Chirality Sensing with Stereodynamic Biphenolate Zinc Complexes

Article abstract of DOI:10.1002/chir.22489

Two bidentate ligands consisting of a fluxional polyarylacetylene framework with terminal phenol groups were synthesized. Reaction with diethylzinc gives stereodynamic complexes that undergo distinct asymmetric transformation of the first kind upon binding of chiral amines and amino alcohols. The substrate-to-ligand chirality imprinting at the zinc coordination sphere results in characteristic circular dichroism signals that can be used for direct enantiomeric excess (ee) analysis. This chemosensing approach bears potential for high-throughput ee screening with small sample amounts and reduced solvent waste compared to traditional high-performance liquid chromatography methods. Chirality 27:700-707, 2015.

Full text of DOI:10.1002/chir.22489

CHIRALITY 27:700–707 (2015)
Special Issue Article
Chirality Sensing With Stereodynamic Biphenolate Zinc Complexes
*
KEITH W. BENTLEY, ZEUS A. DE LOS SANTOS, MARY J. WEISS, AND CHRISTIAN WOLF
Department of Chemistry, Georgetown University, Washington, D.C.
ABSTRACT
Two bidentate ligands consisting of a fluxional polyarylacetylene framework
with terminal phenol groups were synthesized. Reaction with diethylzinc gives stereodynamic
complexes that undergo distinct asymmetric transformation of the first kind upon binding of chi-
ral amines and amino alcohols. The substrate-to-ligand chirality imprinting at the zinc coordina-
tion sphere results in characteristic circular dichroism signals that can be used for direct
enantiomeric excess (ee) analysis. This chemosensing approach bears potential for high-
throughput ee screening with small sample amounts and reduced solvent waste compared to tra-
ditional high-performance liquid chromatography methods. Chirality 27:700–707, 2015. © 2015
Wiley Periodicals, Inc.
KEY WORDS: stereolabile zinc complex; circular dichroism; enantioselective analysis; chemosensor;
chiral amplification
Circular dichroism (CD) spectroscopy has been used ex-
tensively for the stereochemical analysis of the absolute con-
figuration of chiral compounds, to monitor racemization
reactions and other stereomutations, and to investigate mo-
lecular recognition processes involving chiral compounds.1,2
A rapidly increasing number of chiroptical methods that uti-
lize induced CD or CPL (circular polarized luminescence)
signals originating from covalent or noncovalent binding of
a chiral substrate to a UV-active chemosensor have been re-
ported in recent years.3–5 Typically, the binding event affects
the 3D structure of the chemosensor which populates a chi-
ral, CD-active form, providing a characteristic chiroptical
readout. The chiral amplification process and sensing re-
sponse can then be exploited for qualitative and quantitative
stereochemical analysis of the bound substrate.6,7 The gen-
eral utility of this approach has been demonstrated by Rosini,
Toniolo, and Kuwahara, who introduced stereodynamic
probes carrying a rapidly racemizing biphenyl core in close
proximity to a substrate binding unit. The covalent attach-
ment of a chiral amino acid, carboxylic acid, amine, or alcohol
was found to effectively disturb the racemic equilibrium of the
biphenyl conformations in the probe, thus inducing spontane-
ous chirality amplification. Because the bound substrate con-
trols the conformational bias in the biphenyl-derived receptor
the corresponding Cotton effects are indicative of the chiral
origin and can be used to deduce the absolute configuration
of the substrate.8–12 Several probe designs with interesting
CD reporter units including molecular bevel gears13,14 and
propellers,15 have been introduced by Gawronski, Katoono,
and others.16–20 Seminal progress with the development of a
variety of chiroptical chemosensors and powerful chirality
sensing assays that can be used for the determination of the
absolute configuration and enantiomeric excess (ee) of many
compounds has been made by Berova and Nakanishi,21–24
Anslyn,25–29 Canary,30,31 Joyce,32 and Borhan.33–35 To this
end, our group has introduced axially chiral salicylaldehyde-
derived receptors that undergo fast substrate binding and
subsequent asymmetric transformation of the first kind
© 2015 Wiley Periodicals, Inc.
toward
a
highly CD-active conformation.36–41 These
chemosensors can be used for quantitative ee analysis and de-
termination of the absolute configuration of amino acids,
amines, and amino alcohols.
Gasparrini and others have shown that coordination of
stereolabile ligands to a metal center may increase the energy
barrier to stereomutations of the ligand backbone albeit not
dramatically.42 With that in mind we recently prepared a vari-
ety of stereodynamic tropos or meso ligand-derived boron,
zinc, palladium, and cobalt complexes that show strong
substrate-to-ligand chirality imprinting and have proven very
useful for chiroptical ee sensing of a variety of com-
pounds.43–45 Feng and colleagues introduced a racemic N,N-
dioxide iron(III) complex for CD/fluorescence analysis of hy-
droxy acids.46 The fluxional dialdehyde 1 and the corre-
sponding diamine 2 or analogs thereof have been shown to
undergo reversible condensation reactions and form dynamic
covalent assemblies with a wide range of chiral compounds
carrying, either as a complementary amino or aldehyde
group, respectively (Fig. 1). The imine bond formation with
either one or two substrates coincides with “frictionless”
central-to-axial chirality induction and results in distinct Cot-
ton effects at high wavelengths. The strong CD readouts re-
veal pronounced chirality imprinting on the framework of 1
and 2, and the observed sign and amplitude of the CD max-
ima were correlated with the absolute configuration and enan-
tiomeric composition of the analytes tested.47–50
We now introduce bidentate ligands consisting of a flux-
ional polyarylacetylene framework with terminal phenol
groups that readily react with diethylzinc toward
[This article is part of the Thematic Issue: “Chirality in Separation Science
and Molecular Recognition Honoring Prof. F. Gasparrini.” See the first articles
for this special issue previously published in Volume 27:9. More special arti-
cles will be found in this issue as well as in those to come.]
*Correspondence to: C. Wolf, Department of Chemistry, Georgetown Univer-
sity, Washington, D.C. E-mail: cw27@georgetown.edu
Received for publication 28 May 2015; Accepted 09 July 2015
DOI: 10.1002/chir.22489
Published online 24 August 2015 in Wiley Online Library
(wileyonlinelibrary.com).

CHIRALITY SENSING WITH STEREODYNAMIC ZINC
701
7, 8, and 9 were prepared as described previously.46 For electrospray
ionization mass spectrometry (ESI-MS, positive ion mode), a solution of
4 (1.57 mg, 0.005 mmol) and 18 (0.90 mg, 0.005 mmol) in 1 mL of an an-
hydrous THF:MeOH mixture (1:1 v/v) was prepared. Then Et2Zn (5 μl,
0.005 mmol, 1M in hexanes) was added and the mixture was stirred for
10 min prior to analysis via direct injection.
1,4-Bis[2(2-hydroxyphenylenethynyl)phenylenethynyl)], 3. A so-
lution of 9 (971.4 mg, 2.9 mmol), CuI (56.75 mg, 0.29 mmol), Pd(PPh3)
(344.4 mg, 0.29 mmol), 2-iodophenol (1.97 mg, 8.94 mmol), and
4
diisopropylamine (3.4 mL, 23.8 mmol) was stirred at room temperature
in 5 mL of toluene. The mixture was quenched with water and extracted
with dichloromethane. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatography
on silica gel (CH2Cl2:hexanes 1:1) afforded 989.0 mg (1.94 mmol, 65%) of
an orange solid. 1H NMR: δ = 6.34 (s, 2H), 6.92 (dd, J = 7.6 Hz, 7.5 Hz,
2H), 7.00 (d, J = 7.6 Hz, 2H), 7.29 (dd, J = 7.5 Hz 7.6 Hz, 2H), 7.35-7.39
(m, 4H), 7.45 (d, J = 7.5 Hz, 2H), 7.58-763 (m, 8H). 13C NMR (CDCl3:
DMSO-d6 1:1, v/v) δ = 77.8, 84.2, 87.4, 109.9, 110.5, 115.3, 119.4, 122.9,
124.9, 125.7, 127.8, 130.1, 131.6, 131.7, 132.6, 157.9. Anal. Calcd.
C38H22O2: C, 89.39; H, 4.34. Found: C, 89.72; H, 4.27.
Fig. 1. Structures of stereodynamic sensors that form dynamic covalent as-
semblies via imine bond formation with amines or aldehydes.
1,4-Bis(2-bromophenyl)buta-1,3-diyne, 11. A solution of TMEDA
(165.6 μL, 1.10 mmol) and CuI (105.2 mg, 0.55 mmol) was stirred in 10
mL of dichloromethane for 10 min. Then 2-bromophenylacetylene (500
mg, 2.76 mmol) was added and the reaction mixture was stirred under
air at room temperature for 12 h. The mixture was quenched with water
and extracted with dichloromethane. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. Purification by flash chro-
matography on silica gel (CH2Cl2:hexanes 1:1) afforded 983 mg (2.73
mmol, 99% yield) of a white solid. 1H NMR δ = 7.21-7.31 (m, 4H), 7.57-
7.62 (m, 4H). 13C NMR δ = 77.8, 81.0, 124.0, 126.1, 127.1, 130.3, 132.5,
134.5. Anal. Calcd. C16H8Br2: C, 53.38; H, 2.24. Found: C, 53.47; H, 2.46.
Fig. 2. Structures of biphenols 3 and 4.
stereodynamic metal complexes (Fig. 2). In the absence of a
chiral substrate, the zinc complexes exist as a mixture of rap-
idly interconverting enantiomers. The conformational bias in
these racemic complexes is disturbed, however, upon coordi-
nation of a chiral diamine or other substrates due to instanta-
neous asymmetric transformation of the first kind. We now
report that the resulting central-to-axial chirality amplification
affords strong CD effects originating from the chromophoric
arylacetylene framework. The general concept of chirality
sensing with biphenols 3 and 4 is illustrated in Scheme 1.
1,4-Bis[2-(2-trimethylsilylethynyl)phenyl]buta-1,3-diyne, 12. A so-
lution of 11 (983 mg, 2.73 mmol), CuI (52.0 mg, 0.27 mmol), Pd(PPh3)4
(315.5 mg, 0.27 mmol), and trimethylsilylacetylene (1.2 mL, 8.2 mmol) was
stirred in 4 mL of an ACN:NEt3 mixture (1:1 v/v) at 80°C for 12 h in a closed
vessel. The mixture was quenched with water and extracted with dichloro-
methane. The combined organic layers were dried over MgSO4 and concen-
trated in vacuo. Purification by flash chromatography on silica gel (CH2Cl2:
hexanes 1:4) afforded 1.06 g (2.67 mmol, 95%) of a red solid. 1H NMR δ = 0.30
(s, 18H), 7.27-7.32 (m, 4H), 7.46-7.50 (m, 4H). 13C NMR δ = 0.0, 77.9, 81.1,
99.6, 103.0, 125.2, 126.9, 128.2, 128.7, 132.0, 132.6. Anal. Calcd. C26H26Si2:
C, 79.13; H, 6.64. Found: C, 79.17; H, 6.69.
MATERIALS AND METHODS
All reagents and solvents were commercially available and used with-
out further purification. Reactions were carried out under inert atmo-
sphere and anhydrous conditions. Flash chromatography was
performed on silica gel, particle size 40–63 μm. NMR spectra were ob-
tained at 400 MHz (1H-NMR) and 100 MHz (13C-NMR) using CDCl3 as
solvent and TMS as reference unless reported otherwise. Compounds
1,4-Bis(2-ethynylphenyl)buta-1,3-diyne, 13. A solution of 12 (1.02
g, 2.59 mmol) and TBAF (1 M in THF, 13.0 mL, 13.0 mmol) was stirred in
Scheme 1. Illustration of the chirality sensing with stereodynamic zinc complexes derived from biphenols 3 and 4.
Chirality DOI 10.1002/chir

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BENTLEY ET AL.
10 mL of THF for 1 h. The mixture was quenched with water and ex-
tracted with dichloromethane. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. Purification by flash chromatog-
raphy on silica gel (CH2Cl2:hexanes 1:4) afforded 589 mg (1.45 mmol,
75%) of a yellow solid. 1H NMR δ = 3.38 (s, 2H), 7.31-735 (m, 4H), 7.50-
7.56 (m, 4H). 13C NMR δ = 77.6, 80.7, 81.5, 81.7, 124.8, 125.6, 128.4,
128.8, 132.6, 132.9. Anal. Calcd. C20H10: C, 95.97; H, 4.03. Found: C,
95.93; H, 4.07.
153.8, 154.4. Anal. Calcd. C30H18O2: C, 87.78; H, 4.42. Found: C, 87.09;
H, 4.43.
Enantioselective Sensing Experiments
A stock solution of sensor 3 or 4 (0.006 M) in THF was prepared and
portions of 0.5 mL were transferred to 4-mL vials. Solutions of substrates
(0.15 M in THF) were prepared. To each vial containing 0.5 mL of stock
solution was added either 1 equivalent (20 μL, 0.003 mmol) of a diamine
or 2 equivalents (40 μL, 0.006 mmol) of an amino alcohol. To this solution
was added Et2Zn (1M in hexanes, 0.003 mmol) and the mixtures were
allowed to stand for 5 min. The CD analysis was conducted with sample
concentrations of 1.25 x 10-4 M in THF when ligand 3 was used and at
1.25 x 10-4 M in diethyl ether when 4 was used. The CD spectra were col-
lected at 25°C with a standard sensitivity of 100 mdeg, a data pitch of 0.5
nm, a bandwidth of 1 nm, a scanning speed of 500 nm s-1, and a response
of 0.5 sec using a quartz cuvette (1 cm path length). The data were
baseline-corrected and smoothed using a binomial equation. Control ex-
periments with free substrates showed no CD signal in the region of
interest.
1,4-Bis[2(2-hydroxyphenylenethynyl)phenylene]buta-1,3-diyne,
4. A solution of 13 (485.8 mg, 1.94 mmol), CuI (37.0 mg, 0.19 mmol),
Pd(PPh3)4 (224.2 mg, 0.194 mmol), 2-iodophenol (657.7 mg, 5.82 mmol),
and diisopropylamine (2.18 mL, 15.52 mmol) was stirred at room temper-
ature in 10 mL of THF for 24 h. The mixture was quenched with water
and extracted with dichloromethane. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. Purification by flash chro-
matography on silica gel (CH2Cl2:hexanes 1:1) afforded 505.7 mg (1.16
mmol, 60%) of an orange solid. 1H NMR δ = 6.24 (s, 2H), 6.84-6.91 (m,
4H), 7.21 (dd, J = 8.7 Hz, 6.9 Hz, 2H), 7.33-7.45 (m, 6H), 7.57 (d, J = 7.8
Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H). 13C NMR δ = 77.4, 82.7, 88.3, 94.7,
109.2, 114.9, 120.2, 123.8, 126.3, 128.3, 129.2, 130.8, 131.4 131.5, 133.2,
157.1. Anal. Calcd. C32H18O2: C, 88.46; H, 4.18. Found: C, 88.23; H, 4.16.
Quantitative ee Analysis
A calibration curve was constructed using samples of the Zn complex
prepared with 3 and 18 at varying ee. A stock solution of 3 (0.001 M in
THF) was prepared and separated into 0.5-mL portions. Another stock so-
lution of 18 was prepared (0.015 M in THF). Portions of 18 were titrated
into the stock solutions or 3 to generate samples with varying %ee (+100,
+80, +60, +40, +20, 0, -20, -40, -60, -80, -100). To these solutions was added
Et2Zn (1 μL, 1 M in hexanes, 0.001 mmol). After 5 min, CD analysis was
carried out as described above at 1.25 x 10-4 M in anhydrous THF. The
Cotton effect amplitudes at 404 nm were plotted against the ee of 18.
1,2-Bis(2-bromophenyl)ethyne, 14.51
. A solution of 1-bromo-2-
ethynylbenzene (500 mg, 2.76 mmol), 1-bromo-2-iodobenzene (938 mg,
3.32 mmol), Pd(PPh3)4 (160 mg, 0.14 mmol), and CuI (53 mg, 0.276
mmol) in 5 mL of triethylamine was stirred at room temperature for 18
h. The resulting mixture was quenched with water and extracted with
CH2Cl2. The combined organic layers were dried over MgSO4 and con-
centrated in vacuo. Purification by flash chromatography on silica gel
(CH2Cl2/hexanes 1:8) afforded 918 mg (2.73 mmol, 99% yield) of a white
powder. 1H NMR: δ = 7.21 (dd, J = 8.0 Hz, J = 8.0 Hz, 2H), 7.31 (dd, J = 8.0
Hz, J = 8.0 Hz, 2H), 7.61-7.64 (m, 4H). 13C NMR: δ = 92.2, 125.1, 125.5,
127.0, 129.7, 132.5, 133.6.
Crystallography
A single crystal 4 was obtained by slow evaporation of a concentrated
chloroform solution. Formula: C32H18O2, M = 580.48, crystal dimen-
sions 0.12 x 0.14 x 0.11 mm, primitive, space group P21/n, a = 6.1914
(9) Å, b = 9.5908(13) Å, c = 18.537(3) Å, α = 90.0°, β = 94.561(2)°, γ =
90.0°, V = 1097.2 Å3, Z = 2, ρcalcd = 1.315 g cm-3. A single crystal 12
was obtained by slow evaporation of a concentrated chloroform solu-
tion. Formula: C26H26Si2, M = 394.65, crystal dimensions 0.32 x 0.26 x
0.11 mm, primitive, space group P21/c, a = 11.7792(2) Å, b = 9.2719
(2) Å, c = 12.4925(2) Å, α = 90.0°, β = 115.3720(10)°, γ = 90.0°, V =
1232.77(4) Å3, Z = 2, ρcalcd = 1.063 g cm-3. A single crystal 13 was ob-
tained by slow evaporation of a concentrated chloroform solution. For-
mula: C20H10, M = 250.28, crystal dimensions 0.21 x 0.15 x 0.11 mm,
primitive, space group P-1, a = 6.2784(6) Å, b = 7.4159(5) Å, c =
7.4756(6) Å, α = 74.904(5)°, β = 65.602(5)°, γ = 74.157(5)°, V = 348.45
(5) Å3, Z = 1, ρcalcd = 1.193 g cm-3. Single crystal X-ray analysis was per-
formed at 100 K using a Siemens platform diffractometer with graphite
monochromated Mo-Kα radiation (λ = 0.71073 Å). Data were integrated
and corrected using the Apex 2 program. The structures were solved
by direct methods and refined with full-matrix least-square analysis
using SHELX-97-2 software. Nonhydrogen atoms were refined with an-
isotropic displacement parameters.
1,2-Bis(2(2-trimethylsilylethynyl)phenyl)ethyne, 15.51
. A solution
of 14 (179 mg, 0.53 mmol), trimethylsilylacetylene (262 mg, 2.67 mmol),
Pd(PPh3)4 (124 mg, 0.11 mmol), and CuI (20 mg, 0.11 mmol) in 5 mL of
triethylamine was stirred in a sealed vessel at 90°C for 18 h. The resulting
mixture was quenched with water and extracted with CH2Cl2. The com-
bined organic layers were dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography on silica gel (CH2Cl2/hexanes 1:10)
afforded 189 mg (0.51 mmol, 99%) of a yellow solid. 1H NMR: δ = 0.25 (s,
18H), 7.21-7.29 (m, 4H), 7.49-7.55 (m, 4H). 13C NMR: δ = 0.0, 92.1, 98.7,
103.4, 126.0, 126.2, 127.9, 128.1, 131.9, 132.2.
1,2-Bis(2-ethynylphenyl)ethyne, 16.51
. A solution of 15 (127 mg,
0.34 mmol), and TBAF (1M in THF, 1.03 mL, 1.03 mmol) was stirred in
5 mL of THF at room temperature for 1 h. The resulting mixture was
quenched with water and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated in vacuo. Purification
by flash chromatography on silica gel (CH2Cl2/hexanes 1:3) afforded 63
mg (0.28 mmol, 81%) of a yellow solid. 1H NMR: δ = 3.35 (s, 2H), 7.28-
7.36 (m, 4H), 7.54 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H). 13C
NMR: δ = 81.3, 82.1, 91.7, 124.5, 126.2, 128.1, 128.5, 132.2, 132.3.
RESULTS AND DISCUSSION
We started our investigation with the synthesis of the
arylacetylene biphenol ligands (Scheme 2). Sonogashira cou-
pling of 1,4-diethynylbenzene, 6, with 2-bromoiodobenzene
using tetrakis(triphenylphosphine)palladium as catalyst gave
1,4-bis(2-bromophenylethynyl)benzene, 7, in quantitative yield.
Palladium-catalyzed incorporation of trimethylsilylacetylene
units into the periphery of dibromide 7 afforded 8 in 95% yield
and TBAF-promoted deprotection provided 1,4-bis(2-ethynyl
phenylethynyl)benzene, 9, in 75% yield. The desired 1,4-bis[2
1,2-Bis(2-(benzofuran-2-yl)phenyl)ethyne, 17. A solution of 16 (51
mg, 0.23 mmol), 2-iodophenol (150 mg, 0.68 mmol), Pd(PPh3)4 (26 mg,
0.03 mmol), CuI (6 mg, 0.03 mmol), and diisopropylamine (184 mg,
1.82 mmol) in 5 mL of toluene was stirred at room temperature for 18
h. The resulting mixture was quenched with water and extracted with
CH2Cl2. The combined organic layers were dried over MgSO4 and con-
centrated in vacuo. Purification by flash chromatography on silica gel
(CH2Cl2/hexanes 1:1) afforded 75 mg (0.18 mmol, 80% yield) of a pink
1
solid. H NMR: δ = 7.18 (dd, J = 8.0 Hz, J = 8.0 Hz, 2H), 7.28 (dd, J = 8.0
Hz, J = 8.0 Hz, 2H), 7.39 (dd, J = 8.0 Hz, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0
Hz, 2H), 7.48-7.53 (m, 4H), 7.73 (dd, J = 8.0 Hz, J = 8.0 Hz, 2H), 7.77 (s,
2H), 8.09 (dd, J = 8.0 Hz, J = 8.0 Hz, 2H). 13C NMR: δ = 94.2, 106.0,
111.0, 119.7, 121.4, 122.9, 124.7, 126.9, 127.9, 128.9, 129.1, 131.6, 134.0,
(2-hydroxyphenylenethynyl)phenylenethynyl)]benzene,
3,
was obtained by cross-coupling of 9 with 2-iodophenol in 65%
yield. Similar synthetic strategies were applied in the formation
Chirality DOI 10.1002/chir

CHIRALITY SENSING WITH STEREODYNAMIC ZINC
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Scheme 2. Synthesis of biphenols 3 and 4, and crystal structures of 12, 13, and 4.
of 4 and 5. The Glaser coupling of 2-bromophenylacetylene,
10, produced 1,4-bis(2-bromophenyl)buta-1,3-diyne, 11, in
quantitative amounts. Compound 11 was then subjected to a
similar sequence of alkynylation and deprotection steps which
gave 12 and 13 in 95% and 75% yield, respectively. The final
Sonogashira coupling with 2-iodophenol furnished 1,4-bis[2(2-
hydroxyphenylenethynyl)phenylene]buta-1,3-diyne, 4, in 60%
yield.
For the synthesis of 1,3-bis[2(2-hydroxyphenylenethynyl)
phenylene]acetylene, 5, we first prepared 1,2-bis(2-bromo-
phenyl)ethyne, 14, through cross-coupling of 10 and 2-
bromoiodobenzene in 99% yield (Scheme 3). Alkynylation of
14 with trimethylsilylacetylene followed by deprotection with
TBAF gave 15 and 16 in 99% and 81% yield, respectively. The
Sonogashira reaction between trialkyne 16 and 2-iodophenol,
however, did not lead to 5. In contrast to our experience with
Scheme 3. Synthetic route toward 17.
Chirality DOI 10.1002/chir

704
BENTLEY ET AL.
the synthesis of 3 and 4, we obtained the 5-endo-dig cycliza-
tion product 17 in 80% yield. Several attempts to isolate 5 by
modifying the Sonogashira reaction protocol and by careful
work-up were not successful, albeit the monocyclization prod-
uct of 5 was obtained when the reaction was conducted in
THF as solvent. We therefore decided to continue the chiral-
ity sensing with ligands 3 and 4.
We were able to grow single crystals of 4 and its precur-
sors 12 and 13 by slow evaporation of concentrated chloro-
form solutions. As expected, crystallographic analysis
showed that these compounds favor a planar conformation
(Scheme 2). In accordance with the dynamic covalent di-
amine assemblies formed from the parent ligands 1 and 2
and chiral substrates via reversible condensation reactions,
we expected that the achiral ligands 3 and 4 would populate
rapidly interconverting chiral conformations upon coordina-
tion to a metal center. The reaction of these biphenols with
complex of 3 or 4 was expected to afford a tetrahedral com-
plex in which the substrate chirality would affect the chiral
bias of 3 and 4, respectively (Fig. 3).
The substrate-to-ligand chirality induction was verified by
CD analysis of several zinc complexes. We were pleased to
observe strong Cotton effects with chiral diamines even with
highly diluted samples. For example, coordination of (R,R)-
18 to the biphenolate zinc complex derived from 3 gave a
positive CD maximum at 400 nm, while the (S,S)-diamine in-
duced the opposite CD response (Fig. 4). A similar CD sig-
nal having the maximum shifted to ~360 nm was measured
using 4 as ligand. Essentially the same trend was observed
when the enantiomers of the aliphatic diamine 19 were ap-
plied in the same CD sensing experiments. Noteworthy,
the presence of excess of 18 did not give an appreciable dif-
ference in the CD response.
We found that chirality sensing of amino alcohols with the
biphenolate zinc complex prepared in situ with ligand 3 con-
sistently gives a negative CD signal for the (R)-enantiomers,
while all (S)-amino alcohols produce a positive CD amplitude
at the same wavelength (Fig. 5 and Supporting Information).
When ligand 4 was employed in the same sensing experi-
ments we generally observed CD effects at a lower wave-
length, as discussed above for the diamine sensing. In
addition, a consistently positive CD response was measured
for (R)-amino alcohols, while the sensing of the (S)-enantio-
mers gave a negative CD maximum.
diethylzinc is quantitative and yields
a stable albeit
stereodynamic biphenolate zinc complex that exhibits two re-
maining coordination sites for substrate binding. Addition of
diamine or amino alcohol substrates 18–25 to the zinc
We investigated solvent effects on the CD sensing of di-
amine 18 using the zinc biphenolate complex derived from li-
gand 3 (Fig. 6). Comparison of the chiroptical responses
measured in tetrahydrofuran, diethyl ether, chloroform, hex-
anes, and acetonitrile under otherwise the same conditions
shows that the strongest CD readouts were observed in tetra-
hydrofuran and acetonitrile. A reduced chiroptical response
was observed in diethyl ether due to the low solubility of
Fig. 3. Structures of the chiral diamines and amino alcohols used.
Fig. 4. Top: CD Spectra obtained with the biphenolate zinc complex obtained from 3 and Et2Zn upon addition of one equivalent of either (R,R)-18 (solid curve)
or the (S,S)-enantiomer of 18 (dashed curve) at 1.25 x 10-4 M in THF. The corresponding CD response with (R,R)-19 (solid curve) or the (S,S)-enantiomer of 19
(dashed curve) are shown on the right. Bottom: CD Spectra obtained using 4, Et2Zn, and the (R,R)-enantiomers of either 18 or 19 (solid curves) or the (S,S)-en-
antiomers of 18 or 19 (dashed curves) at 1.25 x 10-4 M in diethyl ether.
Chirality DOI 10.1002/chir

CHIRALITY SENSING WITH STEREODYNAMIC ZINC
705
Fig. 5. Top: CD Spectra obtained with the biphenolate zinc complex obtained from 3 and Et2Zn upon addition of two equivalents of either (R)-21 (solid curve) or
the (S)-enantiomer of 21 (dashed curve) at 1.25 x 10-4 M in THF. The corresponding CD response with two equivalents of (R)-22 (solid curve) or the (S)-enantio-
mer of 22 (dashed curve) are shown on the right. Bottom: CD Spectra obtained using 4, Et2Zn, and the (R)-enantiomers of either 21 or 22 (solid curves), or the (S,
S)-enantiomers of 21 or 22 (dashed curves) at 1.25 x 10-4 M in diethyl ether.
the zinc complex. No measurable chiroptical inductions oc-
curred in the other solvents, which in the case of hexane
can be attributed to lack of solubility.
Having established the preferred sensing conditions and
consistent correlations between the sign of the induced CD
effects and the absolute configuration of the diamines and
amino alcohols, we continued to evaluate the possibility of
ee determination using our stereodynamic zinc probe 3. Fol-
lowing our standard protocol, we first measured the CD am-
plitude of the biphenolate zinc complex upon addition of
scalemic mixtures of diamine 18 ranging from +100 to –100
%ee. The plotting of the induced CD maximum at 404 nm ver-
sus the sample %ee showed a linear chiroptical sensor re-
sponse (Fig. 7). We note that zinc biphenolates can form
mixtures of homochiral and heterochiral dimeric complexes,
which are likely to give nonlinear CD responses to the sub-
strate ee.44 The linear relationship between the induced chi-
roptical signal and the enantiomeric sample composition
shown in Figure 7 indicates that in this case a monomeric
[3-Zn-18] complex predominates. We assumed that forma-
tion of oligomeric species might be possible and investigated
this using ligand 4. In fact, mass spectrometric analysis of the
zinc complex prepared from 4, 18, and diethyl zinc suggests
that [4-Zn-18] and [4-Zn-18]2 can coexist (Fig. 8).
Fig. 6. Effects of solvents on the CD response of the biphenolate complex
obtained from 3 and Et2Zn using one equivalent of (R,R)-18 as the sensing
substrate. THF (solid curve), acetonitrile (long dashes), diethyl ether (short
dashes).
Fig. 7. Left: CD Spectra of the Zn complex obtained with 3, Et2Zn, and scalemic samples of one equivalent of 18. Right: Linear relationship between the CD
amplitudes measured at 404 nm and the enantiomeric excess of 18.
Chirality DOI 10.1002/chir

706
BENTLEY ET AL.
Fig. 8. Mass spectrometric analysis of the in situ complex formation with 4, 18 and diethyl zinc.
TABLE 1. Comparison of the actual absolute configuration and
enantiomeric compositions of four samples of diamine 18 and
the chirality sensing results obtained using 3 as CD reporter
ACKNOWLEDGMENT
This material is based on work supported by the NSF under
CHE-1213019.
Actual composition of 18
CD sensing results
SUPPORTING INFORMATION
Sample
Abs. Config.
% ee
Abs. Config.
% ee
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
1
2
3
4
(1R,2R)
(1S,2S)
(1S,2S)
(1S,2S)
12.0
27.0
68.0
89.0
(1R,2R)
(1S,2S)
(1S,2S)
(1S,2S)
10.2
24.3
65.5
84.1
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