Effective chirogenesis in a bis(metallosalphen) complex through host-guest binding with carboxylic acids

Article abstract of DOI:10.1002/anie.201004957

Picking Cotton: Strong host-guest complexation of chiral carboxylic acids results in the amplification of one of the chiral conformers of a bis[Zn ²⁺(salphen)] complex, which can racemize by axis rotation (see picture). The complexation leads to a CD signal for which the sign of the first Cotton effect directly relates to the absolute configuration of the substrate and the amplitude depends on the size and nature of the substituents. Copyright

Full text of DOI:10.1002/anie.201004957

DOI: 10.1002/anie.201004957
Chirality Transfer
Effective Chirogenesis in a Bis(metallosalphen) Complex through
Host–Guest Binding with Carboxylic Acids**
Sander J. Wezenberg, Giovanni Salassa, Eduardo C. Escudero-Adꢀn, Jordi Benet-Buchholz, and
Arjan W. Kleij*
Transfer of chiral information through supramolecular inter-
actions (chirogenesis) has been observed in many natural
systems including DNA and proteins,[1] and is nowadays
widely used in the development of smart artificial and
biomimetic materials.[2] The induction of chirality in bis(me-
talloporphyrins) for example, has been successfully applied in
assigning the absolute configuration of amines,[3] diamines
and aminoamides,[4] aminoalcohols and epoxyalcohols,[5] and
diols[6] by using a circular dichroism (CD) protocol.[7]
Effective chirality transfer with carboxylic acids, however,
Scheme 1. Conformational isomerism of 1. The tBu groups are omitted
for clarity in the line drawings of the conformers. P denotes right-
has proven to be highly difficult, and has only been achieved
by using potassium carboxylate salts followed by tedious
extractions,[8] or by the addition of a huge excess of substrate
to a metal-free host.[9] The low efficiency of chiral induction
with these previous methods is mainly due to the relatively
weak host–guest interactions with carboxylic acid groups.
handedness and M left-handedness.
the product in excellent yield (73%) and purity (see the
Supporting Information). Characterization by NMR spec-
troscopy indicated the presence of one equivalent of acetic
acid,[13] which had formed as a by-product in the synthesis.
Slow evaporation of a solution of the product in toluene/
MeCN 1:1 resulted in single crystals suitable for X-ray
analysis (Figure 1).[14] The solid-state structure revealed that
the two Zn2+ centers of 1 are bridged by AcOH (through the
oxygen atoms of the carboxylic acid unit) to give a complex
with 1:1 stoichiometry (1ꢀAcOH). As anticipated, both the S
and the R conformer were present in a 1:1 ratio in the unit
cell; each conformer has the same dihedral angle (44.98) and
Zn–O(acetate) distance (2.01 ꢀ). This distance is identical to
that previously found in a related acetate-bridged complex.[13]
Since the exact position of the acidic proton of AcOH could
not be resolved by X-ray diffraction, the proton was placed in
To overcome this problem, we have designed
a
bis[Zn2+(salphen)] complex 1 (salphen = N,N’-phenylenebis-
(salicylimine)), which, similar to 2,2’-biphenol units,[10] exists
in dynamic equilibrium between two chiral conformations (S
and R enantiomers; see Scheme 1). We reasoned that the
energy barrier of rotation increases upon binding of a ditopic
ligand to the Lewis acidic Zn2+ centers.[11,12] Herein, we
demonstrate that 1 binds very strongly with acetic acid and
that axial chirality can be effectively induced by exchange for
chiral a-substituted carboxylic acids, with the practical
advantage that substrate derivatization or use of excessive
substrate is not required.
Compound 1 was prepared in a single step by reaction of a
bis(salicylaldehyde) molecule with two equivalents of a
monoimine precursor and Zn(OAc)2 in the presence of
pyridine. Subsequent precipitation from MeOH afforded
[*] S. J. Wezenberg, G. Salassa, E. C. Escudero-Adꢀn,
Dr. J. Benet-Buchholz, Dr. A. W. Kleij
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢁsos Catalans, 16, 43007 Tarragona (Spain)
Fax: (+34)977-920-224
E-mail: akleij@iciq.es
Dr. A. W. Kleij
Catalan Institute of Research and Advanced Studies (ICREA)
Pg. Lluꢂs Companys 23, 08010 Barcelona (Spain)
[**] This work was supported by ICIQ, ICREA, the Spanish Ministry of
Science and Innovation (CTQ 2008-02050/BQU), the Spanish
Ministry of Education (FPU fellowship to S.J.W), and Consolider
Ingenio 2010 (CSD 2006-0003). We thank K. Gꢃmez and Dr. G.
Gonzꢀlez for assistance with NMR experiments. salphen=
N,N’-phenylenebis(salicylimine).
Figure 1. Solid-state structure of 1ꢀAcOH showing the chemically
equivalent S and R conformers. Solvent molecules are omitted for
clarity.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004957.
Angew. Chem. Int. Ed. 2011, 50, 713 –716
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
713

Communications
an idealized position before refinement. Further DFT opti-
mization using the B3P86 level of theory demonstrated that
the most favorable location of this proton is between the
biphenolic oxygen atoms of 1 (see the Supporting Informa-
tion).[15] This binding motif is therefore able to assist in the
stabilization of 1ꢀAcOH and hence the host–guest complex-
ation of acetic acid with 1 resembles the binding of an acetate
molecule.
A range of 1D and 2D 1H NMR experiments (COSY,
NOESY, ROESY, GOESY) in a noncoordinating solvent
(CD2Cl2) confirmed that the structure of 1ꢀAcOH is retained
in solution. The most significant NOE correlations are that
between the tBu group of 1 and the methyl group of AcOH,
and those between the tBu group and opposing aryl and imine
protons (see the Supporting Information). When an excess of
pyridine was added to the sample, competition with AcOH
binding results in disruption of the 1ꢀAcOH complex. This
disruption is accompanied by a large bathochromic shift of the
absorption maximum (lmax: 390!420 nm), and this change
allowed the stability constant to be calculated by competitive
titration experiments. Even though pyridine is known to bind
very strongly to the Zn2+ ion in salphen complexes,[11]
complete dissociation could only be realized beyond the
addition of approximately 1000 equivalents of pyridine.
Multivariate analysis of this titration data provided a very
Figure 2. CD spectra (right-hand y axis) of 1ꢀAcOH in CH2Cl2
(2ꢄ10ꢁ5 m) upon addition of 0.5, 1, 2, 5, 10, and 20 equivalents of
(S)-2 and (R)-2, and corresponding UV/Vis absorption spectra (left-
hand y axis) before and after addition of 10 equivalents of 2. Spectra
were measured at room temperature.
high association constant for 1ꢀAcOH (Ka = 3.8 ꢁ 1010 mꢁ1
;
see the Supporting Information).
When one equivalent of a competing carboxylic acid
(propionic acid) was added to a sample of 1ꢀAcOH in
CD2Cl2, fast exchange was noted on the NMR timescale,
without significant alterations in the chemical shifts of 1. At
lower temperatures, the exchange rate was reduced, and both
AcOH and propionic acid containing complexes were
observed individually in a 4:1 ratio (see the Supporting
Information). We then used optically pure 2-phenylpropionic
acid 2 as guest and measured the CD spectra of 1ꢀAcOH in
the presence of 0–20 equivalents of 2 (see Figure 2). The CD
spectrum of 1ꢀAcOH alone was silent because of the
presence of equimolar amounts of (S)-1 and (R)-1. Addition
of (S)-2 however, induced a negative first and second Cotton
effect, whereas addition of (R)-2 resulted in mirror-image
(that is, positive) signals. A negative first Cotton effect stems
from a counterclockwise coupling of electronic transitions
and corresponds to M helicity.[7,10] It is therefore presumed
that host–guest binding with (S)-2 stimulates predominant
formation of the R conformer of 1 (that is, more (R)-1ꢀ(S)-2
than (S)-1ꢀ(S)-2) and the inverse for (R)-2. After the
addition of 10 equivalents of substrate, virtually no further
increase in molar ellipticity (De) was noted, which indicates
full replacement of AcOH by 2. The corresponding UV/Vis
spectra remained unchanged.
Figure 3. X-ray crystal structure of 1ꢀ(S)-2; the two diastereoisomers
are present in the unit cell. Dotted lines denote both the dihedral
angles and the distances between the a-carbon and the nearest
nitrogen atom. Solvent molecules are omitted for clarity.
case of (R)-1ꢀ(S)-2. This difference results from a more
efficient distribution of the a substituents of (S)-2 in the
R conformer, and leads to less steric crowding compared to
(S)-1ꢀ(S)-2. Single-point DFT calculations (single-point
B3P86) were then carried out to determine the energy of
the structures that were found in the solid state. These
calculations clearly showed that host–guest binding of (S)-2
with the R conformer is energetically more favorable by 1.88
kcalmolꢁ1 than binding with the S conformer. Preferential
diastereoisomer formation was also observed in solution by
1H NMR spectroscopy (see the Supporting Information) and
the 1:1 crystallization of both conformers is therefore ascribed
to a preferred pairwise packing arrangement. Based on the
negative first Cotton effect in the CD spectrum, it was already
expected that (S)-2 induces the R conformer of 1, and
the DFT analysis further supports the observation that
(R)-1ꢀ(S)-2 is indeed the most stable diastereoisomer.
Single crystals of 1ꢀ(S)-2 were obtained by partial
evaporation of a solution of 1ꢀAcOH with 10 equivalents
of (S)-2 in CH2Cl2/MeCN 1:1, followed by cooling to ꢁ308C.
The molecular structure (see Figure 3)[16] showed the pres-
ence of both diastereoisomers in a 1:1 ratio in the unit cell.
Comparison of these isomers revealed significant structural
differences, such as a smaller dihedral angle and a larger
distance of the phenyl substituent to the salphen plane in the
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Angew. Chem. Int. Ed. 2011, 50, 713 –716

Addition of other S-configured carboxylic acids to
1ꢀAcOH gave CD signals identical to those observed with
(S)-2 (the main absorptions are given in Table 1). In general,
the signal amplitude could be directly related to the size of
substituents at the a position. In addition to steric effects, the
concentrations by addition of a chiral acid; no further
derivatization of the substrate was required. The resulting
CD signal of the complexes relates to the chirality of the
substrate, thus allowing for a practical use of this system in
assignments of absolute configurations. Further work on this
and other applications in areas such as supramolecular
enantioselective catalysis, chiral recognition, and molecular
devices (switches) is currently in progress.
Table 1: Acid-induced CD effects.[a]
Acid
Structure
l [nm] De [mꢁ1 cmꢁ1
]
437
366
320
439
371
323
433
371
322
429
369
319
432
370
321
436
370
322
ꢁ2.9
ꢁ2.1
+3.0
ꢁ7.2
ꢁ6.6
+7.3
ꢁ7.3
ꢁ6.5
+7.4
ꢁ5.4
ꢁ6.4
+6.0
ꢁ6.8
ꢁ8.0
+7.5
ꢁ10.7
ꢁ12.7
+12.3
(S)-methylbutyric acid
Experimental Section
Synthesis of bis[Zn2+(salphen)] 1ꢀAcOH: 3,3’-diformyl-2,2’-dihy-
droxy-1,1’-biphenyl (41 mg, 0.17 mmol) and the monoimine precursor
(98 mg, 0.37 mmol) based on 3-tert-butylsalicylaldehyde and
1,2-phenylenediamine were dissolved in CH2Cl2 (4 mL) and the
resulting yellow solution was stirred at room temperature. A solution
of Zn(OAc)2·2H2O in MeOH (2 mL) and pyridine (1 mL) was then
added dropwise to the stirred solution. The color of the solution
slowly turned orange and the solvent was removed in vacuo after 2 h.
After five repetitive dissolution/evaporation sequences using MeOH
to remove residual pyridine, an orange precipitate was obtained,
which was filtered, washed thoroughly with MeOH, and air-dried to
give an orange solid; yield: 115 mg (73%). 1H NMR (400 MHz,
[D6]DMSO): d = 11.93 (br, 1H, CO2H), 9.00 (s, 2H, CHN), 8.91 (s,
2H, CHN), 7.97 (dd, J = 1.78, 7.14 Hz, 2H, ArH), 7.85 (m, 4H, ArH),
7.36 (m, 6H, ArH), 7.24 (dd, J = 1.36, 7.80 Hz, 2H, ArH), 7.20 (dd,
J = 1.32, 7.32 Hz, 2H, ArH), 6.61 (t, J = 7.50 Hz, 2H, ArH), 6.42 (t,
J = 7.52 Hz, 2H, ArH), 1.90 (s, 3H, CH3), 1.44 ppm (s, 18H, tBu), see
the Supporting Information for full assignment; 13C NMR (100 MHz,
[D6]DMSO): d = 171.8, 170.2 (CO), 162.9 (two overlapping peaks)
(CHN), 141.5, 139.7 (two overlapping peaks), 137.3, 134.5, 134.4,
130.2, 130.2, 126.9, 126.8, 119.5, 119.4, 116.3, 116.2, 112.5, 112.1 (ArC),
34.9 (C(CH3)3), 29.6 (C(CH3)3), 21.1 ppm (CH3CO2H), no signal
observed for CH3CO2H; MALDI(+)-MS: m/z 868.0 [M+ꢁAcOH];
elemental analysis calcd (%) for C50H46N4O6Zn2: C 64.60, H 4.99, N
6.03; found: C 64.26, H 4.98, N 6.01.
(S)-2-phenylpropionic acid
2
(S)-ibuprofen
(S)-2-hydroxybutyric acid
(S)-2-hydroxy-3-methylbu-
tyric acid
(S)-hexahydromandelic
acid
428
369
318
425
368
323
424
367
321
432
369
322
ꢁ2.6
ꢁ3.3
+2.7
ꢁ3.7
ꢁ5.2
+3.8
ꢁ4.7
ꢁ6.9
+5.4
ꢁ3.4
ꢁ3.4
+4.2
(S)-mandelic acid
Boc-l-alanine
Boc-l-valine
Received: August 9, 2010
Published online: October 21, 2010
Boc-l-phenylalanine
[a] Measured after addition 10 equivalents of acid to 1ꢀAcOH (2ꢄ
10ꢁ5 m) in CH2Cl2 containing 0.1% diisopropylethylamine (v/v).[17]
Boc=tert-butoxycarbonyl.
Keywords: carboxylic acids · chirality · Schiff bases ·
supramolecular chemistry · zinc
.
signal amplitude also can depend on the acid-exchange
equilibrium, which is reflected in the relatively low De value
of mandelic acid and Boc-protected phenylalanine. This low
value is assumed to result from a lower binding affinity for 1,
although the larger distance between the steric bulk and the
chiral center in phenylalanine may also play a role. Further-
more, the first Cotton effect for the methyl-substituted acids
was larger than the second Cotton effect, whereas the reverse
effect was observed for the hydroxy-substituted acids and the
Boc-protected amino acids. It is possible that the latter two
acids have a different binding mode because of hydrogen
bonding with the phenolic oxygen atoms of 1.
In summary, we have presented an accessible biphenol-
based bis[Zn2+(salphen)] complex, which exists in an equi-
librium between two chiral conformations that interconvert
by axial rotation, and forms strong host–guest complexes with
carboxylic acids. One of the conformations could be effec-
tively induced at ambient temperature and micromolar
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715

Communications
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data
for
1ꢀAcOH·2CH3CN·C7H8:
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C61H60N6O6Zn2; Mr = 1103.89; crystal size 0.40 ꢁ 0.30 ꢁ
0.10 mm3; monoclinic; space group P21/c; a = 12.695, b =
32.852, c = 13.299 ꢀ; a = 908, b = 110.208, g = 908; V=
5205.286 ꢀ3;
Z = 4;
1calcd = 1.409 mgMꢁ13
;
m(MoKa) =
0.981 mmꢁ1; T= 100 K; q(min/max) = 1.7/36.68; 85562 reflec-
tions collected; 23651 unique reflections (Rint = 0.080); refine-
ment method: full-matrix least-squares on F2; data/restraints/
parameters: 23651/1/689; GoF on F2 = 1.056; R1 = 0.0721 and
wR2 = 0.1994 [I > 2s(I) ]; R1 = 0.01095 and wR2 = 0.2185 (all
data); largest diff. peak and hole: 2.538 and ꢁ1.036 eꢀꢁ3
(CCDC 787737 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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[15] Related proton transfer from a 2,2’-biphenol to a chiral diamine
to give an anionic biphenol with only one proton between the
phenolic oxygen atoms resulted in a significant increase in
stability. See reference [10b].
[16] Crystallographic data for 1ꢀ(S)-2·CH3CN: C59H55N5O6Zn2;
Mr = 1060.82; crystal size 0.10 ꢁ 0.08 ꢁ 0.03 mm3; monoclinic;
space group P2(1); a = 13.1305 ꢀ, b = 29.8304 ꢀ, c =
13.5930 ꢀ; a = 908, b = 110.1918, g = 908; V= 4997.0 ꢀ3; Z = 4;
1calcd = 1.410 mgMꢁ13; m(MoKa) = 1.019 mmꢁ1; T= 100 K; q(min/
max) = 1.60/28.558; 85691 reflections collected; 24104 unique
reflections (Rint = 0.066); refinement method: full-matrix least-
squares on F2; data/restraints/parameters: 24104/55/1301; GoF
on F2 = 1.042; R1 = 0.0563 and wR2 = 0.1383 [I > 2s(I)]; R1 =
0.0753 and wR2 = 0.1497 (all data); largest diff. peak and hole:
1.059 and ꢁ1.416 eꢀꢁ3 (CCDC 787738 contains the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.)
[12] For other Zn2+(salphen)-based supramolecular systems, see:
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[13] Although we recently reported that acetate anions can bind
through their oxygen atoms as a ditopic ligand between two
mono[Zn2+(salphen)] complexes, interaction with formally neu-
tral AcOH ligands has not been observed to date. See: S. J.
[17] In the absence of diisopropylethylamine, slight decomposition of
1 was noted after addition of a-hydroxy-substituted acids. Note
that the CD absorption induced by (S)-2 is fairly similar with and
without additive.
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