Chiroptical sensing of citronellal: Systematic development of a stereodynamic probe using the concept of isostericity

Article abstract of DOI:10.1039/c2cc36267h

A rationally designed stereodynamic ICD probe carrying two terminal amino functions for chemo- and enantioselective sensing of citronellal is introduced. The sensor shows strong Cotton effects upon diimine formation which can be used for accurate ee deter

Full text of DOI:10.1039/c2cc36267h

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COMMUNICATION
Chiroptical sensing of citronellal: systematic development of a
stereodynamic probe using the concept of isostericityw
Daniel P. Iwaniuk and Christian Wolf*
Received 28th August 2012, Accepted 29th September 2012
DOI: 10.1039/c2cc36267h
A rationally designed stereodynamic ICD probe carrying two terminal
amino functions for chemo- and enantioselective sensing of citronellal
is introduced. The sensor shows strong Cotton effects upon diimine
formation which can be used for accurate ee determination.
that exploit zinc and copper complexes for quantitative ee
determination of chiral compounds.14 Despite all these efforts,
optical sensing is still limited to few classes of compounds and the
analysis of chiral aldehydes has remained particularly challenging.15
The introduction of new effective ICD probes has proven to be
quite difficult which has hampered the advance of this emerging
field. We have therefore become interested in discovering a rational
approach that would provide a practical venue for systematic sensor
developments. We now wish to report such a case study using
citronellal, arguably one of the most important biologically active
chiral aldehydes, as a sensing target.
The general importance of chiral pharmaceuticals, agrochemicals,
flavors, nutrients and other fine chemicals has stimulated
tremendous activity in asymmetric synthesis.1 The introduction of
high-throughput screening (HTS) technologies that allow parallel
synthesis and time-efficient optimization of reaction condi-
tions has further propelled progress in this field. Consequently,
the development of enantioselective methods for HTS of the
absolute configuration and ee of numerous samples of chiral
compounds generated in parallel has become an increasingly
important challenge. Although chiral chromatography has
been successfully applied in the analysis of multi substrate
reactions,2 spectroscopic techniques are more easily tailored to
HTS of large numbers of samples and have an inherent
sustainability advantage by generating less solvent waste.3,4
Chiroptical spectroscopy is particularly well-suited for
stereochemical analysis of chiral compounds and molecular
recognition events.5 Induced circular dichroism (ICD) measure-
ments6 with stereodynamic chromophoric probes that generate
distinct Cotton effects upon interaction with a chiral substrate
are frequently used for structural investigations of inclusion
complexes,7 chiral ion pairs8 and supramolecular architectures.9
The same principles have been introduced by us and others to
determine the absolute configuration and enantiomeric composition
of chiral compounds that lack a strong chromophore.10 Rosini,
Toniolo and others covalently attached a conformationally flexible
biphenyl reporter moiety to chiral amino acids, carboxylic acids and
alcohols and showed that the induced CD signals are directly
related to the absolute configuration of the substrates used.11
Berova and others demonstrated that configurational analysis
can also be achieved with hydrogen bond adducts12 and
porphyrin-derived metal complexes.13 Similarly, Anslyn and
Kleij introduced exciton-coupled circular dichroism protocols
Our laboratory recently introduced 1 and similar stereodynamic
arylacetylene-based dialdehyde probes that generate a strong ICD
readout upon condensation with amines and amino alcohols.16 The
diimines obtained with 1 and simple aliphatic amines, such as
2-aminoheptane and 1-cyclohexylethylamine, have characteristic
Cotton effects at high wavelengths. We envisioned that due to the
rigidity of the imine bond, the underlying concept of central-to-
axial chirality induction could lead to the development of an
effective ICD sensor for citronellal (Fig. 1). Bisaniline 2 was
expected to exist as a CD-silent mixture of rapidly interconverting
conformations due to the facile rotation about the triple bond axes.
Diimine formation between 2 and citronellal, 3, would then disrupt
this equilibrium and impose axial chirality on the previously
fluxional polyarylacetylene scaffold, resulting in distinct amplifica-
tion of chirality and induced Cotton effects.
We first prepared 1,4-bis((2-bromophenyl)ethynyl)benzene, 4, via
palladium catalyzed double Sonogashira coupling of 2-iodobromo-
benzene, 5, and 1,4-diethynylbenzene, 6, in quantitative amounts.
Department of Chemistry, Georgetown University, Washington,
DC 20057, USA. E-mail: cw27@georgetown.edu;
Fax: +1 202 687 6209; Tel: +1 202 687 3468
w Electronic supplementary information (ESI) available: Synthetic
procedures, and spectroscopic, spectrometric and cystallographic
details. CCDC 895201. For ESI and crystallographic data in CIF or
other electronic format see 10.1039/c2cc36267h
Fig. 1 Chirality imprinting on the arylacetylene scaffold of 1 with
primary amines and sensing of the ICD target citronellal, 3, using 1,4-
bis(2(2-anilinylethynyl)phenylethynyl)benzene, 2.
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By contrast, CD analysis proved that the diimine formed from 2
and citronellal, 3, has distinct chiroptical properties and affords
strong Cotton effects at high wavelengths even at high dilution
(Fig. 3). Control experiments with free citronellal at 100 times
higher concentrations showed that it is essentially CD-silent under
otherwise the same conditions. In light of the distant location of the
chiral center in 3 from the imine functions formed during the
condensation reaction with 2, the strong CD output is quite
remarkable and indicates a pronounced imprinting of chiral
information on the arylacetylene framework. The diimine
formation with 3 occurs smoothly at room temperature and the
condensation adduct can be analyzed in situ, thus eliminating any
purification steps prior to the CD measurement.
Scheme 1 Synthesis of bisaniline 2.
Sensor 2 does not only provide a strong CD readout upon
recognition of a chiral substrate with a remote chiral center, it also
turned out to be chemoselective. We found that 2 does not react
with a-branched substrates such as perillaldehyde and myrtenal
even upon heating and prolonged reaction times. This unexpected
selectivity is probably due to increased repulsion between the
ortho-substituted aniline moieties and these sterically less
accessible aldehydes. As a result, the presence of perillaldehyde
and myrtenal does not affect the ICD analysis of citronellal.20
In order to evaluate the practical use of the stereodynamic
sensor 2 for quantitative ee determination of citronellal, a
calibration curve was constructed using 3 in varying ee. The
condensation reaction was carried out at 3.75 mM and the
samples were diluted to 9.38 Â 10À5 M for CD analysis.
Plotting of the CD amplitudes at 400 nm versus % ee revealed
a perfectly linear relationship (Fig. 4). Three scalemic samples
of 3 covering a wide ee range (À90, 54 and 88% ee) were then
prepared and treated with sensor 2 as described above. Using
the linear regression equation calculated from the calibration
experiment and the CD amplitudes measured at 400 nm, the
enantiomeric excess of these samples was determined. Experi-
mentally obtained data were within 3% of the actual values,
see ESI.w To the best of our knowledge this is the first example
of enantioselective sensing of the ee of a single chiral aldehyde.
The concept of isostericity applied in this work was inspired
by the reciprocity concept used for the rational development of
chiral stationary phases (CSPs) for chromatographic separation
of enantiomers. A seminal example is the introduction of the
Whelk-O HPLC column by Pirkle and coworkers.21 Assuming
reciprocal stereoselective interactions, enantiopure naproxen was
immobilized on silica gel to screen racemic CSP candidates by
HPLC. The enantiomer of a racemate that was separated with
high enantioselectivity was then used to produce a new CSP. The
well separated solute turned out to be the invaluable Whelk-O
selector. The chiral naproxen based CSP was thus used to develop
Fig. 2 Two views of the crystal structure of 2. The dihedral angles between
the central 1,4-disubstituted benzene ring and the adjacent 1,2-disubstituted
arenes were calculated as 117.061 and 123.751, respectively.
The coupling of 4 with 2-ethynylaniline, 7, then gave 1,4-bis(2(2-
anilinylethynyl)phenylethynyl)benzene, 2, in 44% yield (Scheme 1).
A single crystal of 2 suitable for X-ray diffraction was obtained by
slow evaporation of a saturated solution in chloroform (Fig. 2). In
the solid state, bisaniline 2 adopts an essentially flat structure that
has the central benzene ring pointing out and lying about an
inversion center. In solution, one would expect 2 to exist as a
mixture of several conformers that undergo rapid rotation about all
four triple bonds. Incorporation of an acetylene unit increases the
aryl–aryl distance to approximately 4.0 A. Accordingly, the energy
barrier to rotation in diarylacetylenes is typically low and con-
formational isomers cannot be isolated at room temperature.17
This high degree of rotational freedom is a vital property of
diarylacetylene-derived molecular turnstiles18 and gyroscopes.19
The condensation reaction between 2 and two equivalents of
citronellal was monitored by 1H-NMR, UV and IR spectroscopy
(see ESIw). Formation of the expected diimine was evident by
NMR and IR spectroscopy showing quantitative disappearance of
the formyl protons and the characteristic carbonyl stretching of the
aldehyde, respectively. ESI-MS analysis also confirmed conversion
to the diimine showing the expected signal for m/z = 781.5 in the
positive ion mode (Fig. 3). Interestingly, the reaction can be
followed by colorimetric means. While the sensor is colorless the
citronellal-derived diimine is light yellow due to a red shift in the
UV spectrum (see ESIw).
As expected, the bisaniline 2 is CD-silent in solution because it
adopts rapidly interconverting chiral (and achiral) conformations.
Fig. 3 Left: MS spectrum of the diimine obtained from 2 and 3.
Right: CD spectra of the diimine derived from (R)-3 (blue) or (S)-3
(red) at 9.38 Â 10À5 M in CHCl3.
Fig. 4 Plot of the CD amplitude of the diimine at 400 nm vs. the ee of
3. All measurements were conducted at 9.38 Â 10À5 M in CHCl3.
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the Whelk-O column which indeed separates the enantiomers of
naproxen and other profens with excellent selectivity. Our results
with bisaniline 2 and citronellal demonstrate that a similar ratio-
nale, which exploits the central-to-axial chirality induction observed
upon condensation between 1 and aliphatic amines, provides a
systematic approach for the development of an ICD sensor
applicable to enantioselective analysis of a chiral aldehyde.
In summary, the remarkable ICD signals generated upon
diimine formation with the intrinsically stereodynamic sensor 2
allows unprecedented enantioselective detection of citronellal at
micromolar concentrations and quantitative ee analysis with high
accuracy. The use of 2, which is readily prepared by two
Sonogashira couplings, combines several attractive features: (1)
The generation of intense Cotton effects at high wavelength
reduces interference with chiral impurities and thus facilitates
determination of the enantiomeric composition; (2) the in situ
diimine formation and subsequent CD measurements eliminate
elaborate purification steps; (3) the CD assay is operationally
simple and requires only minute sample, sensor and solvent
amounts which reduces waste production; (4) the sensor is highly
selective for citronellal and other chiral aldehydes do not interfere
with the chiral induction and chiroptical sensing processes and
(5) this sensing method avoids the use of enantiopure derivatizing
agents which are often more expensive. Moreover, this work
shows that the concept of isostericity provides new means for the
rational design of ICD probes or stereodynamic receptors used in
chiral amplification processes.
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Funding from the National Science Foundation (CHE-1213019)
is gratefully acknowledged.
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c
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