DOI: 10.1002/cssc.201402464 Ecofriendly Porphyrin Synthesis by using Water under Microwave Irradiation CØsar A. Henriques, [a] Sara M. A. Pinto, [a] Gilberto L. B. Aquino, [b] M. Pineiro, [a] Mµrio J. F. Calvete,* [a] and Mariette M. Pereira* [a] Water, under microwave irradiation and at a temperature of 473 K, reaches pressures above 16 bar, being capable to act as catalyst, without the use of organic solvents and oxidants, for meso-substituted porphyrin synthesis. Sustainability of the re- action is proved by E Factor = 35 and EcoScale value of 50.5, the highest so far obtained for porphyrin synthesis. Methodol- ogy’s wide versatility is clearly demonstrated by the good yields obtained for both aryl and alkyl substituted porphyrins. These reaction conditions represent a huge development, not only by using very high concentrations, minimizing organic solvent usage, but also by eradicating toxic expensive solvents and oxidants. Water, at temperatures above its boiling point and pressures above 16 bar, has recently emerged as potential solvent for hy- drophobic organic compounds [1, 2] acid or base catalyst, [3, 4] and also in very specific conditions as oxidant. [5] The properties en- abling these uses are attributed to a decrease of its dielectric constant and increase of its ionic product under those condi- tions. An easy, fast, and safe way to obtain overheated water is to use a microwave (MW) apparatus dedicated to organic syn- thesis. [1, 6] However, to the best of our knowledge the use of such conditions has not been reported for the synthesis of porphyrins, key compounds in the life of our planet [7] and pre- sumably among the families of compounds with the most practical applications, including medicine, [8] catalysis, [9] and ma- terials. [10] The somewhat troublesome preparation of natural b-substi- tuted porphyrins [11] has motivated the development of new synthetic methodologies for non-natural meso-substituted ones, either by using classical heating [12, 13] or, more recently, by using MW irradiation. [14] Whilst acknowledging the progress achieved so far, we believe that there remains a big leap for- ward to be made, which is the development of a strictly sus- tainable process that avoids the use of unfavorable organic solvents, organic acid catalysts, and oxidants. Nowadays, two main routes for the synthesis of meso-substi- tuted porphyrins are followed: 1) one-pot synthesis, involving acid-catalyzed condensation/cyclization of pyrrole with the de- sired aldehydes into the porphyrinogen, followed by direct oxi- dation to the porphyrin either by air [15] or nitrobenzene; [16, 17] and 2) two-step synthesis, involving acid-catalyzed condensa- tion/cyclization into porphyrinogen, followed by oxidation with high-potential quinones in a separate step. [18–20] The sym- biosis of our interests in porphyrin chemistry with the develop- ment of environmentally sustainable processes prompted us to explore the unique characteristics of overheated water under microwave irradiation, designing the first approach to a fully sustainable synthesis of meso-substituted porphyrins using water, the most benign molecule in nature, as an additive to promote the transformation of the porphyrinogen into the cor- responding meso-substituted porphyrins. Using meso-tetraphenylporphyrin (TPP) 1 as model com- pound, [21] the reaction conditions, temperature, MW irradiation time (CEM microwave reactor), and concentration of the corre- sponding reactants were optimized, and the results are de- tailed in Table 1. Firstly, the influence of the temperature on the reaction yield was evaluated (entries 1–8). When keeping reagent concentration (10 m), reaction time (10 min), and initial MW power (300 W) fixed whilst varying the temperature from 373 K to 513 K, the reaction yield ranged from 0 to 17 % (entry 6). However, by keeping reagent concentration and reac- tion time constant, the yields of isolated TPP increased along with increments of 20 K in temperature, as its yield remained similar at temperatures above 473 K. As a result, we considered 473 K the optimal temperature for further studies (entry 6). Then, setting the temperature at 473 K, using the same reac- tant concentration (10 m) and an initial MW power of 300 W, the effect of time, ranging from 5 to 60 min, on the reaction yield was also evaluated (Table 1, entries 9–14). A reaction time of 10 min gave a maximum TPP yield of 17 % (entry 10). Experi- ments with reaction times above 10 min did not improve the yield of TPP formation, revealing that the consumption of starting materials occurs within the first 10 min of reaction and, based on an energy saving approach, this reaction time was selected as the most suitable for enlarging the scope of the reaction. Because it is well established that the concentration of re- agents is a crucial aspect in the condensation/cyclization reac- tion of pyrrole with aldehydes, [18] reactant concentrations were optimized after selecting the optimal temperature (473 K) and [a] C. A. Henriques, Dr. S. M. A. Pinto, Dr. M. Pineiro, Dr. M. J.F. Calvete, Dr. M. M. Pereira CQC, Department of Chemistry, University of Coimbra Rua Larga, 3004-535 Coimbra (Portugal) E-mail : mcalvete@qui.uc.pt mmpereira@qui.uc.pt [b] Dr. G. L. B. Aquino Faculty of Pharmacy, Exact Sciences and Technology Unit State University of Goiµs 75132400 Anapolis, Goiµs (Brazil) Supporting Information for this article is available on the WWW under http://dx.doi.org/10.1002/cssc.201402464.  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemSusChem 0000, 00, 1 – 4 &1& These are not the final page numbers! ÞÞ CHEMSUSCHEM COMMUNICATIONS