Nitrenium Cation Research Articles

Avoidance of the Ames test liability for aryl–amines via computation

Aryl–amines are commonly used synthons in modern drug discovery, however a minority of these chemical templates have the potential to cause toxicity through mutagenicity. The toxicity mostly arises through a series of metabolic steps leading to a reactive electrophilic nitrenium cation intermediate that reacts with DNA nucleotides causing mutation. Highly detailed in silico calculations of the energetics of chemical reactions involved in the metabolic formation of nitrenium cations have been performed. This allowed a critical assessment of the accuracy and reliability of using a theoretical formation energy of the DNA-reactive nitrenium intermediate to correlate with the Ames test response. This study contains the largest data set reported to date, and presents the in silico calculations versus the in vitro Ames response data in the form of beanplots commonly used in statistical analysis. A comparison of this quantum mechanical approach to QSAR and knowledge-based methods is also reported, as well as the calculated formation energies of nitrenium ions for thousands of commercially available aryl–amines generated as a watch-list for medicinal chemists in their synthetic optimization strategies.

Chemical oxidative polymerization of anilinium sulfate versus aniline: Theory and experiment

The mechanism of the oxidative polymerization of anilinium sulfate with ammonium peroxydisulfate in aqueous medium has been studied by the AM1 and MNDO-PM3 semi-empirical quantum chemical methods combined with the MM2 molecular mechanics force-field method and conductor-like screening model (COSMO) of solvation. The aniline nitrenium cation is the main reactive electrophilic species generated in the initiation phase. It is proposed that the rate and regioselectivity of dimerization is governed by the electrophilic aromatic substitution reaction of non-protonated aniline molecules with aniline nitrenium cations. 4-Aminodiphenylamine and its fully oxidized form, N-phenyl-1,4-benzoquinonediimine, are the main dimeric products. The dominant aniline trimer and tetramer are shown to be linear, N–C coupled, with the prevalence of the para-substitution pattern. The mechanism of oxidation of anilinium sulfate is compared with that of non-protonated aniline molecules; the latter yield also branched trimers and tetramers that are subsequently oxidized to phenazine constitutional units. The differences in morphology of the polyanilines obtained by the oxidation of anilinium sulfate and aniline, granules, nanotubes or nanorods, and in molecular structure reflected by infrared spectra are discussed with respect to the formulated comprehensive mechanistic scheme of the early stages of both anilinium cation and aniline oxidation.

Theoretical study of the oxidative polymerization of aniline with peroxydisulfate: Tetramer formation

AbstractSemi‐empirical quantum chemical study of the oxidative polymerization of aniline with ammonium peroxydisulfate, in aqueous solutions without added acid, has been based on the MNDO‐PM3 computations of thermodynamic, redox, and acid–base properties of reactive species and the intermediates, combined with the MM2 molecular mechanics force‐field method and conductor‐like screening model of solvation. The main reaction routes of aniline tetramerization are proposed. The regioselectivity of the formation of aniline tetramers by redox and electrophilic aromatic substitution reactions is analyzed. It was proved that the linear NC4 coupled tetra‐aniline is formed as a dominant product by three different pathways: comproportionation redox reaction between N‐phenyl‐1,4‐benzoquinonediimine and 4‐aminodiphenylamine, the one‐electron oxidation of aniline with its half‐oxidized NC4 coupled trimer, and the electrophilic aromatic substitution reaction of aniline with fully oxidized NC4 coupled trianiline nitrenium cation. The electrophilic aromatic substitution reaction of the NC4 coupled aniline trimer with aniline nitrenium cation, as well as the oxidation of aniline with half‐oxidized branched trimer, lead to the branched aniline tetramers. The competing character of different tetramerization routes is highlighted. The oxidative intramolecular cyclization of branched oligoanilines and polyaniline, leading to the generation of substituted phenazine units, has been predicted to accompany the classical routes of the polymerization of aniline. Various molecular (branched vs. linear) oligomeric structures produced at different level of acidity during the course of polymerization and their impact on the formation of supramolecular structures of conducting polyaniline (nanorods and nanotubes vs. granular morphology), are discussed. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008

Disproportionation of Clozapine Radical: A Link between One-Electron Oxidation of Clozapine and Formation of Its Nitrenium Cation

The primary products of one-electron oxidation of clozapine and olanzapine, very effective atypical antipsychotic drugs, have been spectroscopically characterized. The oxidation process has been studied under glassy matrix conditions and by a pulse radiolysis technique in aqueous solution. The rate constants for the oxidation of clozapine with dibromide radical anion ( k = 2 x 10 (9) M (-1) s (-1)) and azide radical ( k = 2.3 x 10 (9) M (-1) s (-1)) in aqueous solution were measured. The computational DFT results support the identification of the transient species. The mechanistic aspects of reactivity of radical cations, radicals, and nitrenium cations have been investigated. A disproportionation reaction ( k > or = 1 x 10 (8) M (-1) s (-1)) was proposed as a link between the products of one-electron oxidation and formation of the nitrenium cations of clozapine and olanzapine, products likely responsible for the pathogenesis of adverse drug reactions. The rate constants for the reactions of nitrenium cation of clozapine with glutathione ( k = 3.4 x 10 (4) M (-1) s (-1)) and cysteine ( k = 9.8 x 10 (4) M (-1) s (-1)) were determined.

Ultrafast Spectroscopic and Matrix Isolation Studies of p-Biphenylyl, o-Biphenylyl, and 1-Naphthylnitrenium Cations

p-biphenylyl, o-biphenylyl, and 1-naphthyl azides were deposited in argon at low temperature in the presence and absence of HCl. In the absence of HCl, the known electronic and vibrational spectra of the corresponding triplet nitrenes, azirines, and didehydroazepines were observed, whereas in the presence of HCl, photolysis of these azides produces new electronic spectra assigned to the corresponding nitrenium cations. For p-biphenylyl azide the resulting spectrum of the nitrenium ion is very similar to the previously observed solution-phase spectrum of this species. The vibrational spectrum of this cation was recorded for the first time. Spectroscopic evidence for the previously unknown o-biphenylylnitrenium cation and 1-naphthylnitrenium cation are provided. The spectra of p- and o-biphenylylnitrenium cations and 1-naphthylnitrenium cation are well reproduced by CASSCF and CASPT2 calculations. The same nitrenium cations were detected in solution by femtosecond time-resolved laser flash photolysis of the appropriate azides in 88% formic acid. The transient spectra of the nitrenium cations recorded in solution are in good agreement with the spectra obtained in HCl matrices. The rates of formation of these cations equal the rates of decay of the singlet nitrenes in 88% formic acid and are as follows: p-biphenylyl (taugrowth = 11.5 ps), o-biphenylyl (taugrowth = 7.7 ps), and 1-naphthylnitrenium cations (taugrowth = 8.4 ps). The decay lifetimes of p- and o-biphenylylnitrenium cations are 50 and 27 ns, respectively. The decay lifetimes of 1-naphthylnitrenium cation is 860 ps in 88% formic acid.

Mechanistic Aspects of the Oxidative and Reductive Fragmentation of N-Nitrosoamines: A New Method for Generating Nitrenium Cations, Amide Anions, and Aminyl Radicals

A new method for investigating the mechanisms of nitric oxide release from NO donors under oxidative and reductive conditions is presented. Based on the fragmentation of N-nitrosoamines, it allows generation and spectroscopic characterization of nitrenium cations, amide anions, and aminyl radicals. X-irradiation of N-nitroso-N,N-diphenylamine 1 in Ar matrices at 10 K is found to yield the corresponding radical ions, which apparently undergo spontaneous loss of NO* under the conditions of this experiment (1*+ seems to survive partially intact, but not 1*-). One-electron reduction or oxidation of 1 is observed upon doping of the Ar matrix with DABCO, an efficient hole scavenger, or CH2Cl2, an electron scavenger, respectively. The resulting diphenylnitrenium cation, 2+, and the diphenylamide anion, 2-, were characterized by their full UV-vis and mid-IR spectra. The best spectra of 2+ and 2- were obtained if 1 was homolytically photodissociated to diphenylaminyl radical 2* and NO* prior to ionization. 2+ and 2- are bleached on irradiation at <340 nm to form 2* or, in part, 1. DFT and CCSD quantum chemical calculations predict that the dissociation of 1*+ and 1*- is slightly endothermic, a tendency which is partially reversed if one allows for complexation of the resulting 2+ (and, presumably, 2-) with NO*. The method described in this work should prove generally applicable to the generation and study of nitrenium cations and amide anions R2N+/- under matrix and ambient conditions (i.e., in solution).

Chemical Oxidative Polymerization of Safranines

Phenosafranine and safranine have been oxidized with ammonium peroxydisulfate in acidic aqueous solution. The oxidative coupling of both safranines was proved by gel permeation chromatography demonstrating the presence of oligomeric chains of mass-average molar masses 6500 and 4500 g mol-1 for polyphenosafranine and polysafranine, respectively. A theoretical study of the mechanism of safranine and phenosafranine polymerization was based on the MNDO-PM3 semiempirical quantum chemical computations of the heat of formation of dimeric reaction intermediates, taking into account solvation effects. The study of the redox properties of the hydrated safranines and their reactive species shows that nitrenium cations are the main reactive species generated by the oxidation of the parent safranines with a two-electron oxidant, peroxydisulfate, in the initiation phase. The dominant dimers of safranines are formed by N-C coupling reactions between nitrenium cations and the parent safranines. The main coupling reactions of phenosafranine are N-C2 (C8) and N-C4 (C6); N-C4 (C6) is the dominant coupling mode for safranine. The molecular structure of oligosafranines has been studied by FTIR, Raman, and UV-vis spectroscopies. Besides prevalent unoxidized monomeric units, polymerization products of safranines contain also the iminoquinonoid and newly formed fused phenazine units.

Electrosynthesis of Polyaniline/SiO2 Composite at high pH in the Absence of Extra Supporting Electrolyte

Electropolymerization of aniline was investigated in solutions of different pH from 1.0 to 12.1 without extra supporting electrolyte. FT-IR Spectra of the polymers display characteristic absorptions for polyaniline (PANI) including that for protonated PANI, although some of the polymers were obtained in solutions of high pH. PANI obtained from acidic solutions displayed the usual electroactivities in 0.5 mol·l-1 H2SO4, while those obtained from solutions of pH 6.0 to 12.1 showed an unusual redox pair additionally on cyclic voltammograms at 0.04 V vs. SCE. This redox pair can be ascribed to the redox of phenazine ring, originated from the attack of nitrenium cation to PANI chain in the ortho-position. Electrocodeposition of PANI and SiO2 was conducted through electrophoresis of silica particles towards anode as aniline anodically electropolymerized. Energy dispersive X-ray diffraction (EDX) analysis and SEM inspection were performed on obtained PANI/SiO2 to investigate the composite film.

MNDO-PM3 Study of the Early Stages of the Chemical Oxidative Polymerization of Aniline

The theoretical approach to the study of aniline polymerization mechanism has been based on the MNDO-PM3 semi-empirical quantum chemical computations of the heat of formation of aniline dimer and trimer intermediates. The oxidation in aqueous medium without added acid is analyzed. The aniline nitrenium cation is proposed to be the reactive electrophilic species generated by the oxidation of aniline with a two-electron oxidant, ammonium peroxydisulfate, in the initiation phase. 4-Aminodiphenylamine and its fully oxidized form, N-phenyl-1,4-benzoquinonediimine, are the main dimeric products. 2-Aminodiphenylamine and its fully oxidized form, N-phenyl-1,2-benzoquinonediimine, are the most important side products of aniline dimerization. The influence of protonation on the oxidizability of aniline and reaction intermediates was studied. The dominant aniline oligomers have been shown to be linear as well as branched. The importance of reactivity difference between fully oxidized aniline oligomers composed of odd or even numbers of constitutional aniline units is pointed out. The species with odd numbers of aniline units, having nitrenium cationic nature, are much more reactive. The oxidation combined with intramolecular cyclization reaction pathways leads to substituted phenazines, characteristic of two-dimensional PANI chain-growth.

Amperometric biosensor based on horseradish peroxidase-immobilised magnetic microparticles

Magnetised silica-based microparticles (MMPs) (5 μm) with a high density of nanopores were used for horseradish peroxidase (HRP) immobilization and amperometric biosensor development in batch conditions. The resulting biosensor was applied to study the peroxidation of clozapine (CLZ) which is a dibenzoazepine drug often used in the treatment of neurological disorders. The amperometric response corresponded to the electroreduction of CLZ-oxidized products namely a nitrenium cation and quinoneimine derivative of CLZ. Despite a relatively low amount of immobilized HRP (0.3 μmol/g), clozapine quantification in the micromolar concentration range was achieved by the use of a magnetized solid paraffin carbon paste electrode for microparticles attraction. Diffusion of substrate and products of the enzyme reaction within the nanopores were identified as limiting factors in the biosensor response. This amperometric biosensor configuration has number of interesting advantages such as ease and reproducible microparticle layer renewing, low enzyme consumption, controlled surface immobilization, protective enzyme microenvironment etc.

Reactions of N+ ions with benzene: a theoretical study on the C6NH6+ potential energy surface

The nitrenium ions of formula C6NH6+ arising from the reaction between benzene molecules and atomic nitrogen ions, N+(3P), are investigated by means of theoretical methods so that their structures and relative stabilities are calculated. Our study is carried out by utilizing the DFT hybrid functional B3LYP in conjunction with the split valence 6-31G* basis set. Both the triplet and the singlet state C6NH6+ cations are considered. The electron deficient N+ ions attack the π electron density of benzene and yield the cation labelled T1 in which the nitrogen interacts with the edge of benzene. This addition is exothermic by 7.69 eV and barrierless. From T1, the insertion of N+ into the benzene CC bond gives the triplet azepine nitrenium cation, T5, whilst its insertion into the CH bond yields the triplet phenylnitrenium cation, T6, via the intermediate T3. However, further C6NH6+ structures and isomerization pathways are investigated in order to obtain a comprehensive analysis of the potential energy surface under study.

Mechanistic investigation of the oxidative polymerization of aniline hydrochloride in different media

Oxidative polymerization reaction of the protonated form of aniline (ANI-HCl) was investigated experimentally in acidic solutions with in situ spectrophotometric technique and computationally using molecular mechanics (MM+) calculations. Well-defined absorbance peaks of an intermediate and of an end product were observed after first scan of the spectrogram, using zero- and first-derivative spectroscopic treatment. Increases in the absorbance at λ∼420 nm with increasing the oxidant and/or anionic surfactant (sodium dodecyl sulfate, SDS) content in the polymerization medium were observed. This indicates that the presence of nitrenium cations and suggests that the polyaniline evolution goes towards a two-dimensional (D2) polymer with phenazine rings, which can be formed by a cross-linking reaction. It was confirmed by kinetic studies, as well as verified by MM+ calculations. Absorbance peak at λ∼520 nm (dark brown), in the first scan of the spectrogram was observed. This peak increases with increasing the acid surfactant [poly(acrylic acid)] (PAA) matrix content in the polymerization medium. Kinetic parameters of the oxidative polymerization reaction were deduced employing a computer-aided kinetic analysis of the absorbance ( A) at ∼720 nm against oxidation time ( t) data. The results obtained indicate that the rate controlling process are governed by the two-dimensional (D2) diffusion. Good linearity ( r∼0.985) between Δ H # and Δ S # for the series of acids doped PANI matrix was obtained, which suggests the existence of a compensation (or isokinetic) effect. The proposed mechanism for the oxidation of ANI is also supported by MM+ calculation. Activation parameters for the rate of oxidation process of ANI have been computed and discussed.

Mechanistic investigation of the oxidative polymerization of aniline hydrochloride in different media

Oxidative polymerization reaction of the protonated form of aniline (ANI-HCl) was investigated experimentally in acidic solutions with in situ spectrophotometric technique and computationally using molecular mechanics (MM+) calculations. Well-defined absorbance peaks of an intermediate and of an end product were observed after first scan of the spectrogram, using zero- and first-derivative spectroscopic treatment. Increases in the absorbance at λ∼420 nm with increasing the oxidant and/or anionic surfactant (sodium dodecyl sulfate, SDS) content in the polymerization medium were observed. This indicates that the presence of nitrenium cations and suggests that the polyaniline evolution goes towards a two-dimensional (D2) polymer with phenazine rings, which can be formed by a cross-linking reaction. It was confirmed by kinetic studies, as well as verified by MM+ calculations. Absorbance peak at λ∼520 nm (dark brown), in the first scan of the spectrogram was observed. This peak increases with increasing the acid surfactant [poly(acrylic acid)] (PAA) matrix content in the polymerization medium. Kinetic parameters of the oxidative polymerization reaction were deduced employing a computer-aided kinetic analysis of the absorbance ( A ) at ∼720 nm against oxidation time ( t ) data. The results obtained indicate that the rate controlling process are governed by the two-dimensional (D2) diffusion. Good linearity ( r ∼0.985) between Δ H # and Δ S # for the series of acids doped PANI matrix was obtained, which suggests the existence of a compensation (or isokinetic) effect. The proposed mechanism for the oxidation of ANI is also supported by MM+ calculation. Activation parameters for the rate of oxidation process of ANI have been computed and discussed.

Reactions of N+ ions with benzene: a theoretical study on the C6NH6+ potential energy surface

The nitrenium ions of formula C6NH6+ arising from the reaction between benzene molecules and atomic nitrogen ions, N+(3P), are investigated by means of theoretical methods so that their structures and relative stabilities are calculated. Our study is carried out by utilizing the DFT hybrid functional B3LYP in conjunction with the split valence 6-31G* basis set. Both the triplet and the singlet state C6NH6+ cations are considered. The electron deficient N+ ions attack the π electron density of benzene and yield the cation labelled T1 in which the nitrogen interacts with the edge of benzene. This addition is exothermic by 7.69 eV and barrierless. From T1, the insertion of N+ into the benzene CC bond gives the triplet azepine nitrenium cation, T5, whilst its insertion into the CH bond yields the triplet phenylnitrenium cation, T6, via the intermediate T3. However, further C6NH6+ structures and isomerization pathways are investigated in order to obtain a comprehensive analysis of the potential energy surface under study.

Structure and Reactivity of the 1,10-Phenanthroline Complex with Nitrenium Cation

According to the X-ray diffraction data, the cationic fragment in 1-amino-1,10-phenanthrolinium mesitylenesulfonate is a unidentate n-complex whose asymmetric structure is retained in solution. Quantum-chemical calculations by the AM1 method and ab initio (6-31G, 6-31G*, MP2/6-31G) give geometric parameters of the cation, which are similar to those determined experimentally. No dynamic processes involving intra- or intermolecular transfer of the NH2 group was observed up to 100°C by NMR spectroscopy. 1-Amino-1,10-phenanthrolinium cation does not react with 4-methylpyridine and 4-methyl-1,10-phenan-throline with transfer of the amino group, and it fails to react with mesitylene and anthracene at elevated temperature.

Microwave-assisted generation of carbazolyl nitrenium cation

Carbazolyl nitrenium cations were generated during microwave irradiation of 1-carbazol-9-yl2,4,6-triphenylpyridinium tetrafluoroborate in trifluoroethanoland TFA – arenes mixtures to give desired electrophilic substitution reaction products. Unlike under conventional conditions (thermolysis and photolysis) the parent amine, carbazole, and other side product were detected only in trace amounts.

Relationships between chemical structures and mutagenicity: a preliminary survey for a database of mutagenicity test results of new work place chemicals.

A database of mutagenicity test results of new chemicals has been developed. Based on the amendment of the Industrial Safety and Health Law (ISHL) in 1979, manufacturers and importers in Japan are required to register any new work place chemicals with bacterial mutagenicity test results. At present more than ten thousand substances have been examined. We have surveyed correlations between 44 substructures and mutagenicity in 2,857 ISHL data as well as in 1,207 National Toxicology Program data as a preliminary analysis. The percentages of the mutagenic compounds were calculated. High percentages were found for electrophilic reagents such as epoxides (63%), aromatic nitro compounds (49%) and primary alkyl monohalides (46%). 71% of peroxides was found to be mutagenic. The results suggest that several types of reactions such as nucleophilic substitution reaction, nitrenium cation reaction and radical reaction are included in the process of the mutagenic alterations of DNA.

Novel Thermal Rearrangement of Fused Diaryl-v-Triazolium Salts to Neutral Indazole Derivatives. Fused Azolium Salts. 16

Alkylation of 1,3-diaryl-v-triazolo[1,5-a]benzimidazole (1) by trimethyloxonium salt afforded selectively the 4-methyl quaternary salt 2, whereas reaction with dimethyl sulfate at elevated temperature resulted in ring transformation, implying ring opening to a nitrenium cation and a subsequent electrophilic ring closure to give a benzimidazolylindazole product 5. Independent of the methylation, a similar easy thermal rearrangement was observed with alkylated 1,3-diaryl-v-triazolo[1,5-a]benzimidazolium (2 → 4) and the related benzothiazolium salt (7 → 8). Extension of the reaction to diaryl-v-triazolopyridinium salt (9 → 10 + 11) allowed observation of an additional novel reaction path that provided further support for the supposed reaction mechanism.

A new synthesis of aniline oligomers with three to eight amine units

A new convenient method has been developed for the synthesis of well-defined aniline oligomers containing 3 to 8 aromatic amine units with amino or aryl end-groups. The method consists of a single-step reaction of the aromatic amines having at least one amino end-group with other aromatic amines in an acidic medium with or without external oxidizing agents. The oxidation state of the oligomers can be changed via simple redox reactions. A possible mechanism for the reaction involves an electrophilic aromatic substitution of nitrenium cation to aromatic amines.

Direct evidence of a bipolaron charge carrier in conducting polyazines from carbon-13 and nitrogen-15 solid-state NMR spectroscopy: detection of a nitrenium cation by natural abundance 15N solid-state NMR spectroscopy

Direct evidence of a bipolaron charge carrier in conducting polyazines from carbon-13 and nitrogen-15 solid-state NMR spectroscopy: detection of a nitrenium cation by natural abundance 15N solid-state NMR spectroscopy