@misc{methods of making porphyrins and related compounds with lewis acids_2005, volume={6,849,730}, number={2005 Feb. 1}, publisher={Washington, DC: U.S. Patent and Trademark Office}, year={2005} } @article{geier_lindsey_2004, title={Effects of aldehyde or dipyrromethane substituents on the reaction course leading to meso-substituted porphyrins}, volume={60}, ISSN={["0040-4020"]}, DOI={10.1016/j.tet.2004.09.081}, abstractNote={To better understand the effects of diverse substituents on reactions leading to porphyrins, pyrrole+aldehyde condensations and related reactions of dipyrromethanes were examined. The course of pyrrole+aldehyde condensations was investigated by monitoring the yield of porphyrin (by UV–Vis spectroscopy), reaction of aldehyde (by TLC), and changes in the composition of oligomers (by laser desorption mass spectrometry). Reaction reversibility was examined via exchange experiments. Reversibility of reactions leading to porphyrin was further probed with studies of dipyrromethanes. The reaction course was found to depend on the nature of the substituent and the acid catalyst. Alkyl or electron-donating substituents displayed levels of reversibility (exchange/scrambling) on par or greater than that of the phenyl substituent, whereas electron-withdrawing or sterically bulky substituents exhibited little to no reversibility. The results obtained provide insight into the electronic and steric effects of different substituents and should facilitate the design of synthetic plans for preparing porphyrinic macrocycles.}, number={50}, journal={TETRAHEDRON}, author={Geier, GR and Lindsey, JS}, year={2004}, month={Dec}, pages={11435–11444} } @article{chevalier_geier_lindsey_2002, title={Acidolysis of intermediates used in the preparation of core-modified porphyrinic macrocycles}, volume={6}, ISSN={["1088-4246"]}, DOI={10.1142/S108842460200021X}, abstractNote={ The stability towards acidolysis of intermediates used in the preparation of core-modified porphyrinic macrocycles was examined. Experiments were performed using analogs of 5-phenyldipyrromethane in which one of the two pyrrole rings was modified (XPM). The XPMs utilized in these studies had X = 2-furyl (OPM), 2-thienyl (SPM), 2-selenyl (SePM), or 3-pyrrolyl (NCPPM). The XPMs possess a potentially labile linkage to a heteroatom-modified ring as well as a potentially labile linkage to a pyrrole ring. The stability of the two types of linkages was examined under acid catalysis conditions commonly used in the preparation of porphyrinic macrocycles. The methodology employed enabled characterization of the stability of the XPM (GC analysis), the yield of porphyrin (UV-vis absorption), and the composition of porphyrinic species (laser-desorption mass spectrometry, LD-MS) formed upon acidolysis of the XPM. These experiments showed that (1) the linkage to the heteroatom-modified ring is fairly stable in the presence of a linkage to pyrrole, and (2) the linkage to pyrrole is much more stable in the XPMs than is the case in 5-phenyldipyrromethane. Additional experiments with analogs of 5-phenyldipyrromethane having both rings modified ( X 2 M ), where X = 2- furyl ( O 2 M ), 2- thienyl ( S 2 M ), or 2- selenyl ( Se 2 M ) confirmed that linkages to furyl, thienyl, and selenyl rings are stable towards acidolysis. Taken together, the observations concerning stability of various linkages provide a foundation for understanding the types and yields of core-modified porphyrinic macrocycles formed in reactions with reactants that are not direct precursors to the isolated products. }, number={3}, journal={JOURNAL OF PORPHYRINS AND PHTHALOCYANINES}, author={Chevalier, F and Geier, GR and Lindsey, JS}, year={2002}, pages={186–197} } @article{geier_lindsey_2002, title={Effects of diverse acid catalysts on the reaction course in the two-step one-flask synthesis of meso-tetraphenylporphyrin}, volume={6}, ISSN={["1088-4246"]}, DOI={10.1142/S1088424602000208}, abstractNote={ A set of 45 acids or acid combinations was examined in the condensation of pyrrole + benzaldehyde (10 mM each in CH 2 Cl 2) leading to meso-tetraphenylporphyrin (TPP). Initial screening experiments identified suitable acid catalysts and the optimal concentration (in terms of TPP formation) for each acid. Subsequent experiments followed the time course of reactions using the best conditions identified in the screening experiments. The reaction course was followed by monitoring reactions from 1 min to 24 h for the yield of TPP (by UV-vis and HPLC), the yields of N-confused tetraphenylporphyrin and tetraphenylsapphyrin (by HPLC), the quantity of unreacted benzaldehyde (by TLC), and the oligomer composition (by laser desorption mass spectrometry). Diverse acids (Brønsted or Lewis; soluble or insoluble) were found to provide yields of TPP ranging up to ~50%. Only 10 acids gave no TPP. In addition, N-confused tetraphenylporphyrin was found to be a ubiquitous byproduct, whereas tetraphenylsapphyrin was not widely observed. MgBr 2-etherate and CuCl 2 each catalyzed porphyrinogen formation and resulted in porphyrin metalation following oxidation and neutralization of the reaction mixture, thereby providing direct, one-flask syntheses of magnesium and copper porphyrins. Observations concerning the reaction course obtained from prior studies of TFA or BF 3-etherate catalysis have been found to be quite general across a broad range of acid catalysts. Collectively, these results show that many acids have potential utility in porphyrin syntheses. }, number={3}, journal={JOURNAL OF PORPHYRINS AND PHTHALOCYANINES}, author={Geier, GR and Lindsey, JS}, year={2002}, pages={159–185} } @article{geier_callinan_rao_lindsey_2001, title={A survey of acid catalysts in dipyrromethanecarbinol condensations leading to meso-substituted porphyrins}, volume={5}, ISSN={["1088-4246"]}, DOI={10.1002/jpp.387}, abstractNote={ The successful use of dipyrromethanecarbinols in rational routes to porphyrinic macrocycles requires catalysis conditions that enable irreversible condensation, thereby avoiding substituent scrambling and formation of undesired porphyrin products. Previously, successful conditions of trifluoroacetic acid (TFA) (30 mM) in acetonitrile were identified following a lengthy survey of TFA and BF3-etherate catalysis in diverse solvents. In this study, focus was placed on the acid catalyst by examining 17 acids in CH 2 Cl 2, the traditional solvent for two-step, one-flask porphyrin syntheses. In the self-condensation of the carbinol derived from 1-(4-methylbenzoyl)-5-phenyldipyrromethane, porphyrin yields of 9–55% were obtained from the various acids, compared to 20% under TFA catalysis in acetonitrile. A number of catalytic conditions that produce little to no porphyrin in reactions of pyrrole + benzaldehyde afforded good yields of porphyrin and the suppression of scrambling in reactions of dipyrromethanecarbinols. The four best acid catalysts ( InCl 3, Sc ( OTf )3, Yb ( OTf )3, and Dy ( OTf )3) initially identified were then examined with dipyrromethanecarbinols bearing challenging substituents (alkyl, pyridyl, or no substituent). The greatest improvement was obtained with the pyridyl substrates. Selected reactions performed on a preparative scale (115 to 460 mg of isolated porphyrin) verified the results of the analytical-scale experiments and revealed the more facile isolation of the porphyrin from reactions performed in CH 2 Cl 2 rather than acetonitrile. This study provides alternatives to the use of TFA/acetonitrile that offer advantages in terms of yield and isolation of the porphyrin without sacrificing suppression of scrambling. Furthermore, the finding that poor catalysts for the benzaldehyde + pyrrole reaction can be excellent catalysts for dipyrromethanecarbinols provides guidance for the identification of other catalysts for use with reactive precursors in porphyrin-forming reactions. }, number={12}, journal={JOURNAL OF PORPHYRINS AND PHTHALOCYANINES}, author={Geier, GR and Callinan, JB and Rao, PD and Lindsey, JS}, year={2001}, month={Dec}, pages={810–823} } @article{geier_riggs_lindsey_2001, title={Investigation of acid cocatalysis in syntheses of tetra-phenylporphyrin}, volume={5}, ISSN={["1088-4246"]}, DOI={10.1002/jpp.380.abs}, number={9}, journal={JOURNAL OF PORPHYRINS AND PHTHALOCYANINES}, author={Geier, GR and Riggs, JA and Lindsey, JS}, year={2001}, month={Sep}, pages={681–690} } @article{geier_lindsey_2001, title={Investigation of porphyrin-forming reactions. Part 1. Pyrrole plus aldehyde oligomerization in two-step, one-flask syntheses of meso-substituted porphyrins}, ISSN={["1472-779X"]}, DOI={10.1039/b009088n}, abstractNote={A deep understanding of the two-step, one-flask synthesis of meso-substituted porphyrins requires characterization of the acyclic oligomers, which typically constitute ≥50% of the products. We have employed laser desorption mass spectrometry (LD-MS) to obtain a qualitative yet high resolution view of the oligomer content of crude oxidized reaction mixtures. This methodology complements other analytical methods which provide information regarding yields of porphyrin, other macrocyclic products, and unreacted aldehyde. Our findings include the following. (1) Crude oxidized porphyrin reaction mixtures provided peaks in the LD-MS spectrum which were readily assigned to oligomers (m/z 100–2000) derived from pyrrole–aldehyde condensation. The oligomers comprised one of four series depending on the ratio of pyrrole and aldehyde units. (2) Quite disparate reaction conditions that gave good yields of porphyrin also afforded a similar oligomer composition. (3) The change in the nature of the oligomers over time was readily monitored. (4) The maximum yield of porphyrin and the maximum diversity of the oligomer composition were attained at similar times. (5) The decline in yield of porphyrin at long reaction time was accompanied by truncation, not elongation, of oligomers. (6) The onset of the truncation of oligomers and the decline in yield of porphyrin were accompanied by a decrease of the aldehyde to low levels. (7) Pyrrole was incorporated into the growing oligomers more rapidly than aldehyde. Taken together, these studies show how various conditions alter the course of the pyrrole–aldehyde condensation.}, number={5}, journal={JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2}, author={Geier, GR and Lindsey, JS}, year={2001}, pages={677–686} } @article{geier_lindsey_2001, title={Investigation of porphyrin-forming reactions. Part 2. Examination of the reaction course in two-step, one-flask syntheses of meso-substituted porphyrins}, ISSN={["1472-779X"]}, DOI={10.1039/b009092l}, abstractNote={The reaction course leading to meso-substituted porphyrins was examined for reversibility (formation of oligomers, formation of α- and β-pyrrole linkages), inactivation of the acid catalyst, homogeneity of the reaction medium, and the pathway of oligomer formation. The methodology employed enabled characterization of the oligomer composition (LD-MS), yield of porphyrin (UV–Vis), yield of N-confused porphyrin (HPLC), and level of unreacted aldehyde (TLC). Experiments were performed with benzaldehyde and pyrrole with catalysis by TFA or BF3–Et2O. Key observations include the following. (1) Reactions with BF3–Et2O exhibited reversible exchange of oligomers throughout the reaction. With TFA, the oligomer exchange processes were reversible at short reaction times, but became largely irreversible over the course of several hours. (2) The BF3–Et2O activity declined during the course of the reaction, whereas that of TFA was little changed. (3) The reaction medium remained homogeneous at 10 mM pyrrole + aldehyde. (4) Dipyrromethanes comprised of α- but not β-linkages underwent cleavage with either TFA or BF3–Et2O. (5) Condensations with carbinol intermediates (pyrrole-carbinol, dipyrromethane-monocarbinol, dipyrromethane-dicarbinol) provided rapid reactions, lower yields of porphyrin, and longer oligomers than typical in reactions of pyrrole + benzaldehyde. Higher porphyrin yields were obtained with BF3–Et2O than TFA, which is attributed to the more facile recovery from longer oligomers with the former versus the latter catalyst. Collectively, these and other observations lead to a model for the aldehyde + pyrrole condensation comprised of a combination of irreversible and reversible reactions in oligomer formation, irreversible side reactions (formation of dipyrrins, β-linkages), and slow inactivation of the catalyst (BF3–Et2O).}, number={5}, journal={JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2}, author={Geier, GR and Lindsey, JS}, year={2001}, pages={687–700} } @article{geier_littler_lindsey_2001, title={Investigation of porphyrin-forming reactions. Part 3. The origin of scrambling in dipyrromethane plus aldehyde condensations yielding trans-A(2)B(2)-tetraarylporphyrins}, ISSN={["1472-779X"]}, DOI={10.1039/b009098k}, abstractNote={The dipyrromethane + aldehyde condensation is a common method for the synthesis of trans-A2B2-porphyrins, but is often plagued by scrambling processes that lead to a mixture of porphyrins. The problem of scrambling is more pronounced with unhindered dipyrromethanes (e.g., 5-phenyldipyrromethane) than with hindered dipyrromethanes (e.g., 5-mesityldipyrromethane). We have characterized the oligomer composition (by LD-MS), yield of porphyrin (by UV–Vis), yield of N-confused porphyrin (by HPLC), and level of unreacted aldehyde (by TLC) in dipyrromethane + aldehyde condensations leading to trans-A2B2-porphyrins. Reaction conditions known to suppress scrambling in reactions involving 5-phenyldipyrromethane (PDPM) were compared to conditions known to provide extensive scrambling. The low-scrambling conditions were found to suppress scrambling by inhibiting reaction of oligomer fragments generated by acid-induced cleavage of the dipyrromethane, rather than by inhibiting acidolysis itself. However, such reaction conditions were also found to inhibit the condensation, leading to low yields (<10%) of porphyrin. The condensation of PDPM + aldehyde was also compared to reactions involving 5-mesityldipyrromethane (MDPM) to understand why trans-A2B2-porphyrins can be prepared in good yield devoid of scrambling from reactions using MDPM. The absence of scrambling in MDPM + aldehyde condensations was due to the resistance of MDPM to acidolysis. Taken together, these studies provide insight into the origin of scrambling with different types of substrates under different reaction conditions in the dipyrromethane + aldehyde route to trans-A2B2-porphyrins.}, number={5}, journal={JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2}, author={Geier, GR and Littler, BJ and Lindsey, JS}, year={2001}, pages={701–711} } @article{geier_littler_lindsey_2001, title={Investigation of porphyrin-forming reactions. Part 4. Examination of the reaction course in syntheses of porphyrins via dipyrromethanecarbinols}, ISSN={["1472-779X"]}, DOI={10.1039/b009101o}, abstractNote={The dipyrromethanecarbinol motif is a key component in rational routes to a wide variety of porphyrinic macrocycles. We have investigated the dipyrromethane-monocarbinol self-condensation and the dipyrromethane-dicarbinol + dipyrromethane condensation under four different acid-catalysis conditions and have characterized the oligomer composition (by LD-MS), yield of porphyrin (by UV–Vis), and yield of N-confused porphyrin (by HPLC). Under conditions giving “no-scrambling”, the condensations are rapid and afford an oligomer composition characterized by (1) absence of scrambling, (2) suppression of acidolysis, and (3) a disproportionate amount of long oligomers from which recovery does not occur. The irreversibility of the reaction and lack of recovery from the long oligomers may explain the lower yields of dipyrromethanecarbinol condensations (<30%) compared with reversible reactions of aldehyde + pyrrole (∼50%). Modest levels of acidolysis and scrambling with the dipyrromethanecarbinols are obtained under reaction conditions that cause extensive scrambling in dipyrromethane + aldehyde condensations. Because both reactions give the same porphyrinogen, the scrambling processes must primarily involve the dipyrromethane or oligomer intermediates rather than the porphyrinogen. The dipyrromethane-monocarbinol self-condensation and dipyrromethane-dicarbinol + dipyrromethane condensation afford quite similar oligomer compositions, suggesting that both follow similar pathways to the porphyrinogen. Reaction conditions that suppress scrambling in the dipyrromethanecarbinol condensations were found to dramatically suppress formation of the N-confused porphyrin. Taken together, these experiments show how the greater reactivity of the dipyrromethanecarbinol unit (compared with the pyrrole + aldehyde reaction) facilitates synthesis of meso-substituted porphyrins without scrambling.}, number={5}, journal={JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2}, author={Geier, GR and Littler, BJ and Lindsey, JS}, year={2001}, pages={712–718} } @article{geier_ciringh_li_haynes_lindsey_2000, title={A survey of acid catalysts for use in two-step, one-flask syntheses of meso-substituted porphyrinic macrocycles}, volume={2}, ISSN={["1523-7060"]}, DOI={10.1021/ol005917h}, abstractNote={[reaction: see text] Diverse Lewis acids and Bronsted acids were examined in the two-step, one-flask synthesis of meso-tetraphenylporphyrin, N-confused tetraphenylporphyrin, and tetraphenylsapphyrin. The scope of acid catalysis was found to be very broad, with 35 of 45 acids providing TPP in yields ranging from 5% to 58%. NC-TPP was also widely observed in yields of 1-40%, and TPS was infrequently observed in yields of <1%. Additionally, conditions were found for direct preparation of magnesium TPP and copper TPP.}, number={12}, journal={ORGANIC LETTERS}, author={Geier, GR and Ciringh, Y and Li, FR and Haynes, DM and Lindsey, JS}, year={2000}, month={Jun}, pages={1745–1748} } @article{rao_littler_geier_lindsey_2000, title={Efficient synthesis of monoacyl dipyrromethanes and their use in the preparation of sterically unhindered trans-porphyrins}, volume={65}, ISSN={["0022-3263"]}, DOI={10.1021/jo9915473}, abstractNote={The condensation of an aldehyde with a dipyrromethane bearing a sterically unhindered aryl substituent at the 5-position typically results in low yield and a mixture of porphyrin products derived from acidolytic scrambling. We have developed a concise nonscrambling synthesis of such trans-porphyrins that takes advantage of the availability of multigram quantities of dipyrromethanes. This route involves the selective monoacylation of the dipyrromethanes with a pyridyl thioester, reduction of the monoacyl dipyrromethane to the corresponding carbinol, and self-condensation of the carbinol to form the porphyrin. The monoacylation procedure has wide scope as demonstrated by the preparation of a set of 15 diverse monoacyl dipyrromethanes in good yield at the multigram scale. The dipyrromethanecarbinol self-condensation reaction is extremely rapid (<3 min) under mild room-temperature conditions and affords the trans-porphyrin in 16-28% yield. Analysis by laser-desorption mass spectrometry (LD-MS) of samples from the crude reaction mixture revealed no scrambling within the limit of detection (1 part in 100). The self-condensation is compatible with a range of electron-withdrawing or -releasing substituents as well as substituents for building block applications (TMS-ethyne, ethyne, iodo, ester). The absence of any detectable scrambling in the self-condensation enables a simple purification. The synthesis readily affords gram quantities of pure, sterically unhindered trans-porphyrins in a process involving minimal chromatography.}, number={4}, journal={JOURNAL OF ORGANIC CHEMISTRY}, author={Rao, PD and Littler, BJ and Geier, GR and Lindsey, JS}, year={2000}, month={Feb}, pages={1084–1092} } @article{geier_haynes_lindsey_1999, title={An efficient one-flask synthesis of N-confused tetraphenylporphyrin}, volume={1}, ISSN={["1523-7060"]}, DOI={10.1021/ol9910114}, abstractNote={[formula: see text] N-Confused meso-substituted porphyrin is a porphyrin isomer previously available from one-flask porphyrin syntheses as a low-yield byproduct (< 7.5%). We have found that methanesulfonic acid catalyzed condensation of pyrrole and benzaldehyde followed by DDQ oxidation provides N-confused tetraphenylporphyrin (NC-TPP) in up to 39% yield in analytical scale experiments. Preparative synthesis provided an isolated yield of 35% (800 mg). This represents a > 5-fold yield improvement and makes significant quantities of NC-TPP readily available.}, number={9}, journal={ORGANIC LETTERS}, author={Geier, GR and Haynes, DM and Lindsey, JS}, year={1999}, month={Nov}, pages={1455–1458} } @article{geier_lindsey_1999, title={N-confused tetraphenylporphyrin and tetraphenylsapphyrin formation in one-flask syntheses of tetraphenylporphyrin}, volume={64}, ISSN={["0022-3263"]}, DOI={10.1021/jo982068r}, abstractNote={The yields of tetraphenylporphyrin (TPP), N-confused tetraphenylporphyrin (NC-TPP), and tetraphenylsapphyrin (TPS) were examined under diverse conditions in the one-flask room-temperature reaction of pyrrole and benzaldehyde. The conditions examined included TFA and BF(3)-etherate catalysis, acid concentrations, pyrrole and benzaldehyde concentrations, pyrrole:benzaldehyde ratios, the addition of salt, and reaction times. The quantities of TPP, NC-TPP, and TPS were determined by HPLC. The yield of NC-TPP mirrored that of TPP during systematic variation of reaction parameters but was consistently lower (