A chiral perazamacrocyclic fluorescent sensor for cascade recognition of Cu(II) and the unmodified α-amino acids in protic solutions

Article abstract of DOI:10.1021/ol2013268

A novel chiral Perazamacrocyclic fluorescent sensor (1) was designed and synthesized. It can serve as a fluorescent turn-off sensor with high selectivity toward Cu(II) among 14 metal ions. Furthermore, though 1 exhibits no enantioselectivity, after adding Cu(II), the in situ generated Cu(II)-containing complex of 1 (Cu(II)-1) can exhibit remarkable fluorescent enhancement responses and considerable enantioselectivities toward unmodified α-amino acids in protic solutions via a ligand displacement mechanism; i.e. a cascade recognition of Cu(II) and unmodified α-amino acids has been achieved.

Full text of DOI:10.1021/ol2013268

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3510–3513
A Chiral Perazamacrocyclic Fluorescent
Sensor for Cascade Recognition of Cu(II)
and the Unmodified r-Amino Acids in
Protic Solutions
Xia Yang,† Xuechao Liu,† Kang Shen,† Chengjian Zhu,*,†,‡ and Yixiang Cheng*,†
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical
Engineering, Nanjing University, Nanjing 210093, China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China
cjzhu@nju.edu.cn; yxcheng@nju.edu.cn
Received May 17, 2011
ABSTRACT
A novel chiral Perazamacrocyclic fluorescent sensor (1) was designed and synthesized. It can serve as a fluorescent turn-off sensor with high
selectivity toward Cu(II) among 14 metal ions. Furthermore, though 1 exhibits no enantioselectivity, after adding Cu(II), the in situ generated Cu(II)-
containing complex of 1 (Cu(II)-1) can exhibit remarkable fluorescent enhancement responses and considerable enantioselectivities toward
unmodified R-amino acids in protic solutions via a ligand displacement mechanism; i.e. a cascade recognition of Cu(II) and unmodified R-amino
acids has been achieved.
Chiralrecognition playsanimportantroleinmanyfields
of science and technology.1 Because studies on chiral
recognition might contribute to the understanding of
living systems, much effort has been devoted to the design
and synthesis of artificial enantioselective receptors
and their applications.2 Among these studies, those on
enantioselective recognition of amino acids and their
derivatives are especially attractive, since they are funda-
mental molecules of life and are implicated in different
biomolecular processes.3 Though much research on the
(2) (a) Ariga, K.; Richards, G. J.; Ishihara, S.; Izawa, H.; Hill, J. P.
Sensors 2010, 10, 6796. (b) Anslyn, E. V. J. Org. Chem. 2007, 72, 687.
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Synlett 1999, 161. (e) Hartley, J. H.; James, T. D.; Ward, C. J. J. Chem.
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(g) Moberg, C. Angew. Chem., Int. Ed. 2006, 45, 4721.
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tion and Metabolic Engineering; Springer-Verlag: Berlin, 2007. (b) Jane,
D. E. In Medicinal Chemistry into the Millenium; Campbell, M. M.,
Blagbrough, I. S., Eds.; Royal Society of Chemistry: Cambridge, U.K.,
2001; pp 67ꢀ84. (c) Standaert, D. G.; Young, A. B., Goodman and
gilman’s: The pharmacological basis of therapeutics. In Goodman &
Gilman’s: The Pharmacological Basis of Therapeutics; Hardman, J. G.,
Milinoff, P. B., Ruddon, R. W., Limbird, L. E., Goodman Gilman, A., Eds.
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† Nanjing University.
‡ Chinese Academy of Sciences.
(1) (a) Steed, J. W.; Atwood, J. L. Supramolecular chemistry, 2nd ed.;
John Wiley & Sons: Chichester, 2009. (b) Garten, S.; Biedermann, P. U.; S.,
T.; Agranat, I. Chirality 2010, 22, 662. (c) Scuderi, D.; Maitre, P.;
Rondino, F.; Le Barbu-Debus, K.; Lepere, V.; Zehnacker-Rentien, A.
J. Phys. Chem. A 2010, 114, 3306. (d) Yeh, J. I.; Shivachev, B.;
Rapireddy, S.; Crawford, M. J.; Gil, R. R.; Du, S. C.; Madrid, M.;
Ly, D. H. J. Am. Chem. Soc. 2010, 132, 10717. (e) Bwambok, D. K.;
Challa, S. K.; Lowry, M.; Warner, I. M. Anal. Chem. 2010, 82, 5028.
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M. Angew. Chem., Int. Ed. 2009, 48, 3466. (g) Kelly, A. M.; Perez-
Fuertes, Y.; Fossey, J. S.; Yeste, S. L.; Bull, S. D.; James, T. D. Nat.
Protoc. 2008, 3, 215. (h) Sessler, J. L.; Andrievsky, A.; Kral, V.; Lynch,
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r
10.1021/ol2013268
Published on Web 06/07/2011
2011 American Chemical Society

recognition of modified amino acids has been reported in
recent years,4 recognizing unprotected amino acids in
protic solvent is still a challenge and only a few works
have been reported to date.5 Unlike other organic guest
molecules, most amino acids exist as zwitterions and have
poor solubility in aprotic organic solvent,6 whereas in
protic solvent the competition between solvent molecules
and binding sites exists, not only preventing the formation
ofH-bonds betweenreceptorsand guestmolecules butalso
resulting in low enantioselectivity.1a,7
Scheme 1. Synthesis Route of 1
Perazamacrocycles have been successfully applied in
coordination chemistry, metal catalysis, ion recognition,
supramolecular structures, material chemistry, and catalysis.8
Recently, the research on the fluorescent and colori-
metric molecular probes or chemosensors based on poly-
amines has prospered.9 On the other hand, optically active
1,10-Bi-2-naphthol (BINOL) and trans-cyclohexane-1,
2-diamine (trans-DACH) and their derivatives have been
widely used in molecular recognition and asymmetric
catalysis.10 And some excellent enantioselective fluorescence
sensors based on the building blocks of BINOL derivatives
have been reported since chiral BINOL can effectively
integrate chirality and the fluorescence property.4b,11
In this paper, we synthesized a novel chiral perazama-
crocycle 1 featuring BINOL and trans-DACH units which
could serve as a fluorescent sensor for Cu(II). And the
chiral recognition of the Cu(II)-containing complex of 1
toward unmodified R-amino acids in protic solutions was
studied.
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As shown in Scheme 1, perazamacrocycle 1 was easily
synthesized in 3 steps from (S)-BIONL.
The UVꢀvis and fluorescence spectra of perazamacro-
cycle 1 at various concentrations were studied (Figures
S3ꢀS4). The UVꢀvis spectra of 1 have no change in either
the wavelengths or the shapes of the absorption signals and
obey the LambertꢀBeer Law well as the concentration
increases from 0 to2.5 ꢁ 10ꢀ5 mol/L, indicating that1 does
not form ground state intermolecular aggregates.12 How-
ever, plots of fluorescent intensity vs concentration of 1
suggest that the suitable concentration of 1 for the fluor-
escent studies on recognition preferably should not be
greater than 1 ꢁ 10ꢀ5 mol/L to avoid the violation of the
LambertꢀBeer Law.
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Co2þ, Ni2þ Cu2þ, Zn2þ, Pb2þ, Agþ, Cd2þ, and Ba2þ
,
.
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The fluorescence of 1 could be almost completely
quenched only by Cu(NO3)2 (Figures 1 and 2). Job
plots13 analysis and the mass spectra of ESI and
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Org. Lett., Vol. 13, No. 13, 2011
3511

Figure 3. (a) Fluorescence spectra of 1þCu(II) ((1 ꢁ 10ꢀ5) þ
(2 ꢁ 10ꢀ5) mol/L, λex = 331 nm) with D- or L-Phe (1 ꢁ 10ꢀ4 mol/L)
and (b) plots of (I/I0) vs Phe concentration during the titration of
1þCu(II) with D-orL-Phe (λex =331nm,λem = 380 nm) in a solution
of MeOH/H2O (v/v = 1:1), 25 mM HEPES buffered to pH 7.3.
Figure 1. Fluorescence responses of 1 (1.0 ꢁ 10ꢀ5 mol/L, λex
=
331 nm) to various metal ions (2.0 ꢁ 10ꢀ5 mol/L) in methanolꢀ
water solutions (v/v = 1:1, 25 mM HEPES buffer, pH 7.3).
probably are able to associate with Cu(II) and displace the
ligand 1 in Cu(II)-1, which may conduce to the recovery of
the fluorescence quenched by Cu(II). On the other hand,
since 1 is chiral, one enantiomer of an amino acid may have
more efficiency in displacing 1 and result in more fluores-
cence enhancement than another. Keeping these in mind
and encouraged by the recent brilliant achievements of
Anslyn’s indicator-displacement assays15 and competitive
binding assays such as Wolf’s16 and Feng’s,4a,17 we further
studied the chiral recognition of the in situ generated
Cu(II)-containing perazamacrocyclic complex of 1 (Cu(II)-1)
toward unmodified amino acids.
Initially, 1 equiv of Cu(II) was added to 1and the resulting
mixture was engaged in the recognition of enantiomers of
phenylalanine (Phe) (Figure S8). Both enantiomers of Phe
could induce apparent fluorescence enhancement responses,
whereas D-Phe is more effective than L-Phe. The maximal
fluorescence enhancement ratio IDmax/I0 reached 1.87, and
(ΔI/I0)max = 0.27. That is to say the expected enantioselec-
tive fluorescent enhancement sensing has been achieved.
Noting that 1 equiv of Cu(II) could not quench the
fluorescence of 1 to a minimum (Figure 2), we employed 2
equiv of Cu(II) to ensure thorough quenching and then
performed enantioselective recognition studies. While the
mixture of 1andCu(II) (1:2) wastitratedwithPhe(Figure3),
the flourescence enantioselectively increased as expected.
To our surprise, IDmax/I0 and (ΔI/I0)max amazingly
increased to 14.9 and 4.9 respectively, which are much
higher than 1.87 and 0.27 obtained previously. This sug-
gests that 1þCu(II) (1:2) is superior to 1þCu(II) (1:1) and
could result in great enhancement of both sensitivity and
enantioselectivity. Whereafter, the enantiomers of other
four amino acids alanine (Ala), valine (Val), proline
(Pro), and (PG) were engaged in the titration experi-
ments (Figures S9ꢀS12, Table 1). The enantioselective
fluorescence responses are similar to that of Phe, and in
Figure 2. Fluorescence spectra of 1(1.0ꢁ 10ꢀ5 mol/L, λex = 331 nm)
in the presence of increasing amount of Cu(NO3)2 in a solution
of MeOH/H2O (v/v = 1:1), 25 mM HEPES buffered to pH 7.3.
The inset features the dependence of the intensity emission at
380 nm on the concentration of Cu2þ
.
Scheme 2. In Situ Formation of Cu(II)-Containing Complex of 1
MALDI-TOF reveal that 1 and Cu(II) form a 1:1
complex Cu(II)-1 (Figures S6ꢀS7, Scheme 2). More-
over, the association constant (K) determined from the
Job plot is up to 1.25 ꢁ 106 L/mol. With such a high
selectivity and sensitivity, perazamacrocycle 1 could serve
as a fluorescent ON-OFF sensor for Cu(II).
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As chelating ligands, amino acids are highly associable
with many metal ions, especially with Cu(II).14 Thus, they
(13) Job, P. Ann. Chim. France 1928, 9, 113.
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(b) Liu, S. L.; Pestano, J. P. C.; Wolf, C. J. Org. Chem. 2008, 73, 4267.
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A. E. Critical Stability Constants; Plenum Press: New York, 1974; Vol. 1.
3512
Org. Lett., Vol. 13, No. 13, 2011

Table 1. Amino Acids Employed in Enantioselective Sensing
Studies and the Sensitivities and Enantioselectivities of 1þCu-
(II) towards Thema
Scheme 3. Possible Mechanism of Ligand Displacement
cCu/c1
Amino acids
IDmax/I0
(ΔI/I0)max
1
2
Phe
Phe
Ala
Val
Pro
PG
1.87
14.9
13.2
12.4
14.1
9.7
0.27
4.6
1.4
1.9
3.2
1.6
a c1 = 1 ꢁ 10ꢀ5 mol/L, in a solution of MeOH/H2O (v/v = 1:1), 25
mM HEPES buffered to pH 7.3
most cases, the resulting IDmax/I0 is above 10. The results
also suggest that the increase of bulk of the group in the
R-position of amino acids might be beneficial to the enhan-
cement of enantioselectivity. To the best of our knowledge,
Cu(II)-1 is the first reported metal-containing peraza-
macrocycle sensor which can exhibit remarkable fluorescent
enhancement responses and considerable enantioselectiv-
ities toward unmodified R-amino acids in protic solutions.
It is interesting to find that the excess metal ions could lead
to the enhancement of enantioselectivity. A possible explana-
tion (Scheme 3) might be that the excess Cu(II) (2 equiv)
could drive the balance of eq 1 to move to the left, which not
only ensures the quenching of fluorescence to a minimum but
also promotes the formation of chiral coordination complex
Cu(II)-1 and keeps the chiral ligand displacement proceed-
ing according to the reported machanism.15 Thus, enhanced
sensitivity and enantioselectivity could be observed.
While 1 without Cu(II) was treated with the enantiomers of
Phe (Figure S13), the fluorescence intensity decreased as the
concentration of Phe increased. Even upon addition of 200
equiv of Phe, the difference between the fluorescence re-
sponses of two enantiomers remains very small, indicating
the indispensability of Cu(II) for chiral recognition. Further-
more, the consistency of fluorescent responses of 1toward two
enantiomers also verifies that the distinctly different fluores-
cent responses measured from ligand displacement arises from
enanioselective recognition and is not due to impurities.
The influence of the enantiomeric composition of Phe on
the fluorescence intensity was investigated. As shown in
Figure 4, the intensity of fluorescence enhanced while
adding D-Phe or an enantiomeric mixture of D-Phe. With
the same amount of D-Phe the enantiomeric mixture
(curve a) causes greater fluorescence enhancement than an
optically pure D-Phe (curve b) dose. There is a fairly linear
relationship between I/I0 and the percent of the D-Phe
component (R = 0.998, Figure S14), which indicates that
the enantioselective ligand displacement method can be
effectively applied for the enantiomer composition deter-
mination of amino acids.
Figure 4. Fluorescence enhancement of 1þCu(II) ((1 ꢁ 10ꢀ5) þ
(2 ꢁ 10ꢀ5) mol/L) in the presence of the enantiomeric mixture of
Phe at 3.3 ꢁ 10ꢀ5 mol/L (curve a, top scale) and pure D-Phe
(curve b, bottom scale) (λex = 331, λem = 380 nm) in a solution
of MeOH/H2O (v/v = 1:1), 25 mM HEPES buffered to pH 7.3.
In conclusion, we designed and synthesized a versatile
chiral perazamacrocycle 1 which can serve as a fluorescent
turn-off sensor for Cu(II) and exhibit good selectivity among
14 metal ions. Furthermore, though 1 exhibits no enantios-
electivity, after addition of Cu(II), the in situ generated
Cu(II)-1 can exhibit remarkable fluorescent enhancement
responses and considerable enantioselectivities toward un-
modified R-amino acids in protic solutions via a ligand
displacement mechanism; i.e. a cascade recognition of Cu(II)
and unmodified R-amino acids has been achieved.
Acknowledgment. We are very grateful for the support
of this work from the National Natural Science Foundation
of China (20832001, 20972065, 21074054) and the Na-
tional Basic Research Program of China (2007CB925103,
2010CB92330) for their financial support. The Funda-
mental Research Funds for the Central Universities
(1082020502) is also acknowledged.
Supporting Information Available. Fluorescence, UVꢀ
vis spectroscopic plots, and data mentioned in above
1
paragraphs; H and 13C NMR spectra of all new com-
pounds as well. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
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