Simplified Workup Procedure Research Articles

Sustainable Synthesis of Diamondoid Ethers by High-Temperature Ball Milling

Diamondoids have emerged as promising carbon-based nanomaterial building blocks because of their unique combination of exceptional properties and availability for selective functionalization. Until now, the chemical functionalization of diamondoids was primarily based on solution methods. However, the limited solubility of diamondoid derivatives and their tendency to sublimate at even slightly elevated temperatures made it difficult to prepare more extensive diamondoid scaffolds. Here, we present the first mechanochemical synthesis of several diamondoid ethers differing in the type, size, and number of their hydrocarbon cage subunits. We found that the efficient preparation of these ethers is enabled solely by high-temperature ball milling conditions and does not proceed under ambient conditions. When compared to the conventional synthesis of the same ether derivatives, the calculated green chemistry metrics showed the enormous sustainability benefits of the mechanochemical synthesis. The mechanochemical approach includes shorter reaction times, a green inorganic base, a simplified workup procedure, comparable or superior reaction yields, and the elimination of solvents in the synthesis. Furthermore, crystal structures obtained from single-crystal X-ray diffraction experiments confirmed the molecular structures of the target products and gave insight into their intermolecular interactions in the solid state. From the perspective of the future applicability of these materials in nanotechnology, the cost and sustainability of their preparation are paramount. We demonstrated herein that mechanochemistry is a viable option for this challenge.

Green metrics in mechanochemistry.

The development of new green methodologies and their broader adoption for promoting sustainable development in chemistry laboratories and industry play a significant role in society, due to the economic importance of chemistry and its widespread presence in everyday life. Therefore, a sustainable approach to chemistry contributes to the well-being of the worldwide population and complies with the United Nations Sustainable Development Goals (UN SDGs) and the European Green Deal. The review highlights how batch and continuous mechanochemical methods are an eco-friendly approach for organic synthesis, with a lower environmental footprint in most cases, compared to solution-based procedures. The assessment is objectively based on the use of green metrics (e.g., atom and real atom economy, E-factor, process mass intensity, material parameter recovery, Eco-scale, stoichiometric factor, etc.) and indicators (e.g. DOZN tool and life cycle assessment, LCA, studies) applied to organic transformations such as synthesis of the amide bond, carbamates, heterocycles, active pharmaceutical ingredients (APIs), porphyrins, porous organic polymers (POPs), metal- or acid-catalysed processes, multicomponent and condensation reactions, rearrangements, etc. The generalized absence of bulk solvents, the precise control over the stoichiometry (i.e., using agents in a stoichiometrically rather than in excess), and the more selective reactions enabling simplified work-up procedures are the distinctive factors, marking the superiority of mechanochemical processes over solution-based chemistry.

Sustainable and Scalable Two-Step Synthesis of Thenfadil and Some Analogs in Deep Eutectic Solvents: From Laboratory to Industry

A sustainable two-step protocol was developed for the synthesis of the antihistamine drug Thenfadil by combining a reductive amination process with a Cu-catalyzed Ullmann-type C–N coupling reaction run in environmentally responsible deep eutectic solvents (DESs), constructed from biobased compounds. Under optimized conditions, both reactions proceed smoothly under aerobic conditions and in the absence of any additional ligand, with the desired active pharmaceutical ingredient isolated in an overall reaction yield of 39% with an effective suppression of the side products arising from competitive Cu-catalyzed C–O coupling reactions. A novel and simplified workup procedure has also been set up, which avoids the need for chromatographic purification, while allowing the recovery and the recycling of the unreacted intermediate secondary amine. The potential application and the robustness of the proposed methodology has been demonstrated (a) in scale-up studies up to 50 g of substrate in 0.5 kg of DES, taking place with no decrease in the reaction yield, and (b) in the synthesis of three other ethylenediamine derivatives (Thenfadil’s analogs) like tripelennamine, methaphenilene, and thonzylamine in 39%–44% overall yield. Typical metrics applied at First and Second Pass, according to the CHEM21 Metrics Toolkit, have been calculated as well for the whole synthetic procedure of Thenfadil and results compared with those of the classical procedure.

Solid‐Supported Materials‐Based Synthesis of 2‐Substituted Benzothiazoles: Recent Developments and Sanguine Future

AbstractBenzothiazole and its derivatives have been manifested as an optimistic scaffold due to their immense biological importance. Several methodologies have been reported as modifications after the first report of 2‐substituted benzothiazole. Among them, many involve a shift from the conventional synthetic approach by utilizing different catalytic systems. Moreover, synthetic methodologies focused on improvements in terms of product yield, reaction duration, use of environmentally benign conditions and simplified workup procedures predominate among the recently developed approaches. Solid‐phase organic synthesis received considerable attention with the pioneering findings of Merrifield's solid‐phase peptide synthesis in 1963. A diverse range of organic, inorganic and organic‐inorganic substances have been utilized as polymeric solid supports in various catalytic applications. The recyclability and reusability of the immobilized catalysts over consecutive cycles establish them as an attractive alternative over conventional catalytic systems from the environment as well as industrial perspective. The present review summarizes the recent developments in the environmentally benign synthesis of benzothiazole derivatives using supported reagents. Different solid supports along with their catalytic application, mechanistic perspective and substrate tolerance have been discussed comprehensively.

Diphenylamine-Terephthalaldehyde Resin p-Toluenesulfonate (DTRT) as an Efficient Catalyst for Tetrahydropyranylation, Deprotection of Tetrahydropyranyl and Silyl Ethers, Esterification, and Transesterification

Solid acid catalysts are frequently employed in organic synthesis because of simplified work-up procedure, use of the recycled catalysts, and minimized corrosion of metallic reaction vessels. Altho...

Solvent-Free Aerobic Oxidation of Alcohols to Nitriles Catalyzed by Copper Iodide in Combination with a Quaternary Ammonium Modified TEMPO

A catalytic system consisting of N,N-dimethyl-(4-(2,2,6,6-tetramethyl-1-oxyl-4-piperidoxyl)butyl)dodecyl ammonium bromide (TEMPO-Q), CuI and 2,2′-bipyridine was established. This catalytic system (CuI/bpy/TEMPO-Q) showed high activity and good to excellent selectivity in the oxidative conversion of various alcohols to the corresponding nitriles with molecular oxygen as terminal oxidant and aqueous ammonia as nitrogen source under solvent-free conditions. Besides, the catalytic system also offers the advantages of simplified workup procedure. This protocol thus represents a greener pathway for the synthesis of nitriles from alcohols. TEMPO-Q, a compound with both a TEMPO and a quaternary ammonium moieties, in combination with copper iodide and 2,2′-bipyridine as a catalytic system performed well in the oxidation of alcohols to nitriles with molecular oxygen as terminal oxidant in aqueous ammonia under solvent-free conditions. The catalytic system not only offers the advantages of simplified workup procedure, but also has high activity and selectivity due to the phase transfer catalysis of TEMPO-Q

Solventless mechanosynthesis of N-protected amino esters.

Mechanochemical derivatizations of N- or C-protected amino acids were performed in a ball mill under solvent-free conditions. A vibrational ball mill was used for the preparation of N-protected α- and β-amino esters starting from the corresponding N-unmasked precursors via a carbamoylation reaction in the presence of di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl). A planetary ball mill proved to be more suitable for the synthesis of amino esters from N-protected amino acids via a one-pot activation/esterification reaction in the presence of various dialkyl dicarbonates or chloroformates. The spot-to-spot reactions were straightforward, leading to the final products in reduced reaction times with improved yields and simplified work-up procedures.

ChemInform Abstract: Silica—Sulfuric Acid Catalyzed Nitrodeiodination of Iodopyrazoles.

Abstract We report here the synthesis of nitropyrazoles in good to excellent yields from iodopyrazoles over silica–sulfuric acid catalyst for the first time. The present procedure require less acid, offers a simplified workup procedure, and may be applied for the nitration of a wide variety of iodoazoles in drug and pharmaceutical industries.

Solvent Free Microwave Assisted Isomerization of N‐Nitropyrazoles

AbstractThis paper describes solvent‐free isomerization of N‐nitropyrazoles under microwave irradiation to achieve a new green chemistry procedure for the synthesis of C‐ nitropyrazoles in good to excellent yields. The presented procedure requires less time, offers simplified workup procedure, needs no obnoxious solvents, and may be used for the preparation of several C‐nitropyrazoles.

Silica–Sulfuric Acid Catalyzed Nitrodeiodination of Iodopyrazoles

We report here the synthesis of nitropyrazoles in good to excellent yields from iodopyrazoles over silica–sulfuric acid catalyst for the first time. The present procedure require less acid, offers a simplified workup procedure, and may be applied for the nitration of a wide variety of iodoazoles in drug and pharmaceutical industries.

Critical re-investigation of the alditol acetate method for analysis of substituent distribution in methyl cellulose

The alditol acetate method is a common procedure for sugar analysis, also applied to determine the substituent distribution in monomer units of polysaccharide ethers like methyl cellulose by gas liquid chromatography. Consisting of several preparation and work-up steps this procedure is both time consuming and prone to side reactions that promote discrimination of single constituents, especially when no peralkylation step is performed prior to hydrolysis. As a consequence results scatter in dependence on individual treatment and conditions. In the context of this work these critical points were overcome by strict but simplified work-up procedures and using acid instead of alkaline catalyzed acetylation. Under the acidic conditions the tedious removal of borate is no longer necessary and a reduced time requirement was achieved as well as good reproducibility. Comparison with independent reference methods excluded a systematic error of the method and confirmed the results obtained. Without peralkylation, i.e. in the presence of free hydroxyl groups, another fast modification of the method using DMSO as solvent, no removal of borate, and 1-methylimidazole as catalyst for acetylation was found to produce a systematic error.

ChemInform Abstract: Synthesis of Benzonaphtho[1,4]diazepine Derivatives via the Reaction of 2‐Aminoarylbenzimidamides with 2,3‐Dichloro‐1,4‐naphthoquinone.

A series of (2)-13-(arylimino)-12,13-dihydro-5H-benzo[e]naphtho[2,3-b][1,4]diazepine-6,11-dione derivatives have been synthesised by one pot cyclisation in good yield via electron donor-acceptor complexes by reacting 2-aminoarylbenzimidamides with 2,3-dichloro-1,4-naphthoquinone. The high yield and simplified workup procedure in addition to the mild and neutral reaction conditions are the main advantages of this approach.

Synthesis of Benzonaphtho[1,4]Diazepine Derivatives via the Reaction of 2-Aminoarylbenzimidamides with 2,3-Dichloro-1,4-Naphthoquinone

A series of (Z)-13-(arylimino)-12,13-dihydro-5H-benzo[e]naphtho[2,3-b][1,4]diazepine-6,11-dione derivatives have been synthesised by one pot cyclisation in good yield via electron donor–acceptor complexes by reacting 2-aminoarylbenzimidamides with 2,3-dichloro-1,4-naphthoquinone. The high yield and simplified workup procedure in addition to the mild and neutral reaction conditions are the main advantages of this approach.

Synthesis of 2-(2-Aminophenyl)-4-arylquinazoline Derivatives by Reaction of 2-Aminoarylbenzimidamides with Isatoic Anhydride

A series of 2-(2-aminophenyl)-4-arylquinazoline derivatives (5a - j), with various 4-substituents, have been synthesized by one-pot cyclization in 66 - 79% yield by heating 2-aminoarylbenzimidamides 3a - j with isatoic anhydride (4). The high yield and simplified workup procedure, in addition to the neutral reaction conditions, are the main advantages of our approach. The structure of the product 5e was further confirmed by single-crystal X-ray structure analysis

Synthesis, characterisation and chromatographic evaluation of polyether dendrimer stationary phases

Supercritical carbon dioxide has attracted attention as a potential replacement for traditional organic solvents due to its simplified workup procedures and reduced environmental impact--providing a green chemistry approach for organic solvent-free functionalisation. In addition to the environmental benefits, the enhanced diffusivity observed in supercritical solvents can often enhance reaction rates. We have applied these valuable features to the preparation of silica-bonded stationary phases and examined their potential in liquid chromatography. We report the successful preparation and characterisation of polyether silica based on Frechet dendrimers--this significantly enhances the range of stationary-phase chemistries that can be prepared in supercritical fluids. First- and second-generation polyether silicas were prepared, characterised, end-capped and evaluated for use as stationary phases for liquid chromatography.

Mesoporous Silica SBA-15-supported Norephedrine and Ephedrine as Heterogeneous Chiral Ligands

Successful development of the homogeneous catalysts has been sometimes followed by attempts to attach the catalysts on an insoluble polymeric support. A suitably designed immobilized catalyst can retain the advantages of a heterogeneous catalyst in terms of simplified workup procedure and recyclization while maintaining reactivity and selectivity of a homogeneous catalyst. The immobilization of homogeneous species is of particular interest in the field of asymmetric catalysis since it is desirable to be able to regenerate and reuse expensive chiral catalysts. Polystyrene resin and silica gel have been most commonly used as insoluable supports for the immobilization of the catalysts. Recently, mesoporous silica SBA-15 with large uniform pore diameters and high specific surface areas have become of high interest as inorganic supports. Our interest in the field led to prepare SBA-15-supported ephedrine 1 and norephedrine 2. Herein, we report our investigation on the asymmetric addition of diethylzinc reagent to aldehydes and on the asymmetric transfer hydrogenation of ketones mediated by the supported ligands. As shown in Scheme 1, (−)-ephedrine was anchored on SBA-15 silica in a similar procedure as for silica gelsupported ephedrine 1. Treatment of SBA-15 with an excess of (3-chloropropyl)triethoxysilane in refluxing toluene gave chloropropylated SBA-15. The free silanol group was endcapped by treatment with hexamethyldisilazane (HMDS). Reaction of the samples are summarized in Table 1. The surface area was decreased considerably in the chloropropylation, but the pore diameter was not changed substantially during the modification steps. chloropropylated SBA-15 with 1.5 equiv. excess of (−)-ephedrine in refluxing toluene in the presence of 1 equiv of diisopropylethylamine afforded SBA-15-supported ephedrine 1. SBA-15-supported norephedrine 2 was also prepared from (−)-norephedrine by the same method. The degrees of functionalization were determined by weight gain or nitogen elemental analysis for the modified SBA-15. The characteristics of the two samples are summarized in Table 1. The surface area was decreased considerably during the modification, but the pore diameter was not changed substantially. With the supported ephedrine 1 in hand, we examined its catalytic efficiency in asymmetric addition of diethylzinc to aldehyde in hexane. Aldehydes were converted to the corresponding (R)-secondary alcohols with moderate ee's in high yields. The results were compared to the data previously obtained with amorphrous silica gel-supported ephedrine. As can be seen in Table 2, SBA-supported ephedrine 1 gave much higher reaction rate and better

18] Peptide synthesis using immobilized proteases

This chapter discusses peptide coupling reactions on a preparative scale in which immobilized proteases can be used with the advantage of avoiding reaction conditions, which are normally required for chemical condensations. The simplified work-up procedure that becomes possible when immobilized proteases are used, the long-term stability of the immobilized enzyme preparations, and the successful reutilization experiments are among the advantages to such an approach. The use of enzymes should provide a biological alternative to chemical peptide synthesis. There has been a revival of interest in the ability of proteolytic enzymes to catalyze the formation of peptide bonds for the synthesis of biologically active peptides and the semisynthesis of proteins. The application of enzymes for organic synthesis is increasing rapidly in importance and has been stimulated to a considerable degree by the availability of immobilized enzymes. Proteases can be immobilized without the loss of function, and the potential of immobilized proteolytic enzymes for peptide synthesis is demonstrated in the chapter.

Studies Related to the Synthesis and Properties of 1-Methylphospholene-1-Oxides

Abstract The results of a study of some of the reaction variables (time, temperature, isomer distribution, and solvents) of the 1,4-cycloaddition reaction of methylphosphonous dichloride and butadiene to form 1-methylphospholene-1-oxides are reported and a simplified work-up procedure for the latter is suggested. 31P nmr and mass spectra of the isomeric 1-methylphospholene-1-oxides are presented.