Predictive chirality sensing: Via Schiff base formation

Article abstract of DOI:10.1039/c9ob01265f

Among the large number of chiroptical sensors that have been developed to date, few allow rational determination of the absolute configuration of chiral substrates together with quantitative ee analysis. We have prepared and tested stereodynamic N-aryl aminobenzaldehyde sensors that bind chiral amines via Schiff base formation. The covalent binding of the amine substrate generates a conformational bias in the chromophoric sensor moiety which results in characteristic CD signals. Computational analysis revealed that CD prediction of the sign of the Cotton effect and thus determination of the absolute configuration of the substrate becomes practical with a sterically crowded sensor design because the number of conformations to be considered is largely reduced and the chiroptical sensor response is less sensitive to conformational equilibria. The amplitude of the measured CD signal can be used for quantitative ee analysis of nonracemic amine samples with the help of a calibration curve.

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ARTICLE
Predictive Chirality Sensing via Schiff Base Formation
Samantha L. Pilicer,‡ Michele Mancinelli,† Andrea Mazzanti,*† Christian Wolf*‡
Received 00th January 20xx,
Accepted 00th January 20xx
Among the large number of chiroptical sensors that have been developed to date, few allow rational determination of the
absolute configuration of chiral substrates together with quantitative ee analysis. We have prepared and tested
stereodynamic N-aryl aminobenzaldehyde sensors that bind chiral amines via Schiff base formation. The covalent binding of
the amine substrate generates a conformational bias in the chromophoric sensor moiety which results in characteristic CD
signals. Computational analysis revealed that CD prediction of the sign of the Cotton effect and thus determination of the
absolute configuration of the substrate becomes practical with a sterically crowded sensor design because the number of
conformations to be considered is largely reduced and the chiroptical sensor response is less sensitive to conformational
equilibria. The amplitude of the measured CD signal can be used for quantitative ee analysis of nonracemic amine samples
with the help of a calibration curve.
DOI: 10.1039/x0xx00000x
base formation have been introduced with the common goal to achieve
Introduction
ee analysis for chiral amines with minute analyte quantities. Absolute
The introduction of new methods for the stereochemical analysis of
chiral compounds is essential to enable progress in asymmetric
synthesis, materials sciences and other chemical disciplines. The
determination of absolute configuration and enantiomeric excess (ee)
of chiral amines which play a dominant role in biological processes
and drug development initiatives is particularly important and remains
a challenging task. In this regard, optical methods using UV,
fluorescence and circular dichroism (CD) spectroscopy have become
quite popular in recent years.1 Berova,2 Kim, Hong and Chin,3
configuration, however, cannot often be predicted and must instead be
determined by comparison of the induced UV, fluorescence or CD
signal with the response of the optical sensor to a reference sample.
Stereochemical assignments based on such an empirical approach are
unreliable when the analysis of new compounds is required or when a
reference is unavailable. The possibility to rationally elucidate the
absolute configuration of chiral substrates from the induced Cotton
effect would extend the use of Schiff base chirality sensors to the
stereochemical analysis of new compounds. In the pharmaceutical
sciences, for example, this remains a very important goal. We
therefore have decided to involve computational means to develop a
Schiff base sensor that obviates the need to compare the induced CD
signals observed upon amine binding to those obtained with a
reference of known absolute configuration.
8
Anslyn,4 Anzenbacher,5 Pu,6 Borhan,7 Feng, Wolf9 and others10
have developed a variety of optical probes that undergo chiral
recognition and amplification processes with amines and derivatives
thereof via various covalent binding strategies including Schiff base
formation.
Some of the most successful innovations in the realm of chirality
sensing have undoubtedly been motivated by an increasing demand
for fast optical assays that can exploit parallel screening technology.11
Accordingly, many probes that bind the target substrate through Schiff
NO2
O
O
1. Pd(OAc)2, Cs2CO3,
rac-BINAP, toluene,
100 oC
2
1
Br
2
1
ArNH2
+
2'
NH
1'
2. conc. HCl
2'
NH
1'
49% (over 2 steps)
CHO
1
CHO
2
Department of Chemistry, Georgetown University
37th and O Streets, Washington, DC 20057 (USA)
E-mail: cw27@georgetown.edu
Scheme 1 Preparation and structures of sensors 1 and 2. Blue: CD sensing
chromophore. Red: proximate H-donor, Green: Amine binding site.
Department of Industrial Chemistry “Toso Montanari”, University of Bologna
Viale Risorgimento 4, 40136 Bologna (ITALY)
E-mail: andrea.mazzanti@unibo.it
Homepage: http://www.thewolfgrouponline.com/
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
The readily available 2-aminobenzaldehyde scaffold carrying a
hydrogen bond donating secondary diarylamine unit adjacent to the
formyl group appeared to be an attractive starting point for this study
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because this arrangement was expected to facilitate the condensation dipoles. The synthesis of the desired probes was accomplished via
with an amine substrate and limit the conformational freedom of the conventional coupling chemistry using commercially available aryl
corresponding Schiff base product (Scheme 1). We considered that amines and protected bromobenzaldehyde (Scheme 1 and ESI).
the 2-aminobenzaldehyde core needed to be linked to an additional Subsequent deprotection of the aldehyde group was carried out under
UV-chromophoric group with a strong UV transition in the low- acidic conditions, producing both 1 and 2 in 49% overall yield. The
energy region of the UV spectrum. This is generally considered test amines selected for this study are shown in Figure 1.
desirable because it reduces the possibility that CD-active impurities
interfere with the chiroptical sensing event. In addition, solvents
Results and Discussion
having a relatively high wavelength cut-off (e.g. chloroform) can be
We first investigated the UV properties of the sensors. The
used. Within the obvious choice of an aromatic component as the UV-
geometries of 1 and 2 exhibiting an intramolecular hydrogen bond
absorbing moiety, this could be either a locally C2-symmetric or an
between the NH and the carbonyl moieties were optimized using
asymmetric aryl ring. In the first case, the two conformations
B3LYP12 and the 6-311++G(2d,p) basis set, including the solvent
generated by a 180° rotation of the aryl ring around the N-C bond are
with the IEF-PCM formalism.13 The UV spectra were simulated with
homomeric, whereas in the second case two diastereoisomeric
TD-DFT at the CAM-B3LYP/6-311++G(2d,p) level.14 The sterically
conformations are generated. Since the goal is to develop a strong CD
demanding 2-methylnaphtyl group in 1 is skewed toward an
signal induced by the chirality of the analyte, an highly unbalanced
orthogonal position to reduce steric repulsion, whereas the lack of
conformational equilibrium is advisable in the case of a non-C2-
steric hindrance at the p-nitrophenyl ring in sensor 2 favors a coplanar
symmetric sensor. In an optimal scenario, only one conformation of
arrangement between the two aryl rings due to increased resonance
the sensor would be populated so that the experimental CD spectrum
stabilization.15
is not a complicate weighted average of several conformational
contributions.
H2N
NH2
NH2
NH2
a
b
c
d
NH2
NH2
OH
OH
e
NH2
anti-h
anti-g
NH2
f
Fig. 1 Structures of selected substrates.
We envisioned that the chirality of a covalently attached amine
would control the relative orientation of the chromophores in these
sensor designs and thus generate characteristic Cotton effects that one
could systematically correlate to the absolute configuration of the
substrate. We therefore focused our attention on the two chemical
structures resulting from the coupling of 2-bromobenzaldeyde with 2-
methyl-1-naphthylamine (compound 1) and p-nitroaniline (compound
2). Both designs possess a strong chromophoric group in the low
energy region of the UV spectrum, each with different geometric
constraints and with different orientations of the UV-absorbing
Fig. 2 Experimental and calculated UV spectra of sensors
1 and 2.
Calculations at the TD-CAM-B3LYP/6-311++G(2d,p) level. Calculated spectra
were red-shifted by 25 nm (1) and 55 nm (2). The ground state geometries, where
 defines the dihedral angle between the two aromatic rings, are shown on the
right.
As a result, the two aryl rings in 1 are almost perpendicular, with a
dihedral angle  of about |90|°. On the contrary, the ground state
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geometry of sensor 2 displays the two aromatic rings with a conformations within the 10 kcal/mol energy range. Redundant
significantly smaller dihedral angle of |34|° (the measured dihedral is conformations were then removed (1.0 Å RMS deviation) and the
remaining structures were further optimized with DFT (Gaussian
1617) at the B3LYP/6-31G(d) level of theory. After DFT optimization,
only 4 conformations were found within a 3.0 kcal/mol limit (Figure
4). These conformations all reflect that the imino moiety is stabilized
by an intramolecular hydrogen bond with the NH group intrinsic to
the sensor scaffold. The four conformations differ in regards to the
position of the aromatic ring of the 1-phenylethylamino moiety (c1 vs
c4 and c2 vs c3), and in the dihedral angle between the p-nitrophenyl
ring and the 2-iminophenyl moiety (C2-C1-N-C1’ in Figure 4), that can
be +160° (c1 and c4) or 160° (c2 and c3). When further optimized
defined by C2-C1-C1’-C2’, , as depicted in Figure 2). The two sensors
have a strong UV band in the low-energy region (Figure 2). In sensor
1 the calculated band is centered at 328 nm (experimental value 363
nm), and in sensor 2 it is centered at 347 nm (experimental value 402
nm). In both cases, this band is generated by a single transition, albeit
different molecular orbitals (MO) are involved (Figure 3). In the case
of 1, the main component of the UV transition is the HOMO-LUMO
(81%), with the LUMO localized mainly on the aminobenzaldehyde
ring whereas the HOMO is mainly present on the naphthyl ring. A
minor contribution (13%) comes from the (HOMO-1)–LUMO
transition. In both transitions there is a strong difference in the shapes at the B3LYP/6-311++G(2d,p) level and including the solvent in the
of the MO densities and thus the UV transition of sensor 1 is suggested calculations (IEF-PCM, acetonitrile), conformations c1 and c2 were
to be a charge transfer (CT) absorption band. In compound 2 the MO’s very close in energy, whereas c3 and c4 were significantly higher in
involved in the transition are the HOMO–LUMO (81%) and the energy. It should be noted that in the two most stable conformations,
HOMO–(LUMO+1) (12%). Both transitions (particularly the the CH of the stereogenic carbon is coplanar with the imino CH.
HOMO-LUMO) involve two MO’s that are spread over both aryl Conformations that did not depict the coplanar motif were found to be
rings. Therefore, in the case of 2 the low-energy UV band is suggested much higher in energy.
to be a standard -* band.
Fig. 4 The four available conformations of compound 2a. Relative energies in
kcal/mol at the PCM-B3LYP/6-311++G(2d,p) level.
Fig. 3 MO’s involved in the low energy UV absorption band of sensors 1 and
2.
The molecular mechanics (MM) conformational search
performed for compound 1a led to a similar situation, and only four
conformations were found to exist within the 3 kcal/mol energy
window (Figure 5). Again, the two most stable conformations are very
A full conformational search on compound 2a, derived from
sensor 2 and (R)-1-phenylethylamine, a, was performed using
Macromodel16 and the MMFF force field by retaining all the
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close in energy and possess opposite dihedral angles between the 2-
methylnaphthyl ring and the 2-iminophenyl unit. As in the case of 2a,
the CH of the stereogenic carbon is coplanar with the imino CH.
Fig. 5 Calculated conformations of 1a. Relative energies in kcal/mol at the
PCM-B3LYP/6-311++G(2d,p) level.
The CD spectra of the Schiff bases 1a and 2a were simulated with
TD-DFT18 starting from the geometries obtained with the larger basis
set. CD simulations were obtained using the range-separated CAM-
B3LYP functional and the 6-311++G(2d,p) basis set, a combination
known to have good accuracy at a reasonable computational cost.19
Because of our particular interest in the simulation of the low-energy
region of the ECD spectrum, only this part of the UV/CD spectrum
was simulated (see ESI for details).
Fig. 6. Top: ECD simulations for the four conformations of compound 2a,
obtained at the TD-CAM-B3LYP/6-311++G(2d,p) level. Bottom: Simulated ECD
spectrum obtained using the conformational ratio derived from the energies
reported in Figure 4. The simulated spectrum was shifted by 50 nm.
The lowest energy transition for compound 2a was calculated at
~340 nm, and it was generated mainly by the HOMOLUMO
transition, with a smaller contribution from the HOMO(LUMO+1)
transition (Figure S1 in ESI). Analysis of the MO shapes showed that
only the dipoles of the sensor are involved in this CD transition and
that the sign of the Cotton effect is related to the different helicity of
the p-nitrophenyl ring with respect to the o-aminobenzaldehyde ring
(see ESI). Accordingly, conformations c1 and c4, as well as the c2/c3
pair have the same CD sign.
The opposite Cotton effects of the diastereomeric species
complicate the simulation of the experimental CD which is expected
to be the weighted average of the individual conformational
contributions. Since conformations 2a-c1 and 2a-c2 are calculated to
be very close in energy, the sign of the CD transition will be
determined by the effect of the enantiopure amine on the
conformational balance of the two conformations. A single crystal of
the imine formed from 2 and (S)-1-phenylethylamine was obtained by
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slow evaporation of a methanol solution.20 This solid-state structure
corresponds to conformation c2, which is one of the two calculated to
be most stable. While only this conformation is present in the solid
state, both conformations are expected to be present with similar
populations in solution. Nevertheless, the Boltzmann-weighted
averaged ECD spectrum obtained by using the relative enthalpies§
derived for conformations c1-c4 yields a negative CD band, as
experimentally observed.
NO2
NH
N
Ph
Fig 7. Single crystal structure of 2a.
The rotational asymmetry of the 2-methylnaphtyl moiety in
compound 1a yields different results. The ECD simulations suggest
that the two most stable conformations (1a-c1 and 1a-c2) do not have
opposite signals as was the case for 2a. The spectrum of 1a-c1 is very
weak in the 290-350 nm region, whereas that of c2 is strongly negative
(when R-phenylethylamine a is used). As a result, sensor 1 seems to
be more suitable because the sign of the low-energy Cotton effect
should not be influenced by the conformational isomerism. The low-
energy UV/CD band of 1a mainly originates from the
HOMOLUMO and HOMO(LUMO+1) transitions (see Figure S2
in ESI). It should be noted that the UV spectrum of compound 2a has
a maximum absorbance very close to that of the sensor alone (400 vs
396 nm, respectively, see ESI), whereas the UV spectrum of 1a is red-
shifted by approximately 22 nm with respect to that of the free sensor
(376 vs 354 nm, Figure S3 in ESI). This feature can be related to the
modification of the shapes of the involved MOs because the LUMO
of 1a is localized on both the aryl rings and the transition is therefore
more ascribable to a classical * absorption than to a charge-
transfer transition which is the case with the free sensor 1.
Fig 8. Top: ECD simulations for the four conformations of compound 1a,
obtained at the TD-DFT CAM-B3LYP/6-311++G(2d,p) level. Bottom: Simulated
ECD spectrum obtained using the conformational ratio derived from the energies
reported in Figure 5. The simulated spectrum was red-shifted by 35 nm.
To compare whether the CD spectra are affected by the presence
of the aromatic ring in amine a, we calculated the ECD spectra of the
two compounds (1b and 2b) derived from (R)-1-
cyclohexylethylamine, b, which is devoid of a chromophoric group.
After conducting an MM conformational search and DFT
optimization, four conformers were found within 3.0 kcal/mol from
the global minimum (Figure S4 in ESI). In the two most prevalent
conformations (c1 and c2), the stereogenic carbon of the amine is in
the equatorial position of the cyclohexane ring, whereas it is in the
axial position in c3. In analogy to compounds 1a and 2a, the most
stable conformations display the CH on the stereogenic carbon
coplanar with the CH of the imino group which was also observed in
the solid-state X-ray structure of 2a. By contrast, the fourth
conformation has the methyl group coplanar with the imino CH group,
but its relative energy is quite high (2.96 kcal/mol). However, the two
aromatic rings of the sensor moiety exhibit dihedral angles below |40|°
( defined as in Figures 1). Given the inability of MMFF to
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successfully manage conjugative effects, we envisioned that more
With this analysis in hand, we then tested the utility of both probes
conformations must be considered, because the helicity between the for the sensing of amines c-h. The condensations were carried out
two aromatic rings is a key factor for the profile of the resulting ECD using either dichloromethane or acetonitrile as solvent and the
spectrum. Starting from conformations c1-c4 found by the MM reaction mixtures were then diluted with acetonitrile and subjected to
search, we built four new input geometries (c1’-c4’) with opposite CD analysis without further purification. In all cases, the imine
dihedral angles between the two aromatic groups. As expected, the formation proceeds smoothly at room temperature in the presence of
energies of conformations c1’-c4’ were found to be very close to the molecular sieves and we observed positive Cotton effects at
corresponding conformations c1-c4. Simulation of the ECD spectra micromolar concentrations upon binding of the (S)-amines while the
generated two groups of CD spectra with opposite shape due to the Schiff base formation with the (R)-enantiomers gave the opposite
opposite dihedral angle between the aromatic rings of the sensor. The chiroptical signal (see ESI). Representative examples are shown in
conformational ratio used for the simulation of the experimental Figure 9.
spectrum was derived from optimization at the PCM-B3LYP/6-
R*NH2
NH2
a) Chirality sensing with 1
311++G(2d,p) level including the solvent acetonitrile. As for
compound 2b, the lowest energy CD band is suggested to be negative
and in fair agreement with the experimental data (Figure S5 in ESI).
However, the overall reliability is greatly reduced because the
calculated spectrum is very sensitive to the conformational isomerism
of the sensor.
NH2
Sensor 1
R*NH2
NH
NR*
a
b
4Å MS
When sensor 1 binds 1-cyclohexylethylamine, 1b, the steric bulk
of the 2-methylnaphthyl moiety forces the naphthyl ring to be
perpendicular to the other aromatic ring. Four conformations were
found through the MM search, corresponding to the two different
helicities of the sensor moiety, combined with a different disposition
of the cyclohexane ring, where the axial CH can be anti (c2 and c4)
or gauche (c1 and c3) to the CH at the stereogenic carbon. The
conformations in which the CH resides in the axial position of the
cyclohexane ring (c5) or where the CH of the stereogenic carbon
remains anti to the imine CH (c6) had very high energies (Figure S6
in ESI). Again, the conformation of the sensor is the only apparent
factor responsible for the shape of the ECD spectrum but the number
of conformations to be considered is largely reduced compared to
sensor 2. More importantly, some conformations (c1 and c2) have
very weak bands in the 280-350 nm region (Figure S7 in ESI, top),
whereas conformations c3 and c4 have negative bands in the same
region. Thus, the Boltzmann-averaged spectrum in the UV region of
interest is almost insensitive to the employed conformational ratio
(Figure S5 in ESI, bottom). Altogether, we conclude that sensor 1
greatly simplifies the determination of the absolute configuration of
chiral amines and the sense of chirality induction based on the steric
considerations discussed above is expected to be of general value.
NO2
NH
b) Chirality sensing with 2
R*NH2
NH2
NH2
Sensor 2
R*NH2
a
b
4Å MS
NR*
Fig 9. Representative examples of chiroptical amine sensing. a) CD signals of
the imines obtained using and (R)-1-phenylethylamine (blue) or (S)-1-
1
phenylethylamine (red) at 68 M in ACN (left), 1 and (R)-1-cyclohexylethylamine
(blue) or (S)-1-cyclohexylethylamine (red) at 68 M (right). b) CD results using 2
for (R)-1-phenylethylamine (blue) and (S)-1-phenylethylamine (red) at 60 M
(left), and with (R)-1-cyclohexylethylamine (blue) or (S)-1-cyclohexylethylamine
(red) at 90 M (right).
Finally, we decided to explore the possibility of quantitative ee
analysis of amine e with sensor 1. Using essentially the same sensing
protocol, we first determined a calibration curve of the CD maximum
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of the imine product measured at 354 nm versus the sample ee values Computational analysis revealed that CD prediction and thus
(Figure 10). This was then used to determine the enantiomeric determination of the absolute configuration of the substrate becomes
composition of four nonracemic samples. Our sensing analysis practical with a sterically crowded sensor design as the number of
revealed the correct absolute configuration of the major enantiomer conformations to be considered is largely reduced while the induced
based on the sign of the observed Cotton effect. Additionally, it CD spectrum is less sensitive to conformational equilibria. Finally, the
allowed for the determination of the sample ee values with sufficient possibility of quantitative ee analysis of nonracemic amine samples
accuracy for high-throughput screening purposes (Table 1 and ESI). was demonstrated.
For example, the CD sensing of the samples containing the (S)-amine
in 87 and 76% ee gave 93 and 74% ee, respectively (entries 1 and 2).
Conflicts of interest
There are no conflicts to declare.
Substrate binding and ee sensing
NH2
Sensor 1
Acknowledgements
NH
e
S.L.P. and C.W. are grateful for financial support from the U.S.
National Science Foundation (CHE-1764135). A.M. and M.M.
thank the University of Bologna (RFO funds 2017 and 2018).
ee analysis
N
Ph
nonracemic
samples
Notes and references
§ In the entirety of the manuscript we decided to use the ZPE-corrected
enthalpies instead of the Gibbs free energy because of the presence of
many low-value vibrational normal modes that hamper a correct
evaluation of the entropic factor. See ESI for details and references.
Fig 10. Quantitative ee analysis using sensor 1. Calibration curve of the
chiroptical responses of with varied enantiomeric compositions of 1-
1
phenylpropan-1-amine (left) and polynomial fitting of the sensor-tethered analyte
CD responses at 354 nm versus the ee values of each scalemic sample (blue).
The CD results with random ee compositions of e are shown in orange.
1
2
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Table 1. CD Sensing of nonracemic samples of amine e using sensor 1.
Sample composition
Chiroptical sensing results
absolute
configuration
absolute
ee values (%)
ee values (%)
configuration
S
87
76
64
89
S
S
R
R
93
74
73
97
S
R
R
3
4
Conclusions
In summary, we have prepared and tested chiroptical sensors
exhibiting a 2-aminobenzaldehyde derived scaffold with a hydrogen
bond donating secondary diarylamine unit adjacent to the formyl
group which allows Schiff base formation with amines. The covalent
binding of a chiral amine substrate affects the conformational bias in
the sensor moiety which results in characteristic CD spectra.
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