Paola R. Campodónico

Experimental and theoretical studies on the nucleofugality patterns in the aminolysis and phenolysis of S-aryl O-aryl thiocarbonates.

The reactions of S-phenyl, S-(4-chlorophenyl), and S-(2,3,4,5,6-pentafluorophenyl) 4-nitrophenyl thiocarbonates (9, 11, and 16, respectively) with a series of secondary alicyclic (SA) amines and those of S-(4-methylphenyl) 4-nitrophenyl thiocarbonate (8) and compounds 9 and 11 with a series of phenols are subjected to a kinetic investigation in 44 wt % ethanol-water, at 25.0 degrees C and an ionic strength of 0.2 M. The reactions were followed spectrophotometrically. Under nucleophile excess, pseudo-first-order rate coefficients (k(obsd)) were found. For all these reactions, plots of k(obsd) vs. free amine or phenoxide anion concentration at constant pH are linear, the slope (k(N)) being independent of pH. The Brønsted-type plots (log k(N) vs. pK(a) of the conjugate acids of the nucleophiles) for the aminolysis of 9, 11, and 16 are linear with slopes beta = 0.85, 0.90, and 0.67, respectively. The two former slopes are consistent with a stepwise mechanism, through a zwitterionic tetrahedral intermediate, which breaking to products is rate determining. The latter beta value is consistent with a concerted mechanism. The Brønsted-type plots for the phenolysis of thiocarbonates 8, 9, and 11 are linear with slopes beta = 0.62, 0.70, and 0.69, respectively. These beta values and the absence of curvature at pK(a) = 7.5 confirm a concerted mechanism. In all these reactions, except those of 16, the main nucleofuge is 4-nitrophenoxide, being the thio benzenethiolate the minor nucleofuge. For the reactions of thiocarbonate 16 the main nucleofuge is pentafluorobenzenethiolate whereas little 4-nitrophenoxide was found. The reactions of two SA amines with S-(3-chlorophenyl) 4-nitrophenyl thiocarbonate (10) were subjected to product analysis, showing 60% 4-nitrophenoxide and 40% 3-chlorobenzenethiolate. The study is completed with a theoretical analysis based on the group electrophilicity index, a reactivity descriptor that may be taken as a measure of the ability of a group or fragment to depart from a molecule with the bonding electron pair. The theoretical analysis is in accordance with the experimental results obtained and predicts relative nucleofugalities of O-aryl vs. S-aryl groups in a series of diaryl thiocarbonates not experimentally evaluated to date.

Mechanistic pathways of aromatic nucleophilic substitution in conventional solvents and ionic liquids

Solvation effects on the reaction mechanism of the title reactions have been kinetically evaluated in 21 conventional solvents and 17 ionic liquids. Solvent polarity affects the catalyzed and non-catalyzed SNAr pathways differently. The ambiphilic character of water and formamide, which act as a hydrogen bond donor/acceptor, induces nucleophilic activation at the nitrogen center of the nucleophile. The ionic liquid EMIMDCN appears to be the best solvent for the SNAr route probably due to the high polarizability of the dicyanamide anion.

Specific nucleophile–electrophile interactions in nucleophilic aromatic substitutions

We herein report results obtained from an integrated experimental and theoretical study on aromatic nucleophilic substitution (S(N)Ar) reactions of a series of amines towards 1-fluoro-2,4-dinitrobenzene in water. Specific nucleophile-electrophile interactions in the title reactions have been kinetically evaluated. The whole series undergoes S(N)Ar reactions where the formation of the Meisenheimer complex is rate determining. Theoretical studies concerning specific interactions are discussed in detail. It is found that H-bonding effects along the intrinsic reaction coordinate profile promote the activation of both the electrophile and the nucleophile. Using these results, it is possible to establish a hierarchy of reactivity that is in agreement with the experimental data. Second order energy perturbation energy analysis highlights the strong interaction between the ortho-nitro group and the acidic hydrogen atom of the amine. The present study strongly suggests that any theoretical analysis must be performed at the activated transition state structure, because the static model developed around the reactant states hides most of the relevant specific interactions that characterize the aromatic substitution process.

Hydrogen Bond Contribution to Preferential Solvation in SNAr Reactions

Preferential solvation in aromatic nucleophilic substitution reactions is discussed using a kinetic study complemented with quantum chemical calculations. The model system is the reaction of a series of secondary alicyclic amines toward phenyl 2,4,6-trinitrophenyl ether in aqueous ethanol mixtures of different compositions. From solvent effect studies, it is found that only piperidine is sensitive to solvation effects, a result that may be traced to the polarity of the solvent composition in the ethanol/water mixture, which points to a specific electrophilic solvation in the aqueous phase.

Are electrophilicity and electrofugality related concepts? A density functional theory study.

It is proposed that the electrofugality of a fragment within a molecule is determined by its group nucleophilicity. The variation of electrofugality should be tightly related to the electron releasing ability of the substituent attached to the electrofuge moiety. This contribution closes the set of relationships between philicity and fugality quantities: while nucleofugality appears related to the group electrophilicity of the leaving group, electrofugality is related to the group nucleophilicity of the permanent group.

Structure–reactivity relationships for electrophilic sugars in interaction with nucleophilic biological targets

The global electrophilicity index that incorporates electrostatic and polarizability contributions shows a quantitative correlation with antiviral and cytotoxic activities of electrophilic sugars. The model is applied to a series of compounds that behave as Michael acceptors in interaction with biological nucleophilic targets.

Changes in the SNAr reaction mechanism brought about by preferential solvation

We herein report an experimental and theoretical study on preferential solvation effects for the reactions of 1-fluoro and 1-chloro-2,4-dinitrobenzene towards morpholine in acetonitrile, water and mixtures of them of varying compositions. A detailed kinetic study opens the possibility of analyzing preferential solvation and reaction rates. The kinetic study was complemented with an exploration of the potential energy surface in order to analyze the nature of the molecular interactions. For the fluorine derivative, this analysis reveals that the solvation of the TS in the mode TS1F-water/MeCN clearly outweighs the solvation of TS1F-MeCN/water, thereby suggesting that there is preferential solvation in favor of the aqueous phase.

Ionic liquid binary mixtures: how different factors contribute to determine their effect on the reactivity

We studied how mixing ionic liquids affected the rate of the Diels Alder reaction between 9-anthracenemethanol and N-ethylmaleimide. The mixtures considered spanned the whole compositional range and differed for the anion or the cation. These comprised mixtures of the ionic liquid 1-benzyl-3-butyl-imidazolium bis-(trifluoromethanesulfonyl)imide ([Bzbim][NTf2]) with 1-(2,3,4,5,6-pentafluorophenyl)-3-butyl-imidazolium bis-(trifluoromethanesulfonyl)imide ([Bz(F5)bim][NTf2]) or 1-benzyl-3-butyl-imidazolium tetrafluoroborate ([Bzbim][BF4]). Moreover we studied the reaction in a set of mixtures containing an aliphatic and an aromatic cation, namely [Bzbim+] and N-butyltriethylammonium ([bEt3N+]) sharing the [NTf2−] anion. In this latter case we carried out RLS measurements, UV-Vis spectra of the solvatochromic probe Nile Red and 1H NMR measurements to gain insights into how the structural organization of the mixtures changes as a function of composition. Altogether, these results show a concomitant effect of solvent viscosity and structural organization on the rate of the process. Finally, no obvious correlation was found between the kinetic trend and the polarity of the mixtures, as expressed by solvatochromic parameters.

Site activation effects promoted by intramolecular hydrogen bond interactions in SNAr reactions

The nucleophilic aromatic substitution reaction of benzohydrazide derivatives towards 2-chloro-5-nitropyrimidine is used as model system to experimentally and theoretically show that intramolecular hydrogen-bond formation operates as a perturbation that elicits a dual response at the reaction center of the transition state (TS) structure, by enhancing the electrophilicity of the pyrimidine moiety and the nucleophilicity of the nitrogen atom of the benzohydrazide fragment. The electronic mechanism can therefore be described as a (non-local) site activation problem.

Iso-solvation effects in mixtures of ionic liquids on the kinetics of a model SNAr reaction

The SNAr reaction between 1-chloro-2,4-dinitrobenzene and morpholine was used as a model system to study solvation effects in a series of mixtures involving imidazolium based ionic liquids. Iso-solvation regimes (i.e. a solvent composition regime where the solute is being solvated by approximately the same number of different solvent molecules in the mixture) are reported for the first time in ionic liquid mixtures, for 4 mixtures including [EMIM][SCN][DCN], [BMIM][DCN][BF4], [BMIM][BF4][PF6] and [BMIM][PF6][FAP]. The results show that for significant changes in composition, the rate coefficients remain approximately constant. An additional interesting result is that the mixture [BMIM][BF4][PF6] (in the proportion of 0.9 for the molar fraction of BMIMBF4) shows a slightly better kinetic performance as compared to pure BMIMBF4 and BMIMPF6. Finally, for the [EMIM][SCN][DCN] mixture, an increasing proportion of EMIMSCN with respect to EMIMDCN results in a decrease in the rate coefficient within the range of {0.1–0.75} for the molar fraction of EMIMSCN. This result may be traced to competition between the anions [SCN−] and [DCN−] towards the reaction center driven by the basicity of the reaction medium.