Chapter 31: Saturated Heterocycles and Stereoelectronics

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Welcome to The Deep Dive, the show where we take complex topics, dive deep into the best sources, and pull out the most fascinating insights just for you.

Have you ever looked a medicine bottle or maybe even just a plastic container and wondered about the invisible molecular structures making those things up?

How do chemists not only build these tiny molecular machines but also truly understand their intricate shapes and how they actually react?

Today we're going on a bit of an adventure into that very question.

Yeah, that's right.

Our focus today is a deep dive into saturated heterocycles and stereoelectronics, and we're drawing key insights mainly from chapter 31 of Clayton, Greaves, and Warren's Organic Chemistry.

We'll be exploring how really simple changes in molecular architecture specifically, just putting atoms like oxygen or nitrogen or sulfur into carbon rings, how that dramatically alters a molecule's behavior.

Exactly.

We're talking about the fundamental forces that really govern molecular reactivity, how these rings are actually made, and crucially, how their precise three -dimensional shapes are controlled by something chemists call stereoelectronics.

And of course, how we use really powerful tools like NMR spectroscopy to actually see these hidden geometries.

Yeah, get ready for some genuine aha moments, hopefully, where you'll see chemistry in, well, a whole new light.

Okay, so let's start with the basics.

What exactly are saturated heterocycles?

Well, simply put, they're rings that contain not just carbon atoms but also other atoms, typically oxygen, nitrogen, or sulfur.

And importantly, unlike the flat aromatic rings you might be familiar with,

these are flexible 3D structures.

They've got shape.

And you probably encounter them like every day without even realizing it.

Think about common lab solvents like tetrahydrofuran, THF, and dioxin, but they're also the backbone of just countless natural products and drug molecules.

The pyrrolidine and piperidine rings, for instance, they're found in everything from nicotine to conine, you know, the hemlock poison.

Right, and even familiar drugs like cocaine, heroin, morphine, they all contain these nitrogen -based rings.

They are truly everywhere.

So what makes them so special?

Why dedicate a whole chapter to them?

It really boils down to two key factors, I'd say.

First, the heteroatom itself can make these rings surprisingly easy to form.

Think ring -closing reactions, or in some cases, actually easier to break apart through ring -opening reactions.

And these processes, well, they have some very specific constraints and rules we need to understand.

Okay, that's one factor.

What's the second?

The second, and this is where it gets really, really interesting, is that the ring structure itself actually locks in the orientation of the heteroatom's lone pairs of electrons.

Think about those little electron pairs sticking out.

Their direction gets fixed, and this fixed orientation profoundly influences the molecule's reactivity and its preferred shape, or what we call its conformation.

Okay, so it's not just what atoms are there, but how they're arranged, even down to the lone pairs.

Precisely.

And this brings us right to the core concept of our deep dive today, stereo electronics.

Sounds fancy, but the term just describes the chemical consequences that arise directly from the specific arrangement of orbitals in space.

It's a really fundamental idea that dictates pretty much everything from how fast reaction happens to what signals you'll see in an NMR spectrum.

We'll see it pop up again and again.

Okay, got it.

So let's talk reactivity then, because once these atoms are locked in a ring, they often don't behave quite like their acyclic counterparts, right?

Yeah.

Like an amyamine just floating freely.

Exactly.

Take saturated nitrogen heterocycles like piperidine or morpholine.

They act as nucleophiles, just like typical secondary amines.

That's expected, but here's the surprise.

They are often more nucleophilic than their open chain cousins, like, say,

diethylamine.

More nucleophilic.

Why would tying the ends together make the nitrogen better at attacking things?

It's a fascinating steric effect, actually.

Because the alkyl groups, the carbon chains are tied back into the ring structure, they're sort of held away from the nitrogen's lone pair of electrons.

This means the lone pair has a clear, unhindered path to an incoming electrophile.

Less clutter around the reactive site.

Ah, okay.

So it's like clearing the runway for the lone pair to take off.

That's a great way to put it.

And the difference can be quite dramatic.

For instance, if you compare the reaction rates with methyl iodide for a simple amyamine like triethylamine versus a cyclic one like quinucleidine, quinucleidine reacts over 60 times faster.

It's all because that ring structure clears the way, making the nitrogen's lone pair incredibly accessible.

Wow, 60 times.

But wait, does this also make them stronger bases?

Ah, good question.

But no, interestingly, this tied back effect doesn't really change the basicity much.

A proton is just so tiny, it doesn't really care about that steric bulk around the nitrogen.

It can sneak in regardless.

Okay, so nucleophilicity goes up, but basicity,

not so much affected by that specific steric factor.

Right.

What does affect basicity is the

electron richness of the nitrogen itself.

This explains, for example, why morpholine is less basic than piperdine.

The oxygen atom in morpholine is electronegative, right?

So it pulls electron density away from the nitrogen through the ring, making that nitrogen less eager to accept a proton, less basic.

Gotcha.

Inductive effects are still in play.

Okay, so this enhanced nucleophilicity,

does it lead to any interesting reactions?

Absolutely.

This unique combination of, well, good nucleophilicity and also being part of a structure that can potentially leave later, makes molecules like DABCO, that's a bicyclic diamine, exceptional catalysts.

They're perfect for reactions like the Baylis -Hillman reaction.

DABCO's nucleophilicity lets it add to an activated alkene.

It does its thing in the mechanism, and then it gets recovered at the end, ready to go again.

The catalyst, right.

Though I remember reading the Baylis -Hillman can sometimes be frustratingly slow.

It can be, yeah.

Sometimes it needs a little help, like running it under high pressure to speed things up.

But DABCO's structure is ideal for that catalytic cycle.

And if you need the opposite, not a good nucleophile, but a really strong base that won't act as a nucleophile, you can design cyclic amines for that too.

Think about 20276 tetramethyl piperdine, or TMP.

It's incredibly bulky, super hindered.

It makes a fantastic non -nucleophilic base, kind of like LDA, when you need extreme selectivity.

Okay, cool.

Let's shrink the ring down now.

What about aziridine, the three -membered nitrogen ring?

That must be strange.

Oh, definitely strange.

Aziridine and its four -membered cousin azetidine, they're stable enough to isolate, but they're, well, pretty volatile.

And interestingly, despite being a cyclic amine, aziridine is actually less basic and less nucleophilic than the larger rings like piperdine or pyrolidine.

Less.

But you just said tying back groups made piperdine more nucleophilic.

Why does shrinking the ring make aziridine less reactive?

It's a different effect dominating here.

It's called the scaracter effect.

Because of the extreme angle strain in that tiny three -membered ring, the nitrogen atom has to re -hybridize.

Its lone pair ends up in an orbital with significantly more sec character.

Remember, sorbitals hold electrons closer to the nucleus.

So those lone pair electrons are held tighter, they're less available, less willing to reach out and react as a base or nucleophile.

It's sort of like the nitrogen in an alpine.

Ah, okay.

More sec character pulls the electrons in.

And did that have any other weird consequences?

It does.

And here's a really surprising one.

This increased test character means the nitrogen atom in aziridines undergoes inversion, you know, flipping its umbrella shape very, very slowly.

Normally, anasamine nitrogens flip millions of times per second.

You can't isolate mirror images.

But in these strain aziridines, the nitrogen is essentially forced to hold its position.

It becomes a stereogenic center.

You can actually have distinct isolable enantiomers based on the nitrogen's configuration.

Wow.

Okay, that is surprising.

A chiral nitrogen.

And does the strain make them easy to open like epoxides?

Yes, exactly.

That ring strain makes aziridines susceptible to ring opening, especially if you protonate or alkylate the nitrogen first.

Making the nitrogen positively charged turns it into a much better leaving group, facilitating nucleophilic attack and ring opening very similar to how epoxides react.

Okay, makes sense.

Let's switch heteroatoms.

What about oxygen heterocycles?

You mentioned THF and dioxane earlier as solvents.

Right.

And they're good solvents precisely because as cyclic ethers, they are generally pretty unreactive.

Ethers are famously quite in functional groups.

But like aziridines, you can activate them.

Lewis acids like BF3, boron can coordinate to the oxygen.

This makes the oxygen a better leaving group and primes the ring for nucleophilic attack.

For instance, you can react N -butyl lithium with oxytane, the four -membered ether in the presence of BF3, and you get n -heptanol in a really high yield.

The butyl group attacks, opens the ring, and adds four carbons.

Neat trick.

But I feel like I've heard warnings about using THF with strong bases.

Ah yes, THF's dark side, as the textbook calls it.

You're right to be cautious.

If you're using very strong bases like N -butyl lithium, Buhl, with THF, you absolutely need to keep the reaction cold, usually below zero degrees Celsius, maybe minus 78.

Why?

Because at warmer temperatures, the buhli is strong enough to actually deprotonate the THF next to the oxygen.

This triggers the decomposition pathway, a kind of reverse cycloaddition.

It falls apart to give acetaldehyde enolate, and crucially, ethylene gas.

Ethylene gas.

So your reaction could suddenly have this unexpected alkene floating around.

Exactly.

There's a famous or maybe infamous anecdote about chemists in Belgium who kept finding an unexpected ethyl group attached to their product when running reactions with organolithiums and THF at slightly higher temperatures.

It turned out the ethylene generated from the THF decomposition was slowly but surely reacting with their organolithium region.

A real headache if you're not expecting it.

Well, good to know.

Keep it cold with buhli and THF.

What about the 6 -membered oxygen ring, tetrahydropyrin?

Tetrahydropyrin, or THP, is also pretty stable, but its main use you'll see is as a protecting group for alcohols.

Very common in synthesis.

Okay.

And sulfur, any special properties there?

Sulfur brings its own unique talents.

The key thing about sulfur is its ability to stabilize an adjacent negative charge, an anion, much better than oxygen or carbon.

This makes sulfur heterocycles much easier to deprotonate next to the sulfur atom compared to, say, THF.

The classic most important example is probably 1 -ferry -3 -dithion.

You can easily deprotonate the carbon between the two sulfur atoms using a strong base like dually.

And what can you do with that dithion anion?

That lithiated dithion is a fantastic nucleophile.

It can attack electrophiles, including things like Lewis acid -activated cyclic ethers.

It can even attack THP, which has basically no ring strain if it's activated.

After the dithion adds and opens the ring, you can easily hydrolyze the dithion group back to a ketone.

It's a really powerful way to make ketones, known as the Corey -Sebak reaction, essentially using the dithion as a masked acyl anion.

Okay.

So that covers reactivity pretty well.

How do we actually know the shapes these rings adopt, and how does that tie into stereoelectronics?

You mentioned NMR earlier.

Right.

NMR spectroscopy is absolutely crucial.

It's our molecular spyglass.

We've talked before about how NMR coupling the splitting of signals is a through -bond effect,

and its magnitude, the J value or coupling constant, varies dramatically with the dihedral angle between two coupled CH bonds.

That's the famous Karplus relationship.

Karplus curve, yeah.

Big coupling at 0 and 180 degrees, zero coupling at 90 degrees.

Exactly.

The coupling is strongest when the bonds are aligned anti -paraplanar, 180 degrees, or sin -paraplanar, 0 degrees.

And it basically disappears when they're orthogonal, 90 degrees.

And importantly, the curve is quite steep around the 60 degree and 120 degree angles you often find in staggered conformations.

This means the J value is very sensitive to small changes in dihedral angle in those regions.

So how do you use that sensitivity in practice?

Well, it has direct practical applications.

In six -membered rings, like cyclohexenes, which often adopt chair conformations, you'll see much larger J values for coupling between that are both axial, close to 180 degree dihedral angle, compared to couplings between axial equatorial or equatorial equatorial protons, closer to 60 degrees.

Typical axial -axial couplings might be at 10 -13 hertz, while axial equatorial or equatorial equatorial are usually much smaller, maybe 2 to 5 hertz.

This allows us to distinguish between cis and trans isomers just by looking at the coupling constants, or to deduce the exact 3D confirmation a molecule prefers to adopt.

It's like getting a direct readout of the molecule's posture.

So you can tell if a group is pointing up or down essentially just from the splitting pattern.

Pretty much, yeah.

There's a great example in the book where hydrogenating an unsaturated acetyl gives a product, and the NMR shows specific couplings, like a large 11 .6 hertz coupling, which immediately tells you those two hydrogens must be axial, meaning the bulkier substituents must be equatorial.

It pins down the cis configuration and the chair conformation.

Okay, that's powerful.

But what if things are, you know, flopping around?

Or what if coupling constants aren't helpful, like if you only have one proton on a double bond?

Excellent point.

If a molecule is very flexible, the observed coupling constant is an average over all conformations, which can obscure the details.

And yes, sometimes coupling just isn't there or isn't informative.

That's where another NMR technique comes in, and it's truly remarkable.

The nuclear overhauser effect, or NOE.

NOE, right.

That tells you about atoms that are close in space, not through bonds, correct?

Exactly.

Forget the bonds for a moment.

NOE tells us which hydrogens are physically close to each other in 3D space, regardless of how many bonds separate them.

The simplified explanation is that if you irradiate one set of protons with radio waves, essentially tickle them in the NMR experiment, any other protons that are very close within about five angstroms will show a slight increase in their NMR peak intensity.

This effect falls off very rapidly with distance, like one over the R to the sixth power, so it's really only sensitive to nearby neighbors.

So how would you use that?

Give me an example.

Okay, imagine you have that alkin with only one proton, so no cis -trans coupling to help assign the geometry E or Z.

If you irradiate some protons you know are on one side of the molecule, say in a nearby ring, and you see the NMR signal for that lone alkin proton get slightly stronger, that's an NOE enhancement.

It tells you that alkin proton must be on the same side of molecule as the protons you irradiated.

Boom!

You've assigned the E -Z geometry just based on spatial proximity.

That's like molecular triangulation.

Yeah.

Very cool.

Okay, so NMR gives us shape and proximity.

How does this connect back to stereoelectronics affecting conformation?

Right, let's tie it all together.

We said heteroatoms and rings have lone pairs, and the ring fixes their orientation.

Just like substituents, these lone pairs can be thought of as being either axial or equatorial.

And the alignment of these lone pairs relative to adjacent bonds in the ring, like a CO sigma bond or a CC sigma bond, is absolutely critical.

We need to think about orbital overlap.

Orbital overlap?

Like for hyperconjugation or something similar?

Exactly like that.

It's about whether a filled orbital, like a lone pair, can effectively overlap with an adjacent empty or partially empty orbital, like an antibonding sigma orbital.

This overlap leads to stabilization.

Consider the hydrolysis of acetyls again.

It's usually fast because a lone pair on one oxygen can donate into the sigma orbital of the CO bond that's breaking, stabilizing the transition state.

But there's an example of a rigid bicyclic acetyl where the molecule is locked into a conformation where those lone pairs are torning the wrong way.

They have terrible overlap with the breaking CO bonds sigma orbital and the result.

The hydrolysis rate plummets.

It's slowed down by a factor of about 10 billion just because of poor orbital alignment.

10 billion times slower.

Wow.

Okay.

Orbital alignment is crucial.

It really is.

And this leads us directly to another major stereolatronic effect, the anomeric effect.

Oh, the anomeric effect.

This is the one that always seems backward, right?

Where axial is sometimes better than equatorial.

That's the one.

You'd normally expect bulky substituents on a six -membered ring, like in sugars or tetrahydropyrins, to prefer the equatorial position to minimize steric clashes, 163 -diaxial interactions.

But when you have an electronegative atom or group like OR, OAC, or a halogen attached to the carbon next to the ring oxygen, the anomeric carbon, C1 and glucose, that group surprisingly often prefers to be axial.

So why does it defy the steric rules?

What's the electronic benefit?

It's that orbital overlap again.

It's a stabilizing interaction.

When the electronegative group X is axial, one of the ring oxygen's lone pairs, usually the one that's pseudo -axial, is perfectly aligned anti -paraplanar to the C -X bond.

This allows the lone pair, N, to donate electron density into the antibonding orbital sigma of the C -X bond.

It's an N to sigma donation.

This interaction lowers the energy of the lone pair electrons and stabilizes the whole molecule.

Crucially, this perfect anti -paraplanar alignment for maximum overlap can only happen when X is axial.

If X were equatorial, the alignment would be much poorer.

Okay, so the electronic stabilization from the N to sigma overlap outweighs the steric cost of being axial.

Exactly.

It strengthens the C -O bond within the ring and actually slightly weakens the C -X bond.

You see this effect dominating in many carbohydrate derivatives.

There's even a double anomeric effect seen in spirochadol structures with two rings joined at a carbon that's connected to two oxygens.

They contort themselves to adopt a conformation where both ring oxygens can benefit from an anomeric stabilization from the other ring.

It's maximal stabilization.

Does this anomeric idea apply outside of rings too?

Oh yes, definitely.

It can explain things in seemingly simple acyclic molecules.

For example, why is dichloromethane,

CH2Cl2, surprisingly unreactive as an electrophile compared to, say, methyl chloride?

It benefits from what you could call a permanent anomeric effect.

Each chlorine has lone pairs, and they are always oriented anti -paraplanar to the other C -Cl bonds' sigma orbital, regardless of rotation.

This constant N to sigma stabilization makes the C -Cl bonds less reactive.

Huh.

Never thought of it that way.

What about simple acetyls or esters?

Same principles apply.

Simple acetyls, like dimethoxymethane, tend to prefer a gauche conformation around the C -O bonds rather than fully extended anti.

Why?

Because the gauche arrangement allows lone pairs on one oxygen to align better for donation into the C -O sigma orbital of the other C -O bond.

And esters generally prefer the cis, or Z, conformation.

Part of the reason is that the lone pair on the single bonded oxygen that's not involved in pi resonance can still participate in a stabilizing interaction by donating into the C -O sigma bonds' antibonding orbital.

This is better in the Z conformation.

And that explains why lactones, cyclic esters, are often more reactive.

Precisely.

Because the ring constrains them, they often can't adopt that most stable Z conformation as easily as a cyclic esters.

They're often stuck in a less stabilized state, making them more susceptible to hydrolysis.

Fascinating how these subtle orbital interactions dictate so much.

Okay, let's switch gears slightly.

How are these rings actually made?

Cyclization reactions.

Right.

Most saturated heterocycles are formed through intermolecular reactions.

That just means the nucleophile and the electrophile are part of the same molecule.

Typically, a heteroatom with a lone pair, like O, N, or S, acts as the nucleophile, and it attacks an electrophilic carbon elsewhere on the same chain.

Think intermolecular SN2 for making epoxides, or aziridines, or Williamson ether synthesis for making THF or THP rings.

Okay, intermolecular attack.

But I remember seeing a chart about the rates of ring formation, and it seemed weird.

Five -membered rings form fastest, then six, then three, then seven, then four.

It wasn't just small rings are fast and big rings are slow.

You remember correctly.

It is counterintuitive at first glance.

The general trend for saturated ring formation rates is often five, six, three, seven, four, and then medium rings, eight, ten, are usually the slowest.

So why that specific order?

What's going on?

It's a delicate balancing act between two opposing factors, enthalpy, specifically ring strain, and entropy, specifically the entropy of activation.

Factor one, ring strain related to enthalpy of activation.

Small rings, especially three and four -membered ones, have significant inherent strain, angle strain, torsional strain.

This strain is already developing in the transition state for ring closure, making that transition state higher in energy and slowing the reaction.

Strain generally decreases as the ring gets bigger, up to six.

Okay, so strain penalizes small rings.

That makes sense.

What's the entropy part?

Factor two, entropy of activation.

Think about a long floppy chain.

It has lots of conformational freedom, high entropy disorder.

To form a ring, the two reactive ends have to come together in a very specific orientation in the transition state.

This requires a significant loss of that conformational freedom.

It becomes more ordered.

This loss of entropy, a large negative end, is unfavorable and slows the reaction down.

The longer the chain, the more entropy you lose upon cyclization, so the bigger the entropic penalty.

Okay,

so strain hurts small rings.

Entropy hurts large rings.

How does that explain the five, six, three order?

Let's break it down.

Three -membered rings, high strain, bad, large positive S -deque contribution.

But to us, the two reacting atoms are already very close together in any confirmation of the short chain.

So very little conformational ordering is needed to reach the transition state.

Good, small, negative S -deque.

The result is often a moderate overall rate.

Four -membered rings still have significant strain, bad S -deque, and now the chain is longer, requiring considerably more ordering to bring the ends together.

Bad, large, negative S -deque.

They often get the worst of both worlds, making them very slow to form.

Five -membered rings hit the sweet spot.

Strain is much reduced compared to three or four, and the ends are still relatively close, meaning the entropic cost isn't too bad yet.

This combination often makes five -membered ring formation the fastest.

Six -membered rings.

Essentially strain -free.

Good to ask this, but the chain is longer than for five, so the entropic penalty is larger.

Still generally fast, but often just slightly slower than five.

Seven -membered plus rings.

Strain is low, but the entropic penalty becomes increasingly dominant as the chain gets longer and floppier.

Plus, for medium rings, like 813, you can get unfavorable trans -annular interactions.

Atoms bumping across the rings, so rates drop off.

Wow.

Okay.

That interplay explains the weird order perfectly.

Strain versus entropy.

But you also mentioned kinetic versus thermodynamic control earlier.

Right.

It's crucial to distinguish.

The rates we just discussed are about kinetics, how fast the ring forms.

Thermodynamics is about the final stability of the product ring.

Glicose is the classic example.

It cyclizes, and in solution, it exists overwhelmingly as the six -membered ring, purinose form, even though five -membered rings, furinose form, probably form faster kinetically.

The six -membered ring is just more stable thermodynamically because it's basically strain -free, right?

Exactly.

The equilibrium lies heavily towards the most stable product, the six -membered ring, even if it's not the absolute fastest to form initially.

You see this in protecting group chemistry, too.

Reacting mannitol, a polyol with acetone, tends to form five -membered acetyls, dioxylanes, because that kinetically favored.

But reacting it with benzaldehyde often leads to the six -membered acetyl, because you can arrange things so the bulky phenol groups are equatorial, making that thermodynamically very stable.

So kinetics gives you the fast product.

Thermodynamics gives you the stable product.

Got it.

What was that other effect?

Thorpe -Ingold.

Does that affect rates, too?

Yes.

The Thorpe -Ingold effect is another fascinating kinetic and sometimes thermodynamic phenomenon.

It states that putting substituents, especially geminal substituents, two groups on the same carbon, onto the chain that's about to cyclize, often increases the rate of ring formation.

Increases.

That seems backward, too.

Wouldn't more bulky groups hinder the ends coming together?

You'd think so, but no.

For forming small, strained rings, the idea is that the bulky substituents already repel each other in the starting material chain.

This repulsion forces the bond angle between them to decrease slightly, pushing it closer to the smaller angle required in the strained ring's transition state.

It sort of predistorts the molecule toward cyclization.

Okay.

It lowers the energy needed to reach that strained transition state angle.

What about for larger rings where strain isn't the main issue?

For larger rings, it's mostly an entropy effect again.

Those bulky substituents restrict the number of conformations the starting chain can adopt.

It's less floppy to begin with.

It has lower initial entropy.

This means that less entropy needs to be lost to reach the ordered transition state for cyclization.

The S is less negative, which speeds up the reaction.

There's a fantastic example where adding two methyl groups makes an epoxide form something like 40 ,000 times faster.

40 ,000 times.

Just from adding methyl groups.

Okay.

That's significant.

Now, the last piece of the puzzle for ring formation,

Baldwin's rules.

These always seem like a list to memorize.

They can feel like that, yes.

Baldwin's rules are essentially a set of empirical guidelines based on observing lots and lots of reactions that help predict whether a particular type of intramolecular cyclization reaction is likely to be geometrically feasible or favored versus difficult or impossible disfavored.

They're based on the idea that the nucleophile needs to approach the electrophile along a very specific trajectory for the orbitals to overlap effectively in the transition state.

And there's that classification system, right?

Ring size, exo window, and tetric exactly.

You classify the reaction by one ring size being formed three, four, five, six, seven, two, whether the bond being broken during the nucleophiles attack is outside the newly forming ring exo or part of the newly forming ring endo three, the hybridization of the electrophilic atom being attacked tet for speed three, like SN two trig for CESB two, like carbonyls or alkenes or dig for speed like nitriles or alkenes.

So you get classifications like five exo tet or six endo three.

Okay.

And are there general patterns for what's favored or disfavored?

There are definite patterns, generally speaking.

All exo tet reactions like intramolecular SN two are favored for all ring sizes three through seven plus all enter trig reactions like attacking a carbonyl outside the forming ring are also favored for all ring sizes.

All endo dig reactions like attacking a nitrile carbon to form a ring containing the CN bond are favored for six and seven membered rings.

The disfavored cases are more specific, but the crucial ones involve endo attacks.

Which disfavored rule is the most important one to remember?

If you remember only one, remember this five endo trig reactions are generally disfavored.

This covers cases like trying to do an intramolecular conjugate addition Michael addition to form a five membered ring where the double bond ends up inside the ring.

Five endo trig disfavored.

Why that specific combination?

It comes down to geometry.

For the nucleophiles lone pair to attack the Ceph B2 carbon, the trig part at the correct angle, the burgee doon its trajectory roughly 107 degrees, while also forming a five membered ring where the PI system ends up inside the ring, the endo part, the chain just can't quite reach properly.

The geometry is just wrong for good orbital overlap in the transition state.

It's famously described as like a dog chain just out of reach of a bone.

You can draw it on paper and it looks plausible, but stereoelectronically it doesn't work well.

Okay, five endo trig usually bad news.

Are there exceptions?

Yes.

Like most rules in organic chemistry, there are exceptions.

If the reaction is incredibly thermodynamically favorable, it might overcome the geometric barrier or if there's simply no alternative pathway available.

Also reactions involving second row atoms like sulfur can sometimes get away with formerly disfavored cyclizations because sulfur has longer bonds and potentially de -orbital involvement changing the geometric constraints.

And remember, because of the principle of microscopic reversibility, Baldwin's rules also apply to the reverse reactions ring openings.

A disfavored ring closure implies the corresponding ring opening is also disfavored.

Right, makes sense.

So Baldwin's rules give us a powerful predictive tool based on transition state geometry.

Okay, let's circle back quickly to NMR for the final points.

You mentioned dihedral angles influencing coupling J values, but are there other factors?

Yes.

Besides the Karplus relationship with dihedral angle, there's another subtle effect, especially noticeable in rings.

How spread out the two CH bonds are in space, even if they have the same dihedral angle, can affect the coupling constant.

Generally a wider spread leads to a smaller J value.

Spread out.

How does that work?

Think about cyclic alkenes.

As the ring gets smaller, say from cyclohexane down to cyclobutene or cyclopropane, the angles get more compressed and the CH bonds involved in vicinal coupling across the double bond get sort of splayed further apart spatially.

This leads to a decrease in the vicinal alkenes coupling constant, 3J.

In cyclohexane it might be 912 Hertz, but in cyclopropane it's tiny, like 0 .5, 1 .5 Hertz.

There's a cool example, guiazulene, a blue oil with fused five and seven -membered rings containing double bonds.

The J values are different in the two rings, around 4 Hertz versus 11 Hertz, reflecting the different geometries and spreading out within each ring.

Interesting.

And what about coupling within small rings themselves, like epoxides or cyclopropanes?

Generally all coupling constants tend to be smaller in small rings compared to acyclic systems or larger rings.

For three -membered rings, epoxides, cyclopropanes, they're flat, so the bonds are eclipsed.

Here's another twist.

Cis coupling is usually larger than trans coupling.

This is the opposite of alkenes, where trans is usually larger.

Cis bigger than trans in cyclopropanes.

Okay, another rule reversal.

Yep.

And electronegative atoms like oxygen and epoxides shrink the J values even further, combined with that spreading out effect.

So epoxide couplings are often very small, maybe 2 to 5 Hertz.

This difference between cis and trans can still be used, though.

Chrysanthemum acid cyclopropane shows cis J, 8 Hertz, trans J, 5 Hertz.

Penicillin, 4 -membered ring, shows cis J, 5 Hertz, while phenomycin shows trans J, equals 3 Hertz.

What about 5 -membered rings?

They seem common, but maybe floppy.

They are very common, but yes, they are often highly flexible, rapidly pseudo -rotating between different envelope and twist conformations.

This flexibility means that the average dihedral angles for cis and trans protons can end up being quite similar.

As a result, their coupling constants are often very close in values, typically around 8 .99 Hertz, making it really difficult to

stereochemistry reliably just based on 3 -J couplings.

Uh -oh.

So you might think it's cis when it's trans, or vice versa.

Exactly.

There's a famous cautionary tale recounted in the textbook about the structured determination of kinet and solid.

The initial researchers measured couplings of about 6 .8 Hertz and 4 .5 Hertz in a 5 -membered ring and deduced a trans relationship.

But later, unambiguous synthesis proved it was actually cis, and the real couplings were much smaller.

It highlights the danger of relying solely on J values in flexible 5 -membered rings.

Yikes.

A reminder to use multiple techniques.

Okay, one last NMR topic.

Geminal coupling, 2J.

That's coupling between two protons on the same carbon, right?

Why do they sometimes show up as different signals and split each other?

Right.

That's 2J coupling.

The reason two protons on the same CH2 group can be non -equivalent in the NMR, have different chemical shifts, and couple to each other is usually because they are diastereotopic.

Diastereotopic, okay.

Refresh my memory on that versus enantiotopic and homotopic.

Sure.

Homotopic protons are completely identical.

Replacing either one with a different group, G, gives the exact same molecule.

They always have the same chemical shift.

Enantiotopic protons are mirror images.

Replacing one with G gives one an antium, replacing the other gives the mirror image and an antium.

They are indistinguishable in a normal acryl NMR solvent and have the same chemical shift, but they can be distinguished by chiral environments like enzymes.

This leads to the concept of prochorality.

Diastereotopic protons are chemically different even in an acryl environment.

Replacing one with G gives one diastereomer.

Replacing the other gives a different diastereomer.

Because they are chemically non -equivalent, they will have different chemical shifts in the NMR and will couple to each other.

Geminal coupling, 2J.

Okay, so if there's a chiral center somewhere else in the molecule, the two faces of a nearby CH2 group become different, making those CH2 protons diastereotopic.

That's the most common reason, yes.

The presence of a stereocenter elsewhere makes the local environment of the two CH2 protons non -identical.

In the NMR spectrum, these diastereotopic protons often appear as a pair of doublets since they split each other.

If their chemical shifts are close relative to the coupling constant, J, the inner peaks get taller and the outer peaks get shorter.

We call this roofing, or an AB system.

And what affects the size of that geminal coupling, the 2J value?

Several things influence 2J.

Adjacent pi systems like alkatines, aromatics, carbonals tend to increase the magnitude of 2J, sometimes making it quite large, maybe 15, 20 hertz.

Small ring size tends to decrease 2J.

Electronegative atoms attached to the CH2 group also generally decrease 2J.

It's a complex interplay.

So looking at both 2J and 3J values can really help piece together the structure and

Absolutely.

They provide complementary pieces of the puzzle.

Seeing diastereotopic protons tells you about the symmetry, or lack thereof in the molecule, and the magnitudes of 2J and 3J give you clues about angles, ring size, and electronic environment.

Okay, wow.

We've covered a lot of ground, so let's try to summarize the big picture for everyone listening.

Sounds good.

We started with saturated heterocycles rings with N, O, or S.

We saw how their reactivity differs from acyclic versions, thinking about nucleophilicity being enhanced by hideback groups, or reduced by sick character in strained rings like aziridines.

We saw ring opening driven by strain or Lewis acids.

Right, and we delved into confirmation how we use NMR, particularly the Karplus relationship, 3J versus dihedral angle, and the NOE through space proximity, to figure out the 3D shapes these molecules adopt.

Then came the crucial role of stereoelectronics, how orbital alignment dictates stability and

The anomeric effect, explaining why axial can be preferred, is a prime example.

We saw it affects reactivity in acetyl hydrolysis and even confirmations of esters and stability of things like dichloromethane.

And we looked at how these rings are made.

The kinetics versus thermodynamics of cyclization, that balance between ring strain and entropy leading to the 5, 6, 3, 7, 4 rate order.

The Thorpingold effect accelerating cyclization.

And finally, Baldwin's rules predicting feasibility based on transition state geometry,

especially that disfavored 5 -indo trig pathway.

And wrapped up with more NMR nuances, how ring size and electrine negativity affect J values, the tricky nature of five -membered ring couplings,

and understanding diastereotopic protons and geminal coupling 2J.

So what does this all mean for you listening?

This journey through heterocycles and stereoelectronics, it really reveals the deeper layers of organic chemistry.

This knowledge isn't just academic trivia, it's fundamental for understanding how molecules actually behave.

It's crucial for designing new drug molecules, understanding complex natural products, planning efficient synthetic routes in the lab, and accurately interpreting analytical data like NMR spectra.

It underpins so much of advanced organic chemistry and related fields.

Indeed.

It really makes you think, doesn't it?

In the intricate world of molecules, it's clearly not just about what atoms are connected,

but precisely how their dance in three -dimensional space, governed by these subtle but powerful electronic interactions, determines absolutely everything, whether a reaction even happens, how fast it happens, how a drug binds, or even why a natural product might have a specific biological activity.

The real beauty, the elegance, is hidden in these geometries and electronic effects.

Well said.

We hope this deep dive has given you a new appreciation for the exquisite control exerted by stereoelectronics and the fascinating world of saturated heterocycles.

Maybe think about how these principles apply to even more complex systems you encounter, whether in biology, material science, or further studies.

Thank you, as always, for being part of the Last Minute Lecture Family.

We look forward to our next adventure in understanding the molecular world with you.