Electrophilic substitution, aromatic energetics

Electrophilic substitution, aromatic, 31, 130-167, 381 1,2-ti. 1,4-addition, 195 as addition/elimination, 133 complexing with substituent, 160 deuterium exchange, 131,158 electronic effects in, 148, 158, 159 energetics of, 132, 136 field effect in, 152 hyperconjugation in, 153 inductive effect in, 22,152,153,156, 160... 

Aromatic compounds have a special place in ground-state chemistry because of their enhanced thermodynamic stability, which is associated with the presence of a closed she of (4n + 2) pi-electrons. The thermal chemistry of benzene and related compounds is dominated by substitution reactions, especially electrophilic substitutions, in which the aromatic system is preserved in the overall process. In the photochemistry of aromatic compounds such thermodynamic factors are of secondary importance the electronically excited state is sufficiently energetic, and sufficiently different in electron distribution and electron donor-acceptor properties, ior pathways to be accessible that lead to products which are not characteristic of ground-state processes. Often these products are thermodynamically unstable (though kinetically stable) with respect to the substrates from which they are formed, or they represent an orientational preference different from the one that predominates thermally. 

Spin-coupled studies of Wheland intermediates formed by ring protonation of benzene, phenol and benzonitrile provide ab initio support [7] for the usual qualitative VB arguments used to discuss the energetics and selectivity of aromatic electrophilic substitution reactions. Analogous calculations have also been performed for the reaction between benzene and a methyl cation [9]. 

The Ji-electron cloud above and below the plane of the benzene ring is a source of electron density and confers nucleophilic properties on the system. Thus, reagents that are deficient in electron density, electrophiles, are likely to attack, whilst electron-rich nucleophiles should be repelled and therefore be unlikely to react. Furthermore, in electrophilic substitution the leaving group is a proton, H", but in nucleophilic substitution it is a hydride ion, H the former process is energetically more favourable. In fact, nucleophilic aromatic suhstitution is not common, but it does occur in certain circumstances. 

Hydrogen in the stable bonds of aliphatic and aromatic compounds can be exchanged only under particularly energetic conditions. It is favored, for instance, by solid catalysts, by strong bases which ease the removal of protons in such cases, or by strong acids which act as effective deuteron-donors. An acid-base-catalysed ionic mechanism and an electrophilic substitution mechanism have both been discussed as explaining the formation of deuterated compounds.70,71... 

To explain these patterns, electronic influences are most relevant. In addition, steric factors play a certain role for substitution at the 2-(ortho) position. Substituents Y vith a free electron pair on the atom that is to be attached to the aromatic ring (e.g. OCOR, NHCOR, OR, OH, NH2, NR2) provide this electron pair for conjugative stabilization of the cationic transition state formed after attack of the electrophile. This leads to an acceleration of the reaction (lowering of the energetic level of the transition state) and to preferable electrophilic substitution at ortho- and para-positions. For these positions, stabilization involving the free electron pair of Y is more favorable than for the meta-position. 

We will address this issue further in Chapter 10, where the polar effects of the substituents on both the c and n electrons will be considered. For the case of electrophilic aromatic substitution, where the energetics of interaction of an approaching electrophile with the 7t system determines both the rate of reaction and position of substitution, simple resonance arguments are extremely useful. 

The generation and behaviour in acid media of the radical cations of aromatic compounds investigated by ESR and absorption spectroscopy in the UV and visible regions do not allow us to draw unequivocal conclusions for the role of similar particles in the formation and conversions of arenium ions and hence for electrophilic aromatic substitutions. At a certain ratio of energetic levels the interaction of ArH and X" may be accompanied by the formation of the radical pair [ArH", X"] which is in equilibrium with the free radical ArH" and X , the binding of the X radicals leading to accumulation in the system of the ArH radical cation. It remains unclear, however, whether the formation and recombination of the radicals ArH" - and X (route b, c) may be more favourable than the direct route (a) of a-complex formation. 

It is well within the power of present MO methods to calculate the energy of the reactants and the intermediate. Major difficulties, however, remain (1) Just how closely does the transition state resemble the intermediate (2) How do solvent molecules and other species present in solution enter into the transition state structure, and how significant, energetically, are these interactions This second point is of great importance, since nearly all experimental data on electrophilic aromatic substitution pertain to reactions in solution. The uncertainties that result... 

In a chemical reaction, a more stable transition state, measured by the magnitude of the activation energy, implies an easier chemical reaction. Aromatic transition states are also known to facilitate the chemical reaction. Zhou and Parr defined the activation hardness as the hardness difference of the products and the transition state and found, in the case of electrophilic aromatic substitution, that the smaller the activation hardness, the faster the reaction is. For this specific reaction they also found a correlation of the activation hardness and Wheland s cation localization energy, also proposed as an indicator of aromaticity. This finding can indeed be interpreted as a manifestation of the maximum hardness principle. A transition state with a high hardness is more stable than one with a smaller hardness and is therefore easier to reach energetically. The same can be said about two transition states with different aromaticity. Again, hardness and aromaticity parallel each other. The activation hardness has been used in numerous applications for the prediction of site selectivity in chemical reac-... 

This is formally an El reaction, and the energetic driving force for losing this proton (for the El reaction) is reformation of the aromatic ring. This means that electrophilic aromatic substitution is in reality two reactions from a mechanistic viewpoint. The first is the Lewis acid-Lewis base reaction of benzene with Br+, which is generated from bromine and the Lewis acid. The second is an El-type reaction to give the substitution product and it is also an acid-base reaction. 

Why, then, do electrophiles prefer to attack naphthalene at Cl rather than at C2 Closer inspection of the resonance contributors for the two cations reveals an important difference Attack at Cl allows two of the resonance forms of the intermediate to keep an intact benzene ring, with the full benefit of aromatic cyclic delocalization. Attack at C2 allows only one such structure, so the resulting carbocation is less stable and the transition state leading to it is less energetically favorable. Because the first step in electrophilic aromatic substitution is rate determining, attack is faster at Cl than at C2. 

From a theoretical point of view, the key issue has been the basic nature of the metalation step, where the R groups moves from a R -H bond to a M-R bond. C-H activation is very common in organic chemistry as it allows the formation of functionalized hydrocarbons. Different mechanisms had been proposed for this metalation step, including electrophilic aromatic substitution, a-bond metathesis, oxidative addition/reductiveelimination and Heck-like insertion. Theoretical studies have facilitated narrowing the mechanistic possibilities to two main options oxidative addition/reductive elimination and proton abstraction by a base. In the oxidative addition/reductive elimination process the metal is inserted in the C-H bond with formal increase in the oxidation state of the metal, and the hydride leaves the metal coordination sphere of the metal afterwards. In the proton abstraction mechanism, the metal does not interact directly with the proton, which is captured by a base, with simultaneous formal creation of a carbanion that binds to the metal center. The mechanism of the reaction will depend on the presence of a base able to abstract the proton and of the existence of an energetically accessible oxidation state for the metal. 

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