in situ crystallization - university of...
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Supramolecular Synthesis on the Diffractometer:Supramolecular Synthesis on the Diffractometer:in situin situ CoCo‐‐crystallizationcrystallization
17th Bruker Users17th Bruker Users‘‘ Group Meeting Group Meeting SCSC‐‐XRD 2010 XRD 2010
September 19September 19‐‐21, 201021, 2010Roland BoeseRoland Boese
Sebastian CirkelSebastian CirkelMichael KirchnerMichael Kirchner
FinancialFinancial SupportSupport
DFG DFG ForschergruppeForschergruppe 618618
Dieter BlDieter Blääserser
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Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
synthesis in organic chemistry applies covalent bonds synthesis in organic chemistry applies covalent bonds
supramolecular synthesis applies nonsupramolecular synthesis applies non‐‐covalent bonds covalent bonds
Linkage by covalent bonds between same molecules corresponds to Linkage by covalent bonds between same molecules corresponds to polymerization polymerization
What synthesis is in organic chemistryWhat synthesis is in organic chemistry
Is coIs co‐‐crystallization in supramolecular chemistry crystallization in supramolecular chemistry
Linkage by nonLinkage by non‐‐covalent bonds between same molecules corresponds to crystallizacovalent bonds between same molecules corresponds to crystallizationtion
Linkage by covalent bonds between unlike molecules corresponds tLinkage by covalent bonds between unlike molecules corresponds to organic synthesis o organic synthesis
Linkage by nonLinkage by non‐‐covalent bonds between unlike molecules corresponds to cocovalent bonds between unlike molecules corresponds to co‐‐crystallizationcrystallization
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CoCo‐‐crystallization on the Diffractometercrystallization on the Diffractometer
What is a co‐crystal?
multicomponent crystals salts, solvates (hydrates), clathrates, intercalates, mixed crystals, solid solutions, domain crystals, inclusion compounds, host‐guest compounds,racemates(?), etc….
stoichiometric non‐stoichiometric
no salt!no solvent
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2.23 Å
R. Boese, unpublished
chloroform & acetonechloroform & acetoneCan two solvents make a coCan two solvents make a co‐‐crystal or is it a supercrystal or is it a super‐‐solvate?solvate?
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
Acetylene (mp ‐84 °C) is a very small and versatile molecule with proton donor (pKs = 25) and π‐acceptor abilities.
Acetylene is polymorphic.
Acetylene is the second smallest organic molecule!
‐ and the smallest to make co‐crystals.
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Cmca,V = 209.1
Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Pa3, V=227.54
Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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π‐Acceptorπ‐Acceptor
Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
NN
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
NN
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
NN
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
NN NN
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
OO
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
OO
O
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
OH
O
H
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners, quadropolar interactions
HHδ δδ
O OCδδ δ
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
HH
O OC
O OC
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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Co‐crystallization with small molecules deserves special considerations & techniques
• Selection of partners
HHO
OC
OO
C
OO
C
OO
C HHHH
OO
C
OO
C
OO
C
OO
C
HHHH
HHHH
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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A thermodynamic picture from the viewpoint of a crystallographer
Lattice en
ergy
acetylene
CO2
C2H2 ∙ CO2
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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A thermodynamic picture from the viewpoint of a crystallographer
Lattice en
ergy
acetylene
CO2
C2H2 ∙ CO2
½
½
Supramolecular Synthesis on the DiffractometerSupramolecular Synthesis on the Diffractometer
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HH33CC
HH33CC
OOSS
HH33CC
NN
CCOO OO
OOHH
HHOO
HH
HH33CC
OOHH
PhPh
NNHH
HHHH
NN
NNNNNN
HH33CC
HH33CC
OOOO
HH
HH
NN
FF
FF
FF
FF
FF
FF
CC CC HHHH
Chem. Eur. J. 2010, 16, 2131 – 2146
M.T. Kirchner, D. Bläser, R. Boese
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Acetylene – Benzene (1:1)
R. Boese, T. Clark, A. GavezzottiHel. Chim. Act, 2003, 86, 1085‐1100.
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Acetylene – Benzene (1:1)
Titan – one of Saturn‘ moons
taken from Cassini spacecraft (started 1997, arrived 2004)
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Acetylene – Benzene (1:1)
Comparison of size – Earth – Titan - Moon
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Acetylene – Benzene (1:1)
Huygens shuttle (2005) – atmosphere of Titan
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Acetylene – Benzene (1:1)
‚lake‘ Ontariolacus (mare), the shores – and dunes,Probably consiting of co-crystals with acetylene
Temperature ca. 100 K
Dunes up to 300 m high and several hundred km long
resembling the sit
uation
on earth ca
. 5 billio
n
years ago
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Acetylene – Benzene (1:1)
‚lake‘ Ontariolacus (mare), the shores – and dunes,Probably consiting of cocrystals with acetylene
Temperature ca. 100 K
Mountains existing of
methan hydratesresembling th
e situation
on earth ca
. 5 billio
n
years ago
We were not able so far to cocrystallize hydrogen cyanide and acetylene:
HCN and HCCH
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Acetylene – Benzene (1:1) Acetylene –Perfluorobenzene (1:2)
R. Boese, T. Clark, A. GavezzottiHel. Chim. Act, 2003, 86, 1085‐1100.
unpublished
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Acetylene –m‐Xylene (1:1) Acetylene – Mesitylene (1:2)
Both co‐crystals can be considered as sections from the acetylene orthorhombic lattice, starting with chains (left) or clusters of three molecules (right).
unpublished
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Acetylene – Ammonia (1:1)
The ammonia hydrogen atoms are disordered, so that an alternating coordination is realized as shown in the drawing.
R. Boese, D. Bläser, and G. JansenJ. Am. Chem. Soc., 2009, 131 (6), 2104‐2106
The archetype of organic co‐crysta
ls or supramolecular synthesis!
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Acetylene – Ammonia (1:1)
The ammonia hydrogen atoms are disordered, so that an alternating coordination is realized as shown in the drawing.
R. Boese, D. Bläser, and G. JansenJ. Am. Chem. Soc., 2009, 131 (6), 2104‐2106
The archetype of organic co‐crysta
ls or supramolecular synthesis!
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Acetylene – Ammonia (1:1)
R. Boese, D. Bläser, and G. JansenJ. Am. Chem. Soc., 2009, 131 (6), 2104‐2106
The archetype of organic co‐crysta
ls or supramolecular synthesis!
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Acetylene ‐ Acetonitrile (2:1)
Acetylene is one‐fold coordinated, nitrogen is four‐fold coordinated
unpublished
CN
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acetylene + 2,5‐dimethylpyrazine
M.T. Kirchner, R. Boese, A. Gehrke, and D. BläserCryst. Eng. Comm., 2004, 6, 1‐8.
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acetylene ‐ formaldehyde acetylene ‐ acetone
R. Boese, M. T. Kirchner, W. E. Billups, L. R. Norman, Angew. Chem. Int. Ed. Engl., 2003, 42,
1961‐1963.unpublished
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acetyleneacetylene‐‐acetoneacetone
OO
O
O
R. Boese, M. T. Kirchner, W. E. Billups, L. R. Norman, Angew. Chem. Int. Ed. Engl., 2003, 42,
1961‐1963.
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acetyleneacetylene‐‐acetoneacetone
R. Boese, M. T. Kirchner, W. E. Billups, L. R. Norman, Angew. Chem. Int. Ed. Engl., 2003, 42,
1961‐1963.
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acetylene ‐ DMSO
SSOSS
OSS
OSSO
SSOSS
O
R. Boese, M. T. Kirchner, W. E. Billups, L. R. Norman, Angew. Chem. Int. Ed. Engl., 2003, 42,
1961‐1963.
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acetylene acetylene ‐‐ DMSODMSO
R. Boese, M. T. Kirchner, W. E. Billups, L. R. Norman, Angew. Chem. Int. Ed. Engl., 2003, 42,
1961‐1963.
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acetylene ‐ dioxane
Oxygen is almost trigonal surrounded
unpublished
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acetylene – methanol (1:1)
Acetylene is one‐fold coordinated, the methanol molecules resemble the Form II lattice, with acetylene squeezed into the original lattice.
M.T. Kirchner, D. Das, and R. BoeseCryst. Growth Des., 2008, 8, 763‐765.
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Acetylene ‐ Phenol
Acetylene molecules disordered
unpublished
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Gashydrates
Acetylene + Water
Form I
M.T. Kirchner, R. Boese, W.E. Billups, and L.R. NormanJ. Am. Chem. Soc., 2004, 126, 9407‐
9412.
•• Methane + WaterMethane + Water•• Temperature:Temperature:below 8 below 8 °°C C •• pressurepressureabove 20 barabove 20 bar
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GashydratesGashydrates
'burning ice'
'burning ice'
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Another example
Formic acid ‐ Formamide
O
OH
HN
OH
HH
Most common hetero‐synthon for co‐crystals of APIs
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Another example
Two complexes with each two independent molecules
Common synthon for amides
Uncommon acid‐amide synthon
unpublished
formic acid ‐ formamide
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Co‐crystals
take‐home message
• secondary contacts often dominate the packing• C‐H∙∙∙π is very flexible• two‐ or three‐fold coordinated nitrogen can easily accept three or more hydrogen atoms• the lone pair electron density of nitrogen is rather diffuse• the lone pairs at the carbonyl group do not direct hydrogen atoms; more than two hydrogen bridges are possible
Co‐crystals of small molecules
Co‐crystals of small molecules are difficult to predict!
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Co‐crystallization (supramolecular synthesis)can be performed by various means:
•Co‐crystallization from solution•Co‐grinding•Solvent drop co‐grinding•Co‐sublimation•Co‐melting
in situ Co‐crystallization
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Short version:Short version:
Co‐crystallization
• Fill capillary• Mount it• Switch on LT‐device• Grow crystal• Check crystal quality• Collect data• Solve structure
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with small molecules deserves special considerations & techniques
• Selection of partners (1)• Mixing of liquids in appropriate ratios (2)• Mixing of gases by co‐condensation (3)•Transfer of capillaries to the diffractometer (4)• Cooling and finding appropriate crystallization conditions (5)• Growing crystals preferably by IR‐laser (OHCD) (6)• Checking crystal quality by X‐ray scanning (7)• Selection of reflections belonging to the same reciprocal lattice (8)• Determination of lattice constants (9)• If attributed to that of the neat starting components, overcoming frustration (10)• Start again with one of point 1‐9 • As an alternative install a Raman Spectrometer
Co‐crystallization
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with small molecules deserves special considerations & techniques
• Selection of partners (1)• Mixing of liquids in appropriate ratios (2)• Mixing of gases by co‐condensation (3)•Transfer of capillaries to the diffractometer (4)• Cooling and finding appropriate crystallization conditions (5)• Growing crystals preferably by IRGrowing crystals preferably by IR‐‐laser (OHCD) (6)laser (OHCD) (6)• Checking crystal quality by X‐ray scanning (7)• Selection of reflections belonging to the same reciprocal lattice (8)• Determination of lattice constants (9)• If attributed to that of the neat starting components, overcoming frustration (10)• Start again with one of point 1‐9 • As an alternative install a Raman Spectrometer
Co‐crystallization
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in situin situ Crystallization Techniques:Crystallization Techniques:What is it?What is it?
What is it for?What is it for?What did we do with it?What did we do with it?
Crystallization on the diffractometer in Crystallization on the diffractometer in capillaries (at low temperatures)capillaries (at low temperatures)
Why is simple cooling less successful for Why is simple cooling less successful for growth of single crystals?growth of single crystals?
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TTmeltmelt
TT
VVcrystal growthcrystal growthVVnucleationnucleation
metastable regionmetastable regioncritical size
critical size
in situin situ Crystallization Techniques:Crystallization Techniques:
we need to heat!we need to heat!
time
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in situin situ Crystallization Techniques:Crystallization Techniques:
we need to heat!we need to heat!
••Distortion of cooling processDistortion of cooling process
Lipscomb, 1965Lipscomb, 1965••Wire loop heaterWire loop heater
Struchkov, 1977Struchkov, 1977••Heated plateHeated plate
Simon, 1976Simon, 1976
••Heating with IR light from a halogen lampHeating with IR light from a halogen lampMootz & Boese, 1985Mootz & Boese, 1985
••Controlled up and down with cooling deviceControlled up and down with cooling device
••Heating with IR light from a COHeating with IR light from a CO22‐‐laserlaserBoese, 1992Boese, 1992
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COCO22‐‐laserlaser
laser diodelaser diode
mirrormirror
ZnSeZnSe‐‐lenslens
rotating rotating mirrormirror
LTLT‐‐devicedevice
OOptical ptical HHeating and eating and CCrystallization rystallization DDeviceevice
O.H.C.D.
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in situin situ Crystallization Techniques:Crystallization Techniques:
Boese, 1992Boese, 1992
Why with IRWhy with IR--laser ?laser ?
Advantages:growing from bottom to topoptical observationno mechanical stress for capillarycontrol on heatcontrol on positionhigh temperature gradient
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undistorted undistorted crystallization zonecrystallization zone
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undistortedcrystallization zone
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in situin situ Crystallization Techniques:Crystallization Techniques:What is it?What is it?
What is it for?What is it for?
What did we do with it?What did we do with it?
• low melting compounds
• compounds with low phase transitions
• compounds which decompose without solvent
• crystallization under increased pressure (gases)
• cocrystallization under increased pressure
• gas clathrates
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sample preparationsample preparation
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sample preparationsample preparation
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sample preparationsample preparation
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DiffractometerDiffractometer
detectordetector
XX‐‐ray beamray beam
coolingcooling
observationobservation
laserlaser
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coolingcooling
XX‐‐ray beamray beam
Observation Observation microscopemicroscope COCO22‐‐laserlaser
detectordetector
TVcameraTVcamera
Capillary
DiffractometerDiffractometerwith Raman spectrometerwith Raman spectrometer
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DiffractometerDiffractometerwith Raman spectrometerwith Raman spectrometer
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