**1. Introduction**

Substitution reaction is one of the important classes of organic reactions. The term substitution itself indicates that the organic reaction process in which the one moiety/functional group will be replaced by other new group/moiety. Generally, there are two types of substitution reactions: one is bimolecular substitution reaction and the other is unimolecular substitution (SN1) reaction. The bimolecular reaction is a reaction in which the replacing group generates partially a positive charge on a substrate and a new electron-rich group occupies the position of the replacing group as shown in **Figure 1**. In short, it is referred as bimolecular nucleophilic substitution reactions (SN2) [1]. Aliphatic nucleophilic substitution reaction is generally performed in a non-protic solvent so that the nucleophile will be free

**Figure 1.** *Substitution reactions with metal nucleophile (MNu) in protic solvent.* and flexible to replace the leaving group. In case of a protic solvent, the electronrich species of nucleophile forms the hydrogen bond; thus, it reduces the efficiency of nucleophile, decreases nucleophilicity, and reduces the reaction rate. By contrast, some reactive nucleophiles, which show duel characters, may act as a base as well as a nucleophile; in such case, the possibility to form other side products are more. To improve the selectivity of the product, hydrogen bonding with reactive nucleophile will play a key role. Thus, a number of nucleophilic substitution reactions are performed in protic solvents such as *tert*-butanol, alcohol-functionalized ionic liquids, ammonium ionic liquids, or polyethylene glycols. In this book chapter, the recent development of SN2 reactions in protic solvent to improve the selectivity of substituted product is covered [2].
