Soft electrophile/nucleophile

Soft electrophile/nucleophile A species whose behaviour as an electrophile or nucleophile is mainly governed by the interaction of its frontier orbitals with those of the species being attacked, i.e. the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As deseribed in Chapter 3, Seetion 3, Tt-allylpalladium complexes react with soft carbon nucleophiles such as maionates, /3-keto esters, and enamines in DMSO to form earbon-carbon bonds[2, 3], The characteristie feature of this reaction is that whereas organometallic reagents are eonsidered to be nucleophilic and react with electrophiles, typieally earbonyl eompounds, Tt-allylpalladium complexes are electrophilie and reaet with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

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. 

Nucleophilic attack at sulfur is implicated in many reactions of 1,2,4-thiadiazoles generally, soft electrophiles attack at sulfur, cf. (150)— (151). -Butyllithium with 4,5-diphenyl-l,2,3-thiadiazole yields PhC = CPh, probably by initial nucleophilic attack at sulfur. 

The soft-nucleophile-soft-electrophile combination is also associated with a late transition state, in which the strength of the newly forming bond contributes significantly to the stability of the transition state. The hard-nucleophile-hffld-elechophile combination inqilies an early transition state with electrostatic attraction being more important than bond formation. The reaction pathway is chosen early on the reaction coordinate and primarily on the basis of charge distributiotL... 

Note As measures the difference between the softness of electrophilic attack of the carbon atom of HNC and softness for nucleophilic attack for the X or Y atom of dipolarophile. Values are given in a.u. a Preferred site of attack as determined by barrier height calculations is shown by asterisk ( ). b Correspond to s value. 

S-Alkylation. The nucleophilic character of the C=S bond in thionocarbamates was explored with alkylation reactions. Normally and in agreement with Pearson s theory,56,88,89 the R X reagents behave as soft electrophiles, providing preferential high-yielding b -alkylation. 

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. 

There would seem to be two positions one can take with respect to the interpretation of the behavior revealed by Figs 1 and 2. The first, which would undoubtedly be favored by proponents of HSAB, is that the large deviations of the points for soft-base nucleophiles in Fig. 2 show that HSAB considerations do play an important role in determining the relative order of reactivity of a series of nucleophiles in nucleophilic substitutions at different electrophilic centers when those centers differ significantly in their degree of hardness , and that the failure to observe sizeable deviations from the correlation line in Fig. 1... 

Besides direct nucleophilic attack onto the acceptor group, an activated diene may also undergo 1,4- or 1,6-addition in the latter case, capture of the ambident enolate with a soft electrophile can take place at two different positions. Hence, the nucleophilic addition can result in the formation of three regioisomeric alkenes, which may in addition be formed as E/Z isomers. Moreover, depending on the nature of nucleophile and electrophile, the addition products may contain one or two stereogenic centers, and, as a further complication, basic conditions may give rise to the isomerization of the initially formed 8,y-unsaturated carbonyl compounds (and other acceptor-substituted alkenes of this type) to the thermodynamically more stable conjugated isomer (Eq. 4.1). 

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. 

In contrast, soft electrophiles react with nucleophilic SH groups in GSH and proteins. Soft electrophiles are typically cytotoxic, such as the metabolite of paracetamol, N-acetyl-p-benzoquinoneimine (Fig. 4.73) (see also chap. 7). So reactivity with GSH depends on the hardness/softness of the electrophile. 

Apart from their fundamental role in sulfur ylide chemistry, sulfonium salts have found applications as soft electrophiles. In alkylation of ambident nucleophiles such as the enolates of [3-dicarbonyl compounds they led to selective C-alkylation [205],... 

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. 

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. 

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

For Pd-catalyzed cross-coupling reactions the organopalladium complex is generated from an organic electrophile RX and a Pd(0) complex in the presence of a carbon nucleophile. Not only organic halides but also sulfonium salts [38], iodonium salts [39], diazonium salts [40], or thiol esters (to yield acylpalladium complexes) [41] can be used as electrophiles. With allylic electrophiles (allyl halides, esters, or carbonates, or strained allylic ethers and related compounds) Pd-i73-jt-allyl complexes are formed these react as soft, electrophilic allylating reagents. 

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