14.7.2 Thermodynamics of Direct Chromatographic Enantiomer Separation If a single type of enantioselective solute-selector interaction is solely considered and other adsorption mechanism
Trang 1716 ENANTIOMER SEPARATIONS
here R- or S-enantiomer);
of Equation (14.3) provides two additional relationships:
ln K i= −1
T· H◦i
R +S◦i
and
G◦R,S = G◦R − G◦S = −R · T · ln K i,R
K i,S = −R · T · ln α (14.5)
That is, plots of ln K i against 1/T are predicted to be linear, with a slope that is proportional toH0
i Likewise the separation factorα for two enantiomers R and
S can be related to the difference in their standard free energies of solute-selector
associationG0
R,S, as well as related differences in enthalpy changeH0
R,Sand entropy changeS0
R,S
14.7.2 Thermodynamics of Direct Chromatographic Enantiomer Separation
If a single type of (enantioselective) solute-selector interaction is solely considered
and other adsorption mechanisms do not exist for the solute, K iin Equations (14.3)
to (14.5) can be related to k and
Values ofG0
R,S, H0
R,S, andS0
R,S can be derived from values ofα as a function of T, since the (usually unknown) phase ratio
(but not in Eq 14.4) Plots of ln k against 1/T are usually positive (k decreasing with T), implying a negative value of H0
i or an enthalpically controlled retention
pro-cess That is, attractive (mostly electrostatic type) noncovalent interactions between
solute and selector result in values of K i 1 The latter contributions to retention are usually opposed by entropic effects, since the solute-selector complex is more ordered compared with the solute in the mobile phase That is, H◦> S◦ and
H◦> S◦, as observed for wide variety of different CSP-analyte mobile-phase systems The usual result is a decrease in values ofα for higher temperatures The opposite behavior, an increase in enantioselectivity with T (called entropically con-trolled chiral recognition), has been observed in a few cases involving
polysaccharide-and protein-type CSPs The latter have been related to possible binding site-related (de)solvation phenomena [175] and/or conformational changes in backbones of the
selector [176, 177] Nonlinear plots of ln k against 1/T have also been observed occasionally [36] Similar exceptions to a linear increase in ln k with 1/T have been
observed for achiral separation as well (Section 2.3.2.2), possibly for similar reasons Unusual temperature-induced behaviors of another kind have been observed for the separation of chiral dihydropyrimidinones on polysaccharide CSPs [178]
Plots of ln k against 1/T were obtained by (1) heating the column from 10 to
50◦C and (2) cooling from 50 to 10◦C; the resulting plots for an ethanol-solvated Chiralpak AD-H column were not superimposable That is, the system exhibited significant hysteresis, which was not the result of conformational changes of the polysaccharide column but rather a slow equilibration of the stationary phase when
T is changed.
Trang 214.7.3 Site-Selective Thermodynamics
The discussion above overlooks the fact that enantioselective retention does not necessarily involve a single retention site [179] While this observation is true also for achiral retention, there is an important difference for enantiomeric separation That is, other sites are likely to be non-enantioselective; the latter (referred to as
type I in distinction to enantioselective type II sites [179]) might consist of the
supporting matrix (e.g., silica), linker groups, spacer units, residues stemming from silanol end-capping, and even non-enantioselective binding sites that involve the selector The presence of type-I sites is well known to compromise enantioselectivity While the binding affinity of type-I sites is usually much lower than for type-II sites, the concentration of type-I sites may exceed that of type-II sites by orders
of magnitude, especially for the case of macromolecular selectors such as proteins (Section 14.6.3) Consequently the contribution of type-I sites to overall retention
is usually not negligible, and experimental retention data represent the sum of nonspecific (achiral) and specific (chiral) contributions to k:
and
Values of k in Equations (14.7) and (14.7a) are for the injection of a small
sample (nonoverloaded separation), and subscripts I and II refer to type-I and type-II
sites, respectively; subscripts R and S refer to values for the R- and S-enantiomers,
respectively The experimental enantioselective separation factor is given by α =
k R /k S (for k R > k S), or
α = k I,R + k II,R
k I,S + k II,S
(14.8)
Retention at site I is the same for both enantiomers (i.e., it is non-enantioselective),
so k I,R = k I,S = k I and
α = k I + k II,R
k I + k II,S
(14.8a)
If nonspecific retention is absent, k I = 0 and α = k II,R /k II,S We assume that
the R-enantiomer is more retained so that k II,R /k II,S > 1 For k I > 0, the value
of α in Equation (14.8a) decreases with increasing k I and approaches 1 (no
enantioselectivity) for k I k II,R
It is obvious that a maximization of enantiomer selectivity can be achieved
either by maximizing the selectivity of the enantioselective type-II sites (k II,R /k II,S)
or by minimizing the contribution to retention of the non-enantioselective type-I sites When the goal is the interpretation of selector enantioselectivity (i.e., for type-II sites) as a function of the solute, selector, and experimental conditions, the
intrinsic thermodynamic enantioselectivity (k II,R /k II,S) is the appropriate quantity,
Trang 3718 ENANTIOMER SEPARATIONS
while the experimentally observed enantioselectivity (corresponding to α in Eq.
14.8a) can be misleading [179, 180]
From the preceding discussion it is clear that experimental values ofα are only
indirectly related to the various interactions that involve the solute and selector,
as these values of α will reflect achiral as well as chiral interactions of solute
with the stationary phase The relative contributions of chiral and achiral sites to the observed enantioselectivity can be determined by fitting adsorption isotherm data for each enantiomers to a bi-Langmuir (two-site) model over a wide range
in solute concentration This procedure then provides values of k I,R , k II,R , k I,S,
and k II,S for small samples (linear-isotherm values) If isotherms are acquired at different temperatures, values ofH i can be obtained for each enantiomer at each site (I and II) [181, 182] Values of G0
R,S, H0
R,S, and S0
R,S can be derived and used to interpret the basis of enantioselectivity for a given system By this methodology of adsorption isotherm measurements at variable temperatures, Guiochon and coworkers investigated, for example, the thermodynamics of 2,2,2-trifluoro-1-(9-anthryl)-ethanol (TFAE) [182] and 3-chloro-1-phenylpropanol (3CPP) [181] on O −9-tert-butylcarbamoylquinidine-modified silica under
normal-phase conditions site-selectively
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Trang 10CHAPTER FIFTEEN
PREPARATIVE
SEPARATIONS
with Geoff Cox
15.1 INTRODUCTION, 726
15.1.1 Column Overload and Its Consequences, 726
15.1.2 Separation Scale, 727
15.2 EQUIPMENT FOR PREP-LC SEPARATION, 730
15.2.1 Columns, 730
15.2.2 Sample Introduction, 731
15.2.3 Detectors, 733
15.2.4 Fraction Collection, 735
15.2.5 Product Recovery, 735
15.3 ISOCRATIC ELUTION, 737
15.3.1 Sample-Weight and Separation, 737
15.3.2 Touching-Peak Separation, 739
15.4 SEVERELY OVERLOADED SEPARATION, 748
15.4.1 Recovery versus Purity, 748
15.4.2 Method Development, 749
15.5 GRADIENT ELUTION, 751
15.5.1 Isocratic and Gradient Prep-LC Compared, 752
15.5.2 Method Development for Gradient Prep-LC, 753
15.6 PRODUCTION-SCALE SEPARATION, 754
Introduction to Modern Liquid Chromatography, Third Edition, by Lloyd R Snyder,
Joseph J Kirkland, and John W Dolan
Copyright © 2010 John Wiley & Sons, Inc.
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