Solid-state mechanochemical ω-functionalization of poly(ethylene glycol)

• Michael Y. Malca,
• Pierre-Olivier Ferko,
• Tomislav Friščić and
• Audrey Moores

Beilstein J. Org. Chem. 2017, 13, 1963–1968, doi:10.3762/bjoc.13.191

• yielded the best results with both molecular weight (Mw) mPEGs. NaOH is a strong base, thus favoring deprotonation of mPEG over weaker bases to facilitate subsequent tosylation. The deprotonation step (Scheme 1a) also generates water locally, which may have led to liquid-assisted grinding (LAG) conditions

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• a paste that does not mix well and results in low reaction conversions. Clearly the presence of such a material may have a knock-on effect on any multistep process. Liquid-assisted grinding (LAG) is another phenomenon that can provide enhancement to the reaction outcome and again should be

• considered for use in a multistep format [14][15][16]. Having recently begun our research programme in the area of mechanochemistry, we were particularly intrigued by the compatibility of differing chemical forms and additives across a two-step, one-grinding jar solventless process. To investigate this we

• designed a 2-step reaction related to our recent work on liquid assisted grinding effects of the fluorination of 1,3-dicarbonyl compounds, in which the dicarbonyl will initially form a pyrazolone in the first reaction prior to undergoing difluorination in the second step (Scheme 1) [17]. Notably this

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• global warming, it is important to minimize the usage of hazardous chemicals in both academic and industrial research, elimination of waste, and possibly recycle them to obtain better results in greener fashion. The studies under the area of mechanochemistry which cover the grinding chemistry to ball

• techniques like ball-milling or hand grinding are considered to be promising candidates in solvent-free synthesis [10][11]. Mechanochemical methods deal with chemical transformations induced by mechanical energy, such as compression, shear, or friction [12]. Wilhelm Ostwald, a Russian-German chemist who

• changes of substances of all states of aggregation due to the influence of mechanical energy”. Moreover, according to IUPAC, a mechano-chemical reaction is a ‘Chemical reaction that is induced by the direct absorption of mechanical energy’ and with a note ‘Shearing, stretching, and grinding are typical

Solvent-free sonochemistry: Sonochemical organic synthesis in the absence of a liquid medium

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 1850–1856, doi:10.3762/bjoc.13.179

• . Keywords: mechanochemistry; organic; solvent-free; sonochemistry; synthesis; Introduction Mechanochemistry is typically regarded as the grinding of solid reagents in a ball mill (or mortar and pestle), to instigate and accelerate chemical reactions [1]. In recent years, mechanochemistry has evolved to

• ninhydrin and dimedone. Both systems were investigated in the complete absence of solvent and without the presence of any grinding media (such as inert silica beads) to help mediate the reaction. The aldol reaction was successfully carried out by twin screw extrusion, as I have reported previously [6]. The

• . Stopping the reaction to grind this solid form into a free flowing solid would lead to inaccurate results as mechanical energy in the form of grinding could have a significant effect on the outcome of the reaction. Therefore, as the application of heat may have an effect on the conversion to product and

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• highlighted. While the literature is abundant on their preparation in conventional solution environment, it was not until the advent of solvent-free manual grinding using a mortar and pestle and automated ball milling that new synthetic opportunities have opened. The mechanochemical approach not only has

• transferred from the solution into the solid state. In a typical solid state organic synthesis, reactants are simply ground together in a mortar using a pestle, where the mechanical force is exerted by a hand (manual grinding) [15]. Whereas mechanochemistry [16], at least on the laboratory scale, is usually

• , plastic) and even milling atmosphere allows reproducible solid state syntheses in such instruments. The progress made over the past 15 years has transformed grinding or milling from a purely physical tool for mechanical processing into a synthetic method of choice when one wishes to conduct chemical

Mechanochemical N-alkylation of imides

• Anamarija Briš,
• Mateja Đud and
• Davor Margetić

Beilstein J. Org. Chem. 2017, 13, 1745–1752, doi:10.3762/bjoc.13.169

• addition of a small amount of solvent for LAG (liquid-assisted grinding) [27] was tested as well. The results are collected in Table 1. The best results were achieved by the use of K2CO3 as base, with large excess of dibromide and carbonate. Within one hour of milling, 1 was quantitatively converted to the

• mono-alkylated product 3 which was and isolated in 88% yield by simple work-up consisting of dissolving the reaction mixture in dichloromethane and washing with water (Table 1, entry 8). Under these milling conditions, an excess of inorganic base may have helped by acting as a grinding auxiliary. A

• organic solvents. Ex situ IR spectroscopy (ATR) of milling of imides 11–17 with K2CO3 was used for monitoring the reaction progress, which showed for instance, that potassium phthalimide [29] was formed after one hour of grinding (Figure 2). This salt was, without isolation, subjected to further milling

Mechanochemical enzymatic resolution of N-benzylated-β³-amino esters

• Mario Pérez-Venegas,
• Gloria Reyes-Rangel,
• Adrián Neri,
• Jaime Escalante and
• Eusebio Juaristi

Beilstein J. Org. Chem. 2017, 13, 1728–1734, doi:10.3762/bjoc.13.167

• . Several chiral organocatalysts and even enzymes have proved to be resistant to milling conditions, which allows for rather efficient enantioselective transformations under ball-milling conditions. The present article reports the first example of a liquid-assisted grinding (LAG) mechanochemical enzymatic

Encaging palladium(0) in layered double hydroxide: A sustainable catalyst for solvent-free and ligand-free Heck reaction in a ball mill

• Wei Shi,
• Jingbo Yu,
• Zhijiang Jiang,
• Qiaoling Shao and
• Weike Su

Beilstein J. Org. Chem. 2017, 13, 1661–1668, doi:10.3762/bjoc.13.160

• milling (HSBM) conditions at room temperature. The effects of milling-ball size, milling-ball filling degree, reaction time, rotation speed and grinding auxiliary category, which would influence the yields of mechanochemical Heck reactions, were investigated in detail. The characterization results of XRD

• (Pulverisette 7, Fritsch, Germany). The influence of milling-ball filling degree (ΦMB), reaction time (t), milling-ball size (dMB) and rotation speed (n), along with catalyst loading, alkaline type and grinding auxiliary category were further investigated in detail. Results and Discussion Characteristics of

• condition for the maximum yield. In the ball-milling process, the grinding auxiliary is found to be an efficient transfer medium between energy and reactant [1][2][55][56]. Additional investigations on the effects of the grinding auxiliaries were carried out. The results shown in Table 2 indicate that 5 g

Mechanochemical borylation of aryldiazonium salts; merging light and ball milling

• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1463–1469, doi:10.3762/bjoc.13.144

• . Simultaneous neat grinding/irradiation of the reactants and the photocatalyst led to the formation of boronates in a molten state. On the other hand, the catalyst-free liquid-assisted grinding/irradiation reaction also led to product formation, featuring a direct photolysis pathway facilitated by substrate

• potential of having both activation modes acting simultaneously. In recent years, mechanochemistry, which encompasses the use of mechanical means by milling, grinding, shearing, cavitation or pulling to induce chemical transformations [3] has become fundamental for discovering new chemical reactivity [4][5

• the photodimerizations of olefins by manual grinding of the reactants followed by long UV-light exposure [10], or by vortex grinding [11]. However, until now, studies of photocatalyzed mechanochemical reactions involving, for example, metal complexes [12] or organic photocatalysts (PC) [13] has been

Mechanochemistry-assisted synthesis of hierarchical porous carbons applied as supercapacitors

• Desirée Leistenschneider,
• Nicolas Jäckel,
• Felix Hippauf,
• Volker Presser and
• Lars Borchardt

Beilstein J. Org. Chem. 2017, 13, 1332–1341, doi:10.3762/bjoc.13.130

• of 0.20 cm3 g−1 and a surface area of 291 m2 g−1. Indeed, the high temperature chlorination reaction is essential to obtain the full porosity of the desired carbon. However, when we conducted the mechanochemical polymerization in the presence of small amounts of ethanol (liquid-assisted grinding, LA

• purchased from Sigma-Aldrich. Ethylene glycol (EG, purity 99.5%) was purchased from Fluka Analytics. For the solvent-free synthesis of hierarchical porous carbons, 5.25 g CA were ground with 7.10 g TIPP in a molar ratio of 1:1 in a 45 mL ZrO2 milling cup for 1 min with 700 rpm. Seven grinding balls out of

• ZrO2 with a diameter of 15 mm were used. Afterwards, different amounts of EG are added and the mixture was ball-milled for another 5 min with 700 rpm. The molar ratio of CA and EG was varied from 1:3 to 1:1. For the liquid-assisted synthesis, 5 mL EtOH were added to the first grinding step. The

Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill

• Olga Eguaogie,
• Patrick F. Conlon,
• Francesco Ravalico,
• Jamie S. T. Sweet,
• Thomas B. Elder,
• Louis P. Conway,
• Marc E. Lennon,
• David R. W. Hodgson and
• Joseph S. Vyle

Beilstein J. Org. Chem. 2017, 13, 87–92, doi:10.3762/bjoc.13.11

• ′-tosylates in five to 60 minutes. Under these conditions, commonly-encountered nucleoside cyclisation byproducts (especially of purine nucleosides) were not observed. Liquid-assisted grinding of the same 5'-iodide and 5′-tosylate substrates with potassium selenocyanate in the presence of DMF produced the

• from nucleosides by 4-methoxybenzylthiolate using vibration ball milling (VBM) where competing intramolecular cyclisation reactions are completely avoided. We further demonstrate the application of liquid-assisted grinding to related displacements using potassium selenocyanate. Results and Discussion

• ) remained untransformed during (dry) VBM or liquid-assisted grinding (LAG) in the presence of DMF with excess KSeCN (3 equiv). As found previously, the addition of catalytic TBAI (vide supra) did not alter this outcome nor did the use of a larger excess (5 equiv) of selenocyanate. The addition of DMF to the

Extrusion – back to the future: Using an established technique to reform automated chemical synthesis

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 65–75, doi:10.3762/bjoc.13.9

• just mixing, but also the grinding of the material, which resultantly leads to changes in the material properties, most commonly its rheology [3]. Furthermore, the mechanical energy applied to the system can be controlled by the screw profile, as well as the residence time which is not only dependent

• formation In 2009, Alvarez-Nunez et al. of Amgen used TSE to scale up the synthesis of a cocrystal which had already been reported to be synthesised successfully by ball milling (employing liquid-assisted grinding (LAG)). This was the first example demonstrating that mechanochemical synthesis could be

• amounts of solvent can be added to accelerate reactions (liquid-assisted grinding). Therefore, it can be concluded that the extruder provides most, if not all of the parameters that conventional solvent-based synthesis can provide. In fact, in regards to the current drive towards a more sustainable

Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins

• Andrea Mascitti,
• Massimiliano Lupacchini,
• Ruben Guerra,
• Ilya Taydakov,
• Lucia Tonucci,
• Nicola d’Alessandro,
• Frederic Lamaty,
• Jean Martinez and
• Evelina Colacino

Beilstein J. Org. Chem. 2017, 13, 19–25, doi:10.3762/bjoc.13.3

• investigated in the presence of various poly(ethylene) glycols (PEGs), as safe grinding assisting agents (liquid-assisted grinding, LAG). A comparative study under dry-grinding conditions was also performed. The results showed that the cyclization reaction was influenced by the amount of the PEG grinding

• agents. In general, cleaner reaction profiles were observed in the presence of PEGs, compared to dry-grinding procedures. Keywords: ball-milling; 1,1’-carbonyldiimidazole (CDI); hydantoins; mechanochemistry; liquid-assisted grinding (LAG); poly(ethylene) glycols (PEGs); Introduction Poly(ethylene

• other alternative energy inputs is still scarce. Only three examples highlight their peculiar role for metal-catalysed processes in a ball mill (Mirozoki–Heck reaction) [6], by ultrasound (copper-catalysed cyanation reaction) [7], and for co-crystal formation in the polymer-assisted grinding process

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

• Laszlo Jicsinszky,
• Marina Caporaso,
• Katia Martina,
• Emanuela Calcio Gaudino and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2016, 12, 2364–2371, doi:10.3762/bjoc.12.230

• . As it is previously found [22] applying a wetting substance the grinding temperature is always lower than the dry milling. It was assumed that the very low solubility of both per-halogeno and per-azido-CDs in water or 50% EtOH and complete dissolution of the sodium azide the milling energy was not

• [22] was also tested. In this case, the final grinding temperature was also found lower, approximately 20 °C lower, than the dry milling and no azido-CD was found by IR spectroscopy in the isolated solid. In the TU reactions, we found that the isolated yields depend on batch-size and we studied the

• positive balance in cost-benefit analyses. Wet grinding for the preparation of per-6-azido-CDs, using solubilizing and non-solubilizing solvents, showed practically no reaction in the planetary ball mill. Important intermediates and final products of per-6-amino- and per-6-thio-CDs can be prepared without

Solvent-free, visible-light photocatalytic alcohol oxidations applying an organic photocatalyst

• Martin Obst and
• Burkhard König

Beilstein J. Org. Chem. 2016, 12, 2358–2363, doi:10.3762/bjoc.12.229

• solvent-free conversion of solid reactants. The reaction is driven by mechanical energy, which is for instance realized by grinding in ball mills or pestle and mortar. Obviously, this method possesses several advantages compared to reactions, which are performed in solution: toxic solvents and wastes are

• for the investigation of our solvent-free principle. In mechanochemistry, reactions are performed by grinding the reaction mixture in ball mills, such as the vibrational ball mill or the planetary ball mill, or with a pestle and mortar. In preliminary studies, we tested a vibrational ball mill for

• chamber. The low penetration depth of light led us to the conclusion that thin interfaces of reactants, combined with continuous grinding, are necessary. Based on these considerations, we constructed a rod mill, consisting of a test tube which contains the reaction mixture, a glass rod, which is fixed to

The in situ generation and reactive quench of diazonium compounds in the synthesis of azo compounds in microreactors

• Faith M. Akwi and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 1987–2004, doi:10.3762/bjoc.12.186

• amines. Nonetheless they highlight the green benefits that they offer. For example Noroozi-Pesyan et al. synthesized azo dyes by grinding derivatives of aniline with solid sodium nitrite in the presence of p-toluenesulfonic acid [3]. It was found that the yield of isolated azo dyes obtained increased

Synthesis and properties of fluorescent 4′-azulenyl-functionalized 2,2′:6′,2″-terpyridines

• Adrian E. Ion,
• Liliana Cristian,
• Mariana Voicescu,
• Masroor Bangesh,
• Augustin M. Madalan,
• Daniela Bala,
• Constantin Mihailciuc and
• Simona Nica

Beilstein J. Org. Chem. 2016, 12, 1812–1825, doi:10.3762/bjoc.12.171

• chemical manner, by grinding neat starting materials without the use of classical organic solvents [26]. The α,β-unsaturated ketone was formed in good yields, 72% for 2a and 70% for 2b, respectively using NaOH as base. The azulenyl-substituted chalcones are stable at room temperature for months, whereas at

• characteristic stretching vibrations at 1690, and 1654 cm−1 associated with the CO–C=C bond in the IR spectrum. The subsequent grinding reaction of the azulene-functionalized azachalcone 2 with an equimolar amount of an inorganic base and 2-acetylpyridine affords brownish-red solid compounds. Any attempt to

• -yl)-3-(4,6,8-trimethylazulen-1-yl)prop-2-en-1-one (2b): This compound was prepared following Route A described above for chalcone 2a by grinding neat 2-acetylpyridine (121 mg, 0.11 mL, 1.0 mmol) with 4,6,8-trimethylazulene-1-carbaldehyde (198.0 mg, 1.0 mmol) and NaOH (40 mg, 1.0 mmol). The crude

Synthesis of a deuterated probe for the confocal Raman microscopy imaging of squalenoyl nanomedicines

• Eric Buchy,
• Branko Vukosavljevic,
• Maike Windbergs,
• Dunja Sobot,
• Camille Dejean,
• Simona Mura,
• Patrick Couvreur and
• Didier Desmaële

Beilstein J. Org. Chem. 2016, 12, 1127–1135, doi:10.3762/bjoc.12.109

• , LiHMDS, NaH/DMSO, PhLi) [29][31][32] gave only intractable materials. We finally found that the treatment of 10 with the “instant ylide mixture” of Schlosser made by grinding a solid mixture of 9 and NaNH2 [33] delivered the desired squalene-d6 (11) although in a low 18% yield. However, when applied to

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• ball milling vessel (cylinder of 5 mL) loaded with two grinding balls with a 7 mm diameter. The vessel was placed in a Mixer Mill MM 200 and the mixture was milled at 5 Hz of vibrational frequency at room temperature until consumption of the starting material (monitored by TLC). The vessel and the

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• achieve a homogeneous solid mixture is ball milling. By this method extremely fine powders can be achieved in mineral dressing processes, paints and pyrotechnics, etc. [79]. It is suitable for both batch and continuous operation, it is similarly suitable also for open and closed circuit grinding as well

• as being applicable for materials of all degrees of hardness. Conventional BMs have a cylindrical or conical shell that rotates on a horizontal axis and have an appropriate grinding medium of balls, for example steel, flint or porcelain. The second generation of BMs, which are often called as high

• at least one grinding jar arranged eccentrically on a rotating support. The grinding jar moves in the opposite direction to the sun wheel. The difference in speeds between the balls and grinding jars produces an interaction between frictional and impact forces, which releases high dynamic energies

Inclusion complexes of 2-methoxyestradiol with dimethylated and permethylated β-cyclodextrins: models for cyclodextrin–steroid interaction

• Mino R. Caira,
• Susan A. Bourne,
• Halima Samsodien and
• Vincent J. Smith

Beilstein J. Org. Chem. 2015, 11, 2616–2630, doi:10.3762/bjoc.11.281

• further development of 2ME. Results and Discussion Interaction between 2ME and native CDs Initial studies focused on possible isolation of solid inclusion complexes of 2ME with the native cyclodextrins α-, β- and γ-CD. Following neat co-grinding of each CD and 2ME (1 h, 1:1 molar ratios) and kneading (1 h

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

Inclusion of trans-resveratrol in methylated cyclodextrins: synthesis and solid-state structures

• Lee Trollope,
• Dyanne L. Cruickshank,
• Terence Noonan,
• Susan A. Bourne,
• Milena Sorrenti,
• Laura Catenacci and
• Mino R. Caira

Beilstein J. Org. Chem. 2014, 10, 3136–3151, doi:10.3762/bjoc.10.331

• materials and solvents used were of analytical reagent grade. Preparation of the binary systems Each physical mixture (PM) (1:1 mol/mol) was prepared by gentle co-grinding of the powder components in a mortar with a pestle and passing the resultant material through a 250 μm sieve. Kneaded products (KN) were

• prepared by wetting each PM in a mortar with ethanol/water 4:1 (v/v) and grinding thoroughly with a pestle, after which the product was dried to constant weight at 70 °C in an oven. The entire procedure was repeated in triplicate. The samples were then sieved through a 250 μm sieve. Co-evaporated products

Expeditious, mechanochemical synthesis of BODIPY dyes

• Laramie P. Jameson and
• Sergei V. Dzyuba

Beilstein J. Org. Chem. 2013, 9, 786–790, doi:10.3762/bjoc.9.89

• reagents. The condensation of 2,4-dimethylpyrrole and 4-nitrobenzaldehyde was performed with grinding by using a simple mortar and pestle, followed by the addition of a few drops of TFA (complete consumption of the aldehyde was confirmed by TLC) and oxidation with p-chloranil. The reaction mixture was

• subsequently treated with Et3N and BF3·OEt2 to afford BODIPY dye 1 (Scheme 2). All reagents were added sequentially with grinding in ca. 5 minutes. Each step was accompanied by a color change. The desired product was isolated in 29% yield, which was comparable to those reported in literature protocols, 24–40

• grinding to take place. Next, we examined several different bases for the deprotonation of the dipyrrolium species. Organic bases such as Et3N and DBU (Table 1, entries 1 and 5), proved to be most effective. Although DBU gave comparable results to Et3N, variations in yields were observed, likely due to the

A new synthetic access to 2-N-(glycosyl)thiosemicarbazides from 3-N-(glycosyl)oxadiazolinethiones and the regioselectivity of the glycosylation of their oxadiazolinethione precursors

• El Sayed H. El Ashry,
• El Sayed H. El Tamany,
• Mohy El Din Abdel Fattah,
• Mohamed R. E. Aly,
• Ahmed T. A. Boraei and
• Axel Duerkop

Beilstein J. Org. Chem. 2013, 9, 135–146, doi:10.3762/bjoc.9.16

• , Germany 10.3762/bjoc.9.16 Abstract Glycosylations of 5-(1H-indol-2-yl)-1,3,4-oxadiazoline-2(3H)-thione delivered various degrees of S- and/or N-glycosides depending on the reaction conditions. S-Glycosides were obtained regiospecifically by grinding oxadiazolinethiones with acylated α-D-glycosyl halides

• the N-glycosyl analogues. Grinding the reactants with basic alumina afforded regiospecifically S-linked glycosides 5–7 in 52–63% yields. However, if glycosylations were carried out on the chloromercuric salt of 1 in toluene under reflux, 3-N-linked glycosides 8–10 were regiospecifically obtained in 48