Effective and Versatile Strategy for the Total Solid‐Phase Synthesis of Alkanethiols for Biological Applications

Abstract

Biological applications increasingly demand tailored surfaces with a range of functional groups. Herein we describe a straightforward and inexpensive method based exclusively on solid‐phase synthesis for the preparation of a variety of customized alkanethiols (ATs). The technique overcomes all the difficulties encountered during the preparation of these molecules in solution. The procedure allows the use of ATs without further purification for the preparation of self‐assembled monolayers on gold, typically used to achieve functional group diversity on this surface.

Solid phase synthesis of functionalised SAM-forming alkanethiol–oligoethyleneglycols

“…Post-assembly conjugation requires robust, chemoselective, and mild chemistry to ensure complete surface functionalisation without side reactions. 2,5 For pre-assembly conjugation approaches, total synthesis of LCAT–OEGs terminated with, amongst others, biotin, 6 peptides, 6 c ,7 ferrocene, 8 azides, 9 aminooxy groups, 9 and sugars 10 has been demonstrated. Such functionalised LCAT–OEGs are usually synthesised in solution, which requires multiple chromatographic steps and suffers from poor overall yields.…”

“…Solid phase chemistry presents an attractive alternative for synthesising LCAT–OEGs. The groups of Whitesides and Mrksich have demonstrated the attachment of a thiol-protected LCAT-OEG to resin-bound peptides, 7 b ,11 while Albericio et al . have successfully used 2-chlorotrityl chloride resin to construct biotinylated 6 b and peptide-containing 7 a LCAT–OEGs.…”

“…The groups of Whitesides and Mrksich have demonstrated the attachment of a thiol-protected LCAT-OEG to resin-bound peptides, 7 b ,11 while Albericio et al . have successfully used 2-chlorotrityl chloride resin to construct biotinylated 6 b and peptide-containing 7 a LCAT–OEGs. However, for applications that require a quick, iterative fine-tuning of SAM properties/functionalities, currently available syntheses are often not sufficient.…”

“…OEGs are often linked to LCATs through an ether bond. However, in analogy to Albericio’s approach, 6b,7a we chose to use an amide linker, which has been shown to improve SAM stability through the formation of networks of hydrogen bonds. 12 We first synthesised amino-OEGs 6 through the silver(I) oxide-mediated mono-tosylation of oligoethyleneglycols 4 (ref.…”

“…In conclusion, we have established a robust and versatile solid phase synthesis of LCAT–OEGs functionalised with alcohols, azides, amines, peptides, and the redox probe methylene blue, thereby significantly expanding the range of LCAT–OEGs that are easily accessible through solid phase approaches such as those reported by Albericio. 6 b ,7 a All LCAT–OEGs could be isolated in good yields as pure materials, and were used to form dense and well-defined, high quality mixed SAMs absent of macroscopic island formation (AFM data) and pinholes (EIS and CV data). In addition, the ratios of functionalised LCAT–OEGs and diluents on the surface were directly proportional to the ratios of these molecules in the applied solutions.…”