Alternative Reaction Pathways Research Articles

Approaches and Considerations for the Investigation and Synthesis of N-Nitrosamine Drug Substance-Related Impurities (NDSRIs)

N-Nitrosamine risk assessment of pharmaceuticals has moved from an initial focus on the potential presence of known small-molecule N-nitrosamines such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in active substances toward the potential for generation of more complex nitrosamine drug substance-related impurities (NDSRIs) in drug products. While N-nitrosation of simple secondary amines is well-understood, more complex amines can undergo alternative reaction pathways that can be more challenging to predict. A number of such complex amines are known not to undergo N-nitrosation but are either unreactive or react by alternative pathways such as C-nitrosation or nitration to generate non-N-nitrosamine products. This article proposes a standard set of three orthogonal nitrosation forced degradation type reaction conditions that can be used to investigate the potential for generation of novel N-nitrosamines by nitrosation of complex amines. These complementary reaction conditions are considered to provide a thorough evaluation of the potential for N-nitrosamine formation from complex amines with respect to risk factors within pharmaceutical manufacturing. If, after investigation of nitrosation under the proposed conditions, formation and isolation of an N-nitrosamine is not possible, the resultant understanding of chemical reactivity and stability can be used to justify that the N-nitrosamine in question would not be expected to be generated from the complex amine in the drug substance or product. If an N-nitrosamine is formed under these reaction conditions, the information gained can be used as part of the risk assessment and also provides a starting point for the development of a process to synthesize a discrete sample for further testing. Additionally, synthetic and analytical considerations that should be taken into account during preparation of novel N-nitrosamines for use in analytical or toxicological studies are discussed.

Photocatalysis as an Effective Tool for Upcycling Polymers into Value-Added Molecules.

Shaping a sustainable future is closely tied to the development of advanced plastic recycling technologies. As global recycling rates remain low, the lion's share of post-consumer plastics is either incinerated or disposed of in landfills. This unbalanced plastic waste management not only poses severe environmental risks, but also entails an irrevocable loss of chemical resources that are embedded in synthetic polymers. To give plastic waste a new life, a series of photocatalytic methods has recently been reported that convert polymers directly into value-added organic molecules. These approaches operate at ambient temperature, show high reactivity/selectivity, and provide alternative reaction pathways as compared to thermal depolymerizations. This Minireview highlights the scientific breakthroughs in upcycling polymers through state-of-the-art photocatalysis under environmentally benign conditions.

Photocatalysis as an Effective Tool for Upcycling Polymers into Value‐Added Molecules

AbstractShaping a sustainable future is closely tied to the development of advanced plastic recycling technologies. As global recycling rates remain low, the lion's share of post‐consumer plastics is either incinerated or disposed of in landfills. This unbalanced plastic waste management not only poses severe environmental risks, but also entails an irrevocable loss of chemical resources that are embedded in synthetic polymers. To give plastic waste a new life, a series of photocatalytic methods has recently been reported that convert polymers directly into value‐added organic molecules. These approaches operate at ambient temperature, show high reactivity/selectivity, and provide alternative reaction pathways as compared to thermal depolymerizations. This Minireview highlights the scientific breakthroughs in upcycling polymers through state‐of‐the‐art photocatalysis under environmentally benign conditions.

Alternative surface reaction route in the atomic layer deposition of NbN thin films for reduced resistivity

Transition metal nitride thin films such as TiN are necessary as conducting electrodes in memory and transistor devices. Due to their high work function (> 4.7 eV), NbN thin films have recently attracted attention to replace TiN thin films as capacitor electrodes using atomic layer deposition (ALD) process in dynamic random access memories (DRAMs) to reduce leakage currents in the capacitors. Unfortunately, the NbN ALD process using NbCl5 and NH3 as the Nb precursor and nitrogen source resulted in a high resistivity (> 500 μΩ·cm) despite its low bulk resistivity (∼10 μΩ·cm at 300 K) because of the residual Cl impurity (> 5%) within the NbN film. In this study, an alternative ALD surface reaction pathway is proposed by introducing H2S gas pulses between the NbCl5 and NH3 pulse steps to lower the Cl impurity concentration. Using the alternative ALD reaction, the residual Cl concentration was reduced below 1.5% (decrease by > 50%) at the specific ALD deposition temperature of 673 K. Finally, this reaction produced a greater decrease in the resistivity (> 30%) of NbN thin films than the conventional NbN ALD at 673 K.

Diastereoselective Synthesis of cis-2,6-Disubstituted Dihydropyrane Derivatives through a Competitive Silyl-Prins Cyclization versus Alternative Reaction Pathways

A convenient regioselective synthesis of allyl- and vinylsilyl alcohols, from a common precursor, was described, by selecting the appropriate reaction conditions. Allyl- and vinylsilyl alcohols were tested in silyl-Prins cyclizations for the preparation of disubstituted oxygenated heterocycles in a one-pot sequential reaction. The methodology was sensitive to the structure of the starting alkenylsilyl alcohol and reaction conditions, with competitive pathways observed (particularly for allylsilyl alcohols), such as Peterson elimination and oxonia-Cope reactions. However, the use of vinylsilyl alcohols allowed the preparation of differently disubstituted cis-2,6-dihydropyrans in moderate to good yields. Computational studies support the proposed mechanism.

A Single Active-Site Mutagenesis Confers Enhanced Activity and/or Changed Product Distribution to a Pentalenene Synthase from Streptomyces sp. PSKA01.

Pentalenene is a ternary cyclic sesquiterpene formed via the ionization and cyclization of farnesyl pyrophosphate (FPP), which is catalyzed by pentalenene synthase (PentS). To better understand the cyclization reactions, it is necessary to identify more key sites and elucidate their roles in terms of catalytic activity and product specificity control. Previous studies primarily relied on the crystal structure of PentS to analyze and verify critical active sites in the active cavity, while this study started with the function of PentS and screened a novel key site through random mutagenesis. In this study, we constructed a pentalenene synthetic pathway in E. coli BL21(DE3) and generated PentS variants with random mutations to construct a mutant library. A mutant, PentS-13, with a varied product diversity, was obtained through shake-flask fermentation and product identification. After sequencing and the functional verification of the mutation sites, it was found that T182A, located in the G2 helix, was responsible for the phenotype of PentS-13. The site-saturation mutagenesis of T182 demonstrated that mutations at this site not only affected the solubility and activity of the enzyme but also affected the specificity of the product. The other products were generated through different routes and via different carbocation intermediates, indicating that the 182 active site is crucial for PentS to stabilize and guide the regioselectivity of carbocations. Molecular docking and molecular dynamics simulations suggested that these mutations may induce changes in the shape and volume of the active cavity and disturb hydrophobic/polar interactions that were sufficient to reposition reactive intermediates for alternative reaction pathways. This article provides rational explanations for these findings, which may generally allow for the protein engineering of other terpene synthases to improve their catalytic efficiency or modify their specificities.

Autocatalytic O-Formylation of Alcohols Using CO2

Global drive away from fossil feedstock requires the development of synthetic procedures to enhance the efficiency of CO2 capture and utilization processes using renewable starting materials and catalysts. Here, we report an alternative reaction pathway for the O-formylation of alcohols and bio-alcohols, which affords industrially relevant formate esters. Most products, reported herein, derive their carbon atoms exclusively from renewable sources. The reaction is catalyzed by formic acid, which can also be produced directly from CO2 captured in the reaction. The resulting in situ produced formic acid improves the reaction rate, with each catalyst recycling by simple filtration, product distillation, and reuse of the residual reaction mixture. Hence, CO2 is used as a C1 building block and simultaneously reduced to formic acid, which in turn autocatalytically promotes the reaction.

Surface charge as activity descriptors for electrochemical CO2 reduction to multi-carbon products on organic-functionalised Cu

Intensive research in electrochemical CO2 reduction reaction has resulted in the discovery of numerous high-performance catalysts selective to multi-carbon products, with most of these catalysts still being purely transition metal based. Herein, we present high and stable multi-carbon products selectivity of up to 76.6% across a wide potential range of 1 V on histidine-functionalised Cu. In-situ Raman and density functional theory calculations revealed alternative reaction pathways that involve direct interactions between adsorbed histidine and CO2 reduction intermediates at more cathodic potentials. Strikingly, we found that the yield of multi-carbon products is closely correlated to the surface charge on the catalyst surface, quantified by a pulsed voltammetry-based technique which proved reliable even at very cathodic potentials. We ascribe the surface charge to the population density of adsorbed species on the catalyst surface, which may be exploited as a powerful tool to explain CO2 reduction activity and as a proxy for future catalyst discovery, including organic-inorganic hybrids.

Reduction Kinetics of the Three Nitrothiophenol Isomers on Pt-Coated Gold Nanorods

4-Nitrothiophenol (4-NTP) has been widely used in surface-enhanced Raman scattering (SERS)-based reduction studies for testing the catalytic performance of a variety of noble-metal nanoparticles using hydride or hydrogen as reducing agent. The catalytic conversion of 4-NTP to 4-aminothiophenol (4-ATP) strongly depends on the catalyst’s morphology, size, and material composition. This reduction reaction proceeds via a Langmuir–Hinshelwood mechanism, involving the formation of active Pt–H species. Two alternative reaction pathways with respect to the transferred hydrogen species are in principle possible. The first possible pathway describes the direct transfer of a hydrogen radical or hydride to the molecule (hypothesis 1), while the second pathway describes an electron transfer from the platinum to the 4-NTP followed by a proton transfer from the active species (hypothesis 2). To falsify one of these two contradicting hypotheses, we varied the position of the nitro group relative to the thiol groups and thereby the distance of the nitro group to the metal surface. The reduction kinetics of the three isomers of NTP (2-NTP, 3-NTP, and 4-NTP) on platinum-coated gold nanorods was monitored by SERS with molecular hydrogen as the reducing agent. On the basis of the experimental SERS kinetic data giving first-order rate constants in the order k2-NTP > k3-NTP > k4-NTP, we conclude that the reduction does not proceed via an electron transfer mechanism, but via hydrogen/hydride transfer.

An alternative reaction pathway triggered by oxygen vacancies for boosting selective hydrodeoxygenation reactions

The Co/CoOx catalyst with rich oxygen vacancies was found to be robust for mild and selective hydrodeoxygenation reactions. The oxygen vacancies promote the activation of substrates, and enable the reactions in direct hydrogenolysis pathway.

Tribochemically driven dehydrogenation of undoped sodium alanate under room temperature.

An application of mechanical energy was explored as a new non-thermal method to drive H2 emission from undoped sodium alanate at room temperature. It was found that mild rubbing of NaAlH4 pellets under vacuum led to intensive and almost instantaneous gas emission. The dominating species in the emitted gases was H2 (>99%). Traces of mono- and polyalanes, NaAlH4 vapours, CO2 and other non-identified gases were registered. H2 emission involved several first-order processes, whose characteristic time constants ranged widely from 0.6 to 465 s. None of the dehydrogenation reactions could be connected to either the thermal effect of friction or the direct coupling of mechanical forces to the energy landscape of chemical reactions. In turn, it was suggested that the tribochemical reactions can be triggered by plastic deformation and shearing. A linked diffusion-wear model of NaAlH4 triboinduced dehydrogenation, which consistently explains all empirical findings, was put forward.

Elucidating reaction pathways in CO2 electroreduction: Case study of Ag and Cu2O@Ag catalysts

CO2 electroreduction is a prospective avenue to produce carbon-based fuels, yet atomic-level insights on the mechanistic origin of catalytic selectivity remains elusive. Taking the Ag and Cu2O@Ag electrocatalysts as examples, Fourier-transform infrared spectroscopy in conjunction with theoretical calculations reveal that the hollow-nanostructured Ag promotes CO production through a lower energy barrier of the rate-limiting *CO2 to *COOH, while the Cu2O-Ag boundaries in the honeycomb-like Cu2O@Ag reinforce CO2 physisorption and chemisorption on the catalyst surface. The interfaces of Cu2O@Ag facilitate CO hydrogenation and CC coupling, opening alternative reaction pathways toward CH4 and C2H4. More broadly, this study provides insights to develop effective electrocatalysts in CO2 electroreduction and beyond.

New Multidrug Efflux Systems in a Microcystin-Degrading Bacterium Blastomonas fulva and Its Genomic Feature.

A microcystin-degrading bacterial strain, Blastomonas fulva T2, was isolated from the culture of a microalgae Microcystis. The strain B. fulva T2 is Gram-stain-negative, non-motile, aerobic, non-spore-forming and phototrophic. The cells of B. fulva T2 are able to grow in ranges of temperature from 15 to 37 °C, with a pH of 6 to 8 and a salinity of 0 to 1% NaCl. Here, we sequenced the complete genome of B. fulva T2, aiming to better understand the evolutionary biology and the function of the genus Blastomonas at the molecular level. The complete genome of B. fulva T2 contained a circular chromosome (3,977,381 bp) with 64.3% GC content and a sizable plasmid (145.829 bp) with 60.7% GC content which comprises about 3.5% of the total genetic content. A total of 3842 coding genes, including 46 tRNAs and 6 rRNAs, were predicted in the genome. The genome contains genes for glycolysis, citric acid cycle, Entner–Doudoroff pathways, photoreaction center and bacteriochlorophylla synthesis. A 7.9 K gene cluster containing mlrA, mlrB, mlrC and mlrD1,2,3,4 of microcystin-degrading enzymes was identified. Notably, eight different efflux pumps categorized into RND, ABC and MFS types have been identified in the genome of strain T2. Our findings should provide new insights of the alternative reaction pathway as well as the enzymes which mediated the degradation of microcystin by bacteria, as well as the evolution, architectures, chemical mechanisms and physiological roles of the new bacterial multidrug efflux system.

Solvent Dependent Competitive Mechanisms for the Ugi Multicomponent Reaction: A Joint Theoretical and Experimental Study in the α-Acyl Aminocarboxamides vs α-Amino Amidines Formation.

A synthetic protocol for the preparation of α-acyl aminocarboxamides and α-amino amidines is proposed. The selectivity toward each of these two possible products was tuned by simple modifications of the reaction conditions. A broad scope is presented, allowing access to the desired products in up to 87% (Ugi adduct) and 93% (α-amino amidine). Theoretical calculations were carried out, and the analysis led to the proposal of a new mechanistic pathway for the Ugi reaction, in which methanol acts not only as the solvent but also as a reagent. High-resolution (tandem) mass spectrometry experiments allowed the detection and characterization of the key intermediate associated with this new and alternative reaction pathway, thus supporting the theoretical proposal.

On thermodynamics of electron, proton and PCET processes of catechol, hydroquinone and resorcinol – Consequences for redox properties of polyphenolic compounds

• Systematic DFT study of hydroxybenzene and their semiquinone and quinone forms. • Acidity constants are predicted. • Pourbaix diagrams are evaluated, and redox properties are discussed. • Alternative reaction pathways for radical scavenging activities are investigated. The hydroxyl group acidities represent a characteristic feature of p-hydroquinone, catechol and resorcinol in their electric neutral and charged states. The transformation of dihydroxybenzenes to semiquinone followed by semiquinone to quinone forms can proceed through different proton-coupled electron transfer steps as demonstrated by the Density functional theory calculations combined with solvent continuum model for water environment. These steps were also analysed using the Pourbaix diagram (electrochemical potential vs. pH) diagrams, constructed from the theoretically predicted p K a values, and theoretically estimated electrochemical standard potentials. The obtained results enable the identification of alternative reaction pathways of the radical scavenging abilities of dihydroxybenzenes or polyphenols occurring in redox reactions and biological processes.

Molecular Catalysis in “Green” Hydrogen Production

Molecular hydrogen (H2) is considered an ideal energy vector and a clean fuel, due to its zero-carbon combustion. Nevertheless, despite hydrogen is the most and one of the most abundant elements in the universe and in earth crust, respectively, it is always combined with other elements in our planet and never appears in its elemental state. This means that H2 must be produced through, almost always, endergonic processes, whose sustainability depend not only on the starting material but also on the source of energy necessary for these processes to occur. Colors have been assigned to identify the level of sustainability of H2 production with the green one indicating H2 produced from water using a renewable source of energy, preferably sunlight. Redox water splitting (WS) into H2 (hydrogen evolution reaction, HER) and O2 (oxygen evolution reaction, OER) is, nevertheless, an extremely difficult process not only from the thermodynamic but also from the kinetic point of view. Relevant kinetic barriers are present in both sides of the redox process, especially in OER. For this reason, performing WS in an efficient manner requires the development of active and robust catalysts capable of offering alternative reaction pathways to WS, lowering down the unfavorable kinetic barriers and thus maximizing the energy conversion efficiency. Inspiration for developing efficient catalysts for HER and OER has traditionally derived from Nature, who, over the course of many billions of years, according to the evolutionary theory, has assembled two molecular catalytic pools, namely oxygen evolving complex and ferredoxin/ferredoxin NADP+ reductase, which offer viable kinetic pathways to both OER and reduction of NADP+ (the “biological form” of H2). In reality, after several attempts of mimicking natural catalysts, the efforts of the researchers have been addressed to different molecular systems, which exhibit best performances, unfortunately often based on noble-metal atoms, especially for OER. In this contribution we review the journey of the development of molecular catalysts for both HER and the OER, highlighting selected systems, which have brought us to the current level of knowledge.

Synergistic effect between nanostructured catalysts and high-frequency ultrasound: Application in biomass conversion to specialty chemicals

Within the context of sustainable chemistry, sonochemistry is now emerging as an alternative unconventional technology in catalysis. While ultrasound-generated radicals can participate in chemical reactions, mastering the reaction selectivity of polyfunctional substrates remains an elusive task. To address this challenge, we designed nanostructured metal oxides with leaf-like morphologies (e.g., CuO) by sonochemical synthesis (20 kHz) and investigated their activity for controlling the selectivity of oxidation reactions under ultrasonic irradiation in aqueous solution. We demonstrated that colocalization of the cavitation event onto the CuO surface active sites enables the direct utilization of radicals generated by cavitation for chemo-selective chemical reactions. In particular, we provided evidence for an alternative reaction pathway in glucose selective oxidation through synergistic cavitation–catalyst interactions at 550 kHz. We showed that the unwanted H• radicals stemming from water sonolysis are trapped by the surface lattice oxygen of CuO, thereby increasing the coverage of •OH radicals on the catalyst surface, and steering the selective oxidation of glucose to glucuronic acid, a valuable chemical whose synthesis remains a formidable challenge in the field of catalysis. This work also highlights that the particle size of the sonocatalyst is a key parameter governing an optimal transfer of radicals from the cavitation bubbles to the catalyst surface.

Straightforward Synthesis of Highly Functionalized Indanes and Tetralines through Ene-Cyclopropene Rearrangement Mediated by Ruthenium.

Ene-cyclopropenes give functionalized indanes and tetralines in the presence of ruthenium dimeric catalysts. This reaction involves the cyclopropene opening by the metal catalysts with a different regioselectivity respective to gold chlorides and produces totally different products than when using semisandwich ruthenium complexes. Here, the process leads to a bridged 7-oxanorbornene-type intermediate that is converted into a functionalized aromatic ring through deoxygenative aromatization. Alternative reaction pathways occur with substrates with no possible aromatization.

Investigating students’ argumentation when judging the plausibility of alternative reaction pathways in organic chemistry

Building scientific arguments is a central ability for all scientists regardless of their specific domain. In organic chemistry, building arguments is a necessary skill to estimate reaction processes in consideration of the reactivities of reaction centres or the chemical and physical properties. Moreover, building arguments for multiple reaction pathways might help students overcome the tendency toward one-reason decision-making and offer them an authentic perspective on organic processes. Reasoning about multiple alternative organic reaction pathways requires students to build arguments and then judge and weigh the plausibility of these pathways. However, students often struggle to build strong arguments and use scientific principles appropriately to justify their claims. In the present study, the argumentation patterns of 29 chemistry majors students were analysed using a simplified version of Toulmin's argumentation model (claim–evidence–reasoning). The students solved various tasks related to alternative reaction pathways of a substitution reaction. They supported their claims with evidence and justified the evidence through reasoning. We investigated (a) the extent to which the students use evidence and reasoning in their argumentation (referred to as their argumentation approach), (b) how students with different argumentation approaches rationalised changes in their initial claims, and (c) how students used reasoning to justify their arguments. The results indicate that students need further support to appropriately use evidence and reasoning and to apply conceptual knowledge to build well-grounded arguments.

Closing the gap of organic chemistry students’ performance with an adaptive scaffold for argumentation patterns

Building reasonable scientific arguments is a fundamental skill students need to participate in scientific discussions. In organic chemistry, students’ argumentation and reasoning skills on reaction mechanisms are described as indicators of success. However, students often experience challenges with how to structure their arguments, use scientific principles appropriately and engage in multivariate, instead of one-reason decision-making. Since every student experiences their individual challenges with a multitude of expectations, we hypothesise that students would benefit from scaffolding that is adapted to their needs. In the present study, we investigated how 64 chemistry students interacted with an adaptive scaffold that offered different ways of support based on students’ strengths and limitations with structural and conceptual aspects that are needed to build a scientific argument in organic chemistry. Based on the students’ performance in a diagnostic scaffold in which they were asked to judge the plausibility of alternative organic reaction pathways by building arguments, the students were assigned to one of four support groups that received a scaffold adapted to their respective needs. Comparing students’ performance in the diagnostic and adapted scaffolds allows us to determine quantitatively (1) to what extent the adaptive scaffold closes the gap in students’ performance and (2) whether an adaptive scaffold improves the students’ performance in their respective area of support (argumentation and/or concept knowledge). The results of this study indicate that the adaptive scaffold can adaptively advance organic chemistry students’ argumentation patterns.