ARTICLE
Received 00th January 20xx, Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Improving process efficiency of Gold-Catalyzed Hydration of
Alkynes: Merging Catalysis with Membrane Separation.
Tahani A. C. A. Bayrakdar,a Fady Nahra,a,b Oihane Zugazua,b Lies Eykens,b Dominic Ormerod*b and Steven P. Nolan*a
In this report, we investigate the integration of a membrane separation protocol in line with the gold-catalyzed hydration of alkynes. The catalytic reaction is optimised towards that end and subsequently merged with membrane technology via the development of an organic solvent nanofiltration (OSN) procedure. The protocol is investigated over both ceramic and polymeric membranes. Several gold catalysts were screened in the hydration of diphenylacetylene 1, and high rejection was observed in all cases using Borsig-type polymeric membranes. Catalyst recycling was also achieved up to 4 times using [Au(OTf)(IPr)] (3). In addition, the retained catalyst in the last catalytic cycle was analyzed and readily converted into [Au(Cl) (IPr)] (synthetic precursor to 3), using a straightforward treatment. The sustainability of the process was improved by using a green solvent, 2-methyltetrahydrofuran (Me-THF), and by reducing the amount of solvent used via the implementation of a second membrane.
ARTICLE Journal Name
Introduction
The development of new methodologies for the straightforward preparation of complex molecules in a greener and more sustainable fashion represents a significant challenge in modern chemistry. Catalysis is a key technology to achieve this goal, especially in terms of atom economy and efficiency.1 The majority of large scale metal catalysis carried out within the pharmaceutical industry utilizes second and third row transition metals that have relatively low terrestrial-abundance as compared to first row metals.2 Therefore, reuse or at least recovery of the transition metal is desirable as many of these metals are classified as critical elements.3,4 Transition-metal (TM) catalysts are generally not reused in homogeneous catalytic system, which is reflected in the high cost of the generated products.5 These costs also affect the extent of use within industry of some of these catalysts. Gold complexes are an excellent example of highly efficient homogeneous catalysts6 that remain underused nowadays, mainly due to their high cost, high catalytic charge and lack of reusability. In addition, fine chemicals, especially pharmaceuticals, require a high level of purity and removal of all traces of transition metal catalysts. In response to this, supported-versions of homogeneous catalysts have emerged as alternatives since they can be easily removed from the reaction medium using simple filtration.7 However, the preparation and use of such catalysts has proven more difficult than anticipated. Problems related to synthesis, catalyst cost, catalyst-deactivation, metal leaching and generally lower catalytic activity and efficiency have long plagued these systems, even to the point of hindering their industrial use.8 Because of these concerns, industrial use of heterogenized transition metal catalysts is far from routine, and separation of metals from products remains an important issue. Several methods have been developed to achieve separation, however, many require high energy and also result in irreversible catalyst deactivation.9
Separation using membrane-assisted technology via organic solvent nanofiltration (OSN) is a low energy method that can overcome these issues and even increase reaction efficiency by internal recovery of the catalyst species, leading to more sustainable processes.9-10 The materials used to prepare membranes for OSN applications are polymeric or ceramic in nature.11 Both types of membranes have their advantages and both are capable of affecting separations on a molecular level.11-12 This approach has demonstrated great potential in process intensification (i.e. improving process efficiency and sustainability) of homogeneous catalysis.13 However, in some cases the catalysts are not fully retained by the membranes, due to the intrinsic catalyst-solvent-membrane interactions.
Chemical modification, such as steric enlargement of the catalyst, would make the catalyst separation process significantly easier.14 Furthermore, the separation is not only affected by size exclusion but solvent-membrane-solute interactions11b, 15 are also fundamentally important. Several research groups have published results outlining the application of membrane technology to transition metal catalysis in organic media;13b, 14a, b, 16 however such reports involving gold separation remain scarce with only two reports
dealing with the separation of gold nanocolloids.16d-e Therefore, an attractive solution to greener processes in gold catalysis might very well reside in merging gold-catalyzed reactions with membrane technology thereby combining efficient/selective reactivity with selective separation and recycling of the gold species.
There are numerous possible scenarios in which a membrane can be applied to a transition metal (TM) catalysed reaction.13b In this present case, our intent is to separate the gold catalyst from the reaction product by retaining the gold species and allow the reaction product to permeate through the membrane. As membranes do not require phase transition or operation in biphasic systems, the separation can occur at the same temperature as the reaction, although this is not a prerequisite. As such, if catalyst stability is sufficient, then separation and reaction can be linked into a single process which conceptually can lead to increased catalyst turnover numbers (TON).17 Within this work the processing method used was principally downstream processing, i.e. the reaction and separation phase are separate. The effect of metal ligand and counterion on membrane performance, catalyst stability and recyclability is the principle focus of the investigation. To that end, we herein report the investigation and optimization of the gold catalysed hydration of alkynes, toward the development of a membrane separation protocol, allowing efficient separation of the gold species from the desired ketone products. The model reaction used here is the hydration of diphenylacetylene 1 to produce 2-phenylacetophenone 2 (Scheme 1).
The addition of oxygen nucleophiles to alkynes is a classic tool that has generated many useful transformations for organic synthesis, and has been catalysed by a variety of metal complexes. The utility of this class of reactions has been demonstrated by a several examples in total syntheses of natural products.18 The Au-catalysed hydration of alkynes has a high atom economy and rapidly generates structural complexity with a wide range of functional group tolerance.
Even though several reports have addressed this reaction, several issues remain unsolved. Mainly, the development of an efficient continuous recycling/separation procedure for the gold catalyst is still lacking. This would allow for a more sustainable implementation of the targeted catalytic system in future large scale processes.
O [Au]
solvent
1 2
H2O
Scheme 1. Gold-catalysed alkyne hydration.
Results and discussion
The envisaged membrane process is one in which the catalyst is retained and the reaction product permeates through the membrane. Membrane performance is typically characterized by the membrane rejection and flux. In this work, volumetric flux J, is defined as the volume of solvent passing through the membrane per unit area and unit time. The flux is expressed as
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Journal Name ARTICLE Lm-2h-1 or if normalized to the trans membrane pressure
expressed as Lm-2h-1bar-1 and termed permeance. Comparison of membrane performance with membranes used at different trans membrane pressure is straightforward using permeance instead of flux. Solute rejection R is a function of the solute concentrations in the permeate Cp and the retentate Cr and is expressed as a percentage.11b, 19 Solute-rejection is a measure of the membrane’s ability to retain the solute in question.
Thus, for the required separation, rejection of the catalyst should be as high as possible and for an efficient process the product rejection should be as low as possible. Rejection however is not simply a matter of size exclusion; the solvent used and solubility parameters of the membrane–solvent–
solute all have a fundamental impact upon membrane performance.15c, 20 The choice of reaction solvent can therefore have a significant effect on membrane choice and efficiency of the process.
To-date, a number of gold N-heterocyclic carbene complexes have been developed that have proved to be efficient catalysts in the reaction of interest here.21 The catalysts that are used in this study are illustrated in Scheme 2. A new catalyst 7 bearing NHC with a bulky methyl-adamantyl group in the backbone was designed in this study in order to examine the effect of such a sterically large catalyst on the membrane separation.
(See ESI for ligand and catalyst 7 synthesis).
N N
Au OTf
N N
Au Ph
Ph OTf
Ph Ph Ph
N N
Au OTf
PhPh Ph
N N
Au OH
N N
Au O
3 4 5
6 7
N N
Au
N N Au H O
BF4
8 O [Au]
solvent, 60°C
1 2
[Au] complexes used:
H2O
Scheme 2. Gold complexes used in hydration of diphenylacetelyne 1.
[Au(OTf)(IPr)] (3), [Au(OTf)(IPr*)] (4), and [Au(OTf)(SIPrMe-Ad)]
(7) are catalysts bearing a triflate counterion (OTf−), which generate the cationic gold-active species in situ by simple dissociation of the poorly coordinating OTf- in the presence of the alkyne. In the case of complexes [Au(OH)(IPr)] (5), and [(Au(CH2COCH3)(IPr)] (6), fluoroboric acid (HBF4) was added to the reaction mixture to generate in situ the cationic active species.21c, 22 The dimer [{Au(IPr)}2(µ-OH)][BF4] (8) dissociates spontaneously in situ, in the presence of the alkyne, to generate two fragments; the alkyne-bound cationic fragment and the neutral gold hydroxide 5 (also referred to as a dual activation catalyst or enabler of cooperative catalysis).23 The reaction conditions of choice were different than the previously reported systems; hydration of diphenylacetylene was carried out at lower concentration and temperature than previous literature examples. This is due to the constraints of the membrane filtration system, i.e. its physical volume imposes high dilution with the small scale experiments that were carried out. Also, the maximum usable temperature of many polymeric membranes is 60 °C. Therefore, a number of batch reactions were performed at 60 °C at a concentration of 0.25M with respect to diphenylacetylene and a catalyst loading of 1 mol% Au.
Membrane Performance. The goal of this work is to achieve the separation of gold from the reaction mixture as well as to investigate the reusability of the homogeneous gold catalyst.
Table 1. Performance of different membranes for catalyst rejection.
aBatch Reaction conditions:
Reactions were carried out
with 1 (4.15 mmol) and
catalyst (2 mol %) in (2:1)
solvent/water (12 mL) at
65°C. bReactions mixture
were diluted to a volume
of 750 mL of the solvent
used in each reaction
3
Entrya Catalyst Solvent Membraneb Permeance Rejection (%)
(L.m-2.h-1.bar-1) Au Product
1 5 MeOH/H2O 1.0 nm TiO2 - 72 63
2 1.0 nm C8 TiO2 - 80 71
3 Starmem-122 1.9 99 0
4 Dioxane/H2O 1.0 nm TiO2 1.8 97 63
5 1.0 nm C8 TiO2 4.2 77 14
6 8 MeOH/H2O 1.0 nm TiO2 - 95 48
7 1.0 nm C8 TiO2 - 23 18
8 Starmem-122 2.2 98 0
9 Dioxane/HO 1.0 nm TiO 2.2 97 69
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and then OSN were done at 25°C , P = 10 bars for ceramic membranes and P = 20 bars for polymeric membrane. Ceramic membranes are tubular in nature and bear a TiO2
filtration layer with a 1 nm average pore size distribution.
Therefore, membranes capable of achieving high catalyst and as low as possible product rejections are required. For the model alkyne hydration reaction initial membrane screening was carried out on reaction mixtures, with downstream processing, using the monomer and dimer complexes 5 and 8 (Table 1). As membrane rejection can change significantly over the same membrane simply by changing the solvent the initial screening experiments were carried out in MeOH/H2O and dioxane/H2O mixtures. Both solvents have previously been reported for this type of transformation.21c, d When the reaction and the separation are carried out independently of each other, reactions can be performed in a small volume and at a concentration of 0.35 M with respect to 1; a concentration more suited to the reaction requirements than unit volume.
Thereafter, the reaction mixture was diluted to a volume of 500 mL with the same reaction solvent and membrane performance determined. Although, with both complexes 5 and 8 and with both solvent mixtures, the unmodified membranes, 1.0 nm TiO2, appear to give high Au rejection (Table 1, entries 4,6 and 9), a mass balance based on the metal analysis suggested Au was adhering to the membrane surface.
As rejection was insufficient with all other ceramic membranes used, i.e. the alkyl modified ceramic membranes,15c these membranes were no used in further studies. In contrast, high gold rejection of 98-99% and no product rejection indicates preferential transport of the reaction product through the membrane when using the polymeric Starmem-122 membrane; which is a polyimide-based membrane (Table 1, entries 3 and 8). This membrane has a lower polarity surface than the ceramic membranes; a property that can explain the
higher rejection of the cationic gold complexes and the fact that the hydrophobic reaction product permeates through the membrane.20, 24 Unfortunately, this is a membrane that is no longer commercially available, a key practical issue. However, the results suggest that a hydrophobic membrane would perform in a more optimal manner.
Performance of the cationic Au-NHC complexes in the model alkyne hydration reaction. Although reaction performance in dioxane/H2O mixtures was good, this solvent would not be preferred if the reaction was to be carried out on large scale.25 A somewhat preferable solvent for larger scale applications of similar chemical properties is THF. Therefore, small-scale batch reactions were carried out in THF/H2O with several gold complexes. This was performed in order to evaluate conversion versus time in THF/H2O at 60°C and at a concentration of 0.25M with respect to 1 for each of the individual Au complexes.
Each reaction was sampled regularly and the conversion was obtained using UPLC analysis. As shown in Figure 1, all mononuclear gold complexes showed good to excellent activity with conversions higher than 85% after 29 hours, and almost complete conversion when 3 was used. However the digold hydroxide 8 only led to 23% conversion under the same conditions. The poor conversion obtained with 8 could be attributed to the diluted reaction conditions that might explain the slower rate at which this dimer complex leads in situ to the active species.
Further membrane evaluation. The batch reactions carried in THF/H2O were afterwards diluted with the same solvent to a volume of 500 mL before filtration. Initial experiments were
Table 2. Rejection and permanence data of catalysts (3-8) over polymeric membranes.
Entrya Catalyst Membranec Permeance Rejection (%)
(L.m-2.h-1.bar-1) Au Product
1 3 PuraMem selective 14.65 72.8 24
2 3 Borsig oNF-2 3.98 95.7 53
3 3 Borsig oNF-1 4.87 98.5 53
4 4 Borsig oNF-1 5.16 97.0 48
5 5 Borsig oNF-1 5.61 99.5 36
6 6 Borsig oNF-1 5.40 99.3 53
7 7 Borsig oNF-1 5.94 99.1 60
8 9b
8 3
Borsig oNF-1 Borsig oNF-1d
4.06 10.33
99.4 98.2
53 47
aBatch Reaction conditions: Reactions were carried out with 1 (5.2 mmol) and catalyst (1 mol % with respect to gold) in (10:1) solvent/water (0.25M) at 60 °C.
bReaction was done in Me-THF. cReactions mixture were diluted with THF to a volume of 500 mL and then OSN were done at 25°C , P = 20 bars. d Reaction mixture was diluted with Me-THF to a volume of 500 mL for OSN.
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0 5 10 15 20 25 30
0 10 20 30 40 50 60 70 80 90 100
3 4 5 time (h) 6 7 8
conversion (%)
Figure 1. Kinetic profile of the hydration reaction of 1 with catalysts (3-8).The conversion values provided here are an average of 2 runs.
carried out with polymeric membranes having low polarity surface such as those of the PuraMem range (Evonik, Germany) or the Borsig range of membranes (Borsig membrane technology, Germany). With reaction mixtures containing catalyst 3, a low catalyst rejection of only 72.8% was obtained using the Puramem selective membrane (Table 2, entry 1). A far better rejection was obtained with the Borsig oNF-2; a membrane of reported molecular weight cut-off of 350 Da (MWCO = 350 Da). The gold rejection over this membrane proved very promising, 95.7% (Table 2, entry 2). Somewhat surprisingly, filtration of reaction mixture containing the same catalyst 3 over the more open Borsig oNF-1 membrane (MWCO
= 600 Da) lead to a slightly higher rejection of 98.5% (Table 2, entry 3). This suggests that catalyst transport across the membrane is diffusion dominated. Which means that the membrane is acting more solvent like than a sieve and consequently the relatively polar Au complexes are a mismatch for the low polarity membrane, affording high rejection. Since
Borsig oNF-1 gave the highest Au rejection, it was chosen as the optimal membrane for all subsequent filtrations. The membrane displayed good to excellent rejections with all gold complexes (Table 2, entries 4-8) and displayed no significant difference in rejection of catalysts 4 and 7 which bears bulkier NHC compared to 3, 5, and 6. The product rejection was in the range of 48-60%. Complete product removal from the reaction mixture would therefore, require a diafiltration process.
Diafiltration is a process in which fresh solvent is added to the unit feed tank at the same rate that solvent permeates the membrane and is removed from the system. Through controlled solvent/product permeation through the membrane and addition to the reactor, solvent volume within the unit remains constant and the lower rejecting species (reaction product) are washed through the membrane. It is important to mention that the filtration using Borsig oNF-1 was very fast with a permeance
Table 3. Conversion and retention data obtained after each catalytic cycle using catalyst 3.
Entry Cycle Time (h) Conversion (%)
Retention after diafiltration (%)a Au Product Starting material
1 1 24 92 93.0 0 0
2 2 24 80 96.5 0 0
3
3
24 58
98.3b 0 0
4 40 78
5
4
24 38
99.6b 0 0
6 48 60
aDiafiltration were done at a flow of 45-52 Kg/h (0.3 m/s). bOnly 5 diafiltration volume were done after the fourth catalytic cycle.
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ARTICLE Journal Name ranging from 4.00 to 5.94 (L.m-2.h-1.bar-1).
Catalyst reusability. After identifying the most suitable membrane, Borsig oNF-1, which retained to a high degree all gold catalysts used in this study, the reusability of the retained gold catalyst was then investigated. Typically, the aim of a membrane process is to recover the metal for reprocessing.
However, ligands can also be costly and are often not considered or recovered from such a process. The ideal situation both from an economic and environmental stand point would be to recover either the complex added to the reaction at the outset, or a complex that will lead to the same active catalyst if used again or even in a different reaction. As 3 showed slightly better activity than the other mononuclear gold catalysts, its reusability was tested in this reaction. The reaction was performed inside the membrane unit in which the substrate and the catalyst in 10:1 THF/H2O mixture were inserted in the unit feed tank and circulated through the system at a flow of 294-300 Kg/h (~2m/s), this ensures turbulent flow and therefore appropriate mixing of the reaction components. The reaction mixture was then heated to 60°C and allowed to circulate inside the process setup for 24 hours. During this time the membrane was bypassed to prevent any damage that may occur due to long-term exposure to this temperature and reaction conditions. After 24 hours UPLC analysis showed a conversion of 92% was obtained for the first catalytic cycle (Table 3, entry 1).The reaction mixture was then diverted over the membrane and subjected to diafiltration in which 7 diafiltration volumes26 were washed through the membrane. Although this was an excessively large volume of solvent it does highlight the stability of the catalytic system used. Indeed, after 7 diafiltration volumes, ICP analysis indicated a gold retention of 93%. In this instance, retention is the gold recovered in the retentate after diafiltration to remove all the keto-product (not to be confused with rejection which measures the gold leakage through membrane at a particular point in time). Membrane rejection of the catalyst being ≥99%, also UPLC analysis shows only traces of the keto product in the retentate after the diafiltration process. Although ICP analysis demonstrates that gold species were highly rejected by the membrane, it does not indicate whether the gold is still in a catalytically useful form or a degradation product. To investigate if the rejected gold could still be used as catalyst, the same molar quantity of 1 as used in the first cycle was added to the membrane unit (containing the retained catalyst).
Again the membrane was bypassed and the mixture heated to 60°C for 24 h with the same cross flow velocity as previously used (read this as a second cycling of the catalyst). After which time the ketone was obtained in 80% yield after 24 h (Table 3, entry 2). Due to extensive sampling after each diafiltration volume for UPLC and ICP analysis, gold retention after 7 diafiltration volumes was 96.5%, however, the UPLC analysis indicates that 4 diafiltration volume were sufficient to remove all the keto product from the retentate. This procedure of 1)reaction followed by 2)keto-product separation via extensive diafiltration, followed by 3)re-addition of the substrate then 4)reaction sequence was repeated a further two times, leading to yields of 58% and 38% of the ketone (Table 3, entries 3 and 5), respectively. In both cases catalyst retention was >98%
(Table 3, entries 3 and 5) which is higher than the retention obtained when performing the diafiltration of the reaction mixture of the first two cycles; as the number of diafiltration volumes used in the third and fourth cycles were reduced to five. It is worth mentioning that after the first and the second cycles, the reaction was allowed to react longer than 24 hrs (Table 3, entries 4 and 6) and therefore, the complete procedure required a period of 2 weeks to complete the meticulous testing. Furthermore, the process can be paused upon completion of the diafiltration step, and the catalyst containing retentate solution can be stored at 4°C for a number of days before being further used in reaction further demonstrating the high catalyst stability.
Although this operation used an excessive volume of solvent, it was designed to principally demonstrate the highly stability of the catalyst employed and in principle the retained catalyst could be recovered. Indeed, at the end of the process the retained gold species were isolated as a light brown colored solid and subjected to NMR analysis. This analysis showed the solids to be a mixture of numerous gold containing species, possibly gold clusters and catalyst 3 being visible in traces. However, treatment of this light brown solid with HCl produced a mixture of [Au(Cl)(IPr)] in 44%
yield (a precursor molecule for several other gold NHC complexes)6e and 10% of the degradation product [Au(IPr)2]OTf. It should be noted that in a more developed process in which fewer diafiltration volumes and more targeted sampling can be used, catalyst retention by the membrane would be improved and therefore the yield of the recovered [Au(Cl)(IPr)] would be higher. The two week campaign effectively tested the true stability of the gold catalyst under very harsh operational and testing conditions.
Improving sustainability The initial approach to improve sustainability was to replace THF with a greener and more amenable to scale up solvent such as Me-THF which is derived from renewable resources.27 To that end, a batch reaction was carried out using Me-THF under the same reaction conditions as when using THF. The reaction in Me-THF did not show any significant difference in comparison to the reaction performed in THF (see Figure S1 in the ESI). This demonstrates that the reaction can be carried out in a solvent more sustainable and suitable for large-scale operations. Additionally, catalyst – product separation by membrane filtration was equally successful in Me-THF (Table 2, entry 9 vs 3). Membrane permeance in Me-THF was about twice that of THF, cf 10.33 L.m-2.h-1.bar-1 in Me-THF vs 4.87 L.m-2.h-1.bar-1 in THF; this was attributed to the lower polarity of Me-THF compared with THF and thus Me-THF has a higher affinity to permeate throughout the non-polar membrane used.
The second approach was to reduce the solvent load for the reaction sequence. This can be achieved in two ways primarily by reducing the large quantities of solvent used during the reaction – filter – fill sequence. Large diafiltration volumes were used between each reaction cycle, this is clearly excessive but was carried out to demonstrate the highly stability of the gold catalyst. Indeed, the necessity to completely remove the
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Journal Name ARTICLE reaction product can be brought into question. However, if it is
deemed necessary then the number of diafiltration volumes can be reduced. Simulation of the diafiltration process using the equation:
%Ri = 100 x e-N(1-ri)
where Ri is the quantity of solute i in the retentate, N is the number of diafiltration volumes and Ri is the average rejection of solute r during the process. Using this simulation after 3 diafiltration volumes more than 90% of the reaction product has been moved as the permeate. Furthermore, this solvent volume can be reduced by using a second membrane intended to retain the reaction product and allow solvent recycling through the system as shown in Figure 2. Indeed, this kind of technique has already been shown to reduce solvent volumes of a diafiltration process by a factor of ten.28
Figure 2. Solvent recycle via the introduction of a second membrane.
Conclusion
In summary, excellent membrane performance in separating homogenous gold catalysts used in the alkyne hydration reaction was achieved with solvent stable polymeric membranes. The catalyst proved to be stable under current operating conditions and proved reusable. Though some degradation was observed at the end of the catalytic cycles, a well-defined gold species can be regenerated and isolated from the final mixture, with a relatively simple procedure. The isolated species is a precursor to several of the deployed gold catalysts in this study. Current research to better understand and improve catalyst stability is ongoing in our groups. This investigation is to the best of our knowledge, the first report on homogenous-gold separation and catalyst recyclability. We have also demonstrate that sustainability of the process can be improved by replacing THF with a greener alternative, more amenable to scale up (Me-THF) and the possibility to reduce the amount of solvent used in the diafiltration step via implementation of a second membrane. This preliminary
report brings us a step closer to applying the catalysis/separation in a fully continuous manner.
We gratefully acknowledge financial support for this work by VITO (Flemish Institute for Technological Research), UGENT (starter and project grants to SPN) and VLAIO (SBO project CO2PERATE to SPN). We thank Umicore AG for gifts of materials.
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