Solid-phase catalyst extraction

Fluorous ligands introduce an ease of purification in that the tagged phosphine ligand, the palladium catalyst complexed ligand, and the oxidized ligand can be completely removed by direct fluorous solid-phase separation (F-SPE) prior to product isolation. Similarly, an example of a fluorous palladium-catalyzed microwave-induced synthesis of aryl sulfides has been reported, whereby the product purification was aided by fluorous solid-phase extraction [91]. 

Detection in liquid chromatography is mostly performed by fluorescence and/or ultraviolet absorption. In a few instances, electrochemical detection has also been employed (357, 368). For compounds that exhibit inherent intense fluorescence such as albendazole and metabolites (319, 320, 338, 355), closantel (344), and thiabendazole and metabolites (378), fluorometric detection is the preferred detection mode since it allows higher sensitivity. Compounds that do not fluoresce such as eprinomectin, moxidectin, and ivermectin, are usually converted to fluorescent derivatives prior to their injection into the liquid chromatographic analytical column. The derivatization procedure commonly applied for this group of compounds includes reaction with trifluoroacetic anhydride in presence of A-methylimidazole as a base catalyst in acetonitrile (346, 347, 351, 352, 366, 369, 372-374). The formation of the fluorophore is achieved in 30 s at 25 C and results in a very stable derivative of ivermectin and moxidectin (353) but a relatively unstable derivative of eprinomectin (365). However, the derivatized extracts are not pure enough, so that their injection dramatically shortens the life of the liquid chromatographic column unless a silica solid-phase extraction cleanup is finally applied. 

Systems have been developed that allow the recycling of catalysts. The first case study involved simple adsorption of proline onto silica gel [6], but the system suffered from a loss in enantioselectivity. More recently, promising results have been obtained with fluorous proline derivatives [64] used for aldol reactions the recycling of fluorous catalysts has been demonstrated using fluorous solid-liquid extraction. Solid phase-supported catalysts through covalent bonds [65] and through noncovalent interactions [66] were also used for aldol reactions. Proline and other catalysts can be recycled when ionic liquids or polyethylene glycol (PEG) were used as reaction solvents [67]. 

Fluorous reverse-phase silica gel (separation by solid phase extraction). The hydroxyl residues on silica gel are modified with perfluoroalkyl chains. This causes a fluorophilic effect between the fluorous reagent/ catalyst/product and allows facile separation independent of temperature. 

Fluorous affinity separation was originally used to remove catalysts from complex reaction mixtures [6], A perfluoroalkyl moiety (generally no shorter than -C6F13) is appended to a compound of interest. Tagged molecules are then rapidly separated from other components in the mixture by either liquid-liquid extraction or liquid-solid-phase extraction. Fluorous affinity-based separation has recently been used in biomolecule purification, proteomics, and microarray experiments [15-20],... 

Many compounds have now been used as template molecules in molecular imprinting. Basically, imprinted polymers can be used directly as separation media. Since all separation applications cannot be described here, some studies recently reported are bsted in Table 7.1. In this chapter, only selected topics, including sensor applications, signaling polymers, molecularly imprinted sorbent assays, molecularly imprinted membranes, affinity-based solid phase extraction, in situ preparation of imprinted polymers, and molecularly imprinted catalysts are discussed. For the reader requiring information on other applications, there are many review articles dealing with these, Recent review articles and books are summarized in Table 7.1. For further development of molecular imprinting techniques, newly designed functional monomers would be desirable. Various functional monomers have been reported and many applications have been conducted. These are summarized in Table 7.2. 

As chemical synthesis moves from discovery to production, scales increase and the use of catalytic rather than stoichiometric quantities of reagents is increasingly advantageous from both the economic and environmental standpoints. The vast majority of fluorous catalysts prepared to date are best classified as heavy fluorous catalysts, and they are removed from the reaction mixture by liquid/liquid separation techniques. On the one hand, fluorous silica gel provides another option for these catalysts, which is to use a solid/liquid separation instead. On the other hand, fluorous silica gel enables the use of light fluorous catalysts, such as the palladium catalyst shown in Scheme 36. Mizoroki-Heck reactions are promoted by standard conductive heating (oil bath) or microwave heating. After cooling and solid-phase extraction. 

Researchers further optimized purification of a model ATRP reaction using the same automated parallel synthesizer that was outfitted with a solid-phase extraction (SPE) unit that utilizes silica gel or aluminum oxide filtration cartridges that can interface with synthesizer s liquid-dispensing system. The polymerization of MMA with p-toluenesulfonyl chloride (TsCl) as the initiator and CuCl/4,4 -dinonyl 2,2 -bipyridine (dNbpy) as the catalyst was chosen as a model reaction for this study. The PMMA pol5mier of this reaction was determined to have an MW of 12 000 Da and a PDI of 1.15. Sixty-four different purification conditions were analyzed by vaiying column materials, column lengths, and eluent collected. For the model reaction, a 1.5-cm-long artivated neutral or basic aluminum oxide column with 2 ml of THF eluent was optimal. 

Another fluorous palladium complex that was applied in a Mizoroki-Heck reaction is the SCS pincer palladium complex 24 (Table 15.1, entry 3) [67]. It was applied under thermal and microwave heating. No fluorous solvent was used and the insoluble catalyst dissolved at the reaction temperature of 140 °C. The catalyst was recovered after 30 to 45 min by solid-phase extraction with a fluorous silica gel. Depending on whether activated or nonactivated substrates were coupled, the yields ranged between 76 and 94%. 

Bisprolindiamide 13a proved to be a good catalyst for the aldol reaction of cyclohexanone (57) with 4-nitrobenzaldehyde (2a) (Chart 3.6) [86, 33, 34] Carter et al. designed a proline sulfonamide-derivative possessing a long alkyl chain and applied it to the synthesis of 263 g of the aldol product anti-SSa [87]. Disappointingly, only 63% of the catalyst was recovered. To avoid this drawback, fluorous sulfonamide was synthesized and could be easily recovered from the reaction mixture by fluorous solid-phase extraction [88]. 

Diamine catalyst 10, which gives excellent results in the reaction of isobutyr-aldehyde with aromatic aldehydes, affords only moderate diastereoselectivity when used with aliphatic aldehyde donors [119]. Even C2-symmetric catalysts fail to give significant improvements [34c, 139]. Wang reported that the use of fluorous (5)-pyrrolidine sulfonamide 97 in such reactions give better diastereoselectivity and can easily be recovered by simple fluorous solid-phase extraction (Scheme 3.22) [122, 123]. 

Scheme 1.7 Synthesis of natural product-like molecules with unprecedented scaffold diversity. Initially, building blocks were added iteratively to a fluorous-tagged linker, with intermediates purified by fluorous-solid phase extraction. Metathesis cascades were used to reprogramme the scaffolds and to release final products from the fluorous-tagged linker. Reagents and conditions. (1) Grubbs first-generation catalyst, 21a 23% 21b 56% (2) fluorous-tagged Hoveyda-Grubbs second-generation eatalyst, 21c 33%.

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