Recognition by molecular tweezers
22
Christine Cardin. Howard Colquhoun TWEEZERS AND ZIGZAGS – MODELS FOR SEQUENCE SPECIFIC TWEEZER-POLYMER INTERACTIONS Interactions and reactivity in small and large molecules Darmstadt 2010
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Transcript of Recognition by molecular tweezers
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
TWEEZERS – SHOULD BE ∏ -ELECTRON DONORS
NH
O
HN
O
Fe
6.8 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
ZIGZAGS – THREE ∏-ACCEPTORS
F3C
S
OO
O
CF3
NN
S
OO
O
O
O
O
O
NN
O
O
O
O
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
+
MEASUREMENT, DISORDER, SOLVENT REMOVAL
SHELXL FRAG
R ~9.5%
R ~9.5%
I––––––––––S–––––––––I–––––––––S––––––––I
Modelling of tweezer and linear tri-imide oligomer
Computational
Modelling (MM)
ACKNOWLEDGEMENTS – MOLECULAR TWEEZERS WORK
Reading
Prof. Howard Colquhoun
Dr. Zhixue Zhu
Dr. Yu Gan
Dr Barny Greenland
Claire Murray
Collaborators
Advanced Light Source
Dr Simon Teat
Dr Christine Beavers
Diamond (UK)
Dr. Dave Allan
