Porphyrins are a group of tetrapyrrole pigments. Physical and
chemical properties of porphyrins are often related to their
compositions and structures. We conducted [.sup.1]H solution NMR and
UV-visible spectral analysis to characterize the structural feature of a
water-soluble, synthetic porphyrin i.e. tetrakis (p-sulfonatophenyl)
porphyrin, [TPPS.sub.4], and its interaction with different metal ions
in aqueous solutions. The results indicate that tetrapyrrole and
tetraphenyl rings in [TPPS.sub.4] molecule form a co-planar electron
conjugation system; transition-metal ions show stronger binding capacity
than alkali and alkali-earth metal ions; the relative stabilities of
[TPPS.sub.4]-metal ion complexes can be well assessed by NMR and
UV-visible spectral data.
Key words: Porphyrin; NMR; [TPPS.sub.4]
Porphyrins and their derivatives are a large family of aromatic
pigments. A porphyrin molecule consists of heterocyclic tetrapyrrole
unit, called porphine, and meso-substituents. The complexes of
porphine-metal ions exist as pivotal components in many native proteins
such as chlorophyll and hemoglobin. For synthetic porphyrins, different
meso-substituents can be incorporated into the tetrapyrrole unit, so
that structures and properties of porphyrins can be significantly
Different types of synthetic porphyrins have a broad range of
applications in biological/biomedical field. For instance, some
synthetic porphyrins were used as best catalysts for the bio-oxidation
of certain drugs such as acetaminophen and ellipticine, so these
porphyrins may have a great future in the study of in vivo drug
oxidative metabolite pathways (1). The complexes of porphyrin-nuclease
were used to investigate the DNA cleavage and to get insight into its
mechanism of action (2). More importantly, synthetic porphyrins can
potentially serve as therapeutic drugs (called photosensitizers) for the
photodynamic therapy of cancers (3-5), in which the uptake porphyrins
are irradiated by light of certain wavelength; and the absorbed energy
is transferred to oxygen, converting the regular triplet oxygen to
singlet oxygen - an extremely reactive species that has the power to
destroy the cells. Also, porphyrins can be used as contrast agents or
tumor localizers in the magnetic resonance (MR) imaging (6-10).
In a variety of synthetic porphyrins, the water-soluble porphyrins
are of particular interest. The higher aqueous solubility of a porphyrin
is often desirable, and this can be achieved by preparing a porphyrin
containing positively or negatively charged meso-groups (11-18). The
water-soluble meso-tetrakis (p-sulfonatophenyl) porphyrin, [TPPS.sub.4],
is an important member in this category. Because of its higher aqueous
solubility and uniquely symmetric structure, [TPPS.sub.4] molecule has
become an important target in many recent porphyrin studies (19-23). The
water-soluble [TPPS.sub.4] is also found capable of binding to serum
albumin, a rich transport protein in blood plasma, suggesting that
[TPPS.sub.4] can be delivered in blood stream (14). In spite of these
research developments, however, some fundamental issues regarding
[TPPS.sub.4] structure and [TPPS.sub.4]-metal ion interaction have not
yet been clearly addressed.
To characterize structure of [TPPS.sub.4] in aqueous solutions, we
synthesized [TPPS.sub.4] (see Fig. 1), and conducted [.sup.1]H NMR and
UV-visible spectral analysis for [TPPS.sub.4] samples under varied pH or
metal ion bindings. Our results revealed that tetrapyrrole and
tetraphenyl rings in [TPPS.sub.4] maintain a co-planar structure to
fulfill the p-[pi] electron conjugation over the rings, and such
configuration may further stabilize the entire molecule. This
[TPPS.sub.4] structural characterization is of significance to the
further investigation and elucidation of TPPS. interaction in biological
systems, because structures (planar or non-planar) of porphyrins may
strongly impact their interaction with other biomolecules. For instance,
it has been suggested that when a planar porphyrin interacts with
nucleic acid (DNA or RNA), the porphyrin ring is intercalated into the
G-C base pair to form intercalating complex; in contrast, a non-planar
porphyrin is simply bound onto the major/minor groove of nucleic acid
(15). From the [.sup.1]H NMR and UV-visible spectral data, we also
determined the relative strengths of [TPPS.sub.4] interaction with
different metal ions, which can be used to assess the stabilities of
these [TPPS.sub.4]- metal complexes.
[FIGURE 1 OMITTED]
MATERIALS AND METHODS
[TPPS.sub.4] synthesis: Analytical grade chemicals from
Sigma-Aldrich were used without further purification. Following the
preparation method established earlier (24), typically 0.1 mole pyrrole
and 0.1 mole benzaldehyde were reacted for five hours in 50 ml of
refluxing propionic acid. After cooling down, the product,
meso-tetraphenyl porphyrin, was precipitated in saturated sodium acetate
solution, and was washed with methanol-water solution and dried using an
oven. For further purification, the crude porphyrin was dissolved in
chloroform, and the solution was passed through alumina column, then the
solvent was slowly evaporated. The p-sulfonation on phenyl rings was
achieved by reacting 0.5 g tetraphenyl porphyrin with 15 ml fuming
sulfuric acid (20% free [SO.sub.3]) in a closed vessel, and it was kept
in an oven (80 [degrees] C) overnight. The product was neutralized with
4 M NaOH solution, and treated by Soxhlet extraction using methanol as
solvent. Solid [TPPS.sub.4] was obtained after methanol evaporation, and
the high purity of [TPPS.sub.4] was verified by its characteristic
UV-visible spectrum, as shown in Fig. 2.
[FIGURE 2 OMITTED]
NMR measurements: NMR samples were prepared by dissolving solid
[TPPS.sub.4] in [D.sub.2]0 in absence or presence of metal chloride salt
(KCl, Ca[Cl.sub.2], Ni[Cl.sub.2] or Cu[Cl.sub.2]). [TPPS.sub.4] and salt
concentrations were typically 0.1 M. After taking account of possible
salt hydrolysis effect on sample pH, the final pH was adjusted in
6.1-10.3 range using NaOH and HCl (accurate to pH 0.1). No other pH
buffer substances were used to avoid the interference of impurities. 1H
spectra were acquired on Varian mercury-200 spectrometer at room
temperature, with 90[degrees] pulse-width of 14.5 [mu] s. The chemical
shift values were referenced to TMS.
UV-visible spectra: UV-visible absorbance (in 250-800 nm
wavelength) were recorded on a Beckman DU-7500 spectrophotometer, using
samples of free [TPPS.sub.4] and [K.sup.+]-, [Ca.sup.2+]-, [Zn.sup.2+]-,
[Co.sup.2+]-, [Mn.sup.3+]- or [Fe.sup.2+]-bound [TPPS.sub.4] (1:1 molar
ratio) at pH 7.0.
1. [sup.l]H NMR spectra
[TPPS.sub.4] at neutral pH: Fig. 3 shows a representative [.sup.1]H
spectrum of [TPPS.sub.4] acquired at pH 7.0. The two major peaks, peak a
around 7.59 ppm and peak b around 6.54 ppm, were assigned to
tetraphenyl-H and tetrapyrrole-H, respectively. The p-sulfonate groups
and nitrogens in porphyrin core were deprotonated at pH 7.0, therefore
no proton signals were detected for these sites.
[FIGURE 3 OMITTED]
Effects of pH variation: Because of low solubility of protonated
[TPPS.sub.4] at low pH range, it was not possible to acquire solution
NMR spectra at sample pH below 5.0. When pH was increased in pH ~ 6-10
range, however, we observed that both tetraphenyl-H and tetrapyrrole-H
of [TPPS.sub.4] were somewhat down-field shifted, as shown in Fig. 4.
[FIGURE 4 OMITTED]
Effects of metal ions: Effects of metal-ions on [TPPS.sub.4] are
described in Fig. 5. From bottom up, the [.sup.1]H spectra were obtained
for [TPPS.sub.4] samples in absence or presence of [K.sup.+],
[Ca.sup.2+], [Ni.sup.2+], [Cu.sup.2+], respectively. Relative to free
[TPPS.sub.4], interaction of [K.sup.+] or [Ca.sup.2+] with [TPPS.sub.4]
induced about 0.10-0.30 ppm up-filed shifts, with slightly greater
effect on tetraphenyl-H than on tetrapyrrole-H and greater effect of
[Ca.sup.2+] than [K.sup.+]. In contrast, interaction of transition-metal
ion [Ni.sup.2+] with [TPPS.sub.4] caused about 0.10-0.50 ppm down-filed
shifts, with greater effect on tetrapyrrole-H than on tetraphenyl-H;
while interaction of [Cu.sup.2+] with [TPPS.sub.4] resulted in a very
broad, irresolvable peak.
[FIGURE 5 OMITTED]
2. UV-visible absorbance
Intense Soret-band: The UV-visible spectrum of our free
[TPPS.sub.4] sample at neutral pH was characterized by an intense
Soret-band centered at 414 nm, as shown earlier in Fig. 2. This peak
characterizes the monomeric, deprotonated form of porphyrin (25), (26).
But other peaks (Q-band) at longer wavelengths were found rather week
and insignificant in this case.
Effects of metal ions: By adding different metal ions to
[TPPS.sub.4] solutions, we found that the Soret-band of [TPPS.sub.4] was
more or less red-shifted. Fig. 6 summarizes the wavelength of Soret-band
for [K.sup.+]-, [Ca.sup.2+]-, [Zn.sup.2+]-, [Co.sup.2+]-, [Mn.sup.3+]-,
or [Fe.sup.2+]-bound [TPPS.sub.4]. We found that increases of absorption
wavelength for these [TPPS.sub.4]-metal ion complexes can be correlated
to the decreases of the metal ion radii, with a "best" fitting
to a polynomial curve (Y = 546.1 - 2.86X + 0.022 [X.sup.2] -
[5.8xl0.sup.-5] [X.sup.3]). In particular, the [K.sup.+], [Ca.sup.2+],
[Co.sup.2+] and [Fe.sup.2+] data are well fit to the curve.
[FIGURE 6 OMITTED]
1. The co-planar structure of [TPPS.sub.4]
1H chemical shifts of two raw materials used for our [TPPS.sub.4]
synthesis can be referenced from the on-line spectral database (SDBS),
where phenyl-H of benzaldehyde has 7.56 ppm (3, 5 positions) and 7.87
ppm (2, 6 positions); and pyrrole-H has 6.74 ppm (2, 5 positions) and
6.24 ppm (3, 4 positions), respectively. When [TPPS.sub.4] is formed,
the protons at 3, 4 positions of pyrrole remain in tetrapyrrole ring but
the protons at 2, 5 positions are eliminated. Comparing the SDBS results
with our [TPPS.sub.4] spectral data (Fig. 3), it can be found that the
value of 7.59 ppm (peak a) for tetraphenyl-H is in between the two
resonance values for parent benzaldehyde. However, the value of 6.54 ppm
(peak b) for tetrapyrrole-H is 0.26 ppm down-field shifted from the
parent pyrrole-H at 3, 4 positions.
It should be understood that the tetrapyrrole unit is a highly
conjugated, nearly planar macrocycle with 22 delocalized bonding
[pi]-electrons, obeying the well-known Huckel's 4n+2 rule (where n
is an integer number) for stability or aromaticity of ring structure.
Relative to pyrrole, the down-field shift of peak b in [TPPS.sub.4]
spectrum (Fig, 3) suggests that formation of a large [pi]-conjugation in
porphyrin macrocycle enhances the "ring-current" effect on
nuclear desheilding of tetrapyrrole protons.,
Fig. 4 shows that effects of pH variation on chemical shifts of
tetrapyrrole-H and tetraphenyl-H are nearly identical. Over the entire
pH range of 6.1-10.3, [TPPS.sub.4] should be fully deprotonated.
However, pH changes appear to have similar nuclear shielding/deshielding
at tratrapyrrole and tetraphenyl sites, suggesting a common "ring
current" effect. We believe that this is indicative of an important
structural feature of [TPPS.sub.4], i.e. the tetrapyrrole and
tetraphenyl rings are co-planar with a large p-[pi] electron conjugation
over the entire [TPPS.sub.4] molecule.
To understand this structure feature, it is crucial to know that
both parent materials, pyrrole and benzaldehyde, are also planar
molecules; the carbonyl carbon in benzaldehyde takes [sp.sup.2] hybrid
and keeps in-plane with phenyl ring. During the formation of tetraphenyl
porphyrin, it is four carbonyl carbons that transform into methine
bridges (=C-) to interconnect pyrroles and phenyls. Therefore, it is
very likely that all parent molecules of [TPPS.sub.4] preferably
maintain a co-planar structure throughout the entire synthesis process,
unless there are other significant steric factors to force phenyl rings
out of tetrapyrrole plane; but that appears not happened here. Such
co-planar structure would extend the p-[pi] electron delocalization to
further stabilize [TPPS.sub.4] molecule. As the result, all carbons and
nitrogens in [TPPS.sub.4] keep in-plane with totally 50 delocalized
p-[pi] electrons over the entire conjugation system.
This analysis can be further justified by UV-visible absorbance
data. For the parent materials, the UV absorptions occur at -210 nm
(pyrrole) and -250 nm (benzaldehyde), corresponding to [pi]-electronic
transitions on pyrrole ring and phenyl ring, respectively (27), (28). If
the tetrapyrrole and tetraphenyl rings in [TPPS.sub.4] were still two
separated conjugation systems, we could observe two absorption peaks at
different wavelengths, or at least a much broader peak due to peak
overlap. However, our [TPPS.sub.4] free-base has only one sharp band at
-414 nm, as shown in Fig. 2. The result also agrees with some earlier
measurements (14), (26). This strongly suggests that the pyrroles and
phenyls may indeed form a large, co-planar p-[pi] conjugation, leading
to a single absorption peak in visible-light range. Besides, it was
found by Raman and infrared studies that the p-sulfonation on phenyl
groups of [TPPS.sub.4] may alter the vibrations of C-C bonds between
tetrapyrrole and phenyls and, to some extent, affect the [pi]-electron
system on porphyrin ring (29). This result implies an extended electron
conjugation in [TPPS.sub.4], in consistence with our conclusion.
The co-planar structure of [TPPS.sub.4] meso-tetraphenyl rings and
porphyrincore is novel, and its finding is somewhat unexpected to us.
Such unique structural feature may have its inherent significance to the
stability and interaction of [TPPS.sub.4], as mentioned in Introduction
section. By comparing [TPPS.sub.4] with other porphyrin- or corrin-ring
structures, several interesting points can be further made here. First,
the co-plane of side-rings and porphyrin-core ring in [TPPS.sub.4] is
not the same as that in some synthetic bis-porphyrins, in which only the
space-separated porphyrin-core rings are nearly co-planar (30). Second,
the structures of porphyrins may strongly depend on their substituents
and sample conditions. For instance, X-ray study showed that the
crystalline meso-tetrakis (pentafluorophenyl) porphyrin [(TF.sub.5]PP)
has its phenyl rings twisted by--75[degrees]-88[degrees], making them
almost perpendicular to the tetrapyrrole plane (31). This sharp
difference from our [TPPS.sub.4] sample can be attributed to the
crystallographic packing forces between neighboring molecules in
crystalline [TF.sub.5]PP. Third, it should also be recognized that
[TPPS.sub.4] structure is significantly distinctive from certain corrin
systems such as Vitamin-B12. The [TPPS.sub.4] ring is more rigid and
more flat when viewed from the side, due to its larger conjugation
system consisting of porphyrin-core ring and tetraphenyl rings, as we
justified above; whereas Vitamin-B12 contains a much smaller conjugated
chain within part of the ring system, and thus its side groups are
surely not in-plane with the corrin-ring.
2. The binding strengths of metal-ions
From [.sup.1]H line-shapes of [TPPS.sub.4]-metal ion complexes in
Fig. 5, it can be generally concluded that binding strengths of metal
ions are in a trend of [K.sup.+] < [Ca.sup.2+] < [Ni.sup.2+] <
[Cu.sup.2+]. The up-field shifts of both tetrapyrrole-H and
tetraphenyl-H in [K.sup.+]- or Ca- bound [TPPS.sub.4] are mainly due to
electrostatic interaction between porphyrin-core and metal ion, and such
interaction reduces the "ring current" on both tetrapyrrole
and tetraphenyl (because of their co-planar conjugation), increasing the
nuclear shielding of all these protons. In contrast, the down-field
shifting of [Ni.sup.2+]- bound [TPPS.sub.4] is probably caused by direct
coordination between transition-metal ion and porphyrin-core. Unlike
alkali and alkali-earth ions, transition-metal ions possess d-electrons,
which can be delocalized through their direct coordination with
porphyrin-core, increasing the "ring current" and proton
deshielding. In a [TPPS.sub.4]-metal ion complex, the metal ion
coordinated to tetrapyrrole-core typically adopt [[sp.sup.3]d.sup.2]
hybrid with four orbitals in porphyrin plane and two orbitals in
perpendicular [+ or -] z direction, giving rise to octahedral geometry.
However, [Cu.sup.2+] may experience the so-called "Jahn-Teller
effect" because of its uneven 9 d-electron configuration, which
results in geometry distortion and extra binding strength. The very
broad peak of [TPPS.sub.4] [-Cu.sup.2+] in Fig. 5 is a clear evidence of
strong interaction between [Cu.sup.2+] ion and [TPPS.sub.4].
The direct coordination between metal ion and tetrapyrrole-core
also somewhat extends the conjugation from porphyrin to metal ion.
According to quantum theory, an electronic excitation involved in a
larger conjugated system requires lower energy absorption, corresponding
to lower radiation frequency or longer wavelength. The UV-visible
absorption wavelength of [TPPS.sub.4]-metal complexes, i.e. red-shift of
[TPPS.sub.4] Soret-band upon binding with different metal ions (Fig. 6),
confirms such explanation. Clearly, the effect on red-shift is in a
trend of [K.sup.+] < [Ca.sup.2+] < [Zn.sup.2+] < [Co.sup.2+]
< [Mn.sup.3+] < [Fe.sup.2+], and such trend can be correlated with
different metal ion sizes, i.e. the smaller is a metal ion, the more
red-shifted is the Soret-band of its [TPPS.sub.4] complex. This is in
agreement with the so-called "Irving-Williams series", which
states that the higher is the charge density of a metal ion, the more
stable is its ligand binding. Therefore, by comparing the red-shift of
the Soret-band, we are able to assess the relative stabilities of
[TPPS.sub.4]-metal ion complexes.
It should be noticed that our results presented here are
qualitative. In the future, we will extend our work to quantitatively
determine the [TPPS.sub.4]-metal ion bindings. The strength of
porphyrin-metal ion interaction may depend on various factors, including
the porphyrin (P) species and its charge state (such as [H.sub.2]P or
[P.sup.2-]), the metal ions, solvents, temperature, etc. In fact, the
binding constants (K) were obtained for some porphyrin-metal ion
complexes (32). For instance, when binding to N-alkylated porphyrin
HN-Me-TPPS, [Cd.sup.2+] and [Zn.sup.2+] have the binding constants
K=1.3x10-2 and 3.3x101, respectively; and when binding to TMPyP,
another water-soluble porphyrin, the stability constants are [Zn.sup.2+]
[(8.3xl0.sup.25]) < [[Mg.sup.2+](7.5xl0.sup.17]) < [Li.sup.+]
[(3.8x10.sup.-2]) (32). The binding trends revealed in these
quantitative data are somewhat consistent with our qualitative
prediction, although the literature values are not totally comparable to
ours because they involve fundamentally different materials and
In summary, our [.sup.1]H NMR and UV-visible spectral analysis
suggests that the tetrapyrrole unit and tetraphenyl rings form a large
co-planar conjugation system in water-soluble synthetic porphyrin
[TPPS.sub.4]. For deprotonated [TPPS.sub.4], pH effects on resonance
frequencies of tetraphenyl-H and tetrapyrrole-H are nearly identical,
but [.sup.1]H line-shapes of metal ion bound [TPPS.sub.4] strongly
depend on metal ion species. In general, transition-metal ions show
stronger binding affinity on porphyrin core than alkali and alkali-earth
ions. The relative stabilities of [TPPS.sub.4]-metal ion complexes can
be well assessed by [.sup.1]H NMR and UV-visible data. Elucidation of
these spectral and structure features will be helpful to a broad range
of porphyrin syntheses and applications.
This research was supported by Award Number S06GM060314 from the
National Institute of Health/National Institute of General Medical
Sciences, USA, to Z. Song.
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Zhiyan Song *, Adegboye O. Adeyemo, Jannie Baker, Shakeya M.
Traylor and Marcia L. Lightfoot
Department of Natural Sciences Savannah State University Savannah,
GA 31404 USA
Running Title: [TPPS.sub.4] structure and interaction
* To whom correspondence should be addressed Email: