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Accepted Article Title: C-H Bond Functionalization by Mechanochemistry Authors: José G. Hernández This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Chem. Eur. J. 10.1002/chem.201703605 Link to VoR: http://dx.doi.org/10.1002/chem.201703605
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10.1002/chem.201703605
Chemistry - A European Journal
CONCEPT
C–H Bond Functionalization by Mechanochemistry José G. Hernández*[a]
[a]
Dr. J. G. Hernández Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) E-mail: [email protected]
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CONCEPT Abstract: With the advances made in the mechanosynthesis of inorganic and organometallic complexes and the excellent past experiences on metal-catalyzed cross-coupling reactions by high-speed ball milling, the merging of C–H functionalization and mechanochemical techniques was all set to emerge. In recent years, the fast development of mechanochemical C–H activation have left us examples of metal-catalyzed olefinations, amidations, halogenations and oxidative couplings among others. This concept article will describe some of the events that led to the development of mechanochemical C–H activation, the current state-of-the-art, the present challenges of this merging, and some unique scenarios where mechanochemistry could complement the traditional solution-based approaches.
Introduction The use of mechanical energy to facilitate chemical reactions via grinding, milling, shearing, kneading or pulling known as mechanochemistry,[1,2] has experienced an explosive growth in the past two decades. During this time, organic chemistry have pushed the boundaries of the classical mechanosyntheses[3] involving mostly oxido-redox chemistry, and condensation reactions into a more elaborated set of synthetic transformations.[4] Soon after, metal-catalysis proved also compatible with the typical mechanochemical conditions using ball milling techniques. This merging was fundamental to move the field forward, thanks to the possibility to carry out some of the most venerable cross-coupling transformations such as the Suzuki, Heck-Mizoroki, Sonogashira, and Glaser reactions among others.[5] One common feature in many cross-coupling reactions is the need for the preactivation of the substrate by introduction of a functional group, for instance through the halogenation in the case of aromatic halides, which determines the position where the coupling would occur (Scheme 1; top). Coincidentally, in the same time frame metal-catalyzed C–H bond functionalizations in solution, involving cross-coupling reactions between unactivated substrates and various reaction partners, have evolved at a great pace making possible to directly modify hydrocarbons fragments (Scheme 1; bottom).[6] Not only is the C–H functionalization challenging because of the difficulty to modify the C–H bonds over other more reactive type of linkages in organic molecules, but also those molecules often contain several chemically distinct C–H bonds, making the regioselectivity aspect an additional hurdle in C–H bond functionalization chemistry. To tackle these selectivity and reactivity issues, scientists have made use of subtrates bearing directing groups (DGs) together with transition-metals (e.g., Pd, Ru, Rh, Ir), and nowadays with more earth-abundant metals such as iron, cobalt and nickel.[7]
[a]
Dr. J. G. Hernández Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) E-mail: [email protected]
Mechanochemical cross-coupling reactions Ar
X
+
Metal
R
Y
ball milling
Ar
R
preactivaded substrate Direct C−H bond fuctionalization DG Ar
DG H
+ Y
R
Metal
Ar
DG R
Ar
MLn
unactivated via metallacycle substrate DG = directing group; M = metal; L = ligand Scheme 1. Metal-catalyzed mechanochemical cross coupling reactions (top); metal-catalyzed C–H bond direct functionalizations (bottom).
The idea behind this approach consists in using metal catalysts to perform the activation of a nearby C–H bond guided by the directing group or nowadays by the presence of a template.[8] Along these lines, it has been demonstrated that key in this endeavor is the formation of organometallic metallacycles (Pd[9], Rh,[10] Ir,[11] Co,[12] etc.) as intermediates of many C–H bond direct functionalization. From a mechanochemistry perspective, developing of a C–H direct functionalization reaction in a ball mill would require the organometallic species (catalysts and/or intermediates) to be resilient enough to tolerate the reaction conditions experienced upon ball milling. Pleasingly, in the past years rapid development of mechanosynthesis of organometallic complexes and of their applications under mechanochemical conditions have translated into the fundamental knowledge that paved the way for the initial C–H bond activation and functionalization examples. This concept article, will recapitulate some of the findings that served as the platform for developing mechanochemical C–H bond functionalization reactions, the current state-of-the-art, the challenges still faced to reach a higher level of chemical complexity, and some unique opportunity scenarios where mechanochemistry could complement the traditional solution-based approaches in the search for new chemical reactivity.[13]
Mechanosynthesis of organometallic complexes Given the need to provide oxygen- and water-free environments when handling and reacting many organometallic species, synthesis of organometallic complexes has been mostly governed by the use of solvent-based protocols relying on Schlenk and glovebox techniques. However, the classical mechanosynthesis of ferrocene (1) by milling revealed the strength of the organometallic bonding between the iron (II) and the cyclopentadienyl ligands.[14] Such characteristic was later confirmed by Braga et al. during the mechanochemical Suzuki coupling reaction between ferrocene-1,1′-diboronic acid [Fe(η5C5H4B(OH)2)2] (2) and 4-bromopyridine and 5-bromopyrimidine, which left the organometallic moiety untouched.[15] Likewise, cocrystallization of Fe(η5-C5H4–C5H4N)2 (3) and dicarboxylic acids by grinding led to the clean formation of supramolecular macrocycles,[16] highlighting the stability of the organometallic complex upon mechanical activation (Figure 1).
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CONCEPT triethylsilane in toluene,[23] and very recently the Mn(CO)5Br 8 was used to catalyze the hydroarylation of allenes.[24]
Figure 1. Ferrocene (1) and ferrocene derivative complexes (2-3) made or used under mechanochemical conditions.
In 2014, Ćurić and coworkers reported the mechanochemical cyclometalation and C–H bond activation on an azobenzene derivative.[17] Liquid assisted-grinding (LAG)[18] of an mixture of an activated azobenzene 4 with palladium acetate afforded the dimeric mono palladacycle complex 5. Prolongation of the LAG in the presence of additional Pd(OAc)2 generated the dicyclopalladated product 6.[19] The latter example demonstrates the feasibility to access synthetically valuable Pd-organometallic complexes,[20] and it per se corresponds to a direct C–H bond activation under ball milling conditions (Scheme 2).
Scheme 3. Synthesis of Mn(CO)5Br 8 by ball milling.
Simultaneously, the interest on the mechanosynthesis of organometallics grew steadily with the preparation of Alcomplexes,[25] metal-carbenes[26] and pincer complexes[27] enabled by ball milling. Some of these examples and other relevant contributions have been recently showcased by Rightmire and Hanusa in a comprehensive review article. [28]
Mechanochemical Rh-catalyzed C–H functionalizations Interesting for the development of mechanochemical C–H bond functionalization reactions was the synthesis of [Cp*RhCl2]2 11 in the ball mill reported by Hernández and Bolm.[29] This Rhcomplex is one of the most versatile catalyst in the field of C–H functionalization chemistry (Scheme 4; top). LAG of a mixture of rhodium chloride hydrate (III) (9) and pentamethylcyclopentadiene (Cp*H, 10) afforded the Cp*Rh catalyst 11 in good yield. In Rh-based C–H activation catalysis it has been demonstrated that the reactive catalytic species involves the formation of metallacycle Rh-intermediates.[10,30]
Scheme 2. Mechanochemical C–H activation of 4 in the ball mill.
In the same year, Hernández et al., began a series of studies on rhenium and manganese chemistry by ball milling[21-22] that led to the formation of pentacarbonyl Re and Mn halides, M(CO)5X (M = Re, Mn; X = Cl, Br, I).[22] Noteworthy was the formation of Mn(CO)5Br 8 after a mechanochemical oxidative addition of Mn2(CO)10 7 with Oxone® and NaBr in 88% yield (Scheme 3).[22] This Mn-complex has been reported to catalyze the insertion of aldehydes into aromatic C–H bonds in the presence of
Scheme 4. Mechanochemical synthesis of [Cp*RhCl2]2 11 and rhodacycle 13 and their application in the C–H halogenation of 2-phenylpyridine (12).
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CONCEPT Reacting 2-phenylpyridine (12) and [Cp*RhCl2]2 11 with sodium acetate in a planetary ball mill yielded the rhodacycle 13 in good yield (Scheme 4; middle). Grinding stoichiometric amounts of this Rh-complex 13 and N-bromosuccinimide (NBS) led to the ortho-bromination of 12. Similarly, the use of AgSbF6 permitted utilizing the [Cp*RhCl2]2 11 in catalytic quantities to facilitate the C–H halogenation of 12 after 3 h of milling (Scheme 4; bottom).
hypothesis was backed up after reacting the mechanochemically made 13 with methyl-1,4,2-dioxazol-5-one, which led to the formation of the amidation product in the ball mill.
Earlier in 2015, [Cp*RhCl2]2 11 proved also active to catalyze the solvent-free mechanochemically induced C–H bond functionalization of acetanilides 16 (Scheme 5).[31] A catalytic cocktail involving the Cp*-Rh catalyst 11, copper acetate and silver tetrafluoroborate favored the selective ortho-olefination of various acetanilides 16 with acrylate derivatives 17. After 15 h of milling at 800 rpm the mechanochemical reaction afforded the functionalized acetanilides 18 in moderate yields without the need for additional heating.[32] Noteworthy was the use of dioxygen as terminal oxidant for this solvent-free reaction.
Scheme 6. Mechanochemical rhodium-catalyzed C–H bond amidation of arenes 19 with dioxazolones 20.
In 2017 the [Cp*RhCl2]2 11 was used as the precursor for the synthesis of [Cp*Rh(Me(CN)3][SbF6]2. This cationic rhodium catalyst was then tested in the oxidative coupling of acetanilides and alkynes in the ball mill (Scheme 7).[34] Scheme 5. Selected examples of the mechanochemical rhodium-catalyzed olefination of acetanilides 16.
Very recently Bolm’s group reported the mechanochemical C–H amidation of aromatics with dioxazolones in ball mills. Once again, a combination of [Cp*RhCl2]2 11, AgSbF6 and AgOAc was found superior over Ru- and Ir- catalysts to favor the solvent-free direct amidation.[33] Initially, the screening of the best reaction conditions was conducted using N-(tert-butyl)benzamide and methyl-1,4,2-dioxazol-5-one. However, quickly the mechanochemical amidation demonstrated to be a general protocol tolerating a variety of benzamides and various substituted 1,4,2-dioxazol-5-ones to afford the amidation products in good yield, 45-99%.[33] Compared with the original C–H bond olefination, the Rh-catalyzed amidations were completed in short milling times (1.65 h vs. 15 h) in a mixer mill operated at 30 Hz. Remarkable was the evaluation of numerous commonly used directing groups such as ketoxime, benzo[h]quinolone and pyridine, among others (Scheme 6).[33] Even ketones, which are known for being weakly coordinating directing groups proved suitable for the amidation in the ball mill, albeit longer milling times and a two-fold increase in the catalyst loading were required (Scheme 6). In the case of the experiment using 2-phenylpyridine (12) as substrate, the amidation was proposed to occur via the rhodacycle intermediate 13, this Scheme 7. Rh-catalyzed mechanosynthesis of indoles 23.
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CONCEPT Milling of a mixture of acetanilides 16 and aryl/alkyl-disubstituted alkynes in the presence of the Cp*Rh catalyst and Cu(OAc) 2 as an additive for 15 h rendered a series of substituted indoles 23 (Scheme 7). Similar to the Rh-catalyzed olefination of acetanilides, here dioxygen was used as terminal oxidant as well. Flushing the milling vessels with oxygen prior their closing warranted an oxidizing atmosphere during the milling process. However, the oxidative coupling required long milling times to provide the indoles in moderate yields (Scheme 7). This result could be connected with a lack of a sufficient amount of oxidant inside the milling jar. Nevertheless, parallel reports have made used of the gaseous O2 present inside the milling container to conduct oxidative steps by ball milling. For instance, Lamaty and co-workers demonstrated the utilization of the gaseous dioxygen as reagent during the mechanochemical formation Cu–carbene complexes from N,N-diaryl imidazolium salts and metallic copper.[35] Alternatively, Stolle et al. circumvented the lack of oxidant inside the closed milling vessel by post-reaction exposure of the reaction mixture to air, after a Cu-catalyzed Glaser coupling.[36] Recently, the Schüth’s group reported the mechanochemical oxidation of carbon monoxide with Cu-based catalysts by milling. The authors employed modified milling equipment to permit the safe use and constant flow of gaseous reagents through the milling jar.[37] This alternative type of setups and oxidative strategies could be of great help to improve mechanochemical C–H bond functionalizations.
Mechanochemical Ir-catalyzed C–H bond amidation Besides the Rh-catalyst (III) 11 previously described, additional metal complexes such as [Cp*IrCl2]2 24 have been documented to facilitate the C–H bond amidation reactions under ball milling conditions.[38] In 2016 the Bolm’s group developed a mechanochemical C–N bond formation involving the reaction of benzamides 25 with aryl- or alkyl-sulfonyl azides 26 (Scheme 8). Among the various catalysts/additives combinations tested, the use [Cp*IrCl2]2 24 (2.5 mol%) in the company of AgBF4 (10 mol%) and AgOAc (10 mol%) resulted in a high catalytic system providing the substituted benzamides 27 in high yields after only 99 min of mechanical milling (Scheme 8). The Ir-catalyzed C–H bond direct amidation of benzamides exhibited a broad substrate scope in terms of both the benzamide and the sulfonyl azides reaction partners. Noteworthy for this particular system was the safe use of the azide derivatives 26 under solvent-free high-speed ball milling. In this regard, previous utilization of explosophores such as azides,[39] diazonium salt[40] or contact-unstable mixtures (primary amines-phenyliodine diacetate system)[41] in ball mills has been accomplished without incidents. For instance, in the case of milling azides, it was reported that “at no point during any of these reactions did we [the authors] observe any explosion or increased exothermicity due to milling azides”.[39]
Scheme 8. Ir-catalyzed C–H amidation of benzamides 25 in a ball mill.
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CONCEPT However, extra safety and precaution is always recommended when ball milling hazardous reagents or mixtures. i) Checking beforehand the thermal stability of the chemicals, if available, ii) conducting the screening reactions involving explosophores initially at a small scale, and iii) carrying out the mechanochemical reactions and the workup inside a fume hood could be strategies to keep the risk as low as possible. Moreover, to shed some light on the mechanism of the mechanochemical amidation reactions the authors synthesized the iridacycle 28 in the ball mill. This cyclometalated iridium complex was then found to effectively catalyze the amidation of N-(tert-butyl)benzamide and benzylsulfonyl azide. In addition to this, the kinetic isotopic effect (KIE) study of the iridium(III)catalyzed C−H bond functionalization in a ball mill revealed a KIE value that was almost three times smaller that the one for the same transformation in organic solvents (1,2-dichloroethane) (1.2 vs 3.4).[38] Suggesting, perhaps, a mechanistic change for the C−H bond cleavage by milling, which resulted in a facilitated the C−H bond functionalization of 25 in the ball mill compared with the solution-based protocol.
Mechanochemical coupling
Pd-catalyzed
Activation of the indoles was achieved by LAG (HOAc; = 0.17)[18] using Pd(OAc)2 (10 mol%), MnO2 as the oxidant and SiO2 as milling auxiliary. After short milling times in a mixer mill the reaction afforded a series of 3-vinylindoles 31 in good yields (Scheme 9). Choosing an alternative palladium salt such as PdCl2 led to a double C−H bond activation yielding the ,diindolyl propionates 32 over the mono-addition coupling products 31 (Scheme 9). Particularly important were the blank experiments in organic solvent using PdCl2 as catalyst, which revealed the exclusive formation of 3-vinylindoles 31 in DMF. Spectrometric analysis of the reaction mixture, both from solution and ball milling experiments revealed the presence of a solvent-labile dimeric palladium intermediate, which could explain the differences in product composition between the transformations in DMF and by ball milling.[42]
oxidative
After the initial findings on the palladium C−H bond activation of azobenzenes by milling,[17] the interest in mechanochemical palladium-catalyzed reactions quickly grew. In 2016, Su and coworkers developed a Pd-catalyzed oxidative coupling of indoles 29 with acrylates 30 by ball milling (Scheme 9).[42]
Scheme 9. Palladium-catalyzed oxidative coupling of indoles 29 with acrylates 30.
Scheme 10. Mechanochemical Pd-catalyzed C−H/C−H bond arylation.
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CONCEPT Also in 2016, Xu and co-workers reported the Pd-catalyzed mechanochemical C−H/C−H bond arylation between oximes 33 and arenes 34, employing Pd(OAc)2 as the catalyst and Na2S2O8 as the oxidant (Scheme 10).[43] Compared with the reaction carried out in solution (using the arene both as a reagent and as the reaction media), the reaction in the planetary ball mill proved more advantageous. On the one hand, the amount of the arene and the reaction time could be reduced dramatically, making the C−H/C−H bond ideal for couplings involving expensive or synthetically challenging arenes partners, on the other hand the selectivity of the arylation improved under ball milling conditions. Several electron-donating and electron-withdrawing arenes 34 were tolerated in the mechanochemical reaction. Likewise, various aromatic and aliphatic oximes were compatible with the Pd-catalyzed C−H/C−H bond arylation. Replacing the oximedirecting group for urea or anilide derivatives required longer milling times but it enabled broadening the substrate scope of the arylation (Scheme 10; bottom). Similarly, mechanochemical oxidative C−C bond formation involving cross-dehydrogenative couplings (CDC)[44] between hydrocarbons have been recently studied and reviewed by Su et al.[45] Mainly copper salts in the presence of oxidants such as 2,3-dichloro-5,6-di-cyanoquinone (DDQ) were used to facilitate the oxidative C−H/C−H bond formation. More recently, the use of Fe(NO3)3·9H2O and DDQ by ball milling exposed the catalytic potential of the iron salts under milling conditions to facilitate cross-dehydrogenative couplings.[46] After an initial screening, Fe (III) salts such as FeCl3 and Fe(NO3)3 (anhydrous and hydrated) proved more active than the iron (II) chloride or sulfates. Additionally, experiments using extra pure Fe(NO3)3·9H2O (≥99.95%; with a copper content 0.4 ppm) were done to rule out a copper-catalyzed background reaction.[47] Milling of a mixture of 3-benzyl indole derivatives 36 and methylene reaction partners 37, in combination of Fe(NO3)3·9H2O; DDQ and silica gel led to a fast oxidative C−H/C−H bond formation. After 21 min of milling at 25 Hz, a series of 3-arylmethylindole derivatives 38 were obtained in high yields (Scheme 11; sp3−sp3 CDC couplings). Moreover, indole derivatives performed well as nucleophiles too, yielding various sp3−sp2 CDC coupling products.[46] Worth mentioning was the observation that not only N-substituted indoles could be used as reactants but also N-free indoles were compatible with the iron (III)-catalyzed reaction conditions (Scheme 11; sp3−sp2 CDC coupling).
Comments and Future Perspective It has long been recognized that the application of mechanochemical techniques to chemical synthesis results in shorter reaction times and cleaner reaction mixtures. Along these lines, mechanochemical C−H functionalizations were not exceptions and most C−H bond activations by ball milling proceeded faster than in solution without the need for external heating. In regard to this last aspect, the mechanical dynamics of the ball milling process can inherently impact the temperature inside the milling vessel. Studies on the evolution of the temperature upon milling have tried to unravel the key factors
Scheme 11. Mechanochemical Fe-catalyzed C−H/C−H CDC coupling.
(milling media, operational variables, etc) affecting the final temperature in the milling vessel.[32] However, in addition to the milling material, speed, and mode of milling, other intrinsic chemical events like the release of crystallization water in a chemical reaction have proven to cause fluctuations in the overall temperature of the milling container.[32a] Consequently, a better temperature sensing and temperature control of mechanochemical reactions is foreseen to become popular in the upcoming future. Such improvement would permit tackling more challenging C−H bond functionalizations by simultaneously milling and heating the reaction mixture. On the other hand, variable temperature and reliable cooling systems could facilitate the safe utilization of thermal sensitive reaction partners, and it would boost the number of mechanochemical asymmetric reports too. One more advantage of chemical transformations by ball milling is the possibility to work with reactants of different solubility profiles. Such operational freedom could make
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CONCEPT mechanochemical approaches emerged as standard strategies for the post-modification of low-soluble materials by C−H bond activation (e.g., polymers, metal-organic frameworks, peptides),[48] by overcoming the solubility constrains of using poor-soluble substrates, catalysts or additives. Although the initial mechanochemical C−H bond functionalization examples were developed based on the wellknown catalytic activity of rhodium, palladium, and iridium complexes. It is anticipated that other metals (especially earthabundant metals), could be utilized under ball milling conditions as well. In that sense, achieving high reactivity and regioselectivity using lower catalyst loadings (currently 1−10 mol%) of more readily available metallic species is a global goal in the field of in C−H bond functionalization. Regarding this last goal, the excellent mixing experienced by high-speed ball milling together with the highly concentrated reaction conditions created in the absence of solvent, could enable reducing the amount of the catalyst required to reach high performance. Additionally, the development of C–H bond activations with more earth-abundant metals could facilitate the use of metallic milling media to convey the grinding (container and ball bearing), and at the same time as the catalytic metal specie for the transformations. Until now, the use of copper milling equipment, nickel pellets and the presence of silver-foil upon milling has been used as an strategy for the Cu-catalyzed azide-alkyne cycloaddition,[49] Ni-catalyzed cycloaddition of alkynes[50] and the Ag-catalyzed cyclopropanation of alkenes with diazoacetates, [51] respectively. Facilitating the recovery and the reuse of the metal catalyst. In addition to the above mentioned practical benefits, the application of mechanochemical techniques to C–H bond activation could be an excellent platform for accessing chemical reactivity difficult or impossible to accomplish in solution chemistry.[13] For example, solvent-free reactions by milling could favor the formation of labile metallocycles, whose formation could be prohibited in the presence of coordinating solvents. Having access to non-solvated metal complexes by milling have already been shown to affect their catalytic reactivity compared with the solvated complex counterparts.[25] Regarding this last aspect, examples of solvent-controlled C–H bond functionalization under traditional reaction conditions in solution have been reported. In 2014 Lin, Yao and co-workers published a C–H alkenylation of 3,4-disubstitued pyrroles using Pd(OAc)2 in combination of AgOAc.[52] The regioselectivity of the reaction was found to depend on the organic solvent used. Choosing toluene as the reaction media the process favored the C2products due to the presence of the ester directing group at the C-3 position of the pyrrole (Scheme 12a; top branch), whereas a mixture of DMF/DMSO overweighed the directing group effect of the ester and led predominantly to the formation of the C5alkenylation product (Scheme 12a; bottom branch). For this type of systems, neat or liquid assisted grinding could be the ideal choice to investigate the role of the organic solvent and to potentially tune changes in regioselectivity. More recently, Du et al., reported a divergent C(sp 3)−H functionalization, which was influenced by the strength of the
base and by the organic solvent used (Scheme 12b). [53] In the presence of a Pd-complex, the use of a strong base such as
Scheme 12. Solvent- and base-controlled Pd-catalyzed C–H functionalization reactions in solution-based approaches. t
BuOK and tert-amyl alcohol as the reaction media guided the amide -C–H functionalization (Scheme 12b, left). A shift in the regioselectivity (benzylic C–H activation) was observed when potassium carbonate in xylenes was employed (Scheme 12b, right). The origin of this switch in selectivity was associated with the possibility to dissolve the tBuOK much better in a polar solvent, thus facilitating the deprotonation of -C−H bond. Along these lines, K2CO3 have demonstrated to override the efficiency of strong bases under solvent-free ball milling, and once again not solubility constrains were encountered under those conditions.[54]
Conclusion In summary, in a short period of time the activation of C−H bonds in organic molecules by mechanical ball milling has emerged as an alternative to solution-based methods. The variety of metal complexes and the number of directing groups, which have proven to be compatible under ball milling conditions, together with the high frequency of the reports on C−H bond functionalization represent a forthcoming consolidation of this concept. Future investigations with more emphasis on the mechanisms of the mechanochemical C−H bond reactions [17, 55] are necessary to better understand this alternative activation mode. Such understanding is anticipated to help broadening the scope of this concept by adding examples where mechanochemical protocols could be advantageous over other activation strategies. For example, by this time in the reading one should be already intrigued and tempted to speculate (or better to study), about the regioselectivity of known solvent- or base-depended C–H bond functionalization reactions, now under mechanochemical conditions. Such type of systematic
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CONCEPT work could lead to the discovery of new reaction pathways complementing the current solution-based approaches.
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Acknowledgements
[19]
JGH thanks the financial support from the RWTH Aachen University through: a) the RWTH Start-up grant StUpPD_221-16 funded by the Excellence Initiative of the German federal and state governments, and b) the Distinguished Professorship Program funded by the Excellence Initiative of the German federal and state governments. Keywords: C–H activation • mechanochemistry • ball milling • solvent-free • [1]
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CONCEPT [47] [48] [49] [50] [51]
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S. L. Buchwald, C. Bolm, Angew. Chem. Int. Ed. 2009, 48, 5586–5587; Angew. Chem. 2009, 121, 5694–5695. a) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369–375; b) S. Sengupta, G. Mehta, Tetrahedron Lett. 2017, 58, 1357–1372. D. A. Fulmer, W. C. Shearouse, S. T. Medonza, J. Mack, Green Chem. 2009, 11, 1821−1825. R. A. Haley, A. R. Zellner, J. A. Krause, H. Guan, J. Mack, ACS Sustainable Chem. Eng. 2016, 4, 2464−2469. L. Chen, M. O. Bovee, B. E. Lemma, K. S. M. Keithley, S. L. Pilson, M. G. Coleman, J. Mack, Angew. Chem., Int. Ed. 2015, 54, 11084−11087; Angew. Chem. 2015, 127, 11236–11239. Y. Su, H. Zhou, J. Chen, J. Xu, X. Wu, A. Lin, H. Yao, Org. Lett. 2014, 16, 4884–4887. W. Du, Q. Gu, Z. Li, D. Yang, J. Am. Chem. Soc. 2015, 137, 1130– 1135. V. P. Balema, J. W. Wiench, M. Pruski, V. K. Pecharsky. J. Am. Chem. Soc. 2002, 124, 6244–6245. a) K. Užarević, I. Halasz, T. Friščić, J. Phys. Chem. Lett. 2015, 6, 4129–4140; b) S. Lukin, T. Stolar, M. Tireli, M. V. Blanco, D. Babić, T. Friščić, K. Užarević, I. Halasz, Chem. Eur. J. 2017. DOI: 10.1002/chem.201702489; c) L. Batzdorf, F. Fischer, M. Wilke, K.-J. Wenzel, F. Emmerling. Angew. Chem. Int. Ed. 2015, 54, 1799–1802; Angew. Chem. 2015, 127, 1819–1822.
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CONCEPT Layout 2:
CONCEPT José G. Hernández* Page No. – Page No. C–H Bond Functionalization by Mechanochemistry
MechanoC–Hemical activation. This concept article gives an overview of the events that led to the merging of mechanochemisty and C–H bond functionalization, the stateof-the-art studies and a perspective for future mechanochemical C–H bond activation studies.
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Accepted Article Title: C-H Bond Functionalization by Mechanochemistry Authors: José G. Hernández This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Chem. Eur. J. 10.1002/chem.201703605 Link to VoR: http://dx.doi.org/10.1002/chem.201703605
Supported by
10.1002/chem.201703605
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CONCEPT
C–H Bond Functionalization by Mechanochemistry José G. Hernández*[a]
[a]
Dr. J. G. Hernández Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) E-mail: [email protected]
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CONCEPT Abstract: With the advances made in the mechanosynthesis of inorganic and organometallic complexes and the excellent past experiences on metal-catalyzed cross-coupling reactions by high-speed ball milling, the merging of C–H functionalization and mechanochemical techniques was all set to emerge. In recent years, the fast development of mechanochemical C–H activation have left us examples of metal-catalyzed olefinations, amidations, halogenations and oxidative couplings among others. This concept article will describe some of the events that led to the development of mechanochemical C–H activation, the current state-of-the-art, the present challenges of this merging, and some unique scenarios where mechanochemistry could complement the traditional solution-based approaches.
Introduction The use of mechanical energy to facilitate chemical reactions via grinding, milling, shearing, kneading or pulling known as mechanochemistry,[1,2] has experienced an explosive growth in the past two decades. During this time, organic chemistry have pushed the boundaries of the classical mechanosyntheses[3] involving mostly oxido-redox chemistry, and condensation reactions into a more elaborated set of synthetic transformations.[4] Soon after, metal-catalysis proved also compatible with the typical mechanochemical conditions using ball milling techniques. This merging was fundamental to move the field forward, thanks to the possibility to carry out some of the most venerable cross-coupling transformations such as the Suzuki, Heck-Mizoroki, Sonogashira, and Glaser reactions among others.[5] One common feature in many cross-coupling reactions is the need for the preactivation of the substrate by introduction of a functional group, for instance through the halogenation in the case of aromatic halides, which determines the position where the coupling would occur (Scheme 1; top). Coincidentally, in the same time frame metal-catalyzed C–H bond functionalizations in solution, involving cross-coupling reactions between unactivated substrates and various reaction partners, have evolved at a great pace making possible to directly modify hydrocarbons fragments (Scheme 1; bottom).[6] Not only is the C–H functionalization challenging because of the difficulty to modify the C–H bonds over other more reactive type of linkages in organic molecules, but also those molecules often contain several chemically distinct C–H bonds, making the regioselectivity aspect an additional hurdle in C–H bond functionalization chemistry. To tackle these selectivity and reactivity issues, scientists have made use of subtrates bearing directing groups (DGs) together with transition-metals (e.g., Pd, Ru, Rh, Ir), and nowadays with more earth-abundant metals such as iron, cobalt and nickel.[7]
[a]
Dr. J. G. Hernández Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) E-mail: [email protected]
Mechanochemical cross-coupling reactions Ar
X
+
Metal
R
Y
ball milling
Ar
R
preactivaded substrate Direct C−H bond fuctionalization DG Ar
DG H
+ Y
R
Metal
Ar
DG R
Ar
MLn
unactivated via metallacycle substrate DG = directing group; M = metal; L = ligand Scheme 1. Metal-catalyzed mechanochemical cross coupling reactions (top); metal-catalyzed C–H bond direct functionalizations (bottom).
The idea behind this approach consists in using metal catalysts to perform the activation of a nearby C–H bond guided by the directing group or nowadays by the presence of a template.[8] Along these lines, it has been demonstrated that key in this endeavor is the formation of organometallic metallacycles (Pd[9], Rh,[10] Ir,[11] Co,[12] etc.) as intermediates of many C–H bond direct functionalization. From a mechanochemistry perspective, developing of a C–H direct functionalization reaction in a ball mill would require the organometallic species (catalysts and/or intermediates) to be resilient enough to tolerate the reaction conditions experienced upon ball milling. Pleasingly, in the past years rapid development of mechanosynthesis of organometallic complexes and of their applications under mechanochemical conditions have translated into the fundamental knowledge that paved the way for the initial C–H bond activation and functionalization examples. This concept article, will recapitulate some of the findings that served as the platform for developing mechanochemical C–H bond functionalization reactions, the current state-of-the-art, the challenges still faced to reach a higher level of chemical complexity, and some unique opportunity scenarios where mechanochemistry could complement the traditional solution-based approaches in the search for new chemical reactivity.[13]
Mechanosynthesis of organometallic complexes Given the need to provide oxygen- and water-free environments when handling and reacting many organometallic species, synthesis of organometallic complexes has been mostly governed by the use of solvent-based protocols relying on Schlenk and glovebox techniques. However, the classical mechanosynthesis of ferrocene (1) by milling revealed the strength of the organometallic bonding between the iron (II) and the cyclopentadienyl ligands.[14] Such characteristic was later confirmed by Braga et al. during the mechanochemical Suzuki coupling reaction between ferrocene-1,1′-diboronic acid [Fe(η5C5H4B(OH)2)2] (2) and 4-bromopyridine and 5-bromopyrimidine, which left the organometallic moiety untouched.[15] Likewise, cocrystallization of Fe(η5-C5H4–C5H4N)2 (3) and dicarboxylic acids by grinding led to the clean formation of supramolecular macrocycles,[16] highlighting the stability of the organometallic complex upon mechanical activation (Figure 1).
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CONCEPT triethylsilane in toluene,[23] and very recently the Mn(CO)5Br 8 was used to catalyze the hydroarylation of allenes.[24]
Figure 1. Ferrocene (1) and ferrocene derivative complexes (2-3) made or used under mechanochemical conditions.
In 2014, Ćurić and coworkers reported the mechanochemical cyclometalation and C–H bond activation on an azobenzene derivative.[17] Liquid assisted-grinding (LAG)[18] of an mixture of an activated azobenzene 4 with palladium acetate afforded the dimeric mono palladacycle complex 5. Prolongation of the LAG in the presence of additional Pd(OAc)2 generated the dicyclopalladated product 6.[19] The latter example demonstrates the feasibility to access synthetically valuable Pd-organometallic complexes,[20] and it per se corresponds to a direct C–H bond activation under ball milling conditions (Scheme 2).
Scheme 3. Synthesis of Mn(CO)5Br 8 by ball milling.
Simultaneously, the interest on the mechanosynthesis of organometallics grew steadily with the preparation of Alcomplexes,[25] metal-carbenes[26] and pincer complexes[27] enabled by ball milling. Some of these examples and other relevant contributions have been recently showcased by Rightmire and Hanusa in a comprehensive review article. [28]
Mechanochemical Rh-catalyzed C–H functionalizations Interesting for the development of mechanochemical C–H bond functionalization reactions was the synthesis of [Cp*RhCl2]2 11 in the ball mill reported by Hernández and Bolm.[29] This Rhcomplex is one of the most versatile catalyst in the field of C–H functionalization chemistry (Scheme 4; top). LAG of a mixture of rhodium chloride hydrate (III) (9) and pentamethylcyclopentadiene (Cp*H, 10) afforded the Cp*Rh catalyst 11 in good yield. In Rh-based C–H activation catalysis it has been demonstrated that the reactive catalytic species involves the formation of metallacycle Rh-intermediates.[10,30]
Scheme 2. Mechanochemical C–H activation of 4 in the ball mill.
In the same year, Hernández et al., began a series of studies on rhenium and manganese chemistry by ball milling[21-22] that led to the formation of pentacarbonyl Re and Mn halides, M(CO)5X (M = Re, Mn; X = Cl, Br, I).[22] Noteworthy was the formation of Mn(CO)5Br 8 after a mechanochemical oxidative addition of Mn2(CO)10 7 with Oxone® and NaBr in 88% yield (Scheme 3).[22] This Mn-complex has been reported to catalyze the insertion of aldehydes into aromatic C–H bonds in the presence of
Scheme 4. Mechanochemical synthesis of [Cp*RhCl2]2 11 and rhodacycle 13 and their application in the C–H halogenation of 2-phenylpyridine (12).
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CONCEPT Reacting 2-phenylpyridine (12) and [Cp*RhCl2]2 11 with sodium acetate in a planetary ball mill yielded the rhodacycle 13 in good yield (Scheme 4; middle). Grinding stoichiometric amounts of this Rh-complex 13 and N-bromosuccinimide (NBS) led to the ortho-bromination of 12. Similarly, the use of AgSbF6 permitted utilizing the [Cp*RhCl2]2 11 in catalytic quantities to facilitate the C–H halogenation of 12 after 3 h of milling (Scheme 4; bottom).
hypothesis was backed up after reacting the mechanochemically made 13 with methyl-1,4,2-dioxazol-5-one, which led to the formation of the amidation product in the ball mill.
Earlier in 2015, [Cp*RhCl2]2 11 proved also active to catalyze the solvent-free mechanochemically induced C–H bond functionalization of acetanilides 16 (Scheme 5).[31] A catalytic cocktail involving the Cp*-Rh catalyst 11, copper acetate and silver tetrafluoroborate favored the selective ortho-olefination of various acetanilides 16 with acrylate derivatives 17. After 15 h of milling at 800 rpm the mechanochemical reaction afforded the functionalized acetanilides 18 in moderate yields without the need for additional heating.[32] Noteworthy was the use of dioxygen as terminal oxidant for this solvent-free reaction.
Scheme 6. Mechanochemical rhodium-catalyzed C–H bond amidation of arenes 19 with dioxazolones 20.
In 2017 the [Cp*RhCl2]2 11 was used as the precursor for the synthesis of [Cp*Rh(Me(CN)3][SbF6]2. This cationic rhodium catalyst was then tested in the oxidative coupling of acetanilides and alkynes in the ball mill (Scheme 7).[34] Scheme 5. Selected examples of the mechanochemical rhodium-catalyzed olefination of acetanilides 16.
Very recently Bolm’s group reported the mechanochemical C–H amidation of aromatics with dioxazolones in ball mills. Once again, a combination of [Cp*RhCl2]2 11, AgSbF6 and AgOAc was found superior over Ru- and Ir- catalysts to favor the solvent-free direct amidation.[33] Initially, the screening of the best reaction conditions was conducted using N-(tert-butyl)benzamide and methyl-1,4,2-dioxazol-5-one. However, quickly the mechanochemical amidation demonstrated to be a general protocol tolerating a variety of benzamides and various substituted 1,4,2-dioxazol-5-ones to afford the amidation products in good yield, 45-99%.[33] Compared with the original C–H bond olefination, the Rh-catalyzed amidations were completed in short milling times (1.65 h vs. 15 h) in a mixer mill operated at 30 Hz. Remarkable was the evaluation of numerous commonly used directing groups such as ketoxime, benzo[h]quinolone and pyridine, among others (Scheme 6).[33] Even ketones, which are known for being weakly coordinating directing groups proved suitable for the amidation in the ball mill, albeit longer milling times and a two-fold increase in the catalyst loading were required (Scheme 6). In the case of the experiment using 2-phenylpyridine (12) as substrate, the amidation was proposed to occur via the rhodacycle intermediate 13, this Scheme 7. Rh-catalyzed mechanosynthesis of indoles 23.
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CONCEPT Milling of a mixture of acetanilides 16 and aryl/alkyl-disubstituted alkynes in the presence of the Cp*Rh catalyst and Cu(OAc) 2 as an additive for 15 h rendered a series of substituted indoles 23 (Scheme 7). Similar to the Rh-catalyzed olefination of acetanilides, here dioxygen was used as terminal oxidant as well. Flushing the milling vessels with oxygen prior their closing warranted an oxidizing atmosphere during the milling process. However, the oxidative coupling required long milling times to provide the indoles in moderate yields (Scheme 7). This result could be connected with a lack of a sufficient amount of oxidant inside the milling jar. Nevertheless, parallel reports have made used of the gaseous O2 present inside the milling container to conduct oxidative steps by ball milling. For instance, Lamaty and co-workers demonstrated the utilization of the gaseous dioxygen as reagent during the mechanochemical formation Cu–carbene complexes from N,N-diaryl imidazolium salts and metallic copper.[35] Alternatively, Stolle et al. circumvented the lack of oxidant inside the closed milling vessel by post-reaction exposure of the reaction mixture to air, after a Cu-catalyzed Glaser coupling.[36] Recently, the Schüth’s group reported the mechanochemical oxidation of carbon monoxide with Cu-based catalysts by milling. The authors employed modified milling equipment to permit the safe use and constant flow of gaseous reagents through the milling jar.[37] This alternative type of setups and oxidative strategies could be of great help to improve mechanochemical C–H bond functionalizations.
Mechanochemical Ir-catalyzed C–H bond amidation Besides the Rh-catalyst (III) 11 previously described, additional metal complexes such as [Cp*IrCl2]2 24 have been documented to facilitate the C–H bond amidation reactions under ball milling conditions.[38] In 2016 the Bolm’s group developed a mechanochemical C–N bond formation involving the reaction of benzamides 25 with aryl- or alkyl-sulfonyl azides 26 (Scheme 8). Among the various catalysts/additives combinations tested, the use [Cp*IrCl2]2 24 (2.5 mol%) in the company of AgBF4 (10 mol%) and AgOAc (10 mol%) resulted in a high catalytic system providing the substituted benzamides 27 in high yields after only 99 min of mechanical milling (Scheme 8). The Ir-catalyzed C–H bond direct amidation of benzamides exhibited a broad substrate scope in terms of both the benzamide and the sulfonyl azides reaction partners. Noteworthy for this particular system was the safe use of the azide derivatives 26 under solvent-free high-speed ball milling. In this regard, previous utilization of explosophores such as azides,[39] diazonium salt[40] or contact-unstable mixtures (primary amines-phenyliodine diacetate system)[41] in ball mills has been accomplished without incidents. For instance, in the case of milling azides, it was reported that “at no point during any of these reactions did we [the authors] observe any explosion or increased exothermicity due to milling azides”.[39]
Scheme 8. Ir-catalyzed C–H amidation of benzamides 25 in a ball mill.
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CONCEPT However, extra safety and precaution is always recommended when ball milling hazardous reagents or mixtures. i) Checking beforehand the thermal stability of the chemicals, if available, ii) conducting the screening reactions involving explosophores initially at a small scale, and iii) carrying out the mechanochemical reactions and the workup inside a fume hood could be strategies to keep the risk as low as possible. Moreover, to shed some light on the mechanism of the mechanochemical amidation reactions the authors synthesized the iridacycle 28 in the ball mill. This cyclometalated iridium complex was then found to effectively catalyze the amidation of N-(tert-butyl)benzamide and benzylsulfonyl azide. In addition to this, the kinetic isotopic effect (KIE) study of the iridium(III)catalyzed C−H bond functionalization in a ball mill revealed a KIE value that was almost three times smaller that the one for the same transformation in organic solvents (1,2-dichloroethane) (1.2 vs 3.4).[38] Suggesting, perhaps, a mechanistic change for the C−H bond cleavage by milling, which resulted in a facilitated the C−H bond functionalization of 25 in the ball mill compared with the solution-based protocol.
Mechanochemical coupling
Pd-catalyzed
Activation of the indoles was achieved by LAG (HOAc; = 0.17)[18] using Pd(OAc)2 (10 mol%), MnO2 as the oxidant and SiO2 as milling auxiliary. After short milling times in a mixer mill the reaction afforded a series of 3-vinylindoles 31 in good yields (Scheme 9). Choosing an alternative palladium salt such as PdCl2 led to a double C−H bond activation yielding the ,diindolyl propionates 32 over the mono-addition coupling products 31 (Scheme 9). Particularly important were the blank experiments in organic solvent using PdCl2 as catalyst, which revealed the exclusive formation of 3-vinylindoles 31 in DMF. Spectrometric analysis of the reaction mixture, both from solution and ball milling experiments revealed the presence of a solvent-labile dimeric palladium intermediate, which could explain the differences in product composition between the transformations in DMF and by ball milling.[42]
oxidative
After the initial findings on the palladium C−H bond activation of azobenzenes by milling,[17] the interest in mechanochemical palladium-catalyzed reactions quickly grew. In 2016, Su and coworkers developed a Pd-catalyzed oxidative coupling of indoles 29 with acrylates 30 by ball milling (Scheme 9).[42]
Scheme 9. Palladium-catalyzed oxidative coupling of indoles 29 with acrylates 30.
Scheme 10. Mechanochemical Pd-catalyzed C−H/C−H bond arylation.
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CONCEPT Also in 2016, Xu and co-workers reported the Pd-catalyzed mechanochemical C−H/C−H bond arylation between oximes 33 and arenes 34, employing Pd(OAc)2 as the catalyst and Na2S2O8 as the oxidant (Scheme 10).[43] Compared with the reaction carried out in solution (using the arene both as a reagent and as the reaction media), the reaction in the planetary ball mill proved more advantageous. On the one hand, the amount of the arene and the reaction time could be reduced dramatically, making the C−H/C−H bond ideal for couplings involving expensive or synthetically challenging arenes partners, on the other hand the selectivity of the arylation improved under ball milling conditions. Several electron-donating and electron-withdrawing arenes 34 were tolerated in the mechanochemical reaction. Likewise, various aromatic and aliphatic oximes were compatible with the Pd-catalyzed C−H/C−H bond arylation. Replacing the oximedirecting group for urea or anilide derivatives required longer milling times but it enabled broadening the substrate scope of the arylation (Scheme 10; bottom). Similarly, mechanochemical oxidative C−C bond formation involving cross-dehydrogenative couplings (CDC)[44] between hydrocarbons have been recently studied and reviewed by Su et al.[45] Mainly copper salts in the presence of oxidants such as 2,3-dichloro-5,6-di-cyanoquinone (DDQ) were used to facilitate the oxidative C−H/C−H bond formation. More recently, the use of Fe(NO3)3·9H2O and DDQ by ball milling exposed the catalytic potential of the iron salts under milling conditions to facilitate cross-dehydrogenative couplings.[46] After an initial screening, Fe (III) salts such as FeCl3 and Fe(NO3)3 (anhydrous and hydrated) proved more active than the iron (II) chloride or sulfates. Additionally, experiments using extra pure Fe(NO3)3·9H2O (≥99.95%; with a copper content 0.4 ppm) were done to rule out a copper-catalyzed background reaction.[47] Milling of a mixture of 3-benzyl indole derivatives 36 and methylene reaction partners 37, in combination of Fe(NO3)3·9H2O; DDQ and silica gel led to a fast oxidative C−H/C−H bond formation. After 21 min of milling at 25 Hz, a series of 3-arylmethylindole derivatives 38 were obtained in high yields (Scheme 11; sp3−sp3 CDC couplings). Moreover, indole derivatives performed well as nucleophiles too, yielding various sp3−sp2 CDC coupling products.[46] Worth mentioning was the observation that not only N-substituted indoles could be used as reactants but also N-free indoles were compatible with the iron (III)-catalyzed reaction conditions (Scheme 11; sp3−sp2 CDC coupling).
Comments and Future Perspective It has long been recognized that the application of mechanochemical techniques to chemical synthesis results in shorter reaction times and cleaner reaction mixtures. Along these lines, mechanochemical C−H functionalizations were not exceptions and most C−H bond activations by ball milling proceeded faster than in solution without the need for external heating. In regard to this last aspect, the mechanical dynamics of the ball milling process can inherently impact the temperature inside the milling vessel. Studies on the evolution of the temperature upon milling have tried to unravel the key factors
Scheme 11. Mechanochemical Fe-catalyzed C−H/C−H CDC coupling.
(milling media, operational variables, etc) affecting the final temperature in the milling vessel.[32] However, in addition to the milling material, speed, and mode of milling, other intrinsic chemical events like the release of crystallization water in a chemical reaction have proven to cause fluctuations in the overall temperature of the milling container.[32a] Consequently, a better temperature sensing and temperature control of mechanochemical reactions is foreseen to become popular in the upcoming future. Such improvement would permit tackling more challenging C−H bond functionalizations by simultaneously milling and heating the reaction mixture. On the other hand, variable temperature and reliable cooling systems could facilitate the safe utilization of thermal sensitive reaction partners, and it would boost the number of mechanochemical asymmetric reports too. One more advantage of chemical transformations by ball milling is the possibility to work with reactants of different solubility profiles. Such operational freedom could make
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CONCEPT mechanochemical approaches emerged as standard strategies for the post-modification of low-soluble materials by C−H bond activation (e.g., polymers, metal-organic frameworks, peptides),[48] by overcoming the solubility constrains of using poor-soluble substrates, catalysts or additives. Although the initial mechanochemical C−H bond functionalization examples were developed based on the wellknown catalytic activity of rhodium, palladium, and iridium complexes. It is anticipated that other metals (especially earthabundant metals), could be utilized under ball milling conditions as well. In that sense, achieving high reactivity and regioselectivity using lower catalyst loadings (currently 1−10 mol%) of more readily available metallic species is a global goal in the field of in C−H bond functionalization. Regarding this last goal, the excellent mixing experienced by high-speed ball milling together with the highly concentrated reaction conditions created in the absence of solvent, could enable reducing the amount of the catalyst required to reach high performance. Additionally, the development of C–H bond activations with more earth-abundant metals could facilitate the use of metallic milling media to convey the grinding (container and ball bearing), and at the same time as the catalytic metal specie for the transformations. Until now, the use of copper milling equipment, nickel pellets and the presence of silver-foil upon milling has been used as an strategy for the Cu-catalyzed azide-alkyne cycloaddition,[49] Ni-catalyzed cycloaddition of alkynes[50] and the Ag-catalyzed cyclopropanation of alkenes with diazoacetates, [51] respectively. Facilitating the recovery and the reuse of the metal catalyst. In addition to the above mentioned practical benefits, the application of mechanochemical techniques to C–H bond activation could be an excellent platform for accessing chemical reactivity difficult or impossible to accomplish in solution chemistry.[13] For example, solvent-free reactions by milling could favor the formation of labile metallocycles, whose formation could be prohibited in the presence of coordinating solvents. Having access to non-solvated metal complexes by milling have already been shown to affect their catalytic reactivity compared with the solvated complex counterparts.[25] Regarding this last aspect, examples of solvent-controlled C–H bond functionalization under traditional reaction conditions in solution have been reported. In 2014 Lin, Yao and co-workers published a C–H alkenylation of 3,4-disubstitued pyrroles using Pd(OAc)2 in combination of AgOAc.[52] The regioselectivity of the reaction was found to depend on the organic solvent used. Choosing toluene as the reaction media the process favored the C2products due to the presence of the ester directing group at the C-3 position of the pyrrole (Scheme 12a; top branch), whereas a mixture of DMF/DMSO overweighed the directing group effect of the ester and led predominantly to the formation of the C5alkenylation product (Scheme 12a; bottom branch). For this type of systems, neat or liquid assisted grinding could be the ideal choice to investigate the role of the organic solvent and to potentially tune changes in regioselectivity. More recently, Du et al., reported a divergent C(sp 3)−H functionalization, which was influenced by the strength of the
base and by the organic solvent used (Scheme 12b). [53] In the presence of a Pd-complex, the use of a strong base such as
Scheme 12. Solvent- and base-controlled Pd-catalyzed C–H functionalization reactions in solution-based approaches. t
BuOK and tert-amyl alcohol as the reaction media guided the amide -C–H functionalization (Scheme 12b, left). A shift in the regioselectivity (benzylic C–H activation) was observed when potassium carbonate in xylenes was employed (Scheme 12b, right). The origin of this switch in selectivity was associated with the possibility to dissolve the tBuOK much better in a polar solvent, thus facilitating the deprotonation of -C−H bond. Along these lines, K2CO3 have demonstrated to override the efficiency of strong bases under solvent-free ball milling, and once again not solubility constrains were encountered under those conditions.[54]
Conclusion In summary, in a short period of time the activation of C−H bonds in organic molecules by mechanical ball milling has emerged as an alternative to solution-based methods. The variety of metal complexes and the number of directing groups, which have proven to be compatible under ball milling conditions, together with the high frequency of the reports on C−H bond functionalization represent a forthcoming consolidation of this concept. Future investigations with more emphasis on the mechanisms of the mechanochemical C−H bond reactions [17, 55] are necessary to better understand this alternative activation mode. Such understanding is anticipated to help broadening the scope of this concept by adding examples where mechanochemical protocols could be advantageous over other activation strategies. For example, by this time in the reading one should be already intrigued and tempted to speculate (or better to study), about the regioselectivity of known solvent- or base-depended C–H bond functionalization reactions, now under mechanochemical conditions. Such type of systematic
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10.1002/chem.201703605
Chemistry - A European Journal
CONCEPT work could lead to the discovery of new reaction pathways complementing the current solution-based approaches.
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Acknowledgements
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JGH thanks the financial support from the RWTH Aachen University through: a) the RWTH Start-up grant StUpPD_221-16 funded by the Excellence Initiative of the German federal and state governments, and b) the Distinguished Professorship Program funded by the Excellence Initiative of the German federal and state governments. Keywords: C–H activation • mechanochemistry • ball milling • solvent-free • [1]
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CONCEPT Layout 2:
CONCEPT José G. Hernández* Page No. – Page No. C–H Bond Functionalization by Mechanochemistry
MechanoC–Hemical activation. This concept article gives an overview of the events that led to the merging of mechanochemisty and C–H bond functionalization, the stateof-the-art studies and a perspective for future mechanochemical C–H bond activation studies.
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