A Gallery of Some Interesting Molecules From Nature

by James

in structure determination

[In which we inch our way, very very slowly, towards spectroscopy and structure determination]

Recently I wrote about my experience of finding a bottle of  “White Tail Doe Urine” in the back of my rental car and how this led to a search of the chemical literature for what we know about the molecules (over 60 of them) contained in this golden liquid. If you’ve read that post or for that matter, had any curiosity at all about biology and chemistry, you’ll know by now that living organisms are veritable chemical factories, producing a vast array of molecules that serve as pigments, pheromones, defensive toxins, hormones, sources of energy storage, and many other uses [or sometimes, no discernible use at all]. At last count (2014), over 326,000 compounds have been isolated and characterized from organisms. We refer to these molecules as “natural products”. Among these 326,000 natural products are many familiar names – chlorophyll, caffeine, vitamin C, riboflavin, and erythromycin, to name just a few.  There are whole journals devoted to their study, such as the Journal of Natural Products, Natural Product Reports, Natural Product Updates, and many others.

After you’ve learned some organic chemistry, these become more than just words on the ingredients list of a food wrapper or in a medicine. By being able to “read” chemical structures,  you can start to understand reality at a deeper level.

Have you ever wondered:

• what gives rise to colors?
• what are toxins, specifically? and why are they toxic in the first place? How do toxins work?
• what gives rise to scents and smells? What is specifically responsible for the smell of roses, pine forests, or for that matter, poo ?
• what are pheromones? and do they really work?
• what do drugs and drug-like molecules look like? And are there any features they tend to have in common?

There are molecules responsible for each of these phenomena, and learning about them gives you a greater appreciation for how organisms work at the molecular level, and how organisms evolve and co-evolve.

16-chlorophyll

Photo credit: https://www.flickr.com/photos/dotun55/9583244213/

One of the books that really turned me on to organic chemistry was the Merck Index, which is a doorstop of a tome containing 10,000 entries about molecules from the world around us, along with literature references and historical notes. [Cheap older version on Amazon – there is also an online version, but it doesn’t allow as much serendipitous discovery by browsing en crappeur,  which is the whole point, in my opinion.]

What made the Merck great for me was that it turned all these words I’d learned from reading the sides of cereal boxes as a kid – (riboflavin, Vitamin C, niacin, folic acid, BHT… ) and others picked up along the way (chlorophyll, penicillin, estrogen, acetominophen, THC, morphine, mescaline, Vitamin C, Vitamin B12, calciferol…) –  and showed their structures. Pre-Wikipedia,  having a source that put all these things together was a revelation.

Going through a source like the Merck, you can recognize that the concepts you learn in the first few chapters of an organic chemistry textbook are not esoteric academic curiosities. Bonding, geometry, acid-base characteristics, functional groups,  stereochemistry and even conformations are all relevant to the understanding of molecules from nature as well as the vast array of medicines they have inspired. You also start to see that there are repeating patterns of natural products – steroids, terpenes, polyketides, flavanoids, iridoids, alkaloids, and many others.

Down the road, you might find (as I did) yourself asking questions like:

  • What’s the molecule (or molecules) responsible for that (smell, flavour, poison, color)?
  • What does that [molecule with weird name] look like?
  • What’s the structure of the active ingredient in that [drug, pesticide, supplement]?

Organic chemistry is literally everywhere around you. 

In that vein, this post simply aims to show the structures of some chemicals behind some of our everyday sights and smells (as well as a few more exotic ones). Like the Merck, the the list could be 10,000 molecules long. In the end, it is 15. [If there are other molecules you happen to find particularly interesting, go ahead and leave a comment below]. They all have Wikipedia entries if you find the brief factoids are unsatisfying.

The Smell of Earth – Geosmin

1-Geosmin

Photo credit: https://www.flickr.com/photos/nrcs_south_dakota/7166253549/

Yes – there’s a molecule our noses associate with the smell of earth. Geosmin is produced by actinobacteria in the soil and is largely responsible for that “it just rained” smell.  [As a side note, so does tert-butyldimethylsilyl chloride, which must be hitting the same olfactory receptor]. This molecule has a decalin structure (two fused six-membered rings) and has a tertiary alcohol at one of the ring junctions. I wonder how/if converting the alcohol to an ether would change the odor?  [Interesting paper on how small differences in structure can lead to different smells – stereochemistry is important!]

Rose Oil – Geraniol

A major component of rose oil (but by no means the only one), geraniol  belongs to the large class of molecules known as terpenoids – natural products built from the 5-carbon isoprene unit and modified in thousands of different ways. In the case of geraniol, there are two isoprene units, making it a “monoterpene” in the slightly confusing nomenclature of these molecules. The smell of rose oil is largely due to the contributions of  α-damascenone and β-damascenone , also terpenoids, but there are dozens of individual contributors.

Why would roses (and other plants) bother producing these molecules at all? The answer is that these scents attract pollinators, such as bees and moths, who can detect them at extremely low concentrations.

Geraniol also turns out to be a building block of many terpenes and terpenoids, primarily via geraniol diphosphate (diphosphate is nature’s way of turning alcohols into good leaving groups).

3-geraniol

Photo credit: https://www.flickr.com/photos/stukarp/51716095/

The Smell of Turds – Skatole

The name says it all.   A metabolite of the amino acid tryptophan, skatole has a distinct fecal odor. You can imagine the co-evolution that took place here – we’ve evolved to find the smell of skatole repugnant in response to the harmful nature of e.coli and other harmful bacteria present in feces.

2-skatole

Photo credit: https://www.flickr.com/photos/rachelandrew/245484281/

The “Hot” Taste of Chili Peppers – Capsaicin

Since plants can’t exactly run away, in order to deter predators they often rely on producing molecules that are feeding deterrents.  Capsaicin is the molecule most responsible for the “hotness” of chili peppers: it hits receptors on the cell membrane also activated by heat, abrasion, and acid. Commercially available pepper spray also contains capsaicin.

4-capsaicin

Photo credit: https://www.flickr.com/photos/oregonstateuniversity/14199271264

Housefly Sex Attractant – (9Z Tricosene). 

Insects that wish to mate are trying to solve the same problem as flowering plants that wish to attract pollinators.  In order to do so, they emit characteristic molecules that can be detected by their partners in minute concentrations at a considerable distance. In the case of the silkworm moth bombyx mori, a single molecule of the pheromone bombykol was found to elicit a nervous response. The discovery of insect sex pheromones has led to the development of pheromone traps as a popular alternative to pesticides.

The molecule below is (Z)-9-tricosene, the pheromone that female houseflies release to attract males. This chemical, commercially known as Muscalure, is synthesized in mass quantities and used in traps such as fly paper.

5-tricosene

Photo credit https://www.flickr.com/photos/cats-eye-view/541937335

 

Luminescence of Fireflies – Luciferin

Luciferin, produced by fireflies,  reacts with molecular oxygen to produce an unstable intermediate [1,2-dioxetane] that releases light upon decomposition [glowsticks are based on the same chemical pathway]. The five membered ring containing the sulfur and nitrogen is called a thiazole ; when fused with a benzene ring, it’s a benzothiazole (as in on the left); when one of the double bonds has been removed, it’s a dihydrothiazole.

6-luciferin

Photo credit: https://www.flickr.com/photos/fiskadoro/9209509185/

Frog Toxin – Epibatidine

Many species of tropical frogs produce toxic contact poisons, of which epibatidine is one example of many.  These poisons tend to be part of the large class of nitrogen-containing natural products known as alkaloids .  The production of toxic alkaloids is tied to the frogs’  diet of beetles and other insects: frogs kept in captivity don’t produce the toxin. Another fascinating example is batrachotoxin, a steroid alkaloid, which native tribes in South America have used to tip their spears and arrows for hunting prey.

On the left of the structure of epibatidine you’ll notice an aromatic ring containing a nitrogen (a “pyridine” ring) with an adjacent chlorine. On the right there is a bicyclic structure [7-azabicyclo[2.2.1]heptane] containing a secondary amine.

7-epibatidine

Photo credit: https://www.flickr.com/photos/leeinhisroom/3756992168/

Arrow Poison – Tubocurarine Chloride

Another contact poison (and alkaloid) from South America is tubocurarine chloride , isolated from the vine of chondrodendron tomentosum . Arrow poisons are generally known as “curares” . Note how the molecule is a salt – that nitrogen on the left is a quaternary ammonium with a formal charge of +1. This molecule paralyzes rather than kills – it was used for decades as an anaesthetic, before better alternatives (less troublesome for children and pregnant women) were developed.

8-curare

Photo credit: http://ntbg.org/plants/plant_details.php?plantid=2749

 

The smell of cherries and cinnamon – benzaldehyde and cinnamaldehyde

Crack open a bottle of benzaldehyde and you will be blown away by the concentrated, unmistakable smell of cherries (and the  cherry-ish scent we often encounter in lozenges, shampoos, and soap). The smell of cinnamon comes from a remarkably similar molecule – cinnamaldehyde has a double bond between the benzene ring and the aldehyde. In grad school, my research project required me to work with cinnemaldehyde for a week. That weekend I visited Ikea and they were selling fresh cinnamon buns. Let me tell you – after working with cinnemaldehyde in the lab, the thought of eating cinnamon buns is not tempting.

9-cinnamon_marachino

Photo credits: https://www.flickr.com/photos/88722241@N00/2154228849 https://www.flickr.com/photos/aaronfarmer/6210232218

Smell of pines and other conifers – alpha and beta pinene

If you’ve ever cleaned with Pine-Sol, or worked with turpentine, you’ve smelled the pinenes. These are in the terpene family too, just like geraniol – each are made up of two 5-carbon isoprene units for a total of 10 carbons each. That four-membered ring should scream out “ring strain” to you, but interestingly,  cyclobutanes (and cyclopropanes) are occasionally found in nature.   Interestingly, these molecules are biosynthesized from geraniol.

10-pine

Photo credit: https://www.flickr.com/photos/captions_by_nica/26039017051/

Catnip – Nepetalactone

The catnip plant, Nepata cataria, produces a fragrance that elicits a flurry of rolling, scratching, and purring in about two thirds of domestic cats (and bigger felines, apparently). As it turns out, nepetelactone – the compound produced by the plant – serves as an insect repellent. The effect on cats is an accident of its similarity to cat pheromones.

11-catnip

Photo credit: https://www.flickr.com/photos/10233916@N03/2526930264/

Opium – Morphine

To a beginner, morphine looks hopelessly complex in all its polycyclic three-dimensional glory. Five rings, multiple hydroxyl groups, a cyclic ether, a tertiary amine, 5 stereocenters – that’s a lot of action in a molecule containing only 17 carbons.

Morphine is actually a great lesson in how complex molecules can arise from relatively simple precursors. Oxidation of the benzylisoquinoline alkaloid reticuline – not too complicated a molecule – results in formation of the crucial C-C bond that connects the phenol ring with the bottom-most six membered ring. This is a common theme in natural product biosynthesis, by the way: complexity by way of oxidation of simpler precursors.

Treating morphine with acetic anhydride gives you heroin (not a natural product).  The partially methylated version is codeine (also present in opium).

12-opium

Photo credit: https://www.flickr.com/photos/rogoyski/2189048486

Antibiotic – Penicillin V

Alexander Fleming famously observed in 1928 that one of his staphylcocci cultures had developed a fungus and the colonies around the fungus had been destroyed. The structure of the key antibacterial agent was elucidated in 1945 by Dorothy Crowfoot Hodgkin using X-ray crystallography. The key to antibiotic activity is the beta lactam ring (cyclic amide 4-membered ring) which inhibits formation of the bacterial cell wall. There is a large family of these molecules, largely differing by the identity of the group forming the amide in the bottom left part of the molecule. The molecule shown (Penicillin V)  was later synthesized (after heroic effort) by John Sheehan and colleagues at MIT in 1951.

13-penicillin

Photo credit: https://www.flickr.com/photos/93155645@N08/13477817795

Tomato Pigment – Lycopene

One of the most familiar of  the fifteen causes of color from chemistry and physics is the color arising from molecular orbitals.  Molecules with pi bonds can absorb a photon corresponding to the gap in energy ( ΔE )between their highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). For a molecule like ethene, with one double bond, this requires very high energy photons (in the UV). However, this energy gap decreases as the number of conjugated pi bonds in the pi system increases. In the case of chlorophyll (above) that energy gap corresponds to photons in the

Lycopene is a 40-carbon member of the terpene family (a “tetraterpene”) and has 10 conjugated double bonds. In the case of lycopene, the wavelength of the photon required is in the blue region of the visible spectrum. We see the complementary color (red).

The fact that color is caused by highly conjugated pi systems (e.g. in heme, chlorophyll, b-carotene and others) is one reason why bleach works so well. Bleach + water reacts with the double bonds. This might not remove the molecule, but it removes the source of the color!

15-tomatoes

Photo credit: https://www.flickr.com/photos/sean_hickin/5480422968

Deer Tarsal Pheromone

Let’s end this where we started: with deer.  Male black-tailed deer emit pheromones from their tarsal gland. The major component is the unsaturated lactone below.   The scent emitted from this gland serves an identifier for each deer and is how deer separate “strange” from familiar individuals.

14-deer-tarsal

Credit: http://www.nature.com/nature/journal/v221/n5177/abs/221284a0.html

Screen Shot 2016-04-21 at 3.38.40 PM

 

Top Secret no longer

 

What Next?

That’s enough molecules for now – although if you have “favourite” molecules that you find interesting, by all means post them in the comments below.

Let’s ask the next question. Say you’re curious about the active component of a plant – catnip, for example.  You’re asking yourself, “what’s the molecule (or molecules) responsible for this effect?”.

How do you go from being curious about the active component of a plant, animal, or insect, to isolating it, and then actually determining its structure? What’s the sequence of steps?

In this series of posts, we’re going to start exploring this question!

 

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{ 8 comments… read them below or add one }

Paul Wenthold

Epibatidine is one of my favorites. Notice the similarity of the structure to nicotine – 3-substituted pyridine with a 5-member-N-heterocycle. Therefore, epibatidine targets nicotinic receptors, too. The difference is that they bind to nicotinic receptors in muscles, whereas nicotine binds to those in the brain. Dougherty tried to figure out the difference between the different receptors, and couldn’t pin-point anything specific (subtle differences in bond lengths and angles, etc). Because epibatidine targets the muscles, that’s why it leads to paralysis, while nicotine leads to addiction.

For other options, check out Paul May’s pages

http://www.chm.bris.ac.uk/sillymolecules/sillymols.htm

He has a book on it, too “Molecules with Silly or Unusual Names”

A couple of years ago, I did an exercise with elementary kids where we talked molecular structure with model kits, and we talked about how sometimes molecules have descriptive names (chair vs boat, windowpane, etc). So they made their own molecules and gave them names. Dinosaurane, sure, but my favorite was KeyChainane, with interlocking rings.

Reply

mamid

This a great introduction to the chemistry of natural products.
There are some misspellings, though: cinnemaldehyde (not spelled correctly even once), Nepata, maybe others.
But again, a great post.

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James

Thank you very much, as always.

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azmanam

Vanillin. How could you leave off vanillin? I may or may not have went out of my way to use it as a TLC stain in grad school when just about any other stain would have worked just fine. By far my favorite scent. Soooo good :)

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James

My labmate liked to use vanillin stain, he said, “because it attracts the ladies”. As an organic chemist, you need these small edges.

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Solomon Derese

Thank you for putting all this nice natural products together. I will definitely request my class to visit this cite.

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Ket0ne

Cadaverine – the smell of ‘death’, producing by rotting animal tissues. Interestingly, it is also present in small amounts in the semen. Also quite easy to synthesize (I wouldn’t recommend it!)

More here- https://en.wikipedia.org/wiki/Cadaverine

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James

Oh yeah. Completely forgot about putrescine and cadaverine!

Reply

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