Determination of enantiomer excess

The 191 problems in this book cover most of the area of stereochemistry, including nomenclature, stereogenic elements (centers, axes, planes) and their descriptors, symmetry, inorganic stereochemistry, determination of enantiomer excess, conformation of acyclic and cyclic compounds, and more. The answers, in addition to providing solutions to the problems, frequently include additional explanations of the underlying principles. The problems are ordered more or less in order of increasing difficulty. (I had a hard time with some of the problems toward the end myself )... 

In the field of essential oils, separation of individual enantiomers and determination of enantiomer excess play an important role in the characterization of plant material, in the investigation of the origin of the essential oil, and in the search of possible adulterations. Reliable assessment of the genuineness of essential oils is a difficult task, since synthetic analogs of essential oil components are commercially available. Therefore, suitable specific methods in the authenticity control of essential oils are of fundamental interest. Two-dimensional GC is a useful technique for both analytical and preparative purposes. After a separation of aroma components on a first column, they are on-line transferred to a second... 

NMR shift differences between groups which are enantiotopic by external comparison (i.e. in enantiomers) may likewise be induced by either chiral solvents 26 27) or chiral shift reagents 52). Integration of the areas of signals of enantiomers so shifted is used for the determination of enantiomeric excess, a topic which cannot be taken up here but has been discussed elsewhere 53). 

A review appeared on the practice and theory of enantioselective CGC with optically active selectors, e.g. 3-(perfluorobutyryl)-(17 )-camphorate residues forming complexes on a functionalized polysiloxane stationary phase (e.g. Chirasil, 65) SEC operates at temperatures lower than those of CGC, thus allowing better resolution, especially of thermally unstable enantiomers (e.g. those based on restricted free rotation, as is the case of dimethyl l,l -binaphthyl-2,2 -dicarboxylate, 66 ). Various analytical problems were addressed, such as determination of enantiomeric excess, assignment of absolute configuration, the elusive separation of protio- and deuterio-substituted enantiomers and the semipreparative separation of enantiomers. The following chromatographic parameters are related to the chemical and thermodynamic properties enclosed in parentheses of the enantiomeric system (i) peak retention (chemoselectivity, —AG), (ii) peak separation... 

Preparative Methods cheap and readily available racemic trans-1,2-diaminocyclohexane can be resolved with d-(—)-tartaric acid, giving (15, 25 )-diaminocyclohexane with >98% enantiomeric excess. Detailed procedures for the resolution have been published. Determination of enantiomeric excess is made by HPLC analysis of the A(Af -bis(m-toluyl) derivative on a Pirkle L-Leucine-DNB column. Direct separation of enantiomers by preparative HPLC on a chiral colunrn has also been described. ... 

With chiral stationary phases, chromatographic separation of enantiomeric ferrocene derivatives is possible. An apparatus for the resolution of ferrocenyl alcohols and other compounds on triacetylcellulose has been described [60]. Analytical enantiomer separation of ferrocenyl alcohols, ethers, sulfides, and amines for the determination of enantiomeric excesses is best achieved on cyclodextrin bonded phases [61]. 

Enantiomeric purity and enantiomeric excess (ee) are usual terms used in the determination of enantiomers. Enantiomeric purity is defined as the measured ratio (expressed as a percentage) of the detected enantiomers, whereas ee-values describe the relative difference of the separated enantiomers (expressed as a percentage). Usually quantifications are given in ee-values, but one should note, that convincing results can be concluded only for baseline-resolved enantiomers (cRs > 1.50). Exact calculations of partially resolved mirror images, as frequently happened in the current literature, remain unintelligible in view of differences in sensory qualities and odour thresholds of enantiomers Eig. 6.25, [1-9]. 

R518 R. Rothchild, NMR Methods for Determination of Enantiomeric Excess , Enantiomer, 2000, 5, 457... 

In conclusion, two points must be emphasized. First, the rationales presented in Figures 2.5 and 2.6 are only models, and do not necessarily represent preferred conformations. Second, it should be restated that in order for the CDA method to be accurate, any adventitious kinetic resolution in the derivatization must be quantitated or eliminated. For example, Heathcock has noted that MTPA derivatization of a racemic alcohol (0% ee) afforded a 1.7 1 mixture of Mosher esters (26% de) and the % ee determinations had to be corrected accordingly [42]. More recently, Svatos used a five-fold excess to force a derivatization to completion [43]. If the appropriate control experiments are done, derivatization with Mosher s reagent can be a very reliable method for determination of enantiomer ratios and absolute configuration of amines and alcohols. For the derivatization of ketones, chiral diols may be used [44], but similar control experiments should be undertaken. 

Second, it is easy to reverse the enantiomeric elntion order through the change in configuration of the selector or the enantiomer nsed as target. This appears of very great interest for the determination of enantiomeric excess. 

We found that the C3 chiral pro-azaphosphatrane li is an excellent tagging agent for the direct determination of enantiomeric excesses of chiral azides using both P- and H-NMR spectroscopy [121]. Thus the reaction in Eq. (13) is carried out in an NMR tube at 50 °C for 2 hours, followed by NMR spectroscopic analysis. The excellent separations of the P-NMR chemical shifts (ca 1 ppm) allowed the ratios of the diastereomeric imidophosphorane derivatives to be easily measured and these ratios were very close to the expected values for commercially purchased racemic and chirally pure compounds as well as various mixtures of two enantiomers. These ratios were also in good agreement with those measured by H-NMR spectroscopic integration of the proton shifts in the tagged product [see Eq. (13)]. 

Dauwe and Buddrus [12] tested a series of chiral amines for their ability to discriminate between the enantiomers of several acidic compounds. Strong basic amidines, as shown in Figure 6-8, turned out to be suitable for the resolution of even weak acidic compounds such as phenols, barbiturates and alcohols. The same group [13] developed chiral palladium complexes with diamines for discrimination of a-amino acids and determination of enantiomeric excess resulting from asymmetric synthesis. 

R 675 E.J. Tadeusiak, Studies of Racemate/ Enantiomer Systems and Determination of Enantiomeric Excess by High-Resolution Liquid and Solid State NMR Spectroscopy , Wiadomosci Chemiczne, 2003,57,367... 

The applicability of ROA for the determination of enantiomeric excess in mixtures of chiral enantiomers has been exploited. Using the test compound a-pinene an accuracy of 0.1% enantiomeric excess (ee) was achieved. 

The significant reliance of the pharmaceutical industry on the production of pure enantiomers has lead to an increased need for the rapid determination of enantiomeric composition, often represented as the enantiomeric excess (e.e.). As a result of this need, great efforts have been made to improve existing methods for determination of enantiomeric excess. The sensitivity of fluorescence-based methods have lead to various approaches for examining enantiomeric composition [15,16,36,37]. Recently, the use of fluorescence anisotropy to determine enantiomeric composition has been reported [38] and is detailed in this section. 

Figure 2.24, Determination of the enantiomeric excess of 1-phenylethanol [30, 0.1 mmol in 0.3 ml CDCI3, 25 °C] by addition of the chiral praseodymium chelate 29b (0.1 mmol), (a, b) H NMR spectra (400 MHz), (a) without and (b) with the shift reagent 29b. (c, d) C NMR spectra (100 MHz), (c) without and (d) with the shift reagent 29b. In the C NMR spectrum (d) only the C-a atoms of enantiomers 30R and 30S are resolved. The H and C signals of the phenyl residues are not shifted these are not shown for reasons of space. The evaluation of the integrals gives 73 % R and 27 % S, i.e. an enantiomeric excess (ee) of 46 %...

For the determination of the enantiomeric excess. 23 mg of the mi-hydroxy ester (containing 2 5% //-product) and 9 mg of tris[3-(heptafluoropropylhydroxymethylene)-a-camphorato]europium are dissolved in 0.5 mL of CDC13. The ec is calculated from the peak heights and areas of the resolved doublets, due to the methyl groups attached to C-2. of the minor (f) 1.74) and major (<5 1.98) enantiomers. 

The enantioselectivity of biocatalytic reactions is normally expressed as the enantiomeric ratio or the E value [la], a biochemical constant intrinsic to each enzyme that, contrary to enantiomeric excess, is independent of the extent of conversion. In an enzymatic resolution of a racemic substrate, the E value can be considered equal to the ratio of the rates of reaction for the two enantiomers, when the conversion is close to zero. More precisely, the value is defined as the ratio between the specificity constants (k st/Ku) for tho two enantiomers and can be obtained by determination of the k<-at and Km of a given enzyme for the two individual enantiomers. 

Kwakman et al. [65] described the synthesis of a new dansyl derivative for carboxylic acids. The label, N- (bromoacetyl)-A -[5-(dimethylamino)naphthalene-l-sulfonyl]-piperazine, reacted with both aliphatic and aromatic carboxylic acids in less than 30 min. Excess reagent was converted to a relatively polar compound and subsequently separated from the derivatives on a silica cartridge. A separation of carboxylic acid enantiomers was performed after labeling with either of three chiral labels and the applicability of the method was demonstrated by determinations of racemic ibuprofen in rat plasma and human urine [66], Other examples of labels used to derivatize carboxylic acids are 3-aminoperylene [67], various coumarin compounds [68], 9-anthracenemethanol [69], 6,7-dimethoxy-l-methyl-2(lH)-quinoxalinone-3-propionylcarboxylic acid hydrazide (quinoxalinone) [70], and a quinolizinocoumarin derivative termed Lumarin 4 [71],... 

Recent advances in gas chromatographic separations of enantiomers allow precise determination of the enantiomeric purity of the algal pheromones. The czs-disubstituted cyclopentenes, such as multifidene, viridiene, and caudoxirene, are of high optical purity [ 95% enantiomeric excess (e.e.)] whenever they have been found (32,33). The situation is different with the cyclopropanes and the cycloheptadienes, as shown in Table 2 and Figure 1. Hormosirene from female gametes or thalli of... 

For a nonracemic mixture of enantiomers prepared by resolution or asymmetric synthesis, the composition of the mixture was given earlier as percent optical purity (equation 1), an operational term, which is determined by dividing the observed specific rotation (Mobs) of a particular sample of enantiomer with that of the pure enantiomer ( max), both of which were measured under identical conditions. Since at the present, the amount of enantiomers in a mixture is often measured by nonpolarimetric methods, use of the term percent optical purity is obsolete, and in general has been replaced by the term percent enantiomeric excess (ee) (equation 2) introduced in 197163, usually equal to the percent optical purity, [/ ] and [5] representing the relative amounts of the respective enantiomers in the sample. 

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