Structure Validation: How to distinguish GOOD and reliable single crystal structures from BAD and UGLY reports

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Structure ValidationHow to distinguish GOOD and
reliable single crystal structures from BAD and
UGLY reports

• A.L.Spek
• Utrecht University
• The Netherlands

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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 have been
  ignored.
• This presentation will address a number of
  obvious cases where proper procedures were
  ignored, resulting in erroneous science.
• Automated Structure Validation is offered as a
  tool to add a qualifier Good (Correct),
  Bad(False) or Ugly(Poor) to a structural study.

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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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HOT STRUCTURE FAST LANE PUBLICATION
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Pentamethylcyclopentadienyl Anion (Cp-)
-
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PENTAMETHYLCYCLOPENTADIENYL CATION
ASSIGNED BOND-TYPES
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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
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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 evidence.
• No experienced crystallographer as referee ?
• No unbiased automated CIF-validation.

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Validation of the Deposited CIF
?
?
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WHY AUTOMATED STRUCTURE VALIDATION?

• See Previous Case Study.
• IN THE PAST
• Single crystal structures determined by
  professional crystallographers (Dorothy Hodgkin)
• Using serial detectors ( 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.)

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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 pioneered by
  the
• International Union of Crystallography
• Provide and archive structural data in computer
  readable CIF format.
• Automated validation, with a computer generated
  report for authors and referees.
• Journals enforcing a structure validation
  protocol.
• - 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

• 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

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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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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
• 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).
• MISSYM PLATON/ADDSYM algorithm addresses the
  problem.
• EXAMPLE gt

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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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Validation with PLATON

• - Details www.cryst.chem.uu.nl/platon
• Driven by the file CHECK.DEF with criteria, ALERT
  messages and advice.
• Use (UNIX) platon u structure.cif
• Result on file structure.chk
• Applicable on CIFs and CCDC-FDAT

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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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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 Structure

• Sometimes automatic 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)
• Example (Structure submitted to Acta Cryst. C)
  The chemist involved expects a Cu-complex, so
  that is what he reports (confirmed by X-ray
  crystallography !) and tries to publish and
  fortunately caught by a knowledgeable referee

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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.
• Various ALERTS pointed to the problem but ignored
  by the authors.
• Interestingly, the color of the crystal changed
  from green to colorless in the revised paper ..

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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 the Routine Status of the Determination
  in the Hands of its Investigator

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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 space group
• Please teach me, what does in mean
• space group incorrect

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Additional Info

• http//www.cryst.chem.uu.nl
• Thanks
• for your attention !!