At neutral pH, dendronized deep-cavity cavitands were shown to form supramolecular nano-capsules via assembly around a range of guest molecules.The majority of synthetic supramolecular assemblies rely on enthalpically powerful hydrogenbonding [1][2][3][4][5] and metal coordination to drive assembly; 6-10 motifs that are most powerful in nonaqueous media. In contrast, Nature often relies on entropy -in the guise of the hydrophobic effect -to bring about assembly. Inspired by this point, one of our laboratories has reported on a supramolecular capsule formed by the dimerization of 1a around a guest(s) (Scheme 1 and 2). [11][12][13][14][15] This capsule, soluble in aqueous base by virtue of a coat of sixteen carboxylates, has been shown to affect the separation of hydrocarbon gases, 16 and act as a nano-scale reaction vessel for photochemical reactions. [17][18][19] This type of encapsulation also offers an attractive route to modulating the physical properties of a drug without covalent modification, however for this water solubility close to neutral pH is required. Herein we report on the synthesis and assembly of dendronized cavitand 2 (Scheme 1 and 2). Coated with 128 hydroxy groups, the dimeric capsule formed by 2 encapsulates a range of guests at physiological pH.The attachment of hydroxyl-terminated aliphatic polyester dendrons onto the cavitand core was pursued to impart both pH-independent water solubility and high biocompatibility. The dendritic structure 20 imparts an improved solubility over linear analogs, 21 while the hydroxylated periphery affords a highly biocompatible surface. 22 Similar biocompatible dendritic coats have been applied to small molecule cores, 23 linear polymers, 24 and solid surfaces. 25 While a variety of protecting groups could be used for the diol monomer required for dendronization, the acid sensitive acetonide protecting group proved to be the most compatible with 1b. Thus, 1b treated with 1.5 equiv. per hydroxyl of acetonide-protected bis-(hydroxymethyl)-propanoic anhydride (DMAP catalyst) gave the resulting ester after precipitation from methanol in >90% yield, whilst subsequent deprotection (Dowex acid resin) cleanly affected the removal of the acetonide acetals in quantitative yield. Both the esterification and the deprotection reactions could be monitored by MALDI-TOF MS (supporting information, SI). The resulting firstgeneration (G-1) dendronized cavitand bearing 16 OH groups, Cav-([G-1]-OH 2 ) 8 was then subjected to a second repetition of coupling and bgibb@uno.edu. Solubility studies revealed that the G-1 cavitand was sparingly soluble in methanol, the G-2 soluble in alcohols and mixtures of water and methanol up to 80% water by volume, while the G-3 cavitand 2 was freely soluble in pure water. NIH Public AccessBinding studies began with an NMR analysis of free host 2 (SI). Whereas the spectrum of 2 in MeOH showed well-resolved peaks, in pure D 2 O many signals were broad. This broadness was independent of concentration, but the peaks did sharpen upon capsule ...

Resorcinarene‐based deep‐cavity cavitands (DCCs) are useful components in supramolecular chemistry because their extended cavity enables the encapsulation of relatively large guests. To provide H2O solubility, they have been modified with hydroxyl functionalized dendrons. This has been carried out by the divergent dendronization of aliphatic poly(ester) dendrons through the third dendritic generation. The resultant macromolecule demonstrated the desired H2O solubility.