Intramolecular H-bonding Effects on Ion Binding by Aromatic Amides: An Ab Initio Study

1. Intramolecular H-bonding Effects on Ion Binding by Aromatic Amides: An Ab Initio Study Rubén D. Parra, Ph.D DePaul University Chicago, IL

2. I. Introduction • II. F- - amide Interactions • III. Li+ - amide Interactions • IV. Cooperativity in Ion-Pair Binding • V. Summary and Outlook • VI. References • VII, Questions • VIII. Acknowledgments

3. Introduction • The functional group of an amide is an acyl group (RCO-) bonded to a nitrogen atom. • In particular, the amide RCO-NHR’ exhibits amphiphilic properties. • The C=O group is suitable to interact with other groups, atoms, or ions deficient in electrons. • The N-H group is suitable for interacting with electron-rich units.

4. Introduction • Ion binding is the process by which a molecule, called the host, provides one or more sites to bind an ion, called the guest, by means of non-covalent interactions. • Multiple binding sites are usually needed because non-covalent interactions are generally weak.

5. Introduction Chelate effect Ni2+ + 6 NH3 [Ni(NH3)6]2+ DG = -51.7 kj/mol Ni2+ + 3 NH2CH2CH2NH2 [Ni(NH2CH2CH2NH2)3] 2+ DG = -101.1 kj/mol

6. Introduction Macrocyclic Effect Zn2+ + A  [ZnA]2+ DG = -64.2 kJ/mol Zn2+ + B  [ZnB]2+ DG = -87.5 kJ/mol A B

7. Introduction • Amide-containing ligands have proven valuable in cation and anion binding. The amide group exhibits amphiphilic properties with the carbonyl group serving as a suitable binding site for metal ions, and the N-H group serving as a binding site for anions. • Natural and syntethic amides are used for the transport of ions across bilayer membranes. • The great solubility in organic solvents usually accompanied by a diminished solubility in aqueous solution makes amides appealing for applications in the field of ion-selective electrodes and liquid-liquid separations • Additionally, the hydrogen bonding capabilities of amides are known to be crucial in many relevant systems including enzymes and proteins.

8. Introduction Positive Cooperativity Host compounds containing at least two spatially separated binding sites can show cooperativity due to conformational coupling between sites. Comparatively few cases of amphi-receptors have been reported which show binding properties to both cations and anions.

9. Introduction • The conventional H bond is usually defined as X-H … Y X and Y are typically O, N, F, Cl • H-bonds are ubiquitous in nature. They are responsible for the unusual properties of water, are mediators of chemical reactions, provide for drug-molecule interactions in the body, and are important in the structure of DNA.

10. F- - Amide Interactions • R1 = H or NHC=O • R2 = H or NHC=O

11. F--Binding Amides • DA tA TA

12. Li+-Binding Amides • DA tA TA

13. DA

14. DA

15. DA_F

16. DA_F

17. tA_F

18. TA_F

19. DA

20. DA

21. DA_Li

22. tA_Li

23. TA

24. TA_Li

25. TA_Li

26. TA_LiF

27. Binding Energies (kcal/mol) Li+ Binding Di-amide -109 Tri-amide -107 Tetra-amide -107 F- Binding Di-amide -114 Tri-amide -120 Tetra-amide -127 LiF Binding Tetra-amide -294

28. H22…O11 Li+ Binding Tri-amide 1.779 Ǻ (1.789 Ǻ) Tetra-amide 1.751Ǻ (1.773 Ǻ) F- Binding Tri-amide 1.721 Ǻ (1.773 Ǻ) Tetra-amide 1.717Ǻ (1.773 Ǻ) LiF Binding Tetra-amide 1.696 Ǻ (1.773 Ǻ)

29. NBO analysis lpO11 s*H22N Li+ Binding Tri-amide 30 (30 kcal/mol) Tetra-amide 34 (29 kcal/mol) F- Binding Tri-amide 42 (27 kcal/mol) Tetra-amide 42 (29 kcal/mol) LiF Binding Tetra-amide 48 (29 kcal/mol)

30. NBO Charges Li+ Binding Tri-amide qO11 = -0.69 (-0.70) qH22 = +0.50 (+0.47) Tetra-amide qO11 = -0.69 (-0.69) qH22 = +0.50 (+0.47) F- Binding Tri-amide qO11 = -0.76 (-0.69) qH22 = +0.48 (+0.47) Tetra-amide qO11 = -0.76 (-0.69) qH22 = +0.47 (+0.47) LiF Binding qO11 = -0.75 (-0.69) qH22 = +0.50 (+0.47)

31. Dipole Moments (Debye) Li+ Binding • Di-amide 0.9 • Tri-amide 6.2 • Tetra-amide 3.6 F- Binding • Di-amide 2.9 • Tri-amide 4.3 • Tetra-amide 1.1 LiF Binding • Tetra-amide 11.3

32. N-H Stretching Frequencies Li+ Binding Di-amide nN-H22 = 3769 (3800 cm-1) Tri-amide nN-H22 = 3517 (3608 cm-1) Tetra-amide nN-H22 = 3487 (3608 cm-1) F- Binding Tri-amide nN-H22 = 3457 (3617 cm-1) Tetra-amide nN-H22 = 3295 (3608 cm-1) LiF Binding nN-H22 = 3287 (3608 cm-1)

33. F- Binding H…F Di-amide 1.649 Ǻ Tri-amide 1.561 Ǻ; 1.679 Ǻ Tetra-amide 1.585 Ǻ Li+ Binding O…Li Di-amide 1.771 Ǻ Tri-amide 1.762 Ǻ; 1.780 Ǻ Tetra-amide 1.775 Ǻ LiF Binding H…F 1.588 Ǻ O…Li 1.770 Ǻ

34. F- Binding NCCC (degs.) Di-amide 7 Tri-amide 5 Tetra-amide 4 Li+ Binding CNCC (degs.) Di-amide 47 Tri-amide 31, 34 Tetra-amide 22 LiF Binding NCCC 9 CNCC 24

35. NBO analysis: E2 (kcal/mol) Lp F-  s* N-H, s* C-H Di-amide 197 Tri-amide 187 Tetra-amide 193 Li+ Binding Lp O Li+ Di-amide 45 Tri-amide 43 Tetra-amide 41 LiF Binding Lp F-  s* N-H, s* C-H 204 Lp O Li+ 48

36. Symmetric Stretching frequencies F- Binding nN-H + nC-H Di-amide 3304 cm-1 Tri-amide 3327 cm-1 Tetra-amide 3205 cm-1 Li+ Binding nC=O Di-amide 1813 cm-1 Tri-amide 1814 cm-1 Tetra-amide 1801 cm-1 LiF Binding nN-H + nC-H 3216 cm-1 nC=O 1784 cm-1

37. Summary • Anion (F-) and cation (Li+) binding through aromatic amides has been presented. • Ion binding results in substantial changes in the equilibrium conformation of the amide model systems. • Binding affinity of the anion is greater than that of the cation. • Intramolecular H-bonding enhances F- binding, but has negligible effect on the binding energy of Li+.

38. Summary • The presence of either ion induces significant polarization on the ligand. There is charge transfer from the anion to the ligand, and from the ligand to the metal ion. • Charge separation is notorious in the ion-pair binding which presents the largest dipole moment. • Evidence of positive cooperativity is presented, where binding of an ion at one site enhances significantly the affinity of the ligand for the other ion at the corresponding binding site. • Binding of one ion induces conformational changes along with polarization of the ligand, which is transmitted to the second binding site.

39. References • R. D. Parra, B. Yoo, M. Wemhoff,   J. Phys. Chem. A. 110, 4487 (2006). • Bianchi, A.; Bowman-James, K.; Garcia-Espana, E., Eds. Supramolecular Chemistry of Anions; Wiley-VCH: New York, 1997. • Saenger, Jeffrey G. A. Hydrogen Bonding in Biological Structures; Springer-Verlag: Berlin, 1991. • Kavallieratos, K.; Bertao, C. M.; Crabtree, R. H. J. Org. Chem., 1999, 64, 1675. • Constable, E. C. Metals and Ligand Reactivity (VCH Publishers, New York, 1996). • Desiraju, G. R.; Steiner, T., The Weak Hydrogen Bond In Structural Chemistry and Biology; Oxford University Press, 1999. • Wheeler, O. H.; Rosado, O. in The Chemistry of Amides, Interscience Publishers, 1970, p. 352. • Schneider, H-J; Yatsimirsky, A. Principles and Methods in Supramolecular Chemistry; Wiley, Chichester, 2000. • Steed, J. W.; Atwood, H. L.; Supramolecular Chemistry; Wiley, Chichester, 2000.

40. Acknowledgments • Megan Ghorbanpour • Michael P. Wemhoff • Paul D. Kofoed • Lucia Petkovic and Idaho National Laboratory for the invitation