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transcript
Christine Cardin.Howard Colquhoun
TWEEZERS AND ZIGZAGS – MODELS FOR SEQUENCE SPECIFIC TWEEZER-POLYMER
INTERACTIONS
Interactions and reactivity in small and large molecules
Darmstadt 2010
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.
Osaka 2008
NH
NH+
O
NH2
Br
N
NHBr
O
O
5-bromouridine
5-bromo-9-amino-DACA
Cardin et al, J Med Chem 1999
Inspiration from recognition in nucleic acid structures
Osaka 2008
Teixeira, S.C.M, Cardin C.J., et al.
Disorder also a problem in refining
these structures even with data to 1.2 Ǻ
N
N
OO
OO
CF3OO
O
S
S
O
OO
N
N
OO
OO
F3C
CF3OO
O
S
S
O
OO
N
N
F3C
O O
O O
N
N
O O
O O
1 2
OO
O
S
S
O
OO
OO
O
S
S
O
OO
CF3
N
N
F3C
O O
O O
N
N
O O
O O
N
N
O O
O O
3
4
O
OO
S
OO
O
NH2 H2N
S
NH
O
HN
O
NH
O
HN
ON
NH
O
HN
O
Fe7 8
F3C
NH2
5 6
NH
O OO
9
O
N
N
OO
OO
OO
O
S
S
O
OOO
O
O S
OO
O
N OO
OO N
10
S
N
N OO
OO
F3C
CF3
11
n
12
N
N
OO
OO
OO
O
S
S
O
OO m
N OO
OO
O
S
S
O
OO m
N OO
CF3
CF3
13
SOME TWEEZER DESIGNS
ORGANISED BYHYDROGEN BONDS
∏ - ACCEPTOR MOLECULES
N
N
OO
OO
CF3OO
O
S
S
O
OO
N
N
OO
OO
F3C
CF3OO
O
S
S
O
OO
N
N
F3C
O O
O O
N
N
O O
O O
1 2
OO
O
S
S
O
OO
OO
O
S
S
O
OO
CF3
N
N
F3C
O O
O O
N
N
O O
O O
N
N
O O
O O
3
4
O
OO
S
OO
O
NH2 H2N
S
NH
O
HN
O
NH
O
HN
ON
NH
O
HN
O
Fe7 8
F3C
NH2
5 6
NH
O OO
9
O
N
N
OO
OO
OO
O
S
S
O
OOO
O
O S
OO
O
N OO
OO N
10
S
N
N OO
OO
F3C
CF3
11
n
12
N
N
OO
OO
OO
O
S
S
O
OO m
N OO
OO
O
S
S
O
OO m
N OO
CF3
CF3
13One acceptor Two acceptors
TWEEZER-BINDING TO MACROCYCLIC AROMATIC IMIDES
O
SO
O
O
S
OO
N
O
O
O
O
N
Ka = 24,000 M-1
Colquhoun, Zhu and Williams, Org. Lett., 2003, 5, 4353
NH2
COClClOC
+2
NH
O
NH
O
TWEEZER-BINDING TO THE CORRESPONDING POLYIMIDE?
Ring-opening polymerisation in silico
Crystal packing
PRELIMINARY STUDIES OF TWEEZER-BINDING TO A POLYIMIDE
Determination of binding constant for tweezer 1 with homopolymer 3
y = 0.4143x + 1.4681
R2 = 0.9385
1.4
1.6
1.8
2
2.2
2.4
2.6
2.8
0 0.5 1 1.5 2 2.5 3
1/A1/2
10
3c/A
COMPUTATIONAL MODELLING
S
O
O
OS
O
O
O
NN
O
O
O
O
n
S
O
O
OS
O
O
O
NH2
H2N
OO
O
O
O
O
(i) DMAc
(ii) 280 °C
Mw = 290,000; Mn = 160,000;
NH
O
NH
O
Tweezer shown in magenta
Colquhoun and Zhu, Angew. Chem., Int. Ed.., 2004, 43, 5040
Tweezer-imidebinding constant(UV-vis dilutionmethod) = 9000 M-1
1H NMR STUDIES OF POLYIMIDE-TWEEZER BINDING
S
I
S
PURE POLYMER
TWEEZER : IMIDE1 : 10
TWEEZER : IMIDE4 : 1
N N
O
O
O
O
O
OO
S S
OO
O
O
OO
SS
OO
O
NH
O
NH
O
IMIDE RESONANCE REMAINSA SINGLET, SO FAST EXCHANGE ON NMR TIME-SCALE
MODEL FOR MULTIPLE TWEEZER-BINDING
Computational modelling (molecular mechanics with charge-equlibration) confirms stability of chain-folded, triply-adjacent tweezer-bound structure
A POTENTIALLY CHAIN-FOLDING, DI-IMIDE OLIGOMER
CF3
SO
O
O
F3C
N N
SO
O
O
O
O
O
O
N N
O
O
O
O
S
O O
OH2N
S
OO
ONH2
OO
O
O
O
O
CF3
H2N+ +
n
1 mol equiv. 2 mol equiv. 2 mol equiv.
(n = 1 to ~4)
Oligomer where n = 1 (two diimide residues) successfully isolated by chromatography
PROOF OF CHAIN-FOLDING AND ADJACENT-BINDING
NH
O
HN
O
Fe
F3C
S
OO
O
CF3
NN
S
OO
O
O
O
O
O
NN
O
O
O
O
+
2
Oligomer (n = 1) from end-
-capped polycondensationCrystalline 2:1 complex
NH
O
NH
O
Fe
F3C
S
OO
O
CF3
NN
S
OO
O
O
O
O
O
NN
O
O
O
O
HN
O
HN
O
Fe
?
√
Single-crystal X-ray analysisof tweezer-oligomer complex
Colquhoun, Zhu, Cardin and Gan, Nature Chem., 2010, doi:10.1038/nchem.699.
New tweezer-molecule, with H-bond-constrained conformation
N
HOOO O
N
H COOHHOOC
N
H COClClOC
SOCl2
NEt3
OH
NN
O
O
O
O
CF3
F3C
New tweezer-molecule VERY sensitive to long-range sequences
N
HOOO O
S
O
O
OS
O
O
O
NN
O
O
O
O
mS
N
I
S
O
O
OS
O
O
O
mS
F3C CF3
NN
O
O
O
O
Copolymer +
Copolymer + NH
O
HN
O
Colquhoun, Zhu et al., Faraday Discuss., 2009, 143, 205.
5 mol%
5 mol%
I–––––––––––S––––––––––I–––––––––––S––––––––––I–––––––––––S
Preferred binding of new tweezer at biphenylenedisulfone unit !
X-ray structure
O
SO
O
O
S
OO
N
O
O
O
O
NN
HOOO O
+
I––––––––––S–––––––––I–––––––––S––––––––I
Modelling of tweezer and linear tri-imide oligomer
Computational
Modelling (MM)