Nucleophilic substitution 338 INDEX

If only the electron density of the highest occupied molecular orbital (HOMO) is taken into account, an electrophilic attack is said to be regulated by the frontier electron density index (54JCP1433 79FCF1). In nucleophilic substitutions, the aromatic substrate tends to accept an electron pair in the transition state, and so the frontier orbital is taken as the lowest unoccupied molecular orbital (LUMO). In this case, the frontier electron density is assumed to be as the electron distribution that would be present in the LUMO if it were occupied by two electrons. In contrast to arguments based on the charge or 7c-electron densities, both nucleophilic and electrophilic substitution occur preferentially at the atom with the highest electron density within the appropriate frontier orbital, i.e., LUMO or HOMO, respectively. 

Finally, the global and local electrophilicity indexes may be also used to describe the nucleofugality of classical leaving groups in organic chemistry. This potential application incorporates the important families of nucleophilic substitution and elimination reactions. This study is however a bit more complex than the cases presented in this review, because the systematization of nucleofugality within an absolute scale requires an important number of requisites that must be fulfilled, most of them regarding the different reaction mechanisms involved in these complexe reactions. 

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)]. 

Evaluation of the only appropriate Fukui function is required for investigating an intramolecular reaction, as local softness is merely scaling of Fukui function (as shown in Equation 12.7), and does not alter the intramolecular reactivity trend. For this type, one needs to evaluate the proper Fukui functions (/+ or / ) for the different potential sites of the substrate. For example, the Fukui function values for the C and O atoms of H2CO, shown above, predicts that O atom should be the preferred site for an electrophilic attack, whereas C atom will be open to a nucleophilic attack. Atomic Fukui function for electrophilic attack (fc ) for the ring carbon atoms has been used to study the directing ability of substituents in electrophilic substitution reaction of monosubstituted benzene [23]. In some cases, it was shown that relative electrophilicity (f+/f ) or nucleophilicity (/ /f+) indices provide better intramolecular reactivity trend [23]. For example, basicity of substituted anilines could be explained successfully using relative nucleophilicity index ( / /f 1) [23]. Note however that these parameters are not able to differentiate the preferred site of protonation in benzene derivatives, determined from the absolute proton affinities [24],... 

Besides the applications of the electrophilicity index mentioned in the review article [40], following recent applications and developments have been observed, including relationship between basicity and nucleophilicity [64], 3D-quantitative structure activity analysis [65], Quantitative Structure-Toxicity Relationship (QSTR) [66], redox potential [67,68], Woodward-Hoffmann rules [69], Michael-type reactions [70], Sn2 reactions [71], multiphilic descriptions [72], etc. Molecular systems include silylenes [73], heterocyclohexanones [74], pyrido-di-indoles [65], bipyridine [75], aromatic and heterocyclic sulfonamides [76], substituted nitrenes and phosphi-nidenes [77], first-row transition metal ions [67], triruthenium ring core structures [78], benzhydryl derivatives [79], multivalent superatoms [80], nitrobenzodifuroxan [70], dialkylpyridinium ions [81], dioxins [82], arsenosugars and thioarsenicals [83], dynamic properties of clusters and nanostructures [84], porphyrin compounds [85-87], and so on. 

The reliability and usefulness of a new empirical nucleofugality index, which is defined as the group electrophilicity of the leaving group embedded in the substrate that undergoes the nucleophilic attack, were tested against experimental kinetic data recorded for aminolysis reactions of variously substituted phenoxy- and thiophenoxy-carbonyl and the corresponding thiocarbonyl derivatives.50... 

B3LYP/6-31 lG(d) calculations have used frontier molecular orbitals, chemical potential, and Pearson s electrophilicity index co to study the reactions between allylic and aliphatic alcohols and ethylacetoacetate. All three methods predict the correct product substitution by the R group of the alcohol at the methylene carbon when the alcohol is electrophilic, and transesteriflcation of the ethylacetoacetate when the alcohol is nucleophilic. The results agree with the existing experimental evidence. 

The nucleophilicity N index/ the inverse of the electrophilicity ( / >), and the inverse of the electrodonating power ( / > ) have been checked towards the following reactions (i) 5-substituted indoles for which rate constants were available (ii) para-substituted phenols and (iii) 2,5-disubstituted bicyclic[2.2.1]hepta-2,5-dienes. The nucleophilicity N index was found to work well, especially for more complex molecules, which was not always the case for l/ > and Hco ... 

Can nrr be a successful index for nucleophilic and electrophilic substitution if these are observed to occur at different sites ... 

Where Chomo.tce is the HOMO energy of tetracyanoethylene (TCE) taken as a reference molecule because it exhibits the lowest HOMO energy in a large series of molecules previously considered in the framework of polar DA cydoadditions). N is the global nudeophilidty index and is its local counterpart. This nudeophilicity index has been useful to explain the nucleophilic reactivity of some molecules towards electrophiles in cycloaddition as well as substitution reactions. (Domingo, et al, 2008)... 

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