Vesicles accelerate proton transfer from carbon up to 850-fold

Article abstract of DOI:10.1021/ol991215k

(equation presented) We have analyzed the different catalytic effects of surfactant aggregates upon the rate-determining hydroxide ion induced deprotonation reaction of 1. Vesicles are more effective catalysts than micelles, most likely providing a more a

Full text of DOI:10.1021/ol991215k

ORGANIC
LETTERS
2
000
Vol. 2, No. 2
27-130
Vesicles Accelerate Proton Transfer
from Carbon up to 850-fold
1
1a
1b
1b
Jorge P e´ rez-Juste, Florian Hollfelder, Anthony J. Kirby, and
Jan B. F. N. Engberts*
Department of Organic and Molecular Inorganic Chemistry, UniVersity of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
j.b.f.n.engberts@chem.rug.nl
Received November 3, 1999
ABSTRACT
We have analyzed the different catalytic effects of surfactant aggregates upon the rate-determining hydroxide ion induced deprotonation
reaction of 1. Vesicles are more effective catalysts than micelles, most likely providing a more apolar microenvironment at the substrate
binding sites. We suggest that this leads to a catalytic reaction involving less strongly hydrated hydroxide ions. In the case of DODAB and
DODAC vesicles, binding of cholesterol to the bilayer further increases the catalytic efficiency.
Ever since the thorough mechanistic characterization of the
elimination reaction 1 f 2 by Kemp, this model reaction
for this reaction. In addition, the results could help in
understanding (artificial) enzyme efficiency in terms of
desolvation, entropy factors, etc.
2
for the important proton transfer from carbon has been a
prime target for enzyme mimics. Guided by Kemp’s impera-
tives on how to bring about catalysis, a number of catalytic
Since the Kemp elimination catalyzed by anionic bases is
especially solvent sensitive, we looked at aggregate catalysis
at a high pH value (11.35, [NaOH] ) 2.25 mM) where
turnover is expected to be dominated by the hydroxide-
catalyzed reaction. The reaction rate for the elimination is
considerably increased (up to 400 times) by the presence of
cationic micelles formed from C12PyrI, DTAB, CTAB,
3
systems have been developed. Most notable is a large
solvent effect, in particular for anionic bases, where the rate
differences between aprotic and protic solvents amount to
8
up to 10 . Our objective is to find out whether it is possible
to employ surfactant aggregates as simple enzyme mimics
4
CTACl, and OTACl with regard to the reaction in water.
(1) (a) Permanent addresses: Departamento Qu ´ı mica F ´ı sica y Qu ´ı mica
5
The typical biphasic pattern is observed (Figure 1). In a
Org a´ nica, Universidad de Vigo, Spain. (b) University Chemical Laboratory,
Lensfield Road, Cambridge CB2 1EW, England.
simple model the concentration of reactive hydroxide ions
in the micellar Stern layer increases up to a maximal value.
At still higher surfactant concentrations unreactive counter-
ions lead to a rate decrease as they replace hydroxide ions,
thereby reducing the available species of increased reactivity.
This experimental behavior can be explained quantitatively
on the basis of Romsted’s pseudophase model.6
(
(
2) Kemp, D. S.; Casey, M. L. J. Am. Chem. Soc. 1973, 95, 6670.
3) (a) Thorn, S. N.; Daniels, R. G.; Auditor, M.-T. M.; Hilvert, D. Nature
1
995, 373, 228. (b) Kikuchi, K.; Thorn, S. N.; Hilvert, D. J. Am. Chem.
Soc. 1996, 118, 8184. (c) Kennan, A. J.; Whitlock, H. W. J. Am. Chem.
Soc. 1996, 118, 3027. (d) Na, J.; Houk, K. N.; Hilvert, D. J. Am. Chem.
Soc. 1996, 118, 6462. (e) Hollfelder, F.; Kirby, A. J.; Tawfik, D. S. Nature
1
996, 383, 60. (f) Hannak, R. B.; Rojas, C. M. Tetrahedron Lett. 1998, 39,
3
465. (g) Liu, X. C.; Mosbach, K. Macromol. Rap. Comm. 1998, 19, 671.
(h) Sergeeva, M. V.; Yomtova, V.; Parkinson, A.; Overgaauw, M.; Pomp,
R.; Schots, A.; Kirby, A. J.; Isr. J. Chem. 1996, 36, 177. (i) Genre-
Grandpierre, A.; Loirat, M.-J.; Blanchard, D.; Hodgson, D. R. W.; Hollfelder,
F.; Kirby, A. J.; Tellier, C. Bioorg. Med. Chem. Lett. 1997, 7, 2497.
(5) Garc ´ı a-R ´ı o, L.; Herv e´ s, P.; Leis, Mejuto, J. C.; P e´ rez-Juste, J. J. Phys.
Org. Chem. 1998, 11, 584.
(6) (a) Chaimovich, H.; Bonilha, J. B. S.; Zanette, D.; Cuccovia, I. M.
In Surfactants in Solution; Mittal, K. L., Lindman, B., Eds.; Plenum Press:
New York, 1984; Vol. 2. (b) Romsted, L. S. Surfactants in Solutions; Plenum
Press: New York, 1984. (c) Bunton, C. A.; Savelli, G. AdV. Phys. Org.
Chem. 1986, 22, 213.
+
-
(
4) C12PyrI, 1-methyl-4-dodecylpyridium iodide; DTAB (C123CN Br ),
+
-
dodecyltrimethylammonium bromide; CTAB (C163CN Br ), cetyltri-
methylammonium bromide; CTACl (C163CN Cl ), cetyltrimethylammo-
+
-
+
-
nium chloride; and OTACl (C183CN Cl ), octadecyltrimethylammonium
chloride.
1
0.1021/ol991215k CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/23/1999

shows that a decrease of the polarity of the solvent results
in an increase in reaction rate. Therefore, we contend that
the catalytic effects observed are due to the increase of the
local reagent concentrations in the Stern layer and to the
lower dielectric constant resulting in hydroxide ions that are
9
less strongly hydrated. The catalytic efficiency of the
w
different micelles (kmax/k , Table 1) increases with increasing
the chain length (47:117 for DTAB:CTAB and 230:413 for
CTACl:OTACl); this trend corresponds to the higher value
of the binding constant of 1 to the micelle, Kass. It is also
interesting to point out the different catalytic effects for
micelles with the same chain length but with different
counterions (117:230 for CTAB and CTACl, respectively);
this trend is due to the different ability of the counterions to
-
5
be replaced by OH ions.
We have studied the effects of different vesicle-forming
1
0
surfactants: DDAB, DODAB, and DODAC at a constant
NaOH concentration (2.25 mM, pH ) 11.35). Figure 2 shows
Figure 1. Influence of surfactant concentration on the alkaline
decomposition of 1. (O) CTAB and (•) CTACl. [NaOH] ) 2.25
-
5
mM (pH ) 11.35). [1] ) 2 × 10 M. The lines represent the best
fit to the pseudophase model.
Comparing the reactivities in the micellar pseudophase
2
m
2
w
with the corresponding reactivity in bulk water (k /k , see
2
Table 1), the k values are 3.6-6.6 times larger than the
m
Table 1. Kinetic Parameters for the Alkaline Decomposition of
1
in the Presence of Different Micelles Analyzed in Terms of
the Pseudophase Model
Figure 2. Influence of surfactant concentration on the alkaline
decomposition of 1 in the absence of cholesterol, (∇) DDAB, (Ã)
DODAC, and (2) DODAB, and in the presence of 10.0% (w/w)
cholesterol, (X) DDAB, (∆) DODAB, and (•) DODAC (6.6% (w/
-
5
w)). [NaOH] ) 2.25 mM (pH ) 11.35). [1] ) 2 × 10 M. The
lines represent the best fit to the pseudophase model.
that the reaction rate increases to a maximum with increasing
concentration of the different vesicles, after which a slight
decrease in kobs is observed. The kmax/k
w
values have
magnitudes up to 850 (Table 2) and show the high catalytic
efficiencies of vesicular bilayers.
corresponding value in bulk water (a situation usually not
encountered for nucleophiles). This can be attributed, at least
7
Kinetic data can again be quantitatively analyzed using
partly, to a medium effect. In fact, the Stern layer has a
6
the pseudophase ion-exchange model. As with the cationic
8
dielectric constant of ca. 35, markedly lower than that of
micelles, the cationic nature of the surfactants favors the
water. The influence of the dielectric constant upon the
reaction rate was investigated by studying the elimination
reaction in ethanol. The bimolecular rate constant for the
-
presence of OH ions in the vesicular pseudophase and the
overall reaction rate is equal to the sum of the rates in the
vesicular and aqueous pseudophases.
In applying the pseudophase model (Table 2 summarizes
the kinetic data), we assumed a single kves value correspond-
ing to the rate-determining deprotonation at the inner and
outer sides of the vesicle bilayer and a fast equilibrium of
2
w
-1 -1
2
-1 -1
reaction (k ) 14.69 M s , k
) 6711 ( 65 M s )
ethanol
(
7) Yatsimirski, A. K.; Martinek, K.; Berezin, I. V. Tetrahedrom 1971,
7, 2855.
8) Cordes, E. H. Pure Appl. Chem. 1978, 50, 617.
2
(
128
Org. Lett., Vol. 2, No. 2, 2000

Table 2. Comparison of the Catalytic Efficiency of the Vesicles in the Presence and in the Absence of Cholesterol
the substrate for binding at both reaction sites. The assump-
tion of a single rate constant is reasonable, taking into
account that no two-phase kinetics were found. Moreover,
the outer area in small vesicles corresponds to ca. 70% of
the total available reaction area, and it is expected that the
major site of reaction occurs at the outer surface.
companying lower micropolarity at the vesicular binding
sites. However, the phase transition temperatures10 of the
respective bilayers indicate that the DODAB and DODAC
bilayers are in the rigid state at the reaction temperature and
that the DDAB bilayer is in the fluid (liquid crystalline) state.
Therefore, the relative inefficiency of bilayers with two C18
chains is attributable to membrane rigidity. This peculiar
catalytic effect varying with the ammonium bilayer mem-
11
We have calculated the bimolecular rate constant in the
2
ves
2
ves
bilayer, k . In all the vesicles k is higher than the rate
1
3
constant in water, most likely due to the reduced micropo-
brane rigidity has been observed previously.
2
ves
larity at the vesicular pseudophase. The k values are
2
m
higher than those obtained for the micelles (k ), compare
Tables 1 and 2, which is consistent with the lower micropo-
larity at the vesicular surface relative to that at the micellar
1
2
surface. We note that the different catalytic effects for
vesicles with different chain lengths (kmax/k ), at least for
w
DDAB and DODAC vesicles, are larger than those for the
reactions in the presence of micelles.
The catalytic efficiencies of the vesicles at 25 °C follow
the order DDAB > DODAC > DODAB (kmax/k
w
; 860:550:
160, respectively). Initially we anticipated a higher rate
enhancement with an increasing chain length and an ac-
2
OH
(
9) Consistent with this interpretation, k - is enhanced by a factor of
4
400 going from water to 75 vol % DMSO-H2O.
10) DDAB (2C122CN Br ), didodecyldimethylammonium bromide;
DODAB (2C182CN Br ), dioctadecyldimethylammonium bromide; and
DODAC (2C182CN Cl ), dioctadecyldimethylammonium chloride. Vesicles
have been prepared by the sonication methods (bath, probe). Typically, the
preparation consisted of the sonic dispersion (0.015 M) in 10 mL of water
using a Branson 250 sonicator or an ultrasonic bath (Lab. Supplies Co,
Inc.; model G112SP1T, 600 V, 80KC, 0.5 V) at an average temperature of
+ -
(
+
-
+
-
Figure 3. Influence of cholesterol on the overall reaction rate at
three different DODAC concentrations: (Ã) 3.75 mM, (•) 4.50 mM,
and (∆) 6.00 mM. [NaOH] ) 2.25 mM (pH ) 11.35). [1] ) 2 ×
5
5 °C, which is above the phase transition temperatures of the different
vesicles; 12 °C (DDAB), 34-36 °C (DODAB), 36 °C (DODAC) taken
from Okahata, Y.; Ando, R.; Kunitake, T. Ber. Bunsen-Ges. Phys. Chem.
-
5
10 M. The lines are merely to guide the eye.
1
981, 85, 789 and references therein. We checked out the possibility of
vesicle fusion (increase of turbidity) following the reaction at 250 nm. In
all the cases, we did not observe any change in the absorbance.
(
11) Cuccovia, I. M.; Kawamuro, M. K.; Krutman, M. A. K.; Chaimo-
We note the different catalytic effects for vesicles with
the same chain length but different counterions, DODAB
and DODAC (kmax/k ; 160:550, respectively). Small amounts
w
of NaBr (at constant DODAC concentration) decrease the
rate of the deprotonation reaction considerably near its
vich, H. J. Am. Chem. Soc. 1989, 111, 365.
(
12) Fendler, J. H.; Hinze, W. L. J. Am. Chem. Soc. 1981, 103, 5349.
(13) (a) Kunitake, T.; Okahata, Y.; Ando, R.; Shinkai, S.; Hirakawa, S.
J. Am. Chem. Soc. 1980, 102, 7877. (b) Kunitake, T.; Hirotaka, I.; Okahata,
Y. J. Am. Chem. Soc. 1983, 105, 6070. (c) Patel, M.; Bijma, K.; Engberts,
J. B. F. N. Langmuir 1994, 10, 2491.
Org. Lett., Vol. 2, No. 2, 2000
129

maximum. Addition of 0.50 mM NaBr leads to a decrease
in the reaction rate from 12.9 to 7.60 s .
DODAC concentration close to the maximum reaction rate
(Figure 3), an increase in the binding of cholesterol results
in an increase in the observed rate constant.
-
1 14
We also studied the influence of cholesterol upon the
deprotonation reaction in the presence of vesicles formed
from DDAB, DODAB, and DODAC (Figure 3). Except for
DDAB vesicles, the catalytic efficiency is higher than that
in the absence of cholesterol (Table 2).
In summary, we find that surfactant aggregates efficiently
catalyze the rate-determining deprotonation reaction of 1.
The catalytic effects are reminiscent of those observed for
the unimolecular decarboxylation of 6-nitrobenzisoxazole-
1
3c
Because of the presence of cholesterol, the bilayer initially
becomes less rigid and the phase transition temperature is
lower (33.0 °C with 17.2 wt % of cholesterol) and the
transition range is wider.15 But addition of cholesterol also
leads to a loss of counterion binding to the bilayer, which
becomes more nonpolar and lyophobic.16 Consequently we
have two opposite effects, the lower concentration of the
3
-carboxylate. Vesicles are more effective than micelles,
most likely providing a less polar microenvironment at the
substrate binding sites for the deprotonation of 1. This
probably leads to a catalytic reaction involving less strongly
hydrated hydroxide ions, resulting in overall rate enhance-
ments up to a factor of 850. In the case of DODAB and
DODAC vesicles, binding of cholesterol to the bilayer further
increases the catalytic efficiency.
-
reactive OH ions leading to rate retardation and less polar
vesicular binding sites that increase the reaction rate. In
accord with this rationalization, we find that at a constant
Acknowledgment. F.H. is the Walter Grant Scott Re-
search Fellow at Trinity Hall/Cambridge, U.K. J.P.-J. thanks
the Spanish Ministerio de Educaci o´ n y Cultura for a F.P.U.
research-training grant.
(
C.
14) [DODAC] ) 2 mM, [NaOH] ) 2.25 mM (pH ) 11.35), T ) 25
°
(15) Kano, K.; Romero, A.; Djermouni, B.; Ache, H. J.; Fendler, J. H.
J. Am. Chem. Soc. 1979, 101, 4030.
16) Huffman, R. W.; McBride, P.; Brown, D. M. J. Org. Chem. 1994,
9, 1633.
(
5
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