Chapter 35: Pericyclic Reactions 2: Sigmatropic and Electrocyclic Reactions

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Welcome to the Deep Dive.

Ever look at a complex organic molecule and just wonder how?

How do chemists build these things or how does nature do it so perfectly?

It often seems like, molecular magic, but underneath there are these really elegant rules.

Exactly.

And today we're diving into some of the most elegant transformations out there, paracyclic reactions.

Right.

We're pulling back the curtain using Chapter 35 of Organic Chemistry, the second edition by Clayton, Greaves, and Warren.

Our mission today is to really unpack two key types,

signotropic rearrangements and electrocyclic reactions.

We'll get into the nitty -gritty of the mechanisms, the reaction functional group changes, that all -important stereochemistry, and crucially, how knowing this stuff is just vital for thinking backwards, for retrosynthesis.

Yeah, we want you to have those aha moments.

It's not just what happens, but understanding why it happens and why it's so powerful for making complex molecules.

We'll try to cut through the complexity, keep it engaging.

Ready to jump in?

Let's do it.

Okay, so we've talked about cycloadditions before.

Now, signotropic rearrangements, what really sets this class apart?

Well, the big thing is the moving sigma bond.

Basically, you break one sigma bond and you form a new one somewhere else in the molecule.

The connectivity changes.

And these are concerted, right?

One step, like cycloaddition.

Exactly.

No charged intermediates hanging around.

The electrons just flow in a circle.

But here's the unique bit.

One of those curly arrows actually starts from a sigma bond.

That's the defining feature.

Gotcha.

And the classic, the first one discovered, is the Claisen rearrangement.

That's the one, the historical starting point.

Imagine heating up an aryl allyl ether, you know, benzene ring, oxygen allyl group, and poof, it turns into an orthoallyl phenol.

Seems simple, but it's that 3 .3 sigmatropic shift happening.

Right.

And that 3, 3 notation is key.

It tells you exactly where the new bond forms relative to the old one.

You number out from the breaking bond, 1, 2, 3 on each side.

And the new bond forms between the 2, 3 atoms.

Precisely.

It gives us this predictive power, a way to classify these shifts.

And here's where it gets really interesting for synthesis, I think.

The stereochemistry.

These often go through a chair -like transition state.

Yes.

Typically for the 3, 3 shifts.

A six -membered ring chair -like arrangement.

And why does that matter so much?

Because it lets us predict the stereochemistry of the new double bond formed.

Think about it.

Substituents often prefer to sit equatorially in that chair.

Ah, okay.

So if you have a substituent next to the oxygen, it goes equatorial.

And that often leads to a trans, or E, double bond in the product.

Exactly.

It's an amazing level of control just based on that transition state geometry.

Wow.

So how do you actually make the starting materials for these, say, for the aliphatic Claisen variants?

Good question.

You need that specific vinyl ether structure.

A common way is through acid -catalyzed acetyl exchange.

You take an allelic alcohol, react it with an aldehyde acetyl.

And that sets up the vinyl ether perfectly.

Yep.

It's usually a two -step thing involving SN1 and E1 type processes on the acetyl.

You wouldn't use SN2 here.

It gets you the precise starting material needed.

And the Claisen itself, it's super flexible, right?

A general route to gamma, delta unsaturated carbonyls.

Incredibly flexible.

Aldehydes, ketones, esters, amides.

You can make them all depending on the variation you use, like with ortho -wisters or orthoamides.

If you see that gamma unsaturated carbonyl pattern in a target molecule.

You should immediately thank Claisen for your retrosynthesis.

It should definitely be on your list, yes.

Now, these reactions are reversible in principle, but they usually go one way.

Right.

Orbital symmetry says three -three shifts can go both ways.

But thermodynamics usually takes over.

Forming a really stable group, like a carbonyl -CO bond, provides a huge driving force.

It just pulls the equilibrium completely over to the product side.

Exactly.

The keto form is so much more stable than the enol -ether starting material.

It just doesn't go back.

Okay, so what about the cope rearrangement, the all -carbon version?

The cope, also a three -three shift.

But if you just take the simplest substrate,

1005 -hexadine reactant and product are identical.

It just swaps ends.

So, not immediately useful.

How do you make it go somewhere specific?

You need to introduce a bias.

You can put an activating group on there.

An OH group, for instance, can rearrange to form an enol, which tautomerizes to a ketone.

Again, that carbonyl driving force.

Or it can make it anionic.

Even better.

Use a strong base, like KH, make an alkoxide or an enolate.

This anionic acceleration can make the reaction fly, even allowing you to form really strained things, like bridgehead alkenes sometimes, driven by strain release.

And there's the ireline -Claisen too, more anions.

Yep, the ireline -Claisen.

You start with an allylic ester, make the lithium enolate, maybe trap it as a silt -enol ether.

And it rearranges, still with that great E -selectivity for the double bond, to give you an unsaturated carboxylic acid derivative.

Very neat.

It really is.

And these aren't just textbook reactions.

Think about industrial synthesis.

Citral lemons and its large -scale synthesis uses three shifts back to back.

A Claisen, then a cope.

To sort of walk a group across the molecule.

Essentially, yes.

It walks that pre -enol group into the right position.

Super -efficient.

Or that seaweed example you mentioned.

That's wild.

A pheromone that self -destructs using a 3 -3 shift.

Driven by ring strain release from a cyclopropane.

It's nature using paracyclic chemistry as a biological timer.

How cool is that?

Very cool.

And it's not just CNO, right?

Other elements get involved.

Oh yeah.

Nitrogen, sulfur, even metals like chromium.

Like in the Fischer -Indel synthesis, that's a classic end -containing reaction.

Absolutely.

The key step there is a 3 -bond -3 sigmatropic shift in a phenylhydrazone enamine.

What drives it is breaking that relatively weak N -N bond and gaining aromaticity in the endole ring.

And chromium.

Think about CR -VA oxidations of allylic alcohols.

A 3 -3 shift involving a chromate ester intermediate is part of the mechanism that allows the oxidation to happen specifically at the allylic position.

Okay, let's shift gears.

What about 2 -53 sigmatropic shifts?

Different numbers, different transition state?

Right.

Now we're talking a five -membered transition state.

Big difference geometrically.

Often involves an atom acting as a pivot, frequently a negatively charged one, like a carbanion adjacent to an oxygen or sulfur.

And the driving force.

Is it still stability?

Often, yes.

Take rearranging a benzyl allyl ether using a strong base.

You form a carbanion first.

Then the 2 -3 shift happens to give an oxanion.

Why?

Because that resulting oxanion is way more stable than the initial carbanion.

Makes sense.

And stereochemistry, can we still predict it?

Surprisingly, yes.

Even in that five -membered transition state, it can adopt a sort of chair -like or envelope conformation that often leads to predictable trans or e -stereochemistry for the new double bond.

Those principles still hold.

And this leads to some interesting functional group transformations, especially with sulfur.

Yeah, this is really clever.

You can take an allylic alcohol, make a sulfonate ester, which does a rapid 2 -3 shift to an allylic sulfoxide.

But why?

Because you can then reverse part of it.

The sulfoxide can be trapped or reacted, or sometimes you can drive it back to the sulfonate with a nucleophile.

But overall, it allows you to say, alkylate the allylic alcohol at a carbon you couldn't easily functionalize otherwise.

It's like a temporary scaffold.

Ah, strategic relay.

What about selenium?

Selenium dioxide oxidation of alkanese is another great example.

Does an N reaction or a 4 plus 2 cycloaddition first.

Then a 2 -month 3 -sigma -tropic shift of the selenium group.

The net result.

You oxidize a methyl group next to a double bond into an allylic alcohol or aldehyde.

Very useful.

Okay, one more type of sigma -tropic.

The one air shifts, where one group just migrates along a pi system.

Right.

The one means one end of the migrating sigma bond stays attached to the same atom.

The most common is the 1 -phy -5 hydrogen shift.

And this explains why alkylated cyclopentadines are messy.

Exactly.

Those hydrogens just rapidly walk around the ring via 1 -phy -5 shifts.

Superfacially, meaning across the same face of the pi system, it's thermally allowed by orbital symmetry so it happens fast at room temp, giving you mixtures.

So these orbital symmetry rules, they dictate which shifts are easy and how they happen.

Superfacial versus anterafacial.

Precisely.

For thermal hydrogen shifts,

1 -phy -3 is generally forbidden superficially.

Needs an impossible twist, anterafacial, for such a short chain.

1 -phy -5 is easy, superfacial.

1 -phy -7 is possible, but it needs to be anterafacial, which the longer chain can accommodate.

So the migrating H has to move to the opposite face of the pi system for 1 -phy -7.

Thermally, yes.

The orbital overlap requires it.

And if you shine light on it?

The rules flip.

Photochemical 1 and H shifts follow the opposite stereochemical requirements.

It's a beautiful symmetry.

Which brings us back to vitamin D.

You said the final step is a 1 -phy -7 -H shift.

That's right.

In the body, provitamin D2 converts to vitamin D thermally.

It's a 1 -phy -7 shift so it must be happening anterafacially, which that flexible trion system allows.

Though, you still need sunlight initially, so that first step isn't the 1 -phy -7 shift.

What is it?

Ah, now we get to our second major topic.

Electrocyclic reactions.

That sunlight step is an electrocyclic reaction.

Okay, so third main class of paracyclic reactions.

What defines these?

Electrocyclic reactions involve forming or breaking one sigma bond across the ends of a single conjugated pi system.

Think closing a trion to a cyclohexidine, or opening a cyclobutene to a butadiene.

So, different from cycloadditions, two sigma bonds formed broken, and sigma parpic one broken, one formed but migrating.

Exactly.

And again, governed by strict orbital symmetry rules.

The Woodward -Hoffmann rules are the key here.

And the stereochemistry comes down to how the ends rotate.

Conrotatory versus disrotatory.

That's the heart of it.

Conrotatory means both ends rotate the same way, both clockwise or both counterclockwise, as the sigma bond forms or breaks.

Disrotatory means they rotate in opposite directions.

And which way they rotate depends on the number of pi electrons, and whether it's thermal or photochemical.

You got it.

For thermal reactions,

4n pi electrons, like butadiene, 4e, go conrotatory.

4n plus 2 pi electrons, like hexatrine 6e, go disrotatory.

And these rotations directly determine the relative stereochemistry of substituents at the ends.

Absolutely.

If you have groups on those terminal carbons, conrotation might bring them both up, cis, while this rotation might bring one up and one down, trans, or vice versa, depending on the starting material.

It's incredibly predictive.

So summarizing the rules for electrocyclics.

Okay.

They're all allowed if the orbitals overlap correctly.

Thermally, 4n plus 2 pi is disrotatory, 4n pi is conrotatory, photochemically.

The rules flip again.

Exactly.

Photochemical 4n plus 2 pi is conrotatory, and photochemical 4n pi is disrotatory.

Let's apply this.

Nature's examples.

The endyandric acids.

A fantastic example.

These natural products were proposed to form via a cascade of paracyclic reactions without enzymes, just orbital symmetry control.

And the structure matched the rules.

Perfectly.

The proposed first step was an 8, so 4n, electrocyclicization predicted to be conrotatory.

This set up a 6 -lay 4n plus 2 system, which then did a disrotatory closure.

Nickel as synthesis later confirmed this cascade works exactly as predicted by the rules.

Back to vitamin D.

That first sunlight requiring step is the electrocyclic ring opening of ergosterol.

Opening a cyclohexadine ring within ergosterol to make the triene system of provitamin D2.

So looking at the product, how did it open?

Conrotatory or disrotatory?

Observing the stereochemistry, it's clearly a conrotatory opening.

Now that's a 6 -electron system.

Thermally, it should be disrotatory.

But it needs light.

So it's photochemical.

And the photochemical rule for 6, 4, n plus 2 systems is conrotatory.

It fits perfectly.

The thermal pathway is blocked because disrotation would create an impossibly strained trans double bond in the 6 -membered ring.

Sunlight provides the only way via the allowed conrotatory photochemical path.

Wow.

Orbital symmetry demanding sunlight.

Okay.

What about charge systems?

Maserov's cyclization.

Great example.

Acid catalyzed closure of an unsaturated ketone to a cyclopentanone.

Why acid?

Protonation creates a 4 -electroncation system.

An oxyallylcation conjugated to a double bond.

And four thermal reactions are?

Conrotatory.

Bingo.

So the acid sets up the system and the thermal corrodetory closure happens.

Another neat illustration of the rules.

Do small rings follow these rules when they open?

They're strained, so they probably want to open easily.

They absolutely do.

Take cyclopropolations.

You basically can't even observe them directly.

Why?

Because they undergo instantaneous electrocyclic ring opening.

It's a two -system opening, but effectively driven by the cucation character.

The rules still guide the stereochemistry if you have substituents leading to specific allocations.

So that strain release is a huge driving force channeled through the electrocyclic pathway.

Definitely.

Same with aziridines, those nitrogen -containing 3 -membered rings.

They can ring open thermally or photochemically to azone -thine illids, which are useful for other reactions like 3 plus 2 cycle additions.

And guess what?

The thermal opening is shown to be corrodetory.

Because the something -illid system effectively involves four electrons.

That's the rationale, yes.

The four -system prefers the corrodetory thermal pathway.

Okay, let's bring it all together.

An ultimate example.

Paraplanone B, the cockroach pheromone synthesis.

You mentioned a cascade.

It's a classic, really elegant synthesis by Steli.

It uses a sequence.

First, a photochemical 2 plus 2 cycloaddition to set up a key intermediate.

Okay, a cycloaddition.

Then,

a thermally -induced cope rearrangement.

Our 3 -sigmatropic shift, which is cleverly set up and accelerated.

And finally.

An electrocyclic ring opening.

This final step opens up one of the rings formed earlier to generate the final complex 12 -membered ring structure of Paraplanone B.

Wow, so 2 plus 2 photocycloaddition, 3 -3 cope rearrangement, then an electrocyclic opening.

All paracyclic, all orchestrated.

It just highlights beautifully how powerful these reactions are, working together for building complex targets with high efficiency and control.

So recapping today, we've journeyed through sigmatropic rearrangements, the moving sigma bond, 3 -3 -2 -3 -1 shifts and electrocyclic reactions, the ring formers and breakers.

We've seen how transition state geometries and fundamentally orbital symmetry rules dictate everything.

The pathways, the stereochemistry, the conditions needed, heat or light.

And how understanding this unlocks functional group transformations and powerful retrosynthetic thinking, explaining everything from industrial processes to how your body makes vitamin D.

Right.

These rules, Woodward -Hoffman and related concepts, they provide the logic.

It stops being magic and starts being predictable chemistry, seeing that dance of electrons.

So the final thought for you, our listener.

Where else are these reactions hiding?

Think about complex biological pathways, maybe ones we don't fully understand yet.

Or think about synthesis.

What seemingly impossible molecules could you build if you cleverly applied these principles of orbital symmetry and rotation?

The more you look, the more you see these elegant paracyclic patterns.

They're fundamental tools for understanding and manipulating molecules.

Absolutely.

Well, that's our deep dive for today.

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