Soft electrophile

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. 

The reactions of the xanthate esters with some soft electrophiles proceed with good yields (47) ... 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

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... 

Soft electrophiles will prefer carbon, and it is found experimentally that most alkyl halides react to give C-alkylation. Because of the n character of the HOMO of the anion, there is a stereoelectronic preference for attack of the electrophile approximately perpendicular to the plane of the enolate. The frontier orbital is ip2, with electron density mainly at O and C-2. The tpi orbital is transformed into the C=0 bond. The transition state for an 8 2 alkylation of an enolate can be represented as below. 

In order to gather more information about this problem, it was deemed worthwhile to follow the energetics of the alkylation reaction of water by methyl-, ethyl-, and fluo-roethyldiazonium ions. The main goal of these calculations was to establish whether transition-state calculations can provide information about hard versus soft electrophilic character of these species.12 Computations at Hartree-Fock and MP2 level were performed using the 6-31G basis set. It was found that both at the Hartree-Fock level and when correlation energy affects were included, the ethyl and fluoroethyl species do not show the presence of a transition state, while the methyl species show a small transition state. It was concluded that transition state computations cannot shed light on the characters of these species. 

The Zn11 cation may lend soft electrophilic assistance for transmetalation. The most efficient such assistance is in the intramolecular chelating mode, which is exemplified by cross-coupling of... 

An unusual observation was noted when ethanolic solutions of 2-alkyl-4(5)-aminoimidazoles (25 R = alkyl) were allowed to react with diethyl ethoxymethylenemalonate (62 R = H) [92JCS(P1)2789]. In addition to anticipated products (70), which were obtained in low yield ( 10%), the diimidazole derivatives (33 R = alkyl) were formed in ca.30% yield. The mechanism of formation of the diimidazole products (33) has been interpreted in terms of a reaction between the aminoimidazole (25) and its nitroimidazole precursor (27) during the reduction process. In particular, a soft-soft interaction between the highest occupied molecular orbital (HOMO) of the aminoimidazole (25) and the lowest unoccupied molecular orbital (LUMO) of the nitroimidazole (27) is favorable and probably leads to an intermediate, which on tautomerism, elimination of water, and further reduction, gives the observed products (33). The reactions of amino-imidazoles with hard and soft electrophiles is further discussed in Section VI,C. 

The most common method for the preparation of 1,2,3-benzothiadiazoles is the diazotization of 2-aminobenzenethiol. This method was discussed and exemplified in CHEC-II(1996). The method has been extended in recent years to include heterocyclic derivatives. The 2-aminothiophene 79 can be converted into the thienothiadiazole 82 on treatment with sodium nitrite in HC1 but in poor yield (16%). The bis(BOC)-protected derivative 80 or the mono(BOC)-protected derivative 81 when reacted under similar conditions afford product 82 in much higher yields (BOC = /-butoxycarbonyl Scheme 9). The increase in yield is explained in terms of hard and soft electrophilic character. The intermediate in the BOC-protected examples has a soft character allowing attack by sulfur to proceed more easily <1999JHC761>. 

Other soft, electrophilic metals, including mercury(ll) analogs, are also known to activate methane.16... 

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. 

In HSAB terms sulfonyl sulfur should be a relatively hard electrophilic center, sulfenyl sulfur a relatively soft electrophilic center, and sulfinyl sulfur should occupy a position somewhere in between. 

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). 

Oxazolines and thiazolines are lithiated at the 2-position to give species that, like oxazole (Section III,B,1), are in equilibrium with ring-opened forms [70JA6676 90H(31) 1213]. Subsequent reaction with electrophiles can occur via either form (Scheme 139), with soft electrophiles (e.g.,... 

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