Techniques of Molecular Modelling: Molecular Visualisation

Case Study 1: Environmentally Friendly Herbicides.

The environmental impact of chemicals is of major contemporary concern. When a new herbicide is being developed, one of the very first properties that must be understood is the likely persistence of the substance in soil. As part of a screening program, two closely related potential herbicides were found to have unexpectedly different stabilities in water, one surviving hydrolysis for hours, the other only for a minute or so. There was clearly an important need to understand this behaviour so that some design control could be exercised over this property.

The mechanistic chemists had already established that the critical center was the O-C-O group, in which cleavage of one C-O bond was the important step. In modelling this system, some important early strategic decisions have to be taken. Is the reactivity related to some intermolecular property involving say interaction with water, or is it some structural feature of the molecule itself? Some knowledge of chemistry (the "anomeric" effect) suggests that intramolecular interaction of the C-O bond with the adjacent oxygen electron lone pairs is likely to be important, which may in turn affect say the C-O bond strength and hence its length. This in turn rules out simple molecular mechanics (MM) as the first line of attack, since this is principally a method that does not deal easily with electrons and their wavefunctions. A quantum mechanical (QM) approach should work, but the relative size of the molecule, and its potential conformational complexity implies a major task. Background literature searching and reading shows moreover that QM methods have had a checkered history in dealing with anomeric effects! Its time for a exploratory approach by inspecting the crystal structure.

Using molecular visualisation soon reveals that the solvolytically unstable isomer (4, lhs) has two quite different C-O bond lengths, whereas the relatively stable form (5, rhs) shows almost no difference in these lengths. Thus (4, lhs) is well on the way to breaking a C-O bond, even with no water getting in on the act. Thus this really does appear to be an intramolecular and not an intermolecular problem, where analysing a single structural feature can give great insight into the structure-activity relationships.

Firstly, you notice that the conformations of the two 7-membered rings are quite different, but one common aspect is that in both cases the aryl group is "equatorial", an orientation generally preferred on steric grounds. This "locking" of the 7-ring then induces a particular angular relationship between each C-O bond and the lone pairs of the other oxygen atom. We know that this property should be important from our reading about the "anomeric" effect. Although we cannot easily directly measure angles involving lone pairs, we can "idealize" these with two dummy atoms arranged tetrahedrally around each oxygen atom. By doing this, we discover that for the stable compound, these idealised lone pairs are never quite "antiperiplanar" to the opposite C-O bond (Å 160 degrees) With the unstable isomer however, one particular lone pair is found to be more closely "antiperiplanar" to the elongated C-O bond (Å 173 degrees), a classical manifestation of the anomeric effect. Armed with this highly focussed conformational interpretation of our reactivity, we could now go on to design new variants, hopefully with the particular properties we want.

Literature Citations. Isoxazolinyldioxepines. Part 1. Structure-Reactivity Studies of the Hydrolysis of Oxazolinyl-dioxepin Derivatives, P. Camilleri, D. Munro, K. Weaver, D. J. Williams, H. S. Rzepa and M. Z. Slawin, J. Chem. Soc. Perkin Trans. 2, 1989, 1929.

Case Study 2: Chiral Resolution using the Pirkle Reagent

The so called Pirkle compound is much used as a chiral resolving and nmr shift reagent. In its optically active form, it will help to resolve racemic mixtures of chiral molecules by binding slightly differently with each of the two enantiomers of say an amino acid. Such chiral resolution is of paramount importance in the development of a new drug; the Thalidomide pregnancy pill case arose because of incomplete separation of two such enantiomers, one of which turned out to be toxic to the foetus.

But what sort of intermolecular interactions are involved in the binding process? The simple truth is that for the Pirkle reagent, no-one really knew until recently. Intermolecular interactions can be quite difficult to calculate accurately, especially for a molecule that size and the quickest and most direct way to probe this question is to look at the crystal packing structure if it can be measured. A search of the Cambridge crystal structure data base revealed that although no structures between the Pirkle reagent and chiral molecules had been reported, the structure of the racemic reagent itself had already been determined as part of a study on triboluminescence (the crystals emit purple light when you grind them!). The authors conclusion was that a highly unusual hydrogen bond was formed between the -OH group of one molecule and the F₃C- group of another. But a small alarm bell sounds at this point. The crystallographers had not actually located the position of the hydrogen atom, they had assumed it could only sit between the O and the F. Could they be mistaken? Visualization enables this assumption to be easily tested.

The effect of the crystal lattice diagram can initially be overwhelming, the trees being well and truly hidden by the wood. The tools offered by the molecule editor make a very good wood-cutter, and soon the unique interactions involved can be displayed on the screen. Immediately apparent is that an alternative explanation involving an interaction between the OH group and the p-face of an adjacent molecule is feasible. This hypothesis was rapidly confirmed by explicitly locating the vital hydrogen atom, both in the original racemic crystal and in the optically active form (above). Many profound implications follow from this discovery. It has helped focus on the role of p-facial hydrogen bonding in protein interactions, it has now been discovered as a common feature of certain types of silanols, phenols and amines and it occurs in inclusion compounds known as calixarenes. The implications for modelling are also significant. By their very nature, most molecular mechanics methods would not reproduce the phenomenon. Moreover, the unexpected orientation of the OH bond resulting from p-facial interaction sets up specific "stereoelectronic" interactions in the molecule which profoundly affect calculated quantum mechanical properties such as electrostatic potentials, often used to predict intermolecular interactions. Thus much new insight and direction is given to a project, the germ of which was started by 3D visualization of a structure which revealed detail that others without such a tool had missed.

Literature Citations. A. M. Sweeting and A. L. Rheingold, J. Chem. Phys, 1988, 93, 5648; p-Facial Hydrogen Bonding in the Chiral Resolving agent (S) 2,2,2-Trifluoromethyl-1-(9-Anthryl)ethanol and its Racemic Modification, H.S. Rzepa, M. L. Webb, A. M. Z. Slawin and D. J. Williams, J. Chem. Soc., Chem. Commun., 1991, 765.

Case Study 3: Designing New Materials.

The molecule below was prepared in the hope that it might have interesting electrical properties arising from electron transfer from the anion to the cation. This is clearly an intermolecular interaction problem, and with such complex and unusual functionality, there is little hope of modelling these interactions a priori with MM or QM methods. The crystal structure is the best starting point, but we do need to pull out subtle features by displaying this using a molecular modelling system.

The observation that p-facial hydrogen bonds can form (see above) has a "sensitizing" effect on the perception of this structure! Thus it soon became apparent that this structure also had such interactions, but with some important differences. Here, it is the C-H bonds that interact with the p_p orbitals of the SN ring, in itself quite a novel observation. Moreover, each nitrogen supports two such bonds, and significantly, the two hydrogen bonds are almost co-linear. These interactions dominate the chain stacking of the crystal lattice, and hence directly influence both the color and electrical properties of the compound. Best of all, one can see that by adjusting perhaps the size of the metal or the nature of the rings, one might actually improve the co-linearity of the pairs of C-H...N...H-C interactions and hence potentially tune the properties of such systems! Whilst studying crystal structures, be aware that the structure in solution may be quite different! Thus this compound, although black in the solid state, is pale yellow in solution. Moreover, solvation may entirely alter the intra as well as the intermolecular interactions.

Literature Citations. The Preparation, X-Ray structure and Theoretical Study of [CoCp₂][S₃N₃], a Novel Stacking Complex Incorporating Multiple C-H...N(p_p) Interactions. P. N. Jagg, P. F. Kelly, H. S. Rzepa, D. J. Williams, J. D. Woollins and W. Wylie, J. Chem. Soc., Chem. Commun., 1991, 942.

Return to main course page|| Forward to case Studies 4-6|