**2. Protic solvent substitutions**

#### **2.1 Alcohol-mediated substitution reactions**

Chi et al. developed the nucleophilic substitution reactions using *tert*-alcohol solvents such as *tert*-butanol, *tert*-amyl alcohol, etc [3]. Nucleophiles such as fluorine gave promising results and an excellent desire for the selectivity of fluorinated product with low formation of corresponding by-product alkene. **Figure 1** shows the alkyl sulfonate leaving group replaced by fluorine efficiently in the *tert*-amyl alcohol-mediated reaction conditions. The extreme effect of protic solvent-mediated fluorination with alkali metal fluoride was demonstrated.

They observed that the alcohol solvent particularly nonpolar such as *tert*-alcohol enhances the nucleophilicity of the electron-rich nucleophilic ion, radically in lack of any type of promoter or phase-transfer catalyst, which significantly enhances the rate of the nucleophilic substitutions and reduces the generation of corresponding side products, i.e. alcohols, ethers and alkene, compared with substitution reactions in dipolar aprotic medium. The importance of this reaction method is that it is useful in radiopharmaceuticals for the synthesis of fluorine-18-labelled imaging agents for positron emission tomography (PET) [4]. They demonstrated the application of protic-mediated reactions for radiolabelling of important molecular imaging agents in good yield and quality in shorter time compared to aprotic-mediated reaction conditions of nucleophilic substitution reactions [5]. They further studied the influence of the *tert*-alcohol solvent conditions for nucleophilic substitutions with series of alkali metal fluorides. The possible hydrogen bonding interaction of nucleophile fluorine and the sulfonyloxy substrate promote the rate of reaction [6]. Mechanistically, the hydrogen bonding between alkali metal fluoride and aprotic solvent, the generation of protic alcohol-solvated ion and the hydrogen bonding between the leaving group sulfonate and the alcohol solvent seem to favour the enhancement in the rate of nucleophilic substitutions without PTC. They found that the fluorination with specific substrates with *tert*-butylammonium fluoride in alcohol solvent affords the corresponding fluoroproducts in high yield than that obtained by the conventional methods using dipolar aprotic solvents. The protic medium also suppresses the formation of by-products, such as alkenes, ethers and cyclic adducts.

#### **2.2** *Tert***-alcohol-functionalized ionic liquid**

Shinde et al. exhibited the synergistic effect of *tert*-alcohol and ionic liquids in substitution reactions [7]. They merged the two solvents, ionic liquid (IL) and *tert*-alcohols, into one molecule for nucleophilic substitution as shown in

**209**

temperature.

**Figure 2.**

of side reactions.

with no by-products [7].

functionality and imidazolium salts (**Figure 4**) [9].

**2.3 Protic ethylammonium nitrate**

*Protic Reaction Media for Nucleophilic Substitution Reactions*

*Synthesis of* tert*-alcohol-functionalized ionic liquid for substitution reactions.*

**Figure 2**. These hybridised ILs not only increase the nucleophilic reactivity of the fluoride anion but also reduce the olefin by-product. The preparation of novel imidazolium salts with counter anion [8]. Imidazole reacted with isobutylene oxide without or free solvents to give quantitatively yield N-*tert*alcohol-substituted imidazole. N-*tert*-alcohol-substituted imidazole reacted with methyl, isopropyl, n-butyl, n-hexyl methane sulphonate in acetonitrile at 90°C gave the corresponding N1-alkyl-N3-*tert*-alcohol substituted imidazolium salts (ILs) **1a–1d.** All of these imidazolium mesylates are liquids at room

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 **1a** and that *tert-*alcohol solvents show good performance in nucleophilic fluorination, thereby side reactions are remarkably suppressed via a weak F▬H hydrogen bond, which maintains the inherent nucleophilicity and reduces the basicity of the fluoride anion. The new hybridization of ILs and *tert*-alcohol functionality would provide dual advantages of reaction acceleration and minimization

**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 **1a** as a protic catalyst yielded the fluorinated product (**6a**) in almost quantitative yield

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 *tert-*alcohol

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 [10]. 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

*DOI: http://dx.doi.org/10.5772/intechopen.91395*

**Figure 2.**

*Photophysics, Photochemical and Substitution Reactions - Recent Advances*

substituted product is covered [2].

**2. Protic solvent substitutions**

**2.1 Alcohol-mediated substitution reactions**

ated fluorination with alkali metal fluoride was demonstrated.

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

Chi et al. developed the nucleophilic substitution reactions using *tert*-alcohol solvents such as *tert*-butanol, *tert*-amyl alcohol, etc [3]. Nucleophiles such as fluorine gave promising results and an excellent desire for the selectivity of fluorinated product with low formation of corresponding by-product alkene. **Figure 1** shows the alkyl sulfonate leaving group replaced by fluorine efficiently in the *tert*-amyl alcohol-mediated reaction conditions. The extreme effect of protic solvent-medi-

They observed that the alcohol solvent particularly nonpolar such as *tert*-alcohol enhances the nucleophilicity of the electron-rich nucleophilic ion, radically in lack of any type of promoter or phase-transfer catalyst, which significantly enhances the rate of the nucleophilic substitutions and reduces the generation of corresponding side products, i.e. alcohols, ethers and alkene, compared with substitution reactions in dipolar aprotic medium. The importance of this reaction method is that it is useful in radiopharmaceuticals for the synthesis of fluorine-18-labelled imaging agents for positron emission tomography (PET) [4]. They demonstrated the application of protic-mediated reactions for radiolabelling of important molecular imaging agents in good yield and quality in shorter time compared to aprotic-mediated reaction conditions of nucleophilic substitution reactions [5]. They further studied the influence of the *tert*-alcohol solvent conditions for nucleophilic substitutions with series of alkali metal fluorides. The possible hydrogen bonding interaction of nucleophile fluorine and the sulfonyloxy substrate promote the rate of reaction [6]. Mechanistically, the hydrogen bonding between alkali metal fluoride and aprotic solvent, the generation of protic alcohol-solvated ion and the hydrogen bonding between the leaving group sulfonate and the alcohol solvent seem to favour the enhancement in the rate of nucleophilic substitutions without PTC. They found that the fluorination with specific substrates with *tert*-butylammonium fluoride in alcohol solvent affords the corresponding fluoroproducts in high yield than that obtained by the conventional methods using dipolar aprotic solvents. The protic medium also suppresses the formation of by-products, such as alkenes, ethers and

Shinde et al. exhibited the synergistic effect of *tert*-alcohol and ionic liquids in substitution reactions [7]. They merged the two solvents, ionic liquid (IL) and *tert*-alcohols, into one molecule for nucleophilic substitution as shown in

**208**

cyclic adducts.

**2.2** *Tert***-alcohol-functionalized ionic liquid**

**Figure 2**. These hybridised ILs not only increase the nucleophilic reactivity of the fluoride anion but also reduce the olefin by-product. The preparation of novel imidazolium salts with counter anion [8]. Imidazole reacted with isobutylene oxide without or free solvents to give quantitatively yield N-*tert*alcohol-substituted imidazole. N-*tert*-alcohol-substituted imidazole reacted with methyl, isopropyl, n-butyl, n-hexyl methane sulphonate in acetonitrile at 90°C gave the corresponding N1-alkyl-N3-*tert*-alcohol substituted imidazolium salts (ILs) **1a–1d.** All of these imidazolium mesylates are liquids at room temperature.

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 **1a** and that *tert-*alcohol solvents show good performance in nucleophilic fluorination, thereby side reactions are remarkably suppressed via a weak F▬H hydrogen bond, which maintains the inherent nucleophilicity and reduces the basicity of the fluoride anion. The new hybridization of ILs and *tert*-alcohol functionality would provide dual advantages of reaction acceleration and minimization of side reactions.

**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 **1a** as a protic catalyst yielded the fluorinated product (**6a**) in almost quantitative yield with no by-products [7].

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 *tert-*alcohol functionality and imidazolium salts (**Figure 4**) [9].