My research interest encompasses supramolecular chemistry, organic synthesis, and physical chemistry with a focus on the exploration of emergent properties and functions from the association of two or more chemical species held together by non-covalent interactions.
Project 1: Design and synthesis of new receptors for functional dyes
Perylene diimides (PDI) and porphyrins are leading examples of function dyes which have been extensively explored in chemistry, materials science and medicine. The structures of these two dyes feature large aromatic surfaces, producing outstanding photophysical properties. These large and flat aromatic surfaces also lead to several well-known issues such as dye aggregation, poor solubility and limited processability. We designed and synthesized a new octacationic tricyclic cyclophane, XCage, showing stereoelectronic complementarities toward perylene diimide and porphyrin with extremely high binding affinities in water.
The formation of PDI complexes results in dye solubilization and improvement in optical properties including turn-on fluorescence and red-shifted absorption and emission. The complexes also produce an emergent efficient energy transfer process from XCage to PDI, which was used to perform an unusual single-excitation, dual-emission, imaging study of living cells.
When encapsulated by XCage, the photophysical properties and chemical reactivities of the encapsulated porphyrins are modulated to a considerable extent. Improved fluorescence quantum yields, red-shifted absorptions and emissions, and nearly quantitative energy transfer processes highlight the emergent photophysical enhancements. The encapsulated porphyrins enjoy unprecedented chemical stabilities, where their D/H exchange, protonation, and solvolysis under extremely acidic conditions are completely blocked.
(1) Liu, W.; Lin, C.; Webber, A. J.; Stern, C. L.; Yong, M. R.; Wasielewski, R. M.; Stoddart, J. F. J. Am. Chem. Soc. 2020, 142, 8938–8945. (Cover)
(2) Liu, W.; Bobbala, S.; Stern, C. L.; Hornick, J.; Liu, Y.; Enciso, A. E.; Scott, E. A.; Stoddart, J. F. J. Am. Chem. Soc. 2020, 142, 3165–3173.
Project 2: Exploration of novel mechanically interlocked molecules and molecular machines
All molecules are in constant motion, which includes stretching, bending, and rotation, involving bonds between their atoms as well as their tumbling and traversing (Brownian motion) as a whole in a random manner. Mechanically interlocked molecules (MIMs), constrained by their mechanical bonds, show an additional level of molecular motion, namely, that between their component parts. Developing new kinds of MIMs gives rise to emergent properties associated with mechanical bonds. Suitanes are two-component MIMs in which one component (torso) with several protruding limbs is encompassed by another all-in-one component (suit). This kind of molecular ship-in-a-bottle architecture is rare and remains a challenging one to make. Based on the supramolecular complex of porphyrin ⊂ XCage, we developed a mechanically interlocked molecule, suitane, where a porphyrin with four limbs is encompassed by XCage and rocks back and forth about 1000 time a second inside the cyclophane.
(1) Liu, W.; Stern, C. L.; Stoddart, J. F. J. Am. Chem. Soc. 2020, doi: 10.1021/jacs.0c03408
Thesis title: Molecular recognition using tetralactam macrocycle and development of Synthavidin technology
Biotin/(strept)avidin self-assembly is a powerful platform for nanoscale fabrication and capture with many different applications in science, medicine, and nanotechnology. Synthavidin (Synthetic mimic of streptavidin/biotin binding) technology uses high affinity synthetic association partners that operate in water or biological media to bring two objects A and B together and perform functions. A representative example of Synthavidin pair is the binding between tetralactam macrocycle and squaraine dye.
(1) Liu, W.; Samanta, S. K.; Smith, B. D.; Isaacs, L. Chem. Soc. Rev. 2017, 46, 2391–2403.
Project 1: Structural design to fine tune the binding affinity, threading kinetics and optical properties of Synthavidin pairs
Fundamental investigations on the binding between tetralactam macrocycle and squaraine dye reveal a rapid and strong binding in water. The threading kinetics are found to be insensitive to the long polymer chains but can be greatly influenced by the tiny structural change at X site. By changing from Me to Pr, the kinetics slowed down by a factor of a million. In order to enhance the binding affinity, we developed a novel guest back folding strategy, which pushes the binding strength to a world record with a picomolar affinity. The optical properties were optimized for in vivo imaging applications by designing a new 800 nm thienothiophene dye with excellent binding constants and threading kinetic constants.
(1) Liu, W.; Johnson, A.; Smith, B. D. J. Am. Chem. Soc. 2018, 140, 3361.
(2) Liu, W.; McGarraugh, H. H.; Smith, B. D. Molecules 2018, 23, 2229.
(3) Peck, E. M.; Liu, W.; Spence, G. T.; Shaw, S. K.; Davis, A. P.; Smith, B. D. J. Am. Chem. Soc. 2015, 8668-8671.
(4) Liu, W.; Peck, E. M.; Hendzel, K. D.; Smith, B. D. Org. Lett. 2015, 17, 5268–5271.
(5) Liu, W.; Peck, E. M.; Smith, B. D. J. Phys. Chem. B 2016, 120, 995–1001.
Project 2: Using Synthavidin technology to design supramolecular functional systems
The fundamental studies described in Project 1 provide valuable information for our design of supramolecular functional systems as Synthavidin technology. In one example, we designed a new method that can rapidly report enzyme activity based on the fast threading kinetics between squaraine and tetralactam macrocycle. The threading of squaraine is blocked by a large enzyme substrate. Upon enzyme cleavage, the squaraine can rapidly thread into the macrocycle and report the change of optical signals including color and fluorescence. A second example is to use the Synthavidin pair for the surface functionalization of liposome. We synthesized a cholesterol modified squaraine, which can be inserted on the surface of liposome. The rapid and strong binding between squaraine and tetralactam macrocycle, which is modified with various targeting groups, produces a series of surface-functionalized liposomes that can either be immobilized on cationic polymer bead surface or used to selectively target the anionic cell membranes. In a third example, the slow threading kinetics using the Pr squaraine were investigated to make a library of stable fluorescent probes for cancer targeting. These probes were prepared by a programmed noncovalent pre-assembly process that used near-infrared fluorescent squaraine dyes to thread macrocycles bearing acyclic arginine-glycine-aspartate peptide antagonist (cRGDfK) as cancer targeting units.
(1) Liu, W.; Gómez-Durán, C. F. A.; Smith, B. D. J. Am. Chem. Soc. 2017, 139, 6390–6395.
(2) Shaw, S.; Liu, W.; Fernando Azael Gómez Durán, C.; Schreiber, C.; de Lourdes Betancourt Mendiola, M.; Zhai, C.; Roland, F.; Padanilam, S.; Smith, B. D. Chem. Eur. J. 2018, 13821–13829. (hot paper)
(3) Shaw, S. K.; Liu, W.; Brennan, S. P.; de Lourdes Betancourt-Mendiola, M.; Smith, B. D. Chem. Eur. J. 2017, 23, 12646. (hot paper)
Project 3: Anion receptors based on tetralactam scaffold
Besides organic dye molecules, tetralactam macrocycles are also able to bind anions. One example is illustrated by two tetralactam macrocycles that can selectively encapsulate anionic, square-planar chloride and bromide coordination complexes of gold(III), platinum(II), and palladium(II). Both receptors have a preorganized structure that is complementary to its precious metal guest. The receptors do not directly ligate the guest metal center but instead provide an array of arene π-electron donors that interact with the electropositive metal and hydrogen-bond donors that interact with the outer electronegative ligands. This new insight for the binding of precious metal complexes sets the basis for a wide range of applications including mining, recycling, catalysis, nanoscience and medicine.
Another example is a tetralactam macrocycle with a smaller cavity. We call this macrocycle saddle lactam as the crystal structure reveals a saddle shape upon its binding with anions. We found that this macrocycle has a very strong binding affinity to the fluoride anion, which can be extract out of water at low mM concentrations using the receptor. The crystal structure of the fluoride complex is unusual as we obtained a 2:2 fluoride macrocycle dimer, where the two fluoride ions are separated by 3.39 Å. The electrostatic penalty for this close proximity is compensated by attractive interactions provided by the surrounding tetralactam molecules. Reactivity experiments showed that stabilization of fluoride as a supramolecular complex abrogated its capacity to induce elimination and substitution chemistry. This finding raises the idea of using tetralactam macrocycles to stabilize fluoride-containing liquid electrolytes within redox devices such as room-temperature fluoride-ion batteries.
(1) Liu, W.; Oliver, A. G.; Smith, B. D. J. Am. Chem. Soc. 2018, 140, 6810.
(2) Liu, W.; Oliver, A. G.; Smith, B. D. J. Org. Chem. 2019, 84, 4050–4057.
Supramolecular gels based on self assembly of cyclodextrin
I spent three years in Prof. Hao's lab during my undergraduate study investigating the self assembly of cyclodextrin in organic solvents under the influence of salt effect. An unusual organogel system, which shows a double phase transformation (gel–sol–gel′) behavior upon varying temperatures, was discovered. This system is composed of nontoxic components including β-cyclodextrin (sugar), potassium carbonate (baking agent), and 1,2-propylene glycol (liquid sweeteners). Microscopic studies reveal that the two different gel states present different micro morphologies, i.e. microspheres and microrods. This unique experience guides me to the world of supramolecular chemistry and resulted in three peer-reviewed papers, which gave me an opportunity to pursue an advanced degree in the U.S.
(1) Liu, W.; Xing, P.; Xin, F.; Hou, Y.; Sun, T.; Hao, J.; Hao, A. J. Phys. Chem. B 2012, 116, 13106–13113.
(2) Li, Z.; Liu, W.; Hao, A. Colloids Surfaces A Physicochem. Eng. Asp. 2014, 451, 25–32.
(3) Hou, Y.; Li, S.; Sun, T.; Yang, J.; Xing, P.; Liu, W.; Hao, A. J. Incl. Phenom. Macrocycl. Chem. 2014, 80, 217– 224.