Separation of isomers

Distillation of crude nitrotoluene. The still kettle is of 60 m3 capacity, heated with 18.5 atm steam. The column has 40 plates, 8 m height, 2 m diameter. 

of the crude, steam distilled and dried nitrotoluene are sucked into the still while heating up. Distillation begins under reduced pressure (15 mm Hg on the receiver and 120 mm Hg in the kettle) at a still temperature of 160°C. First runnings (ca. 200 1.) have a setting point lower than -10°C and contain nitrobenzene. As soon as the setting point reaches -10°C the second fraction (mainly o nitrotoluene) is collected at a still base temperature of 180°C. The bulk of this faction has a setting point of -9.2°C. 

When the contents of the still have a setting point of 40°C, the column is emptied into the base and distillation is continued without the column, at the still base temperature 185°C. This third fraction (mainly p-nitrotoluene) has a setting point of 40°C. The residue is tar. 

Crystallization of p- nitrotoluene. 8000 1. of crude molten p- nitrotoluene are charged into a tubular crystallizer, cooled to 39-40°C Mid this temperature is maintained for 24 hr. Then the whole is cooled to 18°C for 24 hr and the crystallizer is opened. The mother liquor is collected Mid the crystalline contents heated slowly to 50°C. The oil that was drawn off is collected sepMately and when it reaches 

Distillation of the mother liquor. 10,000 kg of p- nitrotoluene mother liquor are sucked into a still of 10 m3 capacity with a column of 40 plates, of 8 m height and 1 m diameter. Distillation conditions are the same as in the distillation of crude nitrotoluene. 

Other interesting examples of positional isomer separation involving NPC are (a) the separation of dihydrodipyridopyridopyrazines, a new family of antitumor agents, on a silica Nucleosil 50 A-lOpm column [43] and (b) the separation of celecoxib isomers by Chiralpak AD column [44], NPC was also employed successfully for the resolution of (a) four configurational isomers of a steroidal calyx pyrrole [45], (b) regio- and stereoisomers of eicosanoids [46], (c) retinal and retinol isomers [47], and (d) several ElZ isomers pairs of vitamin A [48], 

In certain cases, such as the separation of PAHs obtained from a coal liquefaction process, using reversed-phase HPLC is complicated as sample preparation is elaborate. This is due in large part to the fact that most complex fuel-related materials contain compounds that are not usually soluble in acetonitrile, the solvent of choice in reversed-phase HPLC. Here, NPC, which employs a variety of solvents, offers an alternative to the analysis of such samples. Separation of five well-studied coal liquefaction process stream samples was achieved and 19 isomers were resolved when NPC was used [33]. The method employed a tetrachlorophthalimidopropyl-modified silica column (TCPP) with a charge-transfer mechanism. 

The mobility coefficient is dependent on shape and charge distribution and not only on mass thus, structural and geometric isomers that are isobaric (and nnresolved in most MSs) may be separated by IMS. This was danonstrated early in development of IMS and seen then as an attraction of mobility-based measurements. This feature of isomer separation can be controlled by the composition of the supporting gas 

The mobilities of 18 amines from three types of strnctnral classes (primary, secondary, and tertiary) were measnred by IMS nsing fonr types of drift gases (helium, argon, nitrogen, and COj). The predictions of mobility valnes based on the commonly used theoretical models were compared with the experimental data. The model that appeared to have the best lit was the model that considered the displacement of the center of mass from the center of charge for the polyatomic ions. However, the main challenge is to separate isomeric ions that overlap in the mobility spectrum in air, the most commonly used drift gas. 

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Sulfonic acids may be hydrolytically cleaved, using high temperatures and pressures, to drive the reaction to completion. As would be expected, each sulfonic acid has its own unique hydrolytic desulfonation temperature. Lower alkane sulfonic acids possess excellent hydrolytic stability, as compared to aromatic sulfonic acids which ate readily hydrolyzed. Flydrolytic desulfonation finds use in the separation of isomers of xylene sulfonic acids and other substituted mono-, di-, and polysulfonic acids. 

More specific methods involve chromatographic separation of the retinoids and carotenoids followed by an appropriate detection method. This subject has been reviewed (57). Typically, hplc techniques are used and are coupled with detection by uv. For the retinoids, fluorescent detection is possible and picogram quantities of retinol in plasma have been measured (58—62). These techniques are particularly powerful for the separation of isomers. Owing to the thermal lability of these compounds, gc methods have also been used but to a lesser extent. Recently, the utiUty of cool-on-column injection methods for these materials has been demonstrated (63). 

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

Activation of the M. citricolor luciferin precursor with decylamine. The following mixture was incubated overnight at room temperature (23 24°C) luciferin precursors before the separation of isomers by F1PLC (50 pi, activity 2 x 1012 photons by the assay method described above), 30 mM Bis-tris buffer (pH 6.4, 4.5 ml) acetonitrile... 

There are two basic procedures that have been successfully used for the separation of isomers. The first is to add a chiral agent to the mobile phase such that it is adsorbed, for example, on the surface of a reverse phase, producing a chirally active surface. This approach has been discussed on page (38) in chapter 2. The alternative is to employ a stationary phase that has been produced with chiral groups bonded to the surface. 

If, 2 substitution is involved, one strategy may avoid separation of isomers in that the other position becomes blocked. 

Separation of isomers is an application where zeolite membranes could be specifically interesting because of their well-defined pores that lead to molecular sieving effects. An application that is often considered is the xylene isomerization and related reactions. 

In the recent past separation of isomers has been attempted using aqueous liquid membranes based on p-cyclodextrin. Thus, separation of a mixture of o- and p-nitroaniline (in 80% i-octanol, 20% -heptane) has been studied, with the p-isomer showing a selectivity of 5 at 0.7 molar p-cyclodextrin. Even stereoisomers of stilbene cis and trans) were separated using a 0.02 to 0.2 M cyclodextrin solution, but the selectivity was less than 2 (Mandal et al, 1998). 

For the chromatography of complex mixtures (separation of isomers or closely related compounds with similar retention), the main problem is to improve the... 

Much remains to be accomplished in the separation, isolation, and identification of both naturally occurring and synthetic bioactive materials effective in the germination of parasitic weed seeds. Structure-activity studies suffer from the lack of separation of isomers in most synthetic samples. Strigol is an important tool in basic studies on the effect of chemicals on seed germination, but it is highly unlikely that the compound will meet practical field... 

Partition chromatography, developed by Martin and Synge (3) for the separation of amino acid derivatives, was employed by Ramsey and Patterson (4) for the separation of isomers of benzene hexachloride (1,2,3,4,5,6-hexachlorocyclohexane) in the technical product. The work of Ramsey and Patterson was extended by Aepli, Munter, and Gall... 

If no separation of isomers is required, as when the mixture is to be hydrogenated, the mixed esters may be obtained by distillation yield, 75-90 g. (71-85%, based on starting aldehyde). It is extremely difficult to separate the A2- from the A3-ester by fractional distillation, as the two boil only 7° apart however, by careful fractionation and refractionation through an 0.8 X 125-cm. simple Podbielniak column with partial-reflux head,4 it is possible to obtain 3 pure ethyl 4-ethyl-2-methyl-2-octenoate, b.p. 102-103°/4.8 mm., o 1.4478, and a nearly pure sample of ethyl 4-ethyl-2-methyl-3-octenoate, b.p. 94-95°/4.8 mm., ng 1-4393. 

Adsorption chromatography on silica is well suited to the separation of less polar compounds such as polyaromatic hydrocarbons, fats and oils, and for the separation of isomers or compounds with differing functional groups. 

Taking into account the capacity of cyclodextrins (CD-s) to entrap a large number of organic and inorganic molecules, due to their hydrophobic cavity, [3-CD has been introduced into PVA in order to obtain a good separation of isomer mixtures. 

This procedure is based upon a study 1 of the method outlined in the patent literature.2 The procedure is a general one and may be used for the condensation of succinic anhydride with naphthalene and with the mono- and dimethylnaphthalenes, although in no other case are the purification and separation of isomers so easily accomplished. In this particular type of condensation, as well as in certain other types of Friedel-Crafts reactions, nitrobenzene is far superior to the solvents which are more frequently employed. This is partly because of its great solvent power and partly because it forms a molecular compound with aluminum chloride, and so decreases the activity of the catalyst in promoting side reactions. 

M.S. Narvekar and A.K. Srivastava, Separation of isomers of aromatic amines on HPTLC plates impregnated with 18-crown-6. J. Planar Chromatogr.-Mod. TLC 15 (2002) 120-123. 

In conclusion, the smaller is the particle size the better the separation however, a high pressure drop requires the optimum design of columns and instruments. A column well packed with spherical small particles has a high plate number, and is suitable for the separation of a homologous series of compounds. However, the separation of isomers requires a high selectivity of stationary and mobile phases as described in Chapters 3 and 4. 

In tandem MS, two or more stages of mass analysis are combined in one experiment. [79,80] Each stage provides an added dimension in terms of isolation, selectivity, or structural information to the analysis. Therefore, a tandem MS stage is equivalent to a chromatographic separation, provided the separation of isomers is not required. While chromatography distinguishes substances by their retention time, tandem MS isolates them by mass. [2,3,25] The principles of tandem MS have been discussed and some applications for stmcture elucidation and quantitation have already been shown (Table 12.1). However, the aspect of increased selectivity has not been addressed so far. [81]... 

Z. (1996) Chemical liquid deposition zeolites with controlled pore-opening size and shape-selective separation of isomers. Ind. Eng. Chem. Res., 35, 430. 

Pervaporation (PV) partial vapor pressure difference separation of isomers dehydration of organic liquids... 

Pure isomers are often used as starting products for fine chemicals (e.g., different drugs). The separation of isomers entails great difficulties because they often have boiling points differing by only a fraction of a degree and they have closely similar solubilities in many solvents. Solvent extraction processes for the separation of isomers, therefore, have to rely more on chemical reactions than on nonspecific physical interactions between the solute and the solvent. 

Institut Francais Du Petrole, Method for regulating a process for the separation of isomers of aromatic hydrocarbons having from 8 to 10 carbon atoms. Inventors F. CanseU, G. Hotter, P. Marteau, and N. Zanier. 29 Oct 1996. 16 pp. (incl. 7 fig.). Appl. 29 Jun 1994. Int. Cl. C07C 700. US Patent Specification 5,569,808... 

Despite its high reactivity, the a-chloro ester 1-Me does not polymerize like simple acrylates. However, in close analogy to other 1,1-disubstituted methyl-enecyclopropanes [29], 1-Me slowly dimerizes in a head-to-head fashion even at room temperature to give the two diastereomeric dimethyl dispiro[2.0.2.2]oc-tanedicarboxylates (E)- and (Z)-16 (ratio 1 1) (Scheme 5), and at 120 °C the dimerization proceeds almost quantitatively (89% isolated yield) [15]. Apparently the dimerization of 1-Me occurs considerably more readily than that of methylenecyclopropane [4a,b] and of bicyclopropylidene [4 d]. Surprisingly, under high pressure (10 kbar) this dimerization did not proceed more efficiently (Scheme 5) [30], but more cleanly, which facilitated the separation of isomers. 

Chromatography on silica and alumina is unique among the liquid chromatographic methods in providing maximum selectivity for tfie separation of isomers. It is no problem to separated m- and p-dibromobenzene (a s 1.8 in pentane) (2) or the three nitroanilines (79) on silica or alumina stationary phases with dichloromethane as eluent. 

Sane RT, Sonawane KK. Gas-chromatographic determination and separation of isomers of cresol from pharmaceutical preparation. Indian Drugs 25(10) 420-424. 

Acid-treated clays Alcylation reactions (e.g. of benzene with benzyl chloride) Dimerization reactions (e.g. of a-methylstyrene) Etherification reactions (e.g. of ferf-butanol with methanol) Condensation reactions (e.g. of cyclohexanone) Separation of close boiling aromatic amines Separation of isomers of xylene... 

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