Julio Casado

Amino Acid Nitrosation Products as Alkylating Agents

Nitrosation reactions of alpha-, beta-, and gamma-amino acids whose reaction products can act as alkylating agents of DNA were investigated. To approach in vivo conditions for the two-step mechanism (nitrosation and alkylation), nitrosation reactions were carried out in aqueous acid conditions (mimicking the conditions of the stomach lumen) while the alkylating potential of the nitrosation products was investigated at neutral pH, as in the stomach lining cells into which such products can diffuse. These conclusions were drawn: (i) The alkylating species resulting from the nitrosation of amino acids with an -NH(2) group are the corresponding lactones; (ii) the sequence of alkylating power is: alpha-lactones > beta-lactones > gamma-lactones, coming respectively from the nitrosation of alpha-, beta-, and gamma-amino acids; and (iii) the results obtained may be useful in predicting the mutagenic effectiveness of the nitrosation products of amino acids.

Kinetic studies on the formation ofN-nitroso compounds VI. The reactivity of N2O3 as a nitrosating agent

Using a differential spectrophotometric technique in water at 25°C measurements were made of the reaction rate in the nitrosation of a number of secondary amines in conditions in which the effective nitrosating agent is thought to be dinitrogen trioxide. Analysis of the rate data leads to values ofk, the true rate coefficient for theN-nitrosation step, which, like the values recalculated here for other systems involving aliphatic and aromatic substrates ofpKa>5, exhibit the same unvarying order of magnitude, 108M−1s−1. This figure together with the invariance already mentioned indicates that the attack of the N2O3 upon free amines must be diffusion controlled; this hypothesis is supported by the values found for the enthalpies of activation (10–20 kJ/mol).ZusammenfassungEs wurde mittels einer differentiellen spektrophotometrischen Methode die Reaktionsgeschwindigkeit derN-Nitrosierung von sekundären Aminen unter Bedingungen untersucht, bei denen N2O3 als nitrosierendes Agens angesehen wird. Der wahre Reaktionsgeschwindigkeitskoeffizientk für denN-Nitrosierungsschritt — sowohl für die oben genannten als auch andere erneut berechnete Systeme mit aliphatischen und aromatischen Substraten mitpKa>5 — ergab immer die gleiche Größenordnung von 108M−1s−1. Dieser Befund zeigt an, daß der Angriff von N2O3 auf die freien Amine diffusionskontrolliert erfolgen muß, wobei diese Annahme auch von den experimentellen Aktivierungsenthalpien von 10–20 kJ/mol gestützt wird.

Revision of the methodology in enzyme kinetics: A fractal approach

A model based on the fractal methodology is proposed for the kinetic study of the mechanisms of enzyme catalysis. The concept of fractal dimension facilitates information concerning the deviation of the mechanism with respect to the Michaelis-Menten model. The concepts of k eff , K eff M and V eff max introduced in the work allow one to conserve the Michaelis-Menten formalism, which apart from providing an overall view of the complexity of the reaction-path of enzyme catalysis, also offers an appreciable economy in numerical treatment and computing time compared with the conventional methods of searching for polynomial rate equations; it also avoids the subjective aspects inherent to this.

A calculator program for the optimization of physico-chemical parameters by unidimensional search

Abstract A calculator program for the numerical optimization of physico-chemical parameters by the algorithm of Davies, Swann and Campey is described which includes estimation of the standard deviations of the optimized parameters.

Computational Calculation of Equilibrium Constants: Addition to Carbonyl Compounds

Hydration reactions are relevant for understanding many organic mechanisms. Since the experimental determination of hydration and hemiacetalization equilibrium constants is fairly complex, computational calculations now offer a useful alternative to experimental measurements. In this work, carbonyl hydration and hemiacetalization constants were calculated from the free energy differences between compounds in solution, using absolute and relative approaches. The following conclusions can be drawn: (i) The use of a relative approach in the calculation of hydration and hemiacetalization constants allows compensation of systematic errors in the solvation energies. (ii) On average, the methodology proposed here can predict hydration constants within +/- 0.5 log K(hyd) units for aldehydes. (iii) Hydration constants can be calculated for ketones and carboxylic acid derivatives within less than +/- 1.0 log K(hyd), on average, at the CBS-Q level of theory. (iv) The proposed methodology can predict hemiacetal formation constants accurately at the MP2 6-31++G(d,p) level using a common reference. If group references are used, the results obtained using the much cheaper DFT-B3LYP 6-31++G(d,p) level are almost as accurate. (v) In general, the best results are obtained if a common reference for all compounds is used. The use of group references improves the results at the lower levels of theory, but at higher levels, this becomes unnecessary.

Computational Study of the Acid Dissociation of Esters and Lactones. A Case Study of Diketene

A computational study of the aqueous pK(a) of some saturated and unsaturated cyclic and linear esters and ketones was carried out at the DFT-B3LYP 6-31++G(2df,2pd), CBS-Q, and G2 levels, with the integral equation formalism polarizable continuum model for solvation, using a proton exchange mechanism. The influence of unsaturation, position of the double bond, and cyclization were studied. The computational results show that (a) in all cases studied except that of diketene (4-methylene-2-oxetanone), the alpha-beta unsaturated isomer is 20-30 kJ mol(-1) lower in energy that the beta-gamma unsaturated one; (b) alpha-beta unsaturation lowers the pK(a) of an ester approximately 6 units, whereas beta-gamma unsaturation lowers it by approximately 10 units, and cyclization lowers the pK(a) by approximately 3 units. In order to check the predictive power of the methodology, the acid dissociation constant of diketene in water was measured via kinetic study of its base-catalyzed hydrolysis. The pK(a) value obtained (15.2 +/- 0.3) is in keeping with the expected value for a beta-gamma unsaturated beta-lactone. This low value also suggests that deprotonated diketene does not interconvert to a more stable, less acidic alpha-beta unsaturated isomer, which is also consistent with computational results.

ESTIMATION OF THE AGGREGATION NUMBER AND CORE RADIUS OF MICROEMULSIONS

SummaryA simple working method for the estimation of the aggregation numbers and core radii from weight measurements of sodium bis-2-ethylhexylsulphosuccinate (aerosol-OT orAOT)/decane/water microemulsions of several compositions is proposed.Starting out from the hypotheses that (i) the density of the water inside the droplets is the same as that of free water, (ii) all the surfactant is localized as interface, and (iii) the penetration of the organic phase into the interface is negligible, values for the aggregation number and core radii comparable to those determined using more sophisticated methods were obtained.The results/methodological simplicity ratio may be of great advantage in kinetic work on reaction mechanisms in microemulsions.ZusammenfassungEs wird eine einfache Methode zur Abschätzung von Aggregationszahl und Core-Radius von Mikroemulsionen aus Gewichtsmessungen von Natriumbis-2-ethylhexylsulphosuccinat (aerosol-OT oderAOT)/Decan/Wasser-Mikroemulsionen verschiedener Zusammensetzung vorgeschlagen. Unter den Annahmen, daß (i) die Dichte von Wasser innerhalb der Aggregationen die gleiche als bei freiem Wasser ist, (ii) das ganze Emulsionsmittel in der Grenzfläche vorliegt und (iii) das Eindringen der organischen Phase in die Grenzfläche vernachlässigbar ist, können Werte für Aggregationszahlen und Core-Radien erhalten werden, die durchaus mit entsprechenden Werten aus aufwendigeren Methoden vergleichbar sind. Das Leistungsverhältnis (Ergebnisse/geringer Aufwand) ist sehr vorteilhaft und macht die Methode für kinetische Arbeiten zur Bestimmung von Reaktionsmechanismen in Mikroemulsionen interessant.

Mechanisms of Lactone Hydrolysis in Neutral and Alkaline Conditions

The neutral and base-catalyzed hydrolysis of nine carboxylic acid esters was studied using a hybrid supermolecule-PCM approach including six explicit water molecules. The molecules studied included two linear esters, four β-lactones, two γ-lactones, and one δ-lactone: ethyl acetate and methyl formate, β-propiolactone, β-butyrolactone, β-isovalerolactone, diketene (4-methyleneoxetan-2-one), γ-butyrolactone, 2(5H)-furanone, and δ-valerolactone. DFT and ab initio methods were used to analyze the features of the various possible hydrolysis mechanisms. For all compounds, reasonable to very good qualitative and quantitative agreement with experimental work was found, and evidence is provided to support long-standing hypotheses regarding the role of solvent molecule as a base catalyst. In addition, novel evidence is presented for the existence of an elimination-addition mechanism in the basic hydrolysis of diketene. A parallel work addresses the acid-catalyzed hydrolysis of lactones.

Kinetic studies on the formation of N-nitroso compounds XI. Nitrosation of dimethylamine by nitrite esters in aqueous basic media

AbstractA kinetic study of the mechanism of the nitrosation of dimethylamine (DMA) by propyl nitrite (PrONO) in basic media to yield N-nitrosodimethylamine (NDMA) has found the rate equation to be