From thioether substituted porphyrins to sulfur linked porphyrin dimers: an unusual SNAr via thiolate displacement?

Aoife A. Ryan, Shane Plunkett, Aoife Casey, Thomas McCabe, Mathias O. Senge
2014 Chemical Communications  
Treatment of meso 2-ethylhexyl-3-mercaptopropionate substituted porphyrins with base at room temperature generated a porphyrin thiolate anion which in situ reacted in a nucleophilic aromatic substitution (S N Ar) reaction with remaining thioether derivative. This reaction yielded S-linked bisporphyrins in good yields, with mechanistic insight obtained via displacement reactions. Additionally, S N Ar of the thioether chain was achieved using S-and organolithium nucleophiles. Owing to their
more » ... wing to their biological and medical importance, 1 the synthesis of organosulfur compounds has been the focus of thorough investigations. 2 One important development is the nucleophilic aromatic substitution (S N Ar) with the thiolate anion. 3 Typically, thiolate S N Ar only occurs with activated aryls with leaving groups such as halides or tosylates, 4 requiring a very strong base, elevated temperature and/or the use of metal catalysts. 3c,5 Additionally, it is often hindered via competing oxidation reactions to form disulfide bonds ( Fig. 1 ). 6 In a remarkable S N Ar, sulfur-linked porphyrin dimers were generated via a simple deprotection of a thioether appended porphyrin. While our initial goal was the synthesis of a free thiol group directly attached to the porphyrin macrocycle via base deprotection, bisporphyrin products were observed predominantly. Such sulfur linked bisporphyrins have not previously been reported and are easily produced, in contrast to other heteroatom linked porphyrin arrays which generally require many synthetic steps. 7 These were generated via S N Ar by the thiolate at the meso position of the substituted porphyrin, with isooctyl-3-mercaptopropionate acting as an excellent leaving group. Substitution reactions on porphyrins are limited, 8 at best, and typically require highly specific activated systems and high temperatures. However, this room temperature in situ S N Ar of a seemingly unactivated porphyrin in such fashion represents, to the best of our knowledge, the first reaction of this type to be documented. This is somewhat reminiscent of previous work in our group, whereby using organolithium reagents a variety of substituents can be introduced to the porphyrin periphery via S N type reactions. 9 Porphyrins bearing thiol and thioether substituents have a diverse range of optical applications due to their ability to form self-assembled monolayers (SAMs) on gold surfaces 10 and this attribute formed the basis for our interest in thioporphyrins. Adopting a versatile Pd-catalyzed porphyrin-sulfur bond forming reaction developed by Itoh and Mase, 11 a library of novel isooctyl-3-mercaptopropionate substituted porphyrins, so-called protected thiols, were synthesized. 12 This involved a Pd-catalyzed reaction of bromoporphyrins 1a-i and the thiol 2-ethylhexyl-3-mercaptopropionate in good to excellent yields of 66-87%. These protected thiols have the potential to be used in Au-NP formulation or as a photosensitizer delivery system in PDT, 13 but our primary goal was for their use in deprotection reactions (Table 1 ). All protected thiols were subjected to base-mediated deprotection 14 in an effort to obtain a free thiol group directly attached to the porphyrin macrocycle. However, deprotection through b-elimination of the thioether chain of masked compounds 2a-g, gave unusual results, with the S-linked bisporphyrins 3a-g isolated as the major products (Table 2) . Here, both the isooctyl-3-mercaptopropionate group acts as an excellent leaving group and the porphyrin thiolate behaves as a very strong nucleophile. The reaction goes to completion in all Fig. 1 Overview of thiolate reactivity.
doi:10.1039/c3cc46828c pmid:24247987 fatcat:nsbftv6tm5f4fjuwsdy2fwlffy