Angew Chem Int Ed - 2003 - Sessler

Reviews J. L. Sessler and D.
Seidel
Porphyrin Chemistry
Synthetic Expanded Porphyrin Chemistry

Jonathan L. Sessler* and Daniel Seidel
Keywords:
antiaromaticity · aromaticity ·
heterocycles · macrocycles ·
porphyrinoids
Angewandte
Chemie
5134 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200200561 Angew. Chem. Int. Ed. 2003, 42, 5134 – 5175
Angewandte
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Expanded Porphyrins Chemie
Expanded porphyrins are synthetic analogues of the porphyrins, From the Contents
and differ from these and other naturally occurring tetrapyrrolic
1. Introduction and Definition 5135
macrocycles by containing a larger central core with a minimum
of 17 atoms, while retaining the extended conjugation features 2. Historical Overview 5136
that are a hallmark of these quintessential biological pigments.
The result of core expansion is to produce systems with novel 3. Systems Containing Four or Fewer
spectral and electronic features, interesting and, often unprece- Heterocyclic Subunits 5137
dented, cation-coordination properties, and, in many cases, an 4. Systems Containing Five Pyrrole Rings 5147
ability to bind anions in certain protonation states. Also adding to
the appeal of expanded porphyrins is their central role in 5. Systems Containing Six Pyrrole Rings 5155
addressing issues of aromaticity. In many cases, they also display
6. Systems Containing Seven Pyrrole
structural features, such as decidedly nonplanar “figure-eight”
Rings 5162
motifs, that have no antecedents in the chemistry of porphyrins or
related macrocyclic compounds. In this Review, the various 7. Compounds Containing Eight or More
synthetic approaches now being employed to produce expanded Pyrrole Rings 5164
porphyrins as well as their various applications-related aspects
8. Recent Advances 5171
are discussed.
9. Outlook 5172
1. Introduction and Definition the initially unexpected finding that expanded porphyrins can
act as anion receptors. This result has made these systems of
Porphyrin (for example, 1) undoubtedly represents one of potential interest for use in a variety of applications, including
the most widely studied of all known macrocyclic ring anion sensing and transport (for example, drug delivery), as
systems.[1] Interest in this naturally occurring tetrapyrrolic well as chromatography-based purification of anions.[7]
macrocycle is broadly based and derives in part from its This Review is focused on expanded porphyrins and is
multiple biological functions as well as its ability to function meant to complement earlier overviews of the field.[2, 3, 8]
as an excellent metal-complexing ligand. This chemical While some historical background will be presented for the
richness has inspired the study of a whole range of porphyrin benefit of the general reader, its primary objective is to
analogues in recent years.[2, 3] Much of the attention devoted provide an update on what has been achieved in the area of
to these latter systems is based on their resemblance to oligopyrrole macrocycles between 1998 and June 2002. The
porphyrins and the hope that they will display a rich main focus will be on systems that bear the greatest formal
coordination chemistry that parallels that of the porphyrins. resemblance to porphyrins, namely conjugated oligopyrroles.
On a different level, the electronic structure of various However, this Review will also cover various “expanded”
larger, or “expanded” porphyrin systems, in particular their systems, whose intellectual antecedents are in phthalocya-
similarities and differences to porphyrins, have made them an nines, porphyrazines, and various non-pyrrolic ring com-
object of intense study. Here, a key objective of both practical pounds. In all cases, the compounds in question will be larger
and theoretical importance has been to explore the limits to than porphyrins and related tetrapyrrolic systems. Specifi-
which the classic H+ckel definition of aromaticity (4n+2 cally, a system must be macrocyclic and contain pyrrole, furan,
p electrons) may be applied to heteroannulenes. A related thiophene, or other heterocyclic subunits linked together
goal was to understand what factors endow a fully conjugated either directly or through one or more spacer atoms in such a
macrocycle with characteristics that can be considered manner that the internal ring pathway contains a minimum of
aromatic or antiaromatic.[4] 17 atoms. In accord with this definition, compounds such as
Another factor driving the study of conjugated expanded corroles,[9] isomeric porphyrins,[10] N-confused porphyr-
porphyrins is that they often display absorbance bands that ins,[11, 12] doubly N-confused porphyrins,[13] N-fused porphyr-
are considerably red-shifted relative to those of porphyrin. ins,[14] benziporphyrin,[15] and carbaporphyrin[16, 17] that con-
This attribute, which is ascribed to an increased p-conjugation
pathway, has led to the consideration that certain expanded
porphyrins could find use as therapeutics for photodynamic [*] Prof. J. L. Sessler, Dr. D. Seidel
therapy.[5, 6] Related properties, including a facilitated ease of Department of Chemistry and Biochemistry
Institute for Cellular and Molecular Biology
reduction, has led to the testing of one particular expanded
University of Texas at Austin
porphyrin (xcytrin; motexafin gadolinium) as an adjuvant for Austin, TX 78712-1167 (USA)
X-ray radiation therapy.[5, 6] Another area of interest, this time Fax: (+ 1) 512-471-7550
without precedence in the porphyrin arena, centers around E-mail: sessler@mail.utexas.edu
Angew. Chem. Int. Ed. 2003, 42, 5134 – 5175 DOI: 10.1002/anie.200200561 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5135
Reviews J. L. Sessler and D. Seidel
tain an internal ring pathway of 16 or fewer atoms are not where appropriate, potential uses of the systems in question
included here.[18] Furthermore, to keep the length of the will be highlighted, for example, in the important area of
review within reasonable limits, nonconjugated systems such cation complexation, anion recognition, waste remediation,
as expanded calixpyrroles (porphyrinogens) and calix[n]phyr- materials development, and biomedicine.
ins, expanded analogues of porphodimethenes, will be for the
most part excluded. Such systems have, however, been the
subject of recent reviews.[19, 20] 2. Historical Overview
Except in those cases where the use of trivial names offers
an heuristic advantage, a generalized version of a nomencla- The beginnings of expanded porphyrin chemistry can be
ture put forward by Franck and Nonn for porphyrinic systems traced back to R. B. Woodward and his research group. Their
will be used.[21] According to this standard system, the name of pioneering efforts directed towards the synthesis of vita-
porphyrinoids consists of three parts: 1) a number in square min B12 led to the serendipitous discovery of sapphyrin, a
brackets corresponding to the number of p electrons in the pentapyrrolic macrocycle (for example, 2) that was first
shortest conjugation pathway, 2) a core name representing the mentioned at the aromaticity conference in Sheffield, UK,
number of pyrroles or other heterocycles in the overall 1966. In contrast to what might have been expected given its
system, and, 3) numbers in round brackets following the main novel structure, sapphyrin wasn't introduced in a glamorous
name that specify the number of bridging carbon atoms manner, rather, Woodward mentioned its isolation and
between each pyrrole subunit, starting with the largest bridge. characterization during the discussion period that followed
For example, porphyrin 1 would be named as [18]por- his formal oral presentation.[22] As a result of being disclosed
phyrin(1.1.1.1), whereas sapphyrin 2 would be named as in this manner, sapphyrin does not appear in the conference
[22]pentaphyrin(1.1.1.1.0). proceedings. While appearing in theses and dissertations from
The focus of this presentation will be on synthesis, Woodward's research group, systematic syntheses of sap-
characterization, and basic chemical properties. However, phyrin were not published until much later on, when two
Jonathan L. Sessler received a B.S. degree in Daniel Seidel was born in M:hlhausen,
chemistry in 1977 from the University of Th:ringen (Germany) in 1972 and studied
California, Berkeley. He obtained a Ph.D. in chemistry at the Friedrich-Schiller-Universit<t
organic chemistry from Stanford University Jena (1993–1998). His Ph.D. research at
in 1982 (supervisor: Professor James P. Coll- the University of Texas at Austin (1998–
man). After postdoctoral research with Prof. 2002) under the supervision of Prof. Jona-
Jean-Marie Lehn at L'Universit2 Louis Pas- than L. Sessler involved the synthesis of new
teur de Strasbourg, France, he worked in the expanded porphyrins with unprecedented
research group of Professor Iwao Tabushi in structural features. In 2001, he received a
Kyoto, Japan. In 1984, he joined the faculty University Co-op Award for Research Excel-
of The University of Texas at Austin, where lence and a Welch Academic Excellence
he is now the Roland K. Pettit Centennial Award. Currently, he is working as an Ernst
Professor of Chemistry. He has authored Schering Postdoctoral Fellow in the research
numerous publications and has co-founded two companies (Pharmacyclics, group of Professor David A. Evans at Har-
Inc. and Anionics, Inc.). vard University.
5136 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2003, 42, 5134 – 5175
Angewandte
independent reports, one by Woodward and co-workers[23] While the above contributions are those that most directly
and another, actually an earlier contribution by Broadhurst helped spawn the growth of the field, it is to be appreciated
et al., were published.[24] However, it was not until 1990, when that there are many other earlier contributions of importance
an improved synthesis of sapphyrin was described, that usable that, sadly, are simply too numerous to detail here. The
quantities of this macrocycle could be obtained.[25] The interested reader is referred to various reviews that cover the
increased availability of sapphyrin spawned an enhanced chemistry of oligopyrrolic macrocycles synthesized prior to
interest in this macrocyle. In fact, a recent search with 1998.[2, 3, 8, 21]
SciFinder for the keyword “sapphyrin” resulted in 147 hits, a
number that reflects in microcosm some of the interest
attendant to expanded porphyrin chemistry. 3. Systems Containing Four or Fewer Heterocyclic
In addition to the synthesis and subsequent study of Subunits
sapphyrin chemistry, which has recently been reviewed in
detail,[7] there are many historical accomplishments that Most of the work on expanded porphyrins containing four
helped define the field of expanded porphyrin chemistry. pyrrole rings or other heterocycles was done early on when
One of these was the seminal characterization of uranyl- the main motivation was to analyze the aromaticity of the
superphthalocyanine (3) by Day, Marks, and Wachter.[26] This resulting systems. While most of the relevant chemistry has
system, obtained from a template synthesis employing been covered in review articles,[2, 3, 8, 21] there are a few new
phthalonitrile and uranyl salts, aroused considerable excite- examples of expanded porphyrin-type macrocycles whose
ment at the time. Unfortunately, all attempts to generalize synthesis was inspired by just these kinds of issues.
this chemistry (that is, produce complexes containing other
metals) or to obtain the metal-free ligand met with failure.
While this limited the study of superphthalocyanine itself, the 3.1. [22]Porphyrin(3.1.3.0)
very fact that it could be made helped inspire a number of
other historically important developments, including the In 1999, Paolesse, Smith, and co-workers reported the
synthesis of pentaphyrin (for example, 4) by Rexhausen and synthesis of a bisvinylogous corrole, [22]porphyrin(3.1.3.0)
Gossauer,[27] the preparation of so-called platyrins (for (16), which they described as the first expanded corrole.[34]
example, 5) by Berger and LeGoff,[28] and the generation of Strictly speaking, this is not formally true since, depending on
a whole series of “stretched” systems (for example, 6) by the definition employed, such venerable systems as sapphyrin,
Franck and co-workers.[21, 29] Another important boost to the rubyrin, and even porphyrin and its isomers constitute
generalized area of porphyrin analogues came with the “expanded corroles”. Nonetheless, macrocycle 16 represents
synthesis of porphycene (7) by Vogel et al. in 1986.[30] This an important new addition to the expanded porphyrin family.
first of now many porphyrin isomers represented a milestone It was obtained in 54 % yield by the oxidative coupling of 15
in the chemistry of oligopyrrolic macrocycles and helped with chloranil (tetrachloro-p-benzoquinone) in ethanol using
highlight the fact that porphyrin analogues need not be NaHCO3 or sodium acetate as a base (Scheme 1). Precursor
expanded to be interesting. This point was subsequently
underscored when the research groups of Furuta[11] and
Latos-Graz̊yński[12] independently reported the synthesis of
so-called “inverted” or “N-confused” porphyrin (8). More
recently, it has been highlighted by the synthesis of a range of
heteroporphyrin systems, including derivatives of carbapor-
phyrin.[16, 17] Although the chemistry of porphyrin analogues is
tremendously interesting, they are excluded from this review
for the reasons outlined above.
The synthesis of texaphyrin (9) is particularly noteworthy
in the area of expanded porphyrins.[5] It was the first expanded
porphyrin to display a diverse metalation chemistry, a
property that had been hoped for (but not seen) with the
earlier expanded porphyrins, such as sapphyrin. On a differ-
ent level, hexaphyrin (10)[31] and rubyrin (11)[32] were
important because they were the first expanded porphyrins
to contain more than five pyrrolic subunits. They thus served
as auguries for the arrival of yet larger oligopyrrolic systems. Scheme 1. Synthesis of expanded corrole 16.
This latter promise was first realized in the case of turcasarin
(12),[33] a decapyrrolic system that adopts a twisted “figure-
eight” conformation both in solution and in the solid state.
While eclipsed now in terms of size, turcasarin remains of 15, in turn, was obtained in 75 % yield from the acid-catalyzed
historical importance because it showed that pyrrole-contain- condensation of two equivalents of 14 with 13. Interestingly,
ing macrocycles need not to be flat or nearly flat to along with the isolation of 16, a small amount of the
demonstrate features characteristic of full conjugation. corresponding bisvinylogous porphyrin was obtained, which
Angew. Chem. Int. Ed. 2003, 42, 5134 – 5175 www.angewandte.org 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5137
was rationalized in terms of cleavage and recombination

reactions involving 15.
As expected for a system with a 22 p-electron periphery,
the presence of a diatropic ring-current effect was evident in
the 1H NMR spectrum of the hydrochloride salt of 16
(H(16+)·Cl). For example, the inner CH protons were
found to resonate at d = 9.2 ppm, while the signals corre-
sponding to the outer CH protons were found to resonate at
d = ~ 11 ppm. The results are similar to what was found for the
analogous bisvinylogous porphyrin 6 (n = 0) reported by
Franck and co-workers.[29] Further support for the aromatic
nature of 16 was obtained from UV/Vis spectroscopic
analyses. The spectrum of 16 was found to contain a strong,
split transition with two absorption maxima at lmax = 468 and
496 nm, which presumably corresponds to the intense,
formally allowed, B, or Soret band seen in the spectra of
porphyrins. This high-energy absorption feature is accompa-
nied by two bands of lesser intensity at lmax = 666 and 714 nm,
which are considered analogous to the weaker, so-called
Q bands seen at lower energy in the spectra of porphyrins
(Figure 1). Characterization by X-ray analysis (Figure 2)
Figure 2. Front (top) and side (bottom) views of the solid-state struc-
ture of H(16+)-Cl .[34] Unless stated otherwise this and all subsequent
figures showing solid-state X-ray crystallographic structures were gen-
erated using information downloaded from the Cambridge Crystallo-
graphic Data Centre. Thermal ellipsoids are scaled to the 50 % level.
Figure 1. UV/Vis spectrum of 16.[34] .
earlier by MOrkl et al.,[37] namely the cis,trans,cis,trans isomer

revealed unambiguously that H(16+)·Cl is almost perfectly 18 a. Compound 18 was calculated to be 90 kcal mol1 higher
planar and exists as a dimer in the solid state. Interestingly, in energy than its bis-trans isomer 18 a. A crystal structure of
the parent peak in the FAB mass spectrum of H(16+)·Cl the octaethyl derivative of the latter compound was reported,
corresponds to this dimer with the loss of one chloride ion. which revealed its almost perfect planarity (Figure 3).
Interesting results were obtained from an analysis of the
UV/Vis spectra of the octaethyl derivatives of 17, 18 a, and 19
3.2. Tetraoxa[22]porphyrin(2.2.2.2) Dication, (Figure 4). Extraordinarily sharp Soret-type bands were
Tetraoxa[26]porphyrin(3.3.3.3) Dication, and N,N’,N’’,N’’’- observed in the spectra of 17 (lmax 400 nm) and 19 (lmax =
Tetramethyl[26]porphyrin(3.3.3.3) Dication 525 nm). For these latter bands, record extinction coefficients
were observed (e = 1.6 P 106 and 1 P 106 m 1 cm1 for 17 and 19,
Intrigued by the exceptional spectroscopic properties of respectively). A split Soret band (lmax = 456 and 474 nm) that
the N,N’,N’’,N’’’-tetramethyl[26]porphyrin(3.3.3.3) dication exhibits a reduced extinction coefficient (e 0.5 P
(21) described by Franck and Nonn,[21] the research group 106 m 1 cm1) was observed in the spectrum of 18 a, with its
of Vogel was prompted to reinvestigate some of its chemical lower (C2h) symmetry, relative to 17 and 19. It is noteworthy
features as well as those of related species.[35, 36] Here, the that the Q-type bands for all three systems are characterized
motivating goal was to perform a spectroscopic comparison by intensities that are significantly lower than those of the
between the D4h-symmetric tetraoxa[18]porphyrin dication 17 corresponding Soret-type bands.
and its homologues, the all-cis-tetraoxa[22]porphyrin(2.2.2.2) Structural and spectroscopic comparisons between the
dication (18) and the tetraoxa[26]porphyrin(3.3.3.3) dication N,N’,N’’,N’’’-tetramethyl[26]porphyrin(3.3.3.3) dication (20)
(19). and the octaethyltetraoxa[26]porphyrin(3.3.3.3) dication (21)
As anticipated by the authors, the synthesis of 18 proved were made.[36] While the X-ray structure of 20 (Figure 5)
elusive. Efforts to prepare it gave rise to a compound reported revealed the presence of a nearly planar macrocyclic frame-
Angewandte
Figure 3. Front (top) and side (bottom) views of the solid-state

structure of 18 a (octaethyl derivative).[35]

structure of 20.[36]
Figure 4. UV/Vis spectra of octaethyl derivatives of 17, 18 a, and 19;

e is in m1 cm1.[35]
work with only slight deviation from the expected D4h sym-
metry, a corresponding structural analysis of 21 (Figure 6)
revealed a macrocycle that is in the shape of a flat bowl. In the Figure 6. Front (top) and side (bottom) views of the solid-state
latter case, all four pyrrole rings were found to point in the structure of 21.[36]
same direction, being tilted up out of the median plane of the epoxy[32]annulene(8.0.8.0) (22), tetraepoxy[36]annulene-
macrocycle by 16–198. It is these deviations from planarity (10.0.10.0) (23), and tetraepoxy[40]annulene(12.0.12.0) (24).
that are proposed to account for an interesting finding, All three compounds were obtained through a double Wittig-
namely that the Soret-type band of 21 is less intense by a type cyclization of appropriately designed precursors.[38]
factor of about 0.6 than that of 20, while the position of this
transition remains almost the same for these two compounds
(Figure 7; lmax 525 nm for 20 and 21).
Figure 7. UV/Vis spectra of 20 and 21.[36]
It was concluded from 1H NMR spectroscopic analyses

1
The H NMR spectra of 20 and 21 are characterized in that macrocycles 22 and 23 exist as a mixture of several
both cases by the presence of strong diamagnetic ring-current configurational isomers (only one of which is shown for each
effects. In particular, Dd values of 25.5 and 26 ppm are macrocycle). Perhaps more importantly, these 1H NMR
observed for the inner and outer perimeter protons of 20 and analyses completed the spectral comparison of the full
21, respectively. Such chemical shift differences were consid- homologous sequence of furan macrocycles ranging from
ered consistent with the proposed aromaticity of the com- tetraepoxy[20]annulene(2.0.2.0) (25) to tetraepoxy[36]annu-
pounds. To provide support for this conclusion the corre- lene(10.0.10.0) (23). Here it was found that the observed
sponding two- and four-electron reduction products of 20 and paratropic character (a generally accepted experimental
21 were generated in situ by reduction with potassium in THF. indicator of antiaromaticity), specifically the Dd values
As expected, remarkable reversals of the chemical shifts were between the outer and inner CH protons, decreases steadily
observed for the formally antiaromatic two-electron reduc- on going from 25 to 22. This result is expected given the
tion products (28 p-electron systems) produced from 20 and increased conformational flexibility (for example, deviation
21: the signals ascribed to the inner CH protons were shifted from planarity) associated with the larger systems. Curiously
to lower fields than in 20 and 21, while those for the outer and rather unexpectedly, however, the Dd value observed for
CH protons were shifted to higher fields. As a result, the 23 is larger than that seen for its smaller congener 22.
Dd values for the two two-electron-reduced species formed However, the authors note that there is some uncertainty
from 20 and 21 are 14 and 13.4 ppm, respectively. Spectral associated with the Dd values for 23; thus, they did not
features consistent with aromaticity are restored in the four- speculate as to the meaning of the differences in the Dd values
electron-reduction products of 20 and 21, with Dd values for between 22 and 23. While further insight into the issue could
these formal 30 p-electron species comparable to those of the come from an analysis of 24, the latter species proved too
parent 26 p-electron systems 20 and 21. insoluble to allow for its analysis by 1H NMR spectroscopy.
Compound 24 was, however, characterized by mass spec-
trometry and UV/Vis spectroscopy, and found to display
3.3. Tetraepoxy[32]annulene(8.0.8.0), features consistent with its proposed antiaromatic structure.
Tetraepoxy[36]annulene(10.0.10.0), In particular, it fit the trend expected by the authors, namely
Tetraepoxy[40]annulene(12.0.12.0), and that the lmax values of furan annulenes are red-shifted by
Their Corresponding Dications approximately 12 nm upon the synthetic “insertion” of each
pair of C=C spacers.
Prior to the above studies, MOrkl et al. sought to inves- Oxidation of 22–24 to the corresponding dicationic
tigate the limits of antiaromaticity and aromaticity as they species was accomplished by treatment with 2,3-dichloro-
relate to heteroannulenes through the synthesis and study of 5,6-dicyano-1,4-benzoquinone (DDQ) in CHCl3 or THF. The
1
tetraepoxy[4n]annulenes and their corresponding dications. H NMR spectra of these dications were recorded and were
These efforts led to the successful syntheses of tetra- found to be consistent with aromatic character that was
Angewandte
structure-dependent. The recorded Dd values were found to As a complement to these studies, an attempt was made to
increase with increasing ring size for what was believed to be prepare tetraepoxy[32]annulene(6.2.6.2) (26) by the
the all-E series of isomers. The Dd value of the largest McMurry coupling of (E,E,E)-5,5’-(hexa-1,3,5-triene-1,6-
dication, tetraoxa[38]porphyrin(12.0.12.0), the two-electron- diyl)bis[furan-2-carbaldehyde]. Instead of the desired prod-
oxidation product of 24, amounts to 25.17 ppm. Interestingly, uct, a dihydro analogue of 26 was obtained. Oxidation of this
the basic correlation between size and Dd values is reversed latter species with DDQ gave a tetraoxa[30]por-
for a different set of isomers containing an increased number phyrin(6.2.6.2) dication, along with a small amount (3 %) of
of Z double bonds compared to the predominantly E ar- what was believed to be a tetraoxa[31]porphyrin(6.2.6.2)
rangement shown for 22–24. The Dd values were found to radical cation. This radical cation was characterized by ESR
decrease with increasing ring size. In this series of macro- spectroscopy.
cycles, the lmax values of the Soret-type bands were found to
undergo a linear bathochromic shift with an increment Dl of
58 nm per two additional double bonds. Meanwhile, the 3.5. Tetraepoxy[36]annulene(6.4.6.4) and
absorptions of the most intense Q-type band of each of these Tetraoxa[34]porphyrin(6.4.6.4) Dication
dications were also found to increase in a linear manner with a
160 nm increment per pair of double bonds inserted. Taken in MOrkl et al. have also reported the synthesis of tetraepoxy-
concert, these findings highlight that spectroscopic features [36]annulene(6.4.6.4) (27).[40] As seen for its smaller congener,
consistent with antiaromaticity continue to remain important tetraepoxy[32]annulene(6.2.6.2) (26), this furan-containing
for large heteroannulene systems with p-electron pathways of
up to 40 electrons (at least), while those associated with
aromaticity (for example, diatropic ring-current effects) are
important in furan–annulene dications containing up to at
least 38 p electrons.
3.4. Tetraepoxy[32]annulene(6.2.6.2) and

Tetraoxa[30]porphyrin(6.2.6.2) Dication
The synthesis of tetraepoxy[32]annulene(6.2.6.2) (isomers

26 a and 26 b) is described in another contribution by MOrkl annulene was obtained in the form of an inseparable mixture
et al.[39] These species were also obtained by a double Wittig of isomers, for example, 27 a and 27 b. The observed para-
reaction involving, in this case, (E,E,E)-5,5’-(hexa-1,3,5- tropicity of 27 a and 27 b is rather low (Dd = 2.3–3.3 ppm), but
triene-1,6-diyl)bis[furan-2-carbaldehyde] and its correspond- nevertheless was considered to be evidence for antiaroma-
ticity. If such an interpretation is correct, 27 a and 27 b would
represent the largest antiaromatic systems prepared to date.
Oxidation of 27 a and 27 b results in the formation of the
corresponding dications. The 1H NMR spectra of these
dications are characterized by spectacular diatropic ring-
current effects that were considered consistent with a strong
aromatic character. Specifically, Dd values of 26.6 and
25.3 ppm are observed for these two cations, respectively,
which match those seen in the dication 21 prepared by Franck
and Nunn and its homologous N,N’,N’’,N’’’-tetramethyl[34]-
ing bisphosphonium salt. Proton NMR spectroscopic studies porphyrin(5.5.5.5) dication (not shown).[21]
of macrocycles 26 a and 26 b revealed their antiaromatic
character, as well as their inherent lack of conformational
rigidity.[39] 3.6. Tetraepoxy[32]annulene(4.4.4.4) and
Oxidation of 26 a and 26 b with DDQ gives rise to the Tetraoxa[30]porphyrin(4.4.4.4) Dication
tetraoxa[30]porphyrin(6.2.6.2) dication, which is obtained as
a mixture of no less than four configurational isomers. A Another contribution from the MOrkl research group
1
H NMR spectroscopic analysis of these latter species describes the synthesis of the tetraepoxy[32]annu-
revealed ring-current effects consistent with aromaticity, lene(4.4.4.4).[41] As is true for the other furan-containing
with Dd values of 26.8, 25.8, and 21.1 ppm being observed annulenes prepared by MOrkl et al., tetraepoxy[32]annu-
for the three most abundant isomers. Further support for the lene(4.4.4.4) exists as a mixture of at least three different
proposed aromatic nature of this mixture came from a UV/ isomers (for example, 28 a–c), all three of which display
Vis spectroscopic analysis. Here, the observation of Soret- antiaromaticity as judged from 1H NMR spectroscopic anal-
type bands at 550 nm, accompanied by Q-type bands between yses. Exposure of this isomeric mixture to DDQ produces the
896 and 1039 nm, was considered as evidence for the presence expected mixture of corresponding tetraoxa[30]por-
of at least one aromatic species. phyrin(4.4.4.4) dications; these species were judged to be
3.8. Tetraphenyl-p-benziporphyrin
To date, systems that contain fewer than four heterocyclic

subunits and which meet our definition of expanded porphyr-
ins have been few in number. This is particularly true for
carbon-linked systems. However, Latos-Graz̊yński and co-
workers have very recently reported the synthesis of a
hitherto unknown carbaporphyrinoid (32).[43] The BF3·OEt2-
catalyzed reaction of the dialcohol 31 with pyrrole and
aldehyde followed by oxidation with DDQ, gave rise to 32 in
approximately 1 % yield (Scheme 2).
aromatic based on the observation of Dd values of approx-

imately 25–27 ppm in their respective 1H NMR spectra.
3.7. Tetraepoxy[26]annulene(4.2.2.2) and

Tetraepoxy[30]annulene(4.4.4.2)
Recently, MOrkl et al. reported the synthesis of tetrae-

poxy[26]annulene(4.2.2.2) (29) and tetraepoxy[30]annu-
lene(4.4.4.2) (30).[42] This work is noteworthy since, unlike Scheme 2. Synthesis of macrocycles 32 containing p-phenylene groups.
The 1H NMR spectrum of 32 a recorded at 168 K was

consistent with the presence of a diatropic ring current. It was
found that the outer phenyl-CH protons exhibit shifts that are
markedly different from those displayed by the corresponding
inner phenyl-CH protons (d = 7.68 and 2.32 ppm, respec-
tively). At higher temperatures these two signals coalesce into
a singlet, presumably as the result of a dynamic process
involving rotation of the phenyl ring.
X-ray crystallographic analyses of 32 b and the bis-HCl
the other tetraepoxyannulene systems discussed above, 29 salt of 32 a revealed that these systems are nonplanar, at least
and 30 possess 4n+2 p-electron pathways in their neutral in the solid state (Figures 8 and 9). The phenyl subunit was
forms. Thus, as expected, these systems display diatropic ring- found to be displaced from the mean plane of the macrocycle,
current effects in their corresponding 1H NMR spectra, with with dihedral angles of 488 and 448 being seen in the case of
Dd values of 6.4 and 4.3 ppm being seen for 29 and 30, 32 b and 32 a·2 HCl, respectively.
respectively. On the other hand, as is true for other furan– Macrocycle 32 represents an intriguing system that is quite
annulene systems, 1H NMR studies of 29 and 30 revealed possibly the first example of a potentially large family of p-
evidence for highly flexible structures and the presence of phenylene-containing expanded porphyrins. While this prom-
isomers. ise remains to be realized, it is important to appreciate that
The presence of isomers complicates an analysis of 29 and the utility of 32 as a metal receptor has already been
30, as it does for the other systems reported by the MOrkl demonstrated, at least in preliminary studies. The CdCl
research group. Nonetheless it is clear that 29 and 30 display complex of 32 a could be stabilized and the X-ray crystal
rather low Dd values as compared to related aromatic structure of this complex determined (Figure 10). The metal
dicationic species (for which Dd values of about 25 ppm are cation was found to be coordinated within a distorted trigonal
routinely observed). This rather large disparity was rational- bipyramidal ligand environment, comprised of the three
ized in terms of the greater planarity presumed to exist in the nitrogen atoms of the ring, the chloride counterion, and a
dications as the result of the stabilization ostensibly provided double bond from the phenylene subunit which acts as a
by the positive charges. Although such rationalizations cannot p donor.
be discounted, a more plausible explanation is that the
number of accessible aromatic resonance structures for the
various dicationic furan–annulene species is much larger than 3.9. Latest Developments in the Chemistry of Texaphyrins
for either 29 or 30, for which only two resonance structures 3.9.1. Synthesis of a Metal-Free Texaphyrin
can reasonably be drawn.
Texaphyrin is one of the best studied expanded porphyr-
ins. The gadolinium(iii) and lutetium(iii) complexes of tex-
aphyrins are in advanced clinical trials as adjuvants for the
Angewandte

structure of 32 b.[43]
structure of a Cd complex derived from 32 a.[43]
radiation- and irradiation-based treatment of cancer and

cardiovascular disease (see Section 3.9.4).[6, 44–47] Other metal
complexes are of interest as potential peroxynitrite decom-
position catalysts and for their inherent structural fea-
tures.[48–50] As a consequence, the preparative chemistry of
metallotexaphyrins has been well studied. Until recently,
however, the metal-free aromatic form of the macrocycle was
not available. In 2001, 13 years after its original discovery, the
preparation of this elusive species was finally achieved.[51]
Addition of four equivalents of ferrocenium hexafluorophos-
phate to a solution of the so-called “sp3-texaphyrin” (33) in
acetonitrile under argon in the presence of 2,6-lutidine
yielded the metal-free texaphyrin in the form of its monop-
rotonated HPF6 salt (34) in 56 % yield (Scheme 3).
Figure 9. Front (top) and side (bottom) views of the solid-state Scheme 3. Synthesis of the metal-free texaphyrin 34: 1) [Cp2Fe][PF6],
structure of 32 a·2 HCl.[43] 2,6-lutidine, CH3CN. Cp = cyclopentadienyl.
Support for the proposed aromatic nature of 34 was in more detail the chemistry of complexes of texaphyrin with
obtained from its 1H NMR spectrum recorded in CD3CN. A late first-row transition metals.[52] By using the same oxidative
broad resonance at d = 9.27 ppm was assigned to the meso insertion methods used to generate the stable 1:1 lanthan-
protons, while the signal at d = 10.52 ppm was assigned to the ide(iii) texaphyrin complexes that were prepared and charac-
imine protons. These chemical shifts were considered con- terized in the late 1980s and early 1990s it proved possible to
sistent with the proposed aromatic character. Also indicative synthesize and isolate MnII, CoII, NiII, ZnII, and FeIII com-
of aromaticity is the upfield position of the two magnetically plexes of texaphyrin 35–39 (water-soluble complexes were
degenerate NH protons at d = 5.66 ppm. also prepared; not shown). While the FeIII complex was
Another product of the oxidation reaction was the bis- obtained in the form of a m-oxo bridged dimer, analogous to
HPF6 salt of the metal-free texaphyrin, which was isolated in
approximately 20 % yield. The free-base form of the metal-
free texaphyrin could be prepared by treating a solution of 34
in acetonitrile with 10 % aqueous NaOH. The spectral
characteristics of the two species were found to be in
agreement with their proposed aromatic structures. Addi-
tionally, the X-ray crystal structure of 34 (Figure 11) revealed
what is seen in the case of ferric porphyrins, the ZnII complex

38 proved notable in that only three of the five texaphyrin
nitrogen atoms were found to be coordinated in the solid
state. This was the case whether a single nitrate anion or two
methanol molecules (see Figure 12) were coordinated to the
ZnII center as ancillary ligands.
In contrast to the ZnII complex 38, X-ray diffraction
analysis of the CoII and MnII complexes showed that the
texaphyrin ligand provided five, near-planar donor atoms,
which resulted in structures that are either six or seven
coordinate about the metal centers. A structure of the
manganese complex 35 is shown in Figure 13. Apart the
rather uncommon coordination mode, what is noteworthy
about these two complexes is the oxidation state in which they
are found. Whereas, MnIII and CoIII porphyrins are normally
Figure 11. Front (top) and side (bottom) views of the solid-state more stable than the corresponding MnII and CoII complexes,
structure of 34.[51] For clarity, the hexafluorophosphate counterion it is the lower oxidation state that is stabilized in the case of
is not shown. the texaphyrin species 35 and 36. Presumably, this is the result
of both reduced ligand charge (fully deprotonated metal-free
texaphyrin represents a monoanionic ligand, whereas depro-
a macrocycle that was essentially flat and which was linked tonated porphyrins are dianionic ligands) and a propitious
through sp2-hybridized meso carbon bridges. The UV/Vis combination of core geometry and size.
spectra of all three metal-free species are characterized by the Electrochemical analysis of the various transition-metal
presence of Soret- and Q-like bands in the 420–480 and 705– complexes texaphyrins revealed, as in the case of the
750 nm spectral regions, respectively. Thus, the spectra are lanthanide(iii) complexes, reduction processes that were
very similar to what is typically seen for metallotexaphyrins. generally ligand, as opposed to metal, centered. However,
This observation supports the suggestion, advanced previ- the corresponding reduction waves were generally shifted
ously,[5] that the basic spectral features of texaphyrins are cathodically by about 250–350 mV relative to the trivalent
ligand, rather than metal, derived. lanthanide complexes, with the NiII and ZnII complexes
approximately 75–125 mV easier to reduce than the CoII and
3.9.2. Texaphyrin Complexes MnII species. In all cases, however, the transition-metal
complexes of texaphyrins proved much easier to reduce
In addition to developing a synthetic approach to metal- than analogous metalloporphyrins, the difference being more
free texaphyrins, efforts were made in recent years to explore than 500 mV in most cases.[53] Such findings are consistent
Angewandte
with the proposal discussed in Section 3.9.5 that certain

metallotexaphyrins, in particular an appropriately solublized
GdIII complex, could act to enhance the effects of ionizing
radiation by capturing electrons and acting as a redox-cycling
agent.[54]
3.9.3. Nonlinear Optical Properties of Texaphyrin
A different kind of new texaphyrin prepared in recent

years by Lawson and co-workers is the functionalized
cadmium complex 40 a.[55, 56] This species 40 a (as well as
several analogues 40 b–h), which differs from the original CdII

complexes by virtue of being far less symmetric, shows
promise as a nonlinear optical material. In particular, it
Figure 12. Front (top) and side (bottom) views of the solid-state displayed a second-order hyperpolarizability of 9.7 P 1031 esu
structure of of complex [38-(MeOH)2]NO3 .[52] For clarity, the nitrate when excited with picosecond pulses from a 532-nm laser, as
counterion is not shown; in the top view, one coordinating methanol well as a saturable absorption at high light fluence.
molecule is omitted.
3.9.4. Medical Applications of Texaphyrins
In addition to the synthesis and study of new texaphyrin

derivatives, considerable effort has been devoted to develop-
ing two known texaphyrin complexes, 41 a and 41 b. The first
of these, the lutetium complex 41 a, known by its trade names
of lutrin and antrin, is being studied clinically by Pharmacy-

clics, Inc., as a potential photosensitizer for the treatment of
cancer and cardiovascular disease. With a long-wavelength
absorption maximum (ca. 732 nm), 41 a shows particular
Figure 13. Front (top) and side (bottom) views of the solid-state struc- promise for the treatment of so-called vulnerable plaque,
ture of complex [35-Cl].[52] The corresponding CoII chloride complex is the hard-to-detect lesions that are thought responsible for as
nearly isostructural to the MnII complex shown. much as 80 % of all myocardial infarctions.
The second texaphyrin complex being developed for finding that xcytrin localized in lysosomes, endoplasmic
medical use is the gadolinium complex 41 b. Known by its reticulum, mitochondria, and Golgi apparatus,[58] rather than
trade and generic names of xcytrin and motexafin gadolinium in the nucleus of cells, led to the consideration that it mediates
(MGd), this species is currently available in large (> 50 kg) its radiation-enhancing effect by acting as a metabolism-
quantities and is being studied by Pharmacyclics, Inc., as a perturbing, redox-cycling agent as illustrated in Scheme 4.[54]
potential adjuvant for radiation therapy. To
date, MGd has been the subject of several
clinical trials, including a recently completed
Phase III trial involving patients with meta-
static brain tumors.[6, 44–47] This study, which
involved 401 patients split into treatment and
control groups, provided support for the
notion that MGd together with whole brain
radiation increased the average time to so-
called neurological progression in patients by
a factor of two or more whose primary disease
was lung cancer relative to similar patients
treated with whole brain radiation alone. In
view of these positive findings, a confirmatory
Phase III trial, involving patients with meta-
static brain cancer whose primary cancer is
lung cancer, has recently been launched.
Meanwhile, clinical tests of MGd as a radia-
Scheme 4. Cellular antioxidant system showing the relationship of ascorbate, glutathione,
tion enhancer for a range of other cancer and NADPH. The positions of proposed Gd-Tex interaction are indicated. Reactive oxygen
types are ongoing (neuroblastoma, pediatric species derived from radiolysis of water (XRT) or metabolism are also shown.[54]
brain stem glioma, pancreatic cancer, non-
small cell lung cancer). Many of these studies
are being carried out in collaboration with the National This mechanism of action is based on the consideration that
Cancer Institute of the United States National Institutes of texaphyrins localize selectively at tumor cells[59] and that such
Health. cells are already the subject of oxidative stress. Thus, as a
result of 1) removing ascorbate and other reducing species
3.9.5. Mechanistic Studies of Gadolinium(iii) Texaphyrin that play a known role in protecting selectively against the
effects of ionizing radiation in cancer cells and 2) producing
To support the clinical studies, considerable effort has concurrently peroxide, a recognized apoptosis-triggering
been devoted in recent years to understanding the mechanism agent, it was proposed that tumors would be rendered more
of action of xcytrin (41 b), as well as the general physical responsive to radiation therapy.
chemical properties of lanthanide(iii) texaphyrin complexes. While the ultimate validity of the above mechanism
In the latter context it was found that lanthanide(iii) remains to be established at the clinical level, one immediate
texaphyrins (abbreviated Ln-Tex in the general case where consequence was the recognition that other cells subjected to
the substituents are different from those present in MGd) are oxidative stress, including those infected with HIV, could be
substantially easier to reduce than porphyrins. (For example, preferentially destroyed by treatment with MGd. A first test
the E1/2 value for the gadolinium(iii) complex was found to be of this hypothesis has now been carried out by Herzenberg,
relatively substituent independent and about 294 mV versus Magda, and co-workers, with the selective eradication of
Ag/AgCl when recorded in DMSO in the presence of 0.1m HIV-infected cells being demonstrated in vitro.[60]
tetrabutylammonium perchlorate.[53]) Furthermore, and per-
haps more importantly, it was found that, once generated, the 3.9.6. Mn-Tex as a Peroxynitrite Decomposition Catalyst
one-electron-reduced form of texaphyrin, Gd-Tex+C, was
capable of reacting with oxygen to form superoxide in a Another consequence of the redox-cycling mechanism put
fast, but slightly unfavorable equilibrium process [Eq. (1)].[57] forward in Scheme 4 was the appreciation that texaphyrins, in
addition to acting as catalysts for the production of reactive
Gd-TexþC þ O2 Ð Gd-Tex2þ þ O2 C ð1Þ oxygen species (for example, superoxide, peroxide), could be
used to effect their removal. One such active oxygen species
It was established independently that various biological whose deleterious nature is increasingly coming to be
reductants, including NADPH, glutathione, and, especially, appreciated is peroxynitrite. Formed in vivo as the result of
the ascorbate anion, were capable of reducing the gadolin- the diffusion-controlled reaction between the superoxide
ium(iii) complex MGd under in vitro conditions to produce anion and NO, peroxynitrite has been implicated in a wide
peroxide via what was presumed to be the intermediate range of diseases, including amyotrophic lateral sclerosis
formation of superoxide (a species that cannot be detected in (ALS; Lou Gehrig's Disease), diabetes, and ischemia-reper-
normal cell-based studies). These results, coupled to the fusion injury.[48–50] As a consequence, catalysts that can effect
Angewandte
the catalytic decomposition of peroxynitrite are being actively

sought. On the basis of precedent from the porphyrin
literature, where water-soluble MnIII and FeIII complexes
have been found to be effective catalysts for this purpose
in vitro, the MnII–texaphyrin complex 35, which has the same
substitution pattern found in the GdIII– and LuIII–texaphyrin
species being developed clinically, was tested for its catalytic
efficacy. It was found to be as good or better than the
analogous MnIII–porphyrin complexes and, perhaps as a
Scheme 6. Formation of heterosmaragdyrins 44.
consequence of a different inferred mechanism of catalysis
(the starting oxidation states of the metals are different), was
found to produce fewer potentially toxic side products than 51 %, while for the corresponding thiasmaragdyrins, the yields
the previously studied systems (Scheme 5).[52] As a conse- are significantly lower, namely, 5 % for 44 a (Ar = Ph). The
only other products from this reaction are oxa- or thiacorroles
which are obtained in varying yields depending on the specific
conditions. For example, the reaction conditions that give rise
to oxasmaragdyrin 44 b (Ar = Ph) in 51 % yield also produces
the corresponding oxacorrole in 3 % yield. The degree of
control achieved in this reaction seems to be remarkable, as
no other products that would be the result of self-coupling of
either precursor were apparently obtained. In fact, several
curious results were reported in a related paper that
summarizes some of the above findings, including the fact
that exposure of 43 b alone to the reaction conditions outlined
above also gives rise to 44 b (Ar = Ph) in 3.5 % yield.[62] Thus,
Scheme 5. Catalytic decomposition of peroxynitrite by a manganese– the presence of 42 is not an absolute requirement for success,
texaphyrin complex. although it is highly likely that it or species akin to it are
formed in situ. The structure of oxasmaragdyrin 44 b (Ar =
Ph) was characterized by X-ray analysis (Figure 14).
quence, this MnII–texaphyrin complex is currently being In a subsequent report, the Chandrashekar and co-work-
subjected to in vivo analysis with the aim of assessing its ers describe the utility of 44 b (Ar = Ph) as a metal-complex-
potential for treating ALS. ing agent.[63] Specifically, a NiII complex as well as a
[Rh(CO)2] complex of this formally trianionic ligand were
described; the X-ray structure of the latter species is shown in
4. Systems Containing Five Pyrrole Rings
Pentapyrrolic macrocycles are among the most studied

macrocycles in the generalized area of expanded porphyrins.
In fact, the first expanded porphyrin ever reported, sapphyrin
(2), possesses five pyrrole rings. Most of the early work
involving this and other pentapyrrolic systems was carried out
using materials bearing substituents in the b-pyrrolic posi-
tions. While important studies of such systems continue,[7]
considerable effort in recent years, especially by the research
group of Chandrashekar but also by others, has been devoted
to developing strategies that allow access to various penta-
pyrrolic macrocycles and heteroatom analogues that bear
meso substituents.
4.1. Heteroatom-Containing Smaragdyrins
Recently, Chandrashekar and co-workers reported the use

of a mixed oxidative coupling strategy to prepare several
previously unknown heteroatom-containing expanded por-
phyrins.[61] For example, an oxidative coupling between the
heterotripyrranes 43 and the dipyrromethane 42 gives rise to
heterosmaragdyrins (Scheme 6). In the case of the oxasmar- Figure 14. Front (top) and side (bottom) views of the solid-state
agdyrin 44 b (Ar = Ph), the reported yields are as high as structure of complex 44 b (Ar = Ph).[61]
Figure 15. In the same report, the possibility of using the 4.2. Meso Substituted [22]Pentaphyrin(1.1.1.0.0)
protonated form of 44 b as an anion receptor was also noted
(see Figure 16 for the X-ray structure). Motivated by the finding that b-unsubstituted expanded
porphyrins often display conformations that differ from their
b-substituted congeners, a partially b-unsubstituted [22]pen-
taphyrin(1.1.1.0.0) 47 was recently prepared.[64] This macro-
cyclic product is both an isomer of smaragdyrin ([22]penta-
phyrin(1.1.0.1.0)), one of the more venerable expanded
porphyrins, and a new analogue of a general class of
pentaphyrins recently described in the form of its all-b-
alkyl-substituted variant.[65] As outlined in Scheme 7, con-
Scheme 7. Synthesis of partially meso-substituted isosmaragdyrins 47.
densation of diformyldipyrromethanes 45 a or 45 b with

hexamethylterpyrrole 46 under acidic conditions gave rise
to the monoprotonated [22]pentaphyrins(1.1.1.0.0) 47 a and
47 b in yields of 44 or 38 %, respectively.
Figure 15. Front (top) and side (bottom) views of the solid-state struc- While the spectral features of macrocycles 47 are in
ture of the [Rh(CO)2] complex complex derived from 44 b (Ar = Ph).[63] agreement with the presence of an aromatic 22 p-electron
system (for example, three NH resonances are seen at D =
5.42, 2.84, and 2.11 ppm in the 1H NMR spectrum of
47 b), no inversion was evident in either the protonated or
free-base forms. However, it was shown that adding increas-
ing amounts of trifluoroacetic acid (TFA) to a solution of 47 b
in CDCl3 resulted in a second protonation event that gave rise
to a new nonaromatic species. The structure of this latter
product was assigned on the basis of 1H NMR spectroscopic
studies to a system wherein a proton had been added to one
meso-carbon bridge to produce an sp3-linked macrocycle. The
structure of 47 a was further determined by an X-ray
crystallographic analysis (Figure 17).
4.3. Heterosapphyrins
As for sapphyrin itself, many b-substituted heteroatom-

containing sapphyrins (referred to here as heterosapphyrins)
are now known. Many of these were reported early on and the
relevant chemistry is covered in several reviews.[2, 3, 7, 8] It is
only in recent years, however, that a large number of meso-
substituted sapphyrins and heterosapphyrins have been
published. Most of these systems have been prepared by
either classic MacDonald-type condensations and/or oxida-
Figure 16. Front (top) and side (bottom) views of the solid-state tive coupling procedures as detailed below. Almost all these
structure of complex 44 b·HCl.[63] new systems fit the general structures 48 a or 48 b.
Angewandte
Scheme 8. Synthesis of heteroporphyrins 50, heterosapphyrins 51, and

heterorubyrin 52.
BF3·Et2O was used as the catalyst. Likewise, the best yield

reported for 52 (14 %) was also obtained under conditions of
BF3·Et2O catalysis, but with 43 b and 49 used as the starting
materials. In all cases but one, the diheteroporphyrins 50
proved to be the dominant products of this reaction. It
appears that the formation of the heterorubyrin 52 is simply
the result of a condensation of 49 with pyrrole, a species
produced in the reaction mixture as the result of an acid-
Figure 17. Front (top) and side (bottom) views of the solid-state catalyzed decomposition of 43 b. While such an explanation
structure of complex 47 a·DMSO.[64] appears plausible, curiously the authors do not discuss the
possibility of replacing 43 b by simple pyrrole to produce 52 in
what would presumably be a far more efficient route.[66]
In many of the heterosapphyrin- Subsequent to this report, Lee and co-workers described
forming reactions, especially the ones the use of a very similar synthetic strategy to obtain
that combine a partial hydrolysis of disubstituted heterosapphyrins.[67] They reported the synthe-
the starting materials with an oxida- sis of heterosapphyrin 55, as outlined in Scheme 9. Of note
tive coupling step, other macrocycles,
such as heteroatom-containing rubyr-
ins, are also obtained. Many of these
hexapyrrolic macrocycles are of
interest in their own right and are
thus discussed explicitly in Sec-
tion 5.2. However, such products only formed as minor by-
products during various heterosapphyrin syntheses are pre-
sented, for the sake of simplicity, only in this Section.
In early work that helped make the chemistry of meso-
substituted sapphyrins more prominent, Chandrashekar and Scheme 9. Synthesis of heterosapphyrin 55.
co-workers reported the synthesis of the two bithiophene
systems 51 a and 51 b. As outlined in Scheme 8, the synthesis
of these systems is based on the condensation of the here is that, in contrast to what was found by Chandrashekar
heterotripyrrane 43 with the bithiophene diol 49, followed and co-workers (see above), condensation of 53 with 54
by treatment with an oxidant.[66] While sapphyrins 51 are the proceeded using p-TsOH as the catalyst and gave macrocycle
expected products of this condensation, other macrocycles, 55 as the only reported product in 6.5 % yield.
specifically 52 and 50, were obtained as well. The presence of An X-ray crystallographic analysis of 55 revealed, as
52 and 50 in the product mixture can be rationalized by partial depicted in the line drawing in Scheme 9, that the furan
hydrolysis and recombination of the starting materials. subunit is inverted in the solid state (that is, the furan oxygen
Interestingly, under conditions of Brønsted acid catalysis atom faces out and away from the macrocyclic core). On the
(for example, with, TFA or p-TsOH), the only products basis of an 1H NMR spectroscopic analysis, in which the b-
isolated were the diheteroporphyrins 50. The best yields for pyrrolic protons of the furan subunit were found to resonate
51 a and 51 b (15 and 3 %, respectively) were obtained when upfield (d = 0.97 ppm), the authors concluded that the furan
subunit is also inverted in solution. The effect of protonation Another publication by Chandrashekar and co-workers
on the conformation of 55 was not discussed. describes the formation of macrocycles 50, 57, and 58. The
In another contribution by Chandrashekar and co-work- synthesis of these heteroatom-containing macrocycles was
ers a different approach to obtaining expanded heteropor- performed by using a procedure nearly analogous to that
phyrins was detailed.[68] This approach involves the acid- described above.[71] However, rather than using precursors 56
catalyzed condensation of 56 a–c with pyrrole, followed by in combination with pyrrole as the starting materials
exposure to chloranil (Scheme 10). The macrocycles 50, 57, (Scheme 10), the heterotripyrranes 43 were used
(Scheme 11). Although both studies were published at the
Scheme 10. Synthesis of heteroporphyrins 50, heterosapphyrins 57,

and heterorubyrins 58.
Scheme 11. Alternate synthesis of heteroporphyrins 50, heterosapphyr-

and 58 were formed in varying yields depending on the nature ins 57, and heterorubyrins 58.
and concentration of the acid catalyst employed. In the
example giving the best yield of expanded porphyrin prod- same time,[68] the choice of precursors is not clear. The use of
ucts, carried out under what are presumably optimized preformed tripyrranes 43, presumed intermediates in the
reaction conditions, condensation of 56 a with pyrrole in the previous synthesis, leads to no improvement in yield.
presence of one equivalent of TFA was found to give rise to One important facet of the study by Chandrashekar and
50 a, 57 a, and 58 a in yields of 13, 27, and 9 %, respectively. co-workers, however, were results from single-crystal X-ray
Latos-Graz̊yński and co-workers,[69] in a report actually diffraction analyses of 58 a and 58 b, which yielded the
published slightly earlier than that of Chandrashekar and co- structures shown in Figures 18 and 19, respectively.[71] In
workers,[68] showed how a procedure very similar to that
shown in Scheme 10 may be used to prepare 57 a and 57 c.
These two heterosapphyrins were obtained in approximately
1 % yield each through condensing 56 a or 56 c with pyrrole in
the presence of BF3·Et2O followed by oxidation with chlor-
anil. Not surprisingly, the dominant products of this reaction
were the heteroporphyrins 50 a and 50 b. However, none of
the corresponding ring-expanded products, for example,
heterorubyrins 58 a and 58 c, was obtained.
Very interesting insights into the conformation of prod-
ucts 57 were inferred from 1H NMR spectroscopic studies. For
example, chemical shifts consistent with an inversion of the
pyrrolic subunit across from the bipyrrolic ring were observed
in the case of the dioxasapphyrin 57 c, thus yielding a
conformation analogous to 55. In contrast to what proved to
be the case for the parent tetraphenyl sapphyrin,[70] a system
that was found to exhibit the same conformation as 57 c in the
absence of added protons but “flip back” to the planar
“pyrrole-in” form upon protonation, the heteroatom system
57 c was found to retain its inverted conformation in both its
mono- and diprotonated forms. The dithiasapphyrin 57 a,
however, does not show evidence of inversion in any
protonation state. These findings highlight the fact that the
nature of the heteroatom plays a role in regulating the overall Figure 18. Front (top) and side (bottom) views of the solid-state
conformation of a given macrocycle. structure of 57 a.[71]
Angewandte
rubyrins and heteroporphyrins) were observed under the

conditions used to obtain 51 and 59, with the yields again
being somewhat variable. The structures shown are the ones
obtained using optimized procedures, in which 51 or 59 are
the main products.
Proton NMR spectroscopic investigations of heterosap-
phyrins 51 and 59 revealed a subunit inversion that is retained
in all protonation states. This conclusion was supported by the
crystal-structure determinations of 51 d and 59 e, which
confirmed the presence of inversion in the solid state
(Figures 20 and 21).[73]
agreement with what one would expect from the NMR

spectroscopic findings of Latos-Graz̊yński and co-workers,[69]
58 a was found to adopt a planar arrangement in the solid
state, with no inversion of the heterocyclic subunits being
observed. The same arrangement was seen in the structure of
the diselenasapphyrin 58 b. The structures of 58 a and 58 b also
revealed interesting supramolecular features: Individual
macrocycles were found to be held together by intermolecular
CH···S and CH···Se bonds, with the ortho and meta hydrogen
atoms of the meso-phenyl rings being engaged in hydrogen- Figure 20. Front (top) and side (bottom) views of the solid-state
structure of 51 d.[73]
bonding interactions involving the ring heteroatoms.
In a different report that summarizes both findings
outlined above, as well as other chemistry that will be
discussed later on, the crystal structure of a TFA salt of 57 a
was reported.[62] In accord with what was inferred from NMR
spectroscopic studies, this particular protonated derivative of
57 a was found to adopt a planar conformation in the solid
state.
In two other related publications, Chandrashekar and co-
workers described the syntheses of several other heterosap-
phyrins,[72, 73] as well as a number that were published
previously (see Scheme 8 and structures 51 and 59). As in
previous syntheses, the same by-products (namely, hetero-
structure of 59 e.[73]
The research group of Latos-Graz̊yński recently described

the synthesis of a somewhat unusual unsymmetric dithiasap-
phyrin, 60.[74] It was isolated in approximately 1 % yield as a
minor constituent of a complex mixture of products generated
Scheme 13. Synthesis of the N-confused heterosapphyrins 63.
by modifying the basic procedure outlined in Scheme 10. graphic analysis of 63 a, wherein inversion of the confused
Macrocycle 60 was found to display a unique conformational pyrrole subunit was confirmed in the solid state (Figure 22).
behavior that differs from that of all other heterosapphyrins However, the structure of 63 a reveals a system that is not
previously described: it was found to exist in an equilibrium perfectly planar; the confused pyrrolic subunit is slightly tilted
between the inverted and planar forms (structures 60 and 60’). out of the mean macrocyclic plane (dihedral angle 258). It was
This equilibrium, in which the inverted form is the dominant
species, exists over a broad temperature range (193–342 K).
Chandrashekar and co-workers have reported the results
of preliminary studies devoted to exploring the metalation
chemistry of heterosapphyrins. In particular, they described
the preparation of the rhodiumcarbonyl complexes of dithia-
sapphyrin 57 a and diselenasapphyrin 57 b.[75] The complexes
61 a and 61 b were obtained in yields of 82 and 62 %,
respectively, upon exposing 57 a and 57 b to [Rh(CO)2Cl]2 in
the presence of base (Scheme 12). On the basis of NMR
spectroscopic studies it was concluded that the metal center in
both 61 a and 61 b is bound to only the two nitrogen atoms of
the bipyrrolic subunit. Unfortunately, no solid-state data have
been put forward to date that support this inference.
structure of 63 a.[76]
Scheme 12. Synthesis of rhodium–heterosapphyrin complexes 61.
concluded from 1H NMR spectroscopic analyses that in

4.4. N-Confused Heterosapphyrins solution macrocycles 63 are aromatic and inverted, both as
a free base and in its protonated forms. For example, the a-
A very interesting contribution, published recently by the and b-CH signals of the N-confused pyrrolic ring in 63 a
research groups of Chandrashekar and Furuta, describes the resonate at d = 2.73 and 9.79 ppm, clearly indicating the
synthesis of heteroatom-containing sapphyrins in which one presence of a diatropic ring current.
pyrrole ring is confused (that is, linked through the 2- and 4-, The Chandrashekar/Furuta paper represents an important
rather than the 2- and 5-positions).[76] Condensation of either step in expanded porphyrin chemistry. Indeed, it is likely that
heterobipyrrole 49 or 49 b with the “N-confused” tripyrrane macrocycles 63 will prove to be the first members of what will
62 followed by oxidation gives rise to 63 a or 63 b in a yield of in due course become a large family of N-confused expanded
24 or 30 %, respectively (Scheme 13). As might have been porphyrins. On the other hand, these systems contain a
anticipated based on the conformational behavior of the feature that makes them of immediate interest in their own
related heteroatom sapphyrins 51 a–f and 59 a–e, the so-called right: the position of the NH proton. On the basis of solution-
confused pyrrolic subunits in 63 a and 63 b were found to be phase NMR spectroscopic data, including the results of a
inverted. This finding is in agreement with an X-ray crystallo- COSY study of 63 a carried out at 228 K, the authors suggest
Angewandte
that this proton is located on the nitrogen atom of the N- able for either the neutral or protonated forms of 66.
confused pyrrolic ring in solution, at least in CDCl3 and Nonetheless, this contribution is important because it shows
[D8]toluene. However, this results in a structure in which the how CH moieties may be incorporated into the inner rim of
heterosapphyrin is cross-conjugated (tautomer 63 a), rather an expanded porphyrin, and highlights the fact that novel
sapphyrin analogues may be prepared without recourse to
meso substitution.
4.6. New Advances in the Area of Sapphyrin Chemistry
As will be detailed later on in the appropriate sections,

considerable effort has been devoted over the past few years
to modifying the classic Rothemund synthesis of porphyrins
to obtain novel porphyrinoid systems. One seminal contribu-
than one wherein a classic 22 p-electron aromatic pathway, tion along these lines was made in 1995 when Latos-
characteristic of all other heterosapphyrins reported to date, Graz̊yński and co-workers reported that tetraphenylsap-
prevails (tautomer 63 a’). While support for this counter- phyrin can be obtained in 1.1 % yield by condensing pyrrole
intuitive structural assignment has come from preliminary and benzaldehyde under appropriate conditions.[70] Subse-
molecular orbital calculations,[77] it is clear that further studies quent efforts by Lindsey and co-workers to optimize the
will be needed to understand the interplay of factors that synthesis of N-confused porphyrin (obtained in remarkable
makes the apparently less aromatic tautomeric form more yields up to 40 %),[79] failed to improve the yield of
stable. tetraphenylsapphyrin obtained from this reaction (namely,
the direct condensation of pyrrole and benzaldehyde).
Indeed, the maximum yield obtained by Lindsey and co-
4.5. The First Sapphyrin-Based Expanded Carbaporphyrinoid workers was 1.2 %.[80]
Chandrashekar and co-workers have also reported on the
In a publication that bears an intellectual relationship to use of dipyrromethanes as potential precursors of sap-
the report of Chandrashekar, Furuta, and co-workers sum- phyrin.[81] Exposure of dipyrromethanes 42 to one equivalent
marized above, Lash and Richter described an interesting of trifluoracetic acid, followed by oxidation with chloranil,
analogue of sapphyrin in which one nitrogen atom is replaced gives rise to sapphyrins 67 in yields of up to 11 % (for Ar =
by a CH group.[78] Condensation of the tetrapyrrole 64 with phenyl, Scheme 15). Although other products, such as por-
diformylindene 65, followed by oxidation, gave rise to
macrocycle 66, a species that was actually isolated in its
monoprotonated form in 18 % yield (Scheme 14). Proton
Scheme 15. Dipyrromethane-based synthesis of sapphyrin 67.
phyrins and N-confused porphyrins, always accompany the

formation of 67, the method could provide an attractive
alternative means of producing all-azasapphyrins, since
dipyrromethanes such as 42 are readily available in multigram
Scheme 14. Synthesis of the sapphyrin-based expanded carbapor- quantities.
phyrinoid 66. In a relevant paper, Ka and Lee describe an attempt to
obtain all-azasapphyrins by the oxidative coupling of penta-
pyrromethanes 68 (Scheme 16).[82] Pentapyrromethanes 68,
NMR spectroscopic analysis of this monocation revealed the
presence of a strong diatropic current, with the internal
CH proton resonating at d = 8 ppm. Addition of excess TFA
was reported to result in C protonation and formation of the
dication of 66. This latter species showed evidence of
aromaticity, as inferred from the fact that signals for the
meso protons were observed at d = 10.4 and 11.0 ppm in the
1
H NMR spectrum while the internal NH and CH2 signals
were found to resonate at d = + 0.67, 0.56, and 3.75 ppm.
Unfortunately, no solid-state information is currently avail- Scheme 16. Unexpected formation of phlorin 69.
presumed intermediates in the synthesis of tetraarylsapphyr- Compared to the 36 % yield obtained when DDQ was used
ins under modified Rothemund conditions, do not give rise to as the oxidant, this augmentation was considered significant.
the expected product 67 when exposed to DDQ. Rather, Oxasapphyrin 73 b and thiasapphyrin 73 c were obtained
phlorins such as 69 are formed. The latter species are not in 68 and 90 % yield, respectively, when 2,5-diformylfuran or
stable when treated with acid, and undergo a pyrrole
elimination to produce the corresponding porphyrins. These
results are rather unexpected, and indeed, at the present time,
one cannot rule out the appealing notion that, by varying
conditions (for example, choice of oxidant), good yields of
sapphyrins such as 67 might still be obtainable from 68.
Recent results obtained by Gross and co-workers are
consistent with this latter suggestion.[83] These researchers
found that pentapyrrole 70 could be converted into the
corresponding sapphyrin quantitatively (Scheme 17) by using
2,5-diformylthiophene was used instead of 72. Likewise, the

yield of carbasapphyrins (for example, 66) could be improved
by using the FeCl3 procedure. In the specific case shown in
Scheme 14 the yield was found to increase from 18 to 38 %
when FeCl3, rather than DDQ, was used as the oxidant.
4.6.2. Synthesis of Sapphyrins by a 3+1+1 Procedure

Scheme 17. Synthesis of a rhodium–sapphyrin complex.
Recently, a synthesis of sapphyrins was reported that does

a variety of oxidants (for example, Na2Cr2O7/TFA, DDQ, and not require the use of a preformed bipyrrolic moiety[85] and
I2). Unfortunately, even though the crude sapphyrin product enabled sapphyrins 76 a–d to be obtained in yields ranging
obtained in this way could be characterized by NMR from 28 to 34 % (Scheme 19) by condensing tripyrranedial-
spectroscopy, it proved unstable to chromatographic
workup. On the other hand, treatment of the crude sapphyrin
product with [Rh(CO)2Cl]2 allowed complex 71 to be isolated
in 90 % yield. Although no solid-state structural data are
currently available for complex 71, the results of NMR
spectroscopic analyses leave little doubt that its structure has
been assigned correctly.
4.6.1. Improved Yields in the 4+1 Synthesis of Sapphyrins
While efforts targeting the synthesis of meso-substituted

sapphyrins are rather recent, much of the chemistry of their b-
substituted congeners was developed early on (and hence
reviewed previously). Nevertheless, improved syntheses of b-
substituted sapphyrins continued to be developed. Scheme 19. Synthesis of sapphyrins 76 a–d.
In 1999, Richter and Lash reported on the use of FeCl3 in
the aromatization step of a 4+1 sapphyrin synthesis.[84]
Condensation of the linear tetrapyrrole 64 with pyrroledial- dehydes 74 a,b with two equivalents of pyrroles 75 a–c under
dehyde 72 followed by oxidation with 0.1m aqueous FeCl3 acidic conditions, followed by oxidation with DDQ. As
gave rise to sapphyrin 73 a in 50 % yield (Scheme 18). expected from such a reaction sequence, the corresponding
porphyrins were also isolated in approximately 10 % yield.
While the overall yield of sapphyrin is somewhat higher
for the more classic 3+2 synthesis than for this new
3+1+1 procedure, this latter approach obviates the need to
prepare bipyrrole and is thus three steps shorter. As such, it
provides a nice complement to existing methods. It also allows
for the synthesis of sapphyrins that contain various symmetric
bipyrrolic subunits that are not currently known.
Scheme 18. Synthesis of sapphyrin 73 a.
Angewandte
4.6.3. Applications of Sapphyrin
In addition to synthetic studies devoted to finding new

ways to prepare known sapphyrins or to generating new kinds
of sapphyrin derivatives, efforts have been made to study the
biolocalization properties of sapphyrin. In this context, it was
found that the water-soluble sapphyrins 77 a–e localized
Scheme 20. Redox behavior of N-confused pentaphyrin 78.
rather selectively in cancers, as judged from studies involving

the use of a murine model of a xenographic pancreatic human
tumor.[86] Whereas little retention and/or rapid clearance was
seen from other tissues, depending on the specific substitution
pattern present on the sapphyrin, the clearance half-life from
the cancerous sites was seen to be on the order of days.
Further work has been devoted to studying the anion-
recognition properties of sapphyrins and to exploiting them in
several analytical applications. For example, ion-selective
electrodes based on sapphyrins have been generated,[87] as
have optical anion sensors.[7, 88, 89] The use of sapphyrins as
possible through-membrane anion carriers has also been
reviewed.[90]
4.7. N-Fused Pentaphyrin
A recent report by Furuta and co-workers describes the

synthesis of an unexpected expanded porphyrin, namely N- structure of 78 a.[91]
fused pentaphyrin 78.[91] Compound 78 was obtained in 15 %
yield as one of a number of products produced from a
modified Rothemund reaction involving the condensation of inferred from its 24 p-electron structure. On the other hand,
pentafluorobenzaldehyde with pyrrole in the presence of the 1H NMR spectrum of 78 b clearly indicates the presence of
BF3·Et2O. An X-ray structural analysis of 78 a revealed not a species with aromatic character, with the signals for the
only the highly unusual connectivity pattern, but also a strong inner NH and CH protons appearing at d = 2.19, 1.70, 1.24,
deviation from planarity. A further, interesting feature of N- and 2.26 ppm. Furuta and co-workers suggest that it is
fused pentaphyrin is that it can exist in two stable oxidation perhaps as a result of the ready formation of species such as 78
states, namely 78 a and 78 b that contain 24 p-electron and that a simple (namely, non N-fused) meso-substituted penta-
22 p-electron peripheries, respectively. Compound 78 was phyrin has yet to be reported.
isolated as a mixture of these two products. Fortunately,
however, the two species are readily interconverted by means
of oxidation with DDQ or by reduction with sodium 5. Systems Containing Six Pyrrole Rings
borohydride (Scheme 20).
On the basis of the nonplanarity of 78 a observed in the As the number of pyrrole rings within a macrocylic core
solid state (Figure 23), it is not surprising that its 1H NMR increases, so does the number of possible combinations for a
spectrum reflects the presence of an essentially nonaromatic given set of pyrroles and meso bridges. It is thus not
species; for example, no paratropic shifts were observed that surprising, therefore, that more hexapyrrolic than pentapyr-
would be consistent with an antiaromatic species as might be rolic macrocycles are now known. Many of these hexapyrrolic
systems are not new, however, and have already been the
subject of several reviews.[2, 3, 8] The latest additions to this
family are summarized below.
5.1. Hexaphyrin(1.1.1.1.1.1)
One of the more interesting new additions to the family of

hexapyrrolic macrocycles was recently described by Cavaleiro
and co-workers and was another product of a modified
Rothemund synthesis. Condensation of pentafluorobenzalde-
hyde with pyrrole in a mixture of boiling acetic acid and
nitrobenzene enabled hexaphyrin(1.1.1.1.1.1) (79) to be
isolated in approximately 1 % yield.[92] The expected por-
phyrin was also obtained in 15 % yield. Macrocycle 79
displayed behavior analogous to that of N-fused pentaphyrin
(78), namely an ability to exist simultaneously in two different
oxidation states with inverted pyrrole rings (Scheme 21). As
Scheme 21. Redox behavior of hexaphyrin 79.

Subsequent to the initial report by Cavaleiro and co-
with the N-fused pentaphyrin species 78, 79 a and 79 b are workers, Furuta and co-workers reported an improved
readily interconverted without inducing large structural procedure that allowed 79 to be isolated in yields of up to
changes (for example, pyrrole ring “flipping”). Oxidation of 20 %.[93]
[28]hexaphyrin(1.1.1.1.1.1) 79 a with DDQ produces the
corresponding (4n+2) p-electron species, [26]hexa-
phyrin(1.1.1.1.1.1) 79 b. Likewise, treatment of 79 b with 5.2. Heteroatom-Containing Rubyrins
tosyl hydrazone results in reduction to 79 a. In accord with
the two-dimensional representation of its 4n+2 p electrons, Chandrashekar and co-workers have described the syn-
the 1H NMR spectrum of 79 b displays features consistent thesis of several heteroatom-containing analogues of
with aromaticity: the signals corresponding to the b-pyrrolic rubyrin.[32] This work was reviewed in part in Section 4.3.
CH protons of the inverted subunit were found to resonate at However, a more focused discussion is appropriate here. One
d = 2.43 ppm while the corresponding NH signals were strategy used to obtain these systems involves the condensa-
observed at d = 1.98 ppm. By contrast, the 1H NMR spec- tion between pyrrole and heterobipyrroles 49, 49 b, or 49 c
trum of 79 a revealed no signals that could be considered to (Scheme 22). This procedure led to the formation of 52 a, 52 b,
reflect an antiaromatic ring-current effect. and 52 c in yields of 28, 24, and 15 %, respectively, as well as to
The crystal structure of 79 b confirmed the inversion of the heteroatom-containing analogues of sapphyrin and por-
two pyrrolic subunits (Figure 24). However, the overall phyrin.[94, 95]
structure was found to deviate from planarity rather substan-
tially. This deviation is important because–-if it persists in
solution—it would reduce the net orbital overlap and hence
ring-current effects associated with the presumed aromaticity
of 79 b. The structure of 79 b is important on another level: it
highlights the difference between the early b-pyrrole-substi-
tuted hexaphyrin (10), reported by Gossauer and co-workers,
wherein “meso inversion” was observed,[31] and the present
system. As such, it underscores nicely the effects that different
kinds of substituents (meso or b-pyrrolic) can play in
controlling the conformational properties of expanded por-
phyrins. Scheme 22. Synthesis of heterorubyrins 52.
Angewandte
The same research group also reported a stepwise

procedure that involved the condensation of 49 or 49 c with
excess pyrrole to produce tetrapyrrolic intermediates that in
turn were condensed with one equivalent of either 49, 49 b, or
49 c. This allowed the synthesis of heterorubyrins 80 a, 80 b,
and 80 c in yields of 23, 28, and 20 %, respectively.[95]
As shown earlier in Schemes 10 and 11, another approach

to obtaining heteroatom analogues of rubyrin involves the
oxidative homocoupling of heterotripyrranes. This approach
has led to the synthesis of rubyrins 58 a–c. Alternatively, by
coupling two different tripyrranes, such as 44 a and 44 b
(Scheme 23), it proved possible to prepare unsymmetrical
one of the pyrrolic subunits contains one large heteroatom.

This observation is supported by X-ray structural analyses of
all three species. The X-ray structure of 58 b is shown as an
example in Figure 26. A different mode of inversion is seen
Scheme 23. Synthesis of heterorubyrins 58.
heterorubyrins such as 58 d (25 % yield). This particular

coupling also produced a small quantity (2.8 %) of the
symmetrical product 58 a.
A quick glance at the heterorubyrins reported to date

highlights their remarkable structural diversity.[62, 96] As illus-
trated by the macrocycles shown above, three basic structural
motifs have been identified so far. For example, as inferred
from spectral and structural studies, 52 b exists in a planar,
noninverted form (Figure 25). This appears to be the general
structure for meso-substituted heterorubyrins in which the
bipyrrolic subunits contain large heteroatoms. Interestingly,
inversion is seen in the systems 58 a, 58 b, and 58 d, in which Figure 26. Front (top) and side (bottom) views of the solid-state
the “normal” bipyrrolic subunits are preserved and at least structure of 58 b.[62]
for 81, in this case one pyrrole ring of each bipyrrolic subunit
is inverted. The latter finding is based solely on NMR
spectroscopic analysis, and has yet to be verified by X-ray
structural analyses. Of further interest is the finding that all
the isolated heterorubyrins, inverted or planar, are 26 p-
electron systems and as such display aromatic character, as
inferred from their spectral features.
The first metalation attempts involving heterorubyrins
showed that 58 a and 58 b give rise to three different types of
[Rh(CO)2] complexes: mono- and bimetallic complexes in
which the inversion is retained, and a bimetallic complex
wherein inversion no longer occurs (Figure 27).[75] Further-
Scheme 24. Formation of hexaphyrins 83 and heptaphyrins 84.
main products, as well as the hetero[26]hexaphyr-

ins(1.1.1.0.1.0) 83 in yields of 3–5 %. As one might expect
given the unsymmetric nature of this coupling procedure,
heterorubyrins are also obtained in varying yields. On the
other hand, no products resulting from the self-coupling of
tetrapyrroles 82 (for example, linear or cyclic octapyrroles)
were reported (see Section 7.5).
The conformations of macrocycles 83 a–83 d were inferred
from 1H NMR spectroscopic analyses. In the case of 83 a, the
b-protons of the inverted thiophene subunit were found to
resonate at d = 0.01 and 1.01 ppm. Although these values
are as expected for a structure wherein these protons are
facing in towards the center of a large aromatic ring, it is
important to appreciate that no solid-state structural infor-
mation is available for 83 a or its congeners 83 b–d.
Figure 27. Front (top) and side (bottom) views of the solid-state struc- 5.4. [26]Hexaphyrin(1.1.1.1.0.0)
ture of the bis-{Rh(CO)2} complex complex derived from 58 a.[75]
The synthesis of a [26]hexaphyrin(1.1.1.1.0.0) (87), an
isomer of rubyrin (11),[32] was targeted[64, 98] in an attempt to
more, a bis-{Rh(CO)2Cl} complex of 81 was reported in which prepare an expanded porphyrin that would exhibit inversion
the conformation of the starting metal-free macrocycle is of a prechosen pyrrolic subunit. The desired compound was
retained. The two RhI fragments coordinate to the inverted obtained in 46 % yield by condensing tripyrrane 85 with
pyrrole rings outside the macrocycle, with the neutral aza diformylhexamethylterpyrrole 86 in ethanol in the presence
donors serving merely to complete the coordination sphere of of p-toluenesulfonic acid and air (Scheme 25). As expected,
the RhI centers.
5.3. [26]Hexaphyrin(1.1.1.0.1.0)
A serendipitous synthesis of several heteroatom ana-

logues of [26]hexaphyrin(1.1.1.0.1.0), a previously unknown
isomer of rubyrin,[32] was recently reported by the Chandra-
shekar research group[97] (Scheme 24). Exposure of the
heteroatom-containing tetrapyrroles 82 and heterotripyr-
ranes 43 to oxidative coupling conditions was found to
produce the expected heptaphyrins 84 (see Section 6) as the Scheme 25. Synthesis of hexaphyrin 87.
Angewandte
inversion of the middle pyrrole ring of the tripyrrane subunit

was in fact observed in the case of 87 and its dihydrochloride
salt. A signal at d = 2 ppm was seen in the 1H NMR
spectrum of the dihydrochloride salt of 87 that was assigned
to the inner CH protons of the inverted pyrrolic ring.
Additionally, the remaining inner NH signals were found to
be shifted to the upfield region of the spectrum between d =
0.05 and 0.75 ppm. By contrast, the outer NH proton was
found to resonate at d = 15 ppm. Subsequent to the spectro-
scopic studies, more definitive support for the proposed
inverted nature of 87 and its dihydrochloride salt was
obtained from solid-state X-ray diffraction analyses. In both
cases the resulting structures proved completely consistent
with the results obtained in solution (Figures 28 and 29).
structure of complex 87.[64]
Scheme 26. Improved synthesis of amethyrin 88.
acid, was characterized structurally. The analysis shows that

the two central pyrrole units are tilted out of the plane
Figure 28. Front (top) and side (bottom) views of the solid-state defined by the other four pyrrolic units (Figure 30). Mean-
structure of 87·2 HCl.[98] while, the methanol molecules are bound to the ligand by two
hydrogen-bonding interactions each.
Treatment of 88 with two equivalents of nickel(ii)
5.5. Improved Synthesis of [24]Hexaphyrin(1.0.0.1.0.0) acetylacetonate in toluene gave rise to a product that was
(Amethyrin) tentatively assigned on the basis of UV/Vis spectroscopic and
mass spectrometric studies as a dinickel(ii) complex of
As a predicate to developing the metalation chemistry of amethyrin with two units of acetylacetonate still present as
amethyrin,[99] a simpler high-yielding synthetic procedure was bridging units (58 % yield). Unfortunately, an X-ray crystal
recently developed that obviates the need for chromato- structure could not be obtained. It was proposed that metal
graphic purification.[100] This procedure involves condensing a complexation is accompanied by ligand oxidation such that
diformylterpyrrole, such as 86, with a terpyrrole, such as 46, in the formally antiaromatic 24 p-electron system 88 becomes
the presence of trifluoroacetic acid. Treatment of the resulting transformed into an aromatic macrocycle with a 22 p-electron
amethyrin–TFA salt with NaOH, followed by crystallization periphery.
from MeOH, then gave the amethyrin–bismethanol complex
88 in 90 % yield (Scheme 26). This complex of amethyrin 88, a
macrocycle that is readily protonated by trace amounts of
Scheme 28. Synthesis of the actinide complexes 91 and 92:

1) UO2(OAc)2·2 H2O, Et3N, MeOH, CH2Cl2 ; 2) NpO2Cl in 1 m HCl,
Et3N, MeOH.
dramatic change in the spectroscopic features. For example,

the signal in the 1H NMR spectrum ascribed to the meso
CH protons is shifted downfield to d = 10.1 ppm from its
original position at d = 3.4 ppm. This shift is consistent with
the ring-current effects becoming “reversed” on oxidation to
the 22 p-electron aromatic system 91.
Further support for the proposed aromaticity came from
an analysis of the UV/Vis spectra of 90 and 91. In particular,
while the UV/Vis spectrum of 90 (CH2Cl2) consists of three
Soret-like bands with a main transition at 497 nm (e =
59 000 m 1 cm1) and no corresponding Q-like transitions,
that of the uranyl complex 91 was found to contain a sharp,
Soret-like transition at 530 nm (e = 330 000 m 1 cm1), as well
5.6. [24]Hexaphyrin(1.0.1.0.0.0) and its Actinide Complexes as two weaker Q-like bands at 791 (e = 56 000 m 1 cm1) and
832 nm (e = 81 000 m 1 cm1). The extinction coefficient of the
The synthesis of [24]hexaphyrin(1.0.1.0.0.0) (isolated in main transition in the uranyl complex 91 was also found to be
the form of its dihydrogenchloride salt 90),[101] which repre- increased by a factor of 5.6 relative to the metal-free starting
sents an isomer of amethyrin (88) was achieved by using a material 90 (Figure 31).[102]
CrVI-based oxidative coupling strategy.[99] Treatment of the To complement and extend the chemistry developed in
open-chain hexapyrrolic precursor 89 with Na2Cr2O7 in the case of the uranyl complex 91, the corresponding NpV
trifluoroacetic acid, followed by chromatographic workup, complex (92) of 90 was also prepared (Scheme 28). The UV/
and subsequent treatment with HCl, provided the target Vis spectral characteristics of 92 were found to be similar to
compound (90) in 77 % yield (Scheme 27). these of 91. However, while confirming the hexadentate
Scheme 27. Synthesis of hexaphyrin 90: 1) Na2Cr2O7, TFA; 2) HCl.
In accord with its 24 p-electron periphery, the diproto-

nated system 90 displays features that are consistent with
antiaromatic character. These include downfield shifts for the
inner NH protons (d = 23.7, 23.9, and 24.2 ppm) and upfield
resonances for the meso CH protons (d = 3.4 ppm) in its
1
H NMR spectrum. Treatment of 90 with uranyl acetate and
base leads to the formation of a uranyl complex 91 Figure 31. UV/Vis spectrum of 91(c), 90 (g), and 89 (a) in
(Scheme 28). This transformation is accompanied by a CH2Cl2.[102]
Angewandte
nature of both complexes, X-ray analysis revealed important

differences between 91 and 92 (Figures 32 and 33). Whereas a
relatively distorted structure was found in 91, a more planar
arrangement and a triethylammonium counterion was seen in
the case of 92, presumably, as a consequence of the larger

ionic radius of NpV as compared to UVI. The structure of
complex 92 is important in that it represents the first
structurally characterized NpV complex bound to an all-aza
donor set.
5.7. Expanded Phthalocyanine Analogues

Scheme 29. Formation of the expanded metallaporphyrazines 94.
Torres and co-workers recently introduced the first
examples of expanded phthalocyanines.[103] Prolonged heating
of the acyclic three-subunit intermediates 93 a–f in ethoxye-
thanol induced their self-condensation, which resulted in the precluded the characterization of free-base analogues of 94.
formation of the metalated heteroannulenes 94 a–f The expanded phthalocyanines 94 possess 28 p-electron
(Scheme 29). The peripherally substituted derivatives 94 b, peripheries. As such they might be expected to show
c, e, and f were obtained as a mixture of seven configurational antiaromatic features. However, the lack of protons attached
isomers in yields between 28 and 59 %, while the unsubstitued directly to the periphery of the macrocycle makes a test of
compounds 94 a and 94 d were isolated in 81 and 69 % yield, such an assumption difficult. On the other hand, the aryl
respectively. Metal-free analogues of 93 did not give rise to protons of the macrocycles 94 were found to display chemical
expanded phthalocyanines when exposed to the reaction shifts (d = 6.6–6.7 ppm) that are similar to those of their
conditions outlined above. Furthermore, compounds 94 related 18 p-electron hemiporphyrazines. Unfortunately, no
proved unstable in strongly acidic media. While such insta- solid-state information on these interesting phthalocyanine
bility was somewhat expected, it has nonetheless so far analogues is currently available.
5.8. Thiadiazole-Containing Expanded Heteroazaporphyrinoids It is important to note that, Kobayashi et al. also reported
the synthesis of macrocycles 96 and 98 at virtually the same
Islyaikin, Torres, and co-workers recently reported the time as Islyaikin, Torres, and co-workers.[105] In this case, 1-
synthesis of another new class of expanded phthalocyanines. butanol rather than 2-ethoxyethanol was used as the solvent
These researchers were able to obtain macrocycle 96 in 54 % for the condensation reaction. Under these conditions,
yield in the form of an orange powder by condensing 5-tert- macrocycle 96 was isolated in 26 % yield and formation of
butyl-1,3-diiminoisoindoline (95) with 2,5-diamino-1,3,4-thia- 97 was not observed. In contrast to the results of the AM1
diazole (Scheme 30).[104] Compound 97 was also obtained in calculations of Islyaikin, Torres, and co-workers, Kobayashi
et al. concluded on the basis of ZINDO/1 and AM1 calcu-
lations that the tris-inverted form of 96 (as shown in
Scheme 30) is energetically similar to the corresponding
non-inverted form. Both studies also describe the formation
of a trinuclear Ni complex. However, neither report contains
solid-state structural information, thus leaving the exact
nature of the species in question uncertain.
6. Systems Containing Seven Pyrrole Rings
Heptapyrrolic macrocycles, in contrast to hexapyrroles,

Scheme 30. Synthesis of the expanded porphyrazine 96. have only a limited history. Indeed, no report of a heptapyr-
rolic expanded porphyrin had appeared in the literature up to
the middle of 1999. However, in a testament to how fast the
15 % yield under these reaction conditions. When 3,4-bis(4- field is developing, five different heptapyrrolic expanded
tert-butylphenyl)pyrroline-2,5-diimine was used in place of porphyrins have now been reported.
95, macrocycle 98 was isolated in 38 % yield. In this case, none
6.1. [28]Heptaphyrin(1.0.0.1.0.0.0)
The first heptapyrrolic expanded porphyrin, [28]hepta-

phyrin(1.0.0.1.0.0.0), was reported in 1999. It was obtained by
a two-step procedure as outlined in Scheme 31.[106] Conden-
sation of 2.5 equivalents of tetramethylbipyrrole (86) with
diformylhexamethylterpyrrole (99 c) gave rise to the open-
chain heptapyrrolic building block 100. This intermediate,
although apparently stable, was not isolated but instead was
treated with aqueous Na2Cr2O7 in trifluoroacetic acid to
produce [28]heptaphyrin(1.0.0.1.0.0.0) in 43 % yield in the
form of its dihydrogen sulfate salt (101).
of the smaller product, which corresponds to a functionalized

analogue of 97, was apparently formed.
Compounds 96 and 98 formally possess 30 p-electron
conjugation pathways, and might thus be expected to display
aromatic features. However, instead of resonating in the
expected upfield region, the inner NH protons displayed
chemical shifts at about d = 12.5 ppm. This finding was
rationalized in terms of deviations from planarity. However,
the structural distortions from planarity would have to be
quite substantial to account for the unusual shifts. Unfortu-
nately, no solid-state structural information for macrocycles
96 and 98 is currently available, but a geometry optimization
(AM1) analysis of these systems was carried out. This study
provided support for inversion of the three thiadiazole
subunits, as indicated in the line drawings. Scheme 31. Synthesis of quaterpyrrole-containing heptaphyrin 101.
Angewandte
The 1H NMR spectrum of the dihydrogen sulfate salt 101

exhibits features that are in agreement with the presence of an
antiaromatic 28 p-electron periphery. Four NH signals in an
integral ratio of 2:2:2:1 are observed in the d = 15.9–18.2 ppm
spectral region, thus lying clearly downfield from those of
“normal” NH pyrrolic protons. Additionally, the signal cor-
responding to the meso proton is shifted upfield to d =
5.42 ppm. Further support for the conclusion that [28]hepta-
phyrin(1.0.0.1.0.0.0) is conjugated comes from the results of a
UV/Vis spectroscopic study: Salt 101 shows two rather strong
absorptions at lmax = 514 nm (84 400 m 1 cm1) and 613 nm
(53 200 m 1 cm1). As one might have expected, the lowest
energy band is red-shifted relative to what is seen in the case
of its smaller congener amethyrin (lmax = 597 nm
(56 500 m 1 cm1) for its diprotonated form).[99] Definite
proof of the structure for 101 came from a single-crystal X- Scheme 32. Formation of heterorubyrins 103 and heteroheptaphyrins
ray diffraction analysis; the macrocycle was found to be fairly 104.
planar and to contain a large cavity into which the sulfate
counterion is bound through no fewer than seven hydrogen- ranes 102 a or 102 b was found to give rise to 103 a or 103 b in
bonding interactions (Figure 34). 15 % yield, while the heptaphyrins 104 a or 104 b were isolated
in 2 % yield.
While the formation of the unexpected heptaphyrins 104 a
or 104 b was rationalized by the partial hydrolysis and
recombination of the heterotripyrranes 102 a or 102 b under
the reaction conditions, it is interesting to note that no
heptaphyrins were isolated when the meso substituent on the
tripyrrane precursor was changed from mesityl to phenyl. This
finding presumably reflects the stability differences of the
tripyrranes involved, with the mesityl-substituted tripyrranes
102 being more readily hydrolyzed under the reaction
conditions.
A more rational synthesis of different heteroanalogues of
[30]heptaphyrin(1.1.0.1.1.0.0) was reported in the same
paper.[107] Reaction of 105 a with 106 b, 106 c, and 106 d was
found to give rise to 107 b, 107 c, and 107 d in yields of 22, 20,
and 15 %, respectively (Scheme 33). Compound 107 a was
obtained in 20 % yield upon reaction of 105 b with 106 a.
ture of complex 101.[106] For clarity, the peripheral substituents were
removed in the side view.
Scheme 33. Synthesis of the terthiophene-containing heterohepta-
phyrins 107.
6.2. Heteroatom Analogues of [30]Heptaphyrin(1.1.0.1.1.0.0)
The first examples of heteroatom analogues of [30]hepta- 6.3. Heteroatom Analogues of [30]Heptaphyrin(1.1.0.1.0.1.0)
phyrin(1.1.0.1.1.0.0) were recently reported by Chandrashe-
kar and co-workers.[107] These novel macrocycles were initially In the study of the different heteroatom analogues 104 a,b
obtained as side products in the synthesis of the heterorubyr- and 107 a–d of [30]heptaphyrin(1.1.0.1.1.0.0), Chandrashekar
ins 103 (Scheme 32). Oxidative coupling of the heterotripyr- and co-workers detailed the synthesis of four different
heteroatom-containing analogues of [30]hepta- group pointing inside the ring and an overall structure that
phyrin(1.1.0.1.0.1.0).[107] As shown previously in Scheme 24, deviates substantially from planarity. Thus, in contrast to the
reaction of 82 a or 82 b with either 43 a or 43 c produced solution-state structure, the solid-state structure was charac-
macrocycles 84 a–d, respectively, in yields ranging from 15 to terized by the presence of a figure-eight motif (Figure 35).
20 %. Curiously, despite the moderate yields obtained, the The disparity between the solid-state and the solution-state
report does not comment on the formation of other macro- structure was rationalized in terms of crystal-packing effects.
cycles that might be expected; for example, products derived
from the self-coupling of the respective precursors (see,
however, Sections 5.3 and 7.5).
All the heteroheptaphyrins produced were judged to be
aromatic on the basis of their spectroscopic properties. For
example, as reported in the Supporting Information of the
paper,[107] the CH protons of the inverted selenophene subunit
in 84 d were found to resonate as a singlet at d = 1.62 ppm,
while two singlets were seen at d = 0.02 and 0.47 ppm which
are ascribed to the two different NH signals. Also in accord
with the proposed aromatic character, signals ascribed to the
“outer” b-CH protons of 84 d were found between d = 9.07
and 10.17 ppm. The conformations of the other heptaphyrins,
as indicated in Scheme 32 and Scheme 33, were assigned
solely on the basis of NMR spectroscopic analyses. There thus
remains a need for X-ray structural data that would confirm
these conformational assignments, at least in the solid state.
6.4. [30]Heptaphyrin(1.1.1.1.1.0.0)
[30]Heptaphyrin(1.1.1.1.1.0.0) (109) was recently synthe-

sized[108] in 16 % yield from the acid-catalyzed condensation
of a 1:1 mixture of the diformylhexamethylterpyrrole (86)
with the tetrapyrrane 108 (Scheme 34). Along with 109,
structure of complex 109.[108] For clarity, the peripheral substituents
were removed in the side view.
6.5. Heptaphyrin(1.1.1.1.1.1.1)
Furuta and co-workers reported the synthesis of a meso-

substituted heptaphyrin(1.1.1.1.1.1.1) derivative. This aesthet-
ically appealing compound was obtained as one of many
Scheme 34. Synthesis of heptaphyrin 109. products produced from a modified Rothemund procedure
that involves the condensation of pyrrole with pentafluoro-
benzaldehyde (see Section 7.6).[93] Unfortunately, little infor-
[26]hexaphyrin(1.1.1.1.0.0) (87) (see Section 5.4.) was isolated mation regarding the exact nature of this macrocycle (for
in 15 % yield. The formation of this latter product was example, its conformational properties) is available at pres-
rationalized in terms of the partial hydrolysis of precursor ent.
tetrapyrrane 108, a conclusion that is in accord with other
examples discussed above.
The aromatic nature of 109 was inferred from its NMR 7. Compounds Containing Eight or More Pyrrole
spectroscopic properties. Although the proposed aromatic Rings
character is noteworthy, perhaps the most interesting features
of 109 that were deduced from the 1H NMR spectrum are the Given the explosive growth now being seen in the area of
inversion of a pyrrole ring bearing two methyl groups as expanded porphyrins, it is interesting that the record for the
b substituents (d(CH3) = 4.2 ppm) and the finding that the greatest number of subunits in a polypyrrole macrocycle
signals corresponding to one phenyl ring are shifted to stood at ten up until 1999. The particular system in question,
considerably higher field than normal (three sets of multiplets turcarsarin,[33] represented an important breakthrough at the
are observed at d = 0.48 (2 H), 3.67 (2 H), and 4.93 ppm (1 H)). time it was reported because it illustrated, as did the
This latter finding was rationalized in terms of the phenyl subsequent cyclic octapyrroles synthesized by Vogel and co-
Angewandte
workers,[109, 110] that expanded porphyrins could adopt figure- the central core, bound by eight NH···O hydrogen-bonding
eight conformations that were the complete antithesis of the interactions (Figure 36). The UV/Vis spectrum of 110 b
flat structures one might have expected for conjugated (Figure 37) was found to be highly unusual; it is characterized
heteroannulenes. Not surprisingly, therefore, the synthesis of by a relatively weak Soret-type absorbance at 431 nm with an
these higher order systems provided an important stimulus for extinction coefficient of 79 800 m 1 cm1 and an intense Q-
the field, both in terms of understanding the basis of these type band at 1112 nm (e = 132 200 m 1 cm1) that is consid-
strange conformational features, and defining an implicit new erably red-shifted relative to the corresponding bands in most
challenge. A central question was whether yet bigger systems expanded porphyrins. It has thus been proposed that the
containing a greater number of pyrrole rings or pyrrole-type unusual spectral features of cyclo[8]pyrroles 110 a–d could
subunits could be made. As implied above, it took some time enable them to be used as an IR filter or in optical storage and
for this challenge to be met. Since 1999, however, driven signaling devices.
mostly by scientific curiosity as well as by the very human
impulse to reach for the limits, a plethora of so-called higher
order (superexpanded) systems have been reported.[111] In this
Section the chemistry of expanded porphyrins and heteroa-
tom analogues containing eight or more heterocyclic subunits
is reviewed.
7.1. [30]Octaphyrin(0.0.0.0.0.0.0.0)
The synthesis of four different cyclo[8]pyrroles ([30]octa-

phyrin(0.0.0.0.0.0.0.0), 110 a–d) has been described very
recently.[112] Cyclo[8]pyrroles 110 a–c were obtained in yields
of over 70 % (110 d was produced in 15 % yield) by means of
an FeIII-based oxidative coupling of bipyrroles 99 a–d
(Scheme 35). Crucial for the successful synthesis was the use
ture of complex 110 b.[112] For clarity, the peripheral substituents were
removed in the side view.
Scheme 35. Formation of cyclo[8]pyrroles 110.
of optimized biphasic reaction conditions (bipyrrole in

CH2Cl2/0.1m FeCl3 in 1m H2SO4).
The NMR spectra of the dihydrogen sulfate salts 110 a–d
are characterized by their unusually high symmetry. They also
provide important support for the conclusion that these
systems contain an aromatic 30 p-electron system. For
example, the signal for the magnetically degenerate methyl
groups in 110 c is found to resonate at d = 3.58 ppm, while the
signal corresponding to the NH protons is seen at d =
0.84 ppm. Although not related to the issue of deducing
the p-electron count, it is noteworthy that the 13C NMR
spectrum of 110 c consists of only three signals at d = 15.6,
123.9, and 125.9 ppm.
An X-ray structural analysis of 110 b revealed that the
macrocycle exists in a flat conformation with a sulfate ion in Figure 37. UV/Vis spectrum of 110 b recorded in dichloromethane.[112]
7.2. [32]Octaphyrin(1.0.0.0.1.0.0.0) however, the deviations from planarity seen in the solid state
were not so great as to cause 112 to adopt a figure-eight
The synthesis of [32]octaphyrin(1.0.0.0.1.0.0.0) was conformation. The UV/Vis spectrum of 112 is characterized
recently reported.[106] This expanded porphyrin was obtained by a broad band at 586 nm (e = 67 300 m 1 cm1) that has a
in the form of its HCl salt 112 in 16 % yield (Scheme 36) by shoulder at approximately 660 nm.
subjecting the linear tetrapyrrole 111 to a CrVI-based oxida-
7.3. Figure-Eight Octaphyrins and Their Metal Complexes
The octaphyrins prepared previously by Vogel et al. (113–

116; shown with the b substituents omitted for clarity)[109, 110]
were the subject of recent studies targeting their electro-
chemical behavior as well as their ability to form metal
Scheme 36. Synthesis of quaterpyrrole-containing octaphyrin 112.
tive coupling procedure analogous to that used to prepare

[28]heptaphyrin(1.0.0.1.0.0.0) (101, see section 6.1).
Despite containing a 32 p-electron periphery, and in
contrast to its smaller congener 101, the 1H NMR spectrum
of 112 does not show any signs of an antiaromatic ring-current
effect. The two NH protons are found to resonate at d = 11.2
and 11.9 ppm, while the signal corresponding to the meso
CH protons is found at d = 7.3 ppm in the 1H NMR spectrum.
This apparent lack of observable ring-current effect was
rationalized in terms of a strong deviation from planarity. The
highly nonplanar nature of 112 was confirmed by an X-ray complexes.[113] Similar redox patterns were observed for the
structural analysis (Figure 38). In contrast to other octaphyr- two free bases 114 and 115: Both undergo five distinct redox
ins containing a greater number of bridging meso groups, steps, two reductions and three oxidations. As confirmed by
cyclic voltammetry, the two reduction as well as the first two
oxidation waves represent reversible one-electron steps.
However, the third oxidation event corresponds to an
irreversible two-electron step. Overall, the redox behavior
of 114 and 115 was considered consistent with the presence of
the proposed fully conjugated p-electron peripheries. Octa-
phyrin 113, on the other hand is not fully conjugated. It thus
shows significantly different redox behavior. In addition to
one irreversible reduction wave at a rather negative potential
(2 V, versus Fc/Fc+), at least four distinct oxidation steps can
be distinguished, only the first two of which are reversible.
Interestingly, the mono- and/or bimetallic complexes 114 a–c
and 115 a–i show redox patterns that are very similar to those
seen for the free bases 114 and 115. However, metalation
generally facilitates slightly both the oxidation and reduction
relative to the corresponding free-base ligands. The largest
change in redox behavior is observed for the Co complexes
115 a and 115 g. In these two species, the third oxidation step is
metal, rather than ligand centered. Interestingly, in this
oxidation step, which corresponds to the CoII/CoIII couple,
the oxidation potential (+ 0.78 V versus Fc/Fc+) is signifi-
cantly higher than those for CoII–tetrapropylporphycene
(+ 0.19 V versus Fc/Fc+) and for CoII–tetraphenylporphyrin
Figure 38. Front (top) and side (bottom) views of the solid-state struc- (+ 0.38 V versus Fc/Fc+). It was concluded that this stabiliza-
ture of complex 112.[106] For clarity, the peripheral substituents were tion of the CoII oxidation state is imposed by the figure-eight
removed in the side view. geometry of the ligand, something that makes it difficult to
Angewandte
achieve the octahedral coordination preferred by the CoIII -

center. In summary, the free-base ligands 114 and 115 as well
as the metal complexes 114 a–c and 115 a–i display electro-
chemical gaps (difference in oxidation and reduction poten-
tials; EOx1ERed1) between 1.43 and 0.85 V that are lower than
the corresponding values for analogous porphyrin or porphy-
cene systems.
As a major proof-of-principle step that could lead to the
eventual development of chiral expanded porphyrin catalysts,
Werner, Vogel, and co-workers recently studied the free-base
macrocycles 113 and 114, as well as the metal complexes 113 a
and 114 a,b, with a view to achieving enantiomeric separa-
tion.[114] Macrocycle 114 was successfully separated into its
constituent enantiomers on an analytical HPLC column
containing commercially available Chiralcel OD as the solid
support. The two fractions showed mirror-image CD spectra,
from which it was concluded that the separation was
successful (Figure 39). The enantiomers of 114 proved very
structure of complex 114 a.[114]
7.4. Figure-Eight Tetrathiaoctaphyrin and

Dihydrotetrathiaoctaphyrin
Latos-Graz̊yński et al. recently succeeded in the isolation

of tetrathia[36]octaphyrin(1.1.1.1.1.1.1.1) (117) and tetra-
thia[38]octaphyrin(1.1.1.1.1.1.1.1) (118) in a total yield of
about 2 % from the mixture produced as the result of
condensing 2,5-bis(p-tolylhydroxymethyl)thiophene and pyr-
Figure 39. CD spectra (CH2Cl2) of the enantiomers of 114.[114]
stable: heating their respective solutions in n-hexanes at 60 8C

for a period of several hours did not result in any measurable
racemization. Octaphyrin 113, the tetrahydro derivative of
114, was also separated into its enantiomers. In this case,
however, racemization occurs readily even at room temper-
ature. The free activation enthalpy DG° 298 of racemization for role under conditions of acid catalysis (the meso substituents
113 was determined to be approximately 96 kJ mol1. have been omitted in the structural formulas).[115] Among the
In a later study the enantiomers of 114 were separated on other products obtained are dithiaporphyrin, two different
a preparative scale. By using medium-pressure liquid chro- dithiasapphyrins, and a dithiaporphyrin with an inverted
matography (closed-loop technique and CDMPC-C8 as the pyrrole ring.
stationary phase), 15 mg of 114 was separated into its Both of the tetrathiaoctaphyrins are interconvertible.
constituent enantiomers. In related work it was found that Exposure of 117 to sodium borohydride in THF readily
the metal complexes 113 a and 114 a,b could also be separated transforms the macrocycle into 118 as the result of what is
into their enantiomeric antipodes using similar techniques. formally a dihydrogenation. In turn, oxidation of 118 with p-
Most notable are the results obtained with 114 a: the high chloranil or DDQ produces 117. Both 117 and 118 were the
enantioselectivity of the chiral cellulose phase CDMP-C8 subject of exhaustive conformational analysis. On the basis of
towards this latter Pd complex enabled the separation to be a range of NMR spectroscopic studies that were supported by
performed successfully on a 100 mg scale. The two resulting MM + calculations, both macrocycles were assigned figure-
enantiomers of 114 a were then characterized by means of X- eight structures in solution; in 117, two thiophene rings are
ray crystallography, and the structure of one enantiomer of located at the crossing point, while in 118 these positions are
114 a is shown in Figure 40. occupied by two pyrrole rings. Stepwise protonation of either
117 or 118 gives rise to symmetric or asymmetric cationic to confirming the proposed thiophene inversion, this structure
species, depending on the number of protons added. The revealed a macrocycle that, except for the meso substituents,
dynamic behavior of 117 was described as a figure-eight is almost perfectly flat (Figure 41).
conveyor-belt-like movement that proceeds without a race-
mization step. Despite the highly nonplanar structures of 117
and 118, the authors observed residual diatropic and para-
tropic ring-current effects in the case of 118 (38 p-electron
periphery, formally aromatic) and 117 (36 p-electron periph-
ery, formally antiaromatic), respectively. Unfortunately, at
present no solid-state structural information is available for
either 117 or 118.
7.5. Meso-Substituted Heteroatom Analogues of

[34]Octaphyrin(1.0.1.0.1.0.1.0)
The first octapyrrolic expanded porphyrin, [34]octa-

phyrin(1.0.1.0.1.0.1.0), was synthesized by Vogel and co-
workers in 1995.[110] This compound had all 16 of its
b positions blocked with ethyl substituents and was found to
adopt a chiral figure-eight conformation both in solution and
in the solid state. Recently, the research group of Chandra-
shekar reported the synthesis of 119 a and 119 b, two
heteroatom analogues of [34]octaphyrin(1.0.1.0.1.0.1.0).
These macrocycles were found to be planar, presumably as
a consequence of having two b-unsubstituted thiophene or
selenophene subunits inverted.[116] The synthesis of 119 a and
119 b is summarized in Scheme 37. It involves the oxidative
structure of complex 119 a.[116]
7.6. Octaphyrin(1.1.1.1.1.1.1.1) and

Scheme 37. Formation of heterooctaphyrins 119. Nonaphyrin(1.1.1.1.1.1.1.1.1)
coupling of the linear heterotetrapyrrolic precursors 106 a and As discussed briefly in Section 5.1, Furuta and co-workers
106 e, and gives rise to 119 a and 119 b, respectively, both of recently reported the synthesis of a variety of meso-aryl-
which were isolated in 5 % yield. Curiously, the authors made substituted expanded porphyrins obtained from a modified
no mention of other macrocycles that might have been Rothemund condensation of pyrrole and pentafluorobenzal-
expected under these reaction conditions that, based on other dehyde.[93] These researchers obtained porphyrin (11–12 %),
examples from their laboratory, are known to promote partial N-fused pentaphyrin 78 (14–15 %), hexaphyrin 79 (16–20 %),
hydrolysis of the starting materials. heptaphyrin (4–5 %), octaphyrin 120 (5–6 %), nonaphyrin 121
As inferred originally from NMR spectroscopic studies, (2–3 %), as well as several higher homologues in very low
119 a is believed to exist as a mixture of two different yield by condensation of both precursors at relatively high
conformers in solution, at least on the NMR time scale. While
neither the ratio of these two conformers nor their rate of
interconversion was detailed, it was proposed that both
contain two inverted thiophene subunits. The 1H NMR
spectrum for the conformer 119 a, which was assumed to be
flatter, showed two sharp doublets at d = 5.3 and
5.89 ppm, which were assigned to the b-CH protons of the
inverted thiophene rings. In this case, direct evidence for
planarity came from an X-ray structural analysis; in addition
Angewandte
concentration (that is, 67 mm in both reactants in CH2Cl2) in conformations.[33, 109, 110] The monoprotonated TFA salt of
the presence of 4.2 mm BF3·Et2O, followed by oxidation with nonaphyrin (121·HTFA) was found to adopt a twisted helix-
DDQ. like conformation with a near mirror plane and a large cleft
Octaphyrin(1.1.1.1.1.1.1.1) (120) and nona- wherein the TFA counterion is bound.
phyrin(1.1.1.1.1.1.1.1.1) (121) were characterized by X-ray In agreement with the solid-state structure of 120, the
1
diffraction analysis (Figures 42 and 43). Octaphyrin 120 H NMR spectrum of this octaphyrin shows a C2-symmetric
adopts a twisted figure-eight conformation with near C2 sym- signal pattern with signals that are in agreement with the
metry. It thus resembles most other higher order expanded proposed nonaromatic 36 p-electron conjugated pathway. By
porphyrins which for the most part display similar nonplanar contrast, the 1H NMR spectral features of 121·HTFA, specif-
ically the finding of markedly different chemically shifts for
the b-pyrrolic protons, led the authors to conclude that 121 is
indeed an aromatic 42 p-electron system, as implied by its
structural formula.
Treatment of 120 with DDQ gives rise to spectral features
in the UV/Vis spectrum (strong Soret-type band at lmax =
738 nm; weaker Q-type bands at 1264 nm) that are in
agreement with an aromatic 34 p-electron system. Likewise,
treatment of 120 with NaBH4 in methanol led to appearance
of spectral features that are consistent with the formation of
an aromatic 38 p-electron system.
This contribution by Furata and co-workers provides an
impressive illustration of just how far the modified Roth-
emund reaction can be pushed in terms of obtaining new
products. Unfortunately, the associated characterization
chemistry is still in its infancy and it may thus be some time
before the properties and potential applications of these new
expanded porphyrins become fully appreciated.
7.7. [48]Dodecaphyrin(1.0.1.0.1.0.1.0.1.0.1.0) and

[64]Hexadecaphyrin(1.0.1.0.1.0.1.0.1.0.1.0.1.0.1.0)
In 1999, Setsune et al. carried out a condensation between

Figure 42. Front (top) and side (bottom) views of the solid-state tetraethylbipyrrole (99 a) and 2,6-dichlorobenzaldehyde
structure of complex 120.[93] For clarity, the peripheral substituents under conditions of acid catalysis and in the presence of
were removed. Zn2+ ions. They obtained a complex mixture that contained,
among other products, [48]dodecaphyrin-
(1.0.1.0.1.0.1.0.1.0.1.0) (124) and [64]hexadecaphyrin-
(1.0.1.0.1.0.1.0.1.0.1.0.1.0.1.0) (125, Scheme 38).[117] A crystal-
ture of complex 121·HTFA.[93] For clarity, the peripheral substituents
were removed. Scheme 38. Synthesis of superexpanded porphyrins 122–125.
structure analysis of 124, obtained from the original reaction

mixture in yields of up to 6 %, revealed the presence of a large
cavity surrounded by a wall of “zigzag-tracked p conjugation”
(Figure 44).
were removed. Figure 45. Front (top) and side (bottom) views of the solid-state
were removed.
By employing a different synthetic strategy, namely the
use of a highly reactive bis(azafulvene) species, Setsune and
Maeda also succeeded in preparing expanded porphyrins with
up to 24 pyrrole rings; the largest characterized structurally
was [64]hexadecaphyrin(1.0.1.0.1.0.1.0.1.0.1.0.1.0.1.0) (125)
containing 16 pyrrole rings (Figure 45).[118] These systems
are of tremendous scientific interest, not only because of their
aesthetically appealing structures, but also because of their
nonplanar conformations that can render them chiral. They
also represent the logical extension of the deca- and
octapyrrolic systems with figure-eight structures and highlight
the fact that as systems get larger the level of conformational
complexity is increased (see Sections 7.1 and 7.8).
7.8. Cyclo[n]thiophenes
In 2000, BOuerle and co-workers reported the synthesis of

very large thiophene-based macrocycles.[119] As outlined in
Scheme 39, reaction of cyclooligothiophenediacetylene 126,
obtained from thiophenediynes under modified Eglington–
Glaser conditions, with Na2S·9 H2O gave rise to cyclo[12]-
thiophene 127 in 23 % yield. Analogous reactions led to the
isolation of cyclo[16]thiophene and cyclo[18]thiophene in
yields of 7 and 27 %, respectively. Although the new macro-
cycles could be considered as (4n) p-electron antiaromatic
species, they displayed no apparent ring-current effects, as
judged from an analysis of their respective 1H NMR spectra.
An X-ray crystallographic analysis of 126 revealed the
presence of an essentially flat macrocycle (Figure 46). Scheme 39. Synthesis of cyclo[12]thiophene 127.
Angewandte
Scheme 40. Synthesis of furan-containing analogues of turcasarin 130.
Cyclo[12]thiophene 127 was calculated to have a diameter

of 2.34 nm. On the basis of its unusually large core size, the
authors anticipate that cyclo[n]thiophenes could act as hosts
for large organic guest molecules. For example, it was
calculated that 127 could serve as a host for fullerene C60.
However, no reports of this promise being realized have so far
appeared in the literature.
7.9. Dioxa[40]decaphyrin(1.0.1.0.0.1.0.1.0.0), an Analogue of

Turcasarin
Furan-containing analogues of turcasarin (12) have been ture of complex 130 a[120] . For clarity, the peripheral substituents were
prepared in the form of dioxa[40]decaphyrins- removed in the side view.
(1.0.1.0.0.1.0.1.0.0) 130 a and 130 b.[120] In analogy to the
synthesis of turcasarin (12),[33] condensation of oxaterpyrrole
128 with diformylbipyrrole 129 a or 129 b under conditions of this derivative adopting a conformation that is too symmetric
acid catalysis was found to give rise to either 130 a or 130 b in to be a figure-eight. Unfortunately, structural support for this
31 and 28 % yield, respectively (Scheme 40). conclusion has yet to be obtained.
On the basis of NMR spectroscopic studies, 113 a was
assigned a figure-eight structure in solution. As confirmed by
an X-ray structural analysis of the free base 130 a, this 8. Recent Advances
conformational motif is also present in the solid state
(Figure 47). Despite their different protonation states, the Subsequent to the time of submission, work in the field of
conformation of the free-base dioxa system 130 a shows a expanded porphyrin chemistry has continued to develop at a
remarkable similarity to the conformation of the tetrahydro- rapid pace. While it is not possible to review this newer work
chloride salt of the all-aza turcasarin (12).[33] These latter in detail, we do think it appropriate to highlight some of the
findings suggest that a figure-eight structure represents the more notable recent contributions. The interested reader is
dominant conformation for [40]decaphyrin(1.0.1.0.0.1.0.1.0.0) referred to references [121–127] and a new review article for
and its heteroanalogues. The results of an 1H NMR spectro- further details of these and other accomplishments.[18]
scopic analysis of the slightly modified dioxaturcasarin 130 b One of the most important recent advances is undoubt-
were, therefore, surprising; these studies were consistent with edly the finding that the yields of one-pot Rothemund-like
syntheses of expanded porphyrins can be greatly improved

through the judicious choice of precursors.[121] Furuta, Osuka,
and co-workers found that condensation of 3,4-difluoropyr-
role with pentafluorobenzaldehyde yielded, in addition to the
expected porphyrin product, the corresponding perfluori-
nated pentaphyrin, hexaphyrin, heptaphyrin, octaphyrin,
nonaphyrin, and decaphyrin in yields sufficient to allow for
ready isolation (up to 7 % in the best of cases, see structures
131). Likewise, Anderson and co-workers have recently
discovered that the BF3·OEt2-catalyzed condensation of

triisopropylsilylpropynal with 3,4-diethylpyrrole yielded a
range of interesting products including the corresponding
meso-alkynyl-substituted [24]pentaphyrin(1.1.1.1.1) and Finally, a new kind of expanded heteroporphyrin was
[28]hexaphyrin(1.1.1.1.1.1), as well as [15]triphyrin(1.1.3) reported quite recently by Furuta and co-workers.[127] By
132.[122] This latter species becomes the dominant product, using a tripyrrane analogue wherein the central pyrrole is
being obtained in 26 % yield, when trifluoroacetic acid is used linked through the 2- and 4-positions (instead of the 2- and 5-
as the catalyst. positions as is normal for precursors of this type) these
In a report that builds on the approach of Paolesse, Smith, researchers were able to isolate the formally aromatic doubly
and co-workers to preparing expanded corroles (see Sec- N-confused dioxohexaphyrin analogue 139, in addition to
tion 3.1), Sengupta and Robinson describe the use of a
bisvinylogous biladiene to prepare an expanded chlorin 133,
which possesses a fused naphthalene ring.[123] Meanwhile,
other species, including the oxygen-free analogue 138, as well

as nonaromatic products corresponding to both of these novel
systems. While these kinds of products are of interest for their
unique structures themselves, the dioxo compound 139 is
particular noteworthy: It could act as a binucleating ligand
Sessler, Furuta, et al. have reported a new type of expanded that stabilized structurally characterized dicopper and
porphyrin, namely Schiff base systems that contain anion- dinickel complexes. Such bimetallic complexes, although
sensing dipyrrolylquinoxaline subunits (134).[124] known in expanded porphyrin chemistry, are still rather rare.
Continued advances in the area of heteroatom-containing
expanded porphyrin chemistry were also reported by Chan-
drashekar and co-workers.[125] They obtained, among other 9. Outlook
species, the new heptapyrrolic macrocycles 135 and 136, and
their conformational behavior was studied in detail. In a The present review, it is hoped, has helped underscore the
separate study, Hung et al. reported that it was possible to richness and vitality of the field of expanded porphyrins.
obtain novel C-N bridged systems such as 137 and 138 by Motivated by factors ranging from intrinsic synthetic appeal
starting with an aryl-substituted tristhiophene-containing to more prosaic targeting of practical application, and
hexaphyrin analogue.[126] substantiated by the plethora of new systems produced in
Angewandte
the last few years alone, it is clear that the chemistry of [10] J. L. Sessler, A. Gebauer, E. Vogel in The Porphyrin Hand-
expanded porphyrins is flourishing. Here, the fact that a book, Vol. 2 (Eds.: K. M. Kadish, K. M. Smith, R. Guilard),
potentially limitless number of new structures can be Academic Press, San Diego, 2000, p. 1.
[11] H. Furuta, T. Asano, T. Ogawa, J. Am. Chem. Soc. 1994, 116,
conceived and that such systems are often endowed with a
767.
rich diversity of unique and useful properties is both inspiring
[12] P. J. Chmielewski, L. Latos-Graz̊yński, K. Rachlewicz, T.
current research efforts and setting the stage for future Glowiak, Angew. Chem. 1994, 106, 805; Angew. Chem. Int.
developments. Particular challenges for the future include Ed. Engl. 1994, 33, 779.
understanding how specific synthetic designs get translated [13] H. Furuta, H. Maeda, A. Osuka, J. Am. Chem. Soc. 2000, 122,
into particular conformations and how details of various 803.
proposed structures are reflected in terms of experimentally [14] H. Furuta, T. Ishizuka, A. Osuka, T. Ogawa, J. Am. Chem. Soc.
observable spectroscopic features or measurable chemical 1999, 121, 2945.
properties, such as anion recognition or cation coordination. [15] T. D. Lash, S. T. Chaney, D. T. Richter, J. Org. Chem. 1998, 63,
9076.
What are the effects, for example, of core size, aromatic
[16] T. D. Lash, M. J. Hayes, Angew. Chem. 1997, 109, 868; Angew.
versus non- or even antiaromatic peripheries, macrocycle Chem. Int. Ed. Engl. 1997, 36, 840.
charge, heteroatom replacements on these and other exper- [17] T. D. Lash, J. L. Romanic, M. J. Hayes, J. D. Spence, Chem.
imentally observable characteristics? Commun. 1999, 819.
On a more general level, it will become increasingly [18] For a recent review highlighting aspects of this chemistry, see H.
important to ask what molecular features are most useful for a Furuta, H. Maeda, A. Osuka, Chem. Commun. 2002, 1795.
given targeted application, whether such applications lie in [19] P. A. Gale, P. Anzenbacher, Jr., J. L. Sessler, Coord. Chem. Rev.
the area of drug development, radioactive waste remediation, 2000, 222, 57.
[20] J. L. Sessler, R. S. Zimmerman, C. Bucher, V. KrYl, B.
coordination chemistry, catalysis, optical materials prepara-
Andrioletti, Pure Appl. Chem. 2001, 73, 1041.
tion, or anion recognition and how one goes about optimizing [21] a) B. Franck, A. Nonn, Angew. Chem. 1995, 107, 1941; Angew.
for such features in a synthetic sense. At the same time, the Chem. Int. Ed. Engl. 1995, 34, 1795; b) see also footnote 20 in T.
synthesis of new systems will remain of interest: How far can Wessel, B. Franck, M. MZller, U. Rodewald, M. LOge, Angew.
we go in terms of extending the size, modifiying the shape, Chem. 1993, 105, 201; Angew. Chem. Int. Ed. Engl. 1993, 32,
increasing the pyrrole content, effecting heteroatom replace- 1148.
ments, and varying the number and nature of meso linkages [22] E. Vogel, personal communication.
before reaching the limits of normal chemical stability or [23] V. J. Bauer, D. L. J. Clive, D. Dolphin, J. B. Paine III, F. L.
Harris, M. M. King, J. Loder, S. W. C. Wang, R. B. Woodward, J.
solubility as a consequence of increasing polymeric character.
Am. Chem. Soc. 1983, 105, 6429.
Finally, an open-ended challenge involves removing the
[24] M. J. Broadhurst, R. Grigg, A. W. Johnson, J. Chem. Soc. Perkin
constraints of conjugation so as to relate the chemistry of Trans. 1 1972, 1124.
expanded porphyrins to that of other pyrrole-containing [25] J. L. Sessler, M. Cyr, V. Lynch, E. McGhee, J. A. Ibers, J. Am.
macrocyclic systems thereby producing mono-, bi-, or poly- Chem. Soc. 1990, 112, 2810.
cyclic systems that may, for example, be topographically [26] V. W. Day, T. J. Marks, W. A. Wachter, J. Am. Chem. Soc. 1975,
nonplanar or intrinsically chiral. Thus, even though the field 97, 4519.
of expanded porphyrin chemistry has advanced rapidly in [27] H. Rexhausen, A. Gossauer, J. Chem. Soc. Chem. Commun.
recent years, it is clear that much, much more remains to be 1983, 275.
[28] R. A. Berger, E. LeGoff, Tetrahedron Lett. 1978, 4225.
done and that not only significant challenges but also multiple
[29] H. Koenig, C. Eickmeier, M. Moeller, U. Rodewald, B. Franck,
opportunities abound. Angew. Chem. 1990, 102, 1437; Angew. Chem. Int. Ed. Engl.
1990, 29, 1393.
This work was supported by NSF grant no. CHE-0107732. [30] E. Vogel, M. KZcher, H. Schmickler, J. Lex, Angew. Chem.
1986, 98, 273; Angew. Chem. Int. Ed. Engl. 1986, 25, 257.
Received: October 8, 2002 [A561] [31] R. Charri[re, T. A. Jenny, H. Rexhausen, A. Gossauer, Hetero-
cycles 1993, 36, 1561.
[32] J. L. Sessler, T. Morishima, V. Lynch, Angew. Chem. 1991, 103,
1018; Angew. Chem. Int. Ed. Engl. 1991, 30, 977.
[1] The Porphyrin Handbook, Academic Press, San Diego, 2000. [33] J. L. Sessler, S. J. Weghorn, V. Lynch, M. R. Johnson, Angew.
[2] A. Jasat, D. Dolphin, Chem. Rev. 1997, 97, 2267. Chem. 1994, 106, 1572; Angew. Chem. Int. Ed. Engl. 1994, 33,
[3] J. L. Sessler, S. J. Weghorn, Expanded, Contracted and Isomeric 1509.
Porphyrins, Pergamon, New York, 1997. [34] R. Paolesse, R. G. Khoury, F. D. Sala, C. D. Natale, F. Sagone,
[4] E. H+ckel, Z. Phys. 1931, 70, 204. K. M. Smith, Angew. Chem. 1999, 111, 2727; Angew. Chem. Int.
[5] J. L. Sessler, G. Hemmi, T. D. Mody, T. Murai, A. Burrell, S. W. Ed. 1999, 38, 2577.
Young, Acc. Chem. Res. 1994, 27, 43. [35] E. Vogel, N. Jux, J. DZrr, T. Pelster, T. Berg, H.-S. BZhm, F.
[6] J. L. Sessler, R. A. Miller, Biochem. Pharmacol. 2000, 59, 733. Behrens, J. Lex, D. Bremm, G. Hohlneicher, Angew. Chem.
[7] J. L. Sessler, J. M. Davis, Acc. Chem. Res. 2001, 34, 989. 2000, 112, 1143; Angew. Chem. Int. Ed. 2000, 39, 1101.
[8] J. L. Sessler, A. Gebauer, S. J. Weghorn, in The Porphyrin [36] M. BrZring, H.-J. Dietrich, J. DZrr, G. Hohlneicher, J. Lex, N.
Handbook, Vol. 2 (Eds.: K. M. Kadish, K. M. Smith, R. Jux, C. P+tz, M. Roeb, H. Schmickler, E. Vogel, Angew. Chem.
Guilard), Academic Press, San Diego, 2000, p. 55. 2000, 112, 1147; Angew. Chem. Int. Ed. 2000, 39, 1105.
[9] R. Paolesse in The Porphyrin Handbook, Vol. 2 (Eds.: K. M. [37] G. MOrkl, H. Sauer, P. Kreitmeier, T. Burgemeister, F. Kastner,
Kadish, K. M. Smith, R. Guilard), Academic Press, San Diego, G. Adolin, H. Noeth, K. Polborn, Angew. Chem. 1994, 106,
2000, p. 201. 1211; Angew. Chem. Int. Ed. Engl. 1994, 33, 1151.
[38] G. MOrkl, T. Knott, P. Kreitmeier, T. Burgemeister, F. Kastner, [68] S. K. Pushpan, J. S. Narayanan, A. Srinivasan, S. Mahajan, T. K.
Helv. Chim. Acta 1998, 81, 1480. Chandrashekar, R. Roy, Tetrahedron Lett. 1998, 39, 9249.
[39] G. MOrkl, R. Ehrl, H. Sauer, P. Kreitmeier, T. Burgemeister, [69] K. Rachlewicz, N. Sprutta, P. J. Chmielewski, L. Latos-Graz̊yń-
Helv. Chim. Acta 1999, 82, 59. ski, J. Chem. Soc. Perkin Trans. 2 1998, 969.
[40] G. MOrkl, R. Ehrl, P. Kreitmeier, T. Burgemeister, Helv. Chim. [70] P. J. Chmielewski, L. Latos-Graz̊yński, K. Rachlewicz, Chem.
Acta 2000, 83, 495. Eur. J. 1995, 1, 68.
[41] G. MOrkl, J. Stiegler, P. Kreitmeier, Helv. Chim. Acta 2001, 84, [71] S. J. Narayanan, B. Sridevi, T. K. Chandrashekar, A. Vij, R.
2022. Roy, Angew. Chem. 1998, 110, 3582; Angew. Chem. Int. Ed.
[42] G. MOrkl, J. Stiegler, P. Kreitmeier, T. Burgemeister, Helv. 1998, 37, 3394.
Chim. Acta 2001, 84, 2037. [72] A. Srinivasan, S. K. Pushpan, M. R. Kumar, S. Mahajan, T. K.
[43] M. Stȩpien, L. Latos-Graz̊yński, J. Am. Chem. Soc. 2002, 124, Chandrashekar, R. Roy, P. Ramamurthy, J. Chem. Soc. Perkin
3838. Trans. 2 1999, 961.
[44] T. D. Mody, J. L. Sessler in Supramolecular Materials and [73] A. Srinivasan, S. J. Narayanan, S. K. Pushpan, M. R. Kumar,
Technologies (Ed.: D. N. Reinhoudt), Wiley, New York, 1999, T. K. Chandrashekar, J. Org. Chem. 1999, 64, 8693.
p. 245. [74] N. Sprutta, L. Latos-Graz̊yński, Org. Lett. 2001, 3, 1933.
[45] T. D. Mody, J. L. Sessler, J. Porphyrins Phthalocyanines 2001, 5, [75] S. J. Narayanan, B. Sridevi, T. K. Chandrashekar, U. Englich, K.
134. Ruhlandt-Senge, Inorg. Chem. 2001, 40, 1637.
[46] M. P. Mehta, W. R. Shapiro, M. J. Glantz, R. A. Patchell, M. A. [76] S. K. Pushpan, A. Srinivasan, V. G. Anand, S. Venkatraman,
Weitzner, C. A. Meyers, C. J. Schultz, W. H. Roa, M. Leiben- T. K. Chandrashekar, B. S. Joshi, R. Roy, H. Furuta, J. Am.
haut, J. Ford, W. Curran, S. Phan, J. A. Smith, R. A. Miller, Chem. Soc. 2001, 123, 5138.
M. F. Renschler, J. Clin. Oncol. 2002, 20, 3445. [77] H. Furuta, private communication.
[47] M. P. Mehta, P. Rodrigus, C. H. J. Terhaard, A. Rao, J. Suh, W. [78] T. D. Lash, D. T. Richter, J. Am. Chem. Soc. 1998, 120, 9965.
Roa, L. Souhami, A. Bezjak, M. Leibenhaut, R. Komaki, C. [79] G. R. Geier III, Y. Ciringh, F. Li, D. M. Haynes, J. L. Lindsey,
Schultz, R. Timmerman, W. Curran, J. Smith, S.-C. Phan, R. A. Org. Lett. 2000, 2, 1745.
Miller, M. F. Renschle, J. Clin. Oncol. 2003, 21, 2529. [80] G. R. Geier III, J. L. Lindsey, J. Org. Chem. 1999, 64, 1596.
[48] M. Kirsch, H.-G. Korth, R. Sustmann, H. De Groot, Biol. [81] S. J. Narayanan, B. Sridevi, A. Srinivasan, T. K. Chandrashekar,
Chem. 2002, 383, 389. R. Roy, Tetrahedron Lett. 1998, 39, 7389.
[49] C. Ducrocq, B. Blanchard, B. Pignatelli, H. Ohshima, Cell. Mol. [82] J. W. Ka, C. H. Lee, Tetrahedron Lett. 2001, 42, 4527.
Life Sci. 1999, 55, 1068. [83] L. Simkhovich, S. Rosenberg, Z. Gross, Tetrahedron Lett. 2001,
[50] J. T. Groves, Curr. Opin. Chem. Biol. 1999, 3, 226. 42, 4929.
[51] S. Hannah, V. M. Lynch, N. Gerasimchuk, D. Magda, J. L. [84] D. T. Richter, T. D. Lash, Tetrahedron Lett. 1999, 40, 6735.
Sessler, Org. Lett. 2001, 3, 3911. [85] S. V. Shevchuk, J. M. Davis, J. L. Sessler, Tetrahedron Lett.
[52] R. Shimanovich, S. Hannah, V. Lynch, N. Gerasimchuk, T. D. 2001, 42, 2447.
Mody, D. Magda, J. L. Sessler, J. T. Groves, J. Am. Chem. Soc. [86] V. KrYl, J. M. Davis, A. Andrievsky, J. KrYlova, A. Aynytsya, P.
2001, 123, 3613. PouckovY, J. L. Sessler, J. Med. Chem. 2002, 45, 1073.
[53] S. Hannah, V. Lynch, D. M. Guldi, N. Gerasimchuk, C. L. B. [87] K. Umezewa, K. Tohda, X. M. Lin, J. L. Sessler, Y. Umezawa,
MacDonald, D. Magda, J. L. Sessler, J. Am. Chem. Soc. 2002, Anal. Chim. Acta 2001, 426.
124, 8416. [88] J. Nishimoto, T. Yamada, M. Tabata, Anal. Chim. Acta 2001,
[54] D. Magda, C. Lepp, N. Gerasimchuk, I. Lee, J. L. Sessler, A. 428, 201.
Lin, J. E. Biaglow, R. A. Miller, Int. J. Radiat. Oncol. Biol. Phys. [89] M. Tabata, K. Kaneko, Y. Murakami, H. Mimura, Microchem.
2001, 51, 1025. J. 1994, 49, 136.
[55] W. Sun, C. C. Byeon, C. M. Lawson, G. M. Gray, D. Wang, [90] W. E. Allen, J. L. Sessler, CHEMTECH 1999, 29, 16.
Appl. Phys. Lett. 1999, 74, 3254. [91] J.-Y. Shin, H. Furuta, A. Osuka, Angew. Chem. 2001, 113, 639;
[56] W. Sun, C. C. Byeon, C. M. Lawson, G. M. Gray, D. Wang, Angew. Chem. Int. Ed. 2001, 40, 619.
Appl. Phys. Lett. 2000, 77, 1759. [92] M. G. P. M. S. Neves, R. M. Martins, A. C. Tom], A. J. Silvestre,
[57] J. L. Sessler, N. A. Tvermoes, D. M. Guldi, G. L. Hug, T. D. A. M. S. Silva, V. F]lix, M. G. B. Drew, J. A. S. Cavaleiro,
Mody, D. Magda, J. Phys. Chem. B 2001, 105, 1452. Chem. Commun. 1999, 385.
[58] K. W. Woodburn, J. Pharmacol. Exp. Ther. 2001, 297, 888. [93] J.-Y. Shin, H. Furuta, K. Yoza, S. Igarashi, A. Osuka, J. Am.
[59] R. A. Miller, K. W. Woodburn, Q. Fan, M. F. Renschler, J. L. Chem. Soc. 2001, 123, 7190.
Sessler, J. A. Koutcher, Int. J. Radiat. Oncol. Biol. Phys. 1999, [94] A. Srinivasan, V. M. Reddy, S. J. Narayanan, B. Sridevi, S. K.
45, 981. Pushpan, M. Ravikumar, T. K. Chandrashekar, Angew. Chem.
[60] O. D. Perez, G. P. Nolan, D. Magda, R. A. Miller, L. A. 1997, 109, 2710; Angew. Chem. Int. Ed. Engl. 1997, 36, 2598.
Herzenberg, Proc. Natl. Acad. Sci. USA 2002, 99, 2270. [95] A. Srinivasan, S. K. Pushpan, M. Ravikumar, T. K. Chandra-
[61] S. J. Narayanan, B. Sridevi, T. K. Chandrashekar, U. Englich, K. shekar, R. Roy, Tetrahedron 1999, 55, 6671.
Ruhlandt-Senge, Org. Lett. 1999, 1, 587. [96] S. J. Narayanan, A. Srinivasan, B. Sridevi, T. K. Chandrashekar,
[62] S. J. Narayanan, B. Sridevi, T. K. Chandrashekar, A. Vij, R. M. O. Senge, K.-i. Sugiura, Y. Sakata, Eur. J. Org. Chem. 2000,
Roy, J. Am. Chem. Soc. 1999, 121, 9053. 2357.
[63] B. Sridevi, S. J. Narayanan, R. Rao, T. K. Chandrashekar, U. [97] S. K. Pushpan, V. R. G. Anand, S. Venkatraman, A. Srinivasan,
Englich, K. Ruhlandt-Senge, Inorg. Chem. 2000, 39, 3669. A. K. Gupta, T. K. Chandrashekar, Tetrahedron Lett. 2001, 42,
[64] J. L. Sessler, D. Seidel, C. Bucher, V. Lynch, Tetrahedron 2001, 3391.
57, 3743. [98] J. L. Sessler, D. Seidel, C. Bucher, V. Lynch, Chem. Commun.
[65] J. L. Sessler, J. M. Davis, V. Lynch, J. Org. Chem. 1998, 63, 7062. 2000, 1473.
[66] A. Srinivasan, S. Mahajan, S. K. Pushpan, M. Ravikumar, T. K. [99] J. L. Sessler, S. J. Weghorn, Y. Hiseada, V. Lynch, Chem. Eur. J.
Chandrashekar, Tetrahedron Lett. 1998, 39, 1961. 1995, 1, 56.
[67] K. Shin, C. Lim, C. Choi, Y. Kim, C.-H. Lee, Chem. Lett. 1999, [100] S. Hannah, D. Seidel, J. L. Sessler, V. Lynch, Inorg. Chim. Acta
1331. 2001, 317, 211.
Angewandte
[101] J. L. Sessler, D. Seidel, A. E. Vivian, V. Lynch, B. L. Scott, D. W. [113] J. P. Gisselbrecht, J. Bley-Escrich, M. Gross, L. Zander, M.
Keogh, Angew. Chem. 2001, 113, 611; Angew. Chem. Int. Ed. Michels, E. Vogel, J. Electroanal. Chem. 1999, 469, 170.
2001, 40, 591. [114] A. Werner, M. Michels, L. Zander, J. Lex, E. Vogel, Angew.
[102] D. Seidel, PhD dissertation, The University of Texas (Austin), Chem. 1999, 111, 3866; Angew. Chem. Int. Ed. 1999, 38, 3650.
2002. [115] N. Sprutta, L. Latos-Graz̊yński, Chem. Eur. J. 2001, 7, 5099.
[103] M. S. Rodriguez-Morgade, B. Cabezon, S. Esperanza, T. Torres, [116] V. G. Anand, S. K. Pushpan, S. Venkatraman, A. Dey, T. K.
Chem. Eur. J. 2001, 7, 2407. Chandrashekar, B. S. Joshi, R. Roy, W. Teng, K. R. Senge, J.
[104] M. K. Islyaikin, E. A. Danilova, L. D. Yagodarova, M. S. Am. Chem. Soc. 2001, 123, 8620.
Rodriguez-Morgade, T. Torres, Org. Lett. 2001, 3, 2153. [117] J.-i. Setsune, Y. Katakami, N. Iizuna, J. Am. Chem. Soc. 1999,
[105] N. Kobayashi, S. Inagaki, V. N. Nemykin, T. Nonomura, Angew. 121, 8957.
Chem. 2001, 113, 2782; Angew. Chem. Int. Ed. 2001, 40, 2710. [118] J.-i. Setsune, S. Maeda, J. Am. Chem. Soc. 2000, 122, 12 405.
[106] J. L. Sessler, D. Seidel, V. Lynch, J. Am. Chem. Soc. 1999, 121, [119] J. KrZmer, I. Rios-Carreras, G. Fuhrmann, C. Musch, M.
11 257. Wunderlin, T. Debaerdemaeker, E. Mena-Osteritz, P. BOuerle,
[107] V. R. G. Anand, S. K. Pushpan, A. Srinivasan, S. J. Narayanan, Angew. Chem. 2000, 112, 3623; Angew. Chem. Int. Ed. 2000, 39,
B. Sridevi, T. K. Chandrashekar, R. Roy, B. S. Joshi, Org. Lett. 3481.
[120] J. L. Sessler, D. Seidel, A. Gebauer, V. Lynch, K. A. Abboud, J.
2000, 2, 3829.
Heterocycl. Chem. 2001, 38, 1.
[108] C. Bucher, D. Seidel, V. Lynch, J. L. Sessler, Chem. Commun.
[121] S. Shimizu, J.-Y. Shin, H. Furuta, R. Ismael, A. Osuka, Angew.
2002, 328.
Chem. 2003, 115, 82; Angew. Chem. Int. Ed. 2003, 42, 78.
[109] E. Vogel, M. BrZring, J. Fink, D. Rosen, H. Schmickler, J. Lex,
[122] A. Krivokapic, A. R. Cowley, H. L. Anderson, J. Org. Chem.
K. W. K. Chan, Y.-D. Wu, D. A. Plattner, M. Nendel, K. N.
2003, 68, 1089.
Houk, Angew. Chem. 1995, 107, 2705; Angew. Chem. Int. Ed.
[123] D. Sengupta, B. Robinson, Tetrahedron, 2002, 58, 8737.
Engl. 1995, 34, 2511.
[124] J. L. Sessler, H. Maeda, T. Mizuno, V. M. Lynch, H. Furuta, J.
[110] M. BrZring, J. Jendrny, L. Zander, H. Schmickler, J. Lex, Y.-D. Am. Chem. Soc. 2002, 124, 13 474.
Wu, M. Nendel, J. Chen, D. A. Plattner, K. N. Houk, E. Vogel, [125] V. G. Anand, S. K. Pushpan, S. Genkatraman, S. J. Narayanan,
Angew. Chem. 1995, 107, 2709; Angew. Chem. Int. Ed. Engl. A. Dey, T. K. Chandrashekar, R. Roy, B. S. Joshi, S. Deepa,
1995, 34, 2515. G. N. Sastry, J. Org. Chem. 2002, 67, 6309.
[111] T. D. Lash, Angew. Chem. 2000, 112, 1833; Angew. Chem. Int. [126] C.-H. Hung, J.-P. Jong, M.-Y. Ho, G.-H. Lee, S.-M. Peng, Chem.
Ed. 2000, 39, 1763. Eur. J. 2002, 8, 4542.
[112] D. Seidel, J. L. Sessler, V. Lynch, Angew. Chem. 2002, 114, 1480; [127] A. Srinivasan, T. Ishizuka, A. Osuka, H. Furuta, J. Am. Chem.
Angew. Chem. Int. Ed. 2002, 41, 1422. Soc. 2003, 125, 878.

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Reviews J. L. Sessler and D.

Synthetic Expanded Porphyrin Chemistry

was rationalized in terms of cleavage and recombination

Figure 1. UV/Vis spectrum of 16.[34] .

earlier by MOrkl et al.,[37] namely the cis,trans,cis,trans isomer

Figure 3. Front (top) and side (bottom) views of the solid-state

Figure 5. Front (top) and side (bottom) views of the solid-state

Figure 4. UV/Vis spectra of octaethyl derivatives of 17, 18 a, and 19;

Figure 7. UV/Vis spectra of 20 and 21.[36]

It was concluded from 1H NMR spectroscopic analyses

3.4. Tetraepoxy[32]annulene(6.2.6.2) and

The synthesis of tetraepoxy[32]annulene(6.2.6.2) (isomers

To date, systems that contain fewer than four heterocyclic

aromatic based on the observation of Dd values of approx-

3.7. Tetraepoxy[26]annulene(4.2.2.2) and

Recently, MOrkl et al. reported the synthesis of tetrae-

The 1H NMR spectrum of 32 a recorded at 168 K was

Figure 8. Front (top) and side (bottom) views of the solid-state

radiation- and irradiation-based treatment of cancer and

what is seen in the case of ferric porphyrins, the ZnII complex

with the proposal discussed in Section 3.9.5 that certain

3.9.3. Nonlinear Optical Properties of Texaphyrin

A different kind of new texaphyrin prepared in recent

several analogues 40 b–h), which differs from the original CdII

In addition to the synthesis and study of new texaphyrin

of lutrin and antrin, is being studied clinically by Pharmacy-

the catalytic decomposition of peroxynitrite are being actively

Pentapyrrolic macrocycles are among the most studied

4.1. Heteroatom-Containing Smaragdyrins

Recently, Chandrashekar and co-workers reported the use

Scheme 7. Synthesis of partially meso-substituted isosmaragdyrins 47.

densation of diformyldipyrromethanes 45 a or 45 b with

As for sapphyrin itself, many b-substituted heteroatom-

Scheme 8. Synthesis of heteroporphyrins 50, heterosapphyrins 51, and

BF3·Et2O was used as the catalyst. Likewise, the best yield

Scheme 10. Synthesis of heteroporphyrins 50, heterosapphyrins 57,

Scheme 11. Alternate synthesis of heteroporphyrins 50, heterosapphyr-

rubyrins and heteroporphyrins) were observed under the

agreement with what one would expect from the NMR

The research group of Latos-Graz̊yński recently described

Scheme 13. Synthesis of the N-confused heterosapphyrins 63.

Scheme 12. Synthesis of rhodium–heterosapphyrin complexes 61.

concluded from 1H NMR spectroscopic analyses that in

4.6. New Advances in the Area of Sapphyrin Chemistry

As will be detailed later on in the appropriate sections,

Scheme 15. Dipyrromethane-based synthesis of sapphyrin 67.

phyrins and N-confused porphyrins, always accompany the

2,5-diformylthiophene was used instead of 72. Likewise, the

4.6.2. Synthesis of Sapphyrins by a 3+1+1 Procedure

Recently, a synthesis of sapphyrins was reported that does

4.6.1. Improved Yields in the 4+1 Synthesis of Sapphyrins

While efforts targeting the synthesis of meso-substituted

Scheme 18. Synthesis of sapphyrin 73 a.

4.6.3. Applications of Sapphyrin

In addition to synthetic studies devoted to finding new

rather selectively in cancers, as judged from studies involving

4.7. N-Fused Pentaphyrin

A recent report by Furuta and co-workers describes the