On the abundance of chiral crystals

(An optimistic lecture for the conclusion of the conference)

David Avnir

Institute of ChemistryThe Hebrew University of Jerusalem, Israel

WithChaim Dryzun

Department of Chemistry, ETH ZürichLugano Campus, Switzerland

Chirality 2012, Fort Worth, Texas June 10 - June 13, 2012

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.

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?

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

Class I:

The 165 space groups which contain at least one improper operation (inversion, mirror, glide or Sn operations).

Always achiral(although the 3D asymmetric unit is always chiral)

The classes of space groups

P m

Class II:

22 chiral-helical space groups (11 enantiomeric pairs)

Contain at least one screw axis which is not the 21-screw axis.

Always chiraleven if the AU is achiral

The confusing class III:

43 space groups that contain only proper rotations and the 21-screw rotation

Examples: P 21, P 4, the abundant P 21 21 21.

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?

# P21 is achiral because reflection of this mathematical entity

results in unchanged P21

# P61 is chiral because its reflection results in P65

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

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.

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

Wrong

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

To remove the confusion we suggest:

Class I: 165 improper-achiral groupsAlways an achiral crystal

Class II: 22 helical-chiral groupsAlways a chiral crystal

Class III: 43 proper-achiral groupsAlways a chiral crystal

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, S4, S6 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

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

Measuring the degree of chirality

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)

N

1k

2

2ˆ1

min100 kk QQNd

)S(G

Mezey, Gilat, Kauzman, Osipov, Mislow, Ruch, Richards, Maruani

S(TP)

[Ta(CCSitBu3)6]- [Ti2(-SMe)3(SMe)6]

2-[Zr(SC6H4-4-OMe)6]2-

1.88

18.8°

1.67

8.27

5.51

1.34

33.3°

4.45

3.94

2.16

30.4°

5.09

S(chir)

S(Oh)

The most chiral monodentate complex

With S. Alvarez, Europ. J. Inorg, Chem., 1499 (2001)

The chirality of a unit-cell

1 sec

S(C2)=0.00

S(chirality)=4.51

S(Ci)=36.54

516 atoms

bis((2-phenoxo)-bis(triphenylphosphine)-copper), C84H70Cu2O2P4

(HEZXEP (P2)); Osakada, K.; Takizawa, T.; Tanaka, M.; Yamamoto, T. J. Organometallic Chem., 1994, 473, 359-369.

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

0.97

1.02

1.07

1.12

1.17

98 298 498 698 898 1098

Temperature ( K)

0.54

0.56

0.58

0.6

0.62

0.64

Temperature (°K)

Le

Cha

teli

er

t

Ch

irality, SiSi4

Chirality t

120 years later: an exact match with quantitative chirality changes

D. Yogev, Tetrahedron: Asymmetry 18, 2295 (2007)

SiSi4

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!

Example 1: C25H18O2

CSD: ABUCOP, space group: P 2 21 21 (#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

CCM of one molecule = 2.82

Example 1: C25H18O2

Example 2: C12H40Cs4N4Si4

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.

CCM of one molecule = 0.47

Example 2: C12H40Cs4N4Si4

Example 3: C16H12N2O2

CSD: BIXLOJ, the most common proper-achiral group: P 21 21 21,(#19)CCM of the UC = 2.01

Example 3: C16H12N2O2 (CSD code: BIXLOJ)

Space group: P 21 21 21 (#19)

CCM of one molecule inside the crystal = 0.19

Example 4: NH3, Ammonia

Space group: P 21 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.

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

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

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

Practical aspects: Chiral Silicate Zeolites

Most silicate-zolites are highly symmetric

ZSM-5, a silicate zeolite: NanAlnSi96-nO192•16H2O

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 zeolitesOnly one was reported

We found 21(!) chiral silicate zeoliteswhich 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)

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 foundAll belong to the non-helical Sohncke space groups

Goosecreekite (GOO)

Chiral zincophosphate I

(CZP)α-Quartz

TT’4 2.05 2.94 0.55

SBU 0.86 0.37 ------

A.U. 14.76 1.28 0.00

Unit cell 4.90 8.91 1.28

The chirality values are comparable or larger than the chirality values of the known chiral zeotypes

and of quartz

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

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