Effect of Carbamoylation and Pendant Carbamate Residue

FIGURE 1.9 Selection of cinchonan carbamate CSPs that have been prepared in the course of selector optimization studies (type I prototype type II, O-9-linked thiol-silica supported prototype type III, C-ll-linked thiol-silica supported CSPs type IV, dimeric selectors). (Adapted from M. Lammerhofer and W. Lindner, J. Chromatogr. A, 741 33 (1996) W. Lindner et al., PCT/EP97/02888, US 6,313,247 B1 (1997) P. Franco et ah, J. Chromatogr. A, 869 111 (2000) C. Czerwenka et ah. Anal. Chem., 74 5658 (2002).) 

Replacement of the carbamate group with isosteric functionalities such as an IV-methyl carbamate, urea, or amide group clearly confirmed the favorable qualities of the carbamate group [57], While the introduction of a urea group, as in case of iV-9-(tert-butylcarbamoyl)-9-desoxy-9-aminoquinine selector, instead of carbamate functionality turned out to be virtually equivalent in terms of enantiorecognition capabilities [57,58], the enantiomer separation potential was severely lost on iV-methylation of the carbamate group, like in 0-9-(N-me hy -N-tert-butylcarbamoyl)quinine [32,58], or its replacement by an amide, such as in case of Af-9-(pivaloyl)-9-desoxy-9-aminoquinine selector [57,58], For example, enantioselectivities dropped for DNB-alanine from 8.1 for the carbamate-type CSP, over 6.6 for thein-ea-type CSP, to 1.7 for the amide-type CSP, and 1.3 for the A -methyl 

FIGURE 1.10 Comparison of enantiomer separations of DNB-Leu on quinine (QN) based and 0-9-(terf-butylcarbamoyl)quinine (tBuCQN) based CSPs. 1, ionic interaction 2, jt-7T-interaction 3, hydrogen bonding 4, steric interaction. Experimental conditions Eluent, methanol-0.1 M ammonium acetate (80 20 v/v) (pHa = 6.0) flowrate, 1 mLmin temperature, 25°C column dimension, 150 x 4 mm ID detection, UV 250 nm. Selector loadings, 0.37 and 0.30 mmol g l for QN- and tBuCQN-based CSPs, respectively. (Reproduced from A. Mandl et ah, J. Chromatogr. A, 858 1 (1999). With permission.) 

Moreover, it could be figured out that an effective means to modulate the stereorecognition capabilities of the cinchonan selector motif may be via the carbamate residue. It offers a way of straightforward introduction of bulky alkyl substituents, which may affect the accessibility of active binding sites and/or lead to additional supportive Van der Waals-type interactions. 

To verify such a steric effect a quantitative structure-property relationship study (QSPR) on a series of distinct solute-selector pairs, namely various DNB-amino acid/quinine carbamate CSPpairs with different carbamate residues (Rso) and distinct amino acid residues (Rsa), has been set up [59], To provide a quantitative measure of the effect of the steric bulkiness on the separation factors within this solute-selector series, a-values were correlated by multiple linear and nonlinear regression analysis with the Taft s steric parameter Es that represents a quantitative estimation of the steric bulkiness of a substituent (Note s,sa indicates the independent variable describing the bulkiness of the amino acid residue and i s.so that of the carbamate residue). For example, the steric bulkiness increases in the order methyl ethyl n-propyl n-butyl i-propyl cyclohexyl -butyl iec.-butyl t-butyl 1-adamantyl phenyl trityl and simultaneously, the s drops from -1.24 to -6.03. In other words, the smaller the Es, the more bulky is the substituent. The obtained QSPR equation reads as follows  

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