Deep cavitands provide organized solvation of reactions

Article abstract of DOI:10.1021/ja052910s

Deep self-folding cavitands have been shown to stabilize the charged enolate intermediate of the α-deuteration of activated olefins by means of a network of organized solvation. Copyright

Full text of DOI:10.1021/ja052910s

Published on Web 08/06/2005
Deep Cavitands Provide Organized Solvation of Reactions
Richard J. Hooley and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
Received May 3, 2005; E-mail: jrebek@scripps.edu
Cavitands 1 are deep, vase-like structures capable of binding
suitably sized neutral and cationic guests.1 The aromatic walls at
the base of the cavity provide an extended π surface, while the
upper rim is an environment rich in H-bond donors and acceptors.
The latter features a ring of eight secondary amides organized in a
head-to-tail manner. These regions are fixed in space through
synthesis and presented to guests independent of the nature of the
external bulk solVent and alter their reactivities. Quinuclidine, for
example, shows much enhanced reactivity as a nucleophile when
the base is detained in a cavitand bearing an inwardly directed
methyl ester.2 The amides of the rim stabilize the developing charge
at the transition state near the reactive centers. Here, we report
effects of organized solvation and catalysis in the R-deuteration of
activated olefins.3,4
Methyl acrylate 2 was combined with stoichiometric amounts
Figure 1. Deep cavitands used.
of diazabicyclo[2.2.2]nonane (DABCO) 3 and cavitand 1c in
acetone-d6 at a concentration of 13.9 mM, and the reaction was
monitored by 1H NMR (600 MHz). Binding of DABCO is shown
1
by H peaks at 0.85 and -0.25 ppm. After 3 days reaction, all of
the methyl acrylate was converted to R-D-methyl acrylate 6. Kinetics
measurements gave an initial rate of reaction of 0.021 mM/min. In
the absence of cavitand, no deuteration was observed by NMR after
5 days at either 23 or 60 °C, nor was deuteration observed when
performed in the presence of 8 equiv of acetanilide, a mimic for
the generic H-bonding abilities of the cavitand. Assuming a
detection limit of 5% for the 1H NMR measurements, this translates
to a rate acceleration of at least 200-fold.
Figure 2. Proposed mechanism of deuteration.
Combination of methyl acrylate and DABCO in CD3OD (a much
stronger acid than acetone-d6) in the absence of cavitand does result
in R-deuteration, albeit slowly (the observed initial rate is 0.008
mM/min). The effect of the addition of cavitand (both stoichiometric
and catalytic amounts) is shown in Figure 3. Even in the presence
of only 2% cavitand 1b (1c is insoluble in CD3OD), a 40% increase
in initial rate is observed. Use of a stoichiometric amount of 1b
provides a 2-fold rate acceleration. Performing the reaction in a
more polar, protic medium reduces the effect of cavitand, but the
organized solvation in the system is still more effective at charge
stabilization than CD3OD solvent.
The scope of deuteration effects was tested, using quinuclidine
4 as catalyst due to its higher reactivity and binding properties.
The results are summarized in Table 1. The rate of deuteration is
generally correlated with the electron-withdrawing abilities of the
activating group; methyl vinyl ketone 7 and phenyl vinyl sulfone
8 both reacted very quickly, with quantitative deuteration in acetone-
d6 observed after only 30 and 120 min, respectively (entries 1 and
2). These more active olefins did show a very slow background
rate (<15% conversion after 8 days), shown as V0(uncat) in Table 1.
This allows a measurement of the relative acceleration V0/V0(uncat)
for the deuteration. The accelerations observed were 1400-fold for
methyl vinyl ketone 7 and 800-fold for phenyl vinyl sulfone 8,
even higher than that estimated previously. Both acrylonitrile 9 and
Figure 3. Rate dependence of formation of 6 on [1b] in CD3OD. Initial
[2] ) 13.9 mM, [3] ) 13.9 mM, (2) ) 13.9 mM 1b; (9) ) 0.3 mM 1b;
(b) ) 0 mM 1b.
methyl acrylate 2 were susceptible to deuteration; however, the
reaction was much slower (entries 3 and 4), and no background
reaction could be observed under the conditions. A similar
assumption for the sensitivity of 1H NMR as before can be used to
give a lower limit on the acceleration. Acrolein was also tested
and reacted quickly but gave a complex mixture of products.
Acrylamide and trans-methyl crotonate were unreactive to deu-
teration, which is consistent with literature observations of their
slow reaction rate in processes of this type.5 Diethylvinylphospho-
nate was unreactive to deuteration under these conditions.
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10.1021/ja052910s CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Scope of the Reactiona
Figure 5. Addition of sulfonyl imine 10.
the addition of (E)-N-benzylidene benzenesulfonamide 108 in the
presence of 1b and quinuclidine 4 using CD3OD as solvent. Methyl
vinyl ketone 7 was quantitatively deuterated (as expected) in less
than 5 min under the reaction conditions, and so the conversion of
R-D-methyl vinyl ketone 9 to adduct 11 was monitored by NMR
(Figure 5). In the absence of cavitand, 7 was completely converted
to 11 in 60 h. However, in the presence of 10% 1b, only 48%
conversion was observed after 89 h, corroborating the hypothesis
that the cavitand stabilizes the enolate intermediate and, in this case,
slows a reaction with a later rate-determining step.
a Substrate (13 mM) was combined with 1c (6.5 mM) and 4 (6.5 mM)
in acetone-d6 at 23 °C.
In summary, it is well-known that cavitands can form host-
guest complexes; however, the new and fixed environs can also
increase guest reactivity by providing a polar nanoenvironment
around the reactive centers that stabilize charged intermediates.
While hydrogen-bonding effects have long been recognized as vital
to the organization of large biomolecules and synthetic receptors,
the use of organized hydrogen-bonded networks for the acceleration
of chemical transformations is just now emerging. The mechanical
barriers of cavitands and capsules are not as passive as they might
at first glance seem.
Figure 4. Representation of bound enolate intermediate (some groups
removed for clarity) and molecular minimization of the same (plan view,
AMBER force field).
Acknowledgment. We are grateful to the Skaggs Institute and
the National Institute of Health (GM27932) for financial support.
R.J.H. is a Skaggs Postdoctoral fellow.
During reaction in both acetone-d6 and CD3OD, the NH’s of
cavitand are rapidly exchanged with deuterium. However, the
significantly different rates of deuterium exchange in acetone-d6
and CD3OD suggest that deuterium exchange occurs via direct
abstraction from solvent and not via exchange through the cavitand
walls. Even so, it is possible to effect deuteration of 7 directly from
the cavitand itself. Cavitand 1c can be easily converted to the
octadeuterio equivalent 1c-d8 by treatment with CD3OD/acetone-
d6. Combination of 1c-d8, 4, and 7 in toluene-d8 (an aprotic solvent
which is a poor cavitand guest) effects deuterium exchange at an
initial rate of 0.26 mM/min at [7] ) 13 mM, approximately half
the exchange rate in acetone.
Molecular modeling suggests reasons for the rate accelerations
observed. Molecular mechanics minimization (using the AMBER
force field) of the bound enolate formed after conjugate addition
of DABCO shows a reorganization of the amide groups on the rim.
They provide two hydrogen-bond donors to the oxyanion, as shown
in Figure 4. The amide groups on the rim need only to rotate in
order to accommodate this interaction and allow the flexible
cavitand walls to fold inward. Hence, the cavitand provides active
stabilization for the addition intermediate. The rate-determining step
for this process is most likely the addition of encapsulated NR3 to
the activated olefin (especially in acidic CD3OD). The stabilization
of intermediate 5 accelerates this process.
Supporting Information Available: Experimental details and
tabulated kinetics data. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) (a) Renslo, A. R.; Tucci, F. C.; Rudkevich, D. M.; Rebek, J. J. Am. Chem.
Soc. 2000, 122, 4573-4582. (b) Rudkevich, D. M.; Hilmersson, G.; Rebek,
J. J. Am. Chem. Soc. 1998, 120, 12216-12225. (c) Rudkevich, D. M.;
Rebek, J. Eur. J. Org. Chem. 1999, 1991-2005.
(2) Purse, B. W.; Ballester, P.; Rebek, J. J. Am. Chem. Soc. 2003, 125, 14682-
14683.
(3) For reviews on H-bonding in catalysis, see: (a) Pihko, P. M. Angew. Chem,
Int. Ed. 2004, 43, 2062-2064. (b) Ooi, T.; Maruoka, K. in Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, Germany,
2000; Chapter 1. (c) Saito, S.; Yamamoto, H. in Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, Germany, 2000;
Chapter 2.
(4) (a) Lee, J. J.; Stanger, K. J.; Noll, B. C.; Gonzalez, C.; Marquez, M.;
Smith, B. D. J. Am. Chem. Soc. 2005, 127, 4184-4185. (b) Unni, A. K.;
Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005,
127, 1336-1337. (c) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002,
124, 9662-9663. (d) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V.
H. Nature 2003, 424, 146-146.
(5) Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 27, 5007-5010.
(6) (a) Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 3, 285-288. (b)
Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew. Chem, Int.
Ed. 2005, 44, 1706-1708. (c) Price, K. E.; Broadwater, S. J.; Jung, H.
M.; McQuade, D. T. Org. Lett. 2005, 7, 147-150. (d) Price, K. E.;
Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org. Chem. 2005,
70, 3980-3987.
Consistent with these calculations, addition of other electrophiles
(where the rate-determining step will be later than the addition of
DABCO to olefin) to the acceptors proved difficult.6 No addition
of a variety of aldehydes to 2 or 7 was observed in the presence of
1.7 However, use of 7 (the most reactive olefin tested) did allow
(7) Aldehydes tested include propionaldehyde, benzaldehyde, p-nitrobenzal-
dehyde, and benzyloxyacetaldehyde, among others.
(8) Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org.
Lett. 2003, 5, 3103-3105.
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