Derivatization Reaction Research Articles

Continuous Flow Synthesis of Nitrosoarenes via Photochemical Rearrangement of Aryl Imines.

Nitrosoarenes are versatile organic building blocks; however, their intrinsic instability and limited synthetic accessibility have so far restricted their widespread use. Herein, we present a new continuous flow route toward these entities that is based on a direct photochemical rearrangement process using o-nitrophenylimines as starting materials. Due to the underlying redox mechanism, a new amide group accompanies the formation of the nitroso group. Crucial to the success of this approach is the use of trifluoroethanol as a solvent and high-power light-emitting diodes (365 nm) as light sources that provide uniform irradiation and high efficiency of the resulting continuous flow method. The process is fast and robust, with high functional group tolerance and high throughput. The formation of the nitroso moiety is supported by full spectroscopic analysis, including X-ray crystallography. The scalability of this flow approach allows access to gram quantities of nitroso species for which we highlight a small set of derivatization reactions underlining their synthetic utility.

Regioselective C3-halogenations of N-(pyrazolo[1,5-a]pyrimidin-7-yl)acetamides

Regioselective C3-halogenations of N-(pyrazolo [1,5-a]pyrimidin-7-yl)acetamide with N-halosuccinimides (NBS or NCS) have been achieved. A diverse array of C3-halogenated products are provided in high yields with excellent regioselectivity. The practicability of this approach is highlighted by simple condition reactions, broad substrate scope, gram-scale reaction. Moreover, further derivatization reactions demonstrated the versatility of the products.

Validated spectrofluorimetric method for the determination of netilmicin based on its interaction with o‐phthalaldehyde/mercaptoethanol: Evaluation of the method's greenness

AbstractIn this study, netilmicin (NTM) was selectively assessed in its dosage forms after a facile derivatization reaction. The proposed approach was based on the interaction between NTM and o‐phthalaldehyde/2‐mercaptoethanol (Roth's reagent). The reaction product was fluorometrically measured at λemission of 434 nm after λexcitation of 338 nm. All reaction conditions for achieving the optimum fluorescence switch‐on activity were visualized and monitored. Moreover, the method was validated under ICH guidelines, and was linear over the range 30–210 ng/ml after plotting netilmicin concentrations against the corresponding fluorescence intensity values. In addition, the selectivity of the developed method was investigated against either the co‐formulated drug (dexamethasone) or a common ophthalmic drop excipient (benzalkonium chloride) without interference from either of them. Furthermore, the developed method was applied to assay netilmicin in various samples of pharmaceutical eye drops with good recovery. Finally, multicriteria greenness and whiteness metrics were used to evaluate the sustainability, greenness, and whiteness of the approach. The applied tools were the AGREE algorithm, the RGB 12 algorithm, and HEXAGON.

Nitrate ester derivatization for the generation of structurally informative ions via gas chromatography-mass spectrometry

Forensic investigations of explosives in post-blast and trace scenarios often utilize gas chromatography-mass spectrometry (GC–MS). Many high explosives (e.g., trinitrotoluene) provide structurally significant ions so that a compound can be confidently identified by GC–MS; however, GC–MS only provides functional group identification for the presence of nitrate esters (e.g., nitroglycerin (NG)), a class of high explosives that is frequently encountered in forensic casework. Nitrate esters vary drastically and are much more accurately identified by their component alcohol structure rather than merely the detection of the nitrate and nitrite ions. Herein, we demonstrate a two-step derivatization reaction requiring no purification steps or advanced sample preparation and characterize several of the reaction byproducts created along with the desired reaction product. In this process, nitrate esters are initially reduced to their component alcohol, and then subsequently silylated. The resulting product, when submitted to GC–MS with positive ion mode chemical ionization, provides mass spectra that characterizes the component alcohol by the pseudo-molecular ion of the reaction product. GC–MS with negative ion mode chemical ionization confirms the presence of a nitrate functional group by the characterization of the unreacted starting material. These results combine to identify nitrate esters in forensic settings, and as a proof of concept, we demonstrate the applicability of the derivatization reaction to pentaerythritol tetranitrate (PETN), NG, and erythritol tetranitrate (ETN) standards, as well as a formulated composition containing PETN-SEMTEX 1A, homemade ETN, and post-burn samples.

Thiol-ene click derivatization reaction coupled with ratiometric surface-enhanced Raman scattering for reproducible and accurate determination of acrylamide.

Acrylamide (AA) is a carcinogen mainly ingested through food and drinking water, making its accurate determination crucial for both food safety and environmental protection. Herein, we proposed a derivatization-based ratiometric surface-enhanced Raman scattering (SERS) method for the quantification of AA. High density Au NPs were anchored to the surface of Cu-TCPP MOF nanosheets (MOFNs) to form the SERS sensor. The abundant Raman "hot spots" at the nanogaps generated by the Au NPs and the internal standard (IS) signal provided by Cu-TCPP MOFNs improved the sensitivity and quantitative accuracy of the method. Following the thiol-ene click derivatization reaction between p-aminothiophenol (PATP) and AA, the Raman peak intensity ratio (I1080/I395) was employed to quantify AA. The linear range was 0.1nM to 10μM, and the limit of detection (LOD) was as low as 0.08nM. Trace amounts of AA in food and water samples were successfully determined using this method.

Mechanisms of chemical vapor generation by aqueous boranes for trace element analysis: a rather long and unfinished story

Abstract This paper reports a summary of the studies on the mechanisms that govern the generation of hydrides and other volatile species through reaction with aqueous boranes (CVG). This derivatization reaction has been used since the early 1970s for elemental determination and speciation from the trace level down to the ultratrace level and below. An IUPAC project, concluded in 2011, reported on the mechanisms of hydrogen transfer from borane to the analytical substrate and served to remove erroneous concepts that had dominated CVG until the early 2000s. Following the conclusion of the IUPAC project, many studies have been published on the mechanisms of CVG under conditions approaching those of analyzes of real samples. These studies included the definition of more general reaction models, which valid under non-analytical conditions, the mechanism of action of additives and interferences in CVG of volatile hydrides. In addition to the analytical utility for CVG, the results represent a contribution to the knowledge of the chemistry of aqueous boranes. Other studies will be necessary to clarify still unknown aspects, among them the identity of volatile transition metal species formed by reaction of metal ions with aqueous boranes.

Colorimetric derivatization of ambient ammonia (NH3) for detection by long-path absorption photometry

Abstract. In the last few decades, various techniques, including spectroscopic, mass spectrometric, chemiluminescence and wet chemical methods, have been developed and applied for the detection of gaseous ammonia (NH3). We developed an online NH3 monitoring system – salicylic acid derivatization reaction and long-path absorption photometer (SAC-LOPAP) – based on a selective colorimetric reaction to form a highly absorbing reaction product and a LOPAP, which could run stably for a long time and be applied to the continuous online measurement of low concentrations of ambient NH3 by optimizing the reaction conditions, adding a constant-temperature module and liquid flow controller. The detection limit reached with this instrument was 40.5 parts per trillion (ppt) with a stripping liquid flow rate of 0.49 mL min−1 and a gas sample flow rate of 0.70 L min−1. An inter-comparison of our system with a commercial Picarro G2103 analyzer (Picarro, USA) in Beijing was presented, and the results showed that the two instruments had a good correlation with a slope of 1.00 and an R2 of 0.96, indicating that the SAC-LOPAP instrument involved in this study could be used for the accurate measurement of NH3.

Location of Double or Triple Bonds in Lipids Using Mass Spectrometry, Part I

Structural analysis of lipids is one of the classical topics of organic mass spectrometry. In recent years, we have witnessed a rapid development of new methods that allow the characterization of lipid structures more accurately, more rapidly, and in more complex samples. These methods are mostly based on derivatization reactions or newly available fragmentation techniques. Basic mass spectrometric analysis of lipids, i.e., determination of lipid class, acyl chain length, and degree of unsaturation, is usually relatively easy but the detailed structural description is more challenging. In this two-part review article, we present advances in mass spectrometry for characterizing double and triple bonds in lipid acyl chains by LC-MS and direct ionization of liquid samples at atmospheric pressure. The first paper discusses charge-switch derivatizations, ozonolysis, and the Paternò-Büchi reaction.

Amide-decorated reusable C18 silica-packed columns for the rapid, efficient and sequential separation of lanthanoids using reversed phase-high performance liquid chromatography

The current work focuses on the sequential separation of trivalent lanthanides (except Pm3+) using modified C18 silica-packed supports through the reversed-phase high-performance liquid chromatography (RP-HPLC) technique. In the current research, four indigenously synthesized amphiphilic aromatic triamide derivatives, namely N1, N1, N3, N3, N5, N5-hexa(alkyl) benzene-1,3,5-tri carboxamide (alkyl = butyl, hexyl, octyl, and decyl), were employed as column modifiers. The results show that the separation of Ln3+ can be achieved systematically (< 12 min) by tuning the modifiers' functional group and hydrophobic chain and fine-tuning the column modification procedure and separation parameters. The chromatographic studies revealed that the use of 0.168 mmol of N1, N1, N3, N3,N5, N5-hexa(hexyl)benzene-1,3,5-tricarboxamide (HHBTA) coated column and 0.419 mmol of N1, N1, N3, N3, N5, N5-hexa(octyl) benzene-1,3,5-tricarboxamide (HOBTA) modified columns offered excellent separation for the lanthanoids, using 0.1 M α-hydroxyisobutyric acid (HIBA), as mobile phase. The separated lanthanoids were quantified by post-column derivatization reaction (after the separation process) using Arsenazo (III) as the post-column reagent by integrating with a UV–Visible detector fixed at 655 nm (λmax). A systematic study on the influence of various analytical features, such as the effect of the modifier's chain length and its concentration, mobile phase composition and pH, was performed and optimized for achieving the best separation protocols.

Isolation and Structure Determination of Akunolides, Macrolide Glycosides from a Marine Okeania sp. Cyanobacterium.

Akunolides A (1), B (2), C (3), and D (4), new macrolide glycosides, were isolated from a marine Okeania sp. cyanobacterium. Their structures were elucidated by spectroscopic analyses and derivatization reactions. Akunolides A-D (1-4) are classified as 16-membered macrolide glycosides, which are relatively rare structures for marine cyanobacterium-derived natural products. Akunolides A-D (1-4) showed moderate antitrypanosomal activities against Trypanosoma brucei rhodesiense, with IC50 values ranging from 11 to 14 μM. Furthermore, akunolides A (1) and C (3) exhibited no cytotoxicity against normal human WI-38 cells even at a concentration of 150 μM.

Palladium-catalyzed synthesis of carboxylic acid anhydrides from alkenes

Hydrocarbonylation of alkenes with nucleophiles – water, alcohols and amines, is widely studied and implemented in synthesis of fine chemicals and natural products. Here, an efficient and additive-free palladium-catalyzed hydrocarbonylation reaction of alkenes is described using carboxylic acids as the nucleophile, by which acid anhydrides are obtained in moderate to excellent yields. The relative concentrations of substrate and reagents play an important role in driving the reaction forward, which reaches an equilibrium at equimolar concentrations under a given CO pressure. A ligand-screening study revealed the use of electron-poor phosphine ligands to be crucial for obtaining higher rates of the catalytic reaction. Several substrates including unactivated alkenes were successfully converted to the corresponding symmetric as well as mixed anhydrides. An additional advantage of our synthetic procedure is that the obtained anhydrides can be converted to (primary) amides, thioesters or esters in situ via a simple one-pot derivatization reaction, since acid anhydrides are prone to degradation on isolation.

A green sustainable ultrasensitive micelle-sensitized spectrofluorimetric approach for the estimation of tafamidis in different matrices at picogram levels

Tafamidis is a novel drug approved by the European Medicines Agency to treat certain forms of transthyretin amyloidosis. The current study introduces a new ultrasensitive validated spectrofluorimetric approach for tafamidis analysis in bulk, capsules, and biological fluids. The present study is considered the first spectrofluorimetry-based approach for tafamidis estimation. The proposed eco-friendly spectrofluorimetric method depended on the measurement of the enhanced native fluorescence of tafamidis exhibited at 310/370 nm without any derivatization reaction. It was found that about two-fold enhancement in the tafamidis fluorescence could be accomplished by the addition of Brij-35. Different experimental parameters affecting the fluorescence of tafamidis were examined to reach the optimal conditions and highest sensitivity. One milliliter of each of 0.02 M Britton-Robinson buffer at pH 2 and Brij-35 was added to give the maximum fluorescence intensity. The drug was successively assayed in the concentration range of (0.1–10.0 ng/mL) with a detection limit of 0.0107 ng/mL and a quantitation limit of 0.0324 ng/mL. Owing to the superior sensitivity and selectivity, the developed method was effectively applied to the quantitation of tafamidis in its capsules and spiked human plasma samples with high % recoveries and low % relative standard deviation values. The validation parameters were assessed by following the International Council for Harmonization (ICH) guidelines. Additionally, the eco-friendly property of the designed approach was considered, and the greenness was evaluated using the Green Analytical Procedure Index (GAPI) and Analytical GREENNESS metric approach (AGREE).

KI‐Facilitated Trifunctionalization of Maleimides in Water: Access to Disulfonylated Diazosuccinimide Derivatives and their Synthetic Applications

AbstractA trifunctionalization cascade reaction of substituted maleimides was developed to generate a series of disulfonylated diazosuccinimides in satisfactory yields by employing readily available sulfonyl hydrazides as both diazo source and sulfonylation reagent. The notable features of this developed method include avoiding the use of transition metal catalysts, environmentally benign H2O as the solvent, mild reaction conditions, good functional group tolerance, and the late‐stage modification of drugs. The derivatization reactions were effectively applied to synthesize aminosulfonylation‐substituted maleimides. The involved radical pathway was also demonstrated by mechanistic studies.

Advancements in Preprocessing and Analysis of Nitrite and Nitrate since 2010 in Biological Samples: A Review.

As a substance present in organisms, nitrite is a metabolite of nitric oxide and can also be ingested. Nitrate is the metabolite of nitrite. Therefore, it is necessary to measure it quickly, easily and accurately to evaluate the health status of humans. Although there have been several reviews on analytical methods for non-biological samples, there have been no reviews focused on both sample preparation and analytical methods for biological samples. First, rapid and accurate nitrite measurement has significant effects on human health. Second, the detection of nitrite in biological samples is problematic due to its very low concentration and matrix interferences. Therefore, the pretreatment plus measuring methods for nitrite and nitrate obtained from biological samples since 2010 are summarized in the present review, and their prospects for the future are proposed. The treatment methods include liquid-liquid microextraction, various derivatization reactions, liquid-liquid extraction, protein precipitation, solid phase extraction, and cloud point extraction. Analytical methods include spectroscopic methods, paper-based analytical devices, ion chromatography, liquid chromatography, gas chromatography-mass spectrometry, electrochemical methods, liquid chromatography-mass spectrometry and capillary electrophoresis. Derivatization reagents with rapid quantitative reactions and advanced extraction methods with high enrichment efficiency are also included. Nitrate and nitrate should be determined at the same time by the same analytical method. In addition, much exploration has been performed on formulating fast testing through microfluidic technology. In this review, the newest developments in nitrite and nitrate processing are a focus in addition to novel techniques employed in such analyses.

Simultaneous analysis of ascorbic and dehydroascorbic acid in fruit juice using HILIC chromatography coupled with mass spectrometry

A HILIC-MS/MS method was developed for the simultaneous analysis of ascorbic acid (AA) and dehydroascorbic acid (DHA). Ammonium acetate buffer and acetonitrile were used as mobile phases under gradient elution mode at a flow rate of 0.3 mL/min. A SCIEX Triple QUAD 5500+ system was operated under MRM mode to acquire data with 175 → 115 and 173→113 as the quantifier ions for AA and DHA, respectively. Samples were prepared with a simple dilute and shoot method. A calibration and accuracy study was performed as part of method validation in fruit juices. The accuracy profiles were estimated from the measurement uncertainty determined from the validation data according to the ISO/DTS 21748. The recoveries of the analytes were between 92 – 130 %. The LOQs achieved in the current study for AA and DHA were 4.5 µg/L and 18 µg/L, respectively. These LOQs were substantially lower than what has been previously reported in the literature. The study concludes with a straightforward analytical method for the determination of total vitamin C content that does not involve timing consuming steps i.e., reduction or derivatization reaction. The method can be implemented in quality control labs for routine analysis of food samples.

Improved analysis of derivatized steroid hormone isomers using ion mobility-mass spectrometry (IM-MS).

Over the last decade, applications of ion mobility-mass spectrometry (IM-MS) have exploded due primarily to the widespread commercialization of robust instrumentation from several vendors. Unfortunately, the modest resolving power of many of these platforms (~40-60) has precluded routine separation of constitutional and stereochemical isomers. While instrumentation advances have pushed resolving power to >150 in some cases, chemical approaches offer an alternative for increasing resolution with existing IM-MS instrumentation. Herein we explore the utility of two reactions, derivatization by Girard's reagents and 1,1-carbonyldiimidazole (CDI), for improving IM separation of steroid hormone isomers. These reactions are fast (≤30min), simple (requiring only basic lab equipment/expertise), and low-cost. Notably, these reactions are structurally selective in that they target carbonyl and hydroxyl groups, respectively, which are found in all naturally occurring steroids. Many steroid hormone isomers differ only in the number, location, and/or stereochemistry of these functional groups, allowing these reactions to "amplify" subtle structural differences and improve IM resolution. Our results show that resolution was significantly improved amongst CDI-derivatized isomer groups of hydroxyprogesterone (two-peak resolution of Rpp = 1.10 between 21-OHP and 11B-OHP), deoxycortisone (Rpp = 1.47 between 11-DHC and 21-DOC), and desoximetasone (Rpp = 1.98 between desoximetasone and fluocortolone). Moreover, characteristic collision cross section (DTCCSN2) measurements can be used to increase confidence in the identification of these compounds in complex biological mixtures. To demonstrate the feasibility of analyzing the derivatized steroids in complex biological matrixes, the reactions were performed following steroid extraction from urine and yielded similar results. Additionally, we applied a software-based approach (high-resolution demultiplexing) that further improved theresolving power (>150). Overall, our results suggest that targeted derivatization reactions coupled with IM-MS can significantly improve the resolution of challenging isomer groups, allowing for more accurate and efficient analysis of complex mixtures.

Potential application of a chromatographic method in the accurate simultaneous determination of amikacin sulfate and its preservation additives in different pharmaceutical dosage forms

Aminoglycosides are antibiotics with high clinical importance that face a great challenge of detection in the UV range. This study aimed to develop an accurate, simple, and sensitive validated high-performance liquid chromatographic (HPLC) method for the determination of amikacin sulfate, one of the widely used aminoglycoside antibiotics in the pharmaceutical formulations, as the target analyte without interference from its preservation additive sodium metabisulfite in the pharmaceutical dosage forms without the usage of any derivatization reactions. The developed method is based on direct UV detection at 205 nm using a gradient mobile phase consisting of acetonitrile as an organic solvent and buffered solution; pH 3.0. This method was developed on a reversed-phase ZORBAX ECLIPSE XDB-C8 (4.6 × 250 mm, 5-μm) analytical column with a flow rate of 1.5 mL min−1 at a column temperature of 35 °C. The separation of amikacin sulfate and sodium metabisulfite was achieved at 3.7, and 1.5 min, respectively. The developed method validation was performed as prescribed by the International Conference on Harmonization (ICH) guidelines to confirm its linearity, precision, and accuracy. Finally, using simple, commonly available analytical tools, safe buffer concentration on the HPLC system, and without any complicated equipment or challenging derivatization steps, our validated HPLC method was applied for the simultaneous determination of amikacin and sodium metabisulfite in commercially available pharmaceutical formulations in a single method of analysis.

Daphnepedunins G and H, anti-HIV macrocyclic 3,4-seco-daphnane orthoesters from Daphne pedunculata.

Daphnepedunins G (1) and H (2) with unusual macrocyclic 3,4-seco-daphnane orthoester structure were isolated from Daphne pedunculata. Their structures were determined by physicochemical and spectroscopic analyses combined with synthetic methods, including methyl esterification, derivatization reaction using a chiral anisotropic agent, and biomimetic conversion. Compounds 1 and 2 along with their methyl esters 1a and 2a were evaluated for anti-HIV activity, among which 1a and 2a exhibited potent activity with IC50 values of 1.08 and 1.17μM, respectively.

Enhanced LC-ESI-MS/MS Sensitivity by Cationic Derivatization of Organophosphorus Acids.

The chemical derivatization to enhance the signal intensity and signal-to-noise (S/N) of several organophosphorus (OP) acids in liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS) is illustrated. The OP class of compounds represents the environmental degradants of OP nerve agents and pesticides. N-(2-(bromomethyl)benzyl)-N,N-diethylethanaminium bromide (CAX-B) was utilized to derivatize a panel of eight acids consisting of five alkyl methylphosphonic acids (ethyl-, isopropyl-, isobutyl-, cyclohexyl-, and pinacolyl-methylphosphonic acid) along with three dialkylphosphate analogs (diethyl-, dibutyl-, and diethyl thio-phosphate). The derivatization reaction with CAX-B was conducted in acetonitrile in the presence of potassium carbonate at 70 °C for 1 h. The resulting acid derivatives were analyzed with an LC-Orbitrap-ESI-MS/MS, and their dissociation processes were investigated. It was found that the derivatization procedure increased the limits of identification (LOIs) by one to over two orders of magnitude from the range of 1 to 10 ng/mL for the intact OP-acids to the range of 0.02-0.2 ng/mL for the derivatized acids utilizing an LC-MS(QqQ) in MRM mode, regardless of the sample matrix (hair, concrete, or plant extracts). The interpretation of the corresponding ESI-MS/MS spectra for each type of derivatized sub-OP family revealed the formation of characteristic neutral losses and a characteristic ion for the organophosphorus core. This derivatization is beneficial and useful for screening and identifying target and "unknown" OP acids.

HPLC with Post-Column Derivatization with Alizarin for Determination of OATD-02, an Anticancer Arginase Inhibitor in Clinical Development

The aim of this study was to develop an analytical method for selective determination of OATD-02 by high-performance liquid chromatography (HPLC) with post-column derivatization and fluorescence detection (FLD). OATD-02, a new boronic acid derivative, is a highly potent anticancer arginase inhibitor in clinical development. Chromatographic analysis of OATD-02 poses problems because this molecule has weak ultraviolet absorption. The derivatization reaction was based on the reaction between boronic acid from OATD-02 and alizarin solution. The optimized mobile phase consisted of a mixture of sodium bicarbonate in water and acetonitrile at a flow rate of 0.50 mL/min. Alizarin solution in methanol was delivered at a flow rate of 0.50 mL/min. The fluorescent complexes were detected by a fluorescence detector (excitation and emission wavelengths at 470 and 580 nm, respectively). The present method demonstrated proper values for selectivity, linearity, recovery (&gt;99%), precision (RSD: 0.6%), sensitivity (LOD: 20 µg/mL and LOQ: 50 µg/mL), stability of solutions, and robustness.