Advances in Host-Guest Chemistry

1
Advances in Host-Guest Chemistry

• Megan Jacobson
• University of Wisconsin-Madison
• April 21, 2005

2
Outline

• Background
• Industrial Applications
• Chemical Applications
• Reactions and Catalysis
• Scavengers
• Receptors
• Sensors
• Host Design
• Conclusions

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Host-Guest Chemistry

• Host-Guest Chemistry involves
• Two or more molecules, a host and a guest,
  involved in non-bonding interactions to form a
  supramolecular complex.
• According to Cram
• The host component is a molecule or ion whose
  binding sites converge in the complex
• The guest component is any molecule or ion whose
  binding sites diverge in the complex

Supramolecular Chemistry, Steed, J. W. Atwood J.
L. John Wiley and Sons, Ltd, 2000.
4
Early Development of Host-Guest Chemistry
Szejtli, J. Chem. Rev. 1998, 98,
1743-1753 Dodziuk, H. Introduction to
Supramolecular Chemistry. Kluwer Academic
Publishers, 2002. Supramolecular Chemistry,
Steed, J. W. Atwood J. L. John Wiley and Sons,
Ltd, 2000.
5
Guest Complexation

• Complexes stabilized by non-covalent
  interactions
• Hydrophobic complexation
• Hydrogen bonding
• Aromatic interactions ??? and edge-face
• Ion-ion and dipolar interactions

Szejtli, J. Chem. Rev. 1998, 98,
1743-1753 Whitlock, B.J. Whitlock, H. W. J. Am.
Chem. Soc. 1994, 116, 2301. Nassimbeni, L. R.
Acc. Chem. Res. 2003, 36, 631. www.yakko.pharm.kum
amoto-u.ac.jp/KH/modb/molst.html
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Advantages of Complexation

• Altered solubility
• Often increased water solubility
• Sequestration and precipitation of products
• Controlled volatility
• Encapsulation of gases
• Perfume release
• Altered reactivity
• Selective catalysis
• Stabilized guests

• Introduction to Supramolecular Chemistry
  Dodziuk, H, Kluwer Academic Publishers, 2002.
• Separations and Reactions in Organic
  Supramolecular Chemistry Lehn, J.-M. Ed Toda,
  F. Bishop, R. Wiley Sons, Ltd, 2004.
• www.yakko.pharm.kumamoto-u.ac.jp/KH/modb/molst.htm
  l

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Structure of Cyclodextrins
Number of Glucose Units A (Å) B (Å)
?-CD 6 5.3 14.6
?-CD 7 6.5 15.4
?-CD 8 8.3 17.5
?-Cyclodextrin (?-CD)
Szejtli, J. Chem. Rev. 1998, 98,
1743-1753 DSouza, V. T. Lipkowitz, K. B. Chem.
Rev. 1998, 98, 5, 1741.
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Manufacture of CDs

• Produced enzymatically from starch by
  cyclodextrin glucosyl transferase
• Precipitation of desired product CDs using guest
  molecules to select CD size
• ?-CD from 1-decanol
• ?-CD from toluene
• ?-CD from cyclohexadecanol

Cyclodextrin Glucosyl Transferase
Szejtli, J. Chem. Rev. 1998, 98,
1743-1753 www.xray.chem.rug.nl/ Gallery1.htm
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Areas of CD Research
Szejtli, J. Chem. Rev. 1998, 98, 1743-1753
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Cyclodextrin Complexed Pharmaceuticals

• Prostavasin (alprostadil alphadex, PGE1)
• Prostaglandin-based treatment of peripheral
  circulatory disorders
• Instability requires intra-arterial
  administration in uncomplexed form.
• ?-CD complex improved metabolic stability,
  injectable formulation.
• Schwartz Pharma product

Davis, M. E. Brewster, M.E. Nature Rev. 2004,
3, 1023-1035
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Cyclodextrin Complexed Pharmaceuticals

• Sporanox (itraconazole)
• Antifungal triazole
• Aqueous solubility estimated 1 ng/mL
• Hydroxypropyl ?-CD complex improves solubility to
  10 mg/mL
• First orally available drug effective against
  Candida spp. and Aspergillus spp.
• Janssen product

Davis, M. E. Brewster, M.E. Nature Rev. 2004,
3, 1023-1035
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Calixarenes

• Vase shaped cavity
• Condensation products of phenols and formaldehyde
• Common host starting point
• Low water solubility
• Many points for further functionalization
• Often used as scaffolds for sensors.

Ikeda, A. Shinkai, S. Chem.Rev. 1997, 97,
1713 Calixarenes 2001 Asfari, Z. Bohmer, V.
Harrowfield, J. Vicens, J. Kluwer Academic
Publishers 2001. filippoberio.com/Tradition/Histor
y.asp
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Possible Applications of Calixarenes

• Ion Sensors
• Selective ion sensing electrodes
• Optical transduction sensors
• Fluorescent sensors
• Separations
• Chiral recognition
• Chromatographic stationary phases
• Solid phase extraction

McMahon, G. OMalley, S. Nolan, K. Diamond, D.
ARKIVOC, 2003, vii, 23.
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Outline

• Background
• Industrial Applications
• Chemical Applications
• Reactions and Catalysis
• Scavengers
• Receptors
• Sensors
• Host Design
• Conclusions

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Directed Aromatic Chlorination

• gt95 para chlorination observed with ?-CD
• 1.48 1.0 p/o without CD
• Internal delivery of Cl from 2 OH
• Methylation of all but C-3 2 OH groups affords
  4.4x tighter binding and improved selectivity

Breslow, R. Campbell, P. J. Am. Chem. Soc. 1969,
91, 3085 Breslow, R. Kohn, H. Siegel, B. Tet.
Lett. 1976, 20, 1645-1646
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Cavity Accelerated Diels-Alder

• Requires small reaction components
• ?-CD shows rate accelerations of up to 1800 x
  rates in isooctane and 2-10 x those in water for
  small substrates.
• ??-CD inhibits reaction even with small
  substrates.

Too large for cavity
Rideout, D. C. Breslow, R. J. Am. Chem. Soc.
1980, 102, 7817-7818
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Cavity Accelerated Diels-Alder

• Modest increase in diastereoselectivity observed
  in cyclodextrins over reactions in water

Dienophile Endo / Exo In Water Endo / Exo in 0.015M ?-CD
1.10 0.05 2.2 0.08
47 4 69 4
48.5 4 112 5
Schneider, H-J. Sangwan, N. K. Angew. Chem.
Int. Ed. Engl. 1987, 26(9), 896-897
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Photochemical Control

• Products of UV irradiation (? 312 nm) of CD
  complexed E-stilbene depend on cavity size.

Herrmann, W. Wehrle, S. Wenz, G. Chem. Commun.
1997, 1709
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Photochemical Control
CD Reaction Time (h) E Stilbene Z Stilbene Trans -Dimer Cis-Dimer Phenanthrene
None 24 10 62 7 2 19
?-CD 24 20 60 0 0 20
?-CD 24 16 83 0 0 1
?-CD 72 0 0 79 19 2

• 11 complexation in ? or ?-CD favors
  isomerization.
• Complexation in ?-CD nearly prevents phenanthrene
  formation.
• 21 Complexation in ?-CD favors dimerization.

Herrmann, W. Wehrle, S. Wenz, G. Chem. Commun.
1997, 1709
20
Biomimetic Steroid Hydroxylation

• Regioselective for C-6
• Stereoselective for the ? face.
• 10 equivalents of PhIO oxidant and pyridine
• Reaction in water

Breslow, R. Zhang, X. Huang, Y. J. Am. Chem.
Soc. 1997, 119, 4535-4536. Breslow, R. Huang,
Y. Zhang, X. Yang, J. Proc. Natl. Acad. Sci.
USA. 1997, 94, 11156-58.
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Biomimetic Steroid Hydroxylation

• t-Butyl-Phenyl groups form CD complex
• Sulfonate groups improve water solubility.

3-5 catalytic turnovers
Breslow, R. Zhang, X. Huang, Y. J. Am. Chem.
Soc. 1997, 119, 4535-4536. Breslow, R. Huang,
Y. Zhang, X. Yang, J. Proc. Natl. Acad. Sci.
USA. 1997, 94, 11156-58.
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Biomimetic Steroid Hydroxylation
Yang, J. Breslow, R. Angew. Chem. Int. Ed.
2000, 39, 15, 2692-2694
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Biomimetic Steroid Hydroxylation

• Oxidative stability of catalyst greatly improved
  by fluorination -
• 95 yield
• 95 turnovers
• at 1 catalyst.

Breslow, R. Gabriele, B. Yang, J. Tet. Lett.
1998, 39, 2887-2890
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Biomimetic Steroid Hydroxylation

• meta-CD placement and altered tether points give
  C-9 OH
• para-CD placement gives a mixture of C-9 and C-15
  OH

Breslow, R. Yan, J. Belvedere, S. Tet. Lett.
2002, 43, 363-365
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Antioxidant Enzyme Mimic

• Glutathione Peroxidase (GPX) mimic - antioxidant
  activity
• Catalyzes reduction of hydroperoxides by
  glutathione using natural coenzymes and cofactors
• Prevents oxidative damage to biological systems

2-TeCD
Luo, G. et al. ChemBioChem 2002, 3, 356-363
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Antioxidant Enzyme Mimic

• Superior to Ebselen, a common GPX mimic
• Slows damage to mitochondria by hydroperoxides
• May be useful in bioelectric devices

GPX mimic Hydroperoxide Activity (U ?m-1)
Ebselen H2O2 0.99
PhSeSePh H2O2 1.95
2-SeCD H2O2 7.4
2-TeCD H2O2 46.7
2-TeCD tBuOOH 32.8
2-TeCD Cumene hydroperoxide 87.3
GSH Glutathione, NADPH ?-nicotinamide
adenine dinucleotide phosphate
Luo, G. et al. ChemBioChem 2002, 3, 356-363
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Outline

• Background
• Industrial Applications
• Chemical Applications
• Reactions and Catalysis
• Scavengers
• Receptors
• Sensors
• Host Design
• Conclusions

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Anesthetic Scavenger

• Rocurionium bromide is a common neuromuscular
  blocking drug.
• Conventional reversal medications have many
  side-effects.
• Org 25969 is currently in Phase II Human Clinical
  Trials.

Rocurionium Bromide
Org 25969
Zhang, M-Q. et al. Angew. Chem. Int. Ed. 2002,
41, 2, 265-270
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Anesthetic Scavenger
Host EC50 ?M Max Reversal
?-CD gt360 9.7
?-CD gt360 29
?-CD 34.6 94.1
Org 25969 1.2 95.1
Data from mouse hemidiaphram studies

• Extending cavity depth from 7.9 to 11 Å greatly
  improves complexation.
• Patients show significant recovery in minutes.

Zhang, M-Q. et al. Angew. Chem. Int. Ed. 2002,
41, 2, 265-270
30
Outline

• Background
• Industrial Applications
• Chemical Applications
• Reactions and Catalysis
• Scavengers
• Receptors
• Sensors
• Host Design
• Conclusions

31
Choline Receptor

• Trimethylammonium moiety challenges receptor
  design
• Quaternary ammonium does not allow hydrogen
  bonding
• Roughly spherical shape limits binding site
  design

Ballester, P. Shivanyuk, A. Far, A. R. J.
Rebek Jr. J. Am. Chem. Soc. 2002, 124,
14014-14016
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Choline Receptor

• Complex stablized by deep aromatic cavity
• Larger NR4 ions excluded from binding
• Vase shaped complex stitched together by DMSO
• Weak H-bond from alcohol to amine (0.6 kcal /mol)

Ka 1.2 x 104
Ballester, P. Shivanyuk, A. Far, A. R. J.
Rebek Jr. J. Am. Chem. Soc. 2002, 124,
14014-14016
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Receptor Synthesis
Ballester, P. Shivanyuk, A. Far, A. R. J.
Rebek Jr. J. Am. Chem. Soc. 2002, 124,
14014-14016
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Outline

• Background
• Industrial Applications
• Chemical Applications
• Reactions and Catalysis
• Scavengers
• Receptors
• Sensors
• Host Design
• Conclusions

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Sensor Requirements

• Selective binding
• Detection at low levels
• Fast response for dynamic sensing
• Tolerance for changing conditions
• Clear, intense signaling

Bell, T.W. Hext, N. M. Chem. Soc. Rev. 2004, 33,
589. Pinalli, R, Suman, M. Dalcanale, E. Eur.
J. Org. Chem. 2004, 451.
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Fluorescent Hg2 Sensor

• Calix4-aza-crown binding site
• Maintains activity in aqueous solution
• Dansyl fluorescence quenched by binding Hg2

Chen, Q-Y Chen, C-F, Tet. Lett. 2005, 46, 165-168
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Fluorescent Hg2 Sensor

• Selective binding over Li, Na, Mg2, K, Ca2,
  Mn2, Co2, Ni2, Ag, Ba2
• Little selectivity over Cu2, Zn2, Cd2, Pb2
• Ka 1.31 x 105 M-1
• Detection Limit 4.1x10-6 mol /L

Chen, Q-Y Chen, C-F, Tet. Lett. 2005, 46, 165-168
38
Radical Cation Sensor for Nitric Oxide
Green

• Radical cation stabilized by electron-rich
  substituents
• Stable at room temperature

Rathore, R. Abdelwahed, S.H. Guzei, I. A. J. Am.
Chem. Soc. 2004, 126, 13582-13583
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Synthesis of NO Binding Calixarene
Rathore, R. Abdelwahed, S.H. Guzei, I. A. J.
Am. Chem. Soc. 2004, 126, 13582-13583
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Radical Cation Sensor for Nitric Oxide

• Electron deficient cavity binds electron-rich
  nitric oxide
• Dramatic color change on binding
• Ka gt 108 M-1

Blue
Rathore, R. Abdelwahed, S.H. Guzei, I. A. J. Am.
Chem. Soc. 2004, 126, 13582-13583
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Outline

• Background
• Industrial Applications
• Chemical Applications
• Reactions and Catalysis
• Scavengers
• Receptors
• Sensors
• Host Design
• Conclusions

42
New Host Design

• Apple peel helix completely encloses water
  molecule

Garric, J. Leger, J-M. Huc, I. Angew. Chem.
Int. Ed. 2005, 44, 1954-1958
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New Host Design

• Soft ball like bimolecular assembly
• Chiral guest templates chirality of assembled
  host
• 8 hydrogen bonds stitch complex together

Rivera, J. M. Craig, S. L. Martin, T. Rebek,
J. Jr. Angew. Chem. Int. Ed. 2000, 39(12)
2130-2132
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New Host Design
Guest exchange is faster than decomposition of
host molecule.
Rivera, J. M. Craig, S. L. Martin, T. Rebek,
J. Jr. Angew. Chem. Int. Ed. 2000, 39, 12
2130-2132
45
Outline

• Background
• Industrial Applications
• Chemical Applications
• Reactions and Catalysis
• Scavengers
• Receptors
• Sensors
• Host Design
• Conclusions

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Summary

• Host-guest chemistry is applied in
• Catalysis
• Scavenging
• Sensors
• Pharmaceuticals - both drugs and delivery
• Mimicking and understanding biological systems
• New host design opens more fields for research

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Conclusions
The field of host-guest chemistry has matured
sufficiently to have utility in many important
and interesting applications and remains a
fruitful area for research.
48
Acknowledgements
Professor Helen E. Blackwell

• Brian Pujanauski
• Adam Siegel
• Emily Guerard
• Jamie Ellis
• Chris Paradise
• Katie Alfare
• Kara Waugh

• Blackwell Group Members
• Matt Bowman
• Qi Lin
• Ben Gorske
• David Miller
• Jenny ONeill
• Sarah Jewell
• Rachel Wezeman
• Grant Geske