Chiral mono boronic acid as fluorescent enantioselective sensor for mono α-hydroxyl carboxylic acids

Article abstract of DOI:10.1021/jo8007622

(Graph Presented) New mono boronic acid was found to be an enantioselective fluorescent chemosensor for mono α-hydroxyl carboxylic acids, such as mandelic acid and lactic acid. The chiral sensor shows lower background fluorescence, higher fluorescence enh

Full text of DOI:10.1021/jo8007622

SCHEME 1. Chiral Fluorescent Sensors for r-Hydroxyl
Acids
Chiral Mono Boronic Acid As Fluorescent
Enantioselective Sensor for Mono r-Hydroxyl
Carboxylic Acids
Lina Chi,† Jianzhang Zhao,*,† and Tony D. James*,‡
State Key Laboratory of Fine Chemicals, Dalian UniVersity
of Technology, 158 Zhongshan Road, Dalian 116012, P.R.
China, and Department of Chemistry, UniVersity of Bath,
Bath BA2 7AY, U.K.
zhaojzh@dlut.edu.cn; t.d.james@bath.ac.uk
ReceiVed April 5, 2008
SCHEME 2. Synthesis of Chiral Fluorescent Sensors 1
New mono boronic acid was found to be an enantioselective
fluorescent chemosensor for mono R-hydroxyl carboxylic
acids, such as mandelic acid and lactic acid. The chiral sensor
shows lower background fluorescence, higher fluorescence
enhancement, and enantioselective recognition kinetics to-
ward mandelic acids and lactic acids.
Much attention has been paid to the enantioselective molec-
ular recognition of chiral analytes, especially R-hydroxyl
acids.1–6 To this end, hydrogen bonding based chiral fluorescent
sensors for R-hydroxyl acids have been developed,3,4,6 e.g.,
sensor 3 (Scheme 1).3,7 In order to improve the chiral
recognition,8,9 coValent bonding based sensors are developed,
such as sensor 4 and 5.10 The enantioselectivity of sensors 4
are good with bis or poly hydroxyl acids, such as tartaric acid
and sugar acids but poor with mono R-hydroxyl acids, such as
mandelic acids or lactic acids.10 Recently, Anslyn et al. have
shown that a mono boronic acid is effective for enantioselective
recognition of mono R-hydroxyl acids, such as phenyl lactic
acid (KS/KR ) 2.8:1) (receptor 5).5 However, an alternative
structural profile has to be found to develop an integrated chiral
† Dalian University of Technology.
‡ University of Bath.
(1) Stibor, I.; Zlatusˇkova´., P. Top. Curr. Chem. 2005, 255, 31.
(2) James, T. D. Top. Curr. Chem. 2007, 277, 107.
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(5) Zhu, L.; Anslyn, E. V. J. Am. Chem. Soc. 2004, 126, 3676.
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4684 J. Org. Chem. 2008, 73, 4684–4687
10.1021/jo8007622 CCC: $40.75 2008 American Chemical Society
Published on Web 05/29/2008

SCHEME 3. Analytes Used in the Studya
a In each case only one enantiomer is shown.
FIGURE 2. Normalized emission spectra of sensors S-1 (a) and S-2
(b) in the presence of D-mandelic acid; 3.99 × 10-6 mol dm-3 sensor
in MeCN; λex ) 351 nm, 20 °C. To compare the fluorescence
enhancement, the y-scales were set the same for a and b.
L-mandelic acid (KD/KL ) 1.8:1.0). Thus the free energy
difference of the diastereomeric complexes is ∆∆G° ) 1.4 (
0.3 kJ mol-1
.
To prove the enantioselectivity, R-1 was also titrated with
mandelic acid. A mirror effect was observed (KD/KR ) 1.0:2.7,
∆∆G° ) 2.4 ( 0.3 kJ mol-1). These ∆∆G° values are
comparable to those of macrocyclic ligands.13
FIGURE 1. Relative fluorescence intensity of S-1 (a) and R-1 (b) versus
concentration of with D- and L-mandelic acid; 3.99 × 10-6 mol dm-3
sensors in MeCN; λex ) 351 nm, λem ) 420 nm; 20 °C.
Compound 2 is not enantioselective for mandelic acid (Figure
S1). With S-2, K values of (4.29 ( 0.03) × 104 and (4.49 (
0.03) × 104 M-1 were found for D- and L-mandelic acid,
respectively, inferring that the extra hydroxyl group in 1 is
essential for the enantioselectivity. We propose that an intramo-
lecular hydrogen binding induced the enantioselectivity (see
Supporting Information).
Lower background and higher enhancement of fluorescence
were recorded for 1 compared with that of 2 (Figure 2).
Compound 1 shows 30- to 40-fold fluorescence enhancement,
versus only 6- to 7-fold observed for 2.19 Enhanced signal
transduction may induce better detection limits.14
Enantioselective recognition of lactic acid is more challenging
because the methyl group in it is less bulky than the phenyl
group in mandelic acid, and the minor steric hindrance may
attenuate the enantioselectivity.5 However, titration shows that
1 is enantioselective toward lactic acid. With D-lactic acid, K
) (1.26 ( 0.21) × 103 M-1 was observed for S-1, whereas for
fluorescent chemosensor (the binding of 5 was evaluated using
a displacement assay).2,5,11
Chiral recognition requires multiple-point interaction.12 We
envision that by using an additional interaction, e.g., hydrogen
binding, a mono boronic acid could be enantioselective toward
mono R-hydroxyl acids. With this concept in mind we synthe-
sized photoinduced electron transfer (PET) chiral sensor 1
(Schemes 1 and 2), and its chiral recogntion toward several
representative R-hydroxyl acids (Scheme 3) was studied.
Sensor 1 was synthesized with 2-amino-2-phenyl-ethanol as
chiral building blocks (Scheme 2).10 R- and S-1 were titrated
with mandelic acid in MeCN (Figure 1). Enantioselective
fluorescence enhancement was observed. With S-1, a binding
constant (K) of (5.04 ( 0.77) × 103 M-1 was observed for
D-mandelic acid, versus K ) (2.77 ( 0.57) × 103 M-1 for
(11) Wulff, G. Pure. Appl. Chem 1982, 54, 2093.
(13) Alfonso, I.; Rebolledo, F.; Gotor, V. Chem. Eur. J. 2000, 6, 3331.
(14) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A. J. M.;
McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. ReV. 1997, 97, 1515.
(12) Salem, L.; Chapuisat, X.; Segal, G.; Hiberty, P. C.; Minot, C.; Leforestier,
C.; Sautet, P. J. Am. Chem. Soc. 1987, 109, 2887.
J. Org. Chem. Vol. 73, No. 12, 2008 4685

TABLE 1. Stability Constants, Fluorescence Enhancement (F) on Binding and Enantioselectivity (KR:KS) of Sensors R-1, S-1, R-2, and S-2a
K
Fb
analytes
R-1
S-1
R-1
S-1
KR:KS
response selectivityc
D-mandelic acid
L- mandelic acid
D-lactic acid
L-lactic acid
D-tartaric acid
L-tartaric acid
(2.11 ( 0.15) × 103
(5.62 ( 0.64) × 103
(4.46 ( 0.57) × 102
(1.05 ( 0.14) × 103
(8.51 ( 0.13) × 103
(7.90 ( 0.37) × 103
(5.04 ( 0.77) × 103
(2.77 ( 0.57) × 103
(1.26 ( 0.21) × 103
(4.72 ( 0.82) × 102
(8.88 ( 0.40) × 103
(8.42 ( 0.31) × 103
41.9 ( 1.1
50.4 ( 2.0
42.5 ( 2.3
44.3 ( 2.0
36.3 ( 0.4
31.5 ( 0.6
49.1 ( 2.1
34.4 ( 2.2
36.2 ( 2.0
34.4 ( 2.4
27.8 ( 0.6
36.6 ( 0.4
1.0:2.4
2.0:1.0
1.0:2.8
2.2:1.0
1.0:1.1
1.0:1.1
1.0:2.8
3.0:1.0
1.0:2.4
2.9:1.0
1.3:1.0
1.0:1.2
K
Fb
analytes
R-2
S-2
R-2
S-2
KR:KS
response selectivityc
D-mandelic acid
L-mandelic acid
D-lactic acid
L-lactic acid
D-tartaric acid
L-tartaric acid
(4.20 ( 0.02) × 104
(4.34 ( 0.02) × 104
(1.63 ( 0.07) × 104
(1.36 ( 0.07) × 104
(3.25 ( 0.14) × 104
(3.24 ( 0.12) × 104
(4.29 ( 0.03) × 104
(4.49 ( 0.03) × 104
(1.74 ( 0.08) × 104
(1.40 ( 0.07) × 104
(3.35 ( 0.12) × 104
(3.22 ( 0.14) × 104
6.6 ( 0.1
7.0 ( 0.1
7.0 ( 0.2
6.7 ( 0.1
11.9 ( 0.6
10.5 ( 0.5
7.7 ( 0.1
7.2 ( 0.2
7.1 ( 0.2
6.8 ( 0.2
11.2 ( 0.6
11.4 ( 0.6
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.2
1.0:1.0
1.0:1.0
1.0:1.1
1.0:1.0
1.0:1.1
a Constants determined by fitting a 1:1 binding model to I/I0; determination coefficients r2 > 0.98 in most cases. b Maximum fluorescence
enhancement. c Response selectivity ) (K(R)F(R))/(K(S)F(S)).
R-1-D-mandelic acid complex, Kapp ) (2.24 ( 0.00) × 10-2
s-1, while for S-1-D-acid complex, Kapp ) (1.45 ( 0.00) × 10-2
s-1. Thus the enantioselectivity on the formation rate constants
of diastereomeric complexes is 1.5:1.0. With L-mandelic acid,
enantioselectivity of 1.0:1.4 was observed (Figure S6).
With lactic acid, simillar enantioselectivity was found (Figure
S7), e.g., Kapp ) (1.24 ( 0.00) × 10-2 s-1 for S-1-D-lactic acid
versus Kapp ) (1.50 ( 0.00) × 10-2 s-1 for R-1-D-acid was
observed (enantioselectivity ) 1:1.2). With tartaric acid, no
enantioselectivity was found (Figure S8). For 2, the fluorescence
enhancements reach the maximum instantlaneously on addition
of acids (Figure S9).
We propose that the slow kinetics of the recogntion is due to
the break of the intramolecular boronic acid ester structure.
Without this extra process, the recognition will be fast, which
is proved with sensor 2 (Figure S9).
Usually molecular recognition is thermodynamically con-
FIGURE 3. Enantioselective recognition kinetics of sensor-1 on
D-mandelic acid. c(R- and S-1) ) 3.99 × 10-6 mol dm-3 in MeCN,
c(D-mandelic acid) ) 2.5 × 10-3 mol dm-3. λex ) 351 nm, λem ) 420
trolled, but in some cases kinetic recognition can be decisive,
such as recognition events involving DNA.15,16 Such kinetically
nm; 20 °C. For clarity, only 2% of the total recorded data points are
shown. The squares and circles are experimental data, and the solid
lines are exponential fitting (extrapolated to the intensity of the blank
sensors).
controlled recognition is widely used in chiral kinetic resolu-
tions17,18 but has rarely been employed in the development of
chemosensors.19–21 We propose that the enantioselective binding
kinetics is due to the difference of the activitation energy to
form the two diastereoisomers. Further investigation of such
an enantioselective kinetics is underway in our laboratories.
The single crystal X-ray structure of 1 illustrates an intramo-
lecular boronate ester structure (Figure 4, mono ester of
methanol; effort to obtain a single crystal of sensor-analyte
complex failed), with a B-N distant of 2.819 Å. Such long
distance rules out a direct B-N interaction,22 as the typical B-N
R-1, K ) (4.46 ( 0.57) × 102 M-1 (KR/KS ) 1:2.8). L-Lactic
acid was also tested, and a mirror effect was observed (Figure
S3, Supporting Information). With 2, no enantioselectivity was
found (Figure S4). To the best of our knowledge, 1 is the first
fluorescent enantioselective mono boronic acid sensor for mono
R-hydroxyl acids, such as mandelic acid. The ee values of
mandelic acids was determined with 1 (Figure S5).10
The recognition of 1 and 2 toward chiral acids is summarized
(Table 1). Compared with 2, lower binding constants were
observed for 1. The enantioselectivity of 1 toward chiral mono
R-hydroxyl acids may be due to the additional hydrogen binding
of the hydroxyl group with the boron center. Recognition of 1
in aqueous solution was carried out, but no enantioselectivity
was found.
The binding of 1 on chiral acids was found to be slow at
room temperature, as time-dependent fluorescence enhancements
were observed with addition of analytes.
Interestingly, the recognition is kinetically enantioselective
(Figure 3). Exponential regression of the time course curves
gives the apparent formation (binding) rate constants (Kapp). For
(15) Nordell, P.; Westerlund, F.; L.; Wilhelmsson, M.; Norde´n, B.; Lincoln,
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Spears, K. G.; Hoffman, B. M. J. Am. Chem. Soc. 1993, 115, 3665.
(17) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J. Am. Chem.
Soc. 2003, 125, 2052.
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Chem., Int. Ed. 2001, 40, 930.
(19) Simonato, J.-P.; Pe´caut, J.; Marchon, J.-C. J. Am. Chem. Soc. 1998,
120, 7363–7364.
(20) Brotherhood, P. R.; Wu, R. A.-S.; Turner, P.; Crossley, M. J. Chem.
Commun. 2007, 225.
(21) Clark, J. L.; Peinado, J.; Stezowski, J. J.; Vold, R. L.; Huang, Y.;
Hoatson, G. L. J. Phys. Chem. B 2006, 110, 26375.
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4686 J. Org. Chem. Vol. 73, No. 12, 2008

Experimental Section
R-1: a mixture of 2-phenyl-2-(anthracen-9-ylmethylamino)-
ethanol (0.3 g, 0.92 mmol), K2CO3 (0.51 g, 3.67mmol), and 2-(2-
bromomethylphenyl)-1,3,2-dioxaborinane (0.374 g, 1.47 mmol) in
dry MeCN was refluxed for 8 h. The reaction mixture was cooled
to room temperature, diluted HCl was added, and the mixture was
stirred for further 1 h (to ensure the deprotection of the boronic
acid group). The solvent was removed under vacuum, the residue
was taken up with 10 mL H2O, the aqueous phase was extracted
with DCM (3 × 30 mL), and the organic phase was washed with
brine (2 × 20 mL) and dried over anhydrous MgSO4. The solvent
was removed under vacuum and the residue was applied to column
chromatography (silica gel, DCM/MeOH, 20/1, v/v). A light yellow
powder was obtained, yield 38.0%. 1H NMR (CDCl3/CD3OD, 400
MHz, TMS): δ 8.45 (s, 1 H), 8.27 (d, 2 H, J ) 8.0 Hz), 7.98 (d,
2H, J ) 8.0 Hz), 7.40-7.52 (m, 5 H), 7.23-7.27 (m, 1 H),
7.13-7.18 (m, 4H), 6.79 (d, 1H, J ) 8.0 Hz), 6.64 (br, 2H), 5.17
(d, 1H, J ) 12.0 Hz), 4.88 (d, 1H, J ) 12.0 Hz), 4.50-4.54 (m, 1
H), 3.95-4.05 (m, 2 H), 3.76-3.88 (m, 2 H). ESI-MS: m/z (positive
ion mode) calcd for C30H27BNO2 ([M - H2O + H]+) 444.2135,
found 444.0978; calcd for C30H29BNO3 ([M + H]+) 462.2240,
found 462.1042.
FIGURE 4. ORTEP view of the single crystal structure of R-1. Thermal
ellipsoids are drawn at the 30% probability level, and the hydrogen
atoms are omitted for clarity.
S-1: synthesized by the same methods. 1H NMR (CDCl3/CD3OD,
400 MHz, TMS): δ 8.45(s, 1 H), 8.27 (d, 2 H, J ) 8.0 Hz), 7.97
(d, 2H, J ) 8.0 Hz), 7.40-7.52 (m, 5 H), 7.23-7.27 (m, 1 H),
7.14-7.18 (m, 4H), 6.79 (d, 1H, J ) 8.0 Hz), 6.62 (d, 2H, J ) 8.0
Hz), 5.17 (d, 1H, J ) 12.0 Hz), 4.88 (d, 1H, J ) 12.0 Hz),
4.50-4.55 (m, 1 H), 3.95-4.06 (m, 2 H), 3.82-3.87 (m, 2 H).
TOF ESI-MS (positive ion mode): calcd for C31H29BNO2 [M +
CH3OH - 2H2O + H] 458.2291, found 457.9589; calcd for
C62H56B2N2NaO4 ([2M + 2CH3OH - 4H2O + Na]+) 937.4324,
found 936.8504.
distance is much shorter, e.g., 1.747 Å.23 The lack of B-N
interaction (due to the formation of intramolecular boronate
esters) may be responsible for the lower background fluores-
cence.2 Binding with analytes induces a bridged B-N interaction
and leads to enhanced fluorescence.10b This structure can be
used to design new boronic acid fluorescent chemosensors with
lower background fluorescence and higher fluorescence en-
hancement in the presence of analytes.
In summary, a mono boronic acid as an intergrated fluorescent
chemosensor for chiral recognition of mono R-hydroxyl acids
is reported. The new sensor displays fluorescence OFF-ON
character, and its recognition of hydroxyl acids is an enanti-
oselective slow process. The structural profile of the sensor may
be used for design of new enantioselective fluorescent boronic
acid sensors for chiral mono R-hydroxyl acids.
Acknowledgment. We thank the NSFC (20634040, 20642003),
Scientific Research Foundation for the Returned Overseas
Chinese Scholars (MOE), PCSIRT (IRT0711), and the Science
Research Foundation of Dalian University of Technology
(SFDUT07005) for support.
Supporting Information Available: Experimental details,
spectra of the sensors, and CIF file. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) Bosch, L. I.; Mahon, M. F.; James, T. D. Tetrahedron Lett. 2004, 45,
2859.
JO8007622
J. Org. Chem. Vol. 73, No. 12, 2008 4687