It’s hard not to *stare* when *I* see me *some* STEREOISOMERS – so can we hold a rally for CHIRALITY? Stereochemistry sounds like it should be about how things sound, but it’s actually about how they “look” – but looks can be deceiving – your right hand looks like your left but it’d be wrong to buy a right-handed baseball mitt for your left hand! Your fingers are basically the same on both hands, but they’re connected differently in 3D space. Similarly, the atoms making up molecules can be connected differently in 3D and we call this stereoisometry! And it’s really important in our bodies because our cells are basically filled with custom baseball mitts!
To explain, I’ll try to draw you in with an example that even non-geeks will find *cool* – and then we’ll get to the stuff I find even cooler (stereochemistry of the molecules of life – amino acids, sugars, etc.) & life-alterers (stereochemistry of pharmaceutical drugs).
MENTHOL (2-isopropyl-5-methylcyclohexanol) is classified as a cyclic monoterpene alcohol 👉 “cyclic” because it has a ring structure, “alcohol” because it has a hydroxyl (-OH) group attached to a carbon (C) http://bit.ly/2QWKWXp & “monoterpene”? That just means 2 of its building blocks were 5-C “isoprene” units
That “minty cool” feeling of peppermint comes because menthol triggers the cold-sensitive TRPM8 receptor, leading to a rush in of calcium ions & a subsequent change in electricity that sends a message to your brain that you’re cold.
Normally, TRPM8 only opens its channel when at cold temps, but menthol “tricks it” into opening up at higher temps. This is similar to how capsaicin (found in red hot chili peppers) triggers the heat-sensitive TRPV1 receptor so you get a burning hot sensation even when you’re not hot.
In addition to naturally occurring in leaves of plants in the Mentha genus (like peppermint), menthol’s added to products like cough drops, mouthwash, lip balms, & more.
Menthol has 8 STEREOISOMERS 👉 stereoisomers are molecules that have the same “ingredients” & same atomic connectivity (the same atoms are bonded to the same atoms 👉 i.e. X-Y-Z & X-Y-Z NOT X-Y-Z & X-Z-Y) BUT their bonds are arranged differently in space
Not all molecules have STEREOISOMERS, only those w/CHIRAL CENTERS (aka STEREOGENIC CENTERS), which are often carbons (Cs) connected to 4 different things 👉 Every carbon (C) has 4 electrons (e⁻) to “spend” in bond formation 👉 it can form up to 4 single bonds & when it bonds to different things it can do so in different ways…
Imagine (or actually do it) taking 4 DIFFERENT rings, arranging 4 fingers in a “circle” like you’re grabbing something, & choosing which ring to put on which finger. If you imagine your fingers are all the same (they’re just “placeholders” & it’s relative positions of rings that matter), you have 2 different options 👉 Each CHIRAL CENTER is like a hand w/4 different 💍
A molecule can have an infinite # of “hands” & each hand gives you 2 stereoisomers 👉 so you end up with 2^n possible stereoisomers, where n is # of chiral centers
Menthol has 3 chiral centers, so 2^3 = 8 stereoisomers 👉 their “common names” are (+) & (-) menthol, (+) & (-) neomenthol, (+) & (-) isomenthol, & (+) & (-) isoneomenthol
Menthol (-) (full name (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol) is the most stable stereoisomer bc when its ring adopts a so-called “chair” configuration, its bulky groups are all sticking out (equatorial) ⬅️➡️ instead of ⬆️⬇️, so they have more “room”
A special type of stereoisomer are ENANTIOMERS 👉 these are “mirror-image” stereoisomers – like your left & right hand 👉 they look like you could just flip 1 over & overlay them, BUT when you do so you have 1 hand palm-side-up & 1 hand palm-side-down 👉 so they’re NOT superimposable ❌ You get pairs of ENANTIOMERS when ALL the chiral centers are “swapped” 👉 if they’re NOT all swapped, they’re DIASTEREOMERS
DIASTEREOMERS have DIFFERENT physical & chemical properties but ENANTIOMERS have the same physical & chemical properties (except for the direction they rotate light, which is what the +/- refers to) BUT enantiomers can have different “biochemical” properties bc our bodies respond differently to them bc they fit (or don’t fit) differently into the molecules in our cell they interact w/(like only having left-handed gloves)
When we make a compound like menthol in a test tube, we get a mix of stereoisomers, BUT when organisms make things naturally, they usually make a single stereoisomer because, just like our receptors are “handed”, so are the proteins (enzymes) that help the cells make the compounds. So we can get by with having receptors that only recognize that 1 stereoisomer
When it comes to menthol, (-) menthol has “got the power” – the cooling power, whereas (+) menthol is ~4X less “refreshing” (as well as being bitterer/mustier)
We’re limited to drawing in 2D, but molecules exist in 3D. So to help show stereochemistry, we use dashed lines to show bonds going “into” the paper (or screen) & solid wedges to show bonds coming out at you. Straight lines (in the context of this dash/wedge notation) indicate that a bond is in the plane of the paper/screen.
But be careful – if ALL the bonds are drawn as straight lines it does NOT mean all the bonds are “flat” 👉 instead it means illustration isn’t showing you stereochemistry
Also, in our drawings, to “decrease clutter” & make it easier to see “more exciting” stuff we often leave out H’s that are attached to C’s 👉 it’s implied that Hs are present to bring C’s up to 4 bonds (e.g. If a C’s attached to 2 other Cs, it’s implied that it’s also attached to 2 H’s). Even when we don’t draw them, H’s do affect bond geometry
If you’re wondering where the Rs & Ss come from – we can describe configuration around a chiral center using R/S notation. Unlike the +/- notation that indicates an empirical property (something that we find out by measuring), the R/S notation is “absolute” – it’s a “constant” of the molecule that doesn’t change depending on your measuring conditions.
In other words, R/S describes how the molecules are actually arranged, whereas +/- describes how they “behave” – and just like how you might behave differently in different circumstances but you’re always “you” molecules can behave differently in different conditions (like in different temperatures). The +/- is the “sign of optical rotation” and it can NOT distinguish the “absolute configuration” of an enantiomer because the +/- rotating is temperature-dependent
The details of assigning absolute configuration are are outside scope of this post, but here’s the gist: basically you rank attached groups by their atomic mass (the heavier the higher the priority – and if the directly-attached atom is the same, you keep going out until you find a point of difference. You want to get the “loser” – the lowest priority one – as far away from you as possible, so you stick it in the back (sticking into the page) and then look if you have to go clockwise R) or counterclockwise (S) to get to “fancier” ones. R is short for the Latin term for “right” – “Rectus” (think clock hand moving right). And S is short for “Sinister” – Latin for “left”
Another Latin term for left is levaoratotory – and this leads to another form of nomenclature (naming system) – the L/D nomenclature – and this one’s weird… Because it originally referred to direction of light rotating but now refers to being configured like something that rotated light a certain way…
You know how I said that our bodies usually exclusively use a single stereoisomer because we have the “gloves” to match it? A common place we see this is with amino acids (protein letters). Our proteins are made with “L” amino acids. There are some uses for D amino acids, such as in bacterial cell walls.
Amino acids have a generic backbone part that allows them to link together and a unique “side chain” aka R group that sticks out and makes the different letters “special.” The C that the side chain sticks off of (which we call the alpha carbon, Ca, is, (except for glycine because it has 2 H’s) a chiral center (and a couple amino acids – isoleucine & threonine – have additional chiral centers in their side chains).
When it comes to amino acids, the L/D notation is based off of comparing it’s configuration L-glyceraldehyde. And for glyceraldehyde the L indicated levarotatory as in it rotates light left. But even though they’re all “hooked up” like glyceraldehyde, not all L amino acids are levorotatory.
For example, L-alanine is dextrorotatory whereas L-serine is levorotatory – to avoid confusion we can write L(+)-alanine and L(-)-serine. This makes clear that the L is meant to indicate configuration, whereas the +/- indicates optical activity
Another place you see stereoisomers in biochemistry is with sugars. Sugars have a carbon backbone with alcohol (-OH) groups sticking off – and they can stick off in different directions. We can represent the direction they stick off with something called a Fischer projection where horizontal lines indicate bonds coming out towards you and vertical lines are bonds going away from you. This form’s helpful for quickly telling apart stereoisomers.
Stereochemistry often comes up in pharmaceutical drug production. Often only a specific stereoisomer of a compound is active. At best the other isomer(s) are inactive but harmless – but at worst they can cause problems.
When you have a even mix of enantiomers (those mirror image “fake-outs” that rotate light oppositely), we call it “racemic.” Since you have half of each and each rotates light in opposite directions, they “cancel out” and you don’t get any rotation of plane-polarized light. If you have more of one than the other, the light rotation will be skewed in one direction
An example is the painkiller/antiinflammatory drug ibuprofen. The (S) form’s active because it can bind to prostaglandin H2 synthase and inhibit it. But the (R) form’s not the right shape so it can’t bind. Thankfully it doesn’t bind other stuff and cause problems and it’s actually isomerize by enzymes in our bodies that convert it to the active form.
But sometimes the “wrong” stereoisomer can be harmful. For example, the S enantiomer of the drug thalidomide can cause birth defects and, in cells, even the “good one” can “turn bad” – they interconvert under biological conditions.