Mechanoradical-driven C–H halogenation and nitration of arenes and vicinal dibromination of alkenes in the solid state

Abstract

We report a solvent-free mechanochemical approach for the C–H halogenation and nitration of arenes. In situ-generated oxygen-centered mechanoradicals readily oxidize halide or nitrite salts, enabling C–H functionalization of arenes. Radical trapping experiments confirm the involvement of bromine radical species, distinct from conventional solution-phase processes that predominantly proceed via brominium intermediates. This operationally simple and carbon-free strategy is further extended to solid-state vicinal dibromination reactions of unactivated alkenes.

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The direct C–H functionalization of arenes represents a powerful transformation in organic synthesis,^1–3 providing critical intermediates for pharmaceuticals, agrochemicals, and advanced materials.^4–7 However, conventional methods often rely on hazardous reagents (e.g., molecular halogens, nitric acid, transition metals or strong Lewis acids) and harsh conditions, generating stoichiometric waste (e.g. increasing carbon footprints) and posing significant safety and environmental concerns (Scheme 1A).^8–15 These persistent challenges underscore the need for new strategies to bypass hazardous reagents, minimize waste, and operate under mild conditions.

Scheme 1 (A) Overview of conventional solution-based strategies of arene C–H halogenation and nitration reactions; and (B) a mechanistically divergent mechanoradical strategy in the solid state (this work).

Mechanochemistry, which exploits the mechanical force to drive chemical reactions, has emerged as an alternative for organic synthesis, offering unparalleled advantages over conventional solution-based approaches in terms of atom economy, reduced energy consumption, and elimination of solvent waste.^16–21 Among all the attributes of mechanochemistry, its ability to directly homolyze chemical bonds to generate radical species, known as mechanoradicals, is distinct from other known reaction driving forces. In theory, the mechanochemical formation of redox neutral radicals does not require external sacrificial reagents, photoredox or piezoelectric catalysts, or electrodes (Scheme 1A).^22–24 Although this idea represents the most straightforward and environmentally benign approach to produce radicals, literature examples employing this strategy in C–H bond activation reactions are scarce. Hong reported mechanochemical fluorination with unactivated C(sp³)–H bonds, but control experiments revealed that the process was likely facilitated by trace metals (e.g. Fe and Ni) in the milling apparatus (e.g. stainless steel (SS) jars and balls).²⁵ Replacing them with non-metal ones completely quenches the reactivity. Mechanochemical halogenation of arenes, especially bromination,²⁶ definitively going through a halogen radical intermediate was reported by Mal,²⁶ which was supported by spin trapping experiments and EPR study.

Although cleavage of O–O bonds in persulfate (S₂O₈²⁻) can be promoted by various sources of energy input (e.g., heat or high-energy photons) in solution, our group recently showed that oxygen-centered mechanoradicals (O-mechanoradicals) can be generated in situ from persulfate salts directly by ball-milling treatments, even at low temperature (−50 °C) with a non-stainless steel milling apparatus (e.g. ZrO₂ balls and polypropylene (PP) tubes).²⁷ These reactive radical species would subsequently oxidize carbon-based nucleophiles to engage in Minisci-type coupling reactions. Building on this foundation, we herein report that O-mechanoradicals could be further employed with simple metal salts (MBr) for bromination of arenes (Scheme 1B). More significantly, although oxidative halogenation reactions employing a combination of halide salts (e.g. NaBr, LiCl, etc.) and oxidants (e.g. H₂O₂, persulfate, etc.) under solution-based conditions were investigated,^28,29 most of these studies suggested the involvement of halonium ion intermediates. This work highlights that an unusual radical-based reaction pathway is operative under ball-milling conditions, divergent from solution-based reactions. The mechanochemical oxidative functionalization is further extended to arene nitration and alkene dibromination reactions, demonstrating the broad applicability of our strategy.

At the outset, bromination of naphthalene (1a) was chosen as a model reaction to test the feasibility of our idea. When a mixture of 1a, (NH₄)₂S₂O₈ (2a), and LiBr in a 1 : 2 : 2 molar ratio was charged in a 5 mL polypropylene (PP) milling vial with stainless steel (SS) balls (15 balls, diameter: 3.0 mm), and subjected to ball-milling treatment in a mixer mill machine for 2 h at 40 Hz, 1-bromonaphthalene (3a) was obtained in 66% NMR yield (Table 1, entry 1). The use of other halides such as NaBr, KBr or NH₄Br afforded lower yields (entry 2). Switching to a smaller vial (2 mL) and utilizing fewer milling balls slightly improved the yield (entries 3–4), apparently providing better filling capacity for more efficient milling. Replacing SS balls with ZrO₂ ones didn't affect the reaction performance (entry 5). This rules out that bromination is promoted by trace metal residues from SS balls. When the reaction time was shortened to 1 h, 3a was obtained in the best yield of 90% (entry 6), but further reduction of reaction time decreased the yield (entry 7). Exchanging 2a with either K₂S₂O₈ (2b) or Na₂S₂O₈ (2c), or using a different 2a/LiBr ratio resulted in a lower yield of 3a (entries 8–12). Meanwhile, a corresponding solution-based (CH₃CN/H₂O = 1 : 1) reaction at 50 °C for 6 h yielded 3i in 15% yield (entry 13).

Table 1 Reaction condition screening in mechanochemical reactions between 1a, LiBr, and 2a.^a

Entry	Tube vol. (mL)	Ball size	X	Y	Time (h)	Yield 3a^a (%)
a Yields determined by ^1H NMR spectroscopy with CH2Br2 as an internal standard. LiBr replaced with. b NaBr, c KBr, or d NH4Br. e Milling conducted at a jar temperature of −10 °C. 2a replaced with f K2S2O8 or g Na2S2O8. h Solution reactions conducted in CH3CN/H2O = 1 : 1 at 50 °C (1i as the starting material).
1	5	SS 15 × 3 mm	2.0	2.0	2	66
2	5	SS 15 × 3 mm	2.0	2.0	2	53^b/58^c/7^d
3	2	SS 15 × 3 mm	2.0	2.0	2	72
4	2	SS 3 × 3 mm	2.0	2.0	2	74
5	2	ZrO2 3 × 3 mm	2.0	2.0	2	71
6	2	SS 3 × 3.0 mm	2.0	2.0	1	90/60 ^e
7	2	SS 3 × 3.0 mm	2.0	2.0	0.5	72
8	2	SS 3 × 3.0 mm	2.0	2.0	1	76^f/79^g
9	2	SS 3 × 3.0 mm	2.0	1.5	1	75
10	2	SS 3 × 3.0 mm	2.0	2.5	1	83
11	2	SS 3 × 3.0 mm	1.5	2.0	1	55
12	2	SS 3 × 3.0 mm	2.5	2.0	1	79
13	—	—	2.0	2.0	6	15^h

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With the optimum reaction conditions in hand, we turned our attention to explore the scope of other arene substrates. The results are summarized in Scheme 2. In short, the mechanochemical method is applicable to a wide range of naphthalene derivatives with different electronic properties, including electron-neutral (3b–e), electron-donating (3f–h), and electron-withdrawing groups (3i) in up to 92% yield of the mono-brominated product. Other arenes such as anthracene derivatives (3j–k), phenanthroline (3l), and fluorene (3m) can also be well tolerated. In addition, to demonstrate the practicality of the mechanochemical reaction, a gram-scale reaction using a 15 mL SS milling vessel and one SS ball (diameter: 16 mm) was conducted and it provided 3i in 72% isolated yield.

Scheme 2 Substrate scope of mechanochemical C–H bromination, chlorination, and nitration reaction between 1, X group precursor (LiBr, CuCl₂ or AgNO₂) and 2a. ^aYields determined by ¹H NMR spectroscopy with CH₂Br₂ as an internal standard. ^bIsolated yield. ^c7 mmol scale reaction with a 15 mL SS milling vessel and one SS ball (diameter: 16 mm) for 1 h.

The advantage of this mechanochemical method with persulfate and inorganic halide salts is that it can be easily extended to other C–H functionalization processes with arenes. By employing different inorganic chlorides (MCl) and nitro sources (MNO_n; n = 2 or 3), the method can be extended to arene C–H chlorination and nitration (Scheme 2). For chlorination, CuCl₂ stood out as the most suitable chlorine source (Table S5). Ball-milling of 2a with CuCl₂ and 1a afforded 1-chloroanthracene (4a) in 46% yield. For nitration, among various inorganic nitro sources tested, AgNO₂ performed the best (Tables S7 and S8). Together, these solvent-free methods can be applied to numerous arene substrates, achieving chlorination and nitration products in yields up to 45% and 89%, respectively.

From a synthetic perspective, the use of persulfate and bromide salts was previously shown to provide a similar C–H bromination outcome.²⁹ To identify a clear mechanistic difference (if any) between solution-based and solvent-free mechanochemical methods, acrylamide (6) was employed under the standard ball-mill conditions (Scheme 3a-i). The reaction provided an alkene dibromination product (7a) in 31% yield. Intriguingly, when an analogous reaction was carried out in CH₃CN/H₂O (v/v = 1 : 1) at 65 °C for 6 h, a completely different ring-closing product (7b) was obtained, albeit in low yield (12%). The conflicting outcomes strongly supported that the solvent-free method undergoes a radical-based process,³⁰ while the solution-based reaction follows a brominium (Br⁺) pathway.³¹ We also ruled out the idea that arene bromination is directed by in situ generated Br₂. When 6 was milled in the presence of Br₂, only 7b was obtained in 23% yield besides the arene bromination product (Fig. S6). 7a was not detected in the reaction mixture. For additional experimental support, N-allylbenzamide (8) was also examined (Scheme 3a-ii). In a similar manner, the ball-milling reaction selectively afforded the alkene dibromination product (9a) in 45% yield, and the solution reaction with CuBr₂, which is known to go through the Br⁺ intermediate,³² gave a dihydrooxazole cyclization species (9b) in a decent 88% yield. Intriguingly, simply adding 2a to the same reaction condition shifts the reaction product from 9b to 9a, suggesting the crucial role of 2a in facilitating radical bromination. The formation of 5e and 3o-Br/3o-2Br is also indicative of radical-based processes (Scheme 2).

Scheme 3 Mechanistic studies: (a) radical-ionic pathway studies; (b) spin trapping experiments; (c) radical clock experiments; and (d) proposed mechanism.

To further confirm the radical-based process, mechanochemical reactions in the presence of various kinds of spin-trapping agents were conducted (Scheme 3b). In the presence of TEMPO (2 equiv.), the reaction was completely suppressed, and 3a was not observed. In the reaction mixture, 10a was identified in APCI-MS data (calc. [M + Na]⁺ 386.1090; found 386.1102). Analogously, the presence of TEMPO or DMPO would also shut down the nitration reaction. In addition to 10b, nitrogen dioxide radical NO₂^• can also be trapped by DMPO, as detected by ESI-MS (11a: calc. [M + 2H]⁺ 161.0921; found 161.0916). Moreover, a radical clock experiment was conducted (Scheme 3c). When a cyclopropyl substrate (12) was co-milled with LiBr and 2a, the ring-opening dibromide product (13) was obtained in 70% yield. The formation of 13 provided strong evidence for the involvement of a carbon radical intermediate (14), which was generated via the addition of the bromine radical to the olefin.

Considering that bromination of 1a takes place effectively even at low temperature (−10 °C) by ball-milling (Table 1, entry 6), the argument for mechanical force (not thermally driven) to induce persulfate O–O bond homolysis is validated. With these mechanistic insights, we tentatively proposed a mechanism where highly oxidizing SO₄˙⁻ (A) is generated upon homolysis of persulfate salt 2, followed by single electron transfer (SET) to generate either an electrophilic halogen or nitrogen dioxide radical (B) from the corresponding inorganic salts MX. The addition of B to arenes provides a dearomatized radical species (C), which could be trapped and detected with TEMPO as shown above. Finally, either a hydrogen atom transfer (HAT) or a SET process with SO₄˙⁻ enables the formation of 3–5 (Scheme 3d).

Notably, the mechanochemical radical bromination strategy can be extended to dibromination of alkenes, affording vicinal dibromides, a common structural motif in pharmaceuticals, agrochemicals, and bioactive natural products.^33–35 Conventional methods³⁶ for vicinal dibromide synthesis typically rely on highly hazardous elemental bromine, posing significant safety concerns. While alternative strategies employing organic bromine sources have been developed, these approaches often require metal catalysts, photosensitizers, or electrochemical setups, along with organic solvents and inert atmospheres.^37–41 More recently, solvent-free mechanochemical methods have emerged, as demonstrated by the pioneering work of Lian⁴² and Katayev.³⁰

In our opinion, the combination of LiBr and 2a was identified as a feasible approach for vicinal dibromination reactions (Scheme 4). Initial optimization of ball-milling conditions revealed that cyclohexene (14a), LiBr, and 2a in a 1 : 4 : 2 ratio afforded trans-1,2-dibromohexane (16a) in 87% yield (dr > 20 : 1) after 1 h at 40 Hz. The protocol proved equally effective for terminal alkenes (14b), while substrates containing both internal and terminal alkenes underwent double dibromination to afford tetrabromide (16c) in 88% yield. A broad scope of styrene derivatives (16d–16l) was generated, encompassing diverse electronic properties (electron-donating and -withdrawing groups) and complex drug-like scaffolds (10-camphorsulfonyl (16j)) and gemfibrozil (16k), all of which were compatible with the standard mechanochemical conditions. The solvent-free mechanochemical dibromination can also be conveniently scaled-up (16i, Scheme 4). Internal aryl olefins such as 14k yielded exclusively the anti-dibromide product (16k), whereas 1,2-diphenylethene (14l) provided dibromide 16l with moderate diastereoselectivity (dr 1.7 : 1). Finally, the methodology was successfully extended to alkynes (15), including both aliphatic and aryl-substituted derivatives to produce dibromoolefins (17) (Scheme 4). For example, aryl alkynes with different electronic properties work well, affording the corresponding 1,2-dibromoethene species in good yield and decent diastereoselectivity (up to E : Z ratio: 20 : 1).

Scheme 4 Substrate scope in mechanochemical vicinal dibromination of alkenes (14) or alkynes (15) with LiBr and 2a.^{a a}Yields and stereochemical ratios determined by ¹H NMR spectroscopy with CH₂Br₂ as an internal standard. ^b Reaction performed on a 3.4 mmol scale with a 15 mL SS milling vessel and one SS ball (diameter: 16 mm) for 1 h.

Conclusions

In summary, we have developed a mechanochemical strategy for C–H bromination, chlorination, and nitration of arenes, mediated by in situ-generated sulfate mechanoradicals (SO₄˙⁻). This method was further extended to vicinal dibromination of unactivated alkenes. Mechanistic studies reveal fundamental divergence between mechanochemical and solution-phase pathways. Specifically, ball milling promotes bromine radical formation, whereas solution conditions favor bromonium intermediates (Scheme 3a-i). This dichotomy underscores how mechanochemistry unlocks distinct reaction manifolds that are inaccessible by conventional solution-based methods. The combined advantages of solvent-free conditions and halide/nitrite salts render this approach both environmentally benign and synthetically versatile, with minimal environmental impact (zero carbon content in MX/2a). As such, the methodology outlined here offers a different approach distinct from that of prior mechanochemical halogenation reports.^43–45 We anticipate that this work will stimulate broader exploration of mechanical-force-driven radical transformations in organic synthesis.

Author contributions

The work was conceptualized by Y. J., X. G. and K. Y. All experiments were conducted by Y. J., X. G. and T. W. The manuscript was written by K. Y. with input from all the authors. Y. J. and X. G. contributed equally to this work.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental procedures, reaction optimizations, analytical and spectroscopic information of the products, detailed mechanistic information and green chemistry metrics. See DOI: https://doi.org/10.1039/d5mr00094g.

Acknowledgements

Financial support for this work was generously provided by the ShanghaiTech University start-up funding. We also thank other staff members at the Analytical Instrumentation Center of SPST, and ShanghaiTech University (contract no. SPST-AIC10112914) for characterization support.

Notes and references

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Footnote

† These authors contributed equally.

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