International Collaboration in Chemistry: Aqueous Host-Guest Chemistry with Self-Assembling Metal-templated Cages

Lead Research Organisation: University of Cambridge
Department Name: Chemistry


We propose to combine theoretical modeling with collaborative experimental synthesis and characterization in order to assess the fundamental factors affecting binding and recognition in the aqueous host-guest chemistry of small to moderate-sized organic molecules inside self-assembling metal-templated cages. By taking advantage of spiral feedback between modeling and experiment, we expect to identify key steric and electrostatic interactions, the control of which will facilitate rational design of improved host-guest combinations. The knowledge thus created will shed light upon a variety of different questions of current interest, from how proteins bind substrates within their hollows, to how new catalytic transformations might be carried out within purposefully-designed hosts.
Theoretical models based on both quantum and molecular mechanics will be employed. Quantum mechanical models will be chosen by validation against available experimental structural data, and then employed in part to provide further benchmark data for the selection of classical mechanical force fields. Quantum mechanical models will also be used to compute spectral data (e.g., NMR and UV/Vis) in order to compare to experimental host-guest combinations where crystal structures are not available. Classical mechanical force field modeling will be used to simulate the dynamical behavior of host-guest combinations and for the prediction of potentials of mean force associated with aqueous binding events. With sufficient validating data in hand, in silico design efforts will next be undertaken with the goal of focusing synthetic efforts on host-guest combinations showing enhanced selectivity and binding efficiencies.
International collaboration is critical to achieving the goals of this proposal, as expertise in synthesis and spectroscopic characterization is concentrated in the Cambridge group while expertise in static and dynamic modeling is concentrated in the Minnesota group. Exchange of graduate student and postdoctoral personnel between laboratories will ensure that junior personnel receive training in complementary experimental and theoretical techniques, and will also afford them opportunities to experience international aspects of the scientific enterprise.

Planned Impact

Who will benefit from this research?

The immediate beneficiaries will be the PhD student and PDRA. Other direct beneficiaries will include researchers from the multidisciplinary training programmes that the Nitschke group takes part in, such as the Nanosciences Doctoral Training Programme, the Cancer Research UK MedChem Programme, and the CamBridgeSENS multidisciplinary network on sensor technology. Other academic groups as well as industrial scientists interested in host-guest chemistry, physical organic chemistry, sensors, and supramolecular systems will also be able to benefit from this work and build upon it in new directions. Other users and beneficiaries of this research will be from outside of the academic/industrial research community, for example the media, publication, and the general public.

How will they benefit from this research?
Research: Due to the multidisciplinary nature of the project, consultations with other experts within the department, the UK and worldwide are expected. The communication would encourage further understanding and investigation of chemistry and technology, which would generate scientific benefit to the University and other researchers worldwide. Our association with the Cambridge EPSRC-funded Nano-DTC can serve as a vector to allow the rules governing host-guest binding of the cages that we will prepare to be expanded to other host-guest systems very rapidly.
Industry: A solid understanding of the rules governing host-guest chemistry is key in the development of host-guest systems in applications such as enzymatic catalysis. Clearly, any input into the field of catalysis research - the basis for one of the largest manufacturing industries in the UK - would be beneficial, for example for the fine chemicals industries.
General public: In addition to the increase in wealth associated with technological progress, the public stands to benefit from synergies between the research proposed herein and an ongoing project in the group that is carried out under the auspices of the Home Office - Counter Terrorism and Intelligence Directorate, in which other cage compounds are projected to trap and render harmless chemical warfare agents. Helping keep the UK safe from rogue CWA release is clearly of vital importance.

What will be done to ensure that they benefit from this research?
Industry: We have entered into discussion with Cambridge Enterprise, the University's technology transfer office, regarding possible IP issuing from the cages that have already been prepared. We will continue these discussions, especially in the context of our UK Home Office contract involving the trapping of harmful chemical warfare agents.
General public: The group participates in the annual Cambridge Science Festival to present posters, deliver public lectures, and organise hands-on scientific activities and demonstrations. Based on our group's recent discovery, we plan to demonstrate how white phosphorous can be rendered air-stable by encapsulation during the week-long Cambridge Science Festival in March. We will use cartoon schemes to help introduce the general public to the basic concepts of supramolecular chemistry - an area of chemistry whose aesthetic appeal can readily be appreciated by the general public - thus helping to inspire young people to devote themselves to scientific research.


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Bolliger JL (2014) Solvent effects upon guest binding and dynamics of a Fe(II)4L4 cage. in Journal of the American Chemical Society

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Browne C (2015) Carbon dioxide fixation and sulfate sequestration by a supramolecular trigonal bipyramid. in Angewandte Chemie (International ed. in English)

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Browne C (2014) Palladium-templated subcomponent self-assembly of macrocycles, catenanes, and rotaxanes. in Angewandte Chemie (International ed. in English)

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Castilla AM (2013) High-fidelity stereochemical memory in a Fe(II)4L4 tetrahedral capsule. in Journal of the American Chemical Society

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Gan Q (2015) Cooperative loading and release behavior of a metal-organic receptor. in Journal of the American Chemical Society

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Jayamurugan G (2015) Selective endo and exo binding of mono- and ditopic ligands to a rhomboidal diporphyrin prism. in Angewandte Chemie (International ed. in English)

Description How to make hollow encapsulant molecules with the ability to bind a wide variety of smaller 'guest' molecules, selectively.
Exploitation Route Our new encapsulants show promise in transforming their guests, protecting them (under different circumstances), or transporting them.
Sectors Aerospace, Defence and Marine,Chemicals,Creative Economy,Manufacturing, including Industrial Biotechology

Description My group's research has explored the preparation of complex, functional structures using chemical self-assembly. A signature feature of our approach is the simultaneous use of different kinds of chemical-bond-forming reactions that operate under thermodynamic control to bring about a substantial increase in structural complexity during a single overall process. I have coined the term 'subcomponent self-assembly' to describe this technique; other research groups worldwide have fruitfully adopted this method and terminology, citing my group's work at the source. Building upon the self-assembly rules that we deciphered, we were able to design a capsule that is capable of binding white phosphorus (P4) within its central hollow (Science 2009, 324, 1697). White phosphorus, which has been known for centuries to catch fire upon contact with atmospheric oxygen, was thus rendered indefinitely air-stable through encapsulation. Our dramatic pacification of this ancient demon attracted substantial media interest, and is discussed in an undergraduate chemistry textbook (Chemistry: The Molecular Science, 4th ed, C. L. Stanitski, P.C. Jurs, M. Sanger, Brooks/Cole, Stamford CT USA, 2011; p. 1024). When collections of subcomponent building blocks come together to form multiple products, reaction patterns can become quite complex. Such mixtures are best considered as molecular networks or systems, in which the introduction of a new subcomponent may have consequences involving many molecules. Understanding signal transduction within such abiological systems may help to illuminate the behaviour of more complex biochemical networks. The originality and impact of our contributions in this area have been recognised by an invitation to write a Q&A piece (Nature 2009, 460, 15) on systems chemistry, an emerging field which I am helping to define. A new line of research for my group has involved the preparation of metal-containing conjugated polymers through the use of our techniques (J. Am. Chem. Soc. 2011, 133, 3158). These polymers have been built into electroluminescent devices with the group of Richard Friend in Physics (J. Am. Chem. Soc. 2012, 135, 19170), and sensors able to determine the handedness of molecules in solution in collaboration with Milko van der Boom's group at the Weizmann Institute (J. Am. Chem. Soc. 2013, 135, in press: This work is demonstrating the utility of our techniques to solve real-world problems, with the creation of economic value as our next goal. A key future direction to my group's effort will be the design and exploration of chemical systems that are capable of evolution towards the achievement of a targeted function, such as electrical conductivity for a polymer or the fit of a capsule to a guest molecule.
First Year Of Impact 2003
Sector Aerospace, Defence and Marine,Chemicals,Creative Economy,Education,Culture, Heritage, Museums and Collections
Impact Types Cultural,Societal,Economic,Policy & public services

Description EPSRC Dynamically Adaptive Metal-organic Nanopores
Amount £301,303 (GBP)
Funding ID 75639 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2015 
End 03/2018
Description EPSRC Iminoboronate Polymers as Dynamically Adaptable, Photoactive Materials
Amount £762,618 (GBP)
Funding ID 76030 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2015 
End 12/2017
Description Pint of Science, Cambridge Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact To provide a platform which allows people to discuss research with the people who carry it out.

Inspired the public.
Year(s) Of Engagement Activity 2014