Stereodynamics of metal-ligand assembly: What lies beneath the 'simple' spectral signatures of c2-symmetric chiral chelates

Article abstract of DOI:10.1002/chem.201204216

A series of C2-symmetric chiral tetra-dentate ligands were prepared by using [4,5]- or [5,6]-pinenefused 2,2'-bipyridyl units that are supported across a rigid arylene-ethynylene backbone. These conformationally pre-organised chelates support stable 1:1 metal complexes, which were fully characterised by UV/Vis, fluorescence, circular dichroism (CD), and 1H NMR spectroscopy. A careful inspection of the exciton-coupled circular dichroism (ECCD) and 1H NMR spectra of the reaction mixture in solution, however, revealed the evolution and decay of intermediate species en route to the final 1:1 metal-ligand adduct. Consistent with this model, mass spectrometric analysis revealed the presence of multiple metal complexes in solution at high ligand-to-metal ratios, which were essentially unobservable by UV/Vis or fluorescence spectroscopic techniques. Comparative studies with a bi-dentate model system have fully established the functional role of the p-conjugated ligand skeleton that dramatically enhances the thermodynamic stability of the 1:1 complex. In addition to serving as a useful spectroscopic handle to understand the otherwise 'invisible' solution dynamics of this metal-ligand assembly process, temperature-dependent changes in the proton resonances associated with the chiral ligands allowed us to determine the activation barrier (DG) for the chirality switching between the thermodynamically stable but kinetically labile (P)- and (M)-stereoisomers.

Full text of DOI:10.1002/chem.201204216

DOI: 10.1002/chem.201204216
Stereodynamics of Metal–Ligand Assembly: What Lies Beneath the
“Simple” Spectral Signatures of C2-Symmetric Chiral Chelates
Jiyoung Jung,[a, b] Junyong Jo,[a] Moitree Laskar,[a] and Dongwhan Lee*[a]
Abstract:
A
series of C2-symmetric
termediate species en route to the final
1:1 metal–ligand adduct. Consistent
with this model, mass spectrometric
analysis revealed the presence of multi-
ple metal complexes in solution at high
ligand-to-metal ratios, which were es-
sentially unobservable by UV/Vis or
fluorescence spectroscopic techniques.
Comparative studies with a bi-dentate
model system have fully established
the functional role of the p-conjugated
ligand skeleton that dramatically en-
hances the thermodynamic stability of
the 1:1 complex. In addition to serving
as a useful spectroscopic handle to un-
derstand the otherwise “invisible” solu-
tion dynamics of this metal–ligand as-
sembly process, temperature-dependent
changes in the proton resonances asso-
ciated with the chiral ligands allowed
us to determine the activation barrier
(DG°) for the chirality switching be-
tween the thermodynamically stable
but kinetically labile (P)- and (M)-ster-
eoisomers.
chiral tetra-dentate ligands were pre-
pared by using [4,5]- or [5,6]-pinene-
fused 2,2’-bipyridyl units that are sup-
ported across a rigid arylene–ethyny-
lene backbone. These conformationally
pre-organised chelates support stable
1:1 metal complexes, which were fully
characterised by UV/Vis, fluorescence,
1
circular dichroism (CD), and H NMR
spectroscopy. A careful inspection of
the exciton-coupled circular dichroism
(ECCD) and 1H NMR spectra of the
reaction mixture in solution, however,
revealed the evolution and decay of in-
Keywords: C2 symmetry · circular
dichroism · ligands · self-assembly ·
switching
Introduction
ACHTUNGTRENmNUGN ers emerge from multiple chiral components that converge
at a single metal centre. For helicates that are comprised of
two or more intertwined coaxial ligand chains running along
the long axis to support multiple metal centres, the configu-
rational stability of the metal-centred chirality is enhanced
further.[7] In addition to the energetic preference induced by
close van der Waals contacts and other non-covalent interac-
tions, molecular symmetry plays a critical role in these com-
plexes by significantly reducing the number of potentially
competing structural isomers and simplifying the reaction
coordinates.
Helical arrangements of self-folded objects are frequently
encountered in biological systems, with prominent examples
including DNA and protein secondary structures. Transition-
metal complexes and clusters having topologically related
axial chirality have been prepared and studied extensively
to develop and refine intuitive models of stereoinduction
(that is, chirality transfer from the ligand to the metal)[1]
that have been widely applied and tested across various dis-
ciplines including: 1) supramolecular self-assembly,[2]
2) asymmetric catalysis,[3,4] and 3) recognition of small-mole-
cule inhibitors and probes by enzymes[5] and nucleic acids.[6]
In the assembly of such chiral complexes, binding to the
metal centre enhances intramolecular contacts between
chiral ligand fragments that are brought into close proximi-
ty, thereby “amplifying” the effects of asymmetric steric
bias. As a consequence, only a finite number of stereoiso-
Within this context, multi-dentate ligands having C2 point-
group symmetry have been studied extensively as building
blocks for the assembly of chiral metal complexes and clus-
ꢀ
ters. As shown in Figure 1, restricted rotation around the C
C bond connecting two ortho-substituted aromatic ring sys-
tems results in two mirror-image isomers. Prominent exam-
ples of such chiral biaryl systems include BINOL[8] and
BINAP (Figure 1),[9] which continue to inspire the design,
synthesis, and applications of a large family of structural an-
alogues.[10] In addition to functioning as chiral bi-dentate li-
gands to support various oxophilic catalytic sites, the parent
BINOL system can also serve as a chiral hydrogen-bond
donor. An increasing number of Brønsted acids, such as A–
E (Figure 1), have also been built upon the axially chiral bi-
naphthyl platform to catalyse a wide range of asymmetric
organic transformations involving carbon–carbon or carbon–
heteroatom bond formation.[11]
[a] Dr. J. Jung, J. Jo, M. Laskar, Prof. Dr. D. Lee
Department of Chemistry, Indiana University
800 East Kirkwood Avenue, Bloomington, Indiana 47405 (USA)
Fax : (+)812-855-8300
E-mail: dongwhan@indiana.edu
[b] Dr. J. Jung
Current Address: Department of Chemistry
Slippery Rock University, 1 Morrow Way
Slippery Rock, Pennsylvania 16057 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204216; it contains experi-
mental details and supporting data.
In the binaphthyl-based C2-symmetric systems shown in
Figure 1, the conformational stability (and therefore practi-
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FULL PAPER
Scheme 1. Dynamic interconversion between the right-handed (P)-J and
left-handed (M)-J conformation of a C2-symmetric structure J. With achi-
ral “arm” units rotating around the horizontal “axle”, (P)-J and (M)-J
are mirror images of each other, and therefore isoenergetic. Installation
of chiral auxiliaries in the arm units should establish a diastereomeric re-
lationship between (P)-J and (M)-J, the energy difference between which
drives asymmetric folding toward one helical screw sense, either P or M,
over the other.
The low energy barrier of the bond rotation around the
arylene–ethynylene unit,[15] such as those in F–I, offers addi-
tional advantages for the operation of these molecular
“hinges”, “tweezers”, and other conceptually related molec-
ular switches and devices.[16] As shown in Scheme 1, the
system can readily sample either right-handed, (P)-J, or left-
handed, (M)-J, helical conformation through the “unfolded”
intermediate J.
Research elsewhere has demonstrated that the conforma-
tional switching shown in Scheme 1 can be driven by: 1) p–p
stacking interactions (for F and H),[12] 2) hydrogen-bonding
interactions (for G),[13] or 3) reversible formation of covalent
bonds with exogenously added amines (for I).[14] Notably,
condensation reactions between the dialdehyde I and chiral
diamines afford macrocyclic Schiff bases, in which a well-de-
fined spatial relationship between the two arylene–ethyny-
lene-based local chromophores gives rise to strong exciton-
coupled circular dichroism (ECCD) signals.[17–24]
Figure 1. Chemical structures of axially chiral ligands BINOL and
BINAP, and structurally related C2-symmetric chiral Brønsted acids A–E
derived from the conformationally well-defined binaphthyl platform. For
each molecule, only the (R)-enantiomer is shown.
cal utility) of the two atropisomers derives from the direct
aryl–aryl linkage and the presence of bulky ortho substitu-
ents, which collectively result in a prohibitively high energy
ꢀ
barrier for their structural interconversion through C C
bond rotation under ambient conditions. In contrast, the C2-
symmetric systems F–I shown in Figure 2[12–14] have ethyny-
lene-based spacer units between the two ortho-substituted
aryl fragments to allow for relatively unrestricted rotation
around the “axle” that is perpendicular to the C2 axis.
We have recently shown that a topologically related C2-
symmetric arylene–ethynylene platform can support two
2,2’-bipyridyl (bipy) ligands that converge at a single metal
centre to define a cis-divacant octahedral coordination envi-
ronment.[25,26] Depending on the absolute spatial relationship
between the two p-extended bipy units with respect to the
bis(ethynylphenyl) linker, both the right-handed (P)- and
left-handed (M)-isomers were obtained for the structurally
characterised [Zn(L1)ACTHNUTRGNE(UGN OTf)2] complex (Figure 3). The re-
stricted swivelling motion of the hinged bipy units that
“flap” around the rigid “axle” of L1 is reminiscent of a
Dutch door (Scheme 2).
As shown in Figure 3, the octahedral complex [Zn(L1)-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ric bias, however, the mirror-image (P)- and (M)-isomers
are isoenergetic, which precludes potential applications of
L1 and its metal complexes for chiral recognition or asym-
metric chemical transformation.
Figure 2. Chemical structures of C2-symmetric arylene–ethynylene sys-
tems F–I as “p-extended” analogues of the biaryl systems shown in
Figure 1.
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D. Lee et al.
Figure 3. Chemical structure of L1 and capped-stick representations of
the solid-state structure of its metal complex [Zn(L1)ACTHNUGTRENUNG(OTf)2] constructed
from the X-ray coordinates.[25] For the two terminally bound triflate li-
gands, only the oxygen donor atoms are shown for clarity.
Scheme 2. A cartoon-type representation of the Dutch-door-like swivel-
ling motions of L1 having two bipy ligand units as “movable panels” to
bind the metal ion (shown as a dark sphere) to form a discrete 1:1
complex.
Figure 4. Chemical structures of the chiral N4 ligands.
As a logical first step to preferentially stabilise one helical
sense over the other (Scheme 1), we thus decided to prepare
chiral derivatives L2R, L2S, L3S and L4R (Figure 4) of the
parent system L1 (Figure 3). With these newly synthesised
C2-symmetric ligands, we investigated their metallation to
form chiral complexes. A combination of UV/Vis, fluores-
which is summarised in Scheme 3 and detailed in the follow-
ing sections.
Background: Ligand design for helical folding: The solid-
state structures of the achiral complex [Zn(L1)ACHTUNGTRENNUNG(OTf)2]
(Figure 3) served as a good starting point for our design of
chiral tetra-dentate ligands to support an asymmetric coordi-
nation environment. As shown in Figure 3, the pseudo-C2-
symmetric arrangement of L1 around the metal centre
brings the two bipy groups into close proximity. We thus
reasoned that annulation of either the [4,5]- or [5,6]-position
of the bipy ligand with appropriate chiral auxiliaries would
introduce sufficient steric bias to energetically differentiate
the (P)- and (M)-isomers of the resulting metal complex
(Scheme 3). For this objective, we have chosen derivatives
of CHIRAGEN ligands (Scheme 4) pioneered by von Ze-
lewsky and others.[1d,27–31]
1
cence, circular dichroism (CD), and H NMR spectroscopic
studies have allowed for a detailed understanding of: 1) the
reaction pathways leading to metal–ligand assembly, and
2) the thermodynamic stability and kinetic lability of the re-
sulting chiral metal complexes. Specifically, we have con-
firmed experimentally that a simple 1:1 binding model
(Scheme 2), suggested by previous Job plot analysis on L1,
is an oversimplification of the actual equilibrium in solu-
tion.[25] The reaction coordinates actually involve multiple
oligomeric species co-existing at low metal-to-ligand ratios,
which converge to a discrete and stable 1:1 adduct with an
increased loading of metal ions. In addition, low-tempera-
By using chiral pinene precursors,[27] these [4,5]- or [5,6]-
annulated bipy derivatives[28] can readily be prepared in
enantiomerically pure forms.[1d,29–31] The absolute configura-
tion of the stereogenic centres residing in the pinene portion
of the CHIRAGEN compound translates directly to the ab-
1
ture H NMR studies revealed the presence of both (P)- and
(M)-isomers in solution, which interconvert through a low
energy barrier (DG°). A coherent mechanistic picture thus
emerges for the stereodynamics of this metal–ligand system,
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Stereodynamics of Metal–Ligand Assembly
FULL PAPER
Results and Discussion
Ligand synthesis: A highly modular synthetic route that we
have developed for the synthesis of L1[25] was readily adapt-
ed to prepare L2R, L2S, L3S and L4R (Figure 4) in a straight-
forward manner. The key building blocks shown in
Scheme 4 were prepared through a common Krçhnke pyri-
dinium intermediate 1,[32] which was subjected to condensa-
tion reactions with either (ꢀ)- or (+)-myrtenal[33] in the
presence of ammonium acetate to furnish pineno-[4,5]-fused
bipy 2R and 2S, respectively, as an enantiomeric pair.[34] An-
other [4,5]-fused bipy derivative 3S was prepared from (ꢀ)-
isomyrtenal by using the same synthetic protocol.[35,36] To in-
vestigate the effects of annulation closer to the nitrogen
donor atom on the asymmetric steric bias upon metallation,
the pineno-[5,6]-fused bipy 4R was synthesised by using
(+)-pinocarvone, which was prepared by oxidation of (ꢀ)-a-
pinene.[37]
Scheme 3. Concentration-dependent dynamics of the metal complexes
supported by the chiral Dutch-door-type ligand in solution.
As outlined in Scheme 5, consecutive Sonogashira–Hagi-
hara cross-coupling reactions transformed 2R into 10, which
was subjected to oxidative
homo-coupling conditions to
afford L2R. By taking similar
synthetic routes, compounds
L2S, L3S and L4R were prepared
and fully characterised (Sche-
AHCTUNGTERGmNNUN es S1–S3 in the Supporting In-
formation). As anticipated, the
optical rotations of L2R ([a]D23 =
ꢀ648 (c=0.980, CHCl3) and
L2S ([a]2D3 = +648 (c=0.985,
CHCl3)) at T=238C were of
the same magnitude but oppo-
site in sign, which fully estab-
lishes their enantiomeric stereo-
chemical relationship.
1H NMR spectroscopy of metal-
lation reactions: With the series
of chiral ligands L2R, L2S, L3S
and L4R newly prepared, we
first investigated their metalla-
tion in solution by 1H NMR
spectroscopy. Upon treatment
with ZnACTHUNGRTENUNG(OTf)2 (2 equiv) at T=
298 K, the 1H NMR spectrum
of L2R in CDCl3 displayed sig-
Scheme 4. Synthesis of bromo-substituted chiral bipyridines.
nificant shifts in the proton res-
onances associated with the
bipy portion of the molecule
solute configuration of the their metal complexes, which
have been studied extensively in supramolecular chemistry
and asymmetric catalysis.[1d,29–31] We thus anticipated that
structural modification of the parent system L1 with pinene-
annulated bipy units 2–4 (Scheme 4) should allow us to con-
trol the absolute stereochemistry of helical folding upon
metallation.
(Figure 5). Under these conditions, the resonances from the
bis(ethynylphenyl) “axle” part of the molecule remained
largely unchanged. The H NMR spectral pattern of the re-
1
action mixture is essentially identical to that of the inde-
pendently prepared and characterised (see below) mononu-
clear zinc(II) complex [Zn
formation of a discrete 1:1 complex. Similar observations
(L2R)
ACHUTGTNRENNGU HCATUNGTERNN(UGN OTf)2], thus confirming the
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D. Lee et al.
were made for L3S (Figure S1
in the Supporting Information).
In contrast to the well-re-
solved spectral changes ob-
served for the metallation of
L2R and L3S built with pineno-
[4,5]-fused bipy motifs, structur-
ally related L4R having pineno-
[5,6]-fused bipy units showed
broad
and
resonances
complicated
upon
1H NMR
treatment with zinc(II) (Fig-
ure S2 in the Supporting Infor-
mation). Such
a convoluted
spectral pattern implies the
evolution of multiple species in
solution with different metal-
to-ligand
stoichiometry
(Scheme 3; see below). With
annulation at the [5,6]-positions
imposing significant steric con-
straints upon metallation of the
bipy units, the formation of dis-
crete 1:1 metal complexes
might be unfavourable for L4R.
Scheme 5. Synthetic route to L2R.
Metallation-induced helical folding: To obtain structural evi-
dence for the metallation-induced structural folding of L2R,
its zinc(II) complex was prepared on a preparatory scale.
An equimolar mixture of the free ligand and ZnACTHNUGTRENUNG(OTf)2 in a
CH2Cl2–MeCN mixed solvent system furnished the antici-
pated 1:1 adduct, which was isolated and fully characterised
(see the Supporting Information). As shown in Figure 5, the
1H NMR spectra of the free ligand L2R and the correspond-
ing zinc(II) complex [ZnACHTNUGRTNENUG CAHTUNGTRNE(NUGN OTf)2] are well-resolved. Al-
(L2R)
though the simple spectral patterns are consistent with the
molecular C2 symmetry of the ligand, which is retained both
for the free ligand and in the metal complex, the resonances
from the H3’ (Dd=0.18 ppm), H4’ (Dd=0.31 ppm) and H3
(Dd=0.10 ppm) protons showed downfield shifts due to the
de-shielding effects of the nearby metal centre (see Figure 6
for the proton numbering scheme). On the other hand, the
resonances corresponding to the protons H6 and H6’ of the
bipy unit, which are at the ortho-positions to the nitrogen
donor atoms, undergo upfield shifts (Dd=0.25 ppm for H6;
d=0.10 ppm for H6’) as a result of the compensating shield-
ing effects from the neighbouring bipy p system.[38] Such
spectral shifts confirmed that, upon metallation, the bipy
units of L2R undergo a conformational change from transoid
to cisoid.[39,40]
Additional structural information for metallated L2R was
obtained by two-dimensional (2D) ROESY 1H NMR spec-
troscopy on the isolated [ZnACHTNUGTRENNUG ACHTUGNTREN(NUGN OTf)2] complex (Figure 6
(L2R)
and Figure S3 in the Supporting Information). Although
conformational analysis by using NOE was rather challeng-
ing for [Zn
correlations between its remotely located pinene moieties
Figure 5. Partial 1H NMR spectra of a) the isolated [Zn(L2R)
ACTHNUTRGNENUG ACHTUNGTREN(NUGN OTf)2] com-
(L2R)
ACHUTNGTRENNUG HCATUNGTRENN(GUN OTf)2], which showed rather weak NOE
plex, b) L2R treated with two equivalents of Zn
ligand L2R in CDCl3 at T=298 K.
AHCTUNGRTEG(NUNN OTf)2 and c) the free
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Stereodynamics of Metal–Ligand Assembly
FULL PAPER
Figure 7. a) UV/Vis and b) fluorescence (lexc =320 nm) spectra of L2R
(a) 10; b) 1.0 mm) in MeCN titrated with Zn
2 equiv) at T=298 K.
ACHTUNGRTEN(NNUG OTf)2 (a) 0–2.5; b) 0–
Figure 6. The 2D ROESY spectrum of [ZnACHTUNGRTENNUG CAHUTNGTREN(NUGN OTf)2] in CD2Cl2 at T=
(L2R)
298 K, and the numbering scheme of the ligand used for the assignment
of the resonances. Due to broadening, H7A and H7B appear as a singlet.
concomitant development of a longer-wavelength transition
at lmax =330 nm. A similar ratiometric change was also ob-
served in the fluorescence spectra (Figure 7b), with a large
enhancement in the emission at lmax =465 nm (from the
metal complex) and a correlated decrease in the emission at
lmax =390 nm (from the free ligand) across an isoemissive
point at l=415 nm. A Job plot analysis (Figure S5 in the
Supporting Information) established a 1:1 binding stoichi-
and suffered from significant broadening of the diastereo-
topic H7 protons, several cross-peaks that were observed
provided compelling evidence for the helical spatial arrange-
ment of the ligand (Figure 6).
Compared with the ROESY spectrum of the free ligand
L2R (Figure S4 in the Supporting Information), the promi-
nent H3–H3’ and H3–H4’ cross-peaks of the metallation
product (Figure 6 and Figure S3 in the Supporting Informa-
tion) confirm twisting of the bipy fragment from a transoid
to a cisoid conformation upon metal binding. As for the
pinene portion of the molecule, the metal-free L2R showed
only an H7–H8 cross-peak, whereas the corresponding
1
ometry, which is consistent with the results from H NMR
spectroscopy shown in Figures 5 and 6. Similar results were
obtained for the titration of L3S with zinc(II) (Figure S6 in
the Supporting Information).
Taken together, the presence of the chiral directing
groups in the pineno-[4,5]-fused ligands L2R or L3S does not
detrimentally affect the inherent metal-binding ability and
the characteristic optical response of the p-conjugated bis-
zinc(II) complex, [Zn
NOE correlation peaks for H7–H11A and H7–H13. Most
importantly, the H10–H12 cross-peak of [Zn (OTf)2] es-
(L2R)
(L2R)
ACHUTGTNRENNGU HCATUNGTERN(NUGN OTf)2], displayed additional
AHCTUNGTREG(NNNU bipy) unit of the “unsubstituted” parent ligand system
A
U
L1.[25] In contrast, the ligand L4R, having the pinene motif
fused at the [5,6]-position of the bipy unit, produced a com-
plicated Job plot (Figure S7 in the Supporting Information).
Apparently, the presence of the rigid ring-fused substituents
pointing towards the primary coordination sphere prevents
the formation of discrete metal complexes of well-defined
stoichiometry. This postulation was also supported by the
tablishes a close spatial relationship between the two pinene
moieties, which can only be established by coordination to
the metal ion as shown in Figure 3.
UV/Vis and fluorescence spectroscopic signatures of metal-
1
lation: The H NMR spectroscopic studies described in the
1
previous section have provided compelling experimental evi-
dence that the pinene-fused chiral ligand L2R can bind
zinc(II) to form a discrete 1:1 complex, in a manner similar
to the behaviour of its achiral and less bulky analogue L1.[25]
We thus decided to investigate metal binding in solution by
UV/Vis (Figure 7a) and fluorescence (Figure 7b) spectro-
scopic titration.
complicated H NMR spectral patterns observed for the re-
action mixture of L4R and Zn
ACTHNUTRGENUN(G OTf)2 (Figure S2 in the Sup-
porting Information).
CD spectroscopic studies of chirality transfer: As a metal
complex with a closed-shell d10 system, the UV/Vis spectrum
of [ZnACHTNUTRGENNGU ACHTUNGTREN(NGUN OTf)2] is dominated by the p–p* electronic
(L2R)
As shown in Figure 7a, metallation of L2R resulted in a
gradual decrease in the absorption at lmax =315 nm with
transitions, which are only slightly shifted from those of the
free ligand L2R and are therefore not very informative (Fig-
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D. Lee et al.
ure 7a and Figure S8 in the Supporting Information). In
contrast, the CD spectrum of [Zn (OTf)2] displays
(L2R)
tion), which collectively established the 1:1 stoichiometry
between the metal and the ligand. This chemically intuitive
assembly model, however, was challenged by the CD titra-
tion studies described below.
G
ACHTUNGTRENNUNG
sharply defined bisignate features, which is distinctly differ-
ent from that of the free ligand L2R (Figure 8).
To study the evolution of helicity as a function of metal
loading, we first monitored the CD intensity of L2R at l=
330 nm upon addition of zinc(II). As anticipated, the CD
band displayed an increase in its intensity with increasing
Zn2+ concentration. In contrast to our anticipated result,
however, the signal intensity reached its maximum value at
only 0.7 equivalents of metal with respect to the ligand (Fig-
ure 9a). After this point, a gradual decrease in the CD in-
Figure 8. CD spectra of i) isolated [Zn
ii) L2R treated with Zn(OTf)2 (1.5 equiv; black solid line), and iii) L2S
(L2R)
ACHUTGTNRENNGU HCATUNGTERNN(UGN OTf)2] (black dotted line),
ACHTUNGTRENNUNG
treated with ZnACHTUNGTRENNUNG(OTf)2 (1.5 equiv; grey solid line), compared with that of
iv) free ligand L2R (grey dashed line) in MeCN at T=298 K.
As shown in Figure 8, the CD spectrum of [ZnACTHNUTRGNEUNG
(L2R)-
ACHTUNGTRENNUNG(OTf)2], either: 1) isolated and re-dissolved in solution
(black dotted line), or 2) generated in situ by mixing the
metal salt and the ligand in solution (black solid line), dis-
plays a negative couplet (shaded in grey) across l=340 nm.
The enantiomeric metal complex [Zn
ed in situ by treating the ligand L2S with Zn
an essentially superimposable UV/Vis spectrum to that of
[Zn (OTf)2], but produces a mirror-image ECCD spec-
(L2R)
(L2S)
ACHUTGTNRENNUG CAHTUNGTRENNUNG
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
Figure 9. CD spectra of L2R (10 mm in MeCN; T=298 K) measured after
trum with a positive couplet (Figure 8; grey solid line). A
direct correlation is thus established between the R versus S
point chirality residing at the pinene-fused bipy portion of
the ligand and the ECCD signal observed upon metal bind-
ing. This empirical relationship is generally applicable for
other transition-metal ions including iron(II), copper(II), co-
balt(II), nickel(II), cadmium(II) and mercury(II) (Figure S9
in the Supporting Information), whereas their fluorescence-
response profile showed significant metal-dependent varia-
tions (Figure S10 in the Supporting Information).
addition of ZnACHTNUGTRENUNG(OTf)2: a) 0–0.7 and b) 0.7–1.5 equivalents. c) A plot of
De330 nm (that is, the change in the intensity of the Cotton effect at l=
330 nm) versus the amount of zinc(II) (in equiv).
tensity was observed (Figure 9b). Beyond one equivalent of
Zn2+, the signal remained invariant (Figure 9c), implying
that the chemical equilibrium between the metal and ligand
has been fully established.
A similar phenomenon was observed for another pineno-
[4,5]-fused ligand L3S (Figure S11 in the Supporting Infor-
mation), suggesting that this rather peculiar behaviour is not
an experimental artefact. This observation rather suggests
the involvement of intermediate species in the conversion of
the free ligand into the discrete 1:1 metal complex. It should
be noted that such a stepwise process was not observable by
titration using either UV/Vis (Figure 7a) or fluorescence
(Figure 7b) spectroscopy, neither showing apparent accumu-
lation of intermediates.
Convoluted reaction pathways of metal–ligand assembly:
With appropriate installation of chiral chromophores, CD
spectroscopy can provide useful structural information for
complicated dynamic processes in solution that are difficult
to probe otherwise. Our UV/Vis and fluorescence spectro-
scopic titration studies on L2R (Figure 7) have revealed sys-
tematic spectral shifts and correlated changes in signal in-
tensities upon metallation. These observations are consistent
with the simple 1:1 binding model involving two chromogen-
ic/fluorogenic species, that is, free and metallated ligands
(Scheme 2). This interpretation was further supported by
the Job plot analysis (Figure S5 in the Supporting Informa-
We thus re-visited the equilibrium in solution by using
1H NMR spectroscopy to probe the nature of the CD-active
species that are not the final assembly product [Zn
(OTf)2]. As shown in Figure 10, a sample of L2R in CDCl3
treated intentionally with substoichiometric amount
(0.5 equiv) of Zn(OTf)2 revealed highly broadened and com-
ACHTUNGTRENNUNG
(L2R)-
AHCTUNGTRENNUNG
1
tion) and H NMR (both 1D and 2D) spectroscopic studies
a
(Figures 5 and 6, and Figure S3 in the Supporting Informa-
ACHTUNGTRENNUNG
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Stereodynamics of Metal–Ligand Assembly
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Figure 10. Partial 1H NMR spectra of L2R (10 mm in CDCl3; T=298 K)
obtained after addition of ZnACHTUNTRGNEUNG(OTf)2: a) 2.0, b) 0.5 and c) 0 equivalents.
plicated spectral patterns (Figure 10b), which are different
Figure 11. a) CD and b) UV/Vis spectra of a 2:1 mixture of L2R (10 mm)
from those found for the free ligand L2R (Figure 10c) or the
and Zn
ACHTUNGRTEN(NNUG OTf)2 in MeCN prior to (dotted lines) and after (solid lines) ad-
isolated metal complex [Zn
ther addition of Zn(OTf)2, however, significantly simplified
the spectrum, which eventually became identical to that of
[Zn (OTf)2] (Figures 5a and 10a).
(L2R)
(L2R)
ACHUTGTNRENUNG HCATUNTGERN(NUGN OTf)2] (Figure 5a). Fur-
dition of an excess (5000 equiv) of pyridine at T=298 K. Shown for com-
parison are the c) CD and d) UV/Vis spectra of [Zn
tained under similar reaction conditions.
(L2R)
ACHUTGTNERNNUG ACHTUNGTREN(NUGN OTf)2] ob-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Such metal-ion-concentration-dependent changes in the
1H NMR spectra and the eventual formation of the discrete
1:1 complex with increasing amount of metal ions imply the
evolution and decay of multiple adducts of different metal-
to-ligand stoichiometry. In support of this notion, MALDI
and ESI mass spectrometric analysis of the reaction mixture
prepared with 0.5 equivalents of zinc(II) (as described in
Figure 10b), revealed the existence of the 1:2 and 1:3 ad-
sity shown in Figure 11a cannot be a consequence of loss of
the bipy ligand from the metal centre. Rather, this behav-
iour reflects the exchange of one type of bipy ligand with
another in the interconversion of various [ZnACTHNUTRGNEUNG
(L2R)n]2+ spe-
cies, which is indistinguishable by UV/Vis spectroscopy (Fig-
ure 11b) but readily discernible by CD spectroscopy (Fig-
ure 11a). Evidently, such ligand-exchange processes are re-
peated until the thermodynamically most stable 1:1 adduct
dominates the population in solution.
ducts, that is, [ZnACHTUNGTRENNUNG ACHUTNGTRENNUGN
(L2R)2]2+ and [Zn(L2R)3]2+, in addition to
the anticipated 1:1 adduct and the free ligand (Figure S12 in
the Supporting Information).
Independent experimental evidence for this interpretation
was provided by H NMR spectroscopic studies, which are
1
shown in Figure S13 in the Supporting Information. Upon
treatment with [D5]pyridine (2500 equiv), the complicated
Thermodynamically driven ligand exchange: The observa-
tion of slowly exchanging intermediates derived from
zinc(II) and L2R (Figure 10 and Figure S12 in the Supporting
Information) prompted us to investigate their interconver-
sion in solution. We postulated that exogenously added ni-
trogen donor ligands, such as pyridine, should accelerate
ligand exchange (either in an associative or dissociative
mechanism) between the initially formed adducts, and facili-
tate the entropically driven transformation of the various
1H NMR spectrum of L2R +Zn
ACTHNUTRGNEUNG(OTf)2 (0.5 equiv) trans-
formed into to a simpler pattern comprised of two inde-
pendent sets of proton resonances associated with the free
ligand L2R and 1:1 adduct [Zn(L2R)
ACTHNUTRGENNGU HCATUNTGERN(NUGN OTf)2]; no other species
were spectroscopically detected. A coherent mechanistic
model that is consistent with all our experimental observa-
tions is summarised in Scheme 3.
[Zn
adduct [Zn
(5000 equiv) of pyridine to a 2:1 mixture of L2R and Zn-
(OTf)2 elicited an immediate decrease in the intensity of the
ECCD couplet (Figure 11a). Under similar conditions, the
CD spectrum of [Zn (OTf)2] showed negligible
(L2R)
change (Figure 11c). These findings confirm that, once
formed, the 1:1 complex retains its structural integrity
against ligand exchange with pyridine.
For both samples that were treated with pyridine and
studied by CD spectroscopy (Figure 11a, c), the correspond-
ing UV/Vis spectra remained essentially invariant (Fig-
ure 11b, d). Therefore, the decrease in the CD signal inten-
A
Metallation of “unlinked” chiral bipyridyl ligand models:
One important consideration behind the design of our chiral
ligands (Figure 4) was the use of a rigid C2-symmetric ary-
lene–ethynylene scaffold to link two chiral bipy units to re-
strict their conformational freedom (Schemes 1 and 2).
Unlike self-assembly in solution from freely diffusing chiral
components, restricted swivelling motions around the rigid
aryl–aryl and/or aryl–ethynyl linkers should allow the bipy
ligand to take a limited number of trajectories in space that
converge to the metal centre to form a stable 1:1 adduct as
the final adduct.
A
.
ACHTUNGTRENNUNG
A
E
a
How would the system behave in the absence of such con-
formational restriction? More specifically, does the arylene–
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5163

D. Lee et al.
ethynylene linker between the two chiral bipy units indeed
play an important functional role, or is it structural “over-
engineering” that does not offer any practical advantage
over simpler bidentate systems in the chiral-selection pro-
establishing a direct correlation between the ligand-based
point chirality and the axial chirality created at the metal
centre resulting from asymmetric inter-ligand steric bias.
Consistent with this empirical trend, similar negative ECCD
couplets are observed for both the tetra-dentate ligand L2R
(Figure 9) and the bi-dentate ligand 6 (Figure 12) upon met-
allation.[45]
ACHTUNGTRENNUNGcess? To address this important scientific question, we car-
ried out metallation studies on the simple chiral bipy deriva-
tive 6 (Scheme 5) as a bidentate “site model” for L2R.
Although the CD spectrum of the free ligand 6 in MeCN
is essentially featureless, a large negative couplet quickly
Unlike the behaviour of L2R under similar conditions
(Figure 9), however, the intensity of the ECCD signal from
emerged upon addition of Zn
N
6+ZnACTHNGUETRN(UNG OTf)2 continues to increase with up to approximately
similar to the behaviour of [Zn
the fully assembled tetra-dentate ligand (Figure 9a).
G
E
two equivalents of zinc(II) (Figure 12a), but starts to de-
crease beyond this point. In the presence of a large excess
(>6 equiv) of ZnACTHNUTRGNEUNG(OTf)2, only a very weak exciton couplet
was observed (Figure 12b). This metal-concentration-de-
pendent spectral change suggests the initial formation of the
bisACHTNUTGRNEUNG
(chelate) adduct [Zn(6)2]2+ (Figure 13), and its subse-
quent disassembly into the 1:1 adduct [Zn(6)]2+ with in-
creasing metal loading. Unlike [Zn(6)2]2+, no intramolecular
exciton coupling is allowed for [Zn(6)]2+, and therefore no
strong ECCD signal was observed at high metal-to-ligand
ratios.
Figure 12. CD spectra of 6 (20 mm in MeCN; T=298 K) measured after
addition of ZnACHTUNGTRENNUNG(OTf)2: a) 0–2.0 and b) 2.0–6.0 equivalents. c) The UV/Vis
spectra obtained under identical conditions, which show continuous spec-
tral change across what appear to be isosbestic points. The negative
ECCD couplet, shaded in (a), results from the through-space interaction
between the two electric transition dipoles (designated as m1 and m2) of
the (P)-helical stereoisomer as schematically shown in (d).
A change in the sign of the CD signal (ECCD) is the sig-
nature of inter-chromophore electronic coupling. For two in-
teracting electric-transition dipoles that are configurationally
or conformationally well-defined in terms of their relative
orientations in space, the change in the sign of the Cotton
effect, that is, a negative or positive couplet, allows for a
direct assignment of the absolute screw-sense of helical
twisting.[17] Based on the ECCD model shown in Figure 12d,
the experimentally observed negative couplet corresponds
to the (P)-helix.
Previous structural studies have established that pineno-
[4,5]-fused bipy derivatives sharing the same absolute con-
figuration as 2R (Scheme 4; synthetic precursor to 6) typical-
ly support a right-handed D-isomer of (P)-helicity with a
negative ECCD couplet.[41–43] As anticipated, enantiomeric
bipy ligands analogous to 2S (Scheme 4) afford L-helicates
of (M)-helicity with a positive ECCD couplet,[42,44] thereby
Figure 13. Models of structure assembly–disassembly of the metal com-
plexes supported by bidentate 6 (bottom) and tetradentate L2R (top)
probed by metal-concentration-dependent changes in the CD signal in-
tensities plotted as DDe300 nm (that is, the change in the intensity of the
*
Cotton effect at l=300 nm) for 6 ( ), and DDe330 nm (that is, the change
in the intensity of the Cotton effect at l=330 nm) for L2R
(
*
) versus the
amount of zinc(II) (in equiv) added.
Consistent with this equilibrium model in solution
(Figure 13), the 1H NMR spectrum of 6 treated with one
equivalent ZnACHTNUTRGNEUNG(OTf)2 (Figure 14b) revealed the development
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Stereodynamics of Metal–Ligand Assembly
FULL PAPER
ligand maintains its structural integrity, as shown by the lack
of changes in the ECCD intensity even after addition of a
large excess of metal ions beyond the 1:1 stoichiometric
point.
Collectively, Scheme 3 and Figure 13 describe the ligand-
dependent and metal-dependent solution-state dynamics
that we have established experimentally for the chiral tetra-
and bi-dentate ligand systems, respectively. A detailed un-
derstanding of this actual assembly–disassembly process was
obtained by ECCD spectroscopy, which directly and sensi-
tively monitors changes in the spatial relationship between
the chiral chromophores constituting the metal coordination
sphere. Our comparative studies on the simple pinene-fused
bipy system 6 and its “linked” derivative L2R convincingly
demonstrated that structural pre-organisation and chelate
effects play a critical role in the thermodynamic stability of
the metal complex.
Figure 14. Partial 1H NMR spectra of 6 (10 mm) in CDCl3/CD3CN (4:1,
v/v) obtained after addition of ZnACHTNUGRTENUNG(OTf)2 at T=298 K (a) 2.0, b) 1.0 and
c) 0.5 equivalents) compared with that of the free ligand 6 shown in (d).
Configurational stability: Selection and switching of metal-
based chirality: Once formed, mono-nuclear zinc(II) com-
plexes supported by the bi-dentate ligand 6 or the tetra-den-
tate ligand L2R both display negative ECCD couplets sug-
gestive of (P)-helicity. We noted, however, that the absolute
magnitude of the change in ellipticity (DDeꢁ12mꢀ1 cmꢀ1 at
of two independent sets of proton resonances, assigned to
[Zn(6)2]2+ and [Zn(6)]2+ (Figure 13). In support of this
notion, HR-ESI mass spectrometric analysis confirmed the
presence of both [Zn(6)2]2+ and [Zn(6)]2+ species in the sol-
ution (Figures S14 and S15 in the Supporting Information).
On the other hand, samples prepared with either lower
l=330 nm) of [ZnACHTNUTRGENNUG ACHTUGNTERN(NUGN OTf)2] is significantly lower than
(L2R)
that (DDeꢁ27mꢀ1 cmꢀ1 at l=300 nm) of its bis
ACHTUNGTREN(NUNG chelate) ana-
(0.5 equiv of Zn
N
logue [Zn(6)2]2+ (Figure 13). This observation raised the
possibility that a fast interconversion between the (P)- and
(M)-isomer [Eq. (1)] might occur at room temperature if the
steric bias imposed by the pinene-fused bipy motifs is not
sufficiently large to differentiate them energetically.
Zn(OTf)2; Figure 14a) loadings of the metal ion furnished
ACHTUNGTRENNUNG
1
simple H NMR spectral patterns dominated by the 1:2 and
1:1 complexes, [Zn(6)2]2+ and [Zn(6)]2+, respectively.
Additional experimental support for our assembly–disas-
sembly model shown in Figure 13 came from independent
CD titration studies of 6 by using ZnCl2 instead of Zn-
ACHTUNGTRENNUNG(OTf)2. We anticipated that the strongly coordinating chlo-
ACHTUNGTRENNUNGride ligand would prevent formation of the bisACHTUNTGREN(NUGN chelate) com-
plexes such as [Zn(6)2]2+. Indeed, the CD spectra obtained
for the reaction mixture 6+ZnCl2 in MeCN (Figure S16 in
the Supporting Information) did not show the strong ECCD
couplet observed for 6+ZnACTHNUTRGNE(UNG OTf)2 (Figure 12). Even with an
increased amount of ZnCl2, only a weak CD signal was ob-
served, which eventually became identical to that of 6 in the
Unlike previously reported chiral bipy complexes of
1
presence of a large excess of Zn
N
zinc(II),[38,39] the H NMR spectra of [Zn
A
R
Although the CD spectroscopy provided significant in-
sights into the complicated dynamics in solutions involving
multiple metal-containing species, the corresponding UV/
Vis spectra (Figure 12c and Figure S16 in the Supporting In-
formation) show a correlated increase and decrease in the
chromophore population across what could be considered to
be isosbestic points. These UV/Vis data thus wrongly impli-
cate simple interconversion between two equilibrating spe-
cies, which is far from what is actually occurring in solution
(Figure 13). Most importantly, the metal-concentration-de-
pendent structural assembly and disassembly observed for
the simple bidentate ligand system 6 (Figures 12 and 13)
ures 5 and 6) and [ZnACTHNGURTENNUG ACHTNUGTRENNUNG
(L3S)
porting Information) showed only one set of proton reso-
nances at T=298 K. Upon lowering the temperature, how-
ever, the spectrum revealed the presence of the two diaste-
AHCTUNGTRENNUNG
slowly to allow for the determination of the coalescence
temperature (Tc) and the activation barrier of isomerisation
[DG° for Eq. (1)] at Tc by using Equations (2) and (3), in
which kc is the exchange rate; Dn is the difference in reso-
nance frequency; k is the Boltzmann constant; Tc is the coa-
lescence temperature; h is the Planck constant; and R is the
gas constant.
stands in stark contrast to the stability of [Zn
exposed to excess Zn(OTf)2 (Figures 9 and 13). Once
formed, the mononuclear complex of the “linked bis(bipy)”
(L2R)
ACHUTGTNRENNUG HCATUNGTERN(NUGN OTf)2]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
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5165

D. Lee et al.
eters (10–16 kcalmolꢀ1) for the isomerisation between (P)-
and (M)-isomers, proceeding through non-dissociative mech-
anisms.[48]
Conclusion
With appropriate ligand design, metal complexes of kineti-
cally labile d10 systems readily undergo dynamic assembly–
disassembly processes in solution to expedite the evolution
of a single dominant structure. Through repetitive self-cor-
rection processes involving facile formation and cleavage of
metal–ligand bonds, energetically less stable earlier adducts
quickly converge to the thermodynamically most stable final
product, in a manner reminiscent of macromolecular folding
through the disassembly and reassembly of multiple non-co-
valent bonds. Our studies on the zinc(II) complexes of
chiral tetra-dentate ligands have revealed the “not-so-
simple” stereodynamic processes of metal–ligand assembly
and helicity switching, which are disguised by apparently
“simple” spectral patterns.
We have shown that what appear to be straightforward
spectroscopic features obtained by UV/Vis and fluorescence
spectroscopy, which are often used as the primary diagnostic
methods to study metal–ligand assembly, could provide an
oversimplified and inaccurate picture of the actual equilibri-
um in solution. By using ECCD spectroscopy as the struc-
ture-sensitive spectroscopic tool, we have experimentally
confirmed: 1) the reaction pathways of metal–ligand assem-
bly involving multiple, slowly exchanging species; 2) the
thermodynamic stability provided by the conformationally
rigid and p-conjugated ligand skeleton; and 3) the kinetic la-
bility responsible for the P-to-M (and vice versa) helicity
switching and the mechanistic implications of the energy
barrier. Although the preferred screw sense seems to still be
dictated by the sterically less-congested conformation, the
small energetic bias and low activation barrier in the chiral
selection need to be improved in future ligand design based
on these proof-of-concept prototypes. Efforts in such direc-
tions are currently under way in our laboratory.
Figure 15. Temperature-dependent (T=213–298 K) changes in the
1H NMR spectra (in CD2Cl2) of [Zn(L2R)
(OTf)2] in the aliphatic reso-
nance region. The unresolved signals from the methyl groups belonging
to each diastereomer [Eq. (1); shaded in grey] split at <286 K (shaded in
red), which corresponds to the estimated exchange rate of kc =104 sꢀ1 at
Tc =279 K.
U
ACHTUNGTRENNUNG
pDn
p
kc ¼
kc ¼
ð2Þ
ð3Þ
2
DG°
RTc
kT
h
c eꢀ
The estimated DG° values were 14.1 and 13.7 kcalmolꢀ1
for [Zn (OTf)2] (at T=286 K) and [Zn (OTf)2] (at
(L2R) (L3S)
A
E
N
ACHTUNGTRENNUNG
T=279 K), respectively, in CD2Cl2. The similar activation
parameters obtained for these two complexes suggest that
the subtle difference in the stereochemistry of the [4,5]-
fused pineno group does not significantly influence the ener-
getics of chirality switching between the (M)- and (P)-iso-
mers [Eq. (1)]. Comparative studies on the bis
complex, [Zn(6)2A(OTf)2], generated in situ by treating 6
with 0.5 equivalents of Zn
(OTf)2, provided a similar DG°
ACHTUNGTRENN(UNG chelate)
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
value of 12.7 kcalmolꢀ1 (Figure S18 in the Supporting Infor-
mation). Evidently, steric constraints imposed by the rigid
and C2-symmetric arylene–ethynylene backbone do not sig-
nificantly influence the inherent activation barrier for the
helicity switching of the metal complexes supported by this
particular chiral bipy ligand.
Acknowledgements
This work was supported by the National Science Foundation (CHE
0547251) and the U.S. Army Research Office (W911NF-07-1-0533).
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Received: November 26, 2012
Published online: February 28, 2013
5168
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