Oligoethylene Glycols as Highly Efficient Mutifunctional Promoters for Nucleophilic‐Substitution Reactions

Abstract

Herein, we report the promising use of n-oligoethylene glycols (oligoEGs) as mutifunctional promoters for nucleophilic-substitution reactions employing alkali metal salts. Among the various oligoEGs tested, pentaethylene glycol (pentaEG) had the most efficient catalytic activity. In particular, when compared with other nucleophiles examined, a fluorine nucleophile generated from CsF was significantly activated by the pentaEG promoter. We also performed various facile nucleophilic-displacement reactions, such as the halogenation, acetoxylation, thioacetoxylation, nitrilation, and azidation of various substrates with potassium halides, acetate, thioacetate, cyanide, and sodium azide, respectively, in the presence of the pentaEG promoter. All of these reactions provided their desired products in excellent yields. Furthermore, the combination of pentaEG and a tert-alcohol medium showed tremendous efficiency in the nucleophilic-displacement reactions (fluorination and methoxylation) of base-sensitive substrates with basic nucleophiles (cesium fluoride and potassium methoxide, respectively). The catalytic role of oligoEGs was examined by quantum-chemical methods. The oxygen atoms in oligoEGs were found to act as Lewis bases on the metal cations to produce the "flexible" nucleophile, whereas the two terminal hydroxy (OH) groups acted as "anchors" to orientate the nucleophile and the substrate into an ideal configuration for the reaction.

Mechanism of Nucleophilic Fluorination Facilitated by a Pyrene‐tagged Ionic Liquids: Synergistic Effects of Pyrene–Metal Cation π‐Interactions

“…F − is surrounded by four H atoms of imidazolium and OMs − with distances of approximately 2.1 Å, in contrast with (Py‐CsF‐1) Pre in which only one strong hydrogen bonding exists between F − and 2‐H. These findings are in line with the promotion of S N 2 reaction rates by the O atoms of Lewis base such as bulky alcohols and oligoethylene glycols acting on the counter cation as described in our previous works . It is also worth noting that the metal counter‐cation Cs + lies above pyrene in both pre‐reaction complexes, suggesting that interactions between Cs + and the π electrons in pyrene play an important role in promoting the S N 2 fluorination reaction as discussed below.…”

“…Recent progress in S N 2 reactions have demonstrated that this fundamental and well‐known chemical reaction may still show some unexpected novelty, especially concerning the role of counter‐cation and solvent for its efficacy . Use of metal salts and ILs seems to have opened a breakthrough for this purpose. Systematic studies have been carried out for the mechanism of rate acceleration by simple or bifunctional ILs, focusing on the role of the ionic liquid cation, anion, and side‐chain.…”

Harnessing Ionic Interactions and Hydrogen Bonding for Nucleophilic Fluorination

“…Besides being considered excellent solvent for chemical reactions because of its many useful physicochemical properties such as very low vapor pressure, non-combustibility, high thermal stability, low viscosity, easy recovery and high ionic conductivity, ionic liquids (ILs) [10][11][12][13][14][15][16][17][18][19] have found further significant role as catalysts/promoters [20,21] in many chemical transformations such as S N 2 [22][23][24][25][26][27][28], Diels-Alder [29], aldol condensation [30], Heck [31][32][33], and Michael addition [34] reactions. The acceleration of reaction rates of organic reactions by IL occur by the nature of the substance comprising cation and anion.…”

Mechanism of nucleophilic fluorination promoted by bis‐tert‐alcohol‐functionalized crown‐6‐calix[4]arene

“…The environment around the fluoride ion is a key point for controlling its reactivity . This goal can be achieved by solvent selection or by supramolecular catalysis . The use of multiple hydrogen bonds to stabilize the anion‐molecule S N 2 transition state (Scheme ) has been envisioned and computationally supported as a promising strategy in supramolecular catalysis .…”