Whenever we see the use of sodium hydride with a quat salt, especially for a simple etherification reaction, PTC experts cringe. After all, phase-transfer catalysis using NaOH is almost always the slam-dunk best option to produce non-commodity ethers through Williamson ether synthesis.
However, this month we saw a reaction that might likely be the first example we have seen that may justify the use of NaH instead of PTC-NaOH for a Williamson ether synthesis.
The reaction involves a diol derivative of trans-cyclooctene (“TCO”). The twisted strained TCO molecule is thermodynamically unfavored relative to the much more stable cis-cyclooctene. In fact, TCO is formed from cis-cyclooctene by high-energy photochemistry that is described in this patent application publication.
The many reactions described in the patent application publication are performed at room temperature or lower and reaction times are minimized. This is done presumably to minimize the heat history of these compounds and minimize isomerization back to the less strained cis isomers.
It is possible that PTC-NaOH conditions could be used to perform the O-alkylation on the primary alcohol with propargyl bromide shown in the diagram. However, it is likely that the reaction temperature and reaction time with PTC-NaOH would be longer which could potentially jeopardize the strained trans configuration staying intact.
For this reason alone, we support the choice of NaH as the base and the use of the polar solvent THF that results in very high yield in just 1 hour at room temperature. We suspect that the reason for adding the tetrabutylammonium iodide is to form the propargyl iodide in-situ to further reduce the energy of activation and minimize heat history.
It is also obvious that the primary alcohol is more reactive than the secondary alcohol. In fact, the secondary alcohol is also axial which makes it even less available for attack. So, selectivity for etherification of the primary alcohol is very high.
In summary, in contrast to what we teach for almost all Williamson ether synthesis applications in our 2-day course “Industrial Phase-Transfer Catalysis,” the specific etherification shown in this patent application publication justifies the use of sodium hydride.
