Nucleophilic substitution reactions factors determining mechanism

We give below the basic data obtained from a systematic study of the factors determining the mechanism and stoichiometry of the nucleophilic substitution reactions used for the synthesis of cellulose derivatives. 

Studies have shown that the HDN of 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline catalyzed by sulfided NiMo/Al203 occur via a nucleophilic substitution mechanism [121]. On the other hand, HDN of aliphatic amines with the same catalyst—N1M0/AI2O3—occurs by -elimination [117]. The nature of the base and the amine structure dictate whether the elimination will proceed via a monomolecular (El) or a bimolecular (E2) mechanism. Similarly, for HDN reactions that occur via nucleophilic substitution, these same factors determine if the reaction will follow a monomolecular (Sn 1) or a bimolecular (Sn2) mechanism. 

The difference between 8 2 and 8 1 reactions can be rationalised by the reaction energy profiles shown in Figure 11.1. The nucleophilic substitutions of bromomethane and of tertiary butyl bromide in aqueous solution illustrate some of the factors that determine the size of the energy barriers and the stability of the intermediate in these mechanisms. 

The comparison between the contributions to the thermodynamic cycle is presented, step-by-step, in Table 11.1. This comparison assigns most of the difference between the enthalpies of reactions (ll.Vni) and (ll.IX) to the ionisation potentials of the radical R. Minor contributions also come from the hydration of the R+ carbocation and from the C-X bond dissociation energy. The factor that controls the mechanism of nucleophilic substitution appears then to be /p(R )- A low /p(R ) favours the 8 1 mechanism because it lowers the enthalpy of its rate-determining step, while a high /p(R ) favours the 8fj2 mechanism. 

The attack of a nucleophile on a carbonyl group can result in substitution or addition (Chapter 16), though the first step of each mechanism is the same. The main factor that determines the product is the identity of the group X in RCOX. When X is alkyl or hydrogen, addition usually takes place. When X is halogen, OH, OCOR, NH2, and so on, the usual reaction is substitution. 

First, identify the leaving group, the electrophilic carbon, and the nucleophile. Then decide whether the reaction follows the SN1 or SN2 mechanism because this determines the stereochemistry. If the leaving group is bonded to a tertiary carbon, then the reaction must occur by the SN1 mechanism. (Later we will learn other factors that control which substitution mechanism a reaction follows.) For an SNI reaction, replace the leaving group on the electrophilic carbon with the nucleophile with loss of stereochemistry at the reaction center. 

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