Ni EnCat™ User Guide - Reaxa EnCat User Guide V2_1 July 12.pdf · Ni EnCat TM User Guide Version 2.1 1 Reaxa Ltd, Leeds Bioincubator, Garstang Building, Leeds, LS2 9JT, UK T: +44

Ni EnCatTM

User Guide

Version 2.1

1

Reaxa Ltd, Leeds Bioincubator, Garstang Building, Leeds, LS2 9JT, UK T: +44 (0)113 234 6153; F: +44 (0)113 242 4105; E: [email protected] ; W: www.reaxa.com

Ni EnCat™

User Guide

Ni EnCatTM

User Guide

Version 2.1

2 Reaxa Ltd, Leeds Bioincubator, Garstang Building, Leeds, LS2 9JT, UK

T: +44 (0)113 234 6153; F: +44 (0)113 242 4105; E: [email protected] ; W: www.reaxa.com

Contents Page

Introduction 3

General

Appearance and Characteristics 3 Safety Profile 3 Storage and Handling 3

Guidelines for Use of Ni EnCat™

Catalyst Quantity 4 Temperature 4 Pressure 4 Stirring 4 Solvent Compatibility 4 Catalyst Mechanical Stability 5 Catalyst Recovery and Re-Use 5 pH Compatibility 5 Disposal 5

Chemical Reactions Using Ni EnCat™ Catalysts

Hydrogenation Reactions Nitrile 6 Nitro 8 Other Hydrogenation Reactions 9 Appendix 1: Using Ni EnCat™ Calculating Ni EnCat™ usage from metal requirement 11 Small Scale Weighing Guide 12 Larger Scale Weighing Guide 14 Appendix 2: Optimisation of Ni EnCat™ Reaction Conditions Reaction Temperature 15 Catalyst Loading 16 Comparison to Raney® Nickel 17

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Introduction

Reaxa’s Nickel EnCat™ extends the benefits of microencapsulation to nickel hydrogenation catalysts.

Ni EnCat™ is non-pyrophoric, giving an improved safety profile over conventional sponge nickel catalysts.

Ni EnCat™ can result in very low metal contamination of product and waste streams, allow reuse of the catalyst in multiple batches and allow easy handling at lab and plant scale.

General

Appearance and Properties

• Ni EnCat™ is supplied as water-wet, dark grey-green beads.

• Ni EnCat™ is an active nickel hydrogenation catalyst encapsulated within a porous polymer bead.

• Average bead size range is 100-400 microns.

• Beads are highly cross-linked and do not swell significantly in most common organic solvents.

• EnCat™ beads are generally mechanically robust under normal process conditions.

The metal composition of Ni EnCat™ is tabulated below.

Product Ni Content

% w/w

Ni EnCat™ 21-30

Bespoke products can be made with different bead size, nickel content and modified polymer cross-linking to meet individual customer requirements.

Safety Profile

Ni EnCat™ has been extensively tested at an internationally recognized process safety laboratory

showing that the product is a non-pyrophoric, non-flammable solid when dried.

Ni EnCat™ meets the United Nations Recommendations for Transportation, and can be safely

transported in bulk form.

These properties make Ni EnCat™ a safer, easier to handle alternative to conventional nickel

catalyst.

Storage and Handling

Store Ni EnCat™ in a cool area, under nitrogen-sparged water, to maintain optimal catalyst activity. The shelf life of Ni EnCat™ is over 6 months, typical for other nickel catalysts.

Nickel EnCat™ users must perform an appropriate process risk assessment for their particular

chemistry, including waste disposal.

Please see the nickel EnCat™ Material Safety Data Sheet for important safety and hazards information.

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Guidelines for Use of Ni EnCat™

Catalyst Quantity

Ni EnCat™ contains 21-30 wt% of active nickel catalyst with the remainder of the weight made up of polymer matrix which supports the catalyst and produces Ni EnCat™’s improved handling properties. Therefore, more Ni EnCat™ must be used to give an equivalent nickel loading to conventional nickel catalysts which contain 85-100% nickel.

As a guideline, four times the weight of Ni EnCat™ will be required to give the same nickel loading for a given weight of standard nickel catalyst:

400g of Ni EnCat™ has approximately the same nickel content as 100g of sponge/Raney nickel.

Due to the polymer matrix, reaction rates may be slower for Nickel EnCat™ compared with conventional catalysts. Reaction rates may be improved by adding more catalyst or by increasing the reaction temperature by 10-20 degrees.

The catalyst can be easily filtered and reused in subsequent batches allowing the overall catalyst usage to be reduced.

Temperature

The polymer matrix can withstand temperatures up to 160 °C in most solvents Pressure

No degradation of the beads has been seen up to 18 bar / 261 psi Stirring

The beads are less dense than sponge nickel and are free flowing within solvent, so vigorous stirring to agitate the catalyst is NOT needed and can cause unwanted damage to the polymer beads.

It is recommended to keep stirring speeds to below 300 rpm.

High-shear, high-speed turbine mixers are NOT recommended.

Use of magnetic stirrer bars in flat-bottomed laboratory glassware may lead to grinding of beads after extended use.

Solvent Compatibility

For hydrogenation reactions, water, alcohols, THF, and ethyl acetate are preferred solvents, with other hydrocarbons also being compatible. Aqueous systems are a good choice for green chemistry, but may require heat and/or higher pressures to operate effectively.

Reaxa does not recommend solvents such as DMF, or DMA or DMSO, due to possible swelling of the polymer at high temperatures.

Bi-phasic solvent systems (e.g. toluene/water) should be avoided as agglomeration of Ni EnCat™ at the aqueous/organic interface can occur.

Most other polar and alcoholic solvents work well with Ni EnCat™ giving very low levels of metal leaching.

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Catalyst Mechanical Stability

Suspensions of Ni EnCat™ (2 g) were stirred using a flat magnetic bar at 20 °C in various solvents (10 ml) for 7 days. The appearance of the beads was analysed by light microscopy to determine any bead degradation.

Over this extended test, no damage was seen with IPA, water or toluene as solvent.

Catalyst Recovery and Re-Use

Ni EnCat™ catalysts can be re-used in multiple batches, and examples are included within this document to demonstrate catalyst recovery and re-use without significant loss in activity.

The catalyst may be recovered by decanting the reaction mixture from the beads, washing and recharging fresh starting materials, or by filtration, washing and re-charging to the reactor vessel. For catalyst storage between batches, it is advisable to keep the catalyst protected from oxygen ingress by storing under nitrogen sparged-water to maintain activity. pH Compatibility

Generally a range of pH 6-14 is recommended. Acidic conditions may deactivate the nickel catalyst. Disposal

Waste materials and spent catalyst should be disposed of in a similar manner to conventional nickel catalysts, as controlled waste via a licensed contractor according to local regulations. Metal value may be reclaimed at a suitable licensed contractor by incineration of the beads to recover the nickel metal.

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Chemical Reactions Using Ni EnCat™ Catalysts Ni EnCat™ quantities are measured assuming 60% water “transfer slurry” and a dry bead nickel content of 25 wt%. If residual water is detrimental to the desired transformation, Ni EnCat™ may be easily washed with the reaction solvent before use.

Hydrogenation Reactions

Nitrile Hydrogenations Reduction of 4-chlorobenzonitrile

Cl N Cl

NH2

H2 (5 bar),

NH3/MeOH, r.t.

10 mol% Ni

Ni EnCat™ (164 mg of 60% wet beads, 10 wt% Ni on substrate) was washed three times with methanol to remove water, decanting the wash solvent from the beads each time. 1-Chloro-4-benzonitrile (137 mg, 1 mmol) and methanolic ammonia (7N, 4 mL) was added and the reaction mixture stirred for 6 hours at room temperature [r.t. (25 °C)] under a 5 bar hydrogen atmosphere. GCMS analysis showed 100% conversion of starting material.

Hydrogenation of 3-(1-Piperidino)-propionitrile

N

NN NH

2

H2 (5 bar),

NH3/MeOH, r.t.

10 mol% Ni

Ni EnCat™ (320 mg of 60% wet beads, 10 wt% Ni on substrate) was washed three times with methanol to remove water, decanting the wash solvent from the beads each time. 3-(1-Piperidino)-propionitrile (276 mg, 2 mmol) and methanolic ammonia (7N, 8 mL) were added and the reaction mixture stirred in a pressure vessel at 25 °C under 5 bar hydrogen. After 6 hours a sample was taken for analysis by GCMS and HPLC which showed 100% conversion of the starting material. The beads were removed by filtration, washed with methanol and the solvent removed in vacuo to give the desired product (258 mg, 1.8 mmol, 91 % yield).

Re-use Example 1: Reuse of Ni EnCat™ in Hydrogenation of an Atorvastatin Intermediate

O O O

ONC

O O O

ONH2

H2 (5 bar),

MeOH, NH3, 45°C

10 wt% Ni

Ni EnCat (270 mg of 60% wet beads, 10 wt% Ni on substrate) was washed three times with methanol to remove water, decanting the wash solvent from the beads each time. (4R,6R)-Tert-butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate 1 (269 mg, 1 mmol), methanol (4 mL) and aqueous ammonia (0.1 mL) were added and the reaction mixture stirred under 5 bar of hydrogen at 45 °C. Samples were taken for analysis by GCMS at 5 and 16 h. For each re-use, the reaction mixture was decanted from the catalyst and the beads washed once with methanol before

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further substrate and reaction solvent were added and the reaction repeated. The conversions to amine product 2 are summarised in Table 1 below.

Cycle Conversion at

16 h

1st cycle >99

2nd cycle >99

3rd cycle >99

4th cycle >99

5th cycle >99

Table 1: Re-use of Ni EnCat™ in the Hydrogenation of Nitrile 1 to Amine 2 Complete conversion to product was seen over 5 re-uses in 16 h reaction times with a 10 wt% Ni catalyst loading.

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Nitro Reductions

Hydrogenation of 1-chloro-3,4-dinitrobenzene

Cl

NO2

NO2

Cl

NH2

NH2

H2 (5 bar),

IPA, 45 °C

10 mol% Ni

Ni EnCat™ (484 mg of 60 % water wet beads, 10 wt% Ni on substrate) was washed three times with IPA to remove water, decanting the wash solvent from the beads each time. 1-Chloro-3,4-dinitrobenzene (404 mg, 2 mmol) and IPA (6 mL) were added and the reaction mixture stirred at room temperature under 5 bar hydrogen. The reaction was run for 22 hours at 45°C after which time a sample was taken for analysis by GCMS. Analysis showed the formation of a single product and complete consumption of the starting material. On completion of the reaction, the beads were filtered, washed three times with IPA and the solvent removed in vacuo to give the desired product (quant., 2 mmol, 100% yield). Hydrogenation of 4-chloro-3-nitrobenzonitrile

Cl

NO2

CN

Cl

NH2

CN

H2 (5 bar),

IPA, 45 °C

10 mol% Ni

Ni EnCat™ (440 mg of 60 % water wet beads, 10 wt% Ni on substrate) was washed three times with IPA to remove water, decanting the wash solvent from the beads each time. 2-Chloro-5-cyano-nitrobenzene (366 mg, 2 mmol) and IPA (6 mL) were added and the reaction mixture stirred at 60°C under 10 bar hydrogen. The reaction was run for 22 hours after which time a sample was taken and the reaction analysed by GCMS. Analysis showed the formation of a single product and near quantitative (>99%) conversion of the starting material. On completion of the reaction, the beads were filtered, washed three times with IPA and the solvent removed in vacuo to give the desired product (286 mg, 1.9 mmol, 94% yield). Re-Use Example 2: Hydrogenation of para-Nitrophenol with re-use of Ni EnCat™

OH

NO2

OH

NH2

H2 (5 bar),

IPA, rt

10 mol% Ni

Small scale experiments were carried out to test the reduction of para-nitrophenol with Ni EnCat™ and the scope for re-use of the EnCat™ catalyst. p-Nitrophenol (0.139 g, 1 mmol), Ni EnCat™ (150 mg of 60% wet beads, 10 wt% Ni on substrate) and AcOH (5 ml) were placed in a 22 ml Parr pressure vessel. The vessel was sealed and pressurised to 6 bar with hydrogen then stirred at r.t (25 °C) for 22 h. The vessel was then vented and the reaction mixture decanted from the catalyst beads which were washed with a small amount of water. Fresh substrate and reaction solvent were added and the pressure vessel sealed and pressurised to 6 bar with hydrogen. This process was repeated for four catalyst runs. The reaction mixture was analysed each time by HPLC (Table 2).

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Catalyst

Run HPLC

Conversion (%) Reaction Time (h)

1 100 22 2 100 22 3 100 22 4 100 22

Table 2: Ni EnCat™ re-use in the hydrogenation of p-nitrophenol No starting material was observed in each case. The Ni EnCat™ catalyst maintained activity over four runs without any decrease in reaction time for complete conversion.

Other Hydrogenation Reactions

Hydrogenation of styrene oxide

O

OHOH+

H2 (5 bar),

MeOH, r.t.

5 mol% Ni

Ni EnCat™ (150 mg of 60 % water wet beads, 5 wt% Ni on substrate) was washed three times with methanol to remove water, decanting the wash solvent from the beads each time. Styrene oxide (250 mg, 2.1 mmol) and MeOH (4 mL) were added and the reaction mixture stirred at r.t (25 °C) and at a hydrogen pressure of 10 bar for 5 hours, after which time a sample was taken and the reaction analysed by GCMS. Analysis showed the formation of a single product and complete consumption of the starting material. On completion of the reaction, the beads were filtered, washed three times with methanol and the solvent removed in vacuo to give the desired product (224 mg, 1.8 mmol, 88% yield). Analysis by HPLC confirmed that 2-phenylethanol was the only regioisomer formed with no 1-phenylethanol detected. Hydrogenation of benzophenone

O OH

H2 (5 bar),

IPA, 60 °C

20 mol% Ni

Ni EnCat™ (874 mg of 60 % water wet beads, 20 wt% Ni on substrate) was washed three times with IPA to remove water, decanting the wash solvent from the beads each time. Benzophenone (364 mg, 2 mmol) and IPA (6 mL) were added and the reaction was run for 22 hours at 60°C at 5 bar after which time a sample was taken and the reaction analysed by GCMS. Analysis showed the formation of a single product and complete consumption of the starting material. On completion of the reaction, the beads were filtered, washed three times with IPA and the solvent removed in vacuo to give the desired product (265 mg, 1.44 mmol, 72% yield).

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Reductive Amination

Cl

NH2

OCl

NH

+H2 (5 bar),

MeOH, r.t.

10 mol% Ni

Ni EnCat™ (146 mg of 60 % water wet beads, 10 wt% Ni on substrate) was washed three times with methanol to remove water, decanting the wash solvent from the beads each time.

Benzaldehyde (102 µl, 1 mmol), 4-chlorobenzylamine (122 µl, 1 mmol) and MeOH (4 mL) were added and the reaction was run for 5 hours at r.t (25 °C) at 5 bar after which time a sample was taken and the reaction analysed by GCMS. Analysis showed complete consumption of the benzaldehyde starting material and a 95% conversion to the desired product. Minimal Metal Leaching from Ni EnCat™ in Hydrogenation of an Atorvastatin Intermediate

O O O

ONC

O O O

ONH2

H2 (5 bar),

MeOH, NH3, 45°C

6.5 wt% Ni

The hydrogenation reaction as for Re-Use Example 1 was set up using Ni EnCat™ (1.0 g of 66% water wet beads, 6.5 wt% Ni), tert-butyl (((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-yl) acetate 1 (0.50 g, 1.86 mmol), methanol (4 ml) and conc. ammonia aq. (0.1 ml). The solution was magnetically stirred at 45 °C for 16 h under 5 bar hydrogen pressure. Reaction mixture was removed from the catalyst by decantation and analysed by GC-MS which showed a conversion to product of >99%.

Nickel content was measured by ICP by dissolving the product in a known mass of DMSO. The unknown was compared against nickel standards of known concentration, taking an average of three measurement. The measured nickel content in the solid was 39 ppm. The nickel content following the re-use of the beads in a second run gave a nickel content 14 ppm, showing consistently low levels of nickel in the products.

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Appendix 1: Using Ni EnCat™

1. Calculating Bead Usage from Metal Requirement

Ni EnCat™ is supplied under water as an active nickel catalyst containing approximately 25 wt% nickel in a porous polymer bead. Quantities of Ni EnCat™ needed for a reaction can be calculated from the nickel loading required. For a mass of substrate operating at a particular wt% loading of Ni, the mass of Ni EnCat™ required is given by:

Or, for a nominal 1 g quantity of substrate the mass of Ni EnCat™ required is given in the table below for some typical Ni loadings.

Required Ni loading (wt%)

5 7.5 10 12.5 15 20

Mass of Ni EnCat™(g) 0.2 0.3 0.4 0.5 0.6 0.8

Example The hydrogenation of 3-chloronitrobenzene (FW = 157.55) with Ni catalyst requires a 5 wt% loading of Ni. The reaction is to be carried out on a 10 mmol scale (1.58g of 3-chloronitrobenzene).

Mass of Ni EnCat™ = (Mass of substrate × wt% Ni) / 25

= (1.576 × 5) / 25

= 0.316 g

This is the dry weight of Ni EnCat™ beads.

N.B. If the catalyst loading is expressed in mol% this can be converted to wt% using:

wt% = (mol% × FW Ni) / FW substrate

= (mol% × 58.69) / FW substrate

Ni EnCat™ should be stored and handled under water and water wet to maintain activity. Two methods to allow dispensing of known weights of Ni EnCat™ while water wet are described below.

Mass substrate × wt% Ni required

25 Mass Ni EnCat™ required =

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2. Small Scale Weighing Guide

1. Ni EnCat™ is supplied as activated catalyst beads under water. Over time the beads settle out.

2. Stir or gently shake the sample to agitate the beads and produce a mobile slurry of beads.

3. Using a wide tipped pipette… …pull some of the slurry into the pipette.

4. Allow the slurry of beads to settle in the pipette for approx. 30 seconds.

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5. Transfer the settled beads dropwise into the required container, taking care not to pull air back through

the beads and disturb the bed in the pipette. Bead slurry dispensed in this manner has a moisture content of 60% (i.e. 1 g of slurry contains 0.4 g Ni EnCat™).

1 Use a wide enough pipette to prevent the

beads locking up in the tip.

6. After dispensing the water wet Ni EnCat™ beads may be washed with solvent to remove the water prior

to reaction as required. For a nominal 1 g quantity of substrate, the mass of 60% water -Ni EnCat™ bead slurry required, is tabulated below. This is typical of Ni loadings, used in other catalytic systems.

Required Ni loading (wt%)

5 7.5 10 12.5 15 20

Grams of 60% wet Ni EnCat™

0.5 0.75 1.0 1.25 1.5 2.0

Example For 0.316 g dry Ni EnCat™ beads in a typical transfer slurry (60% water, 40 % Ni EnCat™).

Mass of transfer slurry required = Mass of dry beads × 100 / (100 - moisture content%)

= 0.316 × 100 / (100 - 60)

= 0.79 g

1

The moisture content of six samples dispensed in this manner was measured using a Mettler-Toledo HG53 Moisture Analyser (30 minute run time, 130 °C). An average value moisture content of 58.46% (standard deviation 0.31) was obtained. The use of 60% as the moisture content ensures that the mass of beads is not underestimated by this method.

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3. Larger Scale Weighing Guide

Larger masses of Ni EnCat™ may be determined by weighing the catalyst under a known volume of water. The Ni EnCat™ should not be exposed to air to avoid catalyst deactivation. A correction needs to be made to allow for the volume of water displaced by the catalyst beads, as described below. 1. Weigh a known volume of water to obtain an initial weight, M1. 2. Remove some of the water and add Ni EnCat™ as a water slurry. 3. Refill with water to the original volume and record the new total weight, M2. 4. The mass of Ni EnCat™ is given by the following calculation: Mass of Ni EnCat™ = (M2 – M1)/0.5

(where 0.5 is the bead volume correction factor)

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Appendix 2: Optimising Ni EnCat™ Reaction Conditions The effect of reaction temperature, Ni loading and comparison to Raney® Nickel for Ni EnCat™ were studied using a standard test reaction. The rate of reaction was followed by hydrogen uptake to give relative rates for the different conditions and catalyst charges studied. Standard Test Reaction and Method

Cl N Cl

NH2

H2 (5 bar), MeOH,

r.t.

20 mol% Ni

Ni EnCat (60% wet, desired wt% Ni on substrate) was weighed out into a 22 ml Parr pressure vessel and washed three times with MeOH. To this was added MeOH (2 ml), 7 N NH3/MeOH (4 ml) and 4-chlorobenzonitrile (206 mg, 1.5 mmol) then the pressure vessel was sealed and stirred at 300-400 rpm with a magnetic stirrer bar. The vessel was pressurised to 1.5 bar with hydrogen, vented, then re-pressurised to 6 bar. The change in pressure was monitored and topped up regularly such that the pressure was maintained between 6.5 and 4.5 bar. Reaction was continued until hydrogen uptake ceased then the pressure was vented and the reaction mixture analysed by GCMS to confirm complete conversion. The hydrogen uptake was expressed as a percentage of total hydrogen used and plotted against time to give relative rate information. Reaction Temperature The standard hydrogenation reaction was run at a Ni loading of 10 wt% on substrate at 20 °C and 40 °C. The results are shown in Figure 1. This clearly demonstrates that a small increase in reaction temperature leads to significant reduction in Ni EnCat™ reaction time, with >95% conversion achieved in 140 minutes at 40 °C compared on 260 minutes at 20 °C.

0

20

40

60

80

100

0 100 200 300 400

Time (minutes)

Hy

dro

ge

n U

se

(%

of

tota

l)

20 °C

40 °C

Figure 1: Comparison of 10 wt% Ni as Ni EnCat™ at two reaction temperatures

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Catalyst Loading Increasing the catalyst loading as expected increased the rate of reaction, as demonstrated for three different Ni EnCat charges at 40 °C in Figure 2. Time to >95% conversion decreased to 70 minutes with a 20 wt% Ni loading. As Ni EnCat™ is straightforward to recycle, even these relatively high loadings can easily become economical.

0

20

40

60

80

100

0 50 100 150 200 250 300

Time (minutes)

Hy

dro

ge

n U

pta

ke

(%

of

tota

l)

5 wt%

10 wt%

20 wt%

Figure 2: Comparison of Ni EnCat™ at three catalyst loading

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Comparison to Raney® Nickel The equivalent test reaction was carried out using different charges of Raney® Nickel (Sigma-Aldrich Raney® 2800) at a temperature of 40 °C. The Raney® catalyst was weighed out as a water wet slurry (assumed 50% wet) and the reaction set up identically to the Ni EnCat™ reactions. The results showed that under these conditions double the loading of Raney® catalyst was required to give the equivalent rate to Ni EnCat™ (Figure 3) with 20 wt% Ni EnCat™ giving equivalent rate to 40 wt% Raney®.

0

20

40

60

80

100

0 50 100 150 200 250

Time (minutes)

Hy

dro

ge

n U

pta

ke

(%

of

tota

l)

EnCat 10 wt%

EnCat 20 wt%

RaNi 20 wt%

RaNi 40 wt%

Figure 3: Comparison of Raney® Nickel and Ni EnCat™ at different loadings

The rate comparisons show that small changes to reaction conditions can be used to greatly enhance the reaction rates obtained using Ni EnCat™ catalyst.

Documents

Ni EnCat™ User Guide - Reaxa EnCat User Guide V2_1 July 12.pdf · Ni EnCat TM User Guide Version 2.1 1 Reaxa Ltd, Leeds Bioincubator, Garstang Building, Leeds, LS2 9JT, UK T: +44