Characterizing the "shell phase" formed from amphiphilic picolinates

Article abstract of DOI:10.1021/ja053432o

The shell phase forms when certain picolinates are subjected to energy input (via sonication or vortexing) while exposed to a water/toluene mixture. A shell, about 600 A thick and containing the picolinate and (very likely) toluene, surround the water droplets that are always produced during the mixing process. Solubility in either phase appears to be deleterious to shell formation. The shells, stable for months, are not easily distorted but can be punctured, even skewered, with a syringe needle without destroying the sphere, yet there is enough mobility among the molecules to repair the physical damage after the needle is removed. This, plus the absence of evidence for crystallinity, suggests a solid or semisolid film forms when picolinates, with the aid of an aromatic solvent, are provided the energy to rearrange themselves on water droplet surfaces. Structure-activity comparisons among the 10 compounds studied indicate that chain-chain association and intermolecular hydrogen bonding are dominant forces in a side-by-side self-assembly of the molecules within the shells. Copyright

Full text of DOI:10.1021/ja053432o

Published on Web 08/04/2005
Characterizing the “Shell Phase” Formed from Amphiphilic Picolinates
Fredric M. Menger,* Ashley L. Galloway, and Dan Lundberg‡
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
Received May 26, 2005; E-mail: menger@emory.edu
Jonathon Filley at the Colorado School of Mines was the first
to synthesize and study 5-(1-dodecylaminocarbonyl) picolinic acid
(
A in Scheme 1) to combine the metal-ligating properties of
1
picolinic acid with a micelle-inducing hydrophobic chain. In the
course of his work, he discovered an unusual phenomenon: When
3
mg of the compound was sonicated and vortexed (10 min each)
with 10 mL of 0.25 M NaOH plus 10 mL of toluene, there were
formed stable, marble-like macroscopic spheres as shown in Figure
1
at two different concentrations of A. Apparently, the spheres are
encased by some sort of outer covering, and (with Filley’s consent)
we decided to further characterize this strange new “shell phase”.
Our initial efforts focused on defining the structural features
necessary for shell formation. This led to our synthesizing nine
analogues of A (Scheme 1) in which the tails, aromatic rings, and
linkers were varied. A representative synthetic route for 8 of the
Figure 1. (a) Shell phase formed from 2.4 mg of A. (b) Shell phase formed
from 5 mg of A. Toluene was used in both.
1
0 compounds (all identified by NMR, MS, and EA) is shown in
2-5
Scheme 2.
Scheme 1. Structures of 10 Compounds Studied
Among the set of 10 compounds, only A and C form stable shells
under the conditions described above. B also forms shells above 4
mg. When a vial of one of these systems was tipped, the spheres
rolled around freely like glass beads. In contrast, D, F, and G
formed only toluene-bearing foams (“aphrons”) which were not
further investigated. E, H, I, and J were intermediate in nature;
their spheres were distorted, cloudy, attached, and poly-disperse
as was also formed with A in heptane (Figure 2a). Thus, shell
formation is favored by the following structural attributes: a
picolinic acid scaffold, an amide linker bearing an NH, and a long
hydrocarbon chain. No correlation was noted between shell
formation and melting points (both A and F, for example, melt at
>
180 °C). Four conventional surfactants (Brij 30, Brij 97, CTAB,
Scheme 2. Synthetic Route to A-H
6
6
and SDS) and a phospholipid (DPPC) all failed to assemble into
the shell phase under similar conditions.
Proof that the spheres are water-filled came from the following
experiment. An orange aqueous solution of thymol blue (1 drop,
0.03 mg/mL) was injected with a syringe into an A-sphere with a
needle syringe (Figure 2b). The interior remained homogeneous
but turned bright blue as would be expected for the dye in basic
aqueous medium. Since the sphere remained blue for months, there
1
is no indication of leakage to the outside. H NMR of liquid
withdrawn from the interior (causing collapse of the shell) revealed
water with no NMR-detectable presence of surfactant. Aside from
identifying the sphere contents, the experiments showed that the
shells can sustain a puncture wound and then quickly repair the
resulting damage. However, spheres removed from the water/
toluene interface (where they tend to reside) did not survive when
they came into contact with the open air.
Under a light microscope, a population of spheres appears
uniformly round (Figure 3a), and the surface of an individual is
roughly textured (Figure 3b). The shell of a 200-µm sphere is much
more difficult to penetrate with a glass micropipet than is a giant
vesicle of equivalent size but composed of phospholipid bilayers.
When tapped quickly with a micropipet, a sphere responds like a
pool ball hit by a cue. No birefringence was observed under a light
microscope with crossed-polarizers. A sphere quickly dried under
high vacuum produced needlelike structures observable by SEM
‡
Visiting Student, Chalmers University of Technology, G o¨ teborg, Sweden.
11914
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J. AM. CHEM. SOC. 2005, 127, 11914-11915
10.1021/ja053432o CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
contrast, D, F, and G which do not form shells, have higher water
solubilities of 0.2, 3.8, and 0.040 mM, respectively. It seems,
therefore, that shell formation is predicated upon low solubility in
both water and toluene. Compound B, with a water solubility of
1.2 mM, is particularly relevant in this regard. At 3 mg/10 mL
base (our standard conditions), the water solubility of B has not
been exceeded, and shells do not form. But at 4 mg/10 mL the
amount of B exceeds its solubility, and shells now form. Thus, the
presence of insoluble compound is necessary for shell formation
in those compounds prone to form this phase. Water-insoluble
amphiphilicity cannot, however, be the only factor dictating shell
7
formation because poorly water-soluble gemini surfactants fail to
form shells. It seems, therefore, that intermolecular hydrogen
bonding involving the amide-NH and pyridine nitrogen, coupled
with toluene-assisted molecular mobility, are the key to the creation
of shells.
Figure 2. (a) “Imperfect” shell phase formed from A using heptane. (b)
Image in which one sphere contains a water-soluble dye.
Average diameter measurements under the microscope showed
that sphere size decreases with amount of compound (Figures 1
and 3a,b). It was a simple matter to estimate the average surface-
area-per-molecule in the shell by knowing the concentration and
2
total surface area. Thus, we calculated 1 ( 0.3 Å per molecule A
1
in agreement with Filley. Assuming that a picolinate molecule fits
in a 5 Å × 5 Å × 23 Å box, and that the boxes close-pack, the
shell thickness is estimated to be roughly 600 Å.
In summary, the shell phase forms when certain picolinates are
subjected to energy input (via sonication or vortexing) while
exposed to a water/toluene mixture. A shell, about 600 Å thick
and containing the picolinate and (very likely) toluene, surround
the water droplets that are always produced during the mixing
process. Solubility in either phase appears to be deleterious to shell
formation. The shells, stable for months, are not easily distorted
but can be punctured, even skewered, with a syringe needle without
destroying the sphere. Yet there is enough mobility among the
molecules to repair the physical damage after the needle is removed.
This, plus the absence of evidence for crystallinity, suggests a solid
or semisolid film forms when picolinates, with the aid of an
aromatic solvent, are provided the energy to rearrange themselves
on water droplet surfaces. Structure-activity comparisons among
the 10 compounds studied indicate that chain-chain association
and intermolecular hydrogen bonding are dominant forces in a side-
by-side self-assembly of the molecules within the shells.
Figure 3. (a) Light microscopy image of spheres formed from 26.9 mg of
A in water/toluene. (b) Light microscopy image of shell formed from 10.3
mg of A in water/toluene. (c) SEM image of dried shell. (3d) SEM image
of shell wall.
(Figure 3c,d), suggesting a propensity to self-assemble tangentially
to the sphere surface. Unfortunately, lack of single-crystal produc-
tion prevented X-ray analysis.
To make well-developed spheres, the organic phase must be
3
aromatic (PhCH , PhCl, PhBr, and PhCN were tested) or cyclo-
hexane. Ether, ethyl acetate, chloroform, n-heptane, and cooking
oils are unsatisfactory solvents (Figure 2a). Addition of 4 parts
toluene to 6 parts n-heptane allowed formation of “clean” spheres,
suggesting that toluene may be a component of the shell structure.
Consistent with this view, spheres made in toluene/water could be
transferred to pure ether or ethyl acetate (two solvents unfavorable
to shell formation) where the spheres persisted happily at the bottom
of the vials. Transfer to protic solvents such as ethanol caused
instant bursting. Although spheres do form in buffers (pH ) 7-9),
an aqueous phase of 0.25 M NaOH (or >1 equiv base) gives the
highest quality and largest volume of spheres. Varying the ionic
strength by adding NaCl (0, 0.25, 0.5, and 3 M) to 0.025 M NaOH
had virtually no effect upon formation of the shell phase.
Acknowledgment. This work was supported by the NIH and a
Woodruff Graduate Fellowship. We also thank Dr. Robert Apkarian
and the Integrated Microscopy and Microanalytical Facility. The
Royal Society of Arts and Sciences in G o¨ teborg sponsored, in part,
the visit of D.L.
References
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(
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Solubility properties in water turned out to be critical for shell
formation. Quantitative HPLC analysis (C18 reverse-phase column;
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(
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3 3
60/40 CHCl /CH OH; evaporative light-scattering detector) showed
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(
a 0.1-0.2 mM toluene solubility for the carboxylate salts of eight
compounds in Scheme 1. Water solubilities for A and C, two
compounds amenable to shell formation, are very low: <10 µM.
Borderline cases H, I, and J also fall below our detectability. In
6) CTAB is an abbreviation for cetyltrimethylammonium bromide, SDS is
sodium dodecyl sulfate, and DPPC is dipalmitoylphosphatidylcholine.
7) Menger, F. M.; Littau, C. A. J. Am. Chem. Soc. 1991, 113, 1451-1452.
(
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