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We’ve talked about benzene a bit already in this series, but did you know that benzene rings are present in all kinds of familiar substances? The styrofoam packaging that comes with new appliances, some pharmaceuticals, pesticides, and even some explosives contain benzene. In this episode of Crash Course Organic Chemistry, we’ll see how we can use electrophilic aromatic substitution to attach stuff to benzene rings like halogens, carbons, and more!

Episode Sources:
Rocke, A.J., 1985. Hypothesis and experiment in the early development of Kekule's benzene theory. Annals of Science, 42(4), pp.355-381.
Martín, N. and Scott, L.T., 2015. Challenges in aromaticity: 150 years after Kekulé's benzene. Chemical Society Reviews, 44(18), pp.6397-6400.
Stuttgart, G., 2018. Charles Friedel (1832–1899) And James Mason Crafts (1839–1917): The Friedel–Crafts Alkylation And Acylation Reactions. [online] Thieme.de. Available at: https://www.thieme.de/statics/bilder/thieme/final/en/bilder/tw_chemistry/CFZ-Synform-Charles-Friedel-James-Crafts-NRBio.pdf

Series Sources:
Brown, W. H., Iverson, B. L., Ansyln, E. V., Foote, C., Organic Chemistry; 8th ed.; Cengage Learning, Boston, 2018.
Bruice, P. Y., Organic Chemistry, 7th ed.; Pearson Education, Inc., United States, 2014.
Clayden, J., Greeves, N., Warren., S., Organic Chemistry, 2nd ed.; Oxford University Press, New York, 2012.
Jones Jr., M.; Fleming, S. A., Organic Chemistry, 5th ed.; W. W. Norton & Company, New York, 2014.
Klein., D., Organic Chemistry; 1st ed.; John Wiley & Sons, United States, 2012.
Louden M., Organic Chemistry; 5th ed.; Roberts and Company Publishers, Colorado, 2009.
McMurry, J., Organic Chemistry, 9th ed.; Cengage Learning, Boston, 2016.
Smith, J. G., Organic chemistry; 6th ed.; McGraw-Hill Education, New York, 2020.
Wade., L. G., Organic Chemistry; 8th ed.; Pearson Education, Inc., United States, 2013.

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Hi! I’m Deboki Chakravarti and welcome to Crash Course Organic Chemistry!

When you buy a new TV, or some bulky kitchen gadget, it often comes packed in that white, solid foam stuff that can make a horrible squeaky noise. That's polystyrene, which we met in episode 35 on polymers. There, we saw that polystyrene is made by joining together lots of styrene monomers.

By the way, you can name these substituted benzenes with the IUPAC rules we learned before, but many of them have been known for a long time. So styrene isn’t just the historical common name – it’s also IUPAC official! That being said, we can't just harvest some styrene molecules from the garden to make polymers.

We have to start with plain benzene, which we met in episode 36, and which we mainly get from crude oil. Then, we stick an ethyl group onto the benzene and remove a couple hydrogens and a pair of electrons in an oxidation reaction called dehydrogenation. Which means… we're using an organic chemist’s favorite trick: making a carbon-carbon bond!

In fact, lots of everyday substances have benzene rings in them, so attaching stuff to benzene rings is really important for the chemical industry. That's what we're going to learn today! [Theme Music]. To warm up and think about how we might put a group on benzene, let’s go back to alkene addition reactions.

If we mix bromine with an alkene at room temperature, the bromine adds across the double bond with no trouble at all. As the bromine gets used up, we see the solution turn from an orangey-brown color to colorless. But this addition reaction just doesn’t happen with benzene.

We need a catalyst to see any kind of reaction at all, and even then, the mechanism and the products are different. Remember, we usually draw benzene with alternating double and single bonds, but really the electrons are delocalized around the ring. We can imagine that each carbon-carbon bond is like one-and-a-half bonds.

As a result, benzene doesn't have true double bonds and is less nucleophilic than plain old alkenes. It’s not enough to throw something potentially electrophilic at benzene – we need a full positive charge, or at least something close to it. We’ll talk about electrophiles for this reaction in a bit, but let’s start with the mechanism.

Electrons in the benzene ring attack the positively-charged electrophile, forming a covalent bond. This leaves a carbocation on the ring. This carbocation intermediate is actually stabilized by resonance, but it’s not aromatic, so it’s not as stable as it could be.

Luckily, there’s an easy fix for that! A base nabs the now-extra hydrogen next to the electrophile, the electrons that were in the C-H bond go into the delocalized pi system, and the aromatic ring is restored. In this reaction, we've actually swapped a hydrogen for the electrophilic atom or group, and we’ve maintained the pi system rather than permanently breaking the double bond.

So although the mechanism looks a bit like the alkene reaction, it’s not the same – that was electrophilic addition, while this is electrophilic aromatic substitution. We added two halogen atoms in the reaction with the alkene, whereas only one swaps onto the ring in this benzene reaction. Also, in the electrophilic addition with an alkene, the halogen molecule was polarized by the electron-dense double bond.

But benzene isn’t a strong enough nucleophile to do that. So we need to do something to make bromine a better electrophile, like tossing some ferric bromide into the mix. FeBr3 is a Lewis acid, which means it's electron-accepting.

Now when the bromine molecule approaches the benzene ring, and it becomes slightly polarized (not enough to react, but a bit) the ferric bromide wanders up and says, “Hey, lemme help you with this!” and gives the bromine an extra yank. With the two compounds working together, the bromine builds up a lot of positive charge on one end. So much so, it is sometimes represented as an ion pair of Br-plus and FeBr-four-minus.

Benzene does its electrophilic aromatic substitution thing and... aha! The extra bromine in the FeBr-four-minus nabs that pesky proton. At the end, we’re left with HBr and the FeBr3 we started with – it’s a catalyst.

The drive for the ring to become aromatic again is super strong, so sometimes we don’t even show a base deprotonating in the reaction mechanism. Instead, we kind of just show the proton falling off, without the FeBr4 acting as a base. Now, we've been talking about bromine this whole time, but electrophilic aromatic substitution happens the same way with chlorine.

Instead of calling it bromination, it's chlorination! Another well-known aromatic substitution reaction is the nitration of benzene. This is where one or more of the hydrogen atoms on the benzene ring are replaced with an NO2 group.

Nitrobenzene has actually been around for a while. It was first prepared in 1834 by the German chemist Eilhardt Mitscherlich, who is famous for proving that benzene’s formula was C6H6 and for naming it after an aromatic resin from Southeast Asia known since the 16th century. Mitscherlich also described an early synthesis of benzene by first isolating benzoic acid from a resin, and then heating that up with calcium oxide.

This gave a compound he called 'benzin', which later became known as the more familiar benzene. Anyway, nitrobenzene is used to make lots of other things, including polymers, dyes, pesticides, pharmaceuticals, and… explosives. It’s also a likely carcinogen that may cause damage to your nervous system, impair vision, and irritate your lungs.

Its potential as a poison is featured at the center of the plot (spoilers!) of the 1929 story ‘The Poisoned Chocolates Case.’ So although it’s extremely useful stuff, we have to be cautious and read our safety data sheets really carefully! Thankfully for me and our director Mark, this is a video not a lab! So I can safely describe these animations from the comfort of my own home.

First, we need some concentrated sulfuric acid and nitric acid. The electrophile in this reaction is actually the nitronium ion, N-O-2-plus, which is produced when these two acids react. This is a neat bit of chemistry: the sulfuric acid acts as a Brønsted-Lowry acid, and donates a proton to form the conjugate base hydrogen sulfate.

Then the nitric acid – which is a strong acid, but is weaker than sulfuric acid – acts as a base and accepts sulfuric acid’s proton – before breaking up to leave a nitronium ion and water. We can summarize the overall process with this equation. And this is just the first step – we haven't even seen benzene yet!

The nitronium ion, with its positive charge, is a great electrophile and irresistible to the pi system in the benzene ring. So it accepts a pair of electrons from benzene, forming our familiar carbocation intermediate. Then, we lose a proton and the aromatic ring system reforms.

So we’re left with nitrobenzene and regenerate a molecule of acid. The sulfuric acid is effectively unchanged throughout this reaction, it’s acting as a catalyst. Because of this, you might sometimes see this mechanism with the bisulfate anion doing the deprotonation, reforming the sulfuric acid.

So that was nitration of benzene, where we added NO2. And it's similar to our next reaction: sulfonation of benzene, adding S-O-3-H. For sulfonation, though, we start by combining concentrated sulfuric acid with sulfur trioxide, S-O-3.

This mixture is known as fuming sulfuric acid or oleum, and is formed during the industrial production of sulfuric acid. Like the first step of nitration, sulfuric acid donates a proton to form its conjugate base. But now the sulfur trioxide is our proton acceptor, and our product is this cation.

This cation is an great electrophile and accepts a pair of electrons from the benzene ring, so we once again form a carbocation intermediate! After losing a proton, the aromatic system reforms, and we’re left with benzenesulfonic acid. Now this has all been fun, but you might be like, "Deboki, come on.

When are we gonna get to the good stuff and make a carbon-carbon bond??" Well, now's the time. In 1877, French chemist Charles Friedel and American chemist James Crafts published their first joint paper, with a reaction that's now called Friedel–Crafts alkylation. It showed that if an alkyl chloride is mixed with the Lewis acid aluminum chloride – which is electron accepting – the alkyl bit would join onto a benzene ring.

Just like the other examples we’ve seen, the carbocation that forms can accept a pair of electrons from the benzene ring to form an intermediate. And then that intermediate loses a proton to form a substituted benzene. From there, we can make all sorts of cool stuff.

For example, let's look at the Friedel–Crafts alkylation mechanism with isopropyl chloride, (which, by the way, we can easily make by mixing HCl with 1-propene). Isopropyl chloride reacts with aluminum chloride to make a carbocation, we add some benzene, and we’ve made isopropylbenzene! And isopropylbenzene, otherwise known as cumene, can help us synthesize lots of industrially important chemicals, like acetone and phenol.

There is one thing we have to watch out for in Friedel–Crafts alkylation reactions: if a carbocation can rearrange to form a more stable carbocation, it will – we saw this in episode 15. For example, if we try to react 1-chloro-2-methylpropane with benzene, we actually get this branched compound called tert-butylbenzene! Not 2-methylpropylbenzene, as we might expect.

This is because the tertiary carbocation is more stable than the primary one, so, as the chlorine is being transferred to the aluminum, there’s a 1,2-hydride shift. The tert-butyl cation reacts as our electrophile, making tert-butylbenzene. We’ll talk about this more in an upcoming episode, and learn how to work around these rearrangements!

Anyway, Friedel and Crafts weren’t done with their organic chemistry innovations! In their next two papers, they extended their work to include acylation. Alkylation and acylation sound similar, but this is a totally different reaction!

Acylation is adding an acyl group to a compound– the thing you get if you remove a hydroxyl group from an organic acid. Acyl groups contain a double-bonded oxygen and an alkyl group. In acylation reactions, an acyl halide (not an alkyl halide) is treated with the metal catalyst.

Specifically in Friedel-Crafts acylation, we react an acid chloride with the Lewis acid aluminum chloride to join an acetyl group onto the benzene. The chlorine in acetyl chloride adds to Al-Cl-three to form Al-Cl-four-minus, and a cation known as an acylium ion that is stabilized by resonance. This acylium ion is now our electrophile.

So, here we go again: it's attacked by electrons in the benzene ring, the carbocation intermediate forms, it loses a proton, and we get our product. In this case, the product is acetophenone. It's the simplest aromatic ketone and a useful starting material for lots of resins and fragrances.

This thorough work of Friedel and Crafts established their reactions as the methods for making carbon–carbon bonds with aromatic rings, so they've been an important part of synthetic organic chemistry toolboxes ever since. Next time we’ll talk about what happens when we add more than one group to a benzene ring, but in this episode we’ve learned:. Halogens will only react with benzene in the presence of a catalyst,.

We can nitrate benzene with a mix of sulfuric acid and nitric acid,. We can sulfonate benzene with fuming sulfuric acid, and. We can make carbon-carbon bonds on benzene rings using Friedel-Crafts alkylation and acylation.

Thanks again for watching this episode of Crash Course Organic Chemistry. If you want to help keep all Crash Course free for everybody, forever, you can join our community on Patreon.