Nucleophilic ‘front-side’ attack

When the chiral a,jS-enone enoate 98 was treated with magnesiocuprates in the presence of 1.5-2 equivalents of diethylaluminium chloride, the anti addition product 99 was obtained in moderate yield and with good diastereoselectivity (Scheme 6.21) [43, 44]. A reasonable explanation might assume a chelating coordination of the aluminium reagent [45]. Thus, if the enone 98 were to adopt an s-trans conformation, as indicated for complex 100, subsequent front side attack of the nucleophile would furnish the major diastereomer anti-99. 

Front-side attack, corresponding to an attack on the big lobe of silicon, leads to retention. When unfavorable, out-of-phase overlap between the nucleophile and the orbitals of the leaving group predominates, nucleophilic attack occurs at the rear of the molecule, opposite X, leading to... 

In the case of the p -methoxyphenoxide anion, Taft et al. (77) have shown that the oxygen atom has a high degree of sp3 character. This nucleophile is quite similar to hard alkyl anions from an electronic point of view, i.e., it is a hard nucleophile with contracted valence orbitals around oxygen, unfavorable out-of-phase overlap with the leaving group is minimized (Scheme 9), and a front-side attack leading to retention is therefore possible. The stereochemical data are summarized in Table XI. 

However, intramolecular nucleophilic participation by the conjugate base during protonolysis of a C—Hg bond is questionable. A study of the acidolysis of the carbon-mercury bond in unsymmetrical di-alkylmercurials rather suggests that the reaction proceeds via a three-center transition state.In any case, substantial kinetic and stereochemical evidence has led to the idea that reaction occurs by a concerted, front side attack with a transition state that involves a pentacoordinate carbon center. In some cases unimolecular mechanisms, SeI, also have been observed. 

Finally, similar hybridization arguments explain the order of reactivity of bicyclic systems. The results of the solvolysis studies show the relative reactivities to follow the same general trend as in nucleophilic substitutions (Scheme 44) (174). Because of the cage structure of the above bicyclic systems, only front-side attack at silicon is possible. Thus, an increase of the reactivity would be observed for the Si-X bonds that have a high degree of s character. Our analysis is as follows. 

Kirmse and coworkers (Kirmse and Siegfried, 1989 Banert et al., 1986) intensively investigated the reactions shown in Scheme 7-21 first, by conducting the reactions with six structurally different amines, and second, by using for each of these deaminations 3-4 solvents of decreasing polarity (water, acetic, 3,3-dimethylbutyric, and 2-ethylhexanoic acid), as shown by their t(30) solvent parameters (see Reichardt, 1988). Water has a much higher nucleophilicity, however, than the carboxylic acids and, therefore, the results in water are not directly comparable with those for the other three solvents. Decreasing polarity of these carboxylic acids increases the extent of front-side attack of the internal nucleophile H2O via collapse of the... 

Comparison of activation barriers values for hydrolysis of oxiiane, catalyzed by oxonium ion, clearly demonstrates the preference of rear-side attack of nucleophile if compared with front-side attack, where transition state destabilized by Coulomb and Pauli repulsion between the electron rich OH " and CH " fragments (Fig. 10.17) [32],... 

By contrast, the front-side attack VIII cannot be supported by an effective n — ff interaction, which is why it is energetically unfavorable, as also are other variants of approach of a nucleophile to the central atom shown in Scheme IX, which have carefully been studied in ab initio (4-3IG) calculations of the reaction F -f- CHjF [24]. The difference between the energies of the structures, which are formed along the paths of the front-side and the rear-side attacks, amounts in the reaction zone to approximately 50 kcal/mol, which is an evidence in favor of the rear-side attack. 

Two stereochemical possibilities present themselves In the pathway shown in Fig ure 8 la the nucleophile simply assumes the position occupied by the leaving group It attacks the substrate at the same face from which the leaving group departs This is called front side displacement or substitution with retention of configuration... 

In a solvolysis reaction, attack on R by a solvent molecule, e.g. H20 , in (26) is likely to lead to inversion, as attack can take place (by the solvent envelope) on the back side of R , but not on the front side where there are no solvent molecules, and which is shielded by the Bre gegen ion. Attack in (27) is more likely to lead to attack from either side, leading to racemisation, while attack on (28) can clearly happen with equal facility from either side. Thus the longer the life of R , i.e. the longer it escapes nucleophilic attack, the greater the proportion of racemisation that we should expect to occur. The life of R is likely to be longer the more stable it is—(a) above—but the shorter the more powerfully nucleophilic the solvent—(b) above. 

As shown in Fig. 1, the big lobes of these hybrids point toward each other. Therefore, if the nucleophile approaches the substrate from the front side, its HOMO overlaps in phase with the big lobe of 0c and out-of-phase with the big lobe of 0x-Numerical calculations show that the unfavourable (nucleophile-leaving group) interaction usually overrides the favourable (nucleophile - reaction center) interaction in this front-side approach, so that back-side attack is finally preferred, leading to inversion of configuration. 

Salem s frontier-orbital treatment is consistent with the fact that retention of configuration is a commonly observed stereochemical outcome at silicon (Tables I and II), whereas there is still no proven example of an Sx2 reaction with retention at carbon (69). Because Si—X bonds are significantly longer than C—X bonds, the unfavorable interaction between X and the nucleophile for front-side RN attack is less for silicon than for carbon (Scheme 9). The valence orbitals also change from 2s and 2p for carbon to 3s and 3p for silicon and therefore become more diffuse and capable of better overlap with the nucleophile at longer distances. Consequently, the probability of attack with retention is enhanced. 

Data for solvolyses of 1 -bromoadamantane (54, X = Br in Scheme 2.19) in ethanol-water in Table 2.3 show that S is approximately independent of solvent composition, but the selectivity is inverse. Why is S < 1 for competing nucleophilic substitutions when ethanol is normally more nucleophilic than water A credible explanation is that the products are formed by front-side collapse of a solvent-separated ion pair (52 in Scheme 2.18) - the caged structure prevents rear-side approach, so attack must occur from the front-side, and the proportion of water in solvent-separated ion pairs must be greater than in the bulk solvent. 

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