A Conceptual Design of Fluorous Surfactants Based on a Heterocyclic Core, Put Into Practice Through Synthesis of Fluorous 1,2,3-Triazoles Roger W

Chiang Mai J. Sci. 2009; 36(2) 247 Chiang Mai J. Sci. 2009; 36(2) : 247-257 www.science.cmu.ac.th/journal-science/josci.html Invited Paper A Conceptual Design of Fluorous Surfactants Based on a Heterocyclic Core, Put into Practice Through Synthesis of Fluorous 1,2,3-Triazoles Roger W. Read* and Xiao Bei Wang School of Chemistry, The University of New South Wales, UNSW Sydney NSW 2052, Australia. *Author for correspondence; e-mail: [email protected] ABSTRACT The concept of a design of fluorous surfactants based on a heterocyclic core molecule is introduced and illustrated through the synthesis of polyfluoroalkyl-substituted 1,2,3-triazoles. A two step, one-pot process is described in which a small range of perfluoroalkylethyl azides is prepared in situ and made to undergo Huisgen 1,3-dipolar cycloaddition with terminal alkynes. Measurement of the changes in surface tension of the library of fluorous triazoles at different concentrations in m-xylene reveals unusual behaviour in molecules with a secondary, C8 alkyl substituent. Keywords: organic synthesis, heterocycles, fluorous chemistry, surfactants, click chemistry, polyfluoroalkyl-1,2,3-triazoles. 1. INTRODUCTION Fluorous surfactants have been studied might have applications in the design of new widely, not least for their interest in drug delivery systems and, through self- combination with perfluorocarbons, as assembly, unique molecular devices. emergency blood replacements.[1] Highly Considerable literature exists in the area of fluorinated amphiphiles and colloid systems fluorous block polymers with localised are chemically stable and can carry high crystalline segments and fluorous liposomes concentrations of oxygen and carbon dioxide, and vesicles for drug delivery, but, with a few and therefore have many applications in the exceptions [8-11], most fluorous components biomedical field [2,3]. Fluorous surfactants have been relatively unsophisticated or difficult have also been studied in combination with to synthesise [12-20]. non-fluorous surfactants, where they can We describe in this paper the concept of influence the properties of the surfactants. The fluorous surfactants based on a heterocyclic unique solubility properties of highly fluorous core. While a number of molecules of this materials also mean that they self associate type have been described, very few have been more readily than non-fluorous surfactants, examined for their self assembly or surfactant and readily form multi-layered architectures properties and there has been no systematic rather than normal bi-layered structures [3-7]. study to our knowledge of surfactants of this This latter feature attracted our interest type. The concept will be illustrated with the because it indicated that fluorous surfactants synthesis of a small library of structurally 248 Chiang Mai J. Sci. 2009; 36(2) 5related fluorous 1,2,3-triazoles and their have been considered as surfactants.[14] This evaluation as surface active agents. There have describes a single family of molecules that are been three reports of fluoroalkylated 1,2,3- carboxylic acid derivatives and there has been triazoles[14,21,22] but only one in which they no more recent development of the work. Figure 1 Traditional surfactants (Figure 1) com- the two moieties are sometimes held together prise one or more lipophilic groups (tails) by an intermediate group, such as in the attached to a polar (neutral or charged) head phospholipids, where often two of the group. The two moieties are often directly hydroxyl groups of glycerol are esterified by attached to each other, as in long chain, saturated saturated or unsaturated fatty acids while the or unsaturated alkanoate salts 1, long chain third forms a half phosphate ester, e.g. 3. alkyl-substituted quaternary ammonium salts Indeed, acetylcholine 4 is just one such 2, or glycolipids (ester conjugates of fatty acids. molecule in which the phosphate group is and short polyalcohols and sugars). In Nature, further esterified. Chiang Mai J. Sci. 2009; 36(2) 249 Fluorous analogues of each of these types in which the heterocyclic core comprises two have been reported, especially in the context or more heterocyclic subunits. The nearest of drug transport in materials related to blood surfactant examples to these in the literature substitutes, but all have been prepared by are referred to as gemini surfactants.[25] The relatively linear synthetic approaches. The latter molecules might serve as useful fluorous species that are conceived of here molecular inclusion species in which the two are of a distinct modular design. They have or more heterocycles could serve as ligands. any one of an array of heterocycles as the A second generation of the core conceptual core of the molecule, including aromatic and molecules might also have heterocycles that non-aromatic nitrogen, oxygen and sulfur are dynamic in their formation and fragmen- containing species. These might provide two, tation. This could lead to valuable dynamic three or more points of attachment of covalent chemistry outcomes, and even more substituents. A few isolated examples of sophisticated self-assembly possibilities. fluorous pyridine derivatives have been As a preliminary study to evaluate the reported.[23-24] concept, a series of n-alkyl and n-polyfluoroalkyl Fluorous materials generally repel aqueous substituted 1,2,3-triazoles was synthesised. and many common organic solvents, therefore Advantage was taken of the very reliable 1,3- one could imagine many interesting situations dipolar cycloaddition of organic azides with with heterocycles bearing combinations of alkynes, as a means of constructing the fluorophilic and lipophilic, 5, or fluorophilic molecules. and hydrophilic substituents, 6. Homogenous A range of perfluoroalkyl iodides 7-9 are materials made up of either of these combi- commercially available and were found to nations might form regular or inverted readily undergo conversion to perfluoroalkyl multilayers or micelles, or even liposomes, in azides in DMSO. Thus, iodides 7-8 were single fluorous, organic or aqueous solvents. treated with a small excess of sodium azide Similarly, heterogenous mixtures of two in DMSO at 60oC to give the corresponding different types of candidate surfactants, say 5 perfluoroalkyl azides 10 and 11 in 80% yield, and 6, might form relatively complex, in each case (Scheme 1, eq. 1). The higher complementary multilayers in biphasic solvent analogue, perfluorooctylethyl iodide 9, systems. appeared to give little or no product under An added dimension to the concept of these conditions, but when the reaction was the heterocycle as the core molecule is the repeated under more forcing conditions, at practical consideration that the heterocycle 75oC for 24 h, the desired azide 12 was isolated might be constructed from fragments that in 85% yield. are fluorophilic and either lipophilic or The Huisgen 1,3-dipolar cycloaddition hydrophilic, or it might be prepared as an approach to 1,2,3-triazoles,[26] popularised intermediate with one type of substituent as an example of ‘click’ chemistry[27] by possibly already attached, and a second type Sharpless in recent years, can, in its copper(I) of substituent added in a subsequent process. catalyzed form,[28-30] provide a highly The concept is also open in some cases to the regioselective outcome. In this case it would use of an heterocycle to which a third provide the desired 1,4-disubsituted substituent, perhaps one with a reporting derivatives in which the n-polyfluoroalkyl and function, could be attached, and to multi n-alkyl groups would be distal in their heterocyclic core modifications, i.e. situations disposition around the ring. In practice, 250 Chiang Mai J. Sci. 2009; 36(2) treatment of each of the fluorous azides 10- with only one isomer detected by 1H NMR 12 with phenylethyne under relatively standard spectroscopy in each of the crude products copper-catalyzed click conditions (CuSO4, (as determined by the absence of isomeric sodium ascorbate, 1:9 water-DMSO, ambient heteroaromatic proton signals). temperature) gave no reaction at all. Fortunately, With this success in hand, the most repetition without the addition of added difficult fluorous azide to make react, namely water and at elevated temperatures (Scheme 12, was subjected to parallel reactions with 1- 1, eq. 2) eventually gave satisfactory to good, hexyne, 1-octyne and 1-decyne, under the isolated yields of triazoles 13-15, respectively. same conditions that had given product with Notably, the higher homologue again required phenylethyne. The desired triazoles, 16-18, a slightly higher reaction temperature and were isolated in equally acceptable though significantly longer reaction time for complete somewhat lower yields (Scheme 1). reaction. The reactions were highly regioselective Scheme 1 Consideration of the recommended combined.[31] dipolar cycloaddition reaction conditions, A set of one pot, parallel reactions was indicated that they were entirely compatible therefore carried out in which triplicate with those of the previous substitution solutions of the iodides 7 and 8, in 1:9 water- reaction, except perhaps for the addition of DMSO, were again treated with sodium azide water. On this point, it seemed most likely (1.1 equivalent) at 60oC for 16 h. The flasks that the initial reactions had failed because they were cooled to room temperature and the were not heated rather than because there three replicates treated with one of 1-hexyne, were issues with solubility. There has also 1-octyne or 1-decyne, then CuSO4 and sodium been one report of the two processes being ascorbate. The mixtures were again allowed Chiang Mai J. Sci. 2009; 36(2) 251 to react at 70oC for 48 h. The resulting crude chromatography and recrystallized. The products were then analysed by 1H NMR triazoles 19-24 were isolated in the yields spectroscopy and finally separated by summarised in Scheme 2. Scheme 2 1H NMR analysis indicated that the The surface tension of solutions of reactions had proceeded again with perfect known concentration of fluorous triazoles regiocontrol, as evidenced by the appearance 16-24 in m-xylene was measured using an of only one triazolyl proton signal at δ 7.31- interfacial tensiometer.

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