Hard electrophile/nucleophile

Hard electrophile/nucleophile A species whose behaviour as an electrophile or nucleophile is mainly governed by Coulombic (i.e. electric charge) interactions. Tends to be difficult to polarise, and so usually acts as a Bronsted-Lowry acid or base. 

Palladium-Catalyzed Coupling Reactions of Propargyl Electrophiles with Hard Carbon Nucleophiles... 

As shown in the previous sections, a (cr-allenyl)palladium species, which is formed from a propargyl electrophile and a Pd(0) catalyst, reacts with a hard carbon nucleophile in a manner analogous to the Pd-catalyzed cross-coupling reaction to give a substituted allene. The results indicate that the reactivity of the (cj-allenyl)palladium species is similar to that of an alkenylpalladium intermediate. Indeed, it was found that the (cr-allenyl)palladium species reacted with olefins to give vinylallenes, a reaction process that is similar to that of the Heck reaction of alkenyl halides [54]. 

To the extent that the N+ correlation is successful it means that the pattern of nucleophilic reactivity is not influenced by the nature of the electrophilic center at which substitution takes place. On the other hand, according to the concepts of the theory of hard and soft acids and bases (HSAB) as applied to nucleophilic substitution reactions (Pearson and Songstad, 1967) one would expect that a significant change in the HSAB character of the electrophilic center as an acid should lead to changes in the pattern of nucleophilic reactivity observed. Specifically, in substitutions occurring at soft electrophilic centers, soft-base nucleophiles should be more reactive relative to other nucleophiles than they are in substitutions at harder electrophilic centers, and in substitutions at hard electrophilic centers hard-base nucleophiles should appear relatively more reactive compared to other nucleophiles than they do in substitutions at softer electrophilic centers. 

Nucleophilic acyl complexes can be 0-alkylated with hard electrophiles to yield the corresponding alkoxy- or (acyloxy)carbene complexes. The first carbene complex ever isolated [61] was prepared by this route the intermediate, anionic acyl complex was generated by addition of phenyllithium to tungsten hexacarbonyl (Figure 2.3). 

Fig. 8.4 Schematic showing relative softness and hardness of nucleophiles and electrophiles as an indicator of sites of reaction of electrophilic metabolites.

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. 

Electrophiles can be hard or soft. Thus hard electrophiles react with nucleophilic sites in molecules such as O, N, C in nucleic acids or the S in methionine in proteins. Hard electrophiles are typically genotoxic such as the benzo(a)pyrene diol epoxide (see chap. 7). 

The magnitude of general-acid-base catalysis by oxygen and nitrogen bases depends only on their pATa s, and is independent of their chemical natures (apart from an enhanced activity of oximes in general-acid catalysis). Nucleophilic reactivity depends markedly on the nature of the reagents. These reactions may be divided into two broad classes nucleophilic attack on soft and on hard electrophilic centers.47... 

Swain and Scott found satisfactory correlations with Equation (27) which provided 5 values for a number of reactants. However, as indicated in Scheme 33, for the limited number of substrates conveniently studied,158,186 variations in 5 did not show a clearly discernible pattern (and no obvious correlation with reactivity). Moreover, Pearson and Songstad demonstrated that the correlations break down if extended to extremes of soft and hard electrophilic centers such as platinum, in the substitution of trara,s-[Pt(pyridine)2Cl2], or hydrogen in proton transfer reactions.255 Despite this, Swain and Scott s equation has stood the test of time and it is noteworthy that a serious breakdown in the correlations occurs only when the reacting atoms of both nucleophile and electrophile are varied. In this chapter we will restrict ourselves to carbon as an electrophilic center, and particularly, although not exclusively, to carbocations. 

A particular difficulty arises for the comparison of hard and soft nucleophiles. This difficulty indeed is amplified if one goes beyond carbocation reactions to consider softer or harder electrophilic centers, such as transition metals or protons. Interpreting differences between reacting atoms presents an ultimate challenge for attempts to understand reactivity. Richard has gone a considerable way toward offering a rational analysis of the principal factors to be considered in such an endeavor. However, this is one issue likely to attract attention in the next one hundred years of carbocation chemistry and in the wider field of electrophile nucleophile combination reactions. 

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

To predict which of the two alkyne carbons, C1 or C2, HNC will preferentially attack, one now invokes the local hard-soft acid-base (HSAB) principle (cf. [157]), which says that interaction is favored between electrophile/nucleophile (or radical/radical) of most nearly equal softness. The HNC carbon softness of 1.215 is closer to the softness of C1 (1.102) than that of C2 (0.453) of the alkyne, so this method predicts that in the reaction scheme above the HNC attacks C1 in preference to C2, i.e. that reaction should occur mainly by the zwitterion A. This kind of analysis worked for -CH3 and -NH2 substituents on the alkyne, but not for -F. 

Aldehydes and ketones have been alkynylated using indium(III) and Hunig s base (PrjNEt) as catalysts.213 IR and NMR evidence support a dual-activation role for indium it is a Lewis acid for the hard electrophile (carbonyl compound), and has sufficient n -coordination ability for a soft nucleophile such as a terminal alkyne. For the latter substrate, the amine then assists proton abstraction. 

Hard nucleophiles tend to react well with hard electrophiles... 

HoMOs are best able to interact with this LUMO—in other words soft nucleophiles. In contrast, the C-H o is higher in energy because the atoms are less electronegative. This, coupled with the hydrogen s small size, makes the C-H bond a hard electrophilic site, and as a result hard nucleophiles favour elimination. 

So the only remaining question is when thioamides combine with a-haloketones, which atom (N or S) attacks the ketone, and which atom (N or S) attacks the alkyl halide Carbonyl groups are hard electrophiles—their reactions are mainly under charge control and so they react best with basic nucleophiles (Chapter 12). Alkyl halides are soft electrophiles—their reactions are mainly under frontier orbital control and they react best with large uncharged nucleophiles from the lower rows of the periodic table. The ketone reacts with nitrogen and the alkyl halide with sulfur. 

We should compare the S reaction at silicon with the S 2 reaction at carbon. There are some iportant differences. Alkyl halides are soft electrophiles but silyl halides are hard electrophiles. Alkyl halides react only very slowly with fluoride ion but silyl halides react more rapidly with fluoride [than with any other nucleophile. The best nucleophiles for saturated carbon are neutral and/or based on elements down the periodic table (S, Se, I). The best nucleophiles for silicon are charged and based on highly electronegative atoms (chiefly F, Cl, and O). A familiar example is the reaction of enolates at carbon with alkyl halides but at oxygen with silyl chlorides (Chapter 21). 

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