Talk from European Crystallographic Meeting 26 in Darmstadt, Sept 2010

1. TWEEZERS AND ZIGZAGS – MODELS FOR
SEQUENCE SPECIFIC TWEEZER-POLYMER
INTERACTIONS
Christine Cardin.
Howard Colquhoun
Interactions and
reactivity in small and
large molecules
Darmstadt 2010

2. SEQUENCE INFORMATION IS DIGITAL INFORMATION
"As soon as heterogeneity enters a polymer chain, information technology becomes a theoretical possibility"
Richard Dawkins, The Blind Watchmaker, Longmans, 1986
NOTE: The "Shannon" information-content of 1 g of a simple A-B copolymer with
a nominal Dp of 100 and monomers of mass 1000 Daltons is ca. 100 billion Gb.

3. Inspiration from recognition in nucleic acid structures
NH2
O NH
Br
NH+
5-bromo-9-amino-DACA
O
Br
NH
N O
5-bromouridine
Cardin et al, J Med Chem 1999
Osaka 2008

4. Disorder also a problem in refining
these structures even with data to 1.2 Ǻ
Teixeira, S.C.M, Cardin C.J., et al.
Osaka 2008

5. TWEEZERS – SHOULD BE ∏ -ELECTRON DONORS
6.8 Ǻ
NH HN
O O
Fe

6. S O
O N O O N O O N O O N O O N O
O N O O N O O N O O N O O N O
O S SOME TWEEZER DESIGNS
O S O S
O O O
F3C O F3 C O O
2 3
H2
O O O O
NH HN NH HN NH HN H
N N
O O O O O O
6 7 8 9
Fe
ORGANISED BY
O n O O
HYDROGEN BONDS
O N O
O O O
S O S O S O
O N O O N O CF3
CF3
O N O O N O O N O
O S O S O S

7. 4 5
∏ - ACCEPTOR MOLECULES
F3C O
O
O S
O N O O N O
O N O O N O
O S
O
CF3 O
One acceptor
10 Two 11
acceptors

8. ZIGZAGS – THREE ∏-ACCEPTORS
O O CF3
N N
O O O
O
O
S S
O
O
O O O
N N
F3C O O

9. TWEEZER-BINDING TO MACROCYCLIC AROMATIC IMIDES
NH2
ClOC COCl
2 +
O O
O O
O S S
NH
O O O O
N N
NH
O O O
Ka = 24,000 M-1
Colquhoun, Zhu and Williams, Org. Lett., 2003, 5, 4353

10. TWEEZER-BINDING TO THE CORRESPONDING POLYIMIDE?
Crystal packing
Ring-opening polymerisation in silico

11. PRELIMINARY STUDIES OF TWEEZER-BINDING TO A POLYIMIDE
NH2
O O
O S S O
O O
COMPUTATIONAL MODELLING
H2N
O O
(i) DMAc
O O
(ii) 280 °C
O O
O O
N N
O O
O S S O O O
O O
n
Mw = 290,000; Mn = 160,000;
Determination of binding constant for tweezer 1
with homopolymer 3
2.8
2.6 y = 0.4143x + 1.4681
Tweezer-imide 2.4
R2 = 0.9385
binding constant 2.2
103c/A
(UV-vis dilution 2
method) = 9000 M-1 1.8 O
NH
1.6
Tweezer shown in magenta
1.4
0 0.5 1 1.5 2 2.5 3
NH
1/A1/2 O
Colquhoun and Zhu, Angew. Chem., Int. Ed.., 2004, 43, 5040

12. 1H NMR STUDIES OF POLYIMIDE-TWEEZER BINDING
TWEEZER : IMIDE
4 : 1
O
O
S O
S S
O
O
IMIDE RESONANCE REMAINS
A SINGLET, SO FAST EXCHANGE
ON NMR TIME-SCALE
OO
NH O O
I N N
TWEEZER : IMIDE
O O
1 : 10
O
NH
O
O
O
S S S
O
O
O PURE POLYMER

13. MODEL FOR MULTIPLE TWEEZER-BINDING
Computational modelling (molecular mechanics with charge-equlibration)
confirms stability of chain-folded, triply-adjacent tweezer-bound structure

14. A POTENTIALLY CHAIN-FOLDING, DI-IMIDE OLIGOMER
O O
S O O CF3
H2N O + O O + H2N
O NH2
S O O
O O
1 mol equiv. 2 mol equiv. 2 mol equiv.
O
O
S O O O
N N
F3C O O
O O CF3
N N
O O O S
O
O n (n = 1 to ~4)
Oligomer where n = 1 (two diimide residues) successfully isolated by
chromatography

15. PROOF OF CHAIN-FOLDING AND ADJACENT-BINDING
O
O O CF3 NH
CF3
O O
N N Fe
N N
O O O NH O O
O O
O
NH HN
O + S
O
S
O ? S
O
S
O
O
O O
O
O O O O O
Fe O O HN
N N N N
Fe
F3C O O O O
2 F3C
HN
O
Oligomer (n = 1) from end-
Crystalline 2:1 complex √
-capped polycondensation

16. Single-crystal X-ray analysis
of tweezer-oligomer complex
Colquhoun, Zhu, Cardin and Gan, Nature Chem., 2010, doi:10.1038/nchem.699.

17. New tweezer-molecule, with H-bond-constrained conformation
HOOC H COOH ClOC H COCl
N SOCl2 N OH
O O O O
NEt3 H
N
O O CF3
N N
F3C O O

18. New tweezer-molecule VERY sensitive to long-range sequences
Copolymer + NH HN 5 mol%
O O
Copolymer + 5 mol%
O O O O
H
N
O O
N N
O O
O S S O O O
O O
I
S m
O F3C CF3 O
N N
O O
O S S O O O
O O
N
S m Colquhoun, Zhu et al., Faraday Discuss., 2009, 143, 205.

19. Preferred binding of new tweezer at biphenylenedisulfone unit !
O O
O O
S S
O O O O
+ O O O O
H
N N N
O O
X-ray structure
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20. MEASUREMENT, DISORDER, SOLVENT REMOVAL
R ~9.5%
SHELXL FRAG
R ~9.5%

21. Modelling of tweezer and linear tri-imide oligomer
Computational
Modelling
(MM)
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22. ACKNOWLEDGEMENTS – MOLECULAR TWEEZERS WORK
Collaborators
Reading Advanced Light Source
Prof. Howard Colquhoun Dr Simon Teat
Dr. Zhixue Zhu Dr Christine Beavers
Dr. Yu Gan
Dr Barny Greenland Diamond (UK)
Claire Murray Dr. Dave Allan