Mechanochemical Bromination of Naphthalene Catalyzed by Zeolites: From Small Scale to Continuous Synthesis

Abstract

Catalyzed reactions of organic substrates that operate continuously by extrusion techniques are rare. In this study, we developed a mechanochemical bromination of unactivated naphthalene (1) with 1,3‐dibromo‐5,5‐dimethylhydantoin (DBDMH), catalyzed by zeolites in a ball mill. The use of DBDMH enabled the atom economy of the reaction to be superior compared to the other brominating agents evaluated. Among the zeolites tested, a FAU‐type zeolite demonstrated high catalytic activity and recyclability. The success of the bromination route on a small scale enabled the development of a continuous catalyzed bromination of 1 by twin‐screw extrusion.

Introduction

Mechanochemical reactions facilitated by grinding, ball milling, or extrusion have in the past two decades grown in popularity in the field of organic chemistry.^[1] Such an increasing interest has been motivated by the sustainability aspects,^[2] and the methodological advantages,^[3] that mechanochemistry offers compared to other more traditional activation modes. Today, a significant number of organic transformations have been demonstrated to proceed under mechanochemical conditions,^[1] many in the total absence of solvents or using small amounts of liquid media.^[4] Among them, mechanochemical formation of C−X bonds (halogenation reactions) has received great attention.^[5] This is understandable, owning the synthetic value of organic halides as substrates in substitution reactions,^[6] cross-coupling chemistry,^[7] and in atom transfer radical cyclization reactions,^[8] etc. For example, pioneering efforts to carry out mechanochemical bromination of organic substrates has been proven feasible using principally brominating agents such as NBS (N-bromosuccinimide),^[9] NaBr/Oxone (Oxone=potassium peroxymonosulfate, 2 KHSO₅ ⋅ KHSO₄ ⋅ K₂SO₄),^[10] and to a lesser extent using 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).^[11] Depending on the substrates tested some of these brominating methods required the use of catalysts,^[9e] whereas in other cases the bromination of activated substrates occurred directly.^[9–11] In general, the mechanochemical brominations reported until now have been carried out in laboratory-size ball mills limiting the scale of the reactions to a hundred milligrams of reactants per reaction. Along these lines, techniques such as twin-screw extrusion (TSE) have proven useful to shift from small-scale milling reactions conducted in batch modes,^[12] into continuous mechanochemical processing.^[13] TSE techniques process materials and mixtures by mixing, heating and also by applying mechanical forces, which makes it attractive and suitable to promote most organic reactions. However, until now the large majority of transformations carried out by TSE involve the reaction of reagents in stoichiometric amounts such as condensation processes^[14] or substitution reactions,^[15] which primarily profit from the thermal activation achieved by heating of the extruder barrel, whereas mechanochemical transformations by extrusion in which catalysts are used have remained scarce.^[16] With this in mind, herein we explore, in a proof-of-concept study, the mechanochemical bromination of naphthalene and its feasibility by TSE. Further, we study zeolites as catalysts for the bromination of naphthalene owing to their compatibility with mechanochemical techniques,^[17] but more importantly, due to their excellent catalytic properties in solution and under solventless conditions.^[18]

Results and Discussion

For this study, we have selected naphthalene (1) as the substrate for the bromination due to it being solid at ambient conditions, available in bulk, affordable, and due to the possibility to generate value-added products such as bromonaphthalenes, which are precursors to various substituted derivatives of naphthalene. As for the bromine source, we focussed our attention on four solid brominating agents, namely N-bromosaccharin (NBSacc), N-bromophthalamide (NBPth), N-bromosuccinamide (NBS), and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (Figure 1).

Figure 1. Structure of brominating agents evaluated in this study.

Initially, we milled naphthalene (1) and the brominating agents for 2 h at a milling frequency of 30 Hz (Table 1). Analysis of the crude mixture by ¹H NMR spectroscopy revealed mostly unreacted naphthalene after the milling process (for details, see Supporting Information). Only in the reaction using NBPth traces of 1-bromonaphthalene (2) were detected (Table 1, entry 2). These results provided the ideal scenario to evaluate the effect of zeolites on the outcome of the bromination. For this, we repeated the experiments yet in the presence of zeolite CBV-760, a FAU-type zeolite with pore apertures of 7.35 Å, cage dimensions of 11.24 Å, and a Si/Al=30, H-form,^[19a,20a] which is a commercial material that is used as catalyst.^[19] This time, analysis of the milled mixtures, immediately after the milling process was halted, revealed the presence of 1-bromonaphthalene (2) as the major product in all the mechanochemical reactions (Table 1, entries 1–4). Although all bromine sources proved active in the presence of zeolite CBV-760, we selected DBDMH as the brominating agent of choice for further experiments. The selection was made based on the price per mmol of the bromine sources and on the molecular weight of the reagents (Table 2). DBDMH is not only the cheapest brominating agent among the reagents tested but it bears two bromine atoms on its structure, which reduces the amount of waste produced, in other words the use of DBDMH could increase the atom economy of the reaction (Table 2). Moreover, the calculation of the E-factor (E for environmental) for the reaction of 1 with DBDMH using recyclable zeolite CBV-760 revealed that the generation of waste was minimal (Table 1).

Table 1 Mechanochemical brominations of naphthalene (1) with various brominating reagents using zeolite CBV-760 as catalyst.^[a]

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Entry	Brominating Reagent (equiv.)	Zeolite CBV-760	Yield (2)[b]
1	NBSacc (1.0 equiv.)	50 mg	57 %; (NR[c])
2	NBPth (1.0 equiv.)	50 mg	90 %; (8 %[c])
3	NBS (1.0 equiv.)	50 mg	78 %; (NR[c])
4	DBDMH (0.5 equiv.)	50 mg	80 %;[d] (NR[c])
5	DBDMH (0.5 equiv.)	75 mg	75 %
6	DBDMH (0.5 equiv.)	25 mg	58 %
7	DBDMH (0.5 equiv.)	10 mg	63 %
8	DBDMH (0.5 equiv.)[e]	50 mg	73 %
9	DBDMH (0.5 equiv.)[f]	50 mg	74 %[g]

[a] Reaction conditions: 1 (100 mg, 0.78 mmol), brominating reagent (0.5–1.0 equiv.), and zeolite CBV-760 (10–75 mg) were milled for 2 h at 30 Hz using a 14 mL Teflon milling jar with one ZrO₂ milling ball weighing 3.0 g. [b] Yields were determined by ¹H NMR spectroscopy using methyl p-toluate as internal standard. [c] Yield in the absence of zeolite CBV-760. [d] The environmental factor (E-factor=mass of total waste/mass of desired product) for the reaction is 0.38. [e] Milling time 1 h. [f] Milling time 3 h. [g] Traces of 1,4-dibromonaphthalene (3) were detected.

Table 2 Price of brominating agents and atom economy of the reaction.

Entry	Br source	Price [Euro [€]/mmol][a]	MW [g/mol]	Atom Economy[c]
1	NBrSacc	4.53	262.08	53 %
2	NBPth	1.22	226.03	58 %
3	NBS	0.92	177.98	67 %
4	DBDMH[b]	0.35	285.92	75 %[d]

[a] Prices checked in late 2021 on Sigma Aldrich and TCI websites. [b] Two bromine atoms available per mol of reagent. [c] Atom Economy=MW (2)/[MW (1)+MW (brominating agent)]. [d] 0.5 equiv. of DBDMH were used for the calculation.

Having identified DBDMH as the most suitable brominating agent, we evaluated the effect of the amount of zeolite on the bromination of 1. Increasing the amount of zeolite CBV-760 during the milling process, from 50 mg to 75 mg, did not improve the yield of brominated product 2, which was obtained in 75 % yield (Table 1, entry 5). Interestingly, when the amount of zeolite was lower than 10 mg per 0.78 mmol of naphthalene (1) the bromination of 1 was still operational giving 1-bromonaphthalene (2) in 63 % yield (Table 1, entry 7). Next, the effect of the milling time on the outcome of the reaction was studied. Shorter milling times (1 h vs. 2 h) afforded 1-bromonaphthalene (2) in comparable yields (Table 1, entry 8). Similarly, extending the milling time to 3 h still afforded 2 as the major product of the reaction, but this time traces of 1,4-dibromonaphthalene (3) were detected as a result of a second bromination 2 has undergone (Table 1, entry 9). The bromination of 1 catalyzed by zeolite CBV-760 was also possible using milling media made of other materials such as stainless steel, however to avoid contamination of the zeolite with, for example iron, the milling experiments were always carried out in milling containers made of Teflon using ZrO₂ milling balls. To better understand the mechanochemical bromination of 1 with DBDMH and zeolite CBV-760, we analyzed the milled reaction mixture by powder X-ray diffraction (PXRD) (Figure 2). The diffraction pattern of the mixture evidenced the absence of naphthalene (1) and DBDMH, while new diffraction reflections belonging to zeolite CBV-760 and the expected 5,5-dimethylhydantoin (DMH) were detected (Figure 2). Analysis by PXRD of the recovered catalyst also confirmed the crystallinity degree of zeolite CBV-760 (see discussion on recyclability below).

Figure 2. Powder X-ray diffraction (PXRD) analysis of the bromination of 1. Reaction conditions: 1 (100 mg, 0.78 mmol), brominating reagent (0.5 equiv.), and zeolite CBV-760 (50 mg) were milled for 2 h at 30 Hz using a 14 mL Teflon milling jar with one ZrO2 milling ball weighing 3.0 g. Simulated PXRD pattern for the published 1 (CCDC: NAPHTA33) and DMH (CCDC: BEPNIT).

Curious to know if other zeolites could also catalyze the bromination of naphthalene (1) by ball milling, we tested the activity of a few more of them (Table 3). In general, all the zeolites tested facilitated the formation of 1-bromonaphthalene (2) after 2 h of milling. However, CBV-8014-calc, an MFI-type zeolite material (Si/Al=40, H-form) showed the lowest activity probably due to smaller pore openings and pore size (4.7 Å and 6.36 Å, respectively)^[20a] compared to FAU-type framework. (Table 3, entry 2). In the case of SK-40 (Si/Al=2.4, Na-form), a zeolite characterized by a FAU-type framework, yet significantly higher content of Al than in CBV-760, the reactivity was moderate (Table 3, entry 3). Interestingly, ion-exchange of SK-40 with NH₄Cl followed by calcination at 450 °C in order to obtain the acidic form of the material did not improve significantly its catalytic activity (Table 3, entry 4). This could be because of higher number of Brønsted acid sites (lower Si/Al) in the SK-40-IE-calc that react promptly and deactivate rapidly. A similar trend was observed in the methanol-to-olefin reaction where catalysts of greater amount of Brønsted sites rendered faster formation of large coke deposits that block the access to the active sites.^[20b]

Table 3 Mechanochemical bromination of naphthalene (1) with DBDMH using various zeolites.^[a]

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Entry	Zeolite [50 mg]	Yield (2)[b]
1	CBV-760	80 %
2	CBV-8014-calc	15 %
3	SK-40	41 %
4	SK-40-IE-calc	48 %

[a] Reaction conditions: 1 (100 mg, 0.78 mmol), DBDMH (0.5 equiv.), and zeolite (50 mg) were milled for 2 h at 30 Hz using a 14 mL Teflon milling jar with one ZrO₂ milling ball weighing 3.0 g. [b] Yields were determined by ¹H NMR spectroscopy using methyl p-toluate as internal standard.

As mentioned above, milling 1 with DBDMH for 3 h in the presence of zeolite CBV-760 gave traces of 1,4-dibromonaphthalene (3). This preliminary result made us wonder if, by adjusting the amount of DBDMH, 3 could be formed preferentially. Thus, we carried out a series of experiments varying the amount of the brominating agent, which confirmed that a stoichiometric amount of DBDMH leads to 1-bromonaphthalene (2), whereas an excess of the bromine source progressively affords the dibrominated product 3. For example, the use of a two-fold amount of DBDMH with respect to naphthalene (1) gave 1,4-dibromonaphthalene (3) in 87 % yield under otherwise identical reaction conditions (Table 4).

Table 4 Mechanochemical bromination of naphthalene (1) with DBDMH using zeolite CBV-760.^[a]

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Entry	DBDMH (equiv.)	Yield (2)[b]	Yield (3)[b]
1	0.5	80 %	–
2	1.0	38 %	28 %
3	1.5	39 %	39 %
4	2.0[c]	–	87 %

[a] Reaction conditions: 1 (100 mg, 0.78 mmol), DBDMH (0.5–2.0 equiv.), and zeolite CBV-760 (50 mg) were milled for 2 h at 30 Hz using a 14 mL Teflon milling jar with one ZrO₂ milling ball weighing 3.0 g. [b] Yields were determined by ¹H NMR spectroscopy using methyl p-toluate as internal standard. [c] DBDMH (446.1 mg, 1.56 mmol, equivalent to four bromine atoms).

Motivated by the excellent catalytic activity of zeolite CBV-760 to facilitate bromination reactions by ball milling we tested its recyclability. Analysis by scanning electron microscopy (SEM) of the pristine zeolite CBV-760 evidenced that the powder sample is composed of crystallites having the size in the range 200–1000 nm, and we could also observe that most of them present irregular shape (Figure 3a). Still, bipyramid morphology typical for FAU-type crystals could be discerned in some of the particles (Figure 3a). After the general bromination reactions zeolite CBV-760 was recovered by centrifugation and analyzed by thermogravimetric analysis (TGA), PXRD, and SEM. TGA showed the presence of organic material in the recovered zeolite, which could be removed after calcination leading to a zeolite with less water content compared to the pristine zeolite CBV-760 (Figure S4 in the Supporting Information). Notably, despite undergoing a milling process, the zeolite remained crystalline (Figure S2 in the Supporting Information) and the SEM image of the recovered zeolite also showed slightly reduced size and preserved morphology of the crystals (Figure 3b).

Figure 3. Recyclability test for zeolite CBV-760 in the mechanochemical bromination of naphthalene (1) with DBDMH. Scanning electron microscopy images of (A) pristine CBV-760, (B) recovered CBV-760 after the first catalytic cycle, and (C) recovered CBV-760 after the second catalytic cycle.

More importantly, the recycled and calcined zeolite CBV-760 was still catalytically active as demonstrated in the second bromination cycle (Figure 3; top). The same test and structural analysis were conducted for the third time confirming the mechanical robustness and recyclability of the catalyst (Figure 3c and top).

After having optimized the reaction by ball milling, we focussed on the possibility to conduct the mechanochemical bromination of naphthalene (1) by TSE (Figure 4a–b), this is because, even though lab-scale twin-screw extruders are costlier than lab-scale ball mills, their implementation permits carrying out mechanochemical reactions in a continuous manner, which can translate into economic advantages.^[21] Initially, we fed the extruder with a manually ground mixture of 1 and DBDMH and processed this mixture at a speed of 20 Hz at room temperature. As in the experiment by ball milling, formation of 1-bromonaphthalene (2) did not occur in the absence of zeolite CBV-760 even after reprocessing the mixture of 1 and DBDMH in several cycles. Next, a mixture of 1 (10.0 g, 0.078 mol, 1.0 equiv.), DBDMH (11.1 g, 0.039 mol, 0.5 equiv.), and zeolite CBV-760 (5.0 g) was fed into the extruder turning at 20 Hz. After the first cycle of extrusion, a free-flowing powder was collected (Figure 4c). Analysis by ¹H NMR spectroscopy of the extruded material showed only starting materials (Table 5, entry 1). However, passing the solid material along the extruder for the second time generated the brominated product 2. The amount of 2 in the extruded mixture increased after the third cycle (Table 5, entries 2 and 3). In this case, formation of 2 (mp. −1 °C) led to rheological changes in the reaction mixture, which prevented further processing due to its waxy state. Then, we repeated the bromination of 1, this time using two equivalents of DBDMH. Under these conditions, the more solid nature of the reaction mixture (Figure 4d) facilitated the extrusion process to be carried out for various cycles. Pleasingly, after only two cycles the analysis by ¹H NMR spectroscopy indicated the full consumption of naphthalene (1), however, using an excess of DBDMH clearly diminishes the atom economy of the reaction. Notably, in contrast to the ball milling experiment using excess of the brominating agent, now 1-bromonaphthalene (2) was obtained as the major product in the extruded mixture. This could be attributed to the milder mechanical conditions used by extrusion (Table 4, entry 4 vs. Table 5, entry 5).

Figure 4. a) Twin-screw extruder configuration and b) extruder barrel of 29.5 cm of length. c) Extruded mixture of 1, DBDMH (0.5 equiv.), and CBV-760 after the 1st cycle. d) Extruded mixture of 1, DBDMH (2.0 equiv.), and CBV-760.

Table 5 Mechanochemical bromination of naphthalene (1) with DBDMH using zeolite CBV-760 by extrusion.^[a]

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Entry	DBDMH (equiv.)	Cycle	Ratio 1 : 2 : 3 [%][b]
1	0.5	1	100 : 0 : 0
2	0.5	2	41 : 59 : 0
3	0.5	3	34 : 66 : 0
4	2.0	1	37 : 63 : 0
5	2.0	2	0 : 86 : 14

[a] Reaction conditions: 1 (5 g, 0.039 mol), DBDMH (0.5–2.0 equiv.), and zeolite CBV-760 (2.5 g) was initially mixed manually using a spatula and fed into the volumetric twin-screw hopper. The reagents were introduced into the screw extruder at 20 Hz with the extruder barrel at room temperature. [b] ¹H NMR analysis was used to determine the ratio between 1, 2, and 3.

Conclusion

We have developed a catalytic mechanochemical route to brominate naphthalene (1) using various solid brominating agents by ball milling. Among them, DBDMH proved to be the most appropriate bromine source based on its reactivity, cost, and green chemistry parameters such as atom economy. The by-product of the reaction was 5,5-dimethylhydantoin (DMH), a compound that is not considered hazardous,^[22] and one which could potentially be mechanochemically halogenated to be reused as demonstrated in similar hydantoin analogues.^[23] Key for the bromination of 1 was the use of zeolites as catalysts, for which both their porosity as well as their Brønsted acid sites were found important for the success of the reaction. In particular, zeolite CBV-760 exhibited remarkable mechanical robustness, as evidenced by PXRD and SEM analysis, to withstand the mechanochemical treatment while remaining active for various catalytic cycles. The selectivity of the bromination process (mono- vs. di-bromination) could also be switched by controlling the stoichiometry of the reaction. All these features facilitated the bromination of naphthalene (1) by twin-screw extrusion, which enabled the mechanochemical bromination to occur continuously. At present, catalyzed mechanochemical reactions by extrusion are scarce compared to catalyzed transformations by ball milling, but they have the potential for unlimited development.

Experimental Section Bromination of naphthalene (1) with DBDMH using zeolite CVB-760 in the mixer mill

A mixture of 1 (100 mg, 0.78 mmol) DBDMH (0.5–2.0 equiv.), and zeolite CBV-760 (50 mg) was milled at 30 Hz for 2 h using a 14 mL Teflon milling jar and one ZrO₂ milling ball (3.0 g). After the milling was stopped, the reaction mixture was dissolved in a minimal amount of ethyl acetate and the zeolite was recovered by centrifugation. Yields of the brominated products 2 and 3 were determined by ¹H NMR spectroscopy using methyl p-toluate as internal standard. The recovered zeolite was calcined at 600 °C for 12 h.

Bromination of naphthalene (1) with DBDMH using zeolite CVB-760 in the extruder

A mixture of 1 (5–10 g), DBDMH (0.5–2 equiv.), and CBV-760 (2.5–5 g) was initially mixed manually using a spatula and fed into the volumetric twin-screw hopper. The reagents were introduced into the screw extruder at 20 Hz with the extruder barrel at room temperature. Two more cycles were repeated using the same conditions of speed, configuration of the extruder and temperature. After the third cycle the material started exiting the extruder as a molten mixture. ¹H NMR analysis was used to determine the ratio between 1 and products 2 and 3.

Acknowledgements

A.P. acknowledges the financial support from the Croatian Science foundation (Grant UIP-2019-04-4977). I.H. and L.V. acknowledge financing from the Croatian Science foundation (Grant Nos. 1419 and 2795). Dr. Željka Petrović, Dr. Sandi Orlić, and Andreja Čačković are thanked for acquiring SEM images.

Conflict of interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.