1. On the abundance of chiral crystals (An optimistic lecture for the conclusion of the conference) David Avnir Institute of Chemistry The Hebrew University of Jerusalem, Israel With Chaim Dryzun Department of Chemistry, ETH Zürich Lugano Campus, Switzerland Chirality 2012, Fort Worth, Texas June 10 - June 13, 2012

2. The unrecognized high abundance of chiral crystals * ~23% of all non-biological crystals are chiral (compared to only ~10% of all non-biological molecules ) * Only ~6% of these are labelled as chiral In numbers: there are out there ~100,000 crystals the chirality of which has been ignored It means that: The library from which one can select enantioselective catalysts, sensing materials, and chromatographic materials is by far larger than envisaged so far.

3. Questions to be addressed: # Why was it overlooked? # Why are chiral crystals much more common than chiral molecules? # What are the practical implications of this finding?

4. What is a chiral crystal? What may be chiral in a crystal? # The molecule # The asymmetric unit # The unit cell # The space-group # The macroscopic habit H. D. Flack, Helv. Chim. Acta, 2003, 86, 905

5. Class I: The 165 space groups which contain at least one improper operation (inversion, mirror, glide or S n operations). Always achiral (although the 3D asymmetric unit is always chiral) The classes of space groups P m

6. Class II: 22 chiral-helical space groups (11 enantiomeric pairs) Contain at least one screw axis which is not the 2 1 -screw axis. Always chiral even if the AU is achiral

7. The confusing class III: 43 space groups that contain only proper rotations and the 2 1 -screw rotation Examples: P 2 1, P 4, the abundant P 2 1 2 1 2 1. Despite the fact that there are no reflections, inversions etc., these space groups are achiral Despite the fact that these space groups are achiral, the crystals which pack by them are always chiral How can that be?

8. # P2 1 is achiral because reflection of this mathematical entity results in unchanged P2 1 # P6 1 is chiral because its reflection results in P6 5 Despite the fact that there are no reflections, inversions etc., these 43 space groups are achiral In general, a crystal may be chiral and yet belong to one of these 43 achiral space groups

9. Despite the fact that these space groups are achiral, the crystals which pack by them are chiral The reason for: * An AU in 3D is always chiral. A chiral AU on which only proper operations are applied, must result in a chiral crystal. * If the AU is achiral (0D, 1D, 2D) – then it will usually pack in a space group which has that achiral operation, coinciding with it.

10. Class II and Class III are collectively known as the 65 Sohncke groups II: 22 of the 65 are chiral (helical) III: 43 of the 65 are achiral Bottom line: All of the 65 Sohncke groups - and only these groups - represent chiral crystals The Sohncke symmetry space groups

11. Wrong H. D. Flack, Helv. Chim. Acta, 2003, 86, 905

12. To remove the confusion we suggest: Class I: 165 improper-achiral groups Always an achiral crystal Class II: 22 helical-chiral groups Always a chiral crystal Class III: 43 proper-achiral groups Always a chiral crystal

13. If the space group contains only proper operations, the crystal is chiral If the space group contains only proper operations, the crystal is chiral Proper operations: rotations, screw-rotations and translations Achiral crystal - improper operations (mirror, inversion, S 4, S 6 or glide) Simple tests for the chirality of a crystal Santiago Alvarez’ Criterion : A crystal is chiral if the symbol of its space group is composed only of a capital letter and simple numbers

14. Number of reported non-biological crystal structures (CSD, ICSD): 574,000 Chiral structures: 131,000 % of all non-biological chiral crystals: 23% Number of structures reported as chiral: 35,000 (6% only) Number of chiral crystals not recognized as such: ~96,000 The numbers

15. Measuring the degree of chirality

17. G: The achiral symmetry point group which minimizes S(G) Achiral molecule: S(G) = 0 The more chiral the molecule is, the higher is S(G) The continuous chirality measure (CCM) Mezey, Gilat, Kauzman, Osipov, Mislow, Ruch, Richards, Maruani

18. The most chiral monodentate complex With S. Alvarez, Europ. J. Inorg, Chem., 1499 (2001)

19. The chirality of a unit-cell 1 sec S(C 2 )=0.00 S(chirality)=4.51 S(C i )=36.54 516 atoms bis((2-phenoxo)-bis(triphenylphosphine)-copper), C 84 H 70 Cu 2 O 2 P 4 (HEZXEP (P2)); Osakada, K.; Takizawa, T.; Tanaka, M.; Yamamoto, T. J. Organometallic Chem., 1994, 473, 359-369.

20. Le Chatelier, H. Compt. Rend de I'Acad. Sciences 1889, 109, 264. The optical rotation of quartz: More than 120 years ago Le Chatelier and his contemporaries

21. Temperature (°K)  Le Chatelier   t  Chirality, SiSi 4 Chirality  t   120 years later: an exact match with quantitative chirality changes D. Yogev, Tetrahedron: Asymmetry 18, 2295 (2007) SiSi 4

22. Examples of publications on chiral crystals where terms such as “Chirality”, “Chiral”, “Optical activity”, etc., do not appear in the title, abstract and the whole text. All are of class III, the 43 proper-achiral space groups A chemist running a search which has any of these keywords, will simply miss 100,000 structures!

23. Example 1: C 25 H 18 O 2 CSD: ABUCOP, space group: P 2 2 1 2 1 (#18), CCM-UC = 11.15 S. Apel, S. Nitsche, K. Beketov, W. Seichter, J. Seidel, E. Weber, J. Chem. Soc., Perkin Trans. 2, 2001, 7, 1212

24. CCM of one molecule = 2.82 Example 1: C 25 H 18 O 2

25. Example 2: C 12 H 40 Cs 4 N 4 Si 4 CSD: JUFWUK, space group: P 3 2 (#195), CCM-UC = 0.47 Tesh, K. F.; Jones, B. D.; Hanusa, T. P.; Huffman, J.C. J. Am. Chem. Soc. 1992, 114, 6590.

26. CCM of one molecule = 0.47 Example 2: C 12 H 40 Cs 4 N 4 Si 4

27. Example 3: C 16 H 12 N 2 O 2 CSD: BIXLOJ, the most common proper-achiral group: P 2 1 2 1 2 1,(#19) CCM of the UC = 2.01

28. Example 3: C 16 H 12 N 2 O 2 (CSD code: BIXLOJ ) Space group: P 2 1 2 1 2 1 (#19) CCM of one molecule inside the crystal = 0.19

29. Example 4: NH 3, Ammonia Space group: P 2 1 3 (#198), UC-CCM = 1.89, CCM one molecule = 0 The terms “chirality”, “optical activity” etc’ do not appear in ANY of the publications on ammonia crystals ! Boese, R.; Niederpruem, N.; Blaeser, D.; Maulitz, A.H.; Antipin, M.; Yu.; Mallinson, P.R.J. Phys. Chem. B, 1997, 101, 5794–5799.

30. Example 5: Crystallization of a racemate leads to a P21 chiral crystal The pair of enantiomers in the AU are related by pseudo-inversion: the phenyl rings, which are twisted differently Steinberg, A., Ergaz, I., Toscano, R.A., Glaser, R. 2011. Cryst. Growth Des. 11, 1262-1270. (±)-(1RS,3SR,4RS)-1- Phenyl-cis-3,4-butano- 3,4,5,6-tetrahydro-1H- 2,5- benzoxazocine hydrochloride

31. Why are chiral crystals much more common than chiral molecules? % of all non-biological chiral crystals: 23% % of all non-biological molecules: ~10% # Solution-achiral molecules need not crystallize in their equilibrium achiral structure # They provide a very rich library of chiral conformers, which is the source of the abundance of chiral crystals

32. Why was it overlooked? * The confusion, even in text books, of what is a chiral crystal. * For a crystallographer the chirality maybe obvious from the space-group. The cost: Chemists searching “chiral” will miss it. * Crystallization from a racemic mixture results in a mixture of right- and left-handed crystals which needs to be separated

33. Practical aspects: Chiral Silicate Zeolites Most silicate-zolites are highly symmetric ZSM-5, a silicate zeolite: Na n Al n Si 96-n O 192 16H 2 O

34. Chiral zeolites Prime importance: * Enantioselective catalysis * Enantiomers separation * Enantioselective sensing Known: Zeolite-like, open-pore crystals, MOF’s, etc. Out of over 700 zeolite structures only 5 are recognized as chiral Desired: Chiral aluminosilicate zeolites Only one was reported

35. We found 21(!) chiral silicate zeolites which have been under the nose all the time! a. Goosecreekite. b. Bikitaite. c. The two enantiomeric forms of Nabesite Ch. Dryzun et al, J. Mater. Chem., 19, 2062 (2009) Editor’s Choice, Science, 323, 1266 (2009)

36. Out of 120 classical silicate zeolites, we found 21 chiral zeolites, that were not recognized as such That is very close to the 23% general abundance we found All belong to the non-helical Sohncke space groups

37. Goosecreekite (GOO) Chiral zincophosphate I (CZP) α-Quartz TT’ 4 2.052.940.55 SBU0.860.37------ A.U.14.761.280.00 Unit cell4.908.911.28 The chirality values are comparable or larger than the chirality values of the known chiral zeotypes and of quartz

38. Adsorption of D-histidine (the lower curve) or L-histidine (the higher curve) on Goosecreekite (GOO): The heat flow per injection The isothermal titration calorimetry (ITC) experiment L-histidine With Y. Mastai and A. Shvalb, Bar-Ilan

39. Conclusion There are some 100,000 unrecognized chiral crystals out there, waiting to be utilized for enantioselective catalysis, sensing, and separation. C. Dryzun and D. Avnir, Chem. Commun., 2012, 48, 5874–5876, Special Chirality web themed issue