The Friedel-Crafts reactions are a family of processes (acylation, alkylation, and some other less i — Organic Chemistry Chemistry Question
Synthesis of 3-(4-Methylbenzoyl)propionic acid
The Friedel-Crafts reactions are a family of processes (acylation, alkylation, and some other less important) developed by C. Friedel and J. Crafts in 1877 at the Sorbonne. The Friedel-Crafts acylation allows introducing of an acyl group into the aromatic ring with a suitable acylating agent (acyl halide or carboxylic acid anhydride) and a strong Lewis acid as a catalyst. Nowadays it is an important synthetic method providing aromatic and alkyl-aromatic ketones, which are important intermediates in the production of pharmaceuticals, dyes and other valuable compounds.
[VISUAL]
The Friedel-Crafts alkylation is less sought, since may lead to a mixture of polyalkylated products. Remarkably, a solution comes from the Friedel-Crafts acylation, since the acylation products are readily reduced to the corresponding alkanes (e.g. via Clemmensen or Wolff-Kishner reactions).
Chemicals and reagents
* Toluene (dry), 25 g,
* Succinic anhydride, 5 g,
* Aluminium chloride anhydrous, 13.3 g,
* Dichloromethane (Methylene chloride), 100 cm3,
* Hexane, 75 cm3,
* Hydrochloric acid, concentrated, 25 cm3,
* Sodium sulfate, calcined, 20 g,
* Distilled water, 100 cm3
Equipment and glassware
* Laboratory stand with clamps,
* Three-necked flask, 250 cm3,
* Reflux condenser with breather tube,
* Dropping funnel, 100 cm3,
* Magnetic stirrer with heating,
* Teflon magnetic stir bar,
* Hoses,
* Thermometer with a tapered joint,
* Tapered joint stopper,
* Ice bath,
* Graduated cylinder, 50 cm3,
* Beaker, 100 cm3,
* Separating funnel, 250 cm3,
* Rotary evaporator,
* Paper filter,
* Fritted glass filter, porosity 2-3,
* Bunsen flask for vacuum filtration,
* Glass rod,
* Melting point apparatus,
* Capillary for melting point determination (2-3 ea.),
* Glass tube for capillary filling,
* Spatula,
* Teflon sleeves for tapered joints or vacuum grease,
* Analytical balances (± 0.001 g).
Procedure
A. Assembly of the apparatus
Assemble the apparatus as shown in the hereunder picture. Equip every joint with the Teflon sleeve or apply vacuum grease.
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B. Preparation of the reagents and synthesis of the product
Fix the three-necked flask at the laboratory stand over the magnetic stirrer. Place 25 g of toluene and 5 g of succinic anhydride into the flask and equip it with the reflux condenser with a breather tube, the dropping funnel and the stir bar. Start stirring the mixture. Use the neck left open to add 13.3 g of the finely-powdered anhydrous aluminum chloride in portions at continuous stirring. When finished, fix the neck with the thermometer so that its tip is submerged into the reaction mixture. Switch on heating. Close the neck with the stopper and vigorously stir the reaction mixture for 1 h at 60 °C.
C. Isolation of the product
Cool the flask down to room temperature and then place it in the ice bath. Fill the dropping funnel with 60 cm3 of ice-cooled water. Add slowly (dropwise) all the water from the funnel to the reaction mixture at constant vigorous stirring. When finished, add dropwise 25 cm3 of concentrated hydrochloric acid add 60 cm3 of dichloromethane. Transfer the reaction mixture to the separatory funnel and tightly close it with the stopper. Keep shaking the reaction mixture vigorously (turning the separatory funnel up and down) for a few minutes, and then allow the phase separation. Add extra 10 cm3 of water and 10 cm3 of dichloromethane if phase separation is not satisfactory. Segregate the well defined organic phase. For better extraction, add 20 cm3 of dichloromethane to the aqueous phase and repeat separation as described above two times. Combine the organic phases in the separatory funnel and wash with 30 cm3 of water. Pour out the organic phase and dry it over calcined Na2SO4 1 hour. Filter the desiccant off using the paper filter or fritted glass filter. Evaporate the filtrate on the rotary evaporator to approximately 20% of the original volume.
D. Purification of the product
Transfer the residue left after the rotary evaporation into the beaker and add 30 cm3 of hexane, which will initiate the crystallization process. Place the beaker in the ice bath for 20 min to complete crystallization. Filter out the precipitate using the fritted glass filter and wash the product three times with 15 cm3 of hexane each.
E. Analysis of the product
Weigh the product. Calculate the yield.
Place the non-sealed end of the capillary into the product crystals, then turn it the sealed end down and throw several times down through a glass tube. Check that the sealed end side of the capillary is filled with the product. Apply the ready capillary to the melting point apparatus and record the melting point of the product. Compare the value with the reference data and draw a conclusion about the product purity.
Note. The resulting product, if pure, can be used as the starting compound in Problem 31.
Reference Data from Solution:
- Product Appearance: Beige crystals (prisms)
- Melting point: 126-127 °C
- Yield: 6.6 g (68 %)
- NMR reference data (CDCl3): 2.42 (s, 3H, CH3), 2.81 (t, 2H, J=6.6 Hz, CH2COOH), 3.30 (t, 2H, J=6.6 Hz, CH2CO), 7.27 (d, 2H, 2H, J=8.0 Hz), 7.89 (d, 2H, 2H, J=8.1 Hz) [ArH]
Is it possible to introduce two acyl groups in the ring via the Friedel-Crafts electrophilic substitution reaction? Propose the way to obtain 1,4-diacetylbenzene.
Model Answer
No, because the first acyl group introduced into the ring exhibits the –M effect, thus deactivating the ring with respect to subsequent electrophilic substitution reactions. To advance on the way to diacylated product, one should temporarily change the first introduced acyl group so that its deactivation effect on the ring is minimized. Reduction of the monoacylated derivative with sodium borohydride followed by introduction of the trimethylsilyl or THP protection can be considered as examples. The synthetic sequence is continued by the second acylation, removal of the protection from the hydroxyl group, and finally by the oxidation of the hydroxyl group with any suitable reagent (PCC, PDC, manganese dioxide, etc.)
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Compare the activity of phenol, p-nitrophenol and p-methoxyphenol in the O-acylation reaction in neutral medium (e.g. in THF). Suggest the reaction scheme of the most active compound (according to your choice) with propionic acid chloride.
Model Answer
A reagent activity in O-acylation reaction depends on the electron density at the oxygen atom (nucleophilicity). As the electron pair of the phenolic oxygen is conjugated with the aromatic π-system, the electron density at this atom depends on the donor-acceptor properties of the ring substituents. Being an acceptor of electron density, the nitro group reveals the –M effect and depletes the ring and the phenolic oxygen. The methoxy group produces the +M effect, thus increasing the electron density in the ring and at the phenolic oxygen. Thus, the activity increases in the following order: p-nitrophenol < phenol < p-methoxyphenol.
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Why is the Friedel-Crafts acylation more often used as compared to the Friedel-Crafts alkylation?
Model Answer
The Friedel-Crafts alkylation leads to a mixture of polyalkylation products. Besides, the reaction proceeds via carbcationic intermediates, which are subject to various rearrangements. As a result, the hydrocarbon skeleton of the starting alkylating agent undergoes isomerization. Thus, alkylation typically leads to a complex mixture of products, which both reduces the product yield and makes its isolation complicated.
By contrast, the Friedel-Crafts acylation always affords a sole product of the known structure.
Which other reagents (besides that considered in the Problem) can be used in the Friedel-Crafts acylation?
Model Answer
Acid halides are often used as acylating agent. Various Lewis acids (zinc chloride, ferric chloride, boron trifluoride, etc.) can be introduced in the reaction mixture instead of aluminum chloride.
Why are the ice-cooled water and concentrated hydrochloric acid added to the mixture once the reaction is complete?
Model Answer
Water is added to decompose the unreacted anhydride, the reaction being exothermic:
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Hydrochloric acid is added to destroy the complex of aluminum chloride with the reaction product and to remove aluminates in the form of H[AlCl4(OH2)2].
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Why aluminum chloride is taken in the two-fold excess?
Model Answer
Aluminum chloride forms complexes with carbonyl and carboxyl groups. The answer comes from the fact that the product contains both of these groups.
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