Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• surfactant and silica as the carrier providing the most promising results. Solid grinding was also employed, removing the need for a solvent and accelerating the reaction rate to 20 minutes and product yields to 99% without the need for conventional heating. Replacement of the Lewis acid or the silica

• the C=O bond. Thus, an innovative approach on nanocatalysis was introduced, incorporating solid grinding in catalyst-free conditions with the challenge of a high catalyst loading and lack of aliphatic aldehydes or ketones being utilized as substrates for the formation of their respective BIMs [118

• ]. In 2021, this methodology was reiterated by Wu et al., who conducted the reaction in the exact same conditions, utilizing the ball milling technique, instead of solid grinding, which slightly reduced reaction times and the catalyst loading necessary from 500 mg to 300 mg [119]. The substrate scope

Facile approach to N,O,S-heteropentacycles via condensation of sterically crowded 3H-phenoxazin-3-one with ortho-substituted anilines

• Eugeny Ivakhnenko,
• Vasily Malay,
• Pavel Knyazev,
• Nikita Merezhko,
• Nadezhda Makarova,
• Oleg Demidov,
• Gennady Borodkin,
• Andrey Starikov and
• Vladimir Minkin

Beilstein J. Org. Chem. 2024, 20, 336–345, doi:10.3762/bjoc.20.34

• . Results and Discussion We found that a convenient way toward 6,8-di-tert-butyl-2-(arylamino)-3H-phenoxazin-3-ones 4 involves the short-term heating (30 min) of a molten mixture of 1 and an arylamine at 250 °C, followed by purification of the products by column chromatography. No preliminary grinding of

Optimizing reaction conditions for the light-driven hydrogen evolution in a loop photoreactor

• Pengcheng Li,
• Daniel Kowalczyk,
• Johannes Liessem,
• Mohamed M. Elnagar,
• Dariusz Mitoraj,
• Radim Beranek and
• Dirk Ziegenbalg

Beilstein J. Org. Chem. 2024, 20, 74–91, doi:10.3762/bjoc.20.9

• Supporting Information File 1, Figure S2b), while maintaining a continuous flow of N2 in the headspace through a septum. The resulting suspension exhibited a yellow/greenish color and was subsequently washed with deionized water 3–5 times, followed by drying at 70 °C overnight and grinding. The synthesized

Facile access to pyridinium-based bent aromatic amphiphiles: nonionic surface modification of nanocarbons in water

• Lorenzo Catti,
• Shinji Aoyama and
• Michito Yoshizawa

Beilstein J. Org. Chem. 2024, 20, 32–40, doi:10.3762/bjoc.20.5

• groups. Aromatic micelle (PA-CH3)n was furthermore found to be stable for at least six days at room temperature in the dark (see Figure S37 in Supporting Information File 1). Noncovalent encircling of various nanocarbons in water By employing a simple grinding–sonication protocol, various nanocarbons

• grinding (3 min) and sonication (30 min) protocol provided a clear yellow aqueous solution of (PA-OCH3)n·(g-C3N4)m. The formation of the host–guest structure was confirmed by UV–visible analysis, which showed a new absorption band around 312 nm (Figure 6b). This result showcased the ability of amphiphile

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• to reduce energy consumption and the carbon footprint. The traditional heating techniques used to synthesize compounds are being replaced by contemporary green alternative energy systems, such as photocatalysis, microwave irradiation, ultrasonic irradiation, grinding, and ball milling processes

Mechanochemical solid state synthesis of copper(I)/NHC complexes with K₃PO₄

• Ina Remy-Speckmann,
• Birte M. Zimmermann,
• Mahadeb Gorai,
• Martin Lerch and
• Johannes F. Teichert

Beilstein J. Org. Chem. 2023, 19, 440–447, doi:10.3762/bjoc.19.34

• approaches have in common that the conjugated acid of the added base is a liquid. In the literature, the improvement of mechanochemical syntheses by addition of small amounts of a liquid have been reported (LAG, liquid-assisted grinding) [43]. However, in our case, the formation of small amounts of liquid

Inclusion complexes of the steroid hormones 17β-estradiol and progesterone with β- and γ-cyclodextrin hosts: syntheses, X-ray structures, thermal analyses and API solubility enhancements

• Alexios I. Vicatos,
• Zakiena Hoossen and
• Mino R. Caira

Beilstein J. Org. Chem. 2022, 18, 1749–1762, doi:10.3762/bjoc.18.184

• to prepare complexes by spray-drying, freeze-drying, co-grinding, kneading and solution-based crystallization; however, this modest type of ‘fingerprinting’ has not generally been pursued further to deduce important features of CD complexes such as the crystal packing of the CD host molecules

• kneading experiments (co-grinding of the respective hosts and guests with water as a medium), the complex identities being subsequently determined unequivocally by powder X-ray diffraction (PXRD). Authentic CD complex formation was deduced from close correlation between the angular peak positions of the

Dissecting Mechanochemistry III

• Lars Borchardt and
• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1454–1456, doi:10.3762/bjoc.18.150

• , Colombia 10.3762/bjoc.18.150 In the past ten years, the use of mechanochemical techniques (e.g., grinding, milling, extrusion, pulsed ultrasonication, resonant acoustic mixing, etc.) have widespread in the field of organic chemistry, enabling the development of new and more sustainable protocols for

• for the halogenation of organic substrates. For example, Banerjee and co-workers reported the mono-, di-, and trihalogenation of aromatics by controlling the stoichiometry of the N-halosuccinimide (NXS) and PEG-400 as the grinding auxiliary in a mechanical grinder (Scheme 1a) [3]. N-Halosuccinimides

Mechanochemical synthesis of unsymmetrical salens for the preparation of Co–salen complexes and their evaluation as catalysts for the synthesis of α-aryloxy alcohols via asymmetric phenolic kinetic resolution of terminal epoxides

• Shengli Zuo,
• Shuxiang Zheng,
• Jianjun Liu and
• Ang Zuo

Beilstein J. Org. Chem. 2022, 18, 1416–1423, doi:10.3762/bjoc.18.147

• , University of Illinois at Chicago, Chicago, Illinois 60612, United States 10.3762/bjoc.18.147 Abstract In this paper, we report the mechanochemical synthesis of unsymmetrical salens using grinding and ball milling technologies, respectively, both of which were afforded in good yield. The chelating effect of

• ]. Inspired by the mechanochemical chemistry technology to simplify chemical processes and eliminate the use of organic solvents, salen compounds have been synthesized by the “green” grinding strategy previously [30][31][32][33][34][35][36][37][38][39]. Herein, we report a one-pot two-step mechanochemical

• ), half equivalent of 5-bromo (Br‒), 5-methyl, 4-diethylamino (Et2N‒), 3,5-dichloro (Cl‒), or 3,5-di-tert-butyl (t-Bu‒) salicylaldehydes (red moieties in Scheme 2), and trace methanol, followed by grinding for 20 minutes for the second reaction step to complete, monitored by TLC. A trace amount of

Polymer and small molecule mechanochemistry: closer than ever

• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1225–1235, doi:10.3762/bjoc.18.128

• mechanochemistry. However, in recent times, manual grinding and ball milling techniques (Figure 1b and Figure 1c) have also been used as alternatives to activate mechanophores incorporated in polymers. Such an application complements the original use of ball milling to generate mechanoradicals through homolytic

• ). Importantly, the BMPF mechanophore was also proven to be thermally stable up to 110 °C, which supports the conclusion that the mechanical force caused by the grinding was responsible for the activation of the BMPF mechanophores [28]. Comparative studies between ultrasound and ball milling have also

• also provided mounting evidence that ball milling and manual grinding, techniques typically used in small molecule mechanochemistry, could trigger chemical reactions in multimechanophore polymers [30], nonsymmetric mechanophores embedded in polymer systems [31], and mixtures of mechanochromic polymers

From amines to (form)amides: a simple and successful mechanochemical approach

• Federico Casti,
• Rita Mocci and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

• ]. In general, mechanochemistry refers to studying solid-state chemical changes promoted by external mechanical energy, such as grinding or milling. A deeper understanding of its mechanistic aspects laid the basis for further growth in this topic, opening new routes to more efficient mechanochemical

• ). Switching to sodium sulfate as a grinding additive significantly enhanced the reaction performance (Table 1, entries 3 and 4). At this stage, we wondered, if using a more efficient dehydrating agent would be mandatory for the reaction to occur. Therefore, we turned our attention toward p-tosylimidazole (p

• efficiently took place even in the presence of a catalytic amount of p-Ts-Im without significant differences in the reactivity. This data led us to question the effective role of p-Ts-Im in promoting the formylation reaction, which could exploit its role as the sole solid auxiliary of grinding. p

Automated grindstone chemistry: a simple and facile way for PEG-assisted stoichiometry-controlled halogenation of phenols and anilines using N-halosuccinimides

• Dharmendra Das,
• Akhil A. Bhosle,
• Amrita Chatterjee and
• Mainak Banerjee

Beilstein J. Org. Chem. 2022, 18, 999–1008, doi:10.3762/bjoc.18.100

• catalyst-free halogenation of phenols and anilines via liquid-assisted grinding using PEG-400 as the grinding auxiliary. A series of mono-, di-, and tri-halogenated phenols and anilines was synthesized in good to excellent yields within 10–15 min in a chemoselective manner by controlling the stoichiometry

• reaction time, and mild reaction conditions are a few noticeable merits of this environmentally sustainable mechanochemical protocol. Keywords: automated grinding; chemoselectivity; mechanochemistry; N-bromosuccinimide; PEG-400; regioselectivity; stoichiometry-controlled halogenation; Introduction Aryl

• mechanical grinding or milling, has garnered massive interest among chemists owing to its green attributes like solvent-free, clean, atom economic, and time-efficient, and has been identified by the IUPAC as one of 10 world-changing technologies [47]. While milling has received more focus, the simpler form

Complementarity of solution and solid state mechanochemical reaction conditions demonstrated by 1,2-debromination of tricyclic imides

• Petar Štrbac and
• Davor Margetić

Beilstein J. Org. Chem. 2022, 18, 746–753, doi:10.3762/bjoc.18.75

• dust. This combination of metals worked well, and the best conditions were obtained with the addition of a small amount of THF (liquid assisted grinding, LAG) [22], η = 0.5 μL·mg−1 (Table 1, entry 19). In contrast, the solution reaction catalyzed by Zn/Cu dust was totally ineffective (Table 1, entry 21

• ), even with the agitation by ultrasound (Table 1, entry 22). The ratios of side-products vary depending on the reaction conditions (Table S1, Supporting Information File 1). The endo-product 15 was dominant in the neat grinding experiment (Table 1, entry 1), whereas phthalimide 16 dominates when NaCl was

• employed as grinding auxiliary (Table 1, entries 2 and 4). The addition of ZnBr2 (which is formed in the reaction and postulated that it could facilitate the oxa-ring opening of 15 to 16) [13] did not notably increase the amount of phthalimide, indicating that rather deoxygenation leading to 16 is

A trustworthy mechanochemical route to isocyanides

• Francesco Basoccu,
• Federico Cuccu,
• Federico Casti,
• Rita Mocci,
• Claudia Fattuoni and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 732–737, doi:10.3762/bjoc.18.73

• mg of NaCl as a grinding auxiliary (0.5 h, 36 Hz, Table S1 in Supporting Information File 1). So, we then looked for a solid base to use in place of triethylamine, avoiding the use of further additives. Unluckily, neither solid inorganic bases such Na, K, and Cs carbonates [37], Mg and Ba oxides, nor

• are high for EDGs (2d,e), while from good to high for the EWGs (2b,c). To confirm what has been previously stated, isonitrile 2a was recovered in lower yields than compound 2e (Scheme 3). At the end of the reaction, adding 0.5 equivalents of water for a 15 minute grinding step was necessary to

Mechanochemical halogenation of unsymmetrically substituted azobenzenes

• Dajana Barišić,
• Mario Pajić,
• Ivan Halasz,
• Darko Babić and
• Manda Ćurić

Beilstein J. Org. Chem. 2022, 18, 680–687, doi:10.3762/bjoc.18.69

• using N-halosuccinimides as the halogen source under neat grinding or liquid-assisted grinding conditions in a ball mill has been described. Depending on the azobenzene substrate used, halogenation of the C–H bonds occurs in the absence or only in the presence of PdII catalysts. Insight into the

• -bromosuccinimide (NBS) under neat grinding (NG) and liquid-assisted grinding (LAG) conditions in a ball mill [51]. Insight into the dynamics of the formation of reaction intermediates and products was obtained by in situ Raman monitoring that provided information on the nature of the catalytically active PdII

• proceeds by electrophilic cleavage with neutral NBS or the hydrogen bond complex NBS∙∙∙TsOH as a bromine source. Here we present the mechanochemical selective halogenation of unsymmetrically substituted azobenzenes by NXS (X = Cl, Br, or I). The liquid-assisted grinding of para-halogenated derivatives of

DDQ in mechanochemical C–N coupling reactions

• Shyamal Kanti Bera,
• Rosalin Bhanja and
• Prasenjit Mal

Beilstein J. Org. Chem. 2022, 18, 639–646, doi:10.3762/bjoc.18.64

• conditions: reactants were milled at 21 Hz in a 25 mL milling jar containing one stainless-steel grinding ball (15 mm in diameter). Optimization of the reaction conditions.a Supporting Information Supporting Information File 46: Experimental details, characterization data, copies of NMR spectra and X-ray

Multi-faceted reactivity of N-fluorobenzenesulfonimide (NFSI) under mechanochemical conditions: fluorination, fluorodemethylation, sulfonylation, and amidation reactions

• José G. Hernández,
• Karen J. Ardila-Fierro,
• Dajana Barišić and
• Hervé Geneste

Beilstein J. Org. Chem. 2022, 18, 182–189, doi:10.3762/bjoc.18.20

• ; sulfonylation; Introduction Mechanosynthesis of organic molecules and materials using mechanochemical techniques such as ball milling, extrusion, grinding, etc. [1][2][3] have enabled the development of known and new chemical transformations in a more sustainable fashion [4]. Commonly, mechanochemical

In-depth characterization of self-healing polymers based on π–π interactions

• Josefine Meurer,
• Julian Hniopek,
• Johannes Ahner,
• Michael Schmitt,
• Jürgen Popp,
• Stefan Zechel,
• Kalina Peneva and
• Martin D. Hager

Beilstein J. Org. Chem. 2021, 17, 2496–2504, doi:10.3762/bjoc.17.166

• literature [31]. In the first step, the sample was hot pressed (at 150 °C, at about 2 t for 3 minutes) in a special manufactured mold. The pressed polymer samples were embedded in epoxy resin consisting of Epoxy Resin L and Hardener CL from R&G Faserverbundstoffe GmbH, followed by grinding of the sample with

Particle size effect in the mechanically assisted synthesis of β-cyclodextrin mesitylene sulfonate

• Stéphane Menuel,
• Sébastien Saitzek,
• Eric Monflier and
• Frédéric Hapiot

Beilstein J. Org. Chem. 2020, 16, 2598–2606, doi:10.3762/bjoc.16.211

• considerable attention as it may be unique in features to selectively direct the reaction pathway. In the continuation of our work on the synthesis of modified cyclodextrins (CDs) via mechanochemical activation, we sought to discriminate the contribution of supramolecular effects and grinding during the course

• the reaction. In this study, we show that grinding β-CD reduces the particles size over time down to a limit of 167 nm. The granulometric composition remains rather invariant for grinding times over 1 h. Each type of β-CD particles reacted with mesitylenesulfonyl chloride (MtsCl) to produce β-CDMts

• . Contrary to what could be intuitively anticipated, smaller particles did not lead to the highest conversions. The impact of grinding on the conversion was limited. Interestingly, the proportion of β-CDMts mono-substituted on the primary face significantly increased over time when the reaction was carried

The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

• Patrizia Andreozzi,
• Lorenza Tamberi,
• Elisamaria Tasca,
• Gina Elena Giacomazzo,
• Marta Martinez,
• Mirko Severi,
• Marco Marradi,
• Stefano Cicchi,
• Sergio Moya,
• Giacomo Biagiotti and
• Barbara Richichi

Beilstein J. Org. Chem. 2020, 16, 2272–2281, doi:10.3762/bjoc.16.188

• reactions, and even in nanomaterials preparation [1][2][3][4][5]. Indeed, solid-state mechanochemical methodologies are a viable alternative to traditional syntheses in solution [4] for the preparation of complex molecules, either under solvent-free conditions, named ‘neat grinding’, or in nearly solvent

• -free conditions, e.g., liquid-assisted grinding (LAG), slurries, and homogenous solutions. Although there are compounds that can only be achieved by conventional solution-based methods, mechanochemistry offers some important advantages over conventional bulk synthesis. These advantages have become more

• by grinding Dex and 1 (in roughly equimolar amounts) at 25 Hz for 90 minutes, in a 10 mL mixer mills using one stainless-steel ball (∅ = 1.0 cm). The product, a red powder (Dex-1b, Scheme 1, route B), was easily recovered from the jar and solubilized in DMSO. Then, the conjugate (Dex-1b, Scheme 1

Mechanochemical green synthesis of hyper-crosslinked cyclodextrin polymers

• Alberto Rubin Pedrazzo,
• Fabrizio Caldera,
• Marco Zanetti,
• Silvia Lucia Appleton,
• Nilesh Kumar Dhakar and
• Francesco Trotta

Beilstein J. Org. Chem. 2020, 16, 1554–1563, doi:10.3762/bjoc.16.127

• drive and control chemical reactions, for example, using grinding or milling to transfer energy to chemical bonds [11]. Mechanochemical transformations are well established in inorganic chemistry and they are easily transferable to an industrial scale [12][13]. Mechanochemistry in organic chemistry

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

Halide metathesis in overdrive: mechanochemical synthesis of a heterometallic group 1 allyl complex

• Ross F. Koby,
• Nicholas R. Rightmire,
• Nathan D. Schley,
• Timothy P. Hanusa and
• William W. Brennessel

Beilstein J. Org. Chem. 2019, 15, 1856–1863, doi:10.3762/bjoc.15.181

• thermodynamic driving forces, intra-alkali metal exchange is one of the most challenging metathetical exchanges to attempt, especially when conducted without solvent. Nevertheless, grinding together the bulky potassium allyl [KA']∞ (A' = [1,3-(SiMe3)2C3H3]–) and CsI produces the heterometallic complex [CsKA'2

• , which promotes reactions through grinding or milling with no, or minimal, use of solvents, has been used in conjunction with halide metathesis to form organometallic compounds of the transition metals [3][4][5][6][7] and both s- [8][9] and p-block [10][11] main group elements. The extent to which the

• coordination polymer. Within these experimental parameters, the general reaction in Equation 5 was examined. When n = 1, a reaction carried to completion would result in full metal exchange, with partial exchange the outcome for any larger values of n. The experimental protocol involved grinding various ratios

Metal-free mechanochemical oxidations in Ertalyte^® jars

• Andrea Porcheddu,
• Francesco Delogu,
• Lidia De Luca,
• Claudia Fattuoni and
• Evelina Colacino

Beilstein J. Org. Chem. 2019, 15, 1786–1794, doi:10.3762/bjoc.15.172

• grinding mixture [51]. Two different mechanisms have been postulated for similar reactions in homogeneous phase: one occurs under acidic conditions, while the other works better in a basic medium through a cyclic dipolar mechanism (Scheme 2) [52][53]. On the contrary, under ball-milling conditions, it is

• reactions of hydantoins [41][59]. However, also using this oxidant, we observed low conversions (31%) and the formation of significant amounts of byproducts, mainly halides and olefins (elimination byproducts). The use of liquid-assisted grinding (LAG) procedures [60][61][62] by adding small quantities of

Mechanochemical Friedel–Crafts acylations

• Mateja Đud,
• Anamarija Briš,
• Iva Jušinski,
• Davor Gracin and
• Davor Margetić

Beilstein J. Org. Chem. 2019, 15, 1313–1320, doi:10.3762/bjoc.15.130

• a few examples of FCRs employing manual grinding: reserpine acylation with AlCl3 [6] and acylation reaction of aromatics [7]. One of the reasons for this scarcity is the hygroscopic nature of the aluminum trichloride catalyst [8][9][10][11][12] when exposed to air humidity. This problem could be

• grinding additives to improve mass transfer and prevent pasting of the reaction mixture [26][27][28] (Table 1, entries 5–8) was detrimental to reaction yields. The addition of a small amount of solvents which was reported to facilitate several ball milling reactions (liquid assisted grinding, LAG) [29][30

• , in which acylation was accompanied with the cleavage of the methoxy group [43][44][45]. A striking advantage of the automated ball milling over manual grinding [46] is evident in the reaction of anthracene with phthalic anhydride which gave no product by manual grinding and the yield of the toluene