Stereoselective UV sensing of 1,2-diaminocyclohexane isomers based on ligand displacement with a diacridylnaphthalene N,N′ -dioxide scandium complex

Article abstract of DOI:10.1021/jo300738s

Stereoselective displacement of diacridylnaphthalene N,N′-dioxide ligands, 1, from a scandium(III) complex can be used for quantitative detection of 1,2-diaminocyclohexane isomers. The diastereoselective sensing assay with Sc(syn-1)₂ shows exce

Full text of DOI:10.1021/jo300738s

Note
pubs.acs.org/joc
Stereoselective UV Sensing of 1,2-Diaminocyclohexane Isomers
Based on Ligand Displacement with a Diacridylnaphthalene N,N′-
Dioxide Scandium Complex
Daniel P. Iwaniuk, Kimberly Yearick-Spangler, and Christian Wolf*
Department of Chemistry, Georgetown University, Washington, D.C. 20057, United States
S
* Supporting Information
ABSTRACT: Stereoselective displacement of diacridylnaphtha-
lene N,N′-dioxide ligands, 1, from a scandium(III) complex can be
used for quantitative detection of 1,2-diaminocyclohexane isomers.
The diastereoselective sensing assay with Sc(syn-1)2 shows
excellent linearity between the sample de and the measured UV
absorption change, and sensing of mixtures comprising both low
and high de values gave results within 5% accuracy. All three
stereoisomers of 1,2-diaminocyclohexane can be differentiated
using Sc[anti-(−)-1]2 in the same ligand displacement assay.
he high demand for pure stereoisomers by the
pharmaceutical, agrochemical, and other industries has
sensors derived from BINOL have been used for chiral
recognition of α-hydroxy acids and amino acids by Lin’s and
Pu’s groups,7 while few modified cyclodextrins and calixarenes
have been found capable of enantioselective fluorosensing.8
Our laboratory has developed several C2-symmetric 1,8-
diquinolyl- and 1,8-diacridylnaphthalene selectors for enantio-
selective UV and fluorescence sensing of minute amounts of a
wide range of chiral compounds.9
Compared to the variety of enantioselective sensing
examples, the analysis of ternary isomeric mixtures, e.g., the
enantiomers and the meso isomer of free 1,2-diaminocyclohex-
ane or similar substrates, is an even more complex task. To the
best of our knowledge, a UV sensor that can be used to
quantitatively distinguish between chiral and meso compounds
without prior derivatization has not been reported to date. We
now introduce a practical ligand displacement assay (LDA)
with a diacridylnaphthalene N,N′-dioxide scandium(III) com-
plex that differentiates between the chiral and meso isomers of
underivatized diamines.
T
been accompanied by significant progress in asymmetric
synthesis1 and by the development of analytical techniques
for the determination of the stereochemical purity of organic
compounds.2 Stereoselective analysis is very important to verify
the purity and the stability to racemization or diastereomeriza-
tion of fine chemicals and drugs. It also plays an integral part in
the development of new asymmetric reactions. High-
throughput screening (HTS) efforts utilizing chiral chromatog-
raphy for the evaluation of one-pot multisubstrate experiments
can provide detailed information on yields and stereo-
selectivity.3 However, the use of HPLC for HTS of large
numbers of samples is generally too time-consuming and
produces substantial amounts of solvent waste. Accordingly,
real-time analysis of minute sample amounts with carefully
designed sensors that translate a molecular recognition event
into a quantifiable signal seems to be more promising to
complement the advance in automated parallel synthesis and
combinatorial methods.
We have previously shown that 1,8-diacridyl- and 1,8-
diquinolylnaphthalenes and their N,N′-dioxides can be used for
highly enantioselective recognition suitable for quantitative UV
and fluorescence detection of chiral amines, amino alcohols,
carboxylic acids, α-hydroxy acids, and amino acids in
acetonitrile, chloroform, and other organic solvents and even
in aqueous solutions.9 This has been accomplished by using
chiral sensor 1 and its analogues in two mechanistically
different experiments that either involve (a) stereoselective
hydrogen bonding of the analytes to the heteroaryl nitrogen or
the heteroaryl N-oxide moieties embedded in the chiral cleft of
the sensor or (b) ligand exchange with N,N′-dioxide-derived
The simplicity, sensitivity, and potential for automation and
real-time analysis make UV- and fluorescence-based assays
particularly attractive for the development of stereoselective
sensing methods. This venue has been pursued by several
groups, and intriguing sensors have been reported in recent
years. For example, Wang, Zhao, James, and Kubik found that
chiral boronic acids can be used for stereoselective recognition
and quantitative detection of monosaccharides and α-hydroxy
acids.4 Anslyn, Corradini, and others have demonstrated the
usefulness of diaminocyclohexane- and β-cyclodextrin-derived
copper(II) complexes for enantioselective colorimetric and
fluorescent sensing.5 Anslyn also introduced compelling
indicator-displacement assays suitable for the determination
of concentration and quantity of chiral α-hydroxy acids and
amino acids.6 Several molecular and supramolecular fluoro-
Received: April 12, 2012
© XXXX American Chemical Society
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scandium(III) complexes. We hypothesized that the design of a
successful diastereoselective sensor that is expected to
recognize a meso substrate in a mixture with chiral isomers
should mimic the symmetry of the target and thus exhibit a
mirror plane. We therefore began this study with the synthesis
of the syn-isomer of N,N′-dioxide 1 (Figure 1).
Figure 2. UV spectrum of Sc(syn-1)2 and disappearance of the charge
transfer absorption at 390 nm upon addition of meso-6. The
concentration of the sensor was 1.83 × 10−5 M in acetonitrile
containing 2% of CHCl3.
Figure 1. Structures of syn- and anti-1.
ligand displacement reaction could be stereoselective. We
assumed that the enantiomers and the meso isomer of diamine
6 are likely to possess different abilities to displace the two
N,N′-dioxide ligands from the scandium center which would
provide a basis for UV analysis of the de of stereoisomeric
mixtures of 6. The titration experiments with meso and racemic
diamine 6 are shown in Figure 3. Both diastereoisomers of 6
Following a previously established synthetic route,9e we
prepared acridylstannane 3 in four steps via ring construction
from commercially available 2-chloro-4-bromobenzoic acid, 2,
in 83% overall yield (Scheme 1). Double Stille coupling with
dibromide 4 then produced an equimolar mixture of syn- and
anti-5 in 89% yield. The diastereomers of 5 were separated by
flash chromatography and oxidized with m-CPBA to give pure
syn- and anti-isomers of N,N′-dioxide 1 in 72−75% yield. After
screening of several chiral HPLC columns, we found that the
enantiomers of anti-1 can be effectively separated on the
WhelkO-1 column. Optimization of HPLC conditions allowed
us to separate 20 mg of anti-1 in 7 min or close to 200 mg
within 1 h based on repetitive injections (see the Experimental
Section).
Having prepared the diastereomers of 1, we continued with
the UV analysis of several transition-metal complexes and
found that coordination of syn-1 to indium(III), scandium(III),
copper(II), and other metal ions gave characteristic UV charge-
transfer bands at 390 nm. Job plot analysis with scandium
triflate revealed formation of Sc(N,N′-dioxide 1)2 (see the
Experimental Section). We were pleased to observe that this
UV absorption fully disappears upon addition of meso-1,2-
diaminocyclohexane, 6 (Figure 2). Apparently, the change in
the UV absorbance at 390 nm is the result of a stepwise
displacement of syn-1 from the metal center by the diamine.
The readily observed UV change of Sc(N,N′-dioxide 1)]2
upon addition of diamine 6 then led us to investigate if this
Figure 3. Ligand displacement assay using Sc(syn-1)2 and meso-6
(blue) and rac-6 (red). The concentration of the sensor was 1.83 ×
10−5 M in acetonitrile containing 2% of CHCl3. Data were recorded at
390 nm.
Scheme 1. Synthesis of syn- and anti-1
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replace the N,N′-dioxide ligand, and the characteristic UV
absorption of Sc(syn-1)2 at 390 nm disappears almost
quantitatively, even when substoichiometric amounts are
used. However, the chiral isomers of 6 proved much more
effective than the meso diamine. While relatively small amounts
of chiral 6 suffice to replace both N,N′-dioxide ligands from the
scandium center, one needs to add twice as much of the meso
isomer to obtain the same UV change. Titration experiments
with diastereomeric mixtures of 6 then showed that the
remarkably different ligand displacement process can be used to
determine the diastereomeric composition of samples with
varying de.
To evaluate the practical use of this sensor, three samples of
6 covering a wide de range were analyzed at micromolar
concentrations (see Table 1). First, a calibration curve was
Table 1. Experimentally Determined de’s of Three Scalemic
Samples of 6
Figure 4. (Left) NMR analysis of the N,N′-dioxide displacement in
CDCl3: (A) free (syn)-1 at 7.45 mM; (B) (syn)-1 and Sc(OTf)3 at 7.45
mM and 3.75 mM, respectively; (C) (syn)-1, Sc(OTf)3 and rac-6 at
7.45, 3.75, and 1.87 mM, respectively. (Right) Colorimetric change
from bright red (free N,N′-dioxide ligand) to maroon (Sc(syn-1)2) and
back to bright red upon addition of 6.
actual % de
calcd % de
90
−50
12
86.4
−45.5
16.9
constructed and the comparison of the UV absorption at 390
nm versus % de revealed a perfectly linear relationship. It is
noteworthy that a linear correlation between the UV change
and the diastereomeric composition of 6 is not necessarily
expected.10 Three mixtures containing 6 in 12, 50, and 90% de,
respectively, were then analyzed immediately after mixing with
Sc(syn-1)2 and without further purification. The results
obtained by this UV sensing method were in excellent
agreement with the theoretical de’s. This time-efficient assay
gave de’s that are generally within 5% of the actual values which
is beyond sufficient for HTS purposes.
The formation of Sc(syn-1)2 and the rapid displacement of
the N,N′-dioxide ligand from the metal center upon addition of
diaminocyclohexane is also evident from 1H NMR and
colorimetric analysis (Figure 4). Coordination of free syn-1 to
scandium(III) in CDCl3 results in characteristic signal shifts
and line broadening. At the same time, the color of the solution
changes from bright red to maroon. Upon addition of rac-6, the
free N,N′-dioxide is regenerated instantaneously and the
original aromatic NMR spectrum and red color can be
observed.
Figure 5. Ligand displacement assay using Sc[(−)-1]2 and the isomers
of 6. The concentration of the Sc complex was 1.79 × 10−5 M in
acetonitrile containing 2% of CHCl3. Data were recorded at 405 nm.
The titration curves obtained with (R,R)-6, (S,S)-6 and meso-6 are
shown in blue, red, and green, respectively.
Scheme 2. LDA with 2 equiv of meso-6
We then applied enantiopure Sc[anti-(−)-1]2 and the
isomers of 1,2-diaminocyclohexane in essentially the same
assay and realized that this LDA provides an entry to
stereoselective UV recognition of the three stereoisomers
(Figure 5). In all cases, the full displacement of anti-(−)-1 from
the scandium center required 2−3 equiv of the diamine
substrate. A comparison of the UV titration curves shows that
the meso form of 6 is most effective in this ligand exchange
reaction, whereas the UV charge transfer band of Sc[anti-
(−)-1]2 disappears more readily upon addition of (R,R)-6 than
in the presence of (S,S)-6.
Based on our UV and NMR analyses, we assume that the
LDA with Sc[anti-(−)-1]2 is based on a two-step ligand
exchange process that is stereoselective because it involves
intermediate diastereomeric complexes 8 (Scheme 2). Displace-
ment of the first N,N′-dioxide ligand in Sc(anti-(−)-1)2, 7, by
meso-diamine 6, generates Sc[(anti-(−)-1)(meso-6)], 8. Further
addition of the diamine then results in the replacement of the
second N,N′-dioxide ligand from the metal center and
formation of scandium complex 9, which is devoid of a UV
charge-transfer band at 390 nm (Scheme 2). Accordingly, the
ligand exchange results in the disappearance of the intense
charge transfer band of the N,N′-dioxide-derived scandium
complexes 7 and 8. Assuming that the stereoisomeric
complexes of 9 have very similar stabilities, the most striking
difference between the LDA with either the meso or the chiral
forms of diamine 6 is the structure and stability of the
intermediate scandium complex 8. The stronger displacement
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Figure 6. HPLC chromatograms using UV detection at 254 nm for detection of the enantiomers of anti-1. The two HPLC chromatograms show an
analytical (left) and a preparative separation (right).
(202 mg, 0.293 mmol) in a 1:1 ratio as yellow crystals in 89% total
yield.
anti-Isomer: H NMR (300 MHz, CDCl3) δ = 2.45 (s, 12 H),
6.62−6.68 (m, 2 H), 6.83−6.86 (m, 4 H), 7.00−7.03 (m, 2 H), 7.07
(s, 2 H), 7.31−7.39 (m, 8 H), 7.67 (d, J = 9.1 Hz, 2 H), 7.73−7.78 (m,
2 H), 7.91 (s, 2 H). 8.31 (d, J = 8.2 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ = 22.3, 124.8, 125.4, 125.5, 125.6, 125.9, 126.2, 126.3, 126.6,
127.0, 129.3, 129.8, 130.1, 130.5, 131.2, 134.2, 134.6, 135.5, 139.0,
140.8, 141.9, 146.1, 147.5, 147.6; mp >275 °C.
aptitude of the meso isomer can then be attributed to the
formation of a relatively unstable complex 8 due to the steric
repulsion between meso 6 and the N,N′-dioxide ligand.
Although the coordination sphere of 8 is unknown,
coordination of a chiral isomer of 6 is expected to result in
less steric repulsion and the generation of a more stable
intermediate 8 thus impedes removal of the second N,N′-
dioxide ligand. Accordingly, the chiral isomers are less effective
in this LDA and the disappearance of the UV charge transfer
band requires higher amounts of the enantiomers of 6.
In summary, we have demonstrated the first example of UV
sensing of enantiomers and diastereomers of an unprotected
substrate. The high sensitivity and diastereoselectivity of the
ligand displacement assay (LDA) with Sc(syn-1)2 allows
quantitative de analysis of minute sample amounts with
sufficient accuracy for high-throughput screening purposes.
The use of meso or enantiopure Sc[N,N′-dioxide 1]2 in
competitive binding assays seems very promising for the
development of practical UV colorimetric assays for rapid
analysis of complex ternary mixtures of stereoisomers. The
LDA presented is expected to be suitable for automation and
has several attractive features: it can be applied to the analysis
of minute amounts of underivatized samples which will simplify
operation, the UV measurement can be performed immediately
after mixing of the sensor and the substrate mixture, and the
quantitation is based on sensitive UV spectroscopic detection
which minimizes solvent waste.
1
syn-Isomer. 1H NMR (300 MHz, CDCl3) δ = 2.26 (s, 12 H), 6.65−
6.70 (m, 2 H), 6.75−6.78 (m, 2 H), 6.85−6.88 (m, 2 H), 6.96−6.99
(m, 4 H), 7.12 (s, 4 H), 7.28−7.31 (m, 2 H), 7.36−7.42 (m, 2 H),
7.69−7.75 (m, 4 H), 7.91 (d, J = 1.7 Hz, 2 H), 8.27 (dd, J = 1.1 Hz, 8.4
Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ = 22.0, 124.8, 125.3, 125.4,
125.5, 125.8, 126.1, 126.3, 126.4, 126.9, 129.4, 129.7, 130.1, 130.4,
131.1, 134.2, 134.7, 135.5, 138.8, 140.7, 142.1, 146.1, 147.4, 147.5; mp
243−244 °C.
anti-1,8-Bis(3-(3′,5′-dimethylphenyl)-9-acridyl)naphthalene
N,N′-Dioxide (anti-1).9h To a solution of anti-5 (100 mg, 0.15 mmol)
in 3 mL of THF was added peroxybenzoic acid (68 mg, 0.30 mmol) in
2 mL of THF. The mixture was allowed to stir at room temperature
for 5 h, and the solvent was removed under reduced pressure. The
residue was dissolved in methylene chloride, washed with 2 N sodium
hydroxide, dried over MgSO4, and concentrated in vacuo. Purification
by flash chromatography (100:10 ethyl acetate/ethanol) afforded 1
(80 mg, 1.11 mmol) as a red solid in 75% yield: 1H NMR (300 MHz,
CDCl3) δ = 2.45 (s, 12H), 6.63−6.69 (m, 2H), 6.81 (d, J = 9.1 Hz,
2H), 6.87 (d, J = 8.0 Hz, 2H), 7.09−7.14 (m, 4H), 7.34−7.41 (m,
8H), 7.77 (dd, J = 7.2 Hz, 8.2 Hz, 2H), 8.32 (dd, J = 1.1 Hz, 8.2 Hz
2H), 8.47 (d, J = 9.1 Hz 2H). 8.69 (d, J = 1.7 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ = 22.3, 117.6, 120.5, 126.1, 126.5, 126.5, 126.6, 126.7,
126.3, 126.9, 127.5, 130.0, 130.7, 131.0, 132.2, 133.4, 134.1, 135.1,
135.9, 138.6, 138.6, 139.2, 140.2, 143.0; mp 250−251 °C dec.
syn-1,8-Bis(3-(3′,5′-dimethylphenyl)-9-acridyl)naphthalene N,N′-
Dioxide (syn-1). To a solution of syn-5 (38 mg, 0.06 mmol) in 5 mL of
THF was added peroxybenzoic acid (102 mg, 77% purity, 0.59 mmol).
The mixture was allowed to stir at room temperature for 13 h and the
solvent was removed by evaporation under reduced pressure. The
residue was dissolved in methylene chloride and washed with 2 N
sodium hydroxide, dried over MgSO4, and concentrated in vacuo.
Purification by flash chromatography (100:10 ethyl acetate/ethanol)
afforded the hydrate of syn-1 (28 mg, 0.04 mmol) as a red solid in 72%
yield. NMR analysis showed that syn-1 cocrystallizes with 3 equivalents
EXPERIMENTAL SECTION
■
1. Synthetic Procedures. All reagents and solvents were
commercially available and used without further purification. Reaction
products were purified by flash chromatography on silica gel (particle
size 0.032−0.063 mm). NMR spectra were obtained at 300 or 400
MHz (1H NMR) and 75 or 100 MHz (13C NMR) using CDCl3 as
solvent. Chemical shifts are reported in ppm relative to TMS.
1,8-Bis(3-(3′,5′-dimethylphenyl)-9-acridyl)naphthalene (5).9h 1,8-
Dibromonaphthalene, 4 (84 mg, 0.293 mmol), CuO (47 mg, 0.585
mmol), and Pd(PPh3)4 (121 mg, 0.11 mmol) were combined under
nitrogen in anhydrous DMF (3 mL). The reaction was heated to 130
°C and stirred for 5 min, and then 3-(3′,5′-dimethylphenyl)-9-
trimethylstannylacridine, 3 (670 mg, 1.17 mmol), in 3 mL of
anhydrous DMF was added in one portion. The reaction proceeded
for 40 h at 130 °C, was quenched with saturated sodium bicarbonate
water, and was extracted with dichloromethane, and solvents were
removed under reduced pressure. The crude material was purified by
silica gel column chromatography (2:2:1:1% dichloromethane/
hexanes/ethyl acetate triethylamine) to afford the diastereomers of 5
1
of water: H NMR (400 MHz, CDCl3) δ = 2.27 (s, 12H), 6.76−6.79
(m, 4H), 6.85 (d, J = 8.7 Hz, 2H), 6.98−6.7.03 (m, 4H), 7.13 (s, 4H),
7.38 (d, J = 6.9 Hz, 2H), 7.41−7.46 (m, 2H), 7.75−7.79 (m, 2H). 8.32
(d, J = 8.5 Hz, 2H), 8.50 (d, J = 9.1 Hz, 2H), 8.63 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ = 20.2, 115.8, 118.7, 124.3, 124.4, 124.5, 124.7,
124.8, 124.9, 125.0, 125.1, 125.2, 125.6, 128.5, 129.0, 129.3, 130.5,
131.6, 134.1, 136.8, 136.9, 137.3, 138.3, 141.7; mp 255−256 °C dec.
D
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Anal. Calcd. for C52H38N2O2·3H2O: C, 80.39; H, 5.71; N, 3.61.
Found: C, 80.01; H, 6.00; N, 3.33.
2. Preparative HPLC Separation of the Enantiomers of anti-
1. The enantiomers of anti-1 were separated on a preparative (R,R)-
Whelk-O 1 column (10 mm × 250 mm) using a mobile phase of
dichloromethane/ethanol (90:10) and injecting 1 mL of a 0.028 M
solution of 1 in dichloromethane/ethanol (20 mg/1 mL). The flow
rate was 5 mL/min, and the column temperature was 25 °C. The
enantiomers of anti-1 have retention times of approximately 3.5 and
6.0 min, and the levorotatory enantiomer was found to elute first.
(Figure 6). With this efficient protocol, 200 mg of the atropisomer was
separated in about 1 h. Solvents were removed under reduced
pressure, and the enantiomeric purity of each enantiomer was
confirmed to be >99% by reinjection on the HPLC using the same
separation conditions.
3. UV Spectroscopy Measurements and Characterization of
Metal Complexes of syn-1. We investigated the formation of a
series of metal complexes of syn-1 in acetonitrile at 25 °C (Figure 7).
Characteristic charge-transfer bands at 390 nm were observed with
In(III), Sn(II), Sc(III), Gd(III). Zn(II), Yb(III), Cu(II), and Cu(I).
Figure 8. Job plot showing the formation of a 2:1 complex between
syn-1 and Sc(III). The total concentration of syn-1 and Sc(OTf)3 was
3.49 × 10−5 M in acetonitrile. The temperature was 25 °C. Data were
recorded at 390 nm.
Figure 9. Linear calibration curve for the LDA with Sc[syn-1]2 and 6.
Figure 7. Change in the UV/vis spectra of syn-1 upon addition of
Sc(OTf)3. The concentrations of syn-1 and Sc(OTf)3 were 3.48 × 10−5
M and 1.74 × 10−5 M, respectively, in ACN/CHCl3 (49:1). The blue
curve represents pure syn-1, and the green curve represents the
complex formed between syn-1 and Sc(OTf)3.
mixture of acetonitrile/chloroform (49:1). Stock solutions of (R,R)-6,
(S,S)-6, and meso-6 were prepared in chloroform (1.74 × 10−3 M), and
then portions of 10 μL of a substrate stock solution were added to 2
mL of the Sc[anti-(−)-1]2 solution. Data were recorded at 405 nm and
at room temperature.
The stoichiometry of the scandium complex of syn-1 was
determined by Job plot analysis (Figure 8). It was found that syn-1
forms a 2:1 complex with Sc(OTf)3.
ASSOCIATED CONTENT
* Supporting Information
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
4. Diastereomeric Excess: Calibration Curve and de
Determination Using Sc[syn-1]2 and 6. In order to evaluate the
practical use of Sc[syn-1]2 for de determination, a calibration curve was
constructed using samples of 6 in varying de at 25 °C. A stock solution
containing syn-1 at a concentration of 3.52 × 10−5 M and Sc(OTf)3 at
a concentration of 1.75 × 10−5 M was prepared in a mixture of
acetonitrile:chloroform (49:1). Stock solutions of 6 (1.73 × 10−3 M)
with varying de (+100.0, +86.0, +46.0 +16.0 −38.0, −54.0, −88.0,
−100.0) were prepared in anhydrous CHCl3. For each ligand
displacement assay, 10 μL of the substrate stock solution was added
to 2 mL of the Sc[syn-1]2 stock solution. UV/vis data were collected at
390 nm. The calibration curve shows a linear relationship: A =
0.0009(% de) + 0.2289, with R2 = 0.9804 (Figure 9).
Three scalemic samples of 6 were prepared and then treated with
Sc[syn-1]2 as described above. Using the linear regression equation
obtained from the calibration curve and the measured UV/vis
absorbance at 390 nm, the diastereomeric composition of these
samples was determined (Table 1). Experimentally obtained data were
within 5% of the actual values.
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: cw27@georgetown.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Funding from the National Science Foundation (CHE-0910604
and CHE-1213019) is gratefully acknowledged.
■
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