Reactions of Aromatic Molecules
Intramolecular Friedel-Crafts Reactions
Last updated: April 27th, 2020 |
The Intramolecular Friedel-Crafts Reaction
We explore the intramolecular Friedel-Crafts reaction in this post. But first, a very quick refresher on intramolecular reactions in general.
Table of Contents
- Quick Recap: Intramolecular Reactions Can Be Tricky
- Intramolecular Friedel-Crafts Alkylation
- Intramolecular Friedel-Crafts Acylation
- Summary: Intramolecular Friedel-Crafts Reactions
- (Advanced) References and Further Reading
Here is an instant formula for an organic chemistry exam question.
Start with a straightforward reaction that students understand fairly well, like the Williamson Ether synthesis….
(drawn weirdly, for a good purpose)
…now, just make a simple modification by adding one bond. Voila. Instant stumper!
The second question above is an example of an intramolecular reaction, where the nucleophile and electrophile are on the same molecule, and the result of their reaction is that a ring is formed. In past posts on this subject, I’ve used the analogy of a belt. It still works.
Why are intramolecular reactions good exam questions? Because they sort out the students who learn the reactions by memorizing a table of simple examples, and those who actually know (and most importantly, can apply!) the pattern of bonds formed and bonds broken. Furthermore, it involves no new concepts, which makes it totally fair game.
[You think I am joking about the “instant stumper” comment? I am not. As one student memorably put it, “Intramolecular Reactions Make Me Crumple Into The Fetal Position Crying For My Mommy” ]
Intramolecular variants exist for a lot of different reactions, and it comes up so often that it’s worth mentioning separately. The Friedel-Crafts alkylation and Friedel-Crafts acylation reactions are no exception.
Here’s an example of an intermolecular Friedel-Crafts alkylation. The nucleophile is the aromatic ring, and the electrophile is the alkyl chloride. Add a little catalyst (AlCl3) and boom! electrophilic aromatic substitution.
Now let’s change things up just a little bit. We’ll attach the alkyl halide to the ring via a new carbon-carbon bond, and then add the catalyst. What’s the product?
No new concepts! Same pattern of bonds that form and break. But if you haven’t seen an example like this before, it might throw you completely off your memorized notes. That’s the plan! [Cue recording of “evil laugh”].
OK. Here’s the mechanism, and the final product is drawn out below left.
I want you to note that the overall pattern of bonds that form and bonds that break is exactly the same in the intramolecular case as it is in the intermolecular case, namely: form C-C and H-Cl, break C-H and C-Cl.
Timeless advice for drawing out the mechanism for a reaction like this:
- number the carbons! it’s really easy “drop” a carbon in your drawings, and that will lose you points.
- draw the “ugly version” first, and THEN re-draw to make it look nice. Don’t worry about making it look pretty until you have drawn in the bonds that form and break.
In the case of the Friedel-Crafts, the intramolecular version works best for making 6-membered rings, but it’s also possible to use the Friedel-Crafts to make 5- and 7- membered rings as well (not shown).
Here’s a slightly more advanced practice problem that starts with benzene. Can you draw the final product? (answer below)
Once you’ve seen the intramolecular Friedel-Crafts alkylation, the intramolecular Friedel-Crafts acylation is not exactly going to come as a surprise.
Again, I want you to verify that the bonds being formed and broken are exactly the same in each case. The only difference is that in the second case, the nucleophile and the electrophile are attached to each other through a tether.
One little wrinkle that you probably won’t see, but what the heck. We’re used to seeing acyl halides (and anhydrides) in the Friedel-Crafts, but one interesting thing to note about the intramolecular Friedel-Crafts acylation is that carboxylic acids can participate too. For example, treating this carboxylic acid with a strong acid such as H2SO4 results in an intramolecular Friedel-Crafts acylation:
One reason why this works well for the intra- versus the intermolecular case is that the nucleophile is held so closely to the electrophile. This has the same effect as if the concentration of the electrophile was increased dramatically. You might see other examples where you can “get away with” using a poor nucleophile (or electrophile) in a given reaction if it’s done in an intramolecular fashion.
Here’s a challenge question for you. Can you draw the product of this sequence of Friedel-Crafts reactions?
No really groundbreaking new concepts here, but it’s always helpful to keep alert for intramolecular examples of reactions. This concept never goes away. You will see it again!
In our next post in this series we’ll cover a completely different class of substitution reactions on aromatic compounds that works well with electron-poor aromatic groups. It’s called Nucleophilic Aromatic Substitution.
Rearrangement vs. ring closure. We’ve seen that primary alkyl halides can rearrange via hydride (and alkyl) shifts to give the “more stable” carbocation intermediates. So what happens when a primary alkyl halide is involved in an intramolecular Friedel-Crafts alkylation reaction? Does rearrangement happen first, or is ring closure faster?
This is not the kind of question you can answer simply by thinking about it. When there are competing reaction rates, the only way to know for sure is through experiment.
This was studied, and the full paper on the study of rates of rearrangement versus ring closure is here. [J. Org. Chem, 1966, 31, 89]. Would indicate that closure to the 6-membered ring is faster than closure to the 5 membered ring in this case.
Friedel-Crafts acylation and alkylation can be intramolecular, and this is useful for the synthesis of bicyclic or polycyclic compounds.
Intramolecular F-C alkylations are most successful for the preparation of 6-membered rings, although 5- and 7-membered rings have also been closed in this manner. It is somewhat easier to form 6-membered than 5-membered rings in these reactions. 4-phenyl-1-butanol gives the cyclized tetralin in 50% yield in phosphoric acid, whereas 3-phenyl-1-butanol is mainly dehydrated to alkenes.
If a potential carbocation intermediate can undergo a hydride or alkyl shift (or Wagner-Meerweein rearrangement), this occurs in preference to ring closure of the 5-membered ring. This reflects a rather general tendency for 6 > 5,7 in ring closure by intramolecular Friedel-Crafts reactions.
- New Friedel—Crafts Chemistry. XVI.1 A Reconsideration of Cyclialkylation and Competing Reactions of Certain Phenylalkyl, Benzoylalkyl, and Acetylphenylalkyl Chlorides
Ali Ali Khalaf and Royston M. Roberts
The Journal of Organic Chemistry 1966, 31 (1), 89-95
- New Friedel-Crafts chemistry. XIX. Cyclialkylations of some phenylalkanols
Ali A. Khalaf and Royston M. Roberts
The Journal of Organic Chemistry 1969, 34 (11), 3571-3574
- Friedel-Crafts cyclialkylations of certain mono- and diphenyl-substituted alcohols and alkyl chlorides
Ali Ali Khalaf and Royston M. Roberts
The Journal of Organic Chemistry 1972, 37 (26), 4227-4235
- Cyclization of 2-[N-(methylsulfonyl)anilino]acetaldehyde diethyl acetals to indoles. Evidence for stereoelectronic effects in intramolecular electrophilic aromatic substitution
Richard J. Sundberg and Joseph P. Laurino
The Journal of Organic Chemistry 1984, 49 (2), 249-254
This paper has a section discussing the differences in the transition state geometries for 5- and 6- membered intramolecular ring closure. 5-membered transition states are significantly more strained, especially if it is assumed that the electrophilic carbon attacks from a direction perpendicular to the plane of the ring.Further examples of intramolecular Friedel-Crafts alkylations:
- Experiments directed toward the total synthesis of terpenes. XVII. Development of methods for the synthesis of pentacyclic triterpenes based on a mechanistic interpretation of the stereochemical outcome of the Friedel-Crafts cyclialkylation reaction
Robert E. Ireland, Steven W. Baldwin, and Steven C. Welch
Journal of the American Chemical Society 1972, 94 (6), 2056-2066
This is an example of a polycyclic ring system, where the product is a 3:1 mixture of b:a methyl isomers at the new ring junction, reflecting a preference for the orientation of the groups in the transition state.
- A systematic study of benzyl cation initiated cyclization reactions
Steven R. Angle and Michael S. Louie
The Journal of Organic Chemistry 1991, 56 (8), 2853-2866
This paper examines intramolecular F-C alkylation onto a benzylic position. 6-membered rings are formed more efficiently than 5- or 7-membered rings.
- Enantiospecific synthesis of (+)-(R)-1-phenyl-3-methyl-1,2,4,5-tetrahydrobenz[d]azepine from (+)-(S)-N-methyl-1-phenyl ethanolamine (halostachine) via arene chromium tricarbonyl methodology
Steven J. Coote, Stephen G. Davies, David Middlemiss, Alan Naylor
Tetrahedron Lett. 1989, 30 (27), 3581-3588
The intramolecular F-C alkylations done with standard conditions (e.g. H2SO4/TFA or HBF4·OMe2) lead to racemic product, as expected. Chirality can be induced through an unusual (but advanced) methodology involving organometallics – reversibly forming an arene-Cr(CO)3 complex.Intramolecular acylation:
- The Synthesis of 2-Hydroxy-17-equilenone
E. Bachmann and W. J. Horton
Journal of the American Chemical Society 1947, 69 (1), 58-61
A classical reagent for intramolecular cyclization of phenalkyl carboxylic acids is PPA (polyphosphoric acid), which can be made by adding P2O5 and phosphoric acid. This is not used all that much anymore, since it is a pain to handle – very corrosive, and extremely viscous.
- Methanesulfonic acid. A useful cyclizing acidic reagent
Alberto A. Leon, Guido Daub, and I. Robert Silverman
The Journal of Organic Chemistry 1984, 49 (23), 4544-4545
MSA (methanesulfonic acid, CH3SO3H) is an alternative for PPA in F-C cyclization reactions. It is cheap, readily available, and is a easily handled liquid, comparable in acidity to PPA.
- Spectroscopic and Other Properties of Large Ring Mono- and Dimeric Benzocyclanones Prepared by a High-dilution Friedel-Crafts Reaction
M. Schubert, W. A. Sweeney, and H. K. Latourette
Journal of the American Chemical Society 1954, 76 (21), 5462-5466
While intramolecular F-C acylation is mainly used to close 5-, 6-, and 7-membered rings, even larger rings can be closed by high-dilution techniques.
- Efficient synthesis of selected indenones
Brawner. Floyd and George Rodger. Allen
The Journal of Organic Chemistry 1970, 35 (8), 2647-2653
Intramolecular F-C acylation can also be done with acyl chloride/AlCl3.Tandem reactions with both acylation and alkylation are also possible; these are termed cycli-acyalkylations. Unsaturated acids or lactones can be used.
Cecil E. Olson, Alfred R. Bader, and G. Dana Johnson
Org. Synth. 1955, 35, 95
The first procedure, submitted by A. R. Bader, uses a lactone to efficiently do a tandem F-C cycli-acylalkylation. A. R. Bader went on to found the Aldrich Chemical company, which made him extremely wealthy and forever changed the course of chemical research – chemists now do not have to spend their efforts resynthesizing common starting materials, as these are available off the shelf at high purities.
- The scope of the Haworth synthesis
Israel Agranat and Yu-Shan Shih
Journal of Chemical Education 1976, 53 (8), 488
The first part of the Haworth synthesis involves F-C acylation with an anhydride, followed by intramolecular F-C alkylation after reducing the ketone.