The cell’s surface is complex and multicomponent in nature. It is the setting where a variety of crucial life processes take place, mediated by the interaction of cell surface receptors with specific molecules outside of the cell. Studying how particular interactions take place in this convoluted environment can be difficult in actual cell membranes. Modeling components of the cell’s surface can be beneficial in studying cellular processes, although mimicking these systems poses a substantial challenge. Synthetic receptors such as calix[n]arenes, cyclophanes, and cyclodextrins are capable of performing molecular recognition of ionic and hydrophobic guests in aqueous environments, however, these synthetic receptors are not useful for molecular recognition studies in membrane environments.

This work studies the molecular recognition abilities of water-soluble deep cavitands in membrane environments. The binding behavior of cavitands in membrane-like envrionments was studied using NMR analysis. The differences in binding behavior were elucidated in lipid environments compared to free solution. Supported lipid bilayers have been previously employed to mimic membrane environments, and the binding of trimethylammonium-tagged compounds and cationic native proteins were monitored via surface plasmon resonance (SPR) spectroscopy. By varying the functionality at the cavitand’s rim, a broader range of interactions were explored. The binding of anionic native proteins was possible by positioning a positive charge at the rim of the cavitand and more complex interactions between host and guest were possible by tailoring guests that utilize dual mode binding. In order to imitate larger structures on cell surfaces such as glycopolymers, cavitand-mediated atom transfer radical polymerization (ATRP) was performed in order to create a functional polymer on the SLB surface. Utilizing aminoethyl methacrylate, an amine polymer was formed that can be further derivatized by reacting fluorescent compounds for visualization, or epitopes for the adhesion of larger biomolecules such as avidin. The versatility of the amine-functionalized polymer was demonstrated with its ability to bind large structures such as cells at the interface of SLBs. The diverse interactions of the variably functionalized cavitands also led to their use in indicator displacement assays (IDA) for sensing a variety of analytes ranging from post translational modifications to metals and steroids.

Supramolecular self-assembled metal-ligand cages have been used as reaction containers, molecular switches, and sensors. While many diamagnetic cage complexes are known, studies into spin-state switching cage complexes have only recently begun to emerge. These magnetically active complexes have applications in information storage, electronic switches, and display devices. To create stable, robust high spin complexes, new ligand structures must be explored focusing on the chelating portion of the ligand to affect the spin state of the metal centers.

This work analyzes the characteristics needed in ligands to form favorable paramagnetic cage complexes, using reversible multicomponent metal-ligand self-assembly methods. Using novel termini to interact as metal coordinators allows the formation of high spin Fe(II) metal centers. High spin Fe(II) can be obtained via two types of ligand interactions, either distortion of the octahedral coordination environment due to excess bulk at the metal center, or using a weak coordinator. The addition of steric bulk near the metal center requires a certain amount of flexibility in the ligand backbone to allow favorable coordination. The spin states of these paramagnetic systems were examined to determine their magnetic moments and define the relationship between the metal centers. Alternatively, spin state switching complexes can be formed by using novel heterocyclic chelators. Using new termini allowed creation of novel paramagnetic cages and subsequently the functional properties of these cages were investigated. Slight differences made it possible to tease out the relative favorability between the two seemingly energetically equivalent coordination positions of imidazole termini. Synthesis of novel ligands with amine termini was pursued to bestow a wider range of functionality on cage systems. New amine capped complexes were characterized and found to bind biological molecules of interest. Additionally, the amine-capped complexes were found to be much more sensitive to the counterion employed, distinctly limiting the number of isomers formed.

The field of molecular recognition illustrates the ability of synthetic receptors to act as hosts for important target molecules. These hosts are capable of binding guests in a manner akin to larger biological systems. Synthetic receptors are ideal molecules for observing host:guest interactions as they possess tunable structures that can be tailored to the desired target. As the differences in many biological targets are relatively small, the use of an array-based system allows for greater discrimination of these slight variations. This approach uses multiple variably functionalized receptors that act as a “chemical nose” for target molecules in a variety of optical sensing applications. This array-based system enables the receptors to sense a broader range of relevant biomacromolecules. The differential sensing of these small molecules can be measured via fluorescence outputs which are deconvoluted using Principal Component Analysis and other statistical methods. The use of water soluble deep cavitands allows for greater scope and tunability of their recognition abilities compared to other macrocyclic receptors. Much previous work has investigated deep cavitands with a negatively charged upper rim, so new structures that incorporate a positive charge were synthesized as a direct comparison of functionality. The diversification of functional groups at the upper rim broadens the scope of target molecules that the cavitands can sense, while the derivatization of the lower rim allows for increased solubility as well as secondary effects of the binding interactions. Deep cavitand hosts exhibit this selective target recognition by utilizing a self-folding deep pocket that provides a defined cavity for binding. This work has highlighted the importance of the synthetic variation of the receptors for sensing specific targets. The novel cationic cavitands remain neutral at the upper rim and only experience charge interactions at the lower rim of the structure. These positively charged receptors have provided an array-based system that is capable of enantioselective sensing of pheromone guests which have small differences in their structures that the array-based system was still able to discriminate between. Additionally, the discrimination of anions with the cationic cavitands showed a strong preference for iodide, despite large concentrations of competitive ions in solution. This secondary interaction at the lower rim of the cavitand structure causes a conformational change in the binding pocket of the cavitand, which influences the affinity of the bound guest for the cavitand. From the success with negatively charged guests, the sensing of phosphosugars has been investigated, and preliminary results show discrimination of fructose-6-phosphate and glucose-6-phosphate using the cavitand array.

An area of supramolecular chemistry that has recently been growing in popularity is the synthesis of metal-ligand cages. These are most commonly comprised of organic ligands and transition metal ions. Cage complexes often take the form of geometric polyhedra such as tetrahedra and octahedra, where the ligands act as the edges or faces and the metals serve as the vertices. Because these complexes have a polyhedral design, there is a central cavity in the cage, and this has been exploited for guest binding. Many types of guests have been bound inside supramolecular cage complexes, and binding is dependent on the environment inside the cage. Encapsulated guests can also react, either with themselves or with a coencapsulated guest.

Host-guest chemistry is often inspired by the selectivity of enzymes for their substrates, and the development of biomimetic systems is one of the goals for these assemblies. While encapsulation has been effective for promoting reactions and accessing novel reactivity, reactions are limited to those that require no additional reagents such as cycloadditions. No functional groups are present to direct reactivity, and reactivity is promoted by an increased effective concentration of guest molecules in the confined interior of a host. Introducing functional groups to cages can mimic the side chains of amino acids that are present in enzyme active sites, and this strategy can lead to more specialized, truly biomimetic reactivity.

This work presents a series of supramolecular cage complexes with varied geometries and assembly properties. Endohedral functionality could be introduced to a series of palladium-pyridine "paddle-wheel" complexes, and functional groups were able to influence assembly. Bidentate hydroxamic acid ligands were shown to complex bismuth and praseodymium, and attempts toward endohedrally-functionalizing these assemblies are discussed. Variable assembly was observed in complexes with 9-coordinate bismuth, and assembly was primarily dependent on metal concentration. Lanthanide complexes were also synthesized, and cooperative, thermodynamic control of selectivity between metal ions was observed. Fluorene-based ligands were combined with lanthanide ions, and complexes differing only in endohedral functionality narcissistically self-sorted despite identical ligand geometry and metal coordinating motif.

Enzymes are catalysts found in nature that show high rate accelerations and substrate selectivity compared to synthetic catalysts. The high selectivity of enzymes derives from their active sites. These sites contain functional groups that allow enzymes to bind to substrates of specific shapes and sizes. The high efficiency and selectivity shown by enzymes has prompted chemists to mimic their behavior in a more easily analyzable system. This has led to the creation of synthetic molecules known as self-assembled metal-ligand cages. However, most cages are featureless, and lack the functional groups found in enzymes needed for binding and catalyzing reactions. My research is, therefore, geared towards overcoming the inherent problems faced when modifying these cage molecules with reactive functions. Past studies have shown that twelve internal acid groups can be incorporated in the active site of a cage complex. My research has investigated the factors that affect the reactivity of the acid cage. The reactivity is controlled by both the nature of the nucleophile and size and orientation of the electrophile when bound. Electrophiles that have more bulk around the basic oxygen are activated less effectively, due to being located further away from the cage’s acid groups. Smaller electrophiles show minimal size-selectivity and react at a slower rate. While spherical guests are highly dependent on substitution, flat guests are unaffected by both size and shape differences in the cage. Further research has shown that the acid cage can activate complex, multistep reaction pathway. This is challenging because most reactions performed with artificial enzymes are relatively simple one or two step processes. Results from this study reveal differences in reactivity based on the size and fitting of the intermediate molecule formed inside the cage. Enzymes can also employ “cofactors.” By adding a small molecule acid to an unfunctionalized version of the acid cage, this allows size-selective, acid-catalyzed substitution reactions to occur with faster rates and variable mechanisms than simply with the acid alone. Finally, my research has formed a cage with twelve internal amine groups inside its cavity. The amine functional groups are protonated due to the water created during the assembly process. The internal amines are less basic than normal, when compared to a molecule in free solution. Similar to an enzyme’s ability to control both acidity and basicity of its side-chain in its active sites, this complex can exhibit the same type of control using its internal amines and the cationic superstructure.

A deep water-soluble cavitand, a synthetic host molecule that can selectively recognize small molecules of the correct size, shape and charge, shows notable selectivity for trimethylammonium (R-NMe3+) salts through cation-π interactions in water. The cavitand possesses a negatively charged hydrophilic rim and a hydrophobic aromatic pocket, and can self-assemble into a vase-like conformation in aqueous solution via intramolecular hydrogen bonding. This host can be incorporated into supported lipid bilayers (SLBs) and retain its binding selectivity.

To study the scope of guests that can be recognized, several proteins were functionalized with R-NMe3+ binding handles and the recognition event between the functionalized proteins and cavitand:SLB system was monitored by Surface Plasmon Resonance (SPR) Spectroscopy. The binding was monovalent, and displayed a binding affinity of >105 M-1, showing that the cavitand is capable of recognizing suitably labeled large proteins via cavity-based recognition.

Underivatized proteins with high isoelectric points also showed strong binding to the cavitand:bilayer system under high salt conditions. This unique binding is due to charge-based interactions between the negatively charged rim of cavitand and the positively charged surfaces of proteins. Moreover, immobilized trypsin on the cavitand:SLB interface maintains its enzymatic function: the adhered trypsin is capable of digestion of insulin B. This indicates that the cavitand:SLB system is tolerant to enzymatic reactions.

From preliminary results on artificial SLBs, our interest has moved on to molecular recognition processes using cavitands in living cells. Shape-based molecular recognition with a synthetic receptor in living cells is far more challenging than in biomimetic membrane systems, simply due to the vast array of competitive species in a living cell. It was observed that the cavitand is capable of selective guest recognition and transmembrane transport in living cells despite the complexity of the environment. The host was combined with a R-NMe3+ labeled fluorescent guest in human cervical cancer cells (HeLa), and selective transport of the guest into the cells was observed. In the absence of cavitands minimal transport was observed, and no transport of fluorescein itself (without a R-NMe3+ binding handle) was observed. This was the first biological application of cavitands in cellular systems.

Enzymes are capable of exquisite selectivity in catalysis chemical reactions because of a well-evolved mechanism that binds substrates in internal active sites based on size and shape complementarity. The cavities of these enzymes are decorated with organic or inorganic groups which can promote reactivity once the substrate is non-covalently bound. Synthetic molecular hosts to date have been able to bind to substrates in a similar, biomimetic fashion, but functionalized molecular hosts are still virtually unknown. One convenient way to prepare molecular hosts is by the self-assembly of organic coordinating ligands with suitable metal salts. The reversible dative bonds holding these cage structures together allow incorrect products to break apart and reform, favoring creation of the most thermodynamically stable product. This leads to discrete, solution phase cages that can function as cavity-containing hosts. Some of these hosts have shown efficacy as catalysts for pericyclic reactions due to favorable transition states of the bound substrates. These cages, however, fail to orient reactive functional groups into their interiors. Truly biomimetic cages will require modifying traditional self-assembled targets to incorporate these reactive functionalities. This work explores the self-assembly of metal-organic cages displaying covalent modifications on their interior. Incorporation of unreactive and poorly reactive groups was found to have a significant impact on the outcome of the self-assembly process. Cages with endohedral alcoholic functionality were found to have different binding properties than unfunctionalized analogs. Cages with introverted alcohol groups were also exploited for their ability to self-catalyze reactions on the interior of the hosts. The metal vertices themselves could also be used as functional groups, and showed the ability to sense neutral analytes in hybrid dative/hydrogen bonded self-assemblies.

The ability to convert feedstock chemicals into synthetically useful derivatives is a major goal in the search for more sustainable and efficient chemical processes. One limitation in the field is the inability of known catalysts to oxidize C-H bonds regioselectively. Traditional synthetic approaches require extreme temperatures and pressures to break the C-H bond; in addition to the high energy cost of these processes, each reaction yields multiple products and over-oxidation is a common problem. In contrast to these harsh reaction conditions, enzymes catalyze C-H oxidations at ambient temperature and pressure with excellent selectivity. More recently, transition metal catalysts have been developed that can oxidize C-H bonds under more mild conditions, but a key difference between enzymes and most synthetic catalysts is that while synthetic catalysts can achieve chemoselectivity based on steric and electronic factors, enzymes exhibit regioselectivity and can selectively oxidize a position on a substrate in the presence of other chemically identical positions.

One problem with using enzymes as catalysts in synthetic organic chemistry is their limited substrate scope. As an alternative, water-soluble synthetic receptors with catalytic functions are an attractive target because they offer the potential to allow regioselective oxidations on a broader range of substrates.

Cavitands provide an alluring scaffold for metalloenzyme mimics because they are capable of displaying four rigid coordinating motifs at defined distances around a hydrophobic cavity that acts as a size-selective recognition motif. A cavitand scaffold is presented that can be smoothly derivatized by CuAAC chemistry to incorporate ligand species at the cavitand rim. The coordination of one or more metals to the scaffold allows self-folding to form a water soluble molecular receptor, without the need for covalent introduction of solubilizing groups such as sulfates or phosphates. Furthermore the hydrophobic binding site allows the cavitands to bind appropriately sized neutral guests. In the presence of a stoichiometric oxidant, the metallocavitands can selectively oxidize unactivated C-H bonds in high yield with good turnover numbers. The catalysts are wide in scope and oxidations are performed cleanly under mild conditions without side oxidation of solvent or catalyst. The cavitands retain the catalytic metal throughout the reaction, and can be recovered from the reaction system by simple filtration. Alternatively, the metallocavitands can be mounted on an SBA-15 solid support, forming highly effective heterogeneous catalysts that can be recovered after reaction in quantitative yield and re-used more than ten times without any decrease in reactivity.

The Cope rearrangement has been used as the key step of several natural products but to date there is only one limited example in the literature that is capable of performing an asymmetric variant of this reaction. The first half of this dissertation focuses on our efforts towards performing a catalytic asymmetric Cope rearrangement to access remote stereocenters. The rearrangement of 2-formyl-1,5-dienes was achieved with both Brønsted and Lewis acid catalysts. The best Lewis acid catalyst was determined to be gold(III)chloride. As there are no examples of asymmetric Au(III) catalysis, we designed and synthesized bis-alpha-chiral dipyrromethanes as potential new ligands for organometallic asymmetric Cope rearrangements.

This work also focuses on the design and synthesis of functionalized deep cavitands for use as biomimetic C-H oxidation catalysts. Enzymes are capable of performing site-selective oxidations by incorporating substrates in their binding pockets and selectively oxidizing the C-H bond closest in proximity to the active site of the enzyme. Cavitands are capable of selectively binding guests of the appropriate size and shape, much like enzymes. Specifically, this work involves the synthesis of cavitands that contain deep cavities with functionalized rims that possess the ability to complex to metals such as iron or copper. These deep functionalized cavitands were found to be capable of binding amines and other small guests as well as performing unprecedented anion binding. Metal coordination was also achieved at the rims of the cavitand making these metallobound cavitands potential enzymes mimics by binding a guest in its cavity and selectively oxidizing the groups closest in proximity to the catalytic site, i.e. the metal bound rims.

One of the ultimate goals within the field of supramolecular chemistry is to mimic the molecular recognition and catalytic activity of enzymes. Enzymes are more effective catalysts compared to human-made catalysts in terms of reaction specificity, rate of reaction, and capacity for substrate regulation, largely due to the characteristics (shape, size, electron density, functional groups) of the interior of the enzyme where the catalytic activity takes place. Supramolecular chemists can achieve this goal by creating assemblies with endohedral functionality that can mimic the interior cage-like nature of enzymes, mimic the asymmetric nature of enzyme active sites, and mimic the allosteric and cooperative nature of enzymes. This thesis takes steps towards achieving that goal by synthesizing and studying cages with endohedral functionality. Particularly, 1) self-assembled transition metal-ligand cages with (and without) endohedral functionality, 2) polyazacryptand cages with homo and hetero dinuclear metallation, and 3) allosterically regulated hydrogen bisulfate anion binding of a series of azacryptand ureas.