Obviously Elusive

For some reason, we always have the knack of missing those things which are simple. And each one of us has a knack of missing a different thing. For me, the question which many synthetic chemists seem to miss is; how can a flexible molecule have a single conformation in solution? And yet, many synthetic chemists publish one solution conformation for their pet macrolide in a good journal, and the journal referees accept it without comment. The conformation is based on NMR coupling constants (Js) and distances (ds) from NOESY spectra, which are average values. In fact, the average structure obtained from these values does not exist in solution at all, and publishing such a structure is basically publishing a 'virtual' structure. In fact, take this structure and minimize it using a good force field, and it will always fall down by 10-12 kcal/mol in energy. Thus, it simply cannot exist as a 'low energy' conformer in solution, which is touted for an NMR structure.

I am not very keen in pointing out specific cases, but Amos Smith's "Solution Structure of (+)-Discodermolide" (Org. Lett.; (Letter); 2001; 3(5); 695-698. DOI: 10.1021/ol006967p) is a good example. For such a flexible molecule, there can never be one single structure in solution. It is a little intriguing for me how this phenomenon keeps on happening. For a rejoinder to Smith's paper, which makes use of a nifty conformer deconvolution method called NAMFIS, see Snyder's "Conformations of Discodermolide in DMSO" (J. Am. Chem. Soc. 2001, 123, 6929-6930). Note the use of the plural. Many such cases abound.

A simple rule to know when a molecule will be especially conformationally mobile in solution is to just count the number of single rotatable bonds in it. For a molecule with, say 15 such bonds, there won't even be one dominant (meaning more than 50%) conformation in solution. For example, Snyder's Disco analysis shows that the 'dominant' conformation of Disco is one with a population of 24% in solution.

I am working on NAMFIS, and not as a favourite method but by an objective assesment, want to say that it is a nifty method. The method was developed by an Italian group and stands for "NMR Analysis of Molecular Flexibility in Solution" (J. Am. Chem. Soc. 1995,117, 1027-1033). What it does is it takes the average NMR data (Js and ds from NOESY) and then matches that against a family of conformers obtained from a good conformational search, often done using multiple force fields and then combining the results. It then calculates the deviation of each structure's calculated Js and ds from the average data, and chooses the best fit as the most dominant structure in solution, with decreasing proportions of the worse fitting ones. Note that the 'dominant' conformation is neither more than 50%, nor does it match all the data, but it is the one that gives the best fit, which in this case is simply the sum of SD (square deviation) values for calculated and experimental NOE ds and Js. NAMFIS has been applied to Taxol and Laulimalide in addition to Disco. It was also applied to the structure of a 7 residue peptide which supposedly formed an alpha-helix in solution. The results? Not only did the peptide exist in many conformations, but the alpha helix was not even a minor one among them! This was "On the Stability of a Single-Turn -Helix: The Single versus Multiconformation Problem" (J. AM. CHEM. SOC. 2003, 125, 632-633)

The reason why synthetic organic chemists often don't end up paying close attention to conformation is simply because that knowledge is seldom something that is useful to them. For them, the principal function of NMR spectroscopy is to assign configuration. However, if they want to go ahead and publish a conformational analysis of their molecule in solution, they would do well to step back and consider the simple fact that if the molecule is even reasonably flexible, it is going to have multiple conformations, and not even a single dominant (more than 50%) one. In my view, not publishing conformational analysis for a highly flexible molecule at all is better than publishing only one conformation. In very special cases, the molecule may be constrained in some way, and then in fact, the average conformation may approach a single dominant conformation. Even then, there still cannot be only one conformation, as was the case for the 'constrained' alpha helix peptide cited in the above paragraph. A JOC paper, "A Test of the Single-Conformation Hypothesis in the Analysis of NMR Data for Small Polar Molecules: A Force Field Comparison" (J. Org. Chem. 1999, 64, 3979-3986), nicely explores NAMFIS and this question for a Diels-Alder adduct. But cases of truly constrained molecules having only one conformation are rare, and chemists' antennas must go up if someone publishes one conformation for your average flexible 'small' molecule.

Unfortunately, they don't seem to largely have.