Wednesday, 15 February 2012

Acetonitrile, Or How I Learned To Stop Worrying And Love An Organic Cyanide Compound

Acetonitrile is a curious organic compound, widely used in analytical chemistry. A clear liquid at room temperature, it is completely miscible in water, and is used a an aprotic, polar solvent.

It is also known by another name: methyl cyanide.

Acetonitrile,a.k.a. methyl cyanide
When I first encountered it during my undergraduate studies, I was rather nervous handling it. Surely as a cyanide compound, one stray drop or errant exposure and I would be done for. With a bit of further reading, I was rather surprised that it had a significantly higher LD50 than other cyanide compounds.

First, a bit of an explanation. The LD50 of a compound is also known as the median lethal dose. In toxicology, it is defined as the dose of a compound that is required to kill half of a tested population over a specified test duration.

With that in mind, it was curious to see a clear and concise comparison of the relative toxicities of a range of aliphatic nitriles (Comparative Toxicologies of Aliphatic Nitriles). To put it plainly, the LD50 of the simple aliphatic nitriles, reported as an oral dose in mg/kg, is as follows:

  • Acetonitile:          2460
  • Propionitrile:        40
  • Butyonitrile:         50

The following two nitriles are also included. Respectively they are propanedinitrile and vinylcyanide, and again, the LD50 is reported in terms of an oral dose in mg/kg:
  • Malononitrile:      60
  • Acrylonitrile:       90

 It can be seen that there is a massive difference in the reported median lethal doses of these compounds. This, of course, was a massive relief to me, as it meant that working with acetonitrile and appropriate PPE wasn't going to send me to an early grave.

But why is there such a difference in the LD50's of these simple organic cyanide compounds? Before we can answer this, we need to know why organic cyanide compounds, in general, are toxic. Upon ingestion, organic cyanides are metabolised in the liver, producing hydrogen cyanide. Hydrogen cyanide, of course, halts cellular respiration by inhibiting a specific enzyme present in the mitochondria, cytochrome c oxidase. Inhibition of this enzyme prevents cellular respiration, which ultimately leads to death of the cell.

So, what makes acetonitrile so special? Well, as it turns out, acetonitrile is metabolised rather slowly by the liver. This means that more acetonitrile can be excreted by the body before being metabolised in to hydrogen cyanide. Also, as the metabolism of acetonitrile is slow, this allows the body time to convert the toxic cyanide ion to the less-toxic thiocyanate ion. For those that are curious, this detoxification is governed by the rhodanese pathway (governed by the rhodanese enzyme present in the mitochondria).

As for the uses of acetonitrile, well, it makes a great organic, aprotic solvent, suitable for use in liquid chromatography. It is produced as a by-product of acrylonitrile manufacture, which leads to an interesting story. Back in 2008 my Honours project started, and methods were being developed and things were going swimmingly. My LC-MS/MS method used acetonitrile as an organic solvent/eluent, and I was getting good results.

Then it happened. And by "it", I mean the 2008 Olympic Games, which shut down the main source of the world's acetonitrile. Around the same time, Hurricane Ike also hit Texas, damaging one of the factories that produced acetonitrile in the U.S. Finally, the slowing economy at the time lead to a downturn in the production of acrylonitrile and related products. This produced a perfect storm, sending acetonitrile prices through the roof.

The gnashing of teeth and howls of dismay from researchers at this news was fierce. People called in favours to secure their own private supply of acetonitrile, lest they have to re-develop their methods with a cheaper solvent, like methanol. Such re-development is not necessarily an easy task, and would require the validation of a new method as well as starting a large number of experiments from scratch.

How many of my colleagues reacted at the news of the shortage.

How bad was the shortage? At my university we had a good relationship with one of the chemical supply companies. Despite being able to secure a suitable amount of acetonitrile, the price skyrocketed from approximately $300 per 4 litres to well over $600 per 4 litres. This meant that many researchers faced the choice of emptying their budget to ensure sufficient quantities of acetonitrile were available, or as mentioned previously, swap to a cheaper solvent. There are other alternatives to acetonitrile, like methanol, acetone and dimethyl sulfoxide, though they don't have quite the same properties.

In the end, production of acetonitrile came back to normal levels towards the end of 2009. Prices stabilised at around $400 per 4 litres, and life continued on as normal. Or at least until the next shortage comes around...

Well, there you have it. A little background on acetonitrile, cyanide poisoning and how for a short time a chemical shortage caused analytical chemists the world over to hoard their own supplies of acetonitrile.

Until next time,
Nathan




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