2. Quantitative Solvent-free Organic Synthesis 2

3. 12 Principles of Green Chemistry 7. USE OF RENEWABLE FEEDSTOCKS: A raw material or feedstock should be renewable whenever technically and economically practical. 8. REDUCE DERIVATIVES: Unnecessary derivatization should be minimized or avoided when possible, because such steps require additional reagents and generate waste. 9. CATALYSTS: Catalysts (as selective as possible) are superior to excess reagents. 10. DESIGN FOR DEGRADATION: Chemical products should be designed so that at the end of their function, they break down into harmless products and do not persist in the environment. 11. REAL-TIME ANALYSIS FOR POLLUTION PREVENTION: Methods need to be in-place to allow real-time monitoring and control prior to the formation of hazardous substances. 12. INHERENTLY SAFER CHEMISTRY FOR ACCIDENT PREVENTION: Chemical processes should be designed to minimize the potential for chemical accidents, including releases, explosions, and fires. 1.PREVENTION: It is better to prevent waste than to treat or clean up waste after it has been created. 2.ATOM ECONOMY: Methods should be designed to maximize the use of all materials used in the process into the final product. 3.LESS HAZARDOUS CHEMICAL SYNTHESIS: Wherever practical, methods should be designed to use and generate substances that possess little or no toxicity to people or the environment. 4.DESIGNING SAFER CHEMICALS: Chemical products should be designed to effect their desired function while minimizing their toxicity. 5.SAFER SOLVENTS AND AUXILIARIES: The use of auxiliary substances (e.g., solvents or separation agents) should be made unnecessary whenever possible and harmless when used. 6.DESIGN FOR ENERGY EFFICIENCY: The economic and environmental impact of the energy requirements of chemical processes should be recognized. When possible, processes should be conducted at ambient temperature and pressure. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press: New York, 1998, p.30 1.PREVENTION: It is better to prevent waste than to treat or clean up waste after it has been created. 5.SAFER SOLVENTS AND AUXILIARIES: The use of auxiliary substances (e.g., solvents or separation agents) should be made unnecessary whenever possible and harmless when used. 3

4. Green Chemistry is about... Reducing Materials Waste Energy Hazard Risk Cost Enviromental impact 4

5. Pollution Prevention Hierarchy Prevention & Reduction Recycling & Re-use Treatment Disposal Increasing greenness 5

6. INDUSTRIAL WASTE Industry Ratio Byproducts/Products Oil Refining<0.1 Bulk Chemicals1 – 5 Fine Chemicals5 – 50 Pharmaceuticals25 – 100+ INDUSTRIAL WASTE Industry Ratio Byproducts/Products Oil Refining<0.1 Bulk Chemicals1 – 5 Fine Chemicals5 – 50 Pharmaceuticals25 – 100+ 6

7. Alternative Solvents: Ionic Liquids Immobilized Solvents Supercritical Fluids (e.g. Sc-CO 2 ) H 2 O 7

8. And what is the greenest solvent at all? No Solvent! 8

9. “No Coopora nisi Fluida” Aristotle “No reaction occurs in the absence of solvent” 9

10. Solventless reactions, why not ?! Milk turnes sour and shaking of milk gives cheese, dried milk can be kept unaltered. Similarly dried meat can be stored for a long time, whereas meat soup rapidly putrefies on standing. 10

11. Quantitative Solvent-Free Organic Reactions How ? Solid-Solid Liquid-Solid Gas-Solid Liquid-Liquid … 11

12. 12

13. Quantitative Cascade Condensations of o-Phenylenediamines and 1,2- Dicarbonyl Compounds without Producing Wastes Gerd Kaupp, M. Reza Naimi-Jamal, Eur. J. Org. Chem. 2002, 8, 1368-1373. 13

14. 14

15. 15

16. Quantitative synthesis of benzo[a]phenazin-5-ol (5). Condensation of o-phenylenediamine with 2-hydroxy-1,4-naphthoquinone 16

17. Condensation of o-phenylenediamine with 2-oxo-glutaric acid 17

18. Condensation of o-phenylenediamine with oxalic acid 18

19. Solvent-free syntheses of mixtures of the compounds 10 and fluoflavin (11) 19

20. Condensation of o-phenylenediamine with alloxane hydrate The solid-state reaction of o-phenylenediamines 1a and 13 with alloxane hydrate 20

21. Condensation of o-phenylenediamine with parabanic acid Reaction of o-phenylenediamine (1a) with parabanic acid (21). 21

22. Waste-Free and Facile Solid-State Protection of Diamines, Anthranilic Acid, Diols and Polyols with Phenylboronic Acid G. Kaupp, M. R. Naimi-Jamal, V. A. Stepanenko, Chem. Eur. J. 2003, 9, 4156-4161. 22

23. Quantitative synthesis of 3 from a stoichiometric melt Quantitative solid-state synthesis of 5 by ball-milling 23

24. Quantitative solid-state synthesis of 7 in a ball-mill Quantitative solid-state synthesis of 9 in a ball-mill 24

25. Quantitative solid-state synthesis of 15 in a ball-mill Quantitative solid-state synthesis of 11 and its use as a protected reagent 25

26. Quantitative solid-state synthesis of heteropropellanes 17 Quantitative solid-state reaction of mannitol with phenylboronic acid 26

27. Quantitative solid-state reaction of myo-inositol with phenylboronic acid 27

28. Unidirectional photoisomerization of cis-3,3’-bis(diphenyl hydroxymethyl) stilbene in inclusion complex crystals Koichi Tanaka, Takaichi Hiratsukaa, Shigeru Ohba, M. Reza Naimi-Jamal and Gerd Kaupp, J. Phys. Org. Chem. 2003, 16, 905-912. 28

29. 29

30. 30

31. Tribochemical decontamination of hazardous and non-disposable wastes G. Kaupp, M. R. Naimi-Jamal, H. Ren and H. Zoz, "Environmentally Protecting Reactive Milling", Chemie Technik 2002, 31(6), 58-60. 31

32. Some inorganic reactions in the Simoloyer ® CM01-2l G. Kaupp, M. R. Naimi-Jamal, H. Ren, H. Zoz, in: Advanced technologies based on self-propagating and mechanochemical reactions for environmental protection, 2003, Chapter 6, Transworld Research Network, The Interuniversity Consortium Chemistry for the Environment. 32

33. Figure 2: pilot-set-up of a high energy ball mill (Simoloyer® VS01a) with air/inert carrier gas-cycle and separation/classification system Figure 1: a 2 L horizontal high energy ball-mill (Simoloyer® CM01-2l) with vacuum and inert- gas loading, operation and unloading. 33

34. Some organic reactions scaled up to 200 g batches in the Simoloyer CM01-2l G. Kaupp, J. Schmeyers, M. R. Naimi-Jamal, H. Zoz, H. Ren, Chem. Engin. Sci. 2002, 57, 763-765. 1:1-complex 34

35. Solvent-Free Knoevenagel Condensations and Michael Additions with Quantitative Yield G. Kaupp, M. R. Naimi-Jamal, J. Schmeyer, Tetrahedron 2003, 59, 3753-3760. 35

36. 36

37. 37

38. 38

39. 39

40. 40

41. Quantitative Reaction Cascades of Ninhydrin in the Solid State Gerd Kaupp, M. Reza Naimi-Jamal, Jens Schmeyers, Chem. Eur. J., 2002, 8(3), 594- 600. 41

42. Quantitative condensation of ninhydrin 1 with dimedone 2 42

43. Quantitative 3-cascade in the solid-state reaction of ninhydrin with (L)-proline. 43

44. Quantitative solid-state 4-cascades of ninhydrin with o-phenylendiamines. 44

45. Quantitative solid-state 3-cascade of ninhydrin and o-mercaptoaniline. 45

46. Quantitative 2-cascades of ninhydrin and (thio)ureas in the solid state. 46

47. 12 47

48. Quantitative solid-state 3-cascade of ninhydrin and methyl-3-aminocrotonate. 48

49. Mechanochemical Solvent-Free and Catalyst-Free One-Pot Synthesis of Pyrano[2,3-d]Pyrimidine-2,4(1H,3H)-Diones with Quantitative Yields a Yields refer to conversion yields. b isolated yield S. Mashkouri, M. R. Naimi-Jamal, Molecules 2009, 14, 474-479 49

50. Sodium Tetraalkoxyborates: Intermediates for the Quantitative Reduction of Aldehydes and Ketones to Alcohols through Ball Milling with NaBH 4 M. R. Naimi-Jamal, J. Mokhtari, M. G. Dekamin and G. Kaupp Eur. J. Org. Chem. 2009, 3567–3572 50

51. Regiospecific reduction of α,β-unsaturated aldehydes Specific and stereoselective solvent-free reduction 51

52. Kneading Ball-Milling and Stoichiometric Melts for the Quantitative Derivatization of Carbonyl Compounds with Gas–Solid Recovery J. Mokhtari, M. R. Naimi-Jamal, H. Hamzeali, M. G. Dekamin, G. Kaupp, ChemSusChem 2009, 2, 248 – 254 Melt reactions for the solvent-free preparation of phenylhydrazones. Solvent-free kneading ball-milling of 1 with 4. 52

53. Chemoselective protection of aldehydes by oximation in the presence of ketones. 53

54. Quantitative regeneration of carbonyl compounds from oximes Proposed mechanism 54

55. Comparison 55

56. Sustainable Synthesis of Aldehydes, Ketones or Acids from Neat Alcohols Using Nitrogen Dioxide Gas, and Related Reactions Benzylic Primary Alcohols 56

57. 57

58. Benzylic Secondary Alcohols Quantitative oxidation of neat benzaldehydes 58

59. Oxidation of solid long-chain primary alcohols with NO 2 gas Stoichiometry of the gas–solid oxidation of 12 with NO 2 ; NO and excess NO 2 equilibrate with N 2 O 3. 13 is obtained in 95% yield upon vacuum evaporation of the gas mixture including the nitric acid. 59

60. Iran University Science & Technology

62. Long reaction times Low yields of the products Tedious work-up Use of expensive reagents Some reagents are not available commercially and difficult procedure for preparation of theirs Use of solvent and catalyst 62

63. Yield (%) T (min) Gas (bar) ProductSubstrate Entr y 60150.21 80150.42 100150.63 63

65. 65

66. 2,4-Dinitrophenyl hydrazine 66

67. m.p. (°C) Yield (%) T (min) ProductSubstrate Entry liq.10051 liq.10052 liq.10053 45100104 12100605 4710056 42100607 561004208 103100609 liq.10010 CH 2 CHO O 2 N CHO CH 2 OSiMe 3 O 2 N O 2 N CHO CH 2 OSiMe 3 NO 2 NO 2 CHO Cl CH 2 OSiMe 3 CHO CH 2 OSiMe 3 CHO CH 2 OSiMe 3 Me Me CHO CH 2 OSiMe 3 MeMe CHO CH 2 OSiMe 3 CHO CH 2 OSiMe 3 O 2 N MeO MeO CHO CH 2 OSiMe 3 MeO MeO 67

68. Yield (%) T (min) ProductSubstrate Entry 10051 80.4852 100103 100604 59605 1004206 68

69. m.p. (°C) Yield (%) T (min) ProductSubstrate Entry liq.100301 liq.100602 45100603 49100304 136100605 48100606 69

70. The oxidation of primary and secondary benzylic silyl ethers were performed as gas-solid reactions. Apart from the aldehydes or ketones, nitrous acids such as NO, N 2 O 3, HONO and HONO 2 are formed. 70

71. 71

72. 72

73. FT-IR data reveals that there are : excess NO 2 (ν = 2918, 2891, 1629, 1598, 752 cm -1 ), excess N 2 O 4 (ν = 1743, 1261, 825, 750 cm -1 ), HONO 2 (ν = 1740, 1392 broad, 855 cm -1 ) in gas-phase. FT-IR spectroscopy reveals no trace of NO, HONO and N 2 O 3. HONO (ν = 1699, 1640, 1265, 853, 791 cm -1 ) NO (ν = 1876, 1835 cm -1 ) N 2 O 3 (ν = 1835,1655, 1305, 773 cm -1 ) 73

74. 74

75. 75

76. FT-IR spectroscopy from liquid-phase of reaction exhibits the anymore peaks in ν = 1473, 1369, 823, 729 cm -1. These peaks could be for Me 3 Si-O-SiMe 3 or Nitrat compound. NO, HONO and N 2 O 3 are not present in liquid-phase. 76

77. Gas chromatogram from liquid phase of p-Chlorobenzyl silyl ether. 2.743 min 9.370 min Me 3 Si-O-SiMe 3 77

78. Mass spectrum from intermediate in 9.370 min. 78

79. 79

80. 80

81. 81

82. 82

83. + 83

84. Solid-State Reactions: Dynamics in Molecular Crystals 84

85. Atomic Force Microscope (AFM): an appropriate tool 85

86. Gerd Binnig (left) and Heinrich Rohrer (right) who were awarded the Nobel Prize for their invention of the scanning tunneling microscope. 86

87. Scheme of a light deflection AFM 87

88. NanoScope II AFM instrument, Digital Instruments Inc. 88

89. 9.5 μm AFM images of Ninhydrin on its (100)-cleavage plane at 0.1 mm distance from a crystal of o-phenylenediamine on it after the times given, showing the formation of small craters that grow gradually. The z-scale is 50 nm, the direction of preference runs along the [001]-direction (the scan direction was changed after 210 min). 89

90. 9.5 μm AFM topographies on the (10–1)-face of Ninhydrin at 0.1 mm distance from a flat crystal of o-phenylenediamine on it; (a) fresh; (b) after 2 min (phase rebuilt); (c) after 15 min; (d) after 60 min (phase transformed). 90

91. 9.5 µm AFM topographies on the (1–10)-face of Ninhydrin at 0.5 mm distance from a flat crystal of o- phenylenediamine on it; (a) fresh; (b) after 15 min (phase rebuilt); (c) after 2 h; (d) after 4 h (phase transformed). 91

92. Stereoscopic face model for the crystal packing of Ninhydrin with (1–10) horizontal on top and (–110) horizontal at the bottom, showing the steep double layers. All hydrogen bonds are drawn. 92

93. 11 µm AFM surfaces on (010) of  -cinnamic acid after 365 nm irradiation: (a) fresh; (b) and (b’) after 30 min, b’ is a 3 µm scan; (c) after 2 times 45 min; (d) after 90 min continuously; the orientation of the crystal varied slightly, but the c-axis was always cut by the parallel fissures and ridges at an angle of 40 ° (crystallographic cleavage plane direction: 39°); the Z-scale covers 10 nm in (a) and 100 nm in (b), (c), (d). UV-Irrdiation of  -Cinnamic Acid 93

94. 9 mm AFM surface of a-cinnamic acid after 6 months daylight irradiation in a Pyrex vessel under Ar through two additional window glass plates showing fence-like features along the cleavage plane direction. G. Kaupp and M. Haak, Mol. Cryst. Liq. Cryst., 1998, 313, 193. 94

95. 16 µm AFM topographies after nanoscratching on (110) of Thiohydantoin at various directions by reference to the long crystal axis showing anisotropic molecular migrations; the applied force was 0–400 µN in (a) and (b); and 0–1000 µN in (c) and (d). Anisotropic Molecular Migration not only by chemical reactions but also by mechanical load: „Nanoscratching“ 95

96. Geometric conditions for the mechanical tests with the vertical force of the indenter as applied to the (110)-face of thiohydantoin. 96

97. New Solid State Mechanism: derived from AFM studies Phase Rebuilding long range anisotropic molecular migrations Phase Transformation formation of product phase Crystall Disintegration provides fresh reactive surfaces 97

98. 98

99. Think Globally Act Locally 99

100. 100

101. Thanks for your attention 101