Supramolecular Arrangement of Molybdenum Carbonyl Metallosurfactants with CO-Releasing Properties

Article abstract of DOI:10.1021/acs.organomet.5b00917

Two families of molybdenum carbonyl metallosurfactants, Mo(CO)₅L and Mo(CO)₄L₂, were synthesized using the functionalized phosphines Ph₂P(CH₂)_nSO₃Na (n = 2, 6, 10) and characterized by the usual spectroscopic and spectrometric methods. The study of the supramolecular arrangements of these compounds in aqueous medium has been performed by surface tension, fluorescence, dynamic light scattering, cryo-TEM, and small-angle X-ray scattering. All data point to the formation of medium and large vesicular structures with a membrane similar to the classical lipid bilayer, but it contains organometallic fragments instead of simple hydrophobic chains. Studies of CO release with these molybdenum carbonyl metallosurfactants have shown their viability as promising CO-releasing molecules.

Full text of DOI:10.1021/acs.organomet.5b00917

Article
pubs.acs.org/Organometallics
Supramolecular Arrangement of Molybdenum Carbonyl
Metallosurfactants with CO-Releasing Properties
Elisabet Parera,§,‡ Maribel Marín-García,†,‡ Ramon Pons,∥ Francesc Comelles,∥ Joan Suades,*,§
and Ramon Barnadas-Rodríguez*,†
†Unitat de Biofísica/Centre d’Estudis en Biofísica, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, and
§Departament de Química, Edifici C, Universitat Auton
̀
oma de Barcelona, 08193 Cerdanyola del Valles
da de Catalunya, IQAC-CSIC, Jordi Girona, 18-26, 08034 Barcelona, Catalonia, Spain
* Supporting Information
̀
, Catalonia, Spain
∥Institut de Química Avanca
̧
S
ABSTRACT: Two families of molybdenum carbonyl metal-
losurfactants, Mo(CO)5L and Mo(CO)4L2, were synthesized
using the functionalized phosphines Ph2P(CH2)nSO3Na (n = 2,
6, 10) and characterized by the usual spectroscopic and
spectrometric methods. The study of the supramolecular
arrangements of these compounds in aqueous medium has
been performed by surface tension, fluorescence, dynamic light
scattering, cryo-TEM, and small-angle X-ray scattering. All data
point to the formation of medium and large vesicular structures
with a membrane similar to the classical lipid bilayer, but it
contains organometallic fragments instead of simple hydro-
phobic chains. Studies of CO release with these molybdenum
carbonyl metallosurfactants have shown their viability as
promising CO-releasing molecules.
some reports, the term metallosurfactant has been associated
with this design,3 it is evident that other approaches are
possible. Hence, an excellent example of an alternative design
for metallosurfactants is found in metal complexes of
functionalized phosphines, in which the phosphine contains a
hydrophobic group and a polar group, such as sulfonate.2,4,5 In
this approach, the polar headgroup and the hydrophobic group
are located in the molecular structure of the ligand, and
consequently, the ligand can act as a surfactant independently
of whether it is free or linked to a metal atom. These former
groups of ligands (surfactant phosphines) have been relevant in
organometallic chemistry, as one important property of
surfactants is the self-aggregation and accumulation at the
interfaces, properties that have incentivized the study of
metallosurfactants in catalytic reactions.4,6 However, in recent
years, a wide range of other attractive possibilities have emerged
for metallosurfactants based on the possible control of the
supramolecular arrangements of metallic compounds and in the
use of these complexes in biology and medicine. Some
examples are templates for mesoporous materials,7 metal-
lomesogens,8 optoelectronic devices,9 ultrathin redox-active
surfaces,10 nanoparticles,11 labeling phospholipid membranes,12
antimicrobial compounds,13 and magnetic resonance imaging.14
In a previous paper,5 we reported the synthesis and study of a
family of platinum metallosurfactants prepared from three
INTRODUCTION
■
The term “metallosurfactant” was created in the 1990s, and it is
commonly used to designate molecules that behave as
surfactants and contain a metal atom in the molecular
structure.1,2 Since a simple design of a surfactant is commonly
based on a molecule that has a linear hydrophobic chain and a
polar headgroup, an important group of metallosurfactants are
molecules in which the metal atom is the polar headgroup of
the surfactant. A classic example of this kind of metal-
losurfactant is a metal complex of metals such as Ni2+ or
Cu2+ with an aliphatic amine that incorporates a long
hydrophobic chain, as shown in Scheme 1.1,3 Although, in
Scheme 1. Structures of Different Surfactants
Received: November 2, 2015
© XXXX American Chemical Society
A
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surfactant phosphines, 1−3 (Scheme 2). Both free phosphines
and cis-PtCl2L2 (L = 1, 2, 3) complexes showed the
shown in Scheme 1, bilayer arrangement implies two different
locations for the metal atoms. In the first kind of metal-
losurfactant, the metal atoms should be located on the surface
of the bilayer (Scheme 3, sketch A), whereas with the
organometallic metallosurfactant the metal atoms have to be
placed in the inner part of the bilayer (Scheme 3, sketch B),
being part of its hydrophobic region. At this point, it is
necessary to highlight that this approach allows placing
organometallic fragments in structures that can mimic
biomembranes, a design that is very attractive for possible
uses of metals in medicine. In this context, we have focused this
work on the potential applications of carbonyl metal-
losurfactants as CO-releasing molecules (CORMs). More
than 10 years ago, Motterlini and co-workers showed the
great potential of some metal carbonyls as therapeutic agents
on the basis of the ability of these compounds to release CO in
biological systems.18 The therapeutic benefits of CORMs have
been demonstrated in different studies; some examples are their
anti-inflammatory and vasodilatory properties, which make
these compounds excellent candidates for the treatment of
different diseases.19 In spite of the large number of related
publications reported, there is still a long way to go to achieve
this goal, because it requires a control of dosage, timing, and
location of the CO. Hence, in this study we report on metal
complexes that combine the ability to act as CO-releasing
molecules with the aggregation properties of metallosurfactants;
therefore we can obtain supramolecular structures that can act
as CO-delivery systems. As far as we know, only one study has
been reported that describes a micellar system that behaves as a
CORM. However, due to the fact that it is based on polymeric
micelles that contain a ruthenium carbonyl,20 the previous
approach is very different from that shown in the present paper.
Part of this work was previously communicated.21
Scheme 2. Phosphine Ligands 1−3
characteristic aggregation properties of surfactants, and it was
possible to study the influence of the hydrocarbon chain length
in the aggregation properties of these metal complexes.
In the present study, we have undertaken a novel approach
that is completely opposite of the design of the earliest
metallosurfactant family (Scheme 1, metallosurfactant with a
neutral ligand). Thus, if in the first metallosurfactants the metal
is coincident with the polar headgroup, in the current work the
metal is included in the hydrophobic group (Scheme 1,
organometallic surfactant). To attain this goal, the organo-
metallic approach is very useful because it allows preparing
metal fragments with the characteristic properties of organic
hydrophobic groups. Very few examples of organometallic
metallosurfactants have been reported, and most of them are
based on ferrocene derivatives (ferrocenyl surfactants)15 and, as
far as we know, only one is based on metal carbonyls. However,
this unique example is an alkoxy Re(I) complex that does not
have an additional polar headgroup; therefore it can be
considered a metallosurfactant with the polarity located around
the metal atom.16
Organometallic metallosurfactants based on metal carbonyls
are attractive molecules because they can lead to singular
supramolecular arrangements and, in addition, the presence of a
metal carbonyl group makes it possible to use these compounds
in different potential applications. As happens with conven-
tional surfactants, which self-assemble in water, metallosurfac-
tant molecules also form aggregated structures. In some cases
they produce micelles, as classic surfactants do, but, in other
cases they mainly generate vesicles, that is, membrane
structures that enclose an aqueous compartment.17 According
to this scenario, a bilayer is the simplest packing arrangement of
these molecules in the membrane (Scheme 3), like
phospholipids. As regards the two different metallosurfactants
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Metallosurfactants.
Molybdenum pentacarbonyl complexes 4−6 {[Mo(CO)5L] (L
= 1, 2, 3)} were prepared from Mo(CO)6 using methods
similar to those reported for the related ionic complexes
[M(CO)5(TPPTS)] (TPPTS = sodium triphenylphosphine
trisulfonate)22 with some modifications in the experimental
procedure (Scheme 4). Thus, complexes [Mo(CO)5L] can be
synthesized by direct reaction with Mo(CO)6 or by a
substitution reaction with a [Mo(CO)5L′] complex that
contains a labile L′ ligand. We found that the direct reaction
Scheme 4. Synthesis of Molybdenum Metallosurfactants 4−
a
9
Scheme 3. Bilayer Arrangement of Metallosurfactants
a
pip = piperidine; L = ligand.
B
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between Mo(CO)6 and ligands 1−3 in a methanol/THF
medium allows obtaining the complexes 4−6 using a
convenient procedure, and, in addition, it leads to pure
products. This procedure is very useful to obtain small
quantities (∼100 mg) of pure complexes 4−6, but it has the
problem that large quantities of Mo(CO)6 are necessary to
prepare the complexes on a larger scale (∼1.0 g). To avoid this
drawback, we have developed an alternative method based on
the preparation of the reaction intermediate [Mo-
(CO)5(CH3CN)] from Mo(CO)6 by decarbonylation with
Me3NO and subsequent reaction with the phosphine (Scheme
4).23 This method allows obtaining the desired products with
similar purity levels, and it is not necessary to use a large excess
of Mo(CO)6.
Figure 1. NMR spectra acquired during the reaction for the synthesis
of 7. (a) Ph2P(O)(CH2)2SO3Na at 34.5 ppm; (b) intermediate at 31.4
ppm; (c) cis-[Mo(CO)4(1)2] at 25.7 ppm; (d) Ph2P(CH2)2SO3Na (1)
at −15.7 ppm.
Complexes 4−6 were characterized by the usual spectro-
1
scopic (IR, H and 31P NMR; see Supporting Information 1)
and spectrometric methods21 (MS/ESI(−), HRMS). The IR
spectrum in the carbonyl region shows the characteristic three
bands for [Mo(CO)5L] complexes with a pattern and positions
nearly identical to those reported for the related complexes
[Mo(CO)5(PPh3)]24 and [Mo(CO)5(TPPTS)].22 The 31P
NMR spectra display a singlet around 27 ppm for the three
complexes, showing the normal shift of this signal after
coordination to the {Mo(CO)5} fragment with respect to the
[Mo(CO)4(pip)2] and the phosphine ligand is high. Taking
into account these results, the posterior fine-tuning of the
reaction conditions (reaction time, reagents’ ratio, and solvents’
volumes) allowed the preparation of the cis-[Mo(CO)4L2] (L =
1, 2, 3) complexes with high yield (∼80%) and purity.
Characterization of 7−9 using the spectroscopic methods
(see Supporting Information 1 and ref 21) confirms the
proposed cis-[Mo(CO)4L2] structure for these complexes. The
IR spectra show, in the carbonyl region, the characteristic four
bands of complexes with C2v symmetry in positions very similar
1
position of free ligands 1−3 (ca. −16 ppm). The H NMR
spectra agree with the proposed structure, and, if we compare
with the spectra of the free ligands, the shift of peaks assigned
to methylene groups linked to a phosphorus atom after
coordination to the metal atom can be observed. Unfortunately,
13C NMR spectra could not be obtained due to the low
solubilities of complexes 4−6.
24
to those reported for the homologous complexes with PPh3
and TPPTS25 ligands. The 31P NMR spectra of 7−9 show the
expected singlet for cis-Mo(CO)4P2 coordination set with a
chemical shift very similar to those observed for complexes 4−
6, but with a very small high-field shift (∼1 ppm; see Figure 2),
The ESI-MS spectrometry (negative ionization mode) of 4−
6 agree with the proposed stoichiometries, and it shows the
signals of the respective anions [M − Na] and/or signals in
which some carbon monoxide molecules have been eliminated
as [M − 2CO − Na]. We note that the loss of CO molecules
decreases with the increase of the alkyl chain. Thus, using
identical experimental conditions, with complex 6 the sole peak
observed corresponds to [M − Na]. In complex 5 the same
signal is observed but also a peak that corresponds to [M −
2CO − Na], and, finally, for complex 4, only the peaks that
correspond to fragments [M − 2CO − Na], [M − 3CO − Na],
and [M − 4CO − Na] can be seen. The signals corresponding
to the [M − Na] anions for the three complexes 4−6 could be
observed in the HRMS-ESI-MS(−) spectra. The great
coincidence between the isotopic pattern of calculated and
experimental spectra for the three complexes should be
highlighted.21
Figure 2. Comparison between the 31P{1H} NMR spectra of mixtures
of complexes [Mo(CO)5(2)] (a) and cis-[Mo(CO)4(2)2] (b) at
different ratios.
a behavior that has also been reported for other [Mo(CO)5L]
and cis-[Mo(CO)4L2] (L = phosphine) complexes.27 The H
1
The metal complexes 7−9 {[Mo(CO)4L2] (L = 1, 2, 3)}
were prepared from the complex [Mo(CO)4(pip)2], which
contains two labile piperidine ligands (Scheme 4), following the
reported method for other [Mo(CO)4L2] (L = neutral
phosphine) complexes,25 but with some significant differences
in the reaction medium due to the ionic nature of ligands 1−3.
Hence, 7−9 were synthesized using a synthetic method similar
to that reported for [Mo(CO)4(TPPTS)2],26 but the
experimental conditions had to be optimized in order to
obtain pure products. Thus, the study of this reaction in an
NMR tube (Figure 1) showed the formation of an intense
signal at 31.4 ppm that has been assigned to the reaction
intermediate [Mo(CO)4(pip)(1)]. This assignment agrees with
the fact that this signal is relevant in experiments at short
reactions times and also if the ratio between the precursor
NMR spectra show all expected signals, and, similarly to the
above complexes 4−6, the shifts of methylene groups located
closer to the phosphorus atom after coordination to the metal
atom can be observed. The 13C NMR spectra of complexes 7−
9 could be obtained because of the higher solubility of these
compounds in methanol with respect to 4−6. The assignment
of significant signals corresponding to the coordinated ligands
has been performed by means of 2D 1H, 13C-HSQC
experiments. It is worth noting the resonances of carbonyl
groups, which are observed as two signals of different
multiplicity at 215 and 210 ppm, and they are respectively
assigned to the CO in cis,cis-position and cis-trans-position to
the phosphorus atom.
The ESI-MS spectrometry (negative ionization mode) of 7−
9 confirms the proposed stoichiometries showing the signals of
C
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the respective anions [M − Na] in all cases. Unlike results
obtained for 4−6, no significant peaks corresponding to CO
elimination were observed. Finally, accurate mass measure-
ments by HRMS-ESI-MS(−) spectrometry provided exact
masses of the main peaks [M − Na] for 7−9, which correspond
to the proposed molecular formulas.
tetracarbonyl 7−9 complexes) and on the total number of
carbon atoms of their hydrocarbon chains. The first depend-
ence can be explained by the different composition of the
hydrophobic end of each type of molecule. The coordination of
the surfactant phosphine ligands with a rigid nonpolar group,
such as {Mo(CO)4} or {Mo(CO)5}, produces a significant
decrease in the CMC. The second dependence is a well-known
phenomenon. It is explained by the increase in the hydrophobic
attraction between the surfactants on increasing the hydro-
phobic chain length. On the other hand, the changes in the
shape and intensity of the fluorescent spectra of the 1, 4, and 7
family obtained at different concentrations indicate that this
technique is also useful for the determination of the CMC of
these compounds. The inset of Figure 4 shows several
Attempts to prepare trans-[Mo(CO)4L2] (L = 1, 2, 3)
complexes by isomerization of cis-[Mo(CO)4L2] were un-
successful. Although it is well-known that the more
thermodynamically stable isomer trans-[Mo(CO)4(PPh3)2]
complex can be prepared by simply heating a solution of cis-
[Mo(CO)4(PPh3)2], the study of this reaction with 7−9 in
nonpolar solvents showed that the starting products are
recovered even using long reaction times. This behavior can
be associated with the low solubility of 7−9 in nonpolar
solvents. On the other hand, the 31P NMR study of this
reaction in more polar solvents as mixtures of THF/MeOH has
demonstrated that the thermal decomposition of cis-[Mo-
(CO)4L2] compounds leads to the formation of mixtures of the
initial complex and the respective [Mo(CO)5L] compound. A
similar behavior has been reported for the cis-[Mo-
(CO)4(TPPTS)2] complex.26
Aggregation Studies by Surface Tension and Fluo-
rescence Measurements. Plots of surface tension versus
concentration for the aqueous solutions of 1−921 show a break-
point, that is, a change in the slope of the curve, which is
characteristic of the formation of aggregates (inset Figure 3). It
Figure 4. Normalized fluorescence intensity ratios of 1 (red circles;
I396 nm/I464 nm, excit. 250 nm; n = 6); 4 (green squares; I566 nm/
I466 nm, excit. 305 nm; n = 4); and 7 (blue triangles; I396 nm/I467
nm, excit. 305 nm; n = 4). Results: mean standard deviation. Inset:
Normalized fluorescence spectra (excitation at 305 nm) of 7 in water
at 8 mM (continuous line), 1.75 mM (dashed line), and 1 mM (dotted
line).
normalized spectra for the case of metal complex 7. The
evolution of the described variation was characterized by
obtaining the intensity ratio at two emission wavelengths,
corresponding to local maxima or to significant shoulders. The
representation of these values versus the concentration allowed
detecting break-points in the curves (Figure 4). The calculated
values were 2 mM for 4 and 7 and 14.2 mM for 1. These
concentrations are equivalent to that obtained by surface
tension measurements. In the case of ligand 1, a second break-
point (not detected by surface tension measurements) was
detected at, approximately, 1.5 mM. This fact could be caused
by the formation of prevesicular aggregates, a phenomenon
described in other charged surfactants.28 Thus, from the surface
tension and fluorescence measurements, it is clear that all the
molybdenum carbonyl complexes undergo self-aggregation
processes in aqueous media.
In addition, the surface tension data allowed obtaining the
surface excess concentration (Γ) and the estimated area per
molecule (A) in the air/water interphase. Although the absolute
values obtained by this technique were questioned by some
authors,30 their relative values make it possible to compare the
characteristics of a family of similar molecules. As can be seen
in Figure 5 (and Supporting Information 2), the free
Figure 3. CMCs of ligand phosphines 1, 2, and 3 (red circles),
pentacarbonyl complexes 4, 5, and 6 (green squares), and
tetracarbonyl complexes 7, 8, and 9 (blue triangles), as a function of
the carbon atoms of each hydrocarbon chain. Inset: Surface tension
measurement of 7 as a function of the concentration.
is known that below this point (critical micelle concentration,
CMC) almost all amphiphiles are in the monomeric form,
although in some cases the formation of dimers or oligomers
has been reported28 or even predicted by molecular
dynamics.29 At surfactant concentrations higher than the
CMC, they undergo self-aggregation and produce, for example,
micelles or vesicles. Figure 3 shows the CMC obtained for the
different surfactants studied in the present work. As can be
observed, it reveals that the evolution of the critical
concentrations depends both on the type of molecule (that
is, phosphine ligands 1−3 and pentacarbonyl 4−6 and
D
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Table 1. Particle Size Analysis of the Substances 1−9
concentration
(mg/mL)
mean diameter (nm; %
intensity)
compound
PDI
1
2
3
4
5
6
7
8
9
40.5
40.5
30.4
6.0
150 20
0.44 0.03
1.00 0.04
0.30 0.02
0.41 0.05
0.46 0.02
0.70 0.20
0.56 0.06
0.34 0.05
0.50 0.01
30
16
4
1
4
2
225
147
4.26
2.26
8.82
8.67
4.00
200 20
250 80
1300 90
127
1
show this circumstance, as they show the existence of various
subpopulations for each compound. In general, and due to their
size, most of the populations are compatible with the existence
of vesicular aggregates with entrapped water, which could be
surrounded by one or more membranes of surfactant. In order
to assign intervals, large (<1000 nm), medium (from 100 to
1000 nm), and small vesicles (from 20 to 100 nm) can be
considered. As the size of the large aggregates are very close to
the upper limit of detection of the instrument (about 6000
nm), the existence of a certain quantity of out of range vesicles
should not be ruled out.
Morphology and Structure of the Aggregates. The
physical characteristics of the spontaneously formed aggregates
constituted by the surfactants in water were studied by cryo-
electron microscopy (cryo-TEM) and small-angle X-ray
scattering (SAXS).
Cryo-TEM results agree with the DLS analyses, and in all
cases the images (Figure 7) show the existence of medium and
large vesicular structures. As regards the morphology, a huge
quantity of multilayered vesicles was expected, because of the
method of preparation (vortex). Surprisingly, this was not the
case, since, as can be observed, the vesicles were constituted
mainly by one or a few membranes, and in some cases
multivesicular vesicles could be detected (but only with a few
internal vesicles). Both phenomena (presence of medium size
and monolayered vesicles) can be explained by the intense
electrostatic repulsion between the membranes originating
from the sulfonate groups of the surfactants. This influence of
the charge on the size and lamerallity of the vesicles was also
described in liposomes constituted by charged phospholipids.32
It is known that the SAXS technique allows getting detailed
information on the morphology of aggregates, as well as of their
packing structure. For this reason, and with the aim of
obtaining preliminary and, at the same time, representative
results, the compounds 1, 4, and 7 were studied by SAXS. Since
they correspond to one of the three families synthesized, the
results would monitor the effects caused by the structural
differences among the molecules, that is, from one ligand to the
corresponding complexes containing one or two hydrocarbon
chains. In Figure 8, we show the experimental scattering curves
for the ligand and both complexes and their corresponding best
fits to the model, which correspond to the lamellar arrangement
present in vesicles, as is schematically shown in Scheme 3.
Other models were also studied, and we found that the fitting
of spherical models (micelles), although feasible, did not result
in good absolute intensity scaling or led to completely
unphysical parameters. The parameters of the fits shown in
Figure 8 correspond to the set of parameters shown in Table 2
and Supporting Information 3.
Figure 5. Estimated area occupied per molecule adsorbed in the
water/air interface obtained from the surface tension measurements of
water solutions of the compounds 1−3 (red circles), 4−6 (green
squares), and 7−9 (blue triangles). Inset: Scheme of the double-loop
conformation of 9.
phosphines 1−3 display no relevant differences between the
values of A. Consequently, packing of the aggregates should be
very similar, with the sulfonate group oriented to water and the
lipophilic (CH2)n-PPh2 group in an extended chain con-
formation. This is not the case for the pentacarbonyl 4−6 and
tetracarbonyl 7−9 complexes, a result that can be attributed to
the existence of the voluminous hydrophobic metal carbonyl
group. In these molecules, the increment of the chain length of
the complexes causes a progressive decrease in the molecular
packing. This effect agrees with an increment of the cross-
sectional area of the hydrophobic part of the molecules, a
phenomenon well-described by the packing parameter,31 which,
for example, in the case of lipids, is modulated by the free
rotation of the carbon−carbon bonds of their hydrocarbon
chains. Note that there is a great increment in the area per
molecule from 8 to 9, not observed in the other cases. This
result parallels the behavior previously observed with cis-
[PtCl2L2] (L = 1, 2, 3) complexes10 and is consistent with a
double-loop conformation of the complex in the interface
(Figure 5 and Supporting Information 2).21
Size Analysis. The surfactant water solutions obtained did
not pellet after their centrifugation, which indicates that
aggregates were well formed. To analyze the size of the
aggregates, aqueous solutions of 1−9 were studied by dynamic
light scattering spectroscopy (DLS). All the experiments were
carried out above the CMC of the molecules, and, therefore,
the results correspond to the supramolecular aggregates formed
by the metallosurfactants. The mean hydrodynamic diameter
and the polydispersity index (PDI) of the studied solutions are
shown in Table 1. The mean diameters have a small error,
which indicates not the width of the population but the
reproducibility of the analyses. The theoretical values for PDI
range from 0 (absolutely monomodal distribution) to 1
(multimodal distribution), and, consequently, the experimental
values obtained show that the spontaneously formed aggregates
form polydisperse populations. This is a common phenomen-
on, taking into account that the suspensions were prepared by
vortex, that is, no size control, such as extrusion, was
performed. The size distributions plotted in Figure 6 clearly
E
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Figure 6. Size distributions of the aggregates formed by the phosphine ligands (1−3), pentacarbonyl (4−6), and tetracarbonyl (7−9) surfactants.
For each type of molecule (ligand, pentacarbonyl, and tetracarbonyl) the mean diameters of the subpopulations are shown in the common left axis,
and their relative amounts are expressed as percentage beside the corresponding symbol. Results: mean standard deviation.
Figure 8. SAXS intensities as a function of scattering vector modulus
(q) for dispersions of 1 (black squares), 4 (green triangles), and 7 (red
circles).
Table 2. Molecular Parameters of the Surfactants When
Forming Macromolecular Aggregates Obtained from the
Fitted Curves Shown in Figure 8
1
4
7
Am (Å2)
Lc (nm)
Lh (nm)
Vc (nm3)
Vh (nm3)
Nw
49
3
72
6
153 10
0.74 0.02
2.25 0.05
0.363 0.025
1.10 0.07
1.13 0.02
4.22 0.2
0.814 0.070
3.04 0.29
100 10
0.75 0.02
2.48 0.05
1.15 0.080
3.79 0.26
115 10
34
5
Figure 7. Cryo-TEM images of pentacarbonyl (4, 5, and 6) and
tetracarbonyl (7, 8, and 9) complexes. The big light areas correspond
to the holes of the grid; they are not vesicles.
compared with those obtained from surface tension results
(Figure 5).
When comparing areas per molecule obtained from surface
tension or other methods, we should bear in mind some of the
problems associated with the application of a Gibbs isotherm to
surface tension,33 as well as to the different situation
corresponding to adsorption to the aqueous surface and to
the formation of condensed phases. Apart from the problems
associated with the sensitivity of surface tension to impurities
(both hydrophobic and to multivalent counterions), the
The trend of the area per molecule (Am) seems to have some
logic. The ligand alone has an area per molecule that increases
somewhat when the complex is formed, and the complex with
two polar heads has an area per molecule comparable to the
summation of the area per molecule of the pentacarbonyl
complex plus an additional ligand. Those values can be
F
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number of adsorbed species and the lack of direct relationship
of surface saturation with micellation may produce discrep-
ancies between the minimum area per molecule determined by
surface tension and the real minimum achievable area per
molecule. This could be the case of ligand 1, for which the
surface tension and SAXS differ significantly. Part of the
discrepancy could be attributed to the different situation
corresponding to the adsorption to the interface and to the
formation of a condensed phase, which is more restrictive in the
sense that the molecules have to completely fill the space.33
The hydrophobic volume (Vc) results from the product of the
hydrophobic length (Lc) times Am. It is apparent that the
hydrophobic volume of the ligand plus that of the
pentacarbonyl complex 4 is very close to that of the
tetracarbonyl complex 7. The hydrophobic length of complex
7 is commensurate with the physical dimensions of the
molecule, as obtained from ChemDraw (0.9 nm from the
sulfonate methylene to the oxygen of the carbonyl plus the van
der Waals radii of oxygen and half the C−S bond), while that of
complex 4 is slightly larger than that obtained from the
ChemDraw configuration (1.0 nm from the sulfonate
methylene to one of the protons of a benzene ring). The
volume of the ligand, as obtained from a solvent-excluded
volume model (see Supporting Information 4), closely fits the
experimentally fitted value, that is, 0.403 nm3 from the excluded
solvent model and 0.430 nm3 for the summation of the
experimentally fitted volume for the hydrophobic contribution
(0.363 nm3) plus the headgroup volume contribution (volume
of the sulfonate group, 0.040 nm3, and volume of the methylene
group, 0.027 nm3).34 Having settled this value, we can estimate
the contribution of the pentacarbonyl group as 0.451 nm3 and
that of the tetracarbonyl as 0.432 nm3. Without additional
reference, we can compare these values with the group volume,
as also obtained from the solvent-excluded volume. The results
were 0.203 nm3 for the pentacoordinated molybdenum and
0.185 nm3 for the tetracoordinated molybdenum. Note that our
experimental results gave values higher than the excluded
solvent volumes. Our conclusion is that, because of the rigidity
and bulkiness of the complexes, the packing in the hydrophobic
part of the membrane is far from being compact. Considering
the hydrophilic domain of the lamellae, the fitted length is
considerably larger than the geometrical length of the polar
groups. This matches with the high number of water molecules
contained in the polar head and calculated from the total polar
volume minus the volume of the sulfonate group and
methylene group. This also may be an indication of the large
rugosity of this surface, which is concomitant with the
difficulties of packing of their bulky and rigid hydrophobic
groups on a flat and compact layer.
Figure 9. Kinetics of formation of CO-Mb in the presence of 1 (red
circles, negative control; n = 2), 4 (green squares; n = 3), and 7 (blue
triangles; n = 4) at 37 °C. Results: mean standard deviation. Inset:
Reference spectra of deoxy-Mb (continuous line) and CO-Mb (dotted
line) and that obtained as a consequence of the CO release from 7
(discontinuous line).
produced. From these data, the time evolution of the CO-Mb
formation was plotted for metal complexes 4 and 7 (Figure 9).
The phosphine ligand 1, which has no CO group, was selected
as a negative control. It did not cause any change in the
spectrum of Mb, showing that the concentration of deoxy-Mb
was maintained constant. In contrast, metal complexes 4 and 7
caused a continuous increase of the CO-Mb form, with initial
rates of CO release of 2.2 × 10−4 mol CO·mol CORM−1·min−1
(r2 = 0.9517) and 3.7 × 10−4 mol CO·mol CORM−1·min−1 (r2
= 0.9631) for 4 and 7, respectively. As can be observed, both
molecules are characterized by a slow release of CO, and their
corresponding half-lives were 2250 min for 4 and 1360 min for
7. The existence of CORMs with elevated half-life is a desired
circumstance, as this behavior allows a sustained release of CO
in the human body.35 Thus, this preliminary study has shown
that two preferred properties of CORMS converge in the
studied metal complexes: They are water-soluble molecules that
self-assemble to form vesicles, and they show a high half-life for
CO release. Consequently, they can be useful as therapeutic
CO-releasing vesicles.
CONCLUSIONS
■
Molybdenum carbonyl complexes with the surfactant phos-
phine ligands 1−3 have been synthesized and characterized by
IR, NMR (1H, 13C, 31P), and MS methods. All these metal
complexes are water-soluble, and surface tension studies of
these solutions have shown that they behave as surfactants,
forming supramolecular aggregates at concentrations above the
CMC. The size of these self-assembled structures was studied
by DLS, which revealed the formation of various subpopula-
tions of aggregates for each compound, in agreement with the
formation of vesicular aggregates with entrapped water. This
hypothesis was confirmed by cryo-TEM studies that show the
presence of medium and large vesicles that contain
predominantly one or a few membranes. This behavior can
be related to an important electrostatic repulsion between the
sulfonated groups located in the membrane surface. The SAXS
CO Release Tests. In order to check if the obtained
molecules could be useful as CORMs, the ability of the ligand 1
(as control) and the metal carbonyl metallosurfactants 4 and 7
to release CO was evaluated according to the myoglobin assay
(thus, as for the case of the SAXS study, the CO release was
performed for the compounds of one family). It is based on
monitoring, by UV−vis spectroscopy, the conversion of
deoxymyoglobin (deoxy-Mb) to carboxymyoglobin (CO-Mb)
as a result of the release of the carbon monoxide from the metal
complex. Thus, after incubating the indicated metal complexes
with deoxy-Mb using previously reported experimental
conditions, a clear increase of the peak corresponding to the
CO-Mb complex with time was detected (inset Figure 9),
indicating that a release of CO from the metallosurfactants was
G
DOI: 10.1021/acs.organomet.5b00917
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
solutions, previously recrystallized and lyophilized surfactants were
resuspended and vortexed with degassed Milli-Q water. Solutions were
allowed to equilibrate for 1 h previous to the analyses. Afterward,
samples were centrifuged in Eppendorf tubes (2−3 min, 13 000 rpm)
to prevent the existence of any nonsolubilized solid particles, which
would interfere with the analyses. Results are expressed as mean
hydrodynamic diameter (% of intensity), main peaks of the
subpopulations, and polydispersity index with their corresponding
standard deviations.
study of complexes 4 and 7 is concordant with DLS and cryo-
TEM results, showing that the best fit with the experimental
data is reached when a lamellar model is used, consistent with
the formation of vesicular aggregates. This technique also
suggests that the packing of the hydrophobic part, which
contains the organometallic fragment, is less compact than it is
in the conventional surfactants, an interesting result that should
be confirmed in subsequent studies.
Finally, the CO-releasing tests performed with the
molybdenum carbonyl complexes 4 and 7 using the myoglobin
assay have shown that these compounds exhibit a slow release
of CO. These properties, in conjunction with their ability to
form supramolecular structures at concentrations higher than
their CMCs, make these metal complexes potential CORMs for
therapeutic applications with no precedents in the literature.
Cryo-Transmission Electron Microscopy. The morphology of
the aggregates formed by the surfactants was studied by imaging the
suspensions by cryo-TEM at the Servei de Microscop
̀ ̀
ia Electronica de
la Universitat Autonoma de Barcelona. A 2 μL amount of the aqueous
̀
samples was blotted onto holey carbon grids (Quantifoil) previously
glow discharged in a BAL-TECMSC 010 glow discharger unit. They
were subsequently plugged into liquid ethane at −180 °C using a Leica
EM CPC cryoworkstation and observed in a Jeol JEM-1400 electron
microscope operating at 120 kV. During imaging the samples were
maintained at −177 °C, and pictures were taken using a CCD
multiscan camera (Gatan).
EXPERIMENTAL SECTION
■
Synthetic and Characterization Methods. All reactions were
performed under nitrogen using standard Schlenk tube techniques.
Tetrahydrofuran and methanol were distilled (respectively over
sodium/benzophenone and over magnesium) and stored over 3 Å
molecular sieves. Pentane was dried with 3 Å molecular sieves. Infrared
spectra were recorded with a PerkinElmer 2000 FT spectrometer. The
Surface Tension Measurements. The surface tension measure-
ments were performed to detect and characterize the formation of
molecular aggregates of the surfactants. The water (degassed, Milli-Q
water) solutions of the compounds were prepared by successive
dilution of a concentrated sample and then aged for 30 min before the
determination of the surface tension. The measurements were
NMR spectra were recorded in the Servei de Ressonan
Nuclear de la Universitat Autonoma de Barcelona on Bruker DPX-250,
DPX-360, and AV400 instruments. Microanalyses were performed by
̀ ̀
cia Magnetica
performed with a Kruss K-12 automatic tensiometer (Hamburg,
̈
̀
Germany) equipped with a platinum Wilhelmy plate, and for each
sample five consecutive measurements, with a stability tuned to 0.1
mN·m−1, were done. The critical micellar concentrations were
obtained from the intersection of the linear parts of the surface
tension versus logarithm of the concentration plots. The area (A, in
Å2) occupied per molecule adsorbed at the water/air interface was
calculated from the equation A = 1016/NA Γ, where NA is Avogadro’s
number and Γ the surface excess concentration (mol/cm2). Γ was
obtained from the Gibbs equation Γ = −(dγ/d log C)/2.303nRT,
where dγ/(d log C) is the slope of the linear part of the graph obtained
immediately below the CMC and n is the number of molecular species
in solution; that is, n = 2 for surfactant phosphine ligands and n = 3 for
the molybdenum metallosurfactants.
́
́
the Servei d’Anal
̀
isi Quimica del Departament de Quimica de la
oma de Barcelona (SAQ-UAB). Mass spectra and
Universitat Auton
̀
exact mass measurements were respectively obtained on an Esquire
3000 with electrospray ionization and an ion trap Bruker Daltonics and
on a Bruker microTOFQ with electrospray ionization Apollo of Bruker
by SAQ-UAB.
Ligands 1−3 were prepared using previously reported methods,5
and complexes 4−9 were synthesized and characterized following
procedures reported in a previous communication.21 However, as
discussed in the Results and Discussion section, a new, more
convenient method for preparing large quantities of complexes 4−6
has been recently developed, which is reported below.
Fluorescence Spectroscopy. The intrinsic fluorescence of the
phenyl groups of the surfactant molecules allowed monitoring by
fluorescence spectroscopy changes in their environment caused by
variations of their state of aggregation. The emission spectra of the
different molecules were obtained with a PTI QuantaMaster
spectrofluorimeter using a sample holder thermostated at 25 °C and
with magnetic stirring. The excitation wavelengths used were from 250
to 305 nm, depending on the sample, in order to obtain a good signal-
to-noise ratio. Samples were progressively diluted, and at each
concentration several consecutive scans were acquired until no
variation of the shape and intensity of the spectra was observed.
Usually, an equilibration time of about 30 min was needed for the
highly concentrated samples, but in all the other cases it did not last
more than 2 to 4 min.
Small-Angle X-ray Scattering. SAXS patterns were recorded
using a S3-MICRO (Hecus X-ray systems, Graz, Austria) coupled to a
GENIX-Fox 3D X-ray source (Xenocs, Grenoble, France) working at
50 kV and 1 mA (λ = 1.542 Å). The working q range was 0.1 ≤ q ≤ 6
nm−1, and the temperature 25.0 0.1 °C, where q = (4 π sin θ)/λ is
the scattering wave vector modulus, θ the scattering angle, and λ the
incident wavelength. For each experiment the scattering pattern was
recorded as a sum of subscans to verify there was no sample evolution.
The curves were fitted to intensity models obtained by either spherical
step electronic density profiles or lamellar step electronic density
profiles.36 Our homemade fitting routines allow for convolution of the
theoretical curves with our experimental detector width smearing
function and use a Leverberg−Marquad scheme for minimization.37 In
the fitting we have let free the area per molecule Am, the hydrophobic
length Lc, and the hydrophilic length Lh. Using these, we have
calculated the hydrophobic electron density ρc, the number of water
Synthesis of Complexes 4 and 5. Trimethylamine N-oxide
dihydrate (3.45 mmol) and molybdenum hexacarbonyl (4.14 mmol)
were added to 15 mL of a dry dichloromethane/acetonitrile mixture
(1:1); the resulting solution was protected from light and maintained
under vigorous stirring at room temperature for 1.5 h. Next, a solution
of the phosphine Ph2P(CH2)nSO3Na (3.12 mmol) in dry methanol
(30−40 mL) was slowly added, and the mixture was allowed to stir at
room temperature for an additional 1.5 h. After this time, a yellow,
turbid solution was obtained, which was filtered through Celite to yield
a clear solution. This solution was evaporated under reduced pressure
to dryness, and a yellow oil was obtained, which became a powdery
yellow solid after scratching the walls with a spatula. This crude
product was purified by dissolution in dry methanol (15−20 mL) and
dropwise addition of freshly distilled diethyl ether (∼10 mL) until a
thin white precipitate of [Mo(CO)6] was formed. The resulting
mixture was centrifuged (10 000 rpm) to eliminate the white solid, and
the filtrate was evaporated under reduced pressure to dryness in order
to obtain the desired compound. Complexes 4 and 5 (1.490 g for 4
and 1.527 g for 5) were isolated as brown solids. The 1H NMR,
31P{1H} NMR, and IR spectra were consistent with previously
reported data.
Particle Size Distribution. The size distributions of the aggregates
formed by the ligands and metallosurfactants were measured by DLS
spectrometry using a UPA 150 (Microtrac Inc., FL, USA) and a
Malvern Zetasizer ZS90 (Malvern Instruments Ltd., UK) particle
analyzer. The instrument can detect particles with diameter ranges
from 2 nm to 6 μm. Each data acquisition was a mean of 10
consecutive analyses, performed at 25 °C, without dilution of the
sample (in order to not alter the phase equilibrium), and each
experiment was repeated three times. To obtain the amphiphile
H
DOI: 10.1021/acs.organomet.5b00917
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
molecules in the polar region Nw, and the hydrophilic electron density
ρh. To do so, we have set the number of electrons of the hydrophobic
region as the total number of electrons of the molecule minus that of
the polar head, which we have fixed as corresponding to the sulfonate
group and one methylene.
(3) Griffiths, P. C.; Fallis, I. A.; Chuenpratoom, T.; Watanesk, R. Adv.
Colloid Interface Sci. 2006, 122, 107−117.
(4) (a) Fell, B.; Pagadogianakis, G. J. Mol. Catal. 1991, 66, 143−154.
(b) Ding, H.; Hanson, B. E.; Bakos, J. Angew. Chem., Int. Ed. Engl.
1995, 34, 1645−1647. (c) Gulyas, H.; Arva, P.; Bakos, J. Chem.
Commun. 1997, 24, 2385−2386. (d) Goedheijt, M. S.; Hanson, B. E.;
Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2000, 122, 1650−1657.
Measurement of CO Release. The CO release from the
metallosurfactant molecules was measured by means of the myoglobin
assay,38 which is based on the high affinity of this protein for the CO
dissolved in an aqueous medium. A solution of reduced myoglobin
(deoxy-Mb) 53 μM in phosphate biological saline buffer (PBS;
previously degassed by bubbling N2) at pH 7.4 was obtained by adding
sodium dithionite at a final concentration of 1% w/w and, afterward,
bubbling N2 again. To obtain a spectrum between 250 and 650 nm, a
spectrophotometer cuvette was filled with an aliquot of this solution
and capped to avoid any entrance of air. The obtained curve
corresponded to a reference sample with no CO bound to Mb and
showed a local maximum at 556 nm. To obtain the spectrum of the
totally CO-saturated Mb (that is, 53 μM of CO-Mb), an aliquot of the
previous solution was intensely bubbled with CO. In this case the
curve showed two local maxima, located at 540 and 580 nm. Both
spectra, from deoxy-Mb and CO-Mb, shared four isosbestic points, at
510, 550, 570, and 585 nm. The release of CO from the samples was
monitored by obtaining the spectra of an aliquot of the previously
described deoxy-Mb solution containing the tested metallosurfactant
at a concentration of 250 μM and at 37 °C. After correction of the
spectra taking into account the isosbestic points, the concentration of
CO-Mb was quantified from the absorbance at 540 nm.
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26, 743−751.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00917.
(9) (a) Nazeeruddin, M. K.; Zakeeruddin, S. M.; Lagref, J. J.; Liska,
P.; Comte, P.; Barolo, C.; Viscardi, G.; Schenk, K.; Graetzel, M. Coord.
Chem. Rev. 2004, 248, 1317−1328. (b) Jayathilake, H. D.; Driscoll, J.
A.; Bordenyuk, A. N.; Wu, L.; da Rocha, S. R. P.; Verani, C. N.;
Benderskii, A. V. Langmuir 2009, 25, 6880−6886. (c) Lesh, F. D.;
Allard, M. M.; Shanmugam, R.; Hryhorczuk, L. M.; Endicott, J. F.;
Schlegel, H. B.; Verani, C. N. Inorg. Chem. 2011, 50, 969−977.
(d) Mauro, M.; De Paoli, G.; Otter, M.; Donghi, D.; D’Alfonso, G.; De
Cola, L. Dalton Trans. 2011, 40, 12106−12116. (e) Fernandez-
Hernandez, J. M.; De Cola, L.; Bolink, H. J.; Clemente-Leon, M.;
Coronado, E.; Forment-Aliaga, A.; Lopez-Munoz, A.; Repetto, D.
Langmuir 2014, 30, 14021−14029.
Spectroscopic data for complexes 4−9; surface excess
concentration and the estimated area per molecule for
compounds 1−9; molecular parameters of macro-
molecular aggregates obtained by SAXS for compounds
1, 4, and 7; excluded volume routine procedure (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: joan.suades@uab.cat.
*E-mail: ramon.barnadas@uab.cat.
■
(10) Joy, S.; Pal, P.; Mondal, T. K.; Talapatra, G. B.; Goswami, S.
Chem. - Eur. J. 2012, 18, 1761−1771.
(11) (a) Iida, M.; Baba, C.; Inoue, M.; Yoshida, H.; Taguchi, E.;
Furusho, H. Chem. - Eur. J. 2008, 14, 5047−5056. (b) Ye, S.; Liu, Y.;
Chen, S.; Liang, S.; McHale, R.; Ghasdian, N.; Lu, Y.; Wang, X. Chem.
Commun. 2011, 47, 6831−6833. (c) Kaur, R.; Mehta, S. K. Coord.
Chem. Rev. 2014, 262, 37−54.
Author Contributions
‡
́
́
E. Parera and M. Marın-Garcıa have contributed equally to
this work.
Notes
(12) Mechler, A.; Stringer, B. D.; Mubin, M. S. H.; Doeven, E. H.;
Phillips, N. W.; Rudd-Schmidt, J.; Hogan, C. F. Biochim. Biophys. Acta,
Biomembr. 2014, 1838, 2939−2946.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(13) Aiad, I. A.; Badawi, A. M.; El-Sukkary, M. M.; El-Sawy, A. A.;
Adawy, A. I. J. Surfactants Deterg. 2012, 15, 223−234.
■
We acknowledge Mr. Jaume Caelles from the SAXS-WAXS
service at IQAC for measurements. This research was
supported by the Spanish MINECO and FEDER funds
through the projects BIO2012-39682-C02-02 and MINECO-
CTQ2013-41514-P.
́
(14) (a) Vaccaro, M.; Mangiapia, G.; Radulescu, A.; Schillen, K.;
D’Errico, G.; Morelli, G.; Paduano, L. Soft Matter 2009, 5, 2504−2512.
(b) Gong, P.; Chen, Z.; Chen, Y.; Wang, W.; Wang, X.; Hu, A. Chem.
Commun. 2011, 47, 4240−4242. (c) Chen, Y.; Zhu, Q.; Tian, Y.; Tang,
W.; Pan, F.; Xiong, R.; Yuan, Y.; Hu, A. Polym. Chem. 2015, 6, 1521−
1526.
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DOI: 10.1021/acs.organomet.5b00917
Organometallics XXXX, XXX, XXX−XXX