus separated ion pairs),among other factors, contribute to the reaction outcome. The typical reaction of Grignard reagents with enones results in mixtures of 1,2- and 1,4-addition products. From their earliest inception, Cu(i) catalysts and reactants have been used to effect selective 1,4-addition in this archetypical transformation of organocuprates. ... 

With the fore-mentioned chemical principles in mind, examination of the oligomeric composition of several extracts which contain tannins is now possible in terms of stereochemistry, functionality and condensation aptitudes of their precursors or intermediates. From this it is evident that condensations follow the path of least resistance, being regulated by the stability of the carbocation arising from the flavan-3,4-diol, by the nucleophilicity of the substrate, by steric factors contributed by both electrophile and nucleophile, by the 2,3-trans or 2,3-m stereochemistry of the electrophile, and by the relative concentrations of reactants. 

However, the situation is not as clear-cut as it might at first seem since a variety of other factors may also contribute to the above-mentioned trend. Abuin et a/.141 pointed out that the transition state for addition is sterically more demanding than that for hydrogen-atom abstraction. Within a given series (alkyl or alkoxy), the more nucleophilic radicals are generally the more bulky (i.e. steric factors favor the same trends). It can also be seen from Tabic 1.6 that, for alkyl radicals, the values of D decrease in the series primary>secondary>tertiary (i.e. relative bond strengths favor the same trend). 

---