Maria J. Climent, Avelino Corma*, Sara Iborra, Maria Mifsud and Alexandra Velty
Instituto de Tecnología Quimica, Universidad Politécnica de Valencia, Avda. de los Naranjos s/n, 46022 Valencia, Spain. E-mail: acorma@itq.upv.es
First published on 26th October 2009
The synthesis of a series of fine chemicals (4-(4-methoxyphenyl)-2-butanone, 4-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)-2-butanone, and 2-cyclopentylcylopentanone) has been performed through a simple process that involves one-pot multi-step reactions (condensation–dehydration–reduction) using multifunctional base–acid-metal catalysts. The E factor for the specific process, as well as for the global process that includes the manufacturing of the reactants, has been calculated and compared with those obtained using conventional methods. In various cases, it is demonstrated that by means of process intensification with multifunctional solid catalysts, it is possible to decrease the E factor by one order of magnitude or more with respect to any of the manufacturing routes reported to date.
Metal supported on alkaline earth layered double hydroxides (LDH) and its mixed oxides have been extensively applied as multifunctional base–acid-metal catalysts for cascade reactions such as the synthesis of methyl isobutyl ketone in one pot from acetone19-23 or from 2-propanol24-27 and for the preparation of fine chemicals such as 2-methyl-3-phenyl propanal,28,29α-alkylated nitriles,30 and the anti-inflamatory nabumetone.11,16
Here, we present that by means of multifunctional base–acid-metal catalysts (Pd-supported alkaline earth oxides and mixed oxides), it is possible to substitute existing processes for the production of a series of fine chemicals (4-(4-methoxyphenyl)-2-butanone, 4-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)-2-butanone, and 2-cyclopentylcylopentanone) by a more simple process that involves one-pot multi-step reactions. We show that by means of process intensification with multifunctional solid catalysts, it has been possible, in various cases, to decrease the E factor by one order of magnitude or more, with respect to any of the manufacturing routes reported up to now. In this work, the E factor for the specific process as well as for the global process that includes the manufacturing of the reactants has been considered.
Scheme 1 |
Heterogeneous catalysts, such as exchanged resins (Dowex-50),33 have also been used for this transformation, however low selectivity for 2 (60–70%) was obtained. Cation exchanged montmorillonite also containing Brønsted acid sites has been utilized, yielding only 25% of 2 at 100 °C after 48 h reaction time.34
There is another route to synthesize 2 (Scheme 2), that involves an aldol condensation between 4-methoxybenzaldehyde and acetone, yielding the α,β-unsaturated compound 1, which is followed by hydrogenation of the CC bond in a two-step reaction. When using homogenous catalysts, the condensation step has been carried out with NaOH as catalyst yielding 98% of the α,β-unsaturated ketone (1).35 While a one-pot process has been carried out under hydrogen atmosphere, in the presence of NaOH and 5% Pd/C, the two step process yields 80% of 4-(4-methoxyphenyl)-2-butanone (2).36
Scheme 2 |
We propose here an alternative one-pot catalytic process to synthesize 2 that consists of reacting 4-methoxybenzaldehyde with acetone under hydrogen atmosphere in the presence of PdMgO catalyst to give an intermediate, 1, which is hydrogenated to give 2 (Scheme 2). The reaction between 4-methoxybenzaldehyde and acetone was performed using 1 wt% of Pd loaded on the nanocrystalline MgO (see Experimental) at 75 °C. The results in Table 1 show that PdMgO is able to convert 100% of 4-methoxybenzaldehyde, giving 99% yield and 99% selectivity for 2.
Catalysts | r°× 104/mmol min−1 g−1 | Conversion (%) | Yield 1 (%) | Yield 2 (%) | Selectivity 2 (%) |
---|---|---|---|---|---|
r°: rate of disappearance of 4-methoxybenzaldehyde. Reaction conditions: 4-methoxybenzaldehyde (3.8 mmol), acetone (37 mmol); 75 °C, catalyst 38 wt% with respect to anisaldehyde. Conversion and yield at 75 min reaction time. The value in brackets is the percentage of Michael adduct. | |||||
PdMgO | 12.0 | 100 | 1 | 99 | 99 |
PdHTc | 5.0 | 89 | 25 | 62 | 68(2) |
PdHTr | 9.7 | 95 | — | 95 | 100 |
It is known that the selection of the most appropriate type of centres for a given base-catalyzed process has a strong impact on the catalyst activity and selectivity.37 Thus, we have also prepared two Pd catalysts supported on Al/Mg calcined hydrotalcite (PdHTc) and on calcined–rehydrated Al/Mg hydrotalcite (PdHTr) which were tested under the same reaction conditions as PdMgO.
As can be seen in Table 1, PdHTc exhibits lower condensation and hydrogenation rates than PdMgO and, consequently, the yield and selectivity of 2 are lower. Moreover, a secondary product resulting from the Michael addition of acetone to 2 was also detected in minor amounts. When the calcined hydrotalcite containing palladium metal was rehydrated (PdHTr), a twofold increase in initial reaction rate was observed. This result is not surprising since by rehydration, a restoration of the layered structure occurs wherein the CO32− counter anions in the interlayer space are replaced by OH−, resulting in strong Brønsted base catalysts that efficiently catalyze a larger number of reactions.38–45 Results in Table 1 indicate that, together with PdMgO, PdHTr is a promising candidate for the preparation of 2, since 95% yield with 100% selectivity is obtained after 75 min reaction time.
Nevertheless, for a potential industrial implementation of the above catalysts (PdMgO and PdHTr) for the preparation of 2, the possibility of catalyst regeneration has to be considered. To study the reusability of the catalysts, the samples were regenerated after the reaction as described in the Experimental section and the catalyst was used again. As it can be seen in Table 2, an important decrease in activity upon regeneration was found with the PdHTr sample, which is probably due to an incomplete reconstruction and/or a decrease in the number of basic and hydrogenating active sites. In contrast, the PdMgO sample was subjected to four cycles of reaction–regeneration (calcination)–reaction, in all cases achieving 100% conversion and similar selectivity of 2 (Table 2).
Catalysts | Cycles | Conversion (%) | Yield 1 (%) | Yield 2 (%) | Selectivity 2 (%) |
---|---|---|---|---|---|
PdHTr | 1 | 95 | — | 95 | 100 |
2 | 25 | 18 | 7 | 28 | |
PdMgO | 1 | 100 | 1 | 99 | 99 |
2 | 100 | 2 | 98 | 98 | |
3 | 100 | 1 | 99 | 99 | |
4 | 100 | 2 | 98 | 98 |
In conclusion, we have shown that by using a multifunctional catalyst based on Pd supported on nanocrystalline MgO, it has been possible to develop a new green process for production of 2 in a one-pot cascade reaction. This new process allows yields of 99% with 99% selectivity for 2. The E factor involved is presented below.
Scheme 3 |
Considering that acetone is an easily recoverable solvent and the hydrogenation process does not produce any waste, the E factor for the one-pot reaction starting from p-methoxybenzaldehyde is 0.01, water being the main waste. The E factors for the syntheses of the reagents, acetone and 4-methoxybenzaldehyde, have also been calculated. For the synthesis of acetone we have selected the cumene route starting from benzene and propylene since this is the main industrial method used to produce acetone (see the ESI†). The total E factor for the production of acetone is 0.16.
On the other hand, the value for 4-methoxybenzaldehyde has been obtained according to two different routes (Scheme 3):
(i) by methylation of p-cresol giving p-methoxytoluene followed by catalytic oxidation with air, which has an E factor of 0.82 (see the ESI†).
(ii) by formylation of anisole through a Vilsmeier reaction,46 which has an E factor of 2.77 (see the ESI†). If we consider the global process, via i and via ii, the global E factors are 0.99 and 2.94, respectively (see Table 3).
If we follow the same methodology for the commercially accepted process where the aldol condensation is carried out using a 10% aqueous solution of NaOH35 (see Scheme 3), the specific E factor is 9.69, and when considering the global process, via i and via ii, the global E factors are 10.67 and 12.62, respectively (see Table 3).
These results indicate that considering the global process starting from p-cresol, the E factor for the procedure presented here with PdMgO is one order of magnitude lower than that of the conventional process (see Table 3). In Table 3, the specific E factors of all compounds involved in the production of compound 2 are summarized, as well as the global E factors following routes i and ii, performed using heterogeneous and homogeneous catalysts in the specific path for the synthesis of 2.
We have also considered here another potential procedure for the synthesis of 2 through two consecutive steps, involving a Heck coupling reaction between p-iodoanisole and methyl vinyl ketone (MVK) followed by hydrogenation (see Scheme 4). It has been reported that the synthesis of 2viaScheme 4 could be performed in a one pot, two-step process using palladium supported on titanium dioxide as a catalyst. Under optimized reaction conditions, this catalytic route gave 2 with 97% yield.12 Thus, for comparison purposes we have calculated the E factor for the synthesis of compound 2 through the Heck coupling reaction under heterogeneous and homogeneous catalysis, and the result, considering that the solvent can be fully recycled, is 1.96 (Scheme 4).
Scheme 4 |
The waste produced during the synthesis of the reagents in Scheme 4 is also considered and, since the synthesis of 4-iodoanisole can be carried out by different methodologies, for calculation of the E factor we have selected a green process recently reported by Earle et al.47 which has an E factor of 0.30 (see the ESI†) This value is lower than E = 0.80 calculated when the iodation of anisole was performed with N-iodosuccinimide48 as the iodating agent in acetonitrile as solvent.
The second reactant, i.e. methyl vinyl ketone, is produced through the aldol condensation between acetone and formaldehyde. The process can be carried out in either the gas phase or liquid phase. In the liquid phase,49 the E factor is 0.99, while in the gas phase50 the E factor is 0.60 (see the ESI†). If we accept the greener, gas phase process for calculating the global E factor for the formation of the 4-(4-methoxyphenyl)-2-butanone via Heck coupling, the calculated value is E = 2.86 (see the ESI†). When this value is compared to that obtained during the aldol condensation with the solid catalyst (Scheme 3) in a one-pot reaction, it can be concluded that the heterogeneous Heck process produces about three times more waste than the heterogeneous aldol condensation.
Finally, we have considered that the synthesis 4-(4-methoxyphenyl)-2-butanone (2) can also be achieved through the Heck reaction by coupling an aryl halide with a α-methylene-β-hydroxy compound in the presence of a Pd complex catalyst (Scheme 5). Specifically, the process involves the reaction between p-bromoanisole and methyl-3-hydroxy-2-methylene butyrate using a tetraphosphine palladium complex as a catalyst, in DMF as a solvent and in the presence of K2CO3 or NaHCO3. The yield reported for 4-(4-methoxyphenyl)-2-butanone is 87%.51 The calculated E factor for the specific process, considering the solvent recoverable, is 3.11 (Scheme 5). The E factor involved in the preparation of the tetraphosphine palladium catalyst has not been considered here.
Scheme 5 |
On the other hand, the calculated E factors for the preparation of p-bromoanisole and methyl-3-hydroxy-2-methylene butyrate are 0.21 and 0.77, respectively (see the ESI†). Considering these two values, plus the value for the reaction in Scheme 5, the global E factor for the preparation of raspberry scent following Scheme 5 is 4.09. This is about 1.5× higher than the heterogeneous process described above, and approximately 5× higher than the one-pot process using the PdMgO catalyst.
In Table 4 the specific E factors of each compound involved in the synthesis of 2 are summarized as well as the global E factor for the heterogeneous and homogeneous Heck coupling rection.
In conclusion, a new synthetic process for 4-(4-methoxyphenyl)-2-butanone with raspberry scent has been outlined that involves a one-pot process with a multifunctional (metal acid–base) solid catalyst and which has a much lower E factor than any reported before.
Scheme 6 |
We have calculated the E factor of each step of the process given in Scheme 7, starting from β-pinene, whose bromination to myrthenyl bromide can be accomplished with N-bromosuccinimide in refluxing CCl4, yielding 51% of myrthenyl bromide.54 Taking into account that solvent and unreacted β-pinene are recoverable, we have calculated an E factor of 1.18 for the production of myrthenyl bromide. On the other hand, the second reactant involved, i.e., ethyl acetoacetate, can be produced by a solvent-free Claisen condensation of ethyl acetate in the presence of tBuOK that yields 75% of ethyl acetoacetate. The calculated E factor for this reaction is 2.78. Thus, the E factor of the global process presented in Scheme 7 to prepare the desired product, 3, is 5.45.
Scheme 7 |
An alternative synthetic approach is presented here (Scheme 8), in which 3 can be prepared in a one-pot cascade reaction which involves an aldol condensation between myrthenal and acetone, followed by dehydration of the aldol formed, and selective double bond hydrogenation. For calculating the E factor of the process, it has been considered that myrthenal can be obtained by oxidation of α-pinene with SeO2.55 The oxidation of α-pinene is carried out with equimolar amounts of SeO2 in the presence of a solvent such as ethanol yielding 50% of myrthenal. The E factor for this step (see Scheme 8), considering that both ethanol and the remaining α-pinene can be recycled, is 1.3. The E factor for the global process given in Scheme 8 is therefore 1.6. This value is 3.4× lower than the homogeneous process described previously for the preparation 4-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)-2-butanone (3).
Scheme 8 |
Scheme 9 |
Scheme 10 |
It appeared to us that if the reaction was performed in a one-pot system in which the rate of hydrogenation of the condensation product was very high, then the second condensation that leads to formation of the trimer (6) could be avoided or, at least, could be strongly diminished, giving a higher final selectivity to 2-cyclopentylcylopentanone (5) (Scheme 10). To do this, cyclopentanone was reacted in the presence of PdMgO under a constant hydrogen pressure at 140 °C. After 8 h reaction time, the conversion was 98% with 91% selectivity for 4. Under our reaction conditions, the hydrogenated trimer (2,5-dicyclopentylcyclopentanone) (6) and 2-cyclopentylcylopentanol were also detected, with yields of 10 and 2%, respectively. The higher selectivity towards 4 achieved in this case, with respect to the conventional procedure, demonstrates the advantage of the one-pot cascade process using the PdMgO catalyst. In this case, it appears that the fast hydrogenation of the intermediary, 2-cyclopentilydene-cyclopentanone, diminishes the rate of the subsequent aldol condensation that leads to the undesired highly-conjugated trimer.
As shown in Scheme 10, the E factor for the heterogeneous-catalyzed, one-pot cascade process is one order of magnitude lower than the conventional method.
Table 5 summarizes the E factors for the synthesis of 4 using heterogeneous and homogeneous catalysts.
Compound | E factor (heterogeneous) | E factor (homogeneous) |
---|---|---|
4 | 0.10 | 1.16 |
Since, in many cases, the new routes proposed require starting from different reactants than the conventional routes, we have also calculated the E factor for the global process starting from the primary products. It has been seen that, in most cases, the new one-pot cascade reactions have E factors which are one order of magnitude lower. The differences in the E factor can be even larger if one considers the energy involved and even the investments, since the one-pot processes do not require intermediate separations.
Finally, it has been shown that, in some cases, higher selectivities can be achieved in the one-pot cascade reactions with multifunctional catalysts, by adjusting the relative rates of the different consecutive steps.
The magnesium–aluminium layered double hydroxide sample (Mg–Al LDH) was prepared from a gel produced by mixing two solutions, A and B. Solution A contained (3 −x) mol of Mg(NO3)2·6H2O and x mol of Al(NO3)3·9H2O in the (Al + Mg) concentration of 1.5 mol L−1 for an Al/(Al + Mg) molar ratio of 0.25. Solution B was formed by (6 + x) mol of NaOH and 2 mol of Na2CO3 dissolved in the same volume as solution A. Both solutions were co-added at a rate of 1 mL min−1 under vigorous mechanical stirring at room temperature. The gel was aged under autogeneous pressure conditions at 333 K for 12 h. Then, the hydrotalcite was filtered and washed until pH = 7 and the solid was dried. The Mg–Al mixed oxide (HTc) base catalyst was obtained by calcination of Mg–Al-LDH at 723 K for 6 h in a dry nitrogen flow.
Pd catalysts at 1 wt% loading were obtained by exposing the Mg–Al-LDH or MgO samples to an anhydrous toluene solution with the required amount of palladium acetylacetonate (Pd(OAc)2) for 12 h. After evaporation of toluene at reduced pressure, the solid was dried overnight at 80 °C in vacuum and then calcined in nitrogen flow at 550 °C for 3.5 h. These samples were denoted as PdHTc (calcined hydrotalcite) and PdMgO
The PdHTc sample was rehydrated at room temperature by direct addition of decarbonated water (MilliQ) (36 wt%) just before their use as catalyst, and was labelled as PdHTr.
Samples of PdMgO and PdHTc were activated before reaction by heating the solid at 450 °C under air for 5 h and then 5 h under nitrogen. Reduction of the Pd(II) was performed by heating the solid at 450 °C in a flow of H2/N2 (90/10) for 2 h.
The catalysts prepared were characterized by XRD (Fig. 1), TEM and nitrogen adsorption. N2 adsorption/desorption isotherms were performed at 77 K in an ASAP 2010 apparatus from Micromeritics, after pre-treating the samples under vacuum at 673 K overnight and the BET surface areas were obtained using the BET methodology. The main characteristics of the catalysts are given in Table 6.
Fig. 1 XRD patterns of the solid catalysts. |
Footnote |
† Electronic supplementary information (ESI) available: Details of E factor calculations. See DOI: 10.1039/b919660a |
This journal is © The Royal Society of Chemistry 2010 |