- Short Report
- Open Access
A reactivity-selectivity study of the Friedel-Crafts acetylation of 3,3′-dimethylbiphenyl and the oxidation of the acetyl derivatives
Chemistry Central Journal volume 6, Article number: 52 (2012)
Friedel-Crafts acetylation is an important route to aromatic ketones, in research laboratories and in industry. The acetyl derivatives of 3,3′-dimethylbiphenyl (3,3′-dmbp) have applications in the field of liquid crystals and polymers and may be oxidized to the dicarboxylic acids and derivatives that are of interest in cancer treatment.
The effect of solvent and temperature on the selectivity of monoacetylation of 3,3’-dmbp by the Perrier addition procedure was studied using stoichiometric amounts of reagents. 4-Ac-3,3′-dmbp was formed almost quantitatively in boiling 1,2-dichloroethane and this is almost twice the yield hitherto reported. Using instead a molar ratio of substrate:AcCl:AlCl3 equal to 1:4:4 or 1:6:6 in boiling 1,2-dichloroethane, acetylation afforded 4,4′- and 4,6′-diacetyl-3,3′-dmbp in a total yield close to 100%. The acetyl derivatives were subsequently converted to the carboxylic acids by hypochlorite oxidation. The relative stabilities of the isomeric products and the corresponding σ-complexes were studied by DFT calculations and the data indicated that mono- and diacetylation followed different mechanisms.
Friedel-Crafts acetylation of 3,3′-dmbp using the Perrier addition procedure in boiling 1,2-dichloroethane was found to be superior to other recipes. The discrimination against the 6-acetyl derivative during monoacetylation seems to reflect a mechanism including an AcCl:AlCl3 complex or larger agglomerates as the electrophile, whereas the less selective diacetylations of the deactivated 4-Ac-3,3′-dmbp are suggested to include the acetyl cation as the electrophile. The DFT data also showed that complexation of intermediates and products with AlCl3 does not seem to be important in determining the mechanism.
The Friedel-Crafts acylation is a powerful and successful way to introduce new carbon-carbon bonds in aromatic compounds and is one of the most important one-step routes for the synthesis of aromatic ketones, in research laboratories and in the chemical and pharmaceutical industries [1–5]. Although the reaction has been known for more than 130 years it still receives attention [6–16] the recent interest being focused on the use of ionic liquids as solvents , selectivity studies [6, 9, 11, 13], the application of solid catalysts , and still, mechanism details [8, 12, 14, 15]. Simple aromatic hydrocarbons and methyl substituted derivatives have featured as substrates in both earlier and more recent studies of the reaction including benzenes [6, 7, 17–19], biphenyls and fluorene [11, 13, 20], naphthalenes [21–23], anthracenes [14, 24, 25], phenanthrenes [12, 26], pyrenes , and chrysenes  and as a part of our continuing interest in Friedel-Crafts acetylations [11, 13, 21, 28–31], we now report details of the acetylation of 3,3′-dimethylbiphenyl (3,3′-dmbp). Compounds and materials derived from this building block are of particular interest in the field of molecular liquid crystals , polymers [32, 33] and metal-complexes .
The literature offers only few studies of the Friedel-Crafts functionalization of 3,3′-dmbp. In the early thirties it was reported  that acylation of 3,3′-dmbp with α-naphthoyl chloride in the presence of AlCl3 resulted in the formation of 4,4′-di(1-naphthoyl)-3,3′- dmbp (41%) and to the best of our knowledge only two studies of the Friedel-Crafts acetylation of 3,3′-dmbp have appeared. Acetylation in 1,2-dichloroethane with acetic anhydride and aluminium chloride was reported  to give the 4-acetyl derivative (50%) and the same product was obtained (38.5%) when the reaction was carried out in carbon disulphide . Diacetylation of 3,3′-dmbp has been mentioned only briefly in the literature . Other electrophilic substitution reactions of 3,3′-dmbp include chlorination that gives a mixture of 2-, 4- and 6-chloro-3,3′-dmbp with the 4-isomer being dominating , bromination and iodination that lead to the 4-halo derivatives  and sulphonation  that with an excess of 98% H2SO4 leads to a 52:48 mixture of the 4,4′-and 4,6′-disulphonic acids.
Below we report the results of an investigation of the distribution of the isomers formed by Friedel-Crafts mono- and diacetylation of 3,3′-dmbp using the Perrier addition procedure, that is the addition of the hydrocarbon to the preformed acetyl chloride-aluminium chloride complex. The study included the effect of solvent and temperature on yields and product distribution. The selectivity of the mono- and diacetylation processes is discussed using theoretical DFT data for the relative stability of the isomeric products and the intermediate σ-complexes. The further oxidation of the resulting mono- and diketones with hypochlorite to the corresponding carboxylic acids is reported as well.
Synthesis of 3,3′-dimethylbiphenyl
The starting material, 3,3′-dmbp, was synthesized by two different methods. Ullman coupling of 3-iodotoluene yielded 60% of a high purity product (99.5% glc), while deamination of 4,4′-diamino-3,3′-dmbp resulted in a somewhat higher yield, 84%. However the latter procedure is slightly more expensive due to the high cost of starting materials.
The acetylation products
The products and yields are summarized in Tables 1 and 2. The abbreviations used for the mono and diketones are x-Ac and x,y′-diAc, respectively, where x and y′ refer to the acetylated positions of the two phenyl rings. The route for the synthesis of the acetyl isomer and the corresponding carboxylic acids is depicted in Scheme 1.
As seen from Table 1 acetylation of 3,3′-dmbp at 25°C and 45°C using equimolar amounts of 3,3′-dmbp, AcCl and AlCl3 in 1,2-dichloroethane, carbon disulfide and nitromethane gave the 4-acetyl isomer, 4-Ac, exclusively in yields in the 50-60% range. At higher temperature, that is at the boiling point of the reaction mixture, 4-Ac was still the only ketone isolated after work-up (Table 2) and in 1,2-dichloroethane the yield had now increased to almost 100% (run no 8). This is a considerable improvement over the yield reported earlier (50%) resulting from acetylation at 50o C with acetic anhydride in the same solvent . In chlorobenzene, the 4-Ac (58.6%) was accompanied by the formation of 4-chloroacetophenone as a byproduct in about 18% yield formed by acetylation of the solvent. In boiling nitromethane the yield was only 11.8% and the reaction was accompanied by the formation of a dark polymeric material. The low yield obtained in nitromethane is not unusual; it was observed also in previous studies of the acetylation of 4,4′-dimethylbiphenyl  and of 9H-fluorene . When the reaction was carried out in boiling nitrobenzene acetylated products could only be detected in trace amounts. Probably the high temperature (bp. 211°C) in this latter case was causing degradation of substrate, intermediates or products.
When acetylation was carried out in boiling 1,2-dichloroethane with an excess of AcCl and AlCl3 (the molar ratio 3,3′-dmbp:AcCl:AlCl3 equal to 1:4:4 or 1:6:6), and conditions that are otherwise the same, a mixture of 4,4′- and 4,6′-diAc in a total yield close to 100% was obtained with the relative yield of the 4,6′-isomer increasing slightly with increasing amounts of the AcCl:AlCl3 mixture (run no 14 and 15).
Thus, similarly to what has been observed earlier [36, 37] we find that acetylation of 3,3′-dmbp takes place in the 4-position and the substitution pattern we observe for diacetylation, 4,4′-and 4,6′-, is the same as that reported earlier for sulfonation .
The spectral data
The 1 H NMR spectral data of the acetyl derivatives illustrate that the chemical shift of the methyl protons could be used as an indication of the position of substitution of an acetyl or a methyl group linked to the aromatic rings [30, 41, 42]. Analysis of the 1 H NMR data showed that the methyl protons chemical shifts (δCH3) for all the three isomers are shifted downfield by 0.15 ppm compared to the methyl protons in the parent compound. This confirms that the acetyl group is situated ortho to the methyl group, whereas the δCH3 for the second ring in 4,6′-diAc-3,3′-dmbp remains almost unaffected (0.49 ppm) as it is far from the methyl group. The results obtained from the 1 H NMR are in agreement with the methyl protons chemical shifts (δCH3) in toluene viz. the δCH3 being shifted downfield from 2.34 to 2.85 ppm on substitution of an acetyl group ortho to the methyl group, while for meta- and para-substitution, the values are 2.27 and 2.52 ppm, respectively .
The IR spectroscopy data further supports the positional assignment. An intense absorption band of the C = O stretching vibration of the acetyl group appeared at 1685–1650 cm−1, which elaborate a carbonyl group sterically hindered by the adjacent tolyl or methyl groups. The carbonyl band shifted to a lower wave number in comparison to acetophenone (1690 cm−1) . In fact, the assignment is in good agreement with the expectation of the orientation during the acetylation reaction due to the directing effect of the methyl and tolyl substituents.
The mass spectra also support the structural assignment by existence of the molecular ion peak [M]+. The breakdown of the two monoacetyl isomers under electron impact follows almost the same mass fragmentation pathways. The major fragment ions observed in the mass spectra were [M-CH3]+, [M-COCH3]+, [M-(CH3 + COCH3)]+, [PhCH3]+, [C6H4]+ and [COCH3]+.
The relative stability of the products
It is well known that the ketones resulting from Friedel-Crafts acetylations exist in the reaction mixtures as the AlCl3 complexes [5, 7, 25, 45] and for that reason the discussion below of the relative stability of the products includes not only the mono- and diketones, x-Ac and x,y′-diAc, as isolated after work-up, but also the AlCl3 complexes; the 1:1 AlCl3 complexes for the monoketones and the 1:1 and 1:2 complexes for the diketones.
Theoretical data obtained by DFT B3LYP 6-31 G(d,p) calculations for the mono- and diketones are summarized in Tables 3 and 4; the results for the AlCl3 complexes are included in Additional file 1: Scheme S1, Tables S1, S2 and S3.
The data in Table 3 show that the biphenyl dihedral angles, θ, for 4-Ac and 5-Ac are close to that for unsubstituted 3,3′-dmbp. All fall in the range 37–39o, which is within the range of values determined for 3,3′-dmbp by photoelectron [46–48] or NMR spectroscopy [49, 50]. It is seen also that the CAr-CAr-C = O dihedral angle, ϕ, between the carbonyl group and the benzene ring to which it is attached is close to 0o for 4-Ac and 5-Ac showing that the steric interactions between the 4-Ac group and the neighboring hydrogen and methyl, and between the 5-Ac group and the two neighboring hydrogens, are negligible. In contrast, the geometries for the two other isomers, 2-Ac and 6-Ac, are both affected by steric interactions between the acetyl group and the 2′- and 6′-hydrogens in the neighboring ring. These interactions cause θ to increase from approximately 38o to 49o (2-Ac) and 54o (6-Ac) and steric interactions also hinder co-planarity of the carbonyl group and the aromatic ring as reflected by ϕ values as high as 60.8o (2-Ac) and 31.3o (6-Ac). As a consequence of this both 2-Ac and 6-Ac suffer from diminished electronic conjugation resulting in values of G298 that are 33.7 and 22.5 kJ mol−1, respectively, higher than G298 for the lowest energy isomer, 5-Ac. It is seen also that 5-Ac is 12 kJ mol−1 more stable than 4-Ac, the only isomer isolated after work-up. The stability of the four monoacetyl derivatives decreases in the order 5 > 4 > 6 > 2 and thus, the isomer with an 1,3,5-arrangement of the three substituents (Ac, Me and Ar) in the acetylated benzene ring is found to be the most stable reminiscent of the relative stability of trialkylbenzenes .
Complexation with AlCl3 has only a minor effect on the structure of the monoketones (Additional file 1: Table S1), but we do notice that 2-AcAlCl3 and 4-AcAlCl3 are both destabilized relative to the two other AlCl3 complexes presumably owing to steric interactions between the bulky AlCl3 group and the neighboring 3-CH3 group. For 4-AcAlCl3 these interactions also cause ϕ to increase from ~0 to 11.4o. However, the order of decreasing stability of the AlCl3 complexes remains the same as that for the uncomplexed ketones.
Comparison of the data in Table 3 for the monoketones with those in Table 4 for the diketones shows that the presence of the 4-Ac group has only little effect on the geometry, and the relative stability of the diketones is found to decrease in the same order as before, that is 4,5′ > 4,4′ > 4,6′ > 4,2′. Similarly, by comparison of the data in Additional file 1: Table S1 for the AlCl3 complexes of the monoketones with those in Tables S2 and S3 for the AlCl3 complexes of the diketones we see no new effects on the structure and the relative stability caused by complexation of the diketones with AlCl3.
Thus, it is clear that the Friedel-Crafts mono- and diacetylation of 3,3′-dmbp with AcCl and AlCl3 under the Perrier conditions does not favor the formation of the most stable ketones or ketone AlCl3 complexes and thus appears, as expected, to be under kinetic control.
The relative stability of the σ-complexes
Let us now briefly examine the classical ionic mechanism for acetylation and test whether the distribution of the products is indeed reflected by the relative stability of the σ-complexes shown in Scheme 2 (for mono-substitution only) as one might expect for a kinetically controlled reaction. The relative stabilities of the four
The relative stabilities of the four σ-complexes leading to monoacetylation are summarized in Table 5 (the data for the corresponding AlCl3 complexes are included Additional file 1: Scheme S2 and Table S4). The order of decreasing stability is seen from Table 5 to be 4 ≈ 6 > 2 > 5 in agreement with the observation that 5-Ac is not formed in spite of the fact that this is the most stable isomer as already mentioned above, but it is noticed also that G298 for 4-Ac,4-H+ that leads to the only product formed is only 0.4 kJ mol−1 lower than G298 for 6-Ac,6-H+. The same is true for the AlCl3 complexes, x-AcAlCl3,x-H+ (Additional file 1: Table S4). Thus, the theoretical data for the relative stability of the σ-complexes for monoacetylation would predict the formation of both 4-Ac and 6-Ac as major products. This is in contrast to the experimental observation that 4-Ac is formed exclusively and therefore it appears that a feature of the reaction, so far not accounted for, causes the discrimination against the formation of 6-Ac. Here we wish to emphasize that the small energy differences found for 4-Ac,4-H+ and 6-Ac,6-H+, and for 4-AcAlCl3,4-H+ and 6-AcAlCl3,6-H+, do not appear to be a computational artifact. More advanced computational strategies including the application of the larger 6-311 + G(d,p) basis set or the inclusion of AlCl4− ion pairs and PCM solvation result in energy differences that are still very small. Thus, the similarity of the energies of the two cations seems to be real. We will return to the implications of this result below.
The theoretical data for the four σ-complexes leading to diacetylation are summarized in Table 6 (the data for the corresponding AlCl3 complexes are included Additional file 1: Scheme S2, Tables S5 and S6).
Comparison of the data in Tables 5 and 6 shows that the presence of the 4-Ac group, as also intuitively expected, does not have a significant effect on the relative stability of the σ-complexes that decreases in the same order as for monoacetylation, that is 4,4′ ≈ 4,6′ > 4,2′ > 4,5′. The same is true for the AlCl3 complexes, but we do notice (Additional file 1: Table S5) that the 1:1 complexes that involve the acetyl group resulting from the electrophilic attack are of significantly higher energies than those involving the 4-Ac group and therefore appear to be of only minor importance. Thus, in contrast to the monoacetylation the theoretical data for diacetylation are indeed in agreement with the assumption that the product distribution, that is the formation 4,4′-diAc and 4,6′-diAc in similar amounts, reflects the relative stability of the σ-complexes. In other words, the classical ionic mechanism may well be in operation for the diacetylation process.
The problem that remains is the effective discrimination against 6-Ac during monoacetylation. Here we should bring into mind that the composition of the AcCl-AlCl3 mixtures, such as those used under the Perrier conditions, may contain not only the free acetyl cations, but also ion-pairs involving this species as well as acetylating species resulting from the complexation between AcCl and AlCl3 and possibly even larger agglomerates, the actual distribution of these species of course being dependent on the solvent and the concentration ratio of AcCl and AlCl3. We find it likely that acetylation of the unsubstituted 3,3′-dmbp may involve such larger acetylation species reminiscent of the substitution mechanism  and that the discrimination against attack at the 6-position is caused by steric hindrance, whereas the deactivated 4-Ac derivative requires the smaller, more potent, and thus less discriminating, acetyl cation as in the ionic mechanism. This is illustrated in Scheme 3. We are presently engaged in more detailed experimental and theoretical studies of this problem.
4,4′-Diamino-3,3′-dimethylbiphenyl, 3-methylaniline, pentyl nitrite, acetyl chloride, anhydrous aluminium chloride, copper powder, potassium hydroxide, sodium hypochlorite (6% available chlorine), silica gel and THF were from BDH and chloroform, dichloroethane, hydrochloric acid, benzene and petroleum ether were from Aldrich. Silica gel used for column chromatography was 230–400 mesh ASTM from Merck. All solvents used were of analytical purity from Fluka and were dried over anhydrous calcium chloride or anhydrous sodium sulfate prior to use in the acetylation reactions.
IR spectra were measured as KBr discs or as thin films of Nujol on a Pye Unicam sp3-300 spectrophotometer. 1 H NMR spectra were recorded on a Varian FT-80 MHz and Bruker 100 MHz for solutions in deuterated chloroform, using tetramethylsilane as an internal standard. GLC analyses were carried out with a stainless steel column (2 m × 2.2 mm i.d.) packed with SE-30 (10%) on acid-washed Chromosorb W (80–100 mesh). Nitrogen (15 lb in−2) was used as carrier gas at 250°C; a Pye Unicam 204 instrument fitted with flame ionization detector was used. Peak areas were measured by Pye Unicam DP 88 electronic integrator. Mass response towards the different compounds was determined and appropriate corrections were applied. Elemental analyses were carried out in Alfred Bernhard Mikroanalytisches Laboratorium, Germany. Mass spectra were obtained on a VG MassLab 12–250 GC mass spectrometer.
General acetylation procedure
The route for the synthesis of the ketones and carboxylic acids is depicted in Scheme 1.
The Friedel-Crafts acetylations were carried out in a three-necked round-bottomed flask placed in oil bath and fitted with a dropping funnel, a thermometer and a reflux condenser with a calcium chloride absorption trap. Equimolar quantities of the reactants in the dry solvent (20 mL) were brought together under the Perrier conditions, where the catalyst and acylating agent were allowed to react prior to addition of the substrate. A stoichiometric amount of 3,3′-dmbp in the same solvent (20 mL) was added drop wise over a period of 5 min to the stirred reaction mixture at the desired temperature. Stirring was continued at the same temperature for the total time shown in the Tables below. The mixture was then added to an excess of crushed ice and 3 M HCl. The organic phase was separated and the water phase was washed with the organic solvent. The combined organic phases were then washed with water (5 × 50 mL), dried with anhydrous sodium sulfate and finally the solvent was removed at reduced pressure using a rotary evaporator. When nitromethane was used as the solvent, the organic layer was washed with (2 × 100 mL) of 3 M NaOH instead of water. The viscous residue was dissolved in benzene and passed through a short column of silica gel to remove any polymeric materials. The reaction mixtures were examined for the content of ketones by GLC analysis. The symmetry of 3,3′-dmbp molecule limits the number of isomeric monosubstituted derivatives to four at 2-, 4-, 5-and 6- position and the identity of each component was established by comparison of the retention time with that of authentic samples and by oxidizing the ketones to the corresponding carboxylic acids. The overall yield of products is presented in Tables 1 and 2 above . The mono-and diketones synthesized were identified by their 1 H NMR, IR, mass spectra and by elemental analysis.
Preparation of 3,3′-dimethylbiphenyl
Two different methods, A and B below, for the preparation of 3,3′-dmbp was followed, both of which gave identical products. (A): 3,3′-dmbp was prepared by deamination of 4,4′-diamino-3,3′-dmbp following a published procedure . 4,4′-diamino-3,3′-dmbp (4.24 g, 0.02 mol) in THF (50 mL) was added drop-wise within 2 h to a boiling solution of pentyl nitrite (23.4 g, 0.2 mol) in THF (30 mL). The obtained mixture was refluxed for 6 h. Distillation of the solvent resulted in a viscous dark brown liquid. The viscous liquid was extracted with chloroform then the solvent was evaporated. The remaining material was distilled under vacuum. An oily colorless liquid of 3,3′-dmbp was obtained (3.1 g, 84%). (B): Ullmann synthesis starting from 3-methylaniline. 3-iodotoluene was prepared from 3-methylaniline using the general method  where a colorless liquid was obtained; bp. 214°C (lit.  213°C). A mixture of 3-iodotoluene (42 g, 0.2 mol) and copper powder (24.4 g, 0.4 mol) was refluxed for 72 h. After cooling the mixture was dissolved in chloroform and filtered off. On evaporation of the solvent a brown liquid was obtained distilled under vacuum which gave a colorless liquid of 3,3′-dmbp (21 g, 60%); b.p. 146°C/17 mmHg. (lit.  135°C/3 mmHg) (Found C, 92.16; H, 7.71%; C14H14 requires C, 92.26; H, 7.74%). δ (CDCl3) 2.43 (6 H, s, 3-CH3 and 3′-CH3), 7.17-7.31 (6 H, m, aromatic H), 7.53 (d, J = 7.8 Hz, 2 H, H-6,6′).
To a stirred solution of acetyl chloride (0.392 g; 0.005 mol) and aluminium chloride (0.666 g; 0.005 mol) in 1,2-dichloroethane (20 mL), 3,3′-dmbp (0.91 g; 0.005 mol) in the same solvent (20 mL) was added and the mixture was stirred at room temperature for 1 h and then refluxed for 22 h. The mixture was then added to an excess of crushed ice and 3 M HCl. The organic phase was separated, the extract was added to the washing (solvent) of the acid layer and the combined extracts were washed with water (5 × 50 mL) and the solvent removed by rotary evaporator. The dark brown oil obtained was dissolved in benzene, chromatographed over silica gel/petroleum ether first to get rid of the remaining starting hydrocarbon, and then the ketone was obtained by using benzene as an eluent. Evaporation of benzene affords pure 4-acetyl-3,3′-dmbp (0.98 g; 87.1%) as a yellow oil: Found C, 85.54; H, 7.19%; C16H16O requires C, 85.68; H, 7.19%). νmax (neat) 1680 (C = O) cm−1; δ (CDCl3) 2.43 (s, 3 H, 3′-CH3), 2.58 (s, 6 H, 3-CH3 and 4-CH3CO), 7.17–7.53 (6 H, m, aromatic H), 7.78 (d, J5,6 = 9 Hz, 1 H, H-6′). m/z 224 [M]+, 209 [base peak, M-CH3]+, 181 [M − COCH3]+, 151 [M-(2CH3 + COCH3)]+, 89 [PhCH3]+, 76 [C6H4]+, 43 [COCH3]+.
A mixture of 4-acetyl-3,3′-dmbp (2.1 g; 0.009 mol), potassium hydroxide (1.5 g) and sodium hypochlorite (150 mL) was heated for 3 h. Additional quantities of hypochlorite solution (45 mL) were added to the mixture after 1 and 2 h. After cooling, the solution was acidified with 50% HCl and the precipitate was extracted with ether (4 × 25 mL), washed with water then with dilute potassium hydroxide. The basic layer was separated, acidified with dilute HCl and a precipitate was formed which was extracted with ether. The acid was obtained after ether evaporation as yellow crystals (1.13 g; 53%), mp 168–170°C. νmax (KBr) 1683 (C = O) and 3040 (OH) cm−1 δ (CDCl3) 2.45 (s, 3 H, 3′-CH3), 2.73 (s, 3 H, 3-CH3), 7.25–7.47 (m, 6 H, aromatic H), 8.14 (d, J5′,6′ = 8.5 Hz, 1 H, H-6′),11.69 (s, 1 H, 4-COOH exchangeable with D2O). (Found C, 79.62; H, 6.24%; C15H14O2 requires C, 79.65; H, 6.19%).
4,4′- and 4,6′-diacetyl-3,3′-dimethylbiphenyl
To a stirred solution of acetyl chloride (3.136 g; 0.04 mol) and aluminium chloride anhydrous (5.323 g; 0.04 mol) in 1,2-dichloroethane (40 mL), 3,3′-dmbp (1.82 g; 0.01 mol) in the same solvent (40 mL) was added drop wise over 5 minutes. The mixture was stirred at room temperature for 1 h then gently refluxed for 22 h. At the end of the reaction time, the resulting mixture was cooled and added to a mixture of conc. HCl and ice. The dark brown viscous oil obtained was chromatographed over silica gel/benzene. The yellow oil obtained on evaporation of benzene. A yellow solid (0.86 g, m.p. 129–131°C) was obtained on adding a little of benzene. Recrystallization of the yellow solid using ether gave 4,4′-diacetyl-3,3′-dmbp as yellow needles (0.79 g, 29%) m.p. 131–3°C. (lit.  136°C). Found C, 81.11; H, 6.74%; C18H18O2 requires C, 81.17; H, 6.81%). νmax (KBr) 1684 (C = O) cm−1 δ (CDCl3) 2.62 (s, 12 H, 3-CH3, 3′-CH3, 4-COCH3, 4′-COCH3), 7.29–7.61 (m, 4 H, aromatic H), 7.83 (d, J5,6 and J5′,6′ = 8.9 Hz, 2 H, H-5, 5′). The mother liquor was subjected to column chromatography, which gave rise to, first, the 4,4′-diacetyl-3,3′-dmbp and, second, 4,6′-diacetyl-3,3′-dmbp (1.13 g, 42.5%). (found C, 81.03; H, 6.71%; C18H18O2 requires C, 81.17; H, 6.81%). νmax (KBr) 1685 (C = O) cm−1 δ (CDCl3) 2.00 (s, 3 H, 3′-CH3), 2.39 (s, 3 H, 3-CH3), 2.56 (s, 6 H, 4-COCH3, 6′-COCH3), 7.14–7.29 (m, 4 H, aromatic H), 7.52 (d, J4′,5′ = 9 Hz, 1 H, H-5′), 7.71 (d, J5,6 = 9 Hz, 1 H, H-5). m/z 266 [M]+, 251 [base peak, M-CH3+, 209 [M-(CH3 + COCH3+, 164 [M-(2CH3 + COCH3)]+, 151 [M-(2CH3 + 2COCH3)]+, 118 [PhCOCH3+, 89 [PhCH3+, 76 [C6H4+, 43 [COCH3+.
A mixture of 4,4′-diacetyl-3,3′-dmbp (0.2 g; 0.007 mol), potassium hydroxide (1.0 g) and sodium hypochlorite (100 mL) was heated for 4 h. Additional quantities of hypochlorite solution (30 mL) were added to the mixture after 1, 2 and 3 h. After cooling, the solution was acidified with 50% HCl and the precipitate was extracted with ether (4 × 25 mL), washed with water then with dilute potassium hydroxide. The basic layer was separated, acidified with dilute HCl and a white precipitate was formed and filtered. The solid acid obtained was recrystallized from benzene which gave a white crystals of 3,3′-dmbp-4,4′-dicarboxylic acid. (0.09 g; 44.3%), mp 190°C(d). νmax (KBr) 1687 (C = O) and 3050 (OH) cm−1 (found C, 71.56; H, 5.28%; C16H14O4 requires C, 71.11; H, 5.19%). δ (CDCl3) 2.67 (s, 6 H, 3-CH3 and 3′-CH3), 7.25–7.67 (m, 4 H, aromatic H), 8.04 (d, J5,6 = 8.5 Hz, 2 H, H-5 and H-5′), 11.83 (s, 2 H, 4- and 4′-COOH exchangeable with D2O)
A mixture of 4,6′-diacetyl-3,3′-dmbp (0.2 g; 0.007 mol), potassium hydroxide (1.0 g) and sodium hypochlorite (100 mL) was heated for 5 h. Additional quantities of hypochlorite solution (30 mL) were added to the mixture after 1, 2, 3 and 4 h. After cooling, the solution was acidified with 50% HCl and the precipitate was extracted with ether (4 × 25 mL), washed with water then with dilute potassium hydroxide. The basic layer was separated, acidified with dilute HCl and a white precipitate was formed and filtered. The white solid obtained was recrystallized from ether/benzene which gave a white crystals of 3,3′-dmbp-4,6′-dicarboxylic acid. (0.076 g; 37.3%), mp >340°C (d). νmax (KBr) 1690 (C = O) and 3050 (OH) cm−1. Found C, 70.96; H, 5.30%; C16H14O4 requires C, 71.11; H, 5.19%). δ (CDCl3) 2.44 (s, 3 H, 3′-CH3), 2.62 (s, 3 H, 3-CH3), 7.15–7.70 (m, 5 H, aromatic H), 8.04 (d, J5,6 = 8.5 Hz, 1 H, H-5), 11.89 (s, 2 H, 4- and 6′-COOH exchangeable with D2O).
All calculations were carried out using the Gaussian 03 package [x86-Linux-G03RevB.05] of programs  installed on a PC cluster or the equivalent G03W suite of programs [version 6.1] installed on standard personal computers. The structure optimizations included the default or the gdiis procedures; geometrical constraints were not imposed. Thermochemical data at T = 298 K were obtained by frequency calculations. The conformational space for the compounds investigated is large and a number of local energy minima were detected. The conformational analysis in this study included the effects (i) the syn/anti orientation of the two methyl-substituted rings, (ii) the orientation of the carbonyl group relative to the plane of the aromatic ring to which it is attached and (iii) the orientation of the carbonyl group in the σ-complexes. Data are given only for the conformers that we have found to be of lowest energy. With respect to the orientation of the acetyl group relative to a neighboring methyl substituent we find that the conformation having the carbonyl oxygen atom pointing towards the methyl group is preferred in agreement with the results obtained by others .
Friedel-Crafts acetylation of 3,3′-dmbp by the Perrier addition procedure in which a solution of the substrate was added to a stirred solution of the preformed complex of acetyl chloride and aluminium chloride has been investigated in detail. At 25, 45°C and higher temperature (reflux conditions) with stoichiometric amounts of reagents, acetylations give 4-acetyl-3,3′-dmbp entirely with almost quantitative yield obtained in boiling 1,2-dichloroethane. In 1,2-dichloroethane at reflux conditions with a hydrocarbon:acetyl chloride:aluminium chloride molar ratio of 1:4:4 or 1:6:6 acetylation affords 4,4′- and 4,6′-diacetyl-3,3′-dmbp as the sole products. The mono- and diketones were subsequently converted to the corresponding 3,3′-dmbp dicarboxylic acids by hypochlorite oxidation. Two of the compounds, 4,6′-diacetyl-3,3′-dmbp and the dicarboxylic acid derived from this species are reported for the first time. The relative stability of the possible acetylation products as evaluated by DFT B3LYP 6–31 G(d,p) calculations indicates that the acetylations do not favor the formation of the most stable products and are under kinetic control.
Gore PH: Aromatic ketone synthesis. Friedel-Crafts and related reactions. Edited by: Olah GA. 1964, New York: Interscience Publ, 1-381.
Olah GA: Friedel-Crafts Chemistry. 1973, New York: Wiley Interscience
Olah GA, Reddy VP, Prakash GKS: Kirk-Othmer Encyclopedia of Chemical Technology. Volume 12. 2005, Hoboken: Wiley, 5
Heaney H: The Bimolecular Aromatic Friedel-Crafts Reaction. Comprehensive Organic Synthesis. Edited by: Trost BM, Fleming I. 1991, Oxford: Pergamon Press, 733-752.
Kurti L, Czako B: Strategic Applications of Named Reactions in Organic Synthesis. 2005, Burtington, MA: Elsevier Academic Press
Effenberger F, Maier AH: Changing the ortho/para ratio in aromatic acylation reactions by changing reaction conditions: a mechanistic explanation from kinetic measurements. J Am Chem Soc. 2001, 123: 3429-3433. 10.1021/ja0022066.
Csihony S, Mehdi H, Homonnay Z, Vértes A, Farkas O, Horváth IT: In situ spectroscopic studies related to the mechanism of the Friedel-Crafts acetylation of benzene in ionic liquids using AlCl3 and FeCl3. J Chem Soc Dalton Trans. 2002, 680-685.
Davlieva MG, Lindeman SV, Neretin IS, Kochi JK: Isolation, X-ray structures, and electronic spectra of reactive intermediates in Friedel-Crafts acylations. J Org Chem. 2005, 70: 4013-4021. 10.1021/jo0501588.
Meneses L, Fuentealba P, Contreras R: Relationship between the electrophilicity of substituting agents and substrate selectivity in Friedel-Crafts reactions. Tetrahedron. 2005, 61: 831-836. 10.1016/j.tet.2004.11.038.
Sartori G, Maggi R: Use of solid catalysts in Friedel-Crafts acylation reactions. Chem Rev. 2006, 106: 1077-1104. 10.1021/cr040695c.
Titinchi SJJ, Kamounah FS, Abbo HS: Preparation of mono- and diacetyl 4,4′-dimethylbiphenyl and their corresponding carboxylic acids: Reactivity, selectivity and isomer distribution studies via Lewis acid catalyzed Friedel-Crafts acetylation/oxidation. J Mol Catal A. 2007, 273: 169-176. 10.1016/j.molcata.2007.03.069.
Levy L, Pogodin S, Cohen S, Agranat I: Reversible friedel-crafts acylations of phenanthrene: Rearrangements of acetylphenanthrenes. Lett Org Chem. 2007, 4: 314-318. 10.2174/157017807781212120.
Titinchi SJJ, Kamounah FS, Abbo HS, Hammerich O: The synthesis of mono-and diacetyl-9 H-fluorenes. Reactivity and selectivity in the Lewis acid catalyzed FriedelCrafts acetylation of 9 H-fluorene. ARKIVOC. 2008, 13: 91-105.
Mala’bi T, Pogodin S, Agranat I: Reversible Friedel-Crafts acylations of anthracene: Rearrangements of acetylanthracenes. Lett Org Chem. 2009, 6: 237-241. 10.2174/157017809787893118.
Yamabe S, Yamazaki S: A remarkable difference in the deprotonation steps of the Friedel-Crafts acylation and alkylation reactions. J Phys Org Chem. 2009, 22: 1094-1103. 10.1002/poc.1564.
Sartori G, Maggi R: Advances in Friedel-Crafts Acylation Reactions: Catalytic and Green Processes. 2010, Boca Raton: CRC Press
Olah GA, Kobayashi S: Aromatic substitution. XXIX. Friedel-Crafts acylation of benzene and toluene with substituted acyl halides. Effect of substituents on substrate and positional selectivity. J Am Chem Soc. 1971, 93: 6964-6967. 10.1021/ja00754a045.
Andreou AD, Bulbulian RV, Gore PH: Friedel-Crafts acetylation of durene, isodurene and prehnitene. Tetrahedron. 1980, 36: 2101-2104. 10.1016/0040-4020(80)80098-6.
Tan LK, Brownstein S: Equilibria and reactions in the systems aluminum chloride-acetyl chloride-aromatic hydrocarbon in sulfur dioxide as solvent. J Org Chem. 1983, 48: 302-306. 10.1021/jo00151a005.
Brown HC, Marino G: Rate data and isomer distributions in aluminum chloride-catalyzed acetylation and benzoylation of biphenyl and fluorene in ethylene dichloride. J Am Chem Soc. 1962, 84: 1236-1238. 10.1021/ja00866a034.
Andreou AD, Bulbulian RV, Gore PH, Kamounah FS, Miri AY, Waters DN: The Friedel-Crafts acetylation of naphthalene. Evidence for concurrent second- and third-order reactions. J Chem Soc Perkin Trans. 1981, 2: 376-378.
Gore PH: The Friedel-Crafts acetylation of naphthalene. Z Phys Chem. 1988, 159: 123-128. 10.1524/zpch.1988.159.Part_1.123.
Dowdy D, Gore PH, Waters DN: The Friedel-Crafts acetylation of naphthalene in 1,2-dichloroethane solution. Kinetics and mechanism. J Chem Soc Perkin Trans. 1991, 2: 1149-1159.
Gore PH, Thadani CK: Formation of mono- and diketones in the Friedel-Crafts acetylation of anthracene. J Chem Soc C: Org. 1966, 1729-1733.
Perin F, Croisy-Delcey M, Jacquignon P: Friedel-Crafts polycyclic aromatic hydrocarbon acylation reactions. IX. Acetylation of anthracene and its meso-methyl homologs. Can J Chem. 1976, 54: 1777-1788. 10.1139/v76-253.
Girdler RB, Gore PH, Thadani CK: The Friedel-Crafts acetylation of phenanthrene. J Chem Soc C: Org. 1967, 2619-2624.
Minabe M, Takeshige S, Soeda Y, Kimura T, Tsubota M: Electrophilic substitution of monosubstituted pyrenes. Bull Chem Soc Jpn. 1994, 67: 172-179. 10.1246/bcsj.67.172.
Gore PH, Kamounah FS, Miri AY: Friedel-Crafts acetylations of two benzophenanthrenes. A study of relative rates of substitution of naphthalene, phenanthrene, chrysene, and triphenylene. J Chem Res (Synopses). 1980, 40: 0530-0548.
Al-Ka’bi J, Gore PH, Moonga B, Al-Shiebani IS, Shibaldain NL, Kamounah FS: The Friedel-Crafts acylation of 1-methoxy-3,5-dimethylbenzene and the kinetics of protiodeacylation of the ketones thus obtained. J Chem Res (Synopses). 1986, 246-247.
Kamounah FS, Titinchi SJJ: 1 H-NMR study of some new acetyl dimethylbiphenyls: unambiguous signal assignment for the methyl groups. Spectroscopy. 1997, 13: 125-129. 10.1155/1997/316271.
Tobolsky AV, Samulski EJ: Solid ‘liquid-crystalline’ films of synthetic polypeptides. New state of matter. Adv Chem Phys. 1971, 21: 529-535.
Shiotani A, Washio K: Preparation of polyamides containing para-linked dimethylbiphenylene moieties. J Appl Polym Sci. 1998, 68: 847-853. 10.1002/(SICI)1097-4628(19980502)68:5<847::AID-APP16>3.0.CO;2-N.
Kim J-H, Kimura M, Higashi F: Thermotropic copolyamides from triethylene glycol bis(4-carboxyphenyl) ether and o-tolidine modified by kinking monomers. J Polym Sci A Polym Chem. 1999, 37: 363-368. 10.1002/(SICI)1099-0518(19990201)37:3<363::AID-POLA14>3.0.CO;2-A.
Kettunen M, Vedder C, Brintzinger H-H, Mutikainen I, Leskela M, Repo T: Alternative coordination modes in palladium(II)-diimino-bispyridine complexes with an axially chiral biphenyl backbone. Eur J Inorg Chem. 2005, 1081-1089.
Cook JW: Polycyclic aromatic hydrocarbons. IV. Condensed derivatives of 1,2-benzanthracene. J Chem Soc. 1931, 499-507.
Dovgosheya MI, Krasovitskii BM: Some biphenyl derivatives as vinyl monomers. Zhur Org Khim. 1966, 2: 1288-1291.
Kotlyarevskii IL, Shvartsberg MS, Volgina GI, Vasilevskii SF: Synthesis of acetylene derivatives of diphenyl oxide and metabitolyl. Izv Akad Nauk SSSR Ser Khim. 1965, 1704-1706.
de la Mare PBD, Hall DM, Harris MM, Hassan M, Johnson EA, Klassen NV: The kinetics and mechanisms of aromatic halogen substitution. XIV. Rates and products of chlorination of methyl-substituted biphenyls in acetic acid. J Chem Soc. 1962, 3784-3796.
Wirth HO, Königstein O, Kern W: Iodination of aromatic compounds with iodine and iodic acid. Justus Liebigs Ann Chem. 1960, 634: 84-104. 10.1002/jlac.19606340109.
Kortekaas TA, Cerfontain H: Aromatic sulfonation. Part 66. Sulfonation of some biphenyl derivatives. J Chem Soc Perkin Trans II:Phys Org Chem. 1979, 224-227. 10.1039/P2979000022.
Clark JH, Miller JM: Hydrogen bonding in organic synthesis. Part 6. Intermolecular self-condensation of some enolisable ketones in the presence of fluoride. J Chem Soc Perkin Trans1:Org Bio-Org Chem. 1977, 2063-2069. 10.1039/P19770002063.
Kamounah FS, Al-Sheibani I, Shibaldain NL, Salman SR: Proton magnetic resonance studies of substituted 3,5-dimethylbenzenes: influence of substituents on the methyl proton chemical shifts. Magn Reson Chem. 1985, 23: 521-523. 10.1002/mrc.1260230707.
Jackman LM, Sternhell S: Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry. 1969, Oxford: Pergamon Press, 546-2
Fiedler P, Exner O: Conformation of aromatic carbonyl derivatives: an infrared study. Collect Czech Chem Commun. 2004, 69: 797-810. 10.1135/cccc20040797.
Tan LK, Brownstein S: Initial products in Friedel-Crafts reactions. J Org Chem. 1983, 48: 3389-3393. 10.1021/jo00168a005.
Maier JP, Turner DW: Steric inhibition of resonance studied by molecular photoelectron spectroscopy. 1. Biphenyls. Faraday Disc Chem Soc. 1972, 54: 149-167.
Modelli A, Distefano G, Jones D: Application of electron transmission spectroscopy to conformational studies: electron affinities of methyl-substituted biphenyls. Chem Phys. 1983, 82: 489-492. 10.1016/0301-0104(83)85253-7.
Dynes JJ, Baudais FL, Boyd RK: Inter-ring dihedral angles in polychlorinated biphenyls from photoelectron spectroscopy. Can J Chem. 1985, 63: 1292-1299. 10.1139/v85-220.
Roberts RMG: Conformational analysis of biphenyls using carbon-13 NMR spectroscopy. Magn Res Chem. 1985, 23: 52-54. 10.1002/mrc.1260230114.
Bates RB, Camou FA, Kane VV, Mishra PK, Suvannachut K, White JJ: Preparations and reactions of symmetrical dimethylenebiphenyl dianions; conformations of [O.n]-o-cyclophanes. A simple NMR method for determining twist angles in biphenyls. J Org Chem. 1989, 54: 311-317. 10.1021/jo00263a011.
Wallace KJ, Hanes R, Anslyn E, Morey J, Kilway KV, Siegel J: Preparation of 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene from two versatile 1,3,5-tri(halo-substituted) 2,4,6-triethylbenzene derivatives. Synthesis. 2005, 12: 2080-2083.
Cadogan JIG, Molina GAA: Simple and convenient deamination of aromatic amines. Org Bio-Org Chem: J Chem Soc Perkin Trans I. 1973, 541-542.
Shoesmith JB, Slater RH: Polarity effects in the isomeric α-bromoxylenes and isomeric iodotoluenes. J Chem Soc. 1924, 125: 2278-2283.
Kornblum N, Kendall DL: The use of dimethylformamide in the Ullmann reaction. J Am Chem Soc. 1952, 74: 5782-10.1021/ja01142a518.
Ehmer A, Jahr K, Kuschinsky G, Luellmann H, Mutschler E, Wollert U: Cardiac activity of simple bis(guanylhydrazones). Arzneimittel-Forschung. 1964, 14: 1273-1277.
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA: Gaussian 03, version Revision B.05. 2004, Wallingford CT: Gaussian, Inc
Boehm S, Gal J-F, Maria P-C, Kulhánek J, Exner O: Steric effects in isolated molecules: gas-phase basicity of methyl-substituted acetophenones. Eur J Org Chem. 2005, 2580-2588.
Prof. Stephan P. Sauer is gratefully acknowledged for giving us access to the computer cluster at which most of the DFT calculations were carried out. University of the Western Cape is gratefully acknowledged for the article-processing charge.
The authors declare that they have no competing interests.
ST contributed to the findings and experimental part of the manuscript. FK contributed in the characterization of the compounds and contributed to the findings and experimental part of the manuscript. HA carried out the experimental work. OH carried out the computational work and contributed to the findings part the manuscript. All authors read and approved the final manuscript.
Electronic supplementary material
Additional file 1: Scheme S1. Illustrations of the AlCl3 complexes of the ketones. Table S1. Total energies, Gibbs free energies (298 K) and structural properties for the AlCl3 complexes, x-AcAlCl3, of the monoacetyl isomers. Table S2. Total energies, Gibbs free energies at (298 K) and structural properties for the 1:1 AlCl3 complexes, 4-AcAlCl3,y′-Ac and 4-Ac,y′-AcAlCl3, of the acetyl substituted 4-acetyl-3,3′-dimethylbiphenyls. Table S3. Total energies, Gibbs free energies at (298 K) and structural properties for the 1:2 AlCl3 complexes, 4,y′-diAcAlCl3, of the four acetyl substituted 4-acetyl-3,3′-dimethylbiphenyls. Scheme S2. Illustrations of the AlCl3 complexed σ-complexes. Table S4. Total energies, E, Gibbs free energies at 298 K, G298, and structural properties for the AlCl3 complexed σ-complexes, x-AcAlCl3,x-H+. Table S5. Total energies, E, Gibbs free energies at 298 K, G298, and structural properties for the 1:1 AlCl3 complexed σ-complexes, 4-AcAlCl3,y′-Ac,y′-H+ and 4-Ac,y′-AcAlCl3,y′-H+. Table S6. Total energies, E, Gibbs free energies at 298 K, G298, and structural properties for the 1:2 AlCl3 complexed σ-complexes, 4-AcAlCl3,y′-AcAlCl3,y′-H+. (DOCX 106 KB)
About this article
Cite this article
Titinchi, S.J., Kamounah, F.S., Abbo, H.S. et al. A reactivity-selectivity study of the Friedel-Crafts acetylation of 3,3′-dimethylbiphenyl and the oxidation of the acetyl derivatives. Chemistry Central Journal 6, 52 (2012). https://doi.org/10.1186/1752-153X-6-52
- Friedel-Crafts reaction
- Carboxylic acids
- DFT calculations