Stereoelectronics nucleophiles

The more stable the LUMO, the stronger is the interaction with the HOMO of the approaching nucleophile. The observed (Cram s rule) stereoselectivity is then a combination of stereoelectronic effects ftiat establish a preference for a perpendicular substituent and a steric effect that establishes a preference for the nucleophile to approach from the direction occupied by the smallest substituent. 

Addition of trimethylaluminum to norcamphor (3), regardless of the stoichiometry of the reactants, leads to a mixture of the diastereomeric alcohols in a ratio of 95 5 also in favor of the erafo-alcohol6. Examination of the norcamphor model indicates that endo attack is sterical-ly more hindered than exo attack. However, steric interaction may not fully account for the exceptionally high exo selectivity. On the other hand, no severe torsional strain is involved if the nucleophile approaches the carbonyl group from the exo side, however, a nucleophile approaching from the endo side encounters torsional strain between the incipient bond and the C-l to C-6 carbon-carbon bond. Thus, in the case of norcamphor, steric and stereoelectronic factors reinforce each other, resulting in a strong directional influence for exo attack. 

These side reactions may occur if the /V-acyliminium ion is not trapped quickly enough by a nucleophile. So problems may arise with relatively poor nucleophiles or if there is too much steric hindrance, while in the case of intramolecular reactions, unfavorable stereoelectronic factors or intended formation of medium- or large-sized rings may play a role. The reaction conditions, such as the nature of the (acidic) catalyst and the solvent, may also be of importance. 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

The nucleophilic carbcnes are phosphine-mimics but they are much more. They reside at the upper end of the Tolman electronic and steric parameter scales. Much remains to be explored with these ligands. With a rudimentary understanding of ligand stereoelectronic properties, we feel confident much exciting chemistry remains to be explored. 

Enamines also react with electrophilic alkenes to give conjugate addition products. The addition reactions of enamines of cyclohexanones show a strong preference for attack from the axial direction.319 This is anticipated on stereoelectronic grounds because the tt orbital of the enamine is the site of nucleophilicity. 

FIGURE 7.13 Molecular model of the pyrrolo [ 1,2-<2] i ndol e showing the site of nucleophile attack that provides a favorable stereoelectronic effect. The inset shows expected orbital interactions. 

In a recent study, we showed that the more flexible pyrido[l,2-a]indole-based cyclopropyl quinone methide is not subject to the stereoelectronic effect.47 Scheme 7.17 shows an electrostatic potential map of the protonated cyclopropyl quinone methide with arrows indicating the two possible nucleophilic attack sites on the electron-deficient (blue-colored) cyclopropyl ring. The 13C label allows both nucleophile attack products, the pyrido[l,2-a]indole and azepino [l,2-a]indole, to be distinguished without isolation. The site of nucleophilic is under steric control with pyrido [1,2-a]indole ring formation favored by large nucleophiles. 

Nuclear motion, the principle of least, and the theory of stereoelectronic control, 24, 113 Nucleophiles, partitioning of carbocations between addition and deprotonation. 35, 67 Nucleophilic aromatic photosubstitution, 11,225 Nucleophilic catalysis of ester hydrolysis and related reactions, 5,237 Nucleophilic displacement reactions, gas-phase, 21, 197... 

The higher nucleophilicity of the yS-oxide ion may be attributed to a steric factor in combination with a kinetically effective stereoelectronic effect that results from repulsions of lone electron pairs, dipole effects, or both (Scheme 5) (45,46). This effect should be more pronounced in anomericy3-oxide ions... 

In 1984, Corey and Boaz rationalized the anti stereochemistry observed in most of the organocopper-mediated SN2 displacements [4]. The stereoelectronic effect arising from a bidentate binding involves a d-orbital of a nucleophilic copper and... 

In conclusion, it is clear that a variety of stereoelectronic (internal) factors and external conditions favor a substantial positive charge in the transition state of diol epoxides as they undergo hydration or react with nucleophiles [115-118], Interpreting the reactivity of diol epoxides (or of numerous other electrophilic metabolites) in terms of toxification vs. detoxification is particularly difficult since toxicity depends as much on the nature of the endogenous nucleophile as on the intrinsic reactivity of the metabolites. 

To explain the stereochemistry of the allylic substitution reaction, a simple stereoelectronic model based on frontier molecular orbital considerations has been proposed (155, Fig. 6.2). Organocopper reagents, unlike C-nucleophiles, possess filled d-orbitals (d configuration), which can interact both with the 7t -(C=C) orbital at the y-carbon and to a minor extent with the o- -(C-X) orbital, as depicted... 

---