Ester hydrolysis by a cyclodextrin dimer catalyst with a metallophenanthroline linking group

Article abstract of DOI:10.1002/chem.200800237

A novel β-cyclodextrin dimer, 1,10-phenanthroline-2,9-dimethyl- bridged-bis(6-monoammonio-β-cyclodextrin) (phenBisCD, L), was synthesized. Its zinc complex (ZnL) has been prepared, characterized, and applied as a new catalyst for diester hydrolysis. The formation constant (logK _ML=9.56±0.01) of the complex and deprotonation constant (pK_a = 8.18±0.04) of the coordinated water molecule were determined by a Potentiometric pH titration at (298±0.1) K. Hydrolytic kinetics of carboxylic acid esters were performed with bis(4-nitrophenyl) carbonate (BNPC) and 4-nitrophenyl acetate (NA) as substrates. The obtained hydrolysis rate constants showed that ZnL has a very high rate of catalysis for BNPC hydrolysis, giving a 3.89×10⁴-fold rate enhancement over uncatalyzed hydrolysis at pH 7.01, relative to only a 42-fold rate enhancement for NA hydrolysis. Moreover, the hydrolysis second-order rate constants of both BNPC and NA greatly increases with pH. Hydrolytic kinetics of a phosphate diester catalyzed by ZnL was also investigated by using bis(4-nitrophenyl) phosphate (BNPP) as the substrate. The pH dependence of the BNPP cleavage in aqueous buffer shows a sigmoidal curve with an inflection point around pH 8.11, which was nearly identical to the pK_a value from the Potentiometrie titration. The K_cat of BNPP hydrolysis promoted by ZnL was found to be 9.9×10^-4M^-1s^-1, which is comparatively higher than most other reported Zn^II-based systems. The possible intermediate for the hydrolysis of BNPP, BNPC, and NA catalyzed by ZnL is proposed on the basis of kinetic and thermodynamic analysis.

Full text of DOI:10.1002/chem.200800237

FULL PAPER
DOI: 10.1002/chem.200800237
Ester Hydrolysis by a Cyclodextrin Dimer Catalyst with a
Metallophenanthroline Linking Group
[
a]
Ying-Hua Zhou, Meng Zhao, Zong-Wan Mao,* and Liang-Nian Ji
Abstract:
A
novel b-cyclodextrin
obtained hydrolysis rate constants
showed that ZnL has a very high rate
of catalysis for BNPC hydrolysis, giving
phenyl) phosphate (BNPP) as the sub-
strate.The pH dependence of the
BNPP cleavage in aqueous buffer
shows a sigmoidal curve with an inflec-
tion point around pH 8.11, which was
dimer, 1,10-phenanthroline-2,9-dimeth-
yl-bridged-bis(6-monoammonio-b-cy-
clodextrin) (phenBisCD, L), was syn-
thesized.Its zinc complex (ZnL) has
been prepared, characterized, and ap-
plied as a new catalyst for diester hy-
drolysis.The formation constant
4
a 3.89”10 -fold rate enhancement over
uncatalyzed hydrolysis at pH 7.01, rela-
tive to only a 42-fold rate enhancement
for NA hydrolysis.Moreover, the hy-
drolysis second-order rate constants of
both BNPC and NA greatly increases
with pH.Hydrolytic kinetics of a phos-
phate diester catalyzed by ZnL was
also investigated by using bis(4-nitro-
nearly identical to the pK value from
a
the potentiometric titration.The kcat of
BNPP hydrolysis promoted by ZnL
ꢁ
4
ꢁ1 ꢁ1
(
logKML =9.56ꢀ0.01) of the complex
was found to be 9.9”10 m s , which
and deprotonation constant (pK =
is comparatively higher than most
a
II
8
.18ꢀ0.04) of the coordinated water
other reported Zn -based systems.The
molecule were determined by a poten-
tiometric pH titration at (298ꢀ0.1) K.
Hydrolytic kinetics of carboxylic acid
esters were performed with bis(4-nitro-
phenyl) carbonate (BNPC) and 4-nitro-
phenyl acetate (NA) as substrates.The
possible intermediate for the hydrolysis
of BNPP, BNPC, and NA catalyzed by
ZnL is proposed on the basis of kinetic
and thermodynamic analysis.
Keywords:
cyclodextrins
·
hydrolysis · kinetics · phosphate
diesters · zinc
Introduction
tional linkers that can be further coordinated to a metal ion
[3–6]
as the active site of a metalloenzyme,
such as porphyrin,
Over these years, a great deal of interest has been focused
on cyclodextrin dimers (BisCDs) that are covalently linked
by some flexible or rigid groups because of the favorable co-
operative binding interactions between the two hydrophobic
bipyridine, and so on.These BisCDs have various compre-
[7]
hensive applications in chiral discrimination, drug carri-
[8]
[9]
[10]
ers, molecular recognition, and enzyme mimics. Mar-
sura et al.synthesized a metallohydrolase model with a
BisCD linked by a long-chained group, and the catalytic hy-
drolysis activity of the ester was low relative to a BisCD
linked by an appropriately lengthened metallobipyri-
[1]
cyclodextrin (CDs) cavities and guest molecules. Relative
to a- or g-CDs, b-CDs have an appropriately sized cavity
and appropriate water solubility; the result of this is that the
synthesis and properties of CD dimers through their primary
[11,12]
dine.
It is well known that in biological systems a sub-
[2]
sides are well documented. Breslow, Nolte, Fujita, and Liu
have synthesized a series of BisCDs with a variety of func-
strate is rigidly immobilized around the catalytic group by
an enzyme exquisitely tailoring both the first and the second
coordination spheres of its active site to afford efficient and
[12,13]
selective catalytic systems for the reactive geometry.
Recently, Liu et al.reported a b-cyclodextrin dimer linked
by telluroxy group, in which the catalytic rate of hydrolysis
[
a] Dr. Y.-H. Zhou, M. Zhao, Prof. Z.-W. Mao, Prof. L.-N. Ji
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
School of Chemistry and Chemical Engineering
Sun Yat-Sen University
Guangzhou 510275 (China)
Fax : (+86)20-8411-2245
of bis(4-nitrophenyl) carbonate (BNPC) was remarkably ac-
[14]
celerated.
However, tellurium compounds are toxic to
living organisms and have not been found in natural bio-
macromolecules, including DNA, proteins, and lipids.To our
best knowledge, artificial hydrolase systems are usually
E-mail: cesmzw@mail.sysu.edu.cn
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
2
+
2+
3+
3+
3+
based on Zn , Cu , Co , Fe , and lanthanide ions (Eu
,
Chem. Eur. J. 2008, 14, 7193 – 7201
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
7193

4
+
2+
2+
2+
Ce ), but natureꢁs choices fall mainly on Mg , Zn , Ca
,
tion, which was deemed to be an appropriate catalytic site
for hydration or hydrolysis. The investigation of esterase
2
+
II
[20]
and Fe .Therefore, the Zn ion is the only metal frequent-
ly encountered in both natural and artificial agents, due to a
variety of factors: The Zn ion is a good Lewis acid, ex-
changes ligands rapidly, is not toxic, and is not redox
active.
activity was performed by using ZnL to promote the hydrol-
ysis of BNPC, 4-nitrophenyl acetate (NA), and bis(4-nitro-
phenyl) phosphate (BNPP).Herein, we report the synthesis,
characterization, and thermodynamic properties of ZnL as
well as detailed hydrolytic kinetics of esters catalyzed by
ZnL.
II
[15]
Moreover, it has no ligand-field stabilization
energy and, as a consequence, it can easily adapt its coordi-
nation geometry to best fulfill the structural requirement of
[16]
a reaction. For all of these reasons, the development of a
II
Zn -based artificial hydrolase would be highly valuable.
Recently, we reported some supramolecular models of
metallohydrolase and superoxide dismutase with the cyclo-
dextrin inclusion complexes constructed by metal-complex
binding into CD or its derivatives.We also reported that
their catalytic activities can be greatly improved due to
Results and Discussion
Synthesis and characterization of ZnL: As illustrated in
Scheme 1, the dimer (L) is synthesized in a yield of 32% by
the reaction of a 6-monodeoxy-6-monoamino-b-cyclodextrin
with 1,10-phenanthroline-2,9-dicarboxaldehyde and is char-
acterized by spectroscopy (see Figures S1–S3 in the Support-
ing Information).The further reaction of L and zinc(II) per-
chlorate gave the zinc(II) complex in a moderate yield
(68%).
[17–19]
second coordination sphere interactions.
We found that
the inclusion complex with CD or its derivatives has poten-
tial in the development of an effective model for metalloen-
zymes.On the basis of the above work, we synthesized a cy-
clodextrin dimer linked by 1,10-phenanthroline-2,9-ammo-
niomethyl (phenBisCD, L) and its zinc complex (ZnL).In
this complex, the zinc ion has a stable ZnN ꢁOH configura-
To obtain information on the role played by the phenan-
throline unit in metal coordination, complex formation was
followed by UV spectral analy-
4
2
sis recorded in aqueous solu-
tions with an identical concen-
II
tration of L and Zn at (298ꢀ
0
.1) K. It has been reported
that a phenanthroline chromo-
phore usually shows two ab-
sorption peaks in the ultravio-
let region, and the UV spectra
of phenanthroline and its de-
rivatives have a great relation-
ship with their complexa-
Scheme 1.Synthetic scheme of the catalyst ZnL.
7194
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7193 – 7201

Ester Hydrolysis
FULL PAPER
[
21]
tion. As illustrated in Figure S4 (see the Supporting Infor-
metric titration at I=0.10m NaClO and (298ꢀ0.1) K. The
4
mation), the ligand shows two absorption peaks at 232 (e=
pH profiles of the titration curves, which include the distri-
ꢁ
1
ꢁ1
ꢁ1
ꢁ1
II
5
0967 mol Lcm ) and 273 nm (e=33177 mol Lcm ),
respectively, which are assigned to absorptions of the phe-
nanthroline chromophore.In the presence of Zn (ClO ) , a
bution curves of the Zn species as a function of pH
(Figure 2), were analyzed by the Hyperquad program.The
calculated results are summarized in Table 1, which includes
AHCTREUNG
4
2
new broad peak of 300 nm appears, and the absorption in-
data from the [Zn(pdma)] complex (pdma=N,N’-dimethyl-
A
H
R
U
G
[22]
tensity at 232 nm obviously decreases (e from 50967 to
1,10-phenanthroline-2,9-dimethanamines),
logue of ZnL.
a simple ana-
ꢁ
1
ꢁ1
4
5509 mol Lcm ) accompanying
a
slight violetshift.
Meanwhile, zinc(II)-ion coordination induces a 4 nm redshift
of the band at 277 nm over the uncomplexed ligand, which
slightly increases in absorbance (e from 32050 to
ꢁ
1
ꢁ1
II
3
3766 mol Lcm ).Since the solution of the Zn ion does
not cause UV spectral changes, these spectrophotometric
data indicate that the phenanthroline group is involved in
metal coordination.
ESIMS spectrometry of ZnL is a more important method
for the investigation into the formation of complexation in
aqueous/MeOH solution.Figure 1 shows both the experi-
mental and calculated isotopic distribution for the peak at
2
+
m/z: 1268.31, which was assigned to [ZnL] .This result in-
dicates that the complexation binding between the zinc ion
1
and L exists.To access the complexation, H NMR spectra
was used to investigate and to distinguish the difference
after L complexation.Some changes in the chemical shift of
the phenanthroline protons in ZnL were observed relative
to those in L (see Figure S5 in the Supporting Information):
the Ha, Hb, and Hc protons shifted downfield by approxi-
mately 0.32, 0.40, and 0.37 ppm, respectively, which indicat-
ed that a complex had formed between the L and zinc(II)
ion.
Figure 2.Distribution plots of species with ZnL (1 .0 0 m m) as a function
of pH at 0.10m NaClO and (298ꢀ0.1) K.
4
Table 1.Equilibrium constants of the ligand and its metal complex.
Chemical equilibrium
Equilibrium constant
phenBisCD
[a]
pdma
3
2
+
+
2+
+
H
H
3
2
L
L
=H
2
L
+H
pK
pK
pK
1
2
3
2.04
8.35
9.71
1.34ꢀ0.03
5.06ꢀ0.06
12.6ꢀ0.04
9.56ꢀ0.01
8.18ꢀ0.04
+
+
=HL +H
Formation and deprotonation constants of ZnL: The proto-
+
+
HL =L+H
2
+
2+
nation constants (K ) of the ligand, their inclusion complex
[Zn
A
H
R
U
G
2
O)
6
]
+L=[ZnL
A
H
R
U
(H
2
O)]
logKML 8.98
pK 8.64
n
2
+
+
+
A
H
R
U
G
A
H
R
U
G
2
O)] =[ZnL(OH)] +H
a
formation constants (KML), and the deprotonation constant
(
pK ) of the coordinated water molecule as well as species
[a] See reference [22], pdma=N,N’-dimethyl-1,10-phenanthroline-2,9-di-
methanamine.
a
distribution in solution were determined by pH potentio-
Figure 1.ESIMS spectra of ZnL.a) Full-range spectra.b) Bivalence ion isotope spectra determined by computer simulation.c) Detected bivalence ion
isotope spectra.
Chem. Eur. J. 2008, 14, 7193 – 7201
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
7195

Z.-W. Mao et al.
II
2+
It is indicated in Figure 2 that five Zn species, [ZnL]
,
3
+
4+
5+
+
[
ZnLH] , [ZnLH2] , [ZnLH3] , and [ZnLH ] , corre-
ꢁ1
sponding to Equations (1–5), respectively, are involved in
the complex formation at pH 2–11.Since the addition of
NaClO does not cause spectral changes, it was also con-
4
II
firmed that the remaining coordination sites of Zn are oc-
cupied by one water molecule.
[19]
Zn þ L ¼ ½ZnLŠ2þ KZnL
2
þ
ð1Þ
ð2Þ
ð3Þ
ð4Þ
ð5Þ
2
þ
þ
3þ
Zn þ L þ H ¼ ½ZnLHŠ
KZnLH
2
þ
þ
4þ
Zn þ L þ 2H ¼ ½ZnLH Š
KZnLH2
2
2
þ
þ
5þ
Zn þ L þ 3 H ¼ ½ZnLH Š
KZnLH3
3
2þ
þ
þ
½
ZnLŠ ¼ ½ZnLH Š þ H Ka1
ꢁ
1
It might be of interest to compare the complex formation
constants of ZnL with that of [Zn(pdma)] complex, which is
an analogue of ZnL.From the catalytic mechanism analysis
of [Zn(pdma)] complex, it was found that three nitrogen
AHCTREUNG
ACHTREUNG
donors are involved in metal coordination.The formation
constant (logK) of ZnL is slightly higher than that of [Zn-
A
C
H
T
R
E
U
N
G
(pdma)] complex (9.56ꢀ0.01 for ZnL and 8.98 for [Zn-
(pdma)], respectively), which implies that all benzylic nitro-
gen donors in the ZnL are coordinated to the zinc ion.Fur-
ACHTREUNG
2
+
thermore, a marked change is that the pK of [ZnL(H O)]
A
H
R
U
G
a
2
Figure 3.Plots of absorbance versus time during BNPC (a) and NA hy-
(
8.18ꢀ0.04) is approximately 0.5 pH units lower than that
A
H
R
U
G
4 2
drolysis (b) catalyzed by Zn(ClO ) , L, and ZnL in a 10% MeCN solu-
2
+
of [Zn(pdma)(H O)] (8.64). This change is probably due
A
C
H
T
R
E
U
N
G
A
C
H
T
R
E
U
N
G
tion of pH 7.01 Tris-HCl buffer with 0.10m NaClO at (298ꢀ0.1) K ([cat-
2
4
to the effect of both the hydrophobic environment around
the metal ion center and weak interactions after complexa-
tion, similar to those in carbonic anhydrase or alkaline phos-
alyst]=50 mm, [BNPC]=50 mm, [NA]=200 mm).
Table 2.Initial rate ( v) for ester hydrolysis promoted by different cata-
lysts.
[23]
phatase.
[
a]
Catalyst
BNPC
NA
)
Hydrolysis of carboxylic acid esters: To demonstrate the
effect of hydrophobic interactions on the catalytic activities
of ZnL, BNPC and NA were also selected as testing sub-
strates on the basis of their structural features.Studies into
the hydrolysis kinetics of BNPC and NA were performed in
a 10% MeCN solution of Tris-HCl (50 mm, pH 7.01) at
ꢁ9
ꢁ1
ꢁ9
ꢁ1
v(10 ms
)
v/vcontr
v(10 ms
v/vcontr
1
buffer
Zn
L
ZnL
(2.45ꢀ0.03)”10ꢁ
1.00
1.07
3.12”10
2.61”10
3.17ꢀ0.10
3.33ꢀ0.17
4.67ꢀ0.3
6.17ꢀ0.20
1.00
1.05
1.47
1.95
II
ꢁ1
(2.62ꢀ0.03)”10
(7.65ꢀ0.20)”10
(6.40ꢀ0.23)”10
2
3
2
[a] Reaction conditions: 50 mm BNPC or 200 mm NA, 50 mm catalyst,
0
.10m NaClO
4
, 50 mm pH 7.01 Tris-HCl buffer, (298ꢀ0.1) K.
(
298ꢀ0.1) K (Figure 3). By means of spectrophotometrical
detection of product 4-nitrophenol at 400 nm (e
8
=
obs
ꢁ
1
ꢁ1 [24]
700m cm ),
the initial hydrolysis rates of BNPC
3
(
50 mm) and NA (200 mm) in the presence of catalysts were
10 -fold higher than BNPC self-hydrolysis.In the case of
NA, however, hydrolysis rates catalyzed by L and ZnL are
only 1.47- and 1.95-fold higher than that of the self-hydroly-
sis, respectively.
calculated (Table 2).
The measured initial rate of spontaneous cleavage of
ꢁ
10
ꢁ1
BNPC (50 mm) is very slow (#control =2.45”10 ms ), which
[14]
is consistent with the value reported. Almost no enhance-
ment in the hydrolysis rate was observed when only the zinc
ion was added to the substrate of BNPC or NA.However,
an enhancement was observed when L was added, which
was 312-fold higher than BNPC self-hydrolysis.A similar
observation has been recently reported in which a cyclodex-
trin dimer linked by tris(2-aminoethyl)amine showed a 150-
fold rate enhancement for BNPC hydrolysis. Most inter-
estingly, under identical conditions, ZnL exhibits an abrupt
enhancement in the rate of BNPC hydrolysis, which is 2.61”
To fully assess the hydrolysis ability of ZnL for BNPC, a
detailed kinetic study was undertaken.Saturation kinetics
were observed (Figure 4) and thus kinetic parameters de-
duced from the Michaelis–Menten equation for the hydroly-
sis are listed in Table 3.Turnover numbers of kcat ((1.88ꢀ
ꢁ1
ꢁ1
0.20)”10 s ) were obtained for BNPC hydrolysis cata-
lyzed by ZnL.The value of k /k
was used to describe
cat uncat
[25]
the catalytic ability of hydrolase mimics, and it showed in
4
our case values up to 3.89”10 .However, for NA hydrolysis,
the value of k /k
was found to be 42.3, which is almost
cat uncat
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Chem. Eur. J. 2008, 14, 7193 – 7201

Ester Hydrolysis
FULL PAPER
from the slope of the straight line of the initial rate con-
stants (k ) versus [ZnL]
of BNPC and NA hydrolysis are 55.5 and 4.87”10
(Figure 5).Calculated k values
obs
in
total
ꢁ
2
ꢁ1 ꢁ1
m
s
Figure 4.Saturation kinetics of BNPC (a) and NA hydrolysis (b) cata-
lyzed by ZnL.Each reaction mixture contained ZnL (50 mm), Tris-HCl
buffer (50 mm pH 7.01) with 0.10m NaClO
4
at (298ꢀ0.1) K.
Table 3.Kinetic parameters for ester hydrolysis in the presence of ZnL
(
(
50 mm) in a 10% MeCN solution of Tris-HCl buffer (50 mm pH 7.01) at
298ꢀ0.1) K.
Figure 5.Dependence of the first-order rate constants for BNPC (a) and
NA hydrolysis (b) on different concentrations of ZnL in a 10% MeCN
Substrate
BNPC
NA
solution of 50 mm Tris-HCl buffer with 0.10m NaClO
([BNPC]=50 mm, [NA]=200 mm).
4
at (298ꢀ0.1) K
ꢁ
1
ꢁ6
ꢁ1
ꢁ6
ꢁ4
k
k
uncat. [s
cat. [s
]
(4.83ꢀ0.16)”10
(1.88ꢀ0.20)”10
0.11ꢀ0.02
(3.95ꢀ0.03)”10
(1.67ꢀ0.33)”10
0.35ꢀ0.03
ꢁ
1
]
K
m
[mm]
3
ꢁ1 ꢁ1
at pH 7.01, and 1.33”10 and 0.39m
s
at pH 8.85, respec-
ꢁ
1
ꢁ1
3
ꢁ1
k
k
cat./K
cat./kuncat.
m
[m
s
]
1.71”10
4.77”10
4
tively.Calculated kobs values of BNPC hydrolysis at pH 8.85
is about 20-fold higher than that of at pH 7.01, whereas NA
increases about 8-fold.More interestingly, the kobs value of
3.89”10
42.3
3
three orders of magnitude lower than that of BNPC.Fur-
BNPC hydrolysis promoted by ZnL at pH 8.85 is 3.41”10 -
thermore, a much better catalytic efficiency k /K was ob-
fold higher than that of NA hydrolysis.
cat
m
3
ꢁ1 ꢁ1
tained for BNPC hydrolysis (1.71”10 m s ) in contrast to
ꢁ
1
ꢁ1 ꢁ1
NA hydrolysis (4.77”10
1
m
s ), which had about a 3.58”
Hydrolysis of phosphate diester: BNPP is often used as a
DNA model compound in the investigation of phosphodies-
terase activity.The test was carried out in buffers to mimic
biological conditions.The initial phosphorylation rate in
aqueous solution at (308ꢀ0.1) K and pH 6.50–9.31 (50 mm
Goodꢁs buffer) was followed by the appearance of p-nitro-
3
0 -fold higher activity than that of NA.
To further demonstrate the effect of pH value on catalytic
hydrolysis, the kinetic experiment with BNPC and NA was
performed at different concentrations of catalyst at pH 8.85
relative to neutral conditions.
[26]
phenolate at 400 nm.
Since the substrate concentration
was essentially constant during the measurement, the initial
v ¼ k ½substrateŠ
¼
in
ð6Þ
first-order rate constant (k , in=initial) of the total catalyst
in
ðkobs½Zn complexŠtotal þ kOHꢁ½OHŠ Þ½substrateŠ
II
þ
[19]
was calculated as in Equation (7):
On the basis of Equation 6, the observed second-order
rate constants (kobs) of ester hydrolysis can be calculated
ꢁ
þ
v ¼ k ½BNPPŠ ¼ ðkBNPP½ZnLŠ
þ kOHꢁ½OH Š Þ½BNPPŠ ð7Þ
in
total
Chem. Eur. J. 2008, 14, 7193 – 7201
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
7197

in which v is the p-nitrophenolate releasing rate.At a given
pH value, the kin values were measured at different concen-
trations of catalyst.Figure 6 shows the effect of ZnL concen-
cule deprotonation in [ZnL(H O)] obtained from the po-
A
H
E
U
G
Z.-W. Mao et al.
2
+
2
tentiometric pH titration (Table 1).Therefore, one can con-
clude that the deprotonated [ZnL(OH)] ion is the only re-
+
active species of the catalytic system.Consequently, the cat-
+
alytic second-order rate constant kMOH of [ZnL(OH)] must
be expressed as in Equation (8):
kMOH½ZnLðOHފ
k
Ka
MOH
þ
kBNPP
¼
¼
ð8Þ
½
ZnLŠ
½H Š þ K
total
a
The kMOH and pKa values were found by curve-fitting
ꢁ
4
ꢁ1 ꢁ1
from Equation (8) to be 9.9”10
[
m
s
and 8.11 for
+
ZnL(OH)] , respectively (R=0.995).
Catalytic mechanism: The enhancement of the rate of hy-
drolysis of the carboxylic acid ester with pH increase is in
good agreement with the percentage of nucleophilic active
+
species [ZnL(OH)] .This result is in agreement with the
analysis of the kBNPP/pH profile in phosphate diester hydrol-
ysis.
Figure 6.Dependence of the initial first-order rate constants on the con-
centration of ZnL at pH 8.85 and (308ꢀ0.1) K (I=0.10m NaClO
4
,
Under identical conditions, the BNPC hydrolysis dramati-
cally increases, whereas NA hydrolysis increases only a
little.To the best of our knowledge, some catalytic groups
introduced into the primary side of monocyclodextrin can
enhance catalytic hydrolysis of the substrate owing to the
hydrophobic interactions between the mimics and sub-
[
BNPP]=0.20 mm, [buffer]=50 mm).
trations on the kin for the cleavage of BNPP at pH 8.85 and
(
308ꢀ0.1) K. The rate of BNPP cleavage initially increases
linearly with the increase of ZnL concentration but gradual-
ly deviates from linearity.The calculated second-order rate
constant of BNPP hydrolysis catalyzed by ZnL, kBNPP, was
determined from the slope of the linear plot.Thus, the slope
of kin versus [ZnL]total from Equation (7) resulted in the
second-order rate constant (kBNPP).The dependence of the
[3,27,28]
strate.
In addition, a cyclodextrin dimer bridged with
metallobipyridyl can effectively catalyze ester hydrolysis, in
which the substrate can be immobilized rightly near the
metal ion by the hydrophobic binding interaction between
[12]
the cavity of the cyclodextrin and substrate. BNPC is a
kind of ditopic hydrophobic substrate and can aesthetically
second-order rate (kBNPP
1.00 mm) cleavage promoted by ZnL (0.10 mm) is illustrat-
) on the pH for the BNPP
[14]
(
bind into the two cavities of cyclodextrin, However, such
binding hardly appears for NA because it has only one hy-
drophobic group.A cyclodextrin dimer can bind strongly to
such a ditopic substrate, which can occupy both cyclodextrin
ed in Figure 7. kBNPP increases sharply as the pH increases
from 7.50 to 8.85 and then slows at higher pH, displaying a
sigmoidal curve for the cleavage reaction.The result indi-
cates a kinetic process controlled by an acid/base equilibri-
um.The data were fitted by means of a Boltzman model,
which resulted in an inflection point at 8.11; this is almost
[29]
cavities as a result of its size/shape, and once the substrate
is split in half by the catalytic group, the monotopic hydro-
phobic product would easily leave because of weakened
[10,12,26]
the same as the pK value of the coordinated water mole-
binding.
a
To observe the role of cyclodextrin cavities on hydrolysis,
we prepared a BNPC analogue, di(p-tert-butylbenzyl) amine
(
DBBA).The rate of catalytic hydrolysis of BNPC can be
dramatically decreased by 59% in the presence of DBBA
see Figure S9 in the Supporting Information), which indi-
(
cates that it is significantly inhibited by DBBA.Because the
p-tert-butyl group can strongly bind into the CD cavity by
[12,17–19]
hydrophobic interactions,
DBBA occupied a position
in the BisCD cavity.As a result, BNPC cannot again bind
into the cavity to form the favorable conformation in which
BNPC is nicely near the zinc ion, which results in the inhibi-
tion of catalytic hydrolysis.To further confirm the above ob-
servation, the inclusion complexation of inhibitor DBBA
and ZnL was investigated by means of 2D NMR spectrosco-
py.In an observed 2D NMR spectrum (Figure 8), interac-
tions between the aryl protons of DBBA and the protons
inside of cyclodextrin were found, which indicated that
DBBA markedly inhibits the catalytic reaction of [ZnL].
Figure 7.The pH dependence of the second-order rate constants of
BNPP hydrolysis ([ZnL]=0.10 mm, [BNPP]=1.00 mm, [buffers]=50 mm,
I=0.10m NaClO
4
, (308ꢀ0.1) K.
7198
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7193 – 7201

Ester Hydrolysis
FULL PAPER
Therefore, the enhanced second-order rate constant should
be contributed to both the binding sites (two hydrophobic
cavities) and the catalytic site (metal ion and its coordinated
groups).The two hydrophobic cavities cooperatively bind
the substrate and juxtapose the ester functional group and
the catalytic metal ion.
To all appearances, the rate acceleration of diester hydrol-
ysis catalyzed by ZnL should be ascribed to the cooperative
binding action of two hydrophobic cavities and the zinc hy-
droxyl active species of metallophenanthroline complex.A
possible intermediate is suggested for ester hydrolysis in
Scheme 2.
Figure 8.COSY spectrum of the inclusion complexation of ZnL and in-
hibitor DBBA.
These observations unambiguously demonstrated that hy-
drophobic interactions play an essential role in catalytic hy-
drolysis.In BNPP hydrolysis, the kMOH value is comparative-
II
ly higher than most other reported Zn -based systems with
[
30–33]
a similar pK in the catalytic hydrolysis of BNPP.
Sur-
a
+
prisingly, the kMOH of [ZnL(OH)] is about 50-fold higher
than that of its a macrocyclic polyamine analogue, [Zn(O-
+
H)([12]aneN4)]
([12]aneN =1,4,7,10-tetraazacyclodode-
4
ꢁ
5
ꢁ1 ꢁ1 [34]
cane, kMOH =2.1”10
those of other reported binuclear complexes (Table 4). It
m
s ),
and is even higher than
[35]
is well-known that the p-nitrophenate group can bind into
[36,37]
the hydrophobic cavity of b-cyclodextrin,
and thus
BNPP with two ditopic groups of p-nitrophenole can strong-
[38]
ly bind into both cavities of some appropriate BisCDs.
Scheme 2.Suggested intermediates for ester hydrolysis catalyzed by ZnL.
Table 4.The second-order rate constants
moted by Zn complex at (308ꢀ0.1) K.
kMOH of BNPP hydrolysis pro-
II
[a]
ꢁ1
ꢁ1
Conclusion
Species
k
MOH [m
s
]
pK
a
Ref.
+
ꢁ5
ꢁ6
[
[
[
[
Zn(OH)([12]aneN4)]
2.1”10
5.2”10
1.31”10
9.9”10
5.6”10
6.9”10
7.9
7.68
8.8
8.18
6.94
10.7
[34]
[35]
[31]
this work
[32]
+
A novel cyclodextrin dimer has been prepared as a catalytic
precursor.Its zinc complex has been successfully synthesized
and fully characterized, and thus demonstrated as a potent
catalyst of diester hydrolysis.The hydrophobic interactions
between catalyst and substrate play an important role in the
catalytic hydrolysis.Therefore, such a stable supramolecular
complex is a promising model compound for mononuclear
metallohydrolase and has potential in the development of
an effective model for metalloenzymes.
Zn(OH)
A
C
H
T
R
E
U
N
G
(mecyclen)]
+
ꢁ5
Zn(OH)([15]aneN
3
O
2
)]
+
ꢁ4
Zn(L)(OH)]
+
ꢁ6
ꢁ5
A
C
H
T
R
E
U
N
G
[Zn
2
A
C
H
T
R
E
U
N
G
(bmxd)(OH)]
2
+
A
C
H
T
R
E
U
N
G
[Zn
2
(OH)
2
{([9]aneN
3
)
2
-phen}]
[33]
[
1
a] [12]aneN
4
=1,4,7,10-tetraazacyclododecane,
,4,7,10-tetraazacyclododecane, [15]aneN =1,4-dioxa-7,10,13-triazacy-
bmxd=3,6,9,17,20,23-hexaazatricyclotriaconta-
,11,13,15,25,27-hexaene, and ([9]aneN -phen=1,10-phenanthroline-2,9-
1,4,7-triazacyclododecane).
mecyclen=N-methyl-
3 2
O
clopentadecane,
1
(
3 2
)
Chem. Eur. J. 2008, 14, 7193 – 7201
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
7199

Z.-W. Mao et al.
a pH of 11 was reached.The mixture was extracted with methylene chlo-
ride, dried over sodium sulfate, filtered, and acidified with concentrated
HCl.After evaporation of the solvents, the oil product was dissolved in
ethanol (95%), acidified with concentrated HCl to pH 3, and the vola-
tiles removed.The crude product obtained was recrystallized from an
ethanol/acetone mixture and afforded pure DBBA (HCl salt) in 52%
Experimental Section
Materials: NA, BNPC, 4-tert-butylbenzyl amine, and p-tertbutyl benzal-
dehyde were purchased from Aldrich. b-CD of reagent grade was recrys-
tallized twice from H
2
O and dried in vacuo for 12 h at 373 K, DMF was
dried over CaH for 2 days and then distilled under reduced pressure
2
1
3
yield. H NMR (300 MHz, CDCl
3
): d=10.01 (brs, 1H; NH), 7.44 (d, J-
prior to use.Common organic reagents were reagent grade and redistil-
led before use.Water used in all physical measurement experiments was
Milli-Q grade.The materials of 6-monodeoxy-6-monoamino- b-cyclodex-
trin were prepared from 6-monodeoxy-6-monoazido-b-cyclodextrin ac-
cording to a previous procedure reported by Jicsinszky et al., with a
3
A
H
R
U
G
J(H,H)=7.7 Hz, 4H;
A
H
R
U
G
phenyl-H-2, 2’), 3.79 (s, 4H; benzyl-3,3’), 1.21 ppm (s, 18H; tert-butyl-H);
+
MS (ESI, MeOH): m/z: calcd: 310.3 [M+H] ; found: 310.0; elemental
analysis calcd (%) for C H N·HCl·0.5H O: C 74.44, H 9.37, N 3.95;
2
2
31
2
[
39]
minor modification, whereas 6-mono(p-toluenesulfonyl)-b-cyclodextrin
found: C 74.29, H 9.27, N 3.74.
[
40]
was prepared in dry pyridine solution rather than aqueous solution.
,10-phenanthroline-2,9-dicarbaldehyde was obtained according to the lit-
Caution: Perchlorate salts of organic compounds are potentially explosive;
these compounds must be prepared and handled with great care!
1
[
41]
erature procedure. All compounds were confirmed by their elemental
1
Potentiometric pH titration: An automatic titrator (Metrohm 702GPD
analyses, ESIMS, and H NMR spectra.
1
Titrino) coupled to a Metrohm electrode was used and calibrated accord-
General methods: H NMR spectra were recorded on a Varian INOVA-
00NB or Mercury plus 300 spectrometers.IR spectra were recorded on
[
42]
ing to the Gran method. The electrode system was calibrated with buf-
fers and checked by titration of HClO with NaOH solution (0.10m).The
3
4
a Brucker FTIR EQUINOX 55 spectrometer.Elemental contents were
analyzed by a Perkin–Elemer 240 elemental analyzer.ESIMS spectra
were performed on a Thremo LCQ-DECA-XP spectrometer.UV/Vis
spectra were monitored with a Varian Cary 300 UV/Vis spectrophotome-
ter equipped with a temperature controller (ꢀ0.1 K).
thermostated cell contained 25 mL of 1.00 mm species in aqueous solu-
tions with the ionic strength maintained at 0.10m by sodium perchlorate.
All titrations were carried out in the aqueous solutions under nitrogen at
(298ꢀ0.1) K, and initiated by adding fixed volumes of 0.10m standard
NaOH in small increments to the titrated solution.Duplicate measure-
ments were performed, for which the experimental error was below 1%.
The titration data were fitted from the raw data with the Hyperquad
1
,10-Phenanthroline-2,9-bis(6-ammoniomethyl-b-cyclodextrin) (L): A so-
lution of 1,10-phenanthroline-2,9-dicarboxaldehyde (0.249 g, 1.056 mmol)
in dry DMF (5 mL) was added dropwise to a solution of 6-monodeoxy-6-
monoamino-b-cyclodextrin (2.395 g, 2.112 mmol) in dry DMF and anhy-
drous MeOH (v/v 2:1) with vigorous stirring.The mixture was then
heated to 353 K for 6 h under nitrogen gas.After this time, the reaction
2000 program to calculate the ligand protonation constants K
plex formation constant KML, and the deprotonation constants of the co-
ordinated water pK
n
, the com-
a
.
was cooled to room temperature, then a slight excess of NaBH
4
(0.096 g,
Kinetics of BNPC and NA hydrolysis: The hydrolysis rate of BNPC and
NA in the presence of ZnL complex was measured by an initial slope
2
.543 mmol) was added to reduce the imine over a period of 2 h. The
mixture was then washed with water and filtered.The filtrate was evapo-
rated to dryness under a reduced pressure, and the resulting residue was
dissolved in a small amount of hot water, and the aqueous solution was
poured into acetone (200 mL) to give a light-yellow precipitate.The
crude product obtained was dried and purified by column chromatogra-
phy over Sephadex G-25 with distilled deionized water as the eluent to
method following the increase in the 400 nm absorption of the released
[14,25]
4
0
-nitrophenolate.
The reaction solution was maintained at (298ꢀ
.1) K. Tris-HCl (pH 7.01, 8.85) buffers were used (50 mm), and the ionic
.In a typical experiment, after
substrate (NA or BNPC) and ZnL complex in 10% (v/v) CH CN solu-
strength was adjusted to 0.10 with NaClO
4
3
tion at an appropriate pH were mixed, the UV absorption decay was re-
corded immediately and was followed generally until 2% decay of 4-ni-
trophenyl acetate.Errors on kobs values were about 5%.
give the pure compound in 32% yield.UV/Vis (H
2
O): lmax (e)=273
ꢁ1
ꢁ1
1
(
33177), 232 nm (50967 mol Lcm ); H NMR (300 MHz, DMSO): d=
3
8
7
4
3
2
1
H
.41 (d,
.84 (d, J
J
A
C
H
T
R
E
U
N
G
(H,H)=8.2 Hz, 2H; phen-H-4,7), 7.89 (s, 2H; phen-H-5,6),
3
A
C
H
T
R
E
U
N
G
(H,H)=8.2 Hz, 2H; phen-H-3,8), 5.68–5.72 (m, 28H; OH-2,3),
Kinetics of BNPP hydrolysis: The rate of hydrolysis of BNPP to give
mono(4-nitrophenyl) phosphate and p-nitrophenolate was measured by
an initial slope method following the increase in the 400 nm absorption
.88–4.82 (m, 14H; H-1), 4.45 (m, 12H; OH-6), 4.22–3.57 (m, 60H; H-
,5,6, phen-CH
2
), 3.36–2.72 (m, 28H; H-2,4, overlaps with
H
2
O),
.10 ppm (brs, 2H; NH); IR (KBr): n˜ =3382, 2927, 1624, 1595, 1503,
[26]
of the released p-nitrophenolate in aqueous solution at (308ꢀ0.1) K.
ꢁ
1
421, 1369, 1157, 1081, 1029, 943, 858, 756, 707, 578 cm ; MS (ESI,
At this wavelength, the absorbance of the ester substrate was negligible.
MES (pH 6.00–6.60), MOPS (pH 6.60.-7.40), HEPES (pH 7.40–8.20),
TAPS (pH 8.20–8.90), and CHES (pH 8.90–9.50) buffers were used
2
+
2+
2
O): m/z: calcd: 1236.4 [M+2H]
,
1247.4 [M+Na+H]
;
found:
O: C
1
236.6, 1247.7; elemental analysis calcd (%) for C98
H
150
N
4
O
68·14H
2
4
3.20, H 6.59, N 2.06; found: C 43.04, H 6.58, N 2.06.
(
4
50 mm), and the ionic strength was adjusted to 0.10 with NaClO .The
Zinc complex (ZnL): A solution of phenBisCD (0.100 g, 0.040 mmol) in
water (5 mL) was added dropwise to a dilute aqueous solution of a slight
pH of the solution was measured after each run, and all kinetic runs with
pH variation larger than 0.1 were excluded. The substrate BNPP, buffers,
and ZnL in aqueous solution were prepared freshly.The reactions were
initiated by injecting a small amount of BNPP into the buffer solutions
of ZnL and followed by fully mixing at (308ꢀ0.1) K. The visible absorp-
tion increase was recorded immediately and was followed generally until
A
C
H
T
R
E
U
N
G
4 2 2
excess of Zn(ClO ) ·6H O (0.016 g, 0.044 mmol) with magnetic stirring at
room temperature.The resultant solution was kept stirring for 2 h, and
then the solution was evaporated under reduced pressure.The precipitate
formed was collected by filtration, washed successively with a small
amount of ethanol and diethyl ether, and then dried in vacuo to give the
2
% formation of p-nitrophenolate, in which e values for 4-nitrophenolate
2
pure complex as a pale-yellow solid in 68% yield.UV/Vis (H O): lmax
ꢁ
1
ꢁ1
were 4069 (pH=6.5), 9610 (pH=7.08), 13745 (pH=7.50), 15788 (pH=
7.79), 16163 (pH=7.86), 16943 (pH=8.04), 17600 (pH=8.26), 18079
(
e): n˜ =277 (33766), 230 nm (45743 mol Lcm ); MS (ESI, H
2
O): m/z:
calcd: 1268.38 [M] ; found: 1268.31; elemental analysis calcd (%) for
(ClO ·14H O: C 39.38, H 6.00, N 1.87; found: C 39.45,
2
+
(
pH=8.52), 18512 (pH=9.05), and 18569 (pH=9.31) at 400 nm. The ini-
C
98
H
150
N
4
O
68·Zn
A
C
H
T
R
E
U
N
G
4
)
2
2
ꢁ
1
tial first-order rate constants, kin (s ), for the cleavage of BNPP were ob-
tained directly from a plot of the 4-nitrophenolate concentration versus
time by the method of initial rates, which was linear with R>0.996. The
second-order rate constants (kBNPP) for the catalyzed reactions were de-
termined as the slope of the linear plots of kin versus ZnL concentration.
To correct for the spontaneous cleavage of BNPP, each reaction was mea-
sured against a reference cell that was identical to the sample cell in com-
H 6.35, N 1.52.
Di(p-tert-butylbenzyl) amine (DBBA): p-tert-Butyl benzaldehyde
1.76 mL, 10 mmol) in absolute ethanol (5 mL) was added dropwise to a
(
stirred solution of 4-tert-butylbenzyl amine (1 mL, 6 mmol) in absolute
ethanol (5 mL) in an ice bath.After 4 h, the solution was cooled to 273 K
and sodium borohydride (0.45 g, 12 mmol) was added in small portions.
After the reaction had been stirred for 12 h at room temperature, aque-
ous HCl (5 mL, 2m) was added slowly and the mixture was stirred for
position except for the absence of ZnL.Errors on
about 5%.
kBNPP values were
1
h.An aqueous solution of sodium hydroxide (2 m) was then added until
7200
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7193 – 7201

Ester Hydrolysis
FULL PAPER
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Received: February 7, 2008
Published online: July 7, 2008
Chem. Eur. J. 2008, 14, 7193 – 7201
ꢀ 2008 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
7201