Quantum Mechanical Calculations on Novel Actinide Chelating Agents Aisha Mehmood, Maria Benavides, PhD Department of Natural Sciences Abstract: Plutonium is produced in significant amounts as the isotope 239 Pu during nuclear reactor operations. The use of actinides such as Pu in energy and weapons production has resulted in major environmental and health concerns. In the event of actinide release it is critical to have the means to treat large number of people in a very short time. Chelation therapy is the approach currently used to treat actinide poisoning because it reduces the deposition of actinides in the internal organs. In order to effectively respond and treat actinide poisoning on a massive scale it is crucial to have access to effective, nontoxic chelating agents that can be orally administered, that are easily produced and safely stored at any location. Specific sequestering agents have been designed and synthesized to bind actinides. Our study focuses on determining the structures and molecular properties of four hydroxypyridinone (HOPO)-based sequestering agents 2,2-Dime-3LI(1,2-HOPO), 3LI-(1,2-HOPO), 4LI(1,2-HOPO) and 5LI(1,2-HOPO) which have been shown to strongly and specifically bind plutonium at physiological pH. Our calculations were carried out using density functional theory (DFT) with the B3LYP functional applied in conjunction with three increasingly larger basis sets (3-21G, 6-31G, and 6-311G) to obtain the equilibrium geometries, vibrational frequencies, and IR spectra for all four ligands. The highest occupied molecular orbital (HOMO) – lowest occupied molecular orbital (LUMO) energy gap values for all four compounds are greater than 4 eV suggesting that the ligands are chemically stable. Two hydrogen bonds are observed in each compound which we suspect contribute to their chemical stability. The four compounds exhibit dipole moments ranging between 3 to 4 Debye which indicates they possess polar character. Our computed vibrational frequencies were found in excellent agreement with the experimental frequencies, suggesting our proposed models are good representations of the actual molecular structures. Introduction: Over the past years concern for harm caused by radiation in human body has increased. Recent disaster such as Fukushima Daiichi nuclear reactor accident in Japan has raised red flags for radiation safety. Such events are not common; however once the damage has happened, it is large and capable of destroying many lives. Nuclear fissions release significant amount of several different actinides that can enter human body through radiation or radioactive substances. All actinides are radioactive and bind with human internal tissue. Chelation therapy has shown positive results for reducing internal human actinide contamination. Plutonium (Pu) is an alpha emitter that is known to have the greatest retention in the human body among actinides. Our studies focuses on four actinide sequestering agent, namely, 2,2- Dime-3 linkage(1-hydroxy-2-pyridinone), 3 linkage(1-hydroxy-2-pyridinone), 4 linkage(1-hydroxy-2-pyridinone) and 5 linkage(1-hydroxy-2-pyridinone) shown to bind Pu [1].The main objective of our studies is to predict their structures as well as other molecular properties so that we gain an understanding of their chemical nature. Method: The chelating agent ligands were modeled using GaussView[4]. The calculations consisted first of a geometry optimization routine that yielded a molecular structure. This calculation was then followed by a frequency calculation that yielded harmonic frequencies that produced the corresponding IR spectrum. The frequency calculation serves as well to confirm that the optimized structure corresponds to the equilibrium geometry, which in turn corresponds to the most stable structure. If no imaginary frequencies are generated during the frequency calculation indicating that the optimized geometry is truly the equilibrium geometry. All calculations were performed using density functional theory (DFT) in combination with the B3LYP hybrid functional. Three sets of basis sets (3-21G, 6-31G, and G ) were used for each compound in order to assess the effect of the basis set size. All calculations were performed using the Gaussian 09 codes [3]. Results and Discussion: A.Geometries: 2,2-Dime-3LI(1,2-HOPO), 3LI-(1,2-HOPO), 4LI(1,2-HOPO) Good structures and dipole moments were obtained for 2,2-Dime-3LI(1,2-HOPO), 3LI-(1,2-HOPO), 4LI(1,2-HOPO). DFT calculations predicted that 2,2-Dime-3LI(1,2- HOPO). The computed equilibrium geometries have suitable orientation for actinide sequestering (see figures 1 - 3). 5LI(1,2-HOPO) The optimized structure for 5LI(1,2-HOPO) was surprisingly rotated invertible (figure 4), which means that the most stable structure is in the trans configuration with respect to the other three compounds. This behavior was only observed in the case of the 5 linkage, this may be due its longer chain of carbon connecting the two hydroxypyridinone groups as compare to the chain lengths of the other compounds. B. Vibrational analysis: An amide and carbonyl group stretch at 1650 cm -1 was reported by David, et al, for the 1,2-HOPO molecule[6]. Under the 6-311G basis sets, all four sequestering agents 2,2- Dime-3LI(1,2-HOPO), 3LI-(1,2-HOPO), 4LI(1,2-HOPO) and 5LI(1,2-HOPO) have an amide stretch ranging in values between 1665 and 1658 cm -1. The ratio of the theoretical and experimental frequency is near unity and our calculated values agree with the experimental values within 1.0% C. HOMO-LUMO energy gaps HOMO-LUMO energy gaps are excellent indicators of chemical stability [5]. HOMO- LUMO energy gaps calculated with 6-321G, and 6-311G basis sets are greater than 3 eV for all four compounds, indicating these molecules possess high chemical stability. D. Hydrogen Bonding Multiple hydrogen bonding is observed in the cases of 2,2-Dime-3LI(1,2-HOPO), 3LI- (1,2-HOPO), and 4LI(1,2-HOPO) molecules. The hydrogen bonding appears between the hydrogen located in two hydroxyl groups on each ring and the oxygen atoms bonded to the nitrogen atoms. Due to the trans configuration of the 5LI(1,2-HOPO) compound, no hydrogen bonding is observed in this molecule. The dipole moment is also lower as there is less interaction between the tetradentate HOPOs. E. Dipole moments All four compounds exhibit large values of dipole moments, ranging from 3 to 6 eV. This suggests all four compounds are highly polar in nature. This is consistent with the presence of various electronegative atoms such as O and N atoms and the fact that these compounds are not symmetrical. Interestingly, the 5LI(1,2-HOPO) compound has the lowest dipole moment value among the four compounds which may be due to the lack of interaction between the tetradentate HOPOs. Conclusion: The calculated dipole moment, large HOMO-LUMO gaps, and hydrogen bonding all indicate that these ligands are highly chemically stable. The results indicate that these molecules possess the necessary chemical properties, molecular geometry and spatial orientation for effective actinide binding. Future Work: In order to broaden the scope this work, it would be of interest to conduct similar studies on Me-3,2-HOPO molecules. Acknowledgements: We would like to thank the Nuclear Regulatory Commission for their generous support of this research (U.S. Nuclear Regulatory Commission (SDB )). References: [1] Gorden, A. E., Xu, J., Raymond, K. N., & Durbin, P. (2003). Rational Design of Sequestering Agents for Plutonium and Other Actinides. Chemical Reviews, 103(11), [2] Durbin, P. W., Kullgren, B., Ebbe, S. N., Xu, J., & Raymond, K. N. (2000). Chelating Agents for Uranium(VI): 2, Efficacy and Toxicity of Tetradentate Catecholate and Hydroxypyridinonate Ligands in Mice. Health Physics, 78(5), [3] Frisch, M. E., et al. (2009). Gaussian 09, Revision A.01. Wallingford, CT: Gaussian, Inc. [4 ] Frisch, A. E., Dennington, R. D., Keith, T. A., Neilsen, A. B. and Holder, A. J. (2003) GaussView, revision 3.0.9, Gaussian, Inc., Pittsburgh PA [5] Aihara, J. (1999) Reduced HOMO-LUMO gaps as index of kinetic stability for polycyclic aromatic hydrocarbons. J. Phys. Chem. A. 103, [6] David L. White., et al. (1986). Specific Sequestering Agents for the Actinides. J Med. Chem. A. 31, Figure 1: 2,2-Dime-3LI(1,2-HOPO) Figure 2: 3LI-(1,2-HOPO), Figure 4: 5LI(1,2-HOPO) Figure 5: IR spectrum for 2,2-Dime-3LI(1,2-HOPO) Figure 6: IR spectrum for 5-LI(1,2-HOPO). Figure 7: IR spectrum for 4LI(1,2-HOPO). Basis SetHydoxypyridinone Chelating Agent Dipole Moment 2,2-Dime-3LI(1,2-HOPO)3LI-(1,2-HOPO)4LI(1,2-HOPO)5LI(1,2-HOPO) 6-21G G G Table 1: Calculated dipole moment of all chelating agent Table 2: HOMO-LUMO Energy Gap Figure 3: 4LI(1,2-HOPO) Basis SetHydoxypyridinone Chelating Agent HOMO-LUMO Energy Gap 2,2-Dime-3LI(1,2-HOPO)3LI-(1,2-HOPO)4LI(1,2-HOPO)5LI(1,2-HOPO) 3-21G G G Basis SetHydoxypyridinone Chelating Agent Frequency Calculations for the Amide and Ring Carbonyl Group 2,2-Dime-3LI(1,2-HOPO)3LI-(1,2-HOPO)4LI(1,2-HOPO)5LI(1,2-HOPO) Experimental Frequency 1650 Computational Frequency Ratio Near Unity Table 3: Frequency data comparison for the Amide and ring Carbonyl group using 6-311G basis set Figure 6: IR spectrum for 3-LI(1,2-HOPO).