Metal porphyrins are prosthetic groups in a number of essential biomolecules, including hemoglobin, chlorophyll, and cytochromes, supporting processes such as oxygen transport, photosynthesis, and electron transfer . Beyond their essential biological roles, porphyrins and their derivatives are employed in a number of applications, acting as catalysts in numerous reactions, including oxidation, reduction, and cycloaddition . Particularly when electron-rich porphyrins act as reducing agents, e.g. in electrocatalytic hydrogen evolution reactions, a proton source is needed . In this context, trifluoroacetic acid is very frequently chosen as the proton source, because it is a strong acid but just not strong enough to destroy (demetallate) the Ni porphyrin . Covalent attachment of acids facilitates proton transfer and increases the efficiency . Three conditions should be met for the target porphyrins of this study. 1. The acid covalently bound to the porphyrin should have an acid strength similar to trifluoroacetic acid. 2. The length of the tether with which the acid group is bound should be sufficient to serve as a proton source for redox reactions at the metal. 3. The electronic properties of the porphyrin, especially the low oxidation potential, should not be increased. We have chosen four-fold meso-3,4,5-trimethoxyphenyl-substituted Ni porphyrin as the electron-rich system, however, the post-synthetic modification of this porphyrin proved to be difficult. Therefore, we have integrated the acid group into the aldehyde component of the Rothemund reaction to prepare the target porphyrin. In initial tests, we have established that trifluoroacetic acid can be replaced by perfluorinated alkyl carboxylic acids . It was therefore obvious to use a perfluoroalkyl chain as a tether. However, a perfluoroalkyl chain as a substituent on the porphyrin has an electron-withdrawing effect and thus a negative influence on the oxidation potential. We have therefore inserted an O–CH2 group between the phenyl group of the porphyrin and the perfluoroalkyl chain. The oxygen atom, especially in the 2-position, should even improve the electronic properties of the porphyrin.

Scheme 1: Synthesis of the starting materials 16, 17, and 18 for the subsequent Williamson ether synthesis with 2-hydroxy-3,4,5-trimethoxybenzaldehyde (21). Conditions: a) K2CO3, benzyl bromide, abs. MeCN, N2, reflux, 18 h; b) TEMPO, KBr, NaOCl, NaHCO3, MeCN, rt, 76 h; c) MeOH, H2SO4, reflux, 18 h; d) Pd/C, H2, EtOH, rt, 24 h; e) Tf2O, pyridine, DCM, rt, 18 h.

Scheme 2: Synthesis of perfluoroalkyl ester-functionalized aldehydes 22, 23, and 24. Conditions: a) NIS, TFA, Na2CO3, MeCN, reflux, 18 h; b) Cu2O·H2O, 2-pyridinaldoxime, TBAB, CsOH, H2O, N2, rt, 18 h; c) Cs2CO3, DMAc, N2, rt, 3 h.

Towards this end, 3,4,5-trimethoxybenzaldehyde (19) was iodinated using N-iodosuccinimide (NIS) to give 20 in a yield of 89% . To convert the iodo to an OH group, compound 20 was reacted with Cu2O, 2-pyridinaldoxime and CsOH to give 2-hydroxy-3,4,5-trimethoxybenzaldehyde (21, 65%) . In a subsequent nucleophilic substitution, the fluorinated alkyl chains of 16, 17, and 18 were linked via a Williamson ether synthesis to yield 22 (78%), 23 (44%), and 24 (44%).

Scheme 3: Porphyrin synthesis. a) Rothemund porphyrin synthesis of metal-free porphyrins 26, 27, and 28; b) metalation of porphyrins with Ni(acac)2; c) ester hydrolysis to generate the free acids 32, 33, and 34. Conditions: a) 1) 22/23/24, TFA, abs. DCM, N2, reflux, 30 min, 2) pyrrole, reflux, 2.5 h, 3) DDQ, reflux, 2 h; b) Ni(acac)2, toluene, reflux, 20 h; c) 1) LiOH, MeOH, rt, 1 h, 2) HCl.

This study reports the synthesis of perfluoroalkyl carboxylic esters with CH2–OTf groups in the ω-position of the type TfO–CH2–(CF2)n–COOCH3 (n = 2, 4, 6, Tf = triflate). The latter compounds were used in Williamson ether reactions with 2-hydroxy-3,4,5-trimethoxybenzaldehyde (21) to prepare the aldehyde component for a Rothemund-type porphyrin synthesis of acid-functionalized electron-rich porphyrins. The corresponding Ni porphyrins are potential compounds for electrocatalysis and sensor applications. The ω-triflated, perfluoroalkylated carboxylic acids 16, 17, and 18 are easily accessible and versatile building blocks for connecting long chain acids (pKa range between 0 and 1) to substrates in Williamson ether-type reactions.