PLATON and STRUCTURE VALIDATION

Ton SpekNational Single Crystal

Service Facility,

Utrecht University,

The Netherlands.

Goettingen, 13-Oct-2007

Overview of the Talk

1. What is PLATON2. Structure Validation3. Concluding Remarks

Copy: http://cryst.chem.uu.nl

What is PLATON

• PLATON is a collection of tools for single crystal structure analysis bundled within a single SHELX compatible program.

• The tools are either extended versions of existing tools or unique to the program.

• The program was/is developed over of period of more than 25 years in the context of our National Single Crystal Service Facility in the Netherlands.

PLATON USAGE

• Today, PLATON is most widely used implicitly in its validation incarnation for all single crystal structures that are validated with the IUCr CHECKCIF utility.

• Tools are available in PLATON to analyze and solve the reported issues that need attention.

OTHER PLATON USAGE

• PLATON also offers guided/automatic structure determination and refinement tools for routine structure analyses from scratch (i.e. the ‘Unix-only’ SYSTEM S tool and the new FLIPPER/STRUCTURE tool that is based on the Charge Flipping Ab initio phasing method).

• Next Slide: Main Function Menu

Selected Tools

• ADDSYM – Detection and Handling of Missed (Pseudo)Symmetry

• TwinRotMat – Detection of Twinning• SOLV – Report of Solvent Accessible Voids• SQUEEZE – Handling of Disordered Solvents in

Least Squares Refinement (Easy to use Alternative for Clever Disorder Modelling)

• BijvoetPair – Post-refinement Absolute Structure Determination (Alternative for Flack x)

• VALIDATION – PART of IUCr CHECKCIF

ADDSYM

• Often, a structure solves only in a space group with lower symmetry than the correct space group. The structure should subsequently be checked for higher symmetry.

• About 1% of the 2006 & 2007 entries in the CSD need a change of space group.

• E.g. A structure solves only in P1. ADDSYM is a tool to come up with the proper space group and to carry out the transformation ( new .res)

• Next slide: Recent example of missed symmetry

Organic Letters (2006) 8, 3175

P1, Z’ = 8 CCo

Correct Symmetry ?

Test for Higher Symmetry

• Start PLATON with a .ins or .cif

• Click on ADDSYM on the main menu

• Analyse automatically generated result Display next

After Transformation to P212121, Z’ = 2

(Pseudo)Merohedral Twinning

• Options to handle twinning in L.S. refinement available in SHELXL, CRYSTALS etc.

• Problem: Determination of the Twin Law that is in effect.• Partial solution: coset decomposition, try all possibilities (I.e. all symmetry operations of the lattice but not of the

structure)• ROTAX (S.Parson et al. (2002) J. Appl. Cryst., 35, 168. (Based on the analysis of poorly fitting reflections of the type

F(obs) >> F(calc) )• TwinRotMat Automatic Twinning Analysis as implemented

in PLATON (Based on a similar analysis but implemented differently)

TwinRotMat Example

• Originally published as disordered in P3.• Solution and Refinement in the trigonal

space group P-3 R= 20%.• Run PLATON/TwinRotMat on CIF/FCF• Result: Twin law with an the estimate of

the twinning fraction and the estimated drop in R-value

• Example of a Merohedral Twin

Ideas behind the Algorithm

• Reflections effected by twinning show-up in the least-squares refinement with F(obs) >> F(calc)

• Overlapping reflections necessarily have the same Theta value within a tolerance.

• Generate a list of implied possible twin axes based on the above observations.

• Test each proposed twin law for its effect on R.

Possible Twin Axis

H H’

H” = H + H’

Strong reflection H’ with theta close to theta of reflection H

Candidate twinning axis(Normalize !)

Reflection withF(obs) >> F(calc)

Solvent Accessible Voids

• A typical crystal structure has only in the order of 65% of the available space filled.

• The remainder volume is in voids (cusps) in-between atoms (too small to accommodate an H-atom)

• Solvent accessible voids can be defined as regions in the structure that can accommodate at least a sphere with radius 1.2 Angstrom without intersecting with any of the van der Waals spheres assigned to each atom in the structure.

• Next Slide: Void Algorithm: Cartoon Style

STEP #1 – EXCLUDE VOLUME INSIDE THE VAN DER WAALS SPHERE

DEFINE SOLVENT ACCESSIBLE VOID

DEFINE SOLVENT ACCESSIBLE VOID

STEP # 2 – EXCLUDE AN ACCESS RADIAL VOLUMETO FIND THE LOCATION OF ATOMS WITH THEIR

CENTRE AT LEAST 1.2 ANGSTROM AWAY

DEFINE SOLVENT ACCESSIBLE VOID

STEP # 3 – EXTEND INNER VOLUME WITH POINTS WITHIN1.2 ANGSTROM FROM ITS OUTER BOUNDS

CgListing of all voids in the triclinic unit cell

VOID APPLICATIONS

• Calculation of Kitaigorodskii Packing Index• As part of the SQUEEZE routine to handle the

contribution of disordered solvents in crystal structure refinement

• Determination of the available space in solid state reactions (Ohashi)

• Determination of pore volumes, pore shapes and migration paths in microporous crystals

SQUEEZE

• Takes the contribution of disordered solvents to the calculated structure factors into account by back-Fourier transformation of density found in the ‘solvent accessible volume’ outside the ordered part of the structure (iterated).

• Filter: Input shelxl.res & shelxl.hkl Output: ‘solvent free’ shelxl.hkl• Refine with SHELXL or Crystals• Note:SHELXL lacks option for fixed

contribution to Structure Factor Calculation.

SQUEEZE Algorithm

1. Calculate difference map (FFT)

2. Use the VOID-map as a mask on the FFT-map to set all density outside the VOID’s to zero.

3. FFT-1 this masked Difference map -> contribution of the disordered solvent to the structure factors

4. Calculate an improved difference map with F(obs) phases based on F(calc) including the recovered solvent contribution and F(calc) without the solvent contribution.

5. Recycle to 2 until convergence.

SQUEEZE In the Complex Plane

Fc(model)

Fc(solvent)Fc(total)

Fobs

Solvent Free Fobs

Black: Split Fc into a discrete and solvent contributionRed: For SHELX refinement, temporarily substract recovered solvent contribution from Fobs.

Comment

• The Void-map can also be used to count the number of electrons in the masked volume.

• A complete dataset is required for this feature.• Ideally, the solvent contribution is taken into

account as a fixed contribution in the Structure Factor calculation (CRYSTALS) otherwise it is substracted temporarily from F(obs)^2 (SHELXL) and re-instated afterwards with info saved beyond column 80 for the final Fo/Fc list.

Publication Note

• Always give the details of the use of SQUEEZE in the comment section

• Append the small CIF file produced by PLATON to the main CIF

• Use essentially complete data sets with sufficient resolution only.

• Make sure that there is no unresolved charge balance problem.

Post-Refinement Absolute Structure Determination

• Generally done as part of the least squares refinement with a ‘twinning’ parameter.(Flack x)

• Determine Flack x parameter + su• Validity Analysis following the Flack &

Bernardinelli criteria.• Often indeterminate conclusions obtained in the

case of light atom structures• Alternative approaches offered by PLATON

Scatter Plot of Bijvoet Differences

• Plot of the Observed Bijvoet Differences against the Calculated Differences.

• A Least-Squares line is calculated• The Green least squares line should run

from the lower left to the upper right corner for the correct absolute structure.

• Vertical bars on data points indicate the su on the Bijvoet Difference. Example

Excellent Correlation

Practical Aspects of Flack x

• The structure should contain atoms with sufficiently strong anomalous dispersion contributions for the radiation used (generally in the experiment (e.g. Br).

• Preferably, but not nesessarily, a full set of Friedel pairs is needed. (danger: correlation !)

• Unfortunately, many relevant pharmaceuticals contain in their native form only light atoms that at best have only weak anomalous scattering power and thus fail the strict Flack conditions.

Light Atom Targets

Options for the Absolute Structure Determination of Light Atom Compounds

• Add HBr in case of tertiary N.• Co-crystallize with e.g. CBr4.• Co-crystallize with compound with known.

absolute configuration.• Alternative: Statistical analysis of Bijvoet

pair differences.

Statistical Analysis of Bijvoet Pairs

• Many experimentalists have the feeling that the official Flack x method is too conservative.

• This Experience is based on multiple carefully executed experiments with compounds with known absolute structure.

• The feeling is that also in light atom structures the average of thousands of small Bijvoet differences will point in the direction of the correct enantiomorph.

• Example: The Nonius CAD4 test crystal

Example: Ammonium Bitartrate Test

MoKa, P212121

Ammonium BiTartrate (MoK

Bayesian Approach

• Rob Hooft (Bruker) has developed an alternative approach for the analyses of Bijvoet differences that is based on Bayesian statistics. (Paper under review)

• Under the assumption that the material is enantiopure, the probability that the assumed absolute structure is correct, given the set of observed Bijvoet Pair Differences, is calculated.

• An extension of the method also offers the Fleq y (Hooft y) parameter to be compared with the Flack x.

• Example: Ascorbic Acid, P21, MoKa data

Natural Vitamin C, L-(+)Ascorbic Acid

MoKa

L-(+) Ascorbic Acid

Hooft y Proper Procedure

• Collect data with an essentially complete set of Bijvoet Pairs

• Refine in the usual way (preferably) with BASF and TWIN instructions (SHELXL)

• Structure Factors to be used in the analysis are recalculated in PLATON from the parameters in the CIF (No Flack x contribution).

Do we need Validation ?Some Statistics

• Validation CSD Entries 2006 + 2007

• Number of entries: 35760

• # of likely Space Group Changes: 384

• # of structures with voids: 3354

• Numerous problems with H, O, OH, H2O etc.

Structure Validation

• Some Examples of Recently Published Structures with a Problem that Apparently Escaped the Attention of the Referees.

• Promote CheckCif as the Current (Partial) IUCr Solution to this problem.

• Details of what PLATON can do in this Context.• Next: An Example of a strange structure in the

CSD

Structure of an Interesting CH3

Bridged Zr Dimer

Paper has been cited

47 times !

So can we believe this structure?

The Referees did …!

H .. H = 1.32 Ang. !

But …

Comment

• The methyl hydrogen atoms are expected outside the Zr2C2 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.

Dalton Trans. (2001), 729-735

Next Slide: ORTEP with downloaded CIF data

From CSD

Organometallics (2006) 25, 1511-1516

Next Slide: This is why the reported density is low and the R and Rw high

Solvent Accessible

Void of

235 Ang3

out of

1123 Ang3

Not Accounted for in the

Refinement Model

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.

- Offer Automated validation, with a computer generated report for authors and referees.

- Have journals enforce a structure validation protocol.- The IUCr journals and most major journals now indeed

implement some form of validation procedure.

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

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 etc.

• + Additional PLATON based tests

Missed Symmetry, Twinning, Voids, Geometry, Displacement Parameters, Absolute Structure etc.

ALERT LEVELS

• 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.

In-House Validation with PLATON

- Details: www.cryst.chem.uu.nl/platon- Available for UNIX/LINUX, Windows,

Mac-OSX - Driven by the file CHECK.DEF with

criteria, ALERT messages and advice.- Unix: platon –u structure.cif- Result on file: structure.chk- Applicable on CIF’s and CCDC-FDAT

EXAMPLE OF PLATON GENERATED

ALERTS FOR A RECENTPAPER PUBLISHED INJ.Amer.Chem.Soc. (2007)

Attracted special attention in Chemical and

Engineering News

Properly Validated ?

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 Type - 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- CH3 Moiety Geometry- To be extended with tests for new problems

‘invented’ by authors.

Additional Problems Addressed byPLATON/FCF-CHECK

• 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• Next Slide: ASYM VIEW Display for the

inspection of the data completeness

Missing cusp of data

Section in reciprocal space

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.

- Next Slide: Example

Organometallics (2004) 23,2310

Change of Space Group ALERT

Things to be Checked when ADDSYM suggests a new

Space Group

• Consistency of the new cell parameters with the new crystal system (90.2 = 90 ?)

• Proposed new symmetry consistent with the reflection data ?

• Analyse the new implied systematic absences• Case of Pseudo-symmetry ?• Analyze potential disorder (real/artifact)• Successful re-refinement

Incorrectly Oriented 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

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

Unsatisfactory Hydrogen Bond Network

Satisfactory Hydrogen Bond Network with new H-position

Example of Misplaced Hydrogen AtomValidation Looks at

inter-molecular contacts

ALERT !

Correct !

Wrong Structures

• Sometimes (semi) 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)

Structure Determination Artifacts

• Pseudo-symmetry easily results in false structures (often requiring a disorder model).

• 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 % ( see next two slides).

Consult the CSD

• It is a good idea to always consult the CSD for previous reports on structures related to the one at hand (in particular when the result looks unique).

• 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

H

S

But with Space Group Symmetry

=> Different structure with S-S Bond !

THE MESSAGE

- 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 additional independent evidence.

- The CSD can be very helpful when looking for possible precedents (but be careful )

CONCLUSION

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.

Additional Info

http://www.cryst.chem.uu.nl (including a copy of this powerpoint presentation)

Thanks

for your attention !!