Study of Friedal-Crafts Acylation reaction Rabiya Javed Awan Contribution from Department of Chemistry, SBA School of Science and Engineering, Opposite U Block, 54792, DHA Received March 5, 2021; Email: 20130026@lums.edu.pk ABSTRACT: Friedel craft acylation involves the preparation of functionalized aromatic ketones by the electrophilic substitution reaction of benzene derivative with acetyl chloride in the presence of a Lewis acid catalyst. In this experiment, p-methyl acetophenone was synthesized by the electrophilic substitution reaction of toluene and acetyl chloride in presence catalyst AlCl3. Product (methyl acetophenone) was obtained in a form of viscous liquid in a moderate yield. TLC was taken to signify that the reaction is complete. IR spectrum, GC-MS data showed close correspondence with literature values, ascertaining the formation and purity of the product. INTRODUCTION Friedel–Crafts (FC) reaction is a fundamental method for obtaining functionalized aromatic ketones. It follows electrophilic aromatic substitution mechanism. Traditionally, the FC acylation of benzenes with acid chlorides has been carried out in the presence of protic acids or strong Lewis acid catalyst. 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. A process related to the Friedel-Crafts alkylation, called Friedel-Crafts acylation, also was discovered by Friedel and Crafts. A Friedel-Crafts acylation is an electrophilic aromatic substitution reaction that introduces an acyl group onto an aromatic ring. The electrophile is an acyl cation that is often coupled to a Lewis acid catalyst, such as aluminum chloride. For the reaction to take place, the aromatic ring system must be very electron rich and thus cannot contain any electron withdrawing groups. The reaction was discovered around the same time (1877) when Friedel Crafts worked on alkylation 1. Friedal craft acylation has few limitations such as the halide must be an alkyl halide. Vinyl or aryl halides do not react (their intermediate carbocations are too unstable). Alkylation reactions are prone to carbocation rearrangements. Polyalkylation can be a problem since the product is more reactive than the starting material. This can usually be controlled with an excess of the benzene. The Lewis acid catalyst AlCl3 often complexes to aryl amines making them very unreactive 2. Traditionally, the FC acylation of benzenes with acid chlorides has been carried out in the presence of protic acids or strong Lewis acid catalysts. Lewis acids such as AlCl3, BF3, TiCl4, Rabiya Javed Awan, LUMS School of Science and Engineering ZnCl2, SbCl5, Fe2(SO4)3 and strong protic acids such as HF and H2SO4 have been employed in these reactions. In particular, the use of metal halides causes problems 1) associated with the strong complex formed between the ketone product and the metal halide itself which provokes the use of more than stoichiometric amounts of catalyst. The workup commonly requires hydrolysis of the complex, leading to the loss of the catalyst and giving large amounts of corrosive waste streams. 2) Moreover, these Lewis acids are moisture sensitive and cannot be recovered and reused after the reactions are complete. Due to these draw backs, during the past decade, the setting up of more ecocompatible Friedel-Crafts acylations has become a fundamental goal of the general “green revolution” that has spread in all fields of synthetic chemistry3. Moreover, following are the few limitations of Friedel craft acylation: Acylation can only be used to give ketones. This is because HCOCl decomposes to CO and HCl under the reaction conditions. Deactivated benzenes are not reactive to Friedel-Crafts conditions The Lewis acid catalyst AlCl3 often complexes to aryl amines making them very unreactive. Amines and alcohols can give competing N or O acylations rather than the require ring acylation. Besides its limitation, Friedel craft acylation is has a significant importance in the field of chemistry, Vitamin D, DNA, and many other important compounds in our bodies all includes an aromatic portion 4 5. But it is very difficult for an aromatic ring to react with other compounds because it is so stable. So, to add an aromatic ring to the rest of the molecule to form these important molecules in our body, Friedel-Crafts Acylation method is used by scientist. The reaction is used commonly in food additives6 and fragrances among other uses. Development of new catalytic transformations with easy separation and recyclability of the catalyst is an essential task in chemical synthesis due to a very high importance of the aromatic ketones which are key intermediates in several fields including fine chemicals and 7 pharmaceuticals . Friedel–Crafts acylation of substituted benzenes proceeded smoothly in the presence of a catalytic amount (5–20%) of lanthanide triflates. Aluminium, titanium and ytterbium bis(triflate)imides were found to be highly effective in acylation reactions of anisole and diphenyl ether. Aromatic ketones can also be prepared by the reaction of carboxylic acids with aromatic compounds catalyzed by Brønsted acids such as methane-sulfonic acid, polyphosphoric acid, NafionH, trifluoromethanesulfonic acid and combinations of Lewis acids–Bronsted acids 3. Another important factor is regioselectivity. Regioselectivity is a process that favors bond formation at a particular atom over other possible atoms. The selectivity of the reaction is determined by the the ability of existing functional groups on the benzene ring to stabilize the high energy arenium intermediate in the reaction. The arenium ion formed by ortho paraattack is more stabilized due to complete octet. Moreover, the arenium ion formed by Meta attack is in return slightly stabilized than benzene because charge is slightly reduced by electronRabiya Javed Awan, LUMS School of Science and Engineering donating character of the group. Electron donating stabilizes the arenium ion by dispersing the positive charge 8. Electron donating groups (EDG) with lone pairs (e.g. -OMe, -NH2) on the atoms adjacent to the π system activate the aromatic ring by increasing the electron density on the ring through a resonance donating effect 9. The resonance only allows electron density to be positioned at the ortho- and para- positions. Hence these sites are more nucleophilic, and the system tends to react with electrophiles at these ortho- and paraposition. Figure 1: Resonating structure substituted with activating group. for benzene Electron withdrawing groups (EWG) with π bonds to electronegative atoms (e.g. -C=O, -NO2) adjacent to the π system deactivate the aromatic ring by decreasing the electron density on the ring through a resonance withdrawing effect. The resonance only decreases the electron density at the ortho- and para- positions 10. Hence these sites are less nucleophilic, and so the system tends to react with electrophiles at the Meta sites. Figure 2: Resonating structure substituted with deactivating group. for benzene Halogen’s substitutions are little unusual as they are very electronegative. This means that inductively they are electron withdrawing. However, due to their ability to donate a lone pair of electrons in resonance forms, they are activators and ortho/para directing. The inductive effect lowers the reactivity, but the resonance effect controls the regio-chemistry due the stability of the intermediates. Because they are electron withdrawing, halogens are very weak activators. Friedel Craft acylation of benzene produces both orth para directing acetophenone. Figure 3 (a): p- methylacetophenone and (b): omethylacetophenone This investigation aims at acylation of aromatic compound according to the following reaction: First step is the formation of acylium ion to form strong electrophile by reaction with lewis acid 5. Rabiya Javed Awan, LUMS School of Science and Engineering EXPERIMENTAL SECTION Chemicals and materials: Chlorobenzene, Dichloromethane, Acetyl chloride, aluminum chloride, heptane, and ethanol. Figure 4: Synthesis of Acylium ion. Acylium ion formed is resonance stabilized. Figure 5: Resonance structure of acylium ion. This acylium ion is then attacked by the benzene ring. Figure 6: Mechanism for acylation of Toluene Glassware and equipment: Round bottom flask (100 mL), stir bar, reflux condenser, hot plate, stem funnel, beaker (100 mL +250 mL), extension clamps and fasteners, grease, aluminum foil, watch glass, ice bath, melting point capillaries, oil bath and Buchner funnel. Procedure: Anhydrous aluminum chloride (27.17 mmol) was suspended in methylene chloride (7 ml) in a twoneck round-bottomed flask suspended in an ice bath. A solution of acetyl chloride (27.17 mmol) in methylene chloride (5 ml) was added dropwise to the flask using a syringe at 0οC and the resulting mixture was stirred for 10 minutes followed by the addition of a solution of the aromatic compound (5.43 mmol) in methylene chloride (5 ml) using a syringe. Once the addition was completed, heat the reaction to a gentle reflux for 1 hour. A small quantity of the product was used to be spotted on a TLC plate, along with the reactants and standard. TLC was run in a solvent system of ethyl acetate and hexane in 7: 13 ratios to analyze the completion of reaction. Isolation of Product: After that the reaction mixture was poured slowly to three-fold water. Extraction process in this experiment was carried out by separating funnel. By carefully planning out and washing sequences (using DCM and water), the desired products was separated from most of the unwanted impurities. The solution Rabiya Javed Awan, LUMS School of Science and Engineering was then dried on MgSO4, filtered and solvent was evaporated on rotary evaporator to get the final product. The yield of final product was calculated. Finally, product was analyzed using IR spectrum and GC-MS. Mass of product obtained (Actual Yield) Percentage yield of product 𝐴𝑐𝑡𝑢𝑎𝑙 𝑦𝑖𝑒𝑙𝑑 𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑦𝑖𝑒𝑙𝑑 RESULTS AND DISCUSSION 0.54 g 0.54 × 100 0.72 = 75 % × 100 % The percentage yield obtained is around 75 %. The loss of product in yield could be due to improper handling. GC-MS: Figure 7: Balanced equations for the reactions C:\Xcalibur\...\AM-LAB-4_200305112641 3/5/2020 11:26:41 AM RT: 0.00 - 31.10 7.67 100 Physical properties of reactants: NL: 3.60E8 TIC MS AM-LAB4_2003051 12641 90 Relative Abundance 80 Table 1: Physical properties of reactants 70 60 50 40 30 20 10 Toluene Molar mass Density g/cm3 Melting/boiling point °C 92.14 0.865 g/mL 110.6 3.60 3.92 4.47 5.81 0 1.104 g/mL 52 Aluminum chloride 133.34 - 190 2 3 4 5 6 7 9.66 8 9 10 10.76 11.82 11 12 13.14 13.63 13 14 15.08 15.60 16.44 15 16 Time (min) 17 18.11 18.86 18 19 20.77 21.29 22.44 23.26 20 21 22 23 24 24.89 26.09 25 26 27.36 27 28.72 29.24 28 70 Moles of acetyl chloride 0.02717 Limiting Reagent Toluene Moles of product expected 0.00543 Mass of product expected (Theoretical Yield) = 0.00543 × 134.17 = 0.72 𝑔 31 91.17 60 50 40 134.17 30 65.15 90.33 77.14 92.16 136.20 0 50 100 176.25 150 207.22 200 245.99 267.17 280.88 250 300 327.10 340.78 383.90 398.81 350 400 425.87 466.33 450 504.08 500 528.41 595.12 611.41 550 600 m/z Figure 3: GC-MS of methyl acetophenone Table 2: Percentage yield of (methyl)acetophenone 0.00543 30.74 30 80 Percentage yield of the product: Moles of toluene used 29 90 10 78.5 1 AM-LAB-4_200305112641 #250 RT: 7.67 AV: 1 NL: 1.18E8 T: {0,0} + c EI Full ms [50.00-700.00] 119.16 100 20 Acetyl chloride 7.57 0 Relative Abundance Reagent Figure 4: MS fragmentation pathway for p-methyl acetophenone The spectrum attached shows that retention time for sample is 31.10 minutes. Molecular ions peak at m/z = 134.17 Rabiya Javed Awan, LUMS School of Science and Engineering 665.69 650 813 Para substitution Out-of-Plane C-H Bending 735 Ortho substitution Out-of-Plane C-H Bending IR Spectrum: The C=O stretching peak in acetophenone is lower than the C=O peak of ketone due to conjugation. The large intense peak at 813 cm-1 shows that the para methyl acetophenone is obtained as major product while ortho is minor product. This is due to the steric hindrance effect. As methyl group, which is already substituted on benzene, slightly creates steric hindrance on the close carbons making the attack difficult for the acylium ion on the adjacent positions (ortho position) of substituent. The IR spectrum was in consonance with those reported in literature 6. 4000 3500 3000 2500 Wavenumber cm-1 2000 1500 813.57 735.70 672.17 636.54 590.69 566.73 1429.92 1405.65 1356.98 1265.63 1181.44 1112.56 1075.09 1044.86 953.28 1736.67 1678.98 1605.39 1573.63 1933.58 3030.67 3003.15 2924.33 2872.19 30 40 50 Transmittance [%] 60 70 80 90 100 The base peak at m/z =119.21 The fragment ion peak at m/z = 91.17: elucidate the structure of toluene (loss of acetyl group) while the peak at 77.13 elucidates the pattern of benzene. 1000 500 Figure 5: IR spectrum of 4-methylacetophenone. C:\PROGRAM FILES\OPUS_65\MEAS\Am-503-EXP4.0 Am-503-EXP4 ATR platinum Diamond 1 Refl 28/02/2020 Post Lab Questions Page 1/1 The major peaks obtained in the IR spectrum of Product methyl acetophenone are interpreted as follow: Table 3: The peaks and associated groups with methyl acetophenone Frequency (cm-1) Functional Group Vibration 1679 C=O (sp2) Stretching 1429 - 1605 C=C (sp2) Aromatic Stretching 3000 - 3030 C-H (sp2) Stretching 2872.19 -3003 C-H (sp3) Stretching 1356 - 1405 C-H (sp3) Bending 1. Discussion of the lab report related to this experiment should encompass the directing ability of substrate, electronic and steric effects of preexisting substitutes on the benzene ring. The pre-existing functional substituents are any functional group which is already attached to benzene ring before it undergoes Friedel craft reaction. The groups determine the reaction direct by resonance and induction effect. Resonance effect is the conjugation between the ring and the substituent, which means the delocalizing of the ππ electrons between the ring and the substituent. Inductive effect is the withdraw of the sigma (the single bond) electrons away from the ring toward the substituent, due to the higher electronegativity of the substituent compared to the carbon of the ring. Rabiya Javed Awan, LUMS School of Science and Engineering The reaction of a substituted ring with an activating pre-existing group is faster than benzene. On the other hand, a substituted ring with a deactivated group is slower than benzene. The activating group directs the reaction to the ortho or para position, which means the electrophile substitute the hydrogen that is on carbon 2 (ortho) or carbon 4 (para). The deactivating group directs the reaction to the meta position, which means the electrophile substitute the hydrogen that is on carbon 3 (meta) except for the halogens that is a deactivating group but directs the ortho or para substitution. intermediate step, thus; the activation energy is increased which slows down the reaction. Figure 7: Substate with activating group or electron donating group. Ortho and Para products produces a resonance structure which stabilizes the arenium ion. This causes the ortho and para products for form faster than meta. Generally, the para product is preferred because of steric effects. As Existing groups can provide steric hindrance on the positions in close carbons making the attack of adjacent positions by the substituents difficult. Figure 6: Products of activating and deactivating group. The substrate has a huge role to determine the reactivity of benzene ring and moreover the possible product to come out. Activating groups speed up the reaction because of the resonance effect. The presence of the unpaired electrons that can be donated to the ring, stabilize the carbocation in the transition state. Thus, stabilizing the intermediate step, speeds up the reaction; and this is due to the decrease of the activating energy. On the other hand, the deactivating groups, withdraw the electrons away from the carbocation formed in the Figure 8: Substrate with deactivating group or electron withdrawing group. Whereas. Electron withdrawing groups are resonance deactivators. Ortho and para-attack on such substrates produces a resonance structure which places the arenium cation next to and additional cation. This destabilizes the arenium cation and slows down ortho and para reaction. Hence, the meta product forms faster because it lacks this destabilizing resonance structure. CONCLUSIONS Rabiya Javed Awan, LUMS School of Science and Engineering Methyl acetophenone was synthesized in moderate yield (75%) by the reaction of toluene with acetyl chloride in the presence of Lewis acid as a catalyst, through Friedel craft acylation reaction. The reactants along with catalyst were moderately heated with gentle reflux for 1 hr. The product was extracted through separating funnel with dichloromethane and dried through rotavap. Around 75% of the product yield was obtained. The product was successfully characterized through IR, GCMS and NMR. The peak at 1678 cm-1 in IR spectrum depicts the presence of C=O of acetophenone in product. The peak at 813 cm-1 shows that para methyl acetophenone is obtained as major product. The results of GCMS and IR are in accordance with the literature value. 6. 7. 8. 9. 10. REFERENCES 1. 2. 3. 4. 5. Parella, R.; Kumar, A.; Babu, S. 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