Altering Product Selectivity by Mechanochemistry - The Journal of

Perspective pubs.acs.org/joc

Altering Product Selectivity by Mechanochemistry José G. Hernández* and Carsten Bolm* Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany ABSTRACT: Mechanochemical activation achieved by grinding, shearing, pulling, or milling opens unique opportunities in synthetic organic chemistry. Common features are that mechanochemistry facilitates reactions with insoluble reactants, enables high-yielding solvent-free synthetic procedures, and shortens reaction times, among others. However, mechanochemical techniques can also alter chemical reactivity and selectivity compared to the analogous solution-based protocols. As a consequence, solvent-free milling can lead to different product compositions or equilibration mixtures than in solution. Reactions by milling have also allowed the trapping and characterization of elusive intermediates and materials. In this Perspective we highlight a few selected examples that illustrate the value of mechanochemistry in uncovering interesting chemical reactivity, which is often masked in typical liquid-phase synthesis.

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INTRODUCTION Mechanochemistry is as a powerful tool with relevance for a variety of multiscale applications ranging from minerals engineering to nanoscience.1 It is often only related to advanced comminution and particle size reduction. However, the perspective of mechanochemistry is wider as it also offers opportunities for chemical activation complementing traditional strategies based on thermal, electrical, or irradiative techniques.2 Along those lines, various scientific communities around organic, inorganic, organometallic, pharmaceutical, and solid-state chemists have recently begun utilizing mechanical energy imposed by grinding, shearing, pulling, or milling for inducing chemical transformations.3,4 In several cases, clean and energy-efficient processes have been developed.5 Interestingly, each activation mode, heat, irradiation, and mechanical action, has its own characteristics as nicely illustrated by early examples from inorganic chemistry. Thus, in the 1890s, Matthew Carey Lea reported that silver halides decomposed upon grinding, while they just melted when heated.6 Apparently, the mechanochemical impact led to a different reaction path and modified the compound behavior. Another illustrative example stems from Boldyrew et al., who investigated the decomposition of alkali bromates. In a very thorough study, they found that the tribomechanical treatment of MBrO3 (with M = Na, K, Rb, and Cs) followed an entirely different reaction path than the thermally induced one (Scheme 1).7 Consequently, both transformations led to different products. Determining the degradation rates of a series of analogous alkali salts revealed similarities between the decompositions induced by tribomechanical treatment and irradiation. The aforementioned studies focused on the solid-state behavior of single-component, high-melting inorganic compounds, where reaction parameters related to temperature, © 2017 American Chemical Society

Scheme 1. Decomposition of Alkali Bromates (with M = Na, K, Rb, or Cs) Induced by Tribomechanical Treatment, Heat, and Irradiation

pressure, shear stress, deformation, and compression forces, etc., can be expected to affect the outcome.1 Quantifying these factors by laboratory experiments or theory proved difficult. Some of them seem to be directly linked, whereas others impact the reaction outcome individually. Pronounced differences between thermo- and mechanochemistry were also revealed in coordination chemistry.8 Investigating the decomposition of thiolate−copper interfaces and junctions, Štich and co-workers found that both activation modes resulted in very different reaction pathways and product classes.9 As early as 1996, Gilman discussed mechanochemical effects with a focus on HOMO−LUMO interactions of bent covalent bonds.10 Subsequently, mechanical activations of covalent bonds in single molecules have been studied in depth.11,12 As a result of intensive theoretical studies of a pericyclic reaction using both the electron density based AIM analysis and the complementary Lewis structure based NRT decomposition, Wollenhaupt and co-workers questioned the Received: December 2, 2016 Published: January 12, 2017 4007

DOI: 10.1021/acs.joc.6b02887 J. Org. Chem. 2017, 82, 4007−4019

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The Journal of Organic Chemistry validity of the Woodward−Hoffmann rules under mechanochemical conditions and suggested complementing the existing ones for thermally and photochemically activated processes by “mechanochemical rules”.13 In polymer chemistry, mechanical to chemical energy transduction pathways have been studied with the goal of developing, for example, mechanoresponsive materials.14,15 The use of mechanical force on mixtures of low-melting (“soft”) organic molecules is attractive because in many instances exceptionally high reactivities have been achieved leading to excellent product yields.16 As most of these transformations are performed without solvent, solvation and desolvation phenomena are of minor relevance,17 and chemical equilibria in reaction mixtures can be affected. Furthermore, being solvent-free, the reactions proceed at maximal reagent concentrations allowing high reactions rates. In most mechanochemically activated reactions involving organic components the resulting products are identical to the ones observed in solution. However, in some cases unexpected reactions and alternations in the product composition have been reported. Those findings are particularly interesting because they reveal changes in reaction pathways resulting in altered chemical reactivity. To the best of our knowledge, there is no overview on such phenomena yet, and thus here, we aim to fill this gap by summarizing the respective observations and discussing possible reasons for the change in product distribution when moving from solution phase to mechanochemistry. The starting point is a brief description of the equipment often utilized in carrying out mechanosynthesis. Undoubtedly, the simplest instrument to conduct a mechanochemical reaction is a mortar and pestle. In fact, historically, manual grinding was the first technique applied for mechanical activations of chemical systems.1b,18 However, the use of this emblematic tool has disadvantages, such as low reproducibility, scale-up restrictions, and safety issues. Furthermore, grinding by hand is often limited to transformations requiring only short reaction times. Consequently, the downsides associated with the manual grinding have triggered the implementation of ball-milling techniques. The use of automated ball mills enables the control of parameters, such as frequency and milling time (energy input),19 assuring a higher reproducibility. Moreover, with respect to experimental safety it is important to note that the milling devices are closed and safe containers charged with ball bearings, reducing significantly the exposure of the operator to potentially dangerous chemicals. Finally, the nature of the milling media (vessels and balls) can be chosen to prevent the formation of side products, avoid wearing,20 promote chemical reactivity,21 or control energy input based on the density of the milling material (e.g., tungsten carbide stainless steel, zirconia ceramic, agate, Teflon, etc.). On a laboratory scale, planetary and mixer ball mills, sometimes called shaker mills, are by far the most used milling devices. In the mixer mill, horizontal or “∞” movements of the milling jars cause the balls to impact the walls, mixing and bringing the reagents in very close proximity (Figure 1a). On the other hand, in a planetary ball mill the milling vessels are located on a disk that rotates in one direction while the vessels themselves rotate toward the opposite direction on their own axes, promoting highly efficient mixing inside the vessel (Figure 1b). Thanks in large part to the availability of electric ball mills, there has been an increasing number of systematic milling

Figure 1. Most commonly used ball-milling equipment and milling media. (a) Mixer mill: (top) shaking direction, (bottom) ZrO2 and stainless steel milling jars (10 mL) and balls. (b) Planetary ball mill: (top) movement description, (bottom) ZrO2 and stainless steel milling vessels (12 mL) and balls.

studies in recent years. The results of these investigations have guided mechanochemistry into various exciting new areas of organic,22 inorganic,23 organometallic,24 enzymatic,25 polymer,14,26 supramolecular,27 environmental,28 pharmaceutical,29 and medicinal chemistry.30 This extensive research has revealed several advantages associated with mechanochemistry. Perhaps the most acclaimed benefit, especially from the green chemistry perception, is the fact that most reactions in ball mills are conducted under solvent-free conditions or using just catalytic amounts of organic solvents.31,32 But the positive impact of mechanochemical activation has been proven to go beyond organic waste reduction and includes, for example, the possibility of bypassing solubility issues in chemical reactions involving reactants with poor solubility, which otherwise would be challenging or impossible to use in solution. Furthermore, reactions carried out by milling are often characterized by shorter reaction times, higher selectivity, lower catalyst loadings, and better stoichiometry control.22−30 In addition to this, mechanochemical techniques have made it even possible to safely study typical explosive chemical reaction mixtures.21b,33 In recent years, liquid-assisted grinding (LAG31) has become of interest for controlling chemical selectivity. By the addition of small amounts of organic solvents, mechanochemical reactions are accelerated and facilitated. Although, traditionally, the choice and quantity of the right additive [η value; where η is the volume of solvent (in μL) divided by the sample weight (in mg)]31a is based on a process of trail and error, some systematic studies have also been reported.31a,c,d In general, choosing an optimal additive for LAG includes the screening of solvents with different polarities. In addition, the stability upon milling and the volatility of the organic solvent should be taken into account. Low-pressure solvents could create difficulties in removal from the mixture after the mechanochemical reaction. On the other hand, too volatile solvents usually bring inaccuracies during the sample preparation or they can be lost during the milling process. Some solvents of choice include alcohols (methanol, ethanol, 1-propanol), ethyl acetate, acetonitrile, nitromethane, and some low-pressure ketones. Most examples discussed herein relate to mechanosyntheses of purely organic compounds through the formation of covalent 4008


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The Journal of Organic Chemistry C−C and C−X bonds. However, we also address a few other mechanochemical syntheses resulting in unique and atypical noncarbon covalent scaffolds, organometallic reagents, metal− organic frameworks, and inorganic materials. Those protocols are of interest for organic chemistry because they can lead to elusive species with great potential for the discovery of new catalytic transformations based on unprecedented chemical reactivity.

Also in a fundamentally different molecular system, neat and liquid-assisted grinding (LAG31) led to altered thermodynamic equilibration mixtures compared to liquid-phase reactions. Belenguer et al. studied the reversibility and thermodynamic control of the formation of covalent disulfide bonds, and in this context, they investigated the exchange of aromatic groups between symmetrical homodimeric disulfides 4 and 5 generating nonsymmetric heterodimer 6 (Scheme 3).41 In

DISCUSSION After the discovery of fullerene (1)34a and the development of efficient routes to synthesize it on a gram scale,34b research devoted to the functionalization of C60 grew quickly, also driven by the need to improve the solubility of 1 and to study the properties of fullerene derivatives. In this context, Wudl and coworkers reported in 1995 the electrophilic addition of NaCN to 1 in a mixture of 1,2-dichlorobenzene (ODCB) and DMF. In solution, the reaction generated the anion C60(CN)−, which after quenching by trifluoroacetic acid (TFA) afforded the functionalized fullerene 2 (Scheme 2; top branch).35

Scheme 3. Difference in the Equilibration Composition of a Disulfide Metathesis Reaction in Solution and under Mechanochemical Conditions

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Scheme 2. Difference in Chemical Reactivity of C60 in Solution and under HSVM Conditions solution, the base-catalyzed disulfide metathesis afforded at the equilibrium a mixture of 4/5/6 with a statistical ratio of 1:1:2. In contrast, the equilibration of the reaction mixture by neat or LAG grinding gave almost exclusively (98%) heterodimer 6 (Scheme 3). It was also observed that milling provided two different polymorphs of the same heterodimer depending on the type of grinding applied; neat or LAG.41,42 Further substrate screening allowed the identification of other homodimers, which upon milling reached equilibration mixtures that significantly differed from those observed in solution. Probably, these alternations were due to differences in the stabilities of the homo- and heterodimers in solution and in the solid state. As discussed above, the mechanochemically formed [2 + 2] C60 dimer 3 was not generated by a formal (thermally forbidden) cycloaddition process but a cyanide-initiated benzoin condensation-type reaction sequence. Considering the temperature and pressure effects in the milling devices, it is not surprising that standard Diels−Alder reactions have also been investigated under solvent-free mechanochemical conditions. Some of those occurred rapidly at room temperature providing the same products as solution-based procedures.43 As Watanabe and Senna showed, hydrogen bond donors such as 2naphthol exhibited a strong promoting effect on Diels−Alder reactions of charge-transfer complexes consisting of anthracenes and p-benzoquinone. Relevant here was the fact that these accelerating effects were much stronger under solventfree conditions than in solution.44 Other mechanochemical Diels−Alder reactions allowed the preparation of products, which had remained entirely inaccessible using solvents as reaction media. An excellent example has recently been reported by Swager and co-workers (Scheme 4).45 In their study, highly rigid iptycenes were prepared with the goal of utilizing them for absorption of aromatic hydrocarbons such as benzene and toluene. At each stage of their multistep syntheses, mechanochemical activations under solvent-free conditions were applied. A particularly impressive transformation was the Diels−Alder reaction between 7 and 1,4-anthraquinone (8) to give extended iptycene 9. Attempts to prepare 9 in solution with AlCl3 as catalyst remained unsuccessful. In contrast, using

Around the same time, the difficulties in solubilizing C60 in common organic solvents encouraged the exploration of alternative approaches including mechanochemical techniques to develop fullerene chemistry.36 In 1996, Komatsu and coworkers demonstrated the value of high-speed vibration ball milling (HSVM) for circumventing the solubility issues encountered in the addition of organozinc reagents to 1.37,38 Soon after, they applied the same mechanochemical technique to attempting to promote the aforementioned reaction between C60 and KCN. The result was surprising. After milling of the two solids for 30 min at 2800 cycles per minute followed by quenching with TFA, unexpected dimer C120 (3) was obtained in 18% yield, only accompanied by unreacted fullerene (Scheme 2; bottom branch).39a The selective formation of 3 by mechanical milling suggested a different reaction path compared to the one occurring in solution. In the absence of solvent and under the ball-milling conditions, the nucleophilicity and the leaving-group properties of the cyanide ion must have been different from the ones in solution. Later, it was reported that besides cyanide also other nucleophilic anions, metal powders and organic bases were suitable for promoting the mechanochemical formation of 3.39b Particularly interesting was the observation of an equilibrium between C60 and C120 in the solid state, which could account for the moderate yield of 3. In the presence of additives, a mechanochemically induced equilibration was observed providing C60 and C120 in a ratio of ca. 7.0:2.5 starting from either the monomer or the dimer.40 4009


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chloroform, complex lat-10 is known to undergo ready isomerization to the more stable diag-10 (Scheme 5b), grinding of pure diag-10 for 2 h at room temperature afforded a 59:41 mixture of diag-10 and lat-10. Performing the ball-milling experiment with diag-10 at low temperature using a milling jar wrapped with dry ice provided an isomeric mixture of 64:36. Similarly, milling the pure lat-isomer led to a diag-10 to lat-10 ratio of 46:54 (Scheme 5c). A thermal isomerization pathway was excluded after the thermal stabilities of both isomers in the solid state were determined by differential scanning calorimetry.49 Even at 180 °C, the level of isomerization was low, confirming the significance of the mechanochemical activation for this unique equilibration. Organometallic synthesis often relies on solution-based procedures utilizing glovebox and Schlenk techniques. The presence of coordinating solvents during the experimental work can then prevent the formation of unsolvated complexes, thus masking interesting chemical reactivity. By following mechanochemical protocols solvate formation can be circumvented, as shown by Hanusa and co-workers.50 In 2014, the authors reported the mechanosynthesis of the first unsolvated tris(allyl) complex of aluminum (12) in yields of up to 88% by simple milling a mixture of K[1,3-(SiMe3)2C3H3] (11) and AlX3 (X = I, Br) for 5 min in a planetary mill (Scheme 6).50 Up to that

Scheme 4. Mechanochemically-Induced Diels−Alder Reaction for the Preparation of an Extended Iptycene

a combination of ZnCl2 and perfluorononanoic acid as promoter under solvent-free mechanochemical conditions gave 9 in 82% yield. Thus, for achieving this challenging synthetic goal, mechanochemistry proved absolutely essential. Until a recent revival,24 the synthesis of organometallics under mechanochemical conditions has largely remained unexplored.46 In 2014, systematic studies aiming at developing rhenium chemistry by ball milling led to the remarkable discovery that mechanochemical activation could improve fundamental organometallic transformations, for instance, oxidative addition, ligand exchange, and one-pot multicomponent organometallic reactions.47 Particular interesting was the possibility of conducting stereoselective oxidative additions of metal halides salts to CpRe(CO)3 and Cp*Re(CO)3 (Cp = η5-C5H5; Cp* = η 5-C5(CH3)5) generating mixtures of the diag- and lat-stereoisomers in different and tunable proportions.47a Such stereocontrol had never been achieved in solution (Scheme 5).

Scheme 6. Mechanosynthesis of the First Unsolvated Tris(allyl)aluminum Complex 12

Scheme 5. (a) Mechanochemical Isomerization of Re Complexes lat-10 and diag-10. (b) Stability of diag-10 and lat-10 in Solution. (c) Change in Composition of Pure diag10 and lat-10 under Milling As Determined by 1H NMR Spectroscopy

moment, all solvent-based strategies, using, for example, pyridine or tetrahydrofuran, had inevitably generated solvates of the aluminum complex. The importance of preparing such elusive nonsolvated complexes was demonstrated by comparing the reactivity of 12 and 12·THF with benzophenone. The results showed that the unsolvated complex 12 underwent the addition process much faster, hence highlighting the importance of mechanochemistry in discovering new organometallic species with enhanced reactivity. More recently, Hanusa and co-workers extended this chemistry by showing differences in the stereoselectivity of halide metathesis reactions carried out by milling and in liquid phase.51 In this study, tris(allyl) complexes AsA′3 and SbA′3 [with A′ = 1,3-(SiMe3)2C3H3)] were generated by milling of 11 with AsI3 and SbCl3, respectively. Both products were obtained as mixtures of diastereoisomers with C1 and C3 symmetry. Interestingly, the compositions of these mixtures differed significantly from the ones observed in organic solvents favoring the C1-symmetric isomers. This altered behavior was explained on the basis of the existence of a lower transition state energy to access the C1-symmetric isomer by milling. In addition, the preferential formation of the C1 diastereomer was related to the asymmetric nature of the metal trihalides, an environment that was inaccessible in solution. Cross-coupling reactions under mechanochemical conditions have been in the focus of several studies, and intriguing observations were reported. For example, grinding facilitated ligand-free palladium-catalyzed Suzuki coupling reactions

Ball milling also induced an isomerization between mechanochemically prepared complexes diag-CpRe(CO)2Br2 (diag-10) and lat-CpRe(CO)2Br2 (lat-10), which was surprising considering the fact that diag-isomer 10 was reported to be stable in both the solid state and solution even under heating (Scheme 5b).48 Whereas, upon heating in dichloromethane or 4010


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The Journal of Organic Chemistry between aryl bromides and boronic acids52 allowing rapid conversions without the exclusion of air and moisture.19,53,54 While the observed reactivity order with respect to the aryl halide (RBr > RI > RCl)19,54,55 was not unprecedented,56 other substitution effects were surprising. Thus, under mechanochemical conditions, electron-rich substrates commonly reacted with higher efficiency than electron-deficient ones in contrast to the observed reactivity pattern in solution-based systems. The same unusual behavior was found in palladium-catalyzed Mizoroki−Heck reactions.32b,57 An example reported by Lamaty and co-workers32b is summarized in Scheme 7. While

Scheme 8. Mechanosynthesis of Palladium Complexes 17 and 18

Scheme 7. Influence of the Para Substitutents of Iodobenzenes 13a−c on the Yields of Resulting CrossCoupling Products 15a−c

in the reaction with acyclic ester 14a p-methoxy- and pbromoiodobenzenes 13a and 13b gave good yields of the crosscoupling products 15a (73%) and 15b (68%), respectively, pnitroiodobenzene 13c provided 15c in only low yield (35%). Ondruschka and co-workers attributed this reactivity difference of substituted aryl halides in solution-phase systems and solvent-free ones by mass-transport limitations in reactions of certain substrates.19 Commonly, under mechanochemical conditions a temperature increase occurs58 and some starting materials form liquids, resulting in a good dispersion of all components. If, on the other hand, the aryl halide (as, presumably, 13c in the case shown in Scheme 7) remains a solid, its reactivity is low due to limited mass transport. Thus, the observed change in the reactivity order is not based on an alternation of the intrinsic reaction behavior of the substrate but related to the physicochemical properties of the starting material.58−60 Applying this phenomenon in cross-coupling scenarios of complex syntheses remains to be demonstrated. The importance of phase changes in seemingly solid/solid organic reactions has also been demonstrated for other systems. Many of them appear to involve eutectic mixtures leading to liquid phases during the mechanical mixing.61 With respect to asymmetric organocatalysis, such effects have been investigated in proline-catalyzed solvent-free aldol reactions under mechanochemical conditions.61 It is possible that solid/liquid phase transitions are also critical for reaching molecular assemblies of substrates and catalysts affected by π−π stacking. In solventfree organocatalytic asymmetric aldol reactions such noncovalent interactions appear to play a significant role.62 Metal-catalyzed C−H bond functionalization is an elegant and powerful tool used for direct structural modifications of organic molecules. Commonly, the mechanism involves the formation of a metal−carbon bond prior to the actual functionalization step. With the aim of gaining a deeper understanding of this initial phase of the catalysis, Ć urić and coworkers monitored the cyclometalation and C−H bond activation of azobenzene 16 under mechanochemical conditions using in situ Raman spectroscopy.63 LAG or ILAG (ionand liquid-assisted grinding)64 of 16 with Pd(OAc)2 afforded a dimeric monopalladated complex 17 (Scheme 8). The same

palladium complex could also be prepared in solution. However, further LAG of a reaction mixture containing 17 in the presence of additional Pd(OAc)2 yielded dicyclopalladated product 18, which was inaccessible by liquid-phase chemistry. Clearly, mechanochemistry helped to access a new organometallic species with potential relevance for catalysis. The fact that such organometallic complexes could be prepared under mechanochemical activation also showed that they tolerated the mechanical stress induced by the ball mills. This stability was essential for recent applications of organometallic complexes as catalysts in other mechanochemical transformation related to C−H bond functionalizations65 and olefin metathesis reactions20e in ball mills. Particularly interesting for this Perspective, was the result of the kinetic isotopic effect (KIE) study of the iridium(III)-catalyzed C−H bond amidation of benzamides in a ball mill. Under solvent-free mechanochemical conditions, the measured KIE value was almost three times smaller that the one for the same transformation in solution (1.2 vs 3.4).65b This substantial difference pointed to a mechanistic change for the C−H bond cleavage under ball-milling conditions, which enabled the C−H functionalization to occur faster compared to the solutionbased method. As an extension of this chemistry, Su and co-workers recently reported a palladium-catalyzed oxidative C−H, C−H-coupling of indoles 19 with acrylate such as 14b in a mixer mill.66 The liquid-phase reaction using PdCl2 as catalyst in DMF led to the exclusive formation of 3-vinylindoles 20. In contrast, under milling conditions, β,β-diindolyl propionates 21 were the major products (Scheme 9). EIS-MS analyses of the reaction solution mixtures and compositions obtained by milling showed the presence of a solvent-labile dimeric palladium species explaining the different products formed in DMF and under mechanochemical activation.66−68 In certain cases, mechanochemical reactions can be catalyzed with metal species lacking an organic ligand, and the chemical reactivity is then induced by the free metal. In particular, the use of reactive milling media, such as steel, copper, or brass milling vessels and balls,21 or reusable additives, like silver foil,69 4011


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context of this Perspective is the fact that the product composition of the milling reaction mixture differed substantially from the one of the reaction in toluene using Ni[COD]2/ PPh3 or Ni(PPh3)4 (COD = 1,5-cyclooctadiene) as catalysts.71 There, the major products were benzenes 27 and 28 (Scheme 10b).72 The use of recyclable reactive milling media was also reported for a copper-catalyzed synthesis of sulfonyl(thio)ureas involving a C−N bond formation.21d Frišcǐ ć and co-workers demonstrated that the coupling between sulfonamides and iso(thio)cyanates could be carried out using a brass milling ball instead of copper salts. Further studies on C−N couplings by the same group led to the discovery of a mechanochemical route for the synthesis of sulfonylguanidines 31 and 32 from sulfonamides 29 and carbodiimides 30. 7 3 Whereas (trifluoromethyl)sulfonamide reacted with alkyl-substituted carbodiimides upon milling with or without the need for a catalyst to generate 31 (Scheme 11a, top), the use of aryl-

Scheme 9. Palladium-Catalyzed C−H/C−H Couplings Leading to 20 and 21 under Mechanochemical and SolutionPhase Conditions

have proven to fulfill the requirements. Such systems can even outperform the catalytic activity of the corresponding organometallic catalysts. Along these lines, Mack, Guan and coworkers recently explored the reactivity of ethyl propiolate (22) in stainless steel milling jars using nickel pellets as milling media (Scheme 10a).70 After being milled at 18 Hz for 16 h,

Scheme 11. (a) Mechanochemical C−N Coupling of Sulfonamides and Carbodiimides under Ball Milling Conditions; (b) Failed Attempts To Synthesize 31 and 32 in Solution

Scheme 10. Ni(0)-Catalyzed Cycloaddition of 22 under Mechanochemical Conditions (a) and in Solution (b)

substituted carbodiimides and (trifluoromethyl)sulfonamide or arylsulfonamides was only enabled by using CuCl as catalyst under LAG conditions (Scheme 11a, bottom). Worth mentioning here were the failed attempts to couple arylsulfonamides and carbodiimides in solution upon prolonged heating in the absence or in the presence of CuCl (Scheme 11b). This new mechanochemically induced C−N coupling reaction clearly exemplified the importance of mechanochemical activation to access chemical reactivity not readily achieved using traditional solution-based methodologies. More recently, the mechanochemical C−N bond formation chemistry was extended, enabling the preparation and isolation of N-(thiocarbamoyl)benzotriazoles 35 (Scheme 12a).74 This type of triazoles prepared by reacting anilines 33 with bis(benzotriazolyl)methanethione (34) had been proposed as intermediate, but due to their high reactivity in organic solvents, they readily reacted further to their corresponding isothiocyanates 37 and benzotriazole (38) (Scheme 12b). However, the LAG approach afforded the elusive N(thiocarbamoyl)benzotriazoles 35 in high yields after short milling times. Being important for organic synthesis, the (thiocarbamoyl)benzotriazoles were found to be stable in the solid-state even after a year of storage, and they could be used in the synthesis of symmetric and nonsymmetrical thioureas 36

the reaction gave a mixture of substituted cyclooctatetraenes 23−26 (tetramers) as major products, along with minor quantities of the trisubstituted benzenes 27 and 28 (trimers). Apparently, these products resulted from mechanochemical nickel-catalyzed [2 + 2 + 2 + 2] cycloadditions or cyclotrimerizations of 22, respectively. In general, the idea of using nickel pellets both as milling media and alternative Ni(0) source for catalysis was perceived as very practical since the applied Ni(0) pellets were inexpensive and recyclable. Furthermore, in contrast to the solution chemistry, where airsensitive, low-valent nickel catalysts are often used, the mechanochemical approach reported here avoided the need for glovebox and Schlenk techniques. Noteworthy in the 4012


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base DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), none of the desired product 40 was obtained. However, when DBU was replaced by the much weaker inorganic base Na2CO3, monoadduct 40 was formed in 51% yield. Entirely different products (41 and 42) were isolated when the milling with Na2CO3 was performed with carbonyl compounds lacking the halo substituent.75 The aforementioned observation that strong bases could be replaced by weak ones was in line with results reported by Balema, Pecharsky, and co-workers, who studied solvent-free Wittig reactions under mechanochemical conditions.77 In their case, K2CO3 proved optimal, allowing even “one-pot” mechanochemical syntheses of alkenes from standard starting materials of Wittig reactions (Scheme 13b). Noteworthy was also the altered stereochemistry of the products. Whereas in solutions mixtures of E/Z-isomers are commonly formed, the mechanochemical approach led predominantely to the thermodynamically more stable E-olefins.78,79 Base-induced enolate alkylation reactions have been investigated by Mack and co-workers.80 After significant optimization they were able to obtain both kinetic and thermodynamic enolates which could be converted to their corresponding dialkylated products (Scheme 14). Noteworthy was the low sensitivity of the mechanochemical procedure toward moisture and air54 and, furthermore, the absence of commonly observed (aldol) byproducts.81

Scheme 12. (a) Mechanosynthesis of N(Thiocarbamoyl)benzotriazoles 35 and Subsequent Preparation of Thioureas 36 by Milling. (b) Synthesis and Degradation of 35 into Isothiocyanates 37 and HBt (38) in Organic solvents

after milling of 35 with diverse anilines. The ability of mechanochemistry to permit the synthesis and trapping of molecules too reactive to be accessed in solution is outstanding and highlights another beneficial aspect of the mechanochemical activation. To a large extent, the success of the fullerene chemistry presented in Scheme 2 relied on the adjustment of the nucleophilicity and the leaving-group properties of the cyanide ion, which was achieved by the possibility to perform the reaction in a solvent-free environment under mechanochemical conditions. Effects of this type are also relevant in basemediated transformations, and the use of mechanochemistry offers interesting opportunities. A few examples are highlighted here. The first transformation stems from Wang and co-workers and relates, one more time, to the functionalization of C60 (1) (Scheme 13a).75 In the attempt to cyclopropanate the fullerene by the Bingel reaction76 under solvent-free mechanochemical conditions using diethyl bromomalonate (39) and the standard

Scheme 14. Enolate Alkylations under Mechanochemical Conditions

As mentioned previously, one of the most routine applications of mechanochemical techniques is the reduction of particle size of materials. In biomass processing, for example, raw wood or lignocellulose is often pretreated by ball milling prior to subjection of the biomass to a solution-based degradation or modification procedure by different means. Alternatively, mechanochemical activation can be used to directly depolymerize cellulose82 and lignin.83 The highly complex molecular architecture present in lignin is commonly a hurdle in the evaluation of new methods to chemically modify this biopolymer. In fact, nowadays the use of lignin model compounds84 has become a recurrent starting point for testing new lignin modification strategies. In this context, Anastas, Crabtree, Hazari, and co-workers used simple lignin-like methoxylated aromatic compounds such as trimethoxybenzene (45) to study the oxidation of molecules in the presence of Oxone (2KHSO5·KHSO4·K2SO4).85 In the liquid phase, the oxidation of 45 proved challenging due to the solubility incompatibilities between the inorganic oxidizing agent and the organic substrate (Scheme 15). Using aqueous solutions

Scheme 13. (a) Mechanochemical Functionalizations of C60 with Na2CO3 as Base. (b) Solvent-Free Wittig Reaction with K2CO3 as Base

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The Journal of Organic Chemistry Scheme 15. Difference in the Oxidation of 45 by Mechanochemical Activation and in Solution Phase

Scheme 17. Reactions of Urea (52) and Dicarbonyl Compounds under Mechanochemical Conditions

containing small amounts of organic cosolvents (acetonitrile, methanol, or acetone; 10% v/v) improved the conversion of 45 significantly, but the selectivity of the reaction toward 46 was poor, affording mixtures of 2,3,4-trimethoxyphenol (47) as the major product accompanied by quinones 46 and 48. In contrast to the reaction in solution, the same oxidative transformation of 45 carried out by manual grinding or mechanical milling proceed much more selectively providing quinone 46 as single product in 81% yield. Clearly, this result was different to the one observed in the water/cosolvent systems, and the high product selectivity led to a synthetically valuable protocol. Also in other transformations involving oxidation reactions, positive effects of mechanochemical applications have been noted. Often, FeCl3 has been used as oxidant,86 and mechanistically, Scholl reaction87 type mechanisms might be involved. Again, a very interesting example stems from fullerene chemistry. As shown by Su and Wang, C60 (1) reacts with Nbenzhydryl sulfonamides 49 under HSVM conditions in the presence of FeCl3 (3 equiv) to give fulleroindanes 50 in good yields (Scheme 16).88 As intermediates, fullerenyl radicals and

Whereas in the multicomponent coupling reported by Mal and co-workers urea (52) was reacted with β-dicarbonyl compounds 51 (Scheme 17, top), an analogous transformation of 52 with α-diketone 54 (benzil) under mechanochemical conditions was studied by Colacino and co-workers (Scheme 17, bottom).92 From results of solution-based studies phenytoin 55 was the expected product being formed by Biltz reaction involving a pinacol rearrangement with a 1,2-shift of a phenyl group.93 Surprisingly, however, 55 was only formed in 10% yield (after 2 h in a vibrational ball mill at 30 Hz). Instead, glycoluril 56 and urea derivative 57 were the major products. Apparently, the favorite pathway in solution was altered providing different products by mechanochemical activation. Most examples presented until this point related to mechanochemically promoted bond formations of carbonbased moieties. Distinct from this is the work by Garcı ́a and coworkers, who reported in 2016 a solvent-free mechanosynthesis of adamantoid cyclophosphazanes representing an example of a mechanochemical activation of a noncarbon covalent backbone.94 In the past, all attempts to prepare tert-butyl-substituted cyclophosphazane P4(NtBu)6 (59) by isomerization of cyclic dimeric phosphazane 58 in solution (diethyl ether, hexane, THF, toluene, or DMF) or by prolonged heating of neat 5895 had failed, categorizing 59 as inaccessible (Scheme 18).96 Then, however, simple milling of 58 in the presence of LiCl (20 wt %) for 1.5 h gave 59 in 53% yield.94 The formation of this adamantoid isomer was confirmed by NMR analysis of the mechanochemically prepared product in solution and in the solid state, along with PXRD and single-crystal X-ray diffraction. Thus, here, mechanochemistry opened access to an entirely new molecular scaffold. Noteworthy, related molecules have already displayed interesting catalytic activity in asymmetric Michael additions.97 Commonly, mechanochemical reactions are conducted in automated ball mills using nontransparent containers made of steel, ceramic, Teflon, and other resistant materials. Although this diversity in milling equipment opens opportunities for chemical reaction design, the nature of these materials prevents the direct observation of the physical and chemical changes during the milling. Furthermore, kinetic analyses can only be

Scheme 16. Reaction of C60 (1) with N-Benzhydryl Sulfonamides 49 under HSVM Conditions Providing Fulleroindanes 50

aryl cations were suggested. Attempts to perform analogous reactions in 1,2-dichlorobenzene or 1,1,2,2-tetrachloroethane at elevated temperature (120 °C) failed. Another stimulating example was reported by Mal and coworkers, who investigated a Biginelli-type multicomponent coupling leading to dihydropyrimidones 53 (Scheme 17, top).89,90 The two-step reaction sequence was initiated by a mechanochemically promoted oxidation of benzyl alcohols to benzaldehydes with a mixture of oxone, KBr, and TEMPO under solvent-free conditions. This process also liberated protons required for the subsequent three-component coupling to generate the desired products. For the initial oxidation, the authors reported “higher efficiency, with better yields and no overoxidized products” than in the comparable solution-phase reaction developed by Togo and co-workers.91 4014


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into the metastable form III, which had never been achieved in solution.103 We wholeheartedly agree when the authors conclude in their article “this new strategy opens the way for further academic research”.

Scheme 18. (a) First Synthesis of Adamantoid Cyclophosphazanes 59 Facilitated by Mechanochemical Activation. (b) Initial Unsuccessful Attempts To Prepare 59

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CONCLUSION

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AUTHOR INFORMATION

Mechanochemistry has successfully been applied in various fields of research, and significant advances have been noted. Mostly, existing processes have been improved, for example, by avoiding the use of solvents, shortening the reaction time, lowering the catalyst loading, etc. However, as we show in this Perspective, mechanochemistry can also reach beyond that stage by uncovering and favoring dormant chemical reactivity, improving the understanding of kinetic and thermodynamic equilibria, allowing identification of elusive intermediates, and providing unexpected products. Furthermore, in many cases, the product composition differs from the one obtained by conventional solution-based methods, making mechanochemistry attractive because it widens the exploratory space of organic synthesis. From a practical point of view, the possibility of exploiting mechanochemically prepared compounds and materials, especially those inaccessible in solution, is tightly linked to the feasibility of scale-up of their synthetic processes. In this regard, the recent approaches utilizing readily available industrial equipment such as large-sized planetary ball mills and extruders are worth mentioning.104 The initial results are promising and represent an excellent starting point for further developments in this field. At first glance, the current number of examples where mechanochemistry has led to unexpected reactivities and products might appear small, but we are convinced that this is only the “tip of the iceberg”.105 Most researchers still follow the traditional routes of improving and optimizing a given process, which mostly involves a solvent screening. Performing the reactions in the absence of a solvent is often out of sight, although a much more pronounced reactivity and perhaps even alternative products might result. Mechanochemistry is a powerful tool for synthesis, and we encourage the community to embrace the exploration of mechanochemical transformations boldly and with eyes wide open.

done ex situ. Recently, however, significant advances have been achieved. By combining translucent milling vessels with synchrotron X-ray powder diffraction or Raman spectroscopy, in situ studies became possible allowing a direct observation of mechanochemically induced transformations.98−100 Along these lines, seminal investigations have focused on the preparation of metal−organic frameworks. Thus, as expected, the in situ analysis of the mechanochemical reaction between 2-methylimidazole 60 (HMeIm) and ZnO (61) led to the detection of ZIF-8 (62) (Scheme 19).101 Then, however, upon further Scheme 19. Real-Time Monitoring of the Milling Process by X-ray Powder Diffraction Using Transparent Milling Jars Allowing the Detection of the Mechanochemical Formation of Metastable Intermediate 64

milling (and observation) of the reaction mixture an amorphization of ZIF-8 occurred to give amorphous Zn(MeIm)2 (63). The subsequent recrystallization of this material led to an entirely new topology metal−organic framework 64. This material was a metastable intermediate in the mechanochemical formation of a nonporous polymorph 65 (dig-ZIF-8). The formation and real-time observation of an hitherto unknown metal−organic framework intermediate, which could not be accessed by traditional methods, features one more time the value of mechanochemistry in providing alternatives to obtain typically elusive materials.101 Recently, Emmerling and co-workers used in situ X-ray diffraction for studying mechanochemical polymorph transformations of benzamide.102 By applying a self-constructed Perspex jar that was transparent to synchroton radiation they were able to follow the complete transformation of benzamide I

Corresponding Authors

*Tel: +49 24 80 94 675. Fax: +49 241 80 92 391. E-mail: jose. [email protected]. *Tel: +49 24 80 94 675. Fax: +49 241 80 92 391. E-mail: [email protected]. ORCID

Carsten Bolm: 0000-0001-9415-9917 Notes

The authors declare no competing financial interest. 4015



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Biographies

REFERENCES

(1) (a) Ball Milling Towards Green Synthesis: Applications, Projects, Challenges; Stolle, A., Ranu, B., Eds.; The Royal Society of Chemistry: Cambridge, 2015. (b) Baláz,̌ P. Mechanochemistry in Nanoscience and Minerals Engineering; Springer: Berlin, 2008. (2) (a) O’Brien, M.; Denton, R.; Ley, S. V. Synthesis 2011, 2011, 1157−1192. (b) Baig, R. B. N.; Varma, R. S. Chem. Soc. Rev. 2012, 41, 1559−1584. (c) For an overview on various activation modes including mechanochemistry for biowaste valorization, see: Tabasso, S.; Carnaroglio, D.; Calcio Gaudino, E.; Cravotto, G. Green Chem. 2015, 17, 684−693. (3) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Frišcǐ ć, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C. Chem. Soc. Rev. 2012, 41, 413−447. (4) Note that biological systems are also affected by mechanical force. As a result, a discipline called “mechanobiology” has emerged that connects biology with engineering.For a highly stimulating review, see: (a) Kung, C. Nature 2005, 436, 647−654. For a recent overview focusing on mechanical force-triggered drug delivery, see: (b) Zhang, Y.; Yu, J.; Bomba, H. N.; Zhu, Y.; Gu, Z. Chem. Rev. 2016, 116, 12536−12563. (5) For a themed issue on mechanochemistry, see: James, S. L.; Frišcǐ ć, T. Chem. Commun. 2013, 49, 5349−5350. (6) (a) Takacs, L. J. Mater. Sci. 2004, 39, 4987−4993. (b) Takacs, L. Bull. Hist. Chem. 2003, 28, 26−34. (7) Boldyrew, W. W.; Awwakumow, E. G.; Harenz, H.; Heinicke, G.; Strugowa, L. I. Z. Anorg. Allg. Chem. 1972, 393, 152−158. (8) For a discussion on similarities and differences of mechanochemistry of inorganic and organic systems, see: Boldyreva, E. Chem. Soc. Rev. 2013, 42, 7719−7738. (9) Konôpka, M.; Turanský, R.; Reichert, J.; Fuchs, H.; Marx, D.; Štich, I. Phys. Rev. Lett. 2008, 100, 115503. (10) Gilman, J. J. Science 1996, 274, 65. (11) Beyer, M. K.; Clausen-Schaumann, H. Chem. Rev. 2005, 105, 2921−2948. (12) Ribas-Arino, J.; Marx, D. Chem. Rev. 2012, 112, 5412−5487. (13) Wollenhaupt, M.; Krupička, M.; Marx, D. ChemPhysChem 2015, 16, 1593−1597. (14) (a) Caruso, M. M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Chem. Rev. 2009, 109, 5755−5798. (b) May, P. A.; Moore, J. S. Chem. Soc. Rev. 2013, 42, 7497−7506. (c) Stauch, T.; Dreuw, A. Chem. Rev. 2016, 116, 14137−14180. (15) For further selected readings on polymer mechanochemistry, see: (a) Li, J.; Nagamani, C.; Moore, J. S. Acc. Chem. Res. 2015, 48, 2181−2190. (b) Lavalle, P.; Boulmedais, F.; Schaaf, P.; Jierry, L. Langmuir 2016, 32, 7265−7276. (16) For a summary on “Organic solid-state reactions with 100% yield”, see: Kaupp, G. Top. Curr. Chem. 2005, 254, 95−183. (17) For reviews covering “solvent-free and highly concentrated reactions”, see: (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025− 1074. (b) Walsh, P. J.; Li, H.; de Parrodi, C. A. Chem. Rev. 2007, 107, 2503−2545. For solvent-free syntheses of heterocycles, see: (c) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem. Rev. 2009, 109, 4140−4182. (d) For a literature update, see: Sarkar, A.; Santra, S.; Kundu, S. K.; Hajra, A.; Zyryanov, G. V.; Chupakhin, O. N.; Charushin, V. N.; Majee, A. Green Chem. 2016, 18, 4475−4525. (18) (a) Takacs, L. Chem. Soc. Rev. 2013, 42, 7649−7659. (b) Kipp, S.; Šepelák, V.; Becker, K. D. Chem. Unserer Zeit 2005, 39, 384−392. (19) (a) Schneider, F.; Szuppa, T.; Stolle, A.; Ondruschka, B.; Hopf, H. Green Chem. 2009, 11, 1894−1899. (b) Trotzki, R.; Hoffmann, M. M.; Ondruschka, B. Green Chem. 2008, 10, 767−772. (c) Thorwirth, R.; Bernhardt, F.; Stolle, A.; Ondruschka, B.; Asghari, J. Chem. - Eur. J. 2010, 16, 13236−13242. (20) (a) Burmeister, C. F.; Kwade, A. Chem. Soc. Rev. 2013, 42, 7660−7667. (b) Štefanić, G.; Krehula, S.; Štefanić, I. Chem. Commun. 2013, 49, 9245−9247. (c) Rak, M. J.; Saadé, N. K.; Frišcǐ ć, T.; Moores, A. Green Chem. 2014, 16, 86−89. (d) Métro, T.-X.; Bonnamour, J.;

José G. Hernández studied chemistry at the Universidad Industrial de Santander in Colombia under the supervision of Professor Vladimir V. Kouznetsov. In 2008 he moved to Mexico to pursue his Ph.D. in chemistry at the CINVESTAV-IPN in the group of Professor Eusebio Juaristi working on mechanochemical organocatalyzed organic reactions. In 2013, he joined Professor Tomislav Frišcǐ ć’s team as a postdoctoral researcher at McGill University in Canada, developing mechanochemical organometallic transformations and solid-state chemistry. In 2015, he received an invitation from Professor Carsten Bolm to move to Aachen and work at the RWTH Aachen University, leading the team focused on mechanochemistry. Currently, he is in the process of starting his independent research career in the field.

Carsten Bolm studied chemistry at the TU Braunschweig (Germany) and at the University of Wisconsin, Madison (USA). In 1987, he obtained his doctorate with Professor Manfred Reetz in Marburg (Germany). After postdoctoral training with Professor Barry Sharpless at MIT, Cambridge (USA), Carsten Bolm worked in Basel (Switzerland) with Professor Bernd Giese to obtain his habilitation. In 1993, he became Professor of Organic Chemistry at the University of Marburg, and since 1996 he has held a chair of Organic Chemistry at RWTH Aachen University (Germany). In 2012, he became an Adjunct Professor at WIT (Wuhan Institute of Technology) (China), and in 2016 he was awarded an Honorary Professorship at Central China Normal University. Since 2014, he has held a Distinguished Professorship at RWTH Aachen University. His publication list has approximately 420 entries, and in 2014, 2015, and 2016 he was selected “Thomson Reuters Highly Cited Researcher”. He has been an Associate Editor for The Journal of Organic Chemistry since 2008 .

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ACKNOWLEDGMENTS

We thank RWTH Aachen University for support from the Distinguished Professorship Program funded by the Excellence Initiative of the German federal and state governments. 4016


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Altering Product Selectivity by Mechanochemistry - The Journal of

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