Optical methods specific rotation

Optically Active PO. The synthesis of optically pure PO has been accompHshed by microbial asymmetric reduction of chloroacetone [78-95-5] (90). (3)-2-Meth5loxirane [16088-62-3] (PO) can be prepared in 90% optical purity from ethyl (3)-lactate in 44% overall yield (91). This method gives good optical purity from inexpensive reagents without the need for chromatography or a fermentation step. (3)-PO is available from Aldrich Chemical Company, having a specific rotation [0 ] ° 7.2 (c = 1, CHCl ). 

Part—IV has been entirely devoted to various Optical Methods that find their legitimate recognition in the arsenal of pharmaceutical analytical techniques and have been spread over nine chapters. Refractometry (Chapter 18) deals with refractive index, refractivity, critical micelle concentration (CMC) of various important substances. Polarimetry (Chapter 19) describes optical rotation and specific optical rotation of important pharmaceutical substances. Nephelometry and turbidimetry (Chapter 20) have been treated with sufficient detail with typical examples of chloroetracyclin, sulphate and phosphate ions. Ultraviolet and absorption spectrophotometry (Chapter 21) have been discussed with adequate depth and with regard to various vital theoretical considerations, single-beam and double-beam spectrophotometers besides typical examples amoxycillin trihydrate, folic acid, glyceryl trinitrate tablets and stilbosterol. Infrared spectrophotometry (IR) (Chapter 22) essentially deals with a brief introduction of group-frequency... 

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amount of enantiomers in a mixture is often measured by nonpolarimetric methods, use of the term percent optical purity is obsolete, and in general has been replaced by the term percent enantiomeric excess (ee) (equation 2) introduced in 197163, usually equal to the percent optical purity, [/ ] and [5] representing the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. 

An interesting example of a chemical method for determining the absolute configuration of diastereomeiic a-phenylethyl p-tolyl sulfoxides 195 based on the stereospecific sulfinate-sulfoxide conversion has been reported by Nishio and Nishihata (206). In this work optically active a-phenylethyl p-tolyl sulfoxides 195 and the corresponding sulfones 196 were prepared in two different ways and their specific rotations compared (see Scheme 18). Thus, oxidation of (-H5c) Phenylethyl p-tolyl sulfide 197 with hydrogen peroxide... 

As in the case of other chiral compounds, the optical and enantiomeric purity of chiral organosulfur compounds can be determined by various methods (241). The simplest and most common method for the determination of optical purity of a mixture of enantiomers is based on polarimetric measurements. However, this method requires a knowledge of the specific rotation of the pure enantiomer. In the... 

The polarimetric method, in combination with the results of chemical correlation, made it possible to determine the optical purity of a range of chiral sulftnates (105-107), thiosulfinates (35,105), and sulfinamides (83) with the sulfur atom as a sole center of chirality. These compounds were converted by means of Grignard or alkyl-lithium reagents into sulfoxides of known specific rotations. This approach to the determination of optical purity of chiral sulfinyl compounds has at least two limitations. The first is that it cannot be applied to sterically hindered compounds [e.g., t-butyl /-butanethio-sulfinate 72 does not react with Grignard reagents]. Second, this... 

An interesting method for the estimation of optical purity of sulfoxides, which consists of the combination of chemical methods with NMR spectroscopy, was elaborated by Mislow and Raban (241). The optical purity is usually determined by the conversion of a mixture of enantiomers into a mixture of diastereomers, the ratio of which may be easily determined by NMR spectroscopy. In contrast to this, Mislow and Raban used as starting material for the synthesis of enantiomeric sulfoxides a diastereomeric mixture of pinacolyl p-toluenesulfinates 210. The ratio of the starting sulfinates 210 was 60.5 39.5, as evidenced by the H NMR spectrum. Since the Grignard reaction occurs with full stereospecificity, the ratio of enantiomers of the sulfoxide formed is expected to be almost identical to that of 210. This corresponds to a calculated optical purity of the sulfoxide of 20%. In this way the specific rotations of other alkyl or aryl p-tolyl sulfoxides can conveniently be determined. 

Since the early times of stereochemistry, the phenomena related to chirality ( dis-symetrie moleculaire, as originally stated by Pasteur) have been treated or referred to as enantiomericaUy pure compounds. For a long time the measurement of specific rotations has been the only tool to evaluate the enantiomer distribution of an enantioimpure sample hence the expressions optical purity and optical antipodes. The usefulness of chiral assistance (natural products, circularly polarized light, etc.) for the preparation of optically active compounds, by either resolution or asymmetric synthesis, has been recognized by Pasteur, Le Bel, and van t Hoff. The first chiral auxiliaries selected for asymmetric synthesis were alkaloids such as quinine or some terpenes. Natural products with several asymmetric centers are usually enantiopure or close to 100% ee. With the necessity to devise new routes to enantiopure compounds, many simple or complex auxiliaries have been prepared from natural products or from resolved materials. Often the authors tried to get the highest enantiomeric excess values possible for the chiral auxiliaries before using them for asymmetric reactions. When a chiral reagent or catalyst could not be prepared enantiomericaUy pure, the enantiomeric excess (ee) of the product was assumed to be a minimum value or was corrected by the ee of the chiral auxiliary. The experimental data measured by polarimetry or spectroscopic methods are conveniently expressed by enantiomeric excess and enantiomeric... 

Following the structure proof of the alkaloids by degradation, Hughes et al. (.18) synthesized (—)-0-methylcryptaustoline iodide (14) by methods elaborated by Schopf and Robinson. ( )-Laudanosine was resolved by quinic acid (79), and (S)-(-)-laudanosine was 0-demethylated by Schopf s procedure, oxidized by chloranil, and remethylated to afford chiral 14 as the iodide in 40% yield. Their product had the same specific rotation and melting point as O-methylcryp-taustoline iodide obtained from the natural alkaloid 1. Methine derivatives obtained from synthetic and natural compounds had identical optical properties. 

A requirement for determination of optical purity (P) is that the specific rotation of the pure enantiomer, [a]max, is known with certainty. This maximum rotation can be established by calculation, e.g., via competitive reaction methods41,42, or by direct determination employing an enantiomerically pure sample. Enantiomerically pure samples are generally believed to arise from enzymatic reactions performed on biogenic substrates, an assumption which in some instances is incorrect31, or are obtained in most cases by crystallization2. As many direct, nonchiroptical methods are available for determining enantiomeric purities, maximum rotations can also be extrapolated from the specific rotation of a sample of known ee. 

The optical properties of the components of petroleum have been of major importance in connection with their identification and in the determination of purity. The primary effort has been directed to the study of pure hydrocarbons and only limited work has been concerned with the prediction of the index of refraction and the specific rotation of hydrocarbon mixtures. Table V summarizes the optical properties of a number of the principal components of petroleum. Only a few references to the optical properties of pure hydrocarbons of primary interest to the analyst have been included. Developments (9) in refractometers have materially increased the potentialities of the index of refraction measurements at atmospheric pressure as an analytical method. Consideration of the pertinent data in this field is beyond the scope of the present discussion. Reviews of developments in infrared (24, 26) and mass spectrometry (68) are available. 

Thus a racemic mixture (n1 = n2) has an enantiomeric purity of zero. Any other enantiomeric composition in principle can be determined provided the mixture has a measurable rotation and the rotation of the pure enantiomer, a0, is known. Unfortunately, there is no simple method of calculating a0 in advance. In fact, specific rotations of optically pure compounds are determined most reliably from Equation 19-4 after measurement of enantiomeric purity by independent methods. 

Racemic V could not be resolved with primary optically active bases presumably because they reacted in a Michael fashion. Formation of the quinine salt and five recrystallizations from a benzene/hexane mixture yielded an acid (after hydrolysis) whose specific rotation was [a]jP -47°. However, since the maximum specific rotation is unknown, an absolute method of determining optical purity is needed. The usual method is treatment with an optically pure derivatizing reagent to form covalent diastereo-mers, whose ratio can be determined by NMR or chromatography. 

Assay, Acidity, and Optical (Specific) Rotation Determine as directed in the monograph for all-rac-a-Tocopherol. Lead Determine as directed in the Flame Atomic Absorption Spectrophotometric Method under Lead Limit Test, Appendix IIIB, using a 10-g sample. 

All of these graft polymers retained some optical activity but the method of synthesis results in racemization thus no specific rotations are recorded b By elemental analysis... 

Z-Glu(OtBu)-Ala-Glu(OtBu)-OPcp [(from EtOAc) yield 78% mp 132-133 C [a]o -13.2 (c 2, CHCI3)] and Z-Glu(OtBu)-Ala-OPcp [(from MeOH) yield 64% mp 171-172 C mp 173-174 C after three crystallizations, [a]o —18.5 (c 1.33, CHCI3)] were prepared from the acid and HOPcp using DCC according to Section 3.2.1.1.3.The protected tripeptide ester had the same specific rotation as that prepared by coupling the protected dipeptide hydrazide and the amino add ester by the acyl azide method. The two esters prepared by direct esterification were demonstrated by indirect optical rotation measurements to be >99.6 and 98% enantiomerically pure, respectively. 

Other methods have also been used for determining absolute configuration in a variety of molecules, including optical rotatory dispersion, circular dichroism, " and asymmetric synthesis (see p. 166). Optical rotatory dispersion (ORD) is a measurement of specific rotation, [a], as a function of wavelength. The change of specific rotation [a] or molar rotation [[Pg.160]

Optical rotation has the dual advantages of historical use and widespread recognition in the compendia. For an enantiopure material, it defines its configuration when used in conjunction with other valid chemical tests. However, optical rotation has been used ineffectively when the primary analytical goal is the determination of stereochemical purity. The limits selected for the specification seem to be unrelated to the purity required by other methods. For example, the compendial monograph for naproxen requires that the drug substance meet a specification of "between -f-63.0 and -1-68.5"" in a chloroform solution. Based on the published specific rotation, this corresponds to a stereochemical purity of 95.5 to 103.7%, compared to the assay limits of 98.5 to 100,5%, determined by titration with sodium hydroxide (5). 

A relatively common use of optical rotation is as an identity test for a racemate with specification limits that are symmetrical around zero. Such a specification has Little if any regulatory significance. Its validation necessarily depends upon knowledge of the specific rotation and thus requires the resolution of the racemate on a laboratory scale. Furthermore, even with such supporting data, the method is dependent upon the accuracy of the sample preparation, since a solvent blank would also show a rotation of zero. Other analytical methods are far more appropriate for the stereochemically specific identification of racemates. 

The product Is very moisture sensitive and should be handled under dry nitrogen or argon. Despite this precaution, the product 1s always contaminated by small amounts of (+)-c1trone11a1, which has an optical rotation opposite to that of the enamlne. To determine the optical purity of the product enamlne, the specific rotation measured therefore must be corrected for the (+)-c1tronellal Impurity. It is more reliable to base optical purity on the specific rotation of the citronellal obtained by hydrolysis of the enamlne (Part C). The absolute method using HPLC of the diastereomeric amide derivative also may be useful as a check of the optical purity. 

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