Towards Greener Mechanosynthesis of Functional Calixarenes †

: The awareness of sustainability led to increasing global demand for processes that use lower energy, produce reduced waste, use fewer organic solvents, and offer improved selectivity. In this context, mechanochemistry re-emerged as a powerful green methodology. The conventional synthesis and functionalization of calixarenes, both on the upper and lower rim, has been the subject of numerous studies but only a few were reported using a mechanochemical approach. Herein, we present new mechanically assisted key synthetic steps towards a more sustainable route to calix[4]arenes functionalized in the lower rim. polymers, by a mechanochemical-as-sisted protocol. Four calixarenes were synthesized in low to moderate yields (10–58%, after recrystallization), in much faster reaction times under solventless conditions. How-ever, we anticipate that is still room for reaction optimization, namely exploring different bases, grinding auxiliaries, catalytic systems, and reaction times. Overall, mechanochemistry is foreseen as a novel, effective, and green strategy for the preparation of advanced calixarenes.


Introduction
Calixarenes are a well-known class of synthetic macrocycles that possess an intramolecular bow-shaped cavity capable of accommodating different types of molecular guests. Their synthesis, properties, and applications have been extensively reviewed [1,2]. Presenting considerable functional and tuneable diversity, their synthesis and functionalization are still challenging. In recent years, the incorporation of calixarenes into polymeric matrices led to the development of smart materials with interesting sensing properties [3], but calixarenes are expanding in different fields, such as chemotherapeutics [4] and nanosciences [5].
Mechanosynthesis is an emergent green technology that proceeds under solventless conditions, at room temperature, or by heating originated from the grinding process. Thus, this methodology allows waste reduction and lower energy consumption, without compromising or even enhancing chemical transformations. Besides matching all these requirements, another major advantage and an extraordinary feature of mechanosynthesis is the elimination of solubility issues due to the highly energetic elastic, plastic, and shear deformations that lead to chemical reactions. Moreover, mechanochemistry is a truly new synthetic tool, by allowing access to products otherwise found possible only in classical solution reactions. Nevertheless, and despite great achievements made in the last few years [6], the field of mechanosynthesis is still rather unexplored. In particular, synthetic reports of calixarenes prepared by a mechanochemical approach are almost nonexistent [7][8][9][10]. Hence, we explored the mechanosynthesis of selected calixarene intermediates, aiming at a greener route for smart calixarene-based materials.

Results and Discussion
The green synthesis of functional calix [4]arenes was performed using a mechanochemical approach. Overall, the solventless synthetic route showed important advantages over conventional protocols. In this work, starting from p-tert-butylcalix [4]arene 1, two functional calixarenes monomers, bearing aryl vinyl or aryl ethynyl pending units, were successfully prepared (Scheme 1). The reactions were conducted in a planetary ball mill using both stainless-steel and zirconium oxide reactors, and the reactor was found to influence the reaction outcome. In most cases, a low yield or no reaction was observed when the stainless-steel was used.
Calixarene 2 [12] was synthesized in one step using 4-vinylbenzyl chloride, KOH as a base, and nitrobenzene as a milling auxiliary (equimolar amount). It is well known that K + ions can be easily trapped in the calixarene cavity, altering the cone configuration, and ultimately decreasing the lower rim reactivity. Therefore, the effect of the addition of 18crown-6, a ligand with an affinity for potassium cations, was investigated. Although a lower yield was observed in comparison with the optimized conventional protocol, 10% vs. 48% yield, the reaction time was reduced from 168 h (reflux in acetonitrile) to 60 h (milling at 500 rpm) ( Table 1). Further reaction optimization to increase the reaction yield is undergoing. Surprisingly, the base selection was also found to be critical. When K2CO3 (conventional route base) was used, only traces of calixarene 2 were obtained.
Similarly, calixarene 5 [13] was prepared in three steps (Table 1). First, calixarene 1 was reacted with 4-iodobenzyl bromide using K2CO3 anhydrous as a base to give calixarene 3 after 7 h of milling at 500 rpm. The yield is much lower than the conventional reaction, 27.2% vs. 81.1% yield; however, the reaction time was reduced from 24 to 7 h under solventless conditions. Next calixarene 4 was obtained from calixarene 3 via a Sonogashira-Hagihara coupling in 8 h of milling at 500 rpm. The reaction yield was optimized by the introduction of MgSO4 anhydrous as a grinding auxiliary and cyclohexene as an additive. Olefins, and 1,5-cyclooctadiene (COD) in particular, have been reported to remarkably accelerate palladium-catalyzed cross-coupling solid-state reactions by acting as efficient molecular dispersants [14]. In this protocol, we chose cyclohexene, a much cheaper and less toxic olefin. Under these conditions, calixarene 4 was obtained in 36.9% yield after 8 h of grinding, which is quite good if compared with conventional conditions (68.1%), using tetrahydrofuran under reflux for 24 h. Finally, calixarene 5 was obtained in 15 min. by removal of the TMS protecting group using n-Bu4NF. The mechanochemicalassisted deprotection, in this case, was even higher than that obtained under conventional conditions (58.2% vs. 49.1% yield), avoiding the use of tetrahydrofuran.

Conclusions
In summary, we present, for the first time, the preparation of key calix [4]arenes monomers, precursors of important calixarene-based polymers, by a mechanochemical-assisted protocol. Four calixarenes were synthesized in low to moderate yields (10-58%, after recrystallization), in much faster reaction times under solventless conditions. However, we anticipate that is still room for reaction optimization, namely exploring different bases, grinding auxiliaries, catalytic systems, and reaction times. Overall, mechanochemistry is foreseen as a novel, effective, and green strategy for the preparation of advanced calixarenes.