Nucleophiles, prediction

We might be tempted to say that methoxide is a much better nucleophile because it is much more basic. This would be a mistake because basicity and nucleophilicity are different properties. Basicity is defined by the equilibrium constant for abstracting a proton. Nucleophilicity is defined by the rate of attack on an electrophilic carbon atom. In both cases, the nucleophile (or base) forms a new bond. If the new bond is to a proton, it has reacted as a base if the new bond is to carbon, it has reacted as a nucleophile. Predicting which way a species will react may be difficult most (but not all) good nucleophiles are also strong bases, and vice versa. 

Q Show how enols, enolate ions, and enamines act as nucleophiles. Predict the products of their reactions with halogens, alkyl halides, and other electrophiles. Show how they are useful in synthesis. 

If you know the product of a reaction, usually it is not too difficult to determine whether an electron-rich reagent is acting as a base or as a nucleophile. Predicting the course of a reaction can be a more difficult task. However, as you work through a number of examples and problems, you will start to develop a feel for this as well. 

Assuming that Fischer-type carbene complexes react similarly to ketones and that phosphorus ylides are good carbon nucleophiles, predict the products in the following reaction ... 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Each of the following nucleophilic substitution reactions has been reported in the chemical literature Many of them involve reactants that are somewhat more complex than those we have dealt with to this point Nevertheless you should be able to predict the product by analogy to what you know about nucleophilic substitution in simple systems... 

Predict which carbon undergoes nucleophilic attack on acid catalyzed ring opening of cis 3 3 3 tnfluoro 2 3 epoxybutane Examine the C—O bond distances of the protonated form of the epoxide on Learning By Modeling How do these bond distances compare with your prediction" ... 

For continuing polymerization to occur, the ion pair must display reasonable stabiUty. Strongly nucleophilic anions, such as C/ , are not suitable, because the ion pair is unstable with respect to THE and the alkyl haUde. A counterion of relatively low nucleophilicity is required to achieve a controlled and continuing polymerization. Examples of anions of suitably low nucleophilicity are complex ions such as SbE , AsF , PF , SbCf, BE 4, or other anions that can reversibly coUapse to a covalent ester species CF SO, FSO, and CIO . In order to achieve reproducible and predictable results in the cationic polymerization of THE, it is necessary to use pure, dry reagents and dry conditions. High vacuum techniques are required for theoretical studies. Careful work in an inert atmosphere, such as dry nitrogen, is satisfactory for many purposes, including commercial synthesis. 

Information on nucleophilic addition chemistry of quinones and various mechanistic rationali2ations have been discussed, and molecular orbital calculations have been proposed as more definitive approaches for explanation and prediction (63). 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Results for the neutral pyrazole molecule show a considerable spread. The tt-electron and total (Tr-l-cr) densities predict electrophilic substitution at the 4-position as found. Results for thiazole also agree with experimentally determined electrophilic and nucleophilic reactivity. 

The LUMO, which is the frontier orbital in reactions with nucleophiles, has a larger coefficient on the /3-carbon atom, whereas the two occupied orbitals are distorted in such a way as to have larger coefficients on oxygen. The overall effect is that the LUMO is relatively low-lying and has a high coefficient on the /3-carbon atom. The frontier orbital theory therefore predicts that nucleophiles will react preferentially at the /3-carbon atom. 

The chemical reactivity of these two substituted ethylenes is in agreement with the ideas encompassed by both the MO and resonance descriptions. Enamines, as amino-substituted alkenes are called, are vety reactive toward electrophilic species, and it is the p carbon that is the site of attack. For example, enamines are protonated on the carbon. Acrolein is an electrophilic alkene, as predicted, and the nucleophile attacks the P carbon. 

A very important relationship between stereochemistry and reactivity arises in the case of reaction at an 5 carbon adjacent to a chiral center. Using nucleophilic addition to the carbonyl group as an example, it can be seen that two diastereomeric products are possible. The stereoselectivity and predictability of such reactions are important in controlling stereochemistry in synthesis. 

There is clearly a conceptual relationship between the properties called nucleophilicity and basicity. Both describe a process involving formation of a new bond to an electrophile by donation of an electron pair. The pA values in Table 5.7 refer to basicity toward a proton. There are many reactions in which a given chemical species might act either as a nucleophile or as a base. It is therefore of great interest to be able to predict viiether a chemical species Y P will act as a nucleophile or as a base under a given set of circumstances. Scheme 5.4 lists some examples. 

The kinetics of the hydrolysis of some imines derived from benzophenone anc primary amines revealed the normal dependence of mechanism on pH with ratedetermining nucleophilic attack at high pH and rate-determining decomposition of the tetrahedral intermediate at low pH. The simple primary amines show a linear correlation between the rate of nucleophilic addition and the basicity of the amine Several diamines which were included in the study, in particular A, B, and C, al showed a positive (more reactive) deviation from the correlation line for the simple amines. Why might these amines be more reactive than predicted on the basis of thei ... 

Table 8-1 shows the application of the Hughes-lngold hypothesis to aliphatic nucleophilic reactions of various charge types. These predictions are borne out by observations on many reactions. It should be noted - that the Hughes—Ingold rule... 

Sn2 reactions with anionic nucleophiles fall into this class, and observations are generally in accord with the qualitative prediction. Unusual effects may be seen in solvents of low dielectric constant where ion pairing is extensive, and we have already commented on the enhanced nucleophilic reactivity of anionic nucleophiles in dipolar aprotic solvents owing to their relative desolvation in these solvents. Another important class of ion-molecule reaction is the hydroxide-catalyzed hydrolysis of neutral esters and amides. Because these reactions are carried out in hydroxy lie solvents, the general medium effect is confounded with the acid-base equilibria of the mixed solvent lyate species. (This same problem occurs with Sn2 reactions in hydroxylic solvents.) This equilibrium is established in alcohol-water mixtures ... 

The product of nucleophilic attack can be anticipated by examining the lowest-unoccupied molecular orbital (LUMO) on protonated cyclopentene oxide. From which direction (top or bottom) would a nucleophile be more likely to approach each epoxide carbon in order to transfer electrons into this orbital Explain. Does one carbon contribute more to the LUMO, or is the orbital evenly spread out over both epoxide carbons Assuming that LUMO shape dictates product stereochemistry, predict which stereoisomers will be obtained, and their approximate relative amounts. Is the anticipated kinetic product also the thermodynamic product (Compare energies of 1,2-cyclopentanediol stereoisomers to tell.)... 

In order to predict the structure of the product, you must identify the factors that will tend to favor selective ketal formation. Consider selective carbonyl protonation first. Obtain energies and atomic charges, and display electrostatic potential maps of the alternative protonated ketones (protonated ketone A, protonated ketone B). Identify the more stable isomer. Compare geometries and draw whatever Lewis structures are needed to account for your data. Why is one isomer more stable than the other Is the more stable isomer also that in which the positive charge is better delocalized Will the more stable isomer undergo nucleophilic attack more or less easily than the other Explain. 

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