Due to the tremendous interest in carbon-fluorine bond-forming reactions, research efforts in this area have been dedicated to the development of facile processes to synthesize small fluorine-containing organic molecules. Among others, PET (Positron Emission Tomography) is one of the most important applications of fluorine chemistry. Recognizing the specific requirements of PET processes, some groups have focused on fluorination reactions using alkali metal fluorides, particularly through SN2-type reactions. However, a common "misconception" about the role of protic solvents and hydrogen bonding interactions in this class of reactions has hampered the employment of these excellent promoters. Herein, we would like to review recent discoveries in this context, showing straightforward nucleophilic fluorination reactions using alkali metal fluorides promoted by protic solvents. Simultaneous dual activation of reacting partners by intermolecular hydrogen bonding and the enhancement of the "effective fluoride nucleophilicity", which is Nature's biocatalytic approach with the fluorinase enzyme, are the key to this unprecedentedly successful nucleophilic fluorination.

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Over the past decade, ionic liquids have received a great deal of attention as a new means for catalyst immobilization. Large numbers of catalysts having polar or ionic character have been successfully immobilized in ionic liquids, thus allowing their recovery and recycling. However, catalyst immobilization is not the only benefit of ionic liquids in catalysis, of greater importance are the positive effects of ionic liquids on catalytic rates. In this Account, we highlight our work in elucidating the origin of the accelerating effects of ionic liquids in a range of catalytic reactions. Lewis acidic metal triflates often become much more reactive in ionic liquids containing noncoordinating anions as a result of "anion exchange." Consequently, the more electrophilic Lewis acidic species generated in situ accelerate the catalytic reactions dramatically. In some cases, highly reactive intermediates, such as vinyl cations, arenium cations, oxygen radical anions, and so forth, can be stabilized in the presence of ionic liquids, thus increasing the reactivity and selectivity of the reactions. Concerted processes such as S(N)2 and Diels-Alder reactions can also be accelerated through the cooperative activation of both the nucleophile and the electrophile by ionic liquids. In transition metal-catalyzed reactions, certain catalytically active oxidation states can be stabilized in ionic liquids against deactivation to catalytically inactive species. Thus it is clear that gaining an understanding of the origin of these "positive ionic liquid effects" is highly important, not only for predicting the effects of ionic liquids on other organic reactions but also for designing new catalytic reactions. Ionic liquids, by virtue of (typically) having a synthetically accessible carbon backbone, are amenable to tailoring by the organic chemist. Accordingly, their molecular structures can be subtly varied to give "tunable" properties, which can then be used to rationally examine the fundamental reasons that they accelerate catalyzed reactions. Although the origins of enhanced catalytic rates by ionic liquids have been elucidated in many areas, other undiscovered ionic liquid phenomena remain to be unearthed. Developing a better understanding of these modularly tunable liquid salts will foster new discoveries of catalytic reactions that are accelerated by ionic liquids as solvents or additives.

In the catalysis of S(N)2 fluorination reactions, the ionic liquid anion plays a key role as a Lewis base by binding to the counterion Cs(+) and thereby reducing the retarding Coulombic influence of Cs(+) on the nucleophile F(-). The reaction rates also depend critically on the structures of ionic liquid cation, for example, n-butyl imidazolium gives no S(N)2 products, whereas n-butylmethyl imidazolium works well. The origin of the observed phenomenal synergetic effects by the ionic liquid [mim-(t)OH][OMs], in which t-butanol is bonded covalently to the cation [mim], is that the t-butanol moiety binds to the leaving group of the substrate, moderating the retarding interactions between the acidic hydrogen and F(-). This work is a significant step toward designing and engineering solvents for promoting specific chemical reactions.

In this report, we demonstrate that self-aggregation is an intrinsic problem of bifunctional organocatalysts, especially in the case when the substrates do not have functional groups which are able to bind strongly with catalyst. Due to their self-association phenomena, the enantioselectivity of bifunctional catalysts dramatically decreases with increasing catalyst concentration or decreasing temperature. Thus, when the substrate concentration is kept constant, the enantioselectivity of bifunctional catalysts dramatically increases with decreasing catalyst loading. The ee values obtained at different catalyst concentrations are fairly consistent with the diffusion coefficients (D) of the catalysts, strongly indicating that their degree of self-association plays a crucial role in determining their enantioselectivity.