Studies in Molecular Recognition

Citation

Petti, Michael Anthony (1988) Studies in Molecular Recognition. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/wvhj-nb98. https://resolver.caltech.edu/CaltechETD:etd-04272006-160954

Abstract

A new class of water-soluble organic molecules containing hydrophobic binding sites is described. These host molecules, macrocycles assembled from 2,6-dihydroxy-9,10-dihydro-9,10-(1,2-dicarbomethoxy)-ethenoanthracene 8, can possess a hydrophobic cavity having a grossly right- (or left-)handed sense of twist. We believe this dissymmetric helical cavity could provide a means for chiral discrimination between the enantiomers of a racemate in aqueous solution.

By varying the shape and size of the hydrophobic receptor site, such questions as the the roles of π-stacking, hydrophobicity and rigidity in molecular recognition are examined. The physical properties of these structures and their binding affinities for various guest molecules in aqueous solution are presented.

These molecules have an especially high affinity for the aliphatic guest adamantyltrimethylammonium iodide (ATMA). In addition, this guest is an elegant probe of host geometry in the binding event. Several lines of evidence indicate that ATMA associates with these hosts in different geometries. Variable-temperature binding studies indicate that the binding of ATMA to hosts 4CMESO and 5CMESO displays a "non-classical hydrophobic effect."

Further studies with other alkyltrimethylammonium salts explore the role of guest shape, size, rigidity and charge on K_a. Studies involving variations of host structure suggest that rigidity, hydrophobicity, charge and donor-acceptor effects can significantly affect K_a.

Two hosts of very similar structure, a p-xylyl-linked macrocycle (P-D) and a trans-1,4-dimethylenecyclohexyl-linked macrocycle (C6-L) are compared. Evidence for a new host geometry, efficient at encapsulating flat aromatic molecules, similar in shape to a naphthalene, is presented. These hosts efficiently bind aromatic heterocyclic guests (e.g., indole, quinoline, isoquinoline) and the N-methyl analogues. In this study, P-D displays an added affinity for the cationic guests. This additional ion-dipole effect is worth at least 1 kcal/mol in binding free energy. The binding of aromatic heterocycles is shown to be driven by donor-acceptor π-stacking interactions and hydrophobic effects.

Thus, high binding affinities are achieved by a combination of forces without resorting to the use of highly lipophilic guests. These hosts maintain a clear separation of hydrophilic and hydrophobic groups, thereby eliminating the generally quite strong electrostatic interactions seen in other synthetic host systems.

Synthetic strategies to novel building blocks for new host structures are presented. These strategies could allow for the preparation of hosts having different solubility profiles, different aggregation properties and enhanced binding characteristics.

Thesis Files