Separation of N‐arylthiazoline‐2‐(thi)‐one atropisomers on p‐methylbenzoyl cellulose beads: A factorial design approach

Abstract

A two level full factorial design has been applied to quantdy the effect of three selected structural parameters on the capacity factors and chiral separation of atropisomers in N-arylthiazoline-2-(thi)-ones derivatives on tris(p-methylbenzoyl) cellulose beads. The behavior of the two enantiomers is influenced by different factors which might result from different retention sites within the same stationary phase. It appears that the two enantiomers behave independently on the CSP, the order of elution and separation being controlled by a minor steric modification in a very precise location in the molecule for one enantiomer. The methodology of the experimental design allows the comparison of equations generated from data issued from designed compounds. These equations afford much more information than the step by step comparison of individual molecules. In our case, the tris(p-methylbenzoy1)cellulose beads and microcrystalline cellulose triacetate appear as complementary CSPs for the resolution of atropisomers of the series studied. The molecular recognition mechanisms in cooperative chiral stationary phases (CSP), such as cellulose ester derivatives, appear to be highly complex since the active sites are not clearly identified, in contrast to the molecular CSPs for which successful models for chiral recognition mechanisms have been proposed. l3All CSPs operate through the formation of temporary diastereomeric complexes between the enantiomers of solute molecules and the phase. The difference in energy between these diastereomeric solute-CSP complexes determines the observed stereoselectivity whereas the capacity factors k' are related to the energy of interaction with the CSP. In the case of cellulose derivatives, the 3D electronic and steric "shape" of the solute appears to be an important factor for a successful separation since inclusion mechanisms are partly involved. It results that minor structural modifications might severely affect the ~eparation.~ In order to address the problem of the 3D electronic and steric "shape," we have applied a two level full factorial design to quantlfy the effect of three selected structural parameters (factors) on the capacity factors and chiral separation (responses) of atropisomers in some N-aryl-substituted heterocycles (general structures shown in Fig. 1). This method, already applied for the study of microcrystalline cellulose tria~e t a t e ,~ is applied in this report for the study of cellulose his@-methylbenzoate) in the pure polymeric form.0 1993 Wiley-Liss, Inc. MATERIALS AND METHODSMaterials Cellulose tris(p-methylbenzoate) was prepared according to the procedure reported for the preparation of cellulose tribenzoate.6Cellulose tris(p-methylbenzoate) beads (i.e., without an achiral support such as silica gel) were prepared according to the procedure reported by Francotte and Wolf. '.' The preparation of beads was limited to 5 g of the support for each batch.The synthesis, stereodynamics, and relationship between the sign of the rotatory power and the absolu...

Bis[oxo/thioxothiazolinyl] Aromatic Compounds - Synthesis and Conformational Assignment

“…The series of bis(oxo/thioxothiazolinyl) aromatic atropisomers with two chiral C(aryl)-N(heterocycle) axes 1a,b-12a,b may contribute, as model compounds, to studies on the chiral recognition mechanism in liquid chromatography on chiral stationary phases as an extension of the systematic studies already performed by some of the present authors on the corresponding atropisomers with only one chiral axis. [18,[28][29][30][31][32][33]…”

Synthesis and chiral separation of atropisomers of 4,5‐Di methyl ∆4 N‐phenyl N‐aryl imidazoline‐2‐thione derivatives

“…Likewise, it is reported in the literature that substituents borne by the aryl group in the series of N-aryl thiazolin (thi)one has an effect on the barrier of rotation which can be large enough, that leads to the resolution of these atropisomers by chiral HPLC and leads to a difference in chiral recognition mechanism. [15][16][17][18][19]37,38 Consequently, electrondonating ability, polarity and particular conformation spatial of ortho-substituent in rotating aryl group present crucial factors affected the atropisomeric resolution of N-aryl imidazoline-2-thiones derivatives and contributed change in chiral recognition between solute and CSP. The following chromatograms given in Figure 4 illustrate the impact of substituents on the separation of the atropisomers of compounds1-3 on Chiralcel® OZ-3.…”

“…11 Many researches concerning the chiral separation of five-member ring atropisomers have been reported. For many years, Roussel et al developed a completely study applied to N-arylthiazolinethione derivatives and their oxygen analogs, [12][13][14][15][16][17] they studied the chiral separation of these derivatives by liquid chromatography, using various chiral stationary phases as triacetylcellulose, microcrystalline cellulose triacetate, and methylbenzoyl cellulose. Further, the authors investigated the effect of substituents in the atropisomeric separation of N-arylthiazolinethione derivatives 18,19 and the mechanism of chiral recognition of these compounds was explored.…”