ACS PRF | ACS | All e-Annual Reports

Reports: G4

Back to Table of Contents

44127-G4
Cooperative Binding of Molecular Oxygen via Mechanochemical Coupling

Martin D. Burke, University of Illinois at Urbana-Champaign

Cooperative Binding of Molecular Oxygen by a Hemoglobin Mimic aims to combine rational design with combinatorial chemistry to d

This project aims to advance our fundamental understanding of mechanochemical coupling, i.e., the coupling of an exergonic chemical reaction with endergonic changes in molecular conformation.  Albeit only minimally studied in small molecule systems to date, this phenomenon is widely utilized by natural macromolecules to perform a variety of important functions. A prototypical example is the respiratory protein hemoglobin, which utilizes mechanochemical coupling to achieve cooperative binding and release of molecular oxygen ligands. The project combines rational design with combinatorial chemistry to develop small molecules with the capacity to replicate these properties.  A new graduate student joined my group this past year and began to lead this project in November, 2007.

The mimimum structural and energetic requirements to display cooperativity in this system are unknown. A model system was envisioned for an initial approach, maintaining the essential rotation scaffold of this proposed structure, but simplifying the binding domains. In this way, the structural details of this rotation are more easily assessed, and this information will be applied to the final design of the hemoglobin mimic. The model system is predicted to display cooperative metal-binding – the porphyrin sites and histidyl ligands are replaced with metal-binding domains, rotating around the same bis-alkynylphenyl-anthryl core (see TOC graphic). The pyridyl ligands bind two equivalents of a Zn(II) salt, with the endothermic rotation to appoximate the pyridyls for the second binding event paid for by the first binding event. This model system will explore the competency of this scaffold for providing the energetic requirements that permit observation of mechanochemical coupling. Our efforts have thus far focused around the synthesis of this model system.

            With examples of the key upper and lower fragments in hand, the fastening of the two coupling partners of the molecule was planned as a very demanding aryl chloride Suzuki coupling. Multiple conditions were screened for the deprotection and subsequent coupling of the MIDA boronate with 9-chloroanthracene as model coupling experiments. Through variation of Pd sources, bases, and reaction conditions, the coupling has been achieved, albeit at very low yield. The coupling is among the most demanding seen in a literature survey, with the added disadvantage of carrying free pyridyl units, potentially complicating the coupling further. While attempts to optimize the coupling are in progress, these results challenge the first generation plan, which hinges around this late-stage aryl chloride Suzuki coupling. Other approaches will also be explored that place the central aryl chloride Suzuki coupling earlier in the route, followed by derivitization around the central bond, but these approaches have not yet provided an efficient solution to the problem.

By modification of the transmetallating partner, the documented anthracene structure can be maintained in the synthetic plan – while departure from the proposed 2,7-dibromo-9-chloro-anthracene and reassessment of the substitutions around this coupling partner also provides avenues by which the target core structure can be assembled. Exploring many synthetic possibilities focused on this core rotational structure may also provide a collection of different compounds with distinct, unpredicted functionality. As the basic structural requirements for displaying mechanochemical coupling are as yet unknown, attempting to circumnavigate the synthetic challenges of this structure may provide even more competent scaffolds. With a structure, or a collection of structures, in hand, we will begin to delve into the fascinating concept driving the project – a small molecule that mimics hemoglobin in function, allowing transfer of the most essential responsibility of human blood from a natural protein to an unnatural synthetic compound.

The funds provided by the PRF G grant have been instrumental in making this project possible, and enabled me to accept this new student into my group with the confidence that partial funding of his graduate education is secured.  This experience will provide this student with the opportunity to gain a world-class education in the synthesis of organic molecules and the systematic testing of their functions. If it were not for the PRF G grant being funded, this high risk (but potentially very high reward) project may have been relegated to later in my career, after my laboratory was more established.  Thanks to this funding, we are poised to commit serious resources and energy in this exciting direction in the coming year.

 

Back to top