Skip to 0 minutes and 23 secondsSo this is a molecular model of 2-methylundecanal. For most of the time the eleven carbon atoms, in the main chain, sit in this zig-zag orientation. We have the aldehyde functional group at the end of the chain and on the carbon atom next door to it we have the methyl substituent. Now there are a number of different ways of making this particular molecule and we are going to look at just one of these, which involves adding the methyl group directly to the eleven-carbon chain. This synthetic approach relies on the fact that undecanal is a readily available starting material and the two hydrogens adjacent to the carbonyl group are the most acidic.
Skip to 1 minute and 1 secondOn deprotonation using a base an anion is formed called an enolate ion - this anion is stabilised by spreading the negative charge from carbon onto the highly electronegative oxygen atom. The enolate ion then reacts with bromomethane in a nucleophilic substitution reaction to introduce the methyl group selectively at the 2-position of the chain. Interestingly, 2-methylundecanal contains a chiral or asymmetric centre. The carbon atom at the 2-position is bonded to four different substituents. Consequently, there are two different ways of arranging the four groups - the methyl group can point up and the hydrogen down, or vice versa.
Skip to 1 minute and 45 secondsIf you flip one of these structures we can see that the two compounds are mirror images of one another - we call these enantiomers and they are non-superimposable mirror images. Our synthetic approach to 2-methylundecanal produces an equal mixture of enantiomers called a racemate, or a racemic mixture. This is because the enolate ion is planar and 50% of the time bromomethane approaches it from the top face and 50% of the time it approaches it from the bottom face. At York we are researching to selectively make just a single enantiomer from this type of reaction. Why you ask? Well enantiomers can have different biological properties, including different aromas. So why can different enantiomers have different smells?
Skip to 2 minutes and 32 secondsTo answer this we need to explore current theories of smell. Surprisingly, the mechanics of how we smell things and recognise odours still aren't fully understood. Of the two theories vibration theory is more controversial and is based on every substance generating a specific vibration frequency that the nose interprets as a distinct smell. This is like a swipe card - the code in the magnetic band, or the vibrations, can trigger the process. The more widely accepted theory is the shape theory otherwise known as the lock and key model. Here part of an odour molecule, the key, docks within a receptor in the upper part of our nose, the lock.
Skip to 3 minutes and 15 secondsThis chemical interaction is converted into an electrical signal that travels to the olfactory bulb in the brain which interprets it as a smell. The shape theory explains why some enantiomers can smell differently - the enantiomers fit into different receptors in our nose, like our left and right hands fitting into different gloves. But there are some question marks hanging over the shape theory. For example, similar shaped and sized molecules can smell very differently. Ethanol has a pleasant smell, try sniffing vodka, whereas ethanethiol has an over-powering garlic or skunk-like odour.
Skip to 3 minutes and 52 secondsSo the shape theory does not answer all of the questions and more research is needed to shed light on how biological systems recognise chemical messages and how the human brain makes sense of the nerves signals it receives. The ultimate aim is rational fragrance design, which is the ability to design a fragrance molecule based on accurate predictions of how different features of its structure contribute to its aroma.
Theories of smell
In the screencast, we mention the two proposed theories for the mechanics of scent recognition; vibration theory and shape theory (or the lock and key model). The mechanics behind both of these theories still aren't fully understood and there are unanswered questions surrounding both theories.
How does vibrational theory work?
Our noses have olfactory receptors that are used to distinguish different scents. The vibrational theory explanation for how this occurs is that atoms are joined together by bonds that are able to vibrate at specific frequencies; these vibration frequencies must be turned into, and delivered to the brain, as electrical signals. The ability to distinguish between different scents occurs due to the activation of specific olfactory pathways by the specific vibration energies of different bonds within different odour molecules.
Therefore, while the lock and key model proposes that if molecules have similar structures they will smell the same, the vibrational model states that molecules with bonds that have similar frequency vibrations, will have the same scent.
A recent study
Recent studies examining the extent of isotopomer discrimination in honeybees, suggest that shape theory might not be enough to fully explain the ability of the honeybees to distinguish between odour compounds. Isotopomers (also known as isotopic isomers) are versions of the same molecule, with identical numbers of each element and isotope, but with differences in their positions; while, isotopomer discrimination is the ability to register differences in the isotopomer odour molecules.
The study used undeuterated and deuterated versions of the same molecules. One of these odour molecules was acetophenone; shown below are the undeuterated (contains H atoms) and fully deuterated (all H atoms replaced by D atoms) versions of acetophenone.
Deuterated molecules are molecules where some, or all, of the hydrogen atoms (H) in the compound are replaced with deuterium (D); which is a stable isotope of hydrogen. The mass of deuterium is approximately double that of hydrogen, which leads to the deuterated and undeuterated molecules having almost identical shapes but significant differences in the stretching frequencies of the C–H and C–D bonds. This results in the C–H and C–D bonds having different specific vibration energies, suggesting that the undeuterated and deuterated molecules will activate different olfactory pathways to the brain, hence registering as different scents.
This was found to be the case when the scientists studied the effects of deuterated and fully undeuterated versions of acetophenone on the activation pathways in honeybees. The analysis determined that there were differences in pathway activation when deuterated molecules of acetophenone were used compared to the undeuterated version; leading to the conclusion that the lock and key model of olfaction might not be able to explain the observed distinction between deuterated and undeuterated acetophenone odour molecules by honeybees.
This study doesn't provide conclusive proof that vibrational theory is the mechanism of odourant reception, as the deuteration ultimately affects more than the vibrational spectrum of the odour molecules. However, it does provide a basis for the assumption that the vibrations of molecules play a part in the odourant-receptor interactions. The true mechanism of scent reception is still indefinable, but this study does suggest that vibration theory is not to be sniffed at!
Cracking the olfactory code
In 2015, a $15 million project, sponsored by the National Science Foundation and the White House Brain Initiative, called Cracking the Olfactory Code was initiated. Scientists hope to unravel how smell (the oldest guidance system in the world) works. Then, the team aims to teach robots how to smell!
Keen sense of smell
So, who has the keenest sense of smell, dogs or humans? Research suggests that, in some cases, our sense of smell rivals that in dogs. For example, we are more sensitive to amyl acetate (pentyl ethanoate), CH3CO2(CH2)4CH3, in bananas than dogs. This is likely explained by identifying ripe fruit being more important to our own ancestors and irrelevant to those of dogs.
On a related subject, you may have heard about canine cancer detection? Recently, four Beagles were shown to be able to distinguish, by smell, between the blood of healthy people and those with lung cancer with ~97% accuracy. Cancerous cells have been reported to emit unique odours (for example, heptanal, CH3CH2CH2CH2CH2CH2CHO, in blood, urine or breath is often quoted as being indicative of certain types of cancers) and it is thought that these can be detected by the dogs. However, more work is needed to verify these and related results. It also raises the intriguing possibility of being able to recognise a specific disease from a breath-print of exhaled substances – perhaps, in the future, this will provide a suitable and reliable method of diagnosing an illness.
Finally, on the subject of blood, the metallic aroma is caused by a compound called trans-4,5-epoxy-(E)-2-decenal, or TED. Interestingly, the odour of TED is attractive to top predators like tigers and wolves (perhaps this helps them find their prey), but it is aversive to prey species like mice and rats (perhaps this conveys information about predation and injury). TED is a chiral compound and both enantiomers have been prepared separately in the lab and each has been smell tested. A panel of flavour scientists perceived each enantiomer to smell similarly, but one to be much more pungent than the other. The results using mice were particularly interesting as the individual enantiomers of TED did not communicate fear in the mice – it was only when they were mixed together that the mice became scared. Fascinating!
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