Poly-proline-based chiral stationary phases are relatively new stationary phases and have shown to be competitive to other commercially available chiral stationary phases for high performance liquid chromatography (HPLC). The conformational studies, solvation properties and enantio-selective mechanism of this chiral stationary phase are the main focus of this thesis. Semi-flexible models are developed based on an extensive series of ab initio calculations for proline selectors from di- to hexa-proline and a series of six chiral analytes. Then molecular dynamics simulations are performed to study the solvation, conformational preferences at the interface, and the selectivity. The solvation and conformational preferences of poly-proline selectors at the interface are examined in a normal phase n-hexane/-2propanol and a reverse phase water/methanol solvent. We noticed a significant difference between conformational preferences of poly-proline chains in these solvents indicating the effect of solvent polarity and hydrogen bonding on the relative stabilities of poly-proline conformers. Solvent partitioning occurs at the interface and this creates a polarity gradient between the stationary phase and the bulk that encourages analyte docking at the interface. Hydrogen bonding to the poly-proline selectors is shown to be a function of solvent composition and poly-proline conformation at the interface. The selectivity of the poly-proline chains was studied by molecular dynamics simulations of chiral analytes docking into the interface. The selectivity factors for a set of enantiomers were predicted successfully. Enantio-resolution has been shown to mostly happen with hydrogen bonding to poly-proline carbonyl oxygens located close to the interface. Steric interactions and conformational flexibility of the analytes are also contributing factors for enantio-resolution. / Thesis (Ph.D, Chemistry) -- Queen's University, 2013-01-28 14:31:53.316

Direct chiral separations of the non-steroidal drugs of 2-methylarylpropionic acids (profens) on the chiral stationary phases (CSPs) of amylose tris(3,5-dimethylphenyl-carbamate), Chiralpak AD, and cellulose tris(3,5-dimethylphenylcarbamate), Chiralcel OD, were investigated. Chiralpak AD and Chiralcel OD are CSPs coated on silica gel and have the same type of constituents. However, they have different higher order structures arising from their different arrangements of the glucose units, i.e., the former has an a-(1,4)-D-glucose linkage and the latter has a b-(1,4)-D-glucose linkage. The orders of optimum enantioselectivity of racemic acids were reversed on the two CSPs which demonstrated that the enantioseparating abilities of these CSPs are complementary. This phenomenon also confirmed that the chiral recognition abilities of both CSPs were dependent on their higher order structures. Mechanisms for retention and chiral recognition for the separation of racemic 2-methylarylpropionic acids on Chiralpak AD and Chiralcel OD were explored. In depth studies of the dependence of retention and enantioselectivity on temperature and mobile phase compositions were made. The thermodynamic parameters, the differences in free energy, enthalpy, and entropy of association between enantiomers and the CSP were evaluated. The results indicated that the retention of racemic acids on both CSPs is mainly dependent on the hydrogen bonding interaction between the acid proton of the carboxyl moiety of the analyte and the carbonyl oxygen of the carbamate moiety of the CSP. The chiral recognition mechanism for Chiralpak AD involves: (1) the formation of transient diastereomeric analyte-CSP complexes through hydrogen bonding interactions between the carboxyl and the carbamate moieties of the acid and CSP, respectively; (2) stabilization of these complexes by insertion of the aromatic portion of the analytes into the chiral cavities of the CSP, as well as pi-pi, dipole-dipole, and additional hydrogen bonding interactions between analyte and CSP; and (3) chiral discrimination between enantiomer analytes arising from the additional hydrogen bond between analyte and CSP. For Chiralcel OD, the chiral recognition mechanisms involve: (1) the formation of transient diastereomeric analyte-CSP complexes through hydrogen bonding interactions between the carboxyl and the carbamate moieties of the acid and CSP, respectively; (2) stabilization of these complexes by insertion of the aromatic portion of the analytes into the chiral cavities of the CSP, as well as pi-pi and dipole-dipole interactions between analyte and CSP; and (3) chiral discrimination due to: (a) the difference in the steric fit of enantiomers into the chiral cavity of the CSP (entropy controlled); and (b) dipole-dipole or p-p interactions between enantiomer analytes and CSP (enthalpy controlled). Chromatographic and quantitative thermodynamic data showed that there are at least two different chiral recognition mechanisms for Chiralcel OD. One mechanism was characterized by negative values for the enthalpy and entropy differences of the association between enantiomers and CSP that classifies the enantioseparation to be enthalpy controlled. This behavior was exhibited by racemic 2-methylarylpropionic acids with fused rings that were favorably separated at low temperatures. The other mechanism was associated with positive values for the enthalpy and entropy differences of the association between enantiomers and CSP, and the enantioseparation is said to be entropy controlled. The analytes with "free" phenyl moieties favored high temperatures for their enantioseparations. Both studies on the effects of temperature and mobile phase composition also indicated that the higher order structures of CSPs influence their chiral recognition abilities. / Ph. D.

The mechanism by which chiral selectivity takes place is complicated by the surface morphology, the possible involvement of the solvent, and the characteristics of the chiral molecules at the surface. My goal is to model and understand the factors which lead to significant discrimination in the case of three closely related chiral stationary phases: N-(1-phenylethyl)-N’-[3-(triethoxysilyl)propyl]-urea (PEPU), [(3,5-dinitrobenzoyl)-amino]-N-[3-(triethoxysilyl)propyl]-2-phenylacetamide (DNB-phenyglycine), and [(3,5-dinitrobenzoyl)amino]-N-[3-(triethoxysilyl)propyl]-4-methylpentanamide (DNB-leucine). Ab initio calculations are used to develop molecular models of these chiral selectors. These models are employed in molecular dynamics (MD) simulations, which provide the theoretical framework for modelling chiral interfaces in different solvent mixtures. The MD simulations of PEPU interfaces show that, in alcohol/water mixtures, the alcohols form domains at the interface with the hydrophobic portions of the molecule tending to orient towards the surface. This disrupts the water hydrogen bonding networks at the interface and leads to the exclusion of water from the surface region relative to the bulk. The MD simulations of DNB-phenylglycine and DNB-leucine selectors in hexane/2-propanol mixtures demonstrate that the interfaces are distinct both in terms of the selector orientations at the surface and in the number of hydrogen bonds formed with 2-propanol. This occurs despite the structural similarity between these two selectors. The interfaces are also prepared experimentally by attaching the chiral selectors onto oxidized Si(111) samples and AFM tips. In particular, for DNB-phenylglycine and DNB-leucine samples, two synthetic routes have been explored. Using AFM, the morphologies of the resulting chiral interfaces are obtained. X-ray photoelectron spectroscopy and refraction-absorption infrared spectroscopy provide information regarding the relative distribution of the compounds on the surface. Using chemical force microscopy (CFM) measurements, chiral self-selectivity is examined in various solvent mixtures. For PEPU interfaces, the extent of hydrogen bonding at the surface is the dominant contributor to the measured forces. In the case of DNB-phenylglycine and DNB-leucine, CFM measurements of the chiral self-selectivity in 2-propanol demonstrate that chiral discrimination is present in both systems, but larger forces are observed for DNB-phenylglycine, consistent with the molecular dynamics study that shows much weaker solvent interactions with this species. / Thesis (Ph.D, Chemistry) -- Queen's University, 2008-08-14 11:26:37.436

The aim of this work was finding suitable conditions for separation of enantiomers of citalopram and citadiol, optimization of chromatographic system and validation of the analytical method for determination of selected enantiomers in drugs. Drugs are often chiral compounds. In many cases, only enantiomer has required pharmacological effects. Advanced chemical technologies associated with the synthesis, separation and analysis of the individual enantiomers caused an increase of the number of new chiral drugs in the form of single pure enantiomers, the chiral switch. Citalopram is one of the widely used antidepressants of selective serotonin reuptake inhibitors (SSRI). Citalopram is used for treatment of depression, panic anxienty or obsessive compulsive disorder of pathological laughing and crying. The pharmacological activity is associated with the S-citalopram, while R-enantiomer is essentially inactive and even counteracts the activity of escitalopram. Citadiol is a chiral syntetic precursor of citalopram. This thesis was focused on monitoring enantioseparation "behaviour" of selected enantiomers. HPLC method with chiral stationary phases based on macrocyclic antibiotics, cyclofructans and cellulose was applied for enantioseparation of the above-mentioned compounds. The optimized chromatographic...

The aim of this work was to develop and to optimize HPLC method for enantioseparation of newly synthesized derivatives of amino acids. The set of these analytes contained four N- blocked derivatives of D,L-Phenylalanine, three N-unblocked derivatives of D,L- Phenylalanine, , one methylated derivative of D,L-Tyrosine and D,L-Tyrosine. Two separation modes i.e. reversed phase and polar-organic modes and two columns i.e. Chirobiotic® T and Chirobiotic® T2 were used. Chiral stationary phases of these columns were composed of macrocyclic antibiotic teicoplanin coated on silica gel support. As mobile phases in revesed phase mode, methanol and acetate buffer were used with Chirobiotic® T column. The most suitable concentration were 20 mM and the most suitable pH value were 4.00. Under the above mentioned conditions eight analytes of ten were separated and the optimal conditions were found. Polar-organic mode and Chirobiotic® T column were suitable only for enantioseparation of three N-blocked derivatives of D,L- Phenylalanine. Mobile phases were composed of methanol with small additions of triethylamine and acetic acid. Chirobiotic® T2 column in reversed phase mode was not suitable for tested set of analytes. Only partial separation of D,L-Tyrosine derivative and one N-unblocked D,L-Phenylalanine...

This diploma thesis is focused on the comparison of enantioselective potential of chiral stationary phases based on derivatized cellulose by high performance liquid chromatography (HPLC). Polysaccharide - based chiral stationary phases are suitable choice for enantioseparation of various chiral compounds. In this work Chiralpak IB column containing cellulose tris(3,5-dimethylphenylcarbamate) selector immobilized onto silica gel and Chiralpak IC column containing cellulose tris(3,5- dichlorophenylcarbamate) selector immobilized onto silica gel were used. Their ability of enantioseparation was tested on 28 structurally different chiral analytes. Reversed- phase separation mode was used for enantioseparation. Mobile phases were composed of organic modifiers acetonitrile or methanol and the aqueous part was selected according to the nature of analytes. Acidic analytes were separated in mobile phases containing aqueous solution of formic acid (pH 2.1). Analytes of bifunctional nature were separated in the presence of aqueous solution of formic acid (pH 2.1), 10 mM ammonium acetate buffer (pH 8.8) or 100 mM solution of KPF6. Mobile phases containing 10 mM ammonium acetate buffer (pH 8.8) or 100 mM solution of KPF6 were used for enantioseparation of alkaline chiral analytes. Twelve chiral analytes were...