Crystal Structure Validation: The IUCr tool to distinguish GOOD and trustable single crystal structures from BAD and UGLY reports

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Crystal Structure ValidationThe 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

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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).

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Small molecule and Protein XtallographyUtrecht
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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.

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People Involved

• The last years 3 to 4 mostly PHDs 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.

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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).

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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 ..

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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. ..

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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.

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THE STABLE PENTAMETHYLCYCLOPENTADIENYL
CATION J.B.Lambert et al. Angew. Chem. Int. Ed.
2002, 41, 1429-1431

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Pentamethylcyclopentadienyl
Common Anionic Form
New Cationic Form
Cp
-
Assigned Bond types
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HOT STRUCTURE FAST LANE PUBLICATION
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Enthusiastic Last Paragraph of CE-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
  cations track record, it might be safer to
  expect more surprises. !!

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NOT SO HOT AFTER ALL !!
Editors Note in the next issue of Angewandte
Chemie
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Strange Bond Pattern and Ring pucker

DoD
Double Bond ?
PACKING EFFECTS ??
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Corrected StructureJ.N. Jones et al.,Chem. Comm.
2002,1520-1521
Additional H-Atoms
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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.

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Validation of the Deposited CIF
?
?
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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.

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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

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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.

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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.

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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.

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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?

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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

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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.

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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 CIFs and CCDC-FDAT
• FCF-Valid platon V structure.cif

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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)

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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.

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Problems Addressed by PLATON

• Reflection Data (.fcf)
• Sufficient Resolution
• Completeness of the data set
• Missed (Pseudo-) Merohedral Twinning
• Friedel pairs, Absolute Structure
• S

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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.

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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 non-centrosymmetric space group.
• Example of a Bad and Ugly Structure from JACS ?

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Praseodymium complex
J.A.C.S. (2000),122,3413 P1, Z 2
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CORRECTLY REFINED STRUCTURE
P-1, Z2
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The Missed Symmetry Problem

• Another Missed symmetry EXAMPLE from a 2004
  Organometallics (23, 3210-3217) paper gt

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Another Missed Symmetry Case

• An example from the space group Cc missed
  symmetry family .

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BAMYEU Dalton Trans 2003,134-140 Cc
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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
  O-H hydrogen atom is in general the cause.
• Molecules have an environment in the crystal !
• Example ?

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Example of Misplaced Hydrogen Atom
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Two ALERTS related to the misplaced Hydrogen Atom
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Unsatisfactory Hydrogen Bond Network
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Satisfactory Hydrogen Bond Network with new
H-position
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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.

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Characterization of compound isolated from marine
invertebrate
Lindquist et al., J. Amer. Chem. Soc.
(1991),113,2303-2304.
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Synthesis Li et al. (2001) Angew. Chem. 113,
4901 -gtSurprise
Solution of the riddle Li et al. (2001) Angew.
Chem. 113,4906 O --gt N-H (Analysis of the
Displacement Ellipsoids)
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Automatic Validation of the coordinate data taken
from the CSD
Result Alert on short intermolecular OO Contact
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O
N
Infinite hydrogen bonded chain
N-HOC
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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)

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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

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R lt 7
Cu not Coordinated gt
ORTEP of the False Structure
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R lt 6
Ortep of the Correct Structure
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Thus

• The original paper indeed mentioned an
  interesting uncoordinated Cu2 but left it with
  this statement.
• The chemistry changed from Cu2L2- to
  LBr- 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 ..

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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

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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

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Entry from the CSD
H
S
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But with Space Group Symmetry
gt Different structure with S-S Bond !
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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)

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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.

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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

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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

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Additional Info

• http//www.cryst.chem.uu.nl
• (including a copy of this powerpoint
  presentation)
• Thanks
• for your attention !!

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