Ball Milling for organic synthesis: A tool for process intensification ... · A. Stolle,...

A. Stolle,

Sustainable Coatings ConferenceDuesseldorf, June 18-19, 2013

Ball Milling for organic synthesis: A tool for process intensification with regard to

energy efficiency and economy of scale

Achim StolleSustainable Coatings Conference

Duesseldorf, June 18-19, 2013

General strategies for process intensification

A B C D

educts synthesis work-up product(s)

A B

solvent(s),catalyst(s),

…

refeeding

A B C

refeeding

product-integration

DA B C D

eductseducts synthesissynthesis work-up product(s)product(s)

A B


…


…

refeeding

A Brefeeding

A B C

refeedingrefeeding

product-integrationproduct-

integration

DD



General strategies for process intensification

Optimize an existing reaction / process. Implementation of alternative solvents / reagents

with enhanced possibility for recycling Alternative reactor / process technology Alternative synthesis concepts …

time, effort,

complexity

Heating through convection Photochemistry Electrochemistry Dielectric heating Mechanical stress



Terminology

M. C. Leah(1823-1897)

founder ofmechanochemistry

W. Ostwald(1853-1932)

definition ofmechanochemistry

Mechanochemistry / Tribochemistry: Breakage of covalent, ionic, or coordinative bonds as well as crystal lattices on mechanical stress.

Ball milling / Grinding: Technical method for the induction of mechanical stress and particle size refinement.

18th century: mortar & pestle today: ball mills

IUPAC Compendium of Chemical Technology (the "Gold Book"), Blackwell Scientific Publications, Oxford, 1997.Takacs, J. Mater. Sci. 2004, 39, 4987.



Pd(OAc)2KF-Al2O3

solvent-freeBr

AcAc

phenyl-boronic acid

Schneider et al., Green Chem. 2009, 11, 1894.

Ball mills have a higher reproducibility then reactions carried out with mortar and pestle. Furthermore, the process stability is increased and tools for process control are available.

“Reagents were triturated in a mortar with pestle for the required reaction time“: min - hours?!

6%

64%

94%

0%

25%

50%

75%

100%

200 rpm 400 rpm 800 rpm

chem

ical

yie

ld

ball milling at different rot

mortar+

pestle



Fields of Application

Fabrication of catalysts (metastable phases, composite catalysts, nanoparticles)

Mechanical alloying (composite materials, alloys, metastable materials)

Particle refinement and homogenization (glass, cellulose, plastics, powders…)

Ore refinery (iron ore, copper ore, gold, …)

Cracking or activation of bacteria

Degradation of dioxins, dehalogenation

Analytics (drugs, metal, waste, …)

Inorganic and Organic Synthesis

G. Kaupp, Top. Curr. Chem. 2005, 254, 95; James et al., Chem. Soc. Rev. 2012, 41, 413.



5 mol% Pd(OAc)2, 2.5 equivalents NaHCO3, 0.2 equivalents HCO2Na,1.2 equivalents nBu4NCl, NaCl; milling time = 60 min.

Frejd et al., J. Organomet. Chem. 2004, 689, 3778.

Technique Yield [%]Planetary ball mill (stainless steel, 13.3 Hz) 77

Heating in a test tube (80 °C) 18

Heating and stirring in a test tube (80 °C) 33

Hydraulic press with preheated anvil (80 °C, 19.6 MPa) 13

The Mizoroki-Heck reaction

NHBoc

CO2R1

R1 = Bn, Me

5 mol% Pd(OAc)2NaHCO3, HCO2Na, nBu4NCl

+ R-X

planetary ball millstainless steel1 h; 13.3 Hz

NHBoc

CO2R1

R10 examples:13-88% yield



chemistry

…

ballpowder

materialdensity

numberof milling

balls

time

frequency

Chemical parameters– Reaction type, mechanism – Reagents, milling auxiliary (EY)– LAG (, )

Technological parameters– Type of ball mill– Material density – Number of grinding bodies nMB

– Diameter of grinding bodies dMB

– Filling degree , ()

Process parameters– Frequency , peripheral velocity vp

– Milling time t

Energy intensity Em, degree of efficiency el



dSD = diameter of the sun disc

dbeaker = inner diameterof the milling beaker

d = distance ofrotation axis

PBM

A = amplitude

MBM VBM

Ax

Az

Ay

planetary ball mill mixer/vibration ball mill

2 2 2 2(rot,osc) 22 2kin kinm IE v E I

Suryanarayana, Progr. Mat. Sci. 2001, 46, 1.Takacs, Progr. Mat. Sci. 2002, 47, 355.Baláz, in Mechanochemistry in Nanoscience and Minerals Engineering, Springer-Verlag, Berlin, 2008, pp. 103.

Ball mills for lab-applications



1

,3 2,

,

1 Y feedstress feed MB p MB

Y MB

EE d v

E

Estress,feed = stress energydMB = diameter of milling balls

vp = peripheral speed MB = density of milling balls

laboratory: planetary ball mill continuous operated stirred media mill

Rosenkranz et al., Powder Technol. 2011, 212, 224. Becker et al., Int. J. Miner. Process. 2001, 61, 189.

Scale-up and modeling



Scale-up and modeling

German Federal Environmental Foundation

Fritsch GmbH

RessourcenEffiziente chemische Synthese – ProzessEntwicklung in Kugelmühlen für lösungsmittelfreie ReakTionen (RESPEKT)

TU BraunschweigFSU Jena

Zoz GmbH

With Evonik Degussa GmbH as associated industrial partner



No general correlation Has to be checked for specific

reaction. Influence of reaction kinetic (k, Ea, T) No intercorrelation between and t

measurable. Yield proportional to 2 and t

Szuppa et al., ChemSusChem 2010, 3, 1181.Stolle et al., Chem. Soc. Rev. 2011, 40, 2317.

OKMnO4Al2O3, H2O

PBMMSZ

Frequency and milling time t



energy intensity Em

Suzuki reaction: Green Chem. 2009, 11, 1894. aniline homo-coupling: Chem.-Eur. J. 2010, 16, 13263. Glaser reaction: Chem.-Eur. J. 2011,

17, 8129. Knoevenagel condensation: Green Chem. 2008, 10, 767.

Correlation to other methods of mechanical activation (cavitation). Radiation-based

methods (e.g. µw) show higer Em.

NH2

KMnO4N

NPhPh

1 10 100 1000

planetary ball mill

mixer ball mill

classic heating

microwave (multimode)

microwave (monomode)

ultrasound

E m [kWh mol-1]without cooling

with cooling

,

gridm

product ii

EE

n

Proven for several organic reactions:– Suzuki-Miyaura cross-coupling– Homo-coupling of aniline – Glaser reaction – Knoevenagel condensation – …



Application in organic synthesis

Redox reactionsMetal-catalyzed reactions

Aldol-type reactionsSynthesis of heterocyclesCarbohydrate chemistry

Peptide synthesisEnantioselective synthesis

Fullerene chemistryDehalogenation

…

A huge variety of organic synthetic transformations have beenreported so far applying ball milling chemistry conditions:

Recent reviews:Stolle et al., Chem. Soc. Rev. 2011, 40, 2317.James et al., Chem. Soc. Rev. 2012, 41, 413.



1st referenced reaction type (organo)catalyst2000 Suzuki-Miyaura Pd(PPh3)4

2003 Suzuki-Miyaura Pd(AcO)2, NEt32004 Aldol-type reaction Mn(AcO)3

2004 Mizoroki-Heck Pd(AcO)2

2007 asymmetric aldol reaction BINAM-prolinamide or proline

2008 Suzuki-Miyaura Pd(AcO)2, KF-Al2O3

2009 Sonogashira Pd(PPh3)4 / Cu-cocatalyst

2010 Sonogashira Pd(AcO)2 / DABCO

2011 Glaser Cu-, Ni- or Co-catalyst

2011 CuAAC Cu-catalyst

under construction Chan-Lam Cu-catalyst

under construction hydroamination heavy group VIII transition metals

Recent reviews:Rodriguez et al., Adv. Synth. Catal. 2007, 349, 2213.Stolle et al., Chem. Soc. Rev. 2011, 40, 2317.Stolle, Bolm et al., in Innovative Catalysis in Organic Synthesis (Ed. P. Andersson), Wiley-VCH, Weinheim 2012, 327-350.

Catalysis in ball mills



R1 R2

alkynesR1 R3

Pd-catalystaryl halide

R2 = H

Sonogashiracross-coupling

R1 R1

Glaser homo-coupling

Cu-catalystoxidant

R2 = H

NN

N

R1

R3

CuAACreaction

Cu-catalystazide

R2 = H

sec. amine

R = Me or EtR2 = H, CO2R

N

RO2C

R2

enamine formationH

NaX,Oxone

R2 = H,Ph; X = Cl, Br

R1 = Ph

PhR2

X

XPh

R2O

X

+

X

(oxidative) halogenation

dieneAlCl3

RR1

R2

Diels-Alder reaction

R1,R2 = CO2MeR = H, Me



Ball mills are devices developed for particle refinement + desagglomeration. continuous generation of fresh surfaces with high defect concentration

Ball mills are scalable from mL- to m3-scale for lab and industry applications. High mixing efficiency helps to overcome mass-transport-limitations. Direct energy entry by friction and impact Robustness and reproducibility (Figure 1)

Solid-state reactions in the field of Organic Synthesis Parameters are classified into:

– chemical parameters, technological parameters, and process parameters.

Performance of reactions depends on various reaction parameters:

– frequency, material density, filling degree, and many more (Figure 2).

Degree of efficiency depending on type of ball mill and reaction scale.

High energy efficiency compared to synthesis with other methods of energy entry (classical as well as non-classical)

6%

64%

94%

0%

25%

50%

75%

100%

200 rpm 400 rpm 800 rpm

chem

ical

yie

ld

ball milling at different rot

mortar+

pestleFigure 1

Figure 2



Speed-up of reactions Intensive mixing efficiency Low energy intensity Lowering the risk potential Decrease of solvent intensity Up-scaling of the reactions possible

Still to come:- Continuous chemical reactions- Temperature and pressure control- Harmonization of reaction variables

All solutions have a solvent (T. Welton), unless they utilize ball mills.

Welton, Green Chem. 2006, 8, 13.

Take home message



Thank you foryour attention!



Thank you foryour attention!

Chem. Soc. Rev. 2011, 40, 2317.



material hardness[Vickers]

density[g cm-3]

energy entry possible impurities in product

stainless steel ~ 550 7.8 high Fe, Cr

hardened steel ~ 750 7.9 high Fe, Cr, C

tungsten carbide ~ 1200 14.8 very high WC, Co

agate ~ 1000 2.7 very low SiO2

corundum ~ 1750 3.9 low (Al2O3, SiO2)

MSZ / YSZ ~ 1200 5.9 moderate (ZrO2, MgO, Y2O3)

PTFE elastic 2.1 very low F, C

2

2kinmE v

The material density determines the • energy density,• material abrasion, and • cross contamination.

Materials for grinding bodies

Ball Milling for organic synthesis: A tool for process intensification ... · A. Stolle,...

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