Механизм нуклеофильного ароматического замещения

Chemical reaction mechanism
A nucleophilic aromatic substitution (SNAr) is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compounds do undergo nucleophilic substitution. Just as normally nucleophilic alkenes can be made to undergo conjugate substitution if they carry electron withdrawing substituents, so normally nucleophilic aromatic rings also become electrophilic if they have the right substituents. This reaction differs from a common SN2 reaction, because it happens at a trigonal carbon atom (sp2 hybridization). The mechanism of SN2 reaction does not occur due to steric hindrance of the benzene ring. In order to attack the C atom, the nucleophile must approach in line with the C LG (leaving group) bond from the back, where the benzene ring lies. It follows the general rule for which SN2 reactions occur only at a tetrahedral carbon atom. The SN1 mechanism is possible but very unfavourable unless the leaving group is an exceptionally good one. It would involve the unaided loss of the leaving group and the formation of an aryl cation. In the SN1 reactions all the cations employed as intermediates were planar with an empty p orbital. This cation is planar but the p orbital is full (it is part of the aromatic ring) and the empty orbital is an sp2 orbital outside the ring.

The following is the reaction mechanism of a nucleophilic aromatic substitution of 2,4 dinitrochlorobenzene (1) in a basic solution in water. Since the nitro group is an activator toward nucleophilic substitution, and a meta director, it is able to stabilize the additional electron density (via resonance) when the aromatic compound is attacked by the hydroxide nucleophile. The resulting intermediate, named the Meisenheimer complex (2a), the ipso carbon is temporarily bonded to the hydroxyl group. This Meisenheimer complex is extra stabilized by the additional electron withdrawing nitro group (2b). In order to return to a lower energy state, either the hydroxyl group leaves, or the chloride leaves. In solution, both processes happen. A small percentage of the intermediate loses the chloride to become the product (2,4 dinitrophenol, 3), while the rest return to the reactant (1). Since 2,4 dinitrophenol is in a lower energy state, it will not return to form the reactant, so after some time has passed, the reaction reaches chemical equilibrium that favors the 2,4 dinitrophenol, which is then deprotonated by the basic solution (4). The formation of the resonance stabilized Meisenheimer complex is slow because the loss of aromaticity due to nucleophilic attack results in a higher energy state. By the same coin, the loss of the chloride or hydroxide is fast, because the ring regains aromaticity. Recent work indicates that, sometimes, the Meisenheimer complex is not always a true intermediate but may be the transition state of a 'frontside SN2' process, particularly if stabilization by electron withdrawing groups is not very strong. A 2019 review argues that such 'concerted SNAr' reactions are more prevalent than previously assumed. Aryl halides cannot undergo the classic 'backside' SN2 reaction. The carbon halogen bond is in the plane of the ring because the carbon atom has a trigonal planar geometry. Backside attack is blocked and this reaction is therefore not possible. An SN1 reaction is possible but very unfavourable. It would involve the unaided loss of the leaving group and the formation of an aryl cation. The leaving group can be a halogen or a sulfide. With increasing electronegativity the reaction rate for nucleophilic attack increases. In the compound methyl 3 nitropyridine 4 carboxylate, the meta nitro group is actually displaced by fluorine with cesium fluoride in DMSO at 120 °C.

With carbon nucleophiles such as 1,3 dicarbonyl compounds the reaction has been demonstrated as a method for the asymmetric synthesis of chiral molecules. First reported in 2005, the organocatalyst (in a dual role with that of a phase transfer catalyst) is derived from cinchonidine (benzylated at N and O).