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Reactions of Aromatic Molecules

By James Ashenhurst

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

  1. Quick Recap: Intramolecular Reactions Can Be Tricky
  2. Intramolecular Friedel-Crafts Alkylation
  3. Intramolecular Friedel-Crafts Acylation
  4. Summary: Intramolecular Friedel-Crafts Reactions
  5. Notes
  6. (Advanced) References and Further Reading

1. Quick Recap: Intramolecular Reactions Can Be Tricky

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)

recap of intramolecular reactions williamson ether synthesis intermolecular

…now, just make a simple modification by adding one bond. Voila. Instant stumper!

recap of intramolecular reactions williamson ether intramolecular

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.

2. Intramolecular Friedel-Crafts Alkylation

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. 

example of intermolecular friedel crafts acylation reaction forming c c bond

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?

example of intramolecular friedel crafts alkylation reaction forminc c c bond produt not drawn

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”].

via GIPHY

OK. Here’s the mechanism, and the final product is drawn out below left.

mechanism of intramolecular friedel crafts alkylation reaction giving cyclic product

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)

quiz practice problem friedel crafts alkylation giving new cyclic product

3. Intramolecular Friedel-Crafts Acylation

Once you’ve seen the intramolecular Friedel-Crafts alkylation, the intramolecular Friedel-Crafts acylation is not exactly going to come as a surprise.

intermolecular friedel crafts acylation example

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:

intramolecular friedel crafts acylation reaction using carboxylic acid and strong acid giving new ring acylium ion

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?

friedel crafts intramolecular reaction challenge question

(answer below)

4. Summary: Intramolecular 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.


Notes

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?

question do you get rearrangement or ring closure in intramolecular friedel crafts reaction

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.

Answer #1

answer for friedel crafts alkylation reaction problem

Answer #2. 

answer for friedel crafts acylation reaction problem

Reference


(Advanced) References and Further Reading

Friedel-Crafts acylation and alkylation can be intramolecular, and this is useful for the synthesis of bicyclic or polycyclic compounds.

Intramolecular alkylation:
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.

  1. 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
    DOI:
    1021/jo01339a018
  2. 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
    DOI:
    1021/jo01263a075
  3. 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
    DOI:
    1021/jo00799a001
  4. 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
    DOI: 10.1021/jo00176a007
    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:
  5. 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
    DOI: 10.1021/ja00761a044
    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.
  6. 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
    DOI: 10.1021/jo00008a049
    This paper examines intramolecular F-C alkylation onto a benzylic position. 6-membered rings are formed more efficiently than 5- or 7-membered rings.
  7. 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
    DOI: 10.1016/S0040-4039(00)99447-4
    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:
  8. The Synthesis of 2-Hydroxy-17-equilenone
    E. Bachmann and W. J. Horton
    Journal of the American Chemical Society 1947, 69 (1), 58-61
    DOI: 10.1021/ja01193a014
    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.
  9. 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
    DOI: 10.1021/jo00197a047
    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.
  10. 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
    DOI: 10.1021/ja01650a060
    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.
  11. Efficient synthesis of selected indenones
    Brawner. Floyd and George Rodger. Allen
    The Journal of Organic Chemistry 1970, 35 (8), 2647-2653
    DOI: 10.1021/jo00833a036
    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.
  12. α-TETRALONE
    Cecil E. Olson, Alfred R. Bader, and G. Dana Johnson
    Org. Synth. 1955, 35, 95
    DOI: 10.15227/orgsyn.035.0095
    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.
  13. The scope of the Haworth synthesis
    Israel Agranat and Yu-Shan Shih
    Journal of Chemical Education 1976, 53 (8), 488
    DOI: 10.1021/ed053p488
    The first part of the Haworth synthesis involves F-C acylation with an anhydride, followed by intramolecular F-C alkylation after reducing the ketone.

Comments

Comment section

14 thoughts on “Intramolecular Friedel-Crafts Reactions

  1. I wonder if there would be any takers to propose the mechanism for the tetralone formation via the above mentioned Friedel-Crafts :) I used to put that one on an exam for like 3 or 4 years. Students didn’t appreciate the challenge…

  2. In practice problem #1 it appears that you changed the reactant from a seven carbon chain in the practice problem to a six carbon chain in the answer key.

  3. But an R group is an ortho para director, and the major product is para, so why isn’t it close and connect to the para position of the aromatic ring?

    1. The answer is that the para product would be very strained. The carbonyl can’t reach the para position in a way that leads to non-strained bond lengths and bond angles. If you are unsure about this I invite you to try to build a model!

  4. The article is very nice. I would like to know source or reference for the particular example where you intramolecular acylation of carboxylic acids as I have some confusion as to why the ether has not been hydrolysed.

    1. The reference is linked at the bottom, but it’s Organic Syntheses, Coll. Vol. 4, p.898 (1963); Vol. 35, p.95 (1955).

      What happens with the alcohol is that it eventually coordinates to AlCl3 which activates it towards attack by the aromatic ring, and it departs as a leaving group.

  5. In the example given for intra mole ular freidal crafts reaction ,acylium
    Cation attacks meta to OCH3 group which is ortho para directing .It is not the major product.

    1. It’s a sequence of friedel-crafts acylation and then friedel-crafts alkylation. First step: AlCl3 reacts with the oxygen of the lactone, resulting in formation of the acylium ion which is attacked by the aromatic ring. Now you have an oxygen coordinated to AlCl3 (a good Lewis acid). The AlCl3 converts the oxygen into a good leaving group. So what can happen next is attack of the aromatic ring at the carbon bearing the oxygen, resulting in formation of a new six-membered ring.

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