Mortar and pestle have been a good means of achieving mechanochemistry since the Stone Age. To this day, mortars and pestles are still used in the laboratory to achieve small chemical reactions. Considering that longer grinding time and larger grinding volume will consume more labor, ball mill came into being. The ball mill contains a longer reaction time, a larger reaction dose, and does not involve human operation, thus enhancing the repeatability of the reaction.

The vibrating ball mill is usually equipped with 2 to 6 ball milling tanks horizontally, moving in the form of horizontal, vertical and elliptical^[21]. The mechanical force is mainly impulsive impact force^[22]. Retsch Company in Germany invented the vibrating ball mill in 1923, and Retsch is still one of the most widely used brands of vibrating ball mills. The container of a vibrating ball mill usually allows gram reaction and is therefore suitable for laboratory use. In the reports of the past ten years, the vibrating ball mill is mostly used for inorganic reactions such as mechanical alloying and organic synthesis. A variety of controlled reactions can be achieved by adding accessories and modifications. For example, low temperatures can be achieved by adding an internal cooling system. At the same time, the stainless steel ball milling tank can be heated by using the resistance ring, so that the temperature-controlled reaction can be realized, and the stainless steel ball milling tank can be used for preparing microporous polymer and metal-organic framework materials^[23][23]. The porous polymer can be produced by increasing the gas pressure while the temperature is controlled^[23,24]. In addition, replacing the stainless steel ball milling jar with the transparent quartz ball milling jar can realize the photochemical reaction or light wave characterization, such as Raman spectroscopy, in situ X-ray diffraction, and in situ solid-state nuclear magnetic resonance spectroscopy, simultaneously with the mechanochemical reaction^{[1,25⇓~27][28⇓~30][25,31⇓~33][34]}.

Planetary ball mill originated from drum ball mill. Drum ball milling has been used industrially in cement clinker and metal grinding since the 1870s, in which the stones act as grinding balls. The drum of the drum ball mill, that is, the ball milling tank, is horizontally installed on the central shaft. Through the rotation of the drum, the gravity acts on the ball and impacts downward to produce force. Therefore, the force of the tumbler ball mill depends on the height of the ball drop. In order to break through the limitation of ball drop height, in 1961, Fritsch Company of Germany placed four ball milling tanks vertically on a counter-rotating disc^[3]. The rotating disk is also called the "sun disk", and the motion of the balls in the ball mill tank relative to the "sun disk" is similar to the planetary motion, so it is named the planetary ball mill. The centrifugal force due to planetary motion produces a larger acceleration than gravity, and therefore a larger force, dominated by shear. Planetary ball mill can accommodate 10 to 100 grams of reaction, which is the main force of most mechanical chemistry laboratories, especially for the synthesis of organic matter. In addition to stainless steel ball milling tanks, zirconia ball milling tanks are also commonly used in planetary ball mills to reduce the effect of metals on the reaction or the corrosion of organic matter on the tank.

Stirred ball mill is often used in pilot plant and actual production. The stirred ball mill was first invented by Andrew Szegvari in 1922^[3]. It consists of a ball mill tank placed vertically and a rotating stirrer. The agitator drives the ball and the grinding material to move circularly under the action of the motor. The fine grinding of the ground material is realized by the mutual collision between the ball and the medium, the stirrer, the ball milling tank, and the like^[35]. Stirred ball mills are now commonly used for physical grinding. In the laboratory, the ball mill tank can be replaced by a container such as a round bottom flask. The advantage of the stirred ball mill is that it can accommodate a large reaction volume. For example, Outotec HIGMill has a capacity of 30 000 L and can be used for more than 1 ton of material^[36]. In addition to the above batch production mode, continuous ball milling production can further expand the reaction scale^[37]. Vibrating ball mill, planetary ball mill, and stirred ball mill are summarized in Table 1.

Liquid-assisted grinding refers to grinding with the addition of a small amount of liquid. The amount of liquid added is measured by η, which is the ratio of the volume of liquid to the amount of reactant, for example, η = 0 for pure grinding, η = 2 to 12 μL/mg for slurry grinding, and η > 12 μL/mg for liquid reaction^[38]. In the range of η = 0 – 2 μL/mg, the solubility of the reactants in the liquid has no effect on the reaction results. However, for slurry grinding and liquid reactions, the reaction rate of the insoluble reactants is slowed down^[39]. Liquid-assisted milling was first used to accelerate the cocrystallization reaction^[40]. Different kinds and amounts of liquids produce different isomorphs^[41]. For example, dimerization of acetylene can selectively form diyne or enyne, depending on the polarity of the auxiliary liquid^[42,43].

The milling auxiliary medium is a non-reactive inert solid substance, such as silicon, aluminum, talc, or an inorganic salt, added during the milling process. In ball milling, when a liquid is used, the reaction mixture takes on a viscous state, similar to toothpaste or chewing gum^[44,45]. In this viscous state, the transfer of mass and energy is weakened. The addition of a milling aid medium can absorb the liquid reactant to enhance mass and energy transfer. James et al. Demonstrated that solid or liquid States result in different reaction rates^[46]. Other auxiliary media have also been used, such as ionic liquid assisted milling, that is, the addition of ionic liquid in the milling^{[46⇓⇓⇓~50]}. Solid polymer PEG was also added to assist grinding^[51,52].

CuAAc is one of the most typical click chemistry reactions, occurring between an azide group and a triple bond group. Although it has been achieved by mechanochemical means of friction or stress, ball milling CuAAc is still one of the best mechanochemical ways to be stable and controllable^[53][54]. In this section, the first realization of ball milling-CuAAc reaction by Stolle et al. Is first introduced. The following articles expand the catalytic conditions: copper monomer, monovalent and divalent compounds, copper balls, and copper pots are all used to catalyze CuAAc in ball milling. Because of the high energy of ball milling, the reaction time is reduced, and the efficient reaction also avoids the use of nitrogen-containing or phosphorus-containing ligands. After that, the one-pot CuAAc was extended to the ball milling conditions, and the safe use of sodium azide was maintained. The last few articles have applied this reaction to the preparation of anticorrosives, dyes, and pesticides.

In 2011, Stolle et al. Published a ligand-free and solvent-free CuAAc reaction in a planetary ball mill^[55]. Because of the risk of explosion caused by short carbon chain azide, they chose safe long carbon chain azide for reaction. As shown in Scheme 1, phenylacetylene a reacts with azidodecane B to produce 1-decyl-4-phenyl-1H-1,2,3-triazole. The reaction was carried out in a Fritsch P6 planetary ball mill. The 45 mL zirconia ball milling tank is equipped with six 15 mm zirconia grinding balls. Under the catalysis of copper acetate, silica was added as an auxiliary grinding, and the ball milling was carried out at 800 revolutions for 10 min. The conversion of the product was high as determined by both NMR and GC. Under the condition of adding sodium ascorbate, the reaction can be completed in only 5 min. In the absence of sodium ascorbate, the reaction took 10 min. This is due to the promoting effect of sodium ascorbate on inactive reactants. A variety of alkynyl compounds have been tried, including diacetylene compounds and non-terminal acetylene compounds, and diazide compounds have also been tried, and all of them have achieved high conversion (more than 98%), which proves that this reaction has general applicability. Among them, the reaction of diacetylene compounds and diazide compounds can be used for condensation polymerization to synthesize polymers, and the high-energy ball milling process has no significant effect on the integrity of polymer chains. In addition, the electron-deficient compound dimethyl acetylenedicarboxylate was also suitable for the cycloaddition reaction, but its yield was 89%, which was slightly lower than that of other reactants.

Cravotto et al. Published the CuAAc reaction using copper powder as catalyst in a planetary ball mill^[56]. When the divalent copper salt is used as a catalyst, it is eliminated under the action of sodium ascorbate to produce a monovalent copper ion catalyst. Similarly, zero-valent copper powder can also be used as a raw material for monovalent copper to carry out CuAAc reaction under ball milling conditions. Phenylacetylene and octane azide were selected as model reactants and first tested in solution reactions. In the solvent of tert-butyl alcohol and water (1:1), the reactants were mixed and reacted at 70 ℃ for 20 H, and the reactants were completely converted. Next, the reaction was carried out in a ball mill as shown in Scheme 2. The reactants were ball milled with equivalent molar amounts of copper powder and silica for 650 revolutions in a 50 mL stainless steel pot of a Retsch planetary ball mill PM100. For different grinding balls, the yield ranged from 67% to 99%. The reaction can produce up to 10 G of product, and the reaction is efficient and can be completed in only 5 min. In addition, the addition of different amounts of silica milling auxiliary medium to the reaction, or even no addition, did not affect the reaction results. This experiment can be extended to a variety of halogenated benzyl azides and nitro-substituted benzyl azides; Hydroxy alkyne and dialkyne, and the yield is more than 95%. The advantage of this reaction is that only a simple copper powder filtration is required in the purification process to obtain the triazole derivative. It is worth noting that this reaction can be applied to cyclodextrins, via solid supported copper catalysts or using metals, to avoid time-consuming competitive chelator purification methods, and can achieve higher yields. Nowadays, CuAAc has been widely used in the functionalization of cyclodextrins, and the problems of low yield and low regioselectivity of cyclodextrin functionalization are expected to be solved by ball milling CuAAc.

U Užarević et al. Made a systematic study on the reaction of CuAAc under ball milling conditions with three valence copper catalysts^[57]. First, 6-phenylquinoline derivative a reacts with bromopropyne in the presence of potassium carbonate to produce an ortho-substituted quinoline derivative B with a triple bond, which is prepared for CuAAc, as shown in Figure 3. Next, the ortho-substituted quinoline derivative B was subjected to CuAAc reaction with 1-azido-4-halobenzene, and N-heterocyclic compounds containing quinoline and 1,2,3-triazole were synthesized. Ball milling takes place in an IST500z vibrating ball mill. Stainless steel grinding balls or brass grinding balls were ball milled at a frequency of 30 Hz in a ball milling jar of Teflon. The monovalent and divalent copper catalysts were used in the solvent reaction and ball milling reaction, respectively. As shown in Table 2, under the same catalyst (copper acetate or copper iodide) and the same reaction time (3.5 H), the yield of the ball milling reaction at room temperature is usually much higher than that of the solvent reaction at 60 ℃. They also explored halogen-substituted azide reactants. For different 1-azido-4-halobenzenes, both the solvent reaction and the ball milling reaction showed a yield trend of I > Br > Cl. For chloro-substituted, bromo-substituted, and unsubstituted benzyl azide, the yield of ball milling is much higher than that of solution reaction under the same catalyst and reaction time. For the iodo-substituted 1-azido-4-iodobenzene, the yield was higher with ball milling when copper iodide was used as catalyst: 92% compared to 52% for the solvent reaction. In 92% yield ball milling, the NMR result indicates that the reactant has been completely converted and consumed. In one example, when copper iodide was used to catalyze 1-azido-4-chlorobenzene, the yield of ball milling was as high as 85%, which was 17 times higher than the 5% yield of solution reaction. In addition, the difference of catalytic efficiency of different catalysts, such as Cu²⁺, Cu⁺ and Cu, in ball milling was also discussed. The effect of catalysts on ball milling reaction will be discussed in Chapter 3 of this review.

Mack et al. Carried out the CuAAc ball milling reaction in a copper ball milling jar filled with copper balls, and realized the reaction mode without adding additional catalyst^[58]. in the Spex certiprep 8000M vibrating ball mill, a 2.0 × 0.5 in screw-top copper pot was custom-made, equipped with a 0.25 in copper ball. The reactants phenylacetylene a and benzyl azide B were milled with copper balls in a copper jar for 15 min, and 99% yield was obtained without adding other additives, as shown in Figure 4. In addition, this condition is also applicable to the one-pot CuAAc reaction between styrene a, benzyl bromide d, and sodium azide. The reaction time was 16 H, and other conditions were the same as the above reaction conditions in a copper pot. The yield reached 95%. Sodium azide, as a common dangerous goods in laboratory, will explode when exposed to metal or vibration. However, in this reaction, no explosion or exotherm caused by ball milling of sodium azide was observed. Because the reaction takes place in a closed metal container rather than in a non-traditional glass instrument, they believe that the azide reaction is safer under mechanochemical conditions than the traditional solvent reaction in a glass container. This one-pot ball milling-CuAAc involving sodium azide is also confirmed by the following article.

Ranu et al. Studied the three-component one-pot ball milling reaction of CuAAc consisting of halide a or arylboronic acid d, alkynyl compound B, and sodium azide^[59]. The catalyst is a Cu/Al₂O₃ catalyst obtained by stirring aqueous solution of copper sulfate pentahydrate and alkaline aluminum oxide at room temperature and evaporating water. Six 10 mm grinding balls were placed in the 25 mL stainless steel ball mill jar of the Retsch planetary ball mill PM100, and the ball milling was carried out at 600 R/min for 1 H. Pause and rest for 30 s every 10 min of ball milling. Under these conditions, one-pot CuAAc was achieved, as shown in Figure 5. The reaction is applied to terminal alkynyl compounds, including phenylacetylene substituted by o-, m-, p-substituted halogen, nitro and other groups, as well as aliphatic terminal alkynyl compounds, various substituted halides or borates; A one-pot method for preparing the corresponding 1, 4-disubstituted-1, 2, 3-triazole compound is realized together with sodium azide. Among them, the reaction of benzene bromide and phenylacetylene with sodium azide produced the highest yield of 96%. The substitution of electron-withdrawing groups and electron-donating groups on the phenyl acetylene benzene ring has no obvious effect on the reaction results. All ortho-, meta-, and para-substituted phenylacetylene reactions were homogeneous. After the reaction, the catalyst can be recycled for subsequent reactions. The catalyst can be reused for more than 8 times.

As a relatively safe pharmaceutical, the synthesis of triazole often faces the problem of non-ideal by-products. In order to improve the yield of drug synthesis and reduce by-products, Sahu et al. Synthesized a series of hybrid antiprotozoan compounds with quinine-triazole molecular skeleton by ball-milling-CuAAc^[60]. To prepare the azide in CuAAc, quinine a was reacted with dichloromethane and methanesulfonyl chloride to form intermediate B, which was then reacted with sodium azide under reflux conditions to form azide-dehydroxyquinine C, as shown in Scheme 6. The next CuAAc reaction takes place on Retsch's planetary ball mill PM100. The triazolyl compound was obtained after 8 H of ball milling of the azide reactant and the triple bond reactant in a 50 mL stainless steel ball mill jar containing ten 10 mm stainless steel grinding balls at a speed of 300 revolutions, catalyzed by copper sulfate and sodium ascorbate. Eighteen kinds of triple bond substrates were extended, and the yield was 45% ~ 91%. Three are listed here, such as d, e, and f. The synthesized quinine-triazole scaffold creates a hybrid antiprotozoal agent with multiple targets, and some of the compounds show significant antimalarial activity. The median lethal dose, no observed adverse effect level, and human equivalent dose of the most effective compound were further determined by acute and subacute toxicity studies in rodent models. Thus, systematic execution of synthetic strategies and careful evaluation of biological inferences enabled the production of antiprotozoan compounds through a series of quinine-triazole molecular hybrids synthesized by click chemistry. It has played a key role in the treatment of malaria and leishmaniasis, two of the most important parasitic threats in developing countries. Triazole contains heteroatomic nitrogen and oxygen, so it can be used as a reaction center to adsorb on the surface of low carbon steel metal to prevent the corrosion of active sites.

Velkannan et al. Synthesized a metal corrosion inhibitor by combining CuAAc under Aldo reaction and ball milling reaction conditions^[61]. As shown in Figure 7, N-propargyl isatin a, acetophenone B, and benzyl azide C were milled with copper oxide nanoparticles and triethylenediamine at a milling speed of 400 R/min for 30 min to give product d in 80% yield. The ball mill used was Fritsch's P6 planetary ball mill equipped with six 15 mm zirconia grinding balls in a 45 mL zirconia ball milling tank. Moreover, increasing the molar amount of copper oxide from 2.5% to 5% could increase the yield of 4A to 92%. The reaction was extended to a variety of substrates, such as substituted benzyl azide and acetophenone or acetone, substituted nitrogen-propargyl isatin, to synthesize 3-hydroxy-3-substituted oxindole-triazoles. Except for the azide of the electron-withdrawing nitro substitution reaction, the yields of the other reactions were 87% ~ 92%. Ten triazole compounds all showed corrosion inhibition for mild steel in 1 M hydrochloric acid solution at 25 ℃, among which compounds e, f, and H had higher corrosion inhibition efficiencies of 75. 2%, 74. 6%, and 79. 5%, respectively. They believe that the improvement of the sustained-release efficiency of the three is due to the following reasons: e has an additional hydroxyl group; The indole moiety at the third position of f has less hindering groups; The methyl substitution in the indole ring of H produces strong adsorption on the surface of low carbon steel by forming a dense film, thus protecting it from acid corrosion. In addition, due to the biological properties of the triazole, all triazole compounds were tested for activity against Aspergillus niger. Some exhibited anti-Candida albicans or anti-Escherichia coli activity.

Hern Hernáiz et al. Reported solvent-free ball milling-CuAAc for the synthesis of glucuronic acid sugar dendrimers for the treatment of dengue virus^[62]. The optimal reaction conditions were as follows: the molar ratio of azide reactant B to triple bond a compound was 7 times, the reaction was catalyzed by copper sulfate pentahydrate and sodium ascorbate, silica gel was added as grinding medium, and the reaction was milled for 11 H at 400 revolutions. In the planetary ball mill PM100 with the ball mill model of Retsch, 200 3 mm grinding balls or 30 5 mm small balls also achieve the optimal reaction conditions, and the conversion rate of the ideal product C is more than 99%, as shown in Figure 8. It was found that the reactant would be degraded when the ball milling rate was between 500 and 600 revolutions. For glucuronic acid sugar dendrimers, a microwave mechanical synthesis method of CuAAc is also adopted, and the used dimethylacetamide solvent can be fully recovered and reused.

The Diels-Alder reaction is a 1,4-cycloaddition reaction between a conjugated diene and a carbon-carbon double bond or a carbon-carbon triple bond to produce a six-membered cyclic olefin, such as norbornene. The product can be used to produce pharmaceutical intermediates, pesticides, fragrances, etc^[63]. Can also be used for ring-opening polymerization to prepare polynorbornene with high glass transition temperature^[64]. In addition, the Diels-Alder reaction induced by ball milling is also used to prepare MOF, functionalized graphene, etc^[65][66]. This chapter introduces the synthesis of aligned products by ball milling-Diels-Alder under non-catalytic and catalytic conditions, and its wide application in graphene.

Zhang et al. Combined solvent-free ball milling with Diels-Alder click reaction without any additives^[67]. Cyclopentadiene and maleic anhydride are milled with a 7 mm diameter grinding ball in a 25 mL ball mill jar at 1800 revolutions (30 Hz) for 30 min, as shown in Figure 9. The ball mill used was a Retsch vibratory ball mill MM 400. This condition applies to maleic anhydride or its derivatives, including oxygen, aliphatic hydrocarbon, or aromatic nitrogen-containing groups substituted at the X position in B. The reaction reached full conversion when the reaction ratio was 4% molar excess of cyclopentadiene. When the amounts of the reactants a and B are in equal proportion, unreacted maleic anhydride or its derivative remains. For this Diels-Alder reaction, ball milling has significant advantages over solution reaction or manual milling. Solution reaction and manual grinding require a longer time to ensure the completion of the reaction, but a longer time also leads to the dimerization of cyclopentadiene, which produces G in addition to the ideal product e. In order to increase the conversion, in the solution reaction, increasing the reaction temperature instead of increasing the reaction time leads to the formation of by-product f. Ball milling is the best way to avoid side reactions.

Li et al. Used ferric chloride to catalyze the Diels-Alder reaction between nitrogen-aryl aldimine C and styrene under room temperature ball milling conditions, which can be applied to the synthesis of tetrahydroquinoline^[68]. Tetrahydroquinolines are of great interest in medicinal chemistry because of their diverse biological activities. Firstly, aniline a and benzaldehyde B were ball-milled at 1800 rpm (30 Hz) for 50 min to generate N-aryl aldimine C, which was prepared for the Diels-Alder reaction with imine, as shown in Figure 10. Styrene and FeCl₃ were then added, and the Diels-Alder cycloaddition of styrene with in situ generated N-aryl aldimine C was promoted with FeCl₃. Cis-2,4-diphenyltetrahydroquinoline d was obtained by ball milling at 800 rpm (30 Hz) for 90 min with a yield of 87%. Both ball mills were carried out in a 25 mL stainless steel ball mill jar of a Retsch vibratory ball mill mm400 with a 7 MM diameter stainless steel ball. A series of aniline and benzaldehyde derivatives were used in this reaction, and the substituted anilines with electron-donating or electron-withdrawing groups on the benzene ring also had high conversion rates, which were more than 70%. Compared with the traditional reaction in organic solvent, the reaction activity of aniline with electron-donating substituents is higher in ball milling. Furthermore, based on high performance liquid chromatography analysis of the resulting reaction mixture, the tetrahydroquinoline promoted by ball milling was exclusively in the cis configuration. The high non-pair-isomerism selectivity may be due to the high local concentration of the reactants, which may lead to an enhancement of the second-order reaction rate, thus favoring the selective generation of products by kinetic control. However, in the synthesis of tetrahydroquinoline in organic solvents such as dichloromethane and tetrahydrofuran at reflux, a small amount of the trans-isomer was detected, the reaction being highly non-enantioselective.

Chiu et al. Applied ball milling Diels-Alder reaction to the modification of crowns^[69]. First, dipropynylammonium tetrafluoroborate B is reacted with crown ether a in acetonitrile to prepare crown compound C, as shown in Scheme 11. Next, crown C and 1,2,4,5-polytetrazine were ball-milled at room temperature for 9 H to form rotaxane d. The reaction took place in a Retsch mm200 vibrating ball mill with two 7 MM diameter stainless steel balls in two 5 mL stainless steel ball milling tanks at a milling frequency of 22.5 Hz. Pyrazine-terminated rotaxane d was formed by the Diels-Alder reaction of the macrocycle during ball milling. This resulted in the highly productive (81%) isolation of the smallest rotaxane reported to date. Rotaxanes, supramolecules composed of interlocking macrocycles and dumbbell-like components, are important materials for the construction of molecular devices due to the mechanical motion of their constituents. The ball milling synthesis method provides an efficient, convenient and environment-friendly method.

Zhang et al. Carried out in-situ Diels-Alder reaction by mechanochemical ball milling to exfoliate graphite and prepare functionalized graphene^[70]. Graphite reacts with maleic anhydride (MA), furfuryl alcohol (FAL) and furoic acid (FAC) respectively, as shown in Figure 12. Here, the multi-directional planetary ball mill is used to turn the planetary disk 360 ° on the basis of normal operation in the radial direction, so as to realize the multi-dimensional and multi-directional movement of the ball and the grinding tank. The ball mill model is QXQM-4L, 0.75 kW, TENCAN POWDER, Changsha, Hunan Province. In the zirconia ball milling tank, a total of 2750 G of zirconia balls were added, in which the mass ratio of grinding balls with diameters of 1 mm, 3 mm, and 5 mm was 5:3:2. The ball mill was rotated at a speed of 560 revolutions while turning at a speed of 20 revolutions for 12 H. Finally, functionalized graphene GMA, GFAL and GFAC were obtained. At the same time of in-situ functionalization, graphite was exfoliated into monolayer or bilayer graphene, and the ball milling process did not cause changes in the chemical structure of graphite. In the reaction process, graphite can be used as a diene or a dienophile for functional modification. Compared with the graphene functionalized with maleic anhydride, the graphene functionalized with furfuryl alcohol and furoic acid has a higher grafting rate. The [2 + 2] + 4] of graphene is more dominant than [4 + 2] in the ball milling process, that is, the reaction of graphene in the form of dienophile is more dominant in the ball milling process. In addition, compared with the heat treatment reaction, the ball milling method has higher efficiency and greater application prospects for the preparation of functionalized graphene. The surface tension test shows that functionalized graphene significantly reduces the original high surface energy characteristics of graphite, which provides a theoretical basis for the dispersion and shedding of graphite in suitable solvents. When the surface of graphite is organically functionalized, its thermal conductivity and electrical conductivity decrease, which is due to the destruction of the ordered electronic arrangement of graphite. Nevertheless, it still has excellent electrical conductivity, which has far-reaching significance for functionalized graphene, polymer composites and related applications.

Baek et al. Prepared graphene by Diels Alder reaction of graphite as diene with maleic anhydride or maleimide^[71]. The ball milling reaction took place in a Fritsch P6 planetary ball mill. In the stainless steel ball milling tank, 500 G of stainless steel with a diameter of 5 mm was added, and the ball was milled at a speed of 500 revolutions for 48 H. The carbon-carbon bonds of graphite are broken, and active carbon species are generated, mainly carbon radicals, carbon anions, and carbon cations, coupled with dienophiles, maleic anhydride, or maleimides, as shown in Scheme 13. Subsequently, the synthesized product was stirred with aqueous hydrochloric acid to completely acidify the remaining active material and remove metal impurities. Graphene was obtained as black powder. It can be found that in the presence of specific dienophiles, such as maleic anhydride (MA) or maleimide (MI), activated carbon species along the broken edge promote [4 + 2] cycloaddition more effectively, i.e., graphene is a diene and the residue is terminated after subsequent exposure to air moisture, forming an oxygen-containing group. The anhydride moiety at the edge of MA-GnPs can be hydrolyzed into carboxylic acid during the acid-mediated reaction. It is found that the graphene prepared by ball milling has edge-selective functionalization, so the graphene can be dispersed in various solvents. In brief, ball milling Diels-Alder reaction is a versatile method to chemically modify graphite into graphene nanosheets.

Chen et al. Said that the solvent-free ball milling Diels Alder reaction was not enough to allow a large number of reactants to fully contact, so the wet ball milling method was used to exfoliate graphite into graphene^[72]. During the experiment, graphite and maleic anhydride were added together to 30 mL of N-methylpyrrolidone and poured into a 50 mL stainless steel container filled with stainless steel balls. The container was sealed, filled/purged with nitrogen, and the mixture was ball-milled at a frequency of 40 Hz for 24 H, as shown in Figure 14. In this paper, the type of ball mill and the grinding ball information are not clearly given. Subsequently, the stainless steel container was placed in an oven at 80 ℃ for 3 d. The product is then treated with 1 M HCI to remove iron impurities, acidify the remaining active material, and rinse with water to a pH close to 7. The obtained product was predispersed in an ultrasonic apparatus for 1 H, and then centrifuged at 2000 revolutions for 20 min to collect the GMA dispersion. The effective functionalization results in good dispersion of GMA. To investigate the dispersion of GMA in water after heating to 200 ° C, the GMA dispersion was directly heated in a hydrothermal synthesis reactor. It can be found that the reverse Diels-Alder reaction endows GMA with reversible characteristics in dispersibility and thermal stability. Therefore, GMA coating was prepared from GMA in binder- and surfactant-free mixed solvent (water-ethanol). Scanning electron microscopy images show that the surface of the G-MA coating is smooth and flat. The conductivity of the GMA coating was 769 S·m^-1 at room temperature, and after heat treatment at 200 ° C for 2 H, the conductivity was greatly improved at 2000 S·m^-1, indicating that the conjugated structure was restored by the reverse Diels Alder reaction. This synthetic method of mechanized exfoliation of graphite into functionalized graphene is simple and convenient, which is conducive to large-scale preparation, and provides a powerful strategy for reversible modification of graphene's electronic properties, which is expected to expand its use.

Amine and isothiocyanate undergo click chemistry to produce thiourea. Thiourea has a wide range of applications in pharmacophysiology, including antibacterial, antimalarial, antiviral, and antitumor^{[73,74][75,76][77,78][79,80]}. Thioureas also have a wide range of applications in organocatalysts, including enantioselective Morita-Bayles-Hillman reactions, Michael additions, aldol reactions, acetalization of aldehydes and ketones, and Friedel-Crafts reactions^{[81⇓⇓⇓⇓⇓⇓⇓⇓~90]}. Therefore, a simple and efficient method for the preparation of thiourea is of great research significance. The method of thiourea formation by click reaction without solvent amine and isothiocyanate was reported by Kaupp et al in 2000, and the reaction was achieved by intermittent grinding within 1 day^[91]. Next, Wang et al. carried out the reaction by continuous grinding for 5 to 40 min^[92]. Later, Eckert-Maksi Maksić et al. Used a Retsch vibrating ball mill MM400 to realize the ball milling reaction, and proposed to use methanol liquid to assist the milling to promote the reaction of sterically and electronically hindered amino groups^[93]. Under the condition of η=0.25μL·mg^-1, the reaction conversion rate is obviously improved. They then compared the effects of manual grinding, ball milling and acetonitrile liquid-assisted grinding on the reaction of amines and isothiocyanates^[94]. In this systematic study, 49 symmetric or asymmetric N, N '-disubstituted thiourea products were synthesized. A series of amines and isothiocyanates were first screened with electron-donating and electron-withdrawing groups on the aromatic ring. The reaction was carried out in a 1: 1stoichiometry, and compared with manual grinding (15 – 20 min), the desired product could be quantitatively obtained in 10 min by automatic ball milling with one 12 mm stainless steel ball at 30 Hz through the click amine-isothiocyanate coupling reaction, proving the high efficiency of rapid thiourea synthesis by ball milling. Ball milling took place in a Retsch vibrating ball mill MM200. The reaction frequency was 30 Hz, and a 12 mm diameter grinding ball was placed in a 10 × 10 × 10 cm stainless steel ball milling tank. In addition, most of the time, simple manual mechanical mixing of the reaction mixture in mortar is used to obtain the product after only a few minutes of grinding. However, the combination of the less nucleophilic electron-withdrawing group in the para-amine and the less electrophilic electron-donating group in the isothiocyanate component results in an extended milling time required to achieve quantitative conversion. In this case, liquid-assisted grinding successfully shortened the reaction time and quantitatively improved the yield of N, N '-disubstituted thiourea. In this study, a variety of reaction scenarios are discussed, including a variety of substituted aromatics, aliphatic, heterologous rings, primary amines, and secondary amines, as shown in Scheme 15.

Anslyn et al. Reacted four acceptors with electron-withdrawing groups with Tris (2-aminoethyl) amine at 25 ℃ for 60 min under ball milling conditions^[95]. Without solvent or catalyst, the polymer is formed by condensation polymerization through the click reaction between amine and thiol, as shown in Figure 16. The reactivity correlates with the electron-withdrawing ability of the four electron-withdrawing group acceptors. For electron-withdrawing group acceptors, the addition reaction of the second amine group is slower than that of the first amine group because the electron-withdrawing ability is reduced after an amine group has been added. The resulting polymer is a thermosetting crosslinked polymer. The degradation ability of thermosetting polymer materials is one of the key points to realize green chemistry. Thermosetting materials generated by amine-thiol click chemistry can undergo unclick reaction by the addition of ethylenediamine under mild conditions. Although the products generated by the click dissociation reaction are different from the initial reactants, the click dissociation reaction realizes the degradation of the polymer, so that the four polymers are degradable thermosetting smart materials.

Oxy-nitrogen radical coupling reaction refers to the coupling reaction between oxy-nitrogen radical and other radicals. Because of the convenience and rapidity of the reaction, some literatures classify it as click chemistry^[96,97]. Kubota et al. Combined ball milling with oxygen-nitrogen radical coupling reaction^[98]. Ball-milling the fluorescent substance a containing oxygen and nitrogen free radicals and a polymer, under the high-energy impact of ball milling, the polymer is degraded and generates free radicals, and the free radicals perform a coupling reaction with the fluorescent substance a containing oxygen and nitrogen free radicals to generate fluorescent polymers B, C, d or e connected by covalent bonds, as shown in Figure 17. Blue fluorescence can be observed by UV-vis, fluorescence spectroscopy, or under UV light. The ball milling condition is that two 10 mm stainless steel balls are placed in a 5 mm stainless steel ball milling tank of a Retsch mm400 vibrating ball mill. Under the condition of ball milling at 30 Hz for 30 min, the oxygen-nitrogen radical coupling reaction can occur without solvents, catalysts and other additives. It was observed that the relative molecular mass of the polymer decreased and the PDI increased after ball milling, which proved that the homolytic cleavage of the main chain chemical bonds in the polymer occurred. The frequency of ball milling is in the range of 15 ~ 30 Hz, and with the increase of frequency, the relative molecular mass is lower, and the product contains more fluorescent substance a. This proves that the stronger the mechanical force, the more mechanical radicals can be generated. However, the oxygen-nitrogen radical coupling reaction could not be achieved by ultrasound. They also tried four polymers: polystyrene, polyethylene, poly (methyl methacrylate), and poly (phenylene sulfide), all of which showed good reactivity.

U Užarević et al. tested the yield of CuAAc reaction using different copper catalysts in the formation of target N-heterocyclic compounds of 1,2,3-triazole by ball milling^[57]. As shown in Table 3, divalent copper: copper acetate, monovalent copper: copper iodide, and zero-valent copper: brass all catalyzed the reaction. Experiments show that the three catalysts can achieve more than 50% and better yield. The order of catalytic effect from strong to weak is copper iodide > brass > copper acetate. Among them, copper acetate catalysis does not require additional additives or auxiliaries. Both copper iodide and brass catalysis require additional additives to maintain good conversion. In the solution reaction, copper iodide deprotonates the alkyne substrate under the action of N-ethyldiisopropylamine, which makes it easier to form the acylate intermediate of reactive Cu (I), thus increasing the yield by 10% to 20%^[99]. Thus, in ball milling, the catalysis of copper iodide is accompanied by N-ethyldiisopropylamine, achieving the best yield of the three catalysts. For the zero-valent metal copper, they used a ball mill jar made of copper, resulting in a yield of only within 20%, and the product contained copper particles. The experimental results can not achieve the high yield of CuAAc reaction obtained by copper ball mill^[56,58]. In order to avoid the presence of copper particles in the product, mechanically strong brass ball milling jars and brass milling balls containing copper and zinc are used. Although copper particles in the product are avoided, the yield is still within 25%. After the addition of N-ethyldiisopropylamine and acetic acid, the catalysis of brass resulted in complete conversion of the reactants to products. However, the catalytic effect of copper on CuAAc in solution reaction is usually very weak^[100]. For the different haloazide reactants, 1-azido-4-halobenzenes, ball milling and solution reactions exhibited the same yield trend, i.e., 1-azido-4-iodobenzene > 1-azidio-4-bromobenzene > 1-azidio-4-chlorobenzene > benzyl azide (without halogen substitution).

Ranu et al. Studied three-component one-pot CuAAc consisting of benzyl halide or arylboronic acid, sodium azide and terminal alkyne under (Cu/Al₂O₃) catalyst^[59]. A series of representative reactions of benzyl bromide, sodium azide and phenylacetylene on alumina-supported copper surface were carried out with varying amounts of catalyst loading, as shown in Table 4. It was found that no product was obtained without the use of a catalyst at the same time. At room temperature, the reaction did not occur after 24 H of conventional stirring with a magnetic stirrer. The addition of catalyst can improve the yield, and increasing the amount of catalyst can improve the yield even more, as shown in Table 4. The yield reached 96% at a molar amount of catalyst of 10%.

Li et al. Studied the effect of Lewis acid and Bronsted acid catalysts on the yield in ball-milled Diels-Alder reaction^[68]. Cis-6-methyl-2- (3-nitrophenyl) -4-phenyl-1,2,3,4-tetrahydroquinoline was selected as the model reaction, and the best catalyst was screened, as shown in Table 5. A variety of Lewis acids and Bronsted acids were tried, which have been extensively studied in the traditional solution synthesis of tetrahydroquinolines. The results, shown in Table, indicate that strong Lewis acids such as ZnCl₂, AlCl₃, FeCl₃, and BF₃·OEt₂ largely promote the Diels-Alder reaction, whereas Bronsted acid and other relatively weak Lewis acids act too inefficiently or not at all. FeCl₃ is the most efficient. It is readily available, inexpensive, sustainable, non-toxic, and environmentally friendly.

Cravotto et al. Studied the effect of the characteristics of the grinding balls on the yield of CuAAc using copper powder as a catalyst and phenylacetylene and azidooctyl ester^[56]. Under the condition that the total mass of the grinding balls is basically unchanged, the influence of the size of the grinding balls on the yield is explored by changing the size and the number of the balls. The conditions are as follows: 10 balls of 10 mm; 625 2 mm small balls and 10 10 mm large balls; 1500 2 mm small balls and 48 5 mm medium balls. With the increase of the number of beads, the conversion rate of the triazole derivative increased from 67% to 80%, and up to 99%, as shown in Table 6. The results show that under the condition of the same total mass, more pellets are beneficial to improve the reaction yield.

Ranu et al. Studied three-component one-pot CuAAc consisting of alkyl (benzyl) halide or arylboronic acid, sodium azide and terminal alkyne under (Cu/Al₂O₃) catalyst^[59]. It was found that when the catalyst (10 mol%) was fixed, the yield was increased by adding 1 equivalent of K₂CO₃, and the yield was basically not affected by increasing the amount of K₂CO₃, as shown in Table 7. Without the addition of catalyst, the reaction could not proceed even with the addition of K₂CO₃. The optimum yield of 91% was obtained with 10 mol% catalyst at K₂CO₃.

Stolle et al. Used the reaction of azidodecane and phenylacetylene to produce 1-decyl-4-phenyl-1H-1,2,3-triazole, as shown in Scheme 1, and investigated the effect of sodium ascorbate on the conversion and selectivity of the product^[55]. It is worth noting that the product was obtained in only 5 min reaction time using copper acetate and sodium ascorbate as catalysts. In the absence of sodium ascorbate, the reaction took 10 min to complete. Therefore, sodium ascorbate, as an additive, has a promoting effect on the reaction of less active substrates. Other copper salts, such as cuprous iodide and copper sulfate, have shown similar results. In the absence of copper salt, no reaction occurred within the reaction time tested.

The ratio of reactants has also been discussed in studies on the synthesis of glucuronic acid sugar dendrimers^[62]. In Table 8, triple bond reactant a has two triple bond groups and azide reactant B has one azide group. The ratio of reactants a and B should be 0.5: 1 when stoichiometry is strictly enforced. However, reaction No.1 according to the reaction conditions does not give a high conversion. As shown in Table 2, increasing the ratio of azide reactant B to catalyst increases the conversion of the reaction. Similarly, the conversion of the product increased to 99% by increasing the ratio of azide reactant to catalyst at 11 H reaction time. In this study, it was concluded that a higher ratio of azide reactant to catalyst led to an increase in triple bond conversion. They also studied the size of the balls in the ball mill, but in this synthesis, the size of the balls had a negligible effect on the reaction compared to the reactant ratio.

Ranu et al. Carried out a one-pot reaction of ball-milled CuAAc on the surface of (Cu/Al₂O₃) catalyst^[59]. Different reaction times were compared to explore the effect of reaction time on the yield. The results are shown in Table 9. Prolongation of the reaction time increases the yield. The best yield of 96% was obtained with a reaction time of 60 min.