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Aida, T. et.al. Angew. Chem. Int. Ed. 2001, 40, 1857.
Caging Molecules: Catch Me If You Can !
Xiaoyong LiDepartment of Chemistry Michigan State University
Nov. 2nd, 2005
• Why ?
Three Questions To Be Answered
• What ?are caging molecules ?
to cage molecules ?
• How ?to cage molecules ?
What are Caging Molecules?
CyclodextrinCyclodextrin
K+
18-Crown-6-K+18-Crown-6-K+
K+
O
OHHO
OH
O
OOH
HO OHO
OOH
OH
OH
O
OO
OHOH
HO
OOH
OHHO
O
OOH
HO
HO
O
n
γ
α
β
CD n1
3
2
Guest
Born, A.; Bradley, M.; Cameron, K.; Clark, J. K.; Egmond, J. van; Feilden, H.; Maclean, E. J.; Muir, A. W.;Palin, R.; Rees, D.C.; Zhang, M.-Q. Agnew. Chem., Int. Ed. 2002, 41, 265.
Rocuronium bromide
Neuromuscular blocker
N
HHO
NO
Br
OAc
-
+
What are Caging Molecules?
Iwamatsu, S.; Murata, S.; Andoh, Y.; Minoura, M.; Kobayashi, K.; Mizorogi, N.; Nagase, S. J. Org. Chem. 2005, 70, 4820.
K+
FullenreneFullenrene
CyclodextrinCyclodextrin
O
OHHO
OH
O
OOH
HO OHO
OOH
OH
OH
O
OO
OHOH
HO
OOH
OHHO
O
OOH
HO
HO
O
n
γ
α
β
CD n1
3
2
Guest
18-Crown-6-K+18-Crown-6-K+
~83%Z = CO2Me
• Encapsulation / imprisonment
• Host-guest chemistry
What are Caging Molecules?
Cram, D. J.; Karbach, S.; Kim, Y. H.; Aczynskyj, L.; Kalleymeyn, G. W. J. Am. Chem. Soc. 1985, 107, 2575.
Host
Cacerand
OO O OO O O O
H3C CH3CH3CH3
H HH H
OO O OO O
O O
CH3CH3CH3 C3H
H HH H
S SSS Guest
Building a host cage
Caging guest molecules
• Synthesis by covalent bonding• Self-assembly by noncovalent interactions
• van der Waals force• Donor-acceptor interaction• π - π stacking / CH - π interaction• Electrostatic attraction
How to Cage Molecules
Why to Cage Molecules?
Molecular storage- stabilize reactive species / dyes / drugs- selective extraction
Acquire insights for enzymatic process- conduct chemical transformations in cages
Molecular storage
Cucurbit[7]urilCucurbit[7]uril
Nau, W. M.; Mohanty J. Angew. Chem. Int. Ed. 2005, 44, 3750.
O NEtEtHN
COOEt
+
rhodamine 6G
Ka> 50000 M-1
Stabilize reactive species / dyes / drugs
• Ultrastable • Extended fluorescence life• Unchanged fluorescent activity
Why to Cage Molecules?
Molecular storage- stabilize reactive species / dyes / drugs- selective extraction
Molecular Extraction of Fullerenes - Aida’s Story
$ 6975mgC84 (98%)$ 15350mgC70 (98%)$ 141500mgC60 / C70 (9:1)$ 2461gC60 (98%)PriceUniteFullerenes
Aldrich Catalog. 2004-2005, 937
C60
Carbon nanotubeSuperconductorHIV protease inhibitor
Caging Fullerenes by Dimeric Metalloporphyrins
Tashiro, K.; Aida, T.; Zheng, J.-Y.; Kinbara, K.; Saigo, K.; Sakamoto, S.; Yamaguchi, K. J. Am. Chem. Soc.1999, 121, 9477.
Ka=6.7X105 M-1 << 3.2X108 M-1Ka=6.7X105 M-1 << 3.2X108 M-1
Dimeric MetalloporphyrinDimeric Metalloporphyrin
Bpy
Guest
N
N
C60
NN N
NZn
Hex Hex
Hex Hex
N
N NN
Zn
Hex Hex
Hex Hex
O O
OO
(CH2)6 (CH2)6
Host
C60
Host
Host-C60
UV titration of host with C60 in benzene
Caging C60 by Dimeric Metalloporphyrins
Free host
C60 as acceptorC60 as acceptor
Zn-C23=2.918 Å
Zn-C24=2.765 Å
Zn-C23=2.918 Å
Zn-C24=2.765 Å
Zheng, J.-Y.;Tashiro, K.; Hirabayashi, Y.; Kinbara, K.; Saigo, K.; Aida, T.; Sakamoto,S.; Yamaguchi, K.; Aida, T. Angew. Chem. Int. Ed. 2001, 40, 1857.
C60
Proof from NMRProof from NMR
Caging Different Fullerenes
Shoji, Y.; Tashiro, K.; Aida, T. J. Am. Chem. Soc. 2004, 126, 6570.
5.0
6.0
7.0
8.0
Log
Kas
soci
atio
n
C60 C70 C96
5.7
5.0
7.1
5.9
7.57.1
Guest
NN N
NZn
Hex Hex
Hex Hex
N
N NN
Zn
Hex Hex
Hex Hex
O O
OO
(CH2)6 (CH2)6
N
N NN
Zn
N
N NN
Zn
O O
OO(CH2)6 (CH2)6
OC12H25
OC12H25C12H25O
C12H25O
Selective Extraction of Higher Fullerenes
Shoji, Y.; Tashiro, K.; Aida, T. J. Am. Chem. Soc. 2004, 126, 6570.
N
N NN
Zn
N
N NN
Zn
O O
OO
(CH2)6 (CH2)6
OC12H25
OC12H25C12H25O
C12H25OMixture of fullerenesMixture of fullerenes
Enriched C96Enriched C96
host
NN
Enriched C102~C110Enriched C102~C110
host
NN
Host-C>70
Host-C>100
Selective Extraction of Higher Fullerenes
20% C70 in C6020% C70 in C60
91% C70 in C6091% C70 in C60
NN N
NZn
EtEt Et
Et
EtEt Et
Et
N
N NN
ZnEt
Et EtEt
EtEt Et
Et
O O
OO
(CH2)6 (CH2)6
‘ Porphyrin column ‘‘ Porphyrin column ‘
Zheng, J.-Y.;Tashiro, K.; Hirabayashi, Y.; Kinbara, K.; Saigo, K.; Aida, T.; Sakamoto,S.; Yamaguchi, K.; Aida, T. Angew. Chem. Int. Ed. 2001, 40, 1857.
Why to Cage Molecules?
Molecular storage- stabilize reactive species / dyes / drugs- selective extraction
Acquire insights for enzymatic process- conduct chemical transformations in cages
A Comparison between Natural Enzyme & Supermolecular Cage
selective substrate bindinginduced proximityhydrophobic interiorcomplex superstructurehard to make
selective substrate bindinginduced proximityhydrophobic interiorcomplex superstructurehard to make
Supermolecular cage:
12 NO3-
12+selective caging by size, shape, etcspace-restricted environmenthydrophobic interiorwell-defined and tunable structure
selective caging by size, shape, etcspace-restricted environmenthydrophobic interiorwell-defined and tunable structure
Natural enzyme:
Approach to Supermolecular Cage
• Synthesis by covalent bonding
• Self-assembly by noncovalent interactions
The Encyclopedia of Twentieth-Century Architecture (Ed.: R.Stephen Sennott),Fitzroy Dearborn, Chicago, 2002.
“Even a common, ordinary brick wants to be something more than it is.”
--Louis Kahn
Self-assembly
- Hydrogen bonding
Self-assembly by Noncovanlent Interactions
- Metal-ligand coordination
fast equilibration / reversible
solvent competition for H-bonding
fast equilibration / reversible
solvent competition for H-bonding
greater strength
more rigidity
stable in aqueous solution
greater strength
more rigidity
stable in aqueous solution
‘Softball’‘Softball’
Kang, J.; Rebek, J., Jr. Nature 1997, 385, 50. Kang, J.; Santamarı´a, J.; Hilmersson,G.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120, 7389.
HN N
NHNNN
NN
OH
OH
O
O
O
O
OH
OH
R R
O
O
NHN
N NHRR
O
O
R= 4-n-heptylphenyl
H-bonding Based Supermolecular Cage
Volume = 320 Å3
Functions of Metal-ligand Based Supermolecular Cages
Fujita’s story - molecular triangles
Hupp’s story – molecular squares
NN
N
N
NN
NN
N
N
NN
N
NN
NN
N
NN
NNN
N
H2N PdNH2
O2NOONO2
http://www.chem.t.u-tokyo.ac.jp/appchem/labs/fujita/paneling.html
NH2
Pd
H2N
Pd =12+, water soluble
Hydrophobic cavity
12+, water soluble
Hydrophobic cavity
M6L4 Host Assembly-Molecular Paneling
12 NO3-
12 NO3-
12 NO3-
N
N
N
N
N
N
Pd
PdPd
N
N
PdPd
Pd
N
N
N
N
12+
‘tube’‘tube’
‘bowl’‘bowl’
‘cage’‘cage’
[2+2] Photodimerization of Olefins within Nanocages
• Poor yield and selectivity in solution phase• Improved reactions need to be conducted in crystalline state• The ‘cage effect’ – restrictions from lattice
2
syn anti
hv +
2
syn anti
hv +D2O
2 mM, 0.5h > 98% yield
Yoshizawa, M.; Takeyama, Y.; Kusukawa, T.; Fujita, M. Angew. Chem. Int. Ed. 2002, 41, 1347.
2hv
+ ++
HT-syn HH-syn HT-anti HH-anti
benzene
[2+2] Photodimerization of Olefins within Nanocages
150mM
X
Yoshizawa, M.; Takeyama, Y.; Kusukawa, T.; Fujita, M. Angew. Chem. Int. Ed. 2002, 41, 1347.
2hv
+ ++
HT-syn HH-syn HT-anti HH-anti
D2O
[2+2] Photodimerization of Olefins within Nanocages
0.5mM, 3h
Yoshizawa, M.; Takeyama, Y.; Kusukawa, T.; Fujita, M. Angew. Chem. Int. Ed. 2002, 41, 1347.
HT-syn
CDCl3
> 98% yield
[2+2] Cross-Photodimerization
A B A'-A' B'-B'A'-B'hv+syn / anti syn / anti syn / anti
+ +
A'-A' B'-B'A'-B'
syn syn syn
+ +
hv
A B A A B BA B+ + ++ caging
[2+2] Cross-Photodimerization of Olefins within Nanocages
97% yield
2N
O
O2+ +
D2O3hhv,
N
O
O
inert to hvinert to hv
N
O
O+ N
O
O
D2O80oC, 10min
Cage (1eq.)
1 1:
size compatibilitysize compatibility
Yoshizawa, M. Takeyama,Y.; Okano,T.; Fujita M. J. Am. Chem. Soc. 2003, 125, 3243.
N
O
OCDCl3
Yoshizawa, M.; Miyagi, S.; Kawano, M.; Ishiguro, K.; Fujita, M. J. Am. Chem. Soc. 2004, 126, 9172.
Photochemical Oxidation of AlkanesOH
hv
Air, Lewis Acid
OOH
+CH3CN2
Can we do it in a greener way?
12 NO3-
Pd = Pd
4
Shul’pin, G. B.; Nizova, G. V.; Kozlov, Y. N. New. J. Chem. 1996, 20, 1243.
Yoshizawa, M.; Miyagi, S.; Kawano, M.; Ishiguro, K.; Fujita, M. J. Am. Chem. Soc. 2004, 126, 9172.
12 NO3-
Pd = Pd
Alkane Oxidation via Photochemical Excitation of Molecular Cage
hvH2O, r.t., 30min
OH
4
12+
OOH
+
1 : 4
Yoshizawa, M.; Miyagi, S.; Kawano, M.; Ishiguro, K.; Fujita, M. J. Am. Chem. Soc. 2004, 126, 9172.
12 NO3-
Pd = Pd
Solvent ?Solvent ?
Metal ?Metal ?
Anion ?Anion ?
H2O CH3CN Solid
Pd2+ Pt2+
NO3- PF6
-
Alkane Oxidation via Photochemical Excitation of Molecular Cage
Ligand ?Ligand ? N N
N
Substrate ?Substrate ?
hvAr
hvH2O, r.t., 30min
OH
4
12+
Ar
Generate radical in triazine ligand by hvGenerate radical in triazine ligand by hv
e transfer from alkane to L generating R. & L-e transfer from alkane to L generating R. & L-
Trap R. by H2O or O2 releasing productTrap R. by H2O or O2 releasing product
Mechanism of Alkane Oxidation in Photo Reactor
G
H
G'
H
G
H'
hv
Yoshizawa, M.; Miyagi, S.; Kawano, M.; Ishiguro, K.; Fujita, M. J. Am. Chem. Soc. 2004, 126, 9172.
12 NO3-
12+
Alkane Oxidation via Photochemical Excitation of Molecular Cage
2.6 Å
Yoshizawa, M.; Miyagi, S.; Kawano, M.; Ishiguro, K.; Fujita, M. J. Am. Chem. Soc. 2004, 126, 9172.
Close contact is crucial !
No oxidation with nanobowl
Close contact is crucial !
No oxidation with nanobowl
12 NO3-
Metal-ligand Based Supermolecular Cages
Fujita’s story - molecular triangles
Hupp’s story – molecular squares
A Paradigm of Artificial Enzyme -Hupp’s Story
Merlau, M. L.; Mejia, M. del P.; Nguyen, S. T.; Hupp, J. T. Angew. Chem. Int. Ed. 2001, 40, 4239.
Cytochrome P450Cytochrome P450TON = 50
t1/2 = 10 minTON = 50
t1/2 = 10 min
NN
N NMnⅢN N
Cl-NN
N NFeⅡ
R2 R3
R1 R4
R2 R3
R1 R4OOxidant
Catalyst+
Collman, J. P.; Kodadek, T.; Raybuck, S. A.; Brauman, J. I. J. Am. Chem. Soc. 1985, 107, 4343.
Cl Cl ClCl
O
MnⅤMnⅢ
O
MnⅤ
R1
R2R2R1R2R1
O+MnⅢ
[O]
Mechanism for MetalloporphyrinCatalyzed Epoxidation
Collman, J. P.; Brauman, J. I.; Meunier, B.; Hayashi, T.; Kodadek, T.; Raybuck, S. A. J. Am.. Chem. Soc.1985, 107, 2000.
Cl Cl
O
MnⅤ+ MnⅣ MnⅣOMnⅢ
oxo-dimer2 Cl -
Artificial Enzyme from Directed Self-assembly of Molecular Squares
18 Å
Design a cageDesign a cage
14 Å
N
N
N
NNN
NN
Cl(OC)3Re Re(CO)3Cl
Re(CO)3ClCl(OC)3Re
Zn
Zn
Zn
Zn
18 Å
Merlau, M. L.; Mejia, M. del P.; Nguyen, S. T.; Hupp, J. T. Angew. Chem. Int. Ed. 2001, 40, 4239.
N
NN
N
N
N
MnⅢ
A perfect cavity !A perfect cavity !
Ka=106 M-1Ka=106 M-1
9 Å
18 Å
TON = 500 t1/2 = 3hTON = 500 t1/2 = 3h
Merlau, M. L.; Mejia, M. del P.; Nguyen, S. T.; Hupp, J. T. Angew. Chem. Int. Ed. 2001, 40, 4239.
NN
N
N
NNN
NN
Cl(OC)3Re Re(CO)3Cl
Re(CO)3ClCl(OC)3Re
Zn
Zn
Zn
Zn
N
MnⅢ
N
N
MnⅢHost +
PhPh
OCatalyst+ PHIOCH2Cl2, r.t.
92%
Artificial Enzyme from Directed Self-assembly of Molecular Squares
Improve the Catalytic Activity of Artificial Enzyme by Enhance the Caging
Ka=107 M-1
TON=1500
Ka=107 M-1
TON=1500
TON= 65TON= 65
Merlau, M. L.; Mejia, M. del P.; Nguyen, S. T.; Hupp, J. T. Angew. Chem. Int. Ed. 2001, 40, 4239.
NN
N
N
NNN
NN
Cl(OC)3Re Re(CO)3Cl
Re(CO)3ClCl(OC)3Re
Zn
Zn
Zn
Zn
N
MnⅢN NNN
N NMnⅢN N
N
N
PhPh
OCatalyst+ PHIOCH2Cl2, r.t.
92%
Summary
“It’s all about the space…”--Julius Rebek Jr.
Caging molecules has been extensively investigated as an important tool for molecule storage, catalysis and mimicking nature
Fabricating supermolecular cages was achieved by many methods especially by self-assembly via noncovalent interactions as H-bonding & metal-ligand coordination
Understanding the nature of caging molecules promotes the development of molecular reactors and artificial enzymes