Synthesis of Metal Organic Frameworks by Ball-Milling

Metal-organic frameworks (MOFs) have been used in adsorption, separation, catalysis, sensing, photo/electro/magnetics, and biomedical fields because of their unique periodic pore structure and excellent properties and have become a hot research topic in recent years. Ball milling is a method of small pollution, short time-consumption, and large-scale synthesis of MOFs. In recent years, many important advances have been made. In this paper, the influencing factors of MOFs synthesized by grinding were reviewed systematically from four aspects: auxiliary additives, metal sources, organic linkers, and reaction specific conditions (such as frequency, reaction time, and mass ratio of ball and raw materials). The prospect for the future development of the synthesis of MOFs by grinding was proposed.


Introduction
Metal organic frameworks (MOFs) are organic-inorganic hybrid materials with ordered pore structures assembled by metal centers and organic ligands through coordination bonds [1]. Due to their high porosity, high specific surface area, good thermal stability, and modified chemical properties, they have potential applications in adsorption, catalysis, separation, luminescent materials, optical films, drug delivery, etc. [2][3][4][5][6][7][8][9][10]. Since Yaghi proposed the concept of MOF [11], the research on MOF materials have been a hotspot over the past decades.
At present, the synthesis methods of MOFs mainly include the hydrothermal method, microwave assisted method, ultrasonic assisted method, electrochemical method, and ball milling (BM) method [12][13][14][15]. Ball milling is a mechanical technique widely used to grind powders into fine particles and blend materials. Being an environmentally-friendly, cost-effective technique, it has found wide application in various areas, such as metallurgy, mineral processing, construction, and synthesis of organic compounds [16], and currently it experiencing a renaissance because of its successful implementation for the synthesis of diverse organic, inorganic, and organic-inorganic hybrid nanomaterials [17]. The ball milling method has the advantages of a short reaction time, large preparation amounts, little or no solvent without heating, and promotion of the industrialization process of MOFs [17]. In 2012, James reviewed the previous application of ball milling in the synthesis of MOFs [15]. In recent years, a series of advances have been made in the synthesis of MOFs by ball milling [18]. In this paper, the influencing factors of the synthesis of MOFs by ball milling are systematically reviewed (Figure 1), including the effect of auxiliary additives, metal source type, ligand type, and reaction conditions, and the future outlook of development will be discussed.

Neat Grinding (NG)
The reported synthesis of MOFs by grinding were summarized in Table 1. Mechanochemical methods are mainly divided into two methods, one is the direct grinding or milling of reactants alone (called neat grinding, NG), and the other is grinding in the presence of additives, usually liquids, and/or ions [19], the latter is the improvement of the former. Sometimes, the addition of a small amount of liquid can significantly increase the activity of the reactants, making the reaction easier and more thorough. The initial ball milling method is a neat grinding method, which is a method in which the product is directly obtained by directly mixing ball milling with solid raw materials. In 2006, Pichon et al. [20] first synthesized porous MOF copper isotonic acid Cu(INA)2 by mechanical ball milling. Since then, this method has attracted much attention. Thereafter, copper-based MOFs [21][22][23], such as Cu(INA)2, HKUST-1 (Cu-BTC, HKUST= Hong Kong University of Science and Technology), MOF-14 (Cu-BTB), Zn-based MOFs [19,[24][25][26][27], such as MOF-5, Zn2(FMA)2(BPY), ZIF-8 (ZIF=Zeolitic Imidazolate Framework), ZIF-4, etc., Ni(ADC)(H2O)4 [21], and so on have been synthesized. Pichon et al. [21] systematically studied the reaction of 60 kinds of metal salts (metal salts of Ni, Cu, or Zn with various counterions) and organic linkers of five carboxylic acids by NG. Analyzed by powder Xray diffraction (PXRD), they found that 38 mixtures produced crystalline products and 29 reactions were quantitative. However, only two porous MOFs (Cu(INA)2 and HKUST-1) were obtained, the others being known or previously unknown coordination polymers. The advantage of the neat grinding method is that it does not require any auxiliary liquid, and it is a completely non-polluting and clean method. However, in many cases, limited by the activity of the raw materials, this method has great limitations for application in synthesis of MOFs.

Neat Grinding (NG)
The reported synthesis of MOFs by grinding were summarized in Table 1. Mechanochemical methods are mainly divided into two methods, one is the direct grinding or milling of reactants alone (called neat grinding, NG), and the other is grinding in the presence of additives, usually liquids, and/or ions [19], the latter is the improvement of the former. Sometimes, the addition of a small amount of liquid can significantly increase the activity of the reactants, making the reaction easier and more thorough. The initial ball milling method is a neat grinding method, which is a method in which the product is directly obtained by directly mixing ball milling with solid raw materials. In 2006, Pichon et al. [20] first synthesized porous MOF copper isotonic acid Cu(INA) 2 by mechanical ball milling. Since then, this method has attracted much attention. Thereafter, copper-based MOFs [21][22][23], such as Cu(INA) 2 , HKUST-1 (Cu-BTC, HKUST = Hong Kong University of Science and Technology), MOF-14 (Cu-BTB), Zn-based MOFs [19,[24][25][26][27], such as MOF-5, Zn 2 (FMA) 2 (BPY), ZIF-8 (ZIF = Zeolitic Imidazolate Framework), ZIF-4, etc., Ni(ADC)(H 2 O) 4 [21], and so on have been synthesized. Pichon et al. [21] systematically studied the reaction of 60 kinds of metal salts (metal salts of Ni, Cu, or Zn with various counterions) and organic linkers of five carboxylic acids by NG. Analyzed by powder X-ray diffraction (PXRD), they found that 38 mixtures produced crystalline products and 29 reactions were quantitative. However, only two porous MOFs (Cu(INA) 2 and HKUST-1) were obtained, the others being known or previously unknown coordination polymers. The advantage of the neat grinding method is that it does not require any auxiliary liquid, and it is a completely non-polluting and clean method. However, in many cases, limited by the activity of the raw materials, this method has great limitations for application in synthesis of MOFs.

Liquid-Assisted Grinding (LAG)
When a small amount of liquid is added, the reaction activity can be greatly enhanced to promote the reaction, that is, the so-called liquid-assisted grinding (LAG) method. Commonly used auxiliary solvents are water [47], ethanol [33], N,N-dimethylformamide (DMF) [28], mixtures thereof [35], and the like. Yang et al. [28] used a water/ethanol mixed solvent as an auxiliary solvent to systematically study the effect of different solvent amounts on the synthesis of Cu 3 (BTC) 2 . They found that in the absence of solvent, anhydrous Cu(OAc) 2 and H 3 BTC can produce Cu 3 (BTC) 2 . If Cu(OAc) 2 containing crystal water, of which crystal water could also be regarded as an auxiliary solvent, the crystallinity of the product can be improved. The addition of an appropriate amount of external solvent to the system not only improves the crystallinity of the reaction product, but also increases the fluidity of the reactant. As the amount of solvent increases from 50 to 400 µL, the crystallinity of the reaction product becomes better.
Stolar et al. [35] systematically studied the effect of nineteen common solvents on the synthesis of HKUST-1 by in-situ XRD. Weak polar liquid additives such as hexane, cyclohexane, toluene, chloroform, dichloromethane, and even polar nitromethane have little enhancement to the reaction compared to NG. In contrast, the aid of protonic liquid additives greatly facilitated the formation of HKUST-1. Alcohols, which are polar protic liquids, are most effective in accelerating the formation of HKUST-1, which provides the fastest reaction and highest yield. Using methanol as an additive, HKUST-1 was observed almost immediately in the reaction mixture, and the maximum conversion was achieved after grinding for 5 min. When the same volume of ethanol or isopropanol was used as the additive, a slower conversion was observed, and it took about 20 min to complete the reaction. Polar aprotic liquid additives, such as acetonitrile, acetone, DMF, N,N-diethylformamide (DEF), are less efficient than protic liquids in promoting HKUST-1 formation. These results indicate that the coordination ability of liquid additives has an important influence on the mechanochemical synthesis of HKUST-1.
The auxiliary solvent not only increases the reaction rate and yield, but also affects the final product type.  6 ] can be obtained with the aid of DMF and water, respectively [47]. The Friščić group [64] also found that different auxiliary fluids would affect the structure of the product.

Ion and Liquid Assisted Grinding (ILAG)
In recent years, ions and liquids have been used simultaneously for assisting the mechanochemical synthesis of MOFs, which is named ion and liquid assisted grinding (ILAG) method. In 2009, Friščić et al. [19] demonstrated that the catalytic amount of simple salts can accelerate the MOF synthesis using ZnO as a metal source and H2BDC and DABCO as mixed ligands for the first time. The salts induce the formation of product structure through template effects. Salts are contained in the pores of MOF under mechanochemical conditions, and ion templates may be an important factor in the synthesis of neutral MOFs. Subsequently, they [27] further studied the three imidazoles (HIm, HMeIm, and HEtIm) under the auxiliary conditions of different solvents (DMF, DEF, and EtOH) and different salts (NH4NO3, NH4CH3SO3, and (NH4)2SO4) with ZnO as the metal source ( Figure 3). They found that the ammonium salt alone promoted the synthesis of ZIF even in the absence of liquid. The substoichiometric ammonium salt promotes the reaction of imidazole with ZnO, and in most cases, quantitative yields are obtained. ILAG is mainly used in the synthesis of MOF using metal oxide as a metal source. In the case of metal salts as a metal source, the anti-anion also plays a role as an ion template to some extent.
Pilloni et al. [30] proposed the first example of synthesis of Fe-MOF by ILAG. A larger amount (5 mL) of an aqueous solution of tetramethylammonium hydroxide was used as an auxiliary solvent to obtain MIL-100 (MIL = Matérial Institut Lavoisier). The tetramethylamine hydroxide acts as a salt and the solvent water acts as the auxiliary liquid. It needs to point out that the amount of auxiliary liquid used in this experiment has been much larger than that used in LAG.

Ion and Liquid Assisted Grinding (ILAG)
In recent years, ions and liquids have been used simultaneously for assisting the mechanochemical synthesis of MOFs, which is named ion and liquid assisted grinding (ILAG) method. In 2009, Friščić et al. [19] demonstrated that the catalytic amount of simple salts can accelerate the MOF synthesis using ZnO as a metal source and H 2 BDC and DABCO as mixed ligands for the first time. The salts induce the formation of product structure through template effects. Salts are contained in the pores of MOF under mechanochemical conditions, and ion templates may be an important factor in the synthesis of neutral MOFs. Subsequently, they [27] further studied the three imidazoles (HIm, HMeIm, and HEtIm) under the auxiliary conditions of different solvents (DMF, DEF, and EtOH) and different salts (NH 4 NO 3 , NH 4 CH 3 SO 3 , and (NH 4 ) 2 SO 4 ) with ZnO as the metal source ( Figure 3). They found that the ammonium salt alone promoted the synthesis of ZIF even in the absence of liquid. The substoichiometric ammonium salt promotes the reaction of imidazole with ZnO, and in most cases, quantitative yields are obtained. ILAG is mainly used in the synthesis of MOF using metal oxide as a metal source. In the case of metal salts as a metal source, the anti-anion also plays a role as an ion template to some extent.
Pilloni et al. [30] proposed the first example of synthesis of Fe-MOF by ILAG. A larger amount (5 mL) of an aqueous solution of tetramethylammonium hydroxide was used as an auxiliary solvent to obtain MIL-100 (MIL = Matérial Institut Lavoisier). The tetramethylamine hydroxide acts as a salt and the solvent water acts as the auxiliary liquid. It needs to point out that the amount of auxiliary liquid used in this experiment has been much larger than that used in LAG.

Salt Assisted Grinding (SAG)
Salt can be regarded as a solid solvent. The ball milling method also can be used to prepare MOF materials under the auxiliary conditions of salt. This process is called saltassisted grinding method, referred to as SAG. Yang et al. [36] used NaCl as a solid solvent and template to assist an efficiently mechanochemical synthesis and postsynthesis of hierarchically micro-, meso-and even microporous HKUST-1, where NaCl were used here as a solid solvent to initially pre-grind with H3BTC and Cu(OAc)2·H 2O, respectively, for 1 min, then both mixtures were combined together for a further 20 min of grinding ( Figure  4). These salt-assisted mechanochemically post-synthesized MOFs show more promising performance on iodine vapor capture than the solvothermally-synthesized product. Steenhaut et al. [37] found that some peak broadening as well as slightly bumpy background features can be observed for the materials synthesized by the SAG method compared to the LAG and single crystal samples. This is indicative of the presence of a significant number of structural defects in those materials. Interestingly, the structure rearranges upon removal of the sodium chloride particles trapped in the cavities formed during the mechanochemical synthesis, and that this rearrangement is dependent on the applied post-synthetic treatment.

Salt Assisted Grinding (SAG)
Salt can be regarded as a solid solvent. The ball milling method also can be used to prepare MOF materials under the auxiliary conditions of salt. This process is called salt-assisted grinding method, referred to as SAG. Yang et al. [36] used NaCl as a solid solvent and template to assist an efficiently mechanochemical synthesis and postsynthesis of hierarchically micro-, meso-and even microporous HKUST-1, where NaCl were used here as a solid solvent to initially pre-grind with H 3 BTC and Cu(OAc) 2 ·H 2 O, respectively, for 1 min, then both mixtures were combined together for a further 20 min of grinding ( Figure 4). These salt-assisted mechanochemically post-synthesized MOFs show more promising performance on iodine vapor capture than the solvothermally-synthesized product. Steenhaut et al. [37] found that some peak broadening as well as slightly bumpy background features can be observed for the materials synthesized by the SAG method compared to the LAG and single crystal samples. This is indicative of the presence of a significant number of structural defects in those materials. Interestingly, the structure rearranges upon removal of the sodium chloride particles trapped in the cavities formed during the mechanochemical synthesis, and that this rearrangement is dependent on the applied post-synthetic treatment.

Salt
The types of salts used as metal sources can be classified into inorganic acid salts (see lines 1-9 and lines 44-52 in Table 1) and organic acid salts (see lines 10-43 in Table 1), of which the most widely used inorganic acid salts are nitrates, sulfates, and carbonates, and the most used organic acid salts are acetates, derivatized acetates, and other carboxylates. For the salts with the same metal ions, the essential difference in them lies in the difference of anti-anions which induced different solubility and coordination ability. However, in general, the counter anions in the inorganic acid salts did not show a significant effect in the ball milling reaction. The most studied metal ions are copper and zinc [21], and later extended to other salts such as Ni [9,21,36], Fe [30,[65][66][67], Co [57,68,69], In [31,46], etc.
The amount of crystal water contained in the salt also influences the reaction, especially for the NG process, because crystal water also plays a role as an auxiliary solvent to some extent. For example, Li et al. [23] used copper nitrate Cu(NO3)2·H 2O containing only one crystal water as the metal source, and obtained HKUST-1 under NG conditions.
The counteractant anion of an organic acid salt may act as a Brønsted base during the reaction to promote deprotonation of the carboxyl group in the ligand, thereby facilitating coordination with the metal ion and promoting the formation of MOF. The earliest research and the most widely studied is the synthesis of MOF using copper acetate as a metal source. Pichon et al. [20] first explored the reaction of Cu(OAc)2 and HINA to form Cu(INA)2 by NG as early as 2006. Subsequently, they [21] studied the reaction of CuX2 (X2 = (OAc)2, (HCO2)2, (F3CCO2)2, (acac)2, (F6acac)2), and H3BTC and also yielded HKUST-1 under NG conditions. When the strong inorganic acid salts are used as the metal sources, the same product can be obtained, which indicates that the anti-anion does not exhibit a significant effect therein. The HKUST-1 was very easily to produced whatever by NG or LAG. Schlesinger et al. [33] successfully prepared HKUST-1 with Cu(OAc)2·H 2O and H3BTC under NG or LAG with DMF as an auxiliary solvent.

Salt
The types of salts used as metal sources can be classified into inorganic acid salts (see lines 1-9 and lines 44-52 in Table 1) and organic acid salts (see lines 10-43 in Table 1), of which the most widely used inorganic acid salts are nitrates, sulfates, and carbonates, and the most used organic acid salts are acetates, derivatized acetates, and other carboxylates. For the salts with the same metal ions, the essential difference in them lies in the difference of anti-anions which induced different solubility and coordination ability. However, in general, the counter anions in the inorganic acid salts did not show a significant effect in the ball milling reaction. The most studied metal ions are copper and zinc [21], and later extended to other salts such as Ni [9,21,36], Fe [30,[65][66][67], Co [57,68,69], In [31,46], etc.
The amount of crystal water contained in the salt also influences the reaction, especially for the NG process, because crystal water also plays a role as an auxiliary solvent to some extent. For example, Li et al. [23] used copper nitrate Cu(NO 3 ) 2 ·H 2 O containing only one crystal water as the metal source, and obtained HKUST-1 under NG conditions.
The counteractant anion of an organic acid salt may act as a Brønsted base during the reaction to promote deprotonation of the carboxyl group in the ligand, thereby facilitating coordination with the metal ion and promoting the formation of MOF. The earliest research and the most widely studied is the synthesis of MOF using copper acetate as a metal source. Pichon et al. [20] first explored the reaction of Cu(OAc) 2 and HINA to form Cu(INA) 2 by NG as early as 2006. Subsequently, they [21] studied the reaction of CuX 2 (X 2 = (OAc) 2 , (HCO 2 ) 2 , (F 3 CCO 2 ) 2 , (acac) 2 , (F 6 acac) 2 ), and H 3 BTC and also yielded HKUST-1 under NG conditions. When the strong inorganic acid salts are used as the metal sources, the same product can be obtained, which indicates that the anti-anion does not exhibit a significant effect therein. The HKUST-1 was very easily to produced whatever by NG or LAG. Schlesinger et al. [33] successfully prepared HKUST-1 with Cu(OAc) 2 ·H 2 O and H 3 BTC under NG or LAG with DMF as an auxiliary solvent.
Besides, Ni-MOF can also be prepared. Our group [9] studied the reaction with carboxylic acid ligands (H 3 BTC) with nickel acetate tetrahydrate as the metal source. It was found that without the aid of any solvent, the Ni-MOF (Ni 3 (BTC) 2 ·12H 2 O, confirmed by XRD) was produced after grinding for only 1 min.
Moreover, Yuan and colleagues [47] explored the ball milling reaction of carbonates of rare earth metals such as Y, Sm, Gd, Tb, Dy, Er, Yb, and H 3 BTC under the assistance of DMF and water, respectively. Y 2 (CO 3 ) 3  In general, weak acid salts have higher reactivity than strong acid salts, and the types of metals that can react are more abundant, and more kinds of MOFs are obtained. Especially, rare earth metal weak acid salts are studied for the synthesis of rare earth metal-based MOFs providing a feasible approach for utilization of rare earth resources more efficiently and valuably.
Besides, Ni-MOF can also be prepared. Our group [9] studied the reaction with carboxylic acid ligands (H3BTC) with nickel acetate tetrahydrate as the metal source. It was found that without the aid of any solvent, the Ni-MOF (Ni3(BTC)2·12H2O, confirmed by XRD) was produced after grinding for only 1 min.
In general, weak acid salts have higher reactivity than strong acid salts, and the types of metals that can react are more abundant, and more kinds of MOFs are obtained. Especially, rare earth metal weak acid salts are studied for the synthesis of rare earth metalbased MOFs providing a feasible approach for utilization of rare earth resources more efficiently and valuably.

Hydride
There are only one case on the preparation of MOF using hydride as a metal source (see line 94 Table 1) [58]. Singh et al. used YH3 as a metal source to study the reaction with H3BTC under LAG conditions, and finally obtained MIL-78. Although there is no report on the reaction of such raw materials after that, the hydrogen in the hydride can act as Figure 6. Images of the mechanochemically synthesized MM -MOF-74 materials. Reprinted with permission from [57]. Copyright © 2020 American Chemical Society.

Hydride
There are only one case on the preparation of MOF using hydride as a metal source (see line 94 Table 1) [58]. Singh et al. used YH 3 as a metal source to study the reaction with H 3 BTC under LAG conditions, and finally obtained MIL-78. Although there is no report on the reaction of such raw materials after that, the hydrogen in the hydride can act as strong basic ions, which can very strongly capture the hydrogen in the ligand, thereby making it easier to coordinate with the metal ions, so there may be a special effect when hydrides reacted with certain ligands containing hydrogen that are not easily dissociated (such as alcoholic hydroxyl groups).

Secondary Building Units (SBU) of Metal Oxygen Clusters
Most of the stable MOFs are composed of SBUs of metal oxygen clusters and ligands. When simple compounds are used as metal sources, the metal ions in these metal sources need to be assembled into metal oxygen clusters first. This is difficult to achieve in ball milling reactions. If SBUs are priorly pre-assembled with other methods, it is easier to produce MOFs with the SBUs and corresponding ligands. For example, Lewiński [24] first synthesized the precursor of zinc for ball milling synthesis of MOF-5 (see line 95 in Table 1). In the process of mechanical synthesis of UiO-66 and its analogues (see lines 96,97 in Table 1), Užarević first synthesizes the precursor of zirconium, Zr 6 O 4 (OH) 4 12+ clusters and then adds the ligand for the ball milling reaction (Figure 7) [59,61]. UiO-67 can also be prepared by the similar method (see lines 98,99 in Table 1) [62]. This is also the only successful route to synthesize zirconium-based MOF by ball milling.   [57]. Copyright © 2020 American Chemical Society.

Hydride
There are only one case on the preparation of MOF using hydride as a metal source (see line 94 Table 1) [58]. Singh et al. used YH3 as a metal source to study the reaction with H3BTC under LAG conditions, and finally obtained MIL-78. Although there is no report on the reaction of such raw materials after that, the hydrogen in the hydride can act as strong basic ions, which can very strongly capture the hydrogen in the ligand, thereby making it easier to coordinate with the metal ions, so there may be a special effect when hydrides reacted with certain ligands containing hydrogen that are not easily dissociated (such as alcoholic hydroxyl groups).

Secondary Building Units (SBU) of Metal Oxygen Clusters
Most of the stable MOFs are composed of SBUs of metal oxygen clusters and ligands. When simple compounds are used as metal sources, the metal ions in these metal sources need to be assembled into metal oxygen clusters first. This is difficult to achieve in ball milling reactions. If SBUs are priorly pre-assembled with other methods, it is easier to produce MOFs with the SBUs and corresponding ligands. For example, Lewiński [24] first synthesized the precursor of zinc for ball milling synthesis of MOF-5 (see line 95 in Table  1). In the process of mechanical synthesis of UiO-66 and its analogues (see lines 96,97 in Table 1), Užarević first synthesizes the precursor of zirconium, Zr6O4(OH)4 12+ clusters and then adds the ligand for the ball milling reaction (Figure 7) [59,61]. UiO-67 can also be prepared by the similar method (see lines 98,99 in Table 1) [62]. This is also the only suc-

Effect of Reaction Conditions
The synthesis of MOF by the ball milling method is also affected by reaction conditions such as frequency or rotation speed, reaction time, and spheres-mass ratio. Different metal sources and ligands have different activities, and the requirements for the reaction conditions are also different.

Frequency or Rotation Speed
In general, only Cu-and Zn-based MOFs can be synthesized at a low frequency of 25-50 Hz, due to Cu ions and Zn ions have good coordination properties. While Fe-MOF always requires 2500 rpm to synthesize [30]. The existing reports have little research on the effect of frequency on synthetic products. Our research group used Ni(OAc)2·2H2O and H3BTC to study the effect of frequency (10-50 Hz) on the reaction results in detail, and found that the product can be obtained from 10 Hz, but the yield of the reaction is low. As the frequency increases, the type of the product does not change and the yield of the reaction increases accordingly [9].

Reaction Time
The reaction time generally only affects the conversion of the reaction but does not affecting the type of product. However, under certain specific reactions, the reaction time affects the type of MOF product and long-term ball milling even makes an MOF structure become amorphous. For example, when ZnO and HEtIm were ball-milled with the aid of DMF and NH4CH3SO3. ZIF of RHO topology was formed at 5 min, and ZIF of ANA type was obtained after 30 min. The product obtained by reaction for 60 min was ZIF of quartz (qtz) topology (Figure 9) [27]. This sequence reflects that as the reaction time increases, the increase in the density of the tetrahedral nodes in the resulting product, and the energy of the framework also increases. The nature of the metastable state of the RHO framework is consistent with its difficulty in reproducible synthesis from solution. This sequence also

Effect of Reaction Conditions
The synthesis of MOF by the ball milling method is also affected by reaction conditions such as frequency or rotation speed, reaction time, and spheres-mass ratio. Different metal sources and ligands have different activities, and the requirements for the reaction conditions are also different.

Frequency or Rotation Speed
In general, only Cu-and Zn-based MOFs can be synthesized at a low frequency of 25-50 Hz, due to Cu ions and Zn ions have good coordination properties. While Fe-MOF always requires 2500 rpm to synthesize [30]. The existing reports have little research on the effect of frequency on synthetic products. Our research group used Ni(OAc) 2 ·2H 2 O and H 3 BTC to study the effect of frequency (10-50 Hz) on the reaction results in detail, and found that the product can be obtained from 10 Hz, but the yield of the reaction is low. As the frequency increases, the type of the product does not change and the yield of the reaction increases accordingly [9].

Reaction Time
The reaction time generally only affects the conversion of the reaction but does not affecting the type of product. However, under certain specific reactions, the reaction time affects the type of MOF product and long-term ball milling even makes an MOF structure become amorphous. For example, when ZnO and HEtIm were ball-milled with the aid of DMF and NH 4 CH 3 SO 3 . ZIF of RHO topology was formed at 5 min, and ZIF of ANA type was obtained after 30 min. The product obtained by reaction for 60 min was ZIF of quartz (qtz) topology (Figure 9) [27]. This sequence reflects that as the reaction time increases, the increase in the density of the tetrahedral nodes in the resulting product, and the energy of the framework also increases. The nature of the metastable state of the RHO framework is consistent with its difficulty in reproducible synthesis from solution. This sequence also reflects the reduction trend in solvent accessible volume: RHO (60.1%) > ANA (44.1%) > qtz (no pores). The reaction follows a path described by Ostwald's rule of stages, i.e., from metastable to increasingly more stable product structures [75], which is quite often found in zeolites [76] and in nature [77].
Crystals 2021, 11, x FOR PEER REVIEW 12 of 20 reflects the reduction trend in solvent accessible volume: RHO (60.1%) > ANA (44.1%) > qtz (no pores). The reaction follows a path described by Ostwald's rule of stages, i.e., from metastable to increasingly more stable product structures [75], which is quite often found in zeolites [76] and in nature [77].

Spheres-Mass Ratio
Spheres-mass ratio is also an important factor in conventional ball milling synthesis, but it is rarely discussed in the synthesis of MOFs. Patrick A. Julien et al. [53] studied the synthesis mechanism of MOF-74 using 2.9 and 3.5 g spheres, respectively (approximately 400 mg of zinc oxide and H4dhta were charged). When water is an auxiliary solvent, a quantitative Zn-MOF-74 product is obtained after 3.5 min of grinding under 3.5 balls, but a quantitative complete reaction is not achieved when 2.9 g of the ball is ground. In the case of DMF as an auxiliary solvent, under 2.9 g of ball milling conditions, an intermediate phase (2) was formed after about 20 min, and the product of Zn-MOF-74 appeared after about 45 min, and when a heavier 3.5 g ball was used, the above-mentioned time was shortened to 10 and 40 min, respectively. This shows that a larger spheres-mass ratio favors a faster reaction.

Microwave or Ultrasonic Wave-Assisted Ball
The microwave-assisted ball milling method was proposed by Ding's group, is based on a solid-liquid ball-milling approach that involves using a ball-milling machine in a microwave oven. The coupling of ball milling and microwave can induce some nanocrystal materials to produce materials like MOFs. Compared to hydro(solvo)thermal methods, the microwave-assisted ball milling method requires less time for preparing MOFs. They have successfully used this method to synthesize a few of MOFs, such as Fe(III)-BTC [65][66][67], Co-BTC [68,69], Cu-BTC [69], Cu-BDC [69], and Co-BDC [69] and explored their application for adsorptive removal of organic dyes from aqueous solutions. This group also developed an ultrasonic wave-assisted ball milling technology to successfully synthesize

Spheres-Mass Ratio
Spheres-mass ratio is also an important factor in conventional ball milling synthesis, but it is rarely discussed in the synthesis of MOFs. Patrick A. Julien et al. [53] studied the synthesis mechanism of MOF-74 using 2.9 and 3.5 g spheres, respectively (approximately 400 mg of zinc oxide and H 4 dhta were charged). When water is an auxiliary solvent, a quantitative Zn-MOF-74 product is obtained after 3.5 min of grinding under 3.5 balls, but a quantitative complete reaction is not achieved when 2.9 g of the ball is ground. In the case of DMF as an auxiliary solvent, under 2.9 g of ball milling conditions, an intermediate phase (2) was formed after about 20 min, and the product of Zn-MOF-74 appeared after about 45 min, and when a heavier 3.5 g ball was used, the above-mentioned time was shortened to 10 and 40 min, respectively. This shows that a larger spheres-mass ratio favors a faster reaction.

Microwave or Ultrasonic Wave-Assisted Ball
The microwave-assisted ball milling method was proposed by Ding's group, is based on a solid-liquid ball-milling approach that involves using a ball-milling machine in a microwave oven. The coupling of ball milling and microwave can induce some nanocrystal materials to produce materials like MOFs. Compared to hydro(solvo)thermal methods, the microwave-assisted ball milling method requires less time for preparing MOFs. They have successfully used this method to synthesize a few of MOFs, such as Fe(III)-BTC [65][66][67], Co-BTC [68,69], Cu-BTC [69], Cu-BDC [69], and Co-BDC [69] and explored their application for adsorptive removal of organic dyes from aqueous solutions. This group also developed an ultrasonic wave-assisted ball milling technology to successfully synthesize Cu-BTC with truncated octahedral shape, and showed significantly reduction of reaction time and effectively improvement of yield [78].

Comparison of Ball-Milling and Solution Method
The ball milling method is not only a green and fast synthesis method compared with the traditional hydrothermal method [79,80], but also would be expected to afford new MOFs, which have been prepared exclusively by ball-milling or prepared for the first time. For example, Beldon et al. [16] found two previously unknown ZIFs in a limited set of 48 experiments. ILAG of ZnO and HIm with DEF and (NH 4 ) 2 SO 4 or NH 4 CH 3 SO 3 resulted in a yet unidentified product that spontaneously transformed into the nog framework upon aging. ILAG of ZnO and HEtIm with NH 4 NO 3 provided an unknown crystalline material, which is a close-packed hexagonal framework with the qtz topology. There are also some MOFs that have been first prepared by ball-milling. Morsali's group [32] reported two new three-dimensional porous Cd(II)-based metal-organic frameworks, [Cd 2 (oba) 2 (bpdb) 2 ] n (TMU-8) and [Cd(oba)(BPY) 2 ] n (TMU-9), synthesized via mechanosynthesis for the first time. Besides, ball milling can obtain products that are completely different from the solution method [79][80][81], even if the metal salt and ligand are the same. For example, PXRD patterns of products obtained by water slurry (WS) and mechanochemical (BM and twin screw extrusion, TSE) are different from the same starting materials of Co(NO 3 ) 2 ·6H 2 O and BPY [80] (Figure 10). Moreover, the ball milling method can introduce more defects into MOFs ( Figure 11) [82,83], which makes their specific surface area larger and pore structure richer, which is conducive to its application in adsorption [23] and catalysis [44]. Li et al. [23] demonstrated that HKUST-1 synthesized by mechanochemical method has a larger specific surface area and higher pore volume than HKUST-1 synthesized by hydrothermal method, and it has a medium-micro and double-pored structure, in which the micropores are conducive to the strong adsorption of adsorbate molecules, and the porous mesopores are conducive to the adsorption and diffusion of adsorbate molecules. In addition, long-term ball milling may also cause the MOF structure to collapse, lose its periodic structure, and become amorphous [84,85], which is difficult to achieve in a solution phase reaction. The ball milling method can also make it more convenient to combine MOFs and other materials to form binary or even multiple composite materials [18,[86][87][88][89][90][91][92][93], such as GO/MOFs composites [94][95][96][97][98][99], POM@MOFs [100][101][102], TiO 2 /UiO-66-NH 2 [103][104][105] composite, etc. Cu-BTC with truncated octahedral shape, and showed significantly reduction of reaction time and effectively improvement of yield [78].

Comparison of Ball-Milling and Solution Method
The ball milling method is not only a green and fast synthesis method compared with the traditional hydrothermal method [79,80], but also would be expected to afford new MOFs, which have been prepared exclusively by ball-milling or prepared for the first time. For example, Beldon et al. [16] found two previously unknown ZIFs in a limited set of 48 experiments. ILAG of ZnO and HIm with DEF and (NH4)2SO4 or NH4CH3SO3 resulted in a yet unidentified product that spontaneously transformed into the nog framework upon aging. ILAG of ZnO and HEtIm with NH4NO3 provided an unknown crystalline material, which is a close-packed hexagonal framework with the qtz topology. There are also some MOFs that have been first prepared by ball-milling. Morsali's group [32] reported two new three-dimensional porous Cd(II)-based metal-organic frameworks, [Cd2(oba)2(bpdb)2]n (TMU-8) and [Cd(oba)(BPY)2]n (TMU-9), synthesized via mechanosynthesis for the first time. Besides, ball milling can obtain products that are completely different from the solution method [79][80][81], even if the metal salt and ligand are the same. For example, PXRD patterns of products obtained by water slurry (WS) and mechanochemical (BM and twin screw extrusion, TSE) are different from the same starting materials of Co(NO3)2•6H2O and BPY [80] (Figure 10). Moreover, the ball milling method can introduce more defects into MOFs ( Figure 11) [82,83], which makes their specific surface area larger and pore structure richer, which is conducive to its application in adsorption [23] and catalysis [44]. Li et al. [23] demonstrated that HKUST-1 synthesized by mechanochemical method has a larger specific surface area and higher pore volume than HKUST-1 synthesized by hydrothermal method, and it has a medium-micro and double-pored structure, in which the micropores are conducive to the strong adsorption of adsorbate molecules, and the porous mesopores are conducive to the adsorption and diffusion of adsorbate molecules. In addition, long-term ball milling may also cause the MOF structure to collapse, lose its periodic structure, and become amorphous [84,85], which is difficult to achieve in a solution phase reaction. The ball milling method can also make it more convenient to combine MOFs and other materials to form binary or even multiple composite materials [18,[86][87][88][89][90][91][92][93], such as GO/MOFs composites [94][95][96][97][98][99], POM@MOFs [100][101][102], TiO2/UiO-66-NH2 [103][104][105] composite, etc.  Reprinted with permission from [80]. Copyright © 2020 American Chemical Society. Crystals 2021, 11, x FOR PEER REVIEW 14 of 20 Figure 11. Schematic illustration of the proposed mechanism of the introduction and defects and breakage of bonds, leading to unsaturated Zn-sites and N-sites. These bonds, in turn, will bind H2O in aqueous environment. Reprinted with permission from [83]. Copyright © 2020 The Royal Society of Chemistry.

Conclusions and Prospects
The ball milling method for synthesizing MOFs is simple and easy, but overall, the types of MOFs that are currently being explored are still very limited, compared to the huge variety of MOFs. It will be an important research direction in the future that how to adjust the various conditions of the ball milling reaction to achieve low-cost and largescale preparation of MOFs with high actual value. Many of the reaction raw materials have insufficient activity and cannot be directly reacted by ball milling, and the activity of the reaction raw materials can be improved by liquid (and/or ion) assisted means. It is important to note that ligands with different substituents, different auxiliary solvents (ions), and metal salts with different counter anions may result in products with different framework structures. An effective way to solve the above problems is to pre-synthesize precursors containing secondary structural units first, and then carry out subsequent ball milling reaction to prepare corresponding MOFs, which have been successful in zinc and zirconium MOFs. This strategy can be used in the future for other types of MOFs which are difficult to directly formed, such as rare earth MOFs with important luminescent properties.
The in-situ monitoring of MOFs by ball milling is an indispensable requirement for the in-depth study of the ball milling reaction [35,51,53,60,71,106]. Although many kinds of MOFs have been successfully synthesized by ball milling, the understanding of the reaction mechanism of these MOFs is still insufficient. The study reveals certain reaction pathways and mesophases, but it is far from enough to design new MOFs and guide the synthesis of MOFs. In the future, with the development of new in situ research methods and more generalized in situ research instruments, there will be a deeper understanding of the essential effects of various factors in the synthesis of MOFs.
It is recognized that the preparation of MOFs by ball milling is of great significance for the realization of large-scale industrial preparation of MOFs. However, there are still some problems that need to be overcome to achieve continuous industrial production. First is the problem of reaction yield, where ball milling often cannot achieve 100% con- Figure 11. Schematic illustration of the proposed mechanism of the introduction and defects and breakage of bonds, leading to unsaturated Zn-sites and N-sites. These bonds, in turn, will bind H 2 O in aqueous environment. Reprinted with permission from [83]. Copyright © 2020 The Royal Society of Chemistry.

Conclusions and Prospects
The ball milling method for synthesizing MOFs is simple and easy, but overall, the types of MOFs that are currently being explored are still very limited, compared to the huge variety of MOFs. It will be an important research direction in the future that how to adjust the various conditions of the ball milling reaction to achieve low-cost and largescale preparation of MOFs with high actual value. Many of the reaction raw materials have insufficient activity and cannot be directly reacted by ball milling, and the activity of the reaction raw materials can be improved by liquid (and/or ion) assisted means. It is important to note that ligands with different substituents, different auxiliary solvents (ions), and metal salts with different counter anions may result in products with different framework structures. An effective way to solve the above problems is to pre-synthesize precursors containing secondary structural units first, and then carry out subsequent ball milling reaction to prepare corresponding MOFs, which have been successful in zinc and zirconium MOFs. This strategy can be used in the future for other types of MOFs which are difficult to directly formed, such as rare earth MOFs with important luminescent properties.
The in-situ monitoring of MOFs by ball milling is an indispensable requirement for the in-depth study of the ball milling reaction [35,51,53,60,71,106]. Although many kinds of MOFs have been successfully synthesized by ball milling, the understanding of the reaction mechanism of these MOFs is still insufficient. The study reveals certain reaction pathways and mesophases, but it is far from enough to design new MOFs and guide the synthesis of MOFs. In the future, with the development of new in situ research methods and more generalized in situ research instruments, there will be a deeper understanding of the essential effects of various factors in the synthesis of MOFs.
It is recognized that the preparation of MOFs by ball milling is of great significance for the realization of large-scale industrial preparation of MOFs. However, there are still some problems that need to be overcome to achieve continuous industrial production. First is the problem of reaction yield, where ball milling often cannot achieve 100% conversion, and sometimes the feed ratio of metal source and ligand is not equal to the stoichiometric number, always resulting in impurities in the product. Second, although no solvent or very small amount of solvent is used in the reaction process, the subsequent cleaning and