& Carbohydrate Chemistry The High-Throughput Synthesis and Phase Characterisation of Amphiphiles: A Sweet Case Study George C. Feast, Oliver E. Hutt, Xavier Mulet, Charlotte E. Conn, Calum J. Drummond,* and G. Paul Savage* [a] Abstract: A new method for the discovery of amphiphiles by using high-throughput (HT) methods to synthesise and characterise a library of galactose- and glucose-containing amphiphilic compounds is presented. The copper-catalysed azide–alkyne cycloaddition (CuAAC) “click” reaction between azide-tethered simple sugars and alkyne-substituted hydro- phobic tails was employed to synthesise a library of com- pounds with systematic variations in chain length and unsa- turation in a 24-vial array format. The liquid–crystalline phase behaviour was characterised in a HT manner by using synchrotron small-angle X-ray scattering (SSAXS). The ob- served structural variation with respect to chain parameters, including chain length and degree of unsaturation, is dis- cussed, as well as hydration effects and degree of hydrogen bonding between head groups. The validity of our HT screening approach was verified by resynthesising a short- chain glucose amphiphile. A separate phase analysis of this compound confirmed the presence of numerous lyotropic liquid–crystalline phases. Introduction Amphiphilic compounds have a variety of uses, from simple surfactants used in household detergents, to cutting-edge drug delivery and nanomedicine applications. [1] In biomedicine these compounds are used for membrane-bound protein crys- tallisation, [2] as magnetic resonance imaging (MRI) agents, [3] for advanced cosmetic and nutriceutical delivery applications, [4] as well as more prospective applications in biosensing and bio- fuel cells. [5] These applications require us to understand and control the nanostructure of the self-assembled materials. The correct prediction of the lyotropic liquid–crystalline phase behaviour of a given amphiphile is not trivial; however, it is well known that the phase adopted by an amphiphile in water is governed, in part, by the local constraints imposed by the effective shape of the molecule. Primarily, those with inter- faces that curve away from water are denoted as normal phases (type I), and those that curve towards water are denot- ed as inverse phases (type II). The typical phase sequence ob- served as the head-group size increases, relative to the effec- tive chain volume (i.e. as the mean interfacial curvature be- comes more positive), is L a !Q I !H I !I I !L 1 . The lamellar (L a ) phase has a mean interfacial curvature of zero and consists of a stack of lipid bilayers separated by water layers. The normal bicontinuous cubic (Q I ) phases are based around the structure of a three-dimensional periodical minimal surface and can be subdivided into three types: diamond (D, space group Pn3 ¯ m), primitive (P, Im3 ¯ m) and gyroid (G, Ia3 ¯ d). [6] As the mean interfa- cial curvature increases, a hexagonal phase (H I ) may form, con- sisting of rods of oil channels packed into a hexagonal lattice (Figure 1). Micelles consisting of spheres of head groups with oil-like centres can form with the highest curvatures. Micelles general- ly form a disordered fluid (L 1 ) phase; however, in some circum- stances, they can pack into a cubic or hexagonal lattice (I I , space groups Pm3 ¯ n, Fm3 ¯ m, Im3 ¯ m, Fd3 ¯ m and P6 3 /mmc). Inverse phases adopt a similar sequence with increasing negative in- terfacial curvature; L a !Q II !H II !I II !L 2 . [7] For any given application, a particular lyotropic phase is usu- ally required. To date, there has been a limited pool of amphi- philes available for task-specific applications, limited by the time-consuming task of synthesis, purification and characterisa- tion. Despite high-throughput methods having been used in- creasingly in materials characterisation, [8] the soft-matter com- munity has generally lagged in adopting these principles to develop fit-for-function mesophases engineered for a specific purpose. [9] Herein, we describe the first high-throughput (HT) synthesis and characterisation of a library of glycosylated amphiphiles with systematic variation in hydrocarbon chain length, degree of unsaturation and head-group geometry. Previous work within our group established a modular, HT amphiphile click- chemistry protocol to synthesise a library of tertiary amino am- phiphiles. [10] In this simple approach, alkyne-substituted side chains undergo the copper-catalysed, Huisgen 1,3-dipolar cy- cloaddition (CuAAC) [11] with azide-substituted tertiary amino [a] Dr. G. C. Feast, Dr. O. E. Hutt, Dr. X. Mulet, Dr. C. E. Conn, Dr. C. J. Drummond, Dr. G. P. Savage CSIRO Materials Science and Engineering Bag 10, Clayton South MDC, VIC 3169 (Australia) E-mail : calum.drummond@csiro.au paul.savage@csiro.au Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/chem.201303514. Chem. Eur. J. 2014, 20, 2783 – 2792  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2783 Full Paper DOI: 10.1002/chem.201303514