Nucleophilic aromatic solvent effects

The range of nueleophiles whieh have been observed to partieipate in nueleophilie aromatie substitution is similar to that for S[, 2 reactions and includes alkoxides, phenoxides, sulftdes, fluoride ion, and amines. Substitutions by earbanions are somewhat less common. This may be because there are frequently complications resulting from eleetron-transfer proeesses with nitroaromatics. Solvent effects on nucleophilic aromatic substitutions are similar to those discussed for S 2 reactions. Dipolar... 

If one limits the consideration to only that limited number of reactions which clearly belong to the category of nucleophilic aromatic substitutions presently under discussion, only a few experimental observations are pertinent. Bunnett and Bernasconi30 and Hart and Bourns40 have studied the deuterium solvent isotope effect and its dependence on hydroxide ion concentration for the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in dioxan-water. In both studies it was found that the solvent isotope effect decreased with increasing concentration of hydroxide ion, and Hart and Bourns were able to estimate that fc 1/ for conversion of intermediate to product was approximately 1.8. Also, Pietra and Vitali41 have reported that in the reaction of piperidine with cyclohexyl 2,4-dinitrophenyl ether in benzene, the reaction becomes 1.5 times slower on substitution of the N-deuteriated amine at the highest amine concentration studied. 

It is more difficult to interpret micellar effects upon reactions of azide ion. The behavior is normal , in the sense that k /kw 1, for deacylation, an Sn2 reaction, and addition to a carbocation (Table 4) (Cuenca, 1985). But the micellar reaction is much faster for nucleophilic aromatic substitution. Values of k /kw depend upon the substrate and are slightly larger when both N 3 and an inert counterion are present, but the trends are the same. We have no explanation for these results, although there seems to be a relation between the anomalous behavior of the azide ion in micellar reactions of aromatic substrates and its nucleophilicity in water and similar polar, hydroxylic solvents. Azide is a very powerful nucleophile towards carboca-tions, based on Ritchie s N+ scale, but in water it is much less reactive towards 2,4-dinitrohalobenzenes than predicted, whereas the reactivity of other nucleophiles fits the N+ scale (Ritchie and Sawada, 1977). Therefore the large values of k /kw may reflect the fact that azide ion is unusually unreactive in aromatic nucleophilic substitution in water, rather than that it is abnormally reactive in micelles. 

Spurred by our desire to avoid use of expensive dipolau aprotic solvents in nucleophilic aromatic substitution reactions, we have developed two alternative phase transfer systems, which operate in non-polar solvents such as toluene, chlorobenzene, or dichlorobenzene. Poleu polymers such as PEG are Inexpensive and stable, albeit somewhat inefficient PTC agents for these reactions. N-Alkyl-N, N -Dialkylaminopyridinium salts have been identified as very efficient PTC agents, which are about 100 times more stable to nucleophiles than Bu NBr. The bis-pyridinium salts of this family of catalysts are extremely effective for phase transfer of dianions such as bis-phenolates. 

A comparison of the suitability of solvents for use in Srn 1 reactions was made in benzenoid systems46 and in heteroaromatic systems.47 The marked dependence of solvent effect on the nature of the aromatic substrate, the nucleophile, its counterion and the temperature at which the reaction is carried out, however, often make comparisons difficult. Bunnett and coworkers46 chose to study the reaction of iodoben-zene with potassium diethyl phosphite, sodium benzenethiolate, the potassium enolate of acetone, and lithium r-butylamide. From extensive data based on the reactions with K+ (EtO)2PO (an extremely reactive nucleophile in Srn 1 reactions and a relatively weak base) the solvents of choice (based on yields of diethyl phenylphosphonate, given in parentheses) were found to be liquid ammonia (96%), acetonitrile (94%), r-butyl alcohol (74%), DMSO (68%), DMF (63%), DME (56%) and DMA (53%). The powerful dipolar aprotic solvents HMPA (4%), sulfolane (20%) and NMP (10%) were found not to be suitable. A similar but more discriminating trend was found in reactions of iodobenzene with the other nucleophilic salts listed above.46 Nearly comparable suitability of liquid ammonia and DMSO have been found with other substrate/nucleophile combinations. For example, the reaction of p-iodotoluene with Ph2P (equation (14) gives 89% and 78% isolated yields (of the corresponding phosphine oxide) in liquid ammonia and DMSO respectively.4 ... 

Alkenyl(phenyl)iodine(III) compounds can also serve as starting materials in rearrangements. Allenyl(aryl)iodine(III) compounds of type 86 can be synthesized from (diacetoxyiodo) derivatives 85 and propargylsilanes [145]. It depends on the leaving group ability of the aromatic substituent on iodine in 86 as to whether the reaction proceeds via nucleophilic substitution to compounds of type 87 or by an iodonio-Claisen rearrangement to compounds 88, Scheme 37 [146,147]. The easy access to propynyl compounds 87 has been shown [148] and solvent effects in these reactions have been investigated as well [149,150]. 

The effect of different solvents has been studied in photoinitiated SRN1 reactions. However, the marked dependence of solvent effects on the nature of the aromatic substrate, the nucleophile, its counterion and the temperature at which the reaction is carried out often make comparisons cumbersome. 

The kinetics of polycondensation hy nucleophilic aromatic substitution in highly polar solvents and solvent mixtures to yield linear, high molecular weight aromatic polyethers were measured. The basic reaction studied was between a di-phenoxide salt and a dihaloaromatic compound. The role of steric and inductive effects was elucidated on the basis of the kinetics determined for model compounds. The polymerization rate of the dipotassium salt of various bis-phenols with 4,4 -dichlorodiphenylsulfone in methyl sulfoxide solvent follows second-order kinetics. The rate constant at the monomer stage was found to be greater than the rate constant at the dimer and subsequent polymerization stages. 

For example, acetylation reactions of alcohols and carbohydrates have been performed in [Bmim]-derived ionic liquids.If the dicyanamide anion [N(CN)2] is incorporated into the liquid, mild acetylations of carbohydrates can be performed at room temperature, in good yields, without any added catalyst.In this example, it was shown that the RTIL was not only an effective solvent but also an active base catalyst. In a recent study, Welton and co-workers performed calculations on the gas phase basicity of the conjugate acids of possible anions from which to construct their liquid.Using these data, they were able to choose the optimum RTIL in which to conduct a nucleophilic aromatic substitution reaction of an activated aniline with an activated arylhalide. Given the enormous number of possible anions and cations from which to build up an ionic liquid, the role of computation in experimental design such as this will become increasingly important. 

Mancini PME, Fortunato G, Adam C, Terenzani A, Vottero LR (2002) Specific tmd nonspecific solvent effects on aromatic nucleophilic substitutions. Kinetics of the reaction of 1-fluoro-2,6-dinitrobenzene and homopiperidine in binary solvent mixtures. J Phys Oig Chem 15 258-269... 

Martinez RD, Mancini PME, Vottero LR, Nudelman NS (1986) Solvent effects on aromatic nucleophilic substitutions. Part 4. Kinetics of the reaction of l-chloro-2,4-dinitrobenzene with piperidine in protic solvents. J Chem Soc Perkin Trans 2 1133-1138... 

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