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Initial stages of crystallisation Elias Vlieg IMM Solid State Chemistry, Radboud University Nijmegen, The Netherlands Nucleation subcritical clusters laser-induced nucleation Chiral purification through crystal grinding

SLIDE 1

E. Vlieg

Initial stages of crystallisation

Elias Vlieg

IMM Solid State Chemistry, Radboud University Nijmegen, The Netherlands

Nucleation
subcritical clusters
laser-induced nucleation
Chiral purification through crystal grinding
crystal size distribution

MID XFEL Workshop, 28-29 October 2009, ESRF

SLIDE 2

E. Vlieg

Classical nucleation theory

Crystal nucleation not well understood
too fast
too few
too small
Important
dictates crystalline form (polymorph)
pharmaceutical industry!
Ostwald’s rule of stages
first least stable crystal is formed, later more stable
happens during nucleation

SLIDE 3

E. Vlieg

Nucleation

dominated by surface/size effects
nucleation barrier
classical nucleation theory
assume spherical nucleus, radius r
driving force: Δμ
surface free energy: γ
volume per growth unit: V0
Free energy:

γ π μ π

2 3 4 3

4 ) ( r V r r G

Δ − =

bulk crystal: gain surface energy: loss

γ

5 10 15 20 2 4 6 8 10 radius energy

nucleation barrier and critical radius

SLIDE 4

E. Vlieg

Effect of supersaturation σ

Probability of nucleation

depends strongly on supersaturation

Solution contains

transient clusters below the critical size

σ μ kT c c kT

= ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ = Δ ln

5 10 15 20 2 4 6 8 10 r (nm) G (eV)

σ = 1 % σ = 10 % σ = 100 %

SLIDE 5

E. Vlieg

Observing nuclei

Two options

1. Watch actual nucleation event
rare
2. Watch transient precritical clusters
lots

SLIDE 6

E. Vlieg

Precritical clusters

sample cell of 5 mm
KCl
critical cluster at σ = 5%, n* = 220

1.E+00 1.E+05 1.E+10 1.E+15 1.E+20 1 10 100 1000 n # observable clusters

0% 5%

SLIDE 7

E. Vlieg

Observable intensity

flux 1012 photons/pulse
after single pulse, cluster destroyed (?)
n ~ 220
F ~ 35

# scattered photons in single pulse

10 x 10 µm2 beam:

~5

1 x 1 µm2 beam:

~500

0.1 x 0.1 µm2 beam:

~50,000

ψ

2

) ( nF r I

e peak ≈

OK?

SLIDE 8

E. Vlieg

Beyond critical clusters

Need larger cluster = growing nucleus
How to find nucleus at the right time and the right place?
random
like winning the lottery
rapidly nucleating system will increase chances
many experiments are possible at rep-rate of XFEL
select only the successful ones
high-energy physics style

SLIDE 9

E. Vlieg

Laser-induced nucleation

Idea: use laser to induce nucleation
has been observed on e.g. KCl in single pulse
A.J. Alexander and P.J. Camp, Cryst. Growth & Design 9

(2009) 958.

‘instantaneous’ (single pulse of 7 ns 1064 nm laser)
Should produce growing nucleus at right time and place
In situ: at least 12.4 keV

supersaturated solution laser XFEL time delay up to seconds

SLIDE 10

E. Vlieg

Intensity from nucleus

Observe growing cluster after small time delay, 1 µm2 beam
radius 10 nm; n = 58,000

3 x 107 photons/pulse

radius 50 nm; n = 7.3 x 106

5 x 1010 photons/pulse

Many experiments needed
orientation of nucleus is random
Determine
shape
crystallinity
Bragg scattering: crystalline part
forward scattering: high-density part
polymorph

SLIDE 11

E. Vlieg

Non-classical nucleation

Two step mechanism
first density change
next crystalline order
Again: Bragg + forward scattering

density

rder

alternative normal

SLIDE 12

E. Vlieg

Experimental geometry

single shot
system needs time to recover or move to fresh position

laser XFEL sample beamstop top view forward Bragg area detectors

SLIDE 13

E. Vlieg

Chirality

Many molecules have handedness
left/right
+/-
D/L
R/S (absolute configuration)
Non-superimposable mirror images
Enantiomers
Chemical synthesis
usually racemic (50:50) mixture
Natural amino acids
(almost all) left-handed
why?

D-tartaric acid L-tartaric acid mirror

SLIDE 14

E. Vlieg

Enantiomers

In achiral environment
same physical properties (melting point, etc.)
In chiral environment (human body)
very different properties
often important to select one enantiomer (drugs, thalidomide )

limonene m

SLIDE 15

E. Vlieg

Chiral purification through crystal grinding

Model system

N-(2-methylbenzylidene)-phenylglycine amide
DBU as racemizing catalyst

Wim Noorduin et al., J. Am. Chem. Soc. 130 (2008) 1158

SLIDE 16

E. Vlieg

Mechanism?

Attrition-enhanced Ostwald ripening

Ostwald ripening
crystals get bigger
Attrition
crystal get smaller

NaClO3, Wim Noorduin et al. Crystal Growth & Des. 8 (2008) 1675

Measure evolution in crystal size distribution

size grinding ripening

nr. of crystals

SLIDE 17

E. Vlieg

Crystal size distribution

tens of thousands of crystals
size from nm (dissolving) to ~10 µm
Smallest crystals are thought to play crucial role
direct incorporation
ideally: distinguish between left and right

SLIDE 18

E. Vlieg

XFEL experiment

Extract size and shape from coherent images along

powder ring

large crystals: easy
small crystals (important!): difficult
Accumulate statistics by several separated shots
give system some recovery time
Watch evolution
hours time scale

XFEL detector

SLIDE 19

E. Vlieg

Conclusion

XFEL should make nucleation visible
For in situ experiments, harder X-rays useful