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How much do van der Waals dispersion forces contribute to molecular recognition in solution?

Nature Chemistry volume 5, pages 1006–1010 (2013)Cite this article

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Abstract

The emergent properties that arise from self-assembly and molecular recognition phenomena are a direct consequence of non-covalent interactions. Gas-phase measurements and computational methods point to the dominance of dispersion forces in molecular association, but solvent effects complicate the unambiguous quantification of these forces in solution. Here, we have used synthetic molecular balances to measure interactions between apolar alkyl chains in 31 organic, fluorous and aqueous solvent environments. The experimental interaction energies are an order of magnitude smaller than estimates of dispersion forces between alkyl chains that have been derived from vaporization enthalpies and dispersion-corrected calculations. Instead, it was found that cohesive solvent–solvent interactions are the major driving force behind apolar association in solution. The results suggest that theoretical models that implicate important roles for dispersion forces in molecular recognition events should be interpreted with caution in solvent-accessible systems.

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Figure 1: Folding equilibrium for a molecular balance in solution.
Figure 2: The crystal structure of compound 1 showing alkyl–alkyl contacts.
Figure 3: Thermodynamic double-mutant cycle used to isolate experimental alkyl–alkyl interaction energies (ΔGDMC).
Figure 4: Experimental folding free energies (ΔG) for compounds 1 to 4 (coloured bars) and alkyl–alkyl interaction energies (ΔGDMC) dissected using the equation shown in Fig. 3 (hollow black bars).
Figure 5: Experimental alkyl–alkyl interaction free energies (ΔGDMC) measured in a range of solvents with different cohesive energy densities.

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References

  1. London, F. Uber einige Eigenschaften und Anwendungen der Molekularkräfte. Z. Phys. Chem. B11, 222–251 (1930).

    Google Scholar 

  2. Joh, N. H., Oberai, A., Yang, D., Whitelegge, J. P. & Bowie, J. U. Similar energetic contributions of packing in the core of membrane and water-soluble proteins. J. Am. Chem. Soc. 131, 10846–10847 (2009).

    Article  CAS  Google Scholar 

  3. Lalatonne, Y., Richardi, J. & Pileni, M. P. Van der Waals versus dipolar forces controlling mesoscopic organizations of magnetic nanocrystals. Nature Mater. 3, 121–125 (2004).

    Article  CAS  Google Scholar 

  4. Atwood, J. L., Barbour, L. J. & Jerga, A. Storage of methane and freon by interstitial van der Waals confinement. Science 296, 2367–2369 (2002).

    Article  CAS  Google Scholar 

  5. Schreiner, P. R. et al. Overcoming lability of extremely long alkane carbon–carbon bonds through dispersion forces. Nature 477, 308–311 (2011).

    Article  CAS  Google Scholar 

  6. Ruoff, R. S., Tersoff, J., Lorents, D. C., Subramoney, S. & Chan, B. Radial deformation of carbon nanotubes by van der Waals forces. Nature 364, 514–516 (1993).

    Article  CAS  Google Scholar 

  7. Koenig, S. P., Boddeti, N. G., Dunn, M. L. & Bunch, J. S. Ultrastrong adhesion of graphene membranes. Nature Nanotechn. 6, 543–546 (2011).

    Article  CAS  Google Scholar 

  8. Rafiee, J. et al. Wetting transparency of graphene. Nature Mater. 11, 217–222 (2012).

    Article  CAS  Google Scholar 

  9. Rodriguez, A. W., Capasso, F. & Johnson, S. G. The Casimir effect in microstructured geometries. Nature Photon. 5, 211–221 (2011).

    Article  CAS  Google Scholar 

  10. Hertlein, C., Helden, L., Gambassi, A., Dietrich, S. & Bechinger, C. Direct measurement of critical Casimir forces. Nature 451, 172–175 (2008).

    Article  CAS  Google Scholar 

  11. Koski, W. S., Kaufman, J. J. & Wilson, K. M. Physicochemical aspects of the action of general anaesthetics. Nature 242, 65–66 (1973).

    Article  CAS  Google Scholar 

  12. Autumn, K. et al. Evidence for van der Waals adhesion in gecko setae. Proc. Natl Acad. Sci. USA 99, 12252–12256 (2002).

    Article  CAS  Google Scholar 

  13. Hunter, C. A. Quantifying intermolecular interactions: guidelines for the molecular recognition toolbox. Angew. Chem. Int. Ed. 43, 5310–5324 (2004).

    Article  CAS  Google Scholar 

  14. Chandler, D., Weeks, J. D. & Andersen, H. C. Van der Waals picture of liquids, solids, and phase transformations. Science 220, 787–794 (1983).

    Article  CAS  Google Scholar 

  15. Chandler, D. Interfaces and the driving force of hydrophobic assembly. Nature 437, 640–647 (2005).

    Article  CAS  Google Scholar 

  16. Schneider, H.-J. Binding mechanisms in supramolecular complexes. Angew. Chem. Int. Ed. 48, 3924–3977 (2009).

    Article  CAS  Google Scholar 

  17. Cabot, R. & Hunter, C. A. Molecular probes of solvation phenomena. Chem. Soc. Rev. 41, 3485–3492 (2012).

    Article  CAS  Google Scholar 

  18. Hunter, C. A. van der Waals interactions in non-polar liquids. Chem. Sci. 4, 834–848 (2013).

    Article  CAS  Google Scholar 

  19. Liu, T. & Schneider, H-J. Additivity and quantification of dispersive interactions—from cyclopropyl to nitro groups: measurements on porphyrin derivatives. Angew. Chem. Int. Ed. 41, 1368–1370 (2002).

    Article  CAS  Google Scholar 

  20. Ngola, S. M. & Dougherty, D. A. Evidence for the importance of polarizability in biomimetic catalysis involving cyclophane receptors. J. Org. Chem. 61, 4355–4360 (1996).

    Article  CAS  Google Scholar 

  21. Eftink, M. R., Andy, M. L., Bystrom, K., Perlmutter, H. D. & Kristol, D. S. Cyclodextrin inclusion complexes: studies of the variation in the size of alicyclic guests. J. Am. Chem. Soc. 111, 6765–6772 (1989).

    Article  CAS  Google Scholar 

  22. Barratt, E. et al. Van der Waals interactions dominate ligand–protein association in a protein binding site occluded from solvent water. J. Am. Chem. Soc. 127, 11827–11834 (2005).

    Article  CAS  Google Scholar 

  23. Malham, R. et al. Strong solute–solute dispersive interactions in a protein–ligand complex. J. Am. Chem. Soc. 127, 17061–17067 (2005).

    Article  CAS  Google Scholar 

  24. Dessent, C. E. H. & Müller-Dethlefs, K. Hydrogen-bonding and van der Waals complexes studied by ZEKE and REMPI spectroscopy. Chem. Rev. 100, 3999–4022 (2000).

    Article  CAS  Google Scholar 

  25. Stone, A. J. Intermolecular potentials. Science 321, 787–789 (2008).

    Article  CAS  Google Scholar 

  26. Johnson, E. R., Mackie, I. D. & DiLabio, G. A. Dispersion interactions in density-functional theory. J. Phys. Org. Chem. 22, 1127–1135 (2009).

    Article  CAS  Google Scholar 

  27. Chai, J.-D. & Head-Gordon, M. Long-range corrected hybrid density functionals with damped atom–atom dispersion corrections. Phys. Chem. Chem. Phys. 10, 6615–6620 (2008).

    Article  CAS  Google Scholar 

  28. Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215–241 (2008).

    Article  CAS  Google Scholar 

  29. Mati, I. K. & Cockroft, S. L. Molecular balances for quantifying non-covalent interactions. Chem. Soc. Rev. 39, 4195–4205 (2010).

    Article  CAS  Google Scholar 

  30. Muchowska, K. B., Adam, C., Mati, I. K. & Cockroft, S. L. Electrostatic modulation of aromatic rings via explicit solvation of substituents. J. Am. Chem. Soc. 135, 9976–9979 (2013).

    Article  CAS  Google Scholar 

  31. Paliwal, S., Geib, S. & Wilcox, C. S. Molecular torsion balance for weak molecular recognition forces. Effects of ‘tilted-T’ edge-to-face aromatic interactions on conformational selection and solid-state structure. J. Am. Chem. Soc. 116, 4497–4498 (1994).

    Article  CAS  Google Scholar 

  32. Hof, F., Scofield, D. M., Schweizer, W. B. & Diederich, F. A weak attractive interaction between organic fluorine and an amide group. Angew. Chem. Int. Ed. 43, 5056–5059 (2004).

    Article  CAS  Google Scholar 

  33. Fischer, F. R., Schweizer, W. B. & Diederich, F. Molecular torsion balances: evidence for favorable orthogonal dipolar interactions between organic fluorine and amide groups. Angew. Chem. Int. Ed. 46, 8270–8273 (2007).

    Article  CAS  Google Scholar 

  34. Fischer, F. R., Wood, P. A., Allen, F. H. & Diederich, F. Orthogonal dipolar interactions between amide carbonyl groups. Proc. Natl Acad. Sci. USA 105, 17290–17294 (2008).

    Article  CAS  Google Scholar 

  35. Martin, S. M., Yonezawa, J., Horner, M. J., Macosko, C. W. & Ward, M. D. Structure and rheology of hydrogen bond reinforced liquid crystals. Chem. Mater. 16, 3045–3055 (2004).

    Article  CAS  Google Scholar 

  36. Cockroft, S. L. & Hunter, C. A. Desolvation tips the balance: solvent effects on aromatic interactions. Chem. Commun. 3806–3808 (2006).

  37. Cockroft, S. L. & Hunter, C. A. Desolvation and substituent effects in edge-to-face aromatic interactions. Chem. Commun. 3961–3963 (2009).

  38. Cockroft, S. L. & Hunter, C. A. Chemical double-mutant cycles: dissecting non-covalent interactions. Chem. Soc. Rev. 36, 172–188 (2007).

    Article  CAS  Google Scholar 

  39. Bhayana, B. & Wilcox, C. S. A minimal protein folding model to measure hydrophobic and CH–π effects on interactions between nonpolar surfaces in water. Angew. Chem. Int. Ed. 46, 6833–6836 (2007).

    Article  CAS  Google Scholar 

  40. Meyer, E. A., Castellano, R. K. & Diederich, F. Interactions with aromatic rings in chemical and biological recognition. Angew. Chem. Int. Ed. 42, 1210–1250 (2003).

    Article  CAS  Google Scholar 

  41. Granick, S. & Bae, S. C. A Curious antipathy for water. Science 322, 1477–1478 (2008).

    Article  CAS  Google Scholar 

  42. Tsuzuki, S. et al., Honda, K., Uchimaru, T. & Mikami, M. Estimated MP2 and CCSD(T) interaction energies of n-alkane dimers at the basis set limit: comparison of the methods of Helgaker and Feller. J. Chem. Phys. 124, 114304 (2006).

    Article  Google Scholar 

  43. Ferrighi, L., Madsen, G. K. H. & Hammer, B. Alkane dimers interaction: a semi-local MGGA functional study. Chem. Phys. Lett. 492, 183–186 (2010).

    Article  CAS  Google Scholar 

  44. Dack, M. R. J. The importance of solvent internal pressure and cohesion to solution phenomena. Chem. Soc. Rev. 4, 211–229 (1975).

    Article  CAS  Google Scholar 

  45. Otto, S. The role of solvent cohesion in nonpolar solvation. Chem. Sci. 4, 2953–2959 (2013).

    Article  CAS  Google Scholar 

  46. Marcus, Y. Internal pressure of liquids and solutions. Chem. Rev. 113, 6536–6551 (2013).

    Article  CAS  Google Scholar 

  47. Bosque, R. & Sales, J. Polarizabilities of solvents from the chemical composition. J. Chem. Inf. Comp. Sci. 42, 1154–1163 (2002).

    Article  CAS  Google Scholar 

  48. Smithrud, D. B. & Diederich, F. Strength of molecular complexation of apolar solutes in water and in organic solvents is predictable by linear free energy relationships: a general model for solvation effects on apolar binding. J. Am. Chem. Soc. 112, 339–343 (1990).

    Article  CAS  Google Scholar 

  49. Mecozzi, S. & Rebek, J. Jr. The 55% solution: a formula for molecular recognition in the liquid state. Chem. Eur. J. 4, 1016–1022 (1998).

    Article  CAS  Google Scholar 

  50. Ehrlich, S., Moellmann, J. & Grimme, S. Dispersion-corrected density functional theory for aromatic interactions in complex systems. Acc. Chem. Res. 46, 916–926 (2013).

    Article  CAS  Google Scholar 

  51. Mal, P., Breiner, B., Rissanen, K. & Nitschke, J. R. White phosphorus is air-stable within a self-assembled tetrahedral capsule. Science 324, 1697–1699 (2009).

    Article  CAS  Google Scholar 

  52. Chapman, K. T. & Still, W. C. A remarkable effect of solvent size on the stability of a molecular complex. J. Am. Chem. Soc. 111, 3075–3077 (1989).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank the Engineering and Physical Sciences Research Council (EP/H02056X/1) for financial support, MTEM and the School of Chemistry for a studentship to L.Y., and Pfizer for a studentship to C.A. The authors thank C.A. Hunter at the University of Sheffield for providing αs and βs hydrogen-bond parameters, and H.P.H. Saifuddin and G.H. Gowrie for the syntheses of some precursor compounds.

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  1. Lixu Yang and Catherine Adam: These authors contributed equally to this work

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  1. EaStCHEM School of Chemistry, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK

    Lixu Yang, Catherine Adam, Gary S. Nichol & Scott L. Cockroft

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Contributions

L.Y. and C.A. performed all synthetic and experimental work. L.Y., C.A. and S.L.C. analysed the data. G.S.N. carried out X-ray crystallography. S.L.C. conceived the experiments and wrote the paper, with input from L.Y., C.A. and G.S.N.

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Correspondence to Scott L. Cockroft.

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Crystallographic data for compound +−1. (CIF 37 kb)

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Yang, L., Adam, C., Nichol, G. et al. How much do van der Waals dispersion forces contribute to molecular recognition in solution?. Nature Chem 5, 1006–1010 (2013). https://doi.org/10.1038/nchem.1779

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