Structure Validation : How to distinguish GOOD and reliable single crystal structures from BAD and UGLY reports A.L.Spek Utrecht University The Netherlands

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 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.

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

HOT STRUCTURE – FAST LANE PUBLICATION

Pentamethylcyclopentadienyl Anion (Cp*-) -

PENTAMETHYLCYCLOPENTADIENYL CATION ASSIGNED BOND-TYPES

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 PACKING EFFECTS ?? DoDDoD Double Bond ?

Corrected Structure J.N. Jones et al.,Chem. Comm. 2002,

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.

  Validation of the Deposited CIF

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.

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.)

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 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.

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 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 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.

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

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 ==>

Praseodymium complex J.A.C.S. (2000),122,3413 – P1, Z = 2

P-1, Z=2 CORRECTLY REFINED STRUCTURE

Validation with PLATON -Details: -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 CIF’s and CCDC-FDAT

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

Characterization of compound isolated from marine invertebrate Lindquist et al., J. Amer. Chem. Soc. (1991),113,

Synthesis: Li et al. (2001) Angew. Chem. 113, >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

Infinite hydrogen bonded chain N-H…O=C O N

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 …

ORTEP of the False Structure R < 7 % Cu not Coordinated =>

Ortep of the Correct Structure R < 6 %

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. 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 …..

Entry from the CSD H S

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

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 space group: Please teach me, what does in mean ‘ space group incorrect’ ……

Additional Info Thanks for your attention !!