Diquats with Robust Chirality: Facile Resolution, Synthesis of Chiral Dyes, and Application as Selectors in Chiral Analysis

Article abstract of DOI:10.1002/chem.201800369

Diquats with extremely high racemization barriers with ΔG^≠_theor of 233 kJ mol^?1 at 180 °C are described. Reported configurational robustness is due to a combination of two structural features: the rigid o-xylylene tether connecting the nitrogen atoms and the presence of two substituents in the bay region of the bipyridinium scaffold. The straightforward synthesis of diquats, plus facile resolution and derivatization make them attractive for chiral application studies. This is demonstrated by: 1) synthesis of the first non-racemic diquat dyes with pronounced chiroptical properties, and 2) capability of diquats to interact stereospecifically with chiral molecules. This suggests potential for diquat derivatives to be used as chiral selectors in separation methods.

Full text of DOI:10.1002/chem.201800369

A Journal of
Accepted Article
Title: Diquats with Robust Chirality: Facile Resolution, Synthesis of
Chiral Dyes and Application as Selectors in Chiral Analysis
Authors: Harish R. Talele, Dusan Koval, Lukas Severa, Paul E. Reyes-
Gutiérrez, Ivana Cisarova, Petra Sazelova, David Saman,
Lucie Bednarova, Vaclav Kasicka, and Filip Teply
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Diquats with Robust Chirality: Facile Resolution, Synthesis of
Chiral Dyes and Application as Selectors in Chiral Analysis
Harish R. Talele,[a] Dušan Koval,*[a] Lukáš Severa,*[a] Paul E. Reyes-Gutiérrez,[a] Ivana Císařová,[b]
Petra Sázelová,[a] David Šaman,[a] Lucie Bednárová,[a] Václav Kašička,[a] and Filip Teplý*[a]
Abstract: Diquats with extremely high racemization barriers with
ΔG≠ of 233 kJ mol-1 at 180°C are described. Reported
comparable to that of axially chiral binaphthyls which have been
widely applied.10 Here, we report configurationally robust diquats,
their synthesis, derivatization and properties (e.g. diquat 1,
Scheme 1c). We describe their straightforward resolution, chiral
analysis, and derivatization. Their application potential is
demonstrated by their use as chiral selectors in capillary
electrophoresis as well as synthesis of the first non-racemic
diquat dyes.
theor
configurational robustness is due to combination of two structural
features: the rigid o-xylylene tether connecting the nitrogen atoms
and the presence of two substituents in the bay region of the
bipyridinium scaffold. Straightforward synthesis of diquats, facile
resolution and derivatization make them attractive for chiral
application studies. This is demonstrated by (i) synthesis of the first
non-racemic diquat dyes with pronounced chiroptical properties and
(ii) capability of diquats to interact stereospecifically with chiral
molecules. This suggests potential of diquat derivatives to be used
as chiral selectors in separation methods.
Diquats are known since 1958 when they have been introduced
as powerful herbicides by scientists at Imperial Chemical
Industries.1 Electron deficient systems based on diquat and
paraquat2 have been also instrumental as building blocks for
supramolecular chemistry3 as well as in design of electron-
transfer systems.2,4 Diquats have helical geometry1b but typically
insufficient configurational stability to allow studies of the two
separate enantiomers with opposite helicity (Scheme 1a, ΔG≠
theor
= 37 kJ mol-1 at 20°C).5 In spite of the great general usefulness
of diquats, no examples with comfortable configurational stability
have been recognized.
It is possible to distinguish in early reports examples of diquat
derivatives with potentially elevated configurational stability.
Spotswood and Tanzer studied a series of dimethyl-substituted
diquats with aliphatic bridge6 and Vögtle and Bombach reported
diquats made by simple quaternization of several 2,2’-
bipyridines with o-xylylene dibromide.7 However, aspect of
configurational stability as well as resolution of enantiomers
were not subject of these reports. More recently, Lacour group
revisited some of these dications (Scheme 1b), addressed their
resolution and determined racemization barriers. This elegant
study found the barriers of the selected example diquats to be
relatively low (ΔG≠ = 106-112 kJ mol-1 at 20°C).8,9
Scheme 1. (a) Typical diquat with low racemization barrier. (b) Rare diquat
with slightly higher barrier allowing resolution of enantiomers. (c) Example of
diquat with great configurational robustness studied in this work. TS =
transition state.
We became interested in configurationally robust diquats
after our theoretical finding that systems such as 1 might have
unusually high racemization barriers and would be therefore
suitable for chiral applications. Detailed DFT-D calculations
revealed relevant non-Cs-symmetric transition state11 on the
racemization pathway with ΔG≠
= 233 kJ mol-1 at 180°C. It
theor
corresponds to racemization half-life of more than 800 000 years
at 180°C (for details see S49 and supplementary movie file).
At the outset of the experimental investigation, we
established a practical route to non-racemic samples of diquat 3.
Starting from commercially available 2,2′-bipyridyl derivative 2,
racemic diquat 3, [rac-3][Br]2, was synthesized in a single step
(Scheme 2, 2→3).7 Next, we addressed resolution of the chiral
Non-racemic diquats with comfortably high barriers
preventing thermal racemization even at 150-200°C will enable a
variety of application studies without being restricted to low
temperatures. Such configurational stability would be
dication
3
via its diastereomeric dibenzoyltartrate salts
[a]
Dr. H. R. Talele, Dr. D. Koval, L. Severa, Dr. P. E. Reyes-Gutiérrez,
Dr. P. Sázelová, Dr. D. Šaman, Dr. L. Bednárová, Dr. V. Kašička,
Dr. F. Teplý
Institute of Organic Chemistry and Biochemistry of the Czech
Academy of Sciences, Flemingovo nam. 542/2, 166 10 Prague 6,
Czech Republic.
E-mail: koval@uochb.cas.cz, severa@uochb.cas.cz,
teply@uochb.cas.cz
Dr. I. Císařová,
Department of Inorganic Chemistry, Charles University, Hlavova
2030/8, 128 43 Prague 2, Czech Republic
Supporting information for this article can be found under:
XXXX
[P-3][R,R-DBT]2 and [M-3][R,R-DBT]2.
This resolution is operationally very straightforward and
consists of simple mixing of aqueous solutions of [rac-3][Br]2 and
monosodium salt of (R,R)-dibenzoyltartrate, [Na][R,R-DBT].
Efficient precipitation of diastereomerically pure [P-3][R,R-DBT]2
takes place spontaneously. Subsequently, direct anion
exchange using triflic acid in diethyl ether affords virtually
enantiopure [P-3][TfO]2 (98% ee) as evidenced by chiral
capillary electrophoresis (CE).12,13 Similarly, tetramethyl diquat
derivative [rac-1][Br]2 was prepared and resolved using our
simple precipitation protocol to obtain [P-1][TfO]2 (Scheme 3).
[b]
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absence of racemization in diquat [P-3][TfO]2 at 180°C was
found (S55).
Figure 1. X-ray crystal structures of: a) diquat [P-1][R,R-DBT]2 (CCDC
1447598) and b) diquat dyes 5 (CCDC 1447601) and 6 (CCDC 1447600).
Anions are omitted for clarity (see S87).
Scheme 2. Synthesis and facile resolution of racemic diquat
3 via
precipitation of diastereomerically pure dibenzoyltartrate salt [P-3][R,R-DBT]2
followed by anion exchange with TfOH.
Presence of two active methyl groups in system 1 calls for
derivatization via methods established for pyridinium type
systems.13 Interestingly, synthesis of non-racemic diquat dyes
has never been addressed so far.14 To this end, we converted
[P-1][TfO]2 to non-racemic dye [P-5][TfO]2 in presence of
triethylamine (Scheme 3). By contrast, reaction of [P-1][TfO]2
Absolute configuration of [P-1][TfO]2 has been
unambiguously assigned from the single crystal X-ray structure
of the dibenzoyl-L-tartrate salt [P-1][R,R-DBT]2 (Figure 1a and
S89) and absolute configuration of [P-3][Br]2 has been
determined by comparison of experimental and simulated
electronic circular dichroism (ECD) data (S78).
with
amino-substituted
benzaldehyde
derivative
via
Knoevenagel condensation in presence of pyrrolidine as catalyst
failed to give the expected [P-6][TfO]2 and only complex reaction
mixture was obtained. To our delight, the desired dye [P-6][TfO]2
can be successfully prepared in absence of pyrrolidine.
Synthesis of the dyes having M configuration, [M-5][TfO]2 and
[M-6][TfO]2, has been accomplished starting from [M-1][TfO]2
precursor (S38, S41).
Br
Br
a)
2TfO-
N
N
4
N+
N+
CH3CN
b) resolution
via simple precipitation
[P-1][TfO]2
then anion exchange
96% ee (CE)
S
O
c)
d)
SMe
TfO-
N+
CH3CN
CH3OH
Me2N
2TfO-
N
S
R
Et3N
2TfO-
N+
N+
N+
R =
N+
Me2N
[P-5][TfO]2
Non-racemic diquat dyes
[P-6][TfO]2
R
N
S
Figure 2. ECD of the individual enantiomers of diquat dyes [5][TfO]2 and
[6][Br]2.
Identity of both dyes 5 and 6 has been unambiguously
confirmed by X-ray crystal structure data in the racemic series
(Figure 1b). ECD of the non-racemic dye samples 6 in the visible
spectral region showed bisignate Cotton effect characteristic for
exciton chirality15 contrary to ECD of the non-racemic dye
samples 5 with large monosignate feature (Figure 2). TD-DFT
calculations of 5 and 6 were performed (see S78), however
without success for compound 5. The similar discrepancy was
already reported in literature16 showing the limitation in
applicability of the standard exciton chirality to systems where
the intrinsic (origin-independent) magnetic transition moment is
negligible.
Scheme 3. Synthesis of non-racemic diquat dyes. Conditions: a) 110°C,
sealed tube, 72 h, 84%, b) resolution via direct precipitation of
diastereomerically pure dibenzoyltartrate salt [P-1][R,R-DBT]2 followed by
anion exchange with TfOH, 56%, c) RT, 2 h, 94%, d) 70°C, 72 h, 65%.
The calculated barrier of diquat 1 ΔG≠
of 233 kJ mol-1 at
theor
180°C corresponds to racemization half-life of more than
800 000 years. In line with this theoretical assessment of the
racemization barrier, prolonged exposure of [P-1][TfO]2 solution
to 180°C did not show any signs of racemization as evidenced
by enantiocomposition analysis by CE with sulfated γ-
cyclodextrin chiral selector (see S54 for details). Similarly,
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presented chiral study of diquats 1, 3 and dyes 5, 6 has been
facilitated by enantiocomposition analysis by capillary
electrophoresis using well available cyclodextrin-based
selectors. (iii) Comfortably robust configurational stability of the
title diquats permits their exploration for range of applications in
chiral science. We demonstrate in conditions of capillary
electrophoresis that diquat 1 can act as a chiral selector to
investigate enantiocomposition of example acidic aromatic
analytes
with
axial
and
central
chirality.
The
enantiodiscrimination aspect shown suggests more general
potential of the dications in chiral separation methods and chiral
supramolecular recognition with prospective use in sensorics.
(iv) Synthesis of non-racemic diquat dyes is described. This is
the first time chiral dyes of that type have been synthesized and
their prominently large chiroptical responses documented. To
this end, their intense ECD in the visible region is of interest
towards applications in polarization-related photonics for data
storage and communication. Overall, our results show diquats
as a class of attractive chiral dicationic scaffolds, which
constitute useful platforms for chiral application studies. Work
towards application of the title diquats as a recognition motif in
chiral stationary phases for liquid chromatography is underway.
Figure 3. a) Enantiodiscrimination of chiral analytes with diquat [P-1][TfO]2 as
a
selector in capillary electrophoretic separation. b)-d) Experimental
arrangement of CE chiral separation in counter-flow of diquat selector: b)
Narrow zone of injected racemic analyte; c) Snapshot in the course of
separation; d) Separated enantiomers of the analyte in the detector area.
We used capillary electrophoresis for rapid investigation17
of chiral discrimination capabilities of diquat 1 (Figure 3a).
Flexible CE setup with both analytes and chiral selector in free
solution (Figure 3b-d) was beneficial in identification of important
chiral molecules specifically interacting with optically pure diquat
enantiomers. Structural diversity of successfully resolved
analytes is a promising starting point for application of novel
diquats as chiral selectors for electrophoresis and
chromatography. Then, principal availability of both diquat
enantiomers is advantageous to control elution order of chiral
analytes. For analysis of trace amounts of optical impurities, it is
beneficial that the minor enantiomer elutes first. This is difficult
to achieve for chiral selectors typically available in only one
optical form, such as cyclodextrins. Extension of this proof-of-
concept study towards design of configurationally robust diquats
as a central stereorecognition motif for enantioseparations of
chiral pharmaceuticals and metabolites or for uses as sensors
thus seems attractive.
Acknowledgements
Financial support by the Czech Science Foundation (17-12648S, 17-
04393S, 17-10832S), the Czech Academy of Sciences (RVO:
61388963) and the computational resources at University of
Chemistry and Technology, Prague (CZ. 1.05/3.2.00/08.0144),
CESNET LM2015042 and CERIT Scientific Cloud LM2015085,
provided under the programme "Projects of Large Research,
Development, and Innovations Infrastructures" are gratefully
acknowledged.
Keywords: helical chirality • N-heterocyclic cations • racemization
In summary, this report introduces detailed experimental
and theoretical investigation of diquats with notably high
racemization barriers. The presented results are significant from
several perspectives: (i) Facile and inexpensive preparative
resolution of two parent diquat systems is described. (ii) The
barrier • chiral selector • capillary electrophoresis
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Harish R. Talele, Dušan Koval*, Lukáš
Severa*, Paul E. Reyes-Gutiérrez, Ivana
Císařová, Petra Sázelová, David
Šaman, Lucie Bednárová, Václav
Kašička, and Filip Teplý*
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Facile access to enantiopure diquats with extreme configurational stability is
described for the first time along their derivatization and application as chiral
selectors.
Diquats with Robust Chirality: Facile
Resolution, Synthesis of Chiral Dyes
and Application as Selectors in Chiral
Analysis
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