Metalloporphyrins as chemical shift reagents: the unambiguous NMR characterization of the cis- and trans-isomers of meso-(bis)-4′-pyridyl-(bis)-4′-carboxymethylphenylporphyrins

Article abstract of DOI:10.1016/j.tet.2007.03.135

The condensation of pyrrole with 4-pyridylcarboxyaldehyde and methyl 4-formyl benzoate under Adler-Longo conditions yielded the series of meso-(4′-pyridyl)/(4′-carboxymethylphenyl)porphyrins as a mixture. Careful column chromatography afforded each isomer in pure form. In this paper we focus on the two bis-substituted isomeric meso-porphyrins, 5,10-bis(4′-pyridyl)-15,20-bis(4′-carboxymethylphenyl)porphyrin and 5,15-bis(4′-pyridyl)-10,20-bis(4′-carboxymethylphenyl)porphyrin, respectively, 4′-cis and 4′-transDPyDMeP. The assignment of the geometry of the two isomers was performed by ¹H NMR spectroscopy on the trinuclear adducts [(4′-cisDPyDMeP){Ru(TPP)(CO)}₂] and [(4′-transDPyDMeP){Ru(TPP)(CO)}₂], obtained by selective coordination of [Ru(TPP)(CO)(EtOH)] (TPP=tetraphenylporphyrin) to the peripheral nitrogen atoms. The axially bound ruthenium porphyrins act as chemical shift reagents on the central porphyrin, allowing a clear distinction of the pyrrole proton resonances and consequent unambiguous assignment of the geometry of each isomer based upon symmetry considerations.

Full text of DOI:10.1016/j.tet.2007.03.135

Tetrahedron 63 (2007) 5006–5013
Metalloporphyrins as chemical shift reagents: the unambiguous
NMR characterization of the cis- and trans-isomers of meso-(bis)-
40-pyridyl-(bis)-40-carboxymethylphenylporphyrins
a
b
b
Teresa Gianferrara,a, Davide Giust, Ioannis Bratsos and Enzo Alessio
*
aDipartimento di Scienze Farmaceutiche, Universitaꢀ di Trieste, Piazzale Europa 1, 34127 Trieste, Italy
bDipartimento di Scienze Chimiche, Universitaꢀ di Trieste, Via L. Giorgieri 1, 34127 Trieste, Italy
Received 28 September 2006; revised 2 March 2007; accepted 22 March 2007
Available online 27 March 2007
Abstract—The condensation of pyrrole with 4-pyridylcarboxyaldehyde and methyl 4-formyl benzoate under Adler–Longo conditions
yielded the series of meso-(40-pyridyl)/(40-carboxymethylphenyl)porphyrins as a mixture. Careful column chromatography afforded each iso-
mer in pure form. In this paper we focus on the two bis-substituted isomeric meso-porphyrins, 5,10-bis(40-pyridyl)-15,20-bis(40-carboxy-
methylphenyl)porphyrin and 5,15-bis(40-pyridyl)-10,20-bis(40-carboxymethylphenyl)porphyrin, respectively, 40-cis and 40-transDPyDMeP.
The assignment of the geometry of the two isomers was performed by 1H NMR spectroscopy on the trinuclear adducts [(40-cisDPyDMeP)-
{Ru(TPP)(CO)}2] and [(40-transDPyDMeP){Ru(TPP)(CO)}2], obtained by selective coordination of [Ru(TPP)(CO)(EtOH)] (TPP¼tetra-
phenylporphyrin) to the peripheral nitrogen atoms. The axially bound ruthenium porphyrins act as chemical shift reagents on the central
porphyrin, allowing a clear distinction of the pyrrole proton resonances and consequent unambiguous assignment of the geometry of each
isomer based upon symmetry considerations.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In particular, we are interested in the class of meso-pyridyl/
carboxyphenyl porphyrins for two main purposes: (i) the
construction of multi-metal assemblies by exploiting the dif-
ferent binding affinities of the two functional groups, as
explained above, and (ii) the preparation of new water-
soluble peripherally-metallated porphyrins to be investigated
in medicinal chemistry (e.g., antiviral and anticancer proper-
ties). One synthetic approach in this field consists in binding
four metal fragments to the peripheral nitrogen atoms of a tet-
rapyridylporphyrin (TPyP). In this case the metal fragments
must be highly water soluble and/or charged to impart solu-
bility to the porphyrin conjugate (Fig. 1). We have already
prepared a novel water-soluble porphyrin of this kind by
binding four charged Ru-nitrosyl fragments, [RuCl4(NO)]ꢀ,
to Zn$40-TPyP.4 Another synthetic strategy is that of binding
the nitrogen atoms of meso-pyridyl/carboxyphenyl porphy-
rins to metal centres and to exploit the deprotonation of the
carboxylic groups at physiological pH 7.4 for making the ad-
duct water soluble (Fig. 1). In this case the metal fragment(s)
need not to be particularly water soluble and/or charged.
Porphyrins bearing electron-donor moieties in peripheral
positions, such as meso-pyridyl/phenyl porphyrins (PyPs),
are capable of exocyclic coordination to metal centres and
for this reason are widely exploited in the metal-driven
construction of robust supramolecular arrays.1,2 The new as-
semblies of chromophores, either discrete or polymeric, are
investigated for their novel functions, that range from photo-
induced processes (i.e., energy and/or electron transfer) to
catalysis and molecular recognition. Very often the nature
of the peripheral moieties dictates the binding preferences
of the porphyrin towards a restricted number of metal ions.
For example, pyridyl porphyrins have high affinity for rela-
tively soft metal ions, such as Zn(II), Ru(II) and Re(I), and
very low binding constants for ‘hard’ metal centres such as
Sn(IV) or Al(III). On the contrary, carboxyphenylporphyrins
bind strongly to Sn(IV) or Al(III) while they have lower af-
finity for Zn(II), Ru(II) and Re(I). Thus, it is quite obvious
that porphyrins bearing two (or more) different peripheral
metal-binding sites are particularly appealing, since they
allow the selective construction of heteronuclear multi-
metal assemblies. Elegant examples in this field were
reported by Sanders, Stulz, and co-workers.3
For these reasons we prepared the series of meso-(40-pyr-
idyl)/(40-carboxymethylphenyl)porphyrins by the ‘mixed-
aldehyde condensation procedure’ under Adler–Longo
conditions.5 Column chromatography of the mixture af-
forded four of the meso-(40-pyridyl)/(40-carboxymethylphe-
nyl)porphyrins in pure form. Ester hydrolysis under basic
* Corresponding author. Tel.: +39 0405587859; fax: +39 04052572; e-mail:
gianfer@units.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.135

T. Gianferrara et al. / Tetrahedron 63 (2007) 5006–5013
5007
is reported in the literature,6 we were able to separate them
by TLC and to obtain them in pure form by careful column
chromatography. The two geometrical isomers, however,
could not be distinguished by conventional spectroscopic
techniques. Herein we report their unambiguous NMR char-
acterization that was performed on the trinuclear adducts
obtained by selective coordination of [Ru(TPP)(CO)-
(EtOH)] (TPP¼tetraphenylporphyrin) to the peripheral ni-
trogen atoms. The axially bound ruthenium porphyrins acted
as chemical shift reagents and provided a clear distinction of
the pyrrole proton resonances of the central porphyrin in the
two isomers. Symmetry considerations allowed us to assign
the geometry of each isomer. This is an application of a more
general method that uses metalloporphyrins as selective
chemical shift reagents.
N
NH
N
R
R
N
HN
R
= water-soluble metal compound
R =
N
CO2H
Figure 1. Schematic representation of potentially water-soluble porphyrins
peripherally coordinated to metal complexes.
2. Results and discussion
conditions in THF/methanol mixtures, performed on se-
lected isomers, yielded the corresponding meso-(40-pyr-
idyl)/(40-carboxyphenyl)porphyrins.
Mixed-aldehyde condensation of pyrrolewith 4-pyridylcarb-
oxyaldehyde and methyl 4-formyl benzoate in refluxing
propionic acid (Adler–Longo conditions)5 yielded, after
work-up, a mixture of all six possible meso-substituted por-
phyrins (Scheme 1): tetra-40-pyridylporphyrin (40-TPyP),
5,10,15-tris(40-pyridyl)-20-(40-carboxymethylphenyl)por-
phyrin (40-TrPyMMeP), 5,10-bis(40-pyridyl)-15,20-bis(40-
carboxymethylphenyl)porphyrin (40-cisDPyDMeP), 5,15-
bis(40-pyridyl)-10,20-bis(40-carboxymethylphenyl)porphyrin
(40-transDPyDMeP), 5-(40-pyridyl)-10,15,20-tris(40-carboxy-
methylphenyl)porphyrin(40-MPyTrMeP), and tetra-(40-carb-
oxymethylphenyl)porphyrin (40-TMeP).
In this paper we focus on the two bis-substituted isomeric
meso-porphyrins, 5,10-bis(40-pyridyl)-15,20-bis(40-carboxy-
methylphenyl)porphyrin and 5,15-bis(40-pyridyl)-10,20-
bis(40-carboxymethyl-phenyl)porphyrin, respectively, 40-cis
and 40-transDPyDMeP. The possibility of obtaining these
two isomeric building blocks in pure form is of great rele-
vance, as they (being carboxylic acids) open the way to the
construction of geometrically very different multi-metal su-
pramolecular assemblies of chromophores. Contrary to what
CHO
N
CHO
+ a
n
+ b
N
H
a + b = n
CO2Me
A
A
Hb
A
Ha
5
Hc
B
Ha
A
NH
N
N
NH
N
NH
N
N
20
A
A
B
A
10
HN
N
HN
HN
Hd
Hb
15
Hd
Hc
A
A
B
4'-TPyP
A
4'-TrPyMMeP
4'-cisDPyDMeP
Ha
B
A
Ha
Hb
B
Hb
B
NH
N
N
NH
N
N
NH
N
N
B
B
B
B
HN
HN
HN
Hb
Hb
Ha
Ha
A
B
B
4'-transDPyDMeP
4'-MPyTrMeP
4'-TMeP
3'
5'
2'
3'
2'
1'
4'
A =
4'
N
B =
CO2Me
6'
5'
6'
Scheme 1.

5008
T. Gianferrara et al. / Tetrahedron 63 (2007) 5006–5013
TLC analysis on silica gel, using a dichloromethane/ethanol
mixture as eluent, allowed us to resolve five of the six por-
phyrins in the mixture. Since the pyridyl groups have
a higher affinity for silica gel compared to methyl-ester
groups, we assumed that 40-TMeP was eluted first, followed
by the tris(40-carboxymethylphenyl)porphyrin, then by the
two bis-substituted geometrical isomers,y and finally by
the mono-(40-carboxymethylphenyl)porphyrin. In accor-
dance with this hypothesis, the spot with the highest Rf
was unambiguously assigned to 40-TMeP by comparison
with a sample of pure porphyrin obtained by condensation
of pyrrole with methyl 4-formyl benzoate. Under our condi-
tions, 40-TPyP was not eluted. Careful (and often repeated)
column chromatography, using different chloroform/ethanol
mixtures as eluents, eventually afforded three pyridyl/carb-
oxymethylphenyl porphyrins in pure form.z
different NMR patterns are indeed observed for meso-
(bis)-40-pyridyl/phenyl porphyrins and allow a clear differ-
entiation of the cis- and trans-isomers.7 However, in the
present case, the spin systems of the pyrrole protons are of
the AB, rather than AX type (in the magnetic field used),
and both geometrical isomers give almost identical
multiplets that do not allow to distinguish their geometry
(Fig. 2).
Other approaches that, in principle, might be used to distin-
guish between the two geometries, such as change of sol-
vent, addition of an acid or 13C NMR spectroscopy are
not useful in this case. In fact, the two isomers are soluble
in a narrow range of solvents and typically their spectra are
always very similar and do not allow resolution of the pyr-
role signals. The addition of an acid would lead to proton-
ation of the inner nitrogens, rather than of the pyridyl
nitrogens affording a mixture of products with different de-
grees of protonation and, in addition, the charge might lead
to aggregation and precipitation of porphyrins. A 13C NMR
experiment should be focused on the number of CH pyrrole
resonances: based on symmetry, a trans-isomer should have
two such resonances and a cis-isomer should have four.
However, pyrrole carbon resonances are even less sensitive
to the nature of the meso-six-membered rings than pyrrole
proton resonances. Thus, typically it is to be expected
that their signals are not sufficiently resolved to allow un-
The electronic absorption spectra of the products are not
diagnostic of the nature and relative geometry of the six-
membered rings at the meso-positions: they are all very sim-
ilar and characterized by a strong Soret band at about 418 nm
and four Q-bands of decreasing intensities between 512 and
645 nm. Similar considerations apply to the IR spectra. On
the contrary, the NMR spectra are diagnostic.
The 1H NMR spectrum of each porphyrin in CDCl3 is char-
acterized by typical resonances in the downfield region:
two doublets for the pyridyl protons (H20,60-py and H30,50-
py) and two doublets for the carboxymethylphenyl protons
(H20,60-Ph and H30,50-Ph), plus a multiplet for the pyrrole
b protons (see Scheme 1 for labelling scheme). The spectra
also include a singlet for the methyl group(s) at ca. d¼4.1
and one for the NH protons at ca. d¼ꢀ2.8. The most down-
field resonance was attributed to the pyridyl H20,60 protons,
closest to the nitrogen atom. The tris-substituted porphyrin
40-MPyTrMeP was easily identified by the relative intensities
of the pyridyl and carboxymethylphenyl proton resonances
(1:3).z However, the spectra of the two bis-substituted geo-
metrical isomers 40-cisDPyDMeP and 40-transDPyDMeP
are almost identical (Fig. 2).
ambiguous distinction of the two isomers. As anticipated,
13
the
C{1H} NMR spectra of both 40-cisDPyDMeP
and 40-transDPyDMeP showed the same number and
pattern of signals in the aromatic region. In addition, as
reported previously for similar systems, the pyrrole carbon
resonances are very broad in both isomers and hardly
detectable.8
Thus, we decided to exploit the reactivity of the two isomers
towards [Ru(TPP)(CO)(EtOH)] as a chemical shift reagent.
The axial ethanol molecule in [Ru(TPP)(CO)(EtOH)] is
weakly bound to ruthenium, and easily replaced by a stronger
d-donor ligand: for example, pyridine replaces ethanol
within minutes and makes a strong and inert axial bond
with ruthenium. Thus, both the 40-cis and 40-transDPyDMeP
isomers are expected to react selectively through their pyr-
idyl nitrogen atoms (the ester groups are unreactive towards
ruthenium) and to bind axially two ruthenium porphyrins,
generating the two isomeric side-to-face trimers [(40-cis-
DPyDMeP){Ru(TPP)(CO)}2] and [(40-transDPyDMeP)-
{Ru(TPP)(CO)}2], that maintain the same symmetry of the
parent porphyrin (Fig. 3).
In meso-substituted A2B2 porphyrins the NMR signals for
the pyrrole protons depend on the symmetry and, in
principle, might allow the distinction of the cis- and trans-
isomers (provided that the difference in chemical shift be-
tween a pyrrole proton adjacent to A and one adjacent to
B is such that to make an AX spin system). A trans-A2B2
porphyrin has two vertical planes of symmetry, while
a cis-A2B2 porphyrin has only one such plane: thus the eight
pyrrole protons are expected to give two equally intense dou-
blets (4H each) in the former case, and two doublets plus two
singlets (2H each) in the latter (Scheme 1). These two
In practice, a CDCl3 solution of each isomer was titrated
with incremental amounts of the commercially available
[Ru(TPP)(CO)(EtOH)] and the 1H NMR spectrum recorded
a few minutes after each addition to allow for complete coor-
dination ([Ru(TPP)(CO)(EtOH)] is actually not very soluble
in chloroform, but pyridyl coordination brings it in solution).
Each titration was stopped when the resonances of the parent
porphyrin and of the intermediate dinuclear species disap-
peared and were replaced by those of the final trinuclear
product. As previously observed in similar systems,9 the re-
actions were quantitative, NMR signals were always sharp
and no exchange between Ru-coordinated and free porphyrin
was observed at NMR concentrations. Signal integration
y
In principle, the chromatographic retention time might be diagnostic of
the geometry of the two bis-substituted geometrical isomers 40-cis and
40-transDPyDMeP. Since in the case of meso-(bis)-40-pyridyl/phenyl por-
phyrins the trans-isomer was eluted before the cis one, it might be argued
that also in this case, under very similar chromatographic conditions, the
40-transDPyDMeP isomer should be eluted first. However, even though
reasonable, this argument alone is insufficient for the unambiguous
assignment of the two isomers.
With the ratio between the two aldehydes used in this work, the amount of
40-TrPyMMeP was always very low and recovery from column chromato-
graphy was not pursued (see also Section 4).
z

T. Gianferrara et al. / Tetrahedron 63 (2007) 5006–5013
5009
H3',5'-Ph
H2',6'-Ph
trans
H
H3',5'-py
H2',6- py
cis
9.2
9.0
8.8
8.6
8.4
8.2
8.0
ppm
Figure 2. Downfield region of the 1H NMR spectra (CDCl3) of 40-cisDPyDMeP (bottom) and 40-transDPyDMeP (top). See Scheme 1 for labelling scheme.
O
C
O
C
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ru
N
Ru
N
2'
3'
6'
5'
6'
5'
2'
3'
Ha
Ha
Hb
Ha
Ph
Ph
Ha
Hb
Hc
5'
Hb
Hb
Hb
5'
6'
NH
N
N
NH
N
N
6'
2'
OC Ru
Ph
N
CO2Me MeO2C
CO2Me
3'
2'
HN
HN
3'
Hb
Hd
Ph
Hc
Hd
Ha
Ha
N
Ph
Ph
Ph
Ph
CO2Me
Ru
C
O
Figure 3. Schematic drawings (with labelling scheme) of the two isomeric side-to-face trimers [(40-cisDPyDMeP){Ru(TPP)(CO)}2] (left) and [(40-transDPyD-
MeP){Ru(TPP)(CO)}2] (right).

5010
T. Gianferrara et al. / Tetrahedron 63 (2007) 5006–5013
CHCl3
ßH-TPP
$ oH-TPP+
H2',6'-Ph
ßHb+ $
oH-TPP
H3',5'-Ph
°
£
#
§
m+pH -TPP
#
mH-TPP
°
§
£
ßHa
trans
ßHc+ $
#
ßH-TPP
°
§
£
ßHd
ßHa
ßHb
cis
8.8
8.6
8.4
8.2
8.0
7.8
ppm
7.6
7.4
7.2
7.0
6.8
1
Figure 4. Downfield region of the H NMR spectra (CDCl3) of [(40-cisDPyDMeP){Ru(TPP)(CO)}2] (bottom) and [(40-transDPyDMeP){Ru(TPP)(CO)}2]
(top). See Figure 3 for proton labelling scheme.
confirmed the stoichiometry of the trimeric adducts and
signal assignment was supported by 2D H–H COSY
experiments.
well resolved doublets (the most upfield at d¼7.20),x thus
unambiguously identifying that porphyrin as the trans-iso-
mer. Conversely, the pyrrole protons in the trimer containing
the isomer with the higher retention time give four equally
intense well resolved resonances, two singlets (the most up-
field, originated by protons adjacent to the shielding cones of
both Ru-porphyrins, at d¼6.99) and two doublets,x thus un-
ambiguously qualifying that porphyrin as the cis-isomer.
A common feature in the NMR spectra of axially ligated
porphyrin aggregates is the dramatic upfield shift of the
resonances of the central porphyrin induced by the
(cumulative) anisotropic shielding effect of the peripheral
porphyrin(s). The upfield shifts of the NMR resonances of
all protons of the central porphyrin are inversely propor-
tional to their distance from the anisotropic shielding of
the ruthenium macrocycle (the largest upfield shift was
that of the H20,60-py protons, from d¼9.06 to d¼1.88 for
both adducts). Thus the resonances of the pyrrole protons
adjacent to the 40-pyridyl rings, i.e. to the shielding cone
of Ru(TPP)(CO), are expected to be shifted upfield more
than those adjacent to the 40-carboxymethylphenyl substitu-
ents. The spread of chemical shifts induced by the axial Ru-
porphyrins is expected to transform the AB spin systems of
the pyrrole protons into an AX system. Indeed, as shown in
Figure 4, the pyrrole proton resonances in the NMR spec-
trum of the trimer containing the bis(40-pyridyl)-bis(40-car-
boxymethylphenyl)porphyrin eluted first consist of two
The NMR data, through chemical shift and symmetry argu-
ments, also indicated that at room temperature all the meso-
six-membered rings experience hindered rotation about the
C(meso)–C(ring) bond and lie essentially perpendicular to
the mean plane of the corresponding porphyrin. Since for the
coordinated Ru(TPP)(CO) chromophores the plane of the
porphyrin is not a symmetry plane, the ortho and meta
protons on opposite sites of the phenyl rings experience dif-
ferent magnetic environments and have resolved multiplets.
x
One doublet overlaps with the H20,60-Ph resonances of the 40-carboxy-
methylphenyl rings and with one set of the phenyl rings of TPP, but was
unambiguously identified in the H–H COSY spectrum.

T. Gianferrara et al. / Tetrahedron 63 (2007) 5006–5013
5011
Finally, ester hydrolysis under basic conditions in THF/
methanol mixtures10 afforded 5-(40-pyridyl)-10,15,20-
tris(40-carboxymethylphenyl)porphyrin in pure form.
in literature (see references below). Compounds [(40-cis-
DPyDMeP){Ru(TPP)(CO)}2] and [(40-transDPyDMeP)-
{Ru(TPP)(CO)}2] have not been isolated from H NMR
1
titration experiments and no further characterization is
given.
3. Conclusions
4.2. Synthesis and characterization
We demonstrated that each porphyrin in the mixture of
meso-(40-pyridyl)/(40-carboxymethylphenyl)porphyrins,
prepared by mixed-aldehyde condensation of pyrrole with 4-
pyridylcarboxyaldehyde and methyl 4-formyl benzoate, can
be resolved by TLC and most of them can be obtained in
pure form by careful column chromatography, including
the two bis-substituted cis and trans geometrical isomers
40-cisDPyDMeP and 40-transDPyDMeP.
Pyrrole and 4-pyridylcarboxyaldehyde (Aldrich) were dis-
tilled prior to use. The other reactants and solvents were
used as received, with the exception of THF that was dis-
tilled over LiAlH4.
4.2.1. meso-(40-Pyridyl)/(40-carboxymethylphenyl)por-
phyrins. A mixture of methyl 4-formyl benzoate (3.5 g,
21 mmol) and 4-pyridylcarboxyaldehyde (0.7 mL, 7 mmol)
in propionic acid (120 mL) was warmed to 120 ꢁC. Pyrrole
(2.0 mL, 28 mmol) was added and the mixture was refluxed
for 1.5 h, then stored at ꢀ10 ꢁC for 12 h after the addition of
ethylene glycol (60 mL). The purple precipitate was re-
moved by filtration, thoroughly washed with cold methanol
and dried in vacuo at room temperature. Yield 1.21 g (25%).
Even though the two isomers could not be distinguished by
conventional spectroscopic techniques, their characteriza-
1
tion was performed by H NMR spectroscopy on the tri-
nuclear adducts [(40-cisDPyDMeP){Ru(TPP)(CO)}2] and
[(40-transDPyDMeP){Ru(TPP)(CO)}2]. In each trimer, the
ruthenium chromophores axially bound to the nitrogen-pyr-
idyl moieties acted as chemical shift reagents on the central
porphyrin and afforded markedly different patterns for the
resonances of its pyrrole protons. Symmetry considerations
afforded the final unambiguous correlation of the NMR pat-
terns to the geometry of each isomer. Our method, a simple
proton NMR titration that required a few milligrams of each
isomeric porphyrin and of the commercially available
[Ru(TPP)(CO)(EtOH)], proved to be very helpful and
straightforward when more conventional approaches to the
resolution of this problem failed.
Thin-layer chromatography of the crude product (dichloro-
methane/ethanol 95:5) showed it to be a mixture of the six
possible porphyrin isomers: 40-TPyP, 40-TrPyMMeP, 40-
cisDPyDMeP, 40-transDPyDMeP, 40-MPyTrMeP and 40-
TMeP. The Rf values of the isomers were
40-TMeP 0.91,
40-MPyTrMeP 0.60,
40-transDPyDMeP 0.55,
40-cisDPyDMeP 0.50,
40-TrPyMMeP 0.44.
Finally, we want to stress that this new method is of general
applicability for the NMR assignment of the geometry of
isomeric porphyrins bearing different peripheral metal-bind-
ing functions, provided that the titration is performed with
a metalloporphyrin that has high affinity for one of the func-
tions and very little (or no) affinity for the other(s), so that
a single multi-porphyrin side-to-face adduct is selectively
obtained in each case.
The Rf of 40-TPyP was too small to be measured.
The isomers were separated using column chromatography.
To purify large amounts of mixture it was easier to use sev-
eral columns in series: one large column to remove 40-TMeP,
which constituted approximately 50% of the initial porphy-
rin mixture, and then smaller columns to separate the other
isomers. This mixture of aldehydes (3:1 excess of methyl
4-formyl benzoate) was chosen to obtain the maximum yield
of 40-MPyTrMeP.11 Consequently, 40-cisDPyDMeP, 40-
transDPyDMeP and 40-TrPyMMeP were obtained in small
amounts, so that the isolation of the latter was not pursued;
a larger amount of this isomer can be obtained by inverting
the relative amounts of the two aldehydes.
4. Experimental
4.1. General
UV–vis spectra were obtained on a Jasco V-550 spectropho-
tometer. 1H and 13C NMR spectra were recorded at 400 and
100.5 MHz, respectively, on a JEOL Eclipse 400 FT instru-
ment. All spectra were run at room temperature in CDCl3 or
DMSO-d6 (Aldrich). Proton peak positions were referenced
to the peak of residual non-deuterated solvent set at d¼7.26
(chloroform) or 2.50 (DMSO). Assignments were made with
the aid of 2D H–H COSY experiments. Carbon signal attri-
butions were based on literature data8 and on H–C correla-
tion spectra. Mass spectra (ESI-MS) were recorded on
a Bruker ESQUIRE 4000 instrument. Analytical thin-layer
chromatography (TLC) was performed on Mackerey-Nagel
ADAMANT UV254 silica gel pre-coated plates (0.25 mm
thick). Column chromatography was performed on silica
˚
Column 1. The column (6ꢂ35 cm) was packed with 60 A sil-
ica gel, loaded with 0.63 g of crude porphyrin mixture and
eluted with a chloroform/ethanol 98:2 mixture (2 L total).
In a typical run, 0.33 g of 40-TMeP (first band) and 0.29 g
of a mixture of 40-MPyTrMeP, 40-cisDPyDMeP and 40-trans-
DPyDMeP (second band) were recovered. As noted above,
40-TrPyMMeP was usually not recovered.
Column 2. Once 40-TMeP had been removed, it was possible
to separate two of the remaining isomers using a smaller col-
umn (5ꢂ35 cm), packed and eluted as above. A typical sep-
aration, starting from 290 mg of crude mixture from column
1, afforded 150 mg of 40-MPyTrMeP (first band), 110 mg of
˚
gel 60 A (Merck, 230–400 mesh ASTM), eluting with chlo-
roform/ethanol mixtures as specified below. Compounds 40-
TMeP, 40-MPyTrMeP, 40-TOHP have been already reported

5012
T. Gianferrara et al. / Tetrahedron 63 (2007) 5006–5013
a mixture of the three isomers (enriched in 40-transDPyD-
MeP) and 25 mg of 40-cisDPyDMeP (third band).
(br, Cb-pyrrole), 130.0 (C10-Ph), 129.5 (C30,50-py), 128.1
(C20,60-Ph), 120.0 and 117.4 (Cmeso), 56.6 (O–CH3). UV–
vis spectrum (lmax (nm), relative intensity (%)) in CH2Cl2:
418 (100), 514 (4.9), 548 (1.9), 588 (1.7), 644 (0.9). MS:
(ESI) m/z 733.3 (M++1).
Column 3. The 110 mg of mixture from column 2 was loaded
on a 4ꢂ32 cm column packed and eluted as above. Three
fractions were obtained: 40-MPyTrMeP (50 mg), 40-MPyTr-
MeP and 40-transDPyDMeP (45 mg) and 40-cisDPyDMeP
(12 mg).
4.2.1.5. [(40-cisDPyDMeP){Ru(TPP)(CO)}2]. 1H NMR
spectrum (d, CDCl3, see Figs. 3 and 4 for labelling scheme):
8.73 (s, 16H, bH-TPP), 8.56 (s, 2H, bHd), 8.31 (m, 12H, oH-
TPP+H20,60-Ph and d, 2H, bHc partially overlapped), 8.12
(d, J¼7.6 Hz, 8H, oH-TPP), 7.96 (d, J¼8.3 Hz, 4H,
H30,50-Ph), 7.76 (m, 16H, mH+pH-TPP), 7.65 (t, J¼
7.2 Hz, 8H, mH-TPP), 7.14 (d, J¼4.9 Hz, 2H, bHb), 6.99
(s, 2H, bHa), 5.85 (d, J¼6.7 Hz, 4H, H30,50-py), 4.07 (s, 6H,
CH3), 1.88 (d, J¼6.6 Hz, 4H, H20,60-py), ꢀ3.78 (s, 2H, NH).
4.2.1.6. [(40-transDPyDMeP){Ru(TPP)(CO)}2]. 1H
NMR spectrum (d, CDCl3, see Figs. 3 and 4 for
labelling scheme): 8.69 (s, 16H, bH-TPP), 8.28 (m,
12H, oH-TPP+H20,60-Ph and d, 2H, bHb partially
overlapped), 8.10 (d, J¼7.8 Hz, 8H, oH-TPP), 7.87 (d, J¼
8.0 Hz, 4H, H30,50-Ph), 7.73 (m, 16H, m+pH-TPP), 7.62 (t,
J¼7.1 Hz, 8H, mH-TPP), 7.20 (d, J¼4.9 Hz, 4H, bHa),
5.92 (d, J¼6.8 Hz, 4H, H30,50-py), 4.10 (s, 6H, CH3), 1.88
(d, J¼6.8 Hz, 4H, H20,60-py), ꢀ3.80 (s, 2H, NH).
4.2.2. meso-(40-Pyridyl)/(40-carboxyphenyl)porphyrins.
Hydrolysis of the ester groups of meso-(40-pyridyl)/(40-carb-
oxymethylphenyl)porphyrins was performed (under basic
conditions in THF/methanol mixtures)10 on the most abun-
dant isomers exclusively, i.e. 40-TMeP and 40-MPyTrMeP,
and yielded the corresponding meso-(40-pyridyl)/(40-carb-
oxyphenyl)porphyrins 40-TOHP and 40-MPyTrOHP, respec-
tively. The reactions were monitored by TLC (silica gel,
chloroform/ethanol 98:2) until disappearance of the original
ester.
Column 4. The 50 mg mixture from column 3 was loaded on
a 4ꢂ27 cm column, packed as above and eluted with a chlo-
roform/ethanol 99:1 mixture (1 L total), affording 17 mg of
40-MPyTrMeP (first band) and 14 mg of 40-transDPyDMeP
(second band).
The identifications of the porphyrins were confirmed by
comparing their Rf values with those of the crude mixture,
and by 1H NMR spectroscopy.
4.2.1.1. 40-TMeP.8 Mp >300 ꢁC. 1H NMR spectrum (d,
CDCl3, see Scheme 1 for labelling scheme): 8.85 (s, 8H,
bH), 8.48 (d, J¼8.3 Hz, 8H, H20,60), 8.32 (d, J¼8.0 Hz,
8H, H30,50), 4.14 (s, 12H, CH3), ꢀ2.80 (s, 2H, NH). UV–
vis spectrum (lmax (nm), relative intensity (%)) in CH2Cl2:
420 (100), 515 (4.0), 550 (2.0), 590 (1.4), 646 (1.0). Selected
IR spectrum (KBr, cmꢀ1): 3313 (m, nNH), 1723 (s, nC]O),
1276 and 1020 (s, nC–O).
4.2.1.2. 40-MPyTrMeP.6 Mp >300 ꢁC. 1H NMR
spectrum (d, CDCl3, see Scheme 1 for labelling scheme):
9.07 (d, J¼5.4 Hz, 2H, H20,60-py), 8.85 (m, 8H, bH), 8.48
(d, J¼8.3 Hz, 6H, H20,60-Ph), 8.32 (d, J¼8.0 Hz, 6H,
H30,50-Ph), 8.18 (d, J¼5.9 Hz, 2H, H30,50-py), 4.14 (s, 9H,
CH3), ꢀ2.83 (s, 2H, NH). UV–vis spectrum (lmax (nm),
relative intensity (%)) in CH2Cl2: 418 (100), 514 (4.5),
549 (1.9), 589 (1.5), 644 (0.8). Selected IR spectrum (KBr,
cmꢀ1): 3318 (m, nNH), 1722 (s, nC]O), 1275 and 1020 (s,
nC–O).
4.2.2.1. 40-TOHP.12
A
100 mg amount of 40-
TMeP (0.12 mmol) was dissolved in a 2:1 THF/methanol
mixture (50 mL). A 40% KOH solution (w/v) (6 mL) was
added and the mixture warmed at 40 ꢁC for 30 min
under magnetic stirring. At reaction completion, the mixture
was acidified to pH 3 with concd HCl and extracted with
chloroform (25 mLꢂ3) after addition of water (40 mL). The
joined organic fractions were washed with water (20 mLꢂ3)
and dried over anhydrous Na2SO4. Solvent removal in vacuo
yielded the product as a purple solid (47 mg, 49%). Mp
4.2.1.3. 40-transDPyDMeP. Mp >300 ꢁC. 1H NMR spec-
trum (d, CDCl3, see Scheme 1 and Fig. 2 for labelling
scheme): 9.06 (d, J¼5.9 Hz, 4H, H20,60-py), 8.85 (m, 8H,
bH), 8.46 (d, J¼8.5 Hz, 4H, H20,60-Ph), 8.30 (d, J¼8.3 Hz,
4H, H30,50-Ph), 8.17 (d, J¼5.9 Hz, 2H, H30,50-py), 4.12 (s,
6H, CH3), ꢀ2.87 (s, 2H, NH). 13C NMR spectrum (d,
CDCl3, see Scheme 1 and Fig. 2 for labelling scheme):
167.3 (COO), 150.2 (C40-py), 148.4 (C20,60-py), ca. 147 (v
br, Ca-pyrrole), 146.4 (C40-Ph), 134.6 (C30,50-Ph), ca. 132
(br, Cb-pyrrole), 130.0 (C10-Ph), 129.5 (C30,50-py), 128.1
(C20,60-Ph), 119.8 and 117.5 (Cmeso), 56.6 (O–CH3). UV–
vis spectrum (lmax (nm), relative intensity (%)) in CH2Cl2:
418 (100), 514 (5.1), 548 (2.1), 589 (1.8), 643 (1.1). MS:
(ESI) m/z 733.3 (M++1).
1
>300 ꢁC. H NMR spectrum (d, DMSO-d6, see Scheme 1
for labelling scheme): 13.30 (v br s, 4H, COOH), 8.87 (s,
8H, bH), 8.38 and 8.37 (two partially overlapping doublets,
16H, H20,60 and H30,50), ꢀ2.94 (s, 2H, NH). UV–vis spec-
trum (lmax (nm), relative intensity (%)) in ethanol: 416
(100), 513 (4.2), 548 (2.1), 590 (1.3), 646 (0.9).
1
4.2.1.4. 40-cisDPyDMeP. Mp >300 ꢁC. H NMR spec-
4.2.2.2. 40-MPyTrOHP. The same procedure as above
was used. A solution of 50 mg amount of 40-MPyTrMeP
(0.063 mmol) in 24 mL of the 2:1 THF/methanol mixture
was warmed at 40 ꢁC for 40 h under magnetic stirring after
addition of 3 mL of the 40% KOH solution. The work-up
afforded the product as a purple solid (24 mg, 51%). Mp
trum (d, CDCl3, see Scheme 1 and Fig. 2 for labelling
scheme): 9.06 (d, J¼5.9 Hz, 4H, H20,60-py), 8.85 (m, 8H,
bH), 8.46 (d, J¼8.3 Hz, 4H, H20,60-Ph), 8.30 (d, J¼8.0 Hz,
4H, H30,50-Ph), 8.17 (d, J¼5.9 Hz, 4H, H30,50-py), 4.12 (s,
6H, CH3), ꢀ2.86 (s, 2H, NH). 13C NMR spectrum (d,
CDCl3, see Scheme 1 and Fig. 2 for labelling scheme):
167.3 (COO), 150.1 (C40-py), 148.4 (C20,60-py), ca. 147 (v
br, Ca-pyrrole), 146.4 (C40-Ph), 134.6 (C30,50-Ph), ca. 132
1
>300 ꢁC. H NMR spectrum (d, DMSO-d6, see Scheme 1
for labelling scheme): 13.31 (v br s, 3H, COOH), 9.05 (d,
J¼5.4 Hz, 2H, H20,60-py), 8.89 (m, 8H, bH), 8.39 (m,

T. Gianferrara et al. / Tetrahedron 63 (2007) 5006–5013
5013
12H, H20,60-Ph and H30,50-Ph), 8.29 (d, J¼5.9 Hz, 2H,
H30,50-py), ꢀ2.97 (s, 2H, NH). 13C NMR spectrum (d,
DMSO-d6): 167.5, 148.3, 145.4, 134.5, 130.5, 129.2,
127.9, 119.4, 117.3. UV–vis spectrum (lmax (nm), 3ꢂ10ꢀ3
(cmꢀ1 Mꢀ1)) in acetone: 415 (442), 512 (21), 545 (8.4),
589 (6.2), 644 (4.1). MS: (ESI) m/z 748.3 (M++1).
(b) Bouamaied, I.; Coskun, T.; Stulz, E. Struct. Bonding
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