Attempts to Quantify the Effect of Selected Structural Parameters on the Separation of Some N-Arylthiazoline-2-Thione and N-Arylthiazolin-2-One Atropisomers on the Chiral Stationary Phase, Cellulose Triacetate (CTAl)

Roussel, Christian; Stein, Jean‐Louis; Sergent, M.; Luu, R. Phan Tan

doi:10.1007/978-1-4684-8282-9_15

Cited by 5 publications

(3 citation statements)

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“…26 The barriers of rotation of each compound as well as the absolute configuration of two atropisomers (+) and (-) have been determined in previous work by the kmetics of ra~emization~~ and by X-ray diffraction after derivatization with optically pure menthyl bromoacetateZ7, respectively. The absolute configuration related with the sign of rotation is shown in Figure 1.…”

Section: Determination Of the Absolute Configuration And Of The Elutimentioning

confidence: 99%

“…As it is interesting to correlate the elution order of the two enantiomers with their spatial arrangement, the elution orders have been determined by injection of partially resolved mixtures obtained by preparative chromatography on a microcrystalhe cellulose triacetate column. 26 The barriers of rotation of each compound as well as the absolute configuration of two atropisomers (+) and (-) have been determined in previous work by the kmetics of ra~emization~~ and by X-ray diffraction after derivatization with optically pure menthyl bro-moacetateZ7, respectively. The absolute configuration related with the sign of rotation is shown in Figure 1.…”

Section: Determination Of the Absolute Configuration And Of The Elutimentioning

confidence: 99%

“…This methodology has already been successfully applied to the results obtained on a cellulose triacetate column. 26…”

Section: Factorial Designmentioning

confidence: 99%

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γ‐Cyclodextrin as chiral mobile phase additive in the HPLC separation of the atropisomers of some N‐arylthiazoline‐2‐thiones and N‐arylthiazoline‐2‐ones: Attempts to quantify the effect of selected structural parameters

Roussel¹,

Favrou

1993

Chirality

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The effect of the position and type of the substituent on the chromatographic separation of N-arylthiazoline-2-thione and arylthiazoline-Zone atropisomers are described in reversed-phase HPLC using p-or y-cyclodextrin as chiral mobile phase additive.A quantitative approach to experimental design has been developed.o 1993 Wiey-Liss, Inc.KEY WORDS: chiral additive, cyclodextrin, RP-HPLC, atropisomers, experimental design a-, p-, and y-cyclodextrins (CDs) are cyclic, nonreducing oligosaccharides consisting of, respectively, 6, 7, and 8 units bonded through a-1,4 M a g e s , which can be represented schematically as a truncated cone. The interior of CD cavities is relatively hydrophobic, being formed by a circular codguration of hydrogen atoms and glucoside oxygen atoms, while all the hydroxyl groups are on the outside of the molecule. The wider side of CD cavity contains secondary hydroxyl groups, while the opposite smaller opening is occupied by primary hydroxyl groups. This arrangement explains the ability of CDs to form inclusion complexes in aqueous solutions. Therefore, they have been used for the separation of geometric, structural, and stereoisomers by thin-layer chromatography (TLC), l3 high-performance liquid chromatography (HPLC), kg and gas chromatography (GC). l'-lz Two different approaches have been designed for the use of CDs in HPLC, the use of chemically bonded CD-silica stationary and the application of CD as mobile phase components of reversed-phase (RP) systems. [20][21][22] Since chiral glucose units form the cyclodextrin cavity, the cavity functions as a chiral selector and CDs are especially useful for the chromatographic separation of enantiomers.The parameters of such a separation are mainly influenced by the stability of the inclusion complexes formed with each enantiomer and as a consequence by the intrinsic structural features of the molecule. Factors which influence the chiral recognition mechanism when p-or y-CD is used in HPLC as a chiral mobile phase additive are still poorly understood. An empirical procedure that uses molecular structure to predict the enantioselectivity of derivatized p-CD bonded stationary phases has been developedz3 for compounds which have four substituents on a stereogenic center. In this paper, we have applied a different approach, namely a two-level full factorial design to quantify the effect of three selected structural parameters (factors) on 0 1993 Wiley-Liss, lnc.the separation and capacity factors (responses) of atropisomers of some N-aryl-substituted heterocycles (Fig. 1) by HPLC using an achiral stationary phase and CDs as mobile phase additives. MATERIAL AND METHODS Chemicals and ReagentsThe synthesis of compounds 1 to 8 (Fig. 1) has been already described, together with their barriers to rotation around the pivot Acetic acid (Carlo Erba) and triethylamine (TEA, Janssen) were purchased. EtOH/H20 (955) was purified by distillation. CDs were obtained from Roquette Freres (Lestrem, France). Chromatography

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Section: Determination Of the Absolute Configuration And Of The Elutimentioning

confidence: 99%

Section: Determination Of the Absolute Configuration And Of The Elutimentioning

confidence: 99%

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γ‐Cyclodextrin as chiral mobile phase additive in the HPLC separation of the atropisomers of some N‐arylthiazoline‐2‐thiones and N‐arylthiazoline‐2‐ones: Attempts to quantify the effect of selected structural parameters

Roussel¹,

Favrou

1993

Chirality

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

et al. 1993

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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...

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Effects of alkyl substituents on chiral separation of N‐arylthiazolin‐2‐(thi)‐one atropisomers on tris (p‐methylbenzoyl)cellulose beads and cellulose triacetate: Lipophilicity aspects

Roussel

Popescu

1994

Chirality

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ABSTRAC7The determination of lipophilicity of the title compounds allowed treatment of the data for chiral separation (capacity factors) on CTA and CTPB accordmg to these parameters. A linear correlation between In k'(+) and log k'w was found on both CTA and CTPB, as far as the substituents are situated in the plane of the aryl ring or the heterocycle. This correlation with a nonchiral descriptor allows treatment of capacity factors for (-)-enantiomers as deviations from the lipophilicity line or derived parallels. It results in a clear description of the molecular area affecting enantioselectivity. Application to larger alkyl derivatives shows that the effect of the substituent should be treated on a basis of attractive effect in the case of CTA and on the basis of attractive and repulsive effects for CTPB. KEY WORDS: chiral HPLC, experimental design, quantitative substituent effects, recognition mechanism Chiral recognition mechanisms in cooperative CSPs such as cellulose derivatives provide a fascinating field of research'" since the discriminating sites are not clearly identified in contrast to the molecular CSPs in which the chiral selector is well defined."6 As a consequence, the methodologies to address chiral discrimination in cooperative phases will be different than those applied in the case of a well-defined molecular selector. Stereoselectivity for a given couple of antipodes results from the energy difference between diastereomeric solute-CSP complexes whereas capacity factors k' are related to the energy of interaction of each enantiomer with the CSP. In cooperative CSP one approach might be to develop a series of molecules which are structurally related and which differ by appropriate substitutions around the same framework. If one can linearize the effect of the substitution pattern for each enantiomer of the same configuration, the enantioselectivity will be simply the difference between these two linearisations for a given set of substituents. Such a linearisation might be performed using the PLS approach,7 however, it seems clear that chiral descriptors as well as nonchiral descriptors are needed.The lipophilicity parameter is one of the nonchiral descriptors generally used in studies of quantitative structure-activity relationship.' To obtain a relationship between chiral retention of enantiomers and their lipophilic interaction within a chiral phase, we have determined the capacity factors on cellulose triacetate CTA and trisu-methylbenzoy1)cellulose beads CTPB chiral stationary phases and the lipophilicity parameters for a series of N-aryl substituted heterocyclic atropisomers (the general structure is given in Fig. 1 1-8 are related by a factorial design approach which allows the quantification of the effects of structural parameters X,, X,, X, on the chiral retention on CTA,' CTPB,l" and on the lipophilicity parameter. In this paper we attempt to relate the capacity factor of the enantiomers of compounds 1-8 with their lipophilicity parameter and to extend the approach to chiral separation...

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Attempts to Quantify the Effect of Selected Structural Parameters on the Separation of Some N-Arylthiazoline-2-Thione and N-Arylthiazolin-2-One Atropisomers on the Chiral Stationary Phase, Cellulose Triacetate (CTAl)

Cited by 5 publications

References 5 publications

γ‐Cyclodextrin as chiral mobile phase additive in the HPLC separation of the atropisomers of some N‐arylthiazoline‐2‐thiones and N‐arylthiazoline‐2‐ones: Attempts to quantify the effect of selected structural parameters

γ‐Cyclodextrin as chiral mobile phase additive in the HPLC separation of the atropisomers of some N‐arylthiazoline‐2‐thiones and N‐arylthiazoline‐2‐ones: Attempts to quantify the effect of selected structural parameters

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

Effects of alkyl substituents on chiral separation of N‐arylthiazolin‐2‐(thi)‐one atropisomers on tris (p‐methylbenzoyl)cellulose beads and cellulose triacetate: Lipophilicity aspects

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