On-Demand Generation and Use in Continuous Synthesis of the Ambiphilic Nitrogen Source Chloramine.

Herein, we demonstrate the on-demand synthesis of chloramine from aqueous ammonia and sodium hypochlorite solutions, and its subsequent utilization as an ambiphilic nitrogen source in continuous-flow synthesis. Despite its advantages in cost and atom economy, chloramine has not seen widespread use in batch synthesis due to its unstable and hazardous nature. Continuous-flow chemistry, however, provides an excellent platform for generating and handling chloramine in a safe, reliable, and inexpensive manner. Unsaturated aldehydes are converted to valuable aziridines and nitriles, and thioethers are converted to sulfoxides, in moderate to good yields and exceedingly short reaction times. In this telescoped process, chloramine is generated in situ and immediately used, providing safe and efficient conditions for reaction scale-up while mitigating the issue of its decomposition over time.

Synthesis and Crystal Chemistry of Octahedral Rhodium(III) Chloroamines.

Rhodium(III) octahedral complexes with amine and chloride ligands are the most common starting compounds for preparing catalytically active rhodium(I) and rhodium(III) species. Despite intensive study during the last 100 years, synthesis and crystal structures of rhodium(III) complexes were described only briefly. Some [RhClx(NH3)6-x] compounds are still unknown. In this study, available information about synthetic protocols and the crystal structures of possible [RhClx(NH3)6-x] octahedral species are summarized and critically analyzed. Unknown crystal structures of (NH4)2[Rh(NH3)Cl5], trans-[Rh(NH3)4Cl2]ClH2O, and cis-[Rh(NH3)4Cl2]Cl are reported based on high quality single crystal X-ray diffraction data. The crystal structure of [Rh(NH3)5Cl]Cl2 was redetermined. All available crystal structures with octahedral complexes [RhClx(NH3)6-x] were analyzed in terms of their packings and pseudo-translational sublattices. Pseudo-translation lattices suggest face-centered cubic and hexagonal closed-packed sub-cells, where Rh atoms occupy nearly ideal lattices.

Carnosine and Carcinine Derivatives Rapidly React with Hypochlorous Acid to Form Chloramines and Dichloramines.

Hypochlorous acid (HOCl) is a highly reactive, toxic species generated by neutrophils via the action of myeloperoxidase in order to destroy invading pathogens. However, when HOCl is produced inappropriately, it can damage host tissue and proteins and plays a role in the initiation and progression of disease. Carnosine, a peptide of ß-alanine and histidine, has been shown to react rapidly with HOCl yielding monochloramines and can undergo intramolecular transchlorination. The current study examines the kinetics and pH dependence of the reactions of carnosine and novel structural derivatives with HOCl and the occurrence of intra- and intermolecular transchlorination processes. We demonstrate that the transchlorination reactions of carnosine are pH dependent, with intramolecular transfer favored at higher pH. Carcinine, having a structure identical to carnosine though lacking the carboxylic acid group of the histidine residue, reacts with HOCl and forms monochloramines though intramolecular transfer reactions are not observed, and this is supported by computational modeling. Novel analogues with one (carnosine+1) and two (carnosine+2) methylene groups in the alkyl chain of the ß-alanine react with HOCl to yield monochloramines that undergo transchlorinations to yield a mixture of mono- and dichloramines. The latter are stable over 24 h. The ability of carnosine and derivatives to react rapidly with HOCl to give long-lived, poorly reactive, species may prevent damage to proteins and other targets at sites of inflammation.

Elimination of chlorine-refractory carbamazepine by breakpoint chlorination: Reactive species and oxidation byproducts.

Breakpoint chlorination can be commonly observed in the chlorination of water treatments when ammonia is present. In this study, it was found that breakpoint chlorination can remarkably eliminate a ubiquitous and chlorine-refractory micropollutant, carbamazepine (CBZ), with the removal of 72% at neutral condition. At neutral pH, low CBZ elimination was observed at a chlorine/ammonia molar ratio (Cl/N) of 1.0 and higher CBZ elimination was observed as Cl/N ratio increased from 1.0 to 1.6 (breakpoint), indicating that CBZ elimination was closely related to the generation and decomposition of chloramines. The chloramines generation and decomposition rates were affected by the pH, so that the CBZ elimination rate was highest at pH 7.0 and lower in acidic and basic solutions (pH 5.5 and pH 9.5, respectively). The CBZ elimination at pH 7.0 was 72.4% after 10 min of breakpoint chlorination, while reaction times about 30 min and 60 min were required to achieve the same elimination at pH 5.5 and pH 9.5, respectively. Breakpoint chlorination of CBZ was strongly suppressed by radical scavenger tBuOH and moderately suppressed by N2 purging, the inhibiting ratios being 87.7% and 27.8% at breakpoint, respectively. Electron spin resonance experiments suggested that unidentified radicals were generated by breakpoint chlorination. The OH and unidentified radical species contributions to CBZ elimination were <23.7% and >76.3%, respectively, when a pseudo steady state breakpoint chlorination was performed in a microinjection system with nitrobenzene as OH probe. Although CBZ were efficiently eliminated, breakpoint chlorination of CBZ generated adsorbable organic chlorine. The cytotoxicity of the CBZ solution was therefore increased by breakpoint chlorination, suggesting that biological risk caused by the breakpoint chlorination of micropollutants should be taken into consideration.

In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of Non-proteinogenic α-Amino Esters.

An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate, and various types of nucleophiles is reported for the synthesis of orthogonally protected α-amino esters. These reactions proceeded rapidly to afford the pivotal α-chloroglycine intermediate in excellent yields, which can be directly functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. To better understand this one-pot transformation and the orchestration of the components' condensations, the investigation of a broader scope of nucleophiles and some kinetic studies are presented. Our findings suggest that the halogenation step toward the formation of α-chloroglycine is the rate-determining step likely proceeding through the formation of N-carbamoyl iminium. Also, the initial kinetic profiling for the nucleophilic substitution supports an SN1-like (SN2C+) mechanism in which nucleophiles add to the iminium-chloride tight ionic pair. These results lead ultimately to the design of a new protocol in which an achiral hydrogen bond donor thiourea catalyst was utilized to enhance the reaction scope and enable silylated nucleophiles to be efficiently exploited to synthesize novel non-proteinogenic α-amino esters.

Visible-light-promoted chloramination of olefins with N-chlorosulfonamide as both nitrogen and chlorine sources.

A visible-light-promoted chloramination of olefins is reported. N-Chlorosulfonamides serve as both nitrogen and chlorine sources. These reactions provide a simple, efficient, regioselective, and atom-economical method for the preparation of vicinal haloamine derivatives under mild reaction conditions. A variety of olefins were tolerated, and chloramination products were obtained in good yields.

Thermodynamic properties of chloramine formation and related reactions during water treatment: a G4MP2, G4, and W1BD theoretical study.

A high-level gas and aqueous phase theoretical thermodynamic study was conducted on the primary and related chemical reactions which occur during chloramination for water treatment using the G4MP2, G4, and W1BD composite methods with the SMD, PCM, and CPCM solvation models. The standard state (298.15 K, 1 atm or 1M) formation of mono-, di-, and tri-chloramines from their precursors via hypochlorous acid chlorination is substantially exothermic and exergonic in both the gas and aqueous phases. The excellent agreement between experimental and theoretical values for a range of structural and thermodynamic calculations on a suite of calibration compounds suggests that the G4MP2, G4, and W1BD calculations meet or exceed criteria for thermochemical accuracy. The temperature influence on the thermodynamics of chloramine formation is projected to be negligible regardless of phase between 0 and 100°C. Additional thermodynamic calculations were undertaken on associated chloramination reactions involving the disproportionation of monochloramine, the decomposition of di- and tri-chloramine, and the reactions of trichloramine with ammonia and dichloramine. The results from these investigations not only provide a better understanding of the reaction thermodynamics, they also allow for a more rigorous interpretation of proposed chloramination mechanisms.

Ultraviolet-induced effects on chloramine and cyanogen chloride formation from chlorination of amino acids.

Ultraviolet (UV)-based treatment is commonly used to augment chlorination in swimming pools. However, the effects of combined application of UV254/chlorine on disinfection byproduct (DBP) formation are incompletely defined. To examine this issue, experiments were conducted with amino acids (l-arginine, l-histidine, and glycine) that are representative of those introduced to swimming pools via human body fluids. For each precursor, stepwise experiments were conducted with chlorination and UV254 exposure, with/without post-chlorination. Net formation and decomposition of chloramines and cyanogen chloride (CNCl) were measured for a range of chlorine/precursor (Cl/P) molar ratios and UV254 doses. Substantial production of NH2Cl from l-arginine and l-histidine was observed at Cl/P = 1.0 and 2.0 when post-chlorination was applied to UV254-irradiated samples. These results suggested a mechanism of rapid N-chlorination, followed by cleavage of NH3 by UV254 irradiation. CNCl formation was observed from UV254-irradiated samples of l-arginine and l-histidine when Cl/P = 2.0 and 3.0, as well as from glycine for Cl/P ≤ 1. Structurally related precursor compounds were examined for CNCl formation potential in chlorination/UV experiments. CNCl formation was promoted by UV254 exposure of chlorinated imidazole and guanidine compounds, which suggested that these groups contributed to CNCl formation. The results have implications with respect to the application of chlorine and UV for water treatment in swimming pools and other settings, such as water reuse and advanced oxidation processes.

Structure stability/activity relationships of sulfone stabilized N,N-dichloroamines.

Structure stability/activity relationships (SXR) of a new class of N,N-dichloroamine compounds were explored to improve antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans while maintaining aqueous solution stability. This study identified a new class of solution-stable and topical antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate appendages as a water solubilizing group. Several unique challenges were confronted in the synthesis of these novel compounds which are highlighted in the discussion.

Quaternary ammonium N,N-dichloroamines as topical, antimicrobial agents.

A series of backbone modified and sulfonic acid replacement analogs of our topical, clinical candidate (iii) were synthesized. Their antimicrobial activities and aqueous stabilities at pH 4 and pH 7 were determined, and has led us to identify quaternary ammonium N,N-dichloroamines as a new class of topical antimicrobial agents.

Formation of organic chloramines during water disinfection: chlorination versus chloramination.

Many of the available studies on formation of organic chloramines during chlorination or chloramination have involved model organic nitrogen compounds (e.g., amino acids), but not naturally occurring organic nitrogen in water. This study assessed organic chloramine formation during chlorination and chloramination of 16 natural organic matter (NOM) solutions and 16 surface waters which contained dissolved organic nitrogen (DON). Chlorination rapidly formed organic chloramines within 10 min, whereas chloramination formed organic chloramination much more slowly, reaching the maximum concentration between 2 and 120 h after the addition of monochloramine into the solutions containing DON. The average organic chloramine formation upon addition of free chlorine and monochloramine into the NOM solutions were 0.78 mg-Cl(2)/mg-DON at 10 min and 0.16 mg-Cl(2)/mg-DON at 24h, respectively. Organic chloramine formation upon chlorination and chloramination increased as the dissolved organic carbon/dissolved organic nitrogen (DOC/DON) ratio decreased (i.e., DON contents increased). Chlorination of molecular weight (10,000 Da) fractionated water showed that molecular weight of DON would not impact the amount of organic chloramines produced. Comparison of three different disinfection schemes at water treatment plants (free chlorine, preformed monochloramine, and chlorine/ammonia additions) indicated organic chloramine formation could lead to a possible overestimation of disinfection capacity in many chloraminated water systems that add chlorine followed by an ammonia addition to form monochloramine.

Aminochlorination in water: first Brønsted acid-promoted synthesis of vicinal chloramines.

A practical and scaleable route for the regio- and diastereoselective synthesis of vicinal chloramines from electron-deficient olefins and Chloramine-T promoted by Brønsted acids in water has been realized for the first time. This novel protocol is efficient, mild, ecofriendly, and broadly applicable for the aminochlorination of various electron-deficient olefins including alpha,beta-unsaturated ketones, cinnamate, and cinnamide. Water represents as a privileged solvent for the aminochlorination reaction in our system.

Stereoselective synthesis of N-alkylaziridines from N-chloroamines.

We report the first racemic and stereoselective synthesis of cis- and trans-N-alkylaziridines viaN-chloroamines; using this methodology an N-3,4,5-trimethoxybenzylaziridine was synthesised and efficiently cleaved, affording the corresponding NH aziridine in high yield.

N,N-dichlorotaurine: chemical and bactericidal properties.

The biogenous antimicrobial agent N-chlorotaurine (NCT) converts by disproportionation to N,N-dichlorotaurine (NDCT) at a rate proportional to acidity. This occurs at appreciable amounts already in weakly acidic biological systems. To understand the consequences of NDCT formation, a thorough investigation of this undescribed compound was mandatory, which needed its synthesis. Differently from NCT, this was possible in the aqueous system using trichloroisocyanuric acid. While the free acid, Cl(2)HNCH(2)CH(2)SO(3)H, was not available in pure form, its sodium and potassium salts were analytically pure and showed melting points (decomposition) of 125-128 degrees C (potassium) and 162-164 degrees C (sodium). The sodium salt demonstrated unexpected long-term stability even at room temperature (8.4 % loss of activity within 4 months). The aqueous solutions of both salts exhibited a weak acid reaction, and they were less stable than NCT. With regard to chlorination of amines (transhalogenation), NDCT was, surprisingly, less efficacious than NCT, which manifested itself by a lack of reactivity at pH < 7, for which a mechanistic explanation is given. Compared on a molar scale, NDCT was more bactericidal than NCT against the gram-negative bacteria E. coli, P. aeruginosa and P. mirabilis, while there was no difference concerning the gram-positive ones, S. aureus and S. epidermidis. The increase of bactericidal activity at acidic pH was the same as observed with NCT and is attributed to a higher susceptibility of bacteria in this environment. Taken together, NDCT seems not to be suited to substitute NCT as a preparation fit for medical practice.

Occurrence and production of chloramines in the chlorination of creatinine in aqueous solution.

Occurrence and production of stable chloramines in the chlorination of creatinine, a constituent of perspiration and urine, in aqueous media were studied. Creatinine (5 x 10(-5)M) was treated with free chlorine in aqueous solutions at molar ratios of 0.5-8 (chlorine/creatinine) at pH 7.0 at room temperature for several days. At lower ratios of chlorine, two stable N-chlorocreatinine derivatives, which were determined as dichloramine fractions by the DPD method, were isolated by HPLC and identified by EI-MS and (1)H-NMR. One was 2-chloroamino-1-methylimidazolin-4-one (creatinine chloramine) and the other was 2-chloroamino-5-hydroxy-1-methylimidazolin-4-one (hydroxycreatinine chloramine). In addition, the formation of methylamine was identified by GC-MS analyses of its imine derivative formed with pentafluorobenzaldehyde. Methylamine forms stable chloramines, which might be determined as mono- and/or di-chloramine fractions together with free chlorine by the DPD method in the reaction mixtures at higher molar ratios of chlorine. In practice, small amounts of methylamine (ca. 19 microg/L) were detected in water samples collected from several swimming pools. Hence, methylamine may be an origin of elusive organic chloramine formed in the chlorination of swimming pools. A probable mechanism of the occurrence and processing of chlorination products of creatinine is suggested.

Hypochlorite and superoxide radicals can act synergistically to induce fragmentation of hyaluronan and chondroitin sulphates.

Activated phagocytes release the haem enzyme MPO (myeloperoxidase) and also generate superoxide radicals (O2*-), and hence H2O2, via an oxidative burst. Reaction of MPO with H2O2 in the presence of chloride ions generates HOCl (the physiological mixture of hypochlorous acid and its anion present at pH 7.4). Exposure of glycosaminoglycans to a MPO-H2O2-Cl- system or reagent HOCl generates long-lived chloramides [R-NCl-C(O)-R'] derived from the glycosamine N-acetyl functions. Decomposition of these species by transition metal ions gives polymer-derived amidyl (nitrogen-centred) radicals [R-N*-C(O)-R'], polymer-derived carbon-centred radicals and site-specific strand scission. In the present study, we have shown that exposure of glycosaminoglycan chloramides to O2*- also promotes chloramide decomposition and glycosaminoglycan fragmentation. These processes are inhibited by superoxide dismutase, metal ion chelators and the metal ion-binding protein BSA, consistent with chloramide decomposition and polymer fragmentation occurring via O2*--dependent one-electron reduction, possibly catalysed by trace metal ions. Polymer fragmentation induced by O2*- [generated by the superoxide thermal source 1, di-(4-carboxybenzyl)hyponitrite] was demonstrated to be entirely chloramide dependent as no fragmentation occurred with the native polymers or when the chloramides were quenched by prior treatment with methionine. EPR spin-trapping experiments using 5,5-dimethyl1-pyrroline-N-oxide and 2-methyl-2-nitrosopropane have provided evidence for both O2*- and polymer-derived carbon-centred radicals as intermediates. The results obtained are consistent with a mechanism involving one-electron reduction of the chloramides to yield polymer-derived amidyl radicals, which subsequently undergo intramolecular hydrogen atom abstraction reactions to give carbon-centred radicals. The latter undergo fragmentation reactions in a site-specific manner. This synergistic damage to glycosaminoglycans induced by HOCl and O2*- may be of significance at sites of inflammation where both oxidants are generated concurrently.

Toxicity of model aliphatic amines and their chlorinated forms.

Aliphatic amines can be found in many wastewater effluents from industry, agriculture, pharmacy, and food processing. Amines can induce toxicological responses that are relevant in biochemical treatment processes, as well as in natural waters. This research compared the toxicity and inhibition caused by three aliphatic amines (n-propylamine, ethylmethylamine, and trimethylamine) and their chlorinated derivatives. The chemistry of chlorine interactions with these compounds was characterized by using membrane introduction mass spectrometry (MIMS). Acute toxicity assays were conducted by using a Microtox system with Phosphobacterium phosphoreum (also known as Vibrio fischeri) for the aliphatic amine compounds and their corresponding chlorinated derivatives, as identified by MIMS. Inhibition tests were conducted by using the oxygen utilization rate test with an enhanced nitrifier culture. The median effective concentration (EC50) values for chloropropylamine, chloroethylmethylamine, and chlorodimethylamine obtained by Microtox with a contact time of 15 min were 12.68, 19.72, and 15.92 microM, respectively. The EC50 values of these aliphatic chloramines from the Microtox test decreased by roughly one order of magnitude as a result of chlorination. Inhibition of nitrifiers also was observed in these amines. Trimethylamine and n-propylamine caused greater inhibition to nitrifiers than did ethylmethylamine under similar concentrations. Nitrifier inhibition from these amines increased after chlorination. The results of these tests indicated that aliphatic amines and their chlorinated derivatives could induce environmentally relevant toxicity responses in treatment settings and in receiving waters.

Hypochlorite-induced oxidation of proteins in plasma: formation of chloramines and nitrogen-centred radicals and their role in protein fragmentation.

Activated phagocyte cells generate hypochlorite (HOCl) via the release of H2O2 and the enzyme myeloperoxidase. Plasma proteins are major targets for HOCl, although little information is available about the mechanism(s) of oxidation. In this study the reaction of HOCl (at least 50 microM) with diluted fresh human plasma has been shown to generate material that oxidizes 5-thio-2-nitrobenzoic acid; these oxidants are believed to be chloramines formed from the reaction of HOCl with protein amine groups. Chloramines have also been detected with isolated plasma proteins treated with HOCl. In both cases chloramine formation accounts for approx. 20-30% of the added HOCl. These chloramines decompose in a time-dependent manner when incubated at 20 or 37 degrees C but not at 4 degrees C. Ascorbate and urate remove these chloramines in a time- and concentration-dependent manner, with the former being more efficient. The reaction of fresh diluted plasma with HOCl also gives rise to protein-derived nitrogen-centred radicals in a time- and HOCl-concentration-dependent manner; these have been detected by EPR spin trapping. Identical radicals have been detected with isolated HOCl-treated plasma proteins. Radical formation was inhibited by excess methionine, implicating protein-derived chloramines (probably from lysine side chains) as the radical source. Plasma protein fragmentation occurs in a time- and HOCl-concentration-dependent manner, as evidenced by the increased mobility of the EPR spin adducts, the detection of further radical species believed to be intermediates in protein degradation and the loss of the parent protein bands on SDS/PAGE. Fragmentation can be inhibited by methionine and other agents (ascorbate, urate, Trolox C or GSH) capable of removing chloramines and reactive radicals. These results are consistent with protein-derived chloramines, and the radicals derived from them, as contributing agents in HOCl-induced plasma protein oxidation.

Formation of chloroamines from styrene under conditions mimicking those of water "chlorination" treatment.

The reaction of styrene with sodium hypochlorite in the presence of ammonium ion in 0.3 M phosphate buffer (pH 6.0) at room temperature afforded N-chloro-1-phenyl-2-chloroethylamine and N,N-dichloro-1-phenyl-2-chloroethylamine. 1-Phenyl-2-chloroethylamine hydrochloride, obtained as the reduction product of the two N-chloroamines, was shown to be mutagenic in the Salmonella typhimurium test.