Selective Silyl Group Protection: A Possible Preparation for Scalable Extractive Separations using Acetonitrile and Hexane Phases

kilomentor | 27 November, 2012 18:21

Kilomentor has written about the selective reactivity of one among several of the same functional groups within a chemical structure at

http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1100_nitriles_separated_by_competitive_reaction_and_then_simple_extraction.html

Protecting groups are often used to differentiate such similar groups. Kilomentor has also already written about catalyzing trimethylsilylation of a wide variety of functional groups at http://kilomentor.chemicalblogs.com/55_kilomentor/archive/200_improved_extractive_separations_with_organicorganic_biphasic_solvent_systems_catalyzed_total_silylation_to_improve_partition_coefficients.html and the use that can be made of this transformation towards increased hydrophobicity to improve the solubility of the protected substrates in hydrocarbon solvents. This means trimethylsilylated substrates can be better extracted from acetonitrile, for example, into, for example, heptane.

I have seen very little about selective trimethylsilylation even though introducing this group ranks among the easiest and cheapest. As an older chemist, the references that I do are also old. In a paper concerning prostaglandin synthesis [G. L. Bundy and D. C. Peterson, Tet. Lett.(1978) 41-44 ] http://cas.illinoisstate.edu/sites/tmitche/files/2012/02/Bundy-G.-TL-1978-1-41.pdf the authors were trying to selectively trimethylsilylate one of two secondary alcohols in the five membered ring of their prostaglandin intermediates.

They reported “attempted selective silylation…. using t-butyldimethylsilyl chloride under standard conditions prove surprisingly unsuccessful. Even at -60 (7 days), a statistical array of products was obtained including starting material, both mono silyl derivatives and the disilyl derivative. Selective silylation ….could be achieved with trimethylsilyldiethylamine, a sterically more discriminating silylating agent, yielding a monosilyl derivative…(70% after rapid chromatography).”

I would not be obvious to me that trimethylsilyldiethylamine should be more discriminating than t-butyldimethylsilyl chloride so what hypothetical explanation could there for this difference? According to Neumann’s Rule of Six for identifying steric hindrance to a nucleophilic attack, the amine derivative would have a score of 6, while the silyl chloride compound would have the surprising score of 0. Counting the attacking oxygen as 1, the attacked Si as 2, and the subsequent carbon chain and then counting the number of hydrogens at position 6, you can see that in fact t-butyldimethylsilyl chloride has no hydrogens 6 atoms away. It has 15 hydrogens five atoms away and most people (including myself) would consider that atoms of this type do impose a steric barrier as in pivalate esters, for example. Perhaps something else explains the selectivity.

Another of my old pertinent papers describes a selective trimethylsilylation with trimethylsilyldiethylamine [Paul Baret, Eliezer Barriero. Andrew E. Greene, Jean-Louis Luche, Marco-Antonio Teixeira and Pierre Crabbe, Tet. Lett. (1979) 29312938.]also in the prostaglandin series.

In any case, it makes me think that N-t-butyl-N-trimethylsilylamine [CAS 5577-67-31] might be a relatively inexpensive and even more selective silylating agent than trimethylsilyldiethylamine because it has a score of 9 according to Neumann’s Rule of Six! Furthermore, what is pragmatic is that it could be easily prepared in situ from one equivalent of hexamethyldisilazane and two equivalents of t-butylamine. Alternatively, for a quick test, it can be bought from Sigma-Aldrich. The co-product t-butylamine b.p. 46 C can be distilled to drive the silylation to the required degree of completion.

Comments

chemical publications

Joshua Frederick | 27/11/2012, 21:37

Nice blog you have here.. I would just like to share a directory list of chemical publications http://www.kosherregister.com/magazine/CATE0000000528&chemical-trade-industry-publications.html . you can check that out! thank you so much! If you know a chemical-related magazine that must be placed there, please let me know. Thank you.. Joshua

Rule of six

vasilij | 27/11/2012, 22:26

Would you be so kind and provide reference for above mentioned Neumann's rule of six? Thank you.

Rule of Six: Kilomentor

kilomentor | 28/11/2012, 05:28

The Rule of Six is taught in the book, Mechanisms and Structure in Organic chemistry, Edwin S. Gould, Holt, Rinehart, Winston 1959 pg 323. The original literature reference is J. Am. Chem. Soc. 72, 4783 (1950).

"a sterically more discriminating silylating agent"

DocMB | 02/05/2013, 05:41

Kilomentor
I believe the authors of the 1978 Tet Lett paper would be stating that trimethylsilyldiethylamine is more sterically discriminating towards the less encumbered environment and are not talking about the increased sterics of the reagent vs TBDMSCl, as you rightly point out it has less. i.e. they want a less steric silylating reagent as TBDMSCl is too bulky. If they don't mean this, then they don't know their gluteus maximus from their humerus.

kilomentor