Mosher s reagent

Diastereomeric derivathation of a chiral alcohol (111) with an enantiopure compound such as Mosher s reagent [20445-33-4] (a-ttifluoromethyl-a-methoxy-a-phenylacetjichloride) (112) (91) results in two distinct compounds (113) and (114) with nonequivalent chemical shifts in the H-nmr spectmm (92). 

Additionally, information about the absolute configuration of the analyte can be obtained from the sign of the chemical shift differences of the diastereomers. This will be discussed here. Use of other substituted phenylacetic acids fulfilling a similar purpose to Mosher s reagent will be described partly in this section and in the following one. 

About 20 different carboxylic acids have been tested by Dale and Mosher for comparison with MTPA 5. Some of them (mandelic and O-methylmandelic acid) have been partly described in the previous section together with MTPA. Some new and important acids have been added since. Figure 1 shows MPTA and a number of carboxylic acids which can be used in a similar way to Mosher s reagent. 

Lactols derived from camphor, such as CT 6 0-octahydro-7,8,8-trimethyl-4,7-methanobenzo-furan-2-ol and its dimer are in many cases advantageous as chiral derivatizing reagents. It is described in the following section as (+)- and (-)-MBF-OH or in accordance with Mosher s reagent as Noe s lactol (Figure 8). 

Mosher s reagent may be used for thiols in a similar way as for alcohols, as demonstrated with 1 -phenylthioethanol46. 

The enantiomeric excess (% ee) of these compounds was determined by the submitters as follows. The ester and acids were first reduced to the corresponding alcohols with DIBAL and LAH, respectively. The alcohols were then allowed to react with 100% excess of (S)-(+)-o-methoxy-o-trifluoromethylphenylacetyl chloride (Mosher s reagent) in (1 1) pyridine-carbon tetrachloride for 18 hr. The diastereomeric ratio of these derivatives was finally determined by isothermal gas chromatography on a capillary OV-17 column at 160°C. 

The keto acid could not be resolved as easily as it was synthesized. Formation of salts with various optically pure bases invariably yielded oils. Ketalization of the keto ethyl ester with ethylene glycol followed by reduction with lithium aluminum hydride and treatment with Mosher s reagent, (+)-a-methoxy-a-trifluoromethylphenylacetyl chloride (17,18,19>, gave a diastereomeric mixture (Scheme 7), which unfortunately was not resolvable by HPLC. 

Hydroxy-3-phenylbutanoic acid lactone Mosher s reagent... 

Alternative Reagents. 1-(1-Phenyl)ethyl isocyanate (PEI) is a cheaper alternative to NEI however, diastereomers formed from NEI are usually easier to separate by liquid chromatography. Other alternatives are also used, e.g. in determining the enantiomeric purity of 3-aminoquinuclidine, PEI, NEI, 2,3,4,6-tetraacetyl-p-D-glucopyranosyl isothiocyanate, and (R,R)- and (S,S)-0,0-dibenzoyltartaric acid anhydride are all employed successfully. Mandelic Acid and Mosher s reagent, a-methoxytrifluoromethylphenylacetyl chloride, may not be quite as effective as NEI when resolutions are carried out by liquid chromatography. ... 

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. 

Apart from chiral HPLC methods, H NMR spectroscopy has often been used to determine the enantiomeric excess (ee[%] = [(R-S)/(R+S) x 100) of an asymmetric synthesis by derivatization with chiral (enantiomerically pure) reagents, e.g. Mosher s reagent, a-methoxy-a-trifluoromethyl-phenylacetic acid (MTPA) [1], Recently, international authorities, e.g. the European Pharmacopoeia Commission, have encouraged for the introduction of NMR spectroscopy for chiral analysis. 

Perhaps no reagent for enantiomeric resolution is more widely known than a-methoxy-a-trifluoro-methylphenylacetic acid (MTPA), otherwise known as Mosher s reagent [1]. Either the acid or acid... 

Me ether [20445-31-2]. OL-Methoxy-OL- trifluoromethyl) benzeneacetic acid, 9CL 2-Methoxy-2-phenyl 3,3,3-trifluoropropanoic acid. MTPA. Mosher s reagent. 3,p,p,-Trifluoro-(X-methoxyhydratropic acid, SCI C,oH9F303 M 234.174... 

Overall, Mosher s reagent, although still useful for the determination of enantiomeric purity by NMR spectroscopy, is not recommended for the determination of the absolute configuration of secondary alcohols by NMR. Such assignments should be made using other, more-reliable reagents. 

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