Protic versus aprotic solvents

There is no question that the solvent chosen for a given reaction has a profound influence on the course of that reaction. Protic versus aprotic solvents as well as polar versus nonpolar solvents can have effects ranging from solubility to solvent assisted ionization or stabilization of transition states. Reactions can... 

The availability of labile protons (protic versus aprotic solvents in Table 7) determines whether anions or cations are solvated more strongly through hydrogen bonding. Because hydrolysis is catalyzed either by hydroxyl... 

SN1 versus S There are two different mechanisms involved in the nucleophilic substitution of alkyl halides. When polar aprotic solvents are used, the SN2 mechanism is preferred. Primary alkyl halides react more quickly than secondary alkyl halides, with tertiary alkyl halides hardly reacting at all. Under protic solvent conditions with non-basic nucleophiles (e.g. dissolving the alkyl halide in water or alcohol), the SN1 mechanism is preferred and the order of reactivity is reversed. Tertiary alkyl halides are more reactive than secondary alkyl halides and primary alkyl halides do not react at all. 

In 2001, Rai and co-workers (114) reported a silver-mediated aziridination of olefins in THF with Chloramine-T. In their case, aprotic solvents gave better yields versus protic solvents. Then, in 2003, Komatsu and co-workers (115) used similar conditions and found no reaction in THF (solvent) while they detected 70% conversion in CH2CI2. Silver nitrate (AgNOs) was required stoichiometrically in this transformation. Komatsu proposed a nitrene-radical mechanism based on the fact that the reaction shut down in the presence of oxygen. They designed a model reaction using 1,6-dienes, and as they expected, bicyclic pyrrolidines were isolated as products instead of aziridines. The role of silver in this reaction is not clear and most likely a free nitrene radical is released with the precipitation of silver(I) chloride (Fig. 18). 

Hence, the more negative the oxidation potential and the larger the YO-R bond energy, the proportionally greater nucleophilic reactivity that will result. The shift in the oxidation potential of HO- from -4-1.89 V versus NHE in H2O to -1-0.92 V in MeCN reflects the "leveling effect" of protic solvents on the nucleophilicity of oxy anions. Likewise, the shift in potential for HOO [-1-0.20 V (H2O) to -0.34 V (MeCN)] is in accord with the exceptional reactivity of HOO" in aprotic solvents. In aqueous media the reactivity of HOO" is leveled by extensive anionic solvation,42 but remains significant with many substrates due to its unique orbital energies S and the presence of an unshared pair of electrons on the atom adjacent to the nucleophilic center (a effect). ... 

The solubility of ionic substances in relatively nonpolar aprotic solvents can be greatly enhanced by using catalytic quantities of macrocyclic polyethers, such as 18-crown-6, the structure of which is shown in Fig. 5.5. These macrocyclic ethers selectively solvate the cation, both enhancing solubility and also leaving the anion in a very weakly solvated state. The anions behave under these conditions as highly reactive species, sometimes termed naked anions. A study of the relative rates of nucleophilic substitution on benzyl tosylate by potassium salts in acetonitrile in the presence of 18-crown-6 revealed a pronounced leveling effect. " All the potassium halides (fluoride, chloride, bromide, and iodide) were approximately equal in their reactivity. Potassium acetate was observed to be almost ten times more reactive than potassium iodide under these conditions—a reversal of the normal reactivity of acetate ion versus iodide ion in nucleophilic substitution reactions. As measured by cHji values in Table 5.5, iodide is 3 log units, i.e., 10 times, more reactive than acetate ion in the protic solvent methanol. 

The results show that there is a marked break between solvation by protic solvents (water, alcohols) and aprotic solvents (MeCN, etc.), and suggest that ammonia and amines resemble aprotic rather than protic solvents. There is a shift to high energy in on going from H2O to MeOH which was interpreted in terms of a higher solvation number for Ij q than Imcoh hence a large cavity for water. I suggest below that such a situation is common for many aqueous versus methanolic solutions. 

The idea of kinetic versus thermodynamic control can be illustrated by a brief discussion of the formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and is discussed more fully in Chapter 6 and in Section 1.1.2 in Part B. Most ketones can give rise to more than one enolate. Many studies have shown that the ratio among the possible enolates that are formed depends on the reaction conditions. " This can be illustrated for the case of 2-hexanone. If the base chosen is a strong, sterically hindered one, such as lithium diisopropylamide, and the solvent is aprotic, the major enolate formed is 3 in the diagram below. If a protic solvent or a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Under these latter conditions, equilibration can occur by reversible formation of the enol. Enolate 3 is the kinetic enolate, but 2 is thermodynamically favored. 

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