Examples of mechanochemical reactions triggered or accelerated by milling, grinding, shearing or cavitation have grown in the past years. Particularly interesting has been the application of mechanical energy to facilitate organic synthesis. Along these lines, this Thematic Series gathers original contributions in the field of organic mechanochemistry, including research and review articles. Altogether, the works within this collection not only highlight the well-known advantages of mechanochemistry but are also anticipated to stimulate future applications of mechanochemistry in organic synthesis and in neighboring areas.
Graphical Abstract
Figure 1: Structures of discrete mechanoradicals and the reaction sequence for their formation from cellulose ...
Figure 2: Schematic structure of amylose, dextran and glycogen.
Figure 3: Progressive changes in observed ESR spectra of fractured amylose [5], Dx, and Gly, together with simul...
Figure 4: Schematic representation of bond cleavage at α-1,4- and α-1,6-bonds.
Figure 5: ESR spectrum of fractured sample of Dx and TCNE (a) before and (b) after visible-light irradiation.
Figure 6: Component spectra of the simulated ESR spectra.
Figure 7: Progressive changes in the intensity of component spectra corresponding to the simulated spectra of...
Figure 8: Changes in Dx molecular-weight distribution (MWD) during vibratory milling.
Figure 9: Changes in Dx weight-average molecular weight (Mw) during vibratory milling.
Figure 10: Change in Gly particle diameter during vibratory milling.
Graphical Abstract
Figure 1: Synthesis of hierarchical porous carbons by mechanochemical polymerization of ethylene glycol (EG) ...
Figure 2: Infrared spectra of the monomers ethylene glycol (EG, blue) and citric acid (CA, green blue), the m...
Figure 3: SEM (A) and TEM (B) images of the Carb-SF-3 sample.
Figure 4: XRD-pattern of the polymeric precursor (Polymer-SF-3, orange), the carbonized composite (Comp-SF-3,...
Figure 5: Nitrogen physisorption isotherms for carbon samples achieved from (A) different amounts of ethylene...
Figure 6: Volume histogram of the different samples calculated using a QSDFT-kernel for slit, cylindrical and...
Figure 7: Cyclic voltammograms performed with different scan rates in (A) 1 M TEA-BF4 (ACN) and (B) EMIM-BF4;...
Graphical Abstract
Figure 1: (a) Cartoon representing the merging of light and mechanical energy. (b) 25 mL transparent PMMA mil...
Scheme 1: Borylation of 1a in the presence of 1,1-diphenylethene (4).
Scheme 2: Light-mediated LAG borylation of 1a. aDetermined by 1H NMR spectroscopy using internal standard. bA...
Graphical Abstract
Scheme 1: Supported catalysts in cross-coupling reactions. MM represents mixer mill; PM represents planetary ...
Figure 1: The XRD patterns for the samples of MgAl-LDHs, MgAl-LDHs-PdCl42− and Pd/MgAl-LDHs.
Scheme 2: Selected model reaction.
Figure 2: Examination of the milling-ball filling degree (ΦMB) and milling-ball sizes on the yield of 3aa. Re...
Figure 3: Examination of ball-milling time and rotation speed on the yield of 3aa. Reaction conditions: 1a (1...
Figure 4: Substrate scope of Pd/MgAl-LDHs catalyzed Heck reactions. Reaction conditions unless otherwise note...
Scheme 3: Pd/MgAl-LDHs catalyzed Heck reactions of heteroaryl bromides. Reaction conditions unless otherwise ...
Figure 5: Recycling studies of the Pd/MgAl-LDH catalyst for Heck reactions. Reaction conditions: 1i or 1m (1....
Graphical Abstract
Scheme 1: N-Propylpropanamide and characteristic infrared active vibrational modes. Modes are in order of low...
Figure 1: Force dependence of the modes shown in Scheme 1 in the fingerprint region from 800 to 2000 cm−1. C–N stretc...
Figure 2: Intensities in fingerprint region of the infrared spectrum obtained for N-propylpropanamide. Spectr...
Figure 3: Fingerprint region of a simulated spectrum of an N-propylpropanamide solid sample at 0.1, 0.3, 0.5 ...
Scheme 2: Propyl propanoate and characteristic infrared active vibrational modes. Modes are in order of lowes...
Figure 4: Force dependence of the modes shown in Scheme 2 in the fingerprint region from 800 to 2000 cm−1. C–O backbo...
Figure 5: Intensities in fingerprint region of the infrared spectrum obtained for propyl propanoate. Spectral...
Figure 6: Fingerprint region of a simulated spectrum of a propyl propanoate solid sample at 0.1, 0.3, 0.5 and...
Graphical Abstract
Scheme 1: Enantioselective enzymatic hydrolysis of racemic β3-amino ester rac-1a using CALB in solution [52] (top...
Figure 1: X-ray crystallographic structure of product (R)-2a (50% of probability ellipsoids). CCDC registry n...
Graphical Abstract
Scheme 1: N-Alkylation of imide 1 with 1,3-dibromopropane (2) in a ball mill.
Scheme 2: Mechanochemical N-alkylation of imide 1.
Figure 1: Products of alkylation of imides 11–17.
Figure 2: Ex situ IR spectroscopy of the reaction of 12 and benzyl bromide in the ball mill: a) phthalimide 12...
Scheme 3: Mechanosynthesis of 7,8-dimethylalloxazine (36) and its N-alkylation.
Scheme 4: Gabriel synthesis of amines in ball mill.
Scheme 5: Three-step, two-pot Gabriel synthesis of amines in ball mill.
Graphical Abstract
Scheme 1: Enzymatic reactions under ball milling conditions.
Figure 1: (a) Molecular representation of lignin. (b) Lignin model compound erythro-1a.
Scheme 2: Chemical and enzymatic esterification of erythro-1a with isopropenyl acetate (2a) in the ball mill....
Scheme 3: CALB-catalyzed esterification of lignin model compounds in the ball mill.
Scheme 4: Selective esterification of erythro-1a using long-chain vinyl esters as acyl donors in the ball mil...
Graphical Abstract
Scheme 1: a) Schematic representations of unsubstituted urea, thiourea and guanidine. b) Wöhler's synthesis o...
Figure 1: Antidiabetic (1–3) and antimalarial (4) drugs derived from ureas and guanidines currently available...
Scheme 2: The structures of some representative (thio)urea and guanidine organocatalysts 5–8 and anion sensor...
Scheme 3: Solid-state reactivity of isothiocyanates reported by Kaupp [30].
Scheme 4: a) Mechanochemical synthesis of aromatic and aliphatic di- and trisubstituted thioureas by click-co...
Figure 2: The supramolecular level of organization of thioureas in the solid-state.
Figure 3: The supramolecular level of organization of thioureas in the solid-state.
Scheme 5: Thiourea-based organocatalysts and anion sensors obtained by click-mechanochemical synthesis.
Scheme 6: Mechanochemical desymmetrization of ortho-phenylenediamine.
Scheme 7: Mechanochemical desymmetrization of para-phenylenediamine.
Scheme 8: a) Selected examples of a mechanochemical synthesis of aromatic isothiocyanates from anilines. b) O...
Scheme 9: In solution, aromatic N-thiocarbamoyl benzotriazoles 27 are unstable and decompose to isothiocyanat...
Scheme 10: Mechanosynthesis of a) bis-thiocarbamoyl benzotriazole 29 and b) benzimidazole thione 31. c) Synthe...
Figure 4: In situ Raman spectroscopy monitoring the synthesis of thiourea 28d in the solid-state. N-Thiocarba...
Scheme 11: a) The proposed synthesis of monosubstituted thioureas 32. b) Conversion of N-thiocarbamoyl benzotr...
Scheme 12: A few examples of mechanochemical amination of thiocarbamoyl benzotriazoles by in situ generated am...
Scheme 13: Mechanochemical synthesis of a) anion binding urea 33 by amine-isocyanate coupling and b) dialkylur...
Scheme 14: a) Solvent-free milling synthesis of the bis-urea anion sensor 35. b) Non-selective desymmetrizatio...
Scheme 15: a) HOMO−1 contours of mono-thiourea 19b and mono-urea 36. b) Mechanochemical synthesis of hybrid ur...
Scheme 16: Synthesis of ureido derivatives 38 and 39 from KOCN and hydrochloride salts of a) L-phenylalanine m...
Scheme 17: a) K2CO3-assisted synthesis of sulfonyl (thio)ureas. b) CuCl-catalyzed solid-state synthesis of sul...
Scheme 18: Two-step mechanochemical synthesis of the antidiabetic drug glibenclamide (2).
Scheme 19: Derivatization of saccharin by mechanochemical CuCl-catalyzed addition of isocyanates.
Scheme 20: a) Unsuccessful coupling of p-toluenesulfonamide and DCC in solution and by neat/LAG ball milling. ...
Scheme 21: a) Expansion of the saccharin ring by mechanochemical insertion of carbodiimides. b) Insertion of D...
Scheme 22: Synthesis of highly basic biguanides by ball milling.
Graphical Abstract
Figure 1: Typical laboratory employed planetary ball mill and ultrasonic bath.
Scheme 1: Reaction between o-vanillin and 1,2-phenylenediamine by ultrasonic irradiation for 60 minutes.
Figure 2: o-Vanillin in its flake form and 1,2-phenylenediamine in its bead form.
Figure 3: Clear separation of the reagents observed, with orange coated beads of 1,2-phenylenediamine residin...
Figure 4: Chemical structures of the products obtained from the reaction between o-vanillin and 1,2-phenylene...
Figure 5: Reaction mixture before and after ultrasonic irradiation for 60 minutes.
Figure 6: 1H NMR spectrum of diimine 1 in CDCl3/EtOD.
Scheme 2: Aldol reaction between ninhydrin and dimedone to form 2.
Figure 7: 1H NMR spectrum of 1,3-indandione 2 in DMSO-d6.
Graphical Abstract
Scheme 1: Nucleophilic substitution of the 4-toluenesulfonyl group. The formalism for the mechanochemical act...
Figure 1: Effect of jar size on the reaction time using an equal number (30) of steel balls (ø 1 mm) for the ...
Figure 2: Effect of ball size on the reaction time to a full conversion of Ts-β-CD: a) reactions performed at...
Figure 3: Reaction time as a function of ball materials at 550 min−1 in glass vials of 25 mL: a) equal weight...
Graphical Abstract
Scheme 1: Mechanochemical aldol condensation reactions [48].
Scheme 2: Enantioselective organocatalyzed aldol reactions under mechanomilling. a) Based on binam-(S)-prolin...
Scheme 3: Mechanochemical Michael reaction [51].
Scheme 4: Mechanochemical organocatalytic asymmetric Michael reaction [52].
Scheme 5: Mechanochemical Morita–Baylis–Hillman (MBH) reaction [53].
Scheme 6: Mechanochemical Wittig reactions [55].
Scheme 7: Mechanochemical Suzuki reaction [56].
Scheme 8: Mechanochemical Suzuki–Miyaura coupling by LAG [57].
Scheme 9: Mechanochemical Heck reaction [59].
Scheme 10: a) Sonogashira coupling under milling conditions. b) The representative example of a double Sonogas...
Scheme 11: Copper-catalyzed CDC reaction under mechanomilling [67].
Scheme 12: Asymmetric alkynylation of prochiral sp3 C–H bonds via CDC [68].
Scheme 13: Fe(III)-catalyzed CDC coupling of 3-benzylindoles [69].
Scheme 14: Mechanochemical synthesis of 3-vinylindoles and β,β-diindolylpropionates [70].
Scheme 15: Mechanochemical C–N bond construction using anilines and arylboronic acids [78].
Scheme 16: Mechanochemical amidation reaction from aromatic aldehydes and N-chloramine [79].
Scheme 17: Mechanochemical CDC between benzaldehydes and benzyl amines [81].
Scheme 18: Mechanochemical protection of -NH2 and -COOH group of amino acids [85].
Scheme 19: Mechanochemical Ritter reaction [87].
Scheme 20: Mechanochemical synthesis of dialkyl carbonates [90].
Scheme 21: Mechanochemical transesterification reaction using basic Al2O3 [91].
Scheme 22: Mechanochemical carbamate synthesis [92].
Scheme 23: Mechanochemical bromination reaction using NaBr and oxone [96].
Scheme 24: Mechanochemical aryl halogenation reactions using NaX and oxone [97].
Scheme 25: Mechanochemical halogenation reaction of electron-rich arenes [88,98].
Scheme 26: Mechanochemical aryl halogenation reaction using trihaloisocyanuric acids [100].
Scheme 27: Mechanochemical fluorination reaction by LAG method [102].
Scheme 28: Mechanochemical Ugi reaction [116].
Scheme 29: Mechanochemical Passerine reaction [116].
Scheme 30: Mechanochemical synthesis of α-aminonitriles [120].
Scheme 31: Mechanochemical Hantzsch pyrrole synthesis [121].
Scheme 32: Mechanochemical Biginelli reaction by subcomponent synthesis approach [133].
Scheme 33: Mechanochemical asymmetric multicomponent reaction[134].
Scheme 34: Mechanochemical Paal–Knorr pyrrole synthesis [142].
Scheme 35: Mechanochemical synthesis of benzothiazole using ZnO nano particles [146].
Scheme 36: Mechanochemical synthesis of 1,2-di-substituted benzimidazoles [149].
Scheme 37: Mechanochemical click reaction using an alumina-supported Cu-catalyst [152].
Scheme 38: Mechanochemical click reaction using copper vial [155].
Scheme 39: Mechanochemical indole synthesis [157].
Scheme 40: Mechanochemical synthesis of chromene [158].
Scheme 41: Mechanochemical synthesis of azacenes [169].
Scheme 42: Mechanochemical oxidative C-P bond formation [170].
Scheme 43: Mechanochemical C–chalcogen bond formation [171].
Scheme 44: Solvent-free synthesis of an organometallic complex.
Scheme 45: Selective examples of mechano-synthesis of organometallic complexes. a) Halogenation reaction of Re...
Scheme 46: Mechanochemical activation of C–H bond of unsymmetrical azobenzene [178].
Scheme 47: Mechanochemical synthesis of organometallic pincer complex [179].
Scheme 48: Mechanochemical synthesis of tris(allyl)aluminum complex [180].
Scheme 49: Mechanochemical Ru-catalyzed olefin metathesis reaction [181].
Scheme 50: Rhodium(III)-catalyzed C–H bond functionalization under mechanochemical conditions [182].
Scheme 51: Mechanochemical Csp2–H bond amidation using Ir(III) catalyst [183].
Scheme 52: Mechanochemical Rh-catalyzed Csp2–X bond formation [184].
Scheme 53: Mechanochemical Pd-catalyzed C–H activation [185].
Scheme 54: Mechanochemical Csp2–H bond amidation using Rh catalyst.
Scheme 55: Mechanochemical synthesis of indoles using Rh catalyst [187].
Scheme 56: Mizoroki–Heck reaction of aminoacrylates with aryl halide in a ball-mill [58].
Scheme 57: IBX under mechanomilling conditions [8].
Scheme 58: Thiocarbamoylation of anilines; trapping of reactive aryl-N-thiocarbamoylbenzotriazole intermediate...
Graphical Abstract
Scheme 1: Factors to be considered regarding the physical form in the one-pot two-step mechanochemical proced...
Scheme 2: Optimised conditions for the one-pot synthesis.
Scheme 3: Substrate scope of the one-pot, 2 step mechanochemical synthesis (isolated yields). a1 equiv Select...
Graphical Abstract
Scheme 1: Our synthetic planning and structural diversity of starting materials employed in our work.
Scheme 2: Pseudo five-component reactions affording symmetrical bispyrrole derivatives joined by a spacer.
Figure 1: Scope of the synthesis of symmetrical bispyrrole derivatives.
Scheme 3: A pseudo-seven-component reaction that affords a terpyrrole derivative with a functionalized spacer....
Scheme 4: Homodimerization of 2-allyl- and 2-homoallylpyrroles via cross-metathesis reactions.
Graphical Abstract
Scheme 1: Developed syntheses for accessing by mechanochemistry: (a) mPEG–OTs, (b) mPEG–Br, (c) mPEG–SH, (d) ...
Figure 1: 1H NMR of sample mPEG2000–OTs (Table 1, entry 5) in CDCl3 showing mPEG end group shift after tosylation.
Graphical Abstract
Figure 1: Overview of the preparation of the nanocomposites based on iron oxide and polysaccharide.
Figure 2: XPS spectra of A: Fe2O3-PS4, B: Fe2O3-PS4-MNP and C: TiO2-Fe2O3-PS4 nanohybrids.
Figure 3: A and B: SEM and TEM images of TiO2-Fe2O3-PS4; C and D: SEM and TEM images of Fe2O3-PS4. E and F: S...
Figure 4: DRIFT spectra of A: TiO2-Fe2O3-PS4 and B: Fe2O3-PS4-MNP nanohybrids.
Scheme 1: Oxidation of benzyl alcohol to benzaldehyde.
Figure 5: Conversion and selectivity of the oxidation of benzyl alcohol for the three catalytic systems.
Scheme 2: Microwave-assisted alkylation of toluene with benzyl chloride.
Figure 6: Conversion and selectivity of the microwave-assisted alkylation of toluene for the three catalytic ...
Scheme 3: Alkylation of toluene with benzyl chloride with conventional heating.
Figure 7: Conversion and selectivity of the alkylation of toluene with conventional heating for the three cat...
Figure 8: Reusability of the iron oxide/polysaccharide nanohybrids.
Graphical Abstract
Scheme 1: Knoevenagel condensation of p-nitrobenzaldehyde (1) with malononitrile (2) yielding p-nitrobenzylid...
Figure 1: X-ray diffraction patterns of the reactants p-nitrobenzaldehyde (1) and malononitrile (2) and the p...
Figure 2: a) Schematic diagram of the in situ setup for investigating mechanochemical reactions in a tandem a...
Graphical Abstract
Scheme 1: TEMPO-catalysed aerobic oxidative procedures of alcohols. a) Anelli–Montanari protocol: NaOCl (1.25...
Scheme 2: TEMPO-assisted oxidation of 4-nitrobenzylic alcohol under mechanical activation conditions [65].
Scheme 3: Scope of primary alcohols in oxidation under ambient air.
Scheme 4: Scope of secondary alcohols in oxidation under ambient air.
Graphical Abstract
Scheme 1: Variables associated with ball-milling (left) and solvent-based methodologies (right).
Scheme 2: Examples of mechanochemically produced species (a [48], b [62], c [63], d [64], e [65], f [66], g [67], h [68]). The symbol for mec...
Scheme 3: Mechanochemical synthesis of SrCp′2(OEt2) (Cp′ = C5Me4(n-Pr)).
Scheme 4: Mechanochemical synthesis of the Ar-BIAN ligands and indium(III) complexes (top). One-pot synthesis...
Scheme 5: Synthesis of germanes from germanium (Ge) or germanium oxide (GeO2).
Scheme 6: Ball-milling nucleophilic substitution reactions to produce acyclic and cyclic cyclodiphosphazanes.
Scheme 7: Mechanochemical reactions of potassium 1,3-bis(trimethylsillylallyl) with group 13 (top) and 15 (bo...
Scheme 8: Synthesis of adamantoid phosphazane framework from its double-decker isomer for R = iPr and t-Bu (l...
Graphical Abstract
Figure 1: Structure of the VVIA peptide.
Scheme 1: Synthesis of Boc-VVIA-OBn by the ball-milling approach.
Scheme 2: Synthesis of tetrapeptide Boc-VVIA-OBn in solution.
Scheme 3: Synthesis of TFA·H-VVIA-OH by SPPS.
Figure 2: Comparison of the reaction time of the coupling steps performed in the BM and in solution.
Graphical Abstract
Scheme 1: Milling synthesis of 2,3-diphenylquinoxaline from benzil and ortho-phenylenediamine [40].
Scheme 2: Movement of the milling jar and sample holder under milling conditions.
Figure 1: Time-resolved Raman spectrum for the double condensation of o-phenylenediamine and benzil to form 2...
Figure 2: Section of the time-resolved Raman spectrum for the model mechanochemical reaction conducted at 30 ...
Figure 3: (Left) Estimated contribution of each component for each Raman spectrum over time of the synthesis ...
Figure 4: The effect of milling frequency on the milling condensation of benzil and o-phenylenediamine to for...
Figure 5: The reproducibility of varying milling frequency on the neat mechanochemical condensation of benzil...
Figure 6: The effect of milling frequency on the internal jar temperature measured immediately after reaction...
Graphical Abstract
Scheme 1: Retrosynthesis of the Pro–Pro DKP framework.
Scheme 2: Coupling with N-hydroxysuccinimide-activated amino acids.
Scheme 3: Synthesis of Pro–Pro DKP.
Scheme 4: Synthesis of substituted Pro–Pro DKP 15a.
Scheme 5: Potential isomers yielded by cyclization of 16.
Figure 1: Optimized geometries for the two conformers presenting interactions with either Ca (16a) or Cb (16b...
Figure 2: Optimized geometries of the extrema located along the pathway for formation of 15a with explicit pa...
Figure 3: Optimized geometries of the extrema located along the pathway for formation of 15b with explicit pa...
Figure 4: Optimized geometries for the transition states associated to alternate position of the methanol mol...
Scheme 6: Synthesis of diketopiperazine 19.
Graphical Abstract
Scheme 1: Synthetic procedures for preparation of p-halogen-substituted and non-substituted phenyl-1,2,3-tria...
Figure 1: Experimental Raman spectra of the alkyne 4 and triazole products 5–8. Bands attributed to the vibra...
Figure 2: In situ Raman monitoring of a) mechanochemical formation of triazole 5 using copper(II) acetate mon...
Figure 3: a) In situ Raman monitoring for mechanochemical synthesis of 5 using brass balls and PMMA reaction ...
Figure 4: ESR spectra of samples obtained after milling by methods 2a (black), 2b (red) and 2c (blue). The in...
Figure 5: X-ray structure of the triazole compounds. (a) Molecular structure of 5, with the atom-numbering sc...
Graphical Abstract
Figure 1: a) Detailed supramolecular packing of a gabapentin–Er network; b) view along the b-axis of the supr...
Figure 2: a) Mechanochemical reactivity between the excipient MgO and carboxylic acid NSAID molecules; b) NSA...
Figure 3: Mechanochemical reaction to form Cu3(BTC)2 and the structure of Cu3(BTC)2·(HKUST-1) as reported by ...
Figure 4: Mechanochemical syntheses of coordination polymers from ZnO and fumaric acid. Reprinted with permis...
Figure 5: Mechanochemical synthesis of pillared MOFs from ZnO, fumaric acid and two auxiliary ligands (bipy a...
Figure 6: a) Synthesis of ZIF-8; b) fragment of the crystal structure of ZIF-8. Reprinted with permission fro...
Figure 7: a) Mechanochemical reaction of salicylic acid with Bi2O3 yielding bismuth mono-, di- and trisalicyl...
Graphical Abstract
Scheme 1: The influence of the milling frequency on the reaction of 1a with NIS.
Scheme 2: Palladium-catalyzed ortho-iodination of 1a in toluene.
Scheme 3: Plausible mechanism.
Scheme 4: Palladium-catalyzed ortho-bromination and chlorination of 1a in a ball mill.
Graphical Abstract
Figure 1: Solution-based Wittig reaction mechanism.
Figure 2: 1H NMR spectra of stilbene mixture (a) and benzyl benzoate (b).
Scheme 1: Possible mechanism of benzyl benzoate formation.
Scheme 2: A possible mechanistic explanation for the E selectivity.
Scheme 3: Ball-milled Wittig reaction using excess benzaldehyde.
Figure 3: Comparison of solution based Wittig reaction (a) with polymer-supported mechanochemical Wittig reac...
Scheme 4: Stepwise ball-milled Wittig reaction with ethanol as the LAG solvent.
Scheme 5: Stepwise ball-milled Wittig reaction with ethanol evaporation between the steps.