Chromogenic chemosensors for N-acetylaspartate based on chiral ferrocene-bearing thiourea derivatives

Article abstract of DOI:10.1002/ejoc.200800961

A series of chiral ferrocene-containing thiourea derivatives have been synthesized, and their enantioselective recognition properties were investigated by UV/Vis titration. Receptors 5a and 6a exhibit excellent chiral recognition abilities towards N-acety

Full text of DOI:10.1002/ejoc.200800961

FULL PAPER
DOI: 10.1002/ejoc.200800961
Chromogenic Chemosensors for N-Acetylaspartate Based on Chiral Ferrocene-
Bearing Thiourea Derivatives
Guang-Yan Qing,*[a,b] Tao-Lei Sun,[b] Feng Wang,[a] Yong-Bing He,[a] and Xi Yang[a]
Keywords: Receptors / Sensors / Chiral anion detection / Ferrocene / Chromogenic receptor / Enantioselectivity / Thiourea
A series of chiral ferrocene-containing thiourea derivatives
can be observed directly by the naked eye. The minimum
have been synthesized, and their enantioselective recogni- energy structures of 5a and 6a were also obtained by theoret-
tion properties were investigated by UV/Vis titration. Recep-
tors 5a and 6a exhibit excellent chiral recognition abilities
towards N-acetylaspartate. The differences in solution colour
ical DFT calculations.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
of functional groups. In the past, Fc derivatives that bind
to and allow the electrochemical sensing of cations[5] and
anions[6] have been reported widely. The various bonding
and nonbonding interactions that allow these charged spe-
cies to be electrochemically recognized have been reviewed
in detail.[7] Many planar chiral Fcs were used as chiral li-
gands in a series of metal-catalyzed processes,[8] which indi-
cate the potential application of chiral Fc derivatives in the
enantioselective recognition of chiral materials.
To the best of our knowledge, chiral anion receptors
based on Fc are still rare,[9] which inspired us to use Fc as
the preorganised platform and introduce strong hydrogen-
bond donors such as amides and thioureas to this system.
In this work, we aimed at the synthesis of a series of chiral
ferrocenium/Fc derivatives bearing thiourea units 5a–5e,
6a–6e and the determination of their binding properties
towards N-protected aspartate or glutamate by UV/Vis
spectroscopy. The main carboxylate binding sites in these
receptors are the thiourea moieties, and the two amide
groups should provide additional hydrogen-bonding func-
tionalities.[4a,b,10] Based on the good preorganised structure
supplied by the Fc unit, the two chiral centres in the two
arms should enable enantioselective recognition, while the
process of recognition could transduce to an optical signal
through the p-nitro phenyl chromogenic group. The results
obtained from UV/Vis titration experiments indicate that
receptors 5a and 6a have excellent enantioselective recogni-
tion abilities towards N-acetylaspartate (NAA); obvious
colour differences could be observed by the naked eye.
Introduction
Molecular recognition lies at the heart of biochemistry.
All biomedical processes inherently require selective molec-
ular recognition and successful complexation. Matching the
degree of exquisite control and efficiency exhibited by natu-
ral systems is a challenging goal for host-guest chemists to
emulate and has led to much interest in the design of a
diverse range of synthetic receptors for important biological
substrates.[1] Anions, especially chiral anions, play numer-
ous fundamental roles in biological and chemical processes
as exemplified by the majority of enzymes binding anions
as either substrates or cofactors, and many anions act as
ubiquitous nucleophiles, bases, redox agents and phase-
transfer catalysts. The enantioselective recognition and
sensing of biologically relevant anions by artificial host
molecules has emerged recently as a key research theme
within the generalized area of supramolecular chemistry.[2]
Aspartate and glutamate have been thoroughly studied
as excitatory amino acid neurotransmitters.[3] -aspartate is
also present in appreciable quantities in fetal tissues and
especially in fetal brain and is a potent agonist of the excit-
atory amino acid receptors, which play a role in brain func-
tion and development. Taking into account their critical im-
portance, some research effort has been devoted to the syn-
thesis of chiral receptors, which are capable of detecting and
distinguishing between the enantiomers of these anions.[2c,4]
Ferrocene (Fc) systems have a well developed organic
chemistry, allowing for their attachment to a wide variety
[a] College of Chemistry and Molecular Sciences, Wuhan Univer-
sity,
Results and Discussion
Wuhan 430072, P. R. China
Fax: +49-251-8333602
E-mail: qingguangyan@hotmail.com
[b] Physikalisches Institut, Universität Münster,
48149 Münster, Germany
Synthesis
The synthesis of compounds 5a–5d and 6a–6d is outlined
in Scheme 1 and Scheme 2. The structures of four reference
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 841–849
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
841

G.-Y. Qing, T.-L. Sun, F. Wang, Y.-B. He, X. Yang
FULL PAPER
Scheme 1. The synthesis of compounds 5a–5c, 6a–6c.
compounds 5e, 6e, 7a–7b are outlined in Scheme 3. They phenomenon, we synthesized 3d and 5d. Interestingly, both
are soluble in CH3OH, DMSO and DMF. Due to the ef- of them provided clear NMR signals, so the paramagnetism
fects of paramagnetism, compounds 3a–3c and 5a–5c did could be attributed to the effect of the amides. Because Fc
not provide signals by liquid NMR spectroscopy, so their undergoes a fast one-electron oxidation to its cationic form
structures were characterized by IR, ESI-MS and elemental (Fc+), for compound 3a–3c, the oxidized ferrocenium cat-
analysis. We also used solid-state NMR to detect the struc-
ture of 5a, but we could not clearly identify NMR signals
due to very strong coupling. We characterized the structures
of other compounds by IR, ESI-MS, 1H and 13C NMR
spectroscopy and elemental analysis. In order to clarify this
Scheme 3. The structures of reference compounds 5e, 6e, 7a and
Scheme 2. The structures of compounds 3d, 5d and 6d.
842
7b.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 841–849

Chromogenic Chemosensors for N-Acetylaspartate
ion could be stabilized by intramolecular hydrogen bond-
ing,[7c] and the possible charge-transfer (CT) processes are
shown in the Supporting Information (Scheme S1). The
paramagnetic character of ferrocenium hampered the use
of NMR spectroscopy in this oxidation state. If the intra-
molecular hydrogen bonding were obstructed by ethyl or
tertiary amine, as in 4a–4c or 3d, the ferrocenium could not
exist stably, and these compounds favoured their Fc forms
and exhibited normal NMR signals.
UV/Vis Spectroscopy
Nowadays, the development of colorimetric anion sens-
ing is particularly challenging since visual detection can
give immediate qualitative information, and it is becoming
increasingly appreciated in term of quantitative analysis;[11]
thus, UV/Vis spectra titration is a proper method to investi-
gate the enantioselective recognition abilities of these recep-
tors. It is known that NAA is present in brain tissue[12] at
concentrations exceeded only by glutamate among the
amino acids, and NAA is confined almost exclusively in
Figure 1. UV/Vis absorption spectra of receptor 5a
(5.0ϫ10–5 moldm–3) upon the addition of various amounts of N-
Ac--aspartate in DMSO at 25 °C. Equivalents of anion: 0, 0.25,
0.75, 1.0, 1.5, 2.0, 2.5, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.5, 11.5, 13,
15, 16.5, 18, 20 and 21.5. The curve-fitting line through the data
points at 500 nm is shown in the inset, where G is the guest and H
is the host. The correlation coefficient (R) of nonlinear curve fitting
is 0.9947.
vertebrates to nervous tissue including the retina.[13] Taking tron-deficient p-nitrophenyl moieties. When the receptor
into account the critical importance of NAA, we chose bound an NAA, hydrogen bonds formed stable complexes,
NAA as the guest and recorded UV/Vis spectra for a solu- and electron density in the supramolecular system increased
tion of 5a or 6a in the absence or presence of N-acetyl-- considerably. This enhanced the CT interaction between the
or -aspartate, with Bu4N+ as the counter cation. We chose electron-rich and -deficient moieties, resulting in a visible
DMSO as the solvent considering the solubility of both the colour change.[15] When a protic solvent such as CH3OH
receptors and anions.
was added to the red solution of 5a and -aspartate or the
The UV/Vis absorption spectra of 5a upon the addition nacarat solution of 5a and -aspartate in DMSO, the col-
of N-acetyl--aspartate are shown in Figure 1. In the ab- our of both solutions became yellowish. These phenomena
sence of anion, 5a had an absorption maximum at 370 nm, indicated that the addition of a protic solvent destroyed the
which can be assigned to an intramolecular charge-transfer complexation between 5a and N-Ac-- or -aspartate, dem-
(ICT) absorption band.[14] With the addition of -aspartate onstrating that the interactions between 5a and - or -
to the solution of 5a in DMSO (5.0ϫ10–5 moldm–3), the aspartate depended very much on hydrogen-bonding inter-
characteristic absorption peak of the host at 370 nm de- actions.[11,16] In many previous studies, it has been reported
creased gradually with a redshift (of approximately 20 nm), that similar Fc receptors bound anions or neutral molecules
and a new absorption peak at 484 nm was produced. The through hydrogen bonding.[6,17] In this system, we did not
new absorption suggested the formation of the complex be- observe clear isosbestic points; this may be due to the
tween 5a and -aspartate. Gradually increasing the concen- change of interaction mode. At lower concentrations of as-
tration of anion changed the colour of the solution from partate, a 1:1 complex may be formed between one arm of
yellowish to red, which could be observed by the naked eye the receptor and the anion, and the electron density in the
directly.
supramolecular system may have increased, which may have
As shown in Figure 2, we observed similar phenomena enhanced the CT interactions between the electron-rich do-
when N-Ac--aspartate was added to a solution of 5a in nor units and electron-deficient p-nitrophenyl moieties, re-
DMSO (5.0ϫ10–5 moldm–3). With the increasing concen- sulting in the new absorption peak. With increasing
tration of -aspartate, the new band at 484 nm increased amounts of anion, the other receptor arm will participate
gradually, 18.5 equiv. of anion led the absorbance intensity in the interaction; two arms could bind an anion in a “sand-
(at 484 nm) to approach 0.73 and the solution colour of wich” mode, resulting in an extension of the supramolec-
solution changed from yellowish to nacarat. While the in- ular system and increased CT interactions with an enhance-
tensity approached 1.05 with the same amount of -aspart- ment of the absorption at 484 nm. The satisfactory result
ate, the solution colour already changed from yellowish to [the correlation coefficient (R) was Ͼ 0.99] of nonlinear
red. Clear differences in the absorbance spectra indicated curve fitting (at 500 nm) confirmed that 5a and N-Ac-- or
that 5a had a good enantioselective recognition ability -aspartate formed a 1:1 complex (see the insets of Figure 1
towards NAA. We attributed the colour change to an obvi- and Figure 2);[18] in addition, the association constants
ous increase of absorption in the visible region at 484 nm, (KA) for - and -aspartate were different [KA(L)
=
which can be ascribed to a CT interaction between the elec- 981.1 dm3 mol–1; KA(D) = 93.5 dm3 mol–1], corresponding to
tron-rich, donor nitrogen of the thiourea units and the elec- an / selectivity [KA(L)/KA(D)] of 10.49 for NAA.
Eur. J. Org. Chem. 2009, 841–849
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G.-Y. Qing, T.-L. Sun, F. Wang, Y.-B. He, X. Yang
FULL PAPER
Figure 2. UV/Vis absorption spectra of receptor 5a
(5.0ϫ10–5 moldm–3) upon the addition of various amounts of N-
Ac--aspartate in DMSO at 25 °C. Equivalents of anion: 0, 0.4,
1.0, 1.5, 2.5, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5, 9.5, 10.5, 12, 13, 14, 15, 16.5
and 18.5. The curve-fitting line through the data points at 500 nm
is shown in the inset, where G is the guest and H is the host. The
correlation coefficient (R) of non-linear curve fitting is 0.9926.
Figure 3. UV/Vis absorption spectra of receptor 6a
(5.0ϫ10–5 moldm–3) upon the addition of various amounts of N-
Ac--aspartate in DMSO at 25 °C. Equivalents of anion: 0, 0.35,
0.75, 1.5, 2.0, 2.75, 3.6, 4.5, 5, 6, 8, 10, 14.5, 16.5, 20, 25, 30, 40,
47.5, 60, 75 and 95. The curve-fitting line through the data points
at 484 nm is shown in the inset, where G is the guest and H is the
host. The correlation coefficient (R) of non-linear curve fitting is
0.9909.
Receptor 6a showed a similar response to 5a upon ad-
dition of N-Ac--aspartate. In the absence of the anion, the
UV/Vis spectrum of 6a in DMSO (5.0ϫ10–5 moldm–3) ex-
hibited an intramolecular CT absorption band (λmax
=
360 nm). With the addition of -aspartate, the ICT band
shifted to 370 nm, and we observed a new absorption band
at 484 nm (see Figure 3). The solution colour changed from
yellowish to red, which could also be attributed to the clas-
sical CT interaction.[15,16] But when N-Ac--aspartate was
added to the solution of 6a, as shown in Figure 4, we ob-
served different phenomena. With the increasing concentra-
tion of anion, the characteristic absorption peak of the host
at 360 nm decreased slightly with a redshift (of approxi-
mately 14 nm); only a weak new absorption peak at 484 nm
was produced, and 30 equiv. of -aspartate led the ab-
sorbance intensity (at 484 nm) to approach only 0.23, while
the solution colour changed from yellowish to yellow. These
results contrasted strongly with those of the 6a/-aspartate
titration, where the absorbance at 484 nm approached 1.14
with 30 equiv. of -aspartate, and the solution colour
changed from yellowish to red. Obvious differences in the
absorbance spectra and solution colour indicated that 6a
had good enantioselective recognition abilities towards the
enantiomers of NAA. The satisfactory nonlinear curve fit-
ting at 484 nm (the correlation coefficient was Ͼ 0.99) con-
firmed that 6a and - or -aspartate formed a 1:1 complex
(see the insets of Figure 3 and Figure 4). The KA values of
Figure 4. UV/Vis absorption spectra of receptor 6a
(5.0ϫ10–5 moldm–3) upon the addition of various amounts of N-
Ac--aspartate in DMSO at 25 °C. Equivalents of anion: 0, 0.05,
0.1, 0.2, 0.5, 1.2, 1.8, 3.0, 4.5, 6.0, 8.5, 11.0, 14.5, 20, 30 and 47.5.
The curve-fitting line through the data points at 484 nm is shown
in the inset, where G is the guest and H is the host. The correlation
coefficient (R) of non-linear curve fitting is 0.9928.
creased considerably to enhance the CT interaction between
the thiourea units and the electron-deficient p-nitrophenyl
moieties, which resulted in a visible colour change. The re-
the two enantiomers with 6a were very different [KA(L)
=
297.9 dm3 mol–1; KA(D) = 3.91ϫ103 dm3 mol–1], which cor-
responded to a / selectivity [KA(D)/KA(L)] of 13.1 for
NAA.
When N-Ac-- or -aspartate was added to a solution of
5a or 6a in DMSO, colour changes of the solution are
shown in the Figure 5. In each case, we added 10 equiv. of
anion. When the receptors bound the anions effectively, hy-
drogen bonds were constructed to form stable complexes,
Figure 5. Effects of N-Ac-- or -aspartate (10 equiv., as Bu4N+
salts) on solution colour changes of 5a or 6a (1ϫ10–4 moldm–3) in
DMSO. From left to right: (a) 5a; (b) 5a + -aspartate; (c) 5a + -
and the electron density in the supramolecular system in- aspartate; (d) 6a; (e) 6a + -aspartate; (f) 6a + -aspartate.
844 Eur. J. Org. Chem. 2009, 841–849
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Chromogenic Chemosensors for N-Acetylaspartate
markable colour changes from yellowish to nacarat or yel-
low of 6a with N-Ac-- or -aspartate, respectively, revealed
that 6a can be used as a colorimetric chemosensor for the
enantiomers of NAA.
Receptors 5a and 6a have similar structures; both of
them could form stable 1:1 complexes with NAA, but their
enantioselective recognition abilities towards NAA are
nearly opposite. Compound 6a had stronger interactions
with  enantiomers (the / selectivity was 13.1), while 5a
was inclined to bind  enantiomers (the / selectivity was
10.49). In addition, the KA values were also different.
KA(6a+D-aspartate) was much larger than KA(5a+L-aspartate)
,
while KA(6a+L-aspartate) was also larger than KA(5a+D-aspartate)
,
suggesting that 6a could bind the guest through stronger
hydrogen-bonding interactions with NAA, possibly due to
the more complementary structure of 6a for NAA than that
of 5a. We presume that these receptors may have different
preorganised structures and could interact with the enantio-
mers through different hydrogen-bonding sites. We carried
out quantum chemical calculations to explain these phe-
nomena further.
We used continuous variation methods to determine the
stoichiometric ratios of the complexes formed between the
receptors 5a and 6a and the anion guests.[19] We maintained
the total concentration of the host and NAA constant
(1.0ϫ10–4 moldm–3) in DMSO, and varied the mole frac-
tion of the guest {[G]/([H]+[G])} continuously. Figure 6
Figure 6. Job plots of 5a (at 500 nm) and 6a (at 484 nm) interacting
with N-Ac-- or -aspartate. The total concentration of the host
(H) and guest (G) was 1.0ϫ10–4 moldm–3 in DMSO.
of host and anion guest. The KA values and correlation
coefficients (R) obtained by a nonlinear least-squares analy-
sis of A versus CH and CG are listed in Table 1.
(1)
From the data listed in Table 1, we found that receptor
shows the Job plots for 5a (at 500 nm) and 6a (at 484 nm) 5a showed a good enantioselective recognition ability
with - or -aspartate in DMSO. When the mole fraction towards N-acetyl-glutamate with a / selectivity [KA(D)
/
of the guest was 0.50, the absorption reached a maximum, KA(L)] of 2.64, while 6a also exhibited a weak chiral recogni-
demonstrating that 5a and 6a both formed a 1:1 complex tion for this anion. When N-Boc-aspartate or N-benzoyl-
with - or -aspartate.
aspartate was used, these receptors showed no enantio-
We also investigated the interactions between receptors selectivities. On the other hand, control binding experi-
5a or 6a and the enantiomers of N-acetyl-, N-Boc- or N- ments with 5a or 6a and malate under the same conditions
benzoyl-protected aspartate or glutamate by UV/Vis ti- revealed no chiral recognition effect. These results demon-
tration experiments. The results are listed in Table 1 and strated that the acetyl group of NAA played an important
show that 5a and 6a have lower chiral recognition abilities role in the chiral recognition process and could largely in-
towards other aspartate and glutamate derivatives. For the fluence the complexation.
1:1 complex, a KA can be calculated using the following
Another interesting phenomenon we found was that the
Equation (1) in Origin 7.0.[20] A represents the absorption KA values between receptors and various N-protected gluta-
intensity, and CH and CG are the respective concentrations mates were generally larger than those with the correspond-
Table 1. KA values, correlation coefficients (R) and enantioselectivities (KL/KD) of receptors 5a or 6a with - or -aspartate or glutamate
in DMSO at 25 °C.
Entry
Guest[a]
5a
6a
KA [dm3 mol–1][b]
R
KD/KL
KA [dm3 mol–1][b]
R
KD/KL
1
2
3
4
5
6
7
8
N-Ac--Asp
N-Ac--Asp
N-Boc--Asp
N-Boc--Asp
N-Bz--Asp
N-Bz--Asp
N-Ac--Glu
N-Ac--Glu
N-Boc--Glu
N-Boc--Glu
N-Bz--Glu
N-Bz--Glu
981.1Ϯ45.2
93.5Ϯ8.6
0.9937
0.9926
0.9915
0.9918
0.9915
0.9936
0.9928
0.9962
0.9910
0.9902
0.9935
0.9922
–
297.9Ϯ24.2
0.9909
0.9912
0.9938
0.9968
0.9977
0.9928
0.9906
0.9915
0.9947
0.9964
0.9905
0.9910
–
13.1
–
1.07
–
0.90
–
0.69
–
1.48
–
0.095
–
1.23
–
0.82
–
2.64
–
(3.91Ϯ0.34)ϫ103
(1.75Ϯ0.11)ϫ103
(1.88Ϯ0.09)ϫ103
(5.22Ϯ0.19)ϫ103
(4.68Ϯ0.30)ϫ103
(2.05Ϯ0.19)ϫ103
(1.41Ϯ0.12)ϫ103
(2.96Ϯ0.20)ϫ103
(4.38Ϯ0.24)ϫ103
(8.18Ϯ0.79)ϫ103
(8.36Ϯ0.81)ϫ103
(4.30Ϯ0.39)ϫ103
(5.30Ϯ0.42)ϫ 103
(4.97Ϯ0.35)ϫ103
(4.07Ϯ0.28)ϫ103
(1.48Ϯ0.12)ϫ103
(3.91Ϯ0.21)ϫ103
(9.27Ϯ0.66)ϫ103
(1.17Ϯ0.72)ϫ104
(1.23Ϯ0.12)ϫ104
(1.30Ϯ0.14)ϫ104
9
10
11
12
1.26
–
1.06
1.02
[a] The anions were used as their Bu4N+ salts. [b] All error values were obtained by the results of nonlinear curve fitting.
Eur. J. Org. Chem. 2009, 841–849
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G.-Y. Qing, T.-L. Sun, F. Wang, Y.-B. He, X. Yang
FULL PAPER
ing N-protected aspartate. For example, KA(5a+N-Ac-L-Glu) the enantiomeric selectivity largely depended on different
was 1480 dm3 mol–1, while KA(5a+N-Ac-L-Asp) was hydrogen-bonding abilities.
981.1 dm3 mol–1, indicating that both receptors have
In the design of chemosensors, the selection of a supra-
stronger hydrogen-bonding interactions with glutamate molecular platform is critically important because it sup-
than with aspartate. We presume the carboxylate group of plies the proper preorganised structure for the recognition.
glutamate could approach the hydrogen-bonding groups of In this work, we introduced Fc as a supramolecular plat-
the receptors closer due to its longer alkyl chain, promoting form and prepared a series of Fc derivatives bearing thio-
the complexation of host and guest.[16]
urea groups, which exhibited excellent chiral recognition
In order to investigate possible interaction mode, we syn- abilities. In order to compare this platform with possible
thesized a series of reference compounds 5b–5e, 6b–6e, 7a alternatives, we synthesized two reference compounds (7a
and 7b and studied their bonding properties towards NAA and 7b) based on 2,6-pyridine dicarboxylic acid, and their
by UV/Vis titration. The data listed in Table 2 demonstrate bonding properties towards NAA are listed in Table 2 (En-
that these receptors formed 1:1 complexes with NAA, but tries 9 and 10). The KA between 7a and -aspartate was
most of them did not have chiral recognition abilities 8.99ϫ103 dm3 mol–1, while that of 7b with -aspartate was
towards this anion, except 5d, which exhibited good selec- 1.19ϫ104 dm3 mol–1, and both of them were significantly
tivity for the aspartate (the / selectivity was 2.92). We larger than the values of the corresponding Fc derivatives
designed receptors 5b–5d and 6b–6d to determine the influ- (5a and 6a), demonstrating that 7a and 7b had substantially
ence of the different amino acid chiral centres, and the re- stronger interactions with aspartate than did the Fc deriva-
sults indicated that only the alanine unit could supply the tives. We presume that 2,6-pyridine dicarboxylic acid has a
proper steric conformation and enable enantioselective re- constrictive structure, as the two functional arms of 7a or
cognition. Increasing the steric hindrance by introducing 7b could only stretch in specific directions, and thus, are
the benzyl or indole group to the chiral centre did not en- inclined to bind the aspartate in a “sandwich” mode, while
hance the chiral discrimination process.
intense hydrogen-bonding interactions could be formed be-
cause the carboxylate units of the anion approach the thio-
urea binding units closely. Although 7a and 7b bound NAA
intensely, neither of them showed chiral selectivity for
NAA, which further demonstrates the advantages of Fc as
the supramolecular platform for this system. The preorgan-
ised structure and favourable conformation of Fc deriva-
tives led to the excellent chiral recognition abilities.
On the basis of the good enantioselective recognition
abilities of receptors 5a and 6a towards NAA, we employed
them as probes to detect the enantiomeric composition of
this anion. We studied the UV/Vis absorbance changes of
5a and 6a versus the enantiomeric composition of NAA.
As shown in the Figure 7, the absorbance intensity of 5a
decreased linearly with increasing  isomer content of the
NAA, and we also observed a similar linear decrease when
6a was used as the probe. Thus, these receptors can be used
as colorimetric sensors to readily determine the enantio-
Table 2. KA values and enantioselectivities (KD/KL) of receptors 5b–
7b with N-acetyl-- or --aspartate in DMSO at 25 °C.
Entry Host N-Ac--Asp[a]
N-Ac--Asp[a]
KD/KL
KA [dm3 mol–1][b]
KA [dm3 mol–1][b]
1
2
3
4
5
6
7
8
9
10
5b
6b
5c
6c
5d
6d
5e
6e
7a
7b
(1.12Ϯ0.09)ϫ103
555.1Ϯ42.8
(1.44Ϯ0.12)ϫ103
423.5Ϯ36.2
1.29
0.76
1.25
1.43
2.92
1.25
1.42
1.20
0.93
1.38
(2.02Ϯ0.17)ϫ103
(3.19Ϯ0.20)ϫ103
779.5Ϯ43.7
(2.52Ϯ0.20)ϫ103
(4.57Ϯ0.43)ϫ103
(2.28Ϯ0.14)ϫ103
879.9Ϯ64.3
700.6Ϯ38.1
102.3Ϯ9.2
145.6Ϯ13.5
155.8Ϯ12.6
187.9Ϯ16.3
(8.99Ϯ0.90)ϫ103
(1.19Ϯ0.20)ϫ104
(8.35Ϯ0.72)ϫ103
(1.65Ϯ0.14)ϫ104
[a] The anions were used as their Bu4N+ salts. [b] All error values
were obtained by the results of nonlinear curve fitting.
Receptors 5e and 6e have similar structures to those of meric composition of NAA.[21]
5a and 6a, respectively, except that the electron-repulsive
p-tolyl units substitute for p-nitrophenyl units. Thiourea is
regarded as a hydrogen-bond donor; introducing an elec-
tron-repulsive unit will significantly reduce the acidities of
the thiourea protons, leading to its hydrogen-bond-donat-
ing ability becoming much weaker. The data obtained from
UV/Vis titration supported this reasoning, as the KA be-
tween 5e and N-Ac--aspartate was only 102.3 dm3 mol–1,
which is much smaller than that of 5a with -aspartate (KA
= 981.1 dm3 mol–1). In the same way, the KA of 6e with -
aspartate was 187.9 dm3 mol–1, much smaller than that of
6a with -aspartate (KA = 3910 dm3 mol–1). Unlike the ex-
cellent enantioselective recognition abilities of 5a and 6a,
we found receptors 5e and 6e did not have chiral recogni-
tion abilities towards NAA. These results indicate that the
Figure 7. The UV/Vis absorbance intensities of receptor 5a (at
500 nm) or 6a (at 484 nm) at 5.0ϫ10–5 moldm–3 versus the enan-
trophenyl group played a critical role in the complexation; tiomeric composition of NAA at 5.0ϫ10–4 moldm–3.
thiourea groups linked to the electron-withdrawing p-ni-
846
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Eur. J. Org. Chem. 2009, 841–849

Chromogenic Chemosensors for N-Acetylaspartate
Theoretical Calculations
enantioselective recognition abilities towards NAA by UV/
Vis titration experiments. Clear differences in the solution
colour and KA values demonstrated that receptors 5a and
6a had excellent chiral recognition abilities towards NAA,
which could be discriminated by the naked eye. In order to
investigate the possible interaction mechanism, we designed
some Fc derivatives with different chiral centres or electron-
repulsive groups. Comparison experiments indicated that
the preorganised conformations of 5a and 6a and the mul-
tiple hydrogen-bonding interactions between the thiourea
groups and the aspartate can contribute to the chiral re-
cognition abilities. We also obtained minimum energy struc-
tures of 5a and 5b through quantum-chemical calculations
at the DFT level of theory, which initially explain why these
receptors show different chiral bonding properties towards
the same guest. In previous studies, such chromogenic chi-
ral Fc derivatives have been seldom reported. Based on
their good optical properties and special hydrogen-bonding
system, these receptors could be used as chiral chromogenic
sensors for the enantiomers of NAA, while the development
of these kinds of Fcs will have potential application in the
research of enantioselective recognition and asymmetric ca-
talysis.
In the UV/Vis titrations described above, we found recep-
tors 5a and 6a had excellent enantioselective recognition
abilities towards NAA, but the / selectivity was nearly
opposite. Receptor 5a was inclined to bind  enantiomers,
while 6a had stronger affinity to  enantiomers. We pre-
sumed these two receptors had different preorganised struc-
tures; their two functional arms containing multiple hydro-
gen-bonding sites stretched in different directions.
In order to obtain information about the possible struc-
tures of 5a and 6a, we carried out quantum chemical calcu-
lations at the DFT level of theory. The minimum energy
structures are shown in Figure 8. We found that 5a adopted
a stretched conformation, with the two functional arms of
this molecule occupying different sides of the Fc; the mini-
mum distance between the two phenyl groups was 18.24 Å,
while the distance between the two sulfurs was 13.70 Å. Re-
ceptor 6a adopted a completely different conformation,
with the two functional arms on the same side of the Fc;
the minimum distance between the two phenyl groups was
13.54 Å, while the distance between the two sulfurs was
14.08 Å. These structures can be described as “foldout”
structures; receptor 5a looks likes an “open foldout”, while
6a looks like a “closed foldout”, with the Fc unit con-
trolling these open/closed conformations like an axis of fol-
dout. Based on these models, we presume NAA may adopt
a stretched conformation when it interacts with 5a, while it
may contract when it interacts with 6a due to the limited
interarm space. Different interaction modes could induce
the different chiral recognition abilities towards the enantio-
mers.
Experimental Section
General: Ethylenediamine was distilled before use. CHCl3 was
washed with water and dried from CaCl2, and Et3N was dried and
distilled from CaH2 and KOH. All other commercially available
reagents were used without further purification. Melting points
were determined with a Reichert 7905 melting-point apparatus (un-
corrected). Optical rotations were recorded with a Perkin–Elmer
Model 341 polarimeter. IR spectra were obtained with a Nicolet
670 FT-IR spectrophotometer. 1H NMR spectra were recorded
with a Varian Inova unity-600 MHz spectrometer. 13C NMR spec-
tra were recorded with a Varian Inova unity-600 MHz spectrome-
ter. Mass spectra were recorded with a Finnigan LCQ advantage
mass spectrometer. Elemental analysis was determined with a
Carlo–Erba 1106 instrument. The UV/Vis spectra were recorded
with a TU-1901 spectrophotomer. The anions were used as their
Bu4N+ salts. 1,1Ј-ferrocenediacetyl chloride (1) was synthesized ac-
cording to the methods reported in the literature.[22]
Synthesis
General Procedure for the Synthesis of the Fc Derivatives 2: To a
solution of -amino acid methyl ester hydrochloride (3 mmol) and
Et3N (4 equiv. for each amino acid methyl ester hydrochloride) in
dry CHCl3 (30 mL), 1,1Ј-ferrocenediacetyl chloride (1, 1.5 mmol)
in dry CHCl3 (20 mL) was added dropwise in an iced brine bath
under a N2 atmosphere. The reaction mixture was stirred at 0 °C
for 1 h, the ice brine bath was removed, and the mixture was stirred
overnight at room temperature. The reaction solution was then
washed with water three times. The organic layer was collected and
dried with anhydrous Na2SO4. After filtration, the solvent was re-
moved under reduced pressure, and the residue was purified by
column chromatography on silica gel.
Figure 8. Calculated (B3LY/6-31G*) structures for receptors 5a
(upper) and 6a (lower).
We tried to calculate the possible interaction mode of
receptors with NAA, but we obtained no reliable data due
to the complicated hydrogen-bonding system. From the
minimum energy structures of these receptors, the opposite
enantioselectivities can be explained to some extent, which
could contribute to the further design of Fc derivatives.
N,NЈ-[(Ferrocene-1,1Ј-diyl)biscarbonyl]bis(L-alanine methyl ester)
(2a): Pure product was obtained by column chromatography on
Conclusion
In summary, we synthesized a series of chiral Fc deriva-
silica gel [eluent: CHCl3/CH3CH2OH = 100:1 (v/v)] as a brown-red
tives containing thiourea groups and investigated their powder (0.50 g) in 75% yield; m.p. 162–163 °C. [α]2D0 = +346.7 (c =
Eur. J. Org. Chem. 2009, 841–849
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
847

G.-Y. Qing, T.-L. Sun, F. Wang, Y.-B. He, X. Yang
FULL PAPER
0.015, CHCl ). IR (KBr): ν = 3349, 1716, 1659, 1522, 1439, 1384,
Compound 6a: 0.28 g was obtained as a filemot powder (81% yield);
˜
3
1373, 1311, 1231, 1179, 1054, 835, 776 cm–1. H NMR (600 MHz,
m.p. 172–174 °C. [α]2D0 = +30.0 (c = 0.005, DMSO). IR (KBr): ν =
1
˜
CDCl3): δ = 1.39 (s, 3 H, CCH3), 1.41 (s, 3 H, CCH3), 3.82 (s, 6 3322, 1634, 1594, 1540, 1510, 1382, 1334, 1303, 1263, 1111, 853
H, OCH3), 4.35 (s, 2 H, Cp-H), 4.55 (s, 2 H, Cp-H), 4.76 (s, 2 H,
cm–1. 1H NMR (600 MHz, [D6]DMSO): δ = 1.25–1.29 (m, 6 H,
Cp-H), 4.81–4.89 (m, 2 H, C*H), 4.91 (s, 2 H, Cp-H), 7.75 (d, J = CH3), 2.70–2.81 (m, 2 H, NCH2C), 2.85–2.92 (m, 2 H, NCH2C),
8.4 Hz, 2 H, CONH) ppm. C20H24FeN2O6 (444.27): calcd. C 54.07, 3.57–3.62 (m, 4 H, NCH2C), 4.25 (s, 2 H, Cp-H), 4.30 (s, 2 H, Cp-
H 5.45, N 6.31; found C 53.82, H 5.57, N 6.20.
H), 4.38 (s, 2 H, Cp-H), 4.70–4.78 (m, 2 H, C*H), 4.84 (s, 2 H,
Cp-H), 7.31 (d, J = 7.2 Hz, 2 H, CONH), 7.75 (s, 4 H, NO2ArH),
7.97 (s, 2 H, CNHCS), 8.17 (s, 4 H, NO2ArH), 8.44 (s, 2 H,
CSNHAr), 10.20 (s, 2 H, CONHC) ppm. 13C NMR (150 MHz,
[D6]DMSO): δ = 18.1, 38.7, 44.1, 48.9, 70.4, 71.6, 72.1, 77.1, 121.3,
123.0, 124.2, 125.2, 125.7, 142.6, 144.1, 145.7, 146.7, 169.3, 175.1,
181.0 ppm. ESI-MS: m/z (%)
C36H40FeN10O8S2 (860.74): calcd. C 50.24, H 4.68, N 16.27; found
C 50.01, H 4.90, N 16.40.
The characterization data of compounds 2b–2d are listed in part
2.1 of the Supporting Information.
General Procedure for the Synthesis of the Fc Derivatives 3: A solu-
tion (20 mL) of 2a–2d (0.5 mmol) in CH3OH was added dropwise
to a stirred solution of hydrazine hydrate (6 equiv. for 2a–2d) in
CH3OH (10 mL). The mixture was stirred for 48 h under N2 pro-
tection at room temperature. The solvent was removed under re-
duced pressure, and water (50 mL) was poured into the residue.
The solid obtained was filtered and washed with cold CH3CH2OH
several times and dried in vacuo to obtain the pure product.
= 861.9 (100) [M +
H]+.
The characterization data of compounds 5b–5d, 6b–6d and 7a–7b
were listed in parts 2.4 and 2.5 of the Supporting Information,
respectively.
Compound 3a: 0.12 g was obtained as a brown powder (54% yield);
the compound decomposed at 196–198 °C. [α]2D0 = +87.2 (c = 0.005,
Bu4N+ Salts: Bu4N+ salts of the amino acids were prepared by
adding 2 equiv. of Bu4NOH in CH3OH to a solution of corre-
sponding N-protected aspartic acid or glutamic acid (1 equiv.) in
CH3OH. The mixture was stirred at room temperature for 2 h, and
the solvents were evaporated to dryness under reduced pressure.
The resulting syrup was dried under high vacuum at 50 °C for 24 h,
checked by NMR and stored in a desiccator.
DMSO). IR (KBr): ν = 3442, 3262, 1661, 1569, 1541, 1458, 1377,
˜
1315, 1276, 1202, 970 cm–1. ESI-MS: m/z (%) = 445.3 (100) [M +
H]+. C18H24FeN6O4 (444.27): calcd. C 48.66, H 5.44, N 18.92;
found C 48.35, H 5.60, N 18.74.
The characterization data of compounds 3b–3d were listed in part
2.2 of the Supporting Information.
Binding Studies: The host compounds were prepared as stock solu-
tions in DMSO at 5ϫ10–4 moldm–3. The anion was dissolved to
approximately 0.015 moldm–3 and 0.15 moldm–3 of stock solution
in DMSO. The working solutions were prepared by adding dif-
ferent volumes of N-protected aspartate or glutamate solution to a
series of test tubes followed by the addition of the same amount of
stock solution of host compound followed by dilution to 3.0 mL
by DMSO. After being shaken for several minutes, the work solu-
tion was measured immediately. KA values were calculated by
means of a nonlinear, least-squares, curve-fitting method with
ORIGIN 7.0 (Origin-Lab Corporation).
General Procedure for the Synthesis of the Fc Derivatives 4: A solu-
tion (20 mL) of 2a–2d (0.5 mmol) in CH3OH was added dropwise
to a stirred solution of ethylenediamine (6 equiv. for 2a–2d) in
CH3OH (10 mL). The mixture was stirred for 48 h under N2 pro-
tection at room temperature. The solvent and excess ethylenedi-
amine were removed under reduced pressure, and the residue was
washed with cold CH3CH2OH and dried in vacuo to give pure
product.
Compound 4a: 0.18 g was obtained as a filemot powder (72% yield);
the compound decomposed at 220 °C. [α]2D0 = +97.0 (c = 0.005,
DMSO). IR (KBr): ν = 3289, 3083, 2936, 1665, 1622, 1556, 1458,
˜
Supporting Information (see also the footnote on the first page of
this article): Scheme of the possible charge transfer process of com-
pounds 3a–3c, 1H NMR spectra of 3d and the characterization
data of reference compounds.
1380, 1316, 1199, 1036, 814 cm–1. 1H NMR (600 MHz, [D6]-
DMSO): δ = 1.26–1.31 (m, 6 H, CCH3), 1.75 (s, 4 H, D2O-exchang-
able, NH2), 2.98–3.16 (m, 8 H, NCH2CH2N), 4.31 (s, 2 H, Cp-H),
4.38 (s, 2 H, Cp-H), 4.46 (s, 2 H, Cp-H), 4.71–4.79 (m, 2 H, C*H),
4.91 (s, 2 H, Cp-H), 7.35 (d, J = 8.4 Hz, 2 H, CONH), 8.66 (s,
2 H, CONHC) ppm. ESI-MS: m/z (%) = 501.5 (100) [M + H]+. Acknowledgments
C22H32FeN6O4 (500.38): calcd. C 52.81, H 6.45, N 16.80; found C
52.57, H 6.58, N 16.72.
We thank the National Natural Science Foundation of China
(Grant No. 20572080), Alexander von Humboldt (AvH) Founda-
tion and the Federal Ministry of Education and Research of Ger-
many (BMBF) for fund support (Sofja Kovalevskaja Award pro-
ject).
The characterization data of compounds 4b–4d were listed in part
2.3 of the Supporting Information.
General Procedure for the Synthesis of the Fc Derivatives 5 and 6:
A solution of p-nitrophenyl isothiocyanate (0.144 g, 0.8 mmol) in
dry DMF (15 mL) was added dropwise to a solution of 3 or 4
(0.4 mmol) in dry DMF (15 mL) at room temperature. The reaction
mixture was then stirred at room temperature for 48 h. A large
amount of water was poured into the solution. The collected pre-
cipitate was washed with CHCl3 and acetone, and the solid was
dried under vacuum to obtain the pure product.
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848
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Chromogenic Chemosensors for N-Acetylaspartate
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Received: October 1, 2008
Published Online: January 8, 2009
Eur. J. Org. Chem. 2009, 841–849
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
849