Structure Validation in Chemical Crystallography Ton Spek Bijvoet

Structure Validation in Chemical Crystallography Ton Spek, Bijvoet Centre for Biomolecular Research, Utrecht University, The Netherlands. CCP 4 -Leeds, 5 -Jan. -2008.

Overview of this Talk • Introduction to the Problems that are addressed by Structure Validation in Chemical Crystallography • The currently implemented IUCr Solution • Evaluation of the Performance • Possible Future work and Extensions • Summary & Conclusion

Chem. Cryst. 40 Years Ago … (when I started in Xtallography) • Datacollection, Structure Solution, Refinement and Publication took generally several months or more. • For my first structure I even had to write my own Direct Methods program to solve it. • Software was not a Black Box. Ad-hoc software development was part of the job. • Paper review was done in those days by experienced crystallographers and took months to publication.

Today • A Routine Datacollection, followed by • Automated Structure Determination, • SHELXL Refinement, • Publ. CIF Paper Preparation and • Electronic Submission to Acta Cryst. , May take an experienced crystallographer just 1 day …for an Acta Cryst. E paper.

Number of Yearly Published Chem. Cryst. Structures • 1967: 936 • 2007: more than 30000 • CSD Nov 2007: 450000 entries • More growth expected (China, India) …

Announced Aug 2007: Tabletop ‘Black Box’ – Smart X 2 S Mount Crystal in a Vial Structure ?

Are all those 450000 Structures Correct and Reliable? • Unfortunately not. • The result of many searches in the CSD for structures that are related to the structure under investigation will include outliers, many of which turn out to be at least suspect. • Following are just three of the examples of chemically wrong structures that obviously passed the refereeing system.

Published with Wrong Composition B O BORAX ! B

Entry from the CSD (IDAKUT) S H Found during search in CSD for short inter S…S Contacts

But with Space Group Symmetry => Different compound with S-S Bond !

Searching for structures with a Methyl Moiety bridging two metals … Structure of a strange CH 3 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 Zr 2 C 2 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.

Partial 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. (Driving force: Syd Hall, Editor Acta Cryst. C) - Implement Automated Validation, with a computer generated report for authors, editors and referees.

The CIF Data Standard - Early Adopted in 1993 by SHELX(T)L and subsequently other packages. - Around 1995: CIF-Format Electronic Submission to Acta Cryst. C/E - Ten Years Ago: Automatic Validation (and possible return to sender) of Acta Cryst. C & E papers at the Gate. - CIF & HKL data are available for referees for detailed inspection (and optional calculations). - Data retrieval from the WEB for published papers

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, Comparison against test criteria etc. • + Additional PLATON based tests Missed Symmetry, Voids, Geometry, Hydrogen atoms, Displacement Parameters, etc.

ALERT LEVELS Check. Cif Report in terms of a list of ALERTS • • 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.

EXAMPLE OF PLATON GENERATED ALERTS FOR A RECENT PAPER PUBLISHED IN J. Amer. Chem. Soc. (2007) Attracted special attention in Chemical and Engineering News (Referees obviously did not Bother)

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 Types 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 CH 3 Moiety Geometry To be extended with tests for new problems ‘invented’ by authors.

The Missed Symmetry Problem - Up to 10 % of the structures in space groups such as Cc have higher symmetry (e. g. C 2/c, R-3 c, Fdd 2 etc. ) than was originally reported. (To be Marshed is not good for your scientific reputation as a crystallographer). - MISSYM (Y. Le. Page) & PLATON/ADDSYM algorithm addresses the problem. - Next Slide: Example

WRONG SPACEGROUP J. A. C. S. (2000), 122, 3413 – P 1, Z = 2

CORRECTLY REFINED STRUCTURE P-1, Z=2

Example of Change of Space Group ALERT

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

Validation Looks at inter-molecular contacts Unsatisfactory Hydrogen Bond Network Correct ! ALERT !

Solvent Accessible Void of 235 Ang 3 out of 1123 Ang 3 Often Not Accounted for in the Refinement Model High R-value

Additional Problems Addressed by PLATON/FCF-CHECK With 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 (comparison of Hooft y with Flack x parameter values)

Missed (Pseudo) Merohedral Twinning A tool (Twin. Rot. Mat) in PLATON automatically analyses a reported structure for missed twinning Example

Evaluation and Performance • The validation scheme has been very successful for Acta Cryst. C & E in setting standards for quality and reliability. • Most major chemical journals currently have some form of a validation scheme implemented. • But does it solve all problems …

Some Recent Statistics • • Validation CSD Entries 2006 + early 2007 Number of entries: 35760 # of likely Space Group Changes: 384 # of structures with (unaccounted for ? ) voids: 3354 • Numerous problems with H, O, OH, H 2 O etc. , etc, .

Problems to be Addressed • Synthetic Chemist View: ‘Addressing Crystallographic Details holds up the Publication of Important Chemistry’ • Author Question: What does it mean “Spacegroup Incorrect” • Crystallographic Education (beyond Pushbutton and Black Box) • Referees that know how to handle ALERTS

Possible Future Extensions • • • Validation of Structures from Powder Data Validation of Inorganic Compounds Validation of Incommensurate Structures Validation of Charge Density Studies Automated check against (average) geometry in the CSD • Check for fabricated data ?

Summary & Conclusions 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 Structural 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 !!

Example of a PLATON/Check Validation Report: Two ALERTS related to the misplaced Hydrogen Atom