title: Equilibria and kinetics of N-hydroxymethylamine formation from aromatic exocyclic amines and formaldehyde. Effects of nucleophilicity and catalyst strength upon mechanisms of catalysis of carbinolamine formation¹.
abstract: The products of the reaction of exocyclic aromatic amines with formaldehyde are hydroxymethylamines and not imines; rate and equilibrium constants for carbinolamine formation have been determined for a series of substituted anilines and 1 -methyl-4-aminopyridiniuim ion. The hydroxymethylamine formation constants (K ₁) from hydrated plus unhydrated formaldehyde and aromatic amines of varying basicity (about pK(a)₁ 6 to -6) are in the range 3-27 M⁻¹ and show a relatively small dependence upon basicity (β(nuc) values 0.04 and 0.16 for substituted anilines and N-methylanilines, respectively). The formation constants for cationic hydroxymethylamines from cationic amines and formaldehyde (K₂) are about two orders of magnitude less favorable than those for the neutral species and, reciprocally, the pK(a) ₂values of N-hydroxymethylanilinium ions are about two pH units lower than their parent anilinium ions. Hydroxymethylamine formation occurs by general and specific acid and general and specific base catalyzed pathways, in addition to a pH-independent pathway. For the anilines, the Bronsted plots for general acid catalysts are nonlinear with the break occurring at a lower pK value than expected from the pK₀ value estimated for the alcoholic group of >N⁺HCH₂0H of ~9. A stepwise preassociation or spectator mechanism is suggested to account for these data and involves a preassociation of catalyzing acid, amine, and aldehyde in an encounter complex ( K (E) ) ,the formation of (k2) and proton transfer from the catalyst to an unstable zwitterionic tetrahedral intermediate (k₃), T±, with in the encounter complex, and dissociation or rotation (k₄) before product formation. With strongly acidic catalysts k₂is the rate-determining step and with more weakly acidic catalysts k₃is the rate-determining step. There appears to be a significant degree of stabilization of the transition state for C-N bond formation by general acids and hydronium ions. For the most weakly basic amine, 1-methyl-4-aminopyridiniuiomn , the hydronium ion and general acid catalyzed pathways appear to be more concerted based upon a linear Bronsted plot (α = 0.28) as a consequence of the decreased stability of T±. The rate constants for the uncatalyzed conversion of T± to a neutral tetrahedral intermediate are 1-5 X IO⁷ s⁻¹ and are consistent with a solvent mediated intramolecular proton-transfer (“proton switch”) mechanism of carbinolamine formation. For a more limited series of general base catalysts (pK = 9-11.5), the rate constants for the proton-transfer processes calculated from the observed rate constants and estimated equilibrium constants (K(n),) for the formation of T± from amine and hydrated and unhydrated formaldehyde are in the range of 10(7.4)-10⁹M⁻¹s⁻¹ for monofunctional general bases. These values approach those expected for diffusion-limited processes but the limited data with linear Bronsted plots (β values of 0.17 ± 0.05, 0.06 ± 0.02, and 0.13 ± 0.01 for the 4-cyano-, 4-nitro-, and 3-fluoro-4-nitroanilines, respectively) for general base catalysts do not unequivocally rule out a concerted mechanism of catalysis with proton removal by the base from the nucleophile as the N-C bond is formed.
authors: Department of Biochemistry and Biophysics, School of Medicine, and the Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19174, USA.
authors: W R
authors: WR
authors: Abrams
authors: R G
authors: RG
authors: Kallen