L. J.
White
a,
N. J.
Wells
b,
L. R.
Blackholly
a,
H. J.
Shepherd
a,
B.
Wilson
a,
G. P.
Bustone
a,
T. J.
Runacres
c and
J. R.
Hiscock
*a
aSchool of Physical Sciences, University of Kent, Park Wood Road, Canterbury, Kent CT2 7NH, UK. E-mail: J.R.Hiscock@Kent.ac.uk; Tel: +44(0) 1227 823043
bSchool of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK
cSchool of Biosciences, University of Kent, Park Wood Road, Canterbury, Kent CT2 7NH, UK
First published on 26th September 2017
Herein, we present a series of five tetrabutylammonium (TBA) sulfonate–urea amphiphilic salts. In solution these amphiphilic salts have been shown to form a variety of self-associated species. The proportion and type of which are both solvent and concentration dependent. In DMSO-d6 a variety of NMR experiments provide evidence towards the formation of mainly dimeric over larger aggregate species. Increasing the percentage of water was shown to increase the concentration of the larger aggregates over dimers in solution. A correlation was established between critical micelle concentration (CMC) values obtained in a 1:19 EtOH:H2O mixture, dimeric self-association constants obtained in a DMSO-d6 – 0.5% H2O and the results of simple semi-empirical PM6 computational modelling methods. This approach begins to quantify the role of hydrogen bonding in amphiphile self-association and the effects it imparts on surfactant properties. This consequently provides preliminary evidence that these properties maybe predicted by simple low level computational modelling techniques.
Many of these self-associated systems are stabilised through the formation of intermolecular hydrogen bonds. This has been highlighted through the work of Steed and co-workers in which covalent bonds were replaced by non-covalent hydrogen bonds in the design of supramolecular gels.12 Zhou and co-workers have also shown the potential of hydrogen-bonded amphiphiles to act as drug/gene delivery systems.13 Yagai and co-workers have utilised hydrogen bonding in the construction of molecular semi-conductors,14 while Ikkala and co-workers have shown that hydrogen bonds can be used to drive the self-assembly of cobalt nanoparticles to form hollow capsids.15 This work highlights the important role hydrogen bonding takes in self-association processes, producing wide-ranging functional materials. Developing an understanding and predictable control of these interactions at a molecular level is therefore of high importance.
The use of neutral hydrogen bond donating (HBD) receptors for the selective coordination of anionic guest species in competitive solvent mixtures is well known.16,17 However, there are relatively few examples of low molecular weight compounds (MW < 500) which incorporate HBD cavities, covalently linked to an anionic substituent. One example of this type of molecular structure published by Gale, Sambrook and co-workers uses this combination of anionic HBA and HBD motifs for the selective hydrogen bonded coordination of a neutral phosphonate over anionic species.18
This class of covalently linked HBD–anion compound, specifically containing a urea-spacer-sulfonate/carboxylate motif was first probed for its surfactant properties by Faustino and co-workers19–22 with examples shown to exhibit similar critical micelle concentrations (CMC) to that of sodium decanoate.23 We have extended this work, producing a series amphiphilic salts containing the covalently linked urea/thiourea–CH2–sulfonate motif. Our preliminary solution state study confirmed that in DMSO solution the anionic portion of these amphiphilic salts self-associates through the formation of intermolecular hydrogen bonds. We have also shown that this self-associative hydrogen bonded network can be modified though the addition of competitive hydrogen bond accepting (HBA) and HBD species.24 A second solid state study showed that in the presence of a weakly-coordinating counter cation, such as tetrabutylammonium (TBA), the urea/thiourea–CH2–sulfonate ion was found to self-associate through intermolecular hydrogen bonded urea:sulfonate complex formation; the hydrogen bond length and angle were influenced by the relative acidity of the HBD groups present within the monomeric structure.25 We have also looked to utilise this motif towards the templating of DNA incorporated nanostructures.26 Herein we present the synthesis of four novel, intrinsically fluorescent, sulfonate–urea based amphiphilic salts 1, 2, 4, 5. Although a single crystal X-ray structure has previously been reported for 3,25 any studies relating to self-association properties of this amphiphile within the solution or gas phase have not been explored. This amphiphile acts as a standard, allowing the effects of amphiphile aromaticity and addition of benzothiazole moieties to be explored.
The self-association properties of these five amphiphiles have been investigated in the solid, gas and solution states. In addition, the surfactant properties for these amphiphilic salts have also been explored, with correlations established between experimentally derived self-association constants, CMC values and computationally derived electrostatic surface potential values. This has allowed us to begin to quantify the contribution of hydrogen bonded complex formation toward global solution state properties, and highlights the possible use of low level theory calculations towards predicting these physical properties for a structurally similar class of amphiphile in a comparable, but more accessible manner to those prognostic studies produced by Nagarajan and Ruckenstein.27
Fig. 1 Single crystal X-ray structure of 2, illustrating dimerization through urea–anion complexation. TBA counter cations have been omitted for clarity. Interior angle of self-association = 180.0°. |
Fig. 2 Single crystal X-ray structure of 4, illustrating dimerization through urea–anion complexation. TBA counter cations and associated water molecules have been omitted for clarity. |
The crystal structure of 5 also forms a sulfonate–urea hydrogen bonded dimer, as shown in Fig. 3. In this example the dimer is only stabilised through the formation of two intermolecular sulfonate–urea hydrogen bonds due to the intramolecular hydrogen bond formed between the HBA benzothiazole nitrogen and a HBD NH urea group. This means that this NH group is no longer free to form dimer stabilising intermolecular hydrogen bonds. As with 2, calculation of the interior angle of self-association shows this dimer to be planar.
It is well known that anthracene undergoes oxidation to form anthraquinone.28 From the crystal structure shown in Fig. 4, we see that the anthracene substituent of 1 is susceptible to this process. However, this crystal structure is also an example of molecular self-sorting. During the two week crystallisation process a proportion of 1 was oxidised to form the analogous anthraquinone. The dimer formed is again stabilised through the formation of four intermolecular sulfonate–urea hydrogen bonds, in an identical arrangement to that observed for 4. This results in the formation of a dimer with an interior hydrogen bond angle of 15.3(4)°, ≈3.5 times smaller than that observed with 4. This is because the dimer is unsymmetrical, containing two different monomeric units, one electron rich (anthracene) and one electron poor (anthraquinone). The interaction of these electron rich and electron poor aromatic ring systems bring together the planes of the dimer. In light of this observation, when studying the self-association properties of 1 in both the solution and gas phase, periodic 1H NMR studies were preformed to ensure the purity of the compound used.
Fig. 4 Single crystal X-ray structure of 1, illustrating dimerization through urea–anion complexation. TBA counter cations have been omitted for clarity. |
Amphiphile | m/z [M]− | m/z [M + M + H+]− | ||
---|---|---|---|---|
Theoretical | Actual | Theoretical | Actual | |
1 | 329.0602 | 329.0567 | 659.1204 | 659.1210 |
2 | 279.0445 | 278.9615 | 559.0890 | 558.9373 |
3 | 229.0289 | 229.0292 | 459.0578 | 459.0649 |
4 | 376.0431 | 376.039 | 753.0862 | 753.0864 |
5 | 362.0275 | 362.0261 | Not observed |
Fig. 5 Graph comparing peak maxima obtained from average intensity particle size distribution of 1 and 3–5 in DMSO by DLS. Samples were measured at 25 °C (dark solid filled circles), then heated to 40 °C (light patterned filled circles) and after cooling back to 25 °C (black unfilled circles). The full data sets, including peak widths, can be found within the ESI.† Red = 1, green = 3, blue = 4, purple = 5. |
DLS studies show the presence of three different sized structures within a DMSO solution of 1–5. The first approximately 1 nM in diameter is likely to be the sulfonate–urea monomer or dimeric species, the second approximately 200–600 nM is attributed to a larger self-associated species, and a third >1000 nm is likely to be an aggregate of the smaller self-associated species. This third species is not observed with 4 and is most prevalent with 5. The concentration of these largest structures decreases when diluted and/or annealed, further supporting the hypothesis that these structures are aggregates of smaller ones. By comparison the mid-size species remain fairly stable in solution throughout the annealing process. Although there is a decrease in size with increasing temperature, the original sized structures are regenerated upon cooling. There is a general decrease in size of these aggregates with decreasing concentration from 111.27 mM to 0.56 mM. The smallest sized aggregates (≈1 nm) are observed primarily with 4 as shown in Fig. 6 however; as this information has been obtained from an intensity distribution the presence of a few large structures in solution can mask the presence of smaller ones, especially in instances where the differences in size of these aggregates can be greater than 1000 nm.
In order to compare the effects of altering solvent conditions on the self-associated aggregates present in solution, comparative DLS studies were conducted with 1–5 in a variety of aqueous mixtures. The concentration of these studies was determined by the solubility of these amphiphiles. A comparison of those structures observed by DLS can be seen in Table 2. Moving from a 100% DMSO solution to a DMSO:H2O 1:1 mixture appears to stabilise larger aggregate structures, whereas further increasing the percentage of H2O results in a general decrease the aggregate size. In order to increase the molarity of amphiphile with increasing proportions of H2O, DMSO was replaced with ethanol. Excluding evidence of dimer/monomer within the solution state, in an EtOH:H2O 1:19 mixture, 1–5 only show the formation of a single type of aggregated structure exhibiting the following tend 3 (400 nm) > 2 (260 nm) > 5 (220 nm) > 1 (160 nm) > 4 (120 nm). In splitting this family of amphiphiles into two sub groups: sub-group one containing 1, 2 and 3 with decreasing aromatic ring system size, and sub-group two containing 4 and 5 which both have benzothiazole substituents. Considering these two sub-groups independently shows the increase the aromatic ring system size (1 > 2 > 3) to correlate with decreasing size aggregates (1 < 2 < 3). We also observe that in general, intramolecular hydrogen bonded 5 forms larger structures than 4.
Solvent | Conc. (mM) | 1 | 2 | 3 | 4 | 5 |
---|---|---|---|---|---|---|
a The absorbance and emission properties of this amphiphile prevented DLS measurements. | ||||||
DMSO | 5.56 | 530, 110 | 620 | 400 | 1100 | |
1.1 | ||||||
0.56 | 530 | 530 | 400 | 530 | ||
0.7 | ||||||
DMSO:H2O, 1:1 | 5.56 | 2000 | 620 | 2000 | 1300 | 2300 |
460 | 220 | 260 | ||||
0.56 | 1100 | 960 | 530 | 960 | 2700 | |
710 | ||||||
DMSO:H2O, 3:7 | 5.56 | 340 | 830 | 1100 | 460 | 1300 |
79 | ||||||
0.56 | 400 | 400 | 620 | 620 | 340 | |
DMSO:H2O, 1:4 | 0.56 | 340 | 340 | 710 | 620 | 830 |
59 | 70 | 91 | ||||
EtOH:H2O, 1:19 | 5.56 | 220 | 160 | 220 | 300 | 300 |
59 | ||||||
0.56 | 160 | 260 | 400 | 120 | 220 | |
0.8 |
λ max (nm) | Solvent | |||||
---|---|---|---|---|---|---|
DMSO | DMSO:H2O, 1:1 | DMSO:H2O, 3:7 | DMSO:H2O, 1:4 | EtOH:H2O, 1:19 | ||
1 | λ ex | 281 | 276 | 272 | 274 | 260 |
λ em | 445 | 441 | 437 | 432 | 437 | |
ΔλST | 164 | 165 | 165 | 158 | 177 | |
2 | λ ex | 315 | 337 | 294 | 296 | 224 |
λ em | 377 | 395 | 377 | 377 | 380 | |
ΔλST | 62 | 58 | 83 | 81 | 156 | |
4 | λ ex | 339 | 335 | 333 | 332 | 331 |
λ em | 392 | 395 | 394 | 397 | 399 | |
ΔλST | 53 | 60 | 61 | 65 | 68 | |
5 | λ ex | 280 | 280 | 283 | 285 | 229 |
λ em | 430 | 419 | 419 | 417 | 415 | |
ΔλST | 150 | 139 | 136 | 132 | 186 |
As the type of aggregate formed is solvent dependent, observing the aggregates directly in the solution state has distinct advantages over methods that involve the de-solvation or freezing of a sample. As with all imaging techniques, observations made may not be representative of the sample bulk. Microscopy results, without comparative studies such as DLS or NMR, should be taken as qualitative rather than quantitative unless otherwise stated. The excitation and emission properties of 1 and 2 prevented observations of those structures in solution by fluorescence microscopy due to inherent background fluorescence and a comparatively small Stoke shift leading to incompatibility with microscope filters respectively. Solutions containing 4 and 5 were successfully visualised at comparative concentrations to those DLS studies, providing unambiguous structure identification.
In line with techniques previously reported by Levin29 the movement of these aggregates in solution was restricted by placing 10 μL of the appropriate solution to be observed onto an agarose pad. A cover slip was then applied to the surface of the sample to prevent solvent evaporation. Interaction of the aggregates with the agarose pad allows clear images to be obtained. Photobleaching during the imaging led to a loss of fluorescence emission intensity, and therefore some amphiphile aggregates could not be successfully captured in one or both images. Comparing the images obtained for 4, it appears that in a DMSO solution (Fig. 7) those structures formed are conglomerates of smaller aggregated species whereas in a DMSO:H2O 1:19 mixture (Fig. 8) there is evidence of larger singular aggregate species with little internal structure. A similar type of structure to that seen in Fig. 8 was observed for 5 in a EtOH:H2O 1:19 mixture (Fig. 9).
Fig. 7 A transmitted light image (left) and DAPI filter composite image (right) of 4 (0.50 mM) in DMSO. An example of those aggregates formed has been circled for clarity. |
Fig. 8 A transmitted light image (left) and DAPI filter composite image (right) of 4 (0.50 mM) in a DMSO:H2O 1:19 mixture. An example of those aggregates formed has been circled for clarity. |
Fig. 9 A transmitted light image (left) and DAPI filter composite image (right) of 5 (0.50 mM) in a EtOH:H2O 1:19 mixture. An example of those aggregates formed has been circled for clarity. |
A comparison of the average size and spread of size for the aggregate structures formed by 4 and 5 in different solvent mixtures obtained by DLS and microscopy techniques is shown in Fig. 10. The average size of those aggregated structures observed by these different methods is in good agreement. In most instances the average size of those structures observed by DLS is slightly higher than those observed by microscopy which is as expected. Using microscopy measurements, we are able to measure the actual size of the aggregate, whereas DLS measurements includes the solvation sphere surrounding the aggregate. The size of all structures observed by microscopy methods lie within the spread of aggregate sizes that are observed by DLS.
The 1H DOSY studies show that the TBA counter cation has a different diffusion constant from that of the sulfonate–urea anion, demonstrating that these two species are not strongly coordinated in solution. The translational diffusion constant obtained from 1H NMR DOSY was used to calculate the hydrodynamic diameter of the anionic species in solution, via the Stokes–Einstein equation.30 As with DLS, the size of these structures should be treated with caution as these approximations assume that the structure observed is a sphere and that the size of the complex is large compared to that of the solvent.31 These systems (as shown by the dilution studies) exist in fast exchange, which can also cause complications with data interpretation.32,33 The use of the NH signals to ascertain translational diffusion constants proved unreliable therefore diffusion constants were obtained from the aromatic CH and CH2 signals, giving upper and lower limits for the hydrodynamic radius of 4 at 26 °C (1.61 nm ≤ dH ≥ 1.66 nm), after being heated to 39 °C (1.44 nm ≤ dH ≥ 1.51 nm) and then cooled back to 26 °C (1.58 nm ≤ dH ≥ 1.61 nm). The comparative size of these structures calculated by DLS, stable during the entire annealing process was 1.12 nm (Fig. 6), which correlates well with the 1H DOSY NMR results. However, we do not observe the formation of the larger structures observed by DLS via this NMR method. In this case it is hypothesised that these larger structures exist in concentrations that are too low or the size of the aggregate is too large to be observed by this NMR method. The DLS experiments had already indicated that these larger structures may not exist in any great quantities within the solution state and a comparative 1H NMR experiment supports this. In this experiment a solution of 4 (111.12 mM) in DMSO-d6 was doped with 5 μL of DCM. Comparative integration of the DCM signal with the aromatic CH and CH2 signals of the sulfonate–urea showed no discernible loss of the sulfonate–urea anion from the solution, showing that the larger aggregated structures exist in very small quantities and therefore cannot be detected under these NMR experimental conditions. An analogous pair of 1H NMR experiments were conducted with 4 (≈6 mM) in D2O (0.5 mL) with the addition of ethanol (25 μL) and DMSO (5 μL) respectively into each experiment. Comparative integration showed the apparent loss of 10% and 14% of 4 in each case respectively. It is hypothesised that this ‘lost’ material is now invisible to the NMR spectrometer as it has effectively been removed from the solution state into the solid state aggregates.
The NMR experiments conducted with 4 show that only a very small percentage of the sulfonate–urea anion is held in the larger aggregate structures. The size of those structures remaining in solution (≈1 nm) would suggest that they are anionic dimers, such as those observed in solid state and gas phase experiments. The downfield change in chemical shift of the urea NHs with increasing concentration of amphiphile confirms the formation of a hydrogen bonded species. These data have been fitted to both dimerization/equal K (EK)34,35 and cooperative equal K (CoEK) models, see Table 4. These models both assume one component, one-dimensional homogenous aggregation36 with all self-association constants assumed equal for the EK model whereas the CoEK model assumes that the first self-association constant differs from that observed for identical subsequent events.37 For those models tested, the EK model gave the best fit to these dilution study data, with >70% monomer present in DMSO-d6 – 0.5% H2O solutions of 1–5 in a concentration less than 0.03 M. This further supports the hypothesis that we are predominately observing dimer formation within this solvent system and makes chemical sense when considering those single crystal X-ray structures presented in Fig. 1–4. Although the self-association constants are low we observe the following trend 4 (2.7 M−1) > 1 (1.5 M−1) > 5 (0.6 M−1) > 3 (0.3 M−1) > 2 (<0.1 M−1). This trend inversely correlates with the size of nanostructure observed by DLS in the solution state, the stronger the self-association the smaller the self-associated aggregate. As we increase the size of the sulfonate–urea anion from benzene to anthracene/benzathiazole we increase the dimerization constant and again see that the presence of the intramolecular hydrogen bond of 5 also lowers the self-association constant when compared to 4.
Amphiphile | EK model (M−1) | CoEK model (M−1) | |||
---|---|---|---|---|---|
K e | K dim | K e | K dim | ρ | |
a Data fitted using L-BFGS-B (quasi-Newtown) rather than Nelder–Mead (simplex) methods. | |||||
1 | 2.9 ± 0.5% | 1.5 ± 0.2% | 8.6 ± 1.1% | 4.3 ± 0.5% | 0.5 ± 2.5% |
2 | <0.1 ± 1.5% | <0.1 ± 0.8% | 0.5 ± 43.1% | 0.3 ± 21.5% | 0.0 ± 47.0% |
3 | 0.6 ± 3.0% | 0.3 ± 1.5% | 13.0 ± 5.7% | 6.5 ± 2.9% | 0.2 ± 23.8% |
4 | 5.3 ± 0.6% | 2.7 ± 0.3% | 13.0 ± 0.7% | 6.5 ± 0.3% | 0.5 ± 2.0% |
5 | 1.2 ± 2.1% | 0.6 ± 1.1% | 6.2 ± 8.8% | 3.1 ± 4.4% | 0.4 ± 17.8% |
The CMC values calculated for a EtOH:H2O 1:19 solution are reviewed in Table 5 with the trend 4 < 1 < 5 < 2 < 3, with over an 80 fold increase in CMC observed between 4 (CMC = 0.50 mM) and 3 (CMC = 40.89 mM). The CMC for our most effective surfactant, 4, was also established in 100% H2O to be 0.81 mM. This is an order of magnitude lower than sodium dodecyl sulfate which has a reported CMC, under the same conditions of 8.08 (ref. 40) – 8.2 (ref. 41) mM. Comparative zeta potential measurements (Table 5), obtained for 1, 2, 4 and 5 (5.56 mM) in a EtOH:H2O 1:19 solution, confirmed that these solutions contained stable aggregates (−30 mV ≥ zeta potential ≥ +30 mV). In comparison a solution of 3 was shown to contain structures with incipient stability. This measurement was obtained at a concentration below the CMC in the case of 3, 2 and 5, however this does not mean that stable aggregated species do not exist in solution.42
Amphiphile | EtOH:H2O 1:19 | H2O | |||
---|---|---|---|---|---|
Zeta potential (mV) | CMC (mM) | Surface tension (mN m−1) | CMC (mM) | Surface tension | |
1 | −82 | 2.52 | 43.15 | ||
2 | −96 | 10.67 | 46.67 | ||
3 | −19 | 40.89 | 47.90 | ||
4 | −101 | 0.50 | 46.50 | 0.81 | 54.68 |
5 | −79 | 9.54 | 48.71 |
A plot of reciprocal CMC (obtained for a EtOH:H2O 1:19 solution) vs. dimerization constant (obtained in DMSO-d6 – 0.5% H2O) reveals a correlation between these two experimentally derived values (Fig. 14). As the strength of dimerization increases the CMC is shown to decrease. Water and DMSO are both highly competitive hydrogen bonding solvents. However as previously demonstrated, DMSO is not hydrophilic enough to extensively stabilise extended self-associated aggregates in solution, whereas an EtOH:H2O 1:19 solution is.
Fig. 15 Electrostatic potential map calculated for 4 using semi-empirical PM6 modelling methods. Emax and Emin values depicted in the figure legend are given in kJ mol−1. |
Comparing computationally derived Emax and Emin values (Fig. 16) across this series of five amphiphiles we see a general increase in both Emax and Emin values with increasing aromaticity from phenyl, to naphyl to anthracene. There is also a decrease in Emax and Emin values from 4 to 5, primarily due to the presence of the intramolecular hydrogen bond in 5. The trend in Emax and Emin values is as follows: 4 > 1 > 2 > 5 > 3. The decrease in Emax can be interpreted as a decrease in partial positive surface charge and therefore deactivation of the HBD group. These trends correlate with those observed for dimerization constant (Fig. 17) and are the inverse of those observed with CMC (Fig. 18). This is evidence that not only is CMC dependent on dimerization process but that these properties, for this class of amphiphile, may be predicted by simple computational modelling techniques.
Footnotes |
† Electronic supplementary information (ESI) available: This includes experimental details and DLS, zeta potential, tensiometry, microscopy, mass spectrometry NMR, crystallography‡ and UV-Vis data. CCDC 1562758–1562761. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc03888g |
‡ A suitable crystal of each amphiphile was selected and mounted on a Rigaku Oxford Diffraction Supernova diffractometer. Data were collected using Cu Kα radiation at 100 K. Structures were solved with the ShelXT45 or ShelXS structure solution programs via direct methods and refined with ShelXL46 on least squares minimisation. Olex2 (ref. 47) was used as an interface to all ShelX programs. |
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