Guests Within Large Synthetic Hydrophobic Pockets Synthesized Using Polymer and Conventional Techniques


Bruce C. Gibb Department of Chemistry, University of New Orleans

Publication Date


Read full article online

Full Article


According to Cram, a “guest” is a molecule or ion that possesses divergent binding sites, while a “host” is a molecule containing convergent binding sites. The combination of the two is a host–guest complex, an incredibly large number of which have been identified and studied. The paradigm of “guests within large synthetic hydrophobic pockets” represents a small subset of host–guest chemistry. Hence, using the adverb “within” limits the discussion to systems in which the (smaller) guest can actually reside inside the host. Likewise, the adjective “large” narrows the coverage further by focusing on sizable cavities that by the laws of physics bind sizable guests. In this review, “sizable guests” refers to those of at least seven nonhydrogen atoms. The term “hydrophobic” is used to focus only on organic guest molecules undergoing solution phase complexations. Finally, and perhaps most importantly, the term “pocket” narrows the review somewhat to focus on hosts that possess well-defined, highly concave surfaces or enclosed surfaces. An arbitrary value of greater than approximately 50% encapsulation has been set. Thus, crown ethers and other “2-D” macrocycles, as well as simple resorcinarenes, calixarenes, and other bowl-shaped cavities do not fall within the purview of this work. Although setting the bar at this height is undoubtedly subjective, it seems reasonable, bearing in mind that the general movement of the field is toward greater “percent encapsulation” and maximal guest control. Finally, one more proviso must be added. The general topic of hosts binding guests within hydrophobic pockets have been reviewed—albeit in several separate contributions—within the major publication, Comprehensive Supramolecular Chemistry. This review is therefore primarily interested with the literature since this publication.

For chemists, the underlying rational for placing molecules or guests within synthetic hydrophobic pockets is straightforward: control. Chemists are interested in placing guest molecules within hydrophobic pockets to gain complete control of the immediate environment around the guest molecule. Why do this? There is a variety of potential applications: protecting the guest from reacting with the surrounding environment, or at the opposite extreme, orchestrating noncovalent or covalent interactions to affect a precise conversion of the guest into a product. Alternatively, the goal may be to bring about a change in the host so that the guest can be detected. These applications—storage/delivery, catalysis, and detection—are powerful motivators for the field of host–guest chemistry in general.

There are three ways in which synthetic hydrophobic pockets can be synthesized. First, they can be constructed in a method analogous to the way Nature does it. In other words, a polymer can be folded into a distinct conformation that possesses the required cavity. At the moment the protein-folding problem is just that, a problem. Consequently, the normal way to build a cavity using polymers is to use one with relatively few conformational degrees of freedom so that some preferred conformation is “guaranteed.” Because there is a distinct qualitative difference between a well-defined hydrophobic pocket and the microenvironment within a dendrimer, dendrimers do not fall under the auspices of this review. Instead, we will focus on systems that possess one principle conformation to define their hydrophobic cavity.

The second approach is to use conventional synthetic techniques and build up the hydrophobic pocket, “brick-by-brick.” This circumnavigates the problem of protein folding and in theory allows precise control of the shape of the cavity. No approach is perfect, however, and this strategy suffers from the problem of hydrophobic pocket collapse. By constructing a “mere” shell to define the pocket, it is hard to build into it design elements that inhibit collapse. The conformational minimum of the target must possess the desired cavity.

The third approach is to use self-assembly. This strategy is treated in a separate review titled “Guest Within Large Hydrophobic Pockets: Synthesis Using Self-Assembly.”