Monday, 22 April 2013

Chemistry Classics: Flash Chromatography


It's #RealTimeChem week! I'm contributing a series of five posts about classic, foundational papers in organic chemistry. #chemclub classics, if you will.

Each day this week I'll post a quick read about a paper which has profoundly affected the work of organic chemists. I'm just going to give a quick outline for historical interest - something you can read while you post your tweets to #RealTimeChem, and hopefully come away with a renewed appreciation for the powerful tools we have at our disposal.

First up: W. Clark Still, Michael Kahn, and Abhijit Mitra, "Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution", J. Org. Chem. 1978, 43, 2923-2925.



This is the paper which gave the world flash column chromatography, the go-to purification technique for the typical organic chemist. It contains only one reference, but has itself been cited over 8,000 times - a modest number for such an important technique! There's a trend towards avoiding chromatography these days, in order to save on solvents and silica and achieve 'smarter' purification. These are grand ambitions, but don't undermine the crucial importance that flash chromatography has held for the past 35 years.

Column chromatography pre-dates the development of flash chromatography. The key innovation is something we perhaps take for granted: by applying pressure to the top of the column, the speed of elution can be greatly increased, allowing the column to be run in 15 minutes rather than several hours! This comes at the cost of decreased resolution compared to the slower techniques.

Flash chromatography was optimised on benzyl alcohol apparently, and the authors used a UV detector to analyse the separation precisely, rather than relying on TLC as we typically do in the lab. Various factors influencing resolution were identified - the kind of silica, rate of elution, presence of polar impurities, sample size (up to 10 g), and column size. Contrary to the lab lore I've been handed, the method of packing (slurry vs. dry) was found to have minimal influence on resolution.

To demonstrate the power of this technique, the authors separated two isomeric alcohols. Perhaps that's not so impressive from our perspective, but I wonder how impressive it looked to be able to do this quickly and cheaply on a gram scale at the time.



The paper is well-written and logical, and actually a great field guide to column chromatography.

If you're prone to chronocentrism, here are some more recent field guides from around the web:
Brandon Findlay's column week
Atoms and Numbers: overcoming separation anxiety
Chemistry Views: Sarah Millar's tips and tricks
(If you've written one I've missed, let me know and I'll add it.)

I hope you enjoyed this quick dip into some chemical history; more to come tomorrow!

7 comments:

  1. I was under the impression that resolution was improved by rapid columning as slower leads to band broadening? Am I wrong?

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    Replies
    1. That is certainly my experience, and they emphasise the need to run flash columns quickly. On the other hand, they report that by flash chromatography, peaks with a difference in Rf of 0.1 to 0.15 could be separated, vs. 0.05 for non-flash techniques.

      I think I've done one non-flash column in my life, so I can't verify this.

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    2. You are right, slow column most of the time means also band broadening (mainly for diffusion problem). The point is to define "slow" and "fast". If you are doing it too slow, you will have diffusion on the silica and therefore crappy separation. If you are too fast then you have small interaction with silica and therefore crappy separation.
      If you use the right flow then the separation is perfect.

      Delete
  2. Chromatography. Often satisfying, occasionally soul-destroying. Nice paper that.

    I didn't know there was lab lore concerning resolution of slurry vs dry. I used to pack dry, but then getting air bubbles out was annoying. So I moved on to slurry, but I got annoyed with the mess. So now I do a mix of both: measure out dry silica, add solvent, stopper the top and shake.

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    Replies
    1. I've gone the opposite way! I was taught to load a slurry, but when starting my D.Phil was advised that dry packing (with plenty of tapping to pack the silica and force air out) gave better separation. I honestly am not sure if it's effective, but like you I find the mess from a slurry irritating so have stuck with dry packing.

      I really like Brandon Findlay's series on chromatography (link in the original post); he looks into lab lore like silica dissolving in methanol and gives it the Mythbusters treatment.

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