Friday 23 October 2015

From schwefeläther to octanol

So in this blog post, written specially for #RealTimeChem week on an #OldTimeChem theme, I'll start ten years after the Kaiser's grandmother became Queen of the United Kingdom of Great Britain and Ireland.  I first came across Ernst Friherr von Bibra while doing some literature work for an article on predicting alkane/water partition coefficients and learned that he was from an illustrious family of Franconian Prince-Bishops. Von Bibra certainly seems to have been a colorful character who is said to have fought no less than 49 duels as a young man. Presumably these were not the duels to the death that did for poor Galois and Pushkin but more like the München frat house duels that leave participants with the dueling scars that München Fräuleins find so irresistible.

So that's how I learned about von Bibra and it was his 1847 study with Harless 'Die Ergebnisse der Versuche über die Wirkung des Schwefeläthers' (The results of the experiments on the effect of the sulfuric ether) that we cited. Schwefeläther is simply diethyl ether and so named because in 1847 you needed to make it from ethanol and sulfuric acid. Von Bibra was a pioneer in the anesthesia field and proposed that anesthetics like ether exerted their effects by dissolving the fatty fraction of brain cells. Now it's easy in 2015 to scoff at this thinking but remember that in 1847 nobody knew about cell membranes or molecules and you couldn't just pick up the phone and expect the ether to arrive the next day. Put another way, if it was 1847 and I was in the laboratory (or kitchen?) gazing at a bowl of brains and a bottle of ether, I would probably have come to a similar conclusion.

What we know now is that anesthetics (and other drugs) dissolve IN lipids as opposed to dissolving THE lipids. Nobody in 1847 knew about partition coefficients and Walther Nernst didn't articulate his famous distribution law (Verteilung eines Stoffes zwischen zwei Lösungsmitteln und zwischen Lösungsmittel und Dampfraum. Z Phys Chem 8:110–139) until 1891 by which time the Kaiser had already handed Bismarck his P45. Within ten years Ernest Overton and Hans Meyer had shown incredible foresight in using amphibians as animal models and the concept of the cell membrane would soon be introduced.

Before moving on, let's take a look at the 'introduction to partition coefficients' graphic below in which the aqueous phase is marked by a the presence of fish (they're actually piranhas and have have graced my partition coefficient powerpoints since my first visit to Brazil in 2009). We would describe the compound on the left as lipophilic because its neutral form prefers the organic phase to water and, for now, I'm not going to be too specific about exactly what that organic phase is. The compound on the right prefers to be in the water so we describe it as hydrophilic.  The red molecule on the left represents an ionized form of the compound on the left and typically these don't particularly like to go into the organic phase (especially not without counter ions for company).  A compound that prefers to to be in the organic phase can still be drawn into the aqueous phase by increasing the extent to which it is ionized (e.g. by decreasing pH if the compound is basic).

Now I'd like to introduce Runar Collander (whom many of you will have heard of) and Calvin Golumbic (whom few of you will have heard of).  Let's first take a look at Golumbic's 1949 study of the effects of ionization on the partitioning of phenols between water and cyclohexane.  Please observe the responses to pH in Fig 1 in that article but also take a look at equation 5 which accounts for self-association in the organic phase and the discussion about how methyl group ortho the phenolic hydroxyl compromises the hydrogen bonding of that hydroxyl group and has observable effects on the partition coefficient.

Collander's study (The Partition of Organic Compounds Between Higher Alcohols and Water) explores how differences in the organic solvent affect partitioning behaviour of solutes.  Collander presented evidence for strong linear relationships between partition coefficients measured using different alcohols (see Fig 1 in his article) although he notes that compounds with two or more hydrophilic groups in their molecular structure tend to deviate from the trend. Now take a look at Fig 2 in Collander's study which shows a plot of octanol/water partition coefficients against their ether/water equivalents. Now the correlation doesn't look so strong although relationships within chemical families appear to be a lot better. In particular, amines appear to be more soluble in octanol than they are in ether and Collander attributes this to the greater acidity of octanol. 

When reading these articles from over sixty years ago, I'm struck by the way the authors ratioanalize their observations in physical terms.  Don't be misled by what we would regard as the obscure use of language (e.g. Collander's "double molecules"  and Golumbic's description of partition coefficients as "true") because the conceptual and linguistic basis of chemistry in 2015 is richer than it was when these pioneering studies were carried out.  How these pioneers would have viewed some of the more mindless metrics by which chemists of 2015 have become enslaved can only be speculated about.

So I'm almost done but one last character in this all-star cast has yet to make his entrance and that, of course, is Corwin Hansch. Most drug discovery scientists 'know' that octanol 'defines' lipophilicity and only a small minority actually question the suitability of octanol for this purpose or even ask how this situation came to be. In order to address the second question, let's take a look at what Hansch et al have to say in this 1963 article,

"We have chosen octanol and water as a model system to approximate the effect of step I on the growth reaction in much the same fashion as the classical work of Meyer and Overton rationalized the relative activities of various anesthetics. This assumption is expressed in 2 where P is the partition coefficient (octanol-water) of the auxin.

          A = f(P)                              (2)

Collander has shown that the partition coefficients for a given compound in two different solvent systems (e.g., ether-water, octanol-water) are related as in 3.

          log P1 = a log P2 + b        (3)

This would also indicate, as does the Meyer-Overton work, that it is not unreasonable to use the results from one set of solvents to predict results in a second set". 

Now if you take another look at Collander's article, you'll see that he only claims that a linear relationship exists between partition coefficients when the organic phase is an alcohol. Collander's Fig 2 seems to suggest that Hansch et al's equation 3 cannot be used to relate octanol/water and ether/water partition coefficients. Can Collander's study be used to justify what appears to be a rather arbitrary choice of octanol as a solvent for partition coefficient measurements? That question, I will leave to you, the reader but, if you're interested, let me point you towards a short talk that I did recently at Ripon College. 

See you next year at #RealTimeChem week and don't forget to take a look at Laura's nails which get my vote for highlight of the week.

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