A chiroptical molecular sensor for ferrocene

Article abstract of DOI:10.1039/c6cc05937f

A homochiral, square-shaped, D₂ symmetrical nanosized metal-linked macrocycle is able to form stable complexes with ferrocene in polar solvents, with detection achieved by means of multiple outputs (optical/chiroptical spectroscopies and cyclic voltammetry). Selective sensing using chiroptical spectroscopy in the presence of interfering analytes is demonstrated.

Full text of DOI:10.1039/c6cc05937f

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A Chiroptical Molecular Sensor for Ferrocene
Marco Agnes,a,b Andrea Nitti,a Douglas A. Vander Griend,c Daniele Dondi,a Daniele Merlia and
Dario Pasini*,a,d
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A homochiral, square-shaped, D2 symmetrical nanosized metal- supramolecular chemistry of metal-linked macrocyles,5 and in
linked macrocycle is able to form stable complexes with ferrocene selected cases demonstrated the possibility to recognize in
in polar solvents, with detection achieved by means of multiple their cavity electron-rich aromatic compounds with high
outputs
(optical/chiroptical
spectroscopies
and
cyclic specificity.6 The extension to chiral metal-linked macrocycles,
voltammetry). Selective sensing using chiroptical spectroscopy in however, has not been fully addressed.7 In this work, we
the presence of interfering analytes is demonstrated.
report the synthesis of conformationally locked metal-linked
homochiral macrocycles, and we demonstrate their ability to
function as chiroptical sensors towards suitable electron-rich
aromatic molecules such as ferrocene. The compounds are
assembled using a stable Pd2+-ethylenediamine complex as the
angular node, so that pyridine moieties which replace the two
labile cis-ligands of the Pd2+ metal centers, could form metal-
linked cyclic species instead of linear coordination polymers.
The m-pyridyl substituted BINOL-based synthon (R)-4, in which
different conformations are present as a consequence of the
rotation around the aryl-aryl bonds joining the naphthalene
and pyridyl fragments, and the p-pyridyl substituted BINOL-
Chiroptical sensors use their molecular chirality as a tool to
detect the binding of a target analyte.1 The most frequent
chiroptical sensing mechanisms are either the interaction
between a non-racemic chiral substrate and a chromophoric
probe which is silent with respect to circular dichroism (CD)
spectroscopy, or the interaction between an achiral analyte
and a chromophoric CD-active probe. The appearance or the
modulation of the CD signal, respectively, represents the
chiroptical readout.2 CD spectroscopy can offer better levels of
detection compared with optical spectroscopies and
electrochemistry-based methods, and it is frequently used in
biosensing, where high sensitivities are required.3
Atropoisomerically-chiral compounds are particularly suitable
for applications in chiroptical sensing, since the expression of
chirality is embedded into a chromophore, resulting in peculiar
CD activity.2 In this context, 1,1'-binaphthyl-2,2'-diol(BINOL)-
based probes have been previously reported to give a “spring-
like” behaviour, with an intense CD signal modulation upon
subtle changes in their conformation upon binding.2h-i Such
probes have also been incorporated into rigid macrocycles,
successfully functioning for the chiroptical detection of species
as diverse as anions, cations or C60, either in water or in
organic solvents.2f-h,4
based synthon (R)-
5 (Figure 1) were investigated. The
treatment of both difunctional ligands with cis-
(ethylenediamine)-Pd2+ nitrate salt, under thermodynamically
controlled conditions, afforded homochiral metal-containing
macrocyclic complexes (RR)-6 and (RR)-7 in high yields, after
counterion exchange of the nitrate salts with
hexafluorophosphate anions. The optimized molecular
structures of the compounds are also shown in Figure 1.
The structures of compounds (RR)-
6 and (RR)-7 were fully
confirmed and characterized by 1H, 13C and 2D NMR
spectroscopies (for full experimental details, see Supporting
Information). The 1H-NMR spectra of the metal-linked
macrocycles showed the same sets of signals of the bidentate
ligands, consistently with a change of overall symmetry of the
molecules from C2 for the ligands to D2 for the macrocycles.
The coordinating Pd2+ nuclei clearly enhance the electron-
withdrawing character of the pyridyl rings, shifting their
proton resonances to higher frequencies (Figures S1-S2).
Fujita, Stang et al., pioneered the synthetic and
a.Department of Chemistry, University of Pavia, Viale Taramelli, 10, 27100 Pavia,
Italy. Email: dario.pasini@unipv.it. Website: www.unipv.it/labt
b.Current address: Institute of Nanoscience & Nanotechnology, NCSR "Demokritos",
Terma Patr. Gregoriou & Neapoleos, Aghia Paraskevi, 15310, Attikis, Greece.
c. Department of Chemistry & Biochemistry, Calvin College, Grand Rapids, MI
49546-4403- USA.
d.INSTM Research Unit, University of Pavia.
Electronic Supplementary Information (ESI) available: overall synthesis, methods
and experimental procedures, and additional titrations studies. See
DOI: 10.1039/x0xx00000x
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Fig 1 Synthesis of metal-linked macrocycles (RR)-6 and (RR)-7, along with their optimized structure, obtained by molecular modelling. Reported
distances refer to the maximum amplitudes of the internal cavities.
MS-ESI spectrometry for both (RR)-6 and (RR)-7 confirmed that methoxy “push” substituents on the naphthyl rings. The D2
for the peak at 1704 m/z, corresponding to the molecular overall symmetry present in both metal-linked macrocyles,
cation [M-PF6]+, the experimental and calculated isotopic asset however, cancel out the local dipoles generated, giving a no
were essentially superimposable (Figure S3). This observation residual molecular dipole in both macrocycles.
rules out the possibility of a doubly charged species (which Although the cavity of (RR)-6 would just be the right fit for
would result in peak intervals of 0.5 Da), and therefore aromatic compounds, electron-rich compounds such as 1,4-
unequivocally establishes the structure of the complexes as dialkoxybenzenes, did not show any binding affinity with either
[2+2] adducts (composed of two dipyridyl ligands and two (RR)-
metal nodes, as those shown in Figure 1). Such homochiral low ferrocene showed a distinct interaction with the square-
dimensionality was not reported before in similar systems.‡
shaped macrocycle (RR)-7 in MeCN, which was initially
The molecular modelling of (RR)- and (RR)-7 highlighted the detected using UV/Vis and CD spectroscopies. Representative
different dimensions of their internal cavities (Figure 1).§ In titrations are shown in Figure 2. In the UV/Vis titration, a weak
(RR)- , the metal corners maintain a perfect square-planar but distinctive decrease of the UV/Vis shoulder band at 350
6 or, not surprisingly, (RR)-7. Pleasingly, however,
6
6
geometry and lock the conformationally-mobile pyridyl nm, upon titration of a solution of (RR)-7 at constant
moieties on the naphthyl subunits of each ligand facing concentration with increasing amounts of ferrocene, could be
internally towards each other, with a dihedral angle between clearly observed. The band at 350 nm also shifted very weakly
the two naphthyl rings of 101°. The near perfect D2 overall upon complexation towards lower energy, indicating that the
symmetry gives rise to a rectangular cavity, with a distance interactions responsible for the binding did not rely on a full,
between the BINOL units (measured between the mean of the potent - stacking interactions, with related charge transfer,
two naphthalene-naphthalene bonds) of 10.3 Å, defining the between the host and the guest. The binding isotherm (see
narrower aperture of the cavity, while the distance between inset, top Figure 2) showed saturation occurring well above 1
the two Pd2+ atoms is 15.3 Å. Compound (RR)-
7
, instead, equivalent of guest added; furthermore, the absence of an
showed
a more square-like geometry in which the isosbestic point, and the impossibility of fitting the data with
naphthalene-naphthalene bonds are 13.3 Å far from each the nonlinear equation for the 1:1 binding pointed strongly
other and the distance between the two Pd2+ atoms is 17.8 Å. towards a situation where multiple equilibria (e.g. the
The four
macrocycles have, especially in the case of the p-substituted are in place.
(RR)- “push-pull” character, owing to the metal- Variations monitored by CD spectroscopy were found to be
coordinated “pull” pyridyl, linked with -conjugation to the much more intense (Figure 2, bottom).
-conjugated panels defining the metal-linked concurrent presence of a 1:2 macrocycle: ferrocene complex)
7
, a

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fit of all UV titration data needed to include both 1:1 and 1:2
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DOI: 10.1039/C6CC05937F
macrocycle:ferrocene complex stoichiometries (Tables S1-S4).
Calculated values for the binding in pure MeCN were log K11
=
4.4 kcal mol-1 and log K12 = 2.7 kcal mol-1. Although some
changes could be observed in the distribution between the 1:1
and 1:2 complexes upon changing the solvent mixture, the
changes in the total binding energy are rather limited,
suggesting that contrasting noncovalent interactions (including
dipole-dipole interactions) are playing a role in the binding,
and that net hydrophobic and/or solvent polarity effects
cannot be considered exclusively. Modelling the data obtained
from the CD titration in MeCN confirmed the presence of both
1:1 and 1:2 host:guest complexes as well as the values for the
binding constants calculated using the UV/Vis data (Table S5).
Further confirmations about the nature and the stoichiometry
1
of the species in solution came from H NMR titrations and
1
cyclic voltammetry experiments. Best results by H NMR were
obtained by titrating a solution of ferrocene in d3-MeCN at
constant concentration with increasing amounts of macrocycle
(Figure 3 top, Figure S6-S11 in Supporting Information). Small
but measurable shifts were in this case observed not only in
the ferrocene protons resonances, but also for selected proton
resonances of the macrocycle which are the closest contacts in
the minimized model of the complex.
Fig 2 Top: UV Titration of metal-linked macrocycle (RR)-7
(2.5 x 10-5 M)
with ferrocene in MeCN at 25 °C. Inset: titration profile vs. ferrocene
added equivalents at 345 nm. Bottom: CD Titration of macrocycle (RR)-
7
(1 x 10-5 M) with ferrocene in MeCN at 25 °C. Inset: titration profile
vs. ferrocene added equivalents at 250 nm.
The exciton couplet band attributable to the
-extended
binaphthyl units, centered at 270 nm, in correspondence to
the max of the UV/Vis spectrum, shows a large modulation
upon binding, which has to be related to a variation of the
dihedral angle between the naphthyl planes of the binaphthyl
units, and therefore to a conformational rearrangement of the
macrocycle upon binding to the guest. Although the dihedral
angle variation and conformational rearrangement is marginal
(see below modelling in Figure 3), the ample change in the
exciton couple once again reinforces the “spring-like” concept
for such axially-chiral probes and it forecasts great utility in
sensing. A weak, but detectable increase in the CD band
appeared in correspondence to the UV/Vis band of the
macrocyle/ferrocene complex at ca. 350 nm, to indicate an
overall chirality of the complex as a whole. Control titrations
1
with compound (RR)-
6 were carried out under identical
Fig 3 Top: different regions of the H NMR spectra (500 MHz, CD3CN)
conditions, and revealed no changes both with UV/Vis or CD
spectroscopy (Figure S4).
showing the titration of ferrocene (2.4 mM) with increasing amounts
of compound (RR)-7. Bottom: molecular modelling of the 1:1 complex.
Further UV/Vis and CD titrations on compounds (RR)-7 were
carried out in different solvents mixtures (MeCN:H2O in
different ratios such as 100:0, 90:10, 70:30, Figure S5) to give
further insights into the binding mechanisms, especially in
terms of solvophobic interactions. In order to adequately
delineate the thermodynamic association constants and the
stoichiometry of the supramolecular complexes, the entire set
of wavelengths were modelled simultaneously using a non-
linear least-squares regression program for performing
equilibrium-restricted factor analysis.8 The model for the best
NMR shifts for the ferrocene protons could be fitted (Table S5)
with a high confidence using a 1:2 host:guest model, giving a
negligible contribution for log K11 and a value for log K12 = 4.8
kcal mol-1.§§
The optimized molecular modelling of the 1:1 complex (Figure
3, bottom) showed the guest sitting on the top of the host
rather than buried inside its molecular cavity. The distance of
closest ferrocene hydrogens from binaphthyl units is in the
range of 3-4 Å. The dihedral angle between the naphthyl
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planes of the binaphthyl units is 83°, virtually the same as that open new avenues in the design of functional organic
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DOI: 10.1039/C6CC05937F
measured for the molecular modelling of (RR)-7 alone. For the materials and sensors through supramolecular chemistry.
1:2 complex (Figure S12) two isomers were found that differ DP acknowledges support by MIUR (Programs of National
by less than 3 kcal/mol. The alignment of the main axis of both Relevant Interest PRIN grant 2009-A5Y3N9) and, in part, by
ferrocene molecules is parallel to that formed by palladium INSTM-Regione Lombardia (2010–2012 and 2013–2015). DVG
atoms. The affinity of ferrocene with (RR)-
7 could also be acknowledges support by the National Science Foundation
monitored using cyclic voltammetry in solution. Again, a shift (grant number CHE-1310402). Additionally, availability and use
in the oxidation and reduction potential of the Fc/Fc+ couple of the 500 MHz NMR instrument of NMR Lab, NCSR
could be observed, reaching a maximum of 40 mV in the "Demokritos", Greece, a member of INSTRUCT-EL, is gratefully
reduction mode when a macrocycle:ferrocene stoichiometry acknowledged.
of 1:2 is reached (Figures S13).
Encouraged by the much larger response using CD with respect
to the UV/Vis techniques in binding ferrocene, we performed
Notes and references
experiments in the presence of a potentially interfering
analyte, 2-hydroxy-4-methoxy-benzophenone, with a distinct
‡ By using an analogue to compound (R)-5 bearing ethoxy instead of
methoxy substituents in the 2,2’ positions of the BINOL skeleton, D4
symmetrical cyclic tetramers, as the only products, using Pd2+-based
corners, were obtained. See ref. 9.
absorbance band (max = 320 nm, 
= 105 M-1 cm-1), right in the
UV/Vis detection region of our complex. The titrations
reported in Figure 2 were thus repeated by adding to the host
a concentrated solution of the benzophenone as a potentially
interfering analyte. In the UV/Vis experiment, the
benzophenone absorbance adds to the decreasing band of the
complex in a disruptive manner, so that the differences
between the detection carried out with or without the
interferent are not marginal (Figure 4, left). In the case of the
CD titration, instead, the interferent is CD silent, and the
results with or without interferent are essentially
superimposable (Figure 4, right).
§ Structure optimization was performed at the semi-empirical PM3
method with force fields present in the Hyperchem package.
§§ The discrepancy between thermodynamic values obtained by UV/Vis
titration and NMR in MeCN, obtained at different concentrations, may
be rationalized by the presence of the soft counteranions, which can
play a role with their ion pairing equilibria, and bring additional variables
in such a dynamic situation. See Ref. 10 for related examples.
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Fig 4 Left: differences in the UV/Vis absorbance at 350 nm upon
3
titration of (RR)-7
(1 x10-5 M in MeCN) with ferrocene, in the absence
(filled dots) or in the presence (empty dots) of 2-hydroxy-4-methoxy-
benzophenone (7 eq vs host, 7 x 10-5 M). Right: differences in the CD
4
5
output (272 nm) upon titration of (RR)-7
(6 x 10-6 M in MeCN) with
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Rather than the host binding selectively one of multiple guests,
the competitive experiment highlights the potential of the
chiroptical readout when other readout techniques (UV/vis
absorbance in our case) are hampered by the presence of an
interfering analyte.
In conclusion, we have presented the first example of host-
guest chemistry related to ferrocene11 in which the detection
is chiroptical. The metal-linked macrocycle is formed in high
yields and with a geometry capable of size selective, strong
binding of ferrocene. Given the complementarity of the CD
and UV/Vis response, our molecular sensor has potential in the
the detection of ferrocene in complex analytical matrices. In
the light of the continuing importance and use of ferrocene
and its derivatives in materials science,12 our discovery may
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11 For recent examples of macrocyclic receptors for ferrocene, see: J. J.
Henkelis, A. K. Blackburn, E. J. Dale, N. A. Vermeulen, M.S. Nassar
and J. F. Stoddart, J. Am. Chem. Soc., 2015, 137, 13252−13255.
12 X. Wang, G. Guerin, H. Wang, Y. Wang, I. Manners and M. A. Winnik,
Science, 2007, 317, 644-647.
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A chiral molecular sensor is used to recognize ferrocene, with the
chiroptical readout used selectively in the presence of competing
analytes.
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