Synthesis and characterisation of thiol peripheral dendrons using xanthates

Recently, xanthates have been used as thiol protecting groups, to prepare thiol protected polymers that can be readily functionalised using thiol Michael addition chemistry.11-13 Deprotection of the xanthate protecting group was achieved by aminolysis using a 2.5 molar excess of n-butylamine per pendant xanthate. After successful deprotection, the functional acrylate was added to the same vessel, without purification, for thiol Michael addition functionalisation. This was a very interesting piece of research, since the purification of the thiol functional material was not required, and instead utilised a one-pot process, significantly reducing the chance of disulfide formation.

Building on these findings, the objective was to prepare a model dendritic compound, whereby a similar one-pot strategy could be applied. The xanthate functional carboxylic acid building block,

103 bromopropanoic acid and potassium ethyl xanthogenate; both cheap and commercially available reagents, Scheme 2.19.

Scheme 2.19 Preparation of Xanthate building block [Xan-P-COOH];[35]

Potassium ethyl xanthate was suspended in acetone and 1-bromopanoic acid was added dropwise to the solution via a dropping funnel. Upon addition, the mixture changed colour from yellow to white, indicating the formation of the potassium bromide (KBr) salt. After stirring at ambient temperature for 18 hours, the mixture was filtered and the acetone removed under vacuum to leave a viscous yellow oil. The viscous oil was re-dissolved in CH2Cl2 and washed three times with brine to remove trace KBr, dried over MgSO4 and evaporated to dryness resulting in a white solid in 70% yield. The material was characterised by 1H and 13C NMR techniques.

Figure 2.221H NMR spectrum (400MHz, CDCl3) of [Xan-P-COOH];[35]

The 1H NMR spectrum of [Xan-P-COOH];[35] confirmed that were 4 proton environments, each of which corresponded to the expected integration ratios, Figure 2.22. Analysis by 13C NMR also resulted in 6 carbon environments, including the acid resonance at 177 ppm and the xanthate thiocarbonyl at 214 ppm, Figure S2.35.

104 Using [Xan-P-COOH];[35], a G0 dendrimer, [Xan3-P-TEA-G0];[36] with 3 peripheral xanthates was constructed using triethanolamine (TEA) as a dendrimer core, Scheme 2.20. It was important to only target ester based materials with alcohol reagents, since the introduction of primary or secondary amines, to synthesise amide based compounds, may cause reaction at the xanthate site within [Xan-P- COOH]. Initial attempts at using CDI chemistry to generate the required ester bonds resulted in an insoluble viscous oil that could not be characterised. It was suggested that the imidazole byproduct that was generated in the first step of the CDI reaction, may have led to aminolysis with the xanthate functionality. Instead a classical DCC esterification reaction that has been used previously to synthesise dendritic materials in high yields was adopted.14, 15

Scheme 2.20 Synthesis of G0 xanthate dendrimer [Xan3-P-TEA-G0];[36]

4-(Dimethylamino)pyridinium p-toluenesulfonate (DPTS) was chosen as the esterification catalyst since it is known to supress the problematic 1,3 rearrangement of the O-acyl intermediate to a N-acyl urea, by maintaining a low pH during the reaction14, 16. See Chapter 3 (section 3.3.4.2) for its synthesis. TEA and [Xan-P-COOH];[35] were added in 1:4 ratio, and dissolved in anhydrous CH2Cl2 along with DPTS. DCC was added slowly to the mixture in a small volume of CH2Cl2, and the reaction was left overnight for 18 hours at ambient temperature. The precipitated DCU byproduct was removed by filtration, washed with CH2Cl2, and the product isolated by diluting the mixture with

105 CH2Cl2 and washing twice with 1M NaHSO4 to remove the DPTS catalyst. The organic layer was dried over MgSO4 and evaporated to dryness. The crude mixture required purification by liquid chromatography (silica gel, eluting hexane increasing to hexane/ethyl acetate 40:60) to synthesise the dendrimer [Xan3-P-TEA-G0];[36] as an orange viscous oil in 60% yield. Characterisation of the trifunctional xanthate dendrimer was obtained by 1H and 13C NMR as well as ESI-MS. 1H NMR confirmed six proton environments, indicating the three symmetrical dendritic arms attached to the core, Figure S2.36. Further analysis by 13C confirmed eight carbon environments, including a single ester carbonyl at 171.4 ppm, and a resonance for the xanthate thiocarbonyl at 214.2 ppm, Figure S2.37. ESI-MS confirmed populations at 678 Da (MH+ = 678 Da), 700 Da (MNa+ = 700 Da) and 716 Da (MK+ = 716 Da), Figure 2.23.

Figure 2.23 ESI-MS (MeOH) spectrum of [Xan3-P-TEA];[36]

Using [36], a one-pot deprotection and functionalisation strategy was evaluated by two model reactions, Schemes 2.21 and 2.22. Following reported procedures, deprotection by aminolysis and subsequent one-pot thiol-acrylate Michael additions were studied in THF, in the presence of n- butylamine.11 [36] was dissolved in THF and vigorously degassed with nitrogen for 10 minutes.

106 Following this, 3.3 equivalents of n-butylamine amine were slowly added, and the reaction was left sealed under nitrogen for 1.5 hours. TLC analysis (hexane/ethyl acetate 60:40) confirmed total loss of the dendrimer starting material after 1.5 hours, at which point 3 equivalents of [BA] were added to the vessel.

Scheme 2.21 Formation of [Bz3-P-TEA];[37] via a one-pot deprotection and functionalisation strategy using dendrimer [Xan3-P-TEA];[36] and [BA]

After 18 hours, purification was achieved by reducing the volume of THF by half under vacuum, and precipitating the mixture twice into hexane. Removal of solvents resulted in [Bz3-P-TEA];[37] as a pale orange oil in 75% yield. Analysis of the functionalised dendrimer by 1H and 13C NMR and ESI- MS confirmed a one-pot deprotection and thiol Michael addition reaction had indeed taken place. As expected, total loss of the characteristic xanthate thiocarbonyl at 214.2 ppm (13C NMR) was observed and the formation of new proton and carbon environments in the 1H and 13C spectra were seen for the Michael adduct, Figure 2.24 and S2.38. ESI-MS confirmed populations at 900 Da (MH+ = 900 Da), 922 Da (MNa+ = 922 Da) and 938 Da (MK+ = 938), Figure 2.25.

107

Figure 2.2413C NMR spectrum (400MHz, CDCl3) of [Bz3-P-TEA-G0];[37]

The reaction was repeated using the exact same methodology, but using [DMAEA], as the acrylate substrate, Scheme 2.22.

Purification following the same procedures as [37] resulted in [Am3-P-TEA];[38] as a viscous yellow oil in 80% yield. Characterisation by 1H and 13C NMR spectroscopy confirmed the expected total number of resonances, Figure 2.26 and S2.39. ESI-MS confirmed populations at 843 Da (MH+ = 843 Da), 865 Da (MNa+ = 865 Da) and 881Da (MK+ = 881 Da), S2.40. The two model reactions clearly demonstrated the effectiveness of this chemistry, and its potential for a highly efficient synthetic technique for the preparation of surface functional dendritic materials.

Chapter 3 will continue from these final successful findings, and a synthetic route will be designed and implemented to target higher generation materials.

108

Figure 2.25 ESI-MS (MeOH) spectrum of [Bz3-P-TEA-G0];[37]

Scheme 2.22 Formation of [Am3-P-TEA];[38] via a one-pot deprotection and functionalisation strategy using dendrimer [Xan3-P-TEA];[36] and [DMAEA]

109

Figure 2.261H NMR spectrum (400MHz, CDCl3) of [Am3-P-TEA-G0];[38]