Routine Synthesis Research Articles

Fortuitous Enantiomeric Self-Rectification of an Unreported Partial Racemisation in the Synthesis of a Chiral Phosphoric Acid: A Warning to Practitioners.

Racemisation without Consequence: MOM deprotection of an ether intermediate during a routine synthesis of phosphoric acid 1 promoted partial racemisation of the product BINOL 5. Surprisingly, however, after phosphorylation of the partially racemised BINOL, enantiopure acid 1 was isolated. Further inspection revealed that during phosphorylation, unhydrolysed racemic phosphorochloridate 6 precipitated, thus restoring homochirality in the product phosphoric acid 1. Moreover, MOM deprotection partial racemisation was avoided by conducting reactions at lower temperatures for no longer than the required deprotection time, and/or by application of other deprotection conditions from the literature.

Mild and efficient catalyst for nitrodopamine synthesis: from milligram to multi-gram scales

Sodium hydrogen sulfate is proposed as a mild acidic catalyst for the dopamine nitration with sodium nitrite. This reagent system gives nitrodopamine in high yield and excellent purity and is suitable for routine synthesis from milligram to multi-gram scale.

Metal‐Organic Frameworks: Direct Synthesis by Organic Acid‐Etching and Reconstruction Disclosure as Oxygen Evolution Electrocatalysts

AbstractMetal‐organic frameworks (MOFs) have emerged as promising oxygen evolution reaction (OER) electrocatalysts. Chemically bonded MOFs on supports are desirable yet lacking in routine synthesis, as they may allow variable structural evolution and the underlying structure‐activity relationship to be disclosed. Herein, direct MOF synthesis is achieved by an organic acid‐etching strategy (AES). Using π‐conjugated ferrocene (Fc) dicarboxylic acid as the etching agent and organic ligand, a series of MFc‐MOF (M=Ni, Co, Fe, Zn) nanosheets are synthesized on the metal supports. The crystal structure is studied using X‐ray diffraction and low‐dose transmission electron microscopy, which is quasi‐lattice‐matched with that of the metal, enabling in situ MOF growth. Operando Raman and attenuated total reflectance Fourier transform infrared spectroscopy disclose that the NiFc‐MOF features dynamic structural rebuilding during OER. The reconstructed one showing optimized electronic structures with an upshifted total d‐band center, high M−O bonding state occupancy, and localized electrons on adsorbates indicated by density functional theory calculations, exhibits outstanding OER performance with a fairly low overpotential (130 mV at 10 mA cm−2) and good stability (144 h). The newly established approach for direct MOF synthesis and structural reconstruction disclosure stimulate the development of more prudent catalysts for advancing OER.

Metal-Organic Frameworks: Direct Synthesis by Organic Acid-Etching and Reconstruction Disclosure as Oxygen Evolution Electrocatalysts.

Metal-organic frameworks (MOFs) have emerged as promising oxygen evolution reaction (OER) electrocatalysts. Chemically bonded MOFs on supports are desirable yet lacking in routine synthesis, as they may allow variable structural evolution and the underlying structure-activity relationship to be disclosed. Herein, direct MOF synthesis is achieved by an organic acid-etching strategy (AES). Using π-conjugated ferrocene (Fc) dicarboxylic acid as the etching agent and organic ligand, a series of MFc-MOF (M=Ni, Co, Fe, Zn) nanosheets are synthesized on the metal supports. The crystal structure is studied using X-ray diffraction and low-dose transmission electron microscopy, which is quasi-lattice-matched with that of the metal, enabling in situ MOF growth. Operando Raman and attenuated total reflectance Fourier transform infrared spectroscopy disclose that the NiFc-MOF features dynamic structural rebuilding during OER. The reconstructed one showing optimized electronic structures with an upshifted total d-band center, high M-O bonding state occupancy, and localized electrons on adsorbates indicated by density functional theory calculations, exhibits outstanding OER performance with a fairly low overpotential (130 mV at 10 mA cm-2 ) and good stability (144 h). The newly established approach for direct MOF synthesis and structural reconstruction disclosure stimulate the development of more prudent catalysts for advancing OER.

Automated Synthesis of [68Ga]Ga-FAPI-46 on a Scintomics GRP Synthesizer.

[68Ga]Ga-FAPI-46 is a radiolabelled fibroblast activation protein inhibitor that selectively binds to fibroblast activation protein (FAP), which is overexpressed by cancer-associated fibroblasts (CAFs) in the tumour microenvironment. In recent years, radiolabelled FAP inhibitors (FAPIs) are becoming increasingly important in cancer diagnostics and also for targeted radionuclide therapy. Because of the increasing demand for radiolabelled FAPIs, automating the synthesis of these compounds is of great interest. In this work, we present a newly programmed automatic synthesis process of [68Ga]Ga-FAPI-46 on a Scintomics GRP module using two Galli Ad generators as a radionuclide source. Dedicated cassettes for the labelling of 68Ga-peptides were used without any modifications. The generators were connected via a three-way valve to the module and eluted automatically over a strong cation exchange (SCX) cartridge by using the vacuum pump of the synthesis module, eliminating the need to transfer the eluates into a separate vial. After a reaction step in HEPES buffer, the compound was purified by solid-phase extraction (SPE) over a Sep-Pak Light C18 cartridge. The evaluation of 10 routine syntheses of [68Ga]Ga-FAPI-46 resulted in a radiochemical yield of 72.6 ± 4.9%. The radiochemical purity was 97.6 ± 0.3%, and the amount of free gallium-68 and colloid was <2%. The final product fulfilled the quality criteria, which were adapted from relevant monographs of the European Pharmacopoeia (Ph. Eur.). This work presents the successful preparation of multiple doses of [68Ga]Ga-FAPI-46 in a GMP-compliant automated process for clinical use.

Solution combustion synthesis of high-entropy metal spinel oxide as oxygen evolution reaction catalyst

High-entropy metal spinel oxide (HEO) is proved to be a promising oxygen evolution reaction (OER) catalyst with high catalytic performance and stability. A short routine synthesis process based on solution combustion synthesis was proposed to prepare (Co0.25Ni0.25Mn0.25Zn0.25)Fe2O4 spinel HEO in this work. During the process, the products were rapidly synthesized and melted due to the high-temperature reaction, and then quickly crystallized on the surface of nickel foam to form a nano-structure coating. With the aid of nano-scale spinel structure, the overpotential of non-activation HEO electrode reaches 276 mV at the current density of 10 mA·cm−2, and after 100 h i-t test, it can be further reduced to 230 mV, which proves the high activity of OER catalysis. The promotion of OER catalytic performance can be attributed to the surface reconstruction caused by the selective element leaching and the boost of oxygen vacancy, leading to the formation of nano-scale flocculation around spinel core after the long-term OER process. This work indicates a special casting process for functional materials and explores the application of rapid crystallization.

Syntheses of three-dimensional catenanes under kinetic control

Although catenanes comprising two ring-shaped components can be made in large quantities by templation, the preparation of three-dimensional (3D) catenanes with cage-shaped components is still in its infancy. Here, we report the design and syntheses of two 3D catenanes by a sequence of SN2 reactions in one pot. The resulting triply mechanically interlocked molecules were fully characterized in both the solution and solid states. Mechanistic studies have revealed that a suit[3]ane, which contains a threefold symmetric cage component as the suit and a tribromide component as the body, is formed at elevated temperatures. This suit[3]ane was identified as the key reactive intermediate for the selective formation of the two 3D catenanes which do not represent thermodynamic minima. We foresee a future in which this particular synthetic strategy guides the rational design and production of mechanically interlocked molecules under kinetic control.

6-Bromo-N-(3-(difluoromethyl)phenyl)quinolin-4-amine

A routine synthesis was performed to furnish the title compound which incorporates a versatile difluoromethyl group on the aniline substitution of a 4-anilinoquinoline kinase inhibitor motif. In addition, the small molecule crystal structure (of the HCl salt) was solved, which uncovered that the difluoromethyl group was disordered within the packing arrangement and also a 126.08(7)° out of plane character between the respective ring systems within the molecule. The compound was fully characterized with 1H/13C-NMR and high-resolution mass spectra (HRMS), with the procedures described.

Solution Phase Peptide Synthesis: The Case of Biphalin.

Solution phase synthesis was the first developed and the only method for peptide synthesis until the solid phase peptide synthesis (SPPS) introduced by Merrifield revolutionized the way peptides and their analogues are prepared nowadays. However, some peptides because of their chemical structure cannot be synthetized by SPPS, and the "old school" technique is still favorable to make them. Biphalin is a good example. It was first synthesized by Lipkowski almost 40years ago as a dimeric analogue of enkephalin in which two tetra-amino acid fragments (Tyr-D-Ala-Gly-Phe-) are joined tail to tail by a hydrazide bridge. The synthesis of this octapeptide (Tyr-D-Ala-Gly-Phe-NH-NH←Phe←Gly←D-Ala←Tyr) and its analogues requires synthesis in solution because routine synthesis on a polymeric support is not possible. Biphalin shows high affinity at both μ and δ opioid receptors and produces a more robust spinal analgesia than morphine after intrathecal administration. Although biphalin and its analogues have been already deeply investigated, a complete description for its analgesic activity is not yet available.Here, we present a detailed procedure for the solution phase synthesis of biphalin.

One-Pot Sequential Multistep Transformation of α,β-Unsaturated Trifluoromethyl Ketones: Facile Synthesis of Trifluoromethylated 2-Pyridones

A one-pot transformation of α,β-unsaturated trifluoromethyl ketones with 2-(phenylsulfinyl)acetamide to give trifluoromethylated 2-pyridones is realized. The reaction proceeds under mild conditions and involves multiple steps in an expeditious and controlled sequence to provide efficient access to a broad range of trifluoromethylated 2-pyridones in moderate to high yields. Moreover, further synthetic manipulations permit the routine synthesis of a diverse array of trifluoromethylated pyridines with good efficiency.

Dynamic and Responsive DNA-like Polymers.

The synthesis of thiolactone monomers that mimic natural nucleosides and engage in robust ring opening polymerizations (ROP) is herein described. As each repeat unit contains a thioester functional group, dynamic rearrangement of the polymer is feasible via thiol-thioester exchange, demonstrated here by depolymerization of the polymers and coalescing of two polymers of different molecular weight or chemical composition. This approach constitutes the first step toward a platform that enables for the routine synthesis of sequence controlled polymers via dynamic template directed synthesis.

Toward Automated Enzymatic Synthesis of Oligosaccharides.

Oligosaccharides together with oligonucleotides and oligopeptides comprise the three major classes of natural biopolymers. Automated systems for oligonucleotide and oligopeptide synthesis have significantly advanced developments in biological science by allowing nonspecialists to rapidly and easily access these biopolymers. Researchers have endeavored for decades to develop a comparable general automated system to synthesize oligosaccharides. Such a system would have a revolutionary impact on the understanding of the roles of glycans in biological systems. The main challenge to achieving automated synthesis is the lack of general synthetic methods for routine synthesis of glycans. Currently, the two main methods to access homogeneous glycans and glycoconjugates are chemical synthesis and enzymatic synthesis. Enzymatic glycosylation can proceed stereo- and regiospecifically without protecting group manipulations. Moreover, the reaction conditions of enzyme-catalyzed glycosylations are extremely mild when compared to chemical glycosylations. Over the past few years methodology toward the automated chemical synthesis of oligosaccharides has been developed. Conversely, while automated enzymatic synthesis is conceptually possible, it is not as well developed. The goal of this survey is to provide a foundation on which continued technological advancements can be made to promote the automated enzymatic synthesis of oligosaccharides.

3-Aminopropyltrimethoxysilane Mediated Controlled Synthesis of Functional Noble Metal Nanoparticles and Its Multi-Metallic Analogues in the Presence of Small Organic Reducing Agents for Selective Application

ABSTRACTSynthesis of functional noble metal nanoparticles (AuNPs, AgNPs, and PdNPs) and its multi-metallic analogues have received greater attentions for selective applications. The selective applications of the these nanoparticles essentially requires the processability of as synthesized nanoparticles in the medium of desired polarity index that manifest the potential exploration of nanomaterial based design in targeted area. The use of conventional reducing and stabilizing agents during routine synthesis of such nanoparticles are not suitable with the system of practical significance and require additional reagents that limit the optimum activity of nanomaterial in targeted design. According there is a challenging issue in the synthesis of noble metal nanoparticles that allow the controlled synthesis of such nanoparticles involving same starting material with option to control the processability of as generated nanomaterial in the system of desired polarity index. The present report is focused on such challenging issues. We have found that 3-aminopropyltrimethoxysilane (3-APTMS) capped noble metal cations can be precisely converted into respective monometallic, bimetallic and trimetallic analogues and can be made processable in water at one end having controlled option to reversed the processability of the same in the toluene as a function of small organic reducing agents. The organic reducing agents not only convert 3-APTMS-capped noble cations into respective nanoparticles but also control the processability of the as generated nanoparticles in the systems of desired polarity index. The similar process also allows the synthesis of function bimetallic and tri-metallic nanoparticles. The role of cyclohexanone, formaldehyde and acetone in the presence of 3-APTMS is reported.

Shock Synthesis of Five-component Icosahedral Quasicrystals

Five-component icosahedral quasicrystals with compositions in the range Al68–73Fe11–16Cu10–12Cr1–4Ni1–2 were recently recovered after shocking metallic CuAl5 and (Mg0.75Fe0.25)2SiO4 olivine in a stainless steel 304 chamber, intended to replicate a natural shock that affected the Khatyrka meteorite. The iron in those quasicrystals might have originated either from reduction of Fe2+ in olivine or from the stainless steel chamber. In this study, we clarify the shock synthesis mechanism of icosahedral quasicrystals through two new shock recovery experiments. When CuAl5 and Fe2+-bearing olivine were isolated in a Ta capsule, no quasicrystals were found. However, with only metallic starting materials, numerous micron-sized five-component icosahedral quasicrystals, average composition Al72Cu12Fe12Cr3Ni1, were found at the interface between CuAl5 and stainless steel, demonstrating nucleation of quasicrystals under shock without any redox reaction. We present detailed characterization of recovered quasicrystals and discuss possible mechanisms for generating sufficiently high temperatures to reach melting with relatively weak shocks. We discuss the implications of our five-component quasicrystal for the stability of quasicrystals, which have previously only been considered in alloy systems with four or fewer components. Even small amounts of additional metals expand the stability range of the icosahedral phase and facilitate routine syntheses without extraordinary precision in preparation of starting mixtures.

ChemInform Abstract: A General Palladium‐Catalyzed Hiyama Cross‐Coupling Reaction of Aryl and Heteroaryl Chlorides.

AbstractThe reaction can be run with low catalyst loadings (0.05‐1 mol%).

PEMFC: Study of the Routine Synthesis of a New Series of SPAES for Use as Proton Exchange Membrane (PEM)

SummaryPoly(arylene ether sulfone)s sulfonated are promising materials for application as proton exchange membranes (PEM) due to their good electrochemical properties. In this study, the synthesis procedure was studied aiming at the production of a new copolymer for use as a PEM. In addition, considering the inefficiency of the recovery route described in the literature, the influence of each monomer in the copolymer recovery from the polymerization solution was evaluated. The monomers were characterized by Fourier Transform Infrared Spectroscopy (FTIR) and Thermogravimetry (TG), confirming their structure and purity. The four copolymers, produced as a result of different monomers’ molar ratios, were recovered in different ways. While those with sulfonic groups were recovered with acidic solution, the other polymers without pending sulfonic groups were recovered with deionized water. The copolymers were characterized by FTIR, wherein the copolymers characteristic bands were observed, including those characteristic of diaryl ethers, evidence of the proposed polymerization mechanism.

A General Palladium-Catalyzed Hiyama Cross-Coupling Reaction of Aryl and Heteroaryl Chlorides.

A general palladium-catalyzed Hiyama cross-coupling reaction of aryl and heteroaryl chlorides with aryl and heteroaryl trialkoxysilanes by a Pd(OAc)2 /L2 catalytic system is presented. A newly developed water addition protocol can dramatically improve the product yields. The conjugation of the Pd/L2 system and the water addition protocol can efficiently catalyze a broad range of electron-rich, -neutral, -deficient, and sterically hindered aryl chlorides and heteroaryl chlorides with excellent yields within three hours and the catalyst loading can be down to 0.05 mol % Pd for the first time. Hiyama coupling of heteroaryl chlorides with heteroaryl silanes is also reported for the first time. The reaction can be easily scaled up 200 times (100 mmol) without any degasification and purification of reactants; this facilitates the practical application in routine synthesis.

Design and automated production of 11C-alpha-methyl-l-tryptophan (11C-AMT)

11C-alpha-methyl-l-tryptophan ([11C]AMT), a tryptophan metabolism PET tracer, has successfully been employed for brain serotonin pathway and indoleamine 2,3-dioxygenase (IDO) pathway related tumor imaging. We here report a reliable, automated procedure for routine synthesis of [11C]AMT based on an Eckert and Ziegler Modular-Lab system. The semi-preparative HPLC was incorporated into the system to improve chemical purity and specific activity. The 6-step radiosynthesis followed by HPLC-purification provided [11C]AMT in 5.3±1.2% (n=6, non-decay-corrected) overall radiochemical yield with radiochemical purity >99% and specific activity of 35–116GBq/μmol. Usually, 2.95±0.65GBq (n=6, EOS) patient ready dose was produced from about 55.5GBq [11C]CO2 in 50min.

Dielectric Properties of Undoped and Li-doped Pb(Fe1/2Nb1/2)O3 Ceramics Sintered from Mechanochemically Synthesized Powders

Optimal sintering temperature of PbFe1/2Nb1/2O3 (PFN) ceramics is 1120–1150°C, but ceramics sintered in this temperature range have low resistivity and high losses. Mechanochemical synthesis allows one to lower the optimal sintering temperature of PFN ceramics down to 1000°C, however dielectric losses remain high and the permittivity exhibits large frequency dispersion. In the present work it has been found that similar to the case of the routine solid state synthesis, Li doping enables one to reduce dramatically the losses of the PFN ceramics obtained by sintering the mechanochemically synthesized powders.

Influence of carbon chain length on the synthesis and yield of fatty amine-coated iron-platinum nanoparticles.

Iron oxide nanoparticles are among the most widely used and characterized magnetic nanoparticles. However, metal alloys such as superparamagnetic iron-platinum particles (SIPPs), which have better magnetic properties, are receiving increased attention. Scalable techniques to routinely synthesize SIPPs in bulk need further study. Here, we focus on the role played by the fatty amine ligand in the formation of the bimetallic FePt nanocrystal. More specifically, we compare the effect of varying lengths of fatty amine ligands on the shape, structure, uniformity, composition, and magnetic properties of the SIPPs. We synthesized SIPPs by employing a ‘green’ thermal decomposition reaction using fatty amine ligands containing 12 to 18 carbons in length. Greater fatty amine chain length increased the polydispersity, particle concentration, iron concentration, and the stability of the SIPPs. Additionally, longer reflux times increased the diameter of the particles, but decreased the iron concentration, suggesting that shorter reaction times are preferable. Fourier transform infrared spectroscopy of the SIPPs indicates that the ligands are successfully bound to the FePt cores through the amine group. Superconducting quantum interference device magnetometry measurements suggest that all of the SIPPs were superparamagnetic at room temperature and that SIPPs synthesized using tetradecylamine had the highest saturation magnetization. Our findings indicate that the octadecylamine ligand, which is currently used for the routine synthesis of SIPPs, may not be optimal. Overall, we found that using tetradecylamine and a 30-min reflux reaction resulted in optimal particles with the highest degree of monodispersity, iron content, stability, and saturation magnetization.PACS81.07.-b; 75.75.Fk; 61.46.Df