Author:

Keywords:

calixarene, pyrimidine

Abstract:

Heteracalixarenes, members of the calixarene family ([1n]metacyclophanes, n = number of bridging units) in which the classical methylene bridges are replaced by heteroatoms, have recently become subject of an increasing amount of studies since they hold high promises within the area of supramolecular chemistry. Oxacalixarene chemistry in particular was revived a few years ago when novel synthetic procedures toward these underexposed macrocycles were disclosed, combining nucleophilic (resorcinol derivatives) and electrophilic (triazines, 1,5-dichloro-2,4-dinitrobenzene, …) building blocks via nucleophilic aromatic substitution (SNAr) reactions. Synthetic pyrimidine chemistry is a well developed part of organic chemistry since the versatile pyrimidine skeleton is commonly found in pharmaceutical drugs, fungicides and herbicides. Dihalopyrimidines have been used extensively for the synthesis of multitopic ligands suitable for the generation of grid-type metal ion architectures. Previous work within the group has focused on the synthesis and reactivity of 4,6-dichloropyrimidines as structural components of meso-pyrimidinyl-substituted porphyrinoids and pyrimidine dendrimers.Inspired by this background in pyrimidine chemistry (and SNAr reactions on heteroaromatic systems) it was envisaged to prepare functional oxacalix[2]arene[2]pyrimidines by SNAr reactions on diverse 4,6-dihalopyrimidine building blocks. Efficient one-pot procedures toward oxacalix[4]arenes were developed. Differentiation of both nucleophilic and electrophilic building blocks allowed variation of the substitution pattern of the heteracalix[m]arene[m]pyrimidines (m = 2–6). Through cultivation of single crystals, solid-state structures were obtained and a highly symmetrical 1,3-alternate conformation was observed for the oxacalix[2]arene-[2]pyrimidine cyclooligomer. Larger oxacalix[n]arenes (n = 6, 8) were synthesized selectively applying fragment-coupling approaches with a variety of linear precursors. Kinetic reaction conditions limiting extensive scrambling (and the concurrent strong bias to the thermodynamically more stable oxacalix[4]arene) were optimized. Similar fragment coupling approaches provided also the first odd-numbered oxacalix[n]arenes (n = 5, 7). In addition, electrophilic 4,6-dichloroquinazoline building blocks gave access to both syn- and anti-heteracalix[2]arene[2]quinazolines, obtained in different ratios depending on the reaction conditions. Once more an 1,3-alternate conformation was observed for all oxacalix[4]arene single crystals.Parallel with the variation of the substituents on the building blocks, post-macrocyclization functionalizations were developed to alter the periphery of the oxacalixarene skeleton more profoundly. One macrocyclic scaffold in particular, 5,17-bis(methylsulfanyl)oxacalix[2]arene[2]pyrimidine, excelled due to the ease by which it could be functionalized in various ways. Later on, the post-macrocyclization functionalizations were also extended to the larger macrocycles. The palladium catalyzed Liebeskind-Srogl reaction allowed the introduction of several aryl substituents by direct replacement of the methylsulfanyl group. After oxidation of the methylsulfanyl groups, SNAr reactions were applied to introduce a wide variety of O-, S-, N- and C-nucleophiles on the oxacalixarene scaffold, providing access to a broad scope of functionalities. By application of this post-macrocyclization SNAr functionalization method, an oxacalix[2]arene[2]pyrimidine-bis(Zn-porphyrin) was prepared and this molecular tweezer was shown to bind fullerene C70 rather selectively. A 1:1 host:guest stoichiometry with Kass = 3.0 104 M-1 was determined by 1H NMR titration experiments in benzene-d6. In addition, an oxacalix[2]arene[2]pyrimidine-bis(Cu-corrole) tweezer was also synthesized. However, no affinity for fullerene C60 nor C70 was observed for this receptor. Further development of the post-macrocyclization functionalizations allowed the preparation of 1,3-alternating bis((thio)ureido)oxacalix[2]arene[2]pyrimidine anion receptors. Connected via 2-aminoethyl linkers to the oxacalixarene platform, the (thio)ureido groups formed complexes (in DMSO-d6/0.5% H2O) with AcO- > BzO- > H2PO4- > Cl- with modest binding constants but showed no affection for NO3-, HSO4- or Br-. The Job’s plots indicated 1:2 host:guest stoichiometry, i.e. complexation of one anion by each (thio)ureido group.