Templated Synthesis of Glycoluril Hexamer and Monofunctionalized Cucurbit[6]uril Derivatives

Abstract

We report that the p-xylylenediammonium ion (11) acts as a template in the cucurbit[n]uril forming reaction that biases the reaction toward the production of methylene bridged glycoluril hexamer (6C) and bis-nor-seco-CB[10]. Hexamer 6C is readily available on the gram scale by a one step synthetic procedure that avoids chromatography. Hexamer 6C undergoes macrocylization with (substituted) phthalaldehydes 12, 14, 15, and 18-in 9 M H(2)SO(4) or concd HCl at room temperature to deliver monofunctionalized CB[6] derivatives 13, 16, 17, and 19-that are poised for further functionalization reactions. The kinetics of the macrocyclization reaction between hexamer and formaldehyde or phthalaldehyde depends on the presence and identity of ammonium ions as templates. p-Xylylenediammonium ion (11) which barely fits inside CB[6] sized cavities acts as a negative template which slows down transformation of 6C and paraformaldehyde into CB[6]. In contrast, 11 and hexanediammonium ion (20) act as a positive template that promotes the macrocyclization reaction between 6C and 12 to deliver (±)-21 as a key intermediate along the mechanistic pathway to CB[6] derivatives. Naphthalene-CB[6] derivative 19 which contains both fluorophore and ureidyl C═O metal-ion (e.g., Eu(3+)) binding sites forms the basis for a fluorescence turn-on assay for suitable ammonium ions (e.g., hexanediammonium ion and histamine).

New homologues of chiral cyclohexylhemicucurbit[n]urils

“…There are several homologues (4 -6) of normal cucurbiturils and a wide variety of analogues (7)(8)(9)(10)(11)(12)(13). In general, glycoluril monomers in these macrocyclic compounds are joined together by two methylene bridges and form strong host-guest pairs with cationic ammonium compounds (3,14,15).…”

“…Ten years ago, Miyahara et al (16) reported that, in strongly acidic conditions, ethyleneurea, in the presence of formalin, can selectively produce two homologues of unsubstituted hemicucurbiturils in very high yields. Hemicucurbit [6]uril (HC [6]) is formed in concentrated HCl at lower temperatures and hemicucurbit [12]uril (HC [12]) in diluted acid at higher temperatures ( Figure 1). It has been shown that unsubstituted hemicucurbituril can catalyse organic reactions (27)(28)(29).…”

Monofunctionalised cucurbit[6]uril synthesis using imidazolium host–guest complexation

“…More recently, Isaacs et al synthesised a methylene bridged glycoluril hexamer, which could then form monofunctionalised cucurbituril derivatives in a subsequent step. 16 Herein, we present a facile route to directly prepare monohydroxylated CB[6] (MonOH) from the parent CB[6] molecule in aqueous solution using host-guest interactions to control the oxidation mechanism and product ratio.The direct functionalisation route to CB[6] reported by Kim et al required more than 14 equivalents of K 2 S 2 O 8 (KPS) per CB[6] molecule to be mixed together as a suspension in water and led to the isolation of the perhydroxylated (12 OH) product. Following the reactions with electrospray ionisation mass spectrometry (ESI-MS) indicated that oxidation of the CH groups occurred in a stepwise process.…”

Synthesis of linear cucurbit[7]uril pendent copolymers through radical polymerization: Polymers with ultra‐high binding affinity

“…In their works, CB [6] and CB [7] derivatives were synthesized by the condensation glycoluril hexamer with phthalaldehydes and glycoluril bis(cyclic ethers), respectively. [18][19][20] Despite these, there is still an unmet need for new and facile methods for the construction of CB covalently linked polymers to broaden their portfolio of potential applications.…”