Quantitative Solvent-free Organic Synthesis

2

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

Green Chemistry is about...

Reducing

Materials

Waste

Energy

Hazard Risk

Cost

Enviromental impact

4

Pollution Prevention Hierarchy

Prevention & Reduction

Recycling & Re-use

Treatment

Disposal

Incre

asin

g

gre

en

ness

5

INDUSTRIAL WASTE

Industry Ratio Byproducts/Products

Oil Refining <0.1Bulk Chemicals 1 – 5Fine Chemicals 5 – 50Pharmaceuticals 25 – 100+

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Alternative Solvents:

Ionic LiquidsImmobilized Solvents Supercritical Fluids (e.g. Sc-CO2)

H2O

7

And what is the greenest solvent at all?

No Solvent!

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“No Coopora nisi Fluida”

Aristotle

“No reaction occurs in the absence of solvent”

9

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.

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Quantitative Solvent-Free

Organic Reactions

How ?

Solid-Solid Liquid-Solid Gas-Solid Liquid-Liquid …

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12

Quantitative Cascade Condensations of o-Phenylenediamines and 1,2- Dicarbonyl Compounds without Producing Wastes

Ar

ArN

N

N

N

OH

N

N COOH

O

H

N

N

O

O

H

H

N

N

N

N

H

H

N

NN

N

H

H

N

N O

N

H

NH2

O

H

N

N O

N NH2

O O

H

H

NH2

NH2

Gerd Kaupp, M. Reza Naimi-Jamal, Eur. J. Org. Chem. 2002, 8, 1368-1373.

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14

15

Quantitative synthesis of benzo[a]phenazin-5-ol (5).

Condensation of o-phenylenediamine with 2-hydroxy-1,4-naphthoquinone

16

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

17

Condensation of o-phenylenediamine with oxalic acid

18

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

19

Condensation of o-phenylenediamine with alloxane hydrate

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

Condensation of o-phenylenediamine with parabanic acid

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

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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.

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Quantitative synthesis of 3 from a stoichiometric melt

Quantitative solid-state synthesis of 5 by ball-milling

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Quantitative solid-state synthesis of 7 in a ball-mill

Quantitative solid-state synthesis of 9 in a ball-mill

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Quantitative solid-state synthesis of 15 in a ball-mill

Quantitative solid-state synthesis of 11 and its use as a protected reagent

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Quantitative solid-state synthesis of heteropropellanes 17

Quantitative solid-state reaction of mannitol with phenylboronic acid

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

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Unidirectional photoisomerization of cis-3,3’-bis(diphenyl hydroxymethyl) stilbene in inclusion complex crystals

Ph

Ph

OH

OH

Ph

PhPhPh

OH OH

PhPh

21

h

solid

guest

guest

Koichi Tanaka, Takaichi Hiratsukaa , Shigeru Ohba, M. Reza Naimi-Jamal and Gerd Kaupp, J. Phys. Org. Chem. 2003, 16, 905-912.

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Ph

Ph

OH

OH

Ph

PhPhPh

OH OH

PhPh

21

h

solid

guest

guest

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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.

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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.

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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.

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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

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Solvent-Free Knoevenagel Condensations and Michael

Additions with Quantitative Yield

G. Kaupp, M. R. Naimi-Jamal, J. Schmeyer, Tetrahedron 2003, 59, 3753-3760.

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36

37

38

39

40

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.

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Quantitative condensation of ninhydrin 1 with dimedone 2

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

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

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

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

46

12

47

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

48

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

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Sodium Tetraalkoxyborates: Intermediates for the Quantitative Reduction of Aldehydes and Ketones to Alcohols through Ball Milling with NaBH4

M. R. Naimi-Jamal, J. Mokhtari, M. G. Dekamin and G. Kaupp Eur. J. Org. Chem. 2009, 3567–3572

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Regiospecific reduction of α,β-unsaturated aldehydes

Specific and stereoselective solvent-free reduction

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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.

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

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Quantitative regeneration of carbonyl compounds from oximes

Proposed mechanism

54

Comparison

55

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

Benzylic Primary Alcohols

56

57

Benzylic Secondary Alcohols

Quantitative oxidation of neat benzaldehydes

58

Oxidation of solid long-chain primary alcohols with NO2 gas

Stoichiometry of the gas–solid oxidation of 12 with NO2 ; NO and excess NO2 equilibrate with N2O3.

13 is obtained in 95% yield upon vacuum evaporation of the gas mixture including the nitric acid.

59

Oxidative Deprotection of Benzylic Silyl Ethers to

Their Corresponding Carbonyl Compounds Using

Nitrogen Dioxide/Dinitrogen Tetroxide Gas

Iran University Science & Technology

C6H5

C6H5

C6H5

C6H5

C6H5

C6H5 C6H5

C6H5

CH3

CH3

Entry Substrate R' Time(h) Yield(%)

1

2

3

4

5

Oxidative deprotection of TMS ethers in CH2Cl2 and THP ethers in CHCl3 with N2O4/charcoal

0.2

0.5

1

1

0.25 95

95

98

95

96

R"

TMS

TMS

TMS

TMS

TMS

TMS

TMS

THP

THP

THP

THP

THP

THP

6

7

8

9

10

11

12

13

4-MeOC6H5

4-MeC6H5

4-ClC6H5

4-NO2C6H5

4-MeOC6H5

4-MeC6H5

4-NO2C6H5

H

H

H

H

H

H

H

H

H

0.5 96

0.2 99

3 90

8 96

0.5 98

3.5 70

2.5 90

3 85

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

Drawbacks of Methods

62

Yield )%(

T (min) Gas (bar)

Product Substrate Entry

60 15 0.2 1

80 15 0.4 2

100 15 0.6 3

CH2OSiMe3

CH2OSiMe3

CH2OSiMe3

CHO

CHO

CHO

Indicate of Value of NO2 / N2O463

R1

OSiMe3

R1

O

R2R2

solvent-free, rt

R1 = H, Me, PhR2 = H, o-,p-Me, m,p-MeO, o-,p-Cl, o-Br, p-F, o-,m-,p-NO2

1 mmol

NO2 / N2O4 (5.8 mmol)

up to 100%

65

2,4-Dinitrophenyl hydrazine

OSiMe3 H

O

solvent-free

NO2 / N2O4 (5.8 mmol)

rt, 5 min, 100 %

1 mmol

66

m.p.°)C(

Yield (%)

T )min(

Product Substrate Entry

liq. 100 5 1

liq. 100 5 2

liq. 100 5 3

45 100 10 4

12 100 60 5

47 100 5 6

42 100 60 7

56 100 420 8

103 100 60 9

liq. 100 10 10CH2CHO

O2N CHO

CH2OSiMe3

O2N O2N

CHO

CH2OSiMe3

NO2 NO2

CHO

Cl CH2OSiMe3 Cl CHO

CH2OSiMe3

Cl Cl

CHO

CH2OSiMe3Me Me CHO

CH2OSiMe

3

Me Me

CHO

CH2OSiMe3 CHO

CH2OSiMe3O2N

MeO

MeO

CHOCH2OSiMe3MeO

MeO

(CH2)2OSiMe3

67

Yield(%)

T )min(

Product Substrate Entry

100 5 1

80.48 5 2

100 10 3

100 60 4

59 60 5

100 420 6

CH2OSiMe3CHO

CH2CHO

CH2OSiMe3

NO2 NO2

CHO

CH2OSiMe3

O2N O2N

CHO

CH2CHO

CH2OSiMe3

O2N O2N

CHO

(CH2)2OSiMe3

(CH2)2OSiMe3

68

m.p.°)C(

Yield (%)

T )min(

Product Substrate Entry

liq. 100 30 1

liq. 100 60 2

45 100 60 3

49 100 30 4

136 100 60 5

48 100 60 6

CH3

O

CH3

OSiMe3

CH3

OSiMe3

NO2

CH3

NO2

O

CH3

OSiMe3

Br

CH3

Br

O

OSiMe3

Ph Ph

O

OSiMe3

O2N

PhO2N

Ph

O

OSiMe3

F

PhF

Ph

O

69

Investigation of the Mechanism

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,

N2O3, HONO and HONO2 are formed.

70

Cl CH2

OSiMe35 min

IR from gas phaseNO2 / N2O4 (5.8 mmol)

1 mmol71

CH3 CH2

OSiMe35 min

IR from gas phaseNO2 / N2O4 (5.8 mmol)

1 mmol

72

FT-IR data reveals that there are :

excess NO2 (ν = 2918, 2891, 1629, 1598, 752 cm-1),

excess N2O4 (ν = 1743, 1261, 825, 750 cm-1),

HONO2 (ν = 1740, 1392 broad, 855 cm-1) in gas-phase.

FT-IR spectroscopy reveals no trace of NO, HONO and N2O3 .

HONO (ν = 1699, 1640, 1265, 853, 791 cm-1)

NO (ν = 1876, 1835 cm-1)

N2O3 (ν = 1835,1655, 1305, 773 cm-1)

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Cl CH2

OSiMe35 min

IR from liquid phaseNO2 / N2O4 (5.8 mmol)

1 mmol

74

CH3 CH2

OSiMe35 min

IR from liquid phaseNO2 / N2O4 (5.8 mmol)

1 mmol

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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 Me3Si-O-SiMe3 or Nitrat compound.

NO, HONO and N2O3 are not present in liquid-phase.

76

Gas chromatogram from liquid phase of p-Chlorobenzyl silyl ether.

2.743 min

9.370 min

Me3Si-O-SiMe3

CH2ONO2Cl

Cl CH2

OSiMe32 h

GC-MS from liquid phaseNO2 / N2O4 (5.8 mmol)

1 mmol 77

- HONO

Mass spectrum from intermediate in 9.370 min.

CH2ONO2Cl

(m/z) = 187

CHOCl

(m/z) = 140

78

ClH

OHH

HH

Cl CH2ONO2

HH

H H

Cl CH2

OSiMe33 h

NMR from liquid phaseNO2 / N2O4 (5.8 mmol)

1 mmol 79

CH3 CH2ONO2

HH

H H

CH3H

OHH

HH

Me CH2

OSiMe33 h

NMR from liquid phaseNO2 / N2O4 (5.8 mmol)

1 mmol 80

ClH

OHH

HH

Cl CH2

OSiMe324 h

NMR from liquid phaseNO2 / N2O4 (5.8 mmol)

1 mmol

81

ClOHC

82

Cl

OSiMe3NO2 / N2O4

Cl

O SiMe3

NO

OO2N

Cl

ONO2 Me3SiONO

A

+

B

Cl

O NO

OH

H

- HONO

Cl

H

O

A

3 HONO HONO2 2 NO H2O

NO

+ +

++H2O 3 NO2 2 HONO2

B

N2O3

2 Me3SiONO Me3SiOSiMe3 NO NO2+ +

83

Solid-State Reactions:

Dynamics in Molecular

Crystals

84

Atomic Force Microscope (AFM): an appropriate tool

85

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

86

Scheme of a light deflection AFM

87

NanoScope II AFM instrument, Digital Instruments Inc.88

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

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

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

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

11 µm AFM surfaces on (010) of a-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 a-Cinnamic Acid

93

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

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).

N

N

S

OH

H(P21/c)

Anisotropic Molecular

Migrationnot only by chemical reactions but also by

mechanical load:

„Nanoscratching“

95

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

96

New Solid State Mechanism:derived from AFM studies

• Phase Rebuildinglong range anisotropic molecular migrations

• Phase Transformationformation of product phase

• Crystall Disintegration

provides fresh reactive surfaces

97

98

Think Globally

Act Locally

99

100

Thanks for your attention

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