in the chemical literature: Williamson ether synthesis

Good day to you from Chem Help ASAP. In this video we will explore one of the classic
organic chemistry reactions – the Williamson ether synthesis. The reaction was reported in an issue of the
Journal of Medicinal Chemistry in a collaborative project between groups at the University of
Montreal, led by Dr. Anne Marinier, and Bristol-Myers Squibb, headed by Dr. Jason Priestley. The citation is on the following slide as
well as in the description of this video. [turn page]
Here is our reaction. We are converting the alcohol in the starting
material – properly a phenol since it is an aromatic alcohol – to a new ether. In addition to an alcohol, we need two things
for a Williamson ether synthesis. One, we need a base. Neutral alcohols are not strong nucleophiles
and cannot perform an SN2 reaction. The base deprotonates the alcohol to give
an O minus, a strong nucleophile. Two, we need an alkyl halide or some alkyl
chain with a leaving group. We have both of these necessities over our
reaction arrow. The base is potassium carbonate, and the alkyl
halide is benzyl bromide. Let’s clarify a couple ideas. First, let’s discuss the base. Normally, in a Williamson ether synthesis,
you need a fairly strong base to do the deprotonation. Sodium hydride (NaH) is common. In this case, however, since the alcohol is
a phenol, the alcohol is more acidic. A normal alcohol, like methanol, has a pKa
around 16. Phenols are around 10, in general. So, the scientists found that a weaker, more
convenient base like potassium carbonate worked just fine. Second, let’s look at the halide – benzyl
bromide. Benzyl bromide is a fantastic halide for SN2
reactions. Remember that SN2 reactions often compete
with E2 reactions because the nucleophile sometimes acts as a base. In the case of benzyl bromide, there are no
beta-hydrogens for an E2, so an E2 is impossible. That is one less thing to worry about. So, our reaction begins with deprotonation
of the phenol oxygen with carbonate, our base. That gives us our O minus species. This is our nucleophile for our SN2 reaction. The resulting anion attacks the carbon of
benzyl bromide, kicks out the halide, and forms the new ether product in essentially
quantitative yield. That is the Williamson ether synthesis. The product molecule was just one of very many
structures made by the joint Montreal-BMS team. The team’s focus ultimately fell to the
molecule shown in the lower right of the slide. The molecule is being used to explore and
develop new anticlotting agents for the prevention of certain strokes and heart attacks. You can see how the core of our product in
the top right is related to the ultimate molecule of interest in the bottom right. In conclusion, this reaction is a nice example
of a Williamson ether synthesis – an old organic chemistry reaction that is still widely
used to create new and useful molecules. If you are interested in seeing the rest of
the synthetic chemistry developed by the Montreal-Bristol-Myers Squibb team, then check out the reference. Please subscribe, like, or leave a comment. Take care.

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