Catalyzing methanolysis of alkyl halides in the interior of an amphiphilic molecular basket

Article abstract of DOI:10.1021/ol701883u

(Figure Presented) A molecular basket with four chelate units assembled on a cone-shaped calix[4]arene assumed reversed micelle-like conformation in 5% methanol/carbon tetrachloride. The inwardly facing hydroxyl groups on the chelates concentrated the pol

Full text of DOI:10.1021/ol701883u

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5147-5150
Catalyzing Methanolysis of Alkyl Halides
in the Interior of an Amphiphilic
Molecular Basket
Eui-Hyun Ryu, HongKwan Cho, and Yan Zhao*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011-3111
zhaoy@iastate.edu
Received August 2, 2007
ABSTRACT
A molecular basket with four cholate units assembled on a cone-shaped calix[4]arene assumed reversed micelle-like conformation in 5%
methanol/carbon tetrachloride. The inwardly facing hydroxyl groups on the cholates concentrated the polar solvent from the mostly nonpolar
mixture. Methanolysis of alkyl halides benefited from the concentrated pocket of methanol if the substrate was capable of entering the basket.
Substrates that were too large or too hydrophobic to fit within the basket showed no rate acceleration.
The behavior of molecules strongly depends on their
environment. In the active site of an enzyme, the microen-
vironment around the substrate differs substantially from the
bulk reaction mixture (i.e., water in most cases). Within this
microenvironment, polarity suitable for the transition, func-
tional groups useful for catalysis, and specific shapes
important to selectivity can be engineered to promote
enzymatic reactions. Not surprisingly, chemists have long
been interested in generating “nanoreactors” to control
chemical reactivity.1,2 Nanoreactors prepared through either
covalent construction or self-assembly have been reported.3
For example, Rebek and co-workers functionalized resor-
cinarene-derived deep cavitands and used them to achieve
molecular recognition and to enhance chemical reactivity.3a
Recently, they reported a self-assembled capsule that dra-
matically shifted the ring/chain isomerization of a Schiff
base.3b Using self-assembled coordination cages, Fujita and
colleagues obtained unusual regioselectivity in a Diels-Alder
reaction and developed efficient catalysts operable in aqueous
solution.3c Although different types of reactions such as
oxidation3d,f and nitrene rearrangement3e have been investi-
gated in recent years, the nanoreactors involved invariably
were rigid structures.3 On the other hand, natural enzymes
are formed by the folding of conformationally mobile peptide
chains, and the controlled conformational changes of en-
zymes are critical to their function and regulation.
Using cholic acid as the building block, we recently
synthesized a series of amphiphiles whose conformations are
controlled by solvent polarity.4 Molecular basket 1 has four
(3) For some recent examples, see: (a) Purse, B. W.; Rebek, J., Jr. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 10777-10782. (b) Iwasawa, T.; Mann,
E.; Rebek, J., Jr. J. Am. Chem. Soc. 2006, 128, 9308-9309. (c) Yoshizawa,
M.; Tamura, M.; Fujita, M. Science 2006, 312, 251-254. (d) Yoshizawa,
M.; Miyagi, S.; Kawano, M.; Ishiguro, K.; Fujita, M. J. Am. Chem. Soc.
2004, 126, 9172-9173. (e) Warmuth, R.; Makowiec, S. J. Am. Chem. Soc.
2007, 129, 1233-1241. (f) 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.
(1) Vriezema, D. M.; Aragone`s, M. C.; Elemans, J. A. A. W.; Cornel-
issen, J. J. L. M.; Rowan, A. E.; Nolte, R. J. M. Chem. ReV. 2005, 105,
1445-1489 and references therein.
(2) Rebek, J., Jr. Angew. Chem., Int. Ed. 2005, 44, 2068-2078 and
references therein.
10.1021/ol701883u CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/08/2007

cholate units assembled on a cone-shaped calix[4]arene
scaffold.4a-c When dissolved in a polar solvent such as
methanol, the hydrophobic faces of the cholates turn inward
to form a conformer that resembles a unimolecular micelle
(1, left). In nonpolar solvents, the hydrophilic faces point
inward instead, resulting in a reversed micelle-like conformer
(1, right).5
To test the hypothesis, we studied the methanolysis of
several alkyl halides (2-6), which differ in size/hydropho-
bicity and in their reactivity toward methanol. Diphenylm-
ethyl chloride (2) was studied initially because its metha-
nolysis only leads to one product (the methyl ether). Under
our experimental conditions (5-15% methanol in CCl4), it
probably solvolyzes through an ion-pair mechanism.7 In
addition to the simplicity of the reaction outcome, the singlet
methine peaks from the starting material and the product have
very different chemical shifts (at ca. δ 6.0 and 5.2 ppm,
respectively), greatly facilitating the kinetic measurements
1
by H NMR spectroscopy.
The reaction was studied in three solvent mixturess5, 10,
and 15% CD3OD/CCl4. Figure 1a shows the yields of the
The reversed micelle-like conformer typically is formed
in a solvent mixture consisting of mostly a nonpolar solvent
(e.g., CCl4, chloroform, or THF) and a small amount of a
polar solvent (e.g, methanol or DMSO).4a-c With the
introverted hydroxyl groups, this conformer can concentrate
the polar solvent from the bulk.4c Tiny pockets of the polar
solvent are located in the interior of basket 1, while the
surrounding medium is largely a nonpolar solvent mixture.
In other words, the highest concentration of the polar solvent
is found in the interior of 1 in such a solvent mixture. As a
result, a substrate reactive toward the polar solVent should
be most reactive if it can enter the molecular basket.
Performing reactions in such a confined environment has
Figure 1. Methanolysis of diphenylmethyl chloride (2) with 20
mol % compound 1 in 5% (9), 10% (2), and 15% ([) CD3OD/
CCl4 at 20 °C. The open data points (0, 4, ]) are for the control
experiments with no compound 1 present in the corresponding
solvent mixtures. [S] is the concentration of the substrate at different
times.
methyl ether product as a function of time. The data fit well
to the first-order kinetics (Figure 1b), from which the rate
constants were obtained. As indicated by Figure 1b, the
reaction was well behaved, showing linearity even at 90%
conversion.
an immediate consequence in selectivity.6 Substrates that can
easily access the pockets of the polar solvent will be helped
by the basket, whereas reactants excluded by the basket will
not.
Table 1 summarizes the kinetic data. The rate constant
was 2.30 × 10-3 h-1 for the methanolysis of substrate 2 in
5% CD3OD/CCl4 (Table 1, entry 1). In the presence of 20
mol % of basket 1, the rate constant more than doubled to
5.31 × 10-3 h-1. Although the rate acceleration (kcat/kuncat
)
(4) (a) Ryu, E.-H.; Zhao, Y. Org. Lett. 2004, 6, 3187-3189. (b) Zhao,
Y.; Ryu, E.-H. J. Org. Chem. 2005, 70, 7585-7591. (c) Ryu, E.-H.; Yan,
J.; Zhong, Z.; Zhao, Y. J. Org. Chem. 2006, 71, 7205-7213. (d) Zhao, Y.;
Zhong, Z. J. Am. Chem. Soc. 2005, 127, 17894-17901. (e) Zhao, Y.; Zhong,
Z.; Ryu, E.-H. J. Am. Chem. Soc. 2007, 129, 218-225.
(5) For some recent examples of interconvertible unimolecular micelles
and reversed micelles, see: (a) Basu, S.; Vutukuri, D. R.; Shyamroy, S.;
Sandanaraj, B. S.; Thayumanavan, S. J. Am. Chem. Soc. 2004, 126, 9890-
9891. (b) Vutukuri, D. R.; Basu, S.; Thayumanavan, S. J. Am. Chem. Soc.
2004, 126, 15636-15637. (c) Ghosh, S.; Maitra, U. Org. Lett. 2006, 8,
399-402.
(6) Phase separation of solvents can be also realized by reversed micelles
formed by the aggregation of conventional surfactantsse.g., a pool of water
is typically used to stabilize reversed micelles formed by surfactants. Even
though reversed micelles have been studied extensively as reaction media
for reactions, their interior tend to be much larger (depending on the amount
of water added) than small organic molecules. For catalysis in micelles
and reversed micelles, see: Fendler, J. H.; Fendler, E. J. Catalysis in Micelles
and Macromolecular Systems; Academic Press: London, 1975.
2.3) was modest, it clearly indicates that the basket compound
is beneficial to the reaction.
With an increase of methanol in the reaction mixture, the
reversed micelle-like conformer of compound 1 becomes less
stable.4a-c In addition, preferential solvation (i.e., the “polar
solvent-concentrating effect”) is less significant when there
is more polar solvent in the bulk mixture.4c Therefore,
catalysis is expected to be less efficient. This prediction was
confirmed. The rate acceleration became less significant (kcat/
kuncat ) 1.2, entry 2) in 10% methanol and almost disappeared
(7) (a) Bunton, C. A.; Mhala, M. M.; Moffatt, J. R. J. Org. Chem. 1984,
49, 3639-3641. (b) Schade, C.; Mayr, H. Tetrahedron 1988, 44, 5761-
5770.
5148
Org. Lett., Vol. 9, No. 25, 2007

not result from its exclusion from the basket but, instead,
could be simply a result of its faster, uncatalyzed reaction.
Therefore, in order to better understand the reason for the
selectivity, we have to use substrates that are different in
size/hydrophobicity but similar in reactivity. Essentially, we
have to change the size/hydrophobicity of the substrate
without changing the stability of the corresponding carboca-
tion significantly.8 Substrates 5 and 6 turned out to fulfill
this criterion. In the presence of 20 mol % basket 1, the
smaller bromide 5 gave a rate constant of 1.26 × 10-3 h-1
in 5% methanol (entry 6). Compared to the uncatalyzed
reaction, the basket-catalyzed reaction was 4.1 times faster.
This rate acceleration was even higher that what was
observed in 2. Hence, a smaller, slower substrate does seem
to benefit more from the basket. Importantly, the basket
conformation of 1 was needed for the observed catalysis,
because the monocholate derivative 7, at 80 mol % (the same
concentration of cholate as 20 mol % of 1), did not help
bromide 5 at all (entry 6).
Table 1. Rate Constants of Methanolysis of Alkyl Halides at
20 °C
entry substrate catalyst CD3OD (%)a
k (h-1
)
kcat/kuncat
1
2
3
4
5
6
2
2
2
2
2
2
3
3
4
4
5
5
5
6
6
5
6
5
6
1b
none
1b
none
1b
none
1b
5
5
5.31 × 10-3
2.30 × 10-3
1.30 × 10-2
1.09 × 10-2
4.29 × 10-2
3.99 × 10-2
1.70 × 10-2
0.92 × 10-2
6.96 × 10-2
6.26 × 10-2
1.26 × 10-3
3.09 × 10-4
3.22 × 10-4
2.3
10
10
15
15
5
5
5
5
5
5
5
5
5
30
30
50
50
1.2
1.1
1.8
1.1
none
1b
none
1b
4.1
1.0
7c
none
1b
d
7
8
9
-
-
d
none
none
none
none
none
-
7.42 × 10-3
2.42 × 10-3
2.31 × 10-2
7.97 × 10-3
3.1e
2.9e
a The volume percentage of CD3OD in CCl4. b The catalyst was used at
20 mol % with respect to the substrate. c The catalyst was used at 80 mol
% with respect to the substrate. d Only 1-2% of the substrate methanolyzed
during 130 h. e The ratio shown is k(5)/k(6).
Bromide 6 was slower in solvolysis than 5, consistent with
the reported effect of alkyl on this type of reaction.9 Only
1-2% of 6 reacted with methanol over 130 h, in the presence
or absence of basket 1 (entry 7). Thus, little, if any, rate
acceleration was obtained for this larger/more hydrophobic
bromide, in contrast to what occurred in 5. When the amount
of methanol was increased to 30 and 50% in the reaction
mixture, the reaction rate became measurable for 6. The data
indicate that the inherent reactivity of 6 is 3 times lower
than that of 5 (entries 8 and 9). Assuming the inherent
reactivity stays the same and bromide 6 is helped by the
basket to the same extent as 5, the rate constant for 6 in the
presence of 1 would be 4 × 10-4 h-1. The real rate constant
must be slower than this because the uncatalyzed reaction
of 5 (k ≈ 3 × 10-4 h-1, entry 6) was measurable, whereas
the reaction of 6 was not (entry 7). Thus, the larger/more
hydrophobic substrate indeed was not catalyzed by 1.
Last, we placed bromides 5 and 6 in the same reaction
mixture and carried out competitive methanolysis. In the
presence of 1, 17% of bromide 5 was converted to the
product after 140 h, whereas a negligible amount of bromide
6 was converted (Figure 2a). In the absence of basket 1, as
shown by Figure 2b, neither showed much reactivity. Hence,
the results once again indicate that the reaction of the smaller/
in 15% methanol (kcat/kuncat ) 1.1, entry 3, also see Figure
1). Note that as the percentage of methanol went from 15 to
5%, the uncatalyzed reactions became slower as well (entries
3-3). The result is reasonable because a decrease in
methanol not only reduces the concentration of the nucleo-
phile, but also makes the overall solvent less polar, unfavor-
able to a reaction with a charge-separated transition state.
To demonstrate the hypothesized selectivity, we studied
the methanolysis of the mononaphthyl chloride 3 and the
dinaphthyl chloride 4 in 5% CD3OD/CCl4. According to our
previous work, the interior of basket 1 is large enough to
accommodate phenyl â-D-glucopyranoside,4b a guest similar
in size to chloride 2. Therefore, the idea was that, as the
two phenyl groups were replaced by the naphthyl one after
another, the substrate would become too large eventually to
fit within the basket, and would not benefit from the methanol
within basket 1. Moreover, the naphthyl groups increase the
substrate’s hydrophobicity, which also discourages the
substrate from entering the polar solvent-filled molecular
basket. The data in Table 1 does support such a notion. With
one of the phenyls replaced by a naphthyl group, the rate
acceleration in substrate 3 decreased to kcat/kuncat ) 1.8 (entry
4) from 2.3 in 1 (entry 1). When both phenyl groups were
replaced, almost no acceleration (kcat/kuncat ) 1.1, entry 5)
was observed in substrate 4.
(8) It is difficult to design experiments to determine whether the size or
the hydrophobicity of the substrate is more important under these conditions.
Attaching hydrophobic groups to the substrate, as in this study, increases
both its size and hydrophobicity. Attaching hydrophilic groups (to increase
the size and decrease the hydrophobicity) is problematic. Hydrophilic groups
typically have heteroatoms that may interfere with the solvolysis, e.g.,
through neighboring group participation. Also, the hydrophilic groups
themselves are likely to alter the local solvent composition around the
substrate and change the rate of methanolysis.
However, we also noticed that, as the phenyl groups were
replaced by naphthyl, the uncatalyzed reaction became faster.
The rate constant was 0.92 × 10-2 h-1 for 3 (entry 4) and
6.26 × 10-2 h-1 for 4 (entry 5), as compared to 2.30 × 10-3
h-1 for 2 (entry 1). Because a faster reactant does not need
as much help from a catalyst as a slower reactant, it is
possible that the diminishing rate acceleration for 4 might
(9) Orlovic´, M.; Kronja, O.; Humski, K.; Borcˇic´, S.; Pollar, E. J. Org.
Chem. 1986, 51, 3253-3256.
Org. Lett., Vol. 9, No. 25, 2007
5149

responsive to solvent polarity, this catalysis can be tuned up
or down, depending on the solvent composition. The rate
acceleration obtained was small but was significant, consid-
ering the unfavorable conditions under which the catalysis
must occursi.e., a hydrophobic substrate has to enter a
hydrophilic cavity. More efficient catalysis is expected if the
catalyst can be equipped with catalytic functionalities10 and
if the substrate can have a higher affinity for the catalyst.
Acknowledgment. Acknowledgment is made to the Roy
J. Carver Charitable Trust for partial support of this research.
We thank Prof. Samuel H. Gellman at the University of
Wisconsin at Madison for encouraging us to use compound
1 to catalyze SN1 reactions.
Figure 2. Competitive methanolysis of compounds 5 (4) and 6
(×) with (a) 20 mol % compound 1 and (b) without compound 1
in 5% CD3OD/CCl4.
Supporting Information Available: Synthetic proce-
dures, procedures for the kinetic measurements, and NMR
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
less hydrophobic substrate is catalyzed by the basket, whereas
the larger/more hydrophobic one is not.
In summary, basket 1 concentrates polar solvent within
its interior from a largely nonpolar solvent mixture. Reactants
capable of entering the basket can be selectively converted
to products in the presence of reactants that do not fit due to
size or hydrophobicity. Because the conformation of 1 is
OL701883U
(10) Recently, we reported a porphyrin catalyst with cholate groups
around the catalytic center, see: Zhou, Y.; Ryu, E.-H.; Zhao, Y.; Woo, L.
K. Organometallics 2007, 26, 358-364.
5150
Org. Lett., Vol. 9, No. 25, 2007