Sonochemicaland MechanochemicalApplications in … MechanochemicalApplications in Organic Synthesis...

Sonochemical and Mechanochemical Applications in Sonochemical and Mechanochemical Applications in Organic Synthesis

HovigHovig KouyoumdjianKouyoumdjian

Wednesday, March 17, 2010

Energy sources of chemical reactionsEnergy sources of chemical reactions

PressurePressureMicrowavesMicrowaves

HeatHeat ElectricityElectricity

2https://www.kintera.com/accounttempfiles/account105257/images/heat_thermometer.jpghttp://www.mdpi.org/ecsoc/ecsoc‐6/Papers/E001/E001_files/208_files/Micro.gifhttp://wpcontent.answers.com/wikipedia/commons/thumb/3/39/ElectrochemCell.png/250px‐ElectrochemCell.pnghttp://www.americanairworks.com/images/dial_a_pressure.gif

Ultrasound: Alternative source of energyUltrasound: Alternative source of energy

• Nanomaterials

S l t h i t• Sonoelectrochemistry

• Organic synthesisOrganic synthesis

• Glassware cleaningUltrasound bathsUltrasound baths

http://www.bransonic.com/pdf/Bransonic%20Brochure.pdf3

OutlineOutline• Ultrasound (US)

– Definition and backgroundDefinition and background

• Cavitation phenomenon– Characteristics and influencing factors

• A sample of sonochemical reactions in organic synthesis– Kornblum‐Russell reaction

Hetero Michael reaction– Hetero‐Michael reaction– Preparation of Grignard reagent– Suzuki coupling

• Cavitation induced mechanochemistry– Cleavage of azo‐linkages– Reconfiguration of atropisomersg p– Electrocyclic opening of benzocyclobutene

4







5

Electromagnetic and sound spectrumElectromagnetic and sound spectrum

GammaGammaUltravioletUltravioletRadioRadio XX‐‐raysraysInfraredInfraredMicrowavesMicrowaves

30EHz300PHz3THz3GHz 750THz430THz

SONAR Medical diagnosisHuman speechEarthquake monitoring

30EHz300PHz3THz3GHz 750THz430THz

SONAR

Low bass notes Animals Sonochemistry

Medical diagnosisHuman speechEarthquake monitoring

InfrasoundInfrasound AcousticAcoustic UltrasoundUltrasound

20Hz 20KHz 2MHz 200MHz 6

Definition of sonochemistryDefinition of sonochemistry

Sonochemistry: A branch of chemical research dealing y gwith the chemical effects and applications of ultrasonic waves, that is, sound with frequencies above 20 kHz th t li b d th li it f h h ithat lie beyond the upper limit of human hearing.

7Luche, J. L. Synthetic Organic Sonochemistry, Plenum Press, New York, 1998, pp. 1–19

Best known uses of ultrasoundBest known uses of ultrasound• Target detection using SONAR

(SOund NAvigation and Ranging)(SOund NAvigation and Ranging)

• Medical applications:pp– Medicalsonography (ultrasonography)– Acoustic targeted drug delivery

Cleaning teeth in dental hygiene– Cleaning teeth in dental hygiene

• Industrial Applications:– Ultrasonic testing (non‐destructive)– Ultrasonic cleaning

http://www.personal.psu.edu/users/k/g/kgc5007/Project%203%20Active%20Sonar.gifhttp://www.advanceusa.org/blog/content/binary/Ultrasound%202.jpghttp://media.noria.com/sites/archive_images/Backup_200411_Tech‐Ultrasound1.jpg

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Ultrasound instruments for organic h ichemistry

Cup‐horn sonicator Probe sonicator

$2 300‐$5 000$1 200‐$1 600

9

$2,300 $5,000$1,200 $1,600

http://www.nano‐lab.com/ultrasonic‐probe‐dispersion‐equipment.html

Ultrasound reactors in process chemistryUltrasound reactors in process chemistry

UIP16000UIP16000 reactor

Ultrasonic reactor

10http://www.hielscher.com/image/7xuip1000hd_flowcell_p0500.jpghttp://www.hielscher.com/image/uip1000_uip16000_p0500.jpg

Development of ultrasound in organic synthesisDevelopment of ultrasound in organic synthesis

19301930 Richards and Loomis applied ultrasound (100‐500KHz) in organic synthesis for the first time (1927)

19501950 Renaud reported that certain organometallics could be prepared in shorter reaction times using ultrasound bath (1950)

19801980 Luche reported metal activation reactions using ultrasound probes (1980)

19901990Mason reported switching reactions using ultrasound Cup‐horn instruments (1995)

20052005Wilson and Moore reported biasing chemical reaction pathways using ultrasound (2007)

11

Richards, W. T.; Loomis, A. L. J. Am. Chem. Soc. 1927, 49, 3086‐3088Renaud, P. Bull. Soc. Chim. Fr. 1950, 1044‐1048Luche, J.‐L.; Damiano, J. C. J. Am. Chem. Soc. 1980, 102, 7926‐7927.







12

Ultrasound effectsUltrasound effects

• Direct effects:– Ultrasound waves have low Energies (20KHz – 500MHz)

(too low to alter electronic, vibrational, or rotational molecular states)

• Indirect effects:– Ultrasound waves cause cavitation phenomenon which generates higher energy

(enough energy to alter vibrational and rotational molecular states)(enough energy to alter vibrational and rotational molecular states)

Rotational and20KHz‐500KHz Ultrasound waves

Rotational and vibrational alterations

XXCavitation Phenomenon


Cavitation phenomenonCavitation phenomenon

At sufficiently high power:

‐ Pressure wave cycle exceeds thePressure wave cycle exceeds the attractive forces of the molecules

‐ Cavitation bubbles forms

‐ Bubbles grow over a few cycles

‐ Bubbles suffer sudden expansion p

‐ Bubbles collapse violently(energy generation)

14

Another way of bubble collapse: i j f iMicrojet formation

S lid f

))))

• Cavitation bubble is trapped between solid surface and liquid flow

Solid surface

)))) Sound waves

Cavitation bubble

15

Another way of bubble collapse: i j f i

Mi j

Microjet formation

))))

Microjet• Cavitation bubble is trapped between solid surface and liquid flow

• liquid jet forms (100 m s‐1) )))) Sound waves

liquid jet forms (100 m.s )

• Violent non‐symmetric bubble collapse

• Microjetting is the reason why ultrasound is effective in cleaning

Cavitation bubble

• Microjetting is the reason why ultrasound is effective in cleaning

• Activates surface catalysis

16

• Increases mass and heat transfer

The example of propeller bladesThe example of propeller blades

Negative pressure originate microbubblesNegative pressure originate microbubbles

When collapsing near the metal, they release enough energy to cause erosion to the blade

http://www.tecplot.com/images/showcase/contours/issue_19/01_propeller.jpghttp://www.fractureinvestigations.com/images/prop.jpg 17

Cavitation bubbleCavitation bubble

Bulk: Intense shear forcesBulk: Intense shear forcesHOHOH ..

2

Interface:Interface:

OOHOH .2

.

22.. OOHOOHOH

Shear forcesShear forces

OHOHH 2..

22.. OHOHOH

Cavity: extreme conditionCavity: extreme condition

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Factors impacting sonochemistryFactors impacting sonochemistry

• Acidity, basicity, dipole moment, etc… do not have significant role in sonochemistry

• Volatility, viscosity, dissolved gases, and surface tension are directly involveddirectly involved

• These factors can be manipulated via two parameters:These factors can be manipulated via two parameters: – Acoustic Pressure (P)– Acoustic Intensity (I)

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Acoustic pressureAcoustic pressure

)2sin()( ftPtP )2sin()( ftPtP AP(t) = pressure at any point of an elastic medium (Pa)PA = acoustic pressure amplitude (Pa) f = frequency of the alternating pressure wave (Hz)t = time (s)

Frequency (KHz scale) amplitude of irradiation constant cavitationFrequency (KHz scale) amplitude of irradiation constant cavitation

Frequency (MHz scale) compression and rarefaction cycles’ duration

1

If compression and rarefaction cycle duration is short, cavitation might be difficult to achieve


Frequency time relationFrequency time relation

• Frequency influences the timeFrequency influences the time taken by a bubble to collapse

• High frequency (500 KHz)HOHOH ..

2 • High frequency (500 KHz)

– Collapse time is 400 ns– Less than the lifetime of most

radicals

OOHOH .2

.

.. OOHOOHOH radicals (radical reaction will be initiated)

• Low frequency (20 KHz) OHOHH ..

22 OOHOOHOH

22.. OHOHOH

• Low frequency (20 KHz) – Collapse time 10 μs– Enough time for radicals to

recombine

OHOHH 2

recombine


Acoustic pressure and frequency effectAcoustic pressure and frequency effect Sono‐oxidation of 2,2,6,6‐tetramethylpiperidin‐4‐one

N

O

O2 or Ar

1

Frequency Gas present Rate of nitroxideformation

.OH form

NO2

2 3 4

formation

520KHz O2 3.6 x 10‐6 M/min Free

520KHz Ar No nitroxide Free

20KHz O2 0.083 x 10‐6 M/min recombined

20KHz Ar 1.08 x 10‐6 M/min recombined

Petrier, C.; Jeunet, A.; Luche, J.‐L.; Reverdy, G. J. Am. Chem. Soc. 1992, 114, 3148‐315222

Sono‐oxidation of h l i idi2,2,6,6‐tetramethylpiperidin‐4‐one

High Frequency 520KHz Low Frequency 20KHz

)))).. OOHOHOH

Presence of Ar Presence of Ar

HOHOH ..))))2

2

2

2 OOOOHOHOH

23Petrier, C.; Jeunet, A.; Luche, J.‐L.; Reverdy, G. J. Am. Chem. Soc. 1992, 114, 3148‐3152

Acoustic intensityAcoustic intensity

PI 2/2 cPI A 2/2I = acoustic intensity (sound strength)P = acoustic pressure amplitudePA = acoustic pressure amplitudeρ = density of the fluidC = speed of transmission

• Acoustic intensity sonochemical effect

• Minimal intensity is required to reach cavitation threshold


Intensity effectIntensity effect

Ph

Chalcone Pentane‐2,4‐dione

Ph Ph

Ph

Ph

O

OOPh

OO

O OO KOH

TBAB

A B

Conditions A (%) B(%)

A B

Stirring 52 0

)))), Cup‐horn 69 0

Sound IntensityProbe >> Cup‐horn 100W 10W

)))), Probe 72 12

Mason, T. J.; Berlan, J. Current Trends in Sonochemistry, G. J. Price, Royal Society of Chemistry, Cambridge, 1992, pp. 148–157 25

Summary (Cavitation)Summary (Cavitation)

• Ultrasound waves indirectly affect chemical reaction through cavitation phenomenon

• Cavitation generates a vacuum form bubbles which grow over a• Cavitation generates a vacuum, form bubbles which grow over a few cycles and collapse violently

• The energy generated by the collapse manipulates the reaction

• High frequency (500KHz) radical mechanism might be favored• High frequency (500KHz), radical mechanism might be favored

26




• Sample sonochemical reactions in organic synthesis– Kornblum‐Russell reaction



27

Sonochemichal reactionsSonochemichal reactions

• Switching reactionsSwitching reactions– Kornblum‐Russell reaction

• Homogeneous reactions• Homogeneous reactions– Hetero Michael reaction

• Heterogeneous reactions– Metal activation reactions

• Grignard reagent preparation

– Palladium catalyzed coupling reactions• Suzuki coupling

28

Ultrasound‐assisted Kornblum‐Russell ireaction

5 6 7

85 6

29Dickens, M. J.;Luche, J. L. Tetrahedron Lett. 1991, 32, 4709‐4712

Kornblum‐Russell reaction mechanismKornblum Russell reaction mechanism

Polar pathway

O2NBr

NO

OLi

Polar pathway

SET pathway

5 6 7

8

5

30Dickens, M. J.;Luche, J. L. Tetrahedron Lett. 1991, 32, 4709‐4712

Ultrasound‐assisted Hetero‐Michael ireaction

OH C HNR

NHRO

OEtHO

H3CH3C

OO

CH3H3C

HN

H2O, r.t., 2 h

NH2R

9

R = 90%

91%

10

11

9

12

Arcadi, A.; Alfonsi, M.; Marinelli, F. Tetrahedron Lett. 2009, 50, 2060–2064Tejedor, D.; Santos‐Expósito, A.; García‐Tellado, F. Synlett 2006, 1607‐1609 31

12

Ultrasound‐assisted Grignard Reagent ipreparation

d l l• Traditional:– Oxide free Magnesium– Periodic crushing of metal

• Ultrasonication:– Any grade of Magnesium– Crushing not requiredg g q

SiMe3 SiMe3Mg, THF,

Br MgBr)))), 45oC, 1 h90%13 14

SiMe3

Br

Mg, THF,

45oC, 1 hX

13

Yamaguchi, R.; Kawasaki, H; Kawanisi, M. Synth. Commun. 1982, 12, 1027‐103732

Ultrasound‐assisted Suzuki couplingUltrasound assisted Suzuki coupling

Ph B(OH)2 Ph Ph1 mol% Pd(OAc)2

Ar, NaOAc[bbim]+BF4

-/MeOH 92%

IPh

15 16 17, r.t., 20 min15 16 17

Ph I Ph B(OH)2 Ph Ph1 mol% Pd(OAc)2

Ar, NaOAc[bbim]+BF4

-/MeOH 25%30oC, 10 h15 16 17

Deshmukh, R. R.; Jarikote, D. V.; Srinivasan, K. V. Chem. Commun. 2002, 616–61733

Summary (Sonochemistry)Summary (Sonochemistry)

• Sonochemistry is utilized in organic synthesis in many areas (switching homogeneous and heterogeneous reactions)(switching, homogeneous and heterogeneous reactions)

• Sonochemistry might lead to better yields faster rates andSonochemistry might lead to better yields, faster rates and milder temperatures

34




• Sample sonochemical reactions in organic synthesis– Kornblum‐Russell reaction



35

Mechanochemistry definitionMechanochemistry definition

• Mechanochemistry is the molecular‐scale coupling of the ec a oc e s y s e o ecu a sca e coup g o emechanical force and the chemical reaction

– Mechanical breakage

– Chemical behavior of mechanically‐stressed solids

C it ti l t d h– Cavitation‐related phenomena

– Shockwave chemistry and physicsShockwave chemistry and physics

36

Cavitation bubble revisitedCavitation bubble revisited

Bulk: shear forcesBulk: shear forces

Interface:Interface:

MechanochemistryMechanochemistry

shear forcesshear forces

Cavity: extreme conditionCavity: extreme condition

37

Cavitation induces shear forcesCavitation induces shear forces

polymer

38

MechanophoresMechanophores

• Possess strategically weakened bonds

• Force transfered to the mechanophore from the polymer chain segments

• Undergo bond breakage or deformation• Undergo bond breakage or deformation

• Many examples for mechanically‐induced chemical processes:Cl f li k– Cleavage of azo‐linkages

– Reconfiguration of atropisomers– Electrocyclic opening of benzocyclobutene

= Mechanophore

= Polymer

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Ultrasound‐induced cleavage of azo‐linkagesUltrasound induced cleavage of azo linkages

))))..

N2

Frequency = 20 kHz

|||

q yIntensity = 8.7 W/cm2

Temperature = 6‐9 °C18

40Berkowski, K. L.; Potisek, S.L.; Hickenboth,C.R.; Moore, J.S. Macromolecules 2005, 38, 8975-8978

Specific chain scissionSpecific chain scission

40KDa

18

40KDa

20KDa18

20KDa

19


Control experiment of non‐specific scissionControl experiment of non specific scission

40KDa 40KDa

20KDa

18 20

42

8 0

Berkowski, K. L.; Potisek, S.L.; Hickenboth,C.R.; Moore, J.S. Macromolecules 2005, 38, 8975-8978

Differentiation from thermolysis productDifferentiation from thermolysis product

ThermolysisCH

3CN sis3CN, 82 oC


13C NMR characterizationC NMR characterization

2219

21

18Black = after sonication for 47 minRed = after thermolysis for 24 hBlue = before thermolysis


Mechanical reconfiguration of i *atropisomers*

S BINOL R BINOLIsomerization barrierS‐BINOL R‐BINOLIsomerization barrier>30kcal mol‐1

S‐BINAP R‐BINAP

*Atropisomers: chiral molecules whose asymmetric structures are derived from hindered rotations about sterically congested bonds

45Wiggins,K. M.; Hudnall,T. W.; Shen, Q.; Kryger, M. J.; Moore, J. S.; Bielawski, C. W. J. Am. Chem. Soc.2010, 132, 3256–3257

about sterically congested bonds

Mechanochemistry is involvedMechanochemistry is involved

)))) ))))

S‐polymer R‐polymer

≡≡

23


Isomerization monitoring by i l i h i ( )Circular Dichroism (CD)

Before sonication

After sonicationAfter sonication

OO O

O

CO2CH3

Br

CO CH

n

))))

CO2CH3

Brn

23

> 95% undergoes > 95% undergoes racimizationracimization

Aliquots removed at 0, 2, 4, 8, 12 and 24hAliquots removed at 0, 2, 4, 8, 12 and 24h


Isomerization monitoring by i l i h i ( )Circular Dichroism (CD)

Before sonication

After sonicationAfter sonication

))))

> 95% undergoes > 95% undergoes racemizationracemization

23

Aliquots removed at 0, 2, 4, 8, 12 and 24hAliquots removed at 0, 2, 4, 8, 12 and 24h


Attempts at thermal racemizationAttempts at thermal racemization

Before heating

270oC

After heating

270 C72h

Thermal Gravimetric Analysis (TGA)


Importance of polymer incorporationImportance of polymer incorporation

))))26

OO O

O

Br

O

O+ ))))27

Br

O

25

OO O

O

O

O+ ))))28

25


Electrocyclic opening of benzocyclobuteneElectrocyclic opening of benzocyclobutene

HN

O

O

PEG

))))

O

O

)))) ciscisLFP LFP

= MechanophoreHN

OO

PEG

29 30= Polymer

PEG = Poly ethylene glycol

29

l k f l d l

30

51Hickenboth, C. R.; Moore, J. S.; White, S. R.; Sottos, N. R.; Baudry, J; Wilson, S. R. Nature 2007, 446, 423‐427

LFPLFP = link‐functionalized polymer

Unexpected results for ring opening?Unexpected results for ring opening?

HO

O

HN

O

PEG

O

O

O

O

O

O

O

O

mPEG-NH2

DCC, DMAP

transtransLFP LFP

Heat (E, E)

O

OH

OO

O

HN

OO

PEG

CH2Cl2 ))))(E, E)

31 32

Heat(E, Z)

ciscisLFP LFP

))))(E E)

Violation of Woodward‐Hoffmann rules

LFPLFP = link‐functionalized polymer 52

(E, E)29 30

Woodward‐Hoffmann rulesWoodward Hoffmann rules

H CH3 H3C CH3HH

Heat

Conrotatory

ConrotatoryH3C H

HH

(E,E)trans-compound

Conrotatory

Disrotatory

Disrotatory

53Woodward, R. B.; Hoffmann, R. Angew. Chem. Int. Ed. 1969, 8, 781‐853

Ultrasound conditionsUltrasound conditions

H CH3 H3C CH3HH

Heat

H3C HHH

(2E,4E)-hexa-2,4-diene(3R,4S)-3,4-dimethylcyclobut-1-ene

XX

54

Ultrasound conditionsUltrasound conditions

H CH3 H3C CH3HH

Heat

H3C HHH

(2E,4E)-hexa-2,4-diene(3R,4S)-3,4-dimethylcyclobut-1-ene

55

Mechanical effect on configurationMechanical effect on configuration

≡

( )trans (E,E)trans

Violation of Woodward‐Hoffmann rules

≡≡

(E,E)cis

56Hickenboth, C. R.; Moore, J. S.; White, S. R.; Sottos, N. R.; Baudry, J; Wilson, S. R. Nature 2007, 446, 423‐427

Do modeling calculations agree?Do modeling calculations agree?

• Minimal energy pathwayMinimal energy pathway (MEP) calculations

• B3LYP density functional theory (DFT)

• 6‐31G** basis set

Ong, M. T.; Leiding, J.; Tao, H.; Virshup, A.M.; Martinez, T. J. J. Am. Chem. Soc. 2009, 131, 6377–637957

Minimal energy pathwaysMinimal energy pathways

Disrotatory ConrotatoryDisrotatory Conrotatory

cis

S.M.Pdt. S.M.S.M.S.M.

Pdt.

cistrans

Pdt.Pdt.

Conrotatory and disrotatory pathways become equivalent at an applied force of 1.5nN

Ong, M. T.; Leiding, J.; Tao, H.; Virshup, A.M.; Martinez, T. J. J. Am. Chem. Soc. 2009, 131, 6377–637958

Trapping the intermediateTrapping the intermediateHO

O

HN

O

PEG

O

O

O

O

O

O

mPEG-NH2

DCC, DMAPCH2Cl2

transtransLFP LFP

))))

OH

OO

HN

OO

PEG3133

32

HO

O

HN

O

PEGN‐(1‐pyrene)‐maleimide

(Dienophile)

34O

O

O

O

O

O

mPEG-NH2

DCC, DMAPCH2Cl2

ciscisLFP LFP

))))One product

34

OH

OO

HN

OO

PEG 59LFPLFP = link‐functionalized polymer

29 30

Control experimentsControl experiments

LFP 3 reaction with the pyrene‐labeled dienophile, without sonicationLFP 3 reaction with the pyrene labeled dienophile, without sonication

Hickenboth, C. R.; Moore, J. S.; White, S. R.; Sottos, N. R.; Baudry, J; Wilson, S. R. Nature 2007, 446, 423‐42760

Proof of incorporationProof of incorporation

• trans polymer product

• cis polymer product

• PEG polymer

This indicates that pyrene‐labeled dienophiles are incorporated to polymers61

13C labeling experimentsC labeling experimentsHN

O

PEG

O

O

O

Heat or US

O*

HNPEG

O

transtransLFP LFP

HN

OO

PEG

N

O

*

*

N

OOO

*32

33

HN

O

PEG

OO

HNPEG

O

O

*

34

O

O

O

O

US

PEG

ciscisLFP LFP

HN

OO

PEG62

30

13C NMR analysis35

C NMR analysis

Control compound

Control compound

Thermal, cis (decomposes)

Thermal, transN‐pyrene‐2,3‐naphthimide

Sonication, cis

Sonication, transSonication, trans

Arnold, B. J.; Sammes, P. G..; Wallace, T. W. J. Chem. Soc. Perkin Trans. I 1974, 41563

Chain length factorChain length factor

4 kDa S.M.

40 kDaSonicated

4 kDaSonicated

13C NMR

cis

32 Sonicated

4 kD S M

32

4 kDa S.M.

40 kDaSonicatedtrans

4 kDaSonicated

13C NMR

30

64

Amide carbonyl (red) in the starting materialEster carbonyl (blue) in the starting materialAmide carbonyl (green) in Diels‐Alder adduct

Summary (Mechanochemistry)Summary (Mechanochemistry)

• Ultrasound can be applied to polymer based reagents to breakUltrasound can be applied to polymer based reagents to break or reconfigure bonds in chemical reactions

• The mechanical effects can be clearly differentiated from the thermal effects in the presence of polymeric chains

• Shear forces generated by cavitation, represent the most accepted explanation for the observed mechanochemical effects

65

ConclusionConclusion

• Although low in energy, ultrasound waves can indirectly effect chemical reactions ia a high energ e ent referred to as thechemical reactions, via a high energy event referred to as the cavitation phenomenon

• Recent advances in mechanochemistry show a considerable potential in the fields of polymer and organic chemistry

• Additional research needs to be conducted to better understand the physical repercussions of the cavitation phenomenon, as well as, to

l th t ti l f lt d t h lexplore the potentials of ultrasound technology

• Ultrasound technology has more potentials, other than glassware gy p , gcleaning application

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AcknowledgmentAcknowledgment

• Prof. Xuefei Huango ue e ua g• Prof. Babak Borhan• Prof James E JacksonProf. James E. Jackson• Labmates• Allison Aman D Monica Gina Luis Q Anil• Allison, Aman D., Monica, Gina, Luis Q., Anil • My family• Audience• Audience

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Now, back to…..Now, back to…..

WORK !!!

St. Patrick’s day March Madness

WORK !!!

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Sonochemicaland MechanochemicalApplications in … MechanochemicalApplications in Organic Synthesis...

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