Research in Professor Isaacs' laboratory is focused on basic and applied problems in the area of self-assembly. We are especially interested in a class of compounds known as cucurbit[n]urils (CB[n]) that function as molecular containers in water. Molecular containers – just like everyday containers – may be used to protect its cargo and ship that cargo to specific locations. Our research has two main goals. First, we aim to synthesize new CB[n] molecular containers (e.g. chiral containers, multi-cavity containers) and delineate their unique recognition properties. We are most interested in systems that display properties that are typically reserved for Natural systems (e.g. allosteric control over geometry and function, catalytic systems, non-natural folding, etc.) The second goal is toward the creation of complex multicomponent systems that exhibit complex function. Toward this goal we have been studying the preparation, characterization, and control over complex self-sorting systems (see below) These projects all draw heavily on the ability to design and synthesize complex molecules that exhibit specific recognition properties, to develop methods to characterize molecular aggregates, and provides insights into non-covalent interactions in aqueous solution. Students working in the group become skilled in synthetic organic chemistry, molecular modeling and design, and a variety of techniques used to characterize non-covalent aggregates (including multidimensional NMR, calorimetry, optical methods (UV/Vis and fluorescence), gel permeation chromatography).
1. The Cucurbit[n]uril Family. The cucurbit[n]uril family of molecular containers – with their remarkable recognition properties toward cationic guests in water – is the subject of intense current interest. As synthetic and physical organic chemists, my group members have pursued an enhanced knowledge of the mechanism of CB[n] formation with the expectation that such knowledge would allow the preparation of new compounds with exciting recognition properties. In recent years, my group has used this knowledge to prepare new structures including cucurbit[n]uril analogues, inverted cucurbit[n]urils, CB[10], bis-nor-seco-CB[10], and most recently the first chiral member of the CB[n] family namely (±)-bis-nor-seco-CB[6]. More importantly, these new structures enable new recognition functions. For example, the CB[6] analogue shown below functions as a fluorescence sensor for dopamine in water. Similarly, the spacious cavity of CB[10] (870 Å3) enables several biomimetic functions including allosteric control over macromolecular geometry, folding of non-natural oligomers in water, and the encapsulation of porphyrins which function as metalloenzyme mimics. The nor-seco-CB[n] compounds represent the next generation of CB[n] host becuase of they may be chiral, possess multiple cavities in intimitate contact, and undergo further derivatization for the creation of advanced molecular devices.
2. Complex Self-Sorting Systems. Over the past two centuries, scientists have employed a reductionist approach. That is -- complex systems have been reduced in complexity to a point at which a complete understanding is possible. Today, scientists in a variety of fields (biology, computer science, etc.) recognize that a complete reductionist understanding of the biology of life is not possible and have embraced "systems biology" which aims to understand and control their behavior. Chemists have been slower to embrace a systems approach to chemistry. As our entry into the area of "systems chemistry" in 2003 we posed the question of what would happen if we mixed the components of a series of well-defined aggregates (structures below) in chloroform solution. Would the components contain enough information in their molecular structures to undergo self-sorting or would they form a complex mixture? In the intervening years, we have been learning how to control the behavior of these systems under both thermodynamic and kinetic control and how to direct their behavior by manipulating the free energy of the system in response to environmental changes like pH, temperature, concentration, or chemical signals in aqueous solution using CB[n] based hosts. In ongoing work we aim to implement biologically relevant phenomena like catalysis, compartmentation, and eventually to allow for replication and evolution.