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

3. Host-Guest Chemistry Host-Guest Chemistry involves: According to Cram:
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,
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,
Whitlock, B.J.; Whitlock, H. W. J. Am. Chem. Soc. 1994, 116, 2301.
Nassimbeni, L. R. Acc. Chem. Res. 2003, 36,

6. 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.

7. 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
Composed of Glucose units alpha 1-4
Numbers for a, b, g
Puckered if bigger
Primary edge, secondary edge
Chiral
-Cyclodextrin (-CD)
Szejtli, J. Chem. Rev. 1998, 98,
D’Souza, V. T.; Lipkowitz, K. B. Chem. Rev. 1998, 98, 5, 1741.

8. 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
Think about cavity size correlation.
Cyclodextrin Glucosyl Transferase
Szejtli, J. Chem. Rev. 1998, 98,
Gallery1.htm

9. Areas of CD Research
Szejtli, J. Chem. Rev. 1998, 98,

10. 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
23 worldwisd
Davis, M. E.; Brewster, M.E.; Nature Rev. 2004, 3,

11. 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,

12. 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/History.asp

13. 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.; O’Malley, S.; Nolan, K.; Diamond, D. ARKIVOC, 2003, vii, 23.

14. Outline Background Industrial Applications Chemical Applications
Reactions and Catalysis
Scavengers
Receptors
Sensors
Host Design
Conclusions

15. Directed Aromatic Chlorination
>95% 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,

16. 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,

17. 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
More compact transition state
Schneider, H-J.; Sangwan, N. K. Angew. Chem. Int. Ed. Engl. 1987, 26(9),

18. 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

19. Photochemical ControlCD
Reaction Time (h)
% E Stilbene
% Z Stilbene
% Trans -Dimer
% Cis-Dimer
% Phenanthrene
None 24 10 62 7 2 19
-CD 20 60
-CD 16 83 1
-CD 72 79
1:1 complexation in  or -CD favors isomerization.
Complexation in -CD nearly prevents phenanthrene formation.
2:1 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 PhI=O oxidant and pyridine
Reaction in water
Breslow, R.; Zhang, X.; Huang, Y. J. Am. Chem. Soc. 1997, 119,
Breslow, R.; Huang, Y.; Zhang, X.; Yang, J. Proc. Natl. Acad. Sci. USA. 1997, 94,

21. “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,
Breslow, R.; Huang, Y.; Zhang, X.; Yang, J. Proc. Natl. Acad. Sci. USA. 1997, 94,

22. “Biomimetic” Steroid Hydroxylation
Yang, J.; Breslow, R. Angew. Chem. Int. Ed. 2000, 39, 15,

23. “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,

24. “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,

25. 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,

26. 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
1.95
2-SeCD
7.4
2-TeCD
46.7
tBuOOH
32.8
Cumene hydroperoxide
87.3
NADPH is beta nicotinamide adenine dinucleotide phosphate
GSH is Glutathione
GPX
Dicyclodextrinyl ditelluride
GSH = Glutathione,
NADPH = -nicotinamide adenine dinucleotide phosphate
Luo, G. et al. ChemBioChem 2002, 3,

27. Outline Background Industrial Applications Chemical Applications
Reactions and Catalysis
Scavengers
Receptors
Sensors
Host Design
Conclusions

28. Anesthetic Scavenger
Rocurionium bromide is a common neuromuscular blocking drug.
Conventional reversal medications have many side-effects.
Org is currently in Phase II Human Clinical Trials.
Rocurionium Bromide
Decreased heart rate, increased salivation, Lowered Blood pressure, nausea, vomiting, abdominal cramping, bronchiochonstriction
Side effect combating drugs cause rapid heart rate, dry mouth, blurred vision
Org 25969
Zhang, M-Q. et al. Angew. Chem. Int. Ed. 2002, 41, 2,

29. Anesthetic Scavenger
Host
EC50 [M]
Max % Reversal
-CD
>360
9.7
-CD 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.
Dosage for 95% reversal is the same as the Rocuronium Bromide dosage
Zhang, M-Q. et al. Angew. Chem. Int. Ed. 2002, 41, 2,

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,

32. 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,

33. Receptor Synthesis
Ballester, P.; Shivanyuk, A.; Far, A. R.; J. Rebek Jr. J. Am. Chem. Soc. 2002, 124,

34. Outline Background Industrial Applications Chemical Applications
Reactions and Catalysis
Scavengers
Receptors
Sensors
Host Design
Conclusions

35. 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.

36. Fluorescent Hg2+ Sensor
Calix[4]-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,

37. 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
Quenching proposed to be by electron transfer from excited dansyl to mercuric ion.
Chen, Q-Y; Chen, C-F, Tet. Lett. 2005, 46,

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,

39. Synthesis of NO Binding Calixarene
Inverse Freidel-Crafts, SN2, Electrophilic Bromination, Kumada Coupling
Rathore, R.; Abdelwahed, S.H.; Guzei, I. A. J. Am. Chem. Soc. 2004, 126,

40. Radical Cation Sensor for Nitric Oxide
Electron deficient cavity binds electron-rich nitric oxide
Dramatic color change on binding
Ka > 108 M-1
Blue
Rathore, R. Abdelwahed, S.H.; Guzei, I. A. J. Am. Chem. Soc. 2004, 126,

41. 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,

43. 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)

44. 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,

45. Outline Background Industrial Applications Chemical Applications
Reactions and Catalysis
Scavengers
Receptors
Sensors
Host Design
Conclusions

46. 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

47. 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 Blackwell Group Members
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 O’Neill
Sarah Jewell
Rachel Wezeman
Grant Geske