In this work, we report our approach for the synthesis of iodinated anilines by exploiting the use of ultrasound activation. We have optimised the reaction conditions by quantitatively assessing the environmental impact of each parameter and maximising its overall efficiency. The reaction medium, acidic additives, iodine sources, and reaction parameters were all optimised using different indicators, such as the E-factor, kg CO2 equivalents, and solvent section guide. Ultrasound assistance has proven to be optimally effective, allowing energy saving (almost 50 % energy consumption reduced), short reaction times (only 1 h reaction time), and selectivity. A final comparison among commonly utilised iodination methods shows the benefits in terms of sustainability of the proposed sonochemical protocol, with an E-factor reduction of at least one order of magnitude.

Within this work, we report a modular, microwave-assisted continuous-flow approach for the selective iodination of unprotected anilines, achieving control of regioselectivity, over-halogenation, and the need for a protecting group. Microwaves (MW) irradiation enables rapid and localised energy transfer to accelerate kinetics and suppress by-product formation, while the use of a recoverable reaction medium as acetonitrile-water azeotrope (ACN/H2Oaz) led to substantial improvements in both reaction mass efficiency (RME) and E-factor. Moreover, it has been demonstrated that the protocol can be telescoped by combining MW/flow iodination and the representative Mizoroki-Heck reaction in continuous flow. The protocol eliminates the need for intermediate isolation and solvent switching. This integrated process delivers functionalized products rapidly, with high selectivity and reduced waste compared to conventional protocols.

Serinol (2-amino-1,3-propanediol) is a key aminodiol used on a multiton industrial scale for the synthesis of iopamidol, a widely employed iodinated contrast agent in computed tomography (CT). Despite its small size and structural simplicity, serinol synthesis and purification remain costly and hazardous. Its isolation from process waste streams typically relies on energy-intensive techniques such as high-vacuum distillation or adsorption-desorption on ion exchange resins, followed by evaporation of large water volumes. Crystallization of serinol offers a more sustainable and potentially scalable alternative. However, systematic crystallographic studies aimed at understanding its solid-state behavior remain scarce. In this work, we report a structural investigation of serinol in its free base form and four of its salts: hemioxalate, hydrochloride, stearate, and adamantane-1-carboxylate. The high density of polar protic functional groups in serinol promotes rich supramolecular architectures, governed by extensive and directional hydrogen-bonding networks. The combined spectroscopic and crystallographic analysis supports the formation of ammonium salts and highlights the structural factors governing their solid-state organization and supramolecular assembly. These insights into the solid-state structure of serinol derivatives lay the groundwork for the rational design of crystallization-based purification of serinol in industrial settings.

Biodiesel, developed as an alternative to natural fossils, is produced by a trans-esterification reaction. The main co-product of this reaction is represented by glycerol, whose production in 2020 exceeded 6 times the current demand. A consequence of the spreading of biodiesel market was a drop of glycerol price. This versatile biomass-derived compound can be used as an important raw material for the manufacture of valuable chemicals including dihydroxyacetone (DHA), which is the most high-valued glycerol derived product. Despite all the research devoted to achieve selective oxidation of the secondary alcohol group, this issue remains a scientific challenge. Among several routes for glycerol valorization, electrochemistry is an attractive process, as it is discussed in this review. After a short introduction, which describes non-electrochemical methods, electrochemical oxidations with precious (based on Pt, Pd, Au and Ag) and non-precious metal electrocatalysts is discussed, with a specific focus on selectivity towards DHA.

Chemical reactions are conventionally carried out in solution, wherein solvents assume a pivotal role in facilitating the dissolution of reagents and thereby enabling molecular interactions. However, this conventional approach is associated with substantial solvent consumption, waste production, and environmental and safety concerns, while also necessitating protracted reaction times. In recent years, there has been an increase in the study of various mechanochemical methods, with the flow-through mechanochemical approach via reactive extrusion (REX) emerging as one of the most promising alternatives. This process employs screws (single, twin or multiple) to generate mechanical energy (shear, compression and friction) to drive chemical reactions, offering precise control over temperature, mixing and residence time. Typically, REX is performed with minimal or no solvents, which significantly reduces its environmental impact. Furthermore, it ensures shorter reaction times and higher yields. In this review, a comprehensive analysis is conducted on the role of screw configuration, temperature control, and residence time in optimising the outcomes of various reaction types.

Digadoglucitol is an extracellular macrocyclic dinuclear gadolinium-based contrast agent (GBCA) based on the association of two [Gd(HP-DO3A)] units conjugated through a spacer containing the glucamine moiety. It displays a relaxivity per Gd that is 2 to 3 times higher than the most currently used GBCAs, allowing the use of reduced doses while ensuring a noninferior image contrast. Its high relaxivity is the result of a rational design aimed at exploiting the intramolecular catalysis of the prototropic exchange of the coordinated -OH groups as well as the second sphere contribution brought about by the presence of the hydroxyl functionalities on glucamine. Digadoglucitol maintains the excellent kinetic and thermodynamic properties of the parent [Gd(HP-DO3A)] with an SAP/TSAP ratio of 2/3. A HPLC workup yielded three fractions of diastereoisomers based on the chirality of the 2-hydroxypropyl pendants with similar relaxometric and stability properties. From pH 5 to 9, the deprotonated glucamine nitrogen acts as base to catalyze the prototropic exchange of the coordinating -OH group bringing an enhancement of 1.5-2.0 mM-1 s-1 of the observed relaxivity with respect to the expected value for a q = 1 complex of a similar formula weight. Biodistribution and the Magnetic Resonance Imaging pharmacokinetics of digadoglucitol resulted very similarly to those found for [Gd(BT-DO3A)].

Mesocyclic chelating agents such as AAZTA and its derivatives have been recently reported to overcome the relatively low thermodynamic stability of metal complexes of acyclic chelating agents and the slow complexation kinetics of macrocyclic chelating agents. This work reports the preparation of a spirobicyclic hexadentate AAZTA-like chelating agent (TRASUTA) and the investigation of the thermodynamic, kinetic, and structural properties of the corresponding chelates with the PET-relevant Ga3+ and selected metal ions. A combination of analytical techniques allowed identification of a coordination isomerization process, involving the coordinating side arms and the inversion of a nitrogen atom and leading to lower thermodynamic and kinetic inertness with respect to mononuclear mesocyclic analogues. The bicyclic system of TRASUTA retains significant dynamics despite the conformational constraint imposed by the spiro-fusion, resulting in a lower stability of the corresponding metal chelates.

Micellar catalysis is becoming an increasingly versatile tool to carry out a wide range of organic transformations using water as the reaction medium. The approach was recently found to be effective also in the case of water sensitive organics such as acyl chlorides. This finding is of great relevance for the manufacturing of challenging substrates such as the known iodinated contrast agent iopamidol, requiring the use of aprotic dipolar solvents (DMF, NMP, DMAc) in the key amidation step of an acyl dichloride intermediate with serinol. These solvents are subjected to an increasing regulatory pressure due to safety and environmental concerns. We show that the amidation step can be straightforwardly performed in water containing the industrial surfactant Triton X-100, provided that the employed amine is not water soluble. Accordingly, we developed suitable lipophilic serinol derivatives that, after amidation and hydrolysis, directly gave iopamidol in a one-pot process.

AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid) is a mesocyclic chelating agent forming stable complexes with several metal ions. Over the past 20 years since its inception, AAZTA and its bifunctional derivatives have gained a growing role in several applications ranging from MRI contrast agents to diagnostics and nuclear medicine. The recent market restrictions applied to nitroethane preclude the easy preparation of AAZTA, prompting the search for a suitable alternative. In this work, we report the synthesis of two structural analogs (AAZTA-Bn and AAZTA-Et) from commercially available chemicals and the thermodynamic and kinetic study of their complexing ability towards selected metal ions. A comparison of the complexing properties of AAZTA-Bn and AAZTA-Et with the former AAZTA allows us to identify the possible heir of this efficient chelating agent.

Magnetic resonance imaging (MRI) is a technique that employs strong magnetic fields and radio frequencies to generate detailed images of the body’s interior. In oncology patients, gadolinium-based contrast agents (GBCAs) are frequently administered to enhance the visualization of tumors. Those contrast agents are gadolinium chelates, characterized by high stability that prevents the release of the toxic gadolinium ion into the body. This work is part of the research for alternative nanoscaled GBCAs. Following the synthesis and characterization of zinc hexacyanoferrate nanoparticles, gadolinium ions were successfully incorporated into a hexacyanoferrate-based matrix, deposited on FTO-coated glass used as working electrode in a gadolinium salt solution, by applying a fixed potential determined through cyclic voltammetry studies. The presence of gadolinium inside the matrix was confirmed by EDX.

An unexpected nitro group displacement during a nitro-Mannich reaction led to the one-pot formation of the octahydro-2H-pyrazino[1,2-a]pyrazine core, representing the shortest access to date to this pharmacologically relevant heterobicyclic system. A mechanistic hypothesis is suggested and supported by specific experiments and HRMS analysis of reaction mixtures.

Optical imaging (OI) is gaining increasing attention in medicine as a non-invasive diagnostic imaging technology and as a useful tool for image-guided surgery. OI exploits the light emitted in the near-infrared region by fluorescent molecules able to penetrate living tissues. Cyanines are an important class of fluorescent molecules and by their conjugation to peptides it is possible to achieve optical imaging of tumours by selective targeting. We report here the improvements obtained in the synthesis of DA364, a small fluorescent probe (1.5 kDa) prepared by conjugation of pentamethine cyanine Cy5.5 to an RGD peptidomimetic, which can target tumour cells overexpressing integrin αvβ3 receptors.

Optical imaging (OI) is gaining increasing attention in medicine as a non-invasive diagnostic imaging technology and as a useful tool for image-guided surgery. OI exploits the light emitted in the near-infrared region by fluorescent molecules able to penetrate living tissues. Cyanines are an important class of fluorescent molecules and by their conjugation to peptides it is possible to achieve optical imaging of tumours by selective targeting. We report here the improvements obtained in the synthesis of DA364, a small fluorescent probe (1.5 kDa) prepared by conjugation of pentamethine cyanine Cy5.5 to an RGD peptidomimetic, which can target tumour cells overexpressing integrin alpha v beta 3 receptors.

The simple modification of the hydroxypropyl arm in Gd(HP-DO3A) complex allows to achieve an increased relaxivity by the activation of the intramolecular catalysis of the proton exchange process.

Eu(HP-DO3A) is present in solution as a mixture of two diastereoisomers whose alcoholic groups are the source of the mobile protons for the CEST effect. The exchange is base catalyzed. Two novel EuIII complexes of HP-DO3A-like ligands containing an amino or a carboxylate functionality in the proximity of the -OH groups showed the occurrence of intramolecular catalysis of the prototropic exchange. New insights into the role of the intramolecular proton exchange on the CEST properties have been gained.

The application of metal ions for diagnostic and therapeutic purposes is nowadays a well consolidated practice in current medicine. Gd3+ for magnetic resonance imaging (MRI), Ga3+ for positron emission tomography (PET), In3+ for single photon emission computed tomography (SPECT) and the beta-emitter Lu3+ for tumour treatment are the most representative examples. Metal ions employed in medicine must be administered as stable and inert metal complexes, mainly for safety reasons and targeting purposes. In the last years many new chelating agents have been designed, prepared and studied in order to improve properties such as thermodynamic stability, kinetic inertness, target selectivity and many other characteristics of complexes thereof. The structure of these chelating agents is almost invariably based on linear or macrocyclic backbones. The chelating agent AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraa cetic acid), featuring a mesocyclic 7-membered ring has found steadily increasing attention since its inception in the early 2000s and is now an affirmed alternative for the formation of stable complexes with several metal ions. The scope of this review is to provide the reader with a comprehensive survey on the synthesis and the applications of AAZTA and its derivatives developed in the last two decades. (C) 2021 Elsevier B.V. All rights reserved.

Mechanochemical activation in planetary ball mills generates energy that is effective for the efficient, solvent-free syntheses of several types of organic molecules, including active pharmaceutical ingredients and diagnostic agents. X-ray-based procedures are the most commonly used of all diagnostic imaging techniques, because they offer several advantages, such as deep penetration, high resolution, and low cost. Iodinated X-ray contrast agents have long been used in medicine to facilitate and improve the acquisition of images by radiographic modalities. Iopamidol was the first agent developed in the field of nonionic X-ray contrast agents for imaging diagnosis and is still one of the most frequently used worldwide. We herein report an experimental investigation aimed to design a mechanochemical synthesis of Iopamidol, with the double goals of process intensification and either the elimination or significant reduction of the use of the high-boiling-point and reprotoxic solvent N,N-dimethylacetamide. The greener wet milling protocol gave Iopamidol in higher yields using safer solvents such as acetonitrile and N,N-dimethyloctanamide.

The set-up of reversible binding interactions between the hydrophobic region of macrocyclic gadolinium based contrast agents and SO3−/OH containing pyrene derivatives provides new insights for pursuing relaxivity enhancement of MRI contrast agents.

A convenient synthesis of two novel macrocyclic bifunctional chelating agents (BFCAs), formally derived from the well-known ligands DO3A and DOTA by selective replacement of one carboxymethyl side arm with a phosphonomethyl residue, is reported.

Two structurally constrained chelators based on a fused bicyclic scaffold, 4-amino-4-methylperhydro-pyrido[1,2-a][1,4]diazepin-N,N ',N '-triacetic acids [(4R*,10aS*)-PIDAZTA (L1) and (4R*,10aR*)-PIDAZTA (L2)], were designed for the preparation of Ga-III-based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected [Ga(L2)OH] species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of Ga-III into the cavity of L2. Fast and efficient formation of the Ga-III chelates at room temperature was observed at pH values between 7 and 8, which enables Ga-68 radiolabeling under truly physiological conditions (pH 7.4).