science/technolog
w^0yk
PORPHYRIN ROUTE REVIVAL Aromatic porphyrinoid compounds synthesized by 3 + V condensation Michael Freemantle C&EN London
A
neglected approach to synthesizing porphyrins—the so-called 3+1 method—is seeing a flurry of new activity that is opening the way to prob ing the nature of aromaticity in such compounds. Timothy D. Lash, professor of organic chemistry at Illinois State Uni versity, Normal, and coworkers are using the strategy to replace one of porphy rin's usual four pyrrole units with other types of rings. "Why nature should have chosen tetrapyrroles for so many important functions remains open to debate," Lash says. "It is not clear whether this was purely acciden tal, but perhaps this will become clearer as we explore the chemistry of an exciting new class of ροφηνήηοΐά pigments." Porphyrins such as the chlorophylls— the green pigments used by plants in photosynthesis—and heme, the nonpro tein red pigment component of hemo globin, are composed of four pyrrole rings. They are highly conjugated. According to Lash, the porphyrins can be considered to be nature's [18]annulene, a cyclic hydrocarbon with 18 carbon atoms and nine conjugated double bonds. "The constituent 18 π-electron delocalization pathways contribute to the re markable stability of the porphyrins," he explains. The "exciting" new pigments synthe sized by Lash's group are porphyrin ana logs in which one of the four pyrrole rings has been replaced by another cy clic subunit. "The new porphyrinoid structures that we have synthesized rep resent fascinating new aromatic systems that resemble the annulenes and there fore may give insights into aromaticity in porphyrinoid structures," he says. Takuzo Aida, professor of chemistry and biotechnology at the University of Tokyo's graduate school of engineering, suggests that it will be interesting to see how an aromatic unit incorporated into a ροφηνηη ring might behave differently.
"I expect that these molecules could have a high potential as a new tool for the basic understanding of the chemistry of large π-conjugate systems," he says. David L. Officer, senior lecturer in or ganic chemistry at Massey University, Palmerston North, New Zealand, com ments that "Lash's elegant work has cer tainly laid the foundation of an exciting area of porphyrin chemistry." "What seems unique about these ma terials is the ability to tailor the porphy rin aromaticity with subtle changes to the carbon framework of the porphyrin," he adds. The syntheses of these porphyrinoid systems is based on the 3 + 1 approach, which involves acid-catalyzed condensa tion of a tripyrrolic intermediate, known as tripyrrane, with a monocyclic subunit such as a pyrroledialdehyde. "Using this approach, we have now demonstrated the efficient synthesis of porphyrin analogs with benzene, pyri dine, cycloheptatriene, azulene, and indene subunits, and this work is likely to have a major impact on the porphyrin field," says Lash. "These novel systems are truly remarkable."
The 3 + 1 approach was introduced by Alan W. Johnson (1917-82), chemistry pro fessor at Nottingham University, England, and coworkers more than 25 years ago in the synthesis of porphyrin analogs with one or two furan or thiophene subunits. It is a variation of the so-called 2 + 2 conden sation of two dipyrrolic units, which is still used for the syntheses of porphyrins and related conjugated macrocycles. For many years, the 3 + 1 route to por phyrins attracted little interest, partly be cause of the difficulty in obtaining the tripyrrane intermediates, notes Lash [Cbem. Eur J., 2,1197 (1996)]. In 1987, Jonathon L. Sessler, professor of organic chemistry at the University of Texas, Austin, and co workers reported a direct route for the synthesis of tripyrranes involving the con densation of two molecules of acetoxymethylpyrrole with a pyrrole unsubstituted in the 2 and 5 positions. Since 1994, several 3 + 1 syntheses of porphyrins and related polycyclic pyr roles have been developed using tripyr ranes and monocyclic moieties. The lat ter are usually dialdehydes. Pyrroledialdehydes are typically used to synthesize porphyrins, but other bifunctional pyr roles have also been used. For example, last year, Kevin M. Smith, professor of chemistry at the University of California, Davis, and coworkers reported the 3 + 1 synthesis of porphyrins from tripyrranes and 2,5-bis(dimethylaminomethyl)pyrroles [/. Org. Chem., 61, 998 (1996)]. "After more than two decades of lying fallow, the 3 + 1 approach has been re vived and shown to be a valuable and versatile route for porphyrin synthesis," notes Lash. He points out, however, that
'3 + Γ condensation yields porphyrin analog
JÛC
OHC ^N CHO Pyridinedicarboxaldehyde
n Co2Hi 5
1. Acid-catalyzed condensation
H3C " V ^ V ^ ^ " C2H5
°2Η5
C2H5
Oxypyriporphyrin ΗΟ20λ H,C 3o
18 π-electron derealization pathway shown in bold
\ ^
\ ^
^y
C2H5
C2H5
DDQ = 2,3-dichloro-5,6-dicyano1,4-benzoquinone
Tripyrrane dicarboxylic acid SEPTEMBER 1, 1997 C&EN
31
science/technolo one of the two condensing units, the tripyrrane or the monocyclic unit, must be symmetrical to prevent formation of isomeric products. Even so, the ap proach allows syntheses of structures that would be difficult to obtain using other synthetic routes. Lash has used the 3 + 1 approach to prepare "truly novel" aromatic porphyri noids containing benzene and pyridine rings which he terms "oxybenziporphyrin" and "οχνρνήροφηνηη," respectively. "The idea was to replace one or more of the porphyrin's pyrrole units with ben zene or pyridine moieties while retaining overall macrocyclic aromaticity," he says. He points out that porphyrinoids in which one or more pyrrole units are re placed by other five-membered rings, such as furan or thiophene, retain macrocyclic aromaticity. Replacement of a pyr role unit with a six-membered aromatic ring such as benzene or pyridine, howev er, tends to disrupt overall π-electron delocalization and therefore macrocyclic aromaticity. Such compounds have been known since the 1950s, says Lash. "Previous attempts to prepare aromatic porphyrinoids have led to the formation of relatively unstable nonaromatic structures, the six-membered ring being unwilling to give up its aromatic resonance stabiliza tion energy to allow macrocyclic dereal ization of π-electrons," Lash explains. For example, in 1994, Eberhard Breitmaier, professor of organic chemistry, and gradu ate student Kurt Berlin at the Kekulé Institute for Organic Chemistry & Biochemistry at Rheinischen-Friedrich-Wilhelms University in Bonn, Germany, described the use of the 3 + 1 approach to synthesize porphyrinoid macrocycles containing pyridine and benzene [Angew. Chem. Int. Ed. Engl, 33, 219 and 1246 (1994)]. But the compounds did not exhibit 18 π-electron aromaticity and the yields were less than 10%. "In our studies," Lash says, "a strategi cally placed hydroxyl unit tips the bal ance by allowing keto-enol tautomeriza tion to occur." Lash's oxybenziporphyrin, a fully aro matic semiquinone porphyrin analog, is prepared by decarboxylating a tripyrrane dicarboxylic acid and condensing it with 5-formylsalicylaldehyde [Angew. Chem. Int. Ed. Engl, 34, 2534 (1995)]. The mix ture is neutralized and oxidized with 2,3dichloro-5,6-dicyano-l,4-benzoquinone. The purple crystalline product, obtained in 35% yield, dissolves in chloroform and dichloromethane to give a deep-green solution. 32
SEPTEMBER 1, 1997 C&EN
w?ê$Î$ ι tronic and optical properties to come out of Lash's laboratory," he says. "These por phyrins will also certainly be of interest to those in materials development." Lash and Chaney suggest that these new structures "open the door to the con struction of many new porphyrin/bridged annulene hybrid structures." One such compound is a cycloheptatrienyl porphy rin analog, termed "tropiporphyrin." The compound is prepared in similar fashion to oxybenziporphyrin and oxypyriporphyrin using a cycloheptatriene dialdehyde as the monocyclic subunit [Tetrahedron lett., 37, 8825 (1996)]. The methodology provides access to "reasonable quantities" of pure tropipor phyrin, note Lash and Chaney. "This will allow the chemistry of this unusual por phyrinoid system to be explored in de Lash: fascinating new aromatic systems tail," they note. More recently, Lash and Chaney used Lash and graduate student Sun T. the 3 + 1 approach to obtain "excellent Chaney employed a similar procedure us yields" of a compound they call "azuliing the same tripyrrane dicarboxylic acid porphyrin" from 1,3-azulenedicarboxaland 3-hydroxy-2,6-pyridinedicarboxyalde- dehyde and a tripyrrane dicarboxylic hyde as the dialdehyde to prepare oxypy- acid [Angew. Chem. Int. Ed. Engl, 36, riporphyrin, "the first fully aromatic por 839 (1997)]. Azulene (C1(flJ is a bicyphyrinoid macrocycle with a pyridine sub- clic benzenoid-type hydrocarbon with unit" [Chem. Eur. J., 2, 944 (1996)]. The seven- and five-membered rings. average yield is almost 70%, notes Lash. The NMR spectrum of azuliporphyrin Once again, the product is purple when shows that the molecule has a weak mac crystalline but deep green in solutions. rocyclic ring current. "It has borderline Chemical shifts of the bridge methine porphyrinoid aromaticity," says Lash. (CH) protons in the proton nuclear mag "What is particularly interesting is that netic resonance (NMR) spectra of both the full aromatic ring current is switched compounds confirm the presence of the on in the presence of acid," he adds. macrocyclic current of 18 π-electrons. Lash and graduate student Michael J. "Both structures give beautiful bright Hayes have also reported the direct syn green solutions and exhibit porphyrin- thesis of an indenylpoφhyrinoid, which, like spectroscopic properties," observes they state, "can be considered as a mem Lash. "The new pyridine version readily ber of the newly discovered family of forms metal chelates, and appears to carbaporphyrins" [Angew. Chem. Int. have as versatile a coordination as the Ed. Engl, 36,840(1997)]. true porphyrins. Lash and Hayes define carbaporphy"Ten examples of oxybenzi- and ^e—""^—"^— oxypyriporphyrins Tautomerization allows macrocyclic have been synthe electron derealization sized in my laborato ry so far," he adds. Massey Universi ty's Officer points out that many of the starting materials used to prepare these aromatic por H,C phyrinoids are readi ly available. "Chem ists can expect a Oxybenziporphyrin wide variety of in Enol Keto teresting materials 18 π-electron derealization pathway shown in bold with intriguing elec
Secure your personal copy of
CHEMICAL & ENGINEERING NEWS
Why Share? Q t t I M · waNtefe M M »
yem9 mety
ΟΜΙΙ|ΗΜΜΙ
by t h · moot
Don't Hesitate! Call today toll-free at:
1-800-333-9511 Outside the U.S. call (614) 447-3776 Fax: (614) 447-3671 or complete and mail the coupon at right to begin you own personalized subscription to Chemical & Engineering News
• Yes! I want to become an ACS member and receive C&EN as a pail of my member benefits. Please send me a membership application right away. SEND NO MONEY NOW! Name: Address: City. State. Zip: Phone:
l'-mail:
J i£l4>>v£itâSl^iâ
&
&s&s&&^
ij
"To you it may be just waste/' .^g*
tr%\
$*&
4
*& h **%&* c^ *$s
& " Λ4ΕΕ»*3 *?&SK LiSfeiia
^s#-j
ï?^
*^î * < ^
*"**£&
?C
"To DSM it's a raw material.
//
Until recently there was only one thing that could be done with an old, worn carpet. Fortunately things have changed, and now old carpets can be recycled. Thanks in part to the RECAM project, which is coordinated by DSM. The reason why we are so closely involved in carpet recycling is that we are one of the world's major producers of caprolactam - the raw material for nylon carpet fibres - and feel responsible for the fate of this product. We want to ensure that old
If you want to know more about Ï llllllllfi
carpets don't just end up on the tip.
the RECAM projects or if you are interested in finding out more about
the measures DSM takes as regards safety, health and the environment, take a look at DSM's 1996 Responsible Care Progress Report. The report, which this year takes waste as its main topic, also includes the results achieved by the various DSM sites in the field of Responsible Care. If you would like a free copy, just call (+31 46-4770138) or fax (+31 46-4770070)
http://www.dsm.nl
DSM φ
CIRCLE 3 9 ON READER SERVICE CARD
Chemicals & Materials
DSM or look us up on the Internet:
SIMPLE EXPERIMENT WITH MOUSE YIELDS AMAZING DISCOVERIES FOR CHEMISTS Now you can cut through the confusion of the Internet and access the world's largest collection of chemistry-related information with ChemCenter,SM the American Chemical Society's new "bookmark" on the World Wide Web.
• Scientific and technical databases, including a link to STN, an international network of nearly 200 on-line databases
• Professional services such as job banks, policy statements, and industry relations services • Educational materials, including continuing education courses
Designed for chemists, other scientists, and the general public, ChemCenter brings together in one place the huge on-line resources of ACS with an array of new and developing services. Available at the site now are: • On-line chemistry publications, interactive journals, abstracts, tables of contents
• Information about ACS meetings and conferences including on-line registration
• Chat rooms and discussion and news groups.
th
ChemCenter A SERVICE OF THE AMERICAN CHEMICAL SOCIETY
With the exception of those areas that already require ACS membership or other payment for access, ChemCenter is free of charge to all Web site visitors. Access ChemCenter today at
http://www.ChemCenter.org
Novel porphyrinoid compounds
Tropiporphyrin
Azuliporphyrin
Benzocarbaporphyrin
rins as porphyrin analogs in which at least one of the pyrrole units has been replaced by a cyclopentadienyl unit and in which macrocyclic aromaticity is retained. In these analogs, one or more of the porphyrin's NH groups are replaced by methine groups. Breitmaier's group reported using the 3 + 1 approach to obtain a mixture of three benzocarbaporphyrins in low yield by the acid-catalyzed condensation of 1,3azulenedicarboxyaldehyde with a tripyrrane dicarboxylic acid [Synthesis, 1996, 336]. The mechanism of the contraction of the seven-membered ring in the azulene moiety to the six-membered benzo component remains obscure, however. "This structure is unexpected and the loss of one carbon cannot be easily explained," state the authors. Lash and Hayes obtained a 43% yield of their benzocarbaporphyrin by the direct 3 + 1 synthesis from 1,3-indenedicarboxaldehyde and a tripyrrane dicarboxylic acid. The isomerically pure product crystallized as flurry, deep-copper/bronze-colored needles. In as yet unpublished work, Lash's group has recently extended the 3 + 1 methodology to the syntheses of "carbachlorins" from cyclopentane dialdehydes. "Chlorins are dihydroporphyrins that provide the central structural unit found in most of the chlorophylls and some other important biological pigments," he explains. "They show strong absorptions in the red part of the visible spectrum, and this feature makes these compounds promising candidates for photodynamic
PHYTOCHEMICALS Your complete source
therapy." This therapy, he points out, is a form of tumor therapy that uses laser light to "activate" a photosensitizer that, in turn, transfers energy to oxygen, thereby producing singlet oxygen at the site of the tumorous tissue. "The carbachlorins, which we have prepared for the first time, differ from true chlorins by having one of the nitrogen atoms replaced with a carbon," he says. "They show the same strong absorption at long wavelengths and so may well be suited for applications as photodynamic therapy." Lash and graduate student Dan Richter also developed a related 4 + 1 route to prepare the first example of a carbasapphyrin. "Sapphyrins are larger-than-life pigments consisting of five pyrrole subunits instead of four," Lash says. "They have significant biological activities." Chemistry Nobel Laureate Robert B. Woodward first observed the sapphyrins as an unexpected by-product during his early studies on the total synthesis of vitamin B-12. "The sapphyrins are quite beautiful," observes Lash. "The name was coined because of the deep-blue color of the solid material. A carbasapphyrin lacks one of the five nitrogen atoms. This new system is likely to have novel reactivity and coordination chemistry. "The versatility of the 3 + 1 methodology is likely to make this an important synthetic route in the future," concludes Lash. "In many respects, we have barely scraped the surface, and many truly novel aromatic structures related to the porphyrins are likely to be obtainable by this approach."^
Boehringer Ingelheim BOEHRINGER INGELHEIM KG Business Unit Fine Chemicals D-55216 Ingelheim Germany Telephone 49/6132-77-38 89 Telefax 49/6132-77-66 80
B.I. CHEMICALS, INC. 3330 South Crater Road Petersburg, VA 23805 USA Telephone 1/804-863-4706 Telefax 1/804-863-2231
• strict cGMP and FDA compliance • highest purity
Yohimbine
BOEHRINGER INGELHEIM (CANADA)LTD./LTEE. Fine Chemicals Division 5180 South Service Road Burlington, Ontario L7L 5H4 Telephone 1/800 263 9107 Telefax 1/905 639 3769
|; . DMF filed CIRCLE 19 ON READER SERVICE CARD
SEPTEMBER 1, 1997 C&EN 3 3
