CSPs effect

The principal idea behind the CSP approach is to use input from Classical Molecular Dynamics simulations, carried out for the process of interest as a first preliminary step, in order to simplify a quantum mechanical calculation, implemented in a subsequent, second step. This takes advantage of the fact that classical dynamics offers a reasonable description of many properties of molecular systems, in particular of average quantities. More specifically, the method uses classical MD simulations in order to determine effective... 

With the above definitions, there is no additional overall phase factor to be included in (27). Eqs. (24)-(27) are the CSP approximation.Like TDSCF, CSP is a separable approximation, using a time-dependent mean potential for each degree of freedom. However, the effective potentials in CSP... 

In addition to wavepackets propagated along effective potentials corresponding to individual trajectories, we also propagate in CI-CSP the CSP wavefunc-tions, governed by the average potentials Vj(qj,t) of Eq. (24). The CI-CSP ansatz for the total wavepacket of the system is then as follows ... 

The intensities are plotted vs. v, the final vibrational quantum number of the transition. The CSP results (which for this property are almost identical with CI-CSP) are compared with experimental results for h in a low-temperature Ar matrix. The agreement is excellent. Also shown is the comparison with gas-phase, isolated I. The solvent effect on the Raman intensities is clearly very large and qualitative. These show that CSP calculations for short timescales can be extremely useful, although for later times the method breaks down, and CTCSP should be used. 

Each glycopeptide CSP has unique selectivity as well as complementary characteristics, and a considerable number of racemates have been resolved on all three of them. Interestingly, most of the resolved enantiomers have the same retention order on these macrocyclic CSPs. When they are mixed or coupled with each other, the selectivity on one CSP will not be canceled by another. Even if some compounds may not have the same retention order, the complementary effects will result in an identifiable selectivity. Therefore, the coupled chiral columns can be used as a screening tool and save chromatographers substantial time in method development. 

Fig. 2-10. The effect of flow rate on the resolution of methylphenidate enantiomers on vancomycin CSP (250 x 4.6 mm). The mobile phase was methanol 1.0 % triethyl-ammonium acetate (95/5 v/v) pH 4.1 at ambient temperature (23 °C).

Table 2-5. The effect of temperature on vancomycin CSP. the separation of N-carbamyl-phenylalanine enantiomers on ...

For most free amino acids and small peptides, a mixture of alcohol with water is a typical mobile phase composition in the reversed-phase mode for glycopeptide CSPs. For some bifunctional amino acids and most other compounds, however, aqueous buffer is usually necessary to enhance resolution. The types of buffers dictate the retention, efficiency and - to a lesser effect - selectivity of analytes. Tri-ethylammonium acetate and ammonium nitrate are the most effective buffer systems, while sodium citrate is also effective for the separation of profens on vancomycin CSP, and ammonium acetate is the most appropriate for LC/MS applications. 

The rapid increase in the separation factors observed for the individual series of columns reflected not only the improvement in the intrinsic selectivities of the individual selectors but also the effect of increased loading with the most potent selector. Although the overall loading determined from nitrogen content remained virtually constant at about 0.7 mmol g for all CSPs, the fractional loading of each selector increased as the number of selectors in the mixture decreased. Thus, the whole method of building block selection and sublibrary synthesis can be also viewed as an amplification process. 

In contrast, there are fewer limitations from the chemical point of view. The preparation of large, well-defined, libraries that involve amino acid building blocks has been demonstrated many times. Carefully optimized reaction conditions for the preparation of other mixed libraries can also ensure that each desired compound is present in sufficient amount. However, the reaction rates of some individual selectors with the activated solid support may be lower than that of others. As a result, the more reactive selectors would occupy a majority of the sites within the beads. Since the most reactive selectors may not be the most selective, testing of a slightly larger number of specifically designed CSPs may be required to reduce the effect of falsenegative results. 

Derivatized amylose is the basis for the Chiralpak AD CSP. This CSP has been utilized for the resolution of ibuprofen and flurbiprofen, as well as other members of the family of nonsteroidal inflammatory drugs (NSAIDs) [39, 61]. Ibuprofen was not resolved on the Chiralpak AD CSP in LC. Pressure-related effects on stereoselectivity were observed by Bargmann-Leyder et al. on a Chiralpak AD CSP [58]. No corresponding effect of pressure on selectivity was observed with a Chiralcel OD CSP. The authors speculated that the helical conformation of the amylose-based CSP is more flexible than that of the cellulose-based CSP. 

Column selection remains the most important factor in successful enantiomeric separations. The CSPs most likely to be effective in SFC are those that have been employed under normal phase conditions in LC. In fact, the tremendous body of knowledge that has been accumulated for LC can also guide column selection in SFC [66]. The likelihood of success with a particular CSP can generally be gauged after one or two injections [67]. If no evidence of separation is observed, another CSP should be investigated. 

In general, retention decreases as the modifier concentration increases because the modifier competes with the analytes for sites on the stationary phase. The effect on retention of changes in modifier concentration seems to be more pronounced for CSPs than for achiral stationary phases in SFC, and peak shapes are apt to degrade rapidly at low modifier concentrations [12]. Efficiency tends to decrease as the modifier concentration increases because analyte diffusion is slowed by the increased viscosity of the eluent [39]. 

Modifier additives also play a role in method optimization and are typically added to the modifier at concentrations less than 1 % (v/v). Additives can provide increased efficiency by minimizing undesirable interactions between the analyte and the CSP, and may be necessary to elute certain types of compounds. The type of additive (acidic or basic) that will produce the best results depends upon the functionality of the analyte [72]. Certain additives are strongly retained on the stationary phase, and their effect may persist even after they are removed from the eluent [22]. The impact of both modifiers and additives can also be affected by the proximity of the operating conditions to the critical point of the eluent [73]. 

Changes in pressure typically have a greater impact on retention than on selectivity. Most studies of CSPs have indicated little effect of pressure on stereoselectivity [28, 31]. However, Bargmann-Leyder et al. reported pressure-related changes in selectivity for an amylose-based CSP, though the magnitude of the pressure effect was not the same for all the compounds studied [58]. Pressures in the range of 15-20 MPa are common for chiral SFC. 

The only groups in Table 9.5 with negative values of CT/ are the alkyl groups methyl and tert-butyl. There has been some controversy on this point. One opinion is that CT/ values decrease in the series methyl, ethyl, isopropyl, /ert-butyl (respectively, — 0.046, —0.057, —0.065, —0.074). Other evidence, however, has led to the belief that all alkyl groups have approximately the same field effect and that the a/ values are invalid as a measure of the intrinsic field effects of alkyl groups. Another attempt to divide ct values into resonance and field contributions is that of Swain and Lupton, who have shown that the large number of sets of ct values (cTm, <3p, a, a+, CT/, csp etc., as well as others we have not mentioned) are not entirely independent and that linear combinations of two sets of new values F (which expresses the field-effect contribution) and R (the resonance contribution) satisfactorily express 43 sets of values. Each set is expressed as... 

The symbol csp is also used in the literature sometimes in place of O/, and sometimes to indicate only the field (not the inductive) portion of the total effect (p. 17). 

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