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kilomentor | 14 May, 2007 09:42
Hydrocarbon solvents like hexane, cyclohexane, heptane and methylcyclohexane are special because they form biphasic mixtures with both methanol and acetonitrile. In addition, cyclohexane, at least, and perhaps the others, also form thermomorphic systems with each of:
Kazuhi Chiba, Yusuke Kono, Shokaku Kim, Kohsuke Nishimoto, Yoshihazu Kitano and Masahiro Tada, teach this in Chem.Commun. 2002 1766-1767.
A thermomorphic system is a combination of liquids that in one temperature range is a homogeneous single phase, but in another range is two immiscible liquids that can be separate by simple extraction. The significance that is the focus of this blog discussion is not that the systems are thermomorphic but only that there is a temperature range where two organic phases that can be used for partition extraction safely coexist. It is also important for this proposed application that all these solvents are aprotic.
The Extraction Difficulty in Organic Biphasic Systems
Biphasic organic solvent systems can in principle be very useful for the simple extractive separation of components of a reaction mixture.
The Kilomentor blog emphasizes the significance to chemical and pharmaceutical process development of simple robust scaleable methods of separation and the significance these can have in the teaching of organic chemical process development.
The shortcoming of these biphasic systems is that for most reaction mixtures very components are poorly soluble in the hydrocarbon phase. What is needed is some means to decrease the overall polarity of all or nearly all the components of the target mixture.
Kilomentor proposes here that because the biphasic organic solvent mixtures enumerated above are all aprotic silylation of all the components of the mixture to be separated should decrease their polar and make them partition more competitively into the hydrocarbon phase. Furthermore, because all the solvents in these systems are aprotic the solvents themselves will not interfere with the silylating procedure or the silylating agent.
Disclaimer
Please be warned that this methodology has not been experimentally verified in any situation that I know about. What I can say is it is simple enough to work and I cannot see any particular difficulty.
I have always urged my coworkers to make a clear distinction between facts and theory and this is my effort to do the same.
Making the Silylation Facile
A necessary capability to proceed in this way is a practice method to persilylate all the functional groups in a all the components in a reaction mixture. Another practically important consideration is that the silylation procedure must be inexpensive otherwise the additional reagent cost will make the procedure uncompetitive with more traditional alternatives. Fortunately it has long been known that there are catalysts for silylation, which allow chemists to use the convenient and inexpensive hexamethyldisilazane reagent for effectively all functional groups. Although this has been in the literature many years, it is infrequently used and seems to have today vanished from our chemical toolboxes.
Cornelis A. Bruynes and Theodorus K. Jurriens, then scientists at Gist-Brocades in Delft, The Netherlands published a paper called Catalysts for Silylations with 1,1,1,3,3,3-hexamethyldisilazane in J. Org. Chem. 1982, 47, 3966-3969. They reported that the following compound types could be trimethyl silylated using the title reagent and an appropriate on of their catalysts with yields of typically more than 90%:
Alcohols, phenols, carboxylic acids, hydroxamic acids, carboxylic amides, and thioamides, sulfonamides, phosphoric amides, mon and dialkyl phosphates, mercaptans, hydrazines, amines, NH groups in heterocyclic rings, and enolizable beta diketones
The silylation times were in all cases no more than two hours and the catalyst concentration can be from 0.001-10.0 mole percent.
Catalyst Structures
Although many catalysts are claimed (there is a corresponding patent EP81200771.4 now expired) five were used in the most examples:
· Saccharin [81-07-2]
· Sodium saccharin [128-44-9]
· Bis(4-nitrophenyl)N-(4-toluenesulfonyl)phosphoramidate [81589-21-`]
· Tetraphenylimidodiphasphate [3848-53-1]
· Bis-(4-nitrophenyl)N-trichloroacetyl)phosphoramidate [38187-67-6]
The registry numbers for these catalysts are given in square brackets.
Method of Application
To use this method of separation al that ought to be necessary after reaction is complete would be to
Potential Problems
It will only be determined by actual experiment with a particular mixture of solutes to determine how high a relative concentration of the solutes can be worked with before the biphasic solvent mixture goes homogeneous. Obviously there is some point where the concentration of the solutes will wreck the balance of solvent properties that allows the two phases to coexist
As is always the case if one adds something to promote a separation that facilitating agent must itself be separated in the end. So it is with the catalyst, which must remain in one or the other phase along with some elements of the mixture being separated.
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