Nucleophilic addition frontier

Self-consistent field molecular orbital calculations by Fenske and coworkers have confirmed that nucleophilic additions to Fischer and related complexes [e.g., (CO)sCr=CXY, (T)5-C5H5)(CO)2Mn=CXY], are frontier orbital-controlled rather than charge-controlled reactions (7-9). Interaction of the HOMO of the nucleophile with the carbene complex LUMO (localized on Ca) destroys the metal-carbon w-interaction and converts the bond to a single one. 

The diastereoselectivities in the nucleophilic addition reactions of l,3-dioxane-5-ones 37 and l,3-dithiane-5-ones 38 were studied by employing two newly available theoretical tools, the exterior frontier orbital electron (EFOE) density of the 7tc=o -orbitals and the 7t-plane-divided accessible space (PDAS) as quantitative measures of the 7t-facial steric effects <1999CRV1243, 1999CC621, 1999CL1161, 2000H(52)1435, 2001HAC358>. The two parameters predict correctly the experimentally observed stereochemical reversal of 37 and 38 (R = Ph see Table 1) in particular, the PDAS values for both substrates clearly show the opposite steric environment about the carbonyl carbon atom of these heterocyclic ketones and prove sizeable ground-state conformational differences to be responsible for the observed reversed facial stereoselection. 

Earlier explanations of the trans-stereoselectivity of nucleophilic additions to ethylenes cited frontier MO symmetry (Fukui, K. Tetrahedron Letters 1965, 2427), steric effects, or electrostatic factors (Benson, S. W., Haugen, G. R. J. Am. Chem. Soc. 87, 4026 (1965). 

For axial and equatorial nucleophilic addition to cyclohexanone, the principle of microscopic reversibility dictates that frontier orbital analysis can be considered for addition of the nucleophile to the carbonyl or loss of nucleophile from the product. Since the reaction is considered to be exothermic the frontier orbital interaction that should best represent the transition energy is the orbital interaction of the nucleophile HOMO with the ketone n (LUMO) (Fig. 6-11). 

Using semiempirical calculations, Shevchenko et al. [100] studied the impact of conformation on charge and frontier molecular orbitals in quinone methides and benzyl cations. Charges were sensitive to conformation, while the frontier molecular orbitals were not. These data were used to interpret the stereoselectivity of quinone methides toward nucleophiles. Additional related work addressed the Z-E conformation about the C-l-C-a double bond in quinone methides. Konshcin et al. 

Using their CNDO results Helland and Skancke calculated indices of reactivity (frontier electron density, FED, for electrophilic substitution frontier orbital density, FOD, for nucleophilic substitution frontier radical density, FRD, for radical substitution) for the thienopyridines. It was indicated that the FED index has its highest value for C-3 in the [2,3-]- and 3,2- -fused systems and for C-2 in the [3,4-1-fused isomers. As far as the former group is concerned, the predictions are in agreement with experimental observations (see Section IV,A.). Little experimental evidence is available for the [3,4-]-fused systems, but it seems highly probable that they would have a considerable tendency to undergo addition reactions at the 1,3-positions, since the product would contain a normal rather than a quinoid pyridine ring [Eq. (23)]. 

Finally, it should perhaps be noted that the catalytic efficiency of lysozyme can be accounted for quantitatively by valence-bond methods which envisage the pyranose ring as merely changing from C, chair to half-chair [45], and that recent thorough theoretical studies of nucleophilic additions to carbonyl compounds (reactions closely resembling the reverse of departure from an acetal centre) indicate that the frontier orbital description is inadequate in general [46]. 

Coefficients of frontier orbitals in monoadducts like CgifCOOEtfj (46) at a given [6,6]-bond are presented in Figs. 24 and 25. LUMO coefficients in a precursor molecule are expected to influence the product distribution of nucleophilic additions and the HOMO coefficients those of additions of electrophiles,... 

The Exterior Frontier Orbital Extension (EFOE) model has been applied to predict r-facial selectivity in nucleophilic additions to imines and iminium ions of the cyclohexanone, tropinone, and adamantan-2-one systems." A review of the EFOE model," and other references to its use, are described later under Regio-, Enantio-, and Diastereo-selective Aldol Reactions. 

Nonparametrized Fenske-Hall molecular orbital calculations on the carbyne complexes fra s-[CrX(CO)4(CR)] (X = Cl, Br, or I R = Me, Ph, or NEt2) support an earlier contention that nucleophilic additions to carbyne ligands are frontier orbital controlled rather than charge controlled. Thus, the only such complex to undergo nucleophilic addition to its carbyne carbon atom, namely, trans-[CrBr(CO)4(CC6H4Me-p)], is the only one whose LUMO corresponds to a Cr-carbyne ir-antibond. 

As a result, we could open the door to a new frontier in indole chemistry. Various 1-hydroxyindoles (4a), l-hydroxytryptophans(la), 1-hydroxytryptamines (lb), and their derivatives have been given birth for the first time. As predicted, 1-hydroxytryptophan and 1-hydroxytryptamine derivatives are found to undergo previously unknown nucleophilic substitution reactions. In addition, we have been uncovering many interesting reactivities characteristic of 1-hydroxyindole structures. From the synthetic point of view, useful building blocks for indole alkaloids, hither to inaccessible by the well-known electrophilic reactions in indole chemistry, have now become readily available. Many biologically interesting compounds have been prepared as well. 

In a, P-unsaturated carbonyl compounds and related electron-deficient alkenes and alkynes, there exist two electrophilic sites and both are prone to be attacked by nucleophiles. However, the conjugated site is considerably softer compared with the unconjugated site, based on the Frontier Molecular Orbital analysis.27 Consequently, softer nucleophiles predominantly react with a, (i-unsaturated carbonyl compounds through conjugate addition (or Michael addition). Water is a hard solvent. This property of water has two significant implications for conjugate addition reactions (1) Such reactions can tolerate water since the nucleophiles and the electrophiles are softer whereas water is hard and (2) water will not compete with nucleophiles significantly in such... 

Carboxymethyl glycoside lactones are easily prepared by diverse routes and react readily with nucleophilic species. Their reaction with amines, a simple addition which does not require any intermediate activation, is very general, and many examples of new pseudo-glycoconjugates prepared by this method are described. Moreover, 1,2-bisfunctionalized carbohydrate systems are efficiently constructed by reaction of the free OH on position 2 obtained after the opening of the lactone ring. Applications at the frontier of materials and biology have been envisaged and further studies in these fields will be reported in the near future. 

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