The “dimer nucleophile mechanism” for reactions with rate‐determining first step: Derivation of the whole kinetic law and further treatment of kinetic results

Overwhelming evidence has been previously reported for the existence of the so‐called “dimer nucleophile mechanism” in aromatic nucleophilic substitutions by amines in aprotic solvents, for which the most prominent feature is the fourth‐order kinetics (third order in amine) that has been observed with many different substrate–nucleophile systems, especially those in which departure of the nucleofuge is the rate‐determining step. The mechanism has been confirmed by several other features, although other alternative mechanisms were suggested to explain the fourth‐order kinetics, no one has been able to explain the other above‐mentioned features. The present paper affords additional experimental evidence and derivation of the kinetic expressions for reactions with good nucleofugues, where the first step is rate determining. The work involves studies of the reactions of 2,4‐dinitrofluorobenzene and 2,4‐dinitrochlorobenzene with aniline and with alkyldiamines in toluene. The novelty of this work lies in the selection of substrate–nucleophile systems exhibiting kinetic behavior that allows estimations of the different k's involved. The satisfactory agreement between the quotients of k's calculated from sets of data obtained under different reaction conditions hereby reported indicates that the assumptions made are correct and that the whole treatment applied to the kinetic data is justified. All together, the results fit well with the reaction scheme involving the dimer nucleophile mechanism, adding new evidence to this mechanism that it is well established in the current literature. © 2010 Wiley Periodicals, Inc. Int J Chem Kinet 42: 735–742, 2010     

An adaptive stepsize method for the chemical Langevin equation

Mathematical and computational modeling are key tools in analyzing important biological processes in cells and living organisms. In particular, stochastic models are essential to accurately describe the cellular dynamics, when the assumption of the thermodynamic limit can no longer be applied. However, stochastic models are computationally much more challenging than the traditional deterministic models. Moreover, many biochemical systems arising in applications have multiple time-scales, which lead to mathematical stiffness. In this paper we investigate the numerical solution of a stochastic continuous model of well-stirred biochemical systems, the chemical Langevin equation. The chemical Langevin equation is a stochastic differential equation with multiplicative, non-commutative noise. We propose an adaptive stepsize algorithm for approximating the solution of models of biochemical systems in the Langevin regime, with small noise, based on estimates of the local error. The underlying numerical method is the Milstein scheme. The proposed adaptive method is tested on several examples arising in applications and it is shown to have improved efficiency and accuracy compared to the existing fixed stepsize schemes.     

Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis,Computational Analysis and Antiproliferative Evaluation

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4′-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC₅₀ = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.     

Utilization of deuterium labelling and 13C NMR spectroscopy in the investigation of the condensation of 1-Methyl-5-nitroimidazole-2-aldehyde and 2-Amino-4-methylpyrimidine

The product obtained condensing l-methyl-5-nitroimidazole-2-aldehyde with 2-amino-4-trideuteriomethyl-pyrimidine and showing total deuterium incorporation at one of the olefinic carbons and partial deuterium incorporation para to the amino group, served to assign ¹³C and ¹H resonances in the condensation products 3. The nature of the species undergoing condensation has been inferred from labelling experiments and from ¹H and ¹³C nmr spectra of precursors and products in dimethylsulfoxide and trifluoroacetic acid.     

Inter‐ and intramolecular hydrogen bonds in polyamines: variable‐concentration 1H‐NMR studies

Inter‐ and intramolecular hydrogen bonding play an important role in determining the arrangement, physical properties, and reactivity of a great diversity of structures in chemical and biological systems. Several aromatic nucleophilic substitutions (ANS) in nonpolar aprotic, (non‐HBD), solvents recently studied in our laboratory have demonstrated the importance of self‐association of amines by hydrogen‐bond interactions. In this paper, we describe ¹H‐NMR studies carried out at room temperature on bi‐ and polyfunctionalized amines, namely: N‐(3‐amino‐1‐propyl)morpholine (3‐APMo), histamine, 2‐guanidinobenzimidazole (2‐GB), 1,2‐diaminoethane (EDA), 3‐dimethylamino‐l‐propylamine (DMPA), and 1‐(2‐aminoethyl)piperidine (2‐AEPip). By ¹H‐NMR measurements of amine solutions at variable concentrations we have shown that 3‐APMo, histamine and 2‐GB are able to form a six‐membered ring by intramolecular hydrogen bonding, while EDA, DMPA, and 2‐AEPip form dimers by intermolecular hydrogen bonds. Likewise, variable concentration ¹H‐NMR studies allowed estimation of the corresponding equilibrium constants for the dimerization. These results are correlated with experimental kinetic results of ANS, confirming hereto the relevance of the “dimer mechanism” in reactions involving these amines. Copyright © 2011 John Wiley & Sons, Ltd.     

PLS and first derivative of ratio spectra methods for determination of hydrochlorothiazide and propranolol hydrochloride in tablets

Two new analytical methods have been developed as convenient and useful alternatives for simultaneous determination of hydrochlorothiazide (HCT) and propranolol hydrochloride (PRO) in pharmaceutical formulations. The methods are based on the first derivative of ratio spectra (DRS) and on partial least squares (PLS) analysis of the ultraviolet absorption spectra of the samples in the 250–350-nm region. The methods were calibrated between 8.7 and 16.0 mg L⁻¹ for HCT and between 14.0 and 51.5 mg L⁻¹ for PRO. An asymmetric full-factorial design and wavelength selection (277–294 nm for HCT and 297–319 for PRO) were used for the PLS method and signal intensities at 276 and 322 nm were used in the DRS method for HCT and PRO, respectively. Performance characteristics of the analytical methods were evaluated by use of validation samples and both methods showed to be accurate and precise, furnishing near quantitative analyte recoveries (100.4 and 99.3% for HCT and PRO by use of PLS) and relative standard deviations below 2%. For PLS the lower limits of quantification were 0.37 and 0.66 mg L⁻¹ for HCT and PRO, respectively, whereas for DRS they were 1.15 and 3.05 mg L⁻¹ for HCT and PRO, respectively. The methods were used for quantification of HCT and PRO in synthetic mixtures and in two commercial tablet preparations containing different proportions of the analytes. The results of the drug content assay and the tablet dissolution test were in statistical agreement (p < 0.05) with those furnished by the official procedures of the USP 29. Preparation of dissolution profiles of the combined tablet formulations was also performed with the aid of the proposed methods. The methods are easy to apply, use relatively simple equipment, require minimum sample pre-treatment, enable high sample throughput, and generate less solvent waste than other procedures. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Approach to the synthesis of cladiell-11-ene-3,6,7-triol

[reaction: see text] The synthesis of an advanced intermediate in the synthesis of the title compound has been achieved. Key steps include an Ireland-Claisen rearrangement to install the C7 tertiary alcohol stereocenter, an SN2' reaction of an alkoxymethyl Cu reagent, and a diastereoselective Re-catalyzed allylic alcohol transposition.     

Antioxidant activity and chemical composition of essential oil from Atriplex undulata

The essential oil from aerial parts (stems and leaves) of Atriplex undulata (Moq) D. Dietr. (Chenopodiaceae) has been studied for its in vitro antioxidant activity. The chemical composition of the oil obtained by hydrodistillation was determined by GC and GC-MS. The major constituents were p-acetanisole (28.1%), beta-damascenone (9.3%), beta-ionone (5.1%), viridiflorene (4.7%) and 3-oxo-alpha-ionol (2.2%). The antioxidant activity of the oil was determined by two methods: Crocin bleaching inhibition (Krel = 0.72 +/- 0.15) and scavenging of the DPPH radical (IC50 = 36.2 +/- 1.6 microg/mL). The presence of active compounds like p-acetanisole, carvone, vanillin, 4-vinylguaiacol, guaiacol, terpinen-4-ol and alpha-terpineol could explain the antioxidant activity observed for this oil.