The importance of the modular structure 'fluor-spacer-amine' is pointed out for the design of fluorescent molecular sensors for p H according to the principle of photoinduced electron transfer (PET). Anthracen-9-yl methylamines (24) and some azacrown ether analogues (1 5 and 23) are examined in this context. They show p H -dependent fluorescence quantum yields describable by eqn. ( 5) while all other electronic spectral parameters remain essentially pH-invariant. The range of pK, values of these sensors are understandable in terms of macrocyclic effects and the transmission of electric fields across the anthracene short axis. Phase-shift fluorometric determination of the fluorescence lifetimes of these sensors allows the calculation of the rate constant of PET in their proton-free form t o be 1 Ole-1 0" s-', with the diamines 23 and 24b exhibiting the faster rates.
The alkylating potential of -propiolactone (BPL), -butyrolactone (BBL), γ-butyrolactone, and δ-valerolactone, which can be formed by the in vivo nitrosation of primary amino acids, was investigated kinetically. The nucleophile NBP, 4-(p-nitrobenzyl)pyridine, a trap for alkylating agents, was used as an alkylation substrate. The alkylation reactions were performed under mimicked cellular conditions at neutral pH in water/dioxane solvent mixtures. To gain insight into the effect of the hydrolysis of lactones on their alkylating efficiency, alkylation and competing hydrolysis were studied in parallel. Conclusions were drawn as follows: (i) γ-Butyrolactone and δ-valerolactone afford neither appreciable NBP alkylation nor hydrolysis reactions; (ii) the alkylating potential of BPL is 10-fold higher than that of BBL, the reactivity of both being essentially enthalpy-controlled; (iii) a correlation was found between the alkylating potential of lactones and their carcinogenicity; (iv) the hydrolysis of lactones is not sufficiently effective to prevent alkylation; (v) the efficiency of alkylation, expressed as the alkylation rate/ hydrolysis rate ratio, decreases strongly with increasing amounts of dioxane in the reaction media; (vi) the absorption coefficients of the NBP-lactone adducts are as follows: NBP-BPL ) 5101 ( 111 M -1 cm -1 (λ ) 584 nm) and NBP-BBL ) 462 ( 19 M -1 cm -1 (λ ) 586 nm), the pronounced difference between these values being rationalized in terms of the adducts' structure; and (vii) linear correlations exist between the adducts' absorption coefficients and the water/dioxane ratio in the reaction media.
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.
Alkylating agents are considered to be archetypal carcinogens. One suitable technique to evaluate the activity of alkylating compounds is the NBP assay. This method is based on the formation of a chromophore in the reaction between the alkylating agent and the nucleophile 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases. NBP is known to react with strong and weak alkylating agents, and much insight into such alkylation mechanisms in vivo can be gained from kinetic study of some alkylation reactions in vitro. Since 1925, the NBP assay has evolved from being a qualitative, analytical tool to becoming a useful physicochemical method that not only allows the rules of chemical reactivity that govern electrophilicity and nucleophilicity to be applied to the reaction of DNA with alkylating agents but also helps to understand some significant relationships between the structure of many alkylation substrates (including DNA) and their chemical and biological responses. Given that advances in this area have the potential to yield both fundamental and practical advances in chemistry, biology, predictive toxicology, and anticancer drug development, this review is designed to provide an overview of the evolution of the NBP method from its early inception until its recent kinetic–mechanistic approach, which allows the pros and cons of NBP as a DNA-model to be analyzed. The validity of NBP as a nucleophilicity model for DNA in general and the position of guanosine at N7 in particular are discussed.
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.
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