Tetrazole (Weird acids)

That was probably the longest break ever. I'm trying to do better, but writing up multiple papers and grant applications, along with a pretty intense summer travel schedule just haven't augured well for the blogging. Onward and upward: tetrazole.


Tetrazole is one of those molecules I didn't believe existed off paper the first time I saw it. Lots of electronegative atoms in a row (usually nitrogens and oxygens) typically indicates something unstable, if not explosive, but aromaticity does its work here, and tetrazole works well. So well, in fact, that it works in that mild-as-mothers-milk environment of biomolecular synthesis. It will protonate a DNA monomer, thus activating it for solid-phase synthesis.


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It also has the interesting property of being quite acidic (pKa 4.89). It is often used as a bioisosteric replacement for a carboxylic acid in medicinal chemistry. Often better bioavailability than the carboxylic acid.
Cool synthesis via cycloaddition of azide with a nitrile and you have your substitutet tetrazole of choice.

Reduce tetrazole's carbon footprint (17.15 wt-% C) as tetrazole azide (10.81 wt-% C) and sell the carbon credits. Isn't that what Enviro-whinerism is all about? Couple the anion with iodine to get a chain of eight nitrogens. That ought to do something.

It is pretty expensive, oligo-people at the institute in Prague where I used to work were making it by diazotation and H3PO2-reduction of diazonium made from 5-aminotetrazole (much cheaper). They shared few grams with me which I had to purify for my own work by sublimation. You have to heat it quite high, close to the melting point -which made me rather nervous - but the sublimation it went without accident.

A great reagent for fosphoramidite method of phosphorylating serine, threonine in peptides, under mild conditions - it works there as acid catalyst and its anion like a supernucleophile, think of acidic DMAP