Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann-Löffler-Freytag Reaction.

The Hofmann-Löffler-Freytag (HLF) reaction serves as a late-stage functionalization technique for generating pyrrolidine heterocyclic ring systems. Contemporary HLF protocols utilize in situ halogenated sulfonamides as precursors in the radical-mediated rearrangement cycle. Despite its well-established reaction mechanism, experiments toward the detection of radical intermediates using EPR techniques have only recently been attempted. However, the obtained spectra lack the distinct features of the N-centered radicals expected for the employed reactants. This paper presents phenylbutylnitrone spin-trapped C-centered and N-centered radicals, generated via light irradiation from N-halogen-tosyl-sulfonamide derivatives and detected using EPR spectroscopy. NMR spectroscopy and DFT calculations are used to explain the observed regioselectivity of the HLF reaction.

Nanoplastics increase in vitro oestrogenic activity of neurotherapeutic drugs.

Environmental pollution with plastic nanoparticles (PNPs) has rendered hazard assessment of unintentional human exposure to neurotherapeutic drugs through contaminated water and food ever more complicated. Due to their small size, PNPs can easily enter different cell types and cross different biological barriers, while their high surface-to-volume ratio enables higher adsorption of chemicals. This is how PNPs take the role of a Trojan horse as they enhance bioaccumulation of many different pollutants. One of the health concerns related to water pollution with neurotherapeutic drugs is endocrine disruption, already evidenced for the anticonvulsant drug carbamazepine (Cbz) and antidepressant fluoxetine (Flx). Our study aimed to evaluate endocrine disrupting effects of Cbz and Flx in mixtures with polystyrene nanoparticles (PSNPs) using the in vitro luciferase assay to measure oestrogen receptor activity in T47D-KBluc cells treated with Cbz-PSNPs or Flx-PSNPs mixtures and compare it with the activities observed in cells treated with individual mixture components (Cbz, Flx, or PSNPs). Dose ranges used in the study were 0.1-10 mg/L, 1-100 µmol/L, and 0.1-10 µmol/L for PSNPs, Cbz, and Flx, respectively. Our findings show that none of the individual components activate oestrogen receptors, while the mixtures induce oestrogen receptor activity starting with 0.1 mg/L for PSNPs, 10 µmol/L for Cbz, and 0.5 µmol/L for Flx. This is the first study to evidence that PSNPs increase oestrogen receptor activity induced by neurotherapeutic drugs at their environmentally relevant concentrations and calls for urgent inclusion of complex mixtures in health hazard assessments to inform regulatory response.

Synthesis and Biological Evaluations of Granulatamide B and its Structural Analogues.

BACKGROUND: While granulatamides A and B have been previously isolated, their biological activities have been only partially examined. The aim of this study was to synthesize granulatamide B (4b), a tryptamine-derivative naturally occurring in Eunicella coral species, using the well-known procedure of Sun and Fürstner and its 12 structural analogues by modifying the side chain, which differs in length, degree of saturation as well as number and conjugation of double bonds. METHOD: The prepared library of compounds underwent comprehensive assessment for their biological activities, encompassing antioxidative, antiproliferative, and antibacterial properties, in addition to in vivo toxicity evaluation using a Zebrafish model. Compound 4i, which consists of a retinoic acid moiety, exhibited the strongest scavenging activity against ABTS radicals (IC50 = 36 ± 2 µM). In addition, 4b and some of the analogues (4a, 4c and 4i), mostly containing an unsaturated chain and conjugated double bonds, showed moderate but non-selective activity with certain IC50 values in the range of 20-40 µM. RESULT: In contrast, the analogue 4l, a derivative of alpha-linolenic acid, was the least toxic towards normal cell lines. Moreover, 4b was also highly active against Gram-positive Bacillus subtilis with an MIC of 125 µM. Nevertheless, both 4b and 4i, known for the best-observed effects, caused remarkable developmental abnormalities in the zebrafish model Danio rerio. CONCLUSION: Since modification of the side chain did not significantly alter the change in biological activities compared to the parent compound, granulatamide B (4b), the substitution of the indole ring needs to be considered. Our group is currently carrying out new syntheses focusing on the functionalization of the indole core.

Ferrocenoyl-adenines: substituent effects on regioselective acylation.

A series of N 6-substituted adenine-ferrocene conjugates was prepared and the reaction mechanism underlying the synthesis was explored. The SN2-like reaction between ferrocenoyl chloride and adenine anions is a regioselective process in which the product ratio (N7/N9-ferrocenoyl isomers) is governed by the steric property of the substituent at the N 6-position. Steric effects were evaluated by using Charton (empirical) and Sterimol (computational) parameters. The bulky substituents may shield the proximal N7 region of space, which prevents the approach of an electrophile towards the N7 atom. As a consequence, the formation of N7-isomer is a kinetically less feasible process, i.e., the corresponding transition state structure increases in relative energy (compared to the formation of the N9-isomer). In cases where the steric hindrance is negligible, the electronic effect of the N 6-substituent is prevailing. That was supported by calculations of Fukui functions and molecular orbital coefficients. Both descriptors indicated that the N7 atom was more nucleophilic than its N9-counterpart in all adenine anion derivatives. We demonstrated that selected substituents may shift the acylation of purines from a regioselective to a regiospecific mode.

Transformation of L-DOPA and Dopamine on the Surface of Gold Nanoparticles: An NMR and Computational Study.

Gold nanoparticles (AuNPs) have found applications in biomedicine as diagnostic tools, but extensive research efforts have been also directed toward their development as more efficient drug delivery agents. The high specific surface area of AuNPs may provide dense loading of molecules like catechols (L-DOPA and dopamine) on nanosurfaces, enabling functionalization strategies for advancing conventional therapy and diagnostic approaches of neurodegenerative diseases. Despite numerous well-described procedures in the literature for preparation of different AuNPs, possible transformation and structural changes of surface functionalization agents have not been considered thoroughly. As a case in point, the catechols L-DOPA and dopamine were selected because of their susceptibility to oxidation, cyclization, and polymerization. To assess the fate of coating and functionalization agents during the preparation of AuNPs or interaction at the nano-bio interface, a combination of spectroscopy, light scattering, and microscopy techniques was used while structural information and reaction mechanism were obtained by NMR in combination with computational tools. The results revealed that the final form of catechol on the AuNP nanosurface depends on the molar ratio of Au used for AuNP preparation. A large molar excess of L-DOPA or dopamine is needed to prepare AuNPs funtionalized with fully reduced catechols. In the case of molar excess of Au, the oxidation of catechols to dopamine quinone and dopaquinone was promoted, and dopaquinone underwent intramolecular cyclization in which additional oxidation products, leukodopachrome, dopachrome, or its tautomer, were formed because of the larger intrinsic acidity of the more nucleophilic amino group in dopaquinone. MD simulations showed that, of the oxidation products, dopachrome had the highest affinity for binding to the AuNPs surface. The results highlight how a more versatile methodological approach, combining experimental and in silico techniques, allows more reliable characterization of binding events at the surface of AuNPs for possible applications in biomedicine.

Electronic Coupling in 1,2,3-Triazole Bridged Ferrocenes and Its Impact on Reactive Oxygen Species Generation and Deleterious Activity in Cancer Cells.

Mixed-valence (MV) binuclear ferrocenyl compounds have long been studied as models for testing theories of electron transfer and in attempts to design molecular-scale electronic devices (e.g., molecular wires). In contrary to that, far less attention has been paid to MV binuclear ferrocenes as anticancer agents. Herein, we discuss the synthesis of six 1,2,3-triazole ferrocenyl compounds for combined (spectro)electrochemical, electron paramagnetic resonance (EPR), computational, and anticancer activity studies. Our synthetic approach was based on the copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition reaction and enabled us to obtain in one step compounds bearing either one, two, or three ferrocenyl entities linked to the common 1,2,3-triazole core. Thus, two series of complexes were obtained, which pertain to derivatives of 3'-azido-3'-deoxythymidine (AZT) and 3-azidopropionylferrocene, respectively. Based on the experimental and theoretical data, the two mono-oxidized species corresponding to binuclear AZT and trinuclear 3-azidopropionylferrocene complexes have been categorized as class II mixed-valence according to the classification proposed by Robin and Day. Of importance is the observation that these two compounds are more active against human A549 and H1975 non-small-cell lung cancer cells than their congeners, which do not show MV characteristics. Moreover, the anticancer activity of MV species competes or surpasses, dependent on the cell line, the activity of reference anticancer drugs such as cisplatin, tamoxifen, and 5-fluorouracil. The most active from the entire series of compounds was the binuclear thymidine derivative with the lowest IC50 value of 5 ± 2 µM against lung H1975 cancer cells. The major mechanism of antiproliferative activity for the investigated MV compounds is based on reactive oxygen species generation in cancer cells. This hypothesis was substantiated by EPR spin-trapping experiments and the observation of decreased anticancer activity in the presence of N-acetyl cysteine (NAC) free-radical scavenger.

Fate and transformation of silver nanoparticles in different biological conditions.

The exploitation of silver nanoparticles (AgNPs) in biomedicine represents more than one third of their overall application. Despite their wide use and significant amount of scientific data on their effects on biological systems, detailed insight into their in vivo fate is still lacking. This study aimed to elucidate the biotransformation patterns of AgNPs following oral administration. Colloidal stability, biochemical transformation, dissolution, and degradation behaviour of different types of AgNPs were evaluated in systems modelled to represent biological environments relevant for oral administration, as well as in cell culture media and tissue compartments obtained from animal models. A multimethod approach was employed by implementing light scattering (dynamic and electrophoretic) techniques, spectroscopy (UV-vis, atomic absorption, nuclear magnetic resonance) and transmission electron microscopy. The obtained results demonstrated that AgNPs may transform very quickly during their journey through different biological conditions. They are able to degrade to an ionic form and again reconstruct to a nanoparticulate form, depending on the biological environment determined by specific body compartments. As suggested for other inorganic nanoparticles by other research groups, AgNPs fail to preserve their specific integrity in in vivo settings.

Combined NMR and Computational Study of Cysteine Oxidation during Nucleation of Metallic Clusters in Biological Systems.

The widespread biomedical applications of silver and gold nanoparticles (AgNPs and AuNPs, respectively) prompt the need for mechanistic evaluation of their interaction with biomolecules. In biological media, metallic NPs are known to transform by various pathways, especially in the presence of thiols. The interplay between metallic NPs and thiols may lead to unpredictable consequences for the health status of an organism. This study explored the potential events occurring during biotransformation, dissolution, and reformation of NPs in the thiol-rich biological media. The study employed a model system evaluating the interaction of cysteine with small-sized AgNPs and AuNPs. The interplay of cysteine on transformation and reformation pathways of these NPs was experimentally investigated by nuclear magnetic resonance (NMR) spectroscopy and supported by light scattering techniques and transmission electron microscopy (TEM). As the main outcome, Ag- or Au-catalyzed oxidation of cysteine to cystine was found to occur through generation of reactive oxygen species (ROS). Computational simulations confirmed this mechanism and the role of ROS in the oxidative dimerization of biothiol during NPs reformation. The obtained results represent valuable mechanistic data about the complex events during the transport of metallic NPs in thiol-rich biological systems that should be considered for the future biomedical applications of metal-based nanomaterials.

Ionization Energy and Reduction Potential in Ferrocene Derivatives: Comparison of Hybrid and Pure DFT Functionals.

Hybrid density functionals have been regularly applied in state-of-the-art computational models for predicting reduction potentials. Benchmark calculations of the absolute reduction potential of ferricenium/ferrocene couple, the IUPAC-proposed reference in nonaqueous solution, include the B3LYP/6-31G(d)/LanL2TZf protocol. We used this procedure to calculate ionization energies and reduction potentials for a comprehensive set of ferrocene derivatives. The protocol works very well for a number of derivatives. However, a significant discrepancy (>1 V) between experimental and calculated data was detected for selected cases. Three variables were assessed to detect an origin of the observed failure: density functional, basis set, and solvation model. It comes out that the Hartree-Fock exchange fraction in hybrid-DFT methods is the main source of the error. The accidental errors were observed for other hybrid models like PBE0, BHandHLYP, and M06-2X. Therefore, hybrid DFT methods should be used with caution, or pure functionals (BLYP or M06L) may be used instead.

Toxicity and safety study of silver and gold nanoparticles functionalized with cysteine and glutathione.

This study was designed to evaluate the nano-bio interactions between endogenous biothiols (cysteine and glutathione) with biomedically relevant, metallic nanoparticles (silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs)), in order to assess the biocompatibility and fate of nanoparticles in biological systems. A systematic and comprehensive analysis revealed that the preparation of AgNPs and AuNPs in the presence of biothiols leads to nanoparticles stabilized with oxidized forms of biothiols. Their safety was tested by evaluation of cell viability, reactive oxygen species (ROS) production, apoptosis induction and DNA damage in murine fibroblast cells (L929), while ecotoxicity was tested using the aquatic model organism Daphnia magna. The toxicity of these nanoparticles was considerably lower compared to their ionic metal forms (i.e., Ag+ and Au3+). The comparison with data published on polymer-coated nanoparticles evidenced that surface modification with biothiols made them safer for the biological environment. In vitro evaluation on human cells demonstrated that the toxicity of AgNPs and AuNPs prepared in the presence of cysteine was similar to the polymer-based nanoparticles with the same core material, while the use of glutathione for nanoparticle stabilization was considerably less toxic. These results represent a significant contribution to understanding the role of biothiols on the fate and behavior of metal-based nanomaterials.

Transacylation in Ferrocenoyl-Purines. NMR and Computational Study of the Isomerization Mechanism.

In the reaction of purines with ferrocenoyl chloride in dimethylformamide (DMF), a regioselective acylation occurred. The two products have been isolated and, according to detailed NMR analysis, identified as N7- and N9-ferrocenoylated isomers. In a more polar solvent, for example, in dimethylsulfoxide (DMSO), the two isomers interconvert to each other. The N7/N9 isomerization was followed by 1H NMR spectroscopy, until dynamic equilibrium was reached. Both kinetics and thermodynamics of the transacylation process are governed by a C6-substituent on the purine ring (R = NH2, Me, NHBz, OBz). The observed rate constant for the N7/N9-isomerization in the adenine system (R = NH2) is kobs = 0.3668 h-1, whereas the corresponding process in the C6-benzyloxypurine is 56 times slower. By use of density functional theory calculations and molecular dynamics simulations, several reaction pathways were considered and explored. Only the reaction mechanism involving DMSO as a nucleophilic reactant is in harmony with the experimental kinetic data. The calculated barrier (ΔG⧧ = 107.9 kJ/mol; at the M06L/6-311+G(d,p)/SDD level of theory) for this SN2-like reaction in the adenine system agrees well with the experimental value of 102.7 kJ/mol. No isomerization was detected in other organic solvents, for example, acetonitrile, N,N-dimethylformamide, or acetone, which indicated the exceptional nucleophilicity of DMSO. Our results raise a warning when treating or dissolving acylated purines in DMSO as they are prone to isomerization. We observed that the N7/N9-group transfer was specific not only for the organometallic moiety only, but for other acyl groups in purines as well. The relevance of this isomerization may be expected for a series of nucleobases and heterocyclic systems in general.

Luminescent pyrenyl-GNA nucleosides: synthesis, photophysics and confocal microscopy studies in cancer HeLa cells.

Glycol nucleic acids (GNA) are synthetic genetic-like polymers with an acyclic three-carbon propylene glycol phosphodiester backbone. Here, synthesis, luminescence properties, circular dichroism (CD) spectra, and confocal microscopy speciation studies of (R,S) and (S,R) pyrenyl-GNA (pyr-GNA) nucleosides are reported in HeLa cells. Enantiomerically pure nucleosides were obtained by a Sharpless asymmetric dihydroxylation reaction followed by semi-preparative high-performance liquid chromatography (HPLC) separation using Amylose-2 as the chiral stationary phase. The enantiomeric relationship between stereoisomers was confirmed by CD spectra, and the absolute configurations were assigned based on experimental and theoretical CD spectra comparisons. The pyr-GNA nucleosides were not cytotoxic against human cervical (HeLa) cancer cells and thus were utilized as luminescent probes in the imaging of these cells with confocal microscopy. Cellular staining patterns were identical for both enantiomers in HeLa cells. Compounds showed no photocytotoxic effect and were localized in the lipid membranes of the mitochondria, in cellular vesicles and in other lipid cellular compartments. The overall distribution of the pyrene and pyrenyl-GNA nucleosides inside the living HeLa cells differed, since the former compound gives a more granular staining pattern and the latter a more diffuse one.

Racemization of oxazepam and chiral 1,4-benzodiazepines. DFT study of the reaction mechanism in aqueous solution.

The tranquilizer and hypnotic drug oxazepam undergoes the racemization process in aqueous medium, which is relevant for its pharmacological profile. The experimental barrier value (ΔG‡298 ≈ 91 kJ mol-1) was determined earlier, but the exact mechanism of enantiomerization is not known. Four different mechanisms have been proposed in the literature: C3-H/H exchange reaction, keto-enol tautomerization, solvolytic identity reaction, and ring-chain tautomerization. However, none of the reported reactions has been confirmed as the main pathway for racemization. In this work, all these mechanisms were subjected to comprehensive analysis performed by high-level quantum-chemical models. Two density functionals (B3LYP and M062X) were employed for geometry optimization of all stationary points at the corresponding potential surfaces, and the double-hybrid model (B2PLYP) was used for improved energy calculations. Out of all the tested mechanisms, only the ring-chain tautomerism fits the two experimental targets: the measured energy barrier and the pH-rate profile of racemization. The latter reveals that no acid/base catalysis is required for racemization to occur. The ring-chain tautomerism is initiated by intramolecular proton transfer from the C3-hydroxyl group to the imine nitrogen, which triggers the benzodiazepine ring opening and the formation of the achiral aldehyde intermediate. The latter undergoes ring closure which results in the inverted configuration at the C3-chiral atom of oxazepam. Our computational results suggest that the same mechanism is operative in the fast racemization of different 1,4-benzodiazepines, which posses the hydroxyl group at the stereogenic C3-centre (e.g. lorazepam or temazepam). In other benzodiazepine members (e.g. cinazepam or camazepam) the keto-enol tautomerization and/or the C3-H/H exchange mechanism may become relevant for their much slower racemization. This computational study is not only revealing in terms of mechanistic details, but also has predictive power for optical stability estimates in the family of benzodiazepines and similar heterocycles.

Chlorination of 5-fluorouracil: Reaction mechanism and ecotoxicity assessment of chlorinated products.

What happens to drugs in the chlorinating environment? Degradation products may vary in pharmacological profiles and in ecotoxicity potentials compared to the parent compound. This study combines synthesis, NMR spectroscopy, quantum chemical calculations, and toxicity experiments on Daphnia magna to investigate chemical fate of antineoplastic drug 5-fluorouracil (5-FU) in chlorinated environment, which is common in waste-water treatment procedures, but also endogenous in activated neutrophils. A reduction of toxicity (EC50 after 48 h is 50% higher than for the parent 5-FU) was observed after the first chlorination step, in which a chlorohydrin 5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracil was formed. Further chlorination leads to N-chlorinated intermediate, that undergoes the pyrimidine ring opening reaction. The final product, 2-chloro-2-fluoro-3,3-dihydroxypropanoic acid was obtained after the loss of the chlorinated urea fragment. This is the most potent compound in the reaction sequence, with toxicity parameter EC50, after 48 h, more than twice lower compared to the parent 5-FU. Clearly, the contact time between chlorinating species and degradation products provide different ecotoxicological properties of reaction mixtures. Interplay between experimental and theoretical procedures, to properly describe reaction pathways and provide more information on toxicity profiles, is a way forward in environmental science research.

Ferrocenyl GNA Nucleosides: A Bridge between Organic and Organometallic Xeno-nucleic Acids.

The enantioselective synthesis and electrochemistry of the first ferrocenyl GNA nucleosides is reported. These compounds were obtained by a Sharpless asymmetric dihydroxylation reaction of [3-(N1-thyminyl)-1-(ferrocenyl)]propene as S,R and R,S enantiomers in about 70 % yield with enantiomeric excesses of >99 % and 71 %, respectively. The absolute configurations of the chiral carbon atoms in the nucleosides were assigned by single-crystal X-ray diffraction analysis of the methyl derivatives in the solid state. The compounds were also studied with circular dichroism (CD) spectroscopy in solution. The enantiomeric relationship between the S,R and R,S isomers was confirmed by the near-mirror-image CD spectra. The redox properties of the nucleosides and their methylated derivatives were investigated using cyclic voltammetry. The cyclic voltammograms revealed reversible redox processes for the entire series of compounds at potentials of -25 mV (for nonmethylated derivatives) and 75 mV (for methylated derivatives) versus the ferrocene/ferrocenium reference redox couple.

Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M ß-Lactamase.

A series of six novel metallocenyl-7-ADCA (metallocenyl = ferrocenyl or ruthenocenyl; 7-ADCA = 7-aminodesacetoxycephalosporanic acid) conjugates were synthesized and their antibacterial properties evaluated by biochemical and microbiological assays. The ruthenocene derivatives showed a higher level of inhibition of DD-carboxypeptidase 64-575, a Penicillin Binding Protein (PBP), than the ferrocene derivatives and the reference compound penicillin G. Protein X-ray crystallographic analysis revealed a covalent acyl-enzyme complex of a ruthenocenyl compound with CTX-M ß-lactamase E166A mutant, corresponding to a similar complex with PBPs responsible for the bactericidal activities of these compounds. Most interestingly, an intact compound was captured at the crystal-packing interface, elucidating for the first time the structure of a metallocenyl ß-lactam compound that previously eluded small molecule crystallography. We propose that protein crystals, even from biologically unrelated molecules, can be utilized to determine structures of small molecules.

Cymantrene, Cyrhetrene and Ferrocene Nucleobase Conjugates: Synthesis, Structure, Computational Study, Electrochemistry and Antitrypanosomal Activity.

A series of 11 cymantrene and cyrhetrene nucleobase conjugates, together with the hitherto unreported N7 isomer of a ferrocene-adenine conjugate were synthesised and characterised. The synthetic approach involved a Michael addition reaction of in-situ-generated acryloylcymantrene, acryloylcyrhetrene and acryloylferrocene with the canonical nucleobases thymine, uracil and adenine. The mechanism of these reactions was investigated by means of density functional theory calculations. The products were characterised by spectroscopic and electrochemical methods. The molecular structure of one cymantrene-adenine conjugate in the solid state was determined by single-crystal X-ray structure analysis, confirming the N9-substitution of the adenine moiety. It was found that the molecule adopts a bent conformation with the adenine and cyclopentadienyl planes in almost perpendicular orientation. The cymantrenyl nucleobases showed an irreversible redox behaviour, which is associated with ligand-exchange reactions of the radical cationic species. The newly synthesised compounds were also tested for their activity against the protozoan parasite Trypanosoma brucei and human myeloid leukaemia HL-60 cells. Some compounds showed promising antitrypanosomal activity, and most of them were non-toxic to HL-60 cells. It was also found that cymantrene and cyrhetrene ketone nucleobases were more active than their alcohol congeners. These findings indicate the potential of cymantrenyl and cyrhetrenyl nucleobase conjugates as possible lead compounds for future antitrypanosomal drug development.

1,1'-Bis(thymine)ferrocene Nucleoside: Synthesis and Study of Its Stereoselective Formation.

The synthesis of 1,1'-bis(thymine)ferrocene nucleoside is reported. This nucleoside was obtained in a two-step synthetic methodology including a Michael addition reaction of 1,1'-bis(3-chloropropionyl)ferrocene with thymine to afford the bis(thymine) adduct in 44 % yield. In the second step, the two prochiral carbonyl functionalities in the Michael adduct were reduced to hydroxyl groups with sodium borohydride. This apparently straightforward reaction proceeds in a highly stereoselective fashion to yield the title ferrocenyl nucleoside as a racemic mixture that consists of the R,R and the S,S isomers. The absolute configuration of the chiral carbon atoms in the nucleoside was assigned on the basis of single-crystal X-ray diffraction analysis of the methyl derivative. Furthermore, the mechanism of reduction of the bis(thymine) adduct was investigated by using DFT calculations. The two critical minima, pre-reactive complex, and semi-reduced intermediate, as well as two corresponding transition states were located to support the observed stereoselectivity. The redox properties of 1,1'-bis(thymine)ferrocene nucleoside, its precursor, and congeners were investigated using cyclic voltammetry. For the title compound a reversible redox process was found at a low potential of -30 mV versus FcH/FcH+ (FcH=Fe(η5 -C5 H5 )2 ) as the reference redox couple.

A quantum chemical study of HOCl-induced transformations of carbamazepine.

The antiepileptic drug carbamazepine (CBZ) is one of the most persistent pharmaceuticals in the environment. Its chemical fate is influenced by the type of wastewater treatment. This study sets out to determine the degradation mechanism and products in the reaction between CBZ and hypochlorous acid (HOCl), which is the main chlorinating species in water. In the search for the most feasible pathways of HOCl-induced transformations of CBZ, a quantum chemical approach was employed. Chlorination and epoxidation of CBZ are two initial, competitive processes that result in two key intermediates: N-chloramide and 10,11-epoxide. The calculated free energy barriers (ΔG) for these reactions are 105.7 and 95.7 kJ mol-1 resp., which is in agreement with the experimental energy barrier of 98.2 kJ mol-1. All transformation products detected in chlorination experiments were located by computational models, and the reaction mechanism underlying their formation was described in detail. Different computational methods (density functional and ab initio theory) were applied, and the double hybrid B2-PLYPD functional was found to be superior in terms of efficiency and accuracy. Of special interest are oxoiminostilbene and formylacridine, which are the final products in the degradation cascade. Their exceptional thermodynamic stability, as predicted by quantum chemical methods, suggests that these structures should be considered as recalcitrants in chlorinated waters. Fruitful interplay between computational models and experimental data proves that the quantum chemical approach can be used as a predictive tool in environmental degradation studies.

A computational study of the chlorination and hydroxylation of amines by hypochlorous acid.

The reactions of hypochlorous acid (HOCl) with ammonia, (di)methylamine, and heterocyclic amines have been studied computationally using double-hybrid DFT methods (B2PLYP-D and BK-PLYP) and a G3B3 composite scheme. In the gas phase the calculated energy barriers for N- and/or C-hydroxylation are ca. 100 kJ mol(-1) lower than the barrier for N-chlorination of amines. In the model solvent, however, the latter process becomes kinetically more favored. The explicit solvent effects are crucial for determination of the reaction mechanism. The N-chlorination is extremely susceptible to the presence of explicit water molecules, while no beneficial solvation effect has been found for the N- or C-hydroxylation of amines. The origin of the observed solvent effects arises from differential solvation of the respective transition states for chlorine- and oxygen-transfers, respectively. The nature of solvation of the transition state structures has been explored in more detail by classical molecular dynamics (MD) simulation. In agreement with the quantum mechanical approach, the most stable structural motif, which includes the amine, HOCl, and two reactive waters, has been identified during the MD simulation. The inclusion of 5 or 6 explicit water molecules is required to reproduce the experimental barriers for HOCl-induced formation of N-chloramines in an aqueous environment.