Tackling Solubility Issues in Organic Synthesis: Solid-State Cross-Coupling of Insoluble Aryl Halides

Abstract

Conventional organic synthesis generally relies on the use of liquid organic solvents to dissolve the reactants. Therefore, reactions of sparingly soluble or insoluble substrates are challenging and often ineffective. The development of a solventindependent solid-state approach that overcomes this longstanding solubility issue would provide innovative synthetic solutions and access to new areas of chemical space. Here, we report extremely fast and highly efficient solid-state palladium-catalyzed Suzuki− Miyaura cross-coupling reactions via a high-temperature ball-milling technique. This solid-state protocol enables the highly efficient cross-couplings of insoluble aryl halides with large polyaromatic structures that are barely reactive under conventional solution-based conditions. Notably, we discovered a new luminescent organic material with a strong red emission. This material was prepared via the solid-state coupling of Pigment violet 23, a compound that has so far not been involved in molecular transformations due to its extremely low solubility. This study thus provides a practical method for accessing unexplored areas of chemical space through molecular transformations of insoluble organic compounds that cannot be carried out by any other approach.

Solvent‐Free Mechanochemical Post‐Polymerization Modification of Ionic Polymers

“…In this context, solvent‐free mechanochemical post‐polymerization modification (PPM) could address this challenge by bypassing the solubility issues [16] . The potential of mechanochemical PPM has been demonstrated previously, including the ω‐functionalization of α‐methoxy‐functionalized poly(ethylene glycol) ( m PEG) in the solid state [17] and thiol substitution in polynorbornene derivatives [18] .…”

Efficient access to materials-oriented aromatic alkynes via the mechanochemical Sonogashira coupling of solid aryl halides with large polycyclic conjugated systems

“…Next, we investigated the applicability of the developed protocol to poorly soluble aryl chlorides. Vat Red 1 (2w) is a pigment derived from thioindigo 23 that has a solubility of 1.0 × 10 -4 M in toluene at room temperature, 12 which is lower than those of the iconic poorly soluble molecules pentacene and phthalocyanine (4.7 × 10 -4 M and 1.9 × 10 -4 M in toluene at room temperature, respectively). 12 After slight modifications of the reaction conditions, the desired doubly alkynylated product 3ae was obtained in 55% yield via the cross-coupling of 2w with 1a under the high-temperature ball-milling conditions (Figure 4a).…”

“…Vat Red 1 (2w) is a pigment derived from thioindigo 23 that has a solubility of 1.0 × 10 -4 M in toluene at room temperature, 12 which is lower than those of the iconic poorly soluble molecules pentacene and phthalocyanine (4.7 × 10 -4 M and 1.9 × 10 -4 M in toluene at room temperature, respectively). 12 After slight modifications of the reaction conditions, the desired doubly alkynylated product 3ae was obtained in 55% yield via the cross-coupling of 2w with 1a under the high-temperature ball-milling conditions (Figure 4a). Notably, the solution-based reactions using the same catalytic system, or the conventional palladium/copper co-catalytic system, provided a significantly lower yield of 3ae (21%) or resulted in no product formation even after prolonged reaction time (24 h), respectively.…”

“…We have previously reported extremely fast and efficient solid-state Suzuki-Miyaura cross-coupling reactions via a hightemperature ball-milling technique with a heat gun. 12 This protocol is applicable to a wide range of aryl halides that bear large polycyclic π-conjugated systems and that are virtually unreactive under either room-temperature ball-milling conditions or conventional solution-based conditions. In this article, we report that mechanochemical Sonogashira coupling reactions of solid polyaromatic halides under high-temperature ball-milling conditions proceed with excellent efficiency, thus providing practical access to materials-oriented aromatic alkynes in excellent yield with short reaction times (Figure 1c).…”

New avenues for mechanochemistry in zeolite science

“…This may be achieved by wrapping the milling vessel in a heated cover as described recently by Cindro et al 128 Similarly, it has been realised by using a heat gun aimed at the milling flask. 129 Still, it could be argued that such a synthesis is not comparable to the conditions employed in a typical mechanochemical MOF synthesis, requiring no additional, secondary heating source. Nonetheless, such a setup may prove to be a crucial step towards the direct synthesis of zeolite products.…”