university of groningen chemo-enzymatic routes to ... · 2.1.1 existing biphasic epoxidation...

University of Groningen

Chemo-enzymatic routes to enantiopure haloalcohols and epoxidesHaak, Robert M.

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2008

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Haak, R. M. (2008). Chemo-enzymatic routes to enantiopure haloalcohols and epoxides. s.n.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 10-10-2020

https://www.rug.nl/research/portal/en/publications/chemoenzymatic-routes-to-enantiopure-haloalcohols-and-epoxides(c24b44f3-2b41-4fa7-9787-5ab756154e52).html

https://www.rug.nl/research/portal/en/publications/chemoenzymatic-routes-to-enantiopure-haloalcohols-and-epoxides(c24b44f3-2b41-4fa7-9787-5ab756154e52).html

Chapter 2 Epoxidation of olefins in a centrifugal contact separator

In this chapter, our investigations towards a continuous transition-metal catalyzed

epoxidation reaction in a centrifugal contact separator (CCS) are described. The results

of two epoxidation methods selected for further study, based on iron and tungsten,

respectively, will be discussed. Furthermore, a number of new iron-based catalysts are

presented that can be used for epoxidations using peracetic acid as the terminal

oxidant.a

a Part of this chapter will be submitted for publication: R. M. Haak, A. J. Minnaard, J. G. de Vries, and B. L. Feringa, Iron-catalyzed epoxidation of olefins, manuscript in preparation.

Part of this chapter will be reported in: G. N. Kraai, B. Schuur, F. van Zwol, R. M. Haak, A. J. Minnaard, B. L. Feringa, H. J. Heeres, and J. G. de Vries, Process Intensification. Continuous Two-Phase Catalytic Reactions in a Table-Top Centrifugal Contact Separator, book chapter on the occasion of the 22nd Biennial ORCS Conference on the Catalysis of Organic Reactions, Richmond, Virginia, 2008.

40

Chapter 2 - Epoxidation of Olefins in a CCS.doc

Chapter 2

2.1 Importance of process intensification − the CCS

Fast and selective epoxidation of olefins remains a challenging goal in organic chemistry.1 Epoxides are especially valuable because of their versatility as intermediates in organic synthesis. The goal of the project described in this thesis is the development of new methods for the production of epoxides and epoxide-derived compounds in high yields and with high stereoselectivities by integration of synthetic, biochemical and chemical engineering methods.

Central to this approach is the shift towards more sustainable and safer processes, especially by using continuous systems, a concept known as process intensification.2 The use of such energetically and environmentally more benign methods is increasingly important based on economic and environmental considerations, but also for reasons of public perception.3

The most often used strategy towards process intensification is the application of continuous flow processes, since they allow the production of large quantities of compound, using equipment that is small compared to batch reactors.4 Within the area of continuous flow reactors, microreactor technology has received a lot of attention.2,5 Compared to conventional reactors, higher heat and mass transfer rates are possible in microreactors. This allows for more selective and higher-yielding reactions, even under more extreme conditions.2 However, there are some disadvantages to microreactors, for instance congestion of the microchannels through fouling. Furthermore, scale-up is only possible by parallel use of a large number of microreactors, which can be costly.6 We set out to investigate another approach towards intensification of processes, namely the use of centrifugal contact separators (CCSs), which are table-top sized flow reactors.

Figure 2.1 Schematic representation of the CCS. In this continuous centrifugal separator, the light and heavy phase are intensively mixed after entering the reactor (indicated by the cross-hatched area) after which they are separated by centrifuging (light gray for the light phase, dark gray for the heavy phase).

41


Epoxidation of olefins in a centrifugal contact separator

CCSs are devices that allow continuous fast mixing and consecutive separation of two phases. They combine very intensive mixing in an annular zone with rapid separation by centrifugation, as illustrated in Figure 2.1. We have investigated the use of a particular CCS, the CINC V-02 separator.7

Since the phases are mixed intensively in the annular zone and the average residence time of reagents in the CCS is of the order of minutes, it should be possible to perform biphasic reactions in the CCS, provided they are fast enough. Following this approach, the lighter, organic stream would contain starting material and eventually product, whereas the heavier phase would consist of an aqueous solution of reagent(s) and catalyst. As shown in Scheme 2.1, a number of CCSs in series would allow a continuous cascade of transformations.

Scheme 2.1 Envisioned catalytic cascade performed in a series of CCSs; TM catal. = transition metal catalyzed.

There are a number of important requirements that reactions should fulfill if they are to be performed in a CCS. First of all, they should be liquid-liquid phase reactions. A common approach is the use of organic-aqueous two-phase systems, but there are organic-organic biphasic systems that can also be used (vide infra). Secondly, reactions conducted in a CCS should be fast, since the residence time of reagents in this type of

42


Chapter 2

reactor is relatively short, of the order of minutes.b Another requirement is that reactions in the CCS should be highly (chemo)selective, since the aim of cascade catalysis requires that the organic outlet stream of one CCS can be used directly as the inlet stream of another reactor.

There are some additional restrictions: gases cannot be used as reactants or produced as by-products, since this would interfere with the separation in the centrifuge. Reactions should run at atmospheric pressure and at a temperature well below the solvent boiling point, since heating is possible in the CCS, but not at reflux conditions.

Based on these considerations − fast, selective, mild conditions, compatible with two-phase systems − reactions catalyzed by enzymes or transition metal catalysts seem most promising.

2.1.1 Existing biphasic epoxidation reactions Initially, we set out to develop the cascade shown in Scheme 2.1, which could, conceivably, be realized by linking multiple CCSs in series. This cascade starts with a transition-metal catalyzed epoxidation, followed by enzymatic enantioselective epoxide ring opening using a halide or other good leaving group as the nucleophile. This biocatalytic reaction is coupled to racemization of the haloalcohol produced by ring opening, so that enantiopure epoxides are eventually obtained in high yield. Hence, for the first step we looked for an epoxidation procedure that fulfilled the requirements for use in the CCS.

Existing procedures for the epoxidation of olefins1 suffer from several drawbacks that complicate their potential use in the CCS. For instance, in phase transfer catalysis a water-soluble reagent is transferred to the organic layer by means of a phase transfer catalyst to perform the reaction.8 In the cascade envisioned (Scheme 2.1), the organic layer is directed to another CCS to engage in a subsequent reaction, and this is complicated if remnants of reagent or catalyst from a previous step are present in the organic stream. Furthermore, existing epoxidation procedures often require reaction times which are too long to be of use in the CCS, are substrate-specific, employ expensive catalysts, or operate at harsh conditions.

A few examples will be evaluated to clarify the specific demands that the use of the CCS places on reactions.

b After technical modifications making it possible to recycle the stream containing the product, this condition became less strict.

43



An elegant system that at first glance seems to be a good candidate for scale-up in general has been reported by Hamilton and coworkers.9 They employ an aqueous solution of sodium hypochlorite for the epoxidation of substrates such as phenanthrene (Scheme 2.2). The required phase-transfer catalyst is available commercially and the reaction conditions are relatively mild (pH 8.5). However, it is effective only for polyaromatic hydrocarbons. Furthermore, reagents such as hypochlorite could damage the CCS.

O

CHCl3, rt

NaOCl aq. pH 8 - 9

[Bu4N]+HSO4− (0.2 - 1 eq.)

90% Scheme 2.2 Epoxidation of phenanthrene using NaOCl.

Another system that employs sodium hypochlorite has been reported by Montanari et al.10 It is based on the manganese-porphyrin catalyst C2.1 (Scheme 2.3) and has the advantage that non-activated olefins such as cyclooctene (S2.1) are epoxidized. However, the catalyst requires a lengthy synthesis and, as in the previous example, the use of hypochlorite in the CCS might not be feasible.

Scheme 2.3 Epoxidation of cyclooctene using a Mn-porphyrin catalyst.

As an oxidant, hydrogen peroxide is clearly preferred over hypochlorite, since its only by-product is water and it does not cause corrosion.11 Various tungstate catalysts have been reported for epoxidation,1 such as that by Venturello et al. in the early eighties, illustrated in Scheme 2.4.12 A range of olefins, including less reactive terminal alkenes such as 1-octene (S2.2), are epoxidized using H2O2 as the terminal oxidant and a catalyst that self-assembles from sodium tungstate and phosphoric acid. As phase transfer catalyst, methyltrioctylammonium chloride is used. Drawbacks of this system include the harsh conditions that are employed (e.g. pH 1.6), as well as the use of environmentally unfriendly dichloroethane. Furthermore, the time-scale of the reaction is too long for application in the CCS.

44


Chapter 2

Scheme 2.4 Tungstate-catalyzed epoxidation of 1-octene (S2.2) under acidic conditions.

An analogous procedure, developed by Noyori and coworkers,11b,13 suffers from similar drawbacks: it employs an expensive ligand and the reaction conditions are relatively harsh. Furthermore, it has an induction time before the epoxidation starts, something more frequently seen in transition-metal catalyzed epoxidations (vide infra). In a batch setup, this is not a problem since the reaction may be allowed to run as long as necessary, but in a CCS there is much less room for variation of the residence time of the reagents. An induction period therefore leads to low conversions.

2.2 Exploring epoxidation reactions for use in a CCS

2.2.1 Manganese-catalyzed epoxidation reactions Considering the drawbacks of several known biphasic procedures for olefin epoxidation (see paragraph 2.1.1), we decided to develop a two-phase epoxidation protocol based on a known fast, clean, and selective method.

Our first attempts were based on the work published by Hage14 and Burgess15 on manganese catalysis. First of all, the manganese-catalyzed epoxidation method developed by Hage and coworkers in collaboration with the group of Feringa was investigated.14 This procedure uses hydrogen peroxide as the oxidant, and in general works under mild conditions. The dinuclear Mn2(μ-O)3 complex C2.2 used as catalyst is based on the 1,4,7-trimethyl-1,4,7-triazacyclononane (tmtacn) ligand. Mechanistic studies performed in our group have revealed, among other things, that the catalyst retains its dinuclear structure throughout the catalytic cycle.16,17

Scheme 2.5 Epoxidation of 1-decene (S2.3) catalyzed by manganese catalyst C2.2.

45



The main disadvantage of this method is the need to add hydrogen peroxide over an extended period of time (using a syringe pump), because of the propensity of C2.2 to catalyse the disproportionation of hydrogen peroxide. In preliminary investigations, it was found that 1-decene (S2.3) was efficiently epoxidized using 0.2 mol% of catalyst and 1.5 equivalent of hydrogen peroxide in the presence of an additive such as glyoxylic acid (Scheme 2.5). Unfortunately, efforts to develop a two-phase system were unsuccessful. Conversion was obtained only in acetonitrile or acetone, whereas in biphasic systems of water and apolar organic solvents, Mn-tmtacn catalyzed epoxidation was ineffective.c

Table 2.1 MnSO4-catalyzed epoxidation of styrene (S2.4).a

Entry Cosolvent t

(h) Conversion

(%) 1 DMF (25 mL) 24 >99 2 DMF (5 mL) / pentane (5 mL) 96 49

a) 15 mL of aqueous NaHCO3 buffer (0.2 M, pH 8) was used.

The manganese-catalyzed epoxidation described by Burgess and coworkers15 provided an alternative method, with the advantage that it uses low-cost, readily available manganese sulfate as catalyst. As expected, it was possible to epoxidize styrene (S2.4) at room temperature using manganese sulfate as catalyst and DMF as cosolvent, but the reaction suffered from reaction times that were prohibitively long for application in the CCS (Table 2.1). Another disadvantage is the fact that 10 equivalents of hydrogen peroxide have to be used, because of the propensity of the manganese salt to catalyze disproportionation of hydrogen peroxide. The subsequent biphasic reaction in a n-pentane/aqueous solvent mixture reached only 46% conversion after 5 days, despite the fact that the concentrations of reagents were much higher than in the single-phase system (Table 2.1, entry 2).

c Subsequent research in our group has shown that certain combinations of water and organic solvents may be used in Mn-tmtacn catalyzed epoxidation and cis-dihydroxylation, see Refs. 16 and 17.

46


Chapter 2

2.2.2 MTO-catalyzed epoxidation of pinenes A number of reactions using methyltrioxorhenium (MTO,18 commercially available) and 30% H2O2 in the presence of pyridine ligands were conducted in dichloromethane, as described by Sharpless and coworkers.19

In preliminary experiments, the substrates 1-octene, (1S)-α-pinene, and (1S)-(−)-β-pinene (S2.2, S2.5, and S2.6, respectively, Figure 2.2) were tested under the conditions of Sharpless et al.19a with the difference that 40 mol% of pyridine was used instead of 12 mol%, to improve reaction rates (Scheme 2.6).

Scheme 2.6 MTO-catalyzed epoxidation of β-pinene (S2.6) using H2O2.

Under these conditions, S2.6 was fully converted in 1.5 h, whereas with S2.5 82% conversion was reached in 1 h. The terminal olefin S2.2 needed 19 h to reach full conversion to P2.2, using 3-cyanopyridine (0.1 eq) instead of pyridine as ligand.19b

The observed reaction rates were too low to be of use in the CCS at that point. Moreover, it was observed that the MTO was predominantly present in the organic phase instead of the aqueous one. This interfered with our intentions to use the CCS for a catalytic cascade as depicted in Scheme 2.1. In the envisioned cascade, the catalyst and reagents constitute one of the streams, typically the aqueous one, whereas the starting material and product are dissolved in the other, usually organic, stream. In conclusion, another epoxidation reaction had to be found for use in the CCS.

2.3 Biphasic iron-catalyzed epoxidation of olefins

Recent years have seen the publication of some notable examples of methods for iron-catalyzed epoxidation. An example is a procedure that uses peracetic acid in combination with an iron(III) catalyst, published by Dubois et al. in 2003.20 Analogous iron systems are known that catalyze the oxidation of alkanes using peracids21 or alkyl hydroperoxides.22 The catalytic mechanism is not known for most of these systems, but it has been observed that “mono and dinuclear iron(III) peroxo complexes were identified in several of them.”22

47



The complexes used as catalyst (C2.3a and C2.3b, Figure 2.4) have been known for several years.23 They form readily from low-cost commercially available starting materials and are active catalysts for the epoxidation of olefins by peracetic acid. Besides alkene epoxidation, they were also reported as catalysts in alkane oxidation.24 First, the original system was investigated (Scheme 2.7).

Scheme 2.7 Fe(III)-catalyzed epoxidation of olefins.

The substrate scope of this epoxidation method is broad. Cyclic olefins such as cyclooctene and cyclohexene are epoxidized efficiently, but the procedure is also effective for terminal alkenes such as 1-octene. Using olefins such as styrene, epoxidation is observed, but in this case the product is unstable under the reaction conditions due to solvolytic ring opening.

In this and the next paragraph, two novel procedures based on this method are described. First of all, a two-phase epoxidation method for application in a centrifugal contact separator, described in this paragraph and secondly, as a spin-off, an epoxidation method that uses a range of iron complexes to catalyze the epoxidation of olefins (Paragraph 2.4). The substrates that were used in these studies are depicted in Figure 2.2.

Figure 2.2 The substrates used in this study, cyclooctene (S2.1), 1-octene (S2.2), 1-decene (S2.3), styrene (S2.4), (1S)-α-pinene (S2.5), and (1S)-(−)-β-pinene (S2.6).

We became interested in the possibility of adapting the iron(III)-based system of Stack and coworkers20 for use in the CCS. First attempts to use catalyst C2.3b in an n-heptane/water biphasic system with water as the (co)solvent were unsuccessful (see Section 2.4). It was thought that the homogeneous system on which it was based, could be converted into a two-phase system by using an alkane as a second solvent in

48


Chapter 2

combination with acetonitrile. In this way, the reactant olefin and the product epoxide would reside preferentially in the hydrocarbon phase, whereas the catalyst and oxidant would stay in the acetonitrile layer. The results of our preliminary studies on batch scale are depicted in Table 2.2. Reactions were run on 10 mmol scale, using 20 mL of both pentane and acetonitrile and 1.0 mol% of catalyst.

Table 2.2 Epoxidation of S2.1 in alkanes / acetonitrile catalyzed by C2.3b.a

Entry t

(h)/cycle Conv. (%)

Solventb Misc.

1a 0.17 73 MeCN/n-pentane slow add. of C2.3bc b 47 93 2a 0.17 63 MeCN/n-pentane slow add. of C2.3b and AcOOHd b 21.5 94 3a 1st 72 MeCN/n-heptane 7 cycles, 15 min each b 2nd 100 c 3rd 91 d 4th 71 e 5th 79 f 6th 72

a) For details see the experimental section; b) Reaction procedure was similar whether n-pentane or n-heptane was used; c) A solution of catalyst C2.3b was added slowly to the reaction; d) Both catalyst C2.3b and peracetic acid were added slowly to the reaction mixture.

As expected, the non-catalyzed reaction takes longer in the two-phase system than in acetonitrile (not shown in the table). Two days are needed to reach >90% conversion. The order of addition of reagents was crucial in obtaining high yields of epoxide. Although the literature mentions slow addition of peracetic acid to a solution already containing the catalyst, we found that adding a stock solution of catalyst to the rest of the reaction mixture gave better results. Epoxidation was fast (73% of P2.1 after 10 min), although the reaction slowed down considerably after this period, suggesting catalyst deactivation (entry 1). Slow addition of both catalyst C2.3b and peracetic acid gave similar results (entry 2). The catalyst loading in this biphasic system was higher than in acetonitrile (1.0 vs. 0.25 mol%). By increasing the catalyst loading even more, we demonstrated that multiple cycles are possible. The experiment shown in entry 3 was an attempt to use a single batch of catalyst (1 equiv. with respect to a single batch of substrate) to catalyze the epoxidation of multiple batches of S2.1. A total of 6 batches of

49



S2.1 (10 mmol each) were epoxidized using 10 mmol of C2.3b, with fair to good conversions after 15 min of reaction for each batch.

In all experiments, gas development was observed in the course of the reaction, suggesting that catalyst C2.3b also catalyzes the disproportionation of peracetic acid. The decline in reaction rate after the first 10 min of reaction further supports this hypothesis. Otherwise, the reactions appear clean, cyclooctene oxide (P2.1) being the only product observed.

Terminal epoxides such as 1,2-epoxyoctane (P2.2) are a valuable class of compounds from an industrial perspective.25 The epoxidation of 1-octene (S2.2) was initially more problematic than that of cyclooctene under these biphasic conditions. However, by increasing the substrate concentration from 0.5 to 1.0 M, S2.2 was converted to the epoxide (Table 2.3). Thus, for a reaction on 10 mmol scale, 10 mL of n-pentane and 20 mL of acetonitrile were used, leading to a maximum of 72% conversion after 24 hours (entry 3). Although the reaction is substantially slower than the corresponding epoxidation of S2.1, (Table 2.2), these results show that biphasic iron-catalyzed epoxidation of less reactive terminal olefins is feasible. Note that under these biphasic conditions, non-catalyzed epoxidation of 1-octene is not observed.

Table 2.3 Epoxidation of S2.2 in alkanes / acetonitrile catalyzed by C2.3b.a

Entryt

(h) Conv. (%)

1 0.17 12 2 3.75 35 3 24 72

a) For details see the experimental section.

There are some drawbacks associated with this alkane/acetonitrile biphasic approach, which make it less convenient for use in the CCS. For instance, the by-product acetic acid has to be separated from the acetonitrile layer in which it is dissolved before this layer can be used as, for instance, the ingoing stream of another CCS. Furthermore, there is considerable decomposition of peracetic acid with concurrent catalyst deactivation during the reaction. These phenomena were most pronounced when both the catalyst and the oxidant are simultaneously added to the acetonitrile layer with no olefin substrate being present. In the CCS setup, the phase containing the substrate is separated from that containing the catalyst and oxidant, compelling us to look for ways

50


Chapter 2

to prevent this highly exothermic and potentially dangerous decomposition of peracetic acid.

It became apparent that another setup of the CCS would be necessary for this reaction. This structural modification would consist of an extra inlet for the catalyst stream, depicted schematically in Figure 2.3. Using this setup, the catalyst could be added to the system slowly. This design was based on the premise that the low-cost catalyst would not need to be recovered.

a) b)

Figure 2.3 a) Setup of the CCS prior to modification: Heptin and MeCNin indicate the ingoing n-heptane and acetonitrile streams, respectively, whereas Heptout and MeCNout indicate the corresponding outgoing streams; b) Setup of the CCS after modification: Catin signifies the ingoing stream of catalyst (dissolved in acetonitrile).

Although it was now thought that the reaction could in principle be conducted safely in the CCS,26 there were some remaining questions about the safety of the iron-catalyzed epoxidation in the CCS reactor, primarily because the reaction is exothermic. Based on calorimetric experiments, performed in order to obtain the adiabatic temperature increase of the epoxidation, the reaction was deemed not to be safe enough for the CCS.27

Successful implementation of this biphasic iron-catalyzed epoxidation method in the CCS will require a more stable catalyst, which should also be less prone to catalysis of peracetic acid decomposition. Given that technical developments make it possible to recycle one or both of the outgoing streams of the CCS (vide infra), slower but less exothermic epoxidation reactions may be feasible, such as Mn-tmtacn catalyzed epoxidation using hydrogen peroxide (see also Paragraph 2.2.1).14,16,17 Unfortunately, there was insufficient time to develop this manganese-catalyzed process in the CCS.

2.4 Epoxidation of olefins catalyzed by Fe/phen and Fe/bipy complexes

Over the course of our investigations, it was discovered that, in addition to C2.3a and C2.3b, other iron complexes catalyze the epoxidation of olefins by peracetic acid. Moreover, some of these complexes, especially complexes of the form FeIIL3, are more

51



stable than μ-oxo complexes C2.3. In the hope of finding a catalyst that combined high activity and stability, we tested a number of iron complexes for their catalytic activity in the epoxidation of olefins.

One of variations investigated was, for instance, the use of 2,2’-bipyridine (bipy) instead of 1,10-phenanthroline (phen) as a ligand. Also iron(II) compounds with the general formulae [FeII(phen)3]X2 and [FeII(bipy)3]X2 were examined. A complete overview of all catalysts employed in these studies is given in Figure 2.4. Complexes C2.4 − C2.6 were prepared as described in the literature.20,23 The blue complex [FeIII(phen)3](ClO4)3 (C2.7) was prepared by oxidation of the corresponding FeII(phen)3SO4 complex with Cl2, followed by precipitation using NaClO4.30,28

Scheme 2.8 Synthesis of C2.8.

Catalyst C2.8, although described in the literature,29,30,31 was synthesized by an alternative, more straightforward method, outlined in Scheme 2.8. When a mixture of iron trichloride hexahydrate and phenanthroline (molar ratio 2:3) is heated at reflux in absolute ethanol for 30 min, the complex precipitates from solution. An overview of the properties of a number of these and similar iron and other transition metal complexes has been given by Figgis and Lewis.32

The iron(II) and iron(III) complexes listed in Figure 2.4 were examined as catalysts in alkene epoxidation using peracetic acid as the oxidant. A number of aspects merit attention. In all reactions, epoxidation takes place, although the yield varies depending on both substrate and catalyst, as does the ratio of epoxidation vs. the major side reaction, decomposition of peracetic acid forming acetic acid and dioxygen. This section will focus on the epoxidation results using a homogeneous solvent system (typically acetonitrile). Iron-catalyzed epoxidation in a two-phase system is described in Section 2.3.

The rate of uncatalyzed epoxidation using peracetic acid is considerable, but dependent on the substrate. For instance, cyclooctene (S2.1) is converted to cyclooctene oxide (P2.1) completely after an overnight reaction (17.5 h). In the case of the terminal olefin 1-octene (S2.2), the reaction is slower, reaching 79% conversion after a reaction period of 24 h. Oxidation of styrene is very fast in the absence of catalyst (64% conversion after 3 h), however, a number of byproducts are formed, notably 2-phenylacetaldehyde.

52


Chapter 2

As already mentioned in the literature, simple iron salts such as Fe(ClO4)3 or Fe(ClO4)2 do not catalyze this epoxidation reaction.20 Furthermore, preliminary experiments with alternative oxidants such as t-BuOOH, cumene hydrogen peroxide, or H2O2, were unsuccessful. It was reported recently that iron-catalyzed epoxidation is possible using peracetic acid formed in situ from hydrogen peroxide and acetic acid.33,34 A preliminary experiment was carried out using this approach. However, epoxidation was not observed.

Figure 2.4 The iron(II) and iron(III) catalysts used in this study.

The results of the screening of substrate S2.1 are described in Table 2.4. In general, reactions were performed using 10 mmol of substrate, 0.5 mol% of catalyst, 2 equivalents of peracetic acid, and 20 mL of acetonitrile.

Complex C2.3a is one of the most extensively used catalysts in this study, together with C2.3b. Since the difference between C2.3a and C2.3b was found to be negligible, they were used interchangeably.20 Epoxidation using C2.3a in acetonitrile, under the

53



conditions mentioned in literature,20 led to full conversion in 5 min (entry 1). In order to investigate to what extent the reaction was compatible with the presence of water, a series of experiments were performed in which the water content of the reaction was increased stepwise from 0 to 40% (entries 1 − 5). The reaction slowed down considerably, showing only 51% conversion after 5 min when 30 or 40% water with respect to acetonitrile was used. A possible explanation is that the presence of water in the reaction mixture favors decomposition of peracetic acid instead of epoxidation. Furthermore, [Fe(phen)3]2+ species are readily formed in the presence of water, which are themselves catalytically inactive, although they may be converted to an active catalyst after an induction period (vide infra).

Table 2.4 Iron-catalyzed epoxidation of cyclooctene (S2.1) by peracetic acid.a

Entry Cat

(mol%) T

(°C) Solvent

t (min)

Induction (min)

Conv. (%)

1 C2.3a 0 → rt MeCN 5 −b >99 2 C2.3a 0 → rt MeCN + 10% H2O 5 −b 64 3 C2.3a 0 → rt MeCN + 20% H2O 5 −b 72 4 C2.3b 0 → rt MeCN + 30% H2O 5 −b 51 5 C2.3b 0 → rt MeCN + 40% H2O 5 −b 51 6 C2.4 0 → rt MeCN 60 −b 96 7 C2.5a rt MeCN 210 n.d.c 98 8 C2.5b rt MeCN 60 n.d.c >99 9 C2.8 rt → 0 MeCN 12 6 100

a) For details, see the experimental section; b) Reaction started immediately; c) Not determined.

Employing C2.4, a μ-oxo FeIII complex with bipyridine ligands (Figure 2.4), led to full conversion after a reaction time of 1 h (entry 6). Use of the [Fe(bipy)3]2+ complexes C2.5a and C2.5b gave good conversion in acetonitrile at room temperature (entries 7 and 8). The bright orange complex C2.8 also turned out to be an efficient catalyst for the epoxidation of S2.1 using peracetic acid, giving full conversion in 6 min after an induction period of 6 min (entry 9).

Epoxidations using catalysts C2.3c and C2.5 − C2.7, both for S2.1 and other substrates, were characterized by an induction period, during which the initial iron(II)-species is presumably oxidized to catalytically active iron(III). Possibly, the active species is the same as in the reactions catalyzed by μ-oxo iron complexes C2.3 and C2.4. During this

54


Chapter 2

activation phase, the complex appears to be going through different oxidation states. This is suggested by striking color changes, going from red to orange to blue to yellow. Catalytic activity is only apparent in the last stage, when the reaction becomes highly exothermic and gas evolution (from decomposition of peracetic acid) is also observed. The induction period ranges from 5 min to 1.5 h (vide infra) and can be shortened by heating the reaction or by including a one-electron oxidant such as CAN. In the reaction using Fe(phen)3(ClO4)2 (C2.6b),35 this series of color changes was: red → brown → blueish grey → light blue → orange → yellow. The different colors likely correspond to iron species of various oxidation states and nuclearity.

Since the color of the final active species is the same in all reactions we performed and the rate of the catalyzed epoxidation itself does not vary significantly with the catalyst, it is presumed that the catalytically active species is the same for all catalysts C2.4 − C2.7. Further evidence to back up this hypothesis still has to be obtained, for example on the basis of ES-MS, UV, or electrochemical measurements. Such measurements may shed light on the molecular origin of the observed lag time, which likely involves ligand dissociation and association processes and possibly dimerization, besides oxidation of the iron center. Crucial for obtaining a molecular understanding of the catalysis in this process will be the identification of the active species. Recently, the epoxidizing agent was identified in other systems, such as Mn-tmtacn catalyzed epoxidation using H2O216,17 and iron-catalyzed epoxidation using H2O2 in the presence of acetic acid,36 using a combination of techniques such as 18O labeling, UV-vis, ESI-MS, GC(-MS), X-band EPR, NMR, and electrochemical measurements. In Mn-tmtacn catalyzed epoxidation and cis-dihydroxylation, it was found that the lag time was caused by the formation of the active catalyst from the resting state of the manganese complex.16,17

Besides S2.1, the linear alkenes S2.2 (1-octene) and S2.3 (1-decene) were investigated in this study. Our interest in the epoxidation of 1-octene stems from the fact that terminal epoxides are very useful synthetic intermediates from an industrial perspective.25 The results are summarized in Table 2.5.

Use of C2.3a (entry 1) led to a conversion of 67% in 6 min, whereas the literature mentions full conversion for this reaction.20 Epoxidation using the similar catalyst C2.3b led to fast initial conversion (79% after 15 min), after which the reaction slowed down considerably, possibly due to catalyst deactivation (entry 2). The use of catalyst C2.3c, the chloride equivalent of C2.3a and C2.3b, led to good conversion (86%) after a lag time of 5 min followed by a reaction time of 10 min (entry 3). Interestingly, in the literature it is indicated that C2.3c is inactive as an epoxidation catalyst under these circumstances.20

55



The use of various iron(II) catalysts in principle led to fast reactions. Similar to the epoxidation of substrate S2.1, epoxidation of S2.2 started only after a certain lag time using catalysts C2.5 and C2.6. When C2.5a was used, this period amounted to 24 min, whereas using C2.5b it was about 1 h and 15 min. The subsequent reaction was typically fast, in the order of 10 min. The highest conversion using bipyridine catalysts C2.5 was a moderate 68% (entries 4 − 6).

Results were better using [Fe(phen)3]2+ complexes C2.6 that have 1,10-phenanthroline instead of 2,2'-bipyridine as ligand. For instance, C2.6a gave 91% conversion after a total of 45 min (entry 7), whereas C2.6b gave conversions to P2.2 of 94% after 165 min, including a lag time of 80 min (entry 8). This period could be considerably shortened by heating the mixture before the reaction started (entry 9) or, surprisingly, by including the reducing agent SmI2 (entry 12). Addition of the one-electron oxidizing agent cerium ammonium nitrate ((NH4)2CeIV(NO3)6, CAN) had little effect (entry 10).

Table 2.5 Iron-catalyzed epoxidation of S2.2 and S2.3 by peracetic acid.a

Entry Substrate Cat

(mol%) T

(°C) t

(min) Conv.(%)

Induction (min)

Additive

1 S2.2 C2.3a rt 12 67 − 2a ,, C2.3b 0 15 79 − b ,, ,, ,, 1000 98 − 3 ,, C2.3c 0 10 86 5 4 ,, C2.5a 0 50 50 24 5 ,, C2.5b rt 200 62 80 6 ,, C2.5b Δ→0 5 68 n.d.b 7 ,, C2.6a rt →0 45 91 36 8 ,, C2.6b rt 165 94 90 9 ,, C2.6b Δ→0 66 88 n.d.b 10 ,, C2.6b 0 69 94 50 (NH4)2CeIV(NO3)6c 11 ,, C2.6c rt→0 29 85 19 12 ,, C2.6d 0 12 58 7 SmI2 0.1M in THFc 13 ,, C2.7 rt→0 35 77 30 14 ,, C2.8 rt→0 10 93 4 15 S2.3 C2.3a 0 11 30 n.d.b 16 ,, C2.8 rt→0 12 86 6

a) For experimental details see the experimental section; b) Not determined; c) 1 equivalent w.r.t. the catalyst.

56


Chapter 2

Fe(phen)3Cl2 (C2.6c) gave a good conversion of 85% after 45 min, in contrast with the literature in which it is stated that C2.6c is inactive.20 However, the corresponding PF6−-complex (C2.6d) led to a disappointing conversion (entries 11 and 12). The FeIII-equivalent of C2.6b, C2.7,30,28 showed a disappointing conversion of only 30% (entry 13). Finally, the orange binuclear catalyst C2.8 was used to catalyze the epoxidation of S2.2 efficiently in a short time of 10 min with an lag time of only 4 min (entry 14). It was also observed that FeII-catalysts C2.5, C2.6, and C2.8 catalyzed the decomposition of peracetic acid, hence an excess (2 equivalents) of peracetic acid was used.

Substrate S2.3 (1-decene) was used in reactions using catalysts C2.3 and C2.8 (Table 2.5, entries 15 and 16). The use of catalyst C2.3a led to disappointing conversion (30% after 10 min, entry 1) for unknown reasons. However, using C2.8 led to 86% conversion in 12 min, including an induction period of only 6 min (entry 2).

Substrate S2.4 (styrene) was epoxidized using catalysts C2.3 and C2.8, with mixed results (Table 2.6). Reasonable to good conversions were generally observed. However, the conversion was not selective since considerable amounts of phenylacetaldehyde were also formed. The ratio of P2.4 vs. byproducts is comparable whether the reaction is catalyzed (by C2.3a and C2.8, entries 2 − 4) or not (entry 1). Full conversion was reached only using catalyst C2.8 (entry 4).

Table 2.6 Iron-catalyzed epoxidation of S2.4 by peracetic acid.a

Entry Cat

(mol%) T

t (h)

Induction (min)

Conv. (%)b Misc.

1 − 0°C 2.82 − 63 (38) AcOOH 2.5 eq 2 C2.3a 0°C→rt 0.25 n.d.c 82 (46) 3 C2.3a 0°C→rt 0.08 n.d.c 46 (31) 4 C2.8 rt, 0°C 0.22 8 97 (46)

a) For experimental details see the experimental section; b) In between brackets is the conversion to the epoxide; c) Not determined.

The pinene substrate S2.6 (1S-(−)-β-pinene) was more extensively tested in another reaction, namely MTO-catalyzed epoxidation (see Paragraph 2.2.2). The reaction of S2.6 with peracetic acid catalyzed by C2.3b led to a disappointing yield of 33% after 7 min (Scheme 2.9).

57



Scheme 2.9 Iron-catalyzed epoxidation of (1S)-(−)-β-pinene (S2.6).

In conclusion, we have demonstrated that various iron(II) and iron(III) complexes with phenanthroline or bipyridine ligands are catalytically active in the epoxidation of unfunctionalized olefins using peracetic acid as the oxidant. In general, the use of complexes with phenanthroline ligands (e.g. C2.3 and C2.6) led to faster epoxidation reactions than their bipyridine analogues (C2.4 and C2.5). As expected, dimeric μ-oxo iron(III) / phenanthroline complexes C2.3, some of which have been described before in oxidation catalysis,20 are efficient epoxidation catalysts. When the cationic complexes C2.3a and C2.3b are used, the reaction starts immediately, whereas the neutral complex C2.3c had a lag time of 5 min. Much longer induction times (up to 90 min) are observed when iron(II) complexes C2.5 and C2.6 and iron(III) complex C2.7 are used as catalyst, although the epoxidation itself is as fast as when using catalysts C2.3. The induction period can be shortened most efficiently by heating the reaction mixture until epoxidation starts. Complex C2.8 has a short lag time of 5 min.

It was observed that the presence of water in the reaction mixture is detrimental to the conversion of the epoxidation reaction. In terms of substrate scope, unfunctionalized olefins such as cyclooctene (S2.1) or 1-octene (S2.2) are converted cleanly to the corresponding epoxides. However, styrene (S2.4), which yields an acid-sensitive epoxide, is converted to a number of products, most notably styrene oxide and phenylacetaldehyde.

2.5 Tungsten-catalyzed epoxidation of cyclooctene in the CCS37

In later stages of the project, developments in the setup of the CCS allowed the recycling of one or both phases. Thus, it became feasible to try other, slower but less violent, epoxidation reactions, such as the one reported by Alsters et al.,38 that uses hydrogen peroxide as the oxidant in the presence of a polyoxometalate catalyst based on tungsten. We chose this reaction because i) it employs hydrogen peroxide, one of the more atom-efficient and environmentally friendly of oxidants, ii) this catalyst is known to have a low extent of aproductive catalase activity, a commonly encountered side-reaction in transition-metal catalyzed oxidations, iii) it lacks an induction period prior to the reaction starting, otherwise common in tungsten-catalyzed epoxidations, iv) the reaction conditions are mild: only slightly elevated temperature and near-neutral pH, v)

58


Chapter 2

the catalyst loading is low, vi) this reaction is performed in a two-phase system (see also Section 2.1 for a list of requirements for reactions that are to be performed in a CCS), and vii) perhaps most importantly, the polyoxometalate has no organic ligands, which are notorious weak spots in oxidation catalysis. The characteristics mentioned under iv and vi were important reasons to prefer POM-based epoxidation over tungsten-catalyzed epoxidation as reported by Noyori and coworkers,11b which employs (aminomethyl)-phosphonic acid as an additive.

Polyoxometalates (POMs) are molecular clusters with a wide variety of structures and physical properties.39 They are applied in various areas such as nanotechnology, biology, medicine, surfaces, supramolecular and molecular materials, and sensors.40 Especially the area of catalysis has been investigated in depth.40,41 One of the developments is the epoxidation on large scale of a number of olefins using the polyoxometalate Na12[WZn3(ZnW9O34)2] (hereafter abbreviated NaZnPOM).38 This POM is conveniently obtained by self-assembly of low-cost, commercially available starting materials, according to the equation:42

19 Na2WO4 + 5 Zn(NO3)2 + 16 HNO3 → Na12[WZn3(ZnW9O34)2] + 26 NaNO3 + 8 H2O

The significance of the work described in this paragraph is that it constitutes the first example of a transition-metal catalyzed reaction in a centrifugal contact separator, and demonstrates that such devices may be used to perform highly sophisticated and valuable chemical transformations at a large scale.

The reaction, that was first optimized in common laboratory glassware, is depicted in Table 2.7. The reactions were performed at 25 mmol scale, using 5 mL of toluene, 5 mL 0.1 M aqueous solution of NaZnPOM (so 0.5 mmol W), 0.25 mmol of phase transfer salt (0.5 equivalent w.r.t. W), and 2.5 equivalents of hydrogen peroxide, at a temperature of 60 °C. To simulate the conditions in the CCS as good as possible, stirring was performed mechanically at 600 rpm.

It was found that the replacement of [(n-Oct)3(Me)N]Cl by [(n-Oct)3(Me)N]HSO4 improved reaction rates considerably (compare entries 1 and 2 in Table 2.7). Other modifications from the literature procedure38 include raising of the catalyst loading from 0.1% to 2% and doubling the amount of hydrogen peroxide used (1.5 eq to 3 eq). The quality of hydrogen peroxide was found to be essential in obtaining good

59



conversions, "medicinal extra pure" being the quality of choice.d Under these new conditions, S2.1 was fully converted to P2.1 after 160 min.

Table 2.7 Optimization of NaZnPOM-catalyzed epoxidation of cyclooctene.a

Entry QX t

(min) Conv. (%)b

1 a [(n-Oct)3(Me)N]Cl 120 46 b 1,300 95 2 a [(n-Oct)3(Me)N]HSO4 90 87 b 160 99

a) For details, see the experimental section; b) Conversion was periodically monitored using GC.

The system was now considered ready for the CCS (Figure 2.5). Nevertheless, extensive optimization was required. The first CCS experiments were conducted with an aqueous stream consisting of 200 g of aqueous NaZnPOM stock solution (0.1 mmol W / g of solution), 320 mL of 30% medicinal extra pure H2O2, and 10 mmol of a phase transfer salt. The organic stream consisted of a solution of 1.5 mol of cyclooctene and 40 mmol of n-dodecane as the internal standard in 2.5 L of toluene. The two vessels containing the aqueous and organic feed streams were heated to 65 °C and two peristaltic tube pumps were used to pump the two solutions through the CCS at a flow rate of 10 mL/min for both streams. After an hour, disproportionation of hydrogen peroxide was observed in the the storage vessel for the aqueous feed stream. The vessel was removed from the heat source and the reaction was stopped. No conversion to the epoxide was observed.

Also in subsequent experiments, disproportionation of H2O2 was observed when the aqueous storage vessel was heated for 1 − 1.5 h at 65 °C. Although NaZnPOM was chosen as a catalyst because it was reported that it only catalyzed the disproportionation of hydrogen peroxide to a minor extent,38 it was concluded that in the absence of olefin, the catalyst behaves differently. This was confirmed by an experiment in which the NaZnPOM solution, [(n-Oct)3(Me)N]HSO4, and H2O2 were combined and heated to 80 d Hydrogen peroxide solutions may contain sequestrants for metal ions that interfere with transition-metal catalyzed epoxidation (personal communication by Dr. J. W. de Boer). Medicinal grade hydrogen peroxide is stabilized using small amounts (0.015%) of phosphate buffer, which is compatible with the reaction.

60


Chapter 2

°C in the absence of olefin. After 5 min, evolution of O2 was observed, indicating H2O2 decomposition.

Figure 2.5 Schematic representation of the setup of the CCS. The aqueous phase consisted of 500 g of NaZnPOM solution (0.1 mmol W/g) and [(n-Oct)3(Me)N]HSO4 (0.5 g, 0.1 mmol) at 70 °C. The organic phase consisted of cyclooctene (135.1 g, 1.23 mol), dodecane (12.34 g, 72.4 mmol), [(n-Oct)3(Me)N]HSO4 (9.68 g, 20.7 mmol) and toluene (total volume 2 L) at 70 °C.

The CCS was then modified to allow separate addition of H2O2 from the rest of the aqueous stream. Further modifications included a doubling of the amount of [(n-Oct)3(Me)N]HSO4 and dissolving it in the organic stream instead of the aqueous one, since its solubility in toluene is much higher than in water. Intially, no conversion was observed under these conditions, but when the aqueous stream was recycled, 20% conversion to P2.1 was observed (Figure 2.5). Details regarding the optimization process are given in the experimental section, Paragraph 2.7.6.

The observation that conversion is only seen after recycling the aqueous stream, might be explained by a possible induction period of the catalyst. This is a common phenomenon in tungsten-catalyzed epoxidation.43 NaZnPOM was chosen specifically because of its reported absence of induction time compared to several other systems.38 However, it is conceivable that NaZnPOM has a very short induction time, e.g. of the order of a few minutes. In a measurement on the time-scale of hours, such a short induction would not be noticed, but in CCS experiments it could have a large effect owing to the short contact time of reagents in the appparatus.

2.6 Conclusions and outlook

As part of the development of a catalytic cascade from olefins to enantiopure epoxides on industrial scale, we aimed to set up an efficient biphasic epoxidation in a centrifugal contact separator (CCS). A number of epoxidation methods were examined, taking into account the specific requirements of the CCS, after which two of them were chosen for

61



further development. These were the iron/phenanthroline-catalyzed epoxidation of various olefins using peracetic acid, and the tungsten-catalyzed epoxidation of cyclooctene using hydrogen peroxide.

Based on an existing homogeneous reaction,20 a fast and selective method was developed for iron-catalyzed epoxidation of unfunctionalized olefins in a two-phase system consisting of acetonitrile and a hydrocarbon such as n-heptane, using peracetic acid as the oxidant. Although this method requires the use of higher loadings of catalysts C2.3a and C2.3b than the original procedure, as well as longer reaction times, it has the advantage that it could be used in a biphasic continuous flow process such as in the CCS. However, some of its features limit its applicability. For instance, the procedure may be too exothermic and too prone to peracetic acid decomposition to be safely performed in the CCS. Furthermore, the need for a separate inlet for the solution containing the catalyst, in order to prevent premature catalyst deactivation and disproportionation of peracetic acid, is inconvenient and makes recycling of the catalyst loop impossible.

As a spin-off of the former project, a method was developed for epoxidation of olefins using a variety of iron(II) and iron(III) catalysts. This method also employs peracetic acid as oxidant. The catalysts, which have a longer shelf-life than C2.3a and C2.3b, especially in stock solution, are conveniently available from various low-cost iron(II) and iron(III) salts using bipyridine or phenanthroline as ligands, the latter being the most efficient. Catalysts C2.3c and C2.5 − C2.7 go through an induction period (ranging from 5 to 90 min, depending on the catalyst) before the catalytically active species is formed. Further experimental data on the formation of the catalytically active species and the mechanism of epoxidation still have to be obtained.

In a later stage of the project, technical improvements on the CCS allowed for the use of elevated temperatures, separate addition of catalyst and other reagents, and facile recycling of the two streams. This made it possible to perform reactions that initially were considered too slow for the CCS. Thus, tungsten-catalyzed epoxidation of cyclooctene in a centrifugal contact separator was investigated, using H2O2 as the oxidant. After a single pass of both streams, no conversion to cyclooctene oxide was observed, however, recycling of the aqueous stream (containing the catalyst and reagents) led to a conversion of 20%. Compared to a batch setup, giving conversions of 87% after 90 min and 99% after 160 min in our hands, the result in the CCS is somewhat disappointing.

If the CCS approach is to be successful, it would be highly beneficial if it were possible to have better control over the average residence time of the reagents in the apparatus, so that high conversions can be obtained with a single pass of both product and catalyst stream.

62


Chapter 2

2.7 Experimental section

2.7.1 General remarks Starting materials were purchased from Aldrich or Acros and used as received unless stated otherwise. All solvents were reagent grade and, if necessary, dried and distilled prior to use. Demineralized water was used in the preparation of all aqueous solutions. In epoxidation reactions, hydrogen peroxide (30%, medicinal extra pure grade)e was used.

CCS experiments were performed in a CINC V-02 separator, also known as the CIT V-02 separator, of either stainless steel or Hastelloy®,44 as indicated for each experiment. Two Verder VL 500 control peristaltic tube pumps equipped with a double pump head (3,2 x 1,6 x 8R) were used to feed the CCS. To operate the reactor at elevated temperature, it was equipped with a jacket which was connected to a temperature controlled water bath that has a temperature accuracy of ± 0.01 °C. 1H NMR spectra were recorded on a Varian VXR300 (299.97 MHz) or a Varian AMX400 (399.93 MHz) spectrometer in CDCl3 unless stated otherwise. Chemical shifts are reported in δ values (ppm) relative to the residual solvent peak (CHCl3, 1H = 7.24). Splitting patterns are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Mass spectra (HRMS) were performed on a Jeol JMS-600H. GC-MS spectra were recorded on a Hewlett Packard HP6890 equipped with an HP1 column and an HP 5973 Mass Selective Detector.

GC analysis was performed on a Shimadzu GC-17A or a Hewlett Packard HP6890 spectrometer equipped with an HP1 column. n-Dodecane was used as internal standard. To monitor reactions, 0.1 mL aliquots were periodically taken from the reaction mixture, filtered over a short plug of silica, diluted with ether, and analyzed using GC or GC-MS.

2.7.2 Biphasic manganese-catalyzed epoxidation of styrene The procedure given by Burgess et al.15 was modified. Thus, to a stirred mixture of DMF (5 mL), n-pentane (5 mL), MnSO4•H2O (16.92 mg, 0.1 mmol, 1 mol%), and styrene (S2.4, 1.15 mL, 1.04 g, 10.0 mmol), a mixture of H2O2 30% (10 mL, 11 g, 97 mmol) and

e See Footnote d on page 59.

63



NaHCO3 bufferf (0.2 M, pH 8, 15 mL) was added dropwise over 0.5 h. After 96 h, maximum conversion was reached (49% by GC).

2.7.3 Biphasic MTO-catalyzed epoxidation of pinene Slightly modified conditions compared to those reported by Sharpless et al.19 were used. Thus, a mixture of MTO (13.3 mg, 0.05 mmol), (1S)-(−)-β-pinene (S2.6, 1.57 mL, 1.35 g, 10 mmol), pyridine 0.33 mL (0.32 g, 4.0 mmol), 30 % H2O2 (1.6 mL, 1.78 g, 15.6 mmol), and 10 mL of DCM, was stirred at room temperature. When the reaction had finished, the mixture was washed successively with water, NaHSO3 aq 10% to remove traces of peroxide, NaHCO3 sat. and brine, dried over MgSO4, filtered and evaporated. Spectral data were in accordance with the literature.45

2.7.4 Iron-catalyzed epoxidation of olefins in a two-phase system Stock solutions of catalysts C2.3a and C2.3b were prepared as described by Dubois et al.20 from Fe(ClO4)3 or Fe(NO3)3 and 1,10-phenanthroline. A representative general procedure for the biphasic epoxidation is as follows:

To a 250 mL three-necked flask equipped with a mechanical stirrer, thermometer, and dropping funnel were added n-heptane (20 mL), acetonitrile (5 mL), cyclooctene (S2.1; 1.37 mL, 1.15 g, 10.4 mmol), and peracetic acid 35% (3 mL, 3.39 g, 15.6 mmol). While this mixture was stirred (600 rpm), a solution of C2.3b in 15 mL acetonitrile was added dropwise to the solution.

When the reaction had finished (as judged from GC measurements), the layers were separated, the acetonitrile layer was extracted with n-heptane, the hydrocarbon layers combined, dried over MgSO4, filtered and evaporated. The spectroscopic data of product P2.1 were in accordance with the literature.20

The corresponding reaction of 1-octene (S2.2) was performed analogously, with the exception that only 10 mL of hydrocarbon solvent was used. The spectral data of product P2.2 were in accordance with the literature.20

f A mixture of NaHCO3 (16.80 g, 0.2 mol) and Na2CO3 (100 mg, 0.9 mmol) in 1 L of H2O, see Supporting Information of Ref. 15.

64


Chapter 2

2.7.5 Epoxidation of olefins catalyzed by Fe/phen and Fe/bipy complexes

Catalyst preparation Stock solutions of catalysts C2.3 and C2.4 were prepared as described by Dubois et al.20 from Fe(ClO4)3 or Fe(NO3)3 and 1,10-phenanthroline (phen) or 2,2'-bipyridine (bipy) in acetonitrile.

Stock solutions (100 mM) of catalysts [FeII(bipy)3]X2 (C2.5) and [FeII(phen)3]X2 (C2.6) were prepared by dissolving the appropriate FeII-salt (1.0 mmol) and 2,2'-bipyridine or 1,10-phenanthroline (3.0 mmol) in H2O or acetonitrile (10 mL). The resulting solutions were pinkish red (complexes with bipyridine) or dark red (complexes with phenanthroline).

To isolate the resulting complexes, FeII-salts (10 mmol) and bipyridine or phenanthroline (30 mmol) were dissolved in demineralized water, after which the solution was concentrated until the pinkish red (bipyridine as ligand) or dark-red (phenanthroline as ligand) complexes precipitated out of solution. They were collected on a glass filter and washed with a small amount of ice-cold water and ether, respectively. Complex C2.6 could also be precipitated from the reaction mixture by the addition of 2 equivalents of NH4PF6, giving C2.6d.

[FeIII(phen)3](ClO4)3 (C2.7) was prepared by oxidizing C2.6b according to the procedure described by Plowman et al.23a

[FeIII(phen)2Cl2]+[FeIII(phen)Cl4]− (C2.8)29,30,31 was prepared by refluxing a solution of FeCl3·6H2O (5.41 g; 20.0 mmol) and 1,10-phenanthroline (5.41 g; 30.0 mmol) in EtOH until an orange solid precipitated, which was filtered and dried in a vacuum desiccator. Yield: 8.70 g (10 mmol, quant); mp 270 − 273 °C; Anal. calc. for C36H24Fe2N6Cl6•H2O: C 49.0, H 2.97, N 9.52, found: C 49.1, H 2.96, N 9.20. When dissolved in water, the solution turned from orange to light brown and the resulting complex was found to be paramagnetic. 1H NMR (D2O) δ 23.74 (br), 18.45 (br), 17.33 (br), 16.26 (s), 15.95 (s), 15.82 (br), 15.21 (s), 14.20 (br), 12.02 (br), 10.79 (s), 8.32 (s).

General procedure for iron-catalyzed olefin epoxidation Epoxidation reactions were conducted according to the following general procedure: The catalyst (C2.4 − C2.7, 0.05 mmol) was suspended in MeCN (20 mL), then substrate (S2.1 − S2.6, 10 mmol) and AcOOH (32% in AcOH, 4.5 mL, 5.1 g, 21 mmol) were added. After an induction period, during which the catalytically active species formed, the reaction started. The reaction was highly exothermic and evolution of dioxygen was

65



observed. The progress of the reaction was monitored by periodically checking samples from the mixture by GC.

2.7.6 NaZnPOM-catalyzed epoxidation of cyclooctene

Preparation of NaZnPOM The procedure of Alsters et al.38 was used. Thus, for the preparation of NaZnPOM, Na2WO4·2H2O (3.3 g, 10.0 mol) was dissolved in 9 mL of water and this mixture was heated to 85 °C. Then, HNO3 conc. (0.67 mL, 0.94 g, 15.0 mmol) was added to the mixture, resulting in a yellow precipitate that gradually dissolved. The mixture was subsequently heated to 95 °C and a solution of [Zn(NO3)2·4H2O] (0.68 g, 2.6 mmol) in 5 mL of water was added dropwise to the mixture, during which care was taken that the resulting white precipitate had completely disappeared before another drop of solution was added to the reaction mixture. When all [Zn(NO3)2·4H2O] had been added, the mixture was decanted in 40 mL of water at room temperature, after which water was added to this solution to give a total weight of 100 g, resulting in a NaZnPOM solution containing 0.1 mmol W / g of solution.

Epoxidation of cyclooctene in batch setup To a 250 mL three-necked flask equipped with a mechanical stirrer, a dropping funnel, and a thermometer, were successively added: dodecane (internal standard, 227 μL, 1 mmol), cyclooctene (3.27 mL, 25 mmol), toluene (distilled over Na, 5 mL), [(n-Oct)3(Me)N]HSO4 (116 mg, 0.25 mmol), NaZnPOM (5 mL 0.1 M solution, 0.5 mmol W), and hydrogen peroxide (medical grade, 30%, 8 mL, 70 mmol). This mixture was stirred at 600 rpm at 60 °C. The conversion was monitored periodically by GC.

Optimization of tungsten-catalyzed epoxidation in the CCS The experiments were performed in collaboration with G. N. Kraai. First, the CCS was fed with pure toluene and pure water at the indicated flow rates. Subsequently, the centrifuge was started (40 Hz, which corresponds to 2400 rpm) and the setup was allowed to equilibrate for a period of 1 h. At this point, the toluene feed stream was replaced by the organic feed stream (composition given below for each experiment). After equilibration for 15 min, the reaction in the CCS was started by replacing the water stream with the aqueous feed stream (composition given below for each experiment). Samples were taken at regular intervals and analysed by GC.

First CCS experiment: A stainless steel CCS was used. The low mix bottom plate was applied. The aqueous stream consisted of aqueous NaZnPOM stock solution (0.1 mmol

66


Chapter 2

W/g, 200 g),38,42 H2O2 30% medicinal extra pure (320 mL), and [(n-Oct)3(Me)N]HSO4 (4.69 g, 10.0 mmol). The organic stream consisted of 2.5 L of a solution of cyclooctene (S2.1, 173.88 g, 1.58 mol) and n-dodecane (internal standard, 9.08 mL, 6.84 g, 40 mmol) in toluene. The two vessels containing the aqueous and organic feed streams were heated to 65 °C. The flow rate for both streams was 10 mL/min. Otherwise, the general procedure was followed. After 60 min, evolution of gas and an increasing temperature were observed in the storage vessel for the aqueous feed stream, indicating the decomposition H2O2. The vessel was removed from the heat source and the reaction was stopped. No conversion to the epoxide was observed.

Second CCS experiment: A Hastelloy CCS was used. The composition of the aqueous and organic feed streams was equal to the first experiment. The feed streams (flow rate 10 mL/min for both) were heated to 65 °C and the mantle of the apparatus to 75 °C. Otherwise, the experiment was performed as the first one. After 90 min, evolution of gas and an increasing temperature were observed in the storage vessel for the aqueous feed stream, indicating the decomposition H2O2. The vessel was removed from the heat source and the reaction was stopped. No conversion to the epoxide was observed.

To probe the propensity of NaZnPOM to catalyze disproportionation of hydrogen peroxide, 360 mg (0.77 mmol) of [(n-Oct)3(Me)N]HSO4 was dissolved in a mixture of 15.29 g aqueous NaZnPOM solution (0.1 mmol W/g, 1.53 mmol) and 24.4 mL of H2O2 (30%, medicinal extra pure grade). This mixture was heated to 80 °C. After 5 min, evolution of gas and an increasing temperature were observed in the storage vessel for the aqueous feed stream, indicating the decomposition of H2O2.

Third CCS experiment: A stainless steel CCS was used. In this experiment, hydrogen peroxide was fed to the CCS separate from the rest of the aqueous stream via an extra inlet and was not heated prior to addition. Both other streams were heated to 65 °C and the mantle to 75 °C, as in the previous reaction. Instead of 200 g, 500 g of NaZnPOM solution was used. The phase transfer salt was dissolved in the organic stream instead of the aqueous one. Flow rates: 5 mL/min for both aqueous streams and 10 mL/min for the organic stream. No reaction was observed, neither in the CCS nor in any of the storage vessels.

In the fourth CCS experiment, the conditions were analogous to those in the third experiment, with the difference that twice the amount of [(n-Oct)3(Me)N]HSO4 was used (10 g instead of 5 g) and that it was dissolved in the toluene stream, in which it is more soluble than in water. For the rest, the conditions were analogous to those in the third CCS experiment. No conversion to the epoxide was observed.

Fifth CCS experiment: A stainless steel CCS was used. The high mix bottom plate was applied. Also in this experiment, hydrogen peroxide was fed to the CCS separate from

67



the rest of the aqueous stream via an extra inlet and was not heated prior to addition. Both other streams were heated to 70 °C and the mantle to 80 °C. Flow rates: 3 mL/min for both aqueous streams and 6 mL/min for the organic stream. Otherwise, the reaction was performed analogously to the previous one. When the aqueous supply had depleted, it was recycled, which resulted in 20% conversion to the epoxide in the organic outgoing stream (quantified by GC and GC-MS).

2.8 Notes and references 1 For recent reviews, see: a) G. Sello, T. Fumagalli, and F. Orsini, Curr. Org. Synth. 2006, 3, 457-476; b) Q.-H. Xia, H.-Q. Ge, C.-P. Ye, Z.-M. Liu, and K.-X. Su, Chem. Rev. 2005, 105, 1603-1662; c) E. M. McGarrigle and D. G. Gilheany, Chem. Rev. 2005, 105, 1563-1602; d) E. Rose, B. Andrioletti, S. Zrig, and M. Quelquejeu-Ethève, Chem. Soc. Rev. 2005, 34, 573-583; e) B. S. Lane and K. Burgess, Chem. Rev. 2003, 103, 2457-2473. 2 J.-C. Charpentier, Chem. Eng. Technol. 2005, 28, 255-258. 3 J. F. Jenck, F. Agterberg, and M. J. Droescher, Green Chem. 2004, 6, 544-556. 4 G. Jas and A. Kirschning, Chem. Eur. J. 2003, 9, 5708-5723. 5 V. Hessel, P. Löb, and H. Löwe, Curr. Org. Chem. 2005, 9, 765-787. 6 J. G. De Vries, G. J. Kwant, and H. J. Heeres, WO 2007/031332, 2007, to DSM IP Assets B.V. 7 D. H. Meikrantz, L. L. Macaluso, H. W. Sams III, C. H. Schardin Jr., and A. G. Federici, US5762800, 1998, to Costner Industries Nevada, Inc. 8 T. Ooi and K. Maruoka, Angew. Chem. Int. Ed. 2007, 46, 4222-4266. 9 a) H. E. Fonouni, S. Krishnan, D. G. Kuhn, and G. A. Hamilton, J. Am. Chem. Soc. 1983, 105, 7672-7676; b) S. Krishnan, D. G. Kuhn, and G. A. Hamilton, J. Am. Chem. Soc. 1977, 99, 8121-8123. 10 F. Montanari, M. Penso, S. Quici, and P. Viganò, J. Org. Chem. 1985, 50, 4888-4893. 11 a) J. Brinksma, J. W. De Boer, R. Hage, and B. L. Feringa, Manganese-based Oxidation with Hydrogen Peroxide, in Modern Oxidation Methods, J.-E. Bäckvall, Ed., Wiley-VCH, Weinheim, 2004, pp. 295-326; b) R. Noyori, M. Aoki, and K. Sato, Chem. Commun. 2003, 1977-1986, and references cited therein. 12 C. Venturello, E. Alneri, and M. Ricci, J. Org. Chem. 1983, 48, 3831-3833. 13 a) K. Sato, M. Aoki, M. Ogawa, T. Hashimoto, D. Panyella, and R. Noyori, Bull. Chem. Soc. Jpn. 1997, 70, 905-915; b) K. Sato, M. Aoki, M. Ogawa, T. Hashimoto, and R. Noyori, J. Org. Chem. 1996, 61, 8310-8311. 14 a) J. W. De Boer, J. Brinksma, W. R. Browne, A. Meetsma, P. L. Alsters, R. Hage, and B. L. Feringa, J. Am. Chem. Soc. 2005, 127, 7990-7991; b) J. Brinksma, L. Schmieder, G. Van Vliet, R. Boaron, R. Hage, D. E. De Vos, P. L. Alsters, and B. L. Feringa, Tetrahedron Lett. 2002, 43, 2619-

68


Chapter 2

2622; c) J. Brinksma, R. Hage, J. Kerschner, and B. L. Feringa, Chem. Commun. 2000, 537-538; d) R. Hage, J. E. Iburg, J. Kerschner, J. H. Koek, E. L. M. Lempers, R. J. Martens, U. S. Racherla, S. W. Russell, T. Swarthoff, M. R. P. Van Vliet, J. B. Warnaar, L. Van Der Wolf, and B. Krijnen, Nature 1994, 369, 637-639. 15 B. S. Lane, M. Vogt, V. J. DeRose, and K. Burgess, J. Am. Chem. Soc. 2002, 124, 11946-11954. 16 a) J. W. De Boer, W. R. Browne, J. Brinksma, P. L. Alsters, R. Hage, and B. L. Feringa, Inorg. Chem. 2007, 46, 6353-6372. 17 J. W. De Boer, cis-Dihydroxylation and Epoxidation of Alkenes by Manganese Catalysts, Ph.D. thesis, University of Groningen, 2008. 18 a) First prepared: I. R. Beattie and P. J. Jones, Inorg. Chem. 1979, 18, 2318-2319; b) First used as a catalyst for epoxidation: W. A. Herrmann, R. W. Fischer, and D. W. Marz, Angew. Chem. Int. Ed. Engl. 1991, 30, 1638-1641. 19 a) J. Rudolph, K. L. Reddy, J. P. Chiang, and K. B. Sharpless, J. Am. Chem. Soc. 1997, 119, 6189-6190; b) C. Copéret, H. Adolfsson, and K. B. Sharpless, Chem. Commun. 1997, 1565-1566. 20 G. Dubois, A. Murphy, and T. D. P. Stack, Org. Lett. 2003, 5, 2469-2472. 21 T. A. Van Den Berg, J. W. De Boer, W. R. Browne, G. Roelfes, and B. L. Feringa, Chem. Commun. 2004, 2550-2551. 22 S. V. Kryatov, E. V. Rybak-Akimova, and S. Schindler, Chem. Rev. 2005, 105, 2175-2226, and references therein. 23 a) J. E. Plowman, T. M. Loehr, C. K. Schauer, and O. P. Anderson, Inorg. Chem. 1984, 23, 3553-3559; b) P. C. Healy, B. W. Skelton, and A. H. White, Aust. J. Chem. 1983, 36, 2057-2064. 24 S. Ménage, J. M. Vincent, C. Lambeaux, G. Chottard, A. Grand, and M. Fontecave, Inorg. Chem. 1993, 32, 4766-4773. 25 O. Pàmies and J.-E. Bäckvall, J. Org. Chem. 2002, 67, 9006-9010. 26 Based in part on a personal communication by safety advisors at the Akzo safety lab, Deventer, the Netherlands, in a meeting on 18 February 2005. 27 The calorimetric experiments were conducted by O. Post at the Department of Process Chemistry of NV Organon, Oss, the Netherlands. 28 C. M. Harris and T. N. Lockyer, Chem. Ind. 1958, 1231. 29 a) B. N. Figgis, J. M. Patrick, P. A. Reynolds, B. W. Skelton, A. H. White, and P. C. Healy, Aust. J. Chem. 1983, 36, 2043-2055; b) R. B. Berrett, B. W. Fitzsimmons, and A. A. Owusu, J. Chem. Soc. A Inorg. Phys. Theor. 1968, 1575-1579. 30 A. E. Harvey Jr. and D. L. Manning, J. Am. Chem. Soc. 1952, 74, 4744-4746. 31 A. S. Abushamleh and H. A. Goodwin, Aust. J. Chem. 1982, 35, 1053-1056. 32 B. N. Figgis and J. Lewis, Prog. Inorg. Chem. 1964, 6, 37-239. 33 M. Fujita and L. Que Jr., Adv. Synth. Catal. 2004, 346, 190-194.

69



34 M. C. White, A. G. Doyle, and E. N. Jacobsen, J. Am. Chem. Soc. 2001, 123, 7194-7195. 35 J. Baker, L. M. Engelhardt, B. N. Figgis, and A. H. White, J. Chem. Soc. Dalton Trans. 1975, 530-534. 36 R. Mas-Ballesté and L. Que Jr., J. Am. Chem. Soc. 2007, 129, 15964-15972. 37 The experiments described in this paragraph were performed in collaboration with G. N. Kraai. 38 P. T. Witte, P. L. Alsters, W. Jary, R. Müllner, P. Pöchlauer, D. Sloboda-Rozner, and R. Neumann, Org. Proc. Res. Devel. 2004, 8, 524-531. 39 Thematic issue on POMs: C. L. Hill, Chem. Rev. 1998, 98, 1-2. 40 D.-L. Long, E. Burkholder, and L. Cronin, Chem. Soc. Rev. 2007, 36, 105-121, and references contained therein. 41 The following review systematically covers the fundamental aspects of POM chemistry: M. T. Pope and A. Müller, Angew. Chem. Int. Ed. Engl. 1991, 30, 34-48. 42 C. M. Tourné, G. F. Tourné, and F. Zonnevijlle, J. Chem. Soc. Dalton Trans. 1991, 143-155. 43 R. Neumann and M. Dahan, J. Am. Chem. Soc. 1998, 120, 11969-11976. 44 Hastelloy® is the registered trademark name of Haynes International, Inc. The trademark is applied as the prefix name of a range of over twenty different highly corrosion resistant metal alloys, with nickel as the typical predominant ingredient. 45 A. Bordoloi, F. Lefebvre, S.B. Halligudi, J. Mol. Catal. A: Chem. 2007, 270, 177-184.

70


Chapter 2

university of groningen chemo-enzymatic routes to ... · 2.1.1 existing biphasic epoxidation...

Documents