Acylation Reactions under Microwaves. 3. Aroylation of Benzene and

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Acylation Reactions under Microwaves. 3. Aroylation of Benzene and Its Slightly Activated or Deactivated Derivatives1 Julien Marquie´ , Christian Laporte, Andre´ Laporterie, and Jacques Dubac* Universite´ Paul-Sabatier, He´ te´ rochimie Fondamentale et Applique´ e (U.M.R. 5069-C.N.R.S.), 118 route de Narbonne, 31062 Toulouse Cedex, France

Jean-Roger Desmurs and Nicolas Roques Rhodia Organique Fine, Centre de Recherche de Lyon, 85 Avenue des Fre` res-Perret, 69192 Saint-Fons Cedex, France

Solvent-free aroylation of benzene and its slightly activated or deactivated derivatives has been carried out under microwave (MW) irradiation, in the presence of iron(III) chloride which, in these conditions, shows better activity than other metallic chlorides (in particular, AlCl3). With the more reactive and/or nonvolatile reagents (naphthalene, mesitylene, p-xylene, ethylbenzene, and cumene), expeditious conditions (constant MW power and short reaction time without temperature control) have been used. With the less reactive and/or low-boiling reagents (benzene, toluene, and fluoro-, chloro-, and m-dichlorobenzene), the rise in temperature and the lengthening of the reaction time have been controlled by sequential MW irradiations. MW has preferential interactions with polar species involved in the reaction, the aroyl chloride and the aryl ketone, especially with their FeCl3-complexed forms. However, a MW nonthermal effect has not been observed when identical temperature gradients are produced by classical heating and MW irradiation, either for the yield or for the regioselectivity of the reaction. 1. Introduction The Friedel-Crafts (FC) acylation reaction,2 main route to aromatic ketones, is a self-blocking reaction. The formation of a stable complex between the aryl ketone and the activator imposes the use of the latter in at least stoichiometric amounts. Consequently, carrying out such a reaction on an industrial scale generates considerable waste. The search for catalytic conditions has instigated numerous works, particularly in the use of Lewis acids (LA) such as FeCl3,3 ZnCl2,4 BiCl3,5 or other metallic chlorides,6 of Bro¨nsted acids, like superacidic systems7 or sulfonic acids,8 more specifically trifluoromethanesulfonic (triflic) acid,8a and zeolites.9 A nonexhaustive listing of catalysts could also include LA-lithium or silver salt mixtures.10 However, the greater part of these catalysts are efficient only for the acylation of activated aromatics (ethers and alkylbenzenes). More recently, a new generation of catalysts has been discovered: the metallic triflates11-13 and their nitrogenous analogues, the bistrifluoromethanesulfonimides.14 Bismuth(III) triflate13 and that of hafnium(IV) in the presence of lithium perchlorate15a,b or triflic acid15c are the more efficient ones and allow the acylation of benzene, toluene, and halobenzenes. Bromopentacarbonylrhenium(I) leads to the acylation of toluene in good yields.16 In the course of these works, aryl ketone-LA decomplexation is sometimes thermally possible, which allows the development of a catalytic cycle. This observation led us to carry out the FC acylation by MW heating, * To whom correspondence should be addressed. E-mail: [email protected]. Phone: (33) 5 61 55 65 57. Fax: (33) 5 61 55 82 04.

first on a graphite support.17 Catalytic activity of metal inclusions of graphite, more particularly those that are iron-based, has been shown.17b Some other works concerning FC acylation-type reactions under MW irradiation have been reported: clay-supported synthesis of quinones18a,b or acridones;18c alumina-supported acylation of aromatics by carboxylic acids;18d Fries rearrangement in the presence of more than stoichiometric amounts of AlCl3.18e Owing to the high polarity of aryl ketone-LA complexes (µ ) 7-9 D for LA ) AlX3, X ) Cl, Br)19 which must absorb MW preferentially to the weakly polar reagents and then give the decomplexation of the catalyst, we have tackled a systematic study of the FC acylation under MW.20 In the previous part,1 we have shown that the MW-LA coupling, especially MWFeCl3, is an efficient process to carry out the acylation of aromatic ethers. Examining the thermal behavior of the MW-benzoylation of anisole, we have observed that the T-profiles are quite different according to the activity of the catalyst. Effectively, the absorption of MW energy by chemical species involved in the reaction is differentiated, the outbreak of methoxybenzophenone, and particularly its FeCl3 complex, being responsible for the starting up of a strong T-gradient leading to an enhancement of the reaction rate. We present here the third part of this study which concerns the acylation of benzene and its slightly activated or deactivated derivatives. At first, the suitable experimental conditions for these reactions, realized in an open reactor, will be searched. Then, the behavior under MW of each chemical species involved will be studied. For typical reactions, considering the rate and the selectivity, a comparison between classical and MW heatings will also be done.

10.1021/ie9908884 CCC: $19.00 © 2000 American Chemical Society Published on Web 04/13/2000

Ind. Eng. Chem. Res., Vol. 39, No. 5, 2000 1125 Table 1. Benzoylation of Toluene (2) under Microwave Irradiationa entry

catalyst (mol %)b

conditionsc

conversionf/yieldg into ketone 18

isomersf o/m/p

1 2 3 4 5 6 7 8 9 10

FeCl3 (10) FeCl3 (10) AlCl3 (10) GaCl3 (10) ZrCl4 (10) FeCl3 (5) GaCl3 (10) AlCl3 (10) AlCl3 (40) ZrCl4 (10)

120 W; 1 mind 120 W; 4 mind 120 W; 1 mind 120 W; 1 mind 120 W; 1 mind 300 W; 20 s × 15 (100 s)e 120 W; 1 min × 10 (1 min)e 300 W; 20 s × 15 (40 s)e 20 s × 15 (40 s)e 120 W; 1 min × 10 (30 s)e

36%f 75%f 8%f 30%f 11%f 90%g 50%g 12%g 43%g 21%g

13/3/84 16/4/80 8/3/89 12/3/85 12/4/84 12/3/85 13/3/84 10/3/87 9/2/89 12/4/84

a 2, 40 mmol; 11, 10 mmol. b Catalyst/11. c Applied incident power (W), irradiation time (t), and period between two irradiations (∆t) in the case of sequential irradiations. d Continuous MW irradiation (111 °C e Tmax e 123 °C). e Sequential MW irradiation (117 °C e Tmax e 125 °C); these conditions have been optimized for each reaction. f GC analysis. g Yield in isolated product with respect to 11; following halides used as catalysts gave only a trace of ketone 18: ZnCl2, YCl3, RuCl3, InCl3, SbCl3, LaCl3, CeCl3, SmCl3, YbCl3, BiCl3; 80 °C e Tmax e 89 °C.

Scheme 1. Starting Compounds

Scheme 2. Acylation Products

2. Results and Discussion 2.1. Acylation of Benzene and Toluene. At the time of the benzoylation of anisole under MW, we have observed the catalytic superiority of several Lewis acids: iron, gallium, aluminum, bismuth, zirconium, and indium chlorides.1 The same study has been carried out with toluene (2) under continuous MW irradiation (120 W; 1 min) (Table 1) (Schemes 1and 2). The benzoylation of 2 is more difficult than that of anisole and the discrimination of catalysts more selective: in the above irradiation conditions only iron and gallium chlorides

led to methylbenzophenone (18) in equal or better than 30% yield. A rise in the MW irradiation time (4 min) provoked an appreciable change of yield (Table 1, entry 2). Two reasons can explain these results: 2 is an arene less activated than anisole (σp+(OMe) ) -0.78; σp+(Me) ) -0.31)21 and more volatile. Consequently, for a temperature close to the bp of 2, the reaction time must be rather long. Effectively, a mixture of 2, 11, and FeCl3 (40/10/1 mmol) introduced into an oil bath at 120 °C led to the ketone 18 in 75% yield after 50 min and in 92% yield after 2.5 h. Two solutions are possible for overcoming the restricting factor of the vaporization of toluene, and a fortiori of benzene: (i) to raise the pressure and to work in a closed reactor; (ii) to control the temperature of the reaction and to increase irradiation time. Despite the formation of gas (HCl) the acylation (by RCOCl) of arenes is possible in an autoclave,3c but the MW technology does not allow safely control of such a process.22 So sequential MW irradiations with controlled temperature have been envisaged to carry out the benzoylation of toluene and benzene. In the presence of only 5 mol % of FeCl3, a 90% yield in ketone 18 has been obtained for a 5-min irradiation time and an overall reaction time of 30 min (Table 1, entry 6). GaCl3 and ZrCl4 were less efficient, whereas AlCl3 gave a yield corresponding to its stoichiometry. The p-18 isomer was always the major one with respect to the o-isomer. Successfully, the same process was

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Table 2. Acylation of Benzene (1) under Microwave Irradiationa entry

acylating reagent

P

1 2

11 12

300 W 300 W

3

13

300 W

conditionsb,c t 15 s × 25 1 min × 4 + 30 s × 10 + 15 s × 12 1 min × 3 + 30 s × 10 + 15 s × 12

∆t

product and conversiond

45 s 15, 72% (61)e 1 min 16f, 84% (75)e 30 s 45 s 1 min 17g, 91% (83)e 30 s 45 s

a 1, 40 mmol; 11, 20 mmol; 12 or 13, 10 mmol; catalyst FeCl , 3 1.6 mmol (entry 1), 0.8 mmol (entry 2), and 0.5 mmol (entry 3). b See Table 1, footnote c. c 110 °C e T d max e 135 °C. Conversion with respect to the acylating reagent calculated by GC. e Yield in isolated product. f 4-Nitrobenzophenone. g 2-Chlorobenzophenone.

Table 3. Aroylation of Arenes 3-10 under Microwave Irradiationa entry arene 1 2 3 4 5 6 7 8 9

3 4 5 6 7 7 7 7 8

10

8

11

8

12 13 14 15

9 9 9 10

conditionsb 120 W; 4 minc 120 W; 5 minc 300 W; 3 minc 300 W; 3 minc 300 W; 1 minc 160 °C; 1 mind 160 °C; 5 mind 160 °C; 20 mind 300 W; 1 min × 1 (1 min) + 30 s × 2 (30 s) + 15 s × 19 (45 s)e 300 W; 3 min × 1 (1 min) + 2 min × 2 (1 min) + 1 min × 5 (1 min)e 300 W; 1.5 min × 1 (1 min) + 30 s × 4 (1 min) + 15 s × 22 (1 min)e 300 W; 4 minc 130 °C; 30 mind 300 W; 30 s × 15 (30 s)e 300 W; 2 min + 1 min × 14 (1 min)e

product and conversionf isomersf 19, 68% (59)g 20, 52% (45)g 24, 85% (76)g 25, 99% (90)g 27, 90% (82)g 27, 70% 27, 86% 27, 82% 21, 65% (57)g

9/5/86h 6/1/93h 67/33i 68/32i 68/32i 64/36i pj

22, 65% (54)g pj 23, 92% (85)g pj 17, 19% pj 17, 22% pj 17, 72% (62)g pj 26, 60% (50)g

a Arene, 40 mmol; acylating agent, 10 mmol (entries 1-4, 9-15); arene and acylating agent, 10 mmol (entries 5-8); FeCl3, 1 mmol; acylating agent, 11 (entries 1-9, 12-15), 12 (entry 10), and 13 (entry 11). b See Table 1, footnote c. c Continuous MW irradiation. d Irradiation controlled to a maximum temperature of 160 °C (entries 6-8) or 130 °C (entry 13). e Sequential MW irradiation. f GC analysis. g Yield in isolated product. h o/m/p isomers. i R-/ β-naphthophenone. j p-Isomers: 4-fluorobenzophenone (entry 9), 4-fluoro-4′-nitrobenzophenone (entry 10), 2-chloro-4′-fluorobenzophenone (entry 11), and 4-chlorobenzophenone (entries 12-14) g 95%.

applied for the benzoylation of benzene (Table 2). The yields obtained (61-83%) with the three acylating reagents, 11-13, were similar to those achieved by classical heating in an autoclave for several hours.3c 2.2. Acylation of Other Arenes. With respect to an acylation reagent, ethylbenzene (3) and cumene (4) have a reactivity a little below that of toluene (2) (σp+(Et) ) -0.30; σp+(iPr) ) -0.28)21 and, like 2, the dipole moment of these molecules is weak (0.2-0.4 D).19 The benzoylation of 3 and 4 has been carried out with good conversion by continuous MW irradiation of 120 W for 4 and 5 min, respectively (Table 3, entries 1 and 2). Despite a boiling point higher than that of 2, the overall conversions of 3 and 4 (o-, m-, and p-isomers of 19 and 20) were weaker, owing to the steric hindrance of the ortho position, especially for 4. The paraxylene (5), the less reactive xylene, and 2 have similar benzoylation rate constants,23 but 5 has a

higher boiling point and permits a stronger MW irradiation. A continuous irradiation of 300 W for 3 min led to ketone 24 with a high conversion (85%) (Table 3, entry 3). The mesitylene (6) is much more reactive than 2,23 and its benzoylation under 300 W was very fast and quantitative (Table 3, entry 4). Figure 1 shows the T ) f(MW irradiation time) curves for the benzoylation reactions of alkylbenzenes 2-6. The benzoylation of naphthalene (7) has been carried out under MW in the presence of 10 mol % of FeCl3 according to two processes: either the expeditious way (irradiation of 300 W for 1 min) or at a controlled temperature (Tmax ) 160 °C) (Table 3, entries 5-8). The expeditious process proved more efficient (entry 5), avoiding a lengthy stay at a high temperature, which can lead to a loss in yield (entry 8). In any case, the reaction gave the predominant formation of R-naphthophenone (R-27), the kinetic product.24 Halobenzenes 8 and 9 have a dipole moment (1.40 and 1.50 D, respectively)19 higher than that of anisole and are good MW absorbers. Fluorobenzene (8) is slightly activated (σp+(F) ) - 0.07)21 but volatile, its bp being close to that of benzene. The experimental conditions of MW heating (by sequential irradiation) used for these two arenes were similar (Tables 2 and 3, entries 9-11). Chlorobenzene (9) has a bp (132 °C) higher than that of 8, but it is a deactivated arene (σp+(Cl) ) 0.11).21 Benzoylation of 9 by MW irradiation of 300 W for 4 min or at 130 °C for 30 min (Table 3, entries 12,13) gave low yields. In contrast, the use of the stoichiometric ratio of reagents connected to a sequential MW irradiation leads to an increase in the yield (Table 3, entry 14). Under similar conditions, the benzoylation of m-dichlorobenzene (10) has been carried out in good yield (Table 3, entry 15). 2.3. Behavior under MW Irradiation of Various Chemical Species Involved in the Benzoylation Reaction of Arenes. Concerning thermodynamic aspects, FC acylation is a borderline reaction for which the reaction enthalpy is very weak.25 The reactions studied here have been carried out solvent-free but with an excess of arene; consequently, ∆Hr has an insignificant effect on the T-profiles of reactions. Figure 1 reports the thermal behavior under MW of FeCl3-catalyzed benzoylation of alkylbenzenes 2-6. These curves show a strong raising of temperature between 5 and 45 s of MW irradiation. For 5 and 6, the most reactive and the least volatile of the studied alkylbenzenes, ∆T ) 112 and 130 °C, respectively. We will demonstrate that the absorption of MW energy by the chemical species involved in the benzoylation of an alkylbenzene, the p-xylene (5), is very differentiated and will show that the aryl ketone 24 formed, especially its complex with FeCl3, strongly absorbs the MW energy. Three mixtures have been irradiated at 300 W for 1 min: mixture A, 5/11 ) 40:10 mmol; mixture B, 5/24 ) 30:10 mmol; mixture C, 5/24/FeCl3 ) 30:10:1 mmol. Mixture A corresponds to the initial reaction conditions (without catalyst), while mixture C corresponds to the final product. The mixture A heated (∆T25s ) 53 °C) with a gradient δT0-25s ) 2.2 °C s-1. Mixtures B and particularly C gave the strongest gradients: ∆T25s ) 69 °C, δT0-25s ) 2.7 °C s-1 and ∆T25s ) 96 °C, δT0-25s ) 3.8 °C s-1, respectively. The T ) f(MW irradiation time) curves (Figure 2) are similar to those observed with anisole-based mixtures.1 However, 5 being nonpolar, contrary to anisole, T-rises (∆T) and T-gradients (δT)

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Figure 1. Thermal behavior of the benzoylation of alkylbenzenes 2-6 (arene/11 ) 40:10 mmol) in the presence of FeCl3 (1 mmol) under MW irradiation of 120 W (2-4) or 300 W (5 and 6).

Figure 2. Thermal behavior of various mixtures A (5/11 ) 40:10 mmol), B (5/24 ) 30:10 mmol), and C (5/24/FeCl3 ) 30:10:1 mmol) under MW irradiation of 300 W for 1 min.

are lower, but the differentiation between the three curves (A, B, C) is still more clear-cut. So the presence

of the polar ketone 24 in B and that of its FeCl3complexed form in C are responsible for the strong

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gradients observed. This type of coordination complex between an aryl ketone and FeCl3 is well-known, and an XRD-crystallographic analysis for one of them has been reported.3b Despite the weak proportion of this complex in mixture C (2.5 mol %), the difference of the T-gradients between B and C is clear. Another experimental series significant to MW absorption by complexes of this type have been carried out for 2-methylbenzophenone (o-18). Two samples, one of these pure ketone and the other of these being ketone in the presence of FeCl3 (10 mol %), have been subjected to MW irradiation of 60, 120, and 195 W for 1 min. The observed temperature differences between these two samples were 23, 40, and 60 °C, respectively, stronger T-gradients being obtained with the o-18 + FeCl3 mixture which reached 130, 210, and 260 °C, respectively, at the end of the MW irradiation. A second polar complex is also present in the reaction medium, 11‚FeCl3. However, in the presence of an acid chloride and a ketone, the complexation of FeCl3 with ketone is prominent.26 But, at the beginning of the reaction, the amount of 11 is much higher than that of ketone, and at this moment, the contribution of the 11‚FeCl3 complex must be considered. So the following mixtures have been irradiated: mixture D, S/11/ FeCl3 ) 40/10/1 mmol; mixture E, S′/24/FeCl3 ) 40:10:1 mmol. S and S′ are nonvolatile solvents, dodecane and 1,4-diisopropylbenzene, respectively, which do not absorb (or little)1 the MW energy. Under 300 W for 1 min, mixture D reached 128 °C, whereas mixture E reached 174 °C. These experiments led to the conclusion that a stronger affinity exists in an FeCl3-aryl ketone complex compared to an FeCl3-aroyl chloride one, toward the MW radiation. Consequently, at the time of MW irradiation of an FeCl3-catalyzed FC benzoylation involving nonpolar or weak polar arenes, the temperature increase (Figure 1) is due to the aroyl chloride and its FeCl3 complex at the beginning of the reaction and to the aryl ketone and its FeCl3 complex when it appears in the reaction medium. Concerning the difference of activity of catalysts in the FC acylation, the literature includes many examples.2,3a,5b,12,13b However, it seems that this discrimination is more pronounced under MW, especially for the expeditious process. For example, some metallic chlorides such as AlCl3 or BiCl3 are efficient for the acylation of the anisole,1 but inefficient for that of toluene (Table 1), while FeCl3 is efficient in all cases (Tables 1-3). In light of the above discussion, these differences in catalytic activity of Lewis acids are not surprising. In addition to the difference in intrinsic activity, the selectivity of their complexation (with the aroyl chloride or the aryl ketone)26 and the differentiated MW absorption by their respective complexes also must be taken into account. The question posed at this point is to know if the absorbed MW energy can induce effects other than purely thermal effects. 3. Comparison between Classical and MW Heatings. FeCl3-Catalyzed Benzoylation of Paraxylene (5) and Naphthalene (7) The two heat treatments, classical (or thermal) and MW, have been applied to the FeCl3-catalyzed benzoylation of 5 and 7 to characterize the possible influence of the heating mode on the reaction rate and regioselectivity. The temperature evolution of a reaction under

Table 4. Benzoylation of Paraxylene (5) and Naphthalene (7) under Microwave Field and Classical Heatinga entry

arene

heating modeb

reaction time

product and conversionc

isomersd

1 2 3 4 5 6 7 8

5 5 5 5 7 7 7 7

TH MW TH MW TH MW TH MW

6 min 6 min 12 min 12 min 5 min 5 min 10 min 10 min

24, 70% 24, 72% 24, 94% 24, 93% 27, 86% 27, 86% 27, 85% 27, 85%

73/27 68/32 70/30 63/37

a 5, 200 mmol; 11, 50 mmol; FeCl , 5 mmol; 7, 10 mmol; 11, 10 3 mmol; FeCl3, 1 mmol. b TH, immersion of the reactor into an oil bath first heated and kept at 160 °C with recording of the temperature evolution by the computer; MW, controlled microwave irradiation with reproduction of the TH profile of temperature up to 160 °C. c Conversion calculated by GC. d R-27/β-27 from GC.

thermal heating has been recorded with a computer, and then the same temperature profile has been reproduced with a suitable MW irradiation. The benzoylation of paraxylene (5) has been carried out using an oil bath thermostated at 160 °C and the temperature evolution reproduced by MW irradiation. After 6 and 12 min, the conversions into ketone 24 were unrelated to the heating mode (Table 4). Concerning the benzoylation of naphthalene (7) the results were also the same, whatever the heating mode, both for yields and isomer ratios R-27/β-27 (Table 4). Consequently, the MW energy absorbed by the polar species is wholly converted into thermal energy which remains responsible for the activation of the reaction. This result is in agreement with recent conclusions concerning the influence of MW on the kinetics of organic reactions in homogeneous media.27 However, specific effects of MW have been observed under heterogeneous conditions,22c for example, at the time of reactions on mineral supports,28 of saponification of esters29 or still of enzymatic catalysis in dry media.30 4. Limitations The catalytic alkanoylation of activated aromatics, for example, the acetylation, is known, in particular in the presence of FeCl3.3b However, the product of this reaction, the arylalkyl ketone, is difficult to obtain due to side reactions involving its alkyl chain.3b We have carried out the FeCl3-catalyzed acylation of aromatic ethers by carboxylic acid halides or anhydrides under MW irradiation with good yield.1 In contrast, the alkanoylation of benzene or toluene by these reagents in the presence of FeCl3, under MW irradiation, does not give the expected ketones with a convenient yield. For example, the action of isobutyryl chloride (14) on the benzene under a sequential MW irradiation (300 W; 12 × 15 s; ∆t ) 45 s), leads to a trace of isobutyrophenone (28) and 14% of the chlorinated product 30. With toluene, from the same acylating reagent and under similar MW irradiation (300 W; 12 × 20 s; ∆t ) 40s), methylisobutyrophenone (o-29/p-29 ) 5/95) was the main product (24% yield), but product 31 has also been

identified (19%). These R-chlorostyrenes, already observed under thermal effects, in particular, in the case

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of the acylation of mesitylene by the isobutyryl chloride,31 could form from enolizable ketones 28 and 29 in the simultaneous presence of FeCl3 and HCl. 5. Conclusion Solvent-free aroylation reactions of aromatic hydrocarbons and halides have been performed under MW irradiation. Expeditious conditions, that is, in short reaction time and without temperature control, have been used with the more reactive and/or nonvolatile reagents (naphthalene, mesitylene, p-xylene, ethylbenzene, and cumene). For the less reactive and/or lowboiling reagents (benzene, toluene, and fluoro-, chloro-, and m-dichlorobenzene), sequential MW irradiations were applied to control the rise in temperature and to lengthen the irradiation time. As for the acylation of aromatic ethers,1 good yields have been obtained in the presence of small amounts of iron(III) chloride which appeared as a very efficient catalyst for FC acylation under MW heating. In that respect, preferential interactions of the MW radiation with polar species involved in the reaction, the aroyl chloride and the aryl ketone produced, especially with their high polar FeCl3-complexed forms, have been proved. When identical Tgradients are produced by classical heating and MW irradiation for the FeCl3-catalyzed benzoylation reactions of p-xylene (5) and naphthalene (7), no particular effect is observed on the reaction rate and on the regioselectivity. However that may be, the acylation of arenes under MW heating presents the characteristics of an economical energy process able to perform clean reactions in reduced time. Moreover, the MW technology having progressed, it is possible to exercise a temperature control of reaction media that allows work in an open reactor and preservation of the stability of products. In FC acylation, a polar solvent is often used to solubilize the metal halide or its complexes. In our experiments, the catalyst is present in only 5-10%. Therefore, a polar solvent is not necessary and the aromatic substrate can replace it. In such conditions, the solution is homogeneous and the polar species (complexes between the catalyst and the ketone or the acid halide) are in sufficient amount to induce a rapid MW heating of the bulk mixture. Eventually, such a methodology will afford real industrial interest if it is possible to process substantial amounts of aromatic compounds. Studies on the scaleup of these FC reactions under MW heating and the research of a better route for alkanoylation reactions are in progress in our laboratories. 6. Experimental Section Reactions have been carried out with a monomode MW oven (Prolabo Synthewave 402) at 2.45 GHz, in a tubular quartz reactor (250 mL; Prolabo ref. 06 402.453). This reactor was equipped with a Teflon paddle stirrer and with a reflux condenser connected to a drying tube (CaCl2). The temperature of reaction media has been measured continuously with an IR-pyrometer which is an integral part of the Synthewave. The equipment is driven by a computer. Because of inertia of the IRpyrometer, actual temperature gradients (measured by a thermocouple after the MW irradiation was stopped) are higher (+5 to +10 °C on the average) than IRmeasured gradients. Consequently, what is important

is the relative temperature data of Figures 1 and 2. Considering that the temperature gradients are conditioned by the irradiated material quantity, the comparative experiments have been carried out with analogous amounts of products. All reagents (1-14) and catalysts were purchased (high-grade purity) and used without purification. The products 15-29 were identified and their isomeric compositions were determined by comparison of their spectral data (NMR, GC-MS) with those of authentic samples: 15, 28 (from Aldrich), 16,32 17,33 18,34 19, 20,35 21,36 22,37 23,38 24,39 25,40 26,41 27,24 2942. GC: HewlettPackard 6890 chromatograph equipped with a 30-m × 0.32-mm column (methyl silicone doped with 5% phenyl silicone, 0.25 µm). Conversion rates were determined by GC using dodecane or tetradecane as an internal standard. GC-MS: Hewlett-Packard MS 5989 apparatus (EI 70 eV) equipped with a GC 5890 chromatograph. The operative conditions have been chosen according to previous work involving iron salts-catalyzed FC acylation under classical heating.3a,b An excess of the acylation reagent giving many side products,3b the reactions have been carried out using an arene/acyl chloride ratio from 1:1 to 4:1, like for part 2 of this work.1 Moreover, this procedure avoids the use of a solvent, a prerequisite condition for efficient and nondangerous MW heating. Typical Procedure for Expeditious Conditions (Continuous MW Irradiation): Synthesis of 2,4,6Trimethylbenzophenone (25) (Table 3, Entry 4). Mesitylene (6) (4.80 g, 40 mmol), benzoyl chloride (11) (1.40 g, 10 mmol), and iron(III) chloride (162 mg, 1 mmol) were introduced together in the quartz reactor of the Synthewave apparatus surrounded by a condenser and a stirrer. The mixture was irradiated under an incident power of 300 W for 1 min. After cooling, the conversion rate was determined by analyzing an aliquot of the reaction mixture by GC, using tetradecane as an internal standard: 99%. The reaction mixture was quenched with 20 mL of a saturated sodium carbonate aqueous solution. The layers were separated, and the aqueous layer was washed three times with 10 mL of dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure up to elimination of 6 in excess. The crude product was purified by flash chromatography (silica gel, pentane/ether, 9:1) to give 25 as an overmelted solid: mp 34-36 °C (lit.40 mp 34-35.5 °C). Mass obtained: δ 2.02 g (90% yield from 11). 1H NMR (80 MHz, CDCl3): δ mesityl protons: 2.10 (s, 6 H, o-Me), 2.34 (s, 3 H, p-Me), 6.91 (s, 2 H, m-H); δ phenyl protons: 7.44 (m, 2 H, m-H), 7.57 (m, 1 H, p-H), 7.82 (m, 2 H, o-H). GC-MS: m/z (%) ) 225 (15), 224 (M+, 88), 223 (96), 209 (42), 208 (38), 207 (16), 206 (13), 165 (11), 147 (57), 119 (36), 117 (14), 115 (17), 105 (27), 103 (14), 91 (48), 78 (18), 77 (100%), 65 (13), 51 (51), 50 (14). Typical Procedure for Sequential MW Irradiation: Synthesis of Methylbenzophenone (17) (Table 1, Entry 6). Toluene (2) (3.69 g, 40 mmol), benzoyl chloride (11) (1.40 g, 10 mmol), and iron(III) chloride (81 mg, 0.5 mmol) were introduced into the same reactor as before and the mixture subjected to stirring. A MW irradiation of 300-W applied power was programmed using the computer according to a sequential process of irradiation in which the sample was exposed to MW for periods of 20 s separated by periods of 100 s. This sequence was repeated 15 times. After cooling, the same

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workup as before gave a crude product which was purified by flash chromatography (silica gel, pentane/ ether, 9:1). Mass of 18 obtained: 1.77 g (90% yield from 11). Isomer ratio (by GC): 2-/3-/4-methylbenzophenone (o-/m-/p-18) ) 12:3:85. 1H NMR (80 MHz; CDCl3): δ 2.33 (s, Me, o-18), 2.42 (s, Me, p-18), 7.2-7.8 (m, aromatic protons). GC-MS: m/z (%) ) o-18, 196 (M+, 60), 195 (100), 119 (24), 105 (55), 91 (41), 77 (89); p-18, 196 (M+, 57), 181 (12), 119 (100), 105 (43), 91 (41), 77 (61). Attempt for Acylation of Benzene by Isobutyryl Chloride. A mixture of 3.40 g (43.6 mmol) of benzene, 1.16 g (10.9 mmol) of isobutyryl chloride, and 171 mg (1.09 mmol) of iron(III) chlloride was irradiated (300-W applied power) for 12 × 15 s, with periods of 45 s between two irradiations. After cooling, the same workup as before gave a crude product analyzed by GC-MS. Two light products were detected: isobutyrophenone (28, 3% yield), 148 (M+, 8), 105 (100), 77 (78), 51 (40); 1-chloro-2-methyl-1-phenylpropene (30, 14%), 166 (M+, 77),131 (100), 115 (61), 91 (57), 77 (14). This product has been isolated by flash chromatography (silica gel, pentane/ether, 98:2). 1H NMR (80 MHz; CDCl3): δ 1.83 and 2.10 (2 s, Me), 7.30-7.45 (m, Ph). 13C NMR (90.32 MHz; CDCl3): δ 22.0 and 22.2 (Me), 125.4 and 139.5 (ethylenic carbons), 127.8, 128.2, 129.3 and 130.6 (aromatic carbons). Acknowledgment Support of this work by the Centre National de la Recherche Scientifique and Rhodia Organique Fine are gratefully acknowledged. We thank Prof. John Wiener (Paul-Sabatier University) for his assistance in the preparation of the manuscript. Literature Cited (1) Part 2: Laporte, C.; Marquie´, J.; Laporterie, A.; Desmurs, J. R.; Dubac, J. Re´actions d’Acylation sous Irradiation Micro-onde. II. Acylation d’Ethers Aromatiques. C. R. Acad. Sci. Paris, Ser. IIc, t. 2, 1999, 455. (2) (a) Olah, G. A. Friedel-Crafts and Related Reactions; WileyInterscience: New York, 1964. (b) Olah, G. A. Friedel-Crafts Chemistry; Wiley-Interscience: New York, 1973; (c) Heaney, H. The Bimolecular Aromatic Friedel-Crafts Reaction. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 3.2, pp 733-752. (d) Taylor R. Electrophilic Aromatic Substitution; Wiley-Interscience: Chichester, 1990; pp 222-238. (3) (a) Pearson, D. E.; Buehler, C. A. Friedel-Crafts Acylations with Little or No Catalyst. Synthesis 1972, 533. (b) Scheele, J. J. Electrophilic Aromatic Acylation. Ph.D. Thesis, Tech. Hogesch, Delft, The Netherlands, 1991; Chem. Abstr. 1992, 117, 130844y. (c) Desbois, M.; Gallo, R.; Scuotto, J. F. (Rhoˆne-Poulenc Spe´cialite´s Chimiques). Phenyl Ketones. French Patents 17,692 and 17,693, 1982; Chem. Abstr. 1984, 101, 130398a and 130399b. (d) Effenberger, F.; Steegmu¨ller, D. Electrophilic Aromatic Substitution. 33. Ferric Chloride Catalyzed Acylation of Aromatic Compounds with N-Phthaloyl R-Amino Acid Chlorides without Racemization. Chem. Ber. 1988, 121, 117. (e) Effenberger, F.; Steegmu¨ller, D.; Null, V.; Ziegler, T. Electrophilic Aromatic Substitution. 34. Intramolecular Friedel-Crafts Acylation of N-Phthaloyl-Substituted Arylalanyl and Homophenylalanyl Chlorides. Chem. Ber. 1988, 121, 125. (4) (a) Corne´lis, A.; Gerstmans, A.; Laszlo, P.; Mathy, A.; Zieba, I. Friedel-Crafts Acylations with Modified Clays as Catalysts. Catal. Lett. 1990, 6, 103. (b) Corne´lis, A;, Laszlo, P.; Wang, S. On the Transition State for Clayzic-Catalyzed Friedel-Crafts Reaction upon Anisole. Tetrahedron Lett. 1993, 34, 3849. (c) Clark, J. H.; Culle, S. R.; Barlow, S. J.; Bastock, T. W. Environmentally Friendly Chemistry Using Supported Reagent Catalysts: StructureProperty Relationships for Clayzic. J. Chem. Soc., Perkin Trans. 2 1994, 1117.

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(27) Recent compilative articles concerning the question of the nonthermal effect of MW in the rate of organic reactions: (a) Gedye, R. N.; Wei, J. B. Rate Enhancement of Organic Reactions by Microwaves at Atmospheric Pressure. Can. J. Chem. 1998, 76, 525. (b) Gedye, R. N. The Question of Non-Thermal Effects in the Rate Enhancement of Organic Reactions by Microwaves. Ceram. Trans. 1997, 80, 165. Recent reviews concerning applications of MW technique in organic chemistry: (c) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathe´, D. New Solvent-Free Organic Synthesis Using Focused Microwaves. Synthesis 1998, 1213. (d) Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A. Microwave Activation in Phase Transfer Catalysis. Tetrahedron 1999, 55, 10851. (e) Loupy, A. Solvent-Free Reactions. In Topics in Current Chemistry; Knochel, P., Ed.; Modern Solvents in Organic Synthesis; 1999; Vol. 206, pp 185-204. See also refs 22a and 22c. (28) (a) Gutierrez, E.; Loupy, A.; Bram, G.; Ruiz-Hitzky, E. Inorganic Solids in Dry Media. An Efficient Way for Developing Microwave Irradiation Activated Organic Reactions. Tetrahedron Lett. 1989, 30, 945. (b) Bram, G.; Loupy, A.; Majdoub, M.; Gutierrez, E.; Ruiz-Hitzky, E. Alkylation of Potassium Acetate in Dry Media. Thermal Activation in Commercial Microwave Ovens. Tetrahedron 1990, 46, 5167. (29) (a) Loupy, A.; Pigeon, P.; Ramdani, M.; Jacquault, P. Solid-Liquid-Phase Transfer Catalysis Without Solvent Coupled with Microwave Irradiation: A Quick and Efficient Method for Saponification of Esters. Synth. Commun. 1994, 159. (b) Loupy, A.; Pigeon, P.; Ramdani, M. Synthesis of Long Chain Aromatic Esters in a Solvent-Free Procedure Under Microwaves. Tetrahedron 1996, 52, 6705. (30) Carrillo-Munoz, J. R.; Bouvet, D.; Guibe´-Jambel, E.; Loupy, A.; Petit, A. Microwave-Promoted Lipase-Catalyzed Reactions. Resolution of (()-1-Phenylethanol. J. Org. Chem. 1996, 61, 7746. (31) Reference 3b, p 64. (32) McEvoy, F. J.; Albright, J. D. Alkylations and Acylations of R-Aryl-4-morpholineacetonitriles (Masked Acyl Anion Equivalents) and Their Use in 1,4-Additions. J. Org. Chem. 1979, 44, 4597. (33) Bunnett, J. F.; Hrutfiord, B. F. Cleavage of o-Halobenzophenones by Potassium Amide in Liquid Ammonia. J. Org. Chem. 1962, 27, 4152. (34) Brown, H. C.; Young, H. L. Isomer Distribution in the Aluminium Chloride-Catalyzed Benzoylation of Toluene in Nitrobenzene. J. Org. Chem. 1957, 22, 719. (35) Bachmann, W. E.; Carlson, E., Jr.; Moran, J. C. The Effect of Halogen Atoms and of Alkyl Groups on the Rates of Dissociation of Pentaarylethanes. J. Org. Chem. 1948, 13, 916. (36) McCarty, F. J.; Tilford, C. H.; Van Campen, M. G., Jr. Central Stimulants. R,R-Disubstituted 2-Piperidinemethanols and 1,1-Disubstituted Heptahydroo¨xazolo[3,4-a]pyridines J. Am. Chem. Soc. 1957, 79, 472. (37) Gravatt, G. L.; Baguley, B. C.; Wilson, W. R.; Denny, W. A. DNA-Directed Alkylating Agents. 4. 4-Anilinoquinoline-Based Minor Groove Directed Aniline Mustards. J. Med. Chem. 1991, 34, 1552. (38) Joshi, K. C.; Giri, S. Organic Pesticides. (XIII). Synthesis of Some Fluoroketones and Their Thiosemicarbazones. J. Indian Chem. Soc. 1963, 40, 42. (39) Keumi, T.; Saga, H.; Taniguchi, R.; Kitajima, H. Application of 2-Trifluoromethanesulfonyloxypyridine in Trifluoroacetic Acid to Acylation of Aromatics. Chem. Lett. 1977, 1099. (40) Wiegers, K. E.; Smith, S. G. Kinetics and Mechanism of Lithium Aluminium Hydride and Lithium Alkoxyaluminohydride Reduction of Ketones in Diethyl Ether. J. Am. Chem. Soc. 1977, 99, 1480. (41) Araki, M.; Mukaiyama, T. Reaction of Mixed Carboxylic Anhydrides with Grignard Reagents. Useful Method for the Preparation of Ketones. Chem. Lett. 1974, 663. (42) Fountain, K. R.; Heinze, P.; Sherwood, M.; Maddex, D.; Gerhardt, G. Acylation of Aromatic Substrate with Ketenes. An Example of Vinyl Oxocation Reactivity. Can. J. Chem. 1980, 58, 1198.

Received for review December 7, 1999 Revised manuscript received February 20, 2000 Accepted February 24, 2000 IE9908884