Toward the selection of sustainable catalysts for Suzuki-Miyaura

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Toward the selection of sustainable catalysts for Suzuki-Miyaura coupling; a gate-to-gate analysis Reuben Hudson, and Jeffrey Louis Katz ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b03400 • Publication Date (Web): 06 Oct 2018 Downloaded from http://pubs.acs.org on October 6, 2018

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ACS Sustainable Chemistry & Engineering

Toward the selection of sustainable catalysts for Suzuki-Miyaura coupling; a gate-to-gate analysis Reuben Hudson* † ‡, Jeffrey L. Katz*† †

Colby College Chemistry Department, 5750 Mayflower Hill, Waterville, ME, USA, 04901

‡

Institut für Chemische Technologie von Materialien, TU Graz, Stremayrgasse 9, 8010 Graz,

Austria. KEYWORDS: Suzuki Coupling, C-C coupling, catalysis, gate-to-gate

ABSTRACT: Reports of homogeneous and heterogeneous methods for Pd-catalyzed SuzukiMiyaura coupling provide a vast data set to establish sustainability targets and parameters for future catalyst development. In this gate-to-gate inventory we estimate energy and palladium usage along with reaction mass efficiency (RME) for a range of palladium catalysts (both singleand multi-use) for the generation of a) 4-phenylphenol from 4-iodophenol and phenylboronic acid or b) 4-methoxybiphenyl from 4-chloroanisole and phenylboronic acid. Small differences were found in calculated energy usage, RME values, and non-palladium reagent toxicities. Palladium usage, however, varied substantially and stood out as the main differentiating consideration from a sustainability standpoint. Reusable heterogeneous catalysts still use more palladium when compared to ultra-low loading homogeneous techniques that are effective for

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conversion of aryl iodides. For aryl chloride substrates, highly active and reusable heterogeneous catalysts become a viable, sustainable alternative to traditional homogeneous systems.

Introduction: Catalytic C-C bond forming reactions garner significant research attention as a means toward industrially relevant chemicals. Since Suzuki’s seminal discovery in 1979 of a palladium-catalyzed method to couple aryl halides with aryl boronic acids,1-3 the reaction continues to drive research efforts worldwide. After nearly forty years, a Nobel prize,4-5 and countless successful applications in materials and pharmaceuticals,6 researchers still strive for novel homogeneous or heterogeneous techniques to minimize palladium loading or reduce reaction time and temperature. In general, homogeneous catalysts are thought to offer superior catalytic properties (conversion, selectivity), while heterogeneous catalysts offer an opportunity for reuse—thereby limiting the amount of precious and potentially hazardous material entering the waste stream. Strategies for heterogeneous catalysis include immobilization on solid supports such as silica,7-9 alumina,10 or MOFs,11-12 polymers13-15 or dendrimers.16-18 In the last quarter century, nanoparticles have emerged as a bridge between homogeneous and heterogeneous catalytic systems.19-21 As their size decreases, their high surface area to volume ratio ensures many accessible active sites, although their recovery from solution can be difficult. To ease recovery and aid in stabilization, nanoparticles, just like their homogeneous counterparts, are often immobilized on solid supports. Alternatively, magnetically recoverable nanoparticles can be used directly as catalysts,22-25 or as supports26-29 for more active metal species.30-32 In an effort to weigh the benefits and drawbacks of various Suzuki coupling catalysts from a sustainability standpoint, we herein analyze the energy consumption, and palladium and reagent usage


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associated with the production 1 kg of 4-phenylphenol from 4-iodophenol and phenylboronic acid as well as the production of 1 kg of 4-methoxybiphenyl from 4-chloroanisole and phenylboronic acid. Scheme 1

Materials

Pharmaceuticals

catalyst prep. NOT ANALYZED X

material sourcing

B(OH)2

+

R

Pd

H 2O OR

O

Base Energy

Normalized to Production of 1 kg

This Analysis

Purification NOT ANALYZED

First Analysis: X = I, R = H Second Analysis: X = Cl, R = Me

Typical Conditions: X

1 mmol

R

Pd

0.05-1 mol%

H 2O

2-10 mL

O B(OH)2

1-1.5 mmol

Base

2-3 mmol (Na2CO3, iPrNH, Et3N, K2CO3, Na3PO4, K3PO4)

This Analysis: Pd

How much Pd used? OR

Energy How much energy needed?

Reaction Mass Efficiency Calculation (mass product/mass reagents)

Scope: Our analysis first includes a limited gate-to-gate inventory of the reagent inputs, energy consumption, and palladium usage associated with the production of 1 kg of 4-phenylphenol from 4-iodophenol and phenylboronic acid and second, the production of 1 kg of 4methoxybiphenyl from 4-chloroanisole and phenylboronic acid (scheme 1). Our intent is to isolate the catalyst performance from upstream and downstream processes, so we do not analyze


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reaction work-up or purification procedures, catalyst preparation or catalyst re-isolation (in part because of limited reported data), or raw material sourcing. The lack of available data on catalyst preparation is rendered a minor consideration given the low catalyst loadings coupled with high variability in performance. In order to offer a reasonably constrained analysis of aryl iodide reactivity, we only consider procedures for the specific production of 4-phenylphenol in aqueous systems. This specific reaction can be benchmarked to an early study with a commercially available Pd/C catalyst,33 and has been used frequently as a reference in later heterogeneous studies. We similarly constrain our aryl chloride reactivity analysis altering only the nature of the aryl halide (4-chloroanisole) and the corresponding product (4-methoxybiphenyl). Reaction mass efficiency (RME) was chosen as a simple mass-based metric to consider reaction waste and material usage for several reasons: a) each reaction is aqueous with the same reactants and product so only the specific additives and catalysts differ b) the range of additives (Et3N, K2CO3, Na2CO3, iPr2NH, Na3PO4, K3PO4, TBAB) have modest and similar toxicities (LD50; rat/oral: 460-4150 mg/kg) as well as similar loadings, so differentiation based on human or ecological hazard would be minimal c) the additives do not have ozone depletion or acidification potential d) other than the starting materials themselves (which are consistent across all studies), only the organic bases could contribute to smog formation, and, most importantly, e) emission data and specific characterization of process waste is not available for the reactions. Because the environmental impact of the various reagents and products are similar from system to system (vide supra), a simple mass-based metric such as RME, E-factor, or Atom Efficiency is suitable for our purposes. Given the available data, RME, which considers product and reagent inputs, is therefore the most comprehensive metric to evaluate waste and general resource use. This common metric also allows comparisons to other recent studies.34


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Assumptions: For homogeneous (single use) catalytic systems, all reactants were scaled to normalize to the production of 1.0 kg of product. For heterogeneous (multiple use) catalytic systems, reaction yields were aggregated over the number of catalytic cycles reported for a given system (3-17 cycles). The aggregate yield was then scaled to normalize to the production of 1.0 kg of product. If recycling tests were performed on substrates other than 4-iodophenol or 4chloroanisole, then recycling yields for 4-iodophenol/4-chloroanisole were extrapolated based on the comparative yields of the single-use reported iodophenol/chloroanisole reactions (see the SI for details). It is not our goal to quantify the impact of the equipment used, so for a generalized energy calculation, we considered only heating of the reaction mixtures (not of stirring, cooling, or maintaining a temperature over a period of time), and we estimated the volume and heat capacity of the reactions to be that of the water used. Energy consumption was therefore estimated with Equation 1: q (J) = Mass H2O (g) x 4.184 J/g˚C x (T (˚C) – 20)

Equation 1

The energy requirements for catalyst recovery/recycling were also ignored, because it is not common practice to report the amount of solvent removed from the used catalyst first by filtration, and second in vacuo. Catalysts Analyzed, 4-phenylphenol via 4-iodophenol: In this analysis, we compare the following catalytic systems for the synthesis of 4-phenylphenol from 4-iodophenol and phenylboronic acid (Table 1): Pd nanoparticles loaded on cellulose paper (PdNPs@paper);35 Pd nanoparticles stabilized by lignin (PdNP@lignin);36 homogeneous Pd(dptf)Cl2 with non-ionic amphiphiles;37 homogeneous Pd(OAc)2/TPPTS;38 homogeneous Pd(OAc)2 with custom phosphine ligands;39 Pd grafted porous metal-organic frameworks (Pd@MOF);40 cyclodextrin-


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grafted silica supported Pd nanoparticles (Pd@SiO2/CD);41 ‘Pd-free’ couplings catalyzed by trace Pd impurities present in other reagents (Impurities)—this method does not rely on the direct addition of Pd, but instead utilizes the trace Pd impurities present in commercial Na2CO3;42-44 Pd nanoparticles on amphiphilic carbon spheres (Pd@CS);45 Pd nanoparticles on SiO2 (Pd@SiO2);46 Pd complexed on N-heterocyclic carbene functionalized graphene oxide (Pd@GO);47 poly(N-isopropylacrylamide)-grafted Pd nanoparticles (PdNP);48 Fe/Pd doped carbon (Pd/C@Fe);49 hydrogel immobilized Pd (Pd@HG);50 Pd/C;33 Pd-based organocatalyst (PdOC);51 Pd immobilized on Schiff base-functionalized multi-walled carbon nanotubes (PdNP@CNT);52 and poly(meta-phenylene oxide) immobilized Pd (Pd@p(mPO)).53 Catalysts Analyzed, 4-methoxybiphenyl via 4-chloroanisole: In this analysis, we compare the following catalytic systems for the synthesis of 4-phenylphenol from 4-chloroanisole and phenylboronic acid (Table 2): Pd(OAc)2;54 Palladium nanoparticles supported on polyaniline nanofibers (Pd@PANI);55 Pd/C;56 self-assembled poly(imidazole-palladium) (MEPI-Pd);15 Nsubstituted main-chain NHC-Pd polymers (NHC-Pd 157 and NHC-Pd 258); poly(meta-phenylene oxide) immobilized Pd (Pd@p(mPO));53 Pd/hydrophilic salen catalysts (Pd/salen);59 and Pd decorated, silica coated Fe3O4 nanoparticles (Pd@Fe3O4NP).60 Table 1. Pd loading and yields for the production of 4-phenylphenol from 4-iodophenol and phenylboronic acid. Yield for each catalytic cycle Catalyst

mol % Pd

1st

2nd

3rd

4th

5th

6th

7th


6

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PdNPs@paper35

0.2

100

100

95

93

97

-

-

PdNP@lignin36

0.222

100

72

23

-

-

-

-

Pd(dptf)Cl237 a

2

96

-

-

-

-

-

-

Pd(OAc)2/TPPTS38 a

2.5

84

-

-

-

-

-

-

Pd(OAc)239

2.6

90

-

-

-

-

-

-

Pd@MOF40

0.19

88

87

87

87

86

86

-

Pd@SiO2/CD41

0.2

98

98

98

98

90

-

-

Impurities42-44

0.00000008

79

-

-

-

-

-

-

Pd@CS45

0.2

95

95

91

85

-

-

-

Pd@SiO246

0.3

95

93

91

89

-

-

-

Pd@GO47

1

90

90

89

85

72

-

-

PdNP48

0.2

99

94

80

70

-

-

-

Pd/C@Fe49

0.5

94

89

86

85

81

-

-

Pd@HG50

0.05

98

99

99

98

96

91

90

Pd/C33

0.3

99

95

94

90

89

89

-

PdOC51

1.05

94

94

92

90

88

-

-

PdNP@CNT52

0.2

96

96

96

90

-

-

-

Pd@p(mPO)53

0.0004

97

-

-

-

-

-

-

Homogeneous / Heterogeneous


7


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Figure 1. Sustainability metrics for the production of 1 kg of 4-phenylphenol by various Suzuki coupling procedures.

Palladium loading (4-phenylphenol via 4-iodophenol): Despite the wide range of reusable heterogeneous catalysts already developed, the ‘palladium-free’ (Impurities) method that relies on trace Pd impurities present in commercial Na2CO3 remains an as yet unapproachable


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benchmark for low palladium loading for the reaction of aryl iodides and bromides with aryl boronic acids. This ratio of 5.9x10-6 mmol Pd/kg coupling product will not be matched by any heterogeneous system unless exceptionally low loading or exceptionally reusable catalysts are developed. With 4 orders of magnitude greater Pd loading (1.6x10-2 mmol Pd/kg coupling product), the Pd@p(mPO) catalyst came closest to the Impurities system. As a further consideration, the low catalyst loadings required for coupling of iodo substrates can render recovery of the catalyst impractical even upon scale-up (for example, as little as 0.1 mg Pd@p(mPO) can be used at 15 mmol scale). Thus, despite the Pd@p(mPO) system being highly recyclable with chloro-substrates that require higher catalyst loadings (100 mg Pd@p(mPO) at 15 mmol scale), we did not consider catalyst recycling for the iodo substrates; it would take over 10,000 recycling runs of Pd@p(mPO) to match the mmol Pd/kg product ratio of the Impurities system. For comparison, with a Pd usage ratio of 3.2 mg/kg coupling product, the commercially available Pd/C would require recycling over 10 million times with little decrease in yield in order to match the overall Pd loading of the Impurities method. This seems unlikely given the reported 10% drop in yield over five recycles (99% à 89%). The 150˚C Impurities based homogeneous system is clearly the superior choice from the standpoint of Pd loading, although other homogeneous systems require much higher loadings. Energy (4-phenylphenol via 4-iodophenol): The reported procedures required an average of 9 and median of 8 MJ/kg coupling product. Systems with lower energy use also tended to require much higher Pd loadings. Exceptions include Pd@p(mPO) and the hydrogel immobilized Pd (Pd@HG), which both ranked in the top 5 for lowest energy requirements and in the top 3 for lowest Pd loading. Given the higher temperatures and solvent volumes required for related


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Sonogashira61 and Heck62 couplings, these energy values are relatively low for C-C bondforming reactions involving aryl iodides. Reaction Mass Efficiency (4-phenylphenol via 4-iodophenol): RME values lie in a narrow range for the various procedures, from 0.12 – 0.29. In figures 1 and 2 we depict reciprocal RME (which could be considered as Process Mass Intensity; mass reactants/mass products), so that lower values are more desirable for all three graphed metrics. The similar RME values coupled with the similarity in toxicity and environmental hazards of the various additives renders this a relatively inconsequential factor in determining overall reaction sustainability. Mass-based metrics such as RME, E-factor, and atom economy rank such Suzuki couplings comparably with other means of sp2-sp2 C-C bond formation (Heck, Negishi, olefin metathesis, etc).62 Table 2. Pd loading and yields for various catalysts toward the production of 4-methoxybiphenyl from 4-chloroanisole and phenylboronic acid. Yield for each catalytic cycle Catalyst

mol % Pd

1st

2nd

3rd

4th

5th

10th

17th

Pd(OAc)254

1.32

65.5

-

-

-

-

-

-

Pd@PANI55

0.05

92

-

-

-

-

-

-

Pd/C56

1

65

-

-

-

-

-

-

MEPI-Pd15

0.1

98

99

97

96

97

-

-

Poly(NHC/Pd) 157

0.05

90

-

-

-

-

-

-

Poly(NHC/Pd) 258

0.1

74

75

74

78

75

74

72

Pd@p(mPO) 53

0.04

94

98

98

98

90

-

-

Pd/salen59

1

93

-

-

-

-

-

-


10

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Pd@Fe3O4NP60

0.5

96

96

95

95

96

95

-

Homogeneous / Heterogeneous

Figure 2. Sustainability metrics for the production of 1 kg of 4-methoxybiphenyl by various Suzuki coupling procedures.

Palladium loading (4-methoxybiphenyl via 4-chloroanisole): No homogeneous techniques have yet been developed to catalyze Suzuki couplings with aryl chlorides at the ultra-low Pd loadings achievable for the conversion of aryl iodides (5.9 nmol Pd/kg 4-phenylphenol), making it viable for highly active and recyclable heterogeneous catalysts to compete with homogenous


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systems with respect to Pd loading. Indeed, both Pd@p(mPO) and Poly(NHC/Pd) 2 can catalyze the production of 1 kg of 4-methoxybiphenyl using less than 1 mmol Pd, while the homogenous Pd(OAc)2 and Pd/salen systems require in excess of 50 mmol Pd. Energy (4-methoxybiphenyl via 4-chloroanisole): Three catalytic procedures require less than 1 MJ/kg of energy: Pd(OAc)2, along with the two heterogeneous systems that offered the lowest Pd loading, Pd(NHC/Pd) 2 and Pd@p(mPO). Pd@Fe3O4 and Pd@PANI each required about 2 MJ/kg, with the remaining catalytic procedures all requiring more than 5 MJ/kg. Given the decreased reactivity of aryl chlorides compared to aryl iodides in Suzuki coupling reactions, the aryl chloride energy values (

Toward the selection of sustainable catalysts for Suzuki-Miyaura

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