Silyl Groups as Protecting Groups

A widely used method of protecting hydroxyl groups in organic molecules is to turn them into silyl ethers. A protecting group is one which reduces the reactivity of the functional group it protects so that chemistry may be carried out elsewhere on the molecule without fear of interference from the protected group.
A silyl ether is quite easy to make – all that is needed is a weak base (usually nitrogen e.g. NEt3 or pyridine) and a tri-alkyl-silyl-chloride (R3SiCl). For example;

Because the trialkyl-silyl group is very bulky (even the tri-methyl version is quite bulky), the silyl ether can be made very selectively on the least sterically hindered hydroxyl group (of a molecule containing more than one).

There are many other tri-alkyl-silyl-chloride reagents besides TMSCl which are far more bulky. Their bulkiness increases their selectivity in formation of silyl ethers and also makes them more difficult to remove. Some commonly encountered silyl reagents;

For the very bulky silyl reagents, a catalytic amount of imidazole (labelled below) is needed to speed up their reaction with the hydroxyl. This increase in rate is due to the formation of a reactive intermediate;

The final vital property of protecting groups is that they should be able to be removed, or cleaved, from the molecule under fairly mild conditions that will not cause reaction of any other part of the molecule.

Silyl ethers will be cleaved by nucleophiles (especially oxygen and fluoride) to form Si-O/F bonds – F is therefore particularly effective because it is small and generally unreactive. They may also be cleaved under a range of acidic and basic conditions. It should be noted that the large range of available silyl ethers display a large range of sensitivity to acid and base (too large to go into here!) which means that careful choice of ether and conditions can ensure only the targeted protecting groups are cleaved when you wish.