Frontier control

Aminothia2ole-3-oxides in neutral medium react differently on alky) isocyanates (355) and arylisocyanates (356) (Scheme 204) (684). The interpretation of this difference rests on the Concepts of charge control versus frontier control reactivity (1594 see also p. 63). Esters of... 

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... 

Klopman, G. 1968. Chemical reactivity and the concept of charge and frontier-controlled reactions. J. Am. Chem. Soc. 90 223-234... 

Another difficulty exists. It has been found that in the gas phase or in dipolar aprotic solutions, small anions (cations) have higher HOMO s (lower LUMO s) than the larger one. It follows that interaction between two hard ions is then favoured by both charge control and frontier control. Therefore, the equivalences suggested by Klopman ... 

These results suggest the presence of two competing pathways to products, which depend upon the location of protonation at the M=C carbyne bond. Charged controlled protonation at the carbyne carbon followed by nucleophilic attack of the CT leads to the butadiene complex. Frontier control of protonation results in attack at the metal center, leading ultimately to the hydride complex164. This has been verified by reaction of the... 

At first sight, radical reactions seem to be ideally adapted to frontier orbital analysis. They are usually exothermic, so their transition states resemble the reagents. Therefore, the starting material frontier orbitals should provide us with a very good approximation. Furthermore, radicals are soft reagents, whose reaction partners are often neutral molecules. Frontier control is dominant in such reactions. 

The E2-Sn2 competition is reasonably easy to evaluate, because basicity (an affinity for H+) is mainly under charge control and nucleophilicity (an affinity for C+) mainly under frontier control. 

Deserves your attention. MOs are given on p. 274 Which sites at dibenzofuran are the most susceptible to attack (a) under frontier control and (b) under charge control ... 

Frontier control favors attack on C3 (rule 3). Note, however, that charge control also favors this regiochemistry if the influence of neighboring charged atoms is taken into account. C3 has in its proximity two charged atoms. The termini have only one such, the second charged atom being further away. 

Note that a frontier interaction such as HOMO(l)-LUMO(2) automatically implies electron transfer from molecule (1) to molecule (2), so that electrostatic factors are already partially taken into account in frontier control. 

Care must be taken in generalizing gas-phase computational results, which tend to overemphasize charge control while underemphasizing frontier control. Indeed, in the absence of solvent, coulombic forces, which vary as the inverse square of the distance, are stronger at large distances than frontier interactions, which diminish exponentially with the separation. The reaction then becomes charge controlled with an early transition state in which the reagents may still be in their most stable conformations. The role of the conformational effect is then somewhat overstated. This is especially true in older calculations in which O or Cl were replaced by F and Na+ and K+ were modeled by Li+. 

When — E 0 interaction between frontier orbitals (HOMO and LUMO) is important and a frontier-controlled reaction involving electron transfer occurs. A totai may then be written as... 

Low (soft) Large orbital Small Very small Large Frontier controlled High... 

---