This chapter deals with the unusual substitution reactions in non-aprotic solvent. Selective protic solvents that are widely being accepted for nucleophilic substitution reactions not only enhance the reaction rate but also give desire for selectivity of substituted product. Protic solvents such as tert-alcohol, primary alcohol, ionic liquids with tert-alcohol and primary alcohol functionality, and bis-cationic ionic liquid with protic functionality were shown best result in substitution reactions. Aliphatic nucleophilic substitution significantly developed in protic reaction medium due to the hydrogen bonding interaction with leaving groups and nucleophile. The development of substitution reactions from past two decades are summarised in this book chapter.
- substitution reactions
- alcohol solvents
- phase transfer catalyst
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) . Aliphatic nucleophilic substitution reaction is generally performed in a non-protic solvent so that the nucleophile will be free and flexible to replace the leaving group. In case of a protic solvent, the electron-rich 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
2. Protic solvent substitutions
2.1 Alcohol-mediated substitution reactions
Chi et al. developed the nucleophilic substitution reactions using
They observed that the alcohol solvent particularly nonpolar such as
Tert-alcohol-functionalized ionic liquid
Shinde et al. exhibited the synergistic effect of
In the development of the fluorination process, ILs play both roles, i.e. reaction media and phase-transfer catalysts. They found that nucleophilic fluorination is accelerated in
Figure 3 depicted the use of protic ionic liquid in nucleophilic fluorination. The reaction of the primary triflate of R-D-galactopyranose in the presence of
The reaction of the secondary mesylate, which could easily be eliminated to the corresponding olefin, showed a similar trend. Such superior reactivity and selectivity were obviously due to the previously mentioned synergistic effect of
2.3 Protic ethylammonium nitrate
Crosio et al. developed a new protic ionic liquid (IL) ethylammonium nitrate (EAN) inside toluene/benzyl-n-hexadecyldimethylammonium chloride (BHDC) as shown in Figure 5 and studied its application on reverse micelles affects . They found the Cl ion nucleophilicity on the bimolecular nucleophilic substitution (SN2) reaction between this anion and dimethyl-4-nitrophenylsulfonium trifluoromethanesulfonate. It was the first study where the polar EAN was used as a suitable reaction medium for toluene-BHDC reverse micelles as a nanoreactor for performing the kinetic studies. The light scattering experiment discloses the formation of RMs containing the protic EAN ionic liquid component. Their experiments demonstrate that the homogeneous reaction medium is low effective compared to EAN-mediated SN2 reaction conditions. The protic ionic liquid EAN acts as a aprotic medium once it is entrapped in BHDC RMs by hydrogen bonding interactions; as a result, nucleophilicity of chloride increases dramatically. Thus, the protic EAN is found as a suitable reaction solvent for nucleophilic bimolecular substitution reactions. These experiments demonstrate the flexibility of this kind of nanoreactor system to alter the polar protic solvent trapping and its impact on the rate of the reaction.
2.4 Polar protic solvent glycol
Song et al. observed that the alcohol contained polyethylene glycol as good reaction media for various nucleophilic substitution reactions . Achiral polyether derivatives have shown dramatic acceleration in the SN2 reactions by the simultaneous activation of both the nucleophile and electrophile sites of the leaving group. They also studied desiylation and found that bis-terminal ▬OH group plays a key role that the desilylative kinetic resolution is successively done of the silyl ethers of racemic secondary alcohols.
2.5 Primary alcohol-functionalized ionic liquid
Further, polyethylene glycol was used for functionalization of imidazolium-based ionic liquid and studied for SN2 reactions. Kim et al.  synthesised hexaehtylene glycol
The author described the role of all functional moieties of ionic liquid in nucleophilic fluorination by using salts of metal nucleophiles (Figure 7).
The application of di-functional polyether chain-substituted imidazolium ionic liquids in the synthesis of various bioactive molecules such as fluoro-flumazenil, fluoropropyl ciprofloxacin, etc., which are useful in molecular probes for PET, is synthesised using a protic ionic liquid as shown in Figure 8.
tert-alcohol-functionalized dicationic ionic liquid
The same research group developed another dicationic protic ionic liquid for substitution reactions. A task-specific hexaethylene glycol bridged bis-cationic ionic liquid (BFIL) such as bis(2-hydroxy-2-methyl-n-propylimidazolium) dimesylate (hexaehtylene glycol chain-DtOHIM) was prepared, and its role in nucleophilic substitution reactions using an alkali metal nucleophiles was investigated . They also compared their activities with a variety of mono-cationic ILs and found that the hexaehtylene glycol chain-functionalized IL more effectively enhanced the reactivity of KX compared with the
The use of bis-functionalized ionic liquid (BFIL) enhances the substitution reaction rate compared to conventional ionic liquid as well as mono-functionalized protic ionic liquid due to the higher activity of BFIL by the additional dicationic moieties compared with the mono-cationic ionic liquid methods. The author found that the hexaethylene glycol moiety of these hexaehtylene glycol chain-functionalized ILs enhances the reactivity of alkali metal fluorides by two effects; one is chelation effect with alkali metal cations, allowing the fluoride to become necked, and the other is the flexible fluoride influence by flexible H-bonding between the hydroxyl groups of BFIL, t-alcohol medium and nucleophile. In the case of t-alcohol-functionalized BFIL, the t-alcohol moiety showed selectively flexible H-bonding in the process. Subsequently, bi-alcohol-functionalized BFIL, having two imidazolium cations functionalized by ethylene glycol chain, showed the excellent catalytic increases in the reactivity of metal fluoride in the nucleophilic substitution among the mono-cationic convention ionic liquids.
The reaction of fluorination on another base-sensitive substrate of secondary alkyl tosylate using hexaehtylene glycol chain-DHIM with KF in
2.7 Protic amine tri-
Shinde et al. developed novel series of protic amines, i.e. tri-
Fluorination reactions on the secondary leaving group of natural steroid substrate, cholesterol that was successfully converted into 2-fluoro-cholesterol in reasonable good yield (Figure 12).
The reaction of OTf-containing substrate in the presence of promoter
Substitution reactions with reactive substrate such as bromoacetophenone to fluoro acetophenone gave poor conversion of corresponding fluorinated product, Figure 14. It may be due to the
The reaction could be conducted in acetonitrile on a wide variety of substrates with little alkene formation observed. Further, Lee et al. studied the quantum chemical calculations of these substitution reactions and suggested that tris-
3. Conclusion remark
In conclusion, the book chapter covers the recent development of protic solvents as reaction media of various substitution reactions. Aliphatic nucleophilic substitution reactions were extensively investigated in protic reaction medium and were found to be better reaction media compared to conventional aprotic solvents conditions. The protic solvents such as
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