Charge/orbital control

If we are comparing reactions which have approximatively the same steric requirements, the first term is roughly constant. If the species are very polar the second term will dominate, and the reaction is charge controlled. This means for example that an electrophihc attack is likely to occur at the most negative atom, or in a more general sense, along a path where the electrostatic potential is most negative. If the molecules are non-polar, the third term in (15.1) will dominate, and the reaction is orbital controlled. 

These concepts play an important role in the Hard and Soft Acid and Base (HSAB) principle, which states that hard acids prefer to react with hard bases, and vice versa. By means of Koopmann s theorem (Section 3.4) the hardness is related to the HOMO-LUMO energy difference, i.e. a small gap indicates a soft molecule. From second-order perturbation theory it also follows that a small gap between occupied and unoccupied orbitals will give a large contribution to the polarizability (Section 10.6), i.e. softness is a measure of how easily the electron density can be distorted by external fields, for example those generated by another molecule. In terms of the perturbation equation (15.1), a hard-hard interaction is primarily charge controlled, while a soft-soft interaction is orbital controlled. Both FMO and HSAB theories may be considered as being limiting cases of chemical reactivity described by the Fukui ftinction. 

A fundament of the quantum chemical standpoint is that structure and reactivity are correlated. When using quantum chemical reactivity parameters for quantifying relationships between structure and reactivity one has the advantage of being able to describe the nature of the structural influences in a direct manner, without empirical assumptions. This is especially valid for the so-called Salem-Klopman equation. It allows the differentiation between the charge and the orbital controlled portions of the interaction between reactants. This was shown by the investigation of the interaction between the Lewis acid with complex counterions 18> (see part 4.4). 

The importance of both frontier orbital-controlled and electronic charge-controlled factors in determining chemical reactivity has been recognized (16). These concepts are the key to interpreting two types of reactivity expected for carbene complexes, i.e., reactions with nucleophilic... 

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 reactions of electrogenerated cation radicals of diarylsulfldes are mainly orbital-controlled and at this level the electronic structure of their frontier orbitals (HOMO-SOMO) has very interesting synthetic consequences. The 3p orbitals of sulfur are conjugated with only one aromatic ring even if there are two aryls bound to sulfur. Therefore, only one ring can be activated electrochemically. The degree of the charge delocalization in the ArS moiety of a cation radical on the one hand, and the availability of p- and o-positions for the substitution on the other, determine quite different reactivity of such species. 

There have been discussions whether the amide addition at C-6 is charge-controlled or orbital-controlled. Charge density calculations in 4-phenylpyrimidine (MNDO method) predict that the addition of the amide ion would preferably take place at position 2 (95UP1) this, however, does not agree with the experimental results. Therefore, the conclusion seems justified that the addition is not charge-controlled. Frontier orbital calculations, using the SCF-PPP method, show that the frontier orbital densities in the LUMO of pyrimidine are zero at C-2 and C-5, making these positions... 

If these three positions are neglected, leaving aromatic positions and the a-carbon of the sidechain, it is found that the size of the negative charge does not reflect the order of the energy differences. In contrast, the HOMO electron density at the various positions increases in the same sequence as the energy barrier toward chlorination. It may be concluded, therefore, that the chlorination reaction is more sensitive toward orbital control, and steric arguments, than simple coulombic attraction. 

For pyrroles with electron acceptor substituents in the 1-position electrophilic substitution with soft electrophiles can be frontier orbital controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles can be charge controlled and occur at the 3-position. 

However, the frontier orbital picture based on the free arene does not account for nearly exclusive meta selectivity in addition to [(anisole)Cr(CO)3] LUMO for anisole shows essentially the same pattern as for toluene.98-100 With a strong resonance electron donor the traditional electronic picture (deactivation of the ortho and para positions) is sufficient to account for the observed meta selectivity. In this case the balance of charge control and orbital control is pushed toward charge control by strong polarization. The same argument applies to the aniline and fluotobenzene complexes. 

A delicate balance of charge and orbital effects can also account for the dependence of selectivity on anion type. The central assumption is that nucleophiles with a higher lying HOMO (softer) should give a better orbital energy match in the HOMO-LUMO interaction and increase the orbital control term. For the toluene ligand, this predicts strong ortho-meta selectivity for more reactive anions. 

The regiochemistry of deuteration of polycyclic carbonyl compounds such as methyl derivatives of benz[de]anthracen-6- and -7-one is subject to orbital control.147 Charge alternation and deuterium isotope effects in these and related compounds were studied by NMR and MNDO methods. 

It is convenient to separate the total electron density at each atom into a- and 71-components. It is likely to be the 7t-density that will be important in reactions with nucleophiles, since in an orbitally controlled reaction (Chapter 1) the donor orbital of the incoming nucleophile will initially interact with the lowest vacant 7i -orbital. The overall pattern of charge alternation is repeated in both the 7t- and the a-electron densities, and nucleophiles are expected to attack at the 2- or 4-positions. This is exactly the pattern that is seen in... 

Lewis acids are atoms or molecules that accept an electron pair (103). Soft acids have polarizable valence electrons, whereas hard acids do not. Lewis bases are atoms or molecules that are capable of donating an electron pair. Soft bases are polarizable, whereas hard ones are not. Hard acids preferentially interact with hard bases the interaction is mainly ionic and charge controlled (104). Conversely, soft acids tend to interact (or react) with soft bases the interaction has covalent character and may be orbital controlled. 

Reactions of carbocations with free CN- occur preferentially at carbon, and not nitrogen as predicted by the principle of hard and soft acids and bases.69 Isocyano compounds (N-attack) are only formed with highly reactive carbocations where the reaction with cyanide occurs without an activation barrier because the diffusion limit has been reached. A study with the nitrite nucleophile led to a similar observation.70 This led to a conclusion that the ambident reactivity of nitrite in terms of charge control versus orbital control needs revision. In particular, it is proposed that SNl-type reactions of carbocations with nitrite only give kinetically controlled products when these reactions proceed without activation energy (i.e. are diffusion controlled). Activation controlled combinations are reversible and result in the thermodynamically more stable product. The kinetics of the reactions of benzhydrylium ions with alkoxides dissolved in the corresponding alcohols were determined.71 The order of nucleophilicities (OH- MeO- < EtO- < n-PrCT < / -PrO ) shows that alkoxides differ in reactivity only moderately, but are considerably more nucleophilic than hydroxide. 

Experimentally, MeBr gives O-methylation in the gas-phase reactions25 but RBr favors C-alkylation in solution. In general, charge control dominates gas-phase reactions because strong Coulombic effects26 are not attenuated by counterions or solvents. Since solution reactions are usually under frontier orbital control, the reactivity... 

The rate of success falls whenever these conditions are not met. For example, condition (1) is not always satisfied in aromatic substitution reactions. The FOs of polycyclic aromatic hydrocarbons are not well separated from the other MOs,66 so subjacent orbital control may intervene. Particular care should be taken with non-alternant hydrocarbons because they tend to react under charge control. This is even truer in heteroaromatic systems (cf. Exercise 15, p. 119, and Exercise 16, p. 121), where Hiickel... 

The results of these calculations are summarized in Table II. Formal charges predict that all nitroquinolines should have their highest reactivity at C-2. This is not confirmed by the experimental results. By comparing the experimental results with the FMO calculations it became evident that the order of reactivity of the ammonia addition is in good agreement. Thus, the addition reaction is orbital-controlled (87JOC5643). 

Table II. The Reactivity Order of Nitroquinolines with Ammonia, Calculated on Formal Charges and Orbital Control...

So the only remaining question is when thioamides combine with a-haloketones, which atom (N or S) attacks the ketone, and which atom (N or S) attacks the alkyl halide Carbonyl groups are hard electrophiles—their reactions are mainly under charge control and so they react best with basic nucleophiles (Chapter 12). Alkyl halides are soft electrophiles—their reactions are mainly under frontier orbital control and they react best with large uncharged nucleophiles from the lower rows of the periodic table. The ketone reacts with nitrogen and the alkyl halide with sulfur. 

The mechanism of the nitration of benzisoxazoles in sulfuric-nitric acid mixture has been studied with 3-methyl-l,2-benzisoxazole [121], It has been found that at a sulfuric acid concentration of about 80-90% the substrate reacts as a free base, and at a higher concentration the conjugated acid undergoes nitration. It is worth mentioning that in 1,2-benzisoxazole and its 3-methyl derivative the higher electron density is concentrated on the C-7 atom and in the case of charge-controlled reactions the nitration would lead to 7-nitro isomers. Since 5-nitro derivatives are formed, the process of nitration seems to be of orbital-controlled character [121],... 

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