Ball milling is an efficient and environmentally friendly synthetic approach that can be used for organic reactions without solvents. It involves using a ball mill to grind reactants into fine powders under solvent-free conditions. Various organic reactions such as aldol condensations, Knoevenagel condensations, and Suzuki couplings have been achieved using ball milling with high yields. Ball milling is beneficial because it follows the principles of green chemistry by avoiding the use of solvents and byproducts, but it also has some drawbacks such as difficulty purifying reaction byproducts.

1. Ball Milling
An efficient and ecologically friendly synthetic approach
‐‐‐ Jackie Ding

2. Content
Ball milling – solvent free approach
Application in organic synthesis
Conclusion
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3. The 12 Principles of Green Chemistry
 Prevention of waste  Reduce Derivatives
 Atom Economy  Use Renewable Feedstocks
 Less Hazardous Chemical  Catalysis
Syntheses
 Design for Degradation
 Design Safer Chemicals
 Real-time Analysis for
 Safer Solvents and Pollution Prevention
Auxiliaries
 Inherently Safer Chemistry
 Design for Energy Efficiency for Accident Prevention
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4. Do I need to use a solvent?
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5. The best solvent is no solvent
 Alternative solvents:
water
supercritical CO2
ionic liquids
 Solventless Chemistry
Mortar and pestle
Ball milling
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6. Content
Principles of green chemistry
Application in organic synthesis
Conclusion
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7. What is ball milling?
 A ball mill is a type of grinder used to grind materials
into extremely fine powder.
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8. Major parameters for ball milling
Temperature
Size and Number of the balls
Nature of the balls
Rotation speed
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9. Types of Ball Mills
 Drum ball mills
 Jet-mills
 Bead-mills
 Horizontal rotary ball mills
 Vibration ball mills
 Planetary ball mills
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10. Vibration Mills
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11. Mixer Mill MM 400
 Feed material: hard, medium-hard, soft, brittle, elastic, fibrous
 Material feed size: ≤ 8 mm
 Final fineness: ~ 5 µm
 Setting of vibrational frequency: digital, 3 - 30 Hz (180 - 1800 min-1)
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12. Planetary Mills
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13. Planetary Ball Mill PM 400
 Feed material: soft, hard,
brittle, fibrous (dry or wet);
 Material feed size: < 10 mm;
 Final fineness < 1 µm;
 No. of grinding stations: 4 / 2
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14. Content
Principles of green chemistry
Ball milling – solvent free approach
Conclusion
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15. Application in Organic Synthesis
 Aldol Condensations
 Knoevenagel Condensations
 Baylis-Hillman Reaction
 Michael Reaction
 Wittig Reaction
 Fullerene Cycloadditions
 Suzuki Reaction
 Heck-Jeffery Reaction
 Radical Additions Mediated by Mn (III)
 Etc.
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16. Suzuki reaction
[Pd(PPh3)4] (5mol%)
K2CO3!(3 equivs.)
B(OH)2 + Br-Ar Ar
NaCl
ball milling
30-60 min
Up to 96% yield
S. F. Nielsen, O. Axelsson, Synth. Commun. 2000, 30, 3501.
Br
KF-Al2O3/ Pd(OAc)2
+ Ar Ac
ball milling
B(OH)2 Ac
Entry Rpm T (min) Yield%
1 400 10 92
2 800 5 94
Franziska Schneider, Org. Proc. Res. & Develop., 2009, 13,44 16

17. Aldol Condensation
O O O OH
(S)-proline
H 10 mol%
+ R R
Ball milling (A)
or stirring (B)
Entry R= Method t/h Yield% anti/syn ee%
1 4-NO2 A 5.5 99 89:11 94
2 4-NO2 B 24 95 89:11 94
3 3-NO2 A 7 94 88:12 >99
4 3-NO2 B 16 89 82:18 98
5 2-NO2 A 7 97 93:7 97
6 2-NO2 B 36 89 91:9 97
B. Rodr´ıguez, Angew. Chem., Int. Ed., 2006, 45, 6924
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18. Oxidation
O O O R2
N N O
R2
R1 + Mn(OAc)3.2H2O
ball milling O
R1 O X X
30Hz, 1h
R1= CH3 X=CH or N
R1
R2 = -C6H5, -C6H5NO2,
-C6H5CN, etc. 18 examples R1
up to 91% yield
Conventional heating in organic solvent:
a. Acetic acid, 80oC, argon atmosphere, yield 32%
b. Ethanol, refluxing temperature for 12h, yield 48%
Guan-Wu Wang, J. Org. Chem. 73, 7088 (2008). 18

19. Other applications of ball milling
 Fine particles
 Inorganic solids
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20. Drawbacks of ball milling
Purification of
byproducts • Solution Benign Solvents
It is not a magic
• Solution Under development
wand.
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21. Conclusion
 Ball milling should be considered as a potentially
attractive solution for solvent-free synthesis.
One-pot Tip of
Solvent free
process iceberg
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22. Reference
 Lance Frazer, Environmental health perspectives, 2003, 111, 10
 Belen Rodríguez, Adv. Synth. Catal. 2007, 349, 2213
 Ana Lazuen Garay, Chem. Soc. Rev., 2007, 36, 846–855
 Raphael Janot, Progress in Materials Science 50 (2005) 1–92
 Andreas Theisen, “Green Chemistry”in the Laboratory, TECHNICAL
REPORT, www.retsch.com
 G Kaupp, Solvent-free organic synthesis, Wiley-VCH, 2009.
 S. F. Nielsen, O. Axelsson, Synth. Commun. 2000, 30, 3501.
 Franziska Schneider, Org. Proc. Res. & Develop., 2009, 13,44
 B. Rodr´ıguez, Angew. Chem., Int. Ed., 2006, 45, 6924
 Guan-Wu Wang, J. Org. Chem. 73, 7088 (2008).
 G.Kaupp, Top. Curr. Chem. 254, 95 (2005).
 M. Reza Naimi-Jamal, Eur. J. Org. Chem. 2009, 3567–3572.
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