Nucleophilic displacement, crown ethers

Recently, the above mentioned model reaction has been extended to polycondensation reactions for synthesis of polyethers and polysulfides [7,81]. In recent reports crown ether catalysts have mostly been used in the reaction of a bifunctional nucleophile with a bifunctional electrophile, as well as in the monomer species carrying both types of functional groups [7]. Table 5 describes the syntheses of aromatic polyethers by the nucleophilic displacement polymerization using PTC. 

The reactions of white phosphorus with tetraalkylammonium cyanides in the presence of a crown ether in acetonitrile give rise to the dicyanophosphide ion, which is found to react with a variety of anionic phosphorus nucleophiles with displacement of cyanide ion to generate new P-P bonded compounds.7... 

In contrast, liquidiliquid phase-transfer catalysis is virtually ineffective for the conversion of a-bromoacetamides into aziridones (a-lactams). Maximum yields of only 17-23% have been reported [31, 32], using tetra-n-butylammonium hydrogen sulphate or benzyltriethylammonium bromide over a reaction time of 4-6 days. It is significant that a solidiliquid two-phase system, using solid potassium hydroxide in the presence of 18-crown-6 produces the aziridones in 50-94% yield [33], but there are no reports of the corresponding quaternary ammonium ion catalysed reaction. Under the liquidiliquid two-phase conditions, the major product of the reaction is the piperazine-2,5-dione, resulting from dimerization of the bromoacetamide [34, 38]. However, only moderate yields are isolated and a polymer-supported catalyst appears to provide the best results [34, 38], Significant side reactions result from nucleophilic displacement by the aqueous base to produce hydroxyamides and ethers. 

Similarly, a lipophilic crown ether is partitioned into the organic phase. Its complexing ability serves to transfer salts with alkali cations into the organic phase. The anions in the organic phase are poorly solvated and highly reactive. The overall reactivity in phase-transfer-catalyzed nucleophilic displacement reactions thus is a function of both the partition coefficient for extraction of the reactive anion into the organic... 

Complexation constants of crown ethers and cryptands for alkali metal salts depend on the cavity sizes of the macrocycles 152,153). ln phase transfer nucleophilic reactions catalyzed by polymer-supported crown ethers and cryptands, rates may vary with the alkali cation. When a catalyst 41 with an 18-membered ring was used for Br-I exchange reactions, rates decreased with a change in salt from KI to Nal, whereas catalyst 40 bearing a 15-membered ring gave the opposite effect (Table 10)l49). A similar rate difference was observed for cyanide displacement reactions with polymer-supported cryptands in which the size of the cavity was varied 141). Polymer-supported phosphonium salt 4, as expected, gave no cation dependence of rates (Table 10). 

Kinetic template effects have been involved in the formation of crown ethers, with respect to the cyclization step involving a nucleophilic displacement of halide or tosylate by alkoxide ions. It has been proposed that cyclization of the linear bifunctional precursor is enhanced by a cyclic conformation in which the alkoxide cation brings the two ends of the molecule into close proximity... 

An important application for the crown ethers in synthetic work is for solubilization of salts such as KCN in nonpolar solvents for use in SN2 displacements. If the solvent has a low anion-solvating capability, then the reactivity of the anion is enhanced greatly. Consequently many displacement reactions that proceed slowly at elevated temperatures will proceed at useful rates at room temperatures, because the energy of desolvating the anion before it undergoes SN2 displacement is low (Section 8-7F). For example, potassium fluoride becomes a potent nucleophilic reagent in nonpolar solvents when complexed with 18-crown-6 ... 

Azide ions are by far the most common nucleophilic species employed in substitution reactions for the preparation of amino sugars. An azido moiety is stable under many reaction conditions but can be reduced to an amino group by a variety of reagents. The nucleophilicity of azido ions can be increased by the addition of a suitable crown ether to complex the counterion.36c,63b In the past, ammonia and hydrazine were used as nucleophiles to overcome unfavourable dipolar interactions that arise when charged nucleophiles were used. However, a drawback of the use of these nucleophiles is that the product is still nucleophilic and can perform a second displacement. Phthalimide ions have successfully been applied in displacement reactions to yield a protected amino sugar derivative.58 63f... 

In initial attempts to prepare ring-fluorinated imidazoles, nucleophilic displacement of activated halogens with fluoride was unsuccessful. However, if sufficiently activated, hahde exchange can occur. Thus, l-methyl-2-fluoro-4,5-dicyanoimidazole was prepared from 1-methyl-2-bromo-4,5-dicyanoimidazole by reaction with spray-dried KF in the presence of 18-crown-6 ether as catalyst. ... 

Nucleophilic displacements under two-phase conditions in the presence of catalytic amounts of crown ether, 4, which is completely dissolved in the organic phase, follow the classical PTC mechanism and the observed pseudo first-order rate constants are linearly correlated with the amount of complexed crown ether in the organic phase. A narrow reactivity range was found for different anionic nucleophiles in the displacement of n-octyl methanesulfonate (Scheme 10). 

Crown ethers are powerful complexing agents for alkali-metal cations, which in turn produce highly reactive naked anions. For example, 2,4-dinitrochloro-benzene reacts with potassium phthalimide in the presence, but not in the absence, of crown ethers. However, a kinetic study of nucleophilic displacement reactions has shown that the relative nucleophilic reactivities are similar in chlorobenzene-water and in chlorobenzene indicating that crown ethers are not a source of naked anions." ... 

Crown ethers have also proven valuable in nucleophilic displacement reactions. The cations of potassium salts, such as KF, KCN, and KNj, are very tightly bound within the solvation cavity of 18-crown-6 molecules. The anions, however, are only weakly solvated, and because of the geometry of cation binding within the cavity of the crown, only loose ion pairing occurs between the anion and cation. Thus, in nonpolar aprotic solvents, these anions are without any appreciable solvent shell and, therefore, are highly reactive as nucleophiles. The nucleophili-city of F, CN , Nj , and other anions in nonpolar aprotic solvents containing an 18-crown-6 equals and often exceeds their nucleophilicity in polar aprotic solvents such as DMSO and acetonitrile. 

Crown ether has been used for nucleophilic displacement of chloride by cyanide at hindered position. At room temperature the reaction of 2-chloro-2-methyl cyclohexanone with potassium cyanide in acetonitrile in presence of 18-crown-6 affords the cyanide in excellent yield, but when the reaction is conducted at reflux temperature Favorskii rearrangement occurs to yield five membered compound in high yield (Scheme 36). 

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