Mechanistic study of structural effects on nucleophilic substitution reactions at sulfonyl centers

Abstract

Nucleophilic substitution processes at the sulphur atom of arenesulfonyl compounds have been the subject of numerous discussions among experts for many years. This is due to the ambiguity of the solvolysis mechanism, which is often treated as a bimolecular with different symmetry at the transition state, catalytic assistance of the solvent, a possible rearrangement during the nucleophilic attack, etc. In the last years, the problem has become more complicated by the study of these reactions involving sterically overloaded sulfonyl systems in which the attack on the sulphur atom presumably is inhibited by the presence of ortho-alkyl groups. However, researchers have paid little attention to the solvolysis of sterically hindered aromatic sulfo derivatives, particularly to arenesulfonyl acid derivatives. Hindered substrates based on derivatives of benzenesulfonyl chlorides show a significant increase in reactivity, and disagree with the classical criteria on the electronic effect of the substituents on the reaction rate of the SN2 process. Nevertheless, it is clear that sterically hindered derivatives of aromatic sulfonic acids have a number of kinetic features that allow having doubts on the existing classical point of view on the mechanism of nucleophilic substitution at sulfonyl atom, and assume the existence of the so called "Positive steric effect" putting these compounds in the category of abnormally reactive. Such "positive ortho-effect" has been widely omitted in the literature with the exception of the neutral hydrolysis of hindered arenesulfonyl chlorides in dioxane-water mixtures. This research is dedicated to the chemical kinetic study of the origin of the positive ortho-effect in the hindered arenesulfonyl chlorides solvolysis. To answer the question on the role of the substrate structure on the reactivity the following central issues should be unravelled: 1. The influence of solvent composition, the nature and the position of the substituents in hindered and unhindered substrates and the nature of the nucleophile on the reaction rate and the substitution kinetic mechanism 2. The values of the thermodynamic transition state parameters in different alcohols (methanol, ethanol, propanol and iso-propanol). 3. The leaving group effect, the secondary kinetic isotope effect (SKIE) and the solvent isotope effect (SIE) on the alcoholysis conditions. Structure and purity of the obtained sulfonyl compounds were confirmed by 1H and 13C NMR spectroscopy and monocrystal X-ray diffraction. Kinetic studies were carried out spectrophotometrically under pseudo-first order with respect to the nucleophile on a Cary 1E UV-Vis spectrophotometer, in a thermostated quartz cuvette l=1 cm, temperature range 303-323K. The alcoholysis of arenesulfonyl chlorides X-ArSO2Cl at 323 K (X=H-, 4-Me-, 4-t-Bu-, 4-Cl-, 4-Br-, 3-NO2-, 2,4,6-Me3-, 2,4,6-Et3-, 2,4,6-i-Pr3-, 2-Me-, 2,4-Me2-, 2,5-Me2-, 2-Me-5-t-Bu-, 2,6-Me2-4-t-Bu-, 2,3,5,6-Me4-, 2-Me-5-NO2-, 2,4-Me2-5-NO2-, 2,4,6-Me3-3-NO2- and 2,4,6-(OMe)3) in methanol, ethanol, propanol and iso-propanol was studied. The obtained kinetic data were analyzed, by the linear regression, using the following models: Hammett equation, Arrhenius equation, Grunwald-Winstein equation, Brønsted equation and Kirkwood function. The electronic nature of the X substituent has ambiguous effect. The process in unbranched alcohols is quite similar: an increase of electron withdrawing properties of the ? substituents in unhindered compounds leads to lower reactivity. The solvolysis by iso-propyl alcohol shows the opposite tendency. On the other hand, sterically-hindered compounds show anomalous acceleration for all alcohols All studied compounds demonstrate similar thermodynamic activation parameters (large negative activation entropy values, and low, and similar, activation enthalpy values) and it is also common the existence of good logkT1 vs. logkT2 correlations, i.e. isokinetic dependences. Studied substrates are characterized by low values of the leaving group effect (kBr/kCl = 4 - 6). The observed SIE is ca. 1.35 for ethanolysis, comparable to literature data. No SKIE was observed when hydrogens of the ortho-alkyl groups are replaced by deuteriums.The reaction order of the nucleophile varies between 2 and 3 in all alcohols. Electron withdrawing substituents tend to decrease both the sensitivity to the ionizing power of solvent and the Brønsted exponent, whereas electron-donor ones increase them. All previous indirect evidences on the mechanism of solvolysis of arenesulfonyl chlorides (kinetic rate laws, kinetic isotope effect, change of the nucleophile, solvent, etc.), as well as the X-ray structures, the presence of isokinetic dependency and the similar thermodynamic activation parameters for all the investigated series of substrates point to a single bimolecular mechanism of substitution similar to SN2 involving the of at least a second molecule of the solvent by the general base catalysis type, and likely the formation of a cyclic transition state. In conclusion, it follows that the positive steric effect is a complex phenomenon that implies the formation of a cyclic TS structure, likely generated by a frontal attack of the nucleophile, the alcohol, and stabilized by additional nonbonded interactions between the o-methyl hydrogens and the oxygen atoms of the sulfonyl group.