Towards the Prediction of Global Solution State Properties for Hydrogen Bonded, Self‐Associating Amphiphiles

Abstract Through this extensive structure–property study we show that critical micelle concentration correlates with self‐associative hydrogen bond complex formation constant, when combined with outputs from low level, widely accessible, computational models. Herein, we bring together a series of 39 structurally related molecules related by stepwise variation of a hydrogen bond donor–acceptor amphiphilic salt. The self‐associative and corresponding global properties for this family of compounds have been studied in the gas, solid and solution states. Within the solution state, we have shown the type of self‐associated structure present to be solvent dependent. In DMSO, this class of compound show a preference for hydrogen bonded dimer formation, however moving into aqueous solutions the same compounds are found to form larger self‐associated aggregates. This observation has allowed us the unique opportunity to investigate and begin to predict self‐association events at both the molecular and extended aggregate level.


Chemical structures
mL), heated at reflux overnight and taken to dryness, dissolved in chloroform (50 mL) and washed with water (50 mL). The organic phase was then taken to dryness. The pure product was obtained by flash chromatography 100 % ethyl acetate followed by 100 % methanol. The methanol fraction was taken to dryness with further addition of TBAOH in methanol (1N) as necessary to give the pure product as a white solid with a yield of 76 % (0.89 g, 1.11 mM); melting point: 149 ⁰C; 1  Compound 13: The compound was produced with an analogous method to that described with the synthesis of compound 9. The pyridinium salt (0.38 g, 1.00 mM) was dissolved in a solution of 40 % THA hydroxide in H 2 O (0.93 g, 1.00 mM) to give the pure product as an oil with a yield of 98 % (0.64 g, 0.98 mM); 1 H NMR (400 MHz, 298.15 K, DMSO-d 6  Compound 19: TBA hydroxide (1N) in methanol (1.73 mL, 1.73 mM) was added to 2aminomethanesulfonic acid (0.19 g, 1.73 mM) and taken to dryness overnight. 4-Methoxyphenyl isothiocyanate (0.24 mL, 1.73 mM) was added to a stirring solution of the TBA salt in ethyl acetate (10 mL), heated at reflux overnight, forming an oil. The oil was decanted, dissolved in chloroform (20 mL) and washed with water (20 mL). The organic phase was then taken to dryness to give the pure product as a white solid with a yield of 50 % (0.45 g, 0.86 mM); melting point: Compound 26: Trifluoroacetic acid (5 mL) was added to a stirring solution of Compound 25 (0.30 g, 0.90 mM) in dichloromethane (10 mL) and left at RT for 30 minutes. Additional dichloromethane (10 mL) was added and the organic layer washed with sodium hydroxide (20 mL, 6 M). The aqueous phase was then taken to dryness, dissolved in H 2 O (20 mL), neutralised by the dropwise addition of Hydrochloric acid (2M), with the precipitate removed by filtration to give the pure product as a brown solid with a yield of 83 % (0. Compounds 32, 34 -39: One equivalent of the appropriate hydroxide salt was added to ethane sulfonic acid (0.22 g, 2.0 mM) in methanol (1 mL) and taken to dryness to give the pure product as a white solid/ clear oil with a yield of 100 %.
Tetramethylammonium hexafluorophosphate: One equivalent of tetramethylammonium hydroxide was added to hexafluorophosphoric acid (2.0 mM) in methanol (1 mL) and taken to dryness to give the pure product as a white solid with a yield of 100 %.
Pyridinium hexafluorophosphate: One equivalent of pyridine was added to hexafluorophosphoric acid (2.0 mM) in methanol (1 mL) and taken to dryness to give the pure product as a white solid with a yield of 100 %.
Compound 33: One equivalent of pyridine was added to ethane sulfonic acid (0.22 g, 2.0 mM) and taken to dryness to give the pure product as a white solid with a yield of 100 %.                                                                        Figure S73 -1 H NMR of pyridinium hexafluorophosphate in DMSO-d 6 conducted at 298.15 K.

Self-association constant calculation
Compound 1 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 2 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 3 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 5 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 6 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 9 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 10 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 11 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 12 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 13 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 14 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 23 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 24 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 25 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 26 -Dilution study in DMSO-d 6

Self-association constant calculation
Compound 27 -Dilution study in DMSO-d 6

DLS data
Size distribution data                                                                                           b -DLS Size distribution in a solution of DMSO for compound 28 could not be gathered due to the inherent absorbance and fluorescent characteristics of this compound. Figure

Low level in-silico modelling
Computational calculations to identify primary hydrogen bond donating and accepting sites were conducted in line with studies reported by Hunter using Spartan 16''. 1 Calculations were performed using semi-empirical PM6 methods, after energy minimisation calculations, to identify E max , E min and polarizability values. PM6 was used over AM1 in line with research conducted by Stewart.                           Figure S302 -ESImass spectrum collected for compound 1.