Teaching old indicators new tricks: A colorimetric chemosensing ensemble for tartrate/malate in beverages

Article abstract of DOI:10.1002/(SICI)1521-3773(19991216)38:24<3666::AID-ANIE3666>3.0.CO;2-E

The competition between tartrate and a common indicator (1) for a synthetic host (2) has been used to quantitate tartrate in beverages derived from grapes. The approach demonstrates a general method for the development of colorimetric assays in highly competitive media.

Full text of DOI:10.1002/(SICI)1521-3773(19991216)38:24<3666::AID-ANIE3666>3.0.CO;2-E

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[2] G. Vidari, G. Lanfranchi, P. Sartori, S.
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2977.
[3] a) G. Vidari, M. Franzini, L. Garlaschelli,
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2685; b) R. A. De Haan, M. J. Heeg, K. F.
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[4] G. Vidari, G. Lanfranchi, N. Pazzi, S.
Serra, Tetrahedron Lett. 1999, 40, 3063;
G. Vidari, N. Pazzi, G. Lanfranchi, S.
Serra, Tetrahedron Lett. 1999, 40, 3067.
Our synthesis was completed at the time
these reports appeared.
[5] K. Tsuji, Y. Terao, K. Achiwa, Tetrahe-
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Chiba, Liebigs Ann. Chem. 1989, 957; Y.-
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25, 4999.
OTES
O
OCH3
b
c
OCH3
OCH3
X
OCH3
46%
O
64%
O
H
H
(99%)
H
H
SO2Ph
20
21
a: X = OH
a
86%
b: X = SO2Ph
O
Ph3P
OTES
O
O
OR
2
O
OCH3
OCH3
d
O
10'
O
O
O
O
90%
H
H
H
H
O
11'
22
22 10', 11'-saturated
(23 10', 11'-unsaturated)
24 R = TES
1b R = H
e
92%
[6] Y. Gao, R. M. Hanson, J. M. Klunder,
S. Y. Ko, H. Masamune, K. B. Sharpless,
J. Am. Chem. Soc. 1987, 109, 5765.
[7] S. V. Ley, J. Norman, W. P. Griffith, S. P.
Marsden, Synthesis 1994, 639.
Scheme 4. a) (C4H9)3P, PhSSPh, PhH, RT then TPAP, NMO, 4-Š MS, CH3CN, 08C; b) n-C4H9Li, THF,
HMPA, 19d, 55 ! 308C; c) 5% Na(Hg), NaH2PO4, CH3OH, 158C; d) CF3CO2H, THF, H2O, RT,
then 2 CH2Cl2, RT; e) TBAF, HOAc, THF, RT. HMPA ˆ hexamethyl phosphoramide. Yields in
parentheses are based upon recovered starting material.
[8] K. R. Guertin, A. S. Kende, Tetrahedron
Lett. 1993, 34, 5369.
Alkylation of a sulfone-stabilized anion was chosen for the
coupling of fragments 3 and 4. The sulfone 20b was prepared
from the corresponding alcohol 20a in 86% yield by sulfide
displacement followed by oxidation[8] (Scheme 4). The alky-
lation of sulfone 20b with iodide 19d proceeded nearly
quantitatively at 50% conversion.
[9] B. M. Trost, H. C. Arndt, P. E. Strege, T. R. Verhoeven, Tetrahedron
Lett. 1976, 3477.
[10] H. Kunzer, M. Stahnke, G. Sauer, R. Wiechert, Tetrahedron Lett. 1991,
32, 1949.
[11] One explanation for the formation of the alkene is hydrogen atom
abstraction via a six-center transition state involving the phenyl-
sulfonyl radical anion competing with simple homolytic cleavage of
C S bond.
Reductive desulfonylation of 21 with sodium amalgam[9]
gave 22 accompanied, surprisingly, by some elimination
product 23. That the alkene 23 did not form by base-catalyzed
elimination is suggested by the absence of any dependence on
the amount of added buffer nor on varying the reductant to
samarium diiodide.[10, 11] The completion of the synthesis
proceeded straightforwardly as outlined (Scheme 4). Olefi-
nation of the aldehyde liberated from the acetal 22 with the
stabilized Wittig reagent 2[12] gave a 13:1 ratio of the E:Z
alkenes. The lower field shift (d ˆ 6.70) of the new olefinic
hydrogen of the major isomer compared to the minor one
(d ˆ 6.19) establishes the former as the E alkene. Desilylation
then delivers synthetic saponaceolide B (1b, [a]2D2 ˆ ‡14.4,
c ˆ 1.54 in CH2Cl2), whose spectral data agrees well with those
recorded for the natural product.[1] The success of this
synthesis derived from its access to a stereodefined cyclohexyl
unit, which in turn is prepared by the palladium-catalyzed
cycloisomerization of enynes or the Heck protocol.[13] The
convergent strategy should also provide access to other
members of the saponaceolide family as well their analogues.
The strategy outlined also provides opportunities to provide
other natural products emanating from the cyclohexyl core 3.
[12] S. Flisar, R. F. Hudson, G. Salvadori, Helv. Chim. Acta 1963, 46, 1580;
T. R. Hoye, A. J. Caruso, J. Org. Chem. 1981, 46, 1198.
[13] B. M. Trost, J. R. Corte, M. S. Gudiksen, Angew. Chem. 1999, 111,
3945 ± 3947; Angew. Chem. Int. Ed. 1999, 38, 3662 ± 3664.
Teaching Old Indicators New Tricks:
A Colorimetric Chemosensing Ensemble for
Tartrate/Malate in Beverages**
John J. Lavigne and Eric V. Anslyn*
The development of general methods for the colorimetric
analysis of small and medium-sized analytes in solution is
highly desirable since visual inspection yields immediate
qualitative information, while absorption spectroscopy gives
quantitative information. Many colorimetric assays exist, but
most often they deal with the analysis of pH,[1] simple
cations[2] and anions,[3] and radicals.[4] The majority of these
sensors have the chromophore covalently attached to the
recognition element. Upon binding of the analyte the
electronic transitions of the chromophore are perturbed. In
contrast, many colorimetric assays for large biological mole-
Received: June 23, 1999 [Z13612IE]
German version: Angew. Chem. 1999, 111, 3947 ± 3949
[*] Dr. E. V. Anslyn, J J. Lavigne
Keywords: asymmetric synthesis ´ natural products ´ spiro
compounds ´ total synthesis ´ Wittig reactions
Department of Chemistry and Biochemistry
The University of Texas at Austin, Austin, TX 78712 (USA)
Fax: (‡1)512-471-8696
E-mail: anslyn@ccwf.cc.utexas.edu
[1] M. De Bernardi, L. Garlaschelli, G. Gatti, G. Vidari, P. Vita Finzi,
Tetrahedron 1988, 44, 235; M. De Bernardi, L. Garlaschelli, L. Toma,
G. Vidari, P. Vita Finzi, Tetrahedron 1991, 47, 7109; C. Geraci, M.
Piattelli, C. Tringali, Magn. Reson. Chem. 1991, 29, 603; Z. Pang, K.
Berquist, O. Sterner, Acta Chem. Scand. 1994, 48, 453.
[**] We gratefully acknowledge funding from the Texas Advanced
Technology Program, the National Institutes of Health, and the
Welch Foundation. We thank Steven Storey and Jim Wallin for
assistance with the NMR analyses.
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Angew. Chem. Int. Ed. 1999, 38, No. 24

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cules are known. These screens most often employ antibodies,
as in common pregnancy tests,[5] or biotin ± avidin-based
sandwich assays. However, another alternative that is ame-
nable to the creation of a colorimetric method, and still used
almost exclusively in biological systems, involves the com-
petition of an indicator with the desired analyte.[6] For
example, upon exposure of an immobilized antibody satu-
rated with a tagged antigen to analyte, a competition for
the antibody binding site takes place between the tagged
antigen and the target analyte, which results in a signal
modulation.
We have recently been exploring fluorescence competition
assays employing synthetic receptors.[7] Fluorescence is useful
for the analysis of analytes that are present at very low
concentrations. However, the concentrations of many com-
mon analytes in beverages, bodily fluids, and environmental
samples are quite amenable to analysis by absorption
spectroscopy. Hence, given the advantage of having a
colorimetric assay we set out to develop a general method
for creating colorimetric assays from synthetic receptors.
Herein we report a specific example: the analysis of tartrate in
beverages.
Tartrate is a common natural product present in wines and
other grape-derived beverages. The structure of tartrate
makes it quite attractive for complexation by a synthetic
receptor since it is relatively small, while still possessing
several functional groups (alcohols and carboxyl groups) for
binding interactions. On the basis of the previous use of
boronic acids to bind 1,2- and 1,3-diols,[8] and guanidinium
groups imbedded in aminoimidazoline groups for binding
carboxylates,[9] we designed synthetic receptor 1 for tartrate
[Eq. (1)].[10] Compound 1 features a single boronic acid and
group.[14] Studies of other secondary amines coordinated to
boronic acids suggest a zwitterionic complex containing
tetracoordinate boron and nitrogen atoms.[15] The strength
of the N B interaction is approximately 19 kcalmol 1.[15a] The
geometry of the boron atom was determined from a 11B NMR
spectrum of 1. Under the assay conditions (see Experimental
Section), the spectrum shows one peak at d ˆ 12.8 (referenced
to BF3Et2O in toluene at d ˆ 0), which is indicative of a
tetrahedral boron atom.[16]
A pH indicator with a chromophore possessing the same
functionalities as tartrate was chosen for use in a competition
assay. Importantly, the choice of indicator was guided by the
expectation that complexation by the receptor would result in
a color change of the indicator. This effect is afforded by a
change in the ªprotonation stateº (for this analysis we
consider the boron atom to be acting like a proton) when
the indicator is either bound to the receptor or free in solution
at a constant pH. We chose alizarin complexone (2) for the
analysis of tartrate [Eq. (1)] since it also possesses a 1,2-diol
and two carboxylate groups. This indicator has been previ-
ously used to signal a change in pH[17] as well as the presence
of lanthanide,[17] and fluoride ions .[18] The functional groups
are not arranged in the same manner as with tartrate, and
hence a lower affinity between 1 and 2 was anticipated. We
predicted that the binding between 1 and 2 would significantly
shift the ªprotonation stateº of the phenols as a result of the
formation of a boronate ester as a result of reaction with to
the boronic acid. Indeed, the color changed from burgundy to
yellow/orange (Figure 1A) upon addition of 1 to a solution of
2 (0.1 mm) in a water/methanol mixture (25 vol% water;
pH 7.3, buffered with 10 mm HEPES). By following the
absorption at 450 nm and fitting the data to a 1:1 binding
algorithm[19] a binding con-
1
stant of 2.7 Â 104 m was ob-
tained.
As expected, the addition
of stock solutions of l-tar-
trate to an ensemble of 1 and
2 (see Experimental section;
this solution is referred to as
the sensing ensemble) result-
ed in a change from yellow/
orange back to burgundy
(Figure 1B). We analyzed
for tartrate as well as several
other possible competing analytes with structures similar to
tartrate, including: ascorbate, l-malate, succinate, lactate, and
sugars, using this colorimetric assay (Figure 2). A binding
constant of 5.5 Â 104 m 1 was calculated for 1 and tartrate using
algorithms for competitive equilibria.[19] In comparison, a
two guanidinium groups preorganized to converge and create
a cavity of the correct dimensions for tartrate. The preorga-
nization comes from the use of a hexasubstituted benzene
ring, where it has been shown that the steric bulk forces the
alternating substituents to opposite sides of the benzene
spacer.[11]
1
binding constant of 150m between 1 and glucose was
measured by UV/Vis spectroscopy; this value is in the range
There is a significant amount of prior precedence for the
use of an aminomethyl moiety in the position ortho to a
boronic acid in a sensor. All of these use a tertiary amine that
is involved in the signal transduction mechanism, usually by
quenching of the signal by photoinduced electron transfer
(PET)[12] or internal charge transfer (ICT).[13] The current
system utilizes a secondary amine solely for linking and
restricting the degrees of freedom of the boronic acid
found for a single boronic acid and a sugar.[12b] We also found
1
that succinate binds to 1 with a binding constant of 350m .
Furthermore, a monohydroxy carboxylate such as lactic acid
1
only had a binding constant of 500m with 1. With the
exception of malate (Ka with 1 is 4.8 Â 104 m 1) we find
excellent selectivity for tartrate. Hence, good cooperativity
exists between the boronic acid and the two guanidinium
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Table 1. Concentration of tartaric and malic acids [mm] in different
solutions as determined by different methods.
Gravi-
metric
NMR
UV/Vis
(1 ‡ 2)
tartaric acid model solution
calibration solution
Ernest & Julio Gallo Sauvignon Blanc
Ste. Genevieve Chardonnay
Henri Marchant Spumante
Talus Merlot
50
50
±
±
±
±
±
±
51.2
±
50.2
47.9
32.9
36.3
24.9
20.3
42.3
71.3
35.6
34.1
26.5
19.5
43.6
69.4
Santa Cruz organic white grape juice
Welchꢁs grape juice
tartrate/malate in the presence of large concentrations of
sugars, electrolytes, pectins, and tannins.
In summary, a colorimetric assay for tartrate using a
synthetic receptor has been created. In this assay a common
pH indicator that has the same or similar functionalities to
that of the analyte of interest has been used. Since the
receptor is most complementary to the analyte there is a lower
relative affinity for the indicator, which leads to the facile
displacement of the indicator from the receptor upon addition
of the analyte and a color change of the indicator occurs. We
are currently exploring this approach for the analysis of many
other analytes in liquids.
Figure 1. UV/Vis spectra of 2. A) Addition of 1 to a constant concen-
tration of 2 (180 mm) results in an increase in the absorbance at 450 nm with
a decrease in absorbance at 525 nm. B) Addition of tartrate to a solution
containing both 1 and 2 (180 mm each) at a constant concentration causes a
decrease in the absorbance at 450 nm and an increase in the absorbance at
525 nm.
Experimental Section
1: 1-aminomethyl-2,4,6-triethyl-3,5-(N-(imidazoline-2-yl-aminomethyl)ben-
zene (300 mg, 0.53 mmol)[20] was mixed with (2-formylphenyl)boronic acid
(87.6 mg, 0.58 mmol) in anhydrous methanol to which was added distilled
triethylamine (360 mL, 2.65 mmol) and activated 3-Š molecular sieves. The
solution was stirred at 258C for 3 h. Sodium borohydride (20.2 mg,
0.53 mmol) was then added to the solution and stirred for an additional
hour. The solution was filtered through a pad of celite to remove the sieves
and the solvent removed by rotary evaporation. The resulting residue was
placed under reduced pressure (6 Torr) for two days to remove the
trimethylborate. This residue was then dissolved in water and filtered
through a pad of celite to remove the reduced aldehyde. The water was
lyophilized to yield a fluffy white solid (366 mg, 99%). M.p. 1978C
(decomp); 1H NMR (300 MHz, CD3OD, 258C): d ˆ 1.12 (t, 6H; CH3),
1.23 (t, 3H; CH3), 1.81 (s, 9H; CH3), 2.74 (q, 2H; CH2), 2.82 (q, 4H; CH2),
3.75 (s, 8H; CH2), 3.97 (s, 2H; CH2), 4.11 (s, 2H; CH2), 4.43 (s, 4H; CH2),
7.11 (d, 1H; Ph), 7.15 ± 7.23 (m, 2H; Ph), 7.49 (d, 1H; Ph); 13C NMR
(75 MHz, CD3OD, 258C): d ˆ 16.4, 16.6, 23.1, 24.1, 42.0, 44.1, 53.5, 116.2,
127.9, 128.4, 130.8, 131.4, 146.7, 161.2, 162.8, 163.2, 178.8; 11B NMR
(160 MHz, CD3OD, 258C): d ˆ 8.2; HR-MS (FAB (gly), as the glycerol
boronate ester): m/z: found: 576.3839; calcd for C31H47BN7O3: 576.3833
Figure 2. Calibration curves at 450 nm used for the sensor assay. Addition
‡
[M ‡1].
~
^
*
^
^
of tartrate ( ), malate ( ), ascorbate ( ), lactate ( ), succinate ( ), and
UV/Vis determination of tartrate/malate: HEPES buffer (10 mm) at
&
glucose ( ). cAnal. ˆ concentration of the analyte.
pH 7.35,
1 (180 mm), alizarin complexone (180 mm) in 25% water in
methanol. Sample preparation involved adjusting the pH of beverage
(5 mL) with aqueous sodium hydroxide and diluting to 10 mL with water.
An aliquot of this dilute wine solution (40 mL) was added to the sensing
ensemble (960 mL; to maintain a constant indicator and host concentra-
tion). A portion of this solution (5± 50 mL) was then added to the sensing
ensemble (1 mL). The average of four scans was used to determine one
value.
groups of 1 for the complexation of the hydroxyl and
carboxylate moieties of tartrate.
For final proof of principle the calibration curves generated
for tartrate and malate (Figure 2) were used to evaluate
various solutions. The addition of microliter quantities of
several grape-derived beverages to the sensing ensemble gave
the concentrations of tartrate/malate present (Table 1). An
NMR assay for the total tartrate/malate concentration was
used as a control. In all cases very good agreement (less than
10% difference) between the two methods was obtained. This
suggests that the sensing ensemble is able to quantitate
NMR determination of tartrate/malate: Beverage (50 mL) was adjusted to
pH 7.35 with aqueous sodium hydroxide and the water removed by
lyophilization. The residue was then dissolved in D2O (5 mL) and the
volume brought to 10 mL with D2O. The internal reference solution was
made by dissolving dichloroacetic acid(0.5 mL) in D2O, the pH brought to
7.35 with sodium deuteroxide, and the volume brought to 10 mL. D2O
(800 mL) was combined with dichloroacetic acid solution (100 mL) in an
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NMR tube and wine solution (100 and 300 mL) added. The area of the
integral for dichloroacetic acid was normalized to the areas from malate
and tartrate and the concentrations calculated.
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Received: May 31, 1999
Revised version: September 15, 1999 [Z13485]
German edition: Angew. Chem. 1999, 111, 3903 ± 3906
Keywords: analytical methods ´ boron ´ molecular recog-
nition ´ sensors ´ tartrate
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New Efficient Multicomponent Reactions with
C C Coupling for Combinatorial Application
in Liquid and on Solid Phase**
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Dedicated to Dr. Pol Bamelis
on the occasion of his 60th birthday
Elegance in chemical synthesis is reflected in the art of
finding simple ways to construct complex structures.[1] In the
age of combinatorial chemistry,[2] multicomponent and dom-
ino reactions[3] are of special importance. This is especially
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the continuing development of classic multicomponent reac-
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Mannich,[6c] the preferential formation of heteroatom ± car-
bon bonds is prominent. We were recently able to extend the
repertoire of less common cascade reactions solely leading to
[*] Prof. Dr. A. de Meijere, Dipl.-Chem. H. Nüske,
Dipl.-Chem. T. Labahn
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Institute für Organische und Anorganische Chemie der Universität
D-37077 Göttingen (Germany)
Fax: (‡49)551-393231
E-mail: ameijer1@uni-goettingen.de
Dr. S. Bräse, M. Schroen
Institut für Organische Chemie der Technischen Hochschule
D-52074 Aachen (Germany)
Fax: (‡49)241-8888127
E-mail: Braese@oc.RWTH-Aachen.de
Dr. M. Es-Sayed
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Bayer AG, GB Pflanzenschutz
D-40789 Monheim (Germany)
Fax: (‡49)2173-383342
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E-mail: Mazen.Es-Sayed.ME@Bayer-ag.de
[**] Cyclopropyl Building Blocks in Organic Synthesis, Part 54, and
Nitrogen-Based Linkers, Part 6. This work was supported by the
Deutsche Forschungsgemeinschaft (BR1750/2) and the Fonds der
Chemischen Industrie (Liebig fellowship for S.B., etc.). We thank
Prof. Dr. Dieter Enders for his generous support and Calbiochem-
Novabiochem AG for gifts of chemicals. Part 53: A. de Meijere, K.
Ernst, B. Zuck, M. Brandl, S. I. Kozhushkov, M. Tamm, D. S. Yufit,
J. K. Howard, T. Labahn, Eur. J. Org. Chem. 1999, in press, and Part 5:
ref. [12a].
Angew. Chem. Int. Ed. 1999, 38, No. 24
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