Stereochemical analysis of chiral amines, diamines, and amino alcohols: Practical chiroptical sensing based on dynamic covalent chemistry

Article abstract of DOI:10.1002/chir.23185

Practical chiroptical sensing with a small group of commercially available aromatic aldehydes is demonstrated. Schiff base formation between the electron-deficient 2,4-dinitrobenzaldehyde probe and either primary amines, diamines, or amino alcohols proceeds smoothly in chloroform at room temperature and is completed in the presence of molecular sieves within 2.5 hours. The substrate binding coincides with a distinct circular dichroism signal induction at approximately 330 nm, which can be correlated to the absolute configuration and enantiomeric composition of the analyte. The usefulness of this sensing method is highlighted with the successful sensing of 18 aliphatic and aromatic amines and amino alcohols and five examples showing quantitative %ee determination with good accuracy.

Full text of DOI:10.1002/chir.23185

Received: 21 November 2019
DOI: 10.1002/chir.23185
Revised: 9 January 2020
Accepted: 10 January 2020
S P E C I A L I S S U E A R T I C L E
Stereochemical analysis of chiral amines, diamines, and
amino alcohols: Practical chiroptical sensing based on
dynamic covalent chemistry
Diandra S. Hassan | F. Yushra Thanzeel
| Christian Wolf
Department of Chemistry, Georgetown
Abstract
University, Washington, D.C., USA
Practical chiroptical sensing with a small group of commercially available aro-
matic aldehydes is demonstrated. Schiff base formation between the electron-
deficient 2,4-dinitrobenzaldehyde probe and either primary amines, diamines,
or amino alcohols proceeds smoothly in chloroform at room temperature and
is completed in the presence of molecular sieves within 2.5 hours. The sub-
strate binding coincides with a distinct circular dichroism signal induction at
approximately 330 nm, which can be correlated to the absolute configuration
and enantiomeric composition of the analyte. The usefulness of this sensing
method is highlighted with the successful sensing of 18 aliphatic and aromatic
amines and amino alcohols and five examples showing quantitative %ee deter-
mination with good accuracy.
Correspondence
Christian Wolf, Department of Chemistry,
Georgetown University, Washington,
D.C., USA.
Email: cw27@georgetown.edu
Funding information
NSF, Grant/Award Number: CHE-
1764135
K E Y W O R D S
absolute configuration, amines, amino alcohols, enantiomeric excess, optical sensing
1 | INTRODUCTION
modern high-throughput experimentation setups, paral-
lel sample screening opportunities with modern multi-
The stereochemical analysis of chiral compounds con-
tinues to be of crucial importance in many areas such as
the discovery and optimization of asymmetric synthetic
methodologies, natural products, materials, and pharma-
ceuticals. The constant search for efficient and reliable
methods that can be used for the determination of the
absolute configuration and enantiomeric excess (ee) of
chiral compounds has been met with the development
and refinement of impressive chromatographic and spec-
troscopic assays. The introduction of ultrafast chiral
high-performance liquid chromatography,1-4 versatile
chiral solvating agents for nuclear magnetic resonance
(NMR) analysis,5-7 and powerful optical sensing assays8-11
has significantly widened the analytical tool box in
recent years. In particular, chiroptical methodologies
have received considerable attention, which may be
attributed in part to the facilitated adaption toward
well plate readers, and reduction of cost, labor, and
solvent waste.12 The exceptional potential of chiroptical
sensing with circular dichroism (CD) probes was noticed
early on by Berova and Nakanishi, who published several
seminal papers with broadly useful zinc porphyrin twee-
zer hosts.13-18 Their outstanding work has spurred the
development of a wide variety of CD sensor designs by
Borhan,19-21 Canary,22,23 Anslyn,24-27 our group,28-38 and
others.39-43
The large majority of CD sensing assays introduced so
far relies on the formation of supramolecular assemblies,
metal coordination complexes, hydrogen bond adducts,
or dynamic covalent chemistry (DCC).12 In addition,
stereodynamic probes that undergo irreversible covalent
bond formation with a chiral analyte to generate a CD
signal that can be used for absolute configuration and ee
determination have been developed by several
Chirality. 2020;1–7.
wileyonlinelibrary.com/journal/chir
© 2020 Wiley Periodicals, Inc.
1

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HASSAN ET AL.
groups.44-52 Nevertheless, reversible Schiff base formation
with chiral amines has become a very popular and highly
successful CD sensing strategy.27,28,30,39,41,53,54 We now
wish to report a highly practical method that allows
chiroptical ee analysis of a wide range of amines and
amino alcohols using an inexpensive commercially avail-
able benzaldehyde derivative as probe. The Schiff base
formation is complete within 2.5 hours at room tempera-
ture and does not require operation under inert atmo-
sphere, which greatly streamlines the workflow and
would simplify automation of the assay and parallel han-
dling of samples if desired. In most cases, strong CD
effects are observed and we demonstrate that ee quantifi-
cation of nonracemic mixtures of 1-phenylethylamine
can be achieved with good accuracy.
2.2 | Quantitative ee analysis
A calibration curve was constructed using samples of 8 at
varying ee. A stock solution of 1 (0.06 M in CHCl3) was
prepared and separated into 0.4-mL portions. Two sepa-
rate stock solutions containing the enantiomers of
8 (0.05 M in CHCl3) were prepared. Portions of 8 were
titrated into the stock solutions of 1 to generate samples
with varying %ee (+100, +80, +60, +40, +20, 0, −20,
−40, −60, −80, and 100). CD analysis was carried out
after 2.5 hours as described above at 0.5 mM in CHCl3.
The CD amplitudes at 334 nm were plotted against the
%ee of 8, and linear regression analysis was used to deter-
mine the enantiomeric composition of scalemic
samples of 8.
2 | MATERIALS AND METHODS
3 | RESULTS AND DISCUSSION
All reagents and solvents were commercially available
and used without further purification. Reactions were
carried out under anhydrous conditions over molecular
sieves under air. NMR spectra were obtained at 400 MHz
(1H-NMR) using CDCl3 as solvent and TMS as reference.
For ultraviolet (UV) analysis, solutions of sensor
1 (400 μL, 0.06 M) and of (R)-1-phenylethylamine
(400 μL, 0.05 M) in either acetonitrile or chloroform were
combined and allowed to stand over 4-Å molecular sieves
in chloroform at room temperature without stirring over-
night. The UV spectra were recorded after dilution with
the same solvent to 0.06 mM (see SI).
At the beginning of this study, we decided to test the pos-
sibility of practical Schiff base formation and subsequent
enantioselective CD sensing with a small group of com-
mercially available aromatic aldehydes at room tempera-
ture. In the hope to accelerate the reaction with the
substrate, we were particularly interested in electron-
deficient
sensors
1-5
but
also
included
4-methoxybenzaldehyde and benzaldehyde, 6-7, in our
library for comparison (Figure 1). All reactions were per-
formed at 25ꢀC in chloroform over 4-Å molecular sieves
to favor the imine formation. Initial screening experi-
ments were performed with 1-phenylethylamine, 8, as
substrate but a wide cariety of aliphatic and aromatic
amines and amino alcohols were later tested as well, vide
infra.
2.1 | Enantioselective sensing
experiments
We were pleased to find that the Schiff base formed
from 2,4-dinitrobenzaldehyde, 1, and amine 8 gave a
strong CD signal at approximately 330 nm at 0.5 mM in
chloroform (Figure 2). The condensation reaction was
complete within 2.5 hours in the presence of 4-Å molecu-
lar sieves according to NMR analysis (see SI). If desired,
the reaction can be completed in a shorter time by addi-
tion of small amounts of a Lewis acid. We found that the
imine was produced quantitatively within 1 hour in the
presence of 20 mol% of zinc triflate. The imine derived
from (R)-8 gave a positive Cotton effect, while the enan-
tiomeric product showed the exact opposite CD signal as
one would expect. The UV absorption of the sensor above
300 nm increased considerably upon Schiff base forma-
tion, which could be exploited for concentration analysis
if desired (see the supporting information). Similar
results but slightly weaker and blue shifted CD signals
were obtained with 2-nitrobenzaldehyde, 2. The other
probes generated significantly lower CD outputs under
A stock solution of the stereodynamic sensor (0.06 M) in
CHCl3 was prepared, and portions of 0.4 mL were trans-
ferred into 4-mL vials. Solutions of the substrates (0.05 M
in CHCl3) were prepared. To each vial containing 0.4 mL
(0.024 mmol) of the sensor, stock solution was added 0.4
mL (0.02 mmol) of the amine or amino alcohol solution
and the mixtures were allowed to stand without stirring
for 2.5 to 3.0 hours over 4-Å molecular sieves. The CD
analysis was conducted with sample concentrations of
0.5 mM in CHCl3. The CD spectra were collected at 25ꢀC
with a standard sensitivity of 100 mdeg, a data pitch of
1 nm, a bandwidth of 1 nm, a scanning speed of 500 nm
s
−1, and a response of 0.5 s using a quartz cuvette (1-cm
path length). The data were baseline-corrected and
smoothed using a binomial equation. Control experi-
ments with free substrates showed no CD signal in the
region of interest.

HASSAN ET AL.
3
the same conditions. Strong CD signals at high wave-
lengths are generally more likely to allow accurate ee
quantification with a reduced chance of interference
from possibly present optically active impurities. We
therefore continued all additional experiments using
aldehyde 1 as our sensor of choice.
We expected that the imine formation is a reversible
process and that our optical assay operates under thermo-
dynamic reaction control based on the principles of DCC.
To test this, we prepared the imine derived from 1 and
(S)-8 and then added one equivalent of (R)-8 to the solu-
tion. As expected, we observed imine metathesis, ie,
exchange of the amine substrate as shown in Figure 3, by
a steady decline of the negative CD signal over time.
Approximately after 3 hours, the equilibrium containing
equal amounts of the free CD-silent amine enantiomers
and of the CD active enantiomeric imines, respectively,
were formed.
Having developed a practical sensing method with
aldehyde 1 and amine 8, we evaluated the scope of this
DCC sensing approach. Without further optimization,
our general sensing protocol was applied to the amines
9-14, the amino alcohols 15-24, and diamine 25. In all
cases, CD signals above 300 nm were measured, and a
few representative examples obtained with 10, 16, 19,
and 24 are shown in Figure 4. In general, we observed
stronger Cotton effects with substrates exhibiting an aro-
matic moiety, but sensing of aliphatic compounds such
as 2-amino-1-propanol, 24, and diaminocyclohexane, 25,
is also possible.
FIGURE 1 Schiff base formation and structures of aldehyde
sensors and substrates studied
FIGURE 2 Circular dichroism sensing of 1-phenylethylamine
with sensors 1-7. The Schiff base formation was achieved using
chloroform as solvent, the amine (25.0 mM) and 1.2 equivalents of
the sensor (30.0 mM) over 4-Å molecular sieves at 25ꢀC for
2.5 hours. All measurements were performed after diluting the
solutions to 0.5 mM with CHCl3 at 25ꢀC
FIGURE 3 Study of the reversibility of the Schiff base
formation. A stoichiometric amount of (R)-8 was added to the
imine formed from 1 and (S)-8 at 25 mM in chloroform and the
substrate exchange over time was monitored by circular dichroism
(CD) spectroscopy. The CD measurements were taken after dilution
of small aliquots to 0.5 mM with the same solvent

4
HASSAN ET AL.
FIGURE 5 Quantitative ee sensing of 1-phenylethylamine, 8.
Top: Circular dichroism (CD) spectra of the imine obtained with
1 and scalemic samples of 8. Bottom: Linear relationship between
the CD amplitudes measured at 334 nm and the ee of 8. For
experimental conditions, see Figure 2
TABLE 1 Comparison of the actual absolute configuration
and %ee of five samples of 8 and the chirality sensing results
obtained using 1 as CD reporter
Actual Composition
of 8
CD Sensing Results
(334 nm)
Sample Abs. Config.
%ee
75.0
10.0
65.0
82.5
90.0
Abs. Config.a
%eeb
1
2
3
4
5
R
R
S
S
S
R
R
S
S
S
73.6
5.8
FIGURE 4 Selected examples of amine and amino alcohol
chirality sensing. See the supporting information for experimental
conditions
61.7
79.5
87.9
Finally, we examined the usefulness of our chiroptical
assay for the determination of the enantiomeric excess of
samples of 8. A calibration curve was obtained using mix-
tures of varying enantiomeric composition and sensor
1 (Figure 5). The linear relationship between the CD sig-
nal output at 334 nm and the ee values of the substrate
set the stage for the analysis of five nonracemic samples.
As shown in Table 1, we can correctly determine the
absolute configuration of the major enantiomer by
Abbreviation: CD: circular dichroism.
aBased on comparison with a reference sample.
bBased on comparison of measured CD amplitudes with the calibration
curve.
comparison of the sign of the induced Cotton effect with
our reference and the ee quantification was achieved with
good accuracy by using the measured CD signal at

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4 | CONCLUSION
The CD sensing capabilities of seven commercially
available aromatic aldehydes were evaluated with
1-phenylethylamine as test compound. The Schiff base
formation was found to proceed smoothly in chloro-
form at room temperature in the presence of molecu-
lar sieves within 2.5 hours. The strongest CD signal
was obtained with 2,4-dinitrobenzaldehyde at approxi-
mately 330 nm. This sensor is broadly useful and gen-
erates characteristic CD outputs for
a variety of
aliphatic and aromatic amines, diamines, and amino
alcohols. The imine formation is reversible, and the
sensing method operates based on the principles of
DCC. The usefulness of DCC chirality sensing with a
simple benzaldehyde derived probe was highlighted
with the stereochemical analysis of the absolute config-
uration and enantiomeric excess of five scalemic amine
samples. This sensing assay is practical, based solely
on the use of inexpensive materials and has potential
in high-throughput screening applications.
15. Huang X, Fujioka N, Pescitelli G, et al. Absolute configura-
tional assignments of secondary amines by CD-sensitive
dimeric zinc porphyrin host. J Am Chem Soc. 2002;124(35):
10320-10335.
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from the
NSF (CHE-1764135).
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ORCID
F. Yushra Thanzeel https://orcid.org/0000-0002-8833-
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Christian Wolf https://orcid.org/0000-0002-4447-3753
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How to cite this article: Hassan DS,
Thanzeel FY, Wolf C. Stereochemical analysis of
chiral amines, diamines, and amino alcohols:
Practical chiroptical sensing based on dynamic
covalent chemistry. Chirality. 2020;1–7. https://doi.
org/10.1002/chir.23185
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.