HDPPBA-C and HDPPBA-N were synthesized via a bottom-up approach (Scheme 1) starting with the functionalization of the thiophene ring and finalizing with a cyclization reaction to form the DPP core. Initially, the thiophene ring was alkylated with hexyl bromide (1) in high yield, and subsequently, a nitrile group was introduced in position 5 after replacement of a bromine atom (Scheme 1). Then 5hexylthiophene-2-carbonitrile (3) reacted with diethylsuccinate in the presence of potassium t-butoxide to form the hexyl-functionalized thiophene-capped DPP main core (4) in 72% yield. In a last step, the lactam rings of the DPP were alkylated with the amide-containing branches that were synthesized in parallel. The mesylated carbon-centered amide (-CONH) branch was synthesized following a synthetic route previously described in the literature. It involves the reaction between ε-caprolactone with hexylamine and subsequently adding the mesylate activating group (Scheme S1). On the other hand, Schotten-Baumann conditions were followed to obtain the N-centered amide (-NHCO) branch (Scheme S2). In this case the acylation of 5-amino-1-pentanol with heptanoyl chloride was carried out in a biphasic system of dichloromethane and a basic aqueous solution. The use of base drives the equilibrium of the reaction towards the formation of the amide, obtained in high yield. Next, the N-centered amide was treated with methanesulfonyl chloride to achieve the mesylated amide-containing branch (Scheme S2). The last step was the alkylation of the DPP core functionalized with hexyl tails in the thiophenes with the amide-containing branches. In this case, we replaced N,N-dimethylformamide (DMF), which is the most commonly employed solvent, by acetonitrile, a greener solvent that allows lowering the reaction temperature and time, as well as the need of dry solvent and inert atmosphere. The purification and isolation of the final product was straightforward since we did not obtain N,O-and/or O,O'alkylated isomers, which are common side products of this reaction. In this sense, the starting material (4) seems to provide higher regioselectivity towards the N,N'-alkylated product. It might be explained by the improved solubility of the starting material (introduction of hexyl groups in the thiophene vs previously reported DPP without functionalization in the thiophenes ), the steric hindrance provided by the hexyl chains with respect to the DPP carbonyl groups, the lower reaction temperature (80 ºC in CH3CN vs 120 ºC in DMF) and the choice of base (cesium carbonate vs potassium carbonate). The improved regioselectivity resulted in higher yields for the alkylation reactions in the lactams, reaching 30% in comparison to the same reaction using non-alkylated thiophene-capped DPP derivatives reported earlier by our group. The control molecule HDPPH was synthesized following the same strategy but the lactam rings were alkylated with hexyl bromide (Scheme S3). All the derivatives were characterized with proton and carbon nuclear magnetic resonance ( 1 H and 13 C-NMR), and mass spectrometry (all the details can be found in the Supporting Information). Scheme 1. Synthetic route towards HDPPBA-C and HDPPBA-N