A computational and spectroscopic study of the gas-phase conformers of adrenaline

Abstract

The conformational landscapes of the neurotransmitter l-adrenaline (l-epinephrine) and its diastereoisomer pseudo-adrenaline, isolated in the gas phase and un-protonated, have been investigated by using a combination of mass-selected ultraviolet and infrared holeburn spectroscopy, following laser desorption of the sample into a pulsed supersonic argon jet, and DFT and ab initio computation (at the B3LYP/6-31+G*, MP2/6-31+G* and MP2/aug-cc-pVDZ levels of theory). Both for adrenaline and its diastereoisomer, pseudo-adrenaline, one dominant molecular conformation, very similar to the one seen in noradrenaline, has been observed. It could be assigned to an extended side-chain structure (AG1a) stabilized by an OH → N intramolecular hydrogen bond. An intramolecular hydrogen bond is also formed between the neighbouring hydroxyl groups on the catechol ring. The presence of further conformers for both diastereoisomers could not be excluded, but overlapping electronic spectra and low ion signals prevented further assignments.

Acknowledgements

The authors are indebted to John Simons for his great enthusiasm, encouragement and insight; may tea-time discussions with him continue to be a source of inspiration to us all!

We gratefully acknowledge the support provided by grants from EPSRC (P.Ç. GR/R98662/01 and T.v.M. GR/R63196/01), the Leverhulme Trust (Grant No. F/08788D), by the Royal Society (L.C.S. and T.v.M., University Research Fellowship), by Corpus Christi College, Oxford (L.C.S, Research Fellowship), and the LSF laser loan pool.

Notes

The greater difference in IR frequencies for the experimentally observed (pseudo)ephedrine conformers is caused by the larger changes in dihedral angles (OCCN), hydrogen bond angles (<OHN) and distances (H … N) between the respective conformers, than seen in adrenaline and pseudo-adrenaline.

The described discrepancy between the observed relative populations (AG₁>GG₁) and the predicted relative energies (GG₁ more stable than AG₁) has been rectified in a recent publication by Miller and Clary [25], who used a torsional path integral Monte Carlo (TPIMC) technique. The TPIMC method is a general approach to the thermodynamic simulation of large molecules that treats anharmonicity and quantum effects within the torsional degrees of freedom.