Mechanochemistry:Solvent‐FreeOrganicReac8onsintheSolidPhase

PeterM.LambertMarch4th,2009

DepartmentofChemistryMichiganStateUniversity

1

Outline

•  Introduc8ontomechanochemistry•  Organicmechanochemicalreac8ons– Oxida8onofalkenes– Amideforma8on– Nitronesynthesis– Asymmetricinduc8on

– Cellulosefunc8onaliza8on•  Conclusion

2

TypesofChemistry

• Mechanochemistry– physicalac8va8on

3J.Fernández‐Bertran,PureAppl.Chem.,1999,71,581‐586.

•  Electrochemistry– electricalac8va8on

•  Photochemistry– lightac8va8on

•  Thermochemistry– heatac8va8on

Combus<on

•  Rubbings8ckstogethertomakefire•  Combus8onstartsabout200˚C

• Mo8onfric8onheatreac8on

4K.N.Palmer,P.S.Tonkin,Combus3onandFlame,1957,14‐18.PhotosbyW.Qualls,h]p://www.caliberdt.com/~bill/tcfire/index.htm

StrikingFlintandSteel

•  Strikingflintandsteeltomakesparkisamechanochemicalprocess

•  Smallpar8clesofsteelareformed•  Oxida8onofironisexothermic•  Highsurfaceareaallowsquickreac8on•  Mo8onpar8clereac8onheat

5Hildorf,WalterG.;McCollam,C.H.IronAge,1929,124,953‐956.

Dimeriza<onofAnthracene

6V.M.Tapilin,N.N.Bulgakov,A.P.Chupakhin,A.A.Politov,J.Struct.Chem.,2008,49,581‐586.

CalculatedTotalEnergy CalculatedHOMOandLUMO

h!

4+4 cyclization

heat

30 kbar

Pressure Cell

Prepara<onofIRPellets

•  KBrorothersaltsmayreactwithanalyteunderhighpressuresusedtopreparepellet.– Ion‐exchange– Complexforma8on• KBrformscomplexeswithsugars,thiourea,succinimide

– Oxida8on‐Reduc8onreac8ons• 

7J.Fernández‐Bertran,PureAppl.Chem.,1999,71,581‐586.

FeIII(CN)6-3 + Br- FeII(CN)6

-4 + 1/2 Br2

Tribochemistry:Fric<onalChemistry

•  Tribochemistryisthestudyofchemistrycausedbyfric8on,specificallyinlubricants

•  Importanttomechanicalengineeringofmovingparts

8S.M.Hsu,J.Zhang,Z.Yin,TribologyLeD.2002,131‐139.

heat

rub+

Fe

O

OH HO+O

O H2O

Addi<vestoLubricants

•  Longpolymerstostabilizeviscosity

•  Zincdialkyldithiophosphatetopassivateiron

9S.M.Hsu,J.Zhang,Z.Yin,TribologyLeD.2002,131‐139.

ZnS

S

S

SP

OR

ORP

RO

RO

Friction orHeating

High

Low

Low

High

Viscosity Viscosity

TypesofGrindingApparatus

• Mortarandpestle

•  Rota8ngballmill

10h]p://www.unitednuclear.com/mills.htm

HighEnergyBallMilling

•  Vibra8ngballmill– laboratoryscale– upto100mg

•  Planetaryballmill– laboratoryscale– upto100gperbowl

•  S8rredballmill– industrialscale– kilograms

11

HowitWorks

•  Crushingofpar8clesresultsinlargesurfaceareas

• Mixingofsolidsallowsreac8onatsurfaces

•  Thermalequilibriumisbroken– “hotspots”,es8matedat10000K,– Las8ng10‐7seconds

•  Collisionsbreakcrystallinematerial

•  Highpressures12

J.Fernández‐Bertran,PureAppl.Chem.,1999,71,581‐586.

Transi<onPressureofMinerals

Mineral Geometry Volumeperformulaunit(Å3)

Calcite Trigonal‐Rhombohedral 61

Aragonite Orthorombic 57

•  Polymorphicmaterialhavegeometriesthatvarywithpressure

•  Phasetransi8onscanbemeasured•  Forexample,calciumcarbonate

–  Calcite,lowpressurephase–  Aragoniteformedabove3000bar

•  Aragoniteismetastableatambientpressure

13J.R.Smyth,T.J.Ahrens,Geophys.Res.LeD.,1997,24,1595‐1598.F.Dachille,R.Roy,Nature,1960,186,34,71.

Calcite

Aragonite

HowMuchPressure?

Substance Transi8onTransi8on

Pressure(bar)HighPressure

PhaseObservedaCaCO3 CalcitetoAragonite 3000 yes

PbO2 LeadOxideItoII 10,000 yes

Sb2O3SenarmonitetoValen8nite

10,000 yes

BeF2 15,500 trace

B2O3 ColemanitetoUlexite 18,500 no

BAsO4 30,000 no

14F.Dachille,R.Roy,Nature,1960,186,34,71.

Aoergrindingwithmortarandpestle,orwithvibratoryballmill:

aSamplesanalyzedwithpowerXRDtodeterminephasespresent.(1bar=14.5psi)

OtherFieldsthatuseBallMills

• Materialscience•  Powdermanufacturing(e.g.gunpowder)

• Metallurgy

•  Inorganicchemistry

15Balema,V.P.,Dennis,K.W.,Pecharsky,V.K.,Chem.Comm.,2000,1665.

3 LiAlH4

Ball Milling, 5 min.

3 mol% TiCl4Room Temp.

Li3AlH6 + 2 Al + 3 H2

100% conversion!G = -6.5 kcal/mol

Outline

•  Introduc8ontomechanochemistry•  Organicmechanochemicalreac8ons– Oxida8onofalkenes– Amideforma8on– Nitronesynthesis– Asymmetricinduc8on

– Cellulosefunc8onaliza8on•  Conclusion

16

Oxida<onwithInorganicSupport

17H.Sohmiya,T.Kimura,P.Bauchat,M.Fujita,T.Ando,Chem.LeD.1991,1391‐1392.

Subtrate Product Yield(%) Substrate Product Yield(%)

65(62a)

82(72a)

74 60

66

Ph

Ph

PhPh

no grindingNoReac8on

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Cl

Cl

Ph

Ph

Ph

Ph O

Ph

Ph

Ph

Cl

OH

Ph

Cl

Ph

Cl

Ph

Ph

Cl

Cl

Solid Substrate Product

PhIO, HCl-Silica gel

Grinding in Mortarand Pestle, 5 min.

aSolu8onphase:Solidsubstrate,PHIOandconc.HCls8rredinether,30min.

IO

Ph n

+ n HCl n

ClI

OH

Ph

Pulverize

Step 1:

Step 2:

Ph Ph

Cl I

OH

Ph

Ph Ph

I

OH

Ph

Cl

Ph Ph

I

HOPhCl

Cl Ph Ph

ClCl

Ph Ph

PhPhCl

IOH

Ph

Ph Ph

PhPh O

HCl

Ph Ph

PhPh O

Step 2:

HH2O

PhI

PhI

HCl

ProposedMechanismofAddi<on

18H.Sohmiya,T.Kimura,M.Fujita,T.Ando,Tetrahedron,1998,13737‐13750.

AmideForma<on

•  Thetradi8onalwaytomakeanamideistouseanacyla8ngagent,suchasanacidchloride,andreactwithanamine.

19Franzen,Hartwig,BerichtederDeutschenChemischenGesellschaM,1909,2465‐2468.H.Nakatsuji,M.Morimoto,T.Misaki,Y.Tanabe,Tetrahedron,2007,12071‐12080.

Ar

O

Cl Ar

O

NH

Ar'H2N Ar'+ + HCl

Benzene

reflux, 8 h

Ar

O

Cl Ar

O

NH

Ar'H2N Ar'+ + HCl

(1.5 eq)TMEDA(1.5 eq)

CH3CN, 0˚C, 1h

N N

AmidefromAldehyde

•  Recently,methodstomakeamidesfromaldehydesandamineswerereported.

20S.Seo,T.J.Marks,Org.LeD.2008,317‐319J.Gao,G.Wang,J.Org.Chem.2008,2955‐2958

R

O

H R

O

NH

R'H2N R'

+benzene, 25 ˚C, 24 h

La[N(TMS)2]3

3 eq.

R

OH+

R

O

H+

H2NR'

OxoneMgSO4

Ball Mill, 30 Hzr.t., 90 min

R

O

NH

R'

Oxidants,Dryingagents,Solvents

Oxidant DryingAgent Solvent Yield(%)

Oxone 61

Oxone 4ÅMS 68

Oxone MgSO4 75

Oxone MgSO4 CH3CN 11

Oxone MgSO4 toluene trace

K2S2O8/CuCl MgSO4 trace

I2 MgSO4 021

J.Gao,G.Wang,J.Org.Chem.2008,2955‐2958

O

H+

NH2Oxidant

Drying agent

Ball Mill, 30 Hzr.t., 90 min

O

NH

O2N O2N

ScopeofReac<on

Product Yield(%) Product Yield(%)

75 38

78 71

65 62

42 65

22

Ar

O

H+

H2NAr'

OxoneMgSO4

Ball Mill, 30 Hzr.t., 90 min

Ar

O

NH

Ar'

O

NH

O2N

O

NH

O

NH

O

NH

O2N

NC

S

O

NH

O2N

O

NH

O

NH

Br

Cl

O

NH

Cl

O2N

Br

NO2

Cl

J.Gao,G.Wang,J.Org.Chem.2008,2955‐2958

MechanismforAmideForma<on•  Twopossiblepathwaysareproposed:

23J.Gao,G.Wang,J.Org.Chem.2008,2955‐2958

Ar

O

H

H2NAr'

Ar

O

HNH2

Ar'

protontransfer

Ar

OH

HNH

Ar'

Path A:

Path B:

Ar

H

NAr'

Ar

O

NH

Ar'

Ar

H

NAr'

O

K S

OO

OH

OO

ArH

NAr'

O

+KHSO4

+ H2O

KH

Ar

O

HHN

Ar'

SO

O

O

H

O

O

Oxone

Oxone

Nitrones

•  Canbeusedinspin‐labelingstudies– Formstableradicals

•  Synthe8cintermediates– Example:[3+2]cycloaddi8onstomakeisoxazoline

24E.Colacino,P.Nun,F.M.Colacino,J.Mar8nez,F.Lamaty,Tetrahedron,2008,5569‐5576.I.S.Young,M.A.Kerr,Angew.Chem.Int.Ed.2003,3023‐3026

NOR1

R2EWG

O

N

EWG

R1

R2

NOR1

R2

+ R• NOR1

R2

R

PreviousSynthesis

25K.Torssell,O.Zeuthen,ActaChem.Scand.Ser.B,1978,118‐124.K.S.Chan,W.‐K.Yeung,R.‐J.Chan,T.‐C.Wang,W.J.Mak,J.Org.Chem.1995,1741‐1747.

• IfR1isabulkygroup,liket‐butyl,thenyieldsarelow.

NOR1

R2

R1NH

OH

R2

O+

R1NH

R2

NOR1

R2

H2O2, Na2WO4 (cat.)

NaHCO3, MgSO4

CH2Cl2, RefluxN2 atmosphere

42-90% yield

MeOH, 0˚C

1.5 eq.

NitroneinaBallMill

R1 R2 Time(h) Yield(%)BallMill

Yield(%)Microwavea

CH3 C6H5 1 82 72

Bn C6H5 1 88 80

C(CH3)3 C6H5 2 100 74

CH3 4‐CN‐C6H4 0.5 93 64

Bn 4‐CN‐C6H4 2 99 n.d.

CH3 4‐I‐C6H4 1 100 n.d.

Bn 4‐I‐C6H4 2 88 65

26

NOR1

R2

R1

NH

OH

R2

O+

Ball Mill, 30 Hz

NaHCO3

E.Colacino,P.Nun,F.M.Colacino,J.Mar8nez,F.Lamaty,Tetrahedron,2008,5569‐5576.

aMicrowaveexperimentdoneat120˚Cfor3hours.

ComparingSolventtoBallMilling

Solvent Condi8on BallMill

40˚C Temperature RoomTemp

CH2Cl2 Solvent None

N2 Atmosphere Air

18–24h Time 0.5‐2h

1:1.5 ReagentRa8o 1:1

Yield:

48% 100%

75% 82%

27E.Colacino,P.Nun,F.M.Colacino,J.Mar8nez,F.Lamaty,Tetrahedron,2008,5569‐5576.

N

O

N

O

AsymmetricInduc<on:OpeningofmesoAnhydrides

MixingCondi8on Temperature Timemolra8o

A:BYield(%) ee(%)

Solvent:toluene roomtemp. 36 1:3 82 79

Solvent:toluene ‐55˚C 96 1:3 96 99

Ballmilling,4Hz roomtemp. 36 1:1 91 61

28

N

OMe

OH

N

Quinidine

C.Bolm,I.Atodiresei,I.Schiffers,Org.Synth.2005,120‐124.B.Rodriguez,T.Rantanen,C.Bolm,Angew.Chem.Int.Ed.2006,6924‐6926.

•  Awaytointroducechiralitytoop8callyinac8vespecies.

O

O

O

+

OH

O

OH

O

Oquinidine (1.1eq)

A B

AsymmetricAldolCondensa<on

Product Method Time(h) Yield(%) an'/syn ee(%)

A 5.5 99 89:10 94

B 96 98 87:13 94

A 7 97 93:7 97

B 36 89(10) 91:9 97

A 36 65(25) 66:34 63

B 96 64(26) 71:29 67

A 19 73 ‐ 56

B 36 69 ‐ 5429

B.Rodriguez,T.Rantanen,C.Bolm,Angew.Chem.Int.Ed.2006,6924‐6926.

O

R1 R1 H

O

R2

(s)-proline (10 mol%)

ball mill (A)or stirring (B) R1 R1

O OH

R2+

O OH

NO2

O OH NO2

O OH OMe

O OH

NO2

MetalCatalyzedReac<ons

•  Oxida8vecouplingof2‐naphthol

•  Heckreac8on

•  Palladiumcatalyzedhydrodechlorina8on

B.Rodriguez,A.Bruckmann,T.Rantanen,C.Bolm,Adv.Synth.Catal.2007,349,2213‐233I.Pri‐Bar,B.James,J.Mol.Cat.A:Chemical2007,264,135‐139

30

COOMe

NHBoc

+ INHBoc

COOMe

NaClball mill (13 Hz), 1 h 76%

Pd(OAc)2 (5 mol%)NaHCO3, n-Bu4NClHCOONa (0.2 eq)

2

OH

FeCl3 • 6 H2O

NaClball mill, 1 h

OH

OH

87%

Cl

Cl

Cl

Cl

Cl

Cl

NaOH, ball mill

Pd/C (5 mol%), CaH2

FullereneFunc<onaliza<on

31

N NNR

RN3

ball mill

Si

PhPh

Ph2SiCl2 + Liball mill

H

R

RBr + Mball mill

M=Na,K,Li,Mg

R =

ball mill KCN

H

CN

o-dichlorobenzenesolution

H

CH2CO2Et

Zn + BrCH2CO2Etball mill

G‐W.Wang,EncyclopediaofNanoscienceandNanotechnology,2003,10,1‐9.

Biomass

• Woodiscomprisedofpolymericmaterials– Rigid‐chaincelluloseinamorphousligno‐carbohydratematrix

•  Chemicalu8liza8onofbiomassishamperedbylowsolubilityinsolvents

32I.V.Mikushina,I.B.Troitskaya,A.V.Dushkin,Y.A.Ol’khov,N.G.Bazarnova,Chem.forSust.Devel.2003,363‐370.h]p://www.fotosearch.com/photos‐images/wood.html

O

H

H

OH

H

H

OH

H

O

HO

O

H

H

OH

H

H

OH

H

O

HO

O

H

H

OH

H

H

OH

H

O

HO

O

H

H

OH

H

H

OH

H

HO

HO

O

H

OH

H

OH

H

H

OH

H

O

HO

O

H

H

OH

H

H

OH

H

O

HO

BallMillingofWood

•  Testsdoneonsawdust•  Par8clesizedecreasesfrom400µmto3‐16µm

•  Specificsurfaceareaincreases(includesporesandchannelsinpar8cles)

•  Fibrousstructureislostquickly•  Cellulosepolymerlengthisshortened•  Crystallinityofcellulosedecreasedbymilling,increasesifheated

33I.V.Mikushina,I.B.Troitskaya,A.V.Dushkin,Y.A.Ol’khov,N.G.Bazarnova,Chem.forSust.Devel.2003,363‐370.

ComparisonofMillingTypes

MillType Time(min)SpecificSurface

(m2/g)CrystallinityDegree(%)

Ini8alWood 0 0.6 81

Rota8ng 315 3.0 63

Planetary 2 2.2 100

VibratoryCentrifugal(balls)

15 2.5 100

VibratoryCentrifugal(cylinders)

15 1.1 63

34I.V.Mikushina,I.B.Troitskaya,A.V.Dushkin,Y.A.Ol’khov,N.G.Bazarnova,Chem.forSust.Devel.2003,363‐370.

CelluloseAcetate

•  Celluloseacetateisusedinfilmsandtex8les•  Tradi8onally,celluloseacetateismadewithsulfuricacidascatalyst– Expensivesolvent– Wastesulfuricacidisgenerated

35L.Yan,W.Li,Z.Qi,S.Liu,J.ofPolymerRes.2006,375‐378.

Ball Milling, 5 Hz

Acetic Anhydride

SO42-/ZrO2 (cat.)

Cellulose Cellulose Acetate + Acetic Acid

LiCl/N,N-dimethylacetamide

Acetic AnhydrideH2SO4 (cat.)

Cellulose Cellulose Acetate + Acetic Acid

SynthesisofCelluloseAcetate

36L.Yan,W.Li,Z.Qi,S.Liu,J.ofPolymerRes.2006,375‐378.

MillingTime(h) 0 1.0 2.5 5.0 7.5

DegreeofSubs8tu8on

0 0.43 1.19 1.65 1.80

DegreeofPolymeriza8on

420 403 397 355 324 0

50

100

150

200

250

300

350

400

450

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 2 4 6 8

DegreeofPolym

eriza<

on

DegreeofSub

s<tu<on

Time(h)

DegreeofSubs8tu8on DegreeofPolymeriza8on

OH

OHOH

OH

Ball Milling Ball Milling

Acetic Anhydride

SO42-/ZrO2 (cat.)

O

O

CH3

O

ORO

OR

R = H, COCH3

OH

HO

HO

HO

SpinLabelingStudy

•  1‐oxyl‐3‐imidazoline‐3‐oxideradicalsstudiedbyEPR

•  Radicalsareevenlydistributedandisolated

•  Tworadicalsseen:–  looselybound

adsorbed–  8ghtlybound

covalentlybonded•  Approximately1

radicalpermonomer37

A.V.Dushkin,I.B.Troitskaya,V.V.Boldyrev,I.A.Grigor’ev,Russ.Chem.Bull.Int.Ed,2005,1155‐1159.

N

N

O

O

N

N

O

OO

OH

N

N

O

OBr

Cellulose

Ball Milling

Cellulose

Ball Milling

Cellulose

Ball MillingNaOH

N

N

O

OO

O

N

N

O

O

O

N

N

O

OH O

FutureResearchPossibili<es

•  Furtherelucida8onofmechanochemicalmechanism– comparereac8onselec8viestotemperaturestudiestofind“effec8vetemperature”

•  Extendmethodtoothersynthe8creac8ons– Seemstoworkwellforcouplingtypereac8ons

•  Con8nuedfocusonbiomassu8liza8on– Solidmaterialsthatarehardtoworkwithchemicallyduetotheirinsolubilityinsolvents

38

Conclusion

• Mechanochemistryoffersasimple,efficient,environmentallyfriendlysynthe8cmethod.

• Manyorganicreac8onsareamenabletouseinballmills.

•  Ofspecialinterestarereac8onsthatusesolidreagents,par8cularlyreagentsnotreadilysolubleinorganicsolvents.

39

Acknowledgements

•  Dr.NedJackson•  Dr.BabakBorhan

•  Karrie,Partha,Misha,Cur8s

•  Mike,Sarah,Gina,Tom

•  Cora,Kamina,Raelani,Bill

40

ThankYouHaveagreatspringbreak!

"PiledHigherandDeeper"byJorgeChamwww.phdcomics.com

HN

OHR1

R2

R1

NH2

OH

R2

O

R1

NH

OH

NaHCO3

O

p.t.N

OR1

R2 O

H

H

NOR1

R2 O

H

H

NOR1

R2

O R1

HR2

OH2

R1 O

HR2

OH2

NOR1

R2

NOR1

R2

Cl

MechanismforNitroneForma<on

42

MechanismofLanthanideMediatedAmida<on

43

NHR1R2

NH(SiMe3)2

La[N(SiMe3)2]3

LaN

O

HR La

N

O HR

O

H R La

N

O R

O

H RH

RHO

O

HR

O

H R

LaN