The Innovation Catalyst - XiMo - ヒドラス化学株式会社

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XiMo - The Innovation Catalyst

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XiMo – The Innovation Catalyst

Timea Ladi, Commercial, Managing DirectorTimea.Ladi@ximo-inc.comXiMo Hungary Kft.Berlini utca 47-49. | H-1045Budapest

Phone: +36 1 580 2000Mobile: +36 30 151 23 88

Levente Ondi, Ph.D., Technology, Managing DirectorLevente.Ondi@ximo-inc.comXiMo Hungary Kft.Berlini utca 47-49. | H-1045Budapest

Phone: +36 1 580 2200Mobile: +36 30 975 18 21

www.ximo-inc.com

Nobel Prize winning technology

Proven technology ready to transform the chemical industryExclusive licenses to metathesis technology

XiMo Founded in 2010 and

Acquired by Verbio in 2018 – Production and Application of Renewables

Verbio is a strategic investor with a focus on renewable fuels and chemicals.

Development, Manufacture and Supply of Highly Active Metathesis Catalysts

Process Development for Large-Scale Metathesis Reaction

Exclusive Licenses in Metathesis

MIT/Boston College, ETH/Osaka, University of Stuttgart, Max Planck Institute

Collaboration Driven Research - Fragrances, Pheromones, performance Polymers

Three partners are actively commercializing products.

XiMo developed catalyst process technology and demonstrated scale production for both Mo- and W-based complexes.

From Glovebox to KiloLab – up to 3 kg / batch

Successful technology transfer with local manufacturer (SONEAS, Hungary)

Initial intermediate production up to 200 kg batch size

Process optimization: 3-4 process steps for catalyst synthesis

Industrial grade solvents with option of recycling

Produced catalysts was successfully applied using tons of feedstocks.

@25 ppm by weight loading 15 kg of catalyst is enough for the transformation of 600 mt of feedstock

Industrialization

Scaling production: Catalyst

• Diverse technology platform with High TON offering a range of transformations including control of stereochemistry.

Industrialization

Scaling production: Commercial ProductsRenewables:

Olefin Feedstock Pretreatment Catalyst Addition Reaction Vessel

from Lab to Pilot Plant

Process Development

Successful Technology Transfer

Predictable results

Market Driven Innovation

Applications for XiMo’s catalystsXiMo’s technology can be used for product solutions in a variety of industries

Industrialization

Some real-life examplesRenewables: Sustainable Products

Industrialization

Some real-life examplesFragrances:

Industrialization

Some real-life examplesSpecialty Chemicals: Performance Polymers

Exchange of alkylidene fragments

Scission and regeneration of carbon-carbon double bonds

Catalyzed by transition-metal alkylidenes

Versatile organic transformations

High potential in

Pharma, Agro, Polymer, Renewable and Fine Chemical Industries

Sustainable Solutions – Energy and Cost Effective with Less Waste

Since 1990 ca. 7500 publications, >900 patents, over 76,000 preparedsubstances *

Olefin metathesis – a powerful synthetic tool

*SciFinder, 2014.

Developing New Catalysts

Stabilizing Active Catalysts – Chemical & Physical Protection

Catalyst Production – From Glovebox to KiloLab and Pilot Plant

Lowering Catalyst Loading – Optimization of reaction conditions: 30-100 ppmwt !!!

Process Development for Metathesis Reaction – from Lab to Pilot Plant

Catalyst Immobilization

Application in continuous processes

Cooperation with ETH Zürich and University of Stuttgart

Innovative R&D activities

Sigman, M. S. and Copéret, C. et al. J. Am. Chem. Soc. 2015, 137, 6699.Buchmeiser, M. and Copéret, C. et al. Angew. Chem. Int. Ed. 2016, 55, 4300.

Air-StableSelf Activating

Catalyst

Supported Catalysts

FormulatedCatalysts

Bulk Catalyst Powder

Special features of Mo/W metathesis catalysts:

High activity - Low catalyst loading in the range of 10 – 100 ppmwt

Z-selective carbon-carbon double bond formation

Enantioselective metathesis reactions

Ethenolysis: Cross metathesis with ethylene

Functional group tolerance:

Amines – frequently present in natural and biologically active substances

Enol ethers – introduction of a readily convertible FG to the molecule

Vinyl halides – introduction of Cl, Br, and F into the molecule

Introduction of a CF3 group into biologically active molecules can beparticularly beneficial; modification of membrane permeability and drugmetabolism

Triple bond – triple bond (alkyne-alkyne) metathesis

Industrial Benefits of XiMo’s Catalysts

Fundamental of Cross Metathesis(Statistical distribution of alkene fragments)

Z-selective Cross Metathesis of Allylic Amides

Hoveyda, et al. Nature 2011, 471, 461.

Literature Examples

Cross Metathesis I.

Direct synthesis of Z-alkenyl fluorides through catalytic cross-metathesis

Demonstration of functional group compatibility

Literature Examples

Cross Metathesis II.

Schrock, Hoveyda, et al. J. Am. Chem. Soc, 2013, 135, 6026.

Synthesis of Z-(Pinacolato)boron Compounds through Stereoselective CatalyticCross Metathesis – Intermediates for Cross Coupling

Literature Examples

Cross Metathesis III.

Z-Selective Cross Metathesis of Enol Ethers

OTBSBr

Literature Examples

Cross Metathesis IV.

Cross Metathesis with Ethylene - Ethenolysis

Schrock, et al. J. Am. Chem. Soc. 2009, 131, 10840.

Literature Examples

Cross Metathesis V.

Bi-functionalization of substrates derived from renewable sources

XiMo unpublished results

Literature Examples

Cross Metathesis VI.

Direct synthesis of Z-alkenyl halides through catalytic ring opening cross-metathesis – Intermediates for Cross Coupling

Literature Examples

Ring Opening Cross Metathesis (ROCM)

Z-selective/Enantioselective RCM towards biologically active products

Hoveyda, et al. Nature 2011, 479, 88. Hoveyda, et al. Nature 2008, 456, 933.

Literature Examples

Ring Closing Cross Metathesis (RCM) I.

Asymmetric Ring Closing Metathesis (ARCM) - Amides

Schrock, Hoveyda, et al. J. Am. Chem. Soc. 2005, 127, 8526.

Literature Examples

Ring Closing Cross Metathesis (RCM) II.

Schrock, Hoveyda, et al. PNAS 2004, 101, 5805.

Schrock, Hoveyda, et al. J. Am. Chem. Soc. 2001, 123, 3139.

Asymmetric Ring Opening and Ring Closing Metathesis

Literature Examples

Tandem Asymmetric ROM/RCM

Stereospecific ROMP of norbornenes to produce polymers with high meltingpoints and crystallinity

Literature Examples

Ring Opening Cross Metathesis Polymerization (ROMP)

Schrock, et al. Macromolecules 2015, 48, 2480.

Literature Examples

Ring Opening Cross Metathesis Polymerization (ROMP)Thermally Latent Catalysts

Tunable onset polymerization temperatureTunable exothermic maximumTailor-made catalysts with high flexible polymerization properties

Neutral Mo-based NHC (N-Heterocyclic Carbenes)

Penta- or hexacoordinate

High structural variability

High stability – air stability

resistance to impurities in monomer

(e.g.: DCPD)

CMe2R1

Pentacoordinate

N N R3R3

R1= Ph;

R2 = 2,6-Me2-C6H3, 3,5-Me2-C6H3, ...

R3= Mesityl, iPr, 2,6-diisopropylphenyl, ...

Hexacoordinate

Elser, I.; Kordes, B.R.; Frey, W.; Herz, K.; Schowner, R.; Stöhr, L.; Altmann, H.J.; Buchmeiser, M.R. Chem. Eur. J. 2018, 24, 12652.

Literature Examples

Ring Opening Cross Metathesis Polymerization (ROMP)

CMe2R1

N N MesMes

I3: R1= Ph; R2 = 2,6-Me2-C6H3,

I4: R1= Ph; R2 = 3,5-Me2-C6H3.

N N MesMes

3: R2 = 2,6-Me2-C6H3,

4: R2 = 3,5-Me2-C6H3.

Elser, I.; Kordes, B.R.; Frey, W.; Herz, K.; Schowner, R.; Stöhr, L.; Altmann, H.J.; Buchmeiser, M.R. Chem. Eur. J. 2018, 24, 12652.

Tunable onset temperature of polymerization (Tonset = 65-140°C)

pre-catalyst Tonset [oC]

I3 100

3 >140

DSC curves of the temperature scan DSCmeasurements of I1-I5.Catalyst/CH2Cl2/DCPD 1 eq./10 µL for 5mgcatalyst/500 eq.Heating program: 0°C for 1 minute, 0 °C to 200°C (10 Kmin-1). Values in brackets: Tonset.

DSC curves of the temperature scan DSC measurements of pentacoordinatecomplexes I3/I4 in comparison to the hexacoordinate pre-catalysts 3/4.Catalyst/TCB/DCPD 1 eq./10 eq./100 eq. Heating program: 0°C for 1 minute,0 °C to 200 °C or 220 °C (5 Kmin-1). TCB: 1,2,4-trichlorobenzene.

Thermally Latent Catalysts

Forbes, et al. J. Am. Chem. Soc. 1992, 114, 10978.

Literature Examples

Acyclic Diene Metathesis Polymerization (ADMET)

Fürstner, et al. Angew. Chem. Int. Ed. 2011, 50, 7829.

Rendering Schrock-type Molybdenum Alkylidene Complexes Air Stable:User-Friendly Precatalysts for Alkene Metathesis

Literature Examples

User-Friendly Pre-catalysts for Alkene Metathesis

Buchmeiser, et al. Angew. Chem. Int. Ed. 2014, 53, 1.

Excellent functional group tolerance

Tolerated functional groups:

Literature Examples

N-Heterocyclic Carbene (NHC) Metathesis Catalysts

TON= 1.200.000 (with in 6 days)

metathesis selectivity greater than 99%

in Propene self-metathesis

Buchmeiser, Coperet, et al. Angew. Chem. Int. Ed. 2016, 55, 4300.

Substrate mol% TONs

Ethyl oleate 0.001 11874 (1h)

Diallyl ether 0.1 780 (24h)

Diallyl diphenylsilane 0.1 880 (24h)

Ethyl oleate ethenolysis 0.1 930 (1h)

Catalytic Activity of 2@SiO2 with functionalized substrates:

Literature Examples

Immobilized Catalyst

2@SiO2 – A remarkable catalyst

Unformulated Schrock-type Mo-/W-based complexes: Extraordinarily effective, but sensitive towards O2 and moisture Their handling and use requires inert atmosphere and appropriate care

Formulation of paraffin pellets from the metathesis complexes: Catalytic performance is retained while bench-top stability is prolonged by hours They can be used in a standard laboratory environment

Isolated, highly active catalyst

Developed formulation technology

Air-tolerant pelletized product

An Easy-to-Use Form of Schrock-type Metathesis Catalysts

• CM

• endoselective ene-yne RCM

• E & Z-selective CM with di-halo ethylene

formation of alkenyl halides

• stereoselective macrocyclic RCM

Formulated catalyst pellets are available at www.ximo-inc.com/webshop

• Cross Metathesis(CM)

• Ring Closing Metathesis(RCM)

• the ‚gold standard’

• highly active and most commonly used in cross metathesis

• substrate pretreatment

XiMoPacs on the Market

• Z-selective (CM)

• ene-ene or ene-yne RCM

enantioselective or

diastereoselective

Formulated catalyst pellets are available at www.ximo-inc.com/webshop

Z-selective CM

• macrocyclization or

• CM with boronic esters

• enantioselective and

• endoselective ene-yne

XiMoPacs on the Market

OTBSBr

XiMoPac-Mo004

Pelletized catalyst is stable on the bench for up to 24 hours*,

Catalytic performance was retained

The same conversion was obtained as in the control experiment

Manipulation on the bench is feasible

Pellet allowed to stand in air [h]

Conversion in HCM of 9DAME [%]

*Catalyst content was determined by 1H-NMR and was identical to the reference sample. Ondi, L. et al. Org. Process Res. Dev. 2016, 20, 1709.

XiMoPacs – Air Stability

Entry TEAl amount Conversion [GC, %] Z/E Ratio

1 NO 74 15/852 0.8 mol% (1 pellet) 91 15/853 1.6 mol% (2 pellets) 97 14/864 2.4 mol% (3 pellets) 91 14/86

Metathesis catalysts are sensitive towards polar impurities of the substrate:water, organic (hydro)peroxides, acids etc., which can be eliminated bytreatment with triethyl aluminum (TEAl).

TEAl is formulated into stable and non-pyrophoric paraffin pellets: XiMoPac-Al001. Use of these pellets obviates the need for tedious substratepretreatment.

XiMoPac - Pretreatment with Triethyl Aluminum Pellets

Direct synthesis of E-alkenyl halides through catalytic cross metathesis:

Synthesis of biologically active compounds, modification of therapeutic agents:

Hoveyda, et al. Science 2016, 352, 569.

XiMoPac – Cross Metathesis I.

Catalyst ReagentH2C=CH(CH2)0-1X

Conditions Conversion[%]

Selectivity [%]

CM Product Yield [%]

XiMoPac-Mo007Acrylonitrile(n=0, X=CN)

Glovebox 84 88 66

Bench 82 81 67

XiMoPac-Mo001Allylphthalimide(n=1, X=NPhth)

Glovebox 93 50 31

Bench 92 69 49

XiMoPac-Mo001BOC-allylamine(n=1, X=NBoc)

Glovebox 79 40 32

Bench 74 38 28

Identical results were obtained in and outside of the glovebox.

XiMoPac-Mo007

N Mo Ph

i-Pr i-Pr

XiMoPac-Mo001

i-Pr i-Pr

XiMoPac – Cross Metathesis II.

Asymmetric Ring Closing Metathesis (ARCM)

XiMo unpublished results, based on Hoveyda, et al. Nature, 2008, 456, 933.

CatalystConversion

(%)Isolated yield

(%)Purity

(%)Enantiomeric ratio

XiMoPac-Mo001 >99 65 96 50 : 50

XiMoPac-Mo006 >99 77 99 96 : 4

XiMoPac-Mo003 >99 73 99 4 : 96

XiMoPac - Enantioselectivity

Ionically-tagged complexes in SILP*

Schowner R. et al. Chem. Eur. J. 2018, 24, 13336.

N+C2H5

C2F5 C2F5

X+Y- = IL: EMIM-FAP

iPriPr

*supported ionic liquid phase

Literature Examples

Metathesis in Liq.-Liq. Biphasic Media

Homo cross metathesis of methyl oleate (MO):

Entry Catalyst Substrate Loading (ppm) Media Conversion (%) TON E/Z ratio1 1000 100 1000 35/652 250 100 4000 2/983 100 66 6600 >2/98

Pyrrole/HeptaneMOX819

Reaction in IL (Ionic Liquid) and reusability of the ionic MAP-type complexes:

Entry Catalyst Substrate Loading (ppm) Media Conversion (%) TON E/Z ratio Recycl.1 100 1000 53/47 #02 100 1000 25/75 #13 64 640 9/91 #24 100 5000 7/93 #05 64 3000 8/92 #1

X819 MO

MOX819 IL/Heptane

IL/Heptane1000

Successful use in IL/heptane biphasic media - stable and highly active complexes Demonstrated good to excellent Z-selectivity in heterogeneous reactions Simplified work-up, recyclable and reusable catalyst Virtually metal free product Opportunity for use in continuous flow processes

Literature Examples

Metathesis in Liq.-Liq. Biphasic MediaCatalytic Performance of Ionically-tagged Catalysts

Location – Budapest, Hungary

The Innovation Catalyst - XiMo - ヒドラス化学株式会社

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