Variable Temperature and Variable Temperature and Pressure Techniques for Pressure Techniques for in situin situ

CrystallizationCrystallization

Roland BoeseRoland Boesecontributions contributions

from:from:D. BläserD. Bläser

V.R. ThalladiV.R. ThalladiC. SchauerteC. Schauerte

M. T. KirchnerM. T. Kirchner

Erice, 16. 6. 2004Erice, 16. 6. 2004

A. GehrkeA. Gehrke

Variable Temperature and Variable Temperature and Pressure Techniques for Pressure Techniques for in situin situ

CrystallizationCrystallization

Erice, 16. 6. 2004Erice, 16. 6. 2004

Roland BoeseRoland Boesefinancial aid:financial aid:

DFGDFGSFBSFB452452 ratiopharmratiopharm

In situ - Crystallization

What is it?

Crystallization on the diffractometer in capillaries

In situ - Crystallization

Why should we do so?Why should we do so?

• Crystals grown outside cannot be transferred to the Crystals grown outside cannot be transferred to the diffractometer without damagediffractometer without damage

• Better control on crystallization processBetter control on crystallization process

In situ - Crystallization

How to do it?How to do it?

• Fill capillaryFill capillary• Mount itMount it• Switch on LT-deviceSwitch on LT-device• Grow crystalGrow crystal• Check crystal qualityCheck crystal quality• Collect dataCollect data• Solve structureSolve structure

Fill capillaryFill capillary

Fill capillaryFill capillary

Fill capillaryFill capillary

Transfer to DiffractometerTransfer to Diffractometer

DetectorDetector

X-ray-SourceX-ray-Source

CoolingCooling

ObservationObservation

LaserLaser

In situ - Crystallization

How to crystallize?How to crystallize?• Simply cool downSimply cool down• And warm up againAnd warm up again Why?

TTmeltmelt

TT

VVcrystal growthcrystal growthVVnucleationnucleation

metastable regionmetastable regioncritical size

critical size

we need to heat!we need to heat!

In situ - Crystallization

In situ - Crystallization

How to crystallize?How to crystallize?• Simply cool downSimply cool down• And warm up againAnd warm up againwith fingerswith fingers

In situ - Crystallization

How to crystallize?How to crystallize?• Simply cool downSimply cool down• And warm up againAnd warm up againwith spatulumwith spatulum

In situ - Crystallization

How to crystallize?How to crystallize?• Simply cool downSimply cool down• And warm up againAnd warm up againwith heated wire (loop)with heated wire (loop)

In situ - Crystallization

How to crystallize?How to crystallize?• Simply cool downSimply cool down• And warm up againAnd warm up againwith heated platewith heated plate

In situ - Crystallization

How to crystallize?How to crystallize?• Simply cool downSimply cool down• And warm up againAnd warm up againwith IR-radiationwith IR-radiation

In situ - Crystallization

How to crystallize?How to crystallize?• Simply cool downSimply cool down• And warm up againAnd warm up againwith IR-laserwith IR-laser

In situ - Crystallization

Why with laser?Why with laser?• Simply cool downSimply cool down• And warm up againAnd warm up againwith IR-laserwith IR-laser

In situ - Crystallization

Why with laser?Why with laser?• Simply cool downSimply cool down• And warm up againAnd warm up againwith IR-laserwith IR-laser

Advantages:Advantages:growing from bottom to topgrowing from bottom to topoptical observationoptical observationno mechanical break of no mechanical break of

capillarycapillarycontrol on heatcontrol on heatcontrol on positioncontrol on positionhigh temperature gradienthigh temperature gradient

COCO22 laser laser

laser diodelaser diode

mirrormirror

ZnSeZnSe--lenslens

turning turning mirrormirror

LT-deviceLT-device

OOptical ptical HHeating and eating and CCrystallization rystallization DDeviceevice

O.H.C.D.

url:

http://www.ohcd-system.com

In situ - Crystallization

undistorted crystallization zone

In situ - Crystallization

… … and Polymorphism studiesand Polymorphism studies

Meat to the

bones

• What for?What for?

• LiquidsLiquids• GasesGases• SolutSolutionionss• Phase transitionsPhase transitions• Trapping of chemical reaction products Trapping of chemical reaction products • Co-crystalsCo-crystals• ClathratesClathrates

• n-nonanen-nonane– ‘‘rotator' phaserotator' phase

circumvent of disordered phasescircumvent of disordered phases

In situ crystallizationIn situ crystallization

25

20

15

10

5

0

-80 -70 -60 -50 -40 -30 -20

-57.03°C-57.03°Cphase transitionphase transition

-54.08°C-54.08°Cmelting pointmelting point

temperature (°C)

hea

t tr

ansf

er(m

W)

DSC heating curve of DSC heating curve of nn-nonane-nonane

shattershatter crystallizationcrystallization

crystallizationcrystallizationfrom solutionfrom solution

ordered phase

melt

rotator phase

• no crystal seedsno crystal seeds– temperature shockstemperature shocks– ultrasonicultrasonic– external seedingexternal seeding– internal seedinginternal seeding

• for ethylenglykol with phenazine (template effect)for ethylenglykol with phenazine (template effect)

problemsproblems

Crystallization techniquesCrystallization techniques

• ethylen glykolethylen glykol– glassy stateglassy state

In situ - Crystallization

phenazine

1,2-diphenyl-ethylene glycol

1,2-diphenyl-ethylene glycol

OH • • •N bridges

OH • • •N bridges

OH • • •N bridges

OH • • •N bridges

ethylen glykol

ethylen glykol oo

o

oo

phenazine

phenazine

Crystallization techniquesCrystallization techniques

crystal structure of ethylen glykolcrystal structure of ethylen glykol

R. Boese, H.-C. Weiss,Acta Crystallogr. 1998, C54, 24.

PyridinePyridine

N H N HN H N H

expected packing pattern

realized:

• D. Mootz and H.-G. Wussow, J. Chem. Phys., 1981, 75, 1517.

• no linear CH···N

• Z' = 4

• no thermodynamic minimum (calculated, S. Price et al., Cryst Eng. Comm. 2002)

DSCs DSCs pyridine and perdeutero-pyridine in pyridine and perdeutero-pyridine in

pentanepentane

-100 -80 -60 -40 -20 0 20Temperatur /°C

-8

-7

-6

-5

-4

-3

-2

-1

0

DSC /(mW/mg)

Kompl.Peakausw : Fläche:Onset:

58.34 J/g-60.8 °C

Kompl.Peakausw : Fläche: -80.19 J/g

Onset*: -72.2 °C

[5.2][5.4] Exo

-100 -80 -60 -40 -20 0 20Temperatur /°C

-4.00

-3.50

-3.00

-2.50

-2.00

-1.50

-1.00

-0.50

0.0

DSC /(mW/mg)

Onset*: -66.7 °C Onset*: -55.1 °C

Kompl.Peakausw : Fläche: 6.137 J/g

Kompl.Peakausw : Fläche: 51.09 J/g

Kompl.Peakausw : Fläche: -53.51 J/g

Onset*: -81.0 °C

[7.2][7.4]

Exo

pyridine perdeutero-pyridine

PyridinePyridine

PyridinePyridine

perdeutero-perdeutero-PyridinePyridine

perdeutero-perdeutero-PyridinePyridine

Same form found by S. Parsons for high pressure form, but also for the non-deuterated pyridine!

α-Form α-Form PP2211//n,n, 107.138°, 107.138°,5.8216, 10.4597, 8.9402Å,5.8216, 10.4597, 8.9402Å,V = 520, ρ = 0.908 g/cm³V = 520, ρ = 0.908 g/cm³

α-Form α-Form PP2211//n,n, 107.138°, 107.138°,5.8216, 10.4597, 8.9402Å,5.8216, 10.4597, 8.9402Å,V = 520, ρ = 0.908 g/cm³V = 520, ρ = 0.908 g/cm³

ß-Form ß-Form PP2211//c,c, 107.209°, 107.209°,7.2414, 8.1909, 10.8014Å, 7.2414, 8.1909, 10.8014Å, V = 612, V = 612, ρ ρ = 0.913 g/cm³= 0.913 g/cm³

ß-Form ß-Form PP2211//c,c, 107.209°, 107.209°,7.2414, 8.1909, 10.8014Å, 7.2414, 8.1909, 10.8014Å, V = 612, V = 612, ρ ρ = 0.913 g/cm³= 0.913 g/cm³

molecular complexes and networksmolecular complexes and networks

Aceton + AcetyleneAceton + AcetyleneAceton + AcetyleneAceton + Acetylene

1 : 1

2 : 1

O

C-H···O

EthynylbenzeneEthynylbenzene + Pyrazine + Pyrazine

N N

??N N

P-Diethinylbenzene + PyridinP-Diethinylbenzene + Pyridin

sublimation energies in kJ/mol

-45.0

-58.7

N N

N N

1x

2x

-162.4

-164.6stabilization by

2.2 kJ/mol

N N

N

-53.3

-75.5

2x

1x

-182.1

-169.6

destabilization by 12.5 kJ/mol

data by Martin U. Schmidt, Frankfurt

(ESP charges, Dreiding2.21, optimized)

Option 1Option 1

N N

NN

NN NN Option 2Option 2

Acetylene + PyridinAcetylene + Pyridin

Acetylene + PyridinAcetylene + Pyridin

Option 3Option 3

Option 4Option 4

OO

OO OO

Acetylene + ….Acetylene + ….

Option 5Option 5O

O

O

O

Acetylene + ….Acetylene + ….

Option 6Option 6

Acetylene + AcetyleneAcetylene + Acetylene

Option 7Option 7

π

π

π

π

π

π

π

π

Acetylene + Acetylene + π-System

in situin situ Cocrystallization Cocrystallizationof Gaseous Compoundsof Gaseous CompoundsAcetylene + AcetonAcetylene + Aceton

Acetylene + Acetylene + BenzeneBenzene

Acetylene + Acetylene + DimethylpyrazineDimethylpyrazineAcetylene + WaterAcetylene + Water

Water + MethaneWater + Methane

Water + Methane + Water + Methane + PropanePropane Water + Methane + Water + Methane + AdamantaneAdamantane

Water + Water + PropanePropane

GashydratesGashydrates

Acetylene + Acetylene + DioxaneDioxaneAcetylene + PyridinAcetylene + Pyridin

Acetylene + MethanolAcetylene + MethanolAcetylene + Acetylene + DimethylpyridinDimethylpyridinAcetylene + Di-Acetylene + Di-terttert-butylpyridin-butylpyridin

Acetylene + DMSOAcetylene + DMSO

molecular complexes and networksmolecular complexes and networks

DMSO + AcetyleneDMSO + Acetylene

Acetylene + BenzeneAcetylene + Benzene

8.21 8.21 ÅÅ

Acetylene + BenzeneAcetylene + Benzene

1.097 ÅÅ at 201K

1.157 ÅÅ at 123K

compare

1.20 ÅÅ Di-tert-butylethyne

Acetylene + Benzene

Acetylene + MethanolAcetylene + Methanol

Cmcm

Cmc21

Acetylene + MethanolAcetylene + Methanol

Acetylene + MethanolAcetylene + Methanol

Acetylene + MethanolAcetylene + Methanol

Space group P Space group P 221122112211

a a = 4.573, = 4.573, b b = 7.327, = 7.327, c c = = 13.158 Å 13.158 Å

Space groupSpace group CmcCmc2211

a a = = 6.417, 6.417, b b = = 7.228, 7.228, c c = = 4.652 4.652 ÅÅ

gas hydrates

below the oceans we have twice as much methane in clathrates than the eqivalent of all

known fossile fuel in the world

up to 10% of the off-shore conveying costs for natural gas is spent to avoid gas hydrates

in the sensitive equilibrium methane/water, natural gas is released by heating the oceans,

which is again the most effective geenhouse gas

GashydratesGashydrates

• Methane + Methane + WaterWater• Temperature:Temperature: below 8 °C below 8 °C • pressurepressure above 20 bar above 20 bar

Evaluation: Single ‚Frame‘Evaluation: Single ‚Frame‘

Multiple Single Crystals Multiple Single Crystals (‚oligocrystalline‘ material)(‚oligocrystalline‘ material)

'oligo'-diffractometry'oligo'-diffractometry

powder-diffractometrypowder-diffractometry

single crystal-diffractometrysingle crystal-diffractometry

occurenceoccurenceeconomical relevanceeconomical relevanceecological relevanceecological relevance

GashydratesGashydrates

'burning ice'

'burning ice'

O-H···OO-H···ODodecahedroDodecahedro

nnMethane (without Methane (without H‘s)H‘s)

Tetrakai-Tetrakai-decahedrodecahedronnMethane (with H‘s)Methane (with H‘s)

PropanPropanee

Hexakai-Hexakai-decahedrondecahedron Form IForm IForm IIForm II

GashydratesGashydrates

PropanPropanee

Hexakai-Hexakai-decahedrondecahedron Form IIForm II

GashydratesGashydrates

GashydrateGashydrate

GashydrateGashydrate

GashydrateGashydrate

GashydrateGashydrate

GashydrateGashydrate

GashydrateGashydrate

GashydrateGashydrate

Acetylen + Acetylen + WasserWasser