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Synlett 2022; 33(09): 898-902
DOI: 10.1055/a-1748-3797
cluster
Mechanochemistry

Insight into the Reactivity Profile of Solid-State Aryl Bromides in Suzuki–Miyaura Cross-Coupling Reactions Using Ball Milling

Koji Kubota  ∗
a   Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
b   Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
,
Keisuke Kondo
a   Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
,
Tamae Seo
a   Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
,
Hajime Ito  ∗
a   Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
b   Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
› Author Affiliations

This work was financially supported by the Japan Society for the Promotion of Science (JSPS KAKENHI grants 18H03907, 17H06370, 20H04795, and 21H01926), by the Japan Science and Technology Agency (JST) via Core Research for Evolutional Science and Technology (CREST grant JPMJCR19R1) and Fusion Oriented REsearch for disruptive Science and Technology (FOREST grant JPMJFR201I), and by the Institute for Chemical Reaction Design and Discovery (ICReDD), established by the World Premier International Research Initiative (WPI), Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
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Abstract

Despite recent advances in solid-state organic synthesis using ball milling, insight into the unique reactivity of solid-state substrates, which is often different from that in solution, has been poorly explored. In this study, we investigated the relationship between the reactivity and melting points of aryl halides in solid-state Suzuki–Miyaura cross-coupling reactions and the effect of reaction temperature on these processes. We found that aryl halides with high melting points showed significantly low reactivity in the solid-state cross-coupling near room temperature, but the reactions were notably accelerated by increasing the reaction temperature. Given that the reaction temperature is much lower than the melting points of these substrates, the acceleration effect is most likely ascribed to the weakening of the intermolecular interactions between the substrate molecules in the solid state. The present study provides important perspectives for the rational design of efficient solid-state organic transformations using ball milling.


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Key words

cross-coupling - solid state - mechanochemistry - ball milling - palladium catalyst

Recently, solid-state organic synthesis using ball milling has attracted considerable interest as a new tool for carrying out organic transformations.[1] [2] The practical advantages of this approach include the avoidance of potentially harmful organic solvents and simpler operational handling. However, the rational development of efficient solid-state organic transformations, whose performance is comparable to that of solvent-based synthetic routes, remains challenging because solid substrates often show unique and unpredictable reactivity profiles based on the dense solid-state reaction environment.[1,2d] , [3–11] Therefore, a fundamental investigation to reveal insight into the reactivity of solid-state organic molecules is essential to unlock versatile applications of solid-state organic synthesis in both academic and industrial settings.

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Scheme 1 Aim of this study

We have previously reported efficient solid-state ­Suzuki–Miyaura cross-coupling reactions using ball milling (Scheme [1]).[12] These solid-state coupling reactions of structurally simple substrates are efficient and proceed at near room temperature. However, reactions of aryl halides that bear large polyaromatic structures are often unsuccessful.[12] Ondruschka and co-workers found that liquid aryl halides are more reactive than solid ones under mechanochemical Suzuki–Miyaura cross-coupling reactions, which is mostly likely due to the better mixing efficiency of liquid substrates.[13] Later, the similar reactivity profile in mechanochemical cross-coupling reactions was also reported by our group.[2d] [12] Unlike these cases, the observed reactivity difference between solid aryl halides at the reaction temperature below the melting points cannot be simply explained by such mass-transport limitations. More recently, we discovered that such polyaromatic halides, including insoluble pigments and dyes, reacted smoothly under high-temperature ball-milling conditions in which ball milling reactions were carried out while applying a heat gun.[8,14] This protocol allows solid-state coupling reactions to be carried out at approximately 120 °C. Although these studies advanced the solid-state cross-coupling chemistry,[2d] [5] [8] , [12] [13] [14] [15] insight into the unique reactivity of solid substrates and the effect of reaction temperature have not been fully investigated. To further expand the scope of solid-state cross-coupling, we realized that fundamental research is necessary to clarify the key factors that determine the reactivity of organic compounds under solid-state ball-milling conditions and the effect of temperature on a broad range of solid substrates with different physical properties (Scheme [1]). This is our motivation for the present study, and the results obtained are described herein.

All mechanochemical reactions were conducted in a Retsch MM400 mill (stainless-steel milling jar; 30 Hz; stainless-steel balls). Initially, we investigated the relationship between the yield of the coupling product and the melting point of aryl bromides because the melting point roughly reflects the strength of the intermolecular interactions of the solid substrates. We selected 17 aryl bromides (1a–q) having different melting points and subjected them to solid-state Suzuki–Miyaura coupling with 4-methoxyphenylboronic acid (2) in the presence of a Pd(OAc)2/SPhos[16] catalytic system under ball-milling conditions near room temperature.[9] We used 1,5-cyclooctadiene (1,5-cod) as an additive, which can act as a dispersant for the palladium-based catalyst to suppress the undesired aggregation of the nanoparticles and also as a stabilizer for the monomeric Pd(0) active species.[2d] [12] [14] Since these substrates have similar steric and electric biases at around a C–Br bond, we expected that the investigation would reveal a correlation between the reactivity and the strength of the intermolecular interactions. The results are presented in Scheme [2] (yield values in blue). For melting points, both values in the catalog and those obtained by differential scanning calorimetry (DSC) analysis are shown. We found that the reactions of solid aryl bromides with melting points ranging from 54–105 °C (1a–e) proceeded smoothly to give the desired coupling products 3a–e in excellent yields. However, when aryl halides with melting points ranging from 105–161 °C (1f–m) were used as substrates, the results were different for each substrate, and many of them provided low yields of the corresponding coupling products (3f–m; Scheme [2] and Figure [1]). Moreover, almost no reactions were obtained when aryl halides with melting points over 180 °C (1n–q) were used (Scheme [2] and Figure [1]). Since aryl bromides with higher melting points exhibit significantly lower reactivity, as shown in Scheme [2], it was suggested that strong intermolecular interactions in the solid-state mixtures would reduce the diffusion efficiency of substrates at the molecular level, making the reaction rate significantly slow.[5] Another possibility is that such strong interactions may prevent the catalytically active species from taking the favorable transition-state structure around the reactive sites of the substrates.

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Figure 1 Relationship between yield of coupling product 3 and melting point of solid aryl bromide 1
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Scheme 2 Correlation between reactivity and melting points of aryl bromides in solid-state Suzuki-Miyaura cross-coupling reactions
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Figure 2 Effect of temperature on the coupling of 1q

Subsequently, we carried out the reaction using high-temperature ball-milling with a heat gun to investigate the effect of reaction temperature on the solid-state coupling.[14] As shown in Scheme [2], the reaction of 1q, which has a melting point of 308 °C, in the presence of a Pd(OAc)2/SPhos/1,5-cod catalytic system at near room temperature did not proceed at all (Figure [2], green line). We used a heat gun with a preset temperature of 250 °C to ensure an internal reaction temperature of 120 °C, which was confirmed by thermography immediately after opening the milling jar. We found that the reaction of 1q at 120 °C was completed within 5 min, providing coupling product 3q in quantitative yield (>99%; Figure [2], red line). DSC analysis of a mixture of 1q, 2, and 3q showed that the melting points of these compounds (1q, 308 °C; 2, 209 °C) did not change significantly, indicating that the melting of these reactants by heating did not occur under the present conditions (for details, see the Supporting Information). When the internal temperature was adjusted to 80 °C (preset temperature of 150 °C) (Figure [2], orange line) or 60 °C (preset temperature of 100 °C, Figure [2], blue line), the acceleration effect was also observed, while the solid-state coupling reactions at these temperatures were slower than that of the reaction at 120 °C (Figure [2], red line). Given that these reaction temperatures are much lower than the melting points of 1q, the acceleration effect is most likely ascribed to the weakening of the intermolecular interactions between the substrate molecules in the solid state.[14]

To investigate the effect of high temperature on a wide range of aryl bromides with different melting points, we carried out solid-state coupling reactions of 1a–q at 120 °C (Scheme [2], yield values in red). The reactions of solid aryl bromides with melting points ranging from 54–105 °C (1a–e) were completed within 5 min to give the desired products 3a–e in an almost quantitative yield. Aryl halides with melting points ranging from 105–161 °C (1f–m), which are not suitable substrates for room-temperature conditions, provided excellent yields of the corresponding coupling products 3f–m. Furthermore, aryl halides with melting points over 180 °C (1n–q), which are barely reactive under room temperature conditions, underwent solid-state coupling reactions efficiently to form the desired products 3n–q in excellent yields. Based on these results, we confirmed that the reactions could be significantly accelerated by increasing the reaction temperature, even though the temperature is still lower than the melting points of various solid aryl halides used as coupling partners. These results also suggest that the weakening of the intermolecular interactions of solid substrates under high-temperature conditions is the key for efficient solid-state cross-coupling reactions.[14]

In summary, we discovered a correlation between the reactivity and melting points of solid aryl bromides in solid-state cross-coupling reactions under mechanochemical conditions. The reactions of aryl bromides with higher melting points were significantly slower than those of substrates with lower melting points. Further, we found that the reactions were notably accelerated by increasing the reaction temperature, even though the reaction temperature was much lower than the melting points of aryl bromides used as coupling partners. Although further systematic investigations are needed, we propose that the acceleration effect of high temperature is most likely ascribed to the weakening of the intermolecular interactions between the substrate molecules in the solid state, which may improve the diffusion efficiency of substrates at the molecular level. Another possibility is that the palladium-based catalytically active species could adopt a favorable transition-state structure around the reactive sites of the substrates when the intermolecular interactions are weakened. The results obtained in this study will constitute an important step toward a fundamental understanding of the unique reactivity profile of solid substrates, which will advance the rational development of solid-state organic reactions.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Nippon Chemical Industrial Co., Ltd. for the generous donation of the Buchwald ligands. We also thank Mitsubishi Chemical Corporation for their cooperation and helpful discussions.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1748-3797.
  • Supporting Information

Corresponding Authors

Koji Kubota
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University
Sapporo, Hokkaido 060-8628
Japan   

Hajime Ito
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University
Sapporo, Hokkaido 060-8628
Japan   

Publication History

Received: 09 December 2021

Accepted after revision: 21 January 2022

Accepted Manuscript online:
21 January 2022

Article published online:
04 March 2022

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Zoom Image
Scheme 1 Aim of this study
Zoom Image
Figure 1 Relationship between yield of coupling product 3 and melting point of solid aryl bromide 1
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Scheme 2 Correlation between reactivity and melting points of aryl bromides in solid-state Suzuki-Miyaura cross-coupling reactions
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Figure 2 Effect of temperature on the coupling of 1q