Submitted to: Journal of Organic Chemistry
Publication Type: Peer reviewed journal
Publication Acceptance Date: 4/21/2006
Publication Date: 5/20/2006
Citation: Bosma, W.B., Bartelt, R.J., Momany, F.A. 2006. Determination of the preferred conformation of the bicyclic Galerucella pheromone using density functional theory optimization and calculations of chemical shifts. Journal of Organic Chemistry. 71(13):4748-4758. Interpretive Summary: The Galerucella calmariensis beetle has been imported for use as a biological control agent for purple loosetrife, a foreign plant that has become an invasive species in wetlands in the northern half of the United States. A pheromone from this beetle, which attracts both males and females, was recently isolated and characterized experimentally using NMR (nuclear magnetic resonance) spectroscopy. The ability to synthesize this molecule will allow scientists to monitor where the beetles are present, and learn more about their habits and populations. This pheromone contains a large flexible ring, and the experimental studies cannot unambiguously determine which of the hundreds of possible conformations of this ring are expected to exist as the predominant species in solution. Knowledge of the precise structure of the molecule is important in biological systems, as it is believed that the insect responds to one particular conformation of the pheromone molecule. Advanced theoretical methods were used to obtain a set of structures for this molecule, and determine the most energetically stable conformers. In addition, the calculations were used to predict the NMR spectra for the conformers, and a direct comparison to the experimental NMR results confirmed that the structures chosen likely correspond to the actual molecule. There were four separate ring conformations found to be important, and calculations were performed to confirm that it is possible for the molecule to convert between these conformations at room temperature. Knowledge of the exact structure of this molecule will aid experimental chemists in designing similar molecules to serve the same purposes, perhaps more efficiently than the naturally occurring pheromone.
Technical Abstract: A pheromone from the beetle, Galerucella calmariensis, was recently isolated and identified  as a 14-carbon, bicyclic dimethylfuran lactone, with the systematic name, 12, 13-dimethyl-5, 14-dioxabicyclo[9.2.1]tetradeca-1(13),11-dien-4-one. The main 12-membered lactone ring is very flexible; as a result, there exists multiple possible conformations. The preferred conformation cannot be deduced solely from room temperature NMR measurements. Using density functional (DFT) studies, twenty-six unique conformers with energies within 10.0 kcal/mol of the global minimum-energy structure were found. A mirror image plane exists so that each conformer has an 'inverse' structure with the same energy, for which the dihedral angles around the flexible ring have opposite sign. The isotrophic 1H and 13C NMR chemical shifts of the DFT-optimized structures were calculated using the gauge-including atomic orbital (GIAO) method. By considering the relative energies of the conformers and calculated and observed NMR spectra, it was concluded that the molecule exists primarily as a mixture of two distinct conformers at room temperature, each being present with its mirror-image inverse. Structural interconversions among these likely occur on a timescale that is fast compared to the NMR experiments. Using mode-following and dihedral-driving techniques, several potential pathways were found for the conversion of the lowest-energy conformer to its mirror-image structure. Ab initio molecular dynamics (AIMD) using the 4-31G basis set was carried out for 50 picoseconds (ps) to test the availability of various low energy minima and the transition states found from the searches noted above.