Probing the tolerance of cucurbit[7]uril inclusion complexes to small structural changes in the guest

Article abstract of DOI:10.1039/c2ob26834e

The binding properties of the cucurbit[7]uril host with three structurally related ferrocene-containing guests, ferrocenyltrimethylammonium, ferrocenylmethyltrimethylammonium and ferrocenylethyltrimethylammonium, have been investigated using ¹H

Full text of DOI:10.1039/c2ob26834e

Organic &
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Probing the tolerance of cucurbit[7]uril inclusion
complexes to small structural changes in the guest†
Song Yi,a Wei Li,a Daniel Nieto,b Isabel Cuadradob and Angel E. Kaifer*a
Cite this: Org. Biomol. Chem., 2013, 11,
287
The binding properties of the cucurbit[7]uril host with three structurally related ferrocene-containing
guests, ferrocenyltrimethylammonium, ferrocenylmethyltrimethylammonium and ferrocenylethyltri-
methylammonium, have been investigated using 1H NMR spectroscopy, mass spectrometry, voltammetry
and computational methods. The experimental and computational data indicate that the stability of the
cucurbit[7]uril inclusion complexes is relatively insensitive to the number of methylenes connecting the
trimethylammonium and the ferrocenyl groups, although some of their properties are affected in signifi-
cant ways.
Received 19th September 2012,
Accepted 9th November 2012
DOI: 10.1039/c2ob26834e
www.rsc.org/obc
While the dicationic CB7·Fc2+ inclusion complex exhibits
extraordinarily high thermodynamic stability, CB7 complexes
Introduction
The cucurbit[n]uril1–5 (CBn) hosts are attracting increasing of monocationic ferrocenyl guests are also very stable. For
attention because, among other reasons, they can reach extre- instance, we have investigated in some detail the properties of
mely high binding affinities with suitable guests. An excellent the CB7 complex formed by the ferrocenylmethyltrimethylam-
example is the inclusion complex formed between cucurbit[7]- monium guest (Fc1+), which shows a K value of 4 × 1012 M−1
uril (CB7) and the dicationic guest 1,1′-bis(trimethylamonio- in pure water at 25 °C.11 This complex is also stabilized by the
methyl)ferrocene (Fc2+), whose association equilibrium con- same combination of ion–dipole interactions and hydrophobic
stant (K) is 3 × 1015 M−1 in pure water at 25 °C,6 a value similar forces. In this work, we compare the properties of the
to that measured with the well-known avidin–biotin pair. The CB7·Fc1+ complex with those of the CB7 complexes formed by
CB7·Fc2+ complex is predominantly stabilized by two noncova- two highly related ferrocenyl guests: ferrocenyltrimethylammo-
lent interactions: (1) ion–dipole forces between each of the tri- nium (Fc0+) and ferrocenylethyltrimethylammonium (Fc2+).
methylammonium groups on the guest and the carbonyl-laced The structures of the guests and the CB7 host are shown in
portals on the host, and (2) hydrophobic forces between the Fig. 1. Clearly, the only structural difference among the three
included ferrocenyl group and the inner surface of the CB7 guests investigated here is the number of methylenes on the
cavity. Furthermore, detailed thermodynamic analysis reveals
that the rather surprising lack of entropic penalty accompany-
ing the host–guest association process is a very important
factor behind the high stability of the CB7·Fc2+ complex.6 In
general terms, high stability CBn inclusion complexes appear
to assemble with relatively small entropic changes, taking
these complexes out of the commonly observed enthalpy–
entropy compensation relations that prevail in other supramo-
lecular host families.7–10
aCenter for Supramolecular Science and Department of Chemistry, University of
Miami, Coral Gables, FL 33143, USA. E-mail: akaifer@miami.edu;
Fax: +1-305-284-4571; Tel: +1-305-284-3468
bDepartamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma
de Madrid, Cantoblanco 29049 Madrid, Spain. E-mail: isabel.cuadrado@uam.es;
Fax: +34 91 497 4833; Tel: +34 91 497 4843
†Electronic supplementary information (ESI) available: Synthetic details and
additional spectroscopic data mentioned in the text. See DOI:
10.1039/c2ob26834e
Fig. 1 Structures of the host and guests used in this work.
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linker between the ferrocenyl and the trimethylammonium corresponding chloride salts, which were used in the electro-
groups. We are interested in understanding the effects that chemical experiments. The structure of the resulting ferroce-
1
this rather minor structural variation on the guest could have nyl-containing cations was confirmed using H and 13C NMR
on the stability and properties of the corresponding CB7 spectroscopies and high resolution ESI-TOF mass
inclusion complexes. We describe here the results of this spectrometry.
investigation.
Equipment
Voltammetric experiments were recorded with a Bioanalytical
Systems BAS-100W electrochemical workstation. A single-com-
Experimental section
Synthesis
partment electrochemical glass cell was fitted with a glassy
carbon working electrode (0.07 cm2), platinum auxiliary and
The preparation of Fc1+ and CB7 has been reported before.
Ag/AgCl reference electrodes. The solution was thoroughly
purged with high-purity nitrogen before the experiments and
Ferrocenylamine [FcNH2, Fc = (C5H5)Fe(η5-C5H4)] was prepared
in several reaction steps by adapting literature procedures,12,13
maintained under an inert nitrogen atmosphere during the
starting with the selective monometalation of ferrocene with
voltammetric scans. The working electrode was polished with
t-BuLi. Subsequently, bromoferrocene (prepared by reaction of
0.050 μm alumina powder on a felt surface using pure water as
lithioferrocene and bromine12), was converted into the key
intermediate N-ferrocenylphthalimide, by treatment with
the lubricant.
phthalimide and cuprous oxide, under Gabriel synthesis con-
ditions. Hydrazinolysis of this intermediate with hydrazine
hydrate in ethanol, gives pure aminoferrocene FcNH2, which
was isolated as a yellow solid in 82% yield. 2-(Ferrocenyl)ethyl-
amine (Fc(CH2)2NH2), was prepared in two steps from N,N,N-
trimethylferrocenylmethylamonium iodide as a commercial
starting material, by adapting literature procedures.14,15 First,
FcCH2N(CH3)3I was reacted with potassium cyanide, resulting
in 1-cyanomethylferrrocene, which was isolated as a yellow
crystalline solid in 63% yield. Cyanomethylferrocene was then
converted into 2-(ferrocenyl)ethylamine by reduction with
LiAlH4 followed by treatment with aqueous sodium hydroxide.
After aqueous workup and distillation in vacuo, the primary
amine Fc(CH2)2NH2 was obtained as an amber-brown oil, in
66% yield (Scheme 1).
Computations
All energy minimizations were done using DFT methods
(B3LYP/3-21G*).16 The complexes were initially assembled
using the reported crystal structure of CB717 and the previously
minimized structure of the guest. The guest was always placed
partially included inside the host before energy-minimization
of the host–guest complex was allowed to proceed. The
inclusion complex converged to the same energy-minimized
structure, regardless of the initial relative positions of host and
guest.
Results
The initial assessment of the binding interactions between any
of the cationic ferrocenyl guests and the CB7 host is best
carried out with 1H NMR spectroscopy. For instance, Fig. 2
shows the spectra for guest Fc0+ in D2O solution in the
absence and in the presence of 0.5 and 1.0 equiv. of the
CB7 host. Clearly all the protons on the guest experience
Both amine compounds were exhaustively methylated with
iodomethane in chloroform–methanol (1 : 3 v/v) to yield Fc0+
and Fc2+, respectively as their iodide salts, which were recrys-
tallized from methanol–chloroform–diethyl ether (1 : 1 : 20
v/v/v). Exposure of an aqueous solution of either salt to an
Amberlite anion exchange resin in its chloride form led to the
Scheme 1 Synthesis of the ferrocenyl amines. Conditions: (a) t-BuLi, −10 °C,
THF/n-hexane, (b) Br2, −80 °C, THF, (c) HN(CO)2C6H6, Cu2O, Py, reflux, (d)
N2H4·H2O, EtOH, reflux, (e) KCN, H2O, reflux, (f) LiAlH4, Et2O, reflux.
Fig. 2 1H NMR spectra (500 MHz, D2O) of 1.0 mM Fc0+ in (A) the absence and
the presence of (B) 0.5 equiv. and (C) 1.0 equiv. of CB7.
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significant upfield shifts upon complexation with CB7, which the relative amounts (molar fractions) of CB7-bound and
is consistent with guest inclusion in the host cavity. Notice unbound Ad-Py+, which led to the determination of the corres-
that in the presence of 0.5 equiv. of CB7 the ferrocenyl protons ponding molar fractions for the ferrocenyl guest. From these
of free Fc0+ are not observed, but the methyl protons of the values, the corresponding equilibrium concentrations were
free guest show a broad resonance at 3.4 ppm in slow exchange computed and the K value for CB7 complexation of the ferroce-
with that corresponding to the CB7-bound guest. Once 1.0 nyl guest was extracted from the already reported K value for
equiv. of host is added, the proton resonances of the free guest complexation of Ad-Py+.19 Using this procedure we extracted K
completely disappear and only the proton resonances for the values of 3.6 × 1010 M−1 and 7.3 × 1010 M−1 for Fc0+ and Fc2+,
CB7-bound Fc0+ are observed. Further additions of CB7 do not respectively, in 50 mM sodium acetate pH 4.5 solution. The
result in any further spectroscopic changes. The quantitative corresponding value for Fc1+ was previously reported as 3.3 ×
formation of the CB7·Fc0+ complex at the millimolar concen- 1011 M−1 in the same aqueous medium.19 These K values indi-
trations of host and guest used in these experiments suggest cate that the structure of Fc1+ is optimal for inclusion com-
that the association equilibrium constant for this complex is plexation with CB7. Obviously, removal of the single
high. Notice also that the CB7 protons at 5.65 ppm, corres- methylene connecting the ferrocenyl and trimethylammonium
ponding to the methylene protons facing the inside of the CB7 groups leads to a 10-fold decrease in the K value for complexa-
cavity show a more complex pattern than the doublet expected tion of Fc0+. Similarly, the addition of an extra methylene to
in free CB7. The splitting of this resonance in two doublets the linker (guest Fc2+) also causes a small decrease in the
reflects the loss of the equatorial symmetry on the host, a stability of the complex.
result of the inclusion of a guest that renders both cavity
portals different, since only one of them can interact directly often detected in the gas phase using mass spectrometric tech-
with the trimethylammonium group.
niques,20,21 which are thus extremely useful to confirm the for-
Highly stable inclusion complexes in aqueous solution are
The same kind of data set obtained with Fc2+ shows rela- mation of supramolecular complexes and to verify their
tively similar results regarding the quantitative formation of stoichiometries. We used high-resolution mass spectrometry
the CB7·Fc2+ complex (Fig. S1†). However, the methyl protons [electrospray (ESI) ionization with time-of-flight (TOF) mass
now experience a downfield shift upon addition of CB7, while analysis/detection] to confirm the formation of complexes
the two different methylene signals show upfield shifts of vari- between CB7 and all three guests. Fig. 3 shows the ESI mass
able magnitude. Of course, the NMR spectroscopic data for the spectrum obtained with an aqueous solution containing equal
formation of CB7·Fc1+ have been previously reported by concentrations of Fc0+ and CB7. The main peak in the spec-
us.11,18 Table 1 collects relevant spectroscopic data contrasting trum, at m/z ratio of 714.7081, corresponds to the doubly
the binding behavior of the three guests with CB7.
charged species Na+·CB7·Fc0+. The formation of this species
In all three guests the ferrocene protons show negative com- suggests that inclusion complexation between Fc0+ and CB7
plexation-induced shifts. This finding clearly indicates that the leaves one of the host portals free to interact with a sodium
ferrocene residue is positioned inside the cavity of the ion. A similar result was obtained with guest Fc1+ leading to
CB7 host in all three complexes. In contrast to this, the the observation of the doubly charged species Na+·CB7·Fc1+ at
measured Δδ values for the methyl protons go from negative an m/z value of 721.7164 (Fig. S2†). In marked contrast to
in Fc0+ to positive in Fc2+, which suggests that, as the distance these results, mass spectrometric experiments with Fc2+ led to
between the trimethylammonium and ferrocene groups
increases, the three equivalent methyl groups on the positively
charged nitrogen move away from the CB7 cavity.
In order to estimate the association equilibrium constants
between CB7 and the guests Fc0+ and Fc2+, we carried out
binding competition experiments19 for a limited amount of
the host between each of these guests and a reference guest
(N-adamantyl-pyridinium, Ad-Py+). After allowing the system to
reach equilibrium, NMR spectroscopy was used to calculate
Table 1 Selected 1H NMR complexation-induced shifts (in ppm) corresponding
to the interaction of CB7 with guests Fc0+–Fc2+ in D2O at 25 °C
Guest
Δδ(α)a
Δδ(β)a
Δδ(γ)a
Δδ(CH3)
Fc0+
Fc1+
Fc2+
−0.96
−0.86
−0.74
−0.94
−0.82
−0.93
−0.67
−0.72
−0.72
−0.23
0.02
0.13
Fig. 3 High-resolution ESI-TOF mass spectrum obtained with an aqueous solu-
tion containing equal concentrations of Fc0+ and CB7. The insert shows the
experimental (top) and calculated (bottom) isotopic distributions corresponding
to the main peak.
a The Δδ values were calculated as δcomplex − δfree guest. The symbols α,
β and γ correspond to the three different types of ferrocene protons as
labelled in the figure.
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Fig. 5 Cyclic voltammetric behavior on glassy carbon (0.07 cm2) of a 1.0 mM
solution of Fc2+ also containing 0.1 M NaCl in the absence (continuous line)
and in the presence of 0.5 equiv. (discontinuous) and 1.0 equiv. (dotted) of CB7.
Fig. 4 Cyclic voltammetric behavior on glassy carbon (0.07 cm2) of a 1.0 mM
solution of Fc0+ also containing 0.1 M NaCl in the absence (continuous line)
and in the presence of 0.5 equiv. (discontinuous) and 1.0 equiv. (dotted) of CB7.
Scan rate: 0.1 V s−1
.
Scan rate: 0.1 V s−1
.
attachment of the trimethylammonium group diminishes the
electronic density in the ferrocene center, making its one-elec-
tron oxidation thermodynamically harder. Addition of 0.5
equiv. of CB7 to the Fc2+ solution does not lead to the obser-
vation of a new set of waves, but simply to a shift of the orig-
inal redox couple to more positive values (Fig. 5). This shift
continues as more CB7 is added, until it reaches saturation
when 1.0 equiv. of host is present in the solution. Clearly, the
K value for the formation of the CB7·Fc2+ complex is high
enough to allow for quantitative formation of the complex at
the millimolar concentrations of host and guest used in these
experiments. However, the observation of a single, shifting set
of waves in this case, instead of the two sets of waves observed
with Fc0+ or Fc1+ in the presence of less than 1.0 equiv. of
host, is due to the smaller difference between the E1/2 values
for oxidation of the complex and the free guest.23 The proxi-
mity (small potential difference) of the two sets of waves
makes its voltammetric resolution impossible and is the key
reason behind the observation of a single redox couple.
the clear observation of the doubly charged species CB7·Fc22+
(m/z = 717.2293, Fig. S3†), which lacks the sodium ion attached
to one of the host portals. In this species the second positive
charge must be centered on the ferrocene group, reflecting
the relative ease of oxidation of this ferrocenyl derivative
(vide infra).
Ferrocene derivatives exhibit very fast and reversible one-
electron oxidation.22 Therefore, the anodic electrochemical be-
havior of the guests Fc0+–Fc2+ and their CB7 complexes is
dominated by the presence of the reversible wave correspond-
ing to the ferrocenium/ferrocene redox couple. For instance,
Fig. 4 shows the cyclic voltammetric behavior recorded with
Fc0+, which shows a set of waves corresponding to the Fc02+/
Fc0+ redox couple centered at a half-wave potential (E1/2) of
0.632 V vs. Ag/AgCl. Upon addition of 0.5 equiv. of CB7, a new
set of waves is observed at a E1/2 value of 0.797 V vs. Ag/AgCl.
The new set of waves is assigned to the one-electron oxidation
of the CB7·Fc0+ complex. Once the added concentration of
CB7 reaches a full equivalent, the original set of waves dis-
appears and the second set of waves reaches full development,
consistent with the quantitative conversion of the free guest to
its CB7 complex. The considerable shift of the E1/2 value
caused by the complexation with CB7 is consistent with the
encapsulation of the ferrocenyl residue inside the CB7 cavity,
which hampers the solvation of the oxidized and positively
charged form of the ferrocenyl residue owing to the hydro-
phobic character of the host cavity. This electrochemical be-
havior is similar to that previously reported for Fc1+,11,18
although the CB7-induced shift of the half-wave potential is
larger with Fc0+.
Table 2 summarizes the parameters obtained from the vol-
tammetric experiments for all three guests and their CB7
inclusion complexes. Several trends are clear from the data in
Table 2. First, the diffusion coefficient of each CB7 complex is
lower than that for the free guest. This finding is an expected
result of the larger effective volume of the complexes relative
Table 2 Electrochemical parameters obtained from the voltammetric exper-
iments in 0.1 M NaCl solution at 25 °C
Compound
Do a (cm2 s−1
)
E1/2 b (V)
k
o c (cm s−1
)
Fc0+
6.9 × 10−6
3.6 × 10−6
5.2 × 10−6
2.6 × 10−6
5.3 × 10−6
2.9 × 10−6
0.632
0.797
0.423
0.541
0.259
0.303
Fast
0.011 0.003
Fast
0.019 0.003
Fast
0.022 0.008
However, the anodic electrochemical behavior of Fc2+
(Fig. 5) offers contrasting features. First, the half-wave poten-
tial for the one-electron oxidation of the free guest is 0.259 V
vs. Ag/AgCl, and the oxidation of the ferrocenyl residue in this
compound is thermodynamically easier than in Fc0+. The
reason for this difference relates to the presence in Fc2+ of two
methylenes, connecting the electron withdrawing trimethylam-
monium group and the ferrocene center. In Fc0+ the direct
CB7·Fc0+
Fc1+
CB7·Fc1+
Fc2+
CB7·Fc2+
a Diffusion coefficients measured using a disk ultramicroelectrode.
Error margin <5%. b Half-wave potentials measured against Ag/AgCl
reference. Error margin: 0.004 V. c Heterogeneous rates of electron
transfer determined using Nicholson’s method.24
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to the free ferrocene derivatives. The thermodynamic ease of thermodynamic measurements with several ferrocene deriva-
oxidation of the free guests decreases in the order Fc2+ > Fc1+ tives suggest that hydrophobic interactions between the ferro-
> Fc0+, due to the decreasing attenuation of the electron with- cenyl residue and the inner cavity of CB7 are more important
drawal effect exerted by the trimethylammonium group as than ion–dipole interactions between the tetramethyl-
methylenes are removed from the tether. The same order is ammonium group and the carbonyl oxygens on the host
maintained with the inclusion complexes. The CB7-induced portal.6,10 A key motivation behind this work was to test this
shift in the half-wave potential (ΔE1/2 = E1/2,complex − E1/2,free
)
hypothesis by varying the distance between the tetramethyl-
follows the opposite trend and is largest for Fc0+ (165 mV) and ammonium and ferrocene residues on the guest and forcing
lowest for Fc2+ (44 mV). Finally, the voltammetric behavior of the complex to favor one of the two interactions, presumably
the complexes was found to be in the quasi-reversible regime, the strongest one. We should note here that the factors
while that of the free guests is fully reversible (fast electron affecting the thermodynamic stability of the inclusion com-
transfer). The standard rate constants (ko) for heterogeneous plexes formed between alkylammonium ions and the smaller
electron transfer for the latter were thus too fast to measure in CB6 host were investigated by Mock and Shih more than two
these cyclic voltammetric experiments. However, the ko values decades ago.28
were measurable for the complexes and show a slight increas-
The equilibrium association constants determined here
ing trend in going from the CB7·Fc0+ to the CB7·Fc2+ complex. suggest that the presence of a single methylene between
Our attempts to crystallize these complexes failed to the tetramethylammonium and ferrocenyl groups leads to the
produce single crystals suitable for X-ray diffraction analysis. optimum development of attractive interactions in the
This problem was not unexpected given the usual difficulties inclusion complex. As a result the measured K values are in
involved in obtaining single crystals of CB7 complexes.25 (Typi- the order CB7·Fc1+ > CB7·Fc2+ > CB7·Fc0+. Nonetheless, the
cally, CB6 and/or CB8 complexes are much easier to crystal- overall variation of the K values is moderate, suggesting that
lize.) In order to gain some information on the structures of the complex can adjust without pronounced stability losses to
the complexes, we resorted to DFT computational methods. In small variations in the distance between the trimethylammo-
our experience, computational methods tend to produce very nium and ferrocene residues. The NMR spectroscopic data
reliable structures for cucurbituril complexes. In those cases in (Table 1) show a very interesting trend in these complexes. The
which we have obtained both the X-ray crystal structure and complexation-induced shift of the guest methyl protons goes
the energy-minimized computational structure, both sets of from −0.23 ppm (CB7 induces an upfield shift) in Fc0+ to
data have shown very good agreement.6,26,27 Therefore, we run +0.13 ppm in Fc2+. The upfield (negative) shift in the former
energy minimizations for the three CB7 complexes surveyed case indicates that the trimethylammonium group is very close
here. The resulting structures are shown in Fig. 6.
to the plane defined by the carbonyl oxygens on the host
Inspection of these structures reveals that as the number of portal, whereas the positive value in the latter case reveals that
methylenes in the tether between the trimethylammonium the trimethylammonium group is further removed from the
group and the ferrocene center increases the complex becomes portal entrance. Guest Fc1+ represents a compromise between
less compact, with larger fractional volumes of the guest pro- both extremes and the trimethylammonium group adopts an
truding out of the cavity through both host portals. The effect intermediate position. This finding is in excellent agreement
of a single methylene addition is relatively subtle, but the with the energy-minimized structures obtained computation-
structural differences between the two extreme cases, CB7·Fc0+ ally (Fig. 6).
and CB7·Fc2+, are clear. A noticeable result from guest
The mass spectrometric data also show an important
elongation is that the ferrocenyl group is not completely encap- difference for the CB7·Fc2+ complex. The CB7·Fc0+ and
sulated in the CB7 cavity and is partially exposed to the solu- CB7·Fc1+ complexes are clearly detected as Na+ adducts, with a
tion in the CB7·Fc2+ complex.
total +2 charge. This finding indicates that both complexes
possess a region that can easily interact with Na+. Based on the
known affinity of CBn carbonyl rims with metal cations,29,30
we postulate that the binding site for Na+ in both complexes
is the cavity portal not occupied by the trimethylammonium
group. In marked contrast to this, CB7·Fc2+ does not form a
Discussion
The high stability of the CB7·Fc1+ complex results from a com-
bination of hydrophobic and ion–dipole interactions. However,
Na+ adduct under our MS conditions, but acquires
a
second charge through oxidation. As indicated before, this is
far from surprising because CB7·Fc2+ has the lowest half-wave
potential (Table 2) for one-electron oxidation among the
three complexes. The presence of a positive charge on the
ferrocenyl center is thus expected to prevent the binding of
any cations to the cavity portal in the immediate vicinity.
Alternatively, another factor that may influence the lack of
bound Na+ ion to the second host portal in this complex, is
the fact that the ferrocenyl group partially protrudes through
Fig. 6 Energy-minimized structures (B3LYP/3-21G*) computed for the
CB7·Fc0+, CB7·Fc1+ and CB7·Fc2+ complexes (from left to right).
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the portal (see Fig. 6), thus hindering the possible binding of
the sodium ion.
Conclusions
The electrochemical behavior of the complexes is also very Overall, the experimental and computational data obtained in
instructive. The most interesting parameter is the already this work show that small variations on the length of the
defined CB7-induced shift of the half-wave potential, which tether (0–2 methylenes) connecting the trimethylammonium
decreases steadily from CB7·Fc0+ to CB7·Fc2+. These values and ferrocenyl groups in these guests lead to subtle, but well
can be interpreted as a measure of the increased thermo- defined changes in the structures of the CB7 complexes, which
dynamic hindrance for the one-electron oxidation of the ferro- translate into significant differences in their voltammetric be-
cenyl residue due to its encapsulation inside the host. havior. The overall thermodynamic stability of the three CB7
While both CB7·Fc0+ and CB7·Fc1+ show values that are complexes studied here is however relatively resilient to the
within the range expected for ferrocenyl groups deeply number of methylenes in the linker.
inserted in the CB7 cavity (ΔE1/2 > 100 mV), the ΔE1/2
The authors are grateful to the National Science Foundation
value measured for CB7·Fc2+ is clearly smaller (44 mV). This for the generous support of this work (to AEK, CHE-0848637)
reflects that the microenvironment of the ferrocenyl residue in and to the Spanish Ministerio de Ciencia e Innovación
this complex is much closer to that experienced by the (CTQ2009-09125-BQU). We also acknowledge the NSF for an
unbound guest as compared to the other two complexes. instrumentation grant (CHE-0946858) that allowed the acqui-
Therefore, we conclude that the ferrocenyl center is partially sition of the high-resolution ESI-TOF mass spectrometer used
exposed to the surrounding aqueous solution, which is in in this work.
excellent agreement with the computational results (Fig. 6).
Overall, the measured CB7-induced ΔE1/2 values in these com-
plexes are extremely sensitive to the location of the ferrocenyl
residue within the CB7 cavity and its relative exposure to water
Notes and references
molecules. This finding illustrates very nicely that electro-
chemical techniques can be very useful to detect small struc-
tural variations.
1 J. W. Lee, S. Samal, N. Selvapalam, H.-J. Kim and K. Kim,
Acc. Chem. Res., 2003, 36, 621.
2 J. Lagona, P. Mukhopadhyay, S. Chakrabarti and L. Isaacs,
Angew. Chem., Int. Ed., 2005, 44, 4844.
3 K. Kim, N. Selvapalam, Y. H. Ko, K. M. Park, D. Kim and
J. Kim, Chem. Soc. Rev., 2007, 36, 267.
4 L. Isaacs, Chem. Commun., 2009, 619.
The standard rate constants for heterogeneous electron
transfer measured here seem to be in agreement with these
conclusions, as they show a slight trend to increase according
to the order CB7·Fc0+ < CB7·Fc1+ < CB7·Fc2+. This trend is in
agreement with expectations based on the relative level of
shielding and insulation from the electrode surface31 that is
imposed on the ferrocenyl groups by their various levels of
encapsulation inside the CB7 host.
It is instructive to analyze the DFT computational data in
further detail. We measured the distance between the posi-
tively charged ammonium nitrogen and the plane defined by
the carbonyl oxygen on the nearest host portal in the struc-
tures of the energy-minimized complexes (Fig. S4†). The
measured values are 0.39, 0.73 and 0.85 Å for CB7·Fc0+,
CB7·Fc1+ and CB7·Fc2+, respectively. We also measured the
corresponding distances between the iron(II) ion in the ferro-
5 E. Masson, X. Ling, R. Joseph, L. Kyeremeh-Mensah and
X. Lu, RSC Adv., 2012, 2, 1213.
6 M. V. Rekharsky, T. Mori, C. Yang, Y. H. Ko, N. Selvapalam,
H. Kim, D. Sobransingh, A. E. Kaifer, S. Liu, L. Isaacs,
W. Chen, S. Moghaddam, M. K. Gilson, K. Kim and
Y. Inoue, Proc. Nat. Acad. Sci. U. S. A., 2007, 104, 20737.
7 M. V. Rekharsky and Y. Inoue, J. Am. Chem. Soc., 2000, 122,
4418.
8 D. H. Williams, E. Stephens, D. P. O’Brien and M. Zhou,
Angew. Chem., Int. Ed., 2004, 43, 6596.
9 C. E. Chang and M. K. Gilson, J. Am. Chem. Soc., 2004, 126,
13156.
cene moiety and the carbonyl oxygen plane on the opposite 10 S. Moghaddam, C. Yang, M. Rekharsky, Y. H. Ko, K. Kim,
portal, finding values of 3.17, 2.33 and 1.22 Å, in the same
order as before. Clearly, both the trimethylammonium and the
Y. Inoue and M. K. Gilson, J. Am. Chem. Soc., 2011, 133,
3570.
ferrocene group experience displacements from their ideal 11 W. S. Jeon, K. Moon, S. H. Park, H. Chun, Y. H. Ko,
positions, defined by those observed in the most stable
complex (CB7·Fc1+). However, the displacements observed
with the ferrocene group are of larger magnitude than those
experienced by the trimethylammonium group. This is slightly
J. Y. Lee, E. S. Lee, S. Samal, N. Selvapalam,
M. V. Rekharsky, V. Sindelar, D. Sobransingh, Y. Inoue,
A. E. Kaifer and K. Kim, J. Am. Chem. Soc., 2005, 127,
12984.
counterintuitive since hydrophobic forces are believed to pre- 12 B. Bildstein, M. Malaun, H. Kopacka, K. Wurst,
dominate in these complexes. On the other hand, the larger
displacements of the ferrocene group may also reflect the fact
M. Mitterbock, K. H. Ongania, G. Opromolla and
P. Zanello, Organometallics, 1999, 18, 4325.
that the hydrophobic contact surface in the host cavity is rela- 13 K. Heinze and M. Schlenker, Eur. J. Inorg. Chem., 2004,
tively large and permits larger shifts on the position of the 2974.
ferrocene residue without significant losses in the stability of 14 K. E. Gonsalves, R. W. Lenz and M. D. Rausch, Appl. Orga-
the complex.
nomet. Chem., 1987, 1, 81.
292 | Org. Biomol. Chem., 2013, 11, 287–293
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
15 D. Lednicer and C. R. Hauser, Org. Synth., 1973, 5, 578.
16 M. J. Frisch, et al., GAUSSIAN 03 (Revision D.1), Gaussian,
Inc., Wallingford, CT, 2004.
23 S. R. Miller, D. A. Gustowski, Z. H. Chen, G. W. Gokel,
L. Echegoyen and A. E. Kaifer, Anal. Chem., 1988, 60, 2021.
24 R. S. Nicholson, Anal. Chem., 1965, 37, 1351.
17 J. Kim, I.-S. Jung, S.-Y. Kim, E. Lee, J.-K. Kang, S. Sakamoto, 25 D. Bardelang, K. A. Udachin, D. M. Leek, J. C. Margeson,
K. Yamaguchi and K. Kim, J. Am. Chem. Soc., 2000, 122,
540.
G. Chan, C. I. Ratcliffe and J. A. Ripmeestert, Cryst. Growth
Des., 2011, 11, 5598.
18 L. Cui, S. Gadde, W. Li and A. E. Kaifer, Langmuir, 2009, 25, 26 V. Sindelar, M. A. Cejas, F. M. Raymo, W. Z. Chen,
13763. S. E. Parker and A. E. Kaifer, Chem.–Eur. J., 2005, 11, 7054.
19 S. Liu, C. Ruspic, P. Mukhopadhyay, S. Chakrabarti, 27 S. Yi, B. Captain, M. F. Ottaviani and A. E. Kaifer, Langmuir,
P. Y. Zavalij and L. Isaacs, J. Am. Chem. Soc., 2005, 127,
15959.
2011, 27, 5624.
28 W. L. Mock and N.-Y. Shih, J. Am. Chem. Soc., 1988, 110,
20 F. Yang and D. V. Dearden, Isr. J. Chem., 2011, 51, 551.
4706.
21 C. A. Schalley and A. Springer, Mass Spectrometry and Gas- 29 W. Ong and A. E. Kaifer, J. Org. Chem., 2004, 69, 1383.
Phase Chemistry of Non-Covalent Complexes, John Wiley & 30 H. Tang, D. Fuentealba, Y. H. Ko, N. Selvapalam, K. Kim
Sons, 2009.
and C. Bohne, J. Am. Chem. Soc., 2011, 133, 20623.
22 N. G. Connelly and W. E. Geiger, Chem. Rev., 1996, 96, 31 S. Gadde, E. K. Batchelor and A. E. Kaifer, Aust. J. Chem.,
877.
2010, 63, 184.
This journal is © The Royal Society of Chemistry 2013
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