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Ind. Eng. Chem. Res. 2006, 45, 6640-6647
Kinetic Study of the Metal Triflate Catalyzed Benzoylation of Anisole in an Ionic Liquid Peter Goodrich,† Christopher Hardacre,† Hasan Mehdi,‡ Paul Nancarrow,† David W. Rooney,*,† and Jillian M. Thompson† QUILL Research Centre and School of Chemistry and Chemical Engineering, Queen’s UniVersity, Belfast, Northern Ireland, and Department of Chemical Technology and EnVironmental Chemistry, Eo¨tVo¨s UniVersity, Pa´ zma´ ny Pe´ ter se´ ta´ ny 1/A, H-1117 Budapest Hungary
The Friedel-Crafts benzoylation of anisole with benzoic anhydride to yield 4-methoxybenzophenone has been performed in a range of ionic liquids, using homogeneous metal triflate catalysts. Of these, indium, scandium, and aluminum triflate were chosen to develop a kinetic model. A complex exchange of ligands between the metal salt, the benzoic anhydride, and the ionic liquids results in the formation of a free acid catalyst. This acid is shown to reversibly deactivated by complexation with the product; the equilibrium constant for this has been measured, and a rate equation has been developed and successfully tested. Introduction Carbon-carbon coupling reactions are used extensively to produce fine and bulk chemicals, and, in particular, FriedelCrafts processes are widely used for alkylation and acylation reactions.1 Commonly, these reactions are performed using aluminum trichloride as a Lewis acid in organic solvents.1 Although this process is extremely effective, acylation requires a molar excess of AlCl3 and, despite being often referenced as a catalyst, the salt cannot be recycled, because it complexes to the ketone product, thus necessitating a hydrolysis step to isolate the product. The workup results in the destruction of the AlCl3 and the formation of large amounts of acid and metal salt waste. Hydrogen fluoride has also been used industrially as a catalyst; however, there are significant health and safety issues, as well as plant construction and operation implications, associated with this process.2 More recently, several catalytic Friedel-Crafts processes have been reported using metal triflates,3 metal triflimides,4 and binary ionic liquid mixtures,5 as well as solid acid catalysts such as Nafion6 and zeolites.7 Although heterogeneous catalysts offer easy recyclability and low cost, the range of substrates that may be used is limited and the catalysts often are deactivated, requiring either regeneration at high temperature or replacement. Homogeneous catalyst systems are more versatile and have greater substrate applicability, as in the case of the metal triflates and triflimides. However, there are many drawbacks to using metal triflates for FriedelCrafts acylation reactions. To achieve a suitable rate of reaction, the reactions are often conducted in nitromethane with perchlorate additives.8 This medium presents significant safety implications, if performed on an industrial scale, which, combined with the high costs of the metal salts and their poor recyclability, has limited their application mainly to that of academic interests. Recently, ionic liquids have been shown to be a versatile medium in which to perform organic reactions; in particular, catalytic processes have been examined using both homoge* To whom correspondence should be addressed. Tel.: +44 28 90974050. Fax: +44 28 90974687. E-mail:
[email protected]. † QUILL Research Centre and School of Chemistry and Chemical Engineering, Queen’s University. ‡ Department of Chemical Technology and Environmental Chemistry, Eo¨tvo¨s University.
neous9 and heterogeneous10-13 catalyst systems. The use of ionic liquids, instead of conventional molecular solvents, has been shown to increase the selectivities and rates of many reactions, while also simplifying the recycle of catalyst and solvent. Friedel-Crafts reactions have been studied extensively in ionic liquids; for example, both metal triflate and triflimide salts have been shown to have good recyclability for a range of reactions in ionic liquids.14 Song et al. reported scandium triflate to be an active catalyst in the alkylation of aromatic compounds in hydrophobic ionic liquids but not in hydrophilic ionic liquids or molecular solvents at 20 °C.15 In this case, the ionic liquidcatalyst system separated into an immiscible phase from the product, allowing the catalyst to be recycled without any loss of selectivity or activity. Ross and Xiao reported that acylation reactions could be performed efficiently using a range of triflate catalysts with enhanced rates in [C4mim][BF4], compared with acetonitrile or 1,2-dichloroethane.16 The acylation rates of aromatics using bismuth(III) salts dissolved in a range of ionic liquids have also been significantly improved, in comparison to conventional organic solvents with good recyclability over four reuses.17 To date, the mechanism that describes how the ionic liquid facilitates the homogeneously catalyzed reaction is not known. Furthermore, it is not clear whether the active catalytic species is the metal salt itself or an acid formed by the hydrolysis of either the catalyst or the anion of the ionic liquid.18 Recently, Hardacre et al. have shown that only parts per million (ppm) levels of acid dissolved in the ionic liquid are required to result in very high Friedel-Crafts activity.12 This paper describes the kinetics of the benzoylation of anisole using benzoic anhydride (Scheme 1) catalyzed by metal triflatessin particular, In(OTf)3s in the ionic liquid [C4mim][NTf2]. From these data, a kinetic model has been developed that has been used to understand the reaction mechanism and causes of catalyst deactivation. The general applicability of the model has been examined by correlating the experimental data of a wide range of catalyst/ solvent systems and reaction conditions. Experimental Section Anisole (99%), benzoic anhydride (98%), and 4-methoxybenzophenone (98%) were obtained from Lancaster. All triflate
10.1021/ie0602714 CCC: $33.50 © 2006 American Chemical Society Published on Web 09/06/2006
Ind. Eng. Chem. Res., Vol. 45, No. 20, 2006 6641 Scheme 1. Reaction Scheme Showing the Formation of 4-Methoxybenzophenone by the Benzoylation of Anisole with Benzoic Anhydride
salts (98%) and benzoic acid (98%) were obtained from Aldrich. All reagents and catalysts were used without further purification. 1-Butyl-3-methylimidazolium ([C4mim]+) tetrafluoroborate ([BF4]-), trifluoromethanesulfonate ([OTf]-), or bis-(trifluoromethylsulfonyl)imide ([NTf2]-) ionic liquids were synthesized in house from the appropriate organic chloride or bromide salt, using standard literature preparative procedures.19 The ionic liquids were dried under high vacuum at 60 °C for 4-5 h prior to use and contained 95% were obtained. Catalyst-product complexation studies were performed by adding 4-methoxybenzophenone and In(OTf)3 or triflic acid (HOTf), in varying proportions to [C4mim][NTf2] (1 g). The samples were treated in an ultrasonic bath at 80 °C for several hours to ensure complete dissolution prior to analysis. 13C NMR spectra were performed on a Bruker Avance DRX spectrometer, operating at 75 MHz and performed at 80 °C using a D2O lock contained within a sealed capillary referenced to HOD at 4.8 ppm. The Mathcad 12 program was used to fit the experimental data to a kinetic model. A least-squares regression analysis technique was used to parametrize the model, and an integral
method was used to compare the resulting theoretical data with the experimental data. Results and Discussion The benzoylation of anisole to form 4-methoxybenzophenone (Scheme 1) was chosen as a test reaction, because the activated aromatic substrate allowed reasonable reaction rates with high selectivity to the para product. Initial screening of the ionic liquids showed that little reaction was observed in the hydrophilic ionic liquids, based on the [BF4]- and [OTf]- anions, using a range of metal triflate catalysts. In contrast, the reaction did proceed in the hydrophobic [C4mim][NTf2] ionic liquid, as shown in Figure 1, with the initial rate and final conversion being strongly dependent on the salt used. In all cases, the selectivity to 4-methoxybenzophenone was >95% and did not change significantly with either the ionic liquid, the extent of conversion, or the catalyst. This observation is in general agreement with the findings of Song et al.15 and Gmouh et al.;17 therein, little reaction was observed in [BF4]-- and [OTf]--based ionic liquids but high conversion was observed in [PF6]-- and [SbF6]--based liquids for the alkylation and benzoylation of aromatic substrates, respectively, using metal salt catalysts. In this case, [PF6]--based ionic liquids were used; however, these readily hydrolyzed to yield HF,18 which, itself, is an active catalyst for the reaction, which complicates the reaction kinetics. The [NTf2]- anion is more stable and was chosen to study the reaction mechanism, using a detailed kinetic analysis. Figure 1 clearly shows that the triflate salts that are based on indium, aluminum, and scandium give the fastest reaction rates of the salts tested, and these were chosen for further study. To ensure that the rate of reaction was not affected by the efficiency of the mixing in the solution, a series of reactions were conducted at different stirrer speeds, ranging from 200 rpm to 1000 rpm. The kinetic profiles obtained were determined to be identical and the mixing in the vessel was assumed to be close to ideal, with a standard stirrer speed of 600 rpm being chosen for further experiments. On doubling the concentration of anisole from 2 mol dm-3 to 4 mol dm-3, the initial rate of reaction approximately doubled, from 0.478 mol dm-3 min-1 to 0.899 mol dm-3 min-1. A similar effect was observed when the concentration of benzoic anhydride was doubled, with the initial rate increasing from 0.478 mol dm-3 min-1 to 1.062 mol dm-3 min-1. This effect is consistent with the reaction being first order in both anisole and benzoic anhydride. Figure 2 shows the effect of changing the reactant ratios on the conversion during a typical reaction. Given the shape of these curves, it would appear that the orders estimated from the initial rates may not be suitable to describe the entire reaction. Similar results were observed for the systems that were catalyzed by aluminum triflate and scandium triflate. Refer to the Supporting Information for further details.) Power law models are often used as a preliminary method to describe the kinetics of a reaction, and these have been applied to the data shown in Figure 2. Its widespread use is due to its simple construction and ability to describe many reactions. For
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Figure 1. Kinetic profile for the formation of 4-methoxybenzophenone by the benzoylation of anisole in [C4mim][NTf2], using various metal triflate catalysts. Experimental conditions were as follows: [A] ) 2 mol dm-3, [B] ) 2 mol dm-3, [C] ) 0.04 mol dm-3, temperature ) 80 °C, and stirrer speed ) 600 rpm.
Figure 2. Effect of the ratio of anisole (A) to benzoic anhydride (B) on the conversion versus time profile for the benzoylation of anisole at 80 °C, [C] ) 0.04 mol dm-3 in [C4mim][NTf2] using In(OTf)3.
the reaction under study here, the power-law model is given by the following equation:
-rA ) k[A]n[B]m[C]
(1)
where rA is the rate of change in concentration of anisole; [A], [B], and [C] are the concentrations of anisole, benzoic anhydride, and catalyst, respectively; and n and m are the reaction orders, with respect to anisole and benzoic anhydride, respectively. When n and m were each fixed to a value of 1, as would be expected from the initial rate data, the model poorly described the data. An correlation factor of R2 ) 0.70 was obtained from the parity plot of predicted conversion versus the experimental conversion calculated for a given reaction time. Optimizing the R2 value resulted in an overall reaction order, n + m, of 4.33 (1.33 with respect to anisole and 3 with respect to benzoic anhydride), clearly indicating that other factors that had not been taken into account by the model were affecting the reaction rate. It is normal to assume that a linear relationship exists between the catalyst concentration and the rate of reaction for homogeneously catalyzed systems. Figure 3 shows the variation in the initial rate of reaction as a function of the In(OTf)3 concentration
Figure 3. Comparison of initial rate versus indium triflate, triflic acid, and bis-triflimide concentration for the benzoylation reaction in [C4mim][NTf2] at 80 °C. Solid line represents the initial rate observed with In(OTf)3, with the catalyst concentration scaled by a factor of 3.
for a 1:1 anisole:benzoic anhydride ratio. Up to indium triflate concentrations of ∼0.02 mol dm-3, the rate increased linearly, as expected; however, at concentrations >0.02 mol dm-3, the order, with respect to catalyst concentration, decreases as the plot becomes curved. For the models described herein, the catalyst concentrations used were all considered to be within the linear range and, hence, the order, with respect to catalyst concentration, is taken as unity. The kinetic profiles shown in Figure 1 and those obtained at different concentrations (Figure 2) show an initially fast reaction, followed by a much slower rate. Because the mass balances for the reactions were >95%, indicating that no reagents or products were lost during the course of the reaction, it was concluded that the catalyst is deactivated as the reaction proceeds. However, the conversions continue to increase with time, with conversions of 100% generally being reached after 24 h; this deactivation is thought to be reversible. Such kinetic profiles are often characteristic of the catalyst being poisoned by the product formed in the reaction. When equimolar amounts of 4-methoxybenzophenone, with respect to the catalyst, were added, no decrease in the initial rate was observed; however, as shown in Figure 4, when the amount of 4-methoxybenzophenone added was increased to concentrations equivalent to that found at 20%, 40%, and 60% conversion, the initial reaction rate decreased significantly. As observed in the absence of added product, although the initial rate decreases, after 24 h of reaction, conversions of >95% were observed. In contrast, when similar concentrations of benzoic acid were added, no appreciable effect on the rate of reaction was observed, thus eliminating it as a poison in the reaction. There are several ways in which the power-law model can be modified to account for deactivation by the product, for example,
-rA ) k[A][B][C]e-KD[M]
(2)
In this equation, an exponential decay function is used to empirically represent the deactivation, where [M] refers to the concentration of the product (4-methoxybenzophenone) and KD is a deactivation factor. Fitting the data to this model was significantly more successful than the simple power-law model, increasing the R2 of the parity plot to 0.92 for an order of unity
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Figure 4. Effect of adding 4-methoxybenzophenone (MBP) on the conversion versus time profile for the benzoylation of anisole using benzoic anhydride (where % MBP refers to the molar amount of methoxybenzophenone added, as a percentage of the molar amount of anisole). Reaction conditions were as follows: [A] ) 2 mol dm-3, [B] ) 2 mol dm-3, and [In(OTf)3] ) 0.04 mol dm-3 in [C4mim][NTf2] at 80 °C.
for each reactant. The maximum value of R2 occurs at KD ) 1.825 M-1, yielding a rate constant (k) of 2.25 dm6 mol-2 min-1 for indium triflate at 80 °C in [C4mim][NTf2]. Although it is clear that the catalyst is poisoned by the product, 4-methoxybenzophenone, the exact nature of this deactivation is still unclear. Many groups have reported the possibility of the metal triflate undergoing a ligand exchange in the presence of an acylating agent, be that an acid anhydride or an acid chloride.20 Re´pichet et al.21 proposed that, in the catalyzed benzoylation of unactivated aromatic substrates by benzoyl chloride, the bismuth triflate reacts with the benzoyl chloride, forming a metal chloride and a mixed anhydride with the triflate ligand. The mixed anhydride is thought to execute the acylation reaction with the aromatic substrate, thus generating triflic acid. The triflic acid then catalyzes the subsequent reactions. However, they also reported that, in the presence of benzoic anhydride rather than benzoyl chloride, the bismuth triflate remains intact and the catalysis occurs via the Lewis acidity of the metal center. In contrast, Dumeunier and Marko´22 proposed that, in the acylation of hex-2-en-1-ol with benzoic anhydride in the presence of several metal triflate catalysts, ligand exchange of the salt can occur. Again, the mixed anhydride is formed and, ultimately, following the FriedelCrafts reaction, triflic acid. However, it is unclear as to whether the triflic acid can react with the metal center to re-form the original catalyst or is itself the active catalytic species. A comparison between the metal salt and the acid (Figure 3) shows that the rate of reaction is comparable to three equivalents of HOTf; i.e., if the concentration of the indium triflate is scaled by a factor of 3, the observed rates are equivalent to the HOTf results. This implies that (i) all three triflate ligands are removed to form HOTf and (ii) this is the active species. This is consistent with the observation by Ross and Xiao,16 that Cu(OCOCH3)2 is formed during the acylation of anisole by acetic anhydride, using Cu(OTf)2 as a catalyst in [C4mim][BF4]. Interestingly, this only occurred in the presence of H2O, because, under strictly anhydrous conditions, the rate of reaction increased and no Cu(OCOCH3)2 was observed. These studies indicate that (i) the In(OTf)3 used in this study may not remain intact throughout the reaction and (ii) the
Figure 5. Rate-inhibiting effect of 4-methoxybenzophenone, compared with that of 4,4-difluorobenzophenone, on the triflic acid-catalyzed benzoylation reaction, in [C4mim][NTf2]. Reaction conditions were as follows: [A] ) 2 mol dm-3, [B] ) 2 mol dm-3, [C] ) 0.04 mol dm-3, [ketone] ) 1 mol dm-3, temperature ) 80 °C, and stirrer speed ) 600 rpm.
deactivation may be associated with triflic acid rather than the metal salt. To determine if acid was also formed in the reactions presented here, three moles of the sterically hindered base, 2,6di-tert-butyl-pyridine were added for each mole of indium triflate used, prior to the addition of reactants, and with no reaction occurring, it can be concluded that acid is formed during the catalytic cycle in this reaction. To determine the nature of the interaction between 4-methoxybenzophenone and the catalyst, be that indium triflate or triflic acid, 13C NMR spectra of solutions of catalyst and 4-methoxybenzophenone in [C4mim][NTf2] were measured. The peak due to the carbonyl group of 4-methoxybenzophenone was observed to shift downfield, from 196 ppm to 202 ppm, when equimolar amounts of both indium triflate and triflic acid were added, indicating that this functional group was involved in the interaction. However, because of the evidence in the literature and the effect of adding 2,6-di-tert-butyl pyridine, further studies on catalyst deactivation have been limited to triflic acid. Further evidence of interaction was obtained by comparing the kinetics when 4-methoxybenzophenone and 4,4-difluorobenzophenone were added. Figure 5 shows that, when 0.5 mol of 4-methoxybenzophenone per mole of anisole was added, the conversion after 30 min had decreased to ∼47%, compared to ∼60% for the reaction with no added ketone. However, the decrease in conversion was less pronounced when the same number of moles of 4,4-difluorobenzophenone was added where the conversion after 30 min was only reduced to ∼56%. This has been attributed to the electron withdrawing effect of the fluorine groups, resulting in a weaker interaction with the HOTf. It is proposed that a hydrogen-bonding type of interaction occurs between the carbonyl group on the ketone and the proton on the triflic acid. The stoichiometry of the interaction between 4-methoxybenzophenone and triflic acid was determined using data obtained from 13C NMR and analyzed using the method of continuous variations (Job’s method).23 A series of solutions were prepared that contained HOTf and 4-methoxybenzophenone in varying proportions, so that the full range of molar ratios was sampled, and the total concentration of substrates ([M] + [C]) remained constant for each solution. The carbonyl peak of the 4-methoxybenzophenone gradually changed from ∼196 ppm in the
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Ind. Eng. Chem. Res., Vol. 45, No. 20, 2006 Table 1. Equilibrium Constants and Maximum Changes in Chemical Shifts of the 13C NMR Carbonyl Peak for the Interaction between Triflic Acid and 4-Methoxybenzophenone, Estimated from the Rose-Drago Treatment of NMR Data temperature (°C)
KI*
∆δmax (ppm)
20 50 80
50.9 36.9 25.7
6.46 6.42 6.38
concentration of the observed species is in large excess. Its concentration can be assumed to be constant and equal to its initial concentration. The following relationship for 1:1 complexes has been derived:24
(∆δmax - ∆δ)KI* )
Figure 6. Job plot to determine the stoichiometry of the complexation between 4-methoxybenzophenone and triflic acid from 13C NMR data. XM refers to the mole fraction of 4-methoxybenzophenone in solution, and ∆δ refers to the associated change in chemical shift of the carbonyl peak in the NMR spectrum.
absence of catalyst to almost 202 ppm when a 10-fold molar excess of catalyst was added. A Job plot (Figure 6) was obtained by plotting XM∆δ versus XM, where XM is the mole fraction of 4-methoxybenzophenone in solution and ∆δ is the observed change in the chemical shift of the carbonyl peak. The maximum of the curve occurs at the value of XM that corresponds to the stoichiometry of the interaction, in this case, at 0.5, giving the expected stoichiometry of 1:1. The aforementioned data show that the active catalyst concentration is strongly dependent on the concentration of the product 4-methoxybenzophenone, because of a reversible interaction between these two species, as shown by the kinetic and NMR studies. The stoichiometry indicates that the equilibrium constant for the interaction is given by
KI* )
[I*] [M][C]
(3)
where [I*] denotes the inactive catalyst-product complex. Also, the concentration of this complex at any given time is related to the catalyst concentration by
[I*] ) [C]0 - [C]
(4)
where [C]0 is the initial concentration of catalyst added. Combining and rearranging these equations gives the free catalyst concentration as a function of product.
[C] )
[C]0 1 + KI*[M]
(5)
For the development of any kinetic model, it is necessary to determine the value of KI* for the product/catalyst interaction to allow a rate equation to be used. Many methods exist for determining KI* from NMR data.24 Most methods require the species that is not being observedsin this case, triflic acidsto be in large excess, so that its concentration may be assumed constant. Under actual reaction conditions, it is 4-methoxybenzophenone, not triflic acid, that exists in large excess; therefore, these methods of analysis were deemed inappropriate. The Rose-Drago method was chosen because it is a graphical solution to the simultaneous equations that relate KI* to ∆δ, and, therefore, it does not require the assumption that the
∆δ∆δmax ∆δmax[C]0 - ∆δ[C]0 - ∆δ[M]0
(6)
where ∆δ is the difference in NMR chemical shifts between that of the observed molecule (4-methoxybenzophenone) and that of the catalyst-product complex (in ppm), with ∆δmax being the value of ∆δ at an infinite concentration of the species that is not being observed (in this case, HOTf). To determine the equilibrium constant, the solutions, which have been described previously, with different [C]0 and [M]0 values, were analyzed by 13C NMR to determine the change in chemical shift (∆δ) of the observed peak. The solution to eq 6 can then be determined either by numerical or graphical methods. Table 1 shows the results of Rose-Drago treatment of 13C NMR data at 20, 50, and 80 °C. The dependence of the equilibrium constant, on temperature, is given by
lnKI* )
-∆Hr ∆Sr + RT R
(7)
Using this relationship, a graph of ln KI* versus T-1 was plotted to give a straight line. The enthalpy and entropy of reaction for the triflic acid-4-methoxybenzophenone interaction were estimated from the slope and intercept and determined to be ∆Hr ) -9750 J/mol and ∆Sr ) -0.510 J mol-1 K-1, respectively. So far, it has been assumed that the ionic liquid acts only as a solvent for this reaction. However, it has been shown that enhanced acid activity was observed at low acid concentration when using the ionic liquid [C4mim][NTf2], indicating that the ionic liquid may enhance the reaction. The effect of ionic liquid concentration on the rate of the benzoylation reaction was examined by adding various masses of [C4mim][NTf2] to the reaction mixture, while maintaining the masses of reagents and catalyst constant. As shown in Figure 7, the addition of small amounts of ionic liquid was observed to have a significant effect on the initial rate of reaction, which reached a maximum at ∼40 mol of ionic liquid per mole of catalyst, which is equivalent to an ionic liquid concentration of 0.65 mol dm-3. The addition of further amounts of [C4mim][NTf2] resulted in a decrease in the initial rate of reaction, and this has been attributed to a dilution effect. The overall effect of adding ionic liquid, exclusive of the dilution effect, can be estimated from the initial rates obtained from each experiment divided by the initial concentrations of anisole, benzoic anhydride, and indium triflate, because the initial kinetics are first order, with respect to each, under the conditions studied. Figure 7 shows the normalized initial rate of reaction as a function of ionic liquid concentration. Over the entire concentration range of [C4mim][NTf2] examined, the overall rate of reaction increased with the addition of ionic liquid. Although it may seem that this is due to the charged intermediate being stabilized in the increasingly ionic environ-
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Figure 7. Effect of ionic liquid concentration on the initial rate of reaction, including and excluding dilution effects. Experimental conditions were as follows: A ) 5 mmol, B ) 5 mmol, and In(OTf)3 ) 0.1 mmol. Closed square symbols (9) represent the initial rate (in units of mol dm-3), and the open circles (O) represent the normalized rate (in units of dm6 mol-2 s-1).
ment, it is more likely that the increased rates are due to the formation of HNTf2, which is generated via the equilibrium that is set up between HOTf and the [NTf2]- anion from the ionic liquid, which becomes more favorable to HNTf2 as the concentration of ionic liquid is increased. From gas-phase calculations, HNTf2 is widely considered to be a stronger acid than HOTf, which implies that it would be a better catalyst;25 however, the behavior of acids in ionic liquids is still largely unknown and, although the relative acidities of these two species cannot be assumed to follow the same trend in this media, Figure 3 shows HNTf2 to be a more active catalyst than HOTf for the benzoylation reaction. To verify the possibility that, with higher ionic liquid concentration, the acidity of the medium increases, leading to the enhanced rate, it would be necessary to correlate the kinetics with the pKa value of the reaction mixture. To date, no methods have been developed to measure the acid equilibrium constant in ionic liquids, although research is ongoing in our laboratory to address this problem. To take into account catalyst deactivation by complexation with the product and, in the case of ionic liquids, the anion exchange equilibrium, the two-cycle mechanism as originally proposed by Dumeunier and Marko´22 has been modified and is shown in Scheme 2. If it is assumed that the individual reactions contained within the cycles shown in Scheme 2 can be represented by elementary reactions, then a series of ordinary
Figure 8. Comparison of the experimental versus predicted conversions, using the model described in eq 8, for In(OTf)3-, Al(OTf)3-, and Sc(OTf)3catalyzed benzoylation reaction in [C4mim][NTf2].
differential equations can be derived to represent each individual reaction (see Table 2). The kinetic parameters for these equations, although being more representative of the true kinetics than power-law models, would be difficult to derive with any accuracy from the kinetic data, because of their complexity. In addition, the table only describes 12 species and does not include the M(OTf)(OCOPh)2 and M(OCOPh)3 salts, the M(NTf2)x(OCOPh)3-x salts, or any deactivation from the 2-methoxybenzophenone. It is also possible that, because these reactions were not performed under strictly anhydrous conditions, exchange with water to yield the hydroxide salt and the acid may occur. However, if one assumes that the bulk of the reaction is catalyzed by the acid either formed by exchange with water or through the two-cycle mechanism, these reactions can be simplified and a rate equation can be derived to model the kinetic behavior of the system. The constant term for catalyst concentration in eq 1 can be replaced with the dynamic term (eq 5), which is dependent on the concentration of 4-methoxybenzophenone through the course of the reaction. The rate equation, including temperature effects, becomes
-rA ) k0e-EA/(RT)[A][B]
(
[C]0
1 + KI*[M]
)
(8)
where EA is the activation energy and k0 is the pre-exponential constant. This model, which has been derived from the
Scheme 2. Proposed Catalytic Cycle for the Benzoylation of Anisole in Ionic Liquids
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Table 2. Reaction Stoichiometries and Differential Rate Equations for a Selection of Reactionsa Reaction Stoichiometries k1
C + B 98 I1 + I2 k2
I2 + A 98 M + Tf k3
I1 + Tf 98 C + Z
Al(OTf)3 and Sc(OTf)3, along with the corresponding activation energies and pre-exponential factors for all three metal triflate salts used. Interestingly, the same model can be applied to all three salts, showing equally good correlation. Small differences that have been observed in the activation energies are compensated by the opposite trend in the pre-exponential factors, resulting in the similar rates that are shown in Figure 1. It is postulated that, for each of these salts, the formation of a Brønsted acid catalyses the reaction, and not the Lewis acidity of the salt that is used in ionic liquids.
k4
Tf + B 98 I2 + Z
Conclusions
k5
Tf + M {\ } I* 1 k -5
k6
Tf + NTf {\ } Tn + OTF k -6
k7
Tn + B 98 I3 + Z k8
I3 + A 98 M + Z k9
Tn + M {\ } I* 2 k -9
Differential Rate Equations
d[A] ) -k2[A][I2] - k8[A][I3] dt d[B] ) -k1[B][C] - k4[Tf][B] - k7[Tn][B] dt d[C] ) -k1[C][B] + k3[I1][Tf] dt d[I1] ) k1[C][B] - k3[I1][Tf] dt d[I2] ) k1[C][B] - k2[I2][A] + k4[Tf][B] dt d[Tf] ) k2[I2][A] - k3[I1][Tf] + k4[Tf][B] -k5[Tf][M] + dt k-5[I*1] - k6[Tf][NTf] + k-6[Tn][OTf] a Table legend: Z, benzoic acid; I , M(OTf) (OCOPh); I , Ph(CO)OTf; 1 2 2 I3, Ph(CO)NTf2; Tf, HOTf; Tn, HNTf2; OTf, C4mimOTf; and NTf, C4mimNTf2. I* 1 and I* 2 are the inactive complexes formed from complexation of the HOTF and HNTf2 acids with the 4-methoxybenzophenone.
postulated reaction mechanism, is preferred to the empirical modified power-law discussed previously. With the equilibrium constant KI* determined, and its relationship to temperature modeled, an algorithm that was based on the integral method was developed in the Mathcad 12 program, to allow the rate constants to be determined and to test the model against the experimental data. Initially, a matrix was constructed for each temperature studied (60, 70, 80, and 90 °C), each consisting of the time, conversion, and initial concentrations of the reactants, catalyst, and product. This information was fitted to eq 8 to yield the reaction rate constant; furthermore, the Arrhenius equation was used to determine the temperature dependence of the rate constant for In(OTf)3. Figure 8 shows that good agreement is observed between the model and the experimental data, with the majority of the points being within the (5% lines. A similar treatment was also applied to data obtained using Al(OTf)3 and Sc(OTf)3 (refer to the Supporting Information for further details). Figure 8 also shows the correlation of predicted versus experimental conversion for
The benzoylation of anisole with benzoic anhydride, using metal triflate salts in [C4mim][NTf2], has been studied in detail. It is proposed that the catalyst undergoes ligand exchange with benzoic anhydride, forming free acid in situ, by which the catalysis occurs. Strong product inhibition was observed to cause a reduction in reaction rate at higher conversions with interaction between the 4-methoxybenzophenone and catalyst being confirmed by observation of a shift in the carbonyl peak in 13C NMR spectrum. This interaction was shown to have a stoichiometry of 1:1, and the equilibrium constant, as a function of temperature, has been measured. The reaction was determined to be first order in regard to both anisole and benzoic anhydride, as well as the catalyst at low concentration. Interestingly, the ionic liquid [C4mim][NTf2] has been shown to enhance the rate of reaction significantly, and it is proposed that this is due to an equilibrium between the ionic liquid and the acid catalyst, which increases the concentration of the more-active HNTf2, relative to HOTf. Based on the evidence from kinetic studies, a simplified reaction mechanism has been developed and used as a basis for a kinetic model. This model, which incorporates the effects of temperature and the concentrations of anisole, benzoic anhydride, the catalyst, and the product on the reaction rate, has been formulated and tested successfully against experimental data over a wide range of reaction conditions. Acknowledgment The authors would like to QUILL, DEL Northern Ireland, LINK, and the EPSRC under Grant Nos. GR/N02085 and GR/ R42061 for funding this project and the Marie Curie Fellowship for additional support. Supporting Information Available: The kinetic profiles of the formation of 4-methoxybenzophenone with Al(OTf)3 at different anisole-to-anhydride ratios are given (Figures S1 and S2); the corresponding information for Sc(OTf)3 is also given (Figures S3 and S4). The effect of catalyst concentration on the initial rate of reaction for all three metal triflates is shown (Figure S5), along with the effect of the addition of 4-methoxybenzophenone on the kinetic profile obtained using Al(OTf)3 and Sc(OTf)3, (Figures S6 and S7) with the corresponding details for the addition of benzoic acid for all three metal triflates (Figures S8-S10). The effect of temperature on the kinetic profile for all three metal salts is given also given (Figures S11S13). (All are PDF files.) This material is available free of charge via the Internet at http://pubs.acs.org. Literature Cited (1) Olah, G. A. Friedel-Crafts and Related Reactions; Interscience: New York, 1963. (2) Meldrum. M. Toxicology of Hydrogen Fluoride in Relation to Major Accident Hazards. Regul. Toxicol. Pharmacol. 1999, 30, 110.
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ReceiVed for reView March 6, 2006 ReVised manuscript receiVed June 26, 2006 Accepted July 29, 2006 IE0602714
