in the chemical literature: methylation of weakly acidic atoms


Welcome to Chem Help ASAP. Let’s see a nice, simple method for performing
methylations of certain nitrogen, oxygen, and sulfur atoms. The work in this video was performed by the
research group of Professor Franziska Schoenebeck at RWTH Aachen University in Germany. The work was published in the journal Organic
Letters. The citation is on the following slides as
well as in the video description. [turn page]
On the screen we have two very similar reactions. The top reaction is a Williamson ether synthesis. An alcohol is deprotonated with a base, often
sodium hydride. The resulting alkoxide then undergoes an SN2
reaction with an alkyl halide, methyl iodide in this case. Amides with an N-H group undergo the same
type of reaction. This is on the bottom of the screen. Again, a common base is sodium hydride. The conjugate base of the amide reacts with
an alkyl halide, again methyl iodide, to give the new product. These reactions work well, but they do require
two steps. It would be nice to add one reagent that accomplishes
both steps of this reaction. The reagent would need to combine both the
base and methyl source into a single reagent. On the next slide we’ll see what the Schoenebeck
group developed. [turn page]
The reagent shown in the top middle of the screen is tetramethylammonium fluoride, TMAF. Fluoride is not a strong base, but it’s
just strong enough to deprotonate an amide N-H to a small degree. The tetramethylammonium ion is not a strong
electrophile, but it’s just strong enough to participate in an SN2 reaction and deliver
a methyl group onto our nitrogen with trimethylamine as the leaving group. The isolated yield for this reaction is 92%. A few points on this reaction… The mechanism I’ve shown is far from proven
but fits with all the published data. The reaction does not work at all with tetramethylammonium
chloride or bromide. This observation reasonably indicates that
the basicity of fluoride is important. The reaction can methylate more than just
amides! Along the bottom of the screen are a number
of transformations and yields. The starting materials all had a weakly acidic
hydrogen, whether on nitrogen or oxygen or sulfur, and these hydrogens were replaced
with a methyl group. The work only covers methylation. This may seem like a limitation, but the methyl
group is frequently encountered in molecules, especially pharmaceuticals. If there is one alkyl group that you want
to add easily, it’s probably the methyl group. In conclusion, the research group of Professor
Schoenebeck at RWTH Aachen has developed a simple, effective method for methylating a
range of weakly acidic functional groups. If you want to see more details of the Schoenebeck
group research, then check out the reference on this slide or in the video description. Please subscribe, like, or leave a comment. Take care.

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