Transcript Automatic Detection of Poor or Incorrect Single Crystal

Crystal Structure Validation:
The IUCr tool to distinguish GOOD and
trustable single crystal structures from
BAD and UGLY reports
Ton Spek
Bijvoet Center for Biomolecular Research
Utrecht University,The Netherlands
Aachen, Nov 10, 2006
Who are we ?
• The National facility for ‘small molecule’
single crystal structure determination since
1971 in the Netherlands.
• Embedded within the Crystal and Structural
Chemistry group in Utrecht.
• Also in Utrecht most of the C & S research
has moved from small molecule to protein
crystallography (Structural Biology).
Small molecule and Protein Xtallography:Utrecht
Some Statistics
• Collaboration of the facility with most
synthetic groups in the Netherlands who
send their samples for analysis to Utrecht.
• We handled over 3500 requests over the
past 35 years. Mainly organometallic and
coordination chemistry.
• Up to now, the results are reported in over
1200 (joint) papers.
People Involved
• The last years 3 to 4 mostly PHD’s of which one
on a postdoc position.
• Currently a permanent staff of 2 + 1 postdoc.
• Dr. Martin Lutz (since 1997)
• Dr. Lars von Chrzanowski
(postdoc since Oct 15, 2006)
• In the past: a few trained chemists in the context
of their synthetic work.
Associated Functions
• Development of crystallographic software
based on local needs: PLATON package.
• Crystal Structure Validation (IUCr)
• Co-Editor of Acta Cryst. C (involved in the
handling of more than 1000 CIF-formatted
papers).
This Talk
• In this talk I will illustrate with a number of real
world examples how the IUCr structure validation
tool CHECKCIF can help to distinguish Good
from Bad and Ugly crystal structures.
• The validation tool was developed in the context
of the journal Acta Cryst. C but is now also used
by many other high standard journals and
pharmaceutical companies.
• Let me start with a quote from a Nobel lecture ..
1964 Nobel Lecture Dorothy Hodgkin
…. [The] great advantage of X-ray
analysis as a method of chemical
structure analysis is its power to
show some totally unexpected and
surprising structure with, at the
same time, complete certainty. ..
With Complete Certainty ?
• Yes, in most cases, in particular in the hands of
experienced investigators.
• No, when proper scientific procedures and signs of
trouble have been ignored.
• This presentation will address a number of
obvious cases where proper procedures were
ignored, resulting in erroneous science.
• There are good scientific reasons for enforcing an
automated validation procedure as illustrated by
the following real world example that apparently
was not properly validated by the referees.
THE STABLE PENTAMETHYLCYCLOPENTADIENYL CATION
J.B.Lambert et al. Angew. Chem. Int. Ed. 2002, 41, 1429-1431
+
Pentamethylcyclopentadienyl
Common Anionic Form
“New” Cationic Form
Cp*
-
Assigned Bond types
HOT STRUCTURE – FAST LANE PUBLICATION
Enthusiastic Last Paragraph of
C&E-News
… The Northwestern chemists are now
exploring the reactivity of C5Me5+. “You
can sit down and write lots of interesting
reactions on paper,” Lambert says, and it
will be interesting to see if the molecule
reacts as expected. But Considering this
cation’s track record, it might be safer to
expect more surprises. [!!]
NOT SO HOT AFTER ALL !!
Editors Note in the next issue of Angewandte Chemie
Strange Bond Pattern and Ring pucker
+
D
o
D
PACKING EFFECTS ??
Double Bond ?
Corrected Structure
J.N. Jones et al.,Chem. Comm. 2002,1520-1521
Additional
H-Atoms
Where did it go Wrong ?
• First impression of the structure was likely based
on a preliminary result (plot) without H-atoms.
• Rushed as a short communication into the
prestigious high impact journal Angewandte
Chemie.
• Ignoring all counter theoretical and spectroscopic
evidence.
• No experienced crystallographer as referee ?
• No unbiased automated CIF-validation.
Validation of the Deposited CIF


So Why (Automated) Structure
Validation?
- See previous case study.
VALIDATION IN THE PAST
- Single crystal structures determined by experienced
professional crystallographers (e.g. Dorothy Hodgkin)
- Using previous generation serial detectors (with at best an
output of ~ 50 datasets/year).
- Using (open source) software they knew in detail.
- Structures were analyzed and discussed in great detail.
- Papers containing crystallographic results were refereed by
fellow crystallographers.
Why Automated Validation?
-
-
PRESENT:
Diminishing number of professional small
molecule crystallographers (sites, teaching).
Many crystal structures done by chemists
with limited crystallographic background.
Using CCD detectors (~ 1000 datasets/year –
when pushed and given enough ‘slaves’).
Crystal structures solved using Black-Box
crystallographic firmware (SHELXTL etc.)
Near Future – AutoCollect & AutoSolve
Why Automated Validation?
-
PROBLEMS:
Exploding # of structural papers to review.
Limited # of referees with sufficient time and
crystallographic knowledge.
Limited supporting information available
for the reviewer (footnote/deposited).
Papers including structural ‘evidence’ are
increasingly refereed by non-crystallographers,
unaware of the many potential pitfalls.
SOLUTION
The solution for the problem was pioneered by the
International Union of Crystallography
- Provide and archive crystallographic data in the computer
readable CIF format.
- Automated validation, with a computer generated report
for authors and referees.
- Journals to enforce a structure validation protocol.
- The IUCr journals and most major journals now implement
validation procedures.
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
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
IUCR-TESTS:
- MISSING DATA, PROPER PROCEDURE, QUALITY
PLATON TESTS:
- SYMMETRY, GEOMETRY, DISPLACEMENT
PARAMETERS, VOIDS, TWINNING etc.
ALERTS :
- ALERT A - SERIOUS PROBLEM
- ALERT B - POTENTIALLY SERIOUS PROBLEM
- ALERT C - CHECK & EXPLAIN
- ALERT G – VERIFY or NOTE
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.
Validation with PLATON
- Details: www.cryst.chem.uu.nl/platon
- Driven by the file CHECK.DEF with
criteria, ALERT messages and advice.
- Use: platon –u structure.cif
- Result on file: structure.chk
- Applicable on CIF’s and CCDC-FDAT
- FCF-Valid: platon –V structure.cif
Problems Addressed by PLATON
-
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)
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.
Problems Addressed by PLATON
S
Reflection Data (.fcf)
Sufficient Resolution
Completeness of the data set
Missed (Pseudo-) Merohedral Twinning
Friedel pairs, Absolute Structure
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.
Why is description in a correct
space group so important ?
• Refinement in a too low symmetry group
may result in geometry artifacts
• In particular when a centro-symmetric
structure is refined in a noncentrosymmetric space group.
• Example of a Bad and Ugly Structure from
JACS =
Praseodymium complex
J.A.C.S. (2000),122,3413 – P1, Z = 2
CORRECTLY REFINED STRUCTURE
P-1, Z=2
The Missed Symmetry Problem
- Another Missed symmetry EXAMPLE
from a 2004 Organometallics (23, 32103217) paper ==>
Another Missed Symmetry Case
• An example from the space group Cc
missed symmetry family ….
BAMYEU
Dalton Trans
2003,134-140
Cc
Misoriented 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 OH hydrogen atom is in general the cause.
• Molecules have an environment in the crystal !
• Example 
Example of Misplaced Hydrogen Atom
Two ALERTS related to the misplaced Hydrogen Atom
Unsatisfactory Hydrogen Bond Network
Satisfactory Hydrogen Bond Network with new H-position
Problem with a Multistep
Synthesis
• Example where synthetic chemists were
seriously mislead by the results of an
erroneous crystal structure in an attempt to
synthesize a natural product.
Characterization of compound isolated from marine invertebrate
Lindquist et al., J. Amer. Chem. Soc. (1991),113,2303-2304.
Synthesis: Li et al. (2001) Angew. Chem. 113, 4901 ->Surprise
Solution of the riddle: Li et al. (2001) Angew. Chem. 113,4906
O --> N-H (Analysis of the Displacement Ellipsoids)
Automatic Validation of the coordinate data taken from the CSD
Result: Alert on short intermolecular O…O Contact
O
N
Infinite hydrogen bonded chain
N-H…O=C
Wrong Structures
• Sometimes 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)
Wrong Structure Example
• Structure submitted to Acta Cryst. C
• The chemist involved expects a Cu coordination
complex, so that is what he reports … (confirmed
by X-ray crystallography !)
• and tries to publish this structure with an
interesting non-coordinated Cu2+
• and fortunately caught by the validation software
• ALERTS related to short O..O and O .. N contacts
Cu not Coordinated =>
R<7%
ORTEP of the False Structure
R<6%
Ortep of the Correct Structure
Thus …
• The original paper indeed mentioned an interesting
uncoordinated Cu2+ but left it with this statement.
• The chemistry changed from [Cu]2+[L]2- to [L]+[Br]- by
also adding some missed Hydrogen atoms.
• HBr was used in the synthesis (but not mentioned in the
original experimental).
• Various ALERTS pointed to the problem but they were
ignored by the authors.
• Interestingly, the color of the crystal changed from green to
colorless in the now published revised paper …..
Structure Determination Artifacts
• Pseudo-symmetry easily results in false
structures.
• 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 %
Consult the CSD
• It is a good idea to always consult the CSD for
previous reports on structures related to the one at
hand.
• 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 !
COMMENTS
- 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 independent evidence.
- The CSD can be very helpful when looking for
possible precedents (but be careful)
CONCLUSION #1
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.
Conclusion #2
Dorothy Hodgkins claim that X-ray
crystallography can deliver new science is
still valid as it was in 1964,
Given:
- Correct procedures
- Structure validation
- Education
Residual Problem
EDUCATION
Response of an author of a structural paper
submitted to the crystallographic journal
Acta Cryst. to an enquiry from a referee on
the reported erroneous space group:
Please teach me, what does in mean
‘ space group incorrect’ ……
Additional Info
http://www.cryst.chem.uu.nl
(including a copy of this powerpoint presentation)
Thanks
for your attention !!