Conformational Studies by Dynamic NMR. 89.¹ Stereomutation and Cryogenic Enantioseparation of Conformational Antipodes of Hindered Aryl Oximes

Abstract

Aryl benzyl oximes having the configuration Z give rise to stereolabile atropisomers when a halogen atom is present in the ortho position of the aryl moiety, as a consequence of the restricted aryl-CN bond rotation. By means of dynamic (1)H NMR spectroscopy it has been possible to determine the corresponding rotation barrier, hence the lifetime of the atropisomers that, in the case of the iodine derivative, was found sufficiently long as to allow a physical separation to be achieved on an appropriately cooled enantioselective HPLC column. Comparison of the barriers determined by dynamic NMR and dynamic HPLC proved the equivalence of the two techniques. When the iodine atom was substituted by an alpha-naphthyl group, two dynamic processes were observed. That with the lower barrier could be determined by NMR and that with the higher barrier by HPLC, thus outlining the complementarity of these two techniques.

Theory and Practice of UHPLC and UHPLC–MS

“…A quite great number of enantiomerizations/diastereomerizations of chiral species have been studied by DC approaches in the past two decades. In several cases, the chromatographic results were supported and/or compared to alternative kinetic methods, such as DNMR spectroscopy (Gasparrini et al, 1995(Gasparrini et al, , 2002aDell'Erba et al, 2002;Dalla Cort et al, 2005) and stopped-flow gas Activation entropies (DS s , e.u.) and free energies (DG s , kcal/mol) of conformational and configurational isomerizations calculated by DHPLC and DHRGC.…”

“…Generally, in the first case, rate constants are underestimated, and quite moderate SP perturbations are observed (Gasparrini et al, 1997a(Gasparrini et al, , 2000(Gasparrini et al, , 2001(Gasparrini et al, , 2002aDell'Erba et al, 2002;Borsato et al, 2004;Dalla Cort et al, 2005;Lunazzi et al, 2010). A logical explanation may be that, after complexation of the labile species on the SP, the hindered bond rotation relevant to the studied conformational stereomutation may easily find an additional physical opposition by the phase, with consequent increasing of the related activation barrier.…”

“…However, because the time of simulation is exponentially related to N th , only separations with not too many marked efficiencies (smaller than about 10,000 theoretical plates) can be treated in an iterative way yielding reasonable simulation times. Examples of widely employed computer programs implementing the TPM model are SIMUL (Jung, 1992), ChromWin (Trapp and Schurig, 2001b), Auto DHPLC y2k (Gasparrini et al, 2002a;Cabri et al, 2008;Cirilli et al, 2009b), and ChromWin_2D (Trapp et al, 2003;Trapp, 2004).…”

“…are ChromWin (Trapp and Schurig, 2001b) and Auto DHPLC y2k (Gasparrini et al, 2002a;Cabri et al, 2008;Cirilli et al, 2009b). To strongly reduce the computational time, which in the aforementioned iterative procedure of comparison between simulated and experimental chromatograms is not negligible, the modification of kinetic and, if desired, chromatographic parameters is automated in the Auto DHPLC y2k program by the use of an algorithm driven by a simplex procedure.…”

“…Conformational changes are normally based on monomolecular mechanisms and, as such, do not require the assistance of a secondary molecular partner. Atropoisomerism is an intramolecular event that falls into this class of reactions, featuring pure first-order kinetics (Gasparrini et al, 1997a(Gasparrini et al, , 2000(Gasparrini et al, , 2001(Gasparrini et al, , 2002aDell'Erba et al, 2002;Andreani et al, 2004;Borsato et al, 2004;Dalla Cort et al, 2005;Lunazzi et al, 2010;Levi Mortera et al, 2012;Rizzo et al, 2013Rizzo et al, , 2014Rizzo et al, , 2015Chiarucci et al, 2014;Sabia et al, 2014Sabia et al, , 2016Menta et al, 2015). On the other hand, configurational isomerizations (i.e., processes involving rupture and reformation of chemical bonds) are commonly promoted by species that act as catalysts and that therefore do not modify their concentration during the interconversion (a bimolecular mechanism).…”