Alkali/alkaline earth metal-mediated mechanochemical Wurtz reactions

Abstract

The Wurtz reaction is a classical C(sp³)–C(sp³) bond-forming reaction involving alkyl halides and alkali metals. However, this reaction generally requires molten or dispersed metals in large amounts of solvent, and has poor functional-group tolerance. Herein, we report a mechanochemical Wurtz reaction by the direct ball-milling of bulk Li, Na, and Ca with haloalkanes. The mechanochemical grinding of these bulk metals with a small amount of a liquid additive (THF) generates highly dispersed reactive metal species, enabling efficient C–C bond formation at room temperature even under air. Under optimized reaction conditions with Li and Na, various primary and secondary haloalkanes are converted into higher-order alkanes. Furthermore, the mechanochemical grinding of Ca is particularly effective for the Wurtz reaction of bromoalkanes bearing various functional groups such as fluoro, chloro, keto, and ester groups, achieving unprecedented C–C coupling and one-step furan synthesis. The developed reaction also allows gram-scale synthesis with a minimal amount of solvent, offering a practical and complementary method to the classical in-solution Wurtz reaction.

---

Introduction

The Wurtz reaction is a classical method for forming C(sp³)–C(sp³) bonds using alkali metals and alkyl halides, and has been widely used to synthesize higher-order hydrocarbons (Fig. 1a).¹ Since the first report on sodium-mediated reactions in 1855,² related protocols employing other alkali metals such as Li³ and K,⁴ as well as transition metal-mediated variants (In, Co, Mn, Cu, Ni), have also been reported.^5–9 Particularly, alkali metals have been widely used as standard reductants owing to their high reduction potentials¹⁰ and relatively low melting points.¹¹ However, for the reaction to proceed efficiently, the alkali metals should be dispersed in solution to increase the active reaction surface area. This typically entails heating (to melt the metals) and prolonged reaction times. Li is potentially more reactive owing to its highest reduction potential among metals (−3.04 V), but is less reactive as a bulk metal owing to its higher atomization enthalpy and melting point than Na and K.¹² Although it is more hazardous and pyrophoric to treat bulk Na and K than Li, these metals have been employed in the Wurtz reaction owing to their ease of dispersion and melting in solution, and consequently, their high practical reactivities.¹³ As a further practical demonstration, Kang recently reported a safer and rapid alternative Wurtz reaction¹⁴ of benzyl halides using a Na dispersion,¹⁵ where the safer, free-flowing metallic Na dispersion offered a high reaction surface area (Fig. 1b). Nevertheless, under the strongly reducing conditions using alkali metals, the functional-group tolerance inevitably remains poor, and large-scale reactions require the use of large amounts of solvent with hazardous alkali metals.^1,2,13 Therefore, the development of complementary Wurtz reactions is imperative and of significant importance in organic synthesis.

Fig. 1 (a) Conventional Wurtz reaction. (b) Recent report of a Wurtz reaction using a Na dispersion. (c) This work.

Recently, mechanochemical reactions using a ball-milling apparatus have pioneered a new trend in organic synthesis in terms of not only improving the reaction efficiency and reducing solvent usage to an additive level, but also enabling difficult-to-achieve reactions that do not occur in solution.^16,17 Mechanochemical grinding without a solvent or with the minimum required amount of solvent additives efficiently generates highly reactive species/intermediates that are difficult to produce in solution.^18–20 For example, the direct grinding of aromatic substrates with pieces of Li wire, which is less reactive as a bulk metal, enables unprecedented cyclodehydrogenation,¹⁸ Birch reduction¹⁹ and Birch reductive arylation,²⁰ as recently demonstrated by us as well as the Ito/Kubota group. Ito/Kubota,^21–23 Aav/Kananovich,²⁴ and Lu²⁵ also demonstrated the usefulness of Na(0),²¹ K(0),²⁵ Mg(0),^22,24 and Ca(0)^23,24 as reducing agents in Birch reduction and metal-halogen-exchanging reactions. The main advantages of these reactions are the ability to generate highly dispersed reactive metal-reactant mixtures from sluggish but intrinsically active bulk metals while minimizing solvent usage, along with air tolerance and the capability for reactions at lower temperatures.

Although the advantages of mechanochemical reactions are remarkable, mechanochemical organometallic transformations²⁶ are still under development, and mechanochemical Wurtz reactions are yet to be realized. As explained above, the development of the mechanochemical Wurtz reaction using bulk metals is expected to offer a higher efficiency and better synthetic benefits than the reaction in solution. Herein, we report the mechanochemical Wurtz reaction using alkali/alkaline earth metals.²⁷ As shown in Fig. 1c, the direct mixing of Li(0), Na(0), and Ca(0) with various alkyl halides and an additive amount of THF using a ball-milling machine enables dimerization very quickly at room temperature (r.t.) even under air. One of the advantages of ball-milling is the flexibility it offers in the selection of the optimal metal reducing agents (Li, Na, or Ca) based on the substrates and reaction scale. The use of Ca(0) also promotes the Wurtz reaction; although the reaction is slower, it is far superior to reactions involving Li or Na in terms of the functional-group tolerability. The use of Ca(0) in this reaction also enables the one-step synthesis of functionalized 1,2-diarylethanes and substituted furans from various alkyl halides and α-bromoketones. In addition, the mechanochemical method presented in this study enables the column chromatography-free, gram-scale synthesis of 1,2-di(naphthalen-2-yl)ethane, which can be easily converted into benzo[ghi]perylene²⁸ by stepwise oxidation. With the optimized reaction conditions using various haloalkanes, diverse kinds of diarylethanes, cycloalkanes, and diarylfuranes are successfully synthesized.

Results and discussion

We first optimized the mechanochemical Wurtz reaction of 2-(bromomethyl)naphthalene (1a, 1.0 mmol, 1.0 eq.) as a model substrate (Table 1). Guided by our previous studies on Li(0)-mediated mechanochemical reactions with minor modifications,^18–20 Li(0) pieces cut from Li wire (4.0 eq.) and dry THF (0.30 mL, 3.7 eq.) were employed as a reductant and liquid-assisted grinding (LAG) additive,²⁹ respectively. In the optimal protocol, 1a, Li(0), THF, and a 10 mm stainless-steel ball were charged in a 5.0 mL stainless-steel jar under air, which was sealed with a cap and polyethylene O-shape packing, and subjected to ball-milling at 30 Hz for 15 min at room temperature (r.t.: 20–25 °C). After quenching with sat. NH₄Cl aq., 1,2-di(naphthalen-2-yl)ethane (2a) was isolated in 82% yield (Table 1, entry 1). Control experiments showed that extending the reaction time from 15 to 60 min did not improve the yield, whereas shortening it to 5 min led to a significant decrease in the yield (entries 2 and 3). These results implied that although the present mechanochemical Wurtz reaction requires an induction period for efficient mixing over 5 min, the reaction exponentially proceeds and completes within 15 min. Other LAG additives such as ethylenediamine, N,N,N′,N′-tetramethylethylenediamine (TMEDA), 1,4-dioxane, and 2-methyltetrahydrofuran (2-MeTHF) significantly decreased the yield (entries 4–7). A reduction in the amount of lithium(0) to 2.1 eq. reduced the yields of 2a to 16% (entry 8). Notably, we often found that a slightly larger amount of lithium(0) than is theoretically required is needed for small-scale mechanochemical reactions due to lithium entering the gaps in the container or the surface oxide film on the lithium wire.^18,20 The use of a Na lump instead of Li wire in the Wurtz reaction at r.t. also resulted in high efficiency, affording 2a in 71% yield (entry 9). The reaction with a Ca shot was very slow at r.t., and the product was obtained in 51% ¹H NMR yield after 120 min of reaction (entry 10). The bulk Ba shot was almost inert, likely due to the difficulty with finely crushing it during ball-milling, and most of the starting material 1a remained unreacted after 120 min of reaction at r.t (entry 11). Consequently, the mechanochemical ball-milling process developed in this study using bulk Li, Na, and Ca was found to be effective for the in situ formation of highly dispersed organometallic species from bromoalkane without heating and prolonged reaction times, enabling rapid and efficient coupling at r.t. even under air. Notably, the Ca(0)-mediated Wurtz reaction was unprecedented but offered a lower reactivity, and would still be of interest in terms of functional-group tolerability (see following sections).

Table 1 Effect of parameters in the mechanochemical Wurtz reaction. The reactions were conducted in a 5.0 mL stainless-steel jar using a 10 mm-diameter stainless-steel ball

Entry	Deviation from standard conditions	Yield of 2a^a
a Isolated yield. 2-MeTHF: 2-methyltetrahydrofuran.
1	None	82%
2	Ball-milling for 60 min	79%
3	Ball-milling for 5 min	trace
4	Ethylenediamine (0.30 mL, 4.5 eq.) used instead of THF	31%
5	TMEDA (0.30 mL, 2.0 eq.) used instead of THF	0%
6	1,4-Dioxane (0.30 mL, 3.5 eq.) used instead of THF	18%
7	2-MeTHF (0.37 mL, 3.7 eq.) used instead of THF	34%
8	Li wire (2.1 eq.) used	16%
9	Na lump (4.0 eq.) used instead of Li	71%
10	Ca shot (4.0 eq.) used instead of Li, and ball-milling for 120 min	51%
11	Ba shot (4.0 eq.) used instead of Li, and ball-milling for 120 min	0%

---

We next assessed the correlations between the yield and (i) the metal employed (Li(0), Na(0), and Ca(0)) and (ii) the halogen substituents (Br, Cl, and F) on 2-(halomethyl)naphthalene 1a–1c, to clarify the reaction profile (Table 2). With all metals, the yields of 2a increased in the order of ease of elimination for typical leaving groups: Br, Cl, and F. The use of 1a (X = Br) and Li afforded the highest GC yield of 2a (85%) with the minimal generation of the dehalogenated side product 3 (1%). The reaction of 1a with Na afforded 2a in a comparable yield (80%) along with the increased formation of 3 (16%), whereas the yield of 2a was slightly decreased using Ca (2a: 67%, 3: 8%). Interestingly, Na provided the best result in terms of the yield of 2a (70%) in all metals when 1b (X = Cl) was used as the substrate. In the reactions of 2-(fluoromethyl)naphthalene (1c), all metals caused reduced GC yields of 2a within 15 min (for Li and Na) and 120 min (for Ca); nevertheless, the use of Ca most effectively suppressed the formation of 3 (0.4%). To summarize these results: (i) the use of Li(0) is effective in the reaction of bromoalkene 1a while minimizing the formation of the side product 3, (ii) Na(0) exhibits similar reactivity to Li(0) in the reaction of bromoalkane 1a, but affords superior results in the reaction of chloroalkane 1b, and (iii) Ca(0) is less reactive than other metals and requires an extended reaction time at r.t., but is particularly effective in the reaction of fluoroalkane 1c, minimizing the formation of the side product 3. The reason for this metal-reactant compatibility is unclear at this time. Nevertheless, factors such as the crushability of bulk metals, atomization enthalpy (Li: 159 kJ mol⁻¹; Na: 107 kJ mol⁻¹, Ca: 177 kJ mol⁻¹),³⁰ reduction electrode potential (Li: −3.04 V; Na: −2.71 V; Ca: −2.76 V vs. standard hydrogen electrode (SHE)),³¹ and/or lattice enthalpies of the resulting salts (MX_n) can influence the reaction progress.

Table 2 Reactions were conducted in a 1.5 mL stainless-steel jar using a 7 mm-stainless-steel ball. The reactions were quenched with sat. NH₄Cl aq. after the indicated reaction times. GC yields using dodecane as an internal standard are shown

Reaction times: 15 min for Li and Na, and 120 min for Ca. A Li wire, Na lump, and Ca shot were used for the reactions.

---

After establishing the optimal conditions for the Li(0)-mediated mechanochemical Wurtz reaction, the scope of alkyl bromides was investigated (Fig. 2). All experiments were performed under air at r.t. The use of 1-(bromomethyl)naphthalene (1d) afforded 1,2-di(naphthalen-1-yl)ethane (2d) in 58% yield. Gram-scale synthesis was also possible using a large-volume stainless-steel jar (10 mL volume) and two 10 mm-diameter stainless-steel balls with 1.11 g (5 mmol) of 1d, affording 2d in a satisfactory yield of 72% (510.9 mg). The reactions with α-bromodiphenylmethane and 3-(bromomethyl)-phenanthrene afforded the corresponding dimers 2e and 2f in 43 and 18% yields, respectively. The use of α,α′-dibromo-o-xylene (1g), which contains two benzylic bromides, afforded the corresponding octagonal cyclic dimer 2g in 16% yield, together with the cyclic trimer 2g′ in 14% yield and cyclic tetramer 2g″ in 7% yield. When the amount of lithium(0) was reduced to 2.1 eq., 1g remained unreacted and was recovered. On the other hand, the use of 6.0 eq. of lithium(0) afforded 2g and 2g′ in 20% and 22% yields, respectively, along with a trace amount of 2g″. The Wurtz coupling of 1g has previously been achieved under solution conditions that required heating to disperse granular Li.³² In comparison, the ball-milling protocol enables the reaction to proceed under simple, ambient conditions, thus providing a practical alternative to the solution-state method. Similarly, cyclization using 2,3-bis(bromomethyl)naphthalene (1h) afforded the cyclic dimer 2h, cyclic trimer 2h′, and linear trimer 2h″ in 33%, 12%, and 7% yields, respectively. When 8,9-bis(bromomethyl)fluoranthene (1i) was employed, an eight-membered ring compound 2i was obtained in 16% yield. The mechanochemical Wurtz reaction can also be applied to intramolecular cyclization using 2,2′-bis(bromomethyl)-1,1′-biphenyl (1j) to afford 9,10-dihydrophenanthrene (2j) in 78% yield. We subsequently achieved the dimerization of alkyl bromides 1k and 1l, other than benzyl bromide derivatives. The use of phenethyl bromide (1k) afforded higher-order hydrocarbons 2k in 78% yield. Notably, the reaction of a secondary alkyl bromide, (2-bromopropane-1,3-diyl)dibenzene (1l), also proceeded slowly, and the sterically congested branched alkane 2l was obtained in 41% yield after reaction for 8 h. Single crystals of 2l were successfully obtained by recrystallization from hexane, and their structure was elucidated by X-ray diffraction analysis. The use of 1-bromododecane (1m) was also applicable to this reaction and afforded n-tetraicosane (2m) in 35% isolated yield. Using a Na lump instead of Li(0) in this reaction resulted in a better yield. Note that several substrates bearing functional groups such as methoxy, trifluoromethyl, or ester groups were found to be incompatible under these conditions. Consequently, the developed Li(0)-mediated mechanochemical Wurtz reaction enables rapid, air-tolerant, and operationally simple C(sp³)–C(sp³) bond formation under ambient conditions, and is particularly adequate for the reaction of bromo alkanes including benzyl- and homobenzyl-type primary and secondary ones, as well as simple linear primary alkyl bromide.

Fig. 2 Substrate scope in the Li(0)-mediated mechanochemical Wurtz reaction and the ORTEP drawing of 2l. Unless otherwise noted, the reactions were conducted in a 5.0 mL stainless-steel jar using a 10 mm stainless-steel ball under ball-milling at 30 Hz. ^aIsolated yields. ^bA 1.0 mmol-scale reaction for 15 min. ^cA 5.0 mmol-scale reaction in a 10 mL stainless-steel jar using two 10 mm-diameter stainless-steel balls for 60 min. ^dCombined yield in two runs of a 0.2 mmol-scale reaction using 4.0 eq. of a Na(0) lump in a 1.5 mL stainless-steel jar with two 7 mm-diameter stainless-steel balls for 3 h. ^eCombined yield in two runs of a 3.0 mmol-scale reaction in a 10 mL stainless-steel jar using four 10 mm-diameter stainless-steel balls for 120 min. ^f6.0 eq. of Li(0) was used. ^gA 1.0 mmol scale reaction for 8 h. ^hA 1.0 mmol scale for 60 min. ⁱA 0.50 mmol scale for 8 h. ^j4.0 eq. of Na(0) lump was used.

Motivated by the fact that the reaction with Ca(0) also proceeded to some extent along with nearly no side reactions (Table 2) and considering the previous demonstrations by the Ito/Kubota group on the mechanochemical generation of Ca-based heavy Grignard reagents,²³ we carried out mechanochemical Wurtz reactions using a Ca shot to realize functional-group-tolerable Wurtz reactions (Fig. 3a). In the reactions of various benzyl bromides with o-fluoro (1n), p-chloro-o-fluoro (1o), perfluoro (1p), p-methoxycarbony (1r), and p-trifluoromethyl groups (1s) with Ca lumps (4.0 eq.) and THF (2.5–4.9 eq.), 1,2-diarylethanes (2n–2p, 2r, and 2s) were obtained in moderate yields (33–78%) without the marked loss of functional groups. In contrast, an o-bromo group on 1-bromo-2-(bromomethyl)benzene (1q) was incompatible with this reaction, likely due to the formation of aryl calcium species, resulting in an inseparable complex mixture.³³ We then achieved the coupling of 2-(bromomethyl)-7-methoxynaphthalene (1t) to afford the corresponding dimethoxynaphthalene dimer (2t) in 62% yield, while 2t was not obtained in the reaction with Li(0) due to demethoxylation. Although the reaction of 9-bromomethylanthracene (1u) by the Li(0)-mediated mechanochemical Wurtz reaction exclusively afforded the dehydrobrominated product 9-methyl-9,10-dihydroanthracene, the Ca(0)-mediated reaction successfully provided the coupling product 2u in 46% yield. Thus, the newly developed Ca(0)-mediated mechanochemical Wurtz reaction offers milder reactivity and a different reaction profile compared with conventional alkali metal-mediated reactions in the solution state, expanding the substrate scope.

Fig. 3 Ca(0)-mediated mechanochemical Wurtz reaction. Unless otherwise noted, the reactions were conducted in a 5.0 mL stainless-steel jar using two 7 mm-diameter stainless-steel balls under ball-milling at 30 Hz. ^a0.50 mmol-scale reaction with 0.20 mL (4.9 eq.) of THF. ^bA 1.0 mmol-scale reaction with 0.20 mL (2.5 eq.) of THF. ^cA 0.30 mmol-scale reaction with 0.20 mL (8.2 eq.) of THF.

Encouraged by the broad functional-group compatibility, the Ca(0)-mediated mechanochemical Wurtz reaction was further applied to the reaction of phenacyl bromide derivatives 4 for the synthesis of 1,4-butanedione derivatives (Fig. 4a). Surprisingly, the mechanochemical grinding of p-(bromoacetyl)toluene (4a) with Ca(0) followed by an aqueous workup unexpectedly furnished 2,4-di(p-tolyl)furan (5a) in 49% yield. Based on related in-solution reactions reported in the literature,^34–36 this reaction is expected to proceed via (i) the generation of ketone enolate by the reaction of 4a with Ca(0), (ii) an aldol reaction to form intermediate A, (iii) the formation of epoxide B or a β-(bromomethyl)chalcone derivative by aldol condensation, and (iv) oxy-cyclization and aromatization (Fig. 4b). This one-step furan synthesis typically occurs in the reaction of various phenacyl bromide derivatives including p-(bromoacetyl)fluorobenzene (4b), p-(bromoacetyl)anisole (4c), and 2-(bromoacetyl)naphthalene (4d), affording the corresponding 2,4-diarylfurans (5b–5d) in 33%, 63%, and 76% yields, respectively (Fig. 4a). The structure of 5d was elucidated by X-ray crystallographic analysis. While this analysis unequivocally confirmed substitution by 2-naphthyl groups at the C2- and C4-positions, the absolute structure could not be reliably determined owing to weak anomalous scattering (see SI for details). Although a trace amount of 2,4-di(naphthalen-1-yl)furan (5e) was detected by GC-MS in a crude mixture of the reaction using 1-bromoacetylnaphthalene (4e), the product 5e could not be isolated. A phenacyl bromide bearing a secondary α-center, 2-bromo-1,2-diphenylethanone (4f), underwent annulation to afford 2,3,4,5-tetraphenylfuran (5f) in 31% yield. Similar reactions were previously demonstrated using CuCl₂/Na₂Te (17% yield of 2,4-diphenylfuran^34b) and [FeCp(cod)]⁻ (Cp = cyclopentadienyl; cod = 1,5-cyclooctadiene, 13% yield of 2,4-diphenylfuran^34b) in the solution state; however, notably, the present one-step mechanochemical synthesis of 2,4-di- and 2,3,4,5-tetra-substituted furans from α-bromo ketones is easier to perform, practical, and more advantageous in terms of the yield and substrate scope compared to previous methods.

Fig. 4 (a) Ca(0)-mediated mechanochemical reductive coupling of phenacyl bromide derivatives for the synthesis of 2,4-diarylfurans. Unless otherwise noted, the reactions were conducted in a 5.0 mL stainless-steel jar using two 7 mm-diameter stainless-steel balls under ball-milling at 30 Hz. ^a1.0 mmol-scale reaction with 0.30 mL (3.7 eq.) of THF. (b) Possible intermediates.

To further highlight the synthetic practicality of this protocol, a gram-scale mechanochemical Wurtz reaction was demonstrated at ambient temperature under air (Fig. 5a). The mechanochemical Wurtz reaction of 1a was conducted in five parallel batches of 10 mL stainless-steel jars containing 4.0 mmol × 5 of 1a using the mixer-mill Retsch MM-500 Vario. Upon ball-milling at r.t. after 30 min, the crude mixture presented as a white foam, with no macroscopic Li remaining. After extraction into organic solvents and concentration in vacuo, the solid residue was further washed with hexane to afford 2a in 93% yield (2.63 g) with sufficient quality (Fig. 4a). Similarly, the parallel four-batch (7.0 mmol × 4) and two-batch (14 mmol × 2) reactions of 1a in the appropriate jars with balls afforded 2a in 86% yield (3.42 g) and 72% yield (2.74 g), respectively. Notably, the easily available Wurtz reaction product 2a was useful in terms of its transformability to valuable benzo[ghi]perylene (6)³⁷ simply by reacting 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and triflic acid (TfOH). Such a simple protocol including the cyclodehydrogenation and aromatization of 2a is yet to be reported (Fig. 5b). Together with the observation that scaling up the reactions from the milligram to gram scale did not cause a loss of yield and significant extension of the reaction time, the use of the minimum amount of solvent (THF: 0.9–1.2 eq.) is also highly beneficial considering green chemistry and mass production in process chemistry. Accordingly, the developed mechanochemical Wurtz reaction provides a rapid and highly time-efficient route to preparative-scale synthesis, readily accommodating larger quantities of target materials.

Fig. 5 (a) Large-scale synthesis of 2a by the Li(0)-mediated mechanochemical Wurtz reaction. (b) Synthesis of benzo[ghi]perylene (6) from 2a.

Conclusions

In summary, a complementary mechanochemical Wurtz reaction of haloalkanes was developed to access diarylethane and higher-order hydrocarbons. The direct ball-milling of easy-to-handle Li wire, Na lump or Ca shot with bromomethyl arenes in the presence of a stoichiometric amount of THF under air at ambient temperature afforded the desired products rapidly. The developed protocol uses a minimal amount of solvent, features short reaction times with straightforward workups, and is readily scalable. Crucially, the ability to choose between Li, Na and Ca allows the reductant to be matched to the substrate class and reaction scale, providing a practical, safe, and robust alternative to conventional solution-state methods. Furthermore, the Ca(0)-mediated mechanochemical grinding of phenacyl bromide derivatives unexpectedly and effectively afforded 2,4-di- and 2,3,4,5-tetra-substituted furans by unsymmetric reductive coupling. We believe that the present work will contribute to advancements not only in mechanochemistry but also in organic synthesis and organometallic chemistry in solid/slurry states.

Author contributions

Y. T. synthesized, analyzed, and characterized all compounds. H. I. designed the study and target compounds, supervised the experiments, and conducted data analyses. The draft manuscript was written by Y. T. and finalized by H. I. All authors approved the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

Supplementary information (SI): experimental and characterization data, including crystallographic data, and NMR spectra. See DOI: https://doi.org/10.1039/d6qo00142d.

CCDC 2519748 (5d) and 2513489 (2l) contain the supplementary crystallographic data for this paper.^38a,b

Acknowledgements

This study was supported by JSPS KAKENHI (JP25K01764 and JP25H01408 to H. I.), the Sumitomo Foundation (2300884), the Mazda Foundation, and the NAGAI Foundation of Science & Technology (to H. I.). Y. T. thanks the Interdisciplinary Frontier Next-Generation Researcher Program of the Tokai Higher Education and Research System for the fellowships. We thank Takato Mori and Kumpei Hasebe for their assistance with the X-ray crystallographic analyses.

References

1. (a) Z. Wang, Comprehensive Organic Name Reactions and Reagents, 2010, vol. 685, p. 3094; (b) B. M. Trost and I. Fleming, Comprehensive Organic Synthesis, 1991, vol. 3, ISBN 978-0-08-052349-1.
2. (a) A. Wurtz, Sur une nouvelle classe de radicaux organiques, Ann. Chim. Phys., 1855, 44, 275; (b) A. Wurtz, Ueber eine neue Klasse organischer Radicale, Justus Liebigs Ann. Chem., 1855, 96, 364.
3. H. Gilman, The Direct Preparation of Benzyllithium, J. Am. Chem. Soc., 1955, 77, 3134.
4. (a) T. J. Cleij, S. K. Y. Tsang and L. W. Jenneskens, Water-soluble poly(4,7,10,13-tetraoxatetradecylmethylsilane): enhanced yield and improved purity via polymerization using graphite-potassium (C8K) as reducing agent, Chem. Commun., 1997, 329, 329–330; (b) X. Lü, J. Wu, T. Lin, D. Wan, F. Huang, X. Xie and M. Jiang, Low-temperature rapid synthesis of high-quality pristine or boron-doped graphene via Wurtz-type reductive coupling reaction, J. Mater. Chem., 2011, 21, 10685.
5. B. C. Ranu, P. Dutta and A. Sarkar, Indium promoted reductive homocoupling of alkyl and aryl halides, Tetrahedron Lett., 1998, 39, 9557–9558.
6. (a) S. Goswami and A. K. Mahapatra, Aromatic aldehydes from benzylbromides via Cobalt(I) mediated benzyl radicals in the presence of aerial oxygen: a mild oxidation reaction in neutral condition, Tetrahedron Lett., 1998, 39, 1981–1984; (b) B. J. Fallon, V. Corcé, M. Amatore, C. Aubert, F. Chemla, F. Ferreira, A. Perez-Luna and M. Petit, A well-defined low-valent cobalt catalyst Co(PMe3)4 with dimethylzinc: a simple catalytic approach for the reductive dimerization of benzyl halides, New J. Chem., 2016, 40, 9912.
7. J. Ma and T. H. Chan, Organometallic-type reactions in aqueous media. Wurtz-coupling of alkyl halides with manganese/cupric chloride, Tetrahedron Lett., 1998, 39, 2499.
8. (a) G. Ebert and R. D. Rieke, Direct formation of organocopper compounds by oxidative addition of zerovalent copper to organic halides, J. Org. Chem., 1984, 49, 5280; (b) F. O. Ginah, T. A. Donovan Jr, S. D. Suchan, D. R. Pfennig and G. W. Ebert, Homocoupling of alkyl halides and cyclization of α,ω-dihaloalkanes via activated copper, J. Org. Chem., 1990, 55, 584.
9. (a) S. Inaba, H. Matsumoto and R. D. Rieke, Metallic nickel as a reagent for the coupling of aromatic and benzylic halides, Tetrahedron Lett., 1982, 23, 4215; (b) S. Inaba and R. D. Rieke, Metallic nickel-mediated synthesis of ketones by the reaction of benzylic, allylic, vinylic, and pentafluorophenyl halides with acid halides, J. Org. Chem., 1985, 50, 1373; (c) S. Inaba, H. Matsumoto and R. D. Rieke, Highly reactive metallic nickel: reductive homocoupling reagent for benzylic mono- and polyhalides, J. Org. Chem., 1984, 49, 2093.
10. Standard Potentials in Aqueous Solution, ed. A. J. Bard, R. Parsons and J. Jordan, Marcel Dekker, New York, 1985.
11. N. Narayana and D. R. Burgess Jr, Melting Points and Boiling Points for the Alkali Metals, 2024.
12. (a) A. M. James and M. P. Lord, Macmillan's Chemical and Physical Data, Macmillan, London, UK, 1992; (b) Nuffield Advanced Science: Book of Data, ed. H. Ellis, Longman, London, UK, revised edn, 1984.
13. D. Seyferth, Alkyl and Aryl Derivatives of the Alkali Metals: Strong Bases and Reactive Nucleophiles, Organometallics, 2006, 25, 2.
14. B. Kang, T. Imamura and T. Satoh, Sodium dispersion-mediated reductive dimerization of benzylic halides for symmetrical bibenzyls: Column-free applications to natural products, Tetrahedron Green Chem, 2024, 4, 100052.
15. (a) J. An, D. N. Work, C. Kenyon and D. J. Procter, Evaluating a Sodium Dispersion Reagent for the Bouveault–Blanc Reduction of Esters, J. Org. Chem., 2014, 79, 6743; (b) S. Asako, L. Ilies and P. B. De, Recent Advances in the Use of Sodium Dispersion for Organic Synthesis, Synthesis, 2021, 3180; (c) D. Seyferth, Alkyl and Aryl Derivatives of the Alkali Metals: Strong Bases and Reactive Nucleophiles, Organometallics, 2006, 25, 2; (d) D. Seyferth, The Grignard Reagents, Organometallics, 2009, 28, 2; (e) M. Schlosser, Organometallics in Synthesis: A Manual, Wiley-VCH, Weinheim, 2nd edn, 2002.
16. Recent reviews on mechanochemistry and mechanochemical transformations: (a) S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friščić, F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L. Maini, A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed and D. C. Waddell, Mechanochemistry: opportunities for new and cleaner synthesis, Chem. Soc. Rev., 2012, 41, 413; (b) G.-W. Wang, Mechanochemical organic synthesis, Chem. Soc. Rev., 2013, 42, 7668; (c) J.-L. Do and T. Friščić, Mechanochemistry: A Force of Synthesis, ACS Cent. Sci., 2017, 3, 13; (d) J. G. Hernández and C. Bolm, Altering Product Selectivity by Mechanochemistry, J. Org. Chem., 2017, 82, 4007; (e) J. L. Howard, Q. Cao and D. L. Browne, Mechanochemistry as an emerging tool for molecular synthesis: what can it offer?, Chem. Sci., 2018, 9, 3080; (f) J. Andersen and J. Mack, Mechanochemistry and organic synthesis: from mystical to practical, Green Chem., 2018, 20, 1435; (g) D. Tan and T. Friščić, Mechanochemistry for Organic Chemists: An Update, Eur. J. Org. Chem., 2018, 18; (h) D. Tan and F. García, Main group mechanochemistry: from curiosity to established protocols, Chem. Soc. Rev., 2019, 48, 2274; (i) C. Bolm and J. G. Hernández, Mechanochemistry of Gaseous Reactants, Angew. Chem., Int. Ed., 2019, 58, 3285; (j) T. Friščić, C. Mottillo and H. M. Titi, Mechanochemistry for Synthesis, Angew. Chem., Int. Ed., 2020, 59, 1018; (k) K. Kubota and H. Ito, Mechanochemistry for Synthesis, Trends Chem., 2020, 2, 1066; (l) K. J. Ardila-Fierro and J. G. Hernández, Sustainability Assessment of Mechanochemistry by Using the Twelve Principles of Green Chemistry, ChemSusChem, 2021, 14, 2145; (m) R. R. A. Bolt, J. A. Leitch, A. C. Jones, W. I. Nicholson and D. L. Browne, Continuous flow mechanochemistry: reactive extrusion as an enabling technology in organic synthesis, Chem. Soc. Rev., 2022, 51, 4243; (n) F. Cuccu, L. De Luca, F. Delogu, E. Colacino, N. Solin, R. Mocci and A. Porcheddu, Mechanochemistry: New Tools to Navigate the Uncharted Territory of “Impossible” Reactions, ChemSusChem, 2022, 15, e202200362; (o) M. T. J. Williams, L. C. Morrill and D. L. Browne, Mechanochemical Organocatalysis: Do High Enantioselectivities Contradict What We Might Expect?, ChemSusChem, 2022, 15, e202102157; (p) S. Hwang, S. Grätz and L. Borchardt, A guide to direct mechanocatalysis, Chem. Commun., 2022, 58, 166.
17. Recent examples of mechanochemical transformation: (a) K. Kubota, J. Jiang, Y. Kamakura, R. Hisazumi, T. Endo, D. Miura, S. Kubo, S. Maeda and H. Ito, Using Mechanochemistry to Activate Commodity Plastics as Initiators for Radical Chain Reactions of Small Organic Molecules, J. Am. Chem. Soc., 2024, 146, 1062; (b) Q. Cao, J. L. Howard, E. Wheatley and D. L. Browne, Mechanochemical Activation of Zinc and Application to Negishi Cross–Couplings, Angew. Chem., Int. Ed., 2018, 57, 11339; (c) M. Mayer, M. Wohlgemuth, A. Salomé Straub, S. Grätz and L. Borchardt, Hydrogenation of Organic Molecules via Direct Mechanocatalysis, Angew. Chem., Int. Ed., 2025, 64, e202424139; (d) A. W. J. Bowles, J. A. Quirk, Y. Liu, G. H. Morritt, M. Freitag, G. F. S. Whitehead, A. W. Woodward, A. Brookfield, C. A. P. Goodwin, D. Collison, F. Tuna, C. L. McMullin, J. A. Dawson, E. Lu and F. Ortu, Mechanochemical Synthesis, Characterization and Reactivity of a Room Temperature Stable Calcium Electride, J. Am. Chem. Soc., 2024, 146, 28914; (e) K. Jana, K. Kubota and H. Ito, A mechanochemical [2 + 2 + 2] cycloaddition facilitated by a cobalt(II) catalyst and piezoelectric materials, Chem. Sci., 2025, 16, 11468.
18. K. Fujishiro, Y. Morinaka, Y. Ono, T. Tanaka, L. T. Scott, H. Ito and K. Itami, Lithium-Mediated Mechanochemical Cyclodehydrogenation, J. Am. Chem. Soc., 2023, 145, 8163.
19. Y. Gao, K. Kubota and H. Ito, Mechanochemical Approach for Air-Tolerant and Extremely Fast Lithium-Based Birch Reductions in Minutes, Angew. Chem., Int. Ed., 2023, 62, e202217723.
20. Y. Toyama, A. Yagi, K. Itami and H. Ito, Birch reductive arylation by mechanochemical anionic activation of polycyclic aromatic compounds, Nat. Commun., 2025, 16, 5044.
21. K. Kondo, K. Kubota and H. Ito, Mechanochemical activation of metallic lithium for the generation and application of organolithium compounds in air, Nat. Synth., 2025, 4, 744.
22. R. Takahashi, A. Hu, P. Gao, Y. Gao, Y. Pang, T. Seo, S. Maeda, J. Jiang, H. Takaya, K. Kubota and H. Ito, Mechanochemical synthesis of magnesium-based carbon nucleophiles in air and their use in organic synthesis, Nat. Commun., 2021, 12, 6691.
23. (a) K. Kubota, Y. Fukuzawa, K. Kondo, Y. Gao and H. Ito, Highly efficient and air-tolerant calcium-based Birch reduction using mechanochemistry, Chem. Lett., 2024, 53, upae060; (b) P. Gao, J. Jiang, Y. Fukuzawa, S. Maeda, K. Kubota and H. Ito, Direct arylation of alkyl fluorides using in situ mechanochemically generated calcium-based heavy Grignard reagents, RSC Mechanochem., 2024, 1, 486; (c) X. Wang, Y. Fukuzawa, P. Gao, J. Jiang, S. Maeda, K. Kubota and H. Ito, Direct arylation of gem-difluorostyrenes using in situ mechanochemically generated calcium-based heavy Grignard reagents, RSC Mechanochem., 2025, 2, 256.
24. J. V. Nallaparaju, R. Satsi, D. Merzhyievskyi, T. Jarg, R. Aav and D. G. Kananovich, Mechanochemical Birch Reduction with Low Reactive Alkaline Earth Metals, Angew. Chem., Int. Ed., 2024, 63, e202319449.
25. (a) N. Davison, J. A. Quirk, F. Tuna, D. Collison, C. L. McMullin, H. Michaels, G. H. Morritt, P. G. Waddell, J. A. Gould, M. Freitag, J. A. Dawson and E. Lu, A room-temperature-stable electride and its reactivity: Reductive benzene/pyridine couplings and solvent-free Birch reductions, Chem, 2023, 9, 576; (b) N. Davison, P. G. Waddell and E. Lu, Reduction of K⁺ or Li⁺ in the Heterobimetallic Electride K⁺[LiN(SiMe₃)₂]e⁻, J. Am. Chem. Soc., 2023, 145, 17007.
26. (a) K. Kubota, Y. Pang, A. Miura and H. Ito, Redox reactions of small organic molecules using ball milling and piezoelectric materials, Science, 2019, 366, 1500; (b) T. Seo, K. Kubota and H. Ito, Selective Mechanochemical Monoarylation of Unbiased Dibromoarenes by in Situ Crystallization, J. Am. Chem. Soc., 2020, 142, 9884; (c) T. Seo, N. Toyoshima, K. Kubota and H. Ito, Tackling Solubility Issues in Organic Synthesis: Solid-State Cross-Coupling of Insoluble Aryl Halides, J. Am. Chem. Soc., 2021, 143, 6165; (d) T. Seo, K. Kubota and H. Ito, Mechanochemistry-Directed Ligand Design: Development of a High-Performance Phosphine Ligand for Palladium-Catalyzed Mechanochemical Organoboron Cross-Coupling, J. Am. Chem. Soc., 2023, 145, 6823; (e) Y. Toyama, T. Nakamura, Y. Horikawa, Y. Morinaka, Y. Ono, A. Yagi, K. Itami and H. Ito, Rh-catalyzed mechanochemical transfer hydrogenation for the synthesis of periphery-hydrogenated polycyclic aromatic compounds, Chem. Sci., 2025, 16, 9117.
27. Y. Toyama and H. Ito, Alkali/Alkaline Earth Metal-Mediated Mechanochemical Wurtz Reactions. Chemrxiv, 2026, Jan. 7th, preprint.  DOI:10.26434/chemrxiv-2026-ppqmj.
28. (a) E. H. Fort and L. T. Scott, One-Step Conversion of Aromatic Hydrocarbon Bay Regions into Unsubstituted Benzene Rings: A Reagent for the Low-Temperature, Metal-Free Growth of Single-Chirality Carbon Nanotube, Angew. Chem., Int. Ed., 2010, 49, 6626–6628; (b) M. Molkenthin, E. Hupf and B. J. Nachtsheim, Dibenzyl Isophthalates as Versatile Hosts in Room Temperature Phosphorescence Host–Guest Systems, Chem. Sci., 2025, 16, 2819.
29. (a) T. Friščić, A. V. Trask, W. Jones and W. D. S. Motherwell, Screening for Inclusion Compounds and Systematic Construction of Three-Component Solids by Liquid-Assisted Grinding, Angew. Chem., Int. Ed., 2006, 45, 7546; (b) T. Friščić, L. Fábián, J. C. Burley and W. Jones, Exploring cocrystal–cocrystal reactivity via liquid-assisted grinding: The assembling of racemic and dismantling of enantiomeric cocrystals, Chem. Commun., 2006, 5009; (c) T. Friščić, S. L. Childs, S. A. A. Rizvi and W. Jones, The role of solvent in mechanochemical and sonochemical cocrystal formation: a solubility-based approach for predicting cocrystallisation outcome, CrystEngComm, 2009, 11, 418.
30. J. D. Cox, D. D. Wagman and V. A. Medvedev, CODATA Key Values for Thermodynamics, Hemisphere Publishing Corp., New York, 1989.
31. A. V. Desai, R. E. Morris and R. Armstrong, Advances in organic anode materials for Na-/K-Ion rechargeable batteries, ChemSusChem, 2020, 13, 4866.
32. G. Franck, M. Brill and G. Helmchen, Dibenzo[a,e]cyclooctene: Multi-gram Synthesis of a Bidentate Ligand, Org. Synth., 2012, 89, 55.
33. M. Westerhausen, M. Gärtner, R. Fischer and J. Langer, Aryl calcium compounds: syntheses, structures, physical properties, and chemical behavior, Angew. Chem., Int. Ed., 2007, 46, 1950.
34. 2,4-Diarylfuran synthesis from phenacyl bromides: (a) R. Noyori and Y. Hayakawa, Reductive Dehalogenation of Polyhalo Ketones with Low-Valent Metals and Related Reducing Agents, Org. React., 2004, 29, 163; (b) S. Padmanabhan, T. Ogawa and H. Suzuki, Formation of Furan Derivatives from Phenacyl Bromides and Sodium Telluride; Attempted Extension to Coumarin Synthesis, Bull. Chem. Soc. Jpn., 1989, 62, 2114; (c) D. H. Hill, M. A. Parvez and A. Sen, Mechanistic Aspects of the Reaction of Anionic Iron(0)–Olefin Complexes with Organic Halides. Detection and Characterization of Paramagnetic Organometallic Intermediates, J. Am. Chem. Soc., 1994, 116, 2889.
35. 2,4-Diarylfuran synthesis from 2-(oxiran-2-yl)acetophenones: (a) R. Tombe and S. Matsubara, Preparation of Furan Ring from 2-(Oxiran-2-yl)-1-alkylethanone Catalyzed by Nafion® SAC-13, Heterocycles, 2012, 84, 775; (b) T. D. Avery, D. K. Taylor and E. R. T. Tiekink, A New Route to Diastereomerically Pure Cyclopropanes Utilizing Stabilized Phosphorus Ylides and γ-Hydroxy Enones Derived from 1,2-Dioxines: Mechanistic Investigations and Scope of Reaction, J. Org. Chem., 2000, 65, 5531.
36. 2,4-Diarylfuran synthesis from β-(bromomethyl)chalcones: (a) L. M. Potikha and V. S. Brovarets, Synthesis of new antineoplastic agents based on imidazo[2,1-a]pyridine, Chem. Heterocycl. Compd., 2020, 56, 1460; (b) R. Faragher and T. L. Gilchrist, Generation and interception of isobenzofurans from 2-(α-bromoalkyl)benzophenones, J. Chem. Soc., Perkin Trans., 1976, 1, 336.
37. (a) J. H. Smith, D. Čavlović, L. T. Lackovic, M. Medina Lopez, E. Meirzadeh, M. L. Steigerwald, X. Roy, C. P. Nuckolls and S. R. Docherty, Molten Metal Synthesis of Nanographenes, J. Am. Chem. Soc., 2025, 147, 111; (b) H. R. Talele, Synthesis of Derivatives of Phenanthrene and Helicene by Improved Procedures of Photocyclization of Stilbenes, Bull. Chem. Soc. Jpn., 2009, 82, 1182.
38. (a) CCDC 2519748: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2ql06k; (b) CCDC 2513489: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qch9x.

---