Preparation of Dinitrogen Trioxide for Organic Synthesis: A Phase Equilibrium Approach.

Dinitrogen trioxide (N2O3) is a potent nitrosating agent featured with high reactivity and appealing atom economy. Because of its instability and the entanglement of chemical and phase equilibria, N2O3 has rarely been utilized in organic synthesis as a stock reagent with well-defined composition. In this review, the preparations of pure N2O3 and its concentrated solution (>0.1 M) are discussed from the aspect of phase equilibrium. Understanding the physical and chemical characteristics of N2O3, along with how reaction parameters (temperature, pressure, molar ratio) interact, plays a crucial role in managing the concentration of N2O3 in the liquid phase. This control holds practical significance in achieving quantitative reactions.

Revisiting the Paradigm of Reaction Optimization in Flow with a Priori Computational Reaction Intelligence.

The use of micro/meso-fluidic reactors has resulted in both new scenarios for chemistry and new requirements for chemists. Through flow chemistry, large-scale reactions can be performed in drastically reduced reactor sizes and reaction times. This obvious advantage comes with the concomitant challenge of re-designing long-established batch processes to fit these new conditions. The reliance on experimental trial-and-error to perform this translation frequently makes flow chemistry unaffordable, thwarting initial aspirations to revolutionize chemistry. By combining computational chemistry and machine learning, we have developed a model that provides predictive power tailored specifically to flow reactions. We show its applications to translate batch to flow, to provide mechanistic insight, to contribute reagent descriptors, and to synthesize a library of novel compounds in excellent yields after executing a single set of conditions.

Intensified Continuous Flow Process for the Scalable Production of Bio-Based Glycerol Carbonate.

A subtle combination of fundamental and applied organic chemistry toward process intensification is demonstrated for the large-scale production of bio-based glycerol carbonate under flow conditions. The direct carbonation of bio-based glycidol with CO2 is successfully carried out under intensified flow conditions, with Barton's base as a potent homogeneous organocatalyst. Process metrics for the CO2 coupling step (for the upstream production, output: 3.6 kg day-1 , Space Time Yield (STY): 2.7 kg h-1 L-1 , Environmental factor (E-factor): 4.7) outclass previous reports. High conversion and selectivity are achieved in less than 30 s of residence time at pilot scale with a stoichiometric amount of CO2 . Supporting DFT computations reveal the unique features of the mechanism in presence of Brønsted bases.

Continuous Flow Upgrading of Selected C2-C6 Platform Chemicals Derived from Biomass.

The ever increasing industrial production of commodity and specialty chemicals inexorably depletes the finite primary fossil resources available on Earth. The forecast of population growth over the next 3 decades is a very strong incentive for the identification of alternative primary resources other than petro-based ones. In contrast with fossil resources, renewable biomass is a virtually inexhaustible reservoir of chemical building blocks. Shifting the current industrial paradigm from almost exclusively petro-based resources to alternative bio-based raw materials requires more than vibrant political messages; it requires a profound revision of the concepts and technologies on which industrial chemical processes rely. Only a small fraction of molecules extracted from biomass bears significant chemical and commercial potentials to be considered as ubiquitous chemical platforms upon which a new, bio-based industry can thrive. Owing to its inherent assets in terms of unique process experience, scalability, and reduced environmental footprint, flow chemistry arguably has a major role to play in this context. This review covers a selection of C2 to C6 bio-based chemical platforms with existing commercial markets including polyols (ethylene glycol, 1,2-propanediol, 1,3-propanediol, glycerol, 1,4-butanediol, xylitol, and sorbitol), furanoids (furfural and 5-hydroxymethylfurfural) and carboxylic acids (lactic acid, succinic acid, fumaric acid, malic acid, itaconic acid, and levulinic acid). The aim of this review is to illustrate the various aspects of upgrading bio-based platform molecules toward commodity or specialty chemicals using new process concepts that fall under the umbrella of continuous flow technology and that could change the future perspectives of biorefineries.

On Demand Flow Platform for the Generation of Anhydrous Dinitrogen Trioxide and Its Further Use in N-Nitrosative Reactions.

Dinitrogen trioxide (N2 O3 ) is a powerful and efficient nitrosating agent that comes with an unprecedented atom economy. However, the synthetic application of N2 O3 is still underdeveloped mostly due to its inherent instability and the lack of reliable protocols for its preparation. This paper presents an open-source setup and procedure for the on-demand generation of anhydrous N2 O3 solution (up to 1 M), which can be further used for reactions under batch and flow conditions. The accuracy and stability of N2 O3 concentration are guaranteed with the absence of head-space in the setup and with the synchronization of the gas flows. The reliability of this protocol is demonstrated by >30 worked examples in the nitrosative synthesis of heterocycles-a library of structurally diverse benzotriazoles and sydnones. Kinetic and mechanistic aspects of the N-nitrosative steps are also explored.

Native Chemical Ligation and Extended Methods: Mechanisms, Catalysis, Scope, and Limitations.

The native chemical ligation reaction (NCL) involves reacting a C-terminal peptide thioester with an N-terminal cysteinyl peptide to produce a native peptide bond between the two fragments. This reaction has considerably extended the size of polypeptides and proteins that can be produced by total synthesis and has also numerous applications in bioconjugation, polymer synthesis, material science, and micro- and nanotechnology research. The aim of the present review is to provide a thorough mechanistic overview of NCL and extended methods. The most relevant properties of peptide thioesters, Cys peptides, and common solvents, reagents, additives, and catalysts used for these ligations are presented. Mechanisms, selectivity and reactivity are, whenever possible, discussed through the insights of computational and physical chemistry studies. The inherent limitations of NCL are discussed with insights from the mechanistic standpoint. This review also presents a palette of O, S-, N, S-, or N, Se-acyl shift systems as thioester or selenoester surrogates and discusses the special molecular features that govern reactivity in each case. Finally, the various thiol-based auxiliaries and thiol or selenol amino acid surrogates that have been developed so far are discussed with a special focus on the mechanism of long-range N, S-acyl migrations and selective dechalcogenation reactions.

Understanding chemical interaction between phosphonate-derivative molecules and a silver surface cluster in SERS: a combined experimental and computational approach.

The interaction between phosphonate functions and a silver surface cluster is investigated using Surface-Enhanced Raman Spectroscopy (SERS). Changing the functional group (methylphosphonic acid based molecule) by studying the effect of protonation, methylation and substitution of the side chain with amine and carboxylate functions enabled us to modulate the chemical interactions between the different functions and the metal cluster. We find that the adsorption energy of the methylphosphonic acid decreases with the protonation, the methylation processes and the substitution of the side chain. In all cases, only the deprotonated phosphonate forms are SERS active. To understand how the molecules interact with the nanoparticle, the electronic structure, adsorption energies and Raman spectra were computed for molecules adsorbed on a 20 atom silver cluster representing a nanoparticle surface. The qualitative agreement between computed static Raman spectra and experimental SERS spectra makes it possible to determine stable geometries of the analyte-silver cluster complexes and to characterize the adsorption modes. The findings presented here provide a framework for designing analytical developments based on SERS for simultaneous detection of phosphonated molecules, including pesticides such as glyphosate, creating practical opportunities in key areas such as environmental and water resource in situ monitoring.

"NOTA-PRGD2 and NODAGA-PRGD2 : Bioconjugation, characterization, radiolabelling, and design space".

This work reports on the development of amide bond bioconjugation for the production of -NOTA and -NODAGA PRGD2 using batch strategy and microfluidic reactor technology. The final radiolabelling step was fully optimized using Design of Experiments and Design Space approaches, hence targeting robust labelling yields in routine. Optimal labelling conditions were defined in sodium acetate buffer as 168 µg/mL peptide concentration, 4.9 pH, 47.5°C temperature, and 12.5-minute reaction time. Upon optimization, the Gallium-68 radiolabelling was fully automated. All the work was designed to be compliant to the GMP environment and to support the pharmaceutical scale-up.

Continuous-Flow N-Heterocyclic Carbene Generation and Organocatalysis.

Two methods were assessed for the generation of common N-heterocyclic carbenes (NHCs) from stable imidazol(in)ium precursors using convenient and straightforward continuous-flow setups with either a heterogeneous inorganic base (Cs2CO3 or K3PO4) or a homogeneous organic base (KN(SiMe3)2). In-line quenching with carbon disulfide revealed that the homogeneous strategy was most efficient for the preparation of a small library of NHCs. The generation of free nucleophilic carbenes was next telescoped with two benchmark NHC-catalyzed reactions; namely, the transesterification of vinyl acetate with benzyl alcohol and the amidation of N-Boc-glycine methyl ester with ethanolamine. Both organocatalytic transformations proceeded with total conversion and excellent yields were achieved after extraction, showcasing the first examples of continuous-flow organocatalysis with NHCs.

Continuous-flow thermolysis for the preparation of vinylglycine derivatives.

Syn sulfoxide elimination was carried out under continuous-flow conditions in a mesofluidic thermolysis reactor. The design of the reactor enabled accurate control of reaction time and conditions, affording a convenient scale-independent procedure for the production of N,C-protected vinylglycine derivatives. Thermolysis at 270 °C under 1000 psi of pressure in superheated toluene enabled typical daily outputs ranging from 11 to 46 g per day with excellent selectivities and ee (>97%). The various competitive reaction pathways were studied and rationalized according to a computational study.

Continuous Flow Synthesis of Functional Isocyanate-Free Poly(oxazolidone)s by Step-Growth Polymerization.

Flow chemistry presents many advantages over batch processes for the fast and continuous production of polymers under more robust, safer, and easily scalable conditions. Although largely exploited for chain-growth polymerizations, it has rarely been applied to step-growth polymerizations (SGP) due to their inherent limitations. Here, we report the facile and fast preparation of an emerging class of nonisocyanate polyurethanes, i.e., CO2-based poly(oxazolidone)s, by SGP in continuous flow reactors. Importantly, we also demonstrate that functional poly(oxazolidone)s are easily prepared by telescoping a flow module where SGP occurs with reagents able to simultaneously promote two polymer derivatizations in a second module, i.e., dehydration followed by cationic thiol-ene to yield poly(N,S-acetal oxazolidone)s. The functional polymer is produced at a high rate and functionalization degree, without requiring the isolation of any intermediates. This work demonstrates the enormous potential of flow technology for the facile and fast continuous production of functional polymers by SGP.

New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model.

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3-5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

Will the next generation of chemical plants be in miniaturized flow reactors?

For decades, a production paradigm based on centralized, stepwise, large scale processes has dominated the chemical industry horizon. While effective to meet an ever increasing demand for high value-added chemicals, the so-called macroscopic batch reactors are also associated with inherent weaknesses and threats; some of the most obvious ones were tragically illustrated over the past decades with major industrial disasters and impactful disruptions of advanced chemical supplies. The COVID pandemic has further emphasized that a change in paradigm was necessary to sustain chemical production with an increased safety, reliable supply chains and adaptable productivities. More than a decade of research and technology development has led to alternative and effective chemical processes relying on miniaturised flow reactors (a.k.a. micro and mesofluidic reactors). Such miniaturised reactors bear the potential to solve safety concerns and to improve the reliability of chemical supply chains. Will they initiate a new paradigm for a more localized, safe and reliable chemical production?

A new benzotriazole-mediated stereoflexible gateway to hetero-2,5-diketopiperazines.

Open chain Cbz-L-aa(1)-L-Pro-Bt (Bt=benzotriazole) sequences were converted into either the corresponding trans- or cis-fused 2,5-diketopiperazines (DKPs) depending on the reaction conditions. Thermodynamic tandem cyclization/epimerization afforded selectively the corresponding trans-DKPs (69-75%). Complementarily, tandem deprotection/cyclization led to the cis-DKPs (65-72%). A representative set of proline-containing cis- and trans-DKPs has been prepared. A mechanistic investigation, based on chiral HPLC, kinetics, and computational studies enabled a rationalization of the results.

Long-range intramolecular S → N acyl migration: a study of the formation of native peptide analogues via 13-, 15-, and 16-membered cyclic transition states.

The intramolecular long-range S → N acyl migration via 13-, 15-, and 16-membered cyclic transition states to form native tetra- and pentapeptide analogues was studied on S-acylcysteine peptides containing ß- or γ-amino acids. The pH-dependency study of the acyl migration via a 15-membered cyclic transition state indicated that the reaction is favored at a pH range from 7.0 to 7.6. Experimental observations are supported by structural and computational investigations.

A convenient synthesis of difficult medium-sized cyclic peptides by Staudinger mediated ring-closure.

Novel, efficient and mild preparation of 7- and 8-membered cyclic di- and 10-membered cyclic tripeptides containing α-, ß- or γ-amino acid residues is effected by a Staudinger-mediated ring closure. Medium-sized cyclic di- and tripeptides--recognized as difficult targets--were obtained in moderate to good yields according to a straightforward sequence. Empirical force-field calculations were undertaken to determine their conformational behaviors and showed high levels of similarity with X-ray results. A computational study at the B3LYP/6-31+G** level of theory afforded information regarding the impact of the sequence, ring-size and substitution on the activation barriers for the cyclization of azido peptide thioesters.

Electron-deficient 1- and 2-azabuta-1,3-dienes: a comprehensive survey of their synthesis and reactivity.

Electron-deficient 1- and 2-azabuta-1,3-dienes are reagents intrinsically able to provide a wide range of cyclic and acyclic N-containing building blocks. Depending on their substitution, they behave as dienes for Diels-Alder reactions, as partners for [4+1], [3+2], [2+2]-cycloadditions, for aziridinations and as electrophiles for 1,2 and 1,4-additions. Nowadays, they are a very versatile family of compounds, despite their usual instability and complex reactivity. Four decades of research in this challenging area are reviewed in this critical review: their synthetic aspects and their reactivity towards a wide range of dienophiles, dipoles and nucleophiles are described as well. The introduction focuses on their electronic properties in order to get a clear picture of their reactivity (190 references).

Perspectives for the Upgrading of Bio-Based Vicinal Diols within the Developing European Bioeconomy.

The previous decade has witnessed a drastic increase of European incentives aimed at pushing forward the transition from an exclusively petro-based economy toward a strong and homogeneous bio-based economy. Since 2012, numerous programs have been developed to stimulate and promote research and innovation relying on sustainable and renewable resources. Terrestrial biomass is a virtually infinite reservoir of biomacromolecules, the biorefining of which provides platform molecules of low complexity yet with tremendous industrial potential. Among such bio-based platform molecules, polyols and, more specifically, molecules featuring vicinal diols have gained tremendous interest and have stimulated an increasing research effort from the chemistry and chemical engineering communities. This Review revolves around the most promising process conditions and technologies reported since 2012 that specifically target bio-based vicinal diols and promote their transformation into value-added molecules of wide industrial interest, such as olefins, epoxides, cyclic carbonates, and ketals.

A perspective on automated advanced continuous flow manufacturing units for the upgrading of biobased chemicals toward pharmaceuticals.

Biomass is a renewable, almost infinite reservoir of a large diversity of highly functionalized chemicals. The conversion of biomass toward biobased platform molecules through biorefineries generally still lacks economic viability. Profitability could be enhanced through the development of new market opportunities for these biobased platform chemicals. The fine chemical industry, and more specifically the manufacturing of pharmaceuticals is one of the sectors bearing significant potential for these biobased building blocks to rapidly emerge and make a difference. There are, however, still many challenges to be dealt with before this market can thrive. Continuous flow technology and its integration for the upgrading of biobased platform molecules for the manufacturing of pharmaceuticals is foreseen as a game-changer. This perspective reflects on the main challenges relative to chemical, process, regulatory and supply chain-related burdens still to be addressed. The implementation of integrated continuous flow processes and their automation into modular units will help for tackling with these challenges.

Development and validation of an integrated microfluidic device with an in-line Surface Enhanced Raman Spectroscopy (SERS) detection of glyphosate in drinking water.

Glyphosate, also known as N-(phosphonomethyl)glycine, is one of the most widely used herbicides in the world. However, the controversy surrounding the toxicity of glyphosate and its main breakdown product, aminomethylphosphonic acid (AMPA), remains a serious public concern. Therefore, there is a clear need to develop a rapid, sensitive and automated alternative method for the quantification of glyphosate and AMPA. In this context, surface enhanced Raman spectroscopy (SERS) coupled with a microfluidic system for the determination of glyphosate in tap water was developed, optimized and validated. The design of the microfluidic configuration for this application was built constructed to integrate the synthesis of the SERS substrate through to the detection of the analyte. To optimize the microfluidic setup, a design of experiments approach was used to maximize the SERS signal of glyphosate. Subsequently, an approach based on the European guideline document SANTE/11312/2021 was used to validate the method in the range of 78-480 µg/L using the normalized band intensities. The limit of detection and quantification obtained for glyphosate were 40 and 78 µg/L, respectively. Recoveries were in the range 76-117%, while repeatability and intra-day reproducibility were ≤17%. Finally, the method was also tested for the determination of AMPA in tap water matrix and for the simultaneous detection of AMPA and glyphosate.