Pseudorotation in pyrrolidine: rotational coherence spectroscopy and ab initio calculations of a large amplitude intramolecular motion

Abstract

Pseudorotation in the pyrrolidine molecule was studied by means of femtosecond degenerate four-wave mixing spectroscopy both in the gas cell at room temperature and under supersonic expansion. The experimental observations were reproduced by a fitted simulation based on a one-dimensional model for pseudorotation. Of the two conformers, axial and equatorial, the latter was found to be stabilized by about 29 +/- 10 cm(-1) relative to the former one. The barrier for pseudorotation was determined to be 220 +/- 20 cm(-1). In addition, quantum chemical calculations of the pseudorotational path of pyrrolidine were performed using the synchronous transit-guided quasi-Newton method at the MP2 and B3LYP levels of theory. Subsequent CCSD(T) calculations yield the energy preference of the equatorial conformer and the barrier for pseudorotation to be 17 and 284 cm(-1), respectively.

The conformational stability of gaseous 1-butene studied by femtosecond nonlinear spectroscopy and ab initio calculations

“…In general, under supersonic expansion conditions vibrational temperatures should be higher than the rotational one, since the cooling rate depends on the energy difference between quantum states [33]. However, as was shown in the cases of pyrrolidine [15] and cyclopentene [16], the vibrational temperature of the low-frequency vibrations can be nearly the same as the rotational temperature. Therefore, it is plausible to assume that the vibrational temperature for the population of the torsional states should be not higher than 100 K.…”

“…Based on the Raman process, this technique has proven to be a powerful tool for structural investigation of molecules and molecular clusters in the electronically ground state even if they do not possess a permanent dipole moment [11][12][13][14]. Recently, fs DFWM was successfully applied for studying large amplitude intramolecular motions in the non-aromatic five-membered ring compounds pyrrolidine [15] and cyclopentene [16]. In this paper the fs DFWM spectrum of 1-butene measured under supersonic expansion conditions will be analysed.…”

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

“…Moreover, knowing the absolute and relative configuration of chiral centers can allow the toxicity or inactivity of one of the enantiomers to be avoided, a concept regulated extensively by US FDA guidelines on the “Development of new stereoisomeric drugs” [ 32 ]. In contrast to the pyrrole ring, thanks to “pseudorotation”, an intrinsic property of saturated five-membered rings, pyrrolidines gain energetically advantageous conformations offering interesting 3D coverings [ 33 ]—a useful tool for the exploration of pharmacophore space via diversity-oriented synthesis (DOS) [ 34 , 35 ]. Overall, based on the electronegativity of C-4 substituents, the pyrrolidine ring of proline acquires two specific conformations called C-4 (or Cγ) -exo and -endo envelope conformers.…”

Exhaustive exploration of the conformational landscape of mono- and disubstituted five-membered rings by DFT and MP2 calculations

“…The transition structure corresponding to nitrogen inversion was found at higher energy (3.4-4.4 kcal mol À1 ), which was in agreement with previous observations. 34, 35 Hence, according to our calculations, the stable conformers of pyrrolidine should interchange following a pseudorotational process rather than N inversion, which is exactly the opposite situation found in the case of piperidine. 5 Dimethylcyclopentanes (10)(11)(12)(13).…”