16: Silylethers

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Another SN2 Or... is it?

Formation of Silyl Ethers

Silyl ethers are functional groups with Si covalently bonded to an alkoxy group. Silyl ethers are inert to many reagents that react with alcohols, so they serve as protecting groups in organic synthesis.

Silicon is capable of making pentavalent and hexavalent complexes.

• Propose a reason. There are several hotly contested theories so there is no “right” answer.

Because of the ability to make 5 or 6 bonds, the mechanism for the formation of silyl ethers could proceed in four ways:

For each of the mechanisms proposed above,

• Draw the arrows showing electron flow.
• Circle the rds.
• Determine the molecularity of the reaction.

Mechanistic Studies

Adapted from: Holmes, Chem. Rev., 1996, 96, p 927.

A number of complexes of the following type have been isolated and characterized by x-ray crystallography.

These complexes lend support to the existence of silicon complexes making 5 and 6 bonds.

• Which mechanisms have five and six coordinate reactive intermediates. The ability to make these stable structures supports the possibility of which reaction mechanisms? (circle one or two)

  SN1-like SN2-like Pentavalent Intermediate Hexavalent Intermediate

The kinetic data suggests that the reaction is second order in the nucleophilic alcohol.

• Which reaction mechanism does this data support? (circle one)

  SN1-like SN2-like Pentavalent Intermediate Hexavalent Intermediate

Removal of a Silyl Ether

The silyl reaction is reversible. Often under acidic aqueous conditions.

• Provide a likely mechanism with a hexavalent intermediate.

  

Bulkier silyl ethers are frequently cleaved via addition of fluoride salts using a similar mechanism. (Bu4NF is frequently abbreviated TBAF)

• Provide a likely mechanism for the reaction below. Include a hexavalent intermediate.

  

• Explain why this bulky silyl group can be reversed under with fluoride but not H₃O⁺. Consider size of H₂O vs F^- as well as bond strengths (Si-O 108 kcal/mol; Si-F 135 kcal/mol).

Use of Silyl Ethers as Protecting Groups

Typically, silyl groups are added to alcohols when they might react with the reagent instead of the intended reaction.

For example, Grignard reagents are strong bases and they tend to deprotonate alcohols rather than react with the carbonyl functional groups in the molecule.

• Complete the diagram below that shows this problem and how silyl groups can protect the alcohol functionality.

  

Common Silyl Ethers

Common silyl ethers are: trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert- butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl (TIPS). They are particularly useful because they can be installed and removed very selectively under mild conditions.

– Small silyl ethers can be removed under acidic conditions.

– Bulky ethers must be removed using TBAF (tetra-butyl ammonium fluoride).

For further information:

1. Wuts and Greene, “Greene’s Protective Groups in Organic Synthesis, 2006, Wiley-Interscience, 4th Edition.

2. Nelson and Crouch, “Selective Deprotection of Silyl Ethers”, Synthesis, 1996, 1031-1069.

Summary of Silyl Ether Protecting Groups

• Provide a mechanism for the formation of a silyl ether.

• Provide a mechanism for the removal of the silyl ether.

• Suggest a time when a silyl ether would be used.

• How does the OTBDMS differ from the OTMS protecting group removal approaches?

• Propose a reason for this difference.

Synthesis Application

1. Leukotrienes

   E. J. Corey, Hokoon Park, Alan Barton and Yasushi Nii, Synthesis of three potential inhibitors of the biosynthesis of leukotrienes A-E, Tetrahedron Letters, Volume 21, Issue 44, 1980, Pages 4243-4246.

   

   • Draw at least two resonance structures for CH2N2 (used in the last step).

     

   • Propose a mechanism that involves an acid-base reaction followed by a substitution.