Sciencemadness Discussion Board

Friedel-Crafts acylation of anilides

Pumukli - 9-1-2021 at 06:53

I have a question for our org.chem. experts!

I played around the ubiquitous reaction of aniline, the synthesis of acetanilide, recently. (Rest assured, this otherwise fairly boring reaction can be "pushed to the extreme" and give you exciting and surprising results.)

While I managed to prepare more and more acetanilide I started wondering about its acylation a la Friedel-Crafts. Then a question arose: how clean the product would be? I mean, if I tried acylating acetanilide with anything but acetyl-chloride (or anhydride), would I get pure acylated products OR the N-protecting acetyl group would be at some point cut off and in a consecutive step attached to the ring yielding some amino-acetophenone, or even maybe a protected amino-acetophenone, if the original acylating agent replaced the acetyl on the N??? AlCl3 can make a lot of tricks, maybe knows this stunt too.

I could not find anything meaningful about this "problem" in the literature, though I'm not even sure how to search it properly. Maybe it is not even a problem, I don't know.

njl - 9-1-2021 at 10:21

Amines are lewis bases while AlCl3 is a lewis acid. So there will probably be some reaction there, maybe an adduct between the two. If that doesn't change much in terms of reactivity, then the amine will be acylated to some extent, although I don't know what the equilibrium would be like without a suitable base. Now, if neither of those things change reactivity too much, then the Friedel Crafts acylation may occur. First of all, amines are activating for electrophilic aromatic substitutions like the FC acylation. While an amine is activating, amides are less activating, and tertiary ammonium salts are deactivating. Without a base, the amine (or amide) would be protonated and might be less activating or even deactivating. That is assuming you use acetyl chloride. If you used acetic anhydride then the reaction would produce acetic acid instead of acetic acid which could be less harmful to reaction rate (because it is a weaker acid). If I had to guess I would say the order in which you introduce the reactants is going to be important as well as the presence of a suitable base like triethylamine or pyridine.

Boffis - 9-1-2021 at 12:58

Hi Pumukli, take a look at these two papers:

Chattaway, Proc. Chem. Soc. 1902, p173 and 1903, p124.

Basically acetanilide can be converted to an N,N-diacetyl aniline by treatment with excess acetic anhydride or acetyl chloride and then rearranged to 4-acetylamino-acetophenone by zinc chloride and the dipropanoyl derivative similarly. Seams to be a bit like Fries reaction except that that give 2-hydroxyacetophenone from phenyl acetate.

Pumukli - 9-1-2021 at 15:11

Thanks, Boffis!

Now I try to reword my original question because it was anything but clear. :-)

If I mixed acetanilide with AlCl3 and RCOCl in an apropriate solvent would it yield pure AcHNPheCOR or an ugly mess of AcHNPheCOR + RCOHNPheCOR + RCOHNPheCOCH3 + AcHNPheCOCH3 + other crap ?

[Edited on 9-1-2021 by Pumukli]

Boffis - 9-1-2021 at 15:39

Tricky :D, As we say "the Devil is in the detail"

If you mix the acetanilide with the acetylation agent first and then add the AlCl3 maybe it will work, particularly if you are using acetyl chloride. It may also work if you mix the acetyl chloride with the AlCl3 first and then mix with the acetanilide. I can't help feeling that AlCl3 would react with the amide creating one of those compounds that act as intermediates in the Vilsmeier Haack reactions and god only knows where that might lead.

Pumukli - 9-1-2021 at 16:04

It seems the odds are not that bad. I found the following:

"p-Chloroacetyl acetanilide (3). To a solution of acetanilide (20.0 g, 148.0 mmol) and α-chloroacetyl
chloride (27.0 mL, 339.5 mmol) in CH2Cl2 (100 mL), aluminum chloride (59.2 g, 444.0 mmol) was
added in portions while stirring, turning the color to dark brown. After completion of addition, the
mixture was heated at reflux for 30 min. The reaction mixture was then allowed to cool to room
temperature and added slowly with stirring to crushed ice (300 g) containing conc. HCl (10 mL). The
precipitate was vacuum filtered, washed thoroughly with water, then left to dry. The solid residue was
crystallized from absolute ethanol to yield 25.4 g of 3 (81.1%) as brownish crystals, mp: 219–221 °C
(published: 213–214 °C [14]); 1
H-NMR (DMSO-d6): δ 2.09 (s, COCH3, 3H); 5.09 (s, 2H, CO-CH2-Cl,
J = 18.1, 3.2 Hz) 7.73 (d, 2H, Ar-H, J = 8.6 Hz); 7.93 (d, 2H, Ar-H, J = 8.5 Hz); 10.34 (s, NH, 1H). "

(In: α-Anilinoketones, Esters and Amides: A Chemical Study
Amjad M. Qandil 1,2,* and Lara I. Fakhouri 1
Pharmaceuticals 2012, 5, 591-612; doi:10.3390/ph5060591)

81% yield is not bad. They managed 70% when starting from benzanilide.

Boffis - 11-1-2021 at 07:55

That is interesting, if it works with p-chloroacetyl chloride I can see no reason why it should not with acetyl chloride.

This raises an interesting question in my mind. Could you prepare phenacyl chloride directly from chloroacetyl chloride and benzene via the FC reaction? This is a very useful reagent for characterising organic compounds and it would be much easier to prepare it this way than by chlorination of the side chain of acetophenone.

njl - 11-1-2021 at 09:26

Note 1 in the following:

Boffis - 11-1-2021 at 12:15

Thanks njl, that is interesting!