Chiral anion-mediated asymmetric induction onto chiral diquats

Article abstract of DOI:10.1016/S0040-4039(01)02163-3

Diquats - which are important electron transfer agents in biological and photocatalytic systems, as well as structural templates for efficient supramolecular synthesis - are noteworthy for their axial chirality and have been so far reported only in racemi

Full text of DOI:10.1016/S0040-4039(01)02163-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 423–426
Chiral anion-mediated asymmetric induction onto chiral diquats
Chiara Pasquini,a,b Vale´rie Desvergnes-Breuil,a Jonathan J. Jodry,a Antonella Dalla Cortb and
Je´roˆme Lacoura,*
aUniversite´ de Gene`ve, De´partement de Chimie Organique, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland
bCentro CNR sui Meccanismi di Reazione and Dipartimento di Chimica, Universita` ‘La Sapienza’, I-00185 Rome, Italy
Received 22 October 2001; accepted 13 November 2001
Abstract—Diquats—which are important electron transfer agents in biological and photocatalytic systems, as well as structural
templates for efficient supramolecular synthesis—are noteworthy for their axial chirality and have been so far reported only in
racemic form due to the rapid interconversion between the atropoisomers. We now report the first example of configurational
ordering of chiral diquats through their asymmetric ion pairing with novel hexacoordinated phosphate anions TRISPHAT,
HYPHAT and BINPHAT. © 2002 Elsevier Science Ltd. All rights reserved.
Tricyclic diquats (1) are important electron transfer
agents in biological and photocatalytic systems and
have been investigated as structural templates for
efficient supramolecular synthesis.1 Diquat derivatives
are also noteworthy for their axial chirality. These
compounds, which bridge two pyridinium rings around
a central s bond, possess two enantiomeric (R and S)
conformations, the dihedral angle between the two
pyridiniums depending upon the size of the non-aro-
matic ring.2
ter-ions; intermolecular diastereoselective interactions
controlling the stereoselectivity (Pfeiffer effect).3
Previously, we reported the synthesis and resolution of
tris(tetrachlorobenzenediolato)phosphate(V) anion or
TRISPHAT 2.4 This D3-symmetric anion is an efficient
NMR chiral shift, resolving and asymmetric inducing
reagent onto organic and organometallic derivatives—
with a predilection for octahedral metallo-organic com-
plexes.5 However, with some chiral C2-symmetric
cations, low NMR shifts and asymmetric inducing
properties were observed.6 Assuming that its D3-sym-
metry was not suitable for the chiral recognition of
such cations, C2-symmetric BINPHAT 36 and
HYPHAT 47—of configuration controlled by BINOL
and hydrobenzoin ligands, respectively—were recently
developed. Higher level of asymmetric induction and
better chiral shift properties were then obtained using—
in rather non-polar solvent conditions—these novel
anions as counter-ions.
R
R
N
N
N
N
n
n
(R)-1
(S)-1
R
R
However, diquats have so far been reported in only
racemic form due to the rapid interconversion of the
atropoisomers at room temperature in solution. To
obtain chiral diquats in a predominant R or S configu-
ration, a possible strategy would be to add stereogenic
elements to the backbone of the compounds;
intramolecular diastereoselective interactions would
then occur and lead—possibly—to the preferred forma-
tion of one diastereomer. An alternative strategy to
control the configuration of the charged diquats is to
consider their asymmetric ion pairing with chiral coun-
Cl
Cl
Cl
Cl
Cl
O
Cl
Cl
O
O
O
O
P
Cl
O
Cl
Cl
∆-2
Cl
* Corresponding author. Tel.: +41 (0)22 702 6062; fax: +41 (0)22 328
7396; e-mail: jerome.lacour@chiorg.unige.ch
TRISPHAT
Cl
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02163-3

424
C. Pasquini et al. / Tetrahedron Letters 43 (2002) 423–426
Cl
lescence temperatures of 363 K (DG"=16.9 kcal
mol−1), 363 K (DG"=16.9 kcal mol−1) and 403 K
(DG"=18.8 kcal mol−1), respectively (400 MHz, Fig.
1), demonstrating the slow interconversion at room
temperature between enantiomeric R and S conforma-
tions.9 However, salts of 5a proved to be rather insolu-
ble in most organic solvents. Further experiments were
therefore performed with [5b]Br2 and [5c]Br2
exclusively.
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O
O
O
O
O
O
O
O
O
P
P
O
Cl
Cl
O
Cl
Cl
BINPHAT
(∆,S)-3
HYPHAT
(R,R)-4
Cl
Cl
Initial experiments to determine the efficiency of the
TRISPHAT anion as an NMR chiral shift agent were
attempted following conditions already reported.10
Racemic diquat derivatives [5b]Br2 and [5c]Br2 were
studied and, as foreseen, salt [5b]Br2 proved to be
insoluble in most solvents or solvent combinations of
low polarity. Only salt [5c]Br2 could be dissolved in
decent amounts in 10% DMSO-d6/CDCl3. We therefore
tested the protocol on such a solution of [5c]Br2 in 10%
DMSO-d6/CDCl3. In a NMR tube, [nBu4N][D-2] was
added as a solid and, after solubilization, a separation
of the signals (Dl) of the enantiomers of 5c was
observed (Fig. 2). It was necessary to add at least 2.0
Cl
Cl
But, doubly charged diquats are noticeably known for
their poor solubility in solvents like C6H6, CHCl3 or
CH2Cl2. Polar solvents, e.g. water or methanol, are
necessary to dissolve the salts. It was then debatable—
in rather polar solvent conditions—whether the cou-
lombic attraction would be sufficiently strong for
anions 2–4 to behave as NMR chiral shift and asym-
metric inducing agents.8 This is indeed the case and we
here report the first example of asymmetric induction
onto chiral diquats (d.e. up to 36%); the selectivity
1
being determined without ambiguity by H NMR.
R
R
N
Br
Br
N
[Br-]2
N
N
acetone
reflux
R
R
R = H
5a (100%)
5b (82%)
R = Me
R = t-Bu 5c (92%)
Good literature precedents convinced us that seven-
membered tricyclic diquat derivatives (5) would be best
for our study: prior experiments by Calder, Spotswood
and Tanzer2d have indeed shown that the atropoiso-
meric conformations of such compounds interconvert
1
Figure 1. Variable temperature H NMR (400 MHz, DMSO-
1
d6) of [rac-5a]Br2. Tc=363 K, Dw=247 Hz and J=14.4 Hz.
slowly on the NMR time scale (e.g. 5a, H NMR in
D2O). Keeping in mind the necessity for the ion pairs
containing the chiral anions to be soluble in rather
non-polar solvent conditions, we considered from the
start the introduction of lipophilic residues on the
pyridinium rings. Diquats with extra methyl (5b) or
t-butyl (5c) groups were thus prepared and—for ease of
synthesis—substitution was realized at the 4,4%-posi-
tions. The synthesis was achieved in a single step by
treatment at reflux of the corresponding 2,2%-bipyridine
with an excess of 1,3-dibromopropane to afford in good
to excellent yields (82–100%) salts [5a–c]Br2 as white
precipitates.
Racemization energies of cations 5b and 5c were how-
ever unknown and we decided to investigate their
configuration stability prior to a study with the chiral
anions. NMR spectra (DMSO-d6) of salts [5a–c]Br2
showed at room temperature a magnetic non-equiva-
lency for the diastereotopic protons of the bridge of all
three derivatives (Fig. 1, R=H). Dynamic conforma-
tional isomerism was then detected for 5a–c with coa-
Figure 2. 1H NMR spectra (400 MHz, 10% DMSO-d6/
CDCl3, 22°C, parts) of [5c]Br2 with (a) 0, (b) 2.0 and (c) 6.0
equiv. of [nBu4N][D-2].

C. Pasquini et al. / Tetrahedron Letters 43 (2002) 423–426
425
equiv. of the reagent to observe the beginning of a
non-equivalence of the signals and, only with 6.0 equiv.
of the shift reagent, could baseline-to-baseline separa-
tions be realized for most of the signals (Dlmax=0.136
ppm). As mentioned, more polar solvent conditions—
28% DMSO-d6/CDCl3—were required for salt [5b]Br2
and under those conditions the addition of 6.0 equiv. of
the shift reagent led to a general broadening for most of
the signals except for a couple better resolved (Dlmax
=
0.100 ppm). Furthermore, we noticed that—in the pres-
ence of the chiral TRISPHAT—the intensities of the
two sets of signals of the enantiomers of 5c were not
equivalent, meaning that an asymmetric induction from
the anion onto the chiral cation had occurred (Fig. 2,
spectrum c, d.e. 25%). With this good preliminary result
on our hand, we turned our attention onto the charac-
terization of this effect.
Figure 3. 1H NMR spectra (400 MHz, 8% acetone-d6/CDCl3,
22°C) of [5c][D-2]2, d.e. 28%.
1
61%, respectively). H NMR analyses were performed
in 8% acetone-d6/CDCl3 for salts [5b][(R,R)-4]2 and
[5c][(R,R)-4]2 salts, respectively (Fig. 4). A better non-
equivalence between the enantiomeric signals (larger
Dl) was observed for salt [5b][(R,R)-4]2 than for
[5c][(R,R)-4]2.11 However, this better NMR separation
of the signals did not translate into a better selectivity
as diastereomeric excesses of 0 and ꢀ10% were mea-
sured for [5b][(R,R)-4]2 and [5c][(R,R)-4]2 salts,
respectively.
Recently, we have observed that TRISPHAT and the
other hexacoordinated phosphate anions 3 and 4 confer
to salts an affinity for low polar organic solvents, as
they usually dissolve in CHCl3/CH2Cl2 and elute
rapidly on chromatography over silica gel/alumina.4b,10
We therefore considered the preparation of the di-
quats salts of anions 2–4, namely salts [5b–5c][D-2]2,
[5b–5c][D-3]2 and [5b–5c][(R,R)-4]2, respectively, and
expected that the increased lipophilicity of the ion pairs
would allow us to dissolve them in less polar NMR
solvents—in particular with cation 5b—leading to bet-
ter separations of the NMR signals of the enantiomers
as well as higher asymmetric inductions.
Association of BINPHAT anion 3 with diquats (5b–5c)
turned out to be more challenging than expected as
prolonged exposure to chromatography of the
BINPHAT salts led to their decomposition. Only a
fraction of [5c][D-3]2 could be isolated; all of the frac-
tions containing the desired ion pair along with some
contamination from BINOL. Nevertheless, 1H NMR
analyses on a small and not too impure sample of
[5c][D-3]2 could be performed and revealed good NMR
chiral shift (Dl=0.56 ppm) and asymmetric inducing
effects from anion 3; in 8% acetone-d6/CDCl3, a 68:32
For the preparation of the salts, solutions in 1:1
methanol/acetone of [ammonium][2–4] and of [5b]Br2
or [5c]Br2 were prepared and mixed together.5e,10
Aliquots were adsorbed on analytical basic alumina
plates. Development by elution with 10% acetone/
CH2Cl2 showed as expected a much-reduced affinity of
the phosphate salts for basic alumina, as they were
retained to a much lower extent (Rf 0.25) than their
bromide precursors (Rf ꢀ0). Preparative column chro-
matography experiments (Al2O3, 10% acetone/CH2Cl2,
1×8 cm) using mixtures of [5b]Br2 or [5c]Br2 (43 mmol)
and the appropriate [ammonium][2–4] source (2.5
equiv., 166 mmol) were performed and the resulting
phosphate salts were isolated in modest to decent yields
(50–75%).
ratio was measured corresponding to
diastereoselectivity (Fig. 5).
a ꢀ36%
Initial experiments were attempted with more robust
TRISPHAT anion 2. As foreseen, TRISPHAT salts
exhibited a higher solubility in low polar solvent condi-
tions and could be dissolved in 20% (5b) or 8% acetone-
1
d6/CDCl3 (5c). H NMR analysis of isolated [5c][D-2]2
salts confirmed our prediction. The signals of both
enantiomers of the cations could be observed in the
solvent conditions that were used and a 64:36 ratio was
measured for the signals of the two enantiomers, (Fig.
3, 8% acetone-d6/CDCl3, d.e. 28%).
As for anion 2, association of HYPHAT 4 with diquats
(5b–5c) was realized under the chromatographic
exchange conditions. Pure samples of [5b][(R,R)-4]2 and
[5c][(R,R)-4]2 were obtained in decent yields (52 and
Figure 4. 1H NMR spectra (400 MHz, 8% acetone-d6/CDCl3,
22°C, parts) of (a) [5b][(R,R)-4]2, d.e. 0% and (b) [5c][(R,R)-
4]2, d.e. ꢀ10%.

426
C. Pasquini et al. / Tetrahedron Letters 43 (2002) 423–426
Thummel, R. P.; Lefoulon, F.; Mahadevan, R. J. Org.
Chem. 1985, 50, 3824–3828; (c) Homer, R. F.; Tomlinson,
T. E. J. Chem. Soc. 1960, 2498; (d) Calder, I. C.;
Spotswood, T.; Tanzer, C. I. Aust. J. Chem. 1967, 20,
1195–1212.
3. (a) Pfeiffer, P.; Quehl, K. Chem. Ber. 1931, 64, 2667–
2671; (b) Kirschner, S.; Ahmad, N. J. Am. Chem. Soc.
1968, 90, 1910–1911; (c) Kirschner, S.; Ahmad, N.;
Munir, C.; Pollock, R. J. Pure Appl. Chem. 1979, 51,
913–923; (d) Owen, D. J.; VanDerveer, D.; Schuster, G.
B. J. Am. Chem. Soc. 1998, 120, 1705–1717; (e) Yeh, R.
M.; Ziegler, M.; Johnson, D. W.; Terpin, A. J.; Ray-
mond, K. N. Inorg. Chem. 2001, 40, 2216–2217.
4. (a) Lacour, J.; Ginglinger, C.; Grivet, C.; Bernardinelli,
G. Angew. Chem., Int. Ed. Engl. 1997, 36, 608–609; (b)
Lacour, J.; Torche-Haldimann, S.; Jodry, J. J.; Gin-
glinger, C.; Favarger, F. Chem. Commun. 1998, 1733–
1734.
Figure 5. 1H NMR spectra (400 MHz, 8% acetone-d6/CDCl3,
22°C, parts) of [5c][D-3]2, d.e. ꢀ36%.
5. (a) Lacour, J.; Ginglinger, C.; Favarger, F.; Torche-
Haldimann, S. Chem. Commun. 1997, 2285–2286; (b)
Lacour, J.; Jodry, J. J.; Ginglinger, C.; Torche-Haldi-
mann, S. Angew. Chem., Int. Ed. Engl. 1998, 37, 2379–
2380; (c) Lacour, J.; Goujon-Ginglinger, C.;
Torche-Haldimann, S.; Jodry, J. J. Angew. Chem., Int.
Ed. 2000, 39, 3695–3697; (d) Ratni, H.; Jodry, J. J.;
Lacour, J.; Ku¨ndig, E. P. Organometallics 2000, 19, 3997–
3999; (e) Giner Planas, J.; Prim, D.; Rose-Munch, F.;
Rose, E.; Monchaud, D.; Lacour, J. Organometallics
2001, 20, 4107–4110.
6. Lacour, J.; Londez, A.; Goujon-Ginglinger, C.; Buß, V.;
Bernardinelli, G. Org. Lett. 2000, 2, 4185–4188.
7. Lacour, J.; Londez, A. J. Organomet. Chem. 2001, in
press.
8. (a) Giner Planas, J.; Prim, D.; Rose-Munch, F.; Rose, E.;
Monchaud, D.; Lacour, J. Organometallics 2001, 20,
4107–4110; (b) Monchaud, D.; Lacour, J.; Coudret, C.;
Fraysse, S. J. Organomet. Chem. 2001, 624, 388–391 and
Ref. 5e.
In conclusion, association of chiral diquats and hexaco-
ordinated phosphate anions was realized and yielded
the first example of configurational ordering of these
cationic species. Importantly, we have observed that the
overall symmetry of the chiral anion (D3 or C2) is not
as important as the resulting solubility of the ion pair;
anion 4 in spite of its C2-symmetry is less efficient than
TRISPHAT 2. Nevertheless, C2-symmetric BINPHAT
anion remains the most efficient asymmetric inducting
agent.
Acknowledgements
We thank the Swiss National Science Foundation, the
Federal Office for Education and Science (COST D11
Supramolecular Chemistry WG 003/98, J.L., C.P.), and
the ‘Fondation de Famille Sandoz’ for a professorship
(J.L.) and a post-doctoral fellowship (V.D.B.).
9. The relationship DG"=RTc (22.96+ln(Tc/ꢀ(Dw2+6J2))
was used to determine the activation energy, DG", from
the coalescence temperature, Tc (K), the frequency sepa-
ration of the peaks, Dw (Hz), and the coupling constant
between the nuclei, J (Hz).
10. Lacour, J.; Barche´chath, S.; Jodry, J. J.; Ginglinger, C.
Tetrahedron Lett. 1998, 39, 567–570.
11. Chemical shifts for each enantiomer of salt [5b][(R,R)-4]2
were assigned using COSY experiments and revealed
upfield or downfield shifts induced by the phosphate
reagent.
References
1. Allwood, B. L.; Kohnke, F. H.; Slawin, A. M. Z.;
Stoddart, J. F.; Williams, D. J. J. Chem. Soc., Chem.
Commun. 1985, 311.
2. (a) Campa, C.; Camps, J.; Font, J.; de March, P. J. Org.
Chem. 1987, 52, 521 and references cited therein; (b)