Electrophilic Aromatic Substitution Reactions (3) – Friedel Crafts Alkylation and Acylation

by James

in Aromatic Reactions, Organic Chemistry 2

Today’s post is on the Friedel-Crafts alkylation and acylation reactions. Quick summary:

This is the third in a series of three posts on the key electrophilic aromatic substitution (EAS) reactions in introductory organic chemistry.

  • In Part 1 we covered halogenation (chlorination, bromination, and iodination) of aromatic rings via EAS.
  • In Part 2 we covered nitration and sulfonylation of aromatic rings via EAS.

Taken together, so far we have learned reactions to form carbon-halogen, carbon-nitrogen, and carbon-sulfur bonds.

What important class of bond is missing so far?

Carbon-carbon bond forming reactions! [note]

In this post, we’ll cover two important C–C bond-forming electrophilic aromatic substitution reactions which bear the names of their discoverers, Charles Friedel and James Crafts: Friedel-Crafts alkylation and Friedel-Crafts acylation.

We’ll also see that these reactions follow the familiar three-step pattern seen in previous electrophilic aromatic substitution reactions, namely:

  • activation of electrophile with a Lewis acid
  • attack of the “activated” electrophile by the aromatic ring
  • deprotonation to restore aromaticity

1. Friedel-Crafts Alkylation

When an alkyl halide is treated with a Lewis acid in the presence of an aromatic ring,  the alkyl group can be added to the ring (forming C-C) with the loss of a C-H bond. This electrophilic aromatic substitution reaction is known as the Friedel-Crafts alkylation reaction.

Generally, no reaction occurs in the absence of Lewis acid. A common choice for the Lewis acid is aluminum chloride, AlCl, but many others may be used, such as FeCl3 among others.

Alkyl halides (typically chlorides, bromides, and iodides) must be used, as the reaction fails completely for alkenyl and alkynyl halides.

Here’s a specific example using ethyl chloride:

The Role of The Lewis Acid

If no reaction occurs in the absence of a Lewis acid, then what is the role of the Lewis acid here?

Like we saw in the two previous posts on electrophilic aromatic substitution reactions, Lewis acids “activate” the electrophile by coordinating to the leaving group, making it a weaker base, and a better leaving group (AlCl4 is a weaker base than Cl ).  The end result is that coordination of the Lewis acid to the electrophile makes the species a better electrophile. 

For example, with isopropyl chloride (below), the first step is coordination of  coordination of AlCl3 to the chlorine atom. This weakens the C-Cl bond, with the result that the Cl can depart (as AlCl4 ) to give a secondary carbocation (a better electrophile than isopropyl chloride itself).

  • With secondary and tertiary halides, full dissociation to a carbocation can occur.
  • In the case of primary (and methyl) alkyl halides, the electrophile is likely not a “free” carbocation, but a “carbocation-like” species where the C–Cl bond is considerably weakened/lengthened.
  • As we mentioned briefly, no reaction occurs with alkenyl or alkynyl halides, largely because the carbocations of these species are so unstable and difficult to generate.

Note: that although here we are showing the carbocation electrophile in the Friedel-Crafts as being generated from an alkyl halide and a Lewis acid, there are other ways to generate a carbocation [such as through protonation of an alkene, see below]. We generally define the Friedel-Crafts alkylation as being the reaction of an aromatic ring with a carbocation (or carbocation-like) intermediate. See this footnote for example. 

Electrophilic Aromatic Substitution

Once the electrophile has been activated, the next step of the Friedel-Crafts is attack of the activated electrophile by the aromatic ring. This is also the rate-determining step, as it disrupts the aromaticity of the ring (and its ~36 kcal/mol of resonance energy).

In this step a C–C (pi) bond from the aromatic ring breaks, and a new C–C sigma bond is formed, leading to a carbocation intermediate:

The last step is deprotonation of  C–H by a weak base (e.g. Cl ) to restore aromaticity at the ring:

[another way to depict the curved arrows in this reaction is to dissociate Cl from AlCl4– and then employ it as the base. Either way it works out to the same thing]. 

Note that AlCl3 is regenerated here, allowing it to be used again in step 1 with another equivalent of the alkyl halide. Hence, AlCl3 can act as a catalyst in this reaction, since it increases the rate of reaction but is not consumed by it.

Uh-Oh – Rearrangements! 

Many university science courses are taught in units, where what you learn in one module has pretty much zero overlap with what you learn in another.

Needless to say, organic chemistry is not like this. You’ve probably already experienced a situation where concepts you learned in Org 1 reverberate back to Org 2 chapters in unexpected ways. Well, get ready for another fun example.

We showed above how ethyl chloride reacts with benzene and AlCl3 in the Friedel-Crafts alkylation to provide ethylbenzene.

Extension of this reaction from ethyl chloride to propyl chloride should correspondingly give propylbenzene.

Right?

What the…. isopropylbenzene? 

How did this happen?

Quick trip down memory lane.  Remember this beloved reaction from Org 1?

Ah, the hydride shift. Carbocations can rearrange via hydride and alkyl shifts such that a less stable carbocation is transformed into a more stable carbocation.

In the Friedel-Crafts, we’ve seen that coordination of a Lewis acid to an alkyl halide resulted in a carbocation (or in the case of primary alkyl halides, at least a “carbocation-like” species) that is then attacked by the aromatic ring in the rate-determining step.

So what is happening here is really no different: if a carbocation can rearrange to a more stable carbocation through a hydride or alkyl shift, it will do so. 

Organic chemistry 2: the course where first-semester concepts come back to bite you in the ass.™

Here’s what happens in the case of propyl chloride.

A shift of hydride from C2 to C1 results in a secondary carbocation, which is then attacked by the aromatic ring.

Bottom line for the Friedel-Crafts alkylation reaction:

  • assume the alkyl halide goes through a carbocation
  • assume that if the carbocation can rearrange to form a more stable carbocation through a hydride (or alkyl) shift,  it will.

Another example of a rearrangement in the FC alkylation included in the footnotes just for fun. [Note]

Limitations of the F-C Alkylation

Final note on the Friedel-Crafts alkylation: a few drawbacks.

  • First, as we’ve seen, carbocation rearrangements can occur. [There are ways of circumventing this issue indirectly, which we’ll hint at below [skip to bottom].
  • Second, the Friedel-Crafts alkylation tends not to work well with electron-poor aromatic rings, particularly strongly deactivating substituents such as CF3, NO2, SO3H, and so forth. Halogens are OK.
  • Third – and this is more of a practical issue than anything else, so is often ignored – the product of the FC alkylation is often a better nucleophile than the starting material. (Recall that alkyl groups are activating.)  The result can be a bit like the Cookie Monster in a Chips Ahoy! factory – it can’t stop at just one, resulting in multiple alkylations.

2. Friedel-Crafts Acylation

A process related to the Friedel-Crafts alkylation, called Friedel-Crafts acylation, was discovered by Friedel and Crafts around the same time (1877). If a Lewis acid is added to an acyl halide in the presence of an aromatic ring, an electrophilic aromatic substitution reaction can occur whereby the acyl group adds to the aromatic ring (with loss of HX).

As with the F.C. alkylation, the specific Lewis acid in the Friedel-Crafts acylation can vary. Aluminum chloride (AlCl3) is often used, but FeCl3 and other Lewis acids will also do the job.

Here’s a general example of the Friedel-Crafts acylation:

A specific example is the reaction between acetyl chloride and benzene catalyzed by aluminum chloride:

So how does the Friedel-Crafts acylation reaction work?

As with FC alkylation, the first step is activation of the electrophile. Lewis acid coordinates to the halogen, and departure of the halogen (as AlCl4) results in a fairly stable, resonance-stabilized carbocation know as the “acylium ion”.

The acylium ion is the active electrophile in the Friedel-Crafts acylation reaction. Once formed, the acylium ion is attacked by the aromatic ring:

As with the Friedel-Crafts alkylation, the final step is deprotonation at carbon to regenerate the aromatic ring.

No Rearrangements Occur In The Friedel-Crafts Acylation

Unlike the Friedel-Crafts alkylation, no rearrangement occurs with the Friedel-Crafts acylation.

This opens up a “workaround” to use the Friedel-Crafts acylation to obtain products that are otherwise difficult to obtain through the Friedel-Crafts alkylation due to carbocation rearrangements. (We’ll talk about this in detail in a future article, but here we’ll just give a taste).

For instance, let’s look at how we could use this to produce propylbenzene, which we saw could not be made from the Friedel-Crafts alkylation reaction of benzene with AlCl3 and 1-propylchloride.

The first step here is to perform a Friedel-Crafts acylation reaction between benzene and propionylchloride, perhaps catalyzed by AlCl3. This gives us ethyl phenyl ketone.

The next step is to perform a reduction of the ketone to an alkane, which (as we’ll soon see) can be performed in various ways. This gives us 1-propylbenzene.

[Commenter Victor, from the Chemistry Help Center, helpfully notes that there is a fourth way of doing it – converting the ketone to a thioketal, and then reducing it down to the alkane with Raney nickel. ]

We will talk more about synthetic pathways for aromatic molecules in a future post.

Limitations of The Friedel-Crafts Acylation

  • Similarly to alkylation, Friedel-Crafts acylation tends to fail on aromatic rings with strongly deactivating groups such as nitro, CF3, sulfonyl and so on. Halogenated aromatics still work, however.
  • Put this in the “probably don’t need to know category”, but catalyst turnover in the Friedel-Crafts acylation isn’t great. In “real life”, a stoichiometric amount of AlCl3 is generally required since the AlCl3 coordinates strongly to the ketone product. 

Conclusion

Since they form carbon-carbon bonds, the Friedel-Crafts alkylation and acylation reactions are particularly important electrophilic aromatic substitution reactions.  Together with bromination, chlorination, nitration, and sulfonylation they round out the six core electrophilic aromatic substitution reactions.

Before we finish our treatment of electrophilic aromatic substitution, it’s worth going into detail on one more facet of the Friedel-Crafts that often gives students headaches; the intramolecular versions.


Notes

Note. Bonus points if you said “carbon-oxygen”  as a type of bond we haven’t seen formed in EAS.  Direct electrophilic oxygenation of benzene rings is tricky to do in the lab. For our purposes, forming C-O on an aromatic ring is usually done indirectly, by means other than a direct EAS. Two ways we’ll explore in due course are the Baeyer-Villiger oxidation and certain reactions of diazonium salts. 

 Another way of performing a Friedel-Crafts alkylation is to generate the carbocation through protonation of an alkene. This works best when a fairly stable carbocation is generated, such as the t-butyl carbocation generated through protonation of 2-methylpropene.

Note. Bonus example with alkyl shift.

Footnote. Last post we learned that sulfonyl groups can be removed with strong acid, and I alluded to another group that can be removed that would be covered in the next post (i.e. this post).  That group is t-butyl, which can be removed under forcing conditions, with strong acid. This works because the t-butyl carbocation is relatively stable and the reverse of the Friedel-Crafts alkylation is therefore feasible.

 

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{ 5 comments… read them below or add one }

mamid

As usual, great post. Some minor corrections needed, though:

– “The end result is that coordination of the Lewis acid to the electrophile makes the species is a better electrophile.” Probably should read “… makes the species a better electrophile.”
– “The first step here is to perform a Friedel-Crafts acylation reaction between benzene and 1-propylchloride, …” Should read: “… reaction between benzene and propionyl chloride, …”
– plus some other minor things, like double or unnecessary spaces, etc.

Reply

James

Thank you very much. Fixed the typos. I am in your debt!

Reply

Victor

Couple of notes:

Minor: missed a negative charge on AlCl4 in step 3 of acylation when it acts as a base.

Major: When you discuss the reduction methods for the product of acylation, you list Kishner-Wolff, Clemmensen, *and* hydrogen on palladium??? as the ways to remove the C=O. The last one will only reduce it to an alcohol. If you wanted to use H2/Ni (not Pd still), you’d need to convert it into a thioacetal first.

Reply

James

Thank you for the typo correction! The hydrogenation works for benzylic ketones (and will reduce benzyl alcohols as well), but I wouldn’t do it on aliphatic ketones.
In contrast, the Raney Nickel reduction of the thioketal that you helpfully mentioned should work on pretty much any ketone.

Reply

Kyoji Kimoto

I would like to know the Friedel Crafts acylation works for CF3COCl or not.
Aromatic ring is activated with an electron donating group.

Reply

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