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44127-G4
Cooperative Binding of Molecular Oxygen via Mechanochemical Coupling
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.
During the past year, there was one rotation student working on this project during the summer months. A new graduate student will begin to lead this project this year.
The initial work has focused on the synthesis of porphyrin systems with the capacity for electronic tuning to modulate the energetics of iron binding. Specifically, substituents at the para-position on tetraphenyl porphyrin derivatives have been shown to influence, via electronic effects, the redox potential of iron complexes,[1] the strength of Fe-axial ligand bonds,[2] and the mobility of the iron atom relative to the porphyrin plane.[3]
We therefore initially focused on the synthesis of a series of porphyrin systems with the potential for this type of electronic tuning. A series of porphyrin macrocycles having a range of electron-donating and withdrawing substituents at the para positions of appended aryl rings were prepared. Specifically, using modifications of reported methodology,[4] a series of porphyrins were prepared from methylenediimidazole and the appropriate benzaldehyde. One of these biarylporpyrin macrocycles was brominated en route to targeted triaryliodoporphyrin intermediates[5]
Although these syntheses were successful, the purification of the porphyrin macrocycles using standard silica gel chromatography proved to be very challenging. Despite extensive efforts, we were unable to achieve the very high level of purities that we anticipate will be critical for the structure/function studies we have envisioned. We therefore utilized ACS PRF G funds to purchase a preparative, reverse-phase column for our HPLC instrument, which has greatly advanced our purification capabilities.
The new student is very well-positioned to push this project forward beginning in November of this year. 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 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.
In summary, it is anticipated that the synthesis and study of a well-defined small molecule system capable of utilizing mechanochemical coupling to achieve protein-like functional properties will advance our fundamental understanding of this potentially generally useful phenomenon. In addition, by illuminating the minimum structural and energetic requirements for the physiologically important process of cooperative oxygen binding, it is anticipated that these studies could facilitate the search for unnatural small molecules with the capacity to replicate the respiratory function of hemoglobin.
[2] (a) F.A. Walker, M.-W. Lo, M.T. Ree, "Electronic Effects in Transition Metal Porphyrins. The Reactions of Imidazoles and Pyridines with a Series of Para-Substituted Tetraphenylporphyrin Complexes of Chloroiron(III)." J. Am. Chem. Soc. 1976, 98, 5552-5560. (b) J. D. Satterlee, G.N. La Mar, J.S. Frye, "Dynamics and Thermodynamics of Axial Ligation in Metalloporphyrins. 5. Affinity of Ferric Porphyrins for Nitrogenous Bases and the Stoichiometry and Spin States of the Product Complexes." J. Am. Chem. Soc. 1976, 98, 7275-7282.
[3] R.V. Snyder, G.N. La Mar, "Dynamics and Thermodynamics of Axial Ligation in Metallophorphyrins. 4. Kinetics of Porphyrin Inversion in High-Spin Ferric Complexes." J. Am. Chem. Soc. 1976, 98, 4419-4424.
[4] F. Odobel and coworkers, "Synthesis of Oligothiophene-Bridged Bisporphyrins and Study of the Linkage Dependence of the Electronic Coupling." Chem. Eur. J. 2002, 8, 3027-3046.
[5] Odobelt and coworkers, Chem. Eur. J. 2002, 8, 3027-3046.
