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Novel Porphyrinoids for Chemistry and Medicine by Biomimetic Syntheses.

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Novel Porphyrinoids for Chemistry and Medicine
by Biomimetic Syntheses
Burchard Franck" and Ansgar Nonn
In 1926 Hans Fischer and Bruno Walach
synthesired the first porphyrins."] Currently more than 1 400 new articles concerning the synthesis and uses of porphyrins are published every year."]
However, the strong interest in these
compounds indicated by this is in sharp
contrast t o their restricted availability.
This is reflected in the current price of
up to 500 DM for 5 mg of the most important porphyrins used in research and
other applications (see Scheme 3).
Rioiniinetic syntheses offer possibilities f o r an improved approach to por-
phyrins. By following theexample set by
nature it is also possible to obtain novel
porphyrinoids which are different from
naturally occurring porphyrins. This is
exemplified by N.N'-bridged porphyrinogens. which have cage structures, inverted porphyrinoids ( N atoms in the
outer periphery) and. in particular, porphyrins with expanded systems. Among
the family of expanded porphyrins are
superarenes with up to 34 T[ electrons.
Their pronounced aromaticity is indicated by ' H N M R spectra, bond length
equivalence. planar structures. and elec-
trophilic substitution. With their strong
absorption bands, the strongest of
which have E values of > 1 000000, a ~ d ue which exceeds the absorption intensity of all other organic pigments observed until now. and their ability to act
as efficient photosensitirers. the expanded porphyrins open interesting perspectives in the fields of photochemistry and
photomedicine.
Keywords: aromaticity . biomimetic
syntheses dyes porphyrins tumor
therapy
L
1. Introduction
Porphyrins are important for all organism^.^^,^^ They are indispensible because of their function as complexing ligands for
catalytically active metals. This relates not only to metabolism,
but also to the provision of energy in living creatures and photosynthesis in the plant kingdom. The deep red porphyrin 1
contains an annulene-type cyclic conjugated 18n-electron system. Addition of six hydrogen atoms leads to the colorless and
highly reactive porphyrinogen 2. The porphyrinogens are air
sensitive and are readily reoxidized to the porphyrins.
Due to the large number of natural products and synthetic
products derived from the porphyrin system, it has proved appropria te to group these products under the heading porplij.ri~ ~ o i i (cf.
l s steroids, alkaloids). This approach can today be furtlierjustified for the naturally occuring porphyrins, porphyrinogens. chlorins, and corrins not only formally but also biogenetically. since. according to current knowledge. all four groups of
compounds are derived from a common precursor, uroporphyrinogen 111 (3) (Scheme l ) . [ 5 - 7 1
I*]
I'm1 Dr. H. Franck
Org.inr\ch-chcmi\ches Institut drr Uni! ersitdt
C (ii rensstra55e 40. D-4x149 Munater (Germany)
~Icli.liiu: i n t . code + (151)8?-9772
c-m,iil. li-;inck ( I un~-muena~er.de
I l r A. N u n n
ILiyei A<;
Rhcinufrrstrasst: 7 - 9 . D-47879 Krefeld (Gcrniany)
rcief.ir: l i l t . code (215l)XX-7703
+
1 8 ~
NH HN
1
Porphyrin
CO2H
2
Porphyr inogen
C02H
COZH
3
Uroporphyrinogen Ill
Scheme 1
In order to satisfy the requirements of living organisms, nature has developed the bioproduction of porphyrinoids, the extent of which can be estimated. Let us begin with the porphyrinoid vitamin B,, , deficiency of which causes pernicious anemia.
Humans have a daily requirement of only 0.001 mg vitamin B, z ,
an extremely tiny amount, corresponding to a total annual requirement for the earth's population of approximately 2000 kg.
Heme. the red blood pigment necessary for respiration, is produced to the extent of 500000 tonnes per year by the world's
population, an amount corresponding to 25 000 full railway
wagons.[', 91 Thus. one can estimate that the total production of
heme by all breathing organisms is of the order of 10 million
tonnes. Even more extensive is the estimated annual production
of i 0 9 t o n ~ i e s [ ' " . ~ofl Jchlorophyll by plants.
REVIEWS
B. Franck and A. Nonn
Aside from the bioproduction of porphyrinoids. their
chemical synthesis is of growing importance. Increasingly,
the porphyrin system is char\
acterized by a multitude of reactions. properties. and transformations. which. given their
Fig. 1 . MOPLO representation [ 121 of
compact
structure (Fig. 1). at
the unsuhatituted porpliyrin rramework
first sight appears to be surprising. In the last 27 years
Chemical A b s t r ~ ~ chas
t s registered more than 20000 publications
relating to porphyrins of various structures.['] In this time the
annual number of publications has risen from 234 (1967) to
1414 (1994). In addition, numerous structurally related porphyrinoids containing ring systems different from that in 1 must
also be taken into consideration. A selection of applications of
porphyrinoids in chemistry and medicine is given in Scheme 2.
2. Do Synthetic Porphyrinoids Have
To Be More Expensive Than Gold?
Despite the promising developments made with porphyrinoids in chemistry and medicine, this area of research suffers
from a severe handicap: Access to the majority of the required
porphyrinoids demands cumbersome, multistep syntheses with
very low overall yields.
In order to illustrate the availability of porphyrins, the current commercial prices of four important examples (1,4-6) are
shown (Scheme 3)
Although the simple porphyrin 1 is one of
E'.
Et
I
Chemistrv
Medicine
complexes
light con\ersion
autoxidation catalysis
aromaticity
UV,'Vis:NIR sensors
diagnosis of porphyria
cytochrome oxidase models
phototonicity
tumor therapy
\irus eradication
I
Et
1
R
R'
R'
Et
5mg16DM
5 rng 596 DM
R'
4
Scheme 2. Applications and research uses of porphyrins
With regard to the areas mentioned in Scheme 2, the following goals can be set: 1) The development of more efficient processes for the synthesis of porphyrinoids. 2) Research into access
to and structural limitations of novel porphyrinoids. 3) The
synthesis of tailor-made porphyrinoids for investigations into
aromaticity. electron spectroscopy, and photomedicinal applications. The results of research into these three areas form the
content of the following discussion.
R = CHzCOzCH,
R' =
R'
R'
R' = CHzCHzCOzh
CH,CH&O,CH,
5
5 mg 474 DM
6
5000 rng 112 DM
Scheme 1. Commercial prices for porphyrin ( I ) , octaethylporphyrin (41, uroporphyrin-I11 octamethyl ester ( 5 ) and hemin 6 (131 ( 5 g of gold cost ca. 90DM [19]).
Burchard Franck, born in 1926 in Hamburg, studied chiwtistry at
the Universities of HanTburg and Gottingen. After his Diplomarheit
on digitalis glycosides with R . Tschesche in Hamburg he received his
doctorate under the supervision of H . Brockmann in Giittingen in
1952for work on antibiotics,from streptomycetes. In 1959 he N'US
awarded his habilitation .for organic cliemistr:,, at the Universitj,of'
G6ttitigen. In 1963 lie accepted a cull to the Universit.r. qf Kiel and
since 1968 he has been Professor of Organic Chernistry at the University of Miinster. He has been a Guest-Professor in the U S A ,
Norway, Switzerlund, China, and India. Among the awards he has
received.for his rc~searchare the Richard-Kulzn-Me~ailledeer G c d l B, Franck
A. Nonn
schufi Deurscher Chemiker and the Adolfl Windaus-Medaillc rler
Universitat Gottingen. His recent rescurch work has ,focussed on inycotouins, biosyntliesis and biomimetic syntheses, isotopic
labeling, novel porpliyrins, superaromaticity, and phototherapy.
Ansgar Nonn, born in 1962 in Bad HonntTJ;studied chemistry,fioni 1984 to 1989 at the Universities of Cologne rind Munster.
He receivedlzis doctorate in 1991 under the supervision qf B. Frunck,fov work on .selectiveporphyrin syntheses by conformationul
control ?f the c,yclization. From 1991 to 1992 lie curried out post-doctorcil reseach with K. P. C . Volllzardt in Berkelel,, USA,
on the cyclization of N-heterocycles rtith cobalt complexes. I n 1992 he joined the Buyer AG and carried out fundamental
research. Since 1993 he has been a preject leader in diagnostics ileveloynient at Baycr AG in Uerdingen.
L
Porphyrins and Their Applications
REVIEWS
the most important naturally occuring aromatic systems, it cannot be easily synthesized. Accordingly, it is very expensive
(Scheme 3 ) . Octaethylporphyrin (4)[14,15] is an intensively used
synthetic porphyrin due to its similarity to the natural porphyrins and its much lower price. Uroporphyrin-I11 octamethyl
ester ( 5 ) is ;I dcrivative of uroporphyrinogen I11 (3),which is the
common biosynthetic precursor to all porphyrins and cyclic
tetrapyrroles in the bi0~phere.l~
-'I Thus, according to what has
previously been stated, the annual natural production of 3 is
more than 1 billion tonnes. Its price is nevertheless very high
(Scheme 3 ) . because. for practical purposes, it cannot be isolated from natural sources and its chemical synthesis requires numerous
':! In contrast, hemin 6 is available in abundance" '1 as a porphyrin raw material from slaughterhouse
blood.
A chemist who considers embarking on the synthesis of porphyrins is well advised to learn from nature and concentrate on
porphyrins bearing substituents in all eight pyrrole /I positions.
Cyclizations leading to porphyrins lacking these substituents. of
which porphyrin 1is an extreme example, suffer from the drawbacks of low cyclization yield, as well as instability and poor
solubility of the product unless the C-H bridges between the
pyrrole nuclei carry stabilizing groups.
The three most commonly used synthetic routes to /I-substituted porphyrinoids are summarized in Scheme 4. These are the
optimized dipyrrylmethane method A of Hans Fischer,[211as
modified by McDonald et a1.,i201the biladiene process B,i221and
the ring-forming cyclization of four monopyrroles (C) which
resembles thc biosynthesis of p~rphyrins.[*~I
All three methods
are based on the tendency of open-chain tetrapyrrole interme-
4-
OHC
:
$
R
+
H
J
J
R
R
Nature provides a model of biomimetic synthesis of porphyrins with the biosynthesis of the essential cyclic tetrapyrroles
from the monopyrrole porphobilinogen 9 (Scheme 5 ) .['. 'I As
HO,C
1
COZH
)
,-
- - - ..
CPzH
H
10
11
Scheme 5 . Pyroles for biomimetic synthesis
first demonstrated by Cookson and R i m i n g t ~ n , ' ~9 ~can
] be
converted under conditions of acid catalysis to uroporphyrinogens and further to uroporphyrins, as represented by path C
in Scheme 4. In order to explore the potential and the limitations of biomimetic syntheses of porphyrins from pyrrole precursors, we synthesized a series of derivatives of 9 (Scheme 5)
and investigated their reactivity towards condensation under
acid catalysis. The results obtained exceeded a11 expectations.
Despite considerable structural variations in the monopyrroles 7,8, 10, and 11 (Scheme 5 ) , in comparison with the biosynthetic starting material 9, the condensations proceeded in high
yields.
R
A
\
3. A Variety of Porphyrins through Biomimetic
Synthesis: Reasonably Priced, N-substituted,
N,N'-Bridged, and Inverted Porphyrinoids
i?q
XH2C q
R
R
R
Scheme 4 Three synthetic routes to porphyrins
Anpm .
R
diates to cyclize in an astonishingly selective manner.['4. 2s1 The
biomimetic route has proved to be the most powerful of the
three methods. not only from the point of view of the yields
attained but also because of the lower number of steps required
and the variety of products which can be synthesized using this
method.[23. 2 6 - 2 9 ]
' h c ~ n i I. f i t .
6 1 . Enpl. 1995, 34. 1795 1811
~~
Due to the presence of different side chains in the /3-positions
of porphobilinogen 9, its acid-catalyzed cyclocondensation
yields a mixture of isomeric uroporphyrins. Thus. the porphobilinogen derivative 7, which contains two identical acetic acid
side chains, is better suited as a reactant for biomimetic synthesis.[*'] Additionally, the amino group of 9 is replaced in 7 by the
better leaving group 0-acetyl and the other x-position is reversibly protected by a carboxyl group. The cyclocondensation
of 7 proceeds to give the porphyrinogen octaacetic acid 12 in
high yield (Scheme 6). This can undergo autoxidation and is
isolated after oxidative workup as the octamethyl ester 14. Compound 14 differs from the expensive uroporphyrin-I11 derivative
5 (see Scheme 3 ) only by the replacement of propionic acid side
chains by acetic acid units and has thus proved itself to be an
1797
B. Franck and A. Nonn
REVIEWS
x
HOZC
N
onate at 6 = - 4.31 .[‘I These values were confirmed by the synthesis of a similar octaethyl-N,N’,N”,N”’-tetramethylporphyrinogen (13, R = CH, instead of C02H)f353361
and also the synthesis and crystal structure of the corresponding porphyrin 16
by Vogel et al.r36)
Encouraged by these findings we took in hand the synthesis
and biomimetic condensation of N,N’-bridged dipyrrole precursors.[2s1 Since in the N,N‘.N”.N”’-tetramethylporphyrinogen
13, the diametrically opposing N-methyl groups project out of
the same side of the molecular plane, it could be possible to
bridge the two nitrogens with an alkylene chain of the appropriate length. To this end the two principle possibilities A (parallel
N,N‘-bridges) and B (crossed N,N’-bridges) shown in Scheme 7
can be considered. In both cases cyclization would lead to novel
polycyclic tetraaza systems.
C~OAC
H
7
i
Me Mk
R
R = COZH
12
I
I
02
R.
6 Equival. Br,
R,
Et
Et
A
B
Scheme 7 . Two product types potentially accessible by the acid-catalyzed condensation of N,N’-a,LI,-alkylenedipyrroles.
14
15 R
16
= W
R=W
Scheme 6. Biomirnetic syntheses of [ I B]porphyrins.
easily accessible, useful model compound for biological investigations.
The fact that exhaustive N-methylation of porphyrins had
been shown not to be possible[30,3 1 1 led to the assumption that
N,N’,N”,N”’-tetramethylporphyrins
are not capable of existence. Thus, the possibility of biomimetic condensation of
the N-methylnorporphobilinogen 8 to the N,N‘,N“,N”‘-tetramethylporphyrinogen 13 seemed rather remote. We could, nevertheless, show that the acid-catalyzed condensation of 8 delivered the crystalline N,N’,N“,N’”-tetramethyporphyrinogen13
in a yield of 17 %.[261 This represents a particularly convincing
example of the capability of the biomimetic principle in the
synthesis of porphyrins. According to its crystal structure,[32113
has a structure unusual for porphyrinogens, in which the neighboring pyrrole rings are highly twisted relative to each other.
This does not, however, lead to instability, but rather to high
resistance towards oxidation.
In order to convert 13, the first autoxidation-resistant porphyrinogen, to the corresponding his-quaternary N,N’,N”,N”’tetramethylporphyrin 15, one requires very powerful oxidants
such as elemental bromine or cerium(rv) ammonium nitrate.[6.3 3 1 Although 15 cannot have a completely planar structure, the ‘H NMR spectrum of the octamethyl ester displays a
significant diamagnetic ring current effect which resembles that
of Sondheimers (18lannulene 33 (see Scheme 12).1341Thus, the
resonance signals of the methine protons are strongly shifted to
low field, appearing a t 6 = 10.40, while the NCH, protons res1798
The synthesis of the required N.N’-a,w-alkylenedipyrroles
19a-e was successfully carried out by condensation of the
potassium salt of the diethylpyrrolecarbaldehyde 17 with the
a,w-alkylene dibromides 18a-e (Scheme 8).I2’] The di(pyrro1eEt
Et
Et
Et
Q C H O
I
Et
21
Et
Et
22
E:
E‘t
23
Scheme 8. Synthesis of N,N’-i,r,~-alkylenedipyrroles 19a-e and the conversion of
19a, 19c. and 19d into the bridged polycycles 21-23 by reduction and biomirnetic
cyclization [28.37]. a) KOH,’DMSO, 2 0 ° C ; b) NaBHJMeOH. 20°C; c) TosOH;
MeOH:AcOH, -60 C .
Anyov Chem Int. Ed. EngI. 1995, 34, 1795-1811
REVIEWS
Porphyrins and Their Applications
carbaldehydes) 19a-e thus obtained are vinylogous amides and
are thus stable compounds capable of being stored. Before further reaction they were activated by reduction with NaBH, to
the diols 20a-e and used in situ. The yields of 21-23 obtained
by the acid-catalyzed condensation over one or four steps display a marked dependency not only on the chain length of the
alkylene moiety but also on the transannular interactions within
the heteropolycycles formed during the reaction (Scheme 8).
While the N,N’-methylenedipyrrole 19a undergoes exclusively intramolecular condensation to give the novel dipyrrolo-I ,3piperazine 21, the ethylenedipyrrole 19 b reacts to give
undefined intermolecular polycondensates. The desired intra-.’
intermolecular condensation leading to ,+‘,”-bridged
[l S]porphyrinogens only succeeds with the higher N.N’-a,walkylenedipyrroles. starting from the 1,3-propanediylpyrrole
19c. This is to be expected from inspection of molecular models.
Compounds 19c and 19d condense intra-/intermolecularly to
the [18]porphyrinogens 22 and 23, respectively. Both of these
structures contain two novel heterotricyclic ring systems which
can be classified as dipyrrolo-I ,5-diazocane and dipyrrolo-l,Sdiazonane. respectively. According to the following evidence, it
can be concluded that both pairs of neighboring N atoms are
connected by parallel bridges (cf. A in Scheme 7) rather than the
alternative arrangement with crossed N,N‘-bridges (B in
Scheme 7): 1 ) In the conversion of 19c. it was possible to isolate
a dipyrrolo-1 .j-diazocane (half molecule) which is an intermediate in the synthesis of the parallel-bridged 22.[2812) The
‘H N M R spectrum of 22 displays two triplets for the ethyl-CH,
groups, which shows that the molecule is not C, symmetrical. and thus is not a [18]porphyrinogen with crossed N , N bridges (cf. B in Scheme 7 ) .
The yields ofporphyrinogens 22 and 23 (Scheme 8), based on
the pyrrolecarbaldehydes, are remarkably high, taking into account the multistep nature of the reaction sequence. Due to
Prelog strain in medium ring systems lower yields are expected
for 25, unless the transannular interactions are reduced by substitution of CH, with oxygen atoms. This effect is clearly seen in
the acid-catalyzed condensation of the bipyrroles 19e and 24
(Scheme 9). While the yield of 25 is only 7 % . due to Prelog
strain in the dipyrrolo-l,5-diazecane ring system, the exchange
of CH2 for 0 in the N,N’-bridge, which leads to the dipyrrole 24,
causes the yield of 26 to jump significantly to 49%.
Similarly to the N.N’,N”,N”’-tetramethyl[l8]porphyrinogen
13. the N,N’-bridged porphyrinogens 22,23 and 25,26 are
stable towards oxidation. As would be expected from their
three-dimensional cage structure. 22 and 26 are incapable of
dehydrogenation to [18]porphyrins even under energetic conditions. this behavior being in contrast to that of 13. The octaethyl
N.N’.N”.IY“’-di(3-oxapentylene)-porphyrinogen26 deserves
consideration a s a potential ligand for metal complexes because
of its spherical center which contains six donor atoms.[371
The question of whether porphyrinogens with inverted
pyrrole units could be obtained by biomimetic condensation
(Scheme 10) was of interest for a variety of reasons. Such invertoporphyrinogens like 30.[381whose nitrogen atoms are located
on the periphery rather than in the center of the molecule,
should provide much revealing information regarding, for example. the electronic structure, the complex formation, and the
conformational control of the cyclocondensation.
Et
Et
Et
Et
=.
&o
i
O H C Q
OHCQ
Et
Et
Et
Et
24
19e
1’”
25
i‘””
26
Scheme 9. Biomimetic condensation of a.w-pentanediyldip!rrole 19e and 3-oxar,w-pentanediyldipyrrole24 to the doubly N.N-bridged [ I Xlporphyrinogens 25 and
26. respectively. (For reaction conditions see Scheme 8) 12x1
133O
151
27
28
29
30
Scheme 10. Comparative bond angles for the formation of porphyrinogens 29 and
invertoporphyrinogens 30.
I t had to be considered for such a cyclocondensation, that the
inverted pyrrole units take up a larger proportion of the sum of
the internal angles of the porphyrinogen product than the noninverted units (Scheme 10). Thus, for the normal porphyrinogen 29, the relevant angle, that between the a-substituents of the
pyrrole unit 27, is 133”,[39’whereas the angle between the
macrocycle-forming substituents for the invertoporphyrinogen
30 is 151’. Thus, each inverted pyrrole nucleus should either
cause an increase in size of the macrocycle formed or lead to
increased ring strain. Accordingly, one would expect that acidcatalyzed condensation would lead to a cyclic pentapyrrole.
The initially considered isomer of porphobilinogen 9
(Scheme S ) , as well as a range of similar monopyrroles. proved
to be unsuitable for the biomimetic synthesis of invertoporphyrinogens. Success in the acid-catalyzed condensation was
achieved by using the N-benzylpyrrole 11, in which the large,
space-filling benzyl groups favor the ring closurerzg1along the
lines of the conformational helix effect (Scheme I
1799
B. Franck and A. Nonn
REVIEWS
azi ,
"
CH,
as Shakespeare's Hamlet was troubled by his famous existential
contemplation.[431Thanks to the pioneering work of Sondheimer[34]we know that the [18]annulene displayed in the upper
right part of the cover, with its cyclic conjugated 18-x-electron
system, can be considered to be a hexavinylogous benzene.
The aromaticity of 33 (Scheme 12) is indicated by the following experimental evidence: The x-electron count of the
[1 8]annulene obeys E. Hiickel's (4t7 2) rule,[441 the crystal
structure analysis[451yields a planar structure with bond length
equivalence. and finally, the 'HN M R spectrum of 33 indicates
a pronounced diatropic ring current. As with 33, the porphyrin
1 contains a cyclic conjugated 18-n electron system. which can
be designated a diazaannulene. Three further azaannulene systems related to the porphyrins are the corrole 34.[461the homoporphyrin 35.I"" and the porphycene 36.[481
"n
BzldN
31
/
Me
Me
'/
Me
32
+
Scheme 11. Biomimetic synthesis of the invertopentaphyrinogen 32 [29]
Compound 11 gave the colorless cyclic pentapyrrole 32 in 71 YO
yield. The pyrrole homolog of porphyrin was named pentaphyrin by Gossauer et al.[401Following this system we have
named 32 in~ertopentaphyrinogen.['~]
The cyclic tetrapyrrole 31 (invertoporphyrinogen) corresponding to 32, which, due to bond angle considerations (see
Scheme 10). should display substantial ring strain, could not
be detected in the condensation. The pentapyrrole 32 is characterized by its high resistance to oxidation. While normal porphyrinogens are very sensitive towards oxidation and the
N,N',N",N"'-tetramethylporphyrinogen 13 can be dehydrogenated to the corresponding deep red porphyrin 15, albeit under more forcing conditions, such a reaction does not take place
with the invertopentaphyrinogen 32. A possible explanation for
this resistance to oxidation[291is the fact that aromatization
of 32 would require a destabilizing accumulation of charge on
quaternary centers.
Recently, Furuta et al.[41a1and Chmilewski et al.[41b1succeeded in demonstrating that, in the non-biomimetic synthesis of
porphyrins from pyrrole and arylaldehydes (Rothemund synthe major products (tetraphenylporphyrins) are accompanied by smaller amounts of isomeric monoinvertoporphyrins. This interesting observation indicates that the
formation of normal porphyrins is preferred to monoinvertoporphyrins in the equilibrium-controlled acid-catalyzed condensation of simple
pyrroles. This is in agreement
with the conclusions which can
be drawn from bond angle considerations.
4. Routes to Novel
Superarenes
Fig. 2 . Front cover of a monograph by Lloyd [42] (Copyright
1989 reprinted with kind permission from John Wiley & Sons Ltd.
New York)
1800
The subtitle of a monograph
by Lloyd[421 (cover design.
Fig. 2) poses the question
which has perplexed chemists
since KekulC, almost as much
1
33
[lB]Annulene
34
Corrole
Porphyrin
35
Homoporphyrin
36
Porphycene
Scheme 12. I8n-electron systems
4.1. Biomimetic Synthesis of 1261- and I34jPorphyrins
We had hoped that it might be possible to prepare vinylogous
porphyrins using the biomimetic approach and related processes. Indeed it was possible to synthesize the four vinylogous porphyrin systems with 22n- (39). 26n-(37,40), and 34n-electron
perimeters (38) shown in Scheme 13. We have proposed a system
of nomenclature for such compounds[49.501 in analogy to that
used for the annulenes. Thus, vinylogous porphyrins are represented by a prefix in square brackets corresponding to the number of x electrons in their conjugated perimeter. Accordingly,
the systems 37-40 in Scheme 13 would be designated [22]-, [26]-,
and [34]porphyrins. Furthermore, it is sensible to extend this
system to the precursors of these porphyrins. In this way one can
use the names [22]-, [26]-, and [34]porphyrinogens.
The experimental[341and theoretical[5 ' I results from annulene chemistry represent the first hurdles standing in the way of
a synthesis of vinylogous porphyrins. It has been shown that
for annulenes. the resonance energies of annulenes up to
[22]annulene allow the stabilization of a planar, aromatic conformation, whereas higher annulenes behave more like conjugated olefins. The experimental and theoretical studies of this
subject are in good agreement. The situation regarding porphyrinoids appears to be more favorable. From the finding that
simple [ 18lporphyrins are more chemically stable than
REVIEWS
Porphyrins and Their Applications
Schenic I : t . w r 1 inylogm~sporphyrinz with 2%.
2 h n . and 34n-electron systems.
[18]annulenes. one can presume that the rigid pyrrole units of
the system can provide conformational stability, without adverse affcct on the annulenoid conjugation.
All four porphyrinoids shown in Scheme 13 are characterized
by prc\,iously unknown extremes in properties related to aromaticity und light absorption. Very high diatropic ring current
effects in their 'HN M R spectra justify the name superarenes.
Their Soret band molar extinction coefficients of c > 10' exceed
the highest previously known, found in pigments.
Following the ring closure principle of porphyrin biosynthesis. p! rrolylpropenuls of type 42 (Scheme 14) were considered as
r
-
R
R'
starting materials for the synthesis of vinylogous porphyrinoThey differ from the biosynthetic precursor of porphyrin. porphobilinogen 9 (see Scheme 5 ) , by the replacement
of the /%position side chains by alkyl groups and the replacement of the aminomethylene group by a propenal unit. Additionally. it was found to be necessary, for reasons of stability, to
replace the NH hydrogen atom with a methyl group. In order to
obtain information about conformational influences on the ring
closure reaction, pyrrole units with increasing steric congestion
at their /I-positions were chosen.
The pyrrolylpropenals 42 a-e were obtained in high yields by
vinylogous Vilsmeier f o r n i y l a t i ~ n '5~3 1~ in
. two steps from the
monopyrroles 41 a -e.IZ4'.491 Finally, reduction of the aldehyde
group and acid-catalyzed condensation of the so-formed reactive pyrrolylpropenols in situ yielded the [26]porphyrinogens
44a-e (Scheme 14). A significant correlation between the yields
of the ring closure and the spatial requirements of the []-substituents can be detected. As in the biominictic synthesis of
normal [ 18]porphyrin~,[~"]
this effect can be explained by a preferred helical conformation in the transition stale of the cyclization of the intermediate tetrapyrrole 43 being favored by interactions between the [I-substituents of neighboring pyrrole units.
When one considers the structures of 44a and 44e (Scheme 15)
it appears at first sight astonishing that the isobutyl groups
which project far out from 44e do not hamper the ring closure,
but rather. in comparison to 44a, significant11 favor it.
1
a+&)
\
44a
L
R,R' =
b: R.R' =
C: R,R' =
d: R.R' =
e: R,R' =
a:
H
-(CHZ)4C~HS
n-C,H9
CH,CH(CH3)2
43
\
44e
Scheme IS. Structures of 44a and 44b
0.1%
8 %
24 %
35 %
52 %
1
R
44
Scheme 14. Biomiine[ic synthesis of the [26]porphyriiiogens 44a e [24c,49]. Rraclion condilion\ '11 dinicthylaminoacrolein (Me,NCH=CH-CHO), POCI,: h )
K O H ' I I M S O . ( H + l , c ) NaBH,:MeOH. d ) 7osOH:AcOH.
The question that arises next is whether the helical effect['"c1
can also play an effective part in the biomimetic cyclotetramerization of monopyrroles carrying pentadienyl side chains. Such
condensations should lead to octavinylogous porphyrinogens
and [34]porphyrins. The starting materials 45a, b were obtained
in a similar manner to the aldehydes 42a-e by the bis-vinylogous Vilsineier formylation of the dialkylpyrroles 41 c,e
(Scheme 14) with dimethylaminopentadienal (Scheme 16). Subsequently, the N H was methylated, the aldehyde function reduced, and the resulting. highly reactive pyrrolylpentadienol
then underwent the acid-catalyzed cyclization in situ. An especially mild workup delivered the [34]porphyrinogens 46 a and
46b.[53.541
The yield of porphyrinogen 46b with its sterically
demanding isobutyl groups is almost twice as high as that of the
octaethylporphyrinogen 46a and indicates that. in this case too,
the helical effectr2"]is active in providing effective conformational control.
1801
B. Franck and A. Nonn
REVIEWS
R
4.2. Synthesis of 1221- and 126lPorphyrins
with the Biladiene Process
45
46a 20 %
46b 38 Z
Scheme 16 Biomimetic synthesis of the [34]porphyrinogens 46a a n d 46b
[53,54].
Because of the already mentioned extensive applications
of Hans Fischer’s octaethyl[l8]porphyrin (4) ,[I4] particular
interest is being shown in its di- and tetravinylogues, the
[22]porphyrin 49a and the [26]porphyrin 49 b, respectively
(Scheme 18). While the synthesis developed for 4 is based on the
condensation of monopyrroles, a vinylogous version of the biladiene process could be applied to the synthesis of the “rectangular” C,-symmetric porphyrins 49 a, b.[221This would require
that the vinylogous biladiene, formed as an intermediate, is
capable of adopting the necessary hairpin conformations 50a or
50b, respectively (Scheme 18). As previously discussed for the
biomimetic synthesis of “square” C,-symmetric porphyrins, helical effects[241of the /l-substituents should favor the required
conformation 50 over the linear form 51. A further prerequisite
is that the biladiene, with its vinylogous amidine structure, must
possess sufficient stability.
The four [26]porphyrinogens 44 b-e and also the two
/34]porphyrinogens 46a and 46b can be dehydrogenated with
exactly six equivalents of bromine in the presence of polymeric
base to give the deeply colored and aromatic porphyrins 47a-d,
48a, and 48 b, respectively (Scheme 17) .[24c3 5 3 3 541 The smooth
Et
44b
- 44%
Et
4:7L,=O
49a: 7~ = 1
46a, 46b
49b: 7 ~ ,= 2
6 Equival. Br,
R
‘
Et
R
R‘
.R
Et
Et
Et
51
50
’yj
, ,
a:
Et
Et
n,=l
b: n , = 2
R
470
RrR’
= -(cH2)4-
4 7 b R.R’ = C2H5
4 7 c R.R‘ = n-C4HB
47d R.R‘ = CH,CH(CH,),
24 %
41 %
39 %
34 %
480 R = C,H,
48b R = CH,CH(CH,),
R
12.6 %
13.0 %
Scheme 17. Dehydrogenation of the tetra- and octavinylogous porphyrinogcns to
the [26]porphyrins 47 and the [34]porphyrins 48.
progress of this dehydrogenation of cyclic polyenes each with
four reactive ally1 groups would be almost inexplicable were it
not for the aromatic stabilization of the reaction products. The
good yields obtained in the dehydrogenation reactions proved
to be essentially independent of the steric demands of the /hubstituents (Scheme 17).
1802
Scheme 18. The octaethyl[lX]porph)rin 4 of Hans Fischer [I41 together with its diand tetravinylogues 49a and 49b. respectively. and the possible conformations 50
and 51 of the biladiene precursor.
The pyrrolylacroleins 53 a and 53 b are key building blocks in
the synthesis of the bisvinylogous biladiene 54a and the tetravinylogous biladiene 54 b, respectively.[24‘, 5 3 1 Their condensation with the dipyrrolylmethane 52, a porphyrin building
block described by Paine and W o o d ~ a r d , [provided
~~]
the highly colored vinylogous biladienes 54a and 54b in surprisingly
high yields (Scheme 19)
561
The highly crystalline, aromatic porphyrinoids 49a and 49b
can be obtained by the acid-catalyzed condensation of 54a and
54 b with formaldehyde, followed by the dehydrogenation of the
initially formed hydroporphyrinoids with 2,3-dichloro-5,6-dicyano-I ,4-benzoquinone (DDQ) (Scheme 20) .[561 Similarly, the
.III@w.
Climi.
I H I .Ed Engl. 1995. 34, 1795- 181 1
REVIEWS
Porphyrins and Their Applications
Et
Et
Et
0
Et
\
\
HBr. MeOH
it
52
54a:
1
81 2
40 X
TI,=
Ilr
\
33a: n =
b:n =
it
54b: m = 2
\
0
1
Scheme 1‘) Synthezis of the di- and tetravinylogous biladienes 54a and 54b. respectively 1%). 561
57
58a: n = 2
b:n = 3
C:n = 4
d:n = 5
Scheme 21. [18]- and (22lannulenes 33a and 33b. respcctivelq (341. as well as kekultne 57 [57] and dehydroannulene 58 [58]
55a: X = C-C&
55b: X = C-C&
26 n
HN
Et
Et
Schcme 10 Acid-catalyzed condensation of the vinylogous biladienes 54a and 54b
10 give 1321-nnd (2hIporphyrins 150,561
phenyl- and cthyl-substituted [26]porphyrins 55a and 55b were
prepared by condensation of the tetravinylogous biladiene 54 b
with benzaldehyde and propionaldehyde, respectively. Condensation of 54h with ammonia gave the aza[26]porphyrin 56.[501
5. The Fascination of Superaromaticity
flexibility of annulenes. Two studies proved to be particularly
informative: The synthesis of the kekulene 57 by Staab et aI.[”]
and of the didehydroannulene 58 by Nagakawa et a1.[581
(Scheme 21). In the case of kekulene 57 the [18]annulene is embedded in a wreath of twelve benzene rings. This allows a direct
comparison of the resonance stabilization of the benzene sextet
with that of the conjugated 18n- and 30~-perimeters(inner and
outer rings in 57). As can be seen from the ‘H N M R spectra, 57
is a system composed of annelated benzenoid n-sextets, in which
annulenoid conjugation plays no part .I5’]
In the cases of the dehydroannulenes 58a-d the alkyne and
allene units provide the conjugated perimeter with steric rigidity
and resonance stabilization. The ‘ H N M R signals of the inner
(Hi)and outer (Ha)protons at the conjugated perimeter indicate
a correspondingly larger ring current effect than that displayed
by annulenes of the same x-electron count (Table 1). The Ah
values (S(Hd) - &Hi)), which serve as a measure of the size of
the ring current effect, become smaller, starting from
[l Sldidehydroannulene 58 a, as the n~olecule becomes less
rigid.[”]
Table 1. ‘ H N M R data Tot- the didehydroannulenes 58a-d 15x1 (see Schcme?!)
6 values of the inner (H’) and outer ( H a )protons at the conjugated perimeter, and
the differences A 6 = @Ha)-6(H’).
Didehydroannuiene
NH’)
d(w)
A6
3.42
9.87
13.2‘)
58a (IXa)
Sondheimers synthesis of the [18]annulene 33a1341
(Scheme 21)
-ax3
9.1 0
9.’)’)
58b (EX)
has had far-reaching implications for organic chemistry. For
1.95
X.23
h.3X
58c ( 2 6 ~ )
3.5
7.5
4.0
example, 40 years after the Huckel rule for benzenoid a r e n e ~ l ~ ~ ]58d ( 3 0 ~ )
was postulated. this synthesis provided confirmation of the
validity of this rule for systems up to and including the hexaAn unequivocal indication of the aromaticity of higher annuvinylogue of benzene 33a. Furthermore, as previously menlene derivatives should include, in addition to the ring current
tioned. the annulenes proved the power and capabilities of
effects in the ‘H N M R spectrum, the proof of a planar structure
HMO calculations as a method for predicting the stability of
with bond length equivalence in the conjugated perimeter, and
unknown molecules.[s1J
the ability of the perimeter to undergo electrophilic substitution.
These findings have stimulated intensive efforts to obtain acTherefore, with regard to theoretical utility, it is desirable that
cess to higher aromatics hy constraining the conformational
~
1803
B. Franck and A. Nonn
REVIEWS
the measures taken to ensure a stable planar structure allow the
molecule to remain structurally as close as possible to the annulenes. These requirements are essentially fulfilled in the case of
the [22]- and [26]porphyrins 49a and 49b, respectively (see
Scheme 20) .r50*5 6 1
The ' H N M R data for Hans Fischer's octaethyl[l8]porphyrin
(4) are summarized in Table2 along with those of the octaethyl[22]porphyrin 49a and the octaethyl[26]porphyrin 49 b.
As is already known, the diatropic ring current effect of the
normal [18]porphyrin 4, with a A6 value of 13.92. is comparable
9
0
Table 2 . ' H NMR data for the vinylogous porphyrinoids. 6 values of the inner
protons (H'. N H ) and outer protons (H". NH) at the conjugated perimeter. the
difference Ad = ij(H") - 6(H'), and the areas S of the ringa in A'.
Porphyrinoid
4 [1XI
49a 1221
49 b [26]
h(H')
-
-9.54
-9.79
ii(~")
10.18
12.78
14.35
6(NH)
A6
S
-3.74
-6.61
13.92
20.2
24. I
50
68
-5.71
Fig. 3. Crystal structure of the bistrifluoroacetate of octaethyl[22]porphyrin 49a;
top: iiewed perpendicular to the crystal plane, bottom. side view [S6].
84
n
to that of the [28]didehydroannulene 58a (Table 1). It must be
kept in mind, however, that, in the case of 4, the 6 values of the
NH protons were used, replacing those of the absent inner C H
protons. For the [22]porpyhrin 49 a and the [26]porphyrin 49 b
the Ah values increase steadily from 20.2 to 24.1, In contrast to
the situation in the corresponding didehydroannulene series
(Table I ) , the criterion of ring current indicates no reduction in
aromaticity due in some way to conformational flexibility.
The rigidity of the three porphyrinoids 4, 49a, and 49b leads
to an almost linear correlation between the magnitude of the
ring current effect, expressed by the A6 values, and the area of
the ring, defined as the area within the dotted line in the formulas of the compounds above Table 2. Thus the ring areas S of 4,
49a, and 49b expressed in Table 2 are approximately proportional to the A6 values of the ring current effect. This relationship corresponds to that developed by Haddon[''] between the
resonance stabilization (RE), the ring current (RC). and the
area (S) of carbocyclic aromatic ring systems [Eq.(a)].
Fig. 4 Crystal structure of the histritluoroacetate of octaethyl[26]porphyrin 49b:
top: viewed perpendicular to the crystal plane. bottom: side view 1501
As already discovered in 1973 with the determination of the
crystal structure of the octaethyl[ 18lporphyrin 4,159a1
porphyrins
with ethyl groups in the 8-positions of the pyrrole units tend to
crystallize readily as single crystals. This was confirmed in the
cases of the vinylogous porphyrins 49. Crystal structures of the
bistrifluoroacetates of the [22]porphyrin 49a and the
[26]porphyrin 49 b indicated molecules with bonds of equivalent
length of 136.6-138.8 pm and 137.1-139.6 pm in their respective perimeters (Figs. 3 and 4). The ring systems are almost
1804
planar with maximum deviation from the central plane of
19 pm.[50.561
The crystal structure data thus obtained for bond
length equivalence and planarity for the [22]porphyrin 49 a and
the [26]porphyrin 49b agree completely with those measured by
Lauher et
and by Cetinkaya et al.[59b1for the
[18]porphyrin 4.
The vinylogous [22]- and [26]porphyrins 49a and 49b, respectively. offered the first opportunity to extend the investigation of
Angeii..
C'hmi.
Int. E d Engl. 1995, 34- 1795-1811
REVIEWS
Porphyrrns and Their Applications
aromaticity i n cyclic conjugated superarenes to the study of
electi-ophilic substitution. The most suitable candidate for this
purpose appeared to be electrophilic deuteration, for which steric considerations are minimal, and the results can be conveniently interpreted by N M R spectroscopy. Both porphyrins were
treated with D2S0,iD20 under identical
and the
extent ofdeuteration was subsequently measured by mass spectrometry and the position and level of deuterium substitution
determined by N M R spectroscopy. Significant differences in the
behavior 01' the two porphyrins were seen (Scheme 22).
Conformationally stabilized diazaannulenes can similarly be
represented by the [22]platyrin 59 and the [26]platyrin 60 of
LeGoff et aI.Ih4."I (Scheme 23). These 22-n- and 26n-electron
systems. prepared by a conceptually different synthetic route,
can be considered to be aromatic according to the ' H N M R ring
current effect. Thus, 59 has a A 6 value of 20.6 and the less stable
60 a value of 26.0, similar to the Ab values found for the [22]and [26]porphyrins 49 (Table 2 ) .
a
22 7r
H3C
49a
HC
,
0
HN
\
'
H3CQH3
H
/
CH3
A
/
CH3
H3
H3C
26
NH
\'
,,HN
/
CH3
D
D
Et
H,
/
CH3
59
Et
TT
60
Scheme 23. Placyrins w t h aromatic Err- and 2hx-electron \ p i e m s [64.65]
[D]-49a
47
x
D
A
An interesting class of expanded porphyrins are the pyrrolehomologous systems, two groups of which are represented in
Scheme 24. Penta- and hexaphyrins 61a and 61 b, respectively,
were described by Gossauer et aLr4'] Pyrrologous macrocycles
55a
it
H
HI
HD
~ Dit
[ 5j- 55a
Scheme 22 Deulcration of octaethyl[22]porphyrin 49a and 14-phenyl octaethyl[?h]porphqriii S5a Reaction conditions: a ) D,SO,.'DIO = 10: 1 , 120 h. 20°C.
I n the case of the [22]porphyrin 49a, the outer perimeter
protons were almost quantitatively substituted with deuterium,
with the formation of the hexadeuterio[22]porphyrin [D]-49a.
Both inner protons proved to be inert towards electrophilic
deuteration. One must assume that the NH groups undergo a
D/H exchange on aqueous workup. The [26]porphyrin 49b
which is more acid sensitive than 49a, was replaced by its phenyl
derivative 55 a. Analysis of its deuteration product [D]-55a indicated that complete electrophilic substitution of the four inner
CH protons by deuterium had taken place.
The preferred exchange of the inner protons in 55a (+ [D]55a) should be attributed to the activating effect of the phenyl
subatituent, rather than to the larger space inside the ring. The
phenyl group proved to be an effective donor under the conditions of deuteration, compared to the more electronegative,
protonated 23-electron system. Correspondingly, the 12phenyl[22]porphyrin underwent complete deuteration of its inner protons under the same conditions.[56b1The deuteration
experinients with the [22]-and [26]porphyrins provide convincing chemical evidence for the aromaticity of these compounds.
They also stimulate further interesting questions about the reactivity and regioreactivity of these novel, easily accessible[62,h 3 1
supcrarenes.
62
Scheme 24 Pyrrole-homologous porphyrins: penta- and he\;,iphqriii 61 a and 61 b.
re5pectively [65]: and turcasarin 62 [6h]
with up to ten pyrrole units, such as the turcasarin 62 which is
turqouise in solution, were achieved by Sessler et al.[hhlby the
insertion of di- and tripyrrole units. As was anticipated from the
consideration of the angles in the perimeters (see Scheme lo),
the additional pyrrole units give rise to increasing deviation
from the planar structure. This leads finally. as with the cyclic
decapyrrole 62. to the formation of twisted conformations with
exciting stereochemistry (Scheme 24).
The octaethyl[26]porphyrin salts 47a-d also display pronounced aromaticity according to the 'H N M R ring current
effect (Table 3) .[24c. 491 The resonance signals of their perimeter
protons are almost completely independent of the nature of the
peripheral alkyl groups and lie at 6 = - 11.45 t o - 11.68 for the
inner protons (Hi) and at b = 8.98-9.10 for the outer protons
(H"). This gives a Ab value of 25.0-25.3, which agrees very well
with the values for the [26]porphyrin 49b (Table 2) and for the
[26]platyrin 60.[64.h 5 1
1805
B. Franck and A. Nonn
REVIEWS
'
Ha
R
' "2-4, a H,CN R
'
Hi 26 n
NCH,
R
/
\@I
,
'
2x9
48
47
H,CN
/
R'
Fi
R
Table 3. ' H NMR data for the salts of octaalkyl[26]porphyrins. 6 values of the
inner protons (HI, CH,N) and outer protons (Ha)a t the conjugated perimeter, and
the difference A6 = &Ha) - &Hi) in CDCI,.
[26]Porphyrin
47a: R, R'
47b: R. R'
47c: R, R'
47d: R, R'
=
-(CHzja- [a]
= C,H, [a]
= n-C,H,[b]
= CH,CH(CH,),[b]
Table 4. ' H NMR data for the octaaikyl[34]porphyrin dibrornides &a, b. 6 values
of the inner protons (HI, CH,N) and outer protons (Ha)at the conjugated perimeter,
and the difference A6 = 6(H") - d(H') in [DJDMSO.
W')
6(W)
6(H,CN)
A6
[ 34lPorphyrin
W'j
6(H"j
R(H,CN)
A6
-11.68
-11.64
-11.54
-11.45
13.52
13.67
13.61
13.58
- 9.10
- 9.09
- 8.98
- 9.01
25.2
25.3
25.2
25.0
48a: R = C,H,
- 14.23
48b: R
-14.13
17.18
17.04
-11.30
-11.16
31.4
31.2
[a] Measured as the bistrifluoroacetate. [b] Measured as the dibromide
Initial attempts to measure the diatropic ring current effect of
the octaethyl[34]porphyrin salts 48 a,b from their 'H NMR
spectra were frustrated by the occurrence of an unexpected
problem. The signals at very high field and at very low field
displayed no spin splitting. It was initially presumed that this
could be attributed to interconversion of conformers, as is the
case with the annulenes. Therefore measurements were performed at -60°C and at 50°C. However, no improvements
were seen. It was found that the inner (Hi) and outer protons
(Ha) gave the expected splitting patterns (Fig. 5) only at extremely high dilution (0.1 mgmL-') in [DJDMSO.
H'
R
LL
=
CH,CH(CH,),
bridges. The resulting A6 value is thus greater than A6 = 31.
Thus, the ring current effects of the [34]porphyrins 4Sa,b are
higher than those measured for all of the previously described
arenes. Such a large span between high and low field signals in
a ' H N M R spectrum has only previously been observed for
organometallic compounds. It is remarkable that the pyrrole
units at the corners of the molecule can stabilize a planar
conformation over bridges as long as C, and thus allow the
[34]porphyrins to display aromaticity.
The fact that the spin splittings in the 'H NMR spectra of the
[34]porphyrins are only resolved at extremely high dilution can
be considered as being due to strong associative behavior in
solution. This behavior, which is also recognizable in the crystal
structures of the porphyrins, might not only be due to the ring
size of the octavinylogous [34]porphyrins, but may also be
strengthened by the possible intercalation of anions. In contrast
to the [18]porphyrins, the inner space of the octavinylogues
would be well suited for this purpose, as is shown by the spacefilling models in Figure 6.
ry
W
20
l
15
-
6
-
-10
-15
Fig. 5. 'H N M R spectrum of the octaethyl[34]porphyrin 48a in [DJDMSO [53]
Concentrations: a) 0.1 g L - ' ; b) 3.OgL-I.
The eight H' protons of the octaethyl[34]porphyrins 48a and
4Sb, which lie in identical positions on the inside of the C,
bridges, display triplets at 6 = -14.13 and -14.23 in their
'H NMR spectra (Table 4). The singlets of the CH,N protons
resonate at slightly lower field, namely 6 = - 11.30 and - 11.16,
because of their somewhat larger distance from the perimeter.
The twelve outer protons (Ha) on the C, bridges of the perimeter
display two signals at 6 = 17.18 and at 17.04, of which the signal
at lower field is derived from the protons in the center of the
1806
Fig. 6. Space-filling representations of the octaethyI[l8]porphyrin 4 (left) and the
N,N'.N",N"'-tetramethyl octaethyl[34]porphyrin dibromide 48a (right) [I 21.
6. High Intensity Pigments with Future Perspectives
Chlorophylls cause the formation of huge amounts of
biomass using energy absorbed from sunlight. In comparison
with this, the light absorption of the other porphyrinoids plays
a relatively minor role. Some porphyrins do have, however,
Angen. Chem. l n t . Ed En$
1995. 34. 1795-1811
Porphyrins and Their Applications
REVIEWS
pathological or medicinally useful effects. Examples include
their role as photosensitizers in p ~ r p h y r i a [ ~ ~or, ~in' ] photodynamic tumor therapy (PDT). [ 6 9 . 7 0 1
The new vinylogous porphyrinoids are of current interest as
pigments because they display the following properties: 1) Extremely high intensity of absorption with values of the molar
extinction coefficient c as high as 1 100000; 2) a linear relationship between the number of n-electrons and the wavelength of
the most intense absorption band (Soret band); 3) high light
stability, and 4) activity as photosensitizers.
The pigments, which are characterized by high extinction coefficients. could allow dyeing techniques with small amounts of
substance. U p until now, the most industrially important pigments have molar extinction coefficients E ranging from 20000
(indigo) up to 220000 (copper p h t h a l o ~ y a n i n ) . [ ~The
~ I E values
of the vi nylogous porphyrinoids are fifty times higher than those
of indigo and three to four times higher than those of the
phthalocyanins (Table 5 ) . This fact, if supported by other useful
pigment properties, may lead to interesting opportunities.
The crystal structures of the bistrifluoroacetate salts of the
[22]porphyrin 49a and the [26]porphyrin 49b (Figs. 3 and 4,
respectively) indicate an almost complete bond length equivalence in the aromatic perimeter. An independent confirmation
of this finding is provided for the vinylogous porphyrins from
their absorption spectra. It can be seen that. ;is for the cyanin
pigments-for the vinylogous C, symmetric 18n-, 26n-, and
34n-porphyrinoids-there
exists a linear relationship between
2,,, and the number of n-electrons in the aromatic perimeter
(Fig. 7). According to this, the vinylogous porphyrins have fully
delocalized n-electron systems comparable to those of the
cyanins.['*] Because of the formal similarity, the term
"Babuschka porphyrins" (in analogy with the Russian dolls in
which a small doll fits inside a larger doll which fits inside an
even larger doll, known as Babuschka dolls in German) is proposed for the C,-symmetric vinylogous porphyrinoids.
7w
1
34n
20
34 7T
49a: IL = 1
49b* = 2
64
Et
30
electrons
Fig 7. Left. [18]-, [26]-. and [34]porphyrins in the colors 01' their solutions in
CH,CI, (simplified formulas). Right: Relationship between /.,, (Soret band) and
the number of rr-electrons in the aromatic perimeter for the porphyrinoids 64.47b.
and 48a with ~XT-. 26-, and 34rr-electron systems. respcctivelq
Et
Et
TI
Et
7. Tailor-Made Porphyrinoids for Photomedicine
Et
E!
48a
47b
Table 5 Absurpuon bands of vinylogous porphyrins.
Soret band
Porphyrinuid
[ I X]isohemntoporphyrin 64121
[22]porpIiyrin(l.?.l.~)49a[b]
[16]porph?rin( 1.5.1.5) 49b[b]
[16]porphyrin(3.3..,~) 47b[a]
[34]porphyrin(5.5.5.5) 48a[c]
[a] CHC'I,. [h] <'H,CI,
Longest wavelength
band
/.",ax
c
/.ms"
I:
399
460
130000
1120000
694000
909600
370000
621
691
694
783
997
2570
7960
40600
28000
24000
512
547
663
+ 1 % TFA. [c] MeOH.
One of the prerequisites for narrow, intense absorption bands
with high t: values and small half widths is a substantially symmetrical structure. Thus, the unprotonated [22]porphyrin 49a
displays a less intense Soret band (j.max
= 463, F = 419000).
when measured without the addition of trifluoroacetic acid
(TFA) (Table 5 ) .
As physiologically acceptable, effective photosensitizers,
which differ only slightly from the body's own blood pigment
heme, the porphyrinoids find two important applications in the
field of photomedicine. These are photodynamic tumor therapy
(PDT)[69.701 and photodynamic destruction of viruses (PDV)[731
in transfusion blood. In connection with the necessity of reliably
preventing viral or parasitic infections arising from blood transfusions. the second technique is of topical significance.
Thus, at the Baylor Research Institute in Dallas, it was found
that viruses and other parasites in transfusion blood can be
destroyed by adding a trace of a suitable photosensitizer to the
blood and then irradiating it with visible light.[731This technique is based on the fact that the photosensitizer causes the
formation of singlet oxygen. which kills the virus. without causing any significant damage to the essential blood cells. Figure S[741shows AIDS viruses which, after multiplication within
a cell, penetrate the membrane and enter into the blood stream
and are, at this point, particularly exposed to attack by singlet
oxygen. At present, thanks to various other techniques, particularly heat treatment of transfusion blood, the risk of infection
can be substantially reduced, but not completely excluded.
In photodynamic therapy (PDT), after uptake of the photosensitizer, the tumor is irradiated with visible laser light of a
suitable wavelength. This leads to inhibition and destruction of
1807
B. Franck and A. Nonn
REVIEWS
L
J
b-d
Scheme 76. Formation of ' 0 : bq \ai-ious plioto~ciisitirersunder standard conditions (79- X I ] . Photosensitizer5 used (yield "1"): octaethyI[lX]porphyr~n4 ( 2 2 ) :ocraetliy1[22]porphyrin 49a (40): octactIiyl[lh]porph~rin49h ( I 2 ) : (iclaelh~1[34]purphyrin 48a (0): Bengal Rose (44): blank (0).
Fig 8 . Electron micioscopic picture of budding AIDS viruses 1741 (reprinted uilh
kind permission of the Dana-Farber Cancer Institute. Division of Huinoii Rctroiirology. Boston. MA. USA)
higher wavelength fluorescence emission (i,,,= 1310 nm)1821
is
not sufficient for * O , formation.
An ideal photosensitizer for photomedicinal applications
should fulfill the following criteria:17011) be readily available
and chemically stable; 2) be a good photosensitizer: 3) its absorption of light should differ from that of the blood pigment
heme; 4) have minimal dark toxicity; 5 ) be pharmacokinetically
innocuous: 6) be rapidly eliminated from the organism after
phototherapy.
The most widely used photosensitizers have been hitherto
derivatives of the hematoporphyrin 63 (Scheme 2 7 ) , which have
the tumor, an effect which has already been demonstrated in
several thousand clinical applications.'691Because of the success
achieved up to now, and the much milder nature of the treatment in comparison to the treatment of cancer by X-ray irradiation, this area is the subject of intensive development in
a worldwide collaboration between medicine and chemistry.[h9.7 0 . 7 3 . 751
To explain the mechanism of action of photosensitisers in
tumor therapy and in the destruction of viruses in transfusion
blood, it has been assumed that the singlet oxygen which is
formed on irradiation in the presence of light and oxygen, reacts
with nucleosides. From this. the rapidly proliferating tumor
cells are more strongly affected than the healthy tissue. Cadet
et al.[761have described oxidative transformation of deoxyguanosine acetate by singlet oxygen in a relevant model study
(Scheme 25).
OH
C02H
COzH
'C02R
COzR
65a R = H
65b R = CH,
I
COzR
640 R = H
64b R = CH,
63
ROzC
COIR
C02R
660 R = H
66b R = CH,
Schemc 27. Hcinatoporphyriii (63),isohciiiatoporph~rin(64a) (771. [22]porphyrinoctaacrtic acid (6%) [7XLi]and[22]coproporphqnn I 1 (66a) [7Xb] and esters
Am
Scheme 25. Reaction of deoxyguanosine acetate with single1 oxygen (761
In order to compare the photosensitizer activity of the vinylogous porphyrins, their ability to form singlet oxygen under the
conditions encountered in photodynamic therapy was chemically determined (Scheme 26). The trapping reaction with 2,sdimethylfuran and the subsequent iodometric titration of the
hydroperoxide formed after the methanolysis, was chosen for
this p u r p o ~ e . [ ~ ~ Th'
- " is
~ indicated that the divinylogous
[22]porphyrin 49a performs almost as efficiently as Rose Bengal, and exceeds the [18]porphyrin system, for example 4. which
has been predominantly used in photomedicine until now. In the
case of the [34]porphyrin 48a, the relatively low energy of the
1808
been named Photofrin.l""] They fulfill the majority of the abovementioned criteria. The hematoporphyrin 63 is somewhat chemically unstable due to its allylic secondary hydroxy group, which
leads to mixtures of derivatives. This problem can be overcome
by the use of the more stable isohematoporphyrin 64.["] Of
g r a t e r significance is the improvement in the penetration depth
of the laser light used for the photosensitization. Due to the
similarity of the chromophore of hematoporphyrin 63 to that of
the natural blood pigment heme. present in large excess, part of
the laser light is lost during phototherapy. A remedy to this
problem is offered by photosensitizers which. as in the case of
the vinylogous porphyrins 65a and 66a, are structurally similar
to the hematoporphyrin 63, but absorb light at longer wavelengths (Scheme 27). Compound 66a17sb1
is a divinylogue ofthe
Porpliqriiix :tiid Their Applications
REVIEWS
naturallq occuring coproporphyrin 11. I t has a more intense
U V Vis absorption which is shifted to longer wavelengths than
the blood pigments. and thus appears to be a candidate for
selective photoactivation (Fig. 9 ) .
!k
5ooT
/a3
550 600
tml-
+ ...
30
h[mI
650
&
-
4
700
600
\pccti-a of[?2]coproporpliyrin I1 ester (66b) () [78b] and isohe- ) [77] in CH,CI, Because of thc instability ofheniatomatoporp1i)rin ih4h) (
Fig. 9 L'L'
\'I,
~
gate this. the ability to inhibit tumors in a leukemia cell line was
studied for two derivatives of the isoheniatoporphyrin 64 b and
67ri7b1
as well as for a [22]porphyrin 65br-"' and a [26]porphyrin 47b'"'l (Table 6).l"j1 This showed that the tumor inhibitory activity of the nonpolar isohematoporphyrin dimethyl
ester 64 b significantly exceeded that of the isolieniatoporphyrin
digalactoside 67. The nonpolar [22]porphyrin octaacetic acid
octamethyl ester 65b has similar activity to 64. while the polar,
hisquaternary [26]porphyrin 47b has a lower activity which corresponds roughly to that of 67.
The isohematoporphyrin dimethyl ester 64b proved itself to
be just as well suited for the photodynamic destruction ofviruses in blood. Table 7 shows the destruction of' Herpes simplex
virus (HSV) using 64b and 458 nm laser light. A concentration
of 1 IigmL-' (corresponding to 0.5 mg in a transfusion blood
unit of 500 mL) is sufficient to kill 99.996% of the virus.
Under the same conditions the blood leukocytes are hardly
affected.
porphyriii (63).hi. \pectruni of64h. which has the ~aniecliroinophore.I S shown for
c0i11pai1\011
Due t o the short half life and therefore limited range of action
of '02.LH2J
the photosensitizer can only display its effect inside
the viral or tumor cells. Therefore. a decisive factor for the
photomedicinal application of porphyrinoids is, apart from
their photosensitizing ability, their polarity. In order to investiOH
Concentration
[ p g niL '1
Destruction of HSV
dark
laser
0
1
2.5
5
1 500 000
I so0 no0
1 400 000
~
18000 000
750
500
2 50
Surviving leukocytes
dark
laser
58
42
36
43
2X
22
In the flow cells of a test apparatus (Fig. 10) the tilm thickness
is so low that the absorption of laser light by blood pigments is
of no importance.[73b,
831 By using the vinylogous porphyrins
which absorb light at longer wavelengths, it would be possible
to photodynamically sterilize blood in thicker films. potentially
directly in the transfusion units. This would not only be of use
in the reduction of infection from AIDS and hepatitis viruses.
but also from malaria parasites. Taking into consideration the
risk of infection which is always present in the use of transfusion
blood and other infusion liquids, the development of safer. more
generally applicable. and cheaper processes of sterilization is
becoming more and more important.
OH
C02H
Table 7. Phototoxicity of the isohematoporphyrin dimethyl cstcr 64h against Herpes simplox mrus (HSV) and against blood leukocytes with Jaber light of 458 nm
1831.
CO2H
67
8. Summary and Outlook
65b
Tahlc 6. Inliibiti~mol'tuniors by the four porphyrinoids 64b. 65b. 67. and 47b of
diffcrcnt po1;irit~ag.iin\t lcukeinia cell lines [83]. Colony building after laser irradii i t i o i i (9?.6 .Icin') a s 'I pcrccntage of the initial value.
Concenti-;ition ["(,]
[fiSIllL
25
5
7.5
10
$1
Colony formation
64b [77b] 67 [77b]
6Sb [78a]
47b [24c]
4X
X
78
49
39
n
10
0
62
48
30
15
32
17
29
1
The results gained with the porphyrins have reinforced the
importance of understanding the biosynthesis of a group of
natural products. the knowledge of which opens the door to a
series of novel methods and insights. In particular this holds true
for the development of biomimetic syntheses, as was shown first
of all in the pioneering work by Robinson and Schopf for the
alkaloid^,"^^ 8 5 1 then Johnson1s61for the steroids. and Rimington et a1.1231for the porphyrins. Through this approach possibilities for efficient syntheses have been realized, which allow an
alternative route to active substances, generally preferable to
their isolation from biological material. In the case of the porphyrins. the biomimetic principle has provided 3 remarkable
versatility and flexibility, which has allowed access to viny1809
B. Franck and A. Nonn
REVIEWS
[ I ] H. Fischer, B. Walach. Jusru.5 L i d i g s Ann. Chcm 1926, 450, 164.-181
(21 CAS Online search for 1994.
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M. M. Cox, Prinzipien dt~rBioC/mlwii<~.
1994
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a ) F. J. Leeper. Nor. Prod Rep. 1989. 6. 171 -203; b) L R. Milgrom. Chm?. Br.
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A. I. Scott. Aiigen. Chem. 1993, 105, 1281- 1302; Aiigciv. Chenz. Int. Ed. EngI.
1993.32, 1223-1243.
The blood of an adult human (ca. 5 L) contains approximately 30 g heme.
Biosynthesis replaces this completely every 120 days [Y].
G . H. Tdit, The Biosynihesis and Degrutlarron u/Heme. in ref.(4]. pp. 1-48.
B. Kriutler. B. Jaun. K . Bortlik. M. Schellenberg. P. Matile. Angm'. Chtw?.
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H . Fischer. R. Ba'umler, Jiisrus Liebi,g.c Ann. Chrm. 1929, 468, 58-98
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i
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The company Harimax, Loenen, Holland recovers annually 10 -12 t hemin
from 40 million liters of blood from slaughterhouses. The hemin is used in
chemical and medicinal applications This amount represents ca 80% of the
Fig. 10. Flow apparatus for the sterilization of blood (Bayloi- Research Foundation) [73b.S3] (reproduced with kind permission of the Baylor Research Institute.
Dallas. Tx. USA). Top: Schematic diagram: A)laser light assembly, 8 ) flow cell. C)
syringe pump, D) sterile collecting vial, E) light meter Bottom: Apparatus in operatioq
logously expanded, N,N',N",N"-tetrasubstituted,
N,N'-bridged,
and inverted ( N atoms in the periphery) porphyrins.
While we are still in the early stages, the new porphyrinoids have already displayed properties which are of great
promise in the fields of chemistry and medicine. If one looks for
a reason for the unusually broad variability encountered in
biomimetic porphyrin synthesis, one is forced to suppose that
this has to do with the very early prebiotic formation of porp h y r i n ~ . [ ~The
' ' evolution of organisms required a versatile system with strong formation tendency, which could satisfy the
demand for ligands for the essential elements Mg, Fe, Co, Ni,
and V.
Our "ark was generously supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and BASF AG
(Ludwigshafen). B. E would, in particular, like to thank ull the
co-authors of the cited work, carried out in Miinster. The readiness of numerous colleagues (rejs. [15, 18, 25, 32, 36, 40, 46, 60,
68,69, 72, 73, 75, 79,82,83/) to contribute muclz valuuhle advice
or to collaborate was decisive ,for the success of' the interdisciplinarj research.
Received February 24. 1995 [A 107 IE]
German version: Angiw Chcwi. 1995, 107. 1941 -1957
Translated by Dr. D. Marquarrie. Naters (Switzerland)
1810
world requirement. Currently. the industrial price of hemin is approximately
600 DM per kg (Personal communication from Harimax, and also Prof.
Mueller von der Haegen. Seehof-Ldboratorium, D-25764 Wesselburenerkoog
Seehof.
Price from February 15. 1995.
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~
1811
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