Dispersive Interactions in Solution Complexes

Abstract

Dispersive interactions are known to play a major role in molecular associations in the gas phase and in the solid state. In solution, however, their significance has been disputed in recent years on the basis of several arguments. A major problem until now has been the separation of dispersive and hydrophobic effects, which are both maximized in water due the low polarizability of this most important medium. Analyses of complexes between porphyrins and systematically varied substrates in water have allowed us to discriminate dispersive from hydrophobic effects, as the latter turned out to be negligible for complexations with flat surfaces such as porphyrins. Also, for the first time, it has become possible to obtain binding free energy increments ΔΔG for a multitude of organic residues including halogen, amide, amino, ether, carbonyl, ester, nitro, sulfur, unsatured, and cyclopropane groups, which turned out to be additive. Binding contributions for saturated residues are unmeasurably small, with ΔΔG > 1 kJ/mol, but they increase to, e.g., ΔΔG = 5 kJ/mol for a nitro group, a value not far from, e.g., that of a stacking pyridine ring. Stacking interactions of heteroarenes with porphyrins depend essentially on the size of the arenes, in line with polarizabilities, and seem to be rather independent of the position of nitrogen within the rings. Measurements of halogen derivatives indicate that complexes with porphyrins, cyclodextrins, and pillarenes as hosts in different media consistently show increasing stability from fluorine to iodine as the substituent. This, and the observed sequence with other substrates, is in line with the expected increase in dispersive forces with increasing polarizability. Induced dipoles, which also would increase with polarizability, can be ruled out as providing the driving source in view of the data with halides: the observed stability sequence is opposite the change of electronegativity from fluorine to iodine. The same holds for the solvent effect observed in ethanol-water mixtures. Dispersive contributions vary not only with the polarizability of the used media but also with the interacting receptor sites; it has been shown that for cucurbiturils the polarizability inside the cavity is extremely low, which also explains why hydrophobic effects are maximized with these hosts. Complexations with other known host compounds, however, such as those between cryptands or cavitands with, e.g., noble gases, bear the signature of dominating dispersive forces. Some recent examples illustrate that such van der Waals forces can also play an important role in complexations with proteins. Again, a clue for this is the increase in ΔG for inhibitor binding by 7 kJ/mol for, e.g., a bromine in comparison to a fluorine derivative.

Unwinding DNA and RNA with Synthetic Complexes: On the Way to Artificial Helicases

“…A better comparison between the effects of heterosubstitution is possible if one compares the ligand effects at 50 μ M for 1 c (R=Cl: Δ T m =−23 °C) and 1 d (R=Br: Δ T m =−35 °C): the fluorine derivative, 1 b , requires a tenfold higher concentration (0.5 m M ) for Δ T m =−26 °C, whereas for R=OMe ( 1 g ) one observes Δ T m =−35 °C at 0.5 m M . The activity sequence Br>Cl≫F≫H and the OMe effect ( 1 g ) agrees well with recently derived numbers for dispersive interactions of corresponding derivatives,19 and illustrates the importance of such van der Waals forces in nucleic acid intercalation. Derivatives containing substituents such as NO 2 or iodine ( 1 e , 1 h ) should, in view of their polarisability, also be effective, but could not be used due to solubility problems.…”

Anion‐Binding Macrocycles Operate Beyond the Electrostatic Regime: Interaction Distances Matter

“…The generality of the conclusions also needs further examination, specifically when considering the role of solvent . Solvation effects, as noted in our earlier work and by Johnson and co‐workers, is rarely studied in a rigorous manner and, for that reason, the comments we offer here from gas‐phase calculations are best considered formative.…”

A Nexus between Theory and Experiment: Non‐Empirical Quantum Mechanical Computational Methodology Applied to Cucurbit[n]uril⋅Guest Binding Interactions

“…These Δ E = E complex −[ E host + E guest ] binding interactions provide insight into the role of analogous processes in biological systems. For specific information about the role of dispersion forces in such systems, we refer the reader to recent reviews on the topic . The chemistry of cucurbit[ n ]uril (CB[ n ], n =5, 6, 7, 8, 10) macrocycles has undergone wide development and growth in the last decade, and great interest has been stimulated, leading to promising applications in materials chemistry, molecular recognition, drug discovery, and chemosensing .…”

“…For specific information aboutt he role of dispersion forces in such systems, we refer the readert or ecent reviews on the topic. [1,2,3,4] Thec hemistry of cucurbit[n]uril (CB[n], n = 5, 6, 7, 8, 10) macrocycles has undergone wide development and growth in the last decade, and great interest has been stimulated, leadingt op romising applications in materialsc hemistry,molecularr ecognition, drug discovery, and chemosensing. [5,6,7,8,9] The strongestn oncovalently bound host-guest complex, CB [7]·diamantane-4,9di(NMe 3 I) (K a = 7.2 10 17 m À1 in pure D 2 Ow ith K d = 1.4 10 À18 m attomolar dissociation constant)h as recentlyb een reported by Isaacs, Glaser,M linarić-Majerski,a nd co-workers.…”

“…[23] No singlec omputational methoda mong the techniques used with various data sets (e.g.,C B [7]·ammonium guest) an-swereda ll the goals of prediction of binding affinities, al-thoughD FT-D3 performed well. [2]1 The largest errors generally came from the fact that the interaction of as mallg uest molecule is very difficult, or even impossible, to be described by as ingle orientation or arrangement within the host cavity. However, the situation is much more straightforward in those cases when one has access to the X-ray structures of systematically varied geometry guest molecules within ap articular host.…”