Soft electrophiles and nucleophiles

You can interpret the stereochemistry and rates of many reactions involving soft electrophiles and nucleophiles—in particular pericyclic reactions—in terms of the properties of Frontier orbitals. This applies in particular to pericyclic reactions. Overlap between the HOMO and the LUMO is a governing factor in many reactions. HyperChem can show the forms of orbitals such as HOMO and LUMO in two ways a plot at a slice through the molecule and as values in a log file of the orbital coefficients for each atom. 

Sn2 reactions usually occur at primary alkyl groups, and often involve soft electrophiles and nucleophiles. As shown in Scheme 4.1, the Sn2 reaction proceeds with (Walden) inversion at the central carbon, and is therefore stereospecific. 

From the relation between Fukui function and local softness, electrophilic and nucleophilic local softnesses can be computed. Donor and acceptor sites can also be identified by large values of both types of local softnesses in addition, it can be used to compare sites of different molecules and to identity which one is softer or harder. The elec-trophilicity index can also be extended to a local context,21 and a comparison of the electrophilicity of sites in different species can be made. 

Since biological systems are rich in nucleophiles (DNA, proteins, etc.) the possibility that electrophilic metabolites may become irreversibly bound to cellular macromolecules exists. Electrophiles and nucleophiles are classified as hard or soft depending on the electron density, with hard electrophiles generally having more intense charge localization than soft electrophiles in which the charge is more diffuse. Hard electrophiles tend to react preferentially with hard nucleophiles and soft electrophiles with soft nucleophiles. 

The case of nonintegral Jf and therefore of partial occupancy of the HOMO, Eq. (38b), occurs when N0 < Jf < N0 + 1 and n0+i =/t = -In0+i [18]. Thus the electrophilic and nucleophilic softnesses relate to situations in which g(r, n) diverges according to Eq. (36), and the isoelectronic softness relates to situations in which g(r, fi) vanishes. The softnesses are correspondingly infinite or zero in the KS formulation of Sect. 3, which coincides precisely with the results of the previous subsection. There is no discrepancy between the two approaches in yielding softnesses which are useless for chemical consideration. 

Similar to the addition reactions of acceptor-substituted dienes (Scheme 16), the outcome of the transformation depends on the regioselectivity of the nucleophilic attack of the organocopper reagent (1,4- vs. 1,6-addition) and of the electrophilic capture of the enolate formed. The allenyl enolate obtained by 1,6-addition can afford either a conjugated diene or an allene upon reaction with a soft electrophile, and thus opens up the possibility to create axial chirality. The first copper-mediated addition reactions to Michael acceptors of this type, for example, 3-alkynyl-2-cyclopentenone 75,... 

Acid anhydrides, being carbonyl electrophiles with polarized C=0 bonds, respond to charge tensity (they are hard electrophiles) and react well with oxygen nucleophiles. Bromine, by - jntrast, is uncharged and unpolarized (it is a soft electrophile) and reacts well with neutral nucleophiles such as alkenes (Chapter 20). Each electrophile reacts regioselectively with the part of --.e enol that suits it best. 

Electrophiles and nucleophiles can be classified as either hard or soft. Hard electrophiles and nucleophiles are more polarized than soft ones. Hard nucleophiles prefer to react with hard electrophiles, and soft nucleophiles prefer to react with soft electrophiles. Therefore, a Grignard reagent with a highly polarized C—Mg bond prefers to react with the harder C=0 bond, whereas a Gilman reagent with a much less polarized C—Cu bond prefers to react with the softer C=C bond. 

Table 2 Examples of hard and soft electrophiles and hard and soft nucleophiles...

Tt-Allylpalladium complexes can be regarded as soft electrophiles, and they react most smoothly with soft nucleophiles. Representative examples as well as their references are shown in Figure 12.3. Typically, C,H-acidic methylene compounds activated by two electron-withdrawing groups are allylated in the... 

In the brief guidelines given above for what makes a good nucleophile and electrophile, we touched on the energy and accessibility of the electrophilic and nucleophilic orbitals. This brings us to another related concept, that of "hard" and "soft" acids and bases. In this definition, the acids and bases are best viewed as being of the Lewis type. Here we examine the "hardness" and "softness" of the acid and base to predict reactivity. In this analysis, the character of a nucleophile or electrophile is most often correlated with the polarizability of the species hard reactants are non-polarizable, whereas soft reactants are polarizable. The... 

Eq. 5.30 is a general relationship for the interactions of electrophiles and nucleophiles, and is not restricted to definitions and discussions of hard and soft acids and bases. It tells us that the relative nucleophilicity of several Lewis bases will depend upon which electrophile is used, because the c s and yS values will change for each different electrophile. Similarly, the relative electrophilicities of several Lewis acids will depend upon what nucleophile is used. We will see exactly such results when we explore quantitative scales for various nucleophiles and electrophiles, where the scales are highly dependent upon the particular reaction that is chosen to analyze relative reactivities (see Chapter 8). Eq. 5.30 nicely explains the reactivity trends for soft acids and bases. It predicts that the Eoveriap will be best for Lewis acids and bases that have electrophilic and nuclephilic orbitals of roughly the same energy, which is the cases for the soft acids and bases of Table 5.8. 

In summary, the concepts of electrophilies and nucleophiles are very similar to those of Lewis acids and bases. A more thorough discussion of what makes good electrophiles and nucleophiles is left to Chapter 8. Until then, it is instructive to simply realize that trends of preferential reactivity fall into classes defined as hard and soft species, where nucleophiles and electrophiles within these individual classes prefer to react. The reactivity of the soft species is primarily due to better overlap of the orbitals, while for the hard species the electrostatic attraction dominates. 

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