The general mechanisms of attack of nitrogen nucleophiles on carbonyl compounds: facts that determine the change of the rate-pH profiles

Journal of the Brazilian Chemical Society

Brighente, Inês Maria Costa¹  Yunes, Rosendo Augusto¹  Universidade Federal de Santa Catarina, Florianópolis, Brazil¹ 

关键词: carbonyl compounds;    nitrogen nucleophiles;    general mechanism of attack   Introduction Sayer et al.1 have described a general mechanism for the reaction between nitrogen nucleophiles and carbonyl compounds in aqueous solution;    based on Scheme 1. This generalization is based on the relative importance of the hydronium-ion catalyzed concerted attack of the nitrogen nucleophile on the carbonyl compound (pathway I - "concerted mechanism") with respect to a mechanism that involves the previous formation of a zwitterionic tetrahedral intermediate (T±) and the posterior proton transfer to it from the hydronium-ion (pathway II - "step wise mechanism"). The importance of stepwise pathway II depends on the stability of the intermediate T± which is related to the pKa of the nitrogen nucleophile and to the equilibrium constant value Kad for the formation of the neutral addition tetrahedral intermediate T0 from the reagents.  ;   

DOI  :  10.1590/S0103-50531997000500018

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

Sayer et al.1 have described a general mechanism for the reaction between nitrogen nucleophiles and carbonyl compounds in aqueous solution, based on Scheme 1. This generalization is based on the relative importance of the hydronium-ion catalyzed concerted attack of the nitrogen nucleophile on the carbonyl compound (pathway I - "concerted mechanism") with respect to a mechanism that involves the previous formation of a zwitterionic tetrahedral intermediate (T±) and the posterior proton transfer to it from the hydronium-ion (pathway II - "step wise mechanism"). The importance of stepwise pathway II depends on the stability of the intermediate T± which is related to the pKa of the nitrogen nucleophile and to the equilibrium constant value Kad for the formation of the neutral addition tetrahedral intermediate T0 from the reagents.   The relative importance of pathway I with respect to pathway II originates different kinds of shape of the profile of log k2 (k2 = second-order rate constant) vs. pH for these reactions. Three profiles were indicated by Sayer1, called types A, B and C. These will be discussed later. It should be noted that Sayer et al.1 based their studies only on the reactions between benzaldehyde and substituted benzaldehydes with amines of different basicity. Thus, an important question is whether the pKa of the amine and the equilibrium constant Kad are of sufficiently equal importance to enable prediction of the profile of reactions of non-aromatic carbonyl compounds with amines. The reaction between norcamphor, a bicyclic ketone of fixed geometry2-4, with amines of different basicity, was studied in order to evaluate the above- mentioned question.  ExperimentalMaterials Organic reagents employed were commercially available products and were either redistilled or recrystallyzed. Inorganic chemicals and carboxylic acids used in buffers were of reagent grade and were used without further purification. Kinetics Reaction of the carbonyl compounds with nitrogen nucleophiles in water at 25.0 °C and ionic strength 0.5 M (KCl) were followed on a Varian DMS 80 spectrophotometer, equipped with a thermostated cell holder, by monitoring the formation of the oxime at 240 nm, the nitrone at 255 nm, the semicarbazone at 255 nm, and the phenylhydrazone at 320 nm. The concentration of norcamphor and ciclopentanone did not exceed 3.3 x 10-2 M. A sufficient excess of nitrogen nucleophile was employed to ensure pseudo first-order kinetic behaviour. The determination of the rate constants was carried out using known procedures5. Reactions were followed for three half-lives (t1/2) and first-order rate constants (kobs) were calculated by computer. Apparent second-order rate constants (k2ap) were calculated by dividing the first-order rate constants (kobs) by the concentration of the free nitrogen nucleophile, Eq. 1. The experimental error in the determination of the pseudo-first order constants (kobs) was ±2%.where fc = 1 + Kad Nul , and Nul is the concentration of free nitrogen nucleophile, calculated by the equation of Henderson-Hasselbalch. Steady-state treatment of the mechanism in Scheme 1 yields Eqs. 2 and 3 for product formation in the regions of rate-determining neutral intermediate formation (kad) and dehydration (kdeh), respectively.k2ap was calculated employing Eq. 4, together with the rate constants inTable 2.      Third-order rate constants (k1, Knk3, Kadk5) were obtained from the slopes of plots of apparent second-order constants against the concentration of hydronium-ion. The pH-independent rate constants (k2, Knk4) were obtained directly from the plot of log k2ap vs. pH.Equilibrium Constants The equilibrium constants - Kad - for the addition intermediate formation from several amines with norcamphor and hydroxylamine with ciclopentanone in aqueous solution and ionic strength 0.5 M (KCl) were determined spectrophotometrically6, from the initial decrease in absorbance of the carbonyl group at 285 nm extrapolated to zero time, on mixing a solution of ketone with several concentrations of amines, at pH 8.5 (0.01 M borate buffer). At this pH, dehydration of the addition intermediate is relatively slow, so that the observed absorbance could be extrapolated to zero time to determine the initial rapid decrease in ketone absorbance caused by addition intermediate formation. The calculated values of the fraction of ketone converted to addition intermediate (T0) were based on an assumed absorbance of zero for the addition compound at 285 nm. The measurements were made in triplicate for each concentration of amine, using the equation Kad = C=Ot - C=Ol / {C=Ol x hydroxylamine}, where C=Ot is the initial carbonyl concentration and C=Ol is the free carbonyl concentration.   Results and Discussion In order to discuss the results of this work, we should consider previously the three types of profiles (A, B, C) indicated by Sayer,1 and a fourth profile (D) indicated by ourselves7,8. Profile of type A: For very weakly basic amines and/or carbonyl compound for which the value of Kad is small, the tetrahedral zwitterionic intermediate should be unstable and consequently the pathway I is predominant. The profile exhibits a linear dependence of the rate as a function of the pH corresponding to hydronium-ion catalized attack (k1) at low pH. When the pH is increased, a break of the linearity with a pH-independent region corresponding to the intramolecular proton transfer in the intermediate T± (Knk4) appers. Finally, there emerges a new pH-dependent region corresponding to the hydronium-ion catalized dehydration of the intermediate T0 (Kadk5). (Fig. 1, III).   Profile of type B: for moderate basic amine or moderate values of the Kad, the contribution of the pathway (II) increases. The profile shows two breaks of linearity with five different kinetic regions: the hydronium-ion catalyzed attack at low pH, the pH-independent uncatalyzed attack (k2), the hydronium-ion proton transfer to the T± intermediate (Knk3), the pH independent intramolecular proton transfer in the T± intermediate, and the hydronium-ion catalyzed dehydration of T0. (Fig. 1, II). Profile of type C: For very strong basic amines or carbonyl compound with high values of Kad, the stability of the T± intermediate is increased still further, so that the rate pathway II is greater than the hydronium-ion catalyzed dehydration of T0, giving a profile where the only change in rate-determining step is the transition at low pH from uncatalyzed attack to hydronium ion-catalyzed dehydration of T0 (Fig. 1, I).Profile of type D: Corresponds to the

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