Persilylation and its Uses

 

The KiloMentor blog emphasizes the usefulness of simple, robust, scalable methods for work-ups and isolations in organic chemical process development.

Biphasic organic solvent systems such as methanol/hexane can in principle be very useful for the simple extractive separation of components of a reaction mixture. The trick for success is to get partition ratios that are neither too small (<0.2) or too large (>5).

The idea being explored in this blog is whether persilylation of a mixture of solutes from a completed reaction could give a modified mixture that could be separated by liquid-liquid extraction between two immiscible aprotic solvents.

While it is true that most biphasic organic solvent systems comprise at least one protic component and such a solvent would use up all the silylating agent and prevent substrate silylation, there are aprotic solvents that can be mixed and retain two liquid phases. Cyclohexane forms two liquid phases with any one of acetonitrile, propionitrile, nitromethane, nitropropane, dimethylsulfoxide, dimethylformamide or dimethylacetamide. Hexane and heptane would likely behave similar to cyclohexane.  Sulfolane and t-butyl methyl ether are both aprotic and only partially miscible. 

KiloMentor proposes that silylation of all the components of a mixture to be separated should either decrease some and retain unaltered some of their polarities and so perhaps cause their partitioning between the component phases of a two-phase solvent pair to become more competitive. Smaller partition ratios could make a couple of stages of counter-current extraction feasible for separation.

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

To proceed in this way, a practical method to persilylate all the applicable functional groups in all the components in a reaction mixture is necessary. A further practical consideration is that such silylation procedure must be inexpensive; otherwise, the additional reagent cost will make the procedure uncompetitive with alternative separation means.  Fortunately, it has long been known that there are catalysts for silylation, which allow chemists to use the convenient and inexpensive hexamethyldisilazane reagent for all functional groups.  Although this has been in the literature for 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 Netherlands, published a paper called Catalysts for Silylations with 1,1,1,3,3,3-hexamethyldisilazane in J. Org. Chem. 47, 3966-3969 1982.  They reported that the following compound types could be trimethylsilylated using the title reagent and an appropriate one of their catalysts with yields of typically more than 90%:

Alcohols, phenols, carboxylic acids, hydroxamic acids, carboxylic amides, and thioamides, sulfonamides, phosphoric amides, mono and dialkyl phosphates, mercaptans, hydrazines, amines, NH groups in heterocyclic rings, and enolizable β-diketones

The silylation times were in all cases no more than two hours and the catalyst concentration is typically from 0.001-10.0 mole percent.

Silylation Catalyst Structures

Although many catalysts are claimed (there is a corresponding patent  EP81200771.4 now expired), five were used in 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.

Methods of Application of this Idea

There are two variants of this idea. In one, all the solutes in a reaction mixture are persilylated and allowed to partition between the two immiscible solvents. In the second, all the solutes in a reaction mixture are mixed with the two immiscible solvents and the silylating reagents are added and the mixture is analyzed as the competitive silylation proceeds and the partitioning of unsilylated, partially silylated, and completely silylated materials accumulate in the two different phases. This second is a kinetic silylation with simultaneous partitioning. 

To use this either strategy all that ought to be necessary would be to

• make a solvent change into acetonitrile, propionitrile, dimethylacetamide, dimethylformamide, nitromethane or nitroethane, whichever is appropriate for the separation trial
• add the minimum necessary amount of a catalyst
• add the calculated amount of hexamethyldisilazane
• heat for the requisite time to get either a complete or another requisite degree of silylation of the mixture with the expulsion of the co-product ammonia
• adjust the solvent volumes so that the biphasic mixture will be produced at the appropriate temperature
• cool to that temperature if necessary
• separate the phases
• repeat extraction if necessary
• hydrolyze the silyl derivatives and recover the products from their respective phases

Potential Problems

It will only be determined by actual experiment with a particular mixture of solutes  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.

Another Possible Approach

Consider the possibility of partitioning a reaction mixture between two of these partially immiscible solvents and then with mild stirring adding a silylation catalyst followed by an insufficient amount of a silylating agent such as hexamethyldisilazane.

What would happen?

I would think that whichever solute silylates faster will be partitioned into the less polar hydrocarbon layer where it would be protected from further reaction. The reagent trimethylsilyldiethylamine is probably the most sterically demanding silylating agent one could try to get kinetically controlled silylation.