Download ppt - National Single Crystal X

PLATON and STRUCTURE
VALIDATION
Ton Spek
National Single Crystal
Service Facility,
Utrecht University,
The Netherlands.
Goettingen, 13-Oct-2007
Overview of the Talk
1. What is PLATON
2. Structure Validation
3. Concluding Remarks
Copy: http://cryst.chem.uu.nl
What is PLATON
• PLATON is a collection of tools for single crystal
structure analysis bundled within a single
SHELX compatible program.
• The tools are either extended versions of existing
tools or unique to the program.
• The program was/is developed over of period of
more than 25 years in the context of our National
Single Crystal Service Facility in the
Netherlands.
PLATON USAGE
• Today, PLATON is most widely used
implicitly in its validation incarnation for
all single crystal structures that are
validated with the IUCr CHECKCIF
utility.
• Tools are available in PLATON to analyze
and solve the reported issues that need
attention.
OTHER PLATON USAGE
• PLATON also offers guided/automatic
structure determination and refinement
tools for routine structure analyses from
scratch (i.e. the ‘Unix-only’ SYSTEM S
tool and the new FLIPPER/STRUCTURE
tool that is based on the Charge Flipping
Ab initio phasing method).
• Next Slide: Main Function Menu 
Selected Tools
• ADDSYM – Detection and Handling of Missed
(Pseudo)Symmetry
• TwinRotMat – Detection of Twinning
• SOLV – Report of Solvent Accessible Voids
• SQUEEZE – Handling of Disordered Solvents in
Least Squares Refinement (Easy to use
Alternative for Clever Disorder Modelling)
• BijvoetPair – Post-refinement Absolute Structure
Determination (Alternative for Flack x)
• VALIDATION – PART of IUCr CHECKCIF
ADDSYM
• Often, a structure solves only in a space group
with lower symmetry than the correct space
group. The structure should subsequently be
checked for higher symmetry.
• About 1% of the 2006 & 2007 entries in the CSD
need a change of space group.
• E.g. A structure solves only in P1. ADDSYM is a
tool to come up with the proper space group and
to carry out the transformation ( new .res)
• Next slide: Recent example of missed symmetry
Organic Letters (2006) 8, 3175
P1, Z’ = 8
C
C
o
Correct Symmetry ?
Test for Higher Symmetry
•
•
•
•
Start PLATON with a .ins or .cif
Click on ADDSYM on the main menu
Analyse automatically generated result
 Display next
After Transformation to P212121, Z’ = 2
(Pseudo)Merohedral Twinning
• Options to handle twinning in L.S. refinement available
in SHELXL, CRYSTALS etc.
• Problem: Determination of the Twin Law that is in effect.
• Partial solution: coset decomposition, try all possibilities
(I.e. all symmetry operations of the lattice but not of the
structure)
• ROTAX (S.Parson et al. (2002) J. Appl. Cryst., 35, 168.
(Based on the analysis of poorly fitting reflections of the
type F(obs) >> F(calc) )
• TwinRotMat Automatic Twinning Analysis as
implemented in PLATON (Based on a similar analysis
but implemented differently)
TwinRotMat Example
• Originally published as disordered in P3.
• Solution and Refinement in the trigonal
space group P-3 R= 20%.
• Run PLATON/TwinRotMat on CIF/FCF
• Result: Twin law with an the estimate of
the twinning fraction and the estimated
drop in R-value
• Example of a Merohedral Twin 
Ideas behind the Algorithm
• Reflections effected by twinning show-up in the
least-squares refinement with F(obs) >> F(calc)
• Overlapping reflections necessarily have the
same Theta value within a tolerance.
• Generate a list of implied possible twin axes
based on the above observations.
• Test each proposed twin law for its effect on R.
Possible Twin Axis
H” = H + H’
H
Reflection
with
F(obs) >>
F(calc)
Candidate twinning axis
(Normalize !)
H’
Strong reflection H’ with theta
close to theta of reflection H
Solvent Accessible Voids
• A typical crystal structure has only in the order of 65% of
the available space filled.
• The remainder volume is in voids (cusps) in-between
atoms (too small to accommodate an H-atom)
• Solvent accessible voids can be defined as regions in the
structure that can accommodate at least a sphere with
radius 1.2 Angstrom without intersecting with any of the
van der Waals spheres assigned to each atom in the
structure.
• Next Slide: Void Algorithm: Cartoon Style 
DEFINE SOLVENT ACCESSIBLE VOID
STEP #1 – EXCLUDE VOLUME INSIDE THE
VAN DER WAALS SPHERE
DEFINE SOLVENT ACCESSIBLE VOID
STEP # 2 – EXCLUDE AN ACCESS RADIAL VOLUME
TO FIND THE LOCATION OF ATOMS WITH THEIR
CENTRE AT LEAST 1.2 ANGSTROM AWAY
DEFINE SOLVENT ACCESSIBLE VOID
STEP # 3 – EXTEND INNER VOLUME WITH POINTS WITHIN
1.2 ANGSTROM FROM ITS OUTER BOUNDS
Listing of all voids in the triclinic unit cell
Cg
VOID APPLICATIONS
• Calculation of Kitaigorodskii Packing Index
• As part of the SQUEEZE routine to handle the
contribution of disordered solvents in crystal
structure refinement
• Determination of the available space in solid state
reactions (Ohashi)
• Determination of pore volumes, pore shapes and
migration paths in microporous crystals
SQUEEZE
• Takes the contribution of disordered solvents to
the calculated structure factors into account by
back-Fourier transformation of density found in
the ‘solvent accessible volume’ outside the
ordered part of the structure (iterated).
• Filter: Input shelxl.res & shelxl.hkl
Output: ‘solvent free’ shelxl.hkl
• Refine with SHELXL or Crystals
• Note:SHELXL lacks option for fixed
contribution to Structure Factor Calculation.
SQUEEZE Algorithm
1.
2.
3.
4.
5.
Calculate difference map (FFT)
Use the VOID-map as a mask on the FFT-map to set all
density outside the VOID’s to zero.
FFT-1 this masked Difference map -> contribution of
the disordered solvent to the structure factors
Calculate an improved difference map with F(obs)
phases based on F(calc) including the recovered solvent
contribution and F(calc) without the solvent
contribution.
Recycle to 2 until convergence.
SQUEEZE
In the Complex Plane
Fc(total)
Fc(solvent)
Fc(model)
Fobs
Solvent Free Fobs
Black: Split Fc into a discrete and solvent contribution
Red: For SHELX refinement, temporarily substract
recovered solvent contribution from Fobs.
Comment
• The Void-map can also be used to count the
number of electrons in the masked volume.
• A complete dataset is required for this feature.
• Ideally, the solvent contribution is taken into
account as a fixed contribution in the Structure
Factor calculation (CRYSTALS) otherwise it is
substracted temporarily from F(obs)^2
(SHELXL) and re-instated afterwards with info
saved beyond column 80 for the final Fo/Fc list.
Publication Note
• Always give the details of the use of
SQUEEZE in the comment section
• Append the small CIF file produced by
PLATON to the main CIF
• Use essentially complete data sets with
sufficient resolution only.
• Make sure that there is no unresolved
charge balance problem.
Post-Refinement Absolute Structure
Determination
• Generally done as part of the least squares
refinement with a ‘twinning’ parameter.(Flack x)
• Determine Flack x parameter + su
• Validity Analysis following the Flack &
Bernardinelli criteria.
• Often indeterminate conclusions obtained in the
case of light atom structures
• Alternative approaches offered by PLATON 
Scatter Plot of Bijvoet
Differences
• Plot of the Observed Bijvoet Differences
against the Calculated Differences.
• A Least-Squares line is calculated
• The Green least squares line should run
from the lower left to the upper right
corner for the correct absolute structure.
• Vertical bars on data points indicate the su
on the Bijvoet Difference. Example 
Excellent Correlation
Practical Aspects of Flack x
• The structure should contain atoms with
sufficiently strong anomalous dispersion
contributions for the radiation used (generally
MoKa) in the experiment (e.g. Br).
• Preferably, but not nesessarily, a full set of
Friedel pairs is needed. (danger: correlation !)
• Unfortunately, many relevant pharmaceuticals
contain in their native form only light atoms that
at best have only weak anomalous scattering
power and thus fail the strict Flack conditions.
Light Atom Targets
•
•
•
•
Options for the Absolute Structure
Determination of Light Atom Compounds
Add HBr in case of tertiary N.
Co-crystallize with e.g. CBr4.
Co-crystallize with compound with known.
absolute configuration.
Alternative: Statistical analysis of Bijvoet
pair differences.
Statistical Analysis of Bijvoet
Pairs
• Many experimentalists have the feeling that the
official Flack x method is too conservative.
• This Experience is based on multiple carefully
executed experiments with compounds with
known absolute structure.
• The feeling is that also in light atom structures
the average of thousands of small Bijvoet
differences will point in the direction of the
correct enantiomorph.
• Example: The Nonius CAD4 test crystal 
MoKa, P212121
Example: Ammonium Bitartrate Test
Ammonium BiTartrate (MoKa)
Bayesian Approach
• Rob Hooft (Bruker) has developed an alternative
approach for the analyses of Bijvoet differences
that is based on Bayesian statistics. (Paper under
review)
• Under the assumption that the material is
enantiopure, the probability that the assumed
absolute structure is correct, given the set of
observed Bijvoet Pair Differences, is calculated.
• An extension of the method also offers the Fleq y
(Hooft y) parameter to be compared with the
Flack x.
• Example: Ascorbic Acid, P21, MoKa data 
MoKa
Natural Vitamin C, L-(+)Ascorbic Acid
L-(+) Ascorbic Acid
Hooft y Proper Procedure
• Collect data with an essentially complete
set of Bijvoet Pairs
• Refine in the usual way (preferably) with
BASF and TWIN instructions (SHELXL)
• Structure Factors to be used in the analysis
are recalculated in PLATON from the
parameters in the CIF (No Flack x
contribution).
Do we need Validation ?
Some Statistics
•
•
•
•
•
Validation CSD Entries 2006 + 2007
Number of entries: 35760
# of likely Space Group Changes: 384
# of structures with voids: 3354
Numerous problems with H, O, OH, H2O
etc.
Structure Validation
• Some Examples of Recently Published Structures
with a Problem that Apparently Escaped the
Attention of the Referees.
• Promote CheckCif as the Current (Partial) IUCr
Solution to this problem.
• Details of what PLATON can do in this Context.
• Next: An Example of a strange structure in the
CSD 
Structure of an
Interesting CH3
Bridged Zr Dimer
Paper has been
cited
47 times !
So can we believe
this structure?
The Referees did …!
But …
H .. H = 1.32 Ang. !
Comment
• The methyl hydrogen atoms are expected outside
the Zr2C2 ring (and indeed have been found in
similar structures)
• Referees likely had no access to (or did not
access) the primary data other than the ORTEP
illustration in the paper.
• General problem: A limited number of experts is
available to referee too many structural papers
that offer only limited primary (deposited) data.
Dalton Trans. (2001), 729-735
Next Slide: ORTEP with downloaded CIF data

From
CSD
Organometallics (2006) 25, 1511-1516
Next Slide: This is why the reported density is low and the R and Rw
high 
Solvent
Accessible
Void of
235 Ang3
out of
1123 Ang3
Not Accounted
for in the
Refinement
Model
SOLUTION
A solution for the structure validation problem was
pioneered by the International Union of Crystallography
- Provide and archive crystallographic data in the computer
readable CIF standard format.
- Offer Automated validation, with a computer generated
report for authors and referees.
- Have journals enforce a structure validation protocol.
- The IUCr journals and most major journals now indeed
implement some form of validation procedure.
THE CIF DATA STANDARD
-
Driving Force: Syd Hall (IUCr/ Acta Cryst C)
Early Adopted by XTAL & SHELX(T)L.
Currently: WinGX,Crystals,Texsan, Maxus etc.
Acta Cryst. C/E – Electronic Submission
Acta Cryst.:Automatic Validation at the Gate
CIF data available for referees for detailed
inspection (and optional calculations).
- Data retrieval from the WEB for published
papers
- CCDC – Deposition in CIF-FORMAT.
VALIDATION QUESTIONS
Single crystal validation addresses three
simple but important questions:
1 – Is the reported information complete?
2 – What is the quality of the analysis?
3 – Is the Structure Correct?
IUCr CHECKCIF WEB-Service
http://checkcif.iucr.org reports the outcome of:
• IUCr standard tests
Consistency, Missing Data, Proper Procedure,
Quality etc.
• + Additional PLATON based tests
Missed Symmetry, Twinning, Voids, Geometry,
Displacement Parameters, Absolute Structure etc.
ALERT LEVELS
•
•
•
•
ALERT A – Serious Problem
ALERT B – Potentially Serious Problem
ALERT C – Check & Explain
ALERT G – Verify or Take Notice
ALERT TYPES
1 - CIF Construction/Syntax errors,
Missing or Inconsistent Data.
2 - Indicators that the Structure Model
may be Wrong or Deficient.
3 - Indicators that the quality of the results
may be low.
4 - Cosmetic Improvements, Queries and
Suggestions.
In-House Validation with
PLATON
- Details: www.cryst.chem.uu.nl/platon
- Available for UNIX/LINUX, Windows,
Mac-OSX
- Driven by the file CHECK.DEF with
criteria, ALERT messages and advice.
- Unix: platon –u structure.cif
- Result on file: structure.chk
- Applicable on CIF’s and CCDC-FDAT
EXAMPLE OF
PLATON GENERATED
ALERTS FOR A RECENT
PAPER PUBLISHED IN
J.Amer.Chem.Soc. (2007)
Attracted special attention
in Chemical and
Engineering News
Properly Validated ?
Problems Addressed by
PLATON/CIF-CHECK
-
Missed Higher Space Group Symmetry
Solvent Accessible Voids in the Structure
Unusual Displacement Parameters
Hirshfeld Rigid Bond test
Misassigned Atom Type
Population/Occupancy Parameters
Mono Coordinated/Bonded Metals
Isolated Atoms (e.g. O, H, Transition Metals)
More Problems Addressed by
PLATON
-
Too Many Hydrogen Atoms on an Atom
Missing Hydrogen Atoms
Valence & Hybridization
Short Intra/Inter-Molecular Contacts
O-H without Acceptor
Unusual Bond Length/Angle
CH3 Moiety Geometry
To be extended with tests for new problems
‘invented’ by authors.
Additional Problems Addressed by
PLATON/FCF-CHECK
•
•
•
•
Information from .cif and .fcf files
Report on the resolution of the data
Report about randomly missing data
Check the completeness of the data (e.g. for
missing cusps of data
• Report on Missed (Pseudo) Merohedral Twinning
• Report on Friedel Pairs and Absolute Structure
• Next Slide: ASYM VIEW Display for the
inspection of the data completeness 
Section in
reciprocal
space
Missing cusp
of data
The Missed Symmetry Problem
- Up to 10 % of the structures in space groups such
as Cc have higher symmetry (e.g. C2/c, R-3c,
Fdd2 etc.) than was originally reported.
(To be Marshed is not good for your scientific
reputation as a crystallographer).
- MISSYM (Y. LePage) & PLATON/ADDSYM
algorithm addresses the problem.
- Next Slide: Example 
Organometallics (2004) 23,2310
Change of Space Group ALERT
Things to be Checked
when ADDSYM suggests a new
Space Group
• Consistency of the new cell parameters with the
new crystal system (90.2 = 90 ?)
• Proposed new symmetry consistent with the
reflection data ?
• Analyse the new implied systematic absences
• Case of Pseudo-symmetry ?
• Analyze potential disorder (real/artifact)
• Successful re-refinement
Incorrectly Oriented O-H
• The O-H moiety is generally, with very few
exceptions, part of a D-H..A system.
• An investigation of structures in the CSD brings
up many ‘exceptions’.
• Closer analysis shows that misplacement of the
O-H hydrogen atom is in general the cause.
• Molecules have an environment in the crystal !
• Example 
Example of a PLATON/Check Validation Report: Two
ALERTS related to the misplaced Hydrogen Atom
Validation Looks at
inter-molecular
contacts
Example of Misplaced Hydrogen Atom
Unsatisfactory Hydrogen Bond
Network
Satisfactory Hydrogen Bond Network with new H-position
Correct !
ALERT !
Wrong Structures
• Sometimes (semi) automatic structure
determination procedures can come up
with ‘reasonably looking’ but wrong
structures.
• Structure validation software should send
out proper ALERTS to the investigators
(e.g. IUCr Checkcif)
Structure Determination
Artifacts
• Pseudo-symmetry easily results in false structures
(often requiring a disorder model).
• Example: An Organometallic-AuCl compound
from the CSD with the Cl in the
wrong position  Very Short C-H..Cl ?!
ALERTED by validation (C..Cl = 2.19 Ang)
• Moving Cl to the correct position drops
R from 4 to 2 % ( see next two slides).
Consult the CSD
• It is a good idea to always consult the CSD for
previous reports on structures related to the one
at hand (in particular when the result looks
unique).
• The statistics provided by VISTA (CCDC) can be
very helpful for this.
• However, be aware, such an analysis often shows
outliers. Many of those appear to be errors.
• Example: A search for short S..S contacts gave:
Entry from the CSD
S
H
But with Space Group Symmetry
=> Different structure with S-S Bond !
THE MESSAGE
- Validation should not be postponed to the
publication phase. All validation issues should be
taken care of during the analysis.
- Everything unusual in a structure is suspect,
mostly incorrect (artifact) and should be
investigated and discussed in great detail and
supported by additional independent evidence.
- The CSD can be very helpful when looking for
possible precedents (but be careful )
CONCLUSION
Validation Procedures are excellent Tools to:
- Set Quality Standards (Not just on R-Value)
- Save a lot of Time in Checking, both by the
Investigators and the Journals (referees)
- Point at Interesting Features (Pseudo-Symmetry,
short Interactions etc.) to be discussed.
- Surface a problem that only an experienced
Crystallographer might be able to Address
- Proof of a GOOD structure.
Additional Info
http://www.cryst.chem.uu.nl
(including a copy of this powerpoint presentation)
Thanks
for your attention !!