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One-pot Mo(CO)₆-facilitated transformation of anilines into benzophenones via in situ pyridinium reconfiguration

Satenik Mkrtchyan^a, Oleksandr Shalimov^b, Michael G. Garcia^c, Gabriela Addová^d, Juraj Filo^d, Sehrish Sarfaraz^e, Khurshid Ayub^e, Vishal B. Purohit^f and Viktor O. Iaroshenko*^aghi
aDepartment of Chemistry, Faculty of Natural Sciences, Matej Bel University, Tajovského 40, 97401, Banska Bystrica, Slovakia. E-mail: iva108@googlemail.com; viktor.iaroshenko@umb.sk; viktor.iaroshenko@tuwien.ac.at; v.iaroshenko@gau.edu.ge
^bDepartment of Heteroatom Chemistry, Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmans'ka, 02660 Kyiv, Ukraine
^cDepartment of Biology/Chemistry, Center for Cellular Nanoanalytics (CellNanOs), Universität Osnabrück, Barbarastr. 7, D-49076 Osnabrück, Germany
^dDepartment of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, Bratislava, 842 15, Slovakia
^eDepartment of Chemistry, COMSATS University, Abbottabad Campus, Abbottabad, KPK 22060, Pakistan
^fDepartment of Chemical Sciences, P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology (CHARUSAT), Changa 388 421, Gujarat, India
^gFunctional Materials Group, Gulf University for Science and Technology, Mubarak Al-Abdullah 32093, Kuwait, Kuwait
^hInstitute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163-OC, Vienna, 1060 Austria
ⁱSchool of Medicine, Georgian American University, 10 Merab Aleksidze Str., Tbilisi 0160, Georgia

First published on 7th August 2025

Introduction

	Scheme 1 Sample reported strategies for activation and late-stage functionalization plus our concept.

Initial approaches for tackling the inert nature of the amine bond were set forth by Katritzky via his work on the interconversion of primary alkyl amines, C(sp³)–NH₂, into reactive pyridinium salts.^4–6 This set the precedent for the development of various pyrylium salts, or Katritzky salts, with the capacity to activate the C–N bond across various molecular systems, altering the view of inactive aliphatic amines towards efficient electrophiles capable of undergoing S_N2 substitution.⁷ In continuation of these results, further studies from Cornella et al. regarding the application of unsubstituted pyrylium tetrafluoroborate salts have extended to S_NAr functionalization in aromatic amines, with focal activities on the selective activation of the C(sp²)–NH₂ bond in primary aromatic amines for further deamination and derivatization, offering an efficient route for late-stage functionalization of aromatic amines.^8–11

Recent advances in the field of mechanochemistry by Ito^12,13 and Bolm¹⁴ have propelled us to develop numerous organic synthetic protocols aimed at utilizing mechanochemistry for developing green approaches that involve piezoelectric materials to produce in situ specialized chemicals.^15–22 Herein, we incorporate pyrylium tetrafluoroborate to design a mechanochemical protocol for late-stage modification of C(sp²)–NH₂ in anilines without resorting to de novo synthesis of organic precursors. Consequently, we expand upon the scope of LSF of anilines to produce benzophenone derivatives via incorporation of molybdenum hexacarbonyl, Mo(CO)₆, which induces reconfiguration of the pyridinium salt intermediate into acyl pyridinium through in situ carbonylation.

Benzophenones represent a prominent class of bioactive molecules distinguished by their structural diversity, which enables a wide range of biological activities, including anti-inflammatory, antibacterial, antiviral, and anticancer properties, making them highly valuable in medicinal chemistry.²³ The organic synthesis transformation of primary amines to benzophenone functional groups is of great significance to medicinal chemistry due to the potential of benzophenones as bioactive compounds.^24–26 A major drawback in their synthesis from primary amines is the requirement for specific amine configurations, activation through pre-functionalization of the C–N bond, and the need for specific reaction conditions for ketone transformation.^24–26 This in turn limits the scope and compatibility with late-stage functionalization due to the need for a defined starting material structure or pre-functionalization steps to synthesize product intermediates. Typical methods for ketone formation from amines are based on the precedent of carbonylation of primary amines, R₂CHNH₂, to R₂CO via transamination of isomeric Schiff bases.^24,25 More recently, methodologies have placed emphasis on LSF by synthesizing several ketones from protected anilines via C(sp²)–O/N bond cleavage to the corresponding imine-ketal core following the reaction with α-bis(boryl)carbanions, which results in the formation of aromatic ketones from bioactive anilines. However, this process requires the isolation of the intermediate at the quin-ketal stage in order to provide a good yield, resulting in product isolation at the intermediate step of the overall synthesis, thereby limiting the scope of the method and making it unsuitable for LSF.²⁷

The inherent stability and inert character of anilines underscore the challenges associated with their use in ketone formation, since there is a requirement for pre-functionalization steps in order to activate them. The C(sp²)–NH₂ bond is almost unreactive in terms of interconversion to other functionalities; it possesses poor heterolytic nucleofugality and a high C–N bond dissociation energy (BDE of C₆H₅–NH₂: 102.6 ± 1.0 kcal mol⁻¹),²⁸ with further consideration of basicity.^29–31 Advancements in the field of C(sp²)–NH₂ bond activation for deaminative functionalization by Cornella led to successful S_NAr reactions in a single step via formation of a pyridinium ion (Scheme 1A and B).^7,11 Inspired by this work, our group previously achieved selective mechanochemical interconversion of primary aromatic amino groups into the –OCF₃ functionality (Scheme 1C).²⁰ This process involved the condensation of anilines, amides, and sulfonamides with the pyrylium reagent (Pyry-BF₄) to form reactive pyridinium salts, followed by an S_NAr reaction with the –OCF₃ source, 1-methyl-1,4-diazabicyclo[2.2.2]octan-1-ium trifluoromethanolate, which resulted in the production of several derivatives.

Since selective activation of anilines entails an in situ, one-pot approach, it is logical to devise an approach that retains the advantages conferred by late-stage functionalization by changing the reaction conditions according to the target compound. In this context, typical CO insertion proceeds via a 1,1-insertion into palladium(II) complexes generated through oxidative coordination of electrophiles to unsaturated palladium(0) species, leading to the formation of a Pd(0)/Pd(II) catalytic cycle.^32–35 The gaseous nature of CO presents a disadvantage in mechanochemical settings due to potential difficulties in experimental design with regard to gas pressurization³⁶ and the toxic, flammable nature of CO.³⁷ A more pragmatic approach involves employing a solid reagent as a CO source, which simplifies the experimental design and enhances safety. In the work of Larhed and co-workers, solid Mo(CO)₆ was utilized as a reliable source of CO for in situ carbonylation reactions, with established precedents in palladium-catalyzed carbonylation of aryl halides.^38,39 In this study, we incorporated Mo(CO)₆ within our specialized mechanochemical protocol to modify the mechanistic pathway responsible for benzophenone formation. CO insertion into the pyridinium intermediate leads to the formation of a reactive acyl pyridinium intermediate, which undergoes direct coupling with organoboron compounds without the requirement of a transition metal catalyst (Scheme 1). Organoboronic acids, as nucleophiles, find their most common utilization in Suzuki–Miyaura transition metal-catalyzed couplings of pyridinium salts for the formation of C–C bonds. However, these couplings are almost exclusively focused on N-alkyl^40,41 and benzylic pyridinium salts,^42,43 as the BDE of the C(sp³)–NH₂ bond is significantly lower than that of the C(sp²)–NH₂ bond (CH₃–NH₂: BDE = 85.1 ± 0.5 kcal mol⁻¹).²⁸ The activation of the C(sp²)–NH₂ bond is more challenging, which explains why deaminative coupling of C(sp²)–NH₂ with organoboron reagents has not been extensively studied.

Results and discussion

	Scheme 2 Reaction scope for boronic acid and trialkoxysilanes.

In the optimization procedure shown in Table S1 (entries 1–15), various metal carbonyls were employed under optimized conditions for the reaction of boronic acids and tested for their potential to produce the desired benzophenone product (3a) from aniline (1a). The milling was conducted at a frequency of 30 Hz for 90 min; the yields changed significantly according to the type of the carbonyl source. A series of metal carbonyls (1.6 equiv.): Fe(CO)₅, Co₂(CO)₈, Ni(CO)₄, Cr(CO)₅, Ru₃(CO)₁₂, and V(CO)₆ were evaluated for the formation of benzophenone (3a) based on the first series of entries (1–6). The solid metal carbonyl reagents were employed in combination with DABCO (1.4 equiv.) and BaTiO₃ (5 equiv.)¹² in a mechanochemical setting, resulting in yields ranging from 0% to 67%. The highest yield was achieved as shown in entry 7 for Rh₄(CO)₁₂ (0.8 equiv.), which produced a 91% yield. In a general approach, the results showed that Mo(CO)₆ was the most versatile among all of the CO sources considered for the optimization of reaction conditions. Accordingly, in entry 8, 1.6 equivalents of Mo(CO)₆ were used, affording an 86% yield. Despite further reducing the quantity to 1 equivalent as in entry 9, a high yield of 87% was maintained. As in entry 10, 0.6 equivalents of Mo(CO)₆, 1.4 equivalents of DABCO, and 5 equivalents of BaTiO₃ were used, and the yield was also 86%. Thus, it was considered the optimum amount due to its balance of efficiency and cost-effectiveness. Further testing of Mo(CO)₆ was performed as shown in entries 11 and 12. In this case, changing the quantity of BaTiO₃ provided yields of 70% and 87%, correspondingly, for 4 or 6 equivalents. The control experiments, entries 13, 14, and 15, in which either DABCO, BaTiO₃, or both were not used, resulted in no product formation, thus stressing the importance of these constituents in guarantying reaction completion. This way, the obtained data allowed for setting the optimal reaction conditions as in entry 10, where 0.6 equiv. of Mo(CO)₆, 1.4 equiv. of DABCO, and 5 equiv. of BatiO₃ were employed for studying the scope of the reaction. Lastly, it may be worth mentioning that Rh₄(CO)₁₂ was not further elaborated as this compound is expensive, and the budget did not give the chance to move forward in this study. It is well known that DABCO is sufficiently basic to promote a variety of coupling reactions by elevating the nucleophilicity of the substrates, which in turn impacts the efficiency and yield of the reactions. For example, DABCO was used in mechanochemical C–N bond formation reactions by the Ito group to obtain high yields with a nickel(II) catalyst and a piezoelectric material under ball-milling conditions.¹² Moreover, our previous studies have shown the remarkable potential of DABCO as a base in a variety of mechanochemically induced cross-coupling reactions. Thus, we opted DABCO to be used directly as the base in the present transformation.

To elaborate further on the role of the mechanochemical conditions in the success of the reaction, a series of control experiments were conducted in the liquid-phase to compare the reaction efficiency with results obtained under mechanochemical conditions (see Table S1). In the solvent-based control experiments, the same reagents and proportions were employed as in the optimized mechanochemical conditions (entry 10: 0.6 equivalents of Mo(CO)₆, 1.4 equivalents of DABCO, and 5 equivalents of BaTiO₃). We tested several different solvents and temperatures for their impact on the efficiency of the reaction and product formation. Entries 16–24 show the conditions that employed several solvents and high temperatures in a classical approach. In methanol (entry 16) and ethanol (entry 17) solutions, the reaction mixtures were subjected to reflux at 100 °C for 20 hours, resulting in no observable product formation of the mixture at the proportions mentioned above. Similarly, using 1,4-dioxane (entry 18) and acetonitrile (entry 19) under reflux conditions at 100 °C for 20 hours also yielded no product. Further experiments with dimethylformamide (DMF) at 100 °C (entry 20) and 130 °C (entry 21), as well as N,N-dimethylacetamide (DMA) at 130 °C (entry 22), resulted in no product formation. In the same manner, benzene at 120 °C (entry 23) and toluene at 120 °C (entry 24) did not result in product formation. The yield for solution-based systems resulted in the formation of 0% target product in contrast to results obtained in a mechanochemical setting, hence putting emphasis on the vital role of mechanochemical activation of BaTiO₃ in driving the reaction to completion. This places emphasis on the importance of mechanical stimulation of BaTiO₃ to generate the necessary energy to drive the reaction by creating temporary polarized particles.

Optimization of the reaction conditions leading to the preparation of benzophenone derivatives involved a detailed evaluation of the applicability of the method using substrates and coupling agents with substituents at the ortho, meta, and para positions. The isolated target products 3a–3z obtained in isolated yields of 50%–92% with boronic acid as the coupling agent confirm the efficiency of the method over a wide scope of the parameters investigated (Scheme 2). The effect of substituent's position on yield efficiency was tested by synthesizing the same product, which are the compounds displaying the same labels in the scope. The results obtained for compounds 3a (86% and 85%), 3b (83% and 88%), 3c (84 and 82%), and 3d (80% and 85%) were quite high in yield and low in variability. Compound 3e was isolated in a fair amount of 90% yield, while both 3f and 3g were obtained in 88% and 85% yields, respectively. Yields of 88% and 90% were obtained for compound 3h, whereas for compounds 3i and 3j, the resulting yields were 86% and 91%, 90% respectively. Compound 3k gave low yields of 68% and 50%. On the other hand, 3l presented higher isolated yields of 89% and 87%, while 3m yield was 87%. For 3n, the yields were a bit more varied at 72% and 81%. For compounds 3p–3r, the yields were 76%, 68%, and 67%. Compounds 3s and 3t provided yields of 81% and 82%. The compounds 3u–3z provided yields of 92%–68%. The viability of the method was evaluated also with respect to reactions employing trialkoxysilanes as the coupling agent, although the efficiency of such reactions was slightly less than that of the reactions that employed boronic acid as the coupling agent. Target products 3a–3z gave yields that ranged from 51% to 79% (Scheme 2). Yields obtained for compound 3a ranged from 74% to 77%, showing good reproducibility regardless of the substituent placement. Compound 3b also gave similar results, with isolated yields of 71% and 79%, which is in line with the trend for efficiency. Compounds 3c and 3d gave yields of 74% and 75%, respectively. Compound 3e produced a high yield of 79%, and similarly the yield for compound 3h was 77%. Products 3j, 3k, and 3n displayed yields of 75%, 65%, and 70%, and the trend remained similar for the series of compounds 3t, 3u, and 3w (74%, 76%, and 74%). The lowest yield of 51% was obtained for compound 3z; in this way, such results allow us to surmise the efficiency of the protocol based on the series of different substituted benzophenones obtained with boronic acid and trialkoxysilanes as coupling agents.

In a similar manner to the reaction series of boronic acids and trialkoxysilanes (Scheme 2), the scope was studied for ortho-hydroxyarylenaminones to further extend the method for targeted production of 3-benzoylchromones (Scheme 4), which are important precursors for compounds with bioactive properties and require a complicated mechanistic pathway for their production.⁴⁶ Isolated yields for this reaction series ranged from 80% to 91%, showing the high efficiency of the approach with ortho-hydroxyarylenaminones. High yields of 83% and 91% were obtained for compounds 7a and 7b. Compound 7c, in turn, accounted for 87% of the total product. 7d and 7e gave yields of 85% and 81%, respectively. Lastly, excellent to acceptable results were obtained for compounds 7f and 7g (90% and 80%). All these data show that the method retains its wide scope of application and efficiency with different substrates, performing with the same high efficiency for ortho-hydroxyarylenaminones, is very versatile, and thus has very good chance to be further optimized for the sake of synthesizing products in high yields.

The mechanochemically driven, transition metal catalyst-free C–C coupling of boronic acids with aniline derivatives to form benzophenones involves in situ reconfiguration to acyl pyridinium (Scheme 3 – mechanism A). Initially, an aniline derivative undergoes condensation with pyrylium tetrafluoroborate under the influence of mechanochemical ball-milling to form active pyridinium species. The mechanochemical polarization of the barium titanate (BaTiO₃) provides necessary energy input to excite the pyridinium intermediate to lead to an active pyridinium species A, which is here used as an on–off switch to access the carbonylation (step B).^12,13,47 Solid Mo(CO)₆ in the ball mill is used as the CO ligand source. CO ligands are released during mechanochemical activation. The CO ligands of the carbonyl complex then aid in promoting carbonylation of the pyridinium salt, which converts it to the acyl pyridinium intermediate. During this step, the pyridinium species changes shape, where the bound CO replaces a pyridinium molecule, allowing the formation of the acyl pyridinium intermediate, which is then attacked by the nucleophile in the next step. This acyl pyridinium subsequently undergoes a mechanochemically driven nucleophilic attack by boronic acid coupling on the source of acyl pyridinium, affording the arylated carbonyl moiety (step C). The benzophenone target is generated by releasing the pyridine moiety (step D). This is the fourth and last step of the C–C coupling reaction, establishing a fully mechanochemical pathway toward benzophenones by late-stage functionalization of anilines. Mechanochemical C–C coupling is a simple, highly efficient example of mechanochemistry in organic synthesis, representing one of the clean and effective ways of realizing sustainable synthesis of complex organic molecules, such as benzophenones.

	Scheme 3 Proposed mechanisms for benzophenone formation.

	Scheme 4 Reaction scope for ortho-hydroxyarylenaminones.

Another important mechanistic proposal was devised according to the principles of redox chemistry, which finds basis in the mechanoredox catalysis precedent of electron transfer from barium titanate to commence a redox cycle within the system (Scheme 3 – mechanism B).^12–14 In the first step, aniline undergoes condensation with pyrylium tetrafluoroborate, resulting in pyridinium species. The mechanical stimulation of barium titanate (BaTiO₃) produces an electrical field that assists in the excitation of the pyridinium salt, which undergoes carbonylation (step A) by Mo(CO)₆ to form the acyl pyridinium intermediate (steps B and C). The mechanochemical polarization of the piezoelectric material BaTiO₃ induces single-electron transfer (SET) from DABCO to the acyl pyridinium intermediate (step D), generating the acyl pyridinium radical intermediate, which acts as a synthetic equivalent of the acyl radical. The resulting acyl pyridinium radical intermediate adds to the ipso position of the arylboronic acid 4 (step E), resulting in the formation of an aryl radical transition state. Finally, the electron transfer from the aryl radical transition state to DABCO (step F) leads to the formation of the expected benzophenone 3, with DABCO cycling between its reduced and oxidized forms.

In the mechanistic account displayed in Scheme 5, ortho-hydroxyarylenaminones are used as coupling agents to give 3-benzoylchromones. Scheme 5, for which the formation of acyl pyridinium in Scheme 4 is the basis, explains the mechanistic steps that lead to the formation of 3-benzoylchromones. In the first step (step A), the acyl pyridinium intermediate is subjected to a nucleophilic attack by the ortho-hydroxyarylenaminones. The alpha carbon of the ortho-hydroxyarylenaminone attacks the carbonyl carbon of the acyl pyridinium intermediate. A tetrahedral intermediate is formed, leading to the next step (step B), in which the tetrahedral intermediate undergoes a rearrangement (step C), facilitating the elimination of the pyridine moiety. This elimination results in a new C–C bond between the ortho-hydroxyarylenaminone and the former acyl pyridinium moiety, from which the reaction can proceed towards the attachment of the aromatic moiety from the acyl intermediate. The hydroxyl group (–OH) on the benzene ring attacks a carbon atom of the side-chain adjacent to a nitrogen atom bearing a positive charge in a dimethylamine group (NMe₂⁺). Subsequently, this step leads the formation of a new C–O bond and cyclisation of a six-membered ring (step D). The BF₄⁻ anion balances the positive charge of the oxonium intermediate (positively charged oxygen), which then transfers its proton to the neighboring nitrogen forming an ammonium leaving group, which upon elimination leads to the formation of 3-benzoylchromone (step E).

	Scheme 5 Proposed mechanism for 3-benzoylchromone formation.

DFT calculations were performed to gain insights into the proposed reaction mechanisms (mechanisms A and B, Scheme 3), and the resulting reaction energy profiles are reported in Fig. 1 and 2. Mechanism A starts with the formation of the van der Waals complex involving reactants R, i.e., a pyridinium species and hexacarbonyl molybdenum, i.e., Mo(CO)₆ (Fig. 1). In the van der Waals complex (or reactant), one CO group (ligand) of Mo(CO)₆ interacts with the active pyridinium species at a distance of 3.62 Å. In this step, the length of the Mo–CO bond increases to 2.05 Å. The first step in the mechanism is the carbonylation of the pyridinium species by the CO ligand. The activation barrier for this step is 30.28 kcal mol⁻¹. In the transition state i.e., TS1, the bond length of the Mo–CO bond increases to 2.44 Å and that of CO to pyridinium decreases to 3.10 Å, resulting in the formation of the acyl pyridinium intermediate (see Fig. 1). In Int1, the bond length of pyridinium to CO further decreases to 2.70 Å, along with the release of Mo(CO)₅. The acyl pyridinium intermediate then undergoes a nucleophilic attack by boronic acid, resulting in the arylated carbonyl moiety through coupling at the acyl pyridinium source. Int2 lies at −50.53 kcal mol⁻¹. In Int2, the bond distance between the boronic acid and CO of acyl pyridinium is 3.46 Å, whereas the bond length of CO to the pyridine ring in acyl pyridinium is 1.49 Å. The activation barrier for this step (i.e., nucleophilic attack) is 32.38 kcal mol⁻¹. The bond distance between boronic acid and acyl pyridinium decreases to 2.22 Å in TS2. Similarly, the bond length of CO to the pyridine ring (in acyl pyridinium) increases to 2.53 Å in TS2. After TS2, in Int3, the bond distance between boronic acid and acyl pyridinium further decreases, and the bond distance of CO to the pyridine ring further increases, resulting in the formation of benzophenone (P) along with the release of a pyridine moiety. This is the last step of the C–C coupling reaction, establishing a fully mechanochemical pathway toward benzophenones by late-stage functionalization of anilines.

	Fig. 1 Free energy diagram showing the proposed free radical mechanism for benzophenone formation via mechanism A (Scheme 4). All the reported energy values are presented in kcal mol−1 with reference initial reactant (R) at 0.00 kcal mol−1. The measured bond lengths are presented in angstroms (Å).

	Fig. 2 Free energy diagram showing the proposed free radical mechanism for benzophenone formation via mechanism B (Scheme 4). All the reported energy values are presented in kcal mol−1 with reference initial reactant (R) at 0.00 kcal mol−1. The measured bond lengths are presented in angstroms (Å).

Another plausible mechanism i.e. mechanism B (Scheme 3) is the free radical mechanism for the formation of benzophenones. As shown in Fig. 2, the initial steps in mechanism B are similar (up to the formation of Int1) to mechanism A, i.e., the formation of the acyl pyridinium intermediate by the attack of the CO ligand on the active pyridinium species, requiring an energy barrier of 30.28 kcal mol⁻¹. The subsequent step is the deamination of the acyl pyridinium intermediate i.e., the removal of aryl amide from acyl pyridinium, resulting in the formation of a radical intermediate. After the deamination of the acyl pyridinium species, the radical intermediate couples with boronic acid. This step of the mechanism proceeds through a free radical mechanism. Int2 is a stable species involving boronic acid and a radical intermediate. The formation of benzophenone through the free radical mechanism involves an activation barrier of 4.15 kcal mol⁻¹. The bond distance between the C of boronic acid and the CO of the free radical in Int2 is 3.51 Å, which decreases to 2.16 Å in TS2, and finally to 1.53 Å in Int3. B(OH)₂ leaves Int3, resulting in the formation of the final product P, i.e., benzophenone. The final product obtained through this mechanism is very stable i.e., lying at an energy of −69.27 kcal mol⁻¹.

The outcomes of the DFT calculations are much appropriate for the reactions that are carried out in the gaseous phase or in the solution phase. It has been well established that mechanochemically promoted reactions proceed along the synthetic pathways different from those described in the solution.^48–51 In a solvothermal process, the interaction between reactant molecules takes place by collisions in the liquid phase, while in the mechanochemical ball-milling process, the reactants are ground between the balls and the vessel surface as well as the between the surface of balls, where the collision between the balls and the vessel supplies the mechanical energy.⁴⁸

During the mechanochemical ball milling, the substrates are subjected to mechanical forces, such as shear and non-hydrostatic compression forces, and combinations thereof.⁵² As a result, the solid reactants undergo several associated physical processes including particle size reduction (comminution), with a consequent surface area increase, and the formation of lattice defects of various types, wherein the reactivity is enhanced due to the reduction of the strength of the attractive interactions that hold the solid together, which also ultimately leads to amorphization. Furthermore, the mechanical energy acts synergistically with the internal energy of the chemical system due to its temperature, further increasing the chemical reactivity of the matter. Herein, the combined effects of grinding, crushing, pulverizing, impacting, and shearing forces can induce a chemical reactivity different from that of solution-based processes.⁵³ These force-induced perturbations induce a change in the energy landscape of chemical reactions and accelerate the dissociation of unloaded bonds and the change sets in the electronic configuration of covalent bonds, enabling a different chemical selectivity than that of conventional solution-based reactions. Moreover, the ball-milling process ensures the feasibility of the reaction by the creation of hot spots (which has a temperature of about 600–1000 K), enhanced solid–solid mixing and contact area, the creation of metastable or unstable structural configurations, or producing reactive surfaces in situ.⁴⁸ Thus, by managing the milling parameters, such as the ball/powder weight ratio, milling frequency, milling time, and atmosphere, it is possible to drive the kinetics of mechanochemical reactions to overcome the energy barrier, which is quite difficult in solution phase processes.

Conclusion

Conflicts of interest

Data availability

Acknowledgements

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