Chapter 14: Stereochemistry

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Welcome back to the Deep Guive.

Today we're taking a shortcut to getting well informed about a really fundamental concept in organic chemistry, stereochemistry.

That's right.

Our mission is to kind of distill the core principles of molecular three -dimensional shape, this idea of handedness, drawing directly from chapter 14 of Clayton Greaves and Warren's Organic Chemistry, second edition.

Exactly.

We're going to try and uncover how this 3D shape of molecules dictates, well, pretty much everything, how they react, their fundamental handedness, and why that handedness is so profoundly important, especially in, you know, natural systems and designing effective drugs.

Right.

We'll touch on mechanistic reasoning and reaction pathways where they connect with these fascinating 3D aspects.

Okay, let's dive in then.

I know we touched on aldehyde reactions way back, I think it was chapter 6, like when an aldehyde reacts with cyanide, but there was a crucial detail we kind of glossed over then, wasn't there?

Something about the carbonyl group having two faces.

Precisely.

Yeah, you can imagine the carbonyl group of the aldehyde.

It effectively has a front face and a back face.

Okay.

And the cyanide ion, it can attack from either of these faces.

Now, what's fascinating here is that the two distinct products you form, they aren't just slightly different.

If you try to superimpose them, you actually can't.

They are non -superimposable mirror images of each other.

We call such structures anantimers.

Anantimers, got it.

And any molecule that is non -superimposable on its mirror image is by definition chiral.

Think of your own hand, they're mirror images, right?

Yeah.

But you can't perfectly overlap your left hand on your right hand, they're chiral.

Yeah, makes sense.

So, what does this mean for the reaction itself?

If you start with something,

i -curl something without this handedness, and you react it to form a new chiral center, are you always going to get a perfect 50 .50 mix of both mirror images, what you call a racemic mixture?

You've hit on a really key point there.

Yes.

When an i -curl starting material reacts to form a chiral product, the attack from either face is equally likely.

Statistically, it's 50 -50.

Okay.

So, this means you almost always end up with that 50 .50 mixture of the two anantimers.

That's your racemic mixture.

Right.

Now, contrast that with, say, adding cyanide to acetone.

If you imagine the two possible products there, C and D in the text, you'll find they are superimposable.

They're actually identical molecules.

Oh, okay.

And such structures, the ones that are superimposable on their mirror images, we call those acryl.

Okay, so the aldehyde product is chiral, the acetone product is acryl.

What's the fundamental difference between them that makes one superimposable and the other not?

Is there a simple way to tell?

The answer really lies in symmetry.

Symmetry.

The acetone cyanohydrin molecule, that's our acryl example, it possesses an internal plane of symmetry.

A plane of symmetry, like a mirror inside the molecule.

Exactly.

You can imagine slicing it right down the middle, and one half is a perfect mirror image of the other half.

Any molecule that has such a plane of symmetry will be chiral.

It cannot exist as anantimers.

Okay.

And this holds true for lots of common structures, planar molecules, obviously, but also things like simple cyclohexanones, even some more complex bicyclic acetyls mentioned in the text.

But our aldehyde cyanhydrin, the chiral one, that doesn't have an internal plane of symmetry.

Correct.

So does that mean the simple rule is basically no plane of symmetry means it's chiral, but if it has a plane of symmetry, it's acryl?

That's a very reliable rule of thumb, yeah.

If you look carefully and you can't find any plane of symmetry, the molecule is almost certainly chiral and it will have an antimer.

This lack of symmetry is what gives molecules their handedness.

Like you said, with hands.

Exactly.

Or think of everyday objects.

A pair of scissors is chiral, a left scissor isn't superimposable on a right one.

A car is chiral.

Huh.

Never thought of a car that way.

But a plain coffee mug or a basic sock.

They have planes of symmetry.

You never worry about which sock goes on which foot.

Right.

Even something like a golf club is chiral, interestingly, but a tennis racket usually is a chiral.

Okay.

Okay.

So we've explored how the 3D shape creates these unique mirror images, these anantimers, but what about other ways molecules with the same atoms can differ?

This gets us into the broader world of isomers, doesn't it?

It does.

And isomers are simply compounds that share the same atoms, same molecular formula, but they're arranged differently.

Right.

Now, if their atomic connectivity is different, how the atoms are actually linked together, we call them constitutional isomers.

Like ethanol and dimethyl ether, same atoms,

C2H6O, but connected differently.

Perfect example.

But if the connectivity is the same and they only differ in their three -dimensional arrangement in space, then they are stereoisomers.

Ah, okay.

And anantimers are non -superimposable mirror images, are one type of stereoisomer.

Other examples you might know are things like E and Z double bonds.

They're also stereoisomers.

Got it.

Now, here's a distinction that I remember always tripping people up.

Configuration versus confirmation.

Yes.

This is crucial.

I always liked the analogy of humans.

Oh.

We all share the same basic configuration, you know, two arms joined to shoulders, two legs from hips.

That's fixed.

Right.

But our confirmations can vary wildly.

Arms folded, arms raised, waving.

That's just how we arrange those basic parts without breaking anything.

That's a perfect analogy.

Changing a molecule's configuration always means breaking and reforming chemical bonds.

You're fundamentally changing the atomic arrangement, creating a different, distinct molecule.

Right.

You need energy.

It's a chemical reaction.

Exactly.

But changing its confirmation just means rotating about single bonds.

No bonds are broken.

The molecule remains chemically the same entity.

It's just adopting a different spatial twist or shape, like twisting your wrist.

Your hand is still connected, but its orientation changes.

Okay.

That makes sense.

So digging a bit deeper into chirality again, our aldehyde cyanohydrin example, the chiral one, it's chiral because it contains a carbon atom bonded to four different groups.

Four different things attached to one carbon.

Yes.

In that case, it was an OH group, a CN group, an RCH2 group, and a hydrogen atom.

Such a carbon atom is called a stereogenic center, or more commonly, people call it a chiral center.

Okay.

Here's another useful rule.

If a molecule has just one chiral center, it must be chiral.

No exceptions there.

One chiral center guarantees chirality.

Got it.

As we said earlier, if you make something like that in the lab, starting from acryl materials, you usually churn out that 50 .5 zero racemic mixture.

Typically, yes.

But nature seems to be much more selective, doesn't it?

It often produces these chiral compounds as single enantiomers.

They're enantiomerically pure.

Absolutely.

Natural alanine, the amino acid, for example, is found solely as one enantiomer in proteins.

If you synthesize alanine in a standard lab reaction, you'd get the racemic mix.

Right.

It highlights that just because a molecule is chiral doesn't automatically mean a sample of it is enantiomerically pure.

You can have chiral molecules in a racemic mixture.

That's a good distinction.

Yeah.

So how do chemists actually describe which specific enantiomer they're talking about?

There must be a system.

There is, and it's essential.

It's the RS notation developed by Kahn, Engold, and Prelog, often just called the CIP rules.

Think of it like a universal GPS for chiral centers.

Okay.

How does it work?

Well, you assign priority numbers, one through four, to each of the four groups attached to the chiral center.

This is based mainly on atomic number higher, atomic number gets higher priority.

Then you orient the molecule in space so the lowest priority group, number four, is pointing directly away from you into the page or screen.

Okay.

Lowest priority back.

Right.

Then you look at the remaining three groups, one, two, and three.

If tracing the path from priority one to two to three goes in a clockwise direction, the center is designated R.

R4.

Rectus, which is Latin for right.

If the path from one to two to three goes anti -clockwise, it's designated S.

S4.

Sinister, Latin for left.

Okay.

R is clockwise, S is anti -clockwise, with group four away.

Exactly.

So for instance, that natural alanine we mentioned, it's consistently designated as S -alanine using these rules.

This system allows chemists anywhere in the world to describe the exact 3D arrangement without any ambiguity.

That's pretty neat.

Now, beyond these structural labels, there's also this other property you mentioned, optical activity.

How does that fit in?

Right.

This is a physical property, and antirumors are identical in almost all physical properties, melting point, boiling point, density, solubility, and normal solvents, except for one critical difference, how they interact with plane polarized light.

Plane polarized light.

Yeah, light where the waves oscillate in only one plane.

When you pass this light through a sample of a pure antirumor, the plane of polarization gets rotated.

One antirumor will rotate the light clockwise, to the right, we call that dexterotatory, and label it plus.

Its mirror image, the other enantiomer, will rotate the light anti -clockwise to the left leverotatory, or by the exact same amount, just in the opposite direction.

Okay.

So plus is right, is left rotation.

And we measure this as a specific rotation.

Precisely.

It's a measurable value unique to each enantiomer under specific conditions.

Now, here's the big question.

Is there a connection between R -S and plus, like, R always plus and S always?

Absolutely not.

And it's critical for you to grasp this.

There is no direct relationship whatsoever between the R -S structural label and the plus optical activity measurement.

Really?

Not at all?

None.

An R compound can be plus, or it can be, S compound can be plus, or you simply cannot predict one from the other just by looking at the structure.

They are independent descriptors.

Okay.

That's a really important point.

Don't mix them up.

What about the DL system?

I see that sometimes with sugars and amino acids.

Right.

The DL nomenclature is a much older historical system.

It actually originated from comparing structures back to a reference molecule, glyceraldehyde.

It's primarily used now for specific classes of natural molecules.

You'll always see biochemists talk about L -amino acids and D sugars.

It's a convention within those fields.

So convention, not a general rule.

Exactly.

And again, just like with plus, you should never try to predict DL from a structure alone unless you know it belongs to that specific class and you know the convention.

Stick with R -S for systematic naming.

Okay.

R -S is the reliable one.

So we've got enantiomers, the perfect mirror images.

But you also mentioned another crucial class of stereoisomers, diastereoisomers.

What are they?

Diastereoisomers are stereoisomers that are not mirror images of each other.

Okay.

So same connectivity, different 3D shape, but not mirror images.

Precisely.

And this is a key distinction because unlike enantiomers, which have identical physical properties, except for optical rotation, diastereoisomers generally have different physical and chemical properties.

That makes them easier to handle in the lab, presumably.

Much easier.

They'll usually have different melting points, different boiling points, different solubilities, different behavior on chromatography columns, even different NMR spectra.

You can separate them using standard techniques.

What are some examples?

Well, think of simple geometric isomers like cis and transbutanedioic acids.

You probably know them as maleic acid and fumaric acid.

Right.

Very different compounds.

They're diastereoisomers.

Same connectivity, different 3D arrangement around the double bond.

Definitely not mirror images.

Or the cis and trans -4T butylcyclohexanols mentioned in the text.

Again, diastereoisomers with distinct properties.

The epoxide examples in your text are also great illustrations.

They show chiral diastereoisomers, where each diastereoamer exists as its own pair of enantiomers.

Okay.

So if a compound has multiple stereogenic centers,

how do we figure out the relationship between the different possibilities?

How do we predict if we're looking at an enantiomer or a diastereoisomer?

There's a helpful rule of thumb that emerges when you have multiple chiral centers.

If you take a molecule and you invert the configuration switch R to S and S to R at all of the stereogenic centers, the new molecule you get is its enantiomer.

Invert everything gives the mirror image.

Makes sense.

But if you invert the configuration at only one of the centers, or some, but not all of them, the molecule you get is a diastereoisomer of the original.

Only change some, not all gives a diastereoisomer.

Exactly.

This is really nicely illustrated by the natural compounds ephedrine and pseudo ephedrine.

They both have two chiral centers.

They are diastereoisomers because they differ in configuration at only one of those two centers.

And interestingly, both are produced in anti -americally pure in nature, but they are diastereomers of each other.

It's like that handshake analogy again, isn't it?

It is.

Shaking right hand with right hand or left with left, those are like enangiomers, a matching interaction, but shaking a right hand with the left hand, that's a different interaction, like diastereoisomer.

That helps visualize it.

So that's clear for one or two centers.

But what happens when you get to more complex molecules like sugars, which can have a whole string of these chiral centers?

Does that 2N rule still hold?

You know, air and chiral centers gives two and stereoisomers?

You're right to be cautious with simple rules.

Generally, yes.

A molecule with indistinct stereogenic centers can exist as up to two when stereoisomers.

Up to?

Up to.

And these usually break down into two and one pairs of diastereoisomers, with each diastereoisomer existing as a pair of enantiomers.

However, this is a general guideline and it needs to be applied carefully because of a fascinating exception, compounds known as mesocompounds.

Mesocompounds.

Okay, so just when I thought I had a handle on counting isomers, there's another twist.

What happens with these?

Is it about that internal symmetry again?

It is.

It's where the molecule's own internal symmetry causes some potential to actually be identical, effectively canceling out the chirality despite having chiral centers.

How did that work?

Let's take tartaric acid, a classic example.

It has two stereogenic centers.

So based on the 2N rule, you might initially expect 22 equals four stereoisomers.

Right, two pairs of enantiomers, maybe.

You'd expect an ROA configuration and its mirror image, the SS configuration, and those two are enantiomers of each other, a chiral pair.

Okay, that's two.

What about the others?

Then you'd consider the RS configuration and its mirror image, the SR configuration.

But here's the twist.

If you draw these out or build models and look closely, you'll discover that the RS molecule and the SR molecule are actually identical.

They are superimposable.

Wait, how can that be?

They both have stereogenic centers, one R and one S.

It's because the molecule as a whole possesses an internal plane of symmetry.

Ah, that plane again.

Exactly.

A meso compound is defined as a molecule that contains stereogenic centers, but is overall acryl because it possesses this internal plane of symmetry, making it superimposable on its mirror image.

The plane essentially creates an internal mirror with R stereochemistry on one half, canceling out the S stereochemistry on the other half in terms of overall chirality.

So it has chiral centers, but isn't chiral overall.

Precisely.

So tartaric acid actually exists as only three distinct stereoisomers, not four.

These group into two diastereoisomers.

One is the chiral pair of enantiomers, RR and SS, and the other is the single acromesocompound, RS, which is identical to SR.

This means it's much safer, like you said, not to just blindly apply the Jordan rule.

You should probably identify the possible diastereoisomers first by looking at the combinations of R and S and then check each one individually for chirality, looking for that internal plane of symmetry.

That's definitely the more rigorous and safer approach, yes.

You won't miss a mesocompound that way.

Fascinating stuff.

Are there other weird cases, like can molecules be chiral even without having those typical tetrahedral carbon chiral centers?

Oh, absolutely.

What's truly intriguing is that chirality isn't limited to molecules with stereogenic carbon atoms.

A few classes of compounds are chiral due to their overall molecular shape or restricted rotation without having any traditional stereogenic centers.

Like what?

Well, examples include certain allines.

These have two consecutive double bonds, basically.

This forces the groups at the ends to be perpendicular to each other, which can create a non -superimposable mirror image if the substituents are right.

There's no single chiral carbon, but the molecule as a whole has handedness.

Ah, a twist in the molecule itself.

Exactly.

Another important class involves viral compounds, like the ligand binapp used in catalysis.

Here, you have two aromatic rings joined by a single bond.

If there are bulky groups near that bond,

rotation around it can be severely restricted or even prevented at room temperature.

So they get locked in place.

They get locked into specific conformations that are mirror images of each other but can't interconvert easily.

These are called atroposomers, isomers arising from restricted rotation.

Again, chiral, but no classic chiral center.

Even some spiral compounds where you have rings sharing a single atom can be chiral if their overall 3D structure lacks a plane of symmetry.

It really shows chirality is about the overall symmetry of the molecule.

This really deepens the whole symmetry picture, then.

We started saying a plane of symmetry means achiral.

Are there other symmetry elements we should be aware of when predicting chirality?

Yes, it's worth mentioning briefly.

We know a plane of symmetry, often denoted, means the molecule is achiral.

Another element that guarantees achorality is the center of symmetry or inversion center.

If a molecule has one of those, it's achiral.

Okay, plane or center means achrial.

But then there are axes of symmetry, CN.

A C2 axis, for example, means you can rotate the molecule 180 degrees and get an identical structure.

Now, here's the nuance.

Having an axis of symmetry, like a C2 axis, is compatible with chirality.

Wait, you can have an axis of symmetry and still be chiral?

Yes.

Provided the molecule doesn't also possess a plane of symmetry or a center of symmetry, think of a propeller shape.

It might have rotational symmetry, but it can still be chiral, left -handed or right -handed twist.

So the absence of improper rotation axes, which include planes and centers of symmetry, is the ultimate criterion for chirality.

But for most common cases, looking for a plane or center is sufficient.

Okay, that's a subtle but important point.

So wrapping back,

nature often gives us these enantiomerically pure compounds, right?

Often, yes.

But lab synthesis, starting from acryl stuff, usually gives us those 50 .5 -euro racemic mixtures.

So how do chemists actually get the pure single enantiomers in the lab when they need them?

Which they obviously do for drugs and things.

This essential process is called resolution, breaking a racemic mixture into its constituent enantiomers.

Resolution, okay.

Since enantiomers have identical physical properties in an acryl environment, same boiling point, same solubility in normal solvents, same density, you can't separate them by typical physical methods like distillation or standard chromatography.

They behave identically.

So you can't just like filter one out?

Nope.

So the clever trick, the classic method, is to temporarily convert the enantiomers into something that can be separated.

Diastereoasomers.

Oh, back to diastereoasomers.

Because they do have different properties.

Exactly.

So what you do is you take your racemic mixture, say a racemic acid, a 50 .5 -euro mix of R acid and S acid, and you react it with an already enantiomerically pure compound.

This resolving agent is often something readily available and cheap from nature, like a pure enantiomer of an M amine base, say R amine.

Okay, mix the racemic acid with a pure amine.

Right.

The R acid reacts with the R amine to form a salt, which we can call the R salt.

The base acid reacts with the same R amine to form the SR salt.

Okay, so now you have two salts, R, R, and SR.

And what's the relationship between R, R, and SR?

They are not mirror images.

They are diastereoasomers.

Ah, and diastereoasomers can be separated.

Precisely.

Because they are diastereoasomers, these two salts will have different physical properties, most usefully different solubilities.

So you might find that one salt crystallizes out of solution more easily than the other.

So you could filter off the crystals of one diastereomeric salt?

You got it.

You separate the two diastereomeric salts, maybe by crystallization, maybe by chromatography since they'll behave differently there too.

Once you have the pure diastereomeric salt separated… Then you just need to get your original acid back.

Exactly.

You reverse the salt formation reaction, maybe by adding a strong acid, to regenerate your original carboxylic acid, but now it's enantiomerically pure.

You get pure acid from the S -ol and pure S -acid from the SR salt.

That's incredibly clever.

So you're essentially borrowing nature's handedness in the resolving agent to sort out the handedness of your lab -made mixture.

That's a great way to put it.

We leverage existing chirality to induce separation.

Are there good real -world examples of this?

Oh, absolutely.

A classic one is the resolution of naproxen.

You probably know it.

It's a lay, a common painkiller.

Only the S -enantiomer of naproxen is the active anti -inflammatory drug.

The R -enantiomer is actually a liver toxin, so you really want only the S.

Wow.

Okay.

So purity is critical there.

Critical.

And naproxen is a carboxylic acid.

Historically, it was resolved on an industrial scale by forming salts with an enantiomerically pure amine, just like we described.

The diastereomeric salts had different solubilities, allowing chemists to crystallize and isolate the salt containing the desired S -naproxen.

That really brings home why this is so important, especially in pharmacology.

Why is it so absolutely crucial for drugs, often to be single enantiomers?

It sounds like a huge amount of extra effort and cost for drug companies.

It is a significant effort, but it's often absolutely necessary, sometimes literally a matter of life and death.

The reason boils down to the fact that biological systems, your body, are themselves fundamentally enantiomerically pure, or at least highly enantioselective.

How so?

Well, think about drug receptors.

These are typically large protein molecules embedded in cell membranes or inside cells.

And what are proteins made of?

Amino acids.

Exactly.

And naturally occurring amino acids used to build proteins are almost exclusively the L -enantiomers.

So the drug receptors themselves are chiral entities.

They have a specific 3D shape, a specific handedness.

Like a glove.

Precisely like a glove.

A receptor is like a left -handed glove.

One enantiomer of a drug might be the left hand that fits perfectly into that glove, binds strongly, and triggers the desired therapeutic effect.

Its mirror image, the other enantiomer, is like the right hand.

It might not fit into the left -handed glove receptor at all, making it inactive, or, maybe if it's poorly, giving a weaker effect.

Or worse.

Or worse.

It might bind to a completely different receptor, a different glove elsewhere in the body, and trigger a completely different, perhaps undesirable or even toxic effect.

That's scary.

It is.

The most tragic example, which really hammered this home, was the thalidomide disaster in the late 50s and early 60s.

Thalidomide was sold as a racemic mixture.

One enantiomer was an effective sedative, prescribed for morning sickness in pregnant women.

The other enantiomer, unfortunately, was a potent teratogen, causing severe birth defects.

Oh, terrible.

A truly awful lesson in the importance of stereochemistry.

The text cites a less tragic, but equally illustrative example, darvon.

One enantiomer is a painkiller.

Its mirror image, novrad, which is darvon spelled backwards, is actually an anticoff agent.

Same molecule, just mirrored, but completely different biological activity.

It really underlines the profound impact of stereochemistry in biology.

So it's not just an academic detail.

It's about life -saving or life -altering precision.

Now, what if those classical resolution methods, like crystallization of diastereomers, don't work well?

Yeah.

Are there other techniques?

You mentioned chromatography briefly.

Yes, absolutely.

If classical resolution is difficult, we can turn to chiral chromatography.

This is a more modern and often very powerful technique.

How does that work differently?

Instead of making diastereomers before the separation, you use a chromatography column, where the stationary phase, the stuff packed inside the column that the mixture flows through, has itself been made chiral.

You make the column handed.

Exactly.

You chemically bond an enantiomerically pure compound, maybe an amino acid derivative or a polysaccharide or some other chiral molecule, onto the surface of the stationary phase material, like silica gel.

Now, the whole column environment is chiral.

When you pass your racemic mixture through this chiral column, the two enantiomers will interact differently with the chiral stationary phase.

It's like they're trying to shake hands with the chiral surface.

Ah, like the glove analogy again?

Precisely.

One enantiomer might bind more strongly or fit better with the chiral stationary phase than its mirror image.

This difference in interaction strength causes one enantiomer to travel more slowly through the column, while the other moves faster.

So they come out at different times?

They come out at different times, allowing you to collect them separately.

Think of it like trying to sort a big pile of left shoes and right shoes in the dark, and you can only use your right foot.

You'll find the right shoes kind of stick or fit onto your foot momentarily, slowing them down, while the left shoes just slide past easily.

Chiral chromatography works on a similar principle of differential interaction.

That's a really elegant solution, wow.

This deep dive, it's really shown us that this whole area of stereochemistry, the three -dimensional shape of molecules, it's far from being just some minor detail in organic chemistry, isn't it?

Not at all.

It's absolutely fundamental.

It dictates precisely how molecules recognize each other, how they interact, how reactions occur, and as we've seen, it profoundly affects their biological activity.

We've really unpacked those crucial distinctions, chiral versus achiral, enantiomers versus stereoisomers, and we've seen how these subtle symmetry elements, like planes and centers and even axes, play a critical role in defining a molecule's handedness.

And understanding the different notations, the systematic RS, the experimental plus the historical DL, helps us describe these 3D differences accurately, even while stressing, importantly, that there's no simple correlation you can just guess between them.

And it's fascinating how chemists, often drawing inspiration directly from nature's own selectivity, have developed these clever resolution techniques, whether classical or chromatographic, to separate mirror image molecules and create those enantiomerically pure compounds that are so vital for everything from, well, new materials, perhaps, right through to engineering life -saving drugs.

Absolutely.

And you know, the fact that enantiomers behave identically in every respect, except when they are placed in a chiral environment, whether that's plane polarized light, a chiral stationary phase, or a biological receptor that's a really powerful and perhaps slightly humbling concept.

Well, it just begs the question, doesn't it?

What hidden roles might molecular handedness play in other complex systems or areas that we're maybe only just beginning to understand?

Thinking about things like material science, self -assembly, maybe even the very origins of life on Earth.

Why did biology choose one hand over the other for amino acids and sugars?

It's a deep question.

It really is.

A truly thought -provoking question to perhaps mull over as you go about your day.

Thank you for being part of the Last Minute Lecture family.