#RealTimeChem week rolls on to day three, and part three of 'chemistry classics' is here. This series of five posts is intended to give you a quick dip into the history of chemistry with a look at classic papers. The first two posts covered purification and analysis techniques; today, we're looking at some synthesis!
In honour of Nature Chemistry's focus on prebiotic chemistry this month, and given my own love of the subject, I thought I'd cover a classic paper about the origins of life. Not just a classic paper, but the classic paper: the famous Miller-Urey experiment.
Stanley L. Miller, "A Production Of Amino Acids Under Possible Primitive Earth Conditions", Science, 1953, 117, 528-529.
This paper is doubtlessly the most famous experiment in prebiotic chemistry, and surely is one of the chemistry papers that is most widely-known amongst the general public. The gist of the paper, as you probably know, is this: take a bunch of simple, high-energy molecules that look like they might have been around on the early earth, zap them with a wee spark, and hey presto! you get amino acids and all kinds of biological-looking stuff out.
But what did Miller actually do?
The concept behind Miller's experiment was simple. Based on Oparin's work in the 30s, it was believed that the early earth's atmosphere was a strongly reducing environment composed largely of methane, ammonia, and hydrogen gases, as well as water (both liquid and gaseous). To test this, a specialised piece of glassware which simulated a spatially-separated 'ocean' of water and 'atmosphere' of CH4, NH3, and H2 was built. The gas mixture had a pair of electrodes poking into it to allow for an electrical discharge, meant to simulate lightning and other high energy sources.
The water was boiled, allowing steam to mix with the gases. The design of the glassware prevents backflow: steam rises through the high, inverted U-bend, mixes with the gases, and then any products condense below the gas chamber and settle back into the water chamber. Contrary to popular imagination, the experiment didn't involve a single dramatic spark, but a continuous discharge for a week, during which products accumulated in the refluxing water.
According to Miller, within a day a pink colour developed in the water bath, and after a week it was "deep red and turbid", apparently largely due to the accumulation of the organic products onto colloidal silica produced from the glassware itself. A second collection of yellow, largely insoluble compounds - one of those notorious "intractable mixtures" - also accumulated, but was not analysed here.
The work-up and isolation aren't appealing from a modern perspective. HgCl2 was added to kill anything living in there (just in case!); Ba(OH)2 was added and amines were distilled off; for the acids, H2SO4 was added and again the products were distilled off; and finally, the mixture was neutralised with more Ba(OH)2 and the solution was concentrated to the remaining products.
The analytic method of choice was paper chromatography (if you've been following, you'll know that flash chromatography is a child of the 70s) and the cunning use of stains. The eluent was a mixture of n-butanol, acetic acid, and water, followed by wet phenol. Lovely. Staining with ninhydrin and comparing the products with samples of various amino acids allowed for the identification of products. Doesn't sound too much fun, but it's probably nicer than running a column in phenol!
As you can see, Miller identified milligram quantities of a handful of amino acids: glycine, α- and β-alanine, aspartic acid, and α-amino-butanoic acid. Later work by Miller and others has identified many, many more compounds from this reaction, including dozens of amino acids, sugars (produced by the formose reaction), and other biologically-significant molecules.
It's notable that Urey, Miller's supervisor, appears on the paper only as an acknowledgement. Urey won the 1934 Nobel Prize in Chemistry (for his work on isotopes), and apparently didn't want to receive credit for Miller's pet project, which he had rather gently opposed.
The actual prebiotic relevance of this particular experiment is debatable (and debated!), but it's indisputable that it helped kick-start the field of prebiotic synthesis, and remains practically synonymous with it in the popular imagination.
If you enjoyed this and want more classic synthesis, I can't recommend enough BRSM's 'Woodward Wednesday' series. If you have know any other blogs doing this kind of thing, leave links in the comments below!