J. Am. Chem. Soc. 1996, 118, 3027-3028
3027
Host-Catalyzed Isoxazole Ring Opening: A
Rationally Designed Artificial Enzyme
Alan J. Kennan and H. W. Whitlock*
Samuel M. McElVain Laboratories of Organic Chemistry
Department of Chemistry, UniVersity of Wisconsin
Madison, Wisconsin 53706
ReceiVed NoVember 20, 1995
Figure 1. The “enzymes”.
The recent surge of interest in the field of host-guest
chemistry1 has resulted in several applications of host molecules
as organic catalysts.2 In this communication we report the arti-
ficial enzyme behavior of xylene-bridged hosts 1 and 2 (Figure
1). Both compounds catalyze the base-promoted decomposition
of 5-nitrobenzisoxazole 3 to cyanophenol 4 with unusually large
rate accelerations (Figure 2), via a Michaelis-like complex. The
fragmentation was originally investigated by Kemp, who
established it as an E2 elimination which could be performed
by simple amines.3 More recently, Hilvert and co-workers have
reported catalytic antibodies which perform the reaction with
impressive rate enhancements and turnover numbers.4
Hosts 1 and 2 bind phenols tightly in nonpolar organic
solvents.5 When either host is mixed with isoxazole 36 in
CDCl3, rapid conversion to 4 takes place, resulting in the
Figure 2. The system: (a) general reaction and (b) mechanism of
intracavity process.
1
formation of the host-product complex, as observed by H-
NMR.7 A kinetic isotope effect of 5.2 (kH/kD) is observed in
the reaction with host 1,8 and cyanophenol 4 is the only
observable product.
The kinetics of the system are described by eq 1; there is a
fast pre-equilibrium, followed by a slow intracavity reaction,
product release, and subsequent sequestration of the host as the
product complex. The kinetic parameters (association constants
for substrate and product, intracavity rate constant) were
obtained by nonlinear least-squares fitting of time-concentration
Figure 3. Plots of [1‚4] versus time for the reaction of proximal xylene
host 1 (7 mM) and isoxazole 3 in CDCl3 at room temperature. The
initial isoxazole concentrations were: (b) 45, (2) 16, and (9) 10 mM.
Solid lines represent derived fits as described in text.
(1) (a) Bell, D. A.; Anslyn, E. V. Tetrahedron 1995, 26, 7161-7172.
(b) Breslow, R.; Duggan, P. J.; Wiedenfeld, D.; Waddell, S. T. Tetrahedron
Lett. 1995, 36, 2707-2710. (c) Vondembusschehunnefeld, C.; Buhring, D.;
Knobler, C. B.; Cram, D. J. J. Chem. Soc., Chem. Commun. 1995, 1085-
1087. (d) Peterson, B. R.; Mordasinidenti, T.; Diederich, F. Chem. Biol.
1995, 2, 139-146. (e) Goodman, M. S.; Jubian, V.; Hamilton, A. D.
Tetrahedron Lett. 1995, 36, 2551-2554. (f) Wurthner, F.; Rebek, J. Angew.
Chem., Int. Ed. Engl. 1995, 34, 446-448. (g) Torneiro, M.; Still, W. C. J.
Am. Chem. Soc. 1995, 117, 5887-5888. (h) Webb, T. H.; Wilcox, C. S.
Chem. Soc. ReV. 1993, 22, 383-395. (i) Zimmerman, S. C.; Murray, T. J.
Tetrahedron Lett. 1994, 35, 4077-4080. See also: Tetrahedron 1995, 26
(2) (whole issue).
(2) (a) Desper, J. M.; Breslow, R. J. Am. Chem. Soc. 1994, 116, 12081-
12082. (b) Kirby, A. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 551-553.
(c) Breslow, R. Acc. Chem. Res. 1995, 28, 146-153. (d) Jubian, V.;
Veronese, A.; Dixon, R. P.; Hamilton, A. D. Angew. Chem., Int. Ed. Engl.
1995, 34, 1237-1239. (e) Pieters, R. J.; Huc, I.; Rebek, J. Angew. Chem.,
Int. Ed. Engl. 1995, 34, A183-A192. (f) Tsao, B. L.; Pieters, R. J.; Rebek,
J. J. Am. Chem. Soc. 1995, 117, 2210-2213. (g) Walter, C. J.; Sanders, J.
K. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 217-219.
(3) (a) Casey, M. L.; Kemp, D. S.; Paul, K. G.; Cox, D. D. J. Org. Chem.
1973, 38, 2294-2301. (b) Kemp, D. S.; Casey, M. L. J. Am. Chem. Soc.
1973, 95, 6670-6680. (c) Kemp, D. S.; Paul, K. G. J. Am. Chem. Soc.
1975, 97, 7305-7312. (d) Kemp, D. S.; Cox, D. D.; Paul, K. G. J. Am.
Chem. Soc. 1975, 97, 7312-7318.
(4) (a) Thorn, S. N.; Daniels, R. G.; Auditor, M.-T. M.; Hilvert, D. Nature
1995, 373, 228-230. (b) Hilvert, D. Curr. Opin. Struct. Biol. 1994, 4, 612-
617.
data to this model (Figure 3), using the DNRP-RKF program
developed by Duggleby.9 The parameters for the reaction
with proximal xylene host 1 are Ka ) 96 ( 12 M-1, k ) (6.3
( 0.3) × 10-4 s-1, and Kp ) 6 × 1011 M-1. The large value
for Kp is consistent with our previous results.10 The derived
values for both association constants were corroborated by
independent titrations.11,12 The parameters for the distal xylene
host 2 are Ka ) 13 ( 1 M-1, k ) (7.6 ( 0.5) × 10-4 s-1, and
(9) Duggleby, R. G. Biochim. Biophys. Acta 1994, 1205, 268-274. We
thank professor Duggleby for supplying a copy of the program.
(10) The error in Kp is large (i.e., >100 × Kp), and the value given is
only meant to demonstrate that Kp is large (see ref 12). Performing the
kinetic analysis with Kp fixed at values over several orders of magnitude
above a certain threshold value (ca. 10 000) has very little effect on the
calculated values for the other parameters. This is not surprising since it is
difficult to distinguish values this large from infinity using NMR techniques.
This is also why we are hesitant to ascribe detailed physical significance to
the apparently large difference in Kp for 1 and 2, although previous work5,14
has demonstrated the general superiority of the proximal-xylene-bridged
hosts. For a further discussion of large Ka values, see ref 14c and: Wilcox,
C. S. In Frontiers in Supramolecular Organic Chemistry and Photochem-
istry; Schneider, H. J., Du¨rr, H., Eds.; VCH Publishers: New York, 1991;
pp 123-143.
(5) (a) Whitlock, B. J.; Whitlock, H. W. J. Am. Chem. Soc. 1990, 112,
3910-3915. (b) Cochran, J. E.; Parrott, T. J.; Whitlock, B. J.; Whitlock,
H. W. J. Am. Chem. Soc. 1992, 114, 2269-2270.
(6) Prepared in 89% yield from salicylaldehyde using the procedure of
(11) The value for Ka was obtained by rapid, dilute titration to avoid
formation of phenol 4.
Kemp and Casey.3a
(7) All studies described in this work were performed in CDCl3 at 25
°C. The spectrum was identical to that obtained by complexation of a known
sample of 4.3a
(12) Standard methods which follow weighted average shifts could not
be used for Kp due to slow exchange at 25 °C. An estimate of Kp g 10 000
was obtained by direct integration of both free and bound species at low
temperature. Since there is hardly any free guest, the error is large.
(8) The 7-D analog of 3 was prepared according to Kemp and Casey.3a
0002-7863/96/1518-3027$12.00/0 © 1996 American Chemical Society