C.L.D. Gibb, B.C. Gibb / Tetrahedron 65 (2009) 7240–7248
7247
formation, but only when present in up to stoichiometric amounts.
Beyond a 2:1 host to guest ratio the ethylene glycol tail of this guest
is sufficiently water soluble that it is thermodynamically more fa-
vorable to form 1:1 complex at the expense of capsule. This phe-
nomenon was also observed with di(ethylene glycol) hexyl ether 5.
However, with this guest the 1:1 complex is less stable relative to
the 2:1 capsular complex and more of an excess of 5 is required to
break its capsular complex than was the case with guest 4. A sig-
nificant break in capsule forming propensity is seen with highly
oxygenated tri(ethylene glycol) propyl ether) 6. This guest, with
nearly a 40% polar surface area, does form a capsular complex, but
its kinetic stability is relatively low and exchange between 1:1
complex and 2:1 capsular complex is close to the NMR timescale.
Finally, there was no evidence that the most polar guest,
tetra(ethylene glycol) 7, formed capsular complex. Nevertheless,
this weakest of guests still forms a 1:1 complex with host 1, and in
doing so liberates almost 5 kcal molꢀ1 of free energy.
Although not perfect isosteres, these guests provide a valuable
picture of how changes in polarity/water solubility control capsule
formation. In related work, we are also looking at (isosteric) con-
stitutional isomers that differ in where a functional group is located
in the guest. These will provide further information pertaining to
the assembly and complexation properties of 1, and will be repor-
ted in due course.
and the product extracted twice with CHCl3 from water. The
product (an oil) was isolated by column chromatography (CHCl3
mobile phase) in 16% yield. 1H NMR (500 MHz, CDCl3)
d 3.78–3.68
(m, 2H), 3.54 (m, 6.2, 2H), 3.47 (t, J¼6.7 Hz, 2H), 1.97 (t, J¼6.1 Hz,
1H), 1.27 (m, 14H), 0.88 (t, J¼6.9 Hz, 3H); MS (ES): calcd [MþNaþ]
211; found [MþNaþ] 211.3.
4.4. Synthesis of 2-[2-(2 propoxyethoxy)ethoxy] ethanol
(tri(ethylene glycol) propyl ether) 632
To a 50 mL round bottom flask was added, 5 mL of THF, 0.5 g
(3.3 mmol) of triethylene glycol, and 3.3 mmol of 1-bromopropane.
To this solution was slowly added a pentane washed suspension of
3.6 mmol NaH in 5 mL THF. The reaction was stirred at 60 ꢂC for 3
days. The reaction was allowed to cool down to room temperature
before quenching with methanol. The solvent was removed under
reduced pressure and the product extracted twice with CHCl3 from
water. The product (an oil) was isolated by column chromatography
(CHCl3, then 5% acetone 95% CHCl3 mobile phase) with a yield of
37%. 1H NMR (500 MHz, CDCl3)
d 3.82–3.53 (m, 12H), 3.42 (t,
J¼6.8 Hz, 2H), 2.60 (s, 1H), 1.68–1.52 (m, 2H), 0.91 (t, J¼7.4 Hz, 3H).
MS (ES): calcd [MþNaþ] 215; found [MþNaþ] 215.2.
Acknowledgements
4. Experimental
4.1. Materials
CLDG and BCG gratefully acknowledge the National Institutes of
Health for financial support (GM074031).
References and notes
Tridecane 2, dodecanol 3, 1-bromononane, ethylene glycol, tri-
ethylene glycol, tetraethylene glycol 7, sodium hydride, and sodium
tetraborate were purchased from Aldrich. Diethylene glycol mono-
hexyl ether 5 and 1-bromopropane were purchased from Fluka. All
chemicals were used without further purification. The synthesis of
host 1 has been previously reported.19 The guests 2-nonyloxy eth-
anol (ethylene glycol monononyl ether) 4 and 2-[2-(2 propoxy-
ethoxy)ethoxy] ethanol (tri(ethylene glycol) propyl ether) 6 were
prepared by mono-alkylation of tri(ethylene glycol) and di(ethylene
glycol), respectively. All solvents were used directly from the bottle
without additional purification. Deuterated solvents were pur-
chased from Aldrich. NMR (1H) spectra were recorded on Varian
Inova 500 MHz spectrometer at room temperature unless otherwise
stated. Spectra processing were carried out using Mnova software
(Mestrelab Research S.L). Chemical shifts are reported in parts per
million (ppm) relative to H2O as internal reference.
1. Kang, J.; Rebek, J., Jr. Nature 1996, 382, 239–241.
2. Parac, T. N.; Scherer, M.; Raymond, K. N. Angew. Chem., Int. Ed. 2000, 39, 1239–
1242.
3. Fochi, F.; Jacopozzi, P.; Wegelius, E.; Rissanen, K.; Cozzini, P.; Marastoni, E.;
Fisicaro, E.; Manini, P.; Fokkens, R.; Dalcanale, E. J. Am. Chem. Soc. 2001, 123,
7539–7552.
4. Hof, F.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4775–4777.
5. Rebek, J. J. Angew. Chem., Int. Ed. 2005, 44, 2068–2078.
6. MacGillivray, L. R.; Atwood, J. L. Nature 1997, 389, 469–472.
7. Atwood, J. L.; Barbour, L. J.; Jerga, A. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4837–
4841.
8. McKinlay, R. M.; Thallapally, P. K.; Atwood, J. L. Chem. Commun. 2006, 2956–
2958.
9. Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Angew. Chem., Int. Ed. 2007, 46,
8587–8589.
10. Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Science 2007, 316, 85–88.
11. Fujita, M.; Umemoto, K.; Yoshizawa, M.; Fujita, N.; Kusukawa, T.; Biradha, K.
Chem. Commun. 2001, 509–518.
12. Fujita, M.; Tominaga, M.; Hori, A.; Therrien, B. Acc. Chem. Res. 2005, 38,
369–378.
13. Harano, K.; Hiraoka, S.; Shionoya, M. J. Am. Chem. Soc. 2007, 129, 5300–5301.
14. Caulder, D. L.; Raymond, K. N. J. Chem. Soc., Dalton Trans. 1999, 1185–1200.
15. Davis, A. V.; Yeh, R. M.; Raymond, K. N. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
4793–4796.
16. Gibb, B. C. Nano-Capsules Assembled by the Hydrophobic Effect. In Organic
Nano-Structures; Atwood, J. L., Steed, J. W., Eds.; John Wiley and Sons: Wein-
heim, 2007.
17. Liu, S.; Gibb, B. C. Chem. Commun. 2008, 3709–3716.
18. For a dendronized water soluble cavitand see: Giles, M. D.; Liu, S.; Emanuel, R.
L.; Gibb, B. C.; Grayson, S. M. J. Am. Chem. Soc. 2008, 130, 14430–14431.
19. Gibb, C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2004, 126, 11408–11409.
20. Gibb, C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2006, 128, 16498–16499.
21. Gibb, C. L. D.; Gibb, B. C. Chem. Commun. 2007, 1635–1637.
22. Gibb, C. L. D.; Sundaresan, A. K.; Ramamurthy, V.; Gibb, B. C. J. Am. Chem. Soc.
2008, 130, 4069–4080.
4.2. NMR studies
Titration studies were carried on a 0.6 mL sample of a 1 mM
solution of host 1 in D2O containing 10 mM sodium tetraborate. The
guests were dissolved in DMSO-d6 to give a 60 mM solution. Ali-
quots of 2.5 mL of each guest solution were added to host solution
and the NMR recorded. Diffusion experiments were carried on
according to a previously published procedure.20 Binding constant
determinations was performed by fitting the binding isotherm with
Origin.30 The reported value is the average of two values.
4.3. Synthesis of 2-nonyloxy ethanol (ethylene glycol
monononyl ether) 431
23. Kaanumalle, L. S.; Gibb, C. L. D.; Gibb, B. C.; Ramamurthy, V. J. Am. Chem. Soc.
2004, 126, 14366–14367.
24. Kaanumalle, L. S.; Gibb, C. L. D.; Gibb, B. C.; Ramamurthy, V. J. Am. Chem. Soc.
2005, 127, 3674–3675.
25. Kaanumalle, L. S.; Gibb, C. L. D.; Gibb, B. C.; Ramamurthy, V. Org. Biomol. Chem.
2007, 5, 236–238.
26. Natarajan, A.; Kaanumalle, L. S.; Jockusch, S.; Gibb, C. L. D.; Gibb, B. C.; Turro, N.
J.; Ramamurthy, V. J. Am. Chem. Soc. 2007, 129, 4132–4133.
27. Vriezema, D. M.; Aragone`s, M. C.; Elemans, J. A. A. W.; Cornelissen, J. J. L. M.;
Rowan, A. E.; Nolte, R. J. M. Chem. Rev. 2005, 105, 1445–1489.
28. Koblenz, T. S.; Wassenaar, J.; Reek, J. N. H. Chem. Soc. Rev. 2008, 37, 247–262.
To a 50 mL round bottom flask was added, 5 mL of THF, 0.206 g
(3.3 mmol) of ethylene glycol and 3.3 mmol of 1-bromononane. To
this solution was slowly added a pentane washed suspension of
3.6 mmol NaH in 5 mL THF. The reaction was stirred at 60 ꢂC for 3
days. The reaction was allowed to cool down to rt before quenching
with methanol. The solvent was removed under reduced pressure