A rose by any other name...

...would smell as sweet. But I have recently wondered why. Maybe the question has to do with my almost neurotic sense of smell. I used to know who walked down the hallway at work just by smelling the perfume trace they left behind, much to the annoyance of my office coleague who was getting a bit paranoid about this sensitivity. In any case, during the writing of my thesis, as a sign of avoiding behaviour I assume the question popped into my head. Ok, stuff smells, but why? What is the structural relationship which makes cabbage smell different than peaches? I shamefully admit that for a person who wanted to work in perfume research it was a bit late to ask this question, but whatever kept me from writing about plasma reactors was a good excuse. I was familiar with the usual story which said that small, hydrophobic and volatile molecules bind to the receptors in the nose and then the neurons take it from there. Now I was curious why do similar molecules (let’s say two alcohols, the well known ethanol and it’s cousin propylalcohol, who just has an extra methyl group) smell different.

The two major theories describing the structure-odor relationship are the odotope theory and the vibrational theory. The first one assumes that the different parts of smelly compounds (odotopes) can be bind to the receptors. More graphically , if we imagine the odor molecule as a small dog, some receptors will pull it’s tail, some will accomodate the belly and some the fluffy ears. By putting all the signals together we can label the obtained sum as „dog“. Seems easy, right?

However, there seem to be some issues with this theory. Good experimental chemists can detect class of substances by their smell. I remember one of my former supervisors telling me that he can smell tert-buthyl groups. But tBu is a relatively voluminous group and hence one could imagine it is selectively detected. If we take for example thiols – all thiols stink and regardless what accompanies the SH-group. But then again, thiols and alcohols are quite similar, Turin argues and hence they should smell the same. The oxygen atom is however smaller than the sulphur one so an alcohol and it’s corresponding thiol will not have exactly the same shape; a slight difference, but a difference however. And we all know how picky nature is about „small“ differences.
Another issue taked with this theory is that if one „burries“ the smelling group between more voluminous groups (and thus the molecule cannot bind its smelly head in the receptor) it should not smell. However 2,4 and 2,6 disubstituted phenols smell the same. But phenols again are not the best example of „hidden“ odotopes.
Finally, if one exchanges an atom in the molecule for an isotope (like hydrogen for deuterium), the resulting molecules should differ only in molecular vibrations, but not in shape or binding ability.

The second theory put forward to counteract the above objections is a bit more complicated and it suggests that the receptors behave like a vibrational spectroscope. More explicitly, if we imagine a Y shape receptor with an arm of the Y more poor in electrons than the other arm, then electron conduction from one side to the other can occur if the receptor catches a molecule able to vibrate at exactly this energy difference. All this talk about spectra can be a bit scary, but as a comfort, other two of our senses (vision and hearing) also heavily relay on spectral aquisition and interpretation.This type of nose-spectrometer would have quite poor resolution, and hence a large number of receptors would be needed to do the job (which by the way, we have; about 1000 genes code their expression).

However this mechanism does not explain why some enantiomers – molecules with the same composition and structure but containing an assymetric atom around which the substituents arange in different ways- smell completely different (the carvone pairs with spearmint and caraway smells respectively, limonene with mint and citrus and citronellol with citrus and rose are just a few examples).

And finally there is the problem of odorless molecules which both theories cannot explain. If we assume that the shape of different molecular parts matter, it would mean that larger molecules, with more „paws“ or „ears“ has more chances to conect to a receptor and should be smelly. But most odorless molecules are particularly the big ones. If we accept the vibration theory it would mean that all molecules binding to receptors should smell (because all molecules vibrate).

The vibration theory was put to the test by a group at Rockefeller University in 2004. Human subjects failed to differentiate acetophenone and it’s deuterated counterpart. This lead them to dismiss „an universal theory based on one man’s sense of smell“. It is worthy to mention at this point that this man’s sense of smell did benefit a successfull company working in the field of synthetic odorant rational design and earned him the surname of „The Emperor of Smell“ (mental note to self to read the book).

In 2007 another group took a look at this problem and their conclusion is a bit more inbetween, namely that besides size and shape other features (like, say, vibration) could also plays a role in olfaction.

So to sum up, as much as I enjoy the idea of being a high tech analytical facility with indirect tunelling happening every time I sniff my favourite perfumes, I cannot completely disagree with the odotope theory. I will try to follow-up on this issue and check the work of people who like to reconciliate the two and admit that size and chemical detection do not mutually exclude.