Bromine-lithium exchange as a straightforward method to obtain meso-tetrakis(4-formylphenyl)porphyrin: A versatile intermediate

Article abstract of DOI:10.1016/j.tetlet.2015.07.021

A three step, one-pot reaction has been developed for the introduction of the formyl functional group to the meso position of porphyrins. Symmetric meso-tetrakis(4-formylphenyl)porphyrin ((CHO)₄TPPH2), an important cornerstone in porphyrin chemistry, was obtained selectively in good yields via bromine-lithium exchange and subsequent Bouveault reaction. The meso-tetrakis(4-formylphenyl)porphyrin was fully characterized by HR-ESI, UV-vis, NMR, and single crystal X-ray diffraction.

Full text of DOI:10.1016/j.tetlet.2015.07.021

Tetrahedron Letters 56 (2015) 5157–5160
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bromine–lithium exchange as a straightforward method to obtain
meso-tetrakis(4-formylphenyl)porphyrin: a versatile intermediate
b,
Emel Önal a,b, Vefa Ahsen b, Jacques Pécaut c, Dominique Luneau a, , Catherine Hirel
⇑
⇑
a Université Claude Bernard Lyon 1, Laboratoire des Multimatériaux et Interfaces (UMR 5615), Campus de La Doua, 69622 Villeurbanne Cedex, France
b Gebze Technical University, Department of Chemistry, PO Box 141, 41400 Kocaeli, Turkey
c Service de Chimie Inorganique et Biologique (SCIB), Institut Nanosciences et Cryogénie (INAC), CEA, F-38054 Grenoble, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A three step, one-pot reaction has been developed for the introduction of the formyl functional group to
the meso position of porphyrins. Symmetric meso-tetrakis(4-formylphenyl)porphyrin ((CHO)4TPPH2), an
important cornerstone in porphyrin chemistry, was obtained selectively in good yields via bromine–
lithium exchange and subsequent Bouveault reaction. The meso-tetrakis(4-formylphenyl)porphyrin
was fully characterized by HR-ESI, UV–vis, NMR, and single crystal X-ray diffraction.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 13 February 2015
Revised 17 June 2015
Accepted 6 July 2015
Available online 10 July 2015
Keywords:
Porphyrin
Bromine–lithium exchange
Bouveault reaction
Formyl group
Porphyrins are the object of a broad spectrum of research in
diverse areas including dyes,1 solar cells,2 sensors,3 photodynamic
therapy,4 or the recently emerging field of Metal Organic
Framework (MOF).5 This is due to their relatively easy synthesis,
robustness, high chemical versatility, relation to natural sub-
stances, and optical and electrochemical properties. Among these,
the meso-tetraphenylporphyrins’ subfamily are easy to prepare
and are readily soluble in organic solvents. In addition, their struc-
ture can be efficiently tuned in simple ways by modifying the num-
ber, position, and nature of the functional groups introduced onto
the (meso-)phenyl substituents.6 In this regard, the formylation of
meso-tetraphenylporphyrin is an important reaction as it opens the
way for a plethora of further functionalization such as, condensa-
tion with primary amines to obtain Schiff base type molecules;
Canizzaro disproportionation into the corresponding acid and alco-
hol; Wittig olefination, and nucleophilic addition by Grignard or
organolithium reagents to give substituted alcohols. Moreover,
aromatic aldehydes are precursors for the porphyrins themselves,
as well as for the well-known fluorescent dye boron-dipyrro-
methene (Bodipy).7 However, to date, there are few reported meth-
ods for the functionalization of porphyrins by formyl groups and in
many cases they are not well described.
Direct formylation of the meso-tetraphenylporphyrin is com-
monly achieved by the Vilsmeier reaction (DMF/POCl3 at 0 °C)
which has an excellent yield but only allows mono-formylation
at the b-pyrrolic positions to give 2-formyl-5,10,15,20-te-
traphenylporphyrin.8,9 Regioselective formylation of the meso-phe-
nyl substituents cannot be directly achieved and requires multiple
steps which lowers the total yield of the synthesis. Considering
porphyrin synthetic methods based on the condensation of pyrrole
and benzaldehyde, the incorporation of formyl groups may be
achieved by introduction of a suitable group on benzaldehyde
which can be removed afterward. One representative method for
formylation at the para-position of the meso-phenyl substituent
proceeding through an acetal-protected precursor utilizes 4-(4,4-
dimethyl-2,6-dioxan-1-yl)benzaldehyde. Starting from 4-bro-
mobenzaldehyde, the formyl group is protected as an acetal group
which after treatment with n-BuLi followed by quenching with
DMF10 gives the condensation precursor. Following this so-called
‘acetal group protecting route’ the corresponding porphyrin is
obtained in 21% yield using the Lindsey method (DDQ, CH2Cl2,
TFA, RT)11 to give an overall yield of 17%.
When the acetal protecting group is on the meta-position of the
meso-phenyl substituent, the yield of the acetal protected route is
even less (15%). Deprotection of the acetal group is completed in
CHCl3–H2SO4 with a 95% yield.12 Therefore, the acetal group pro-
tecting route needs four time consuming steps, that require work-
ing at low-temperature (À78 °C), as well as usage of a Dean-Stark
apparatus. Moreover, the synthesis of the acetal protected
⇑
Corresponding authors. Tel.: +33 47 243 1418; fax: +33 47 244 0618 (D.L.); tel.:
+90 262 605 3021; fax: +90 262 605 3105 (C.H.).
E-mail addresses: dominique.luneau@univ-lyon1.fr (D. Luneau), chirel@gtu.edu.
tr (C. Hirel).
http://dx.doi.org/10.1016/j.tetlet.2015.07.021
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

5158
E. Önal et al. / Tetrahedron Letters 56 (2015) 5157–5160
First, meso-tetrakis(4-bromophenyl)porphyrin (Br4TPPH2) was
prepared by a slightly modified Adler procedure20 from pyrrole
and 4-bromobenzaldehyde in refluxing propionic acid in 25% yield.
The formyl group was then introduced by the bromine–lithium
exchange reaction. As the reactivity and selectivity of the bro-
mine–lithium exchange is dependent on the chemical environ-
ment, the conditions and parameters of the reaction needed to
be carefully chosen and controlled.21,22 During the reaction, the
temperature was kept low to prevent decomposition. As
organometallic compounds are highly reactive, contaminants such
as water, alcohols, and oxygen were carefully excluded and all sol-
vents were carefully dried.
Figure 1. The color of the different reaction steps.
porphyrin is achieved in the presence of TFA as catalyst, a strong
acid which may induce deprotection of acetal.12 Consequently,
the usage of this reaction process is tedious and requires great
expertise.
Tetrahydrofuran (THF) and diethylether (Et2O) are the preferred
solvents for organometallic reactions. The first attempts were
performed in THF, due to the greater solubility of the starting com-
pound (Br4TPPH2) in this solvent, however this gave only an
unidentified, green product. Fortunately, in Et2O, porphyrins con-
taining formyl groups were obtained as the only products.
However, the solubility of Br4TPPH2 in Et2O was low and
decreased dramatically at the low temperature required to carry
out the bromine–lithium exchange reaction. Therefore, this reac-
tion was conducted under very dilute conditions. Variation of the
equivalents of n-BuLi (from 6.25 equiv to 32 equiv) demonstrated
that an excess of n-BuLi did not influence the reaction yield. The
A second method proceeding through the reduction of a cyano
group by sodium triethyoxyaluminohydride in THF, has been
reported to give 5-(4-formylphenyl)-10,15,20-triphenylporphyrin,
but without any synthetic description or yield mentioned.13 In a
third method, formylation on the meso-phenyl substituents is
achieved by a regioselective bromine–lithium exchange mecha-
nism known as the Bouveault aldehyde synthesis. However this
has been reported only for mono- or di- formylation and with
moderate yields.14–16 Concerning the synthesis of meso-
tetrakis(4-formylphenyl)porphyrin, it has been reported but
without synthetic description.17–19
These examples show that there is still a need for straightfor-
ward formylation methods on the meso-phenyl substituents of
meso-tetraphenylporphyrin. Herein, we report the controlled
synthesis of meso-tetrakis(4-formylphenyl)porphyrin ((CHO)4
TPPH2). This was obtained in only two-steps using a regioselective
and stoichiometric bromine–lithium exchange mechanism that
avoids the formation of by products. The conditions have been
optimized, and on the basis of reaction conditions and color
changes involved, a reaction mechanism has been proposed involv-
ing the replacement of the bromines by the formyl groups proceed-
ing through the formation of an O–Li complex. This compound has
been characterized by UV–vis, NMR, HR-ESI-MS, and single-crystal
X-ray diffraction methods.
optimal conditions found were
a
solution of Br4TPPH2
(8 Á 10À3 M) and 6.25 equiv. of n-BuLi in Et2O at À50 °C. The
meso-tetrakis(4-formylphenyl)porphyrin ((CHO)4TPPH2) was
obtained in 80% yield as a purple material after addition of 100
equiv. of DMF followed by treatment with acid (5% HCl) and purifi-
cation by silica gel column chromatography. A small amount of the
triformylated
derivative
meso-5,10,15-(4-formylphenyl)-20-
phenylporphyrin (5%) was also observed.
To avoid the possible interaction of n-BuLi with the NH groups
of the central core, the reaction was initially carried out using the
zinc
metallated
meso-tetrakis(4-bromophenyl)porphyrin
(Br4TPPZn). However, this route was abandoned because treat-
ment with acid led to partial demetallation of the formylated por-
phyrin as evidenced from the crystal structure. This increased the
number of products obtained resulting in complicated purification
by column chromatography as well as lowering the yield of the
Br
OHC
80%
N
N
NH
NH
CHO
Br
OHC
Br
HN
HN
N
N
CHO
Br
(CHO)4TPPH2
Br4TPPH2
n-BuLi
Et2O, -50 oC
HCl, rt.
DMF
LiO
DMF
Li
Li
O
H
H
(H3C)2N
N(CH3)2
OLi
H
N
N
NLi
N
Li
n-BuLi
+
N
Et2O, -50 o
C
Li
LiN
N
N
N
LiO
H
N(CH3)2
H
Li
(H3C)2N
LiO
Li
DMF
DMF
Li2TPPLi2
(DMFLi)4TPP(DMF)4Li2
Scheme 1. Putative bromine–lithium exchange reaction mechanism for meso-tetrakis(4-bromophenyl)porphyrin (Br4TPPH2).

E. Önal et al. / Tetrahedron Letters 56 (2015) 5157–5160
5159
Table 1
reaction. Performing, the synthetic route with the free porphyrin
proved to be the best for the formylation reaction and made the
route more versatile for further functionalization and metallation.
We became interested in the mechanism of the reaction as the
different steps were accompanied by significant color changes
(Fig. 1).
UV–vis data of the porphyrins involved in the reaction
Compounds
k (nm)
Solvent
Br4TPPH2
Li4TPPLi2
(DMFLi)4TPP(DMF)4Li2
(CHO)4TPPH2
418, 512, 547, 588, 644
437, 459, 502, 577, 629
439, 579, 625
DCM
DMF
DMF
CHCl3
419, 523, 559, 600, 653
At
each
step
an
aliquot
of
Li4TPPLi2
and
(DMFLi)4TPP(DMF)4Li2 was taken by syringe and diluted with
DMF in a closed quartz UV cuvette. The UV spectra were recorded
at this unknown concentration. Upon addition of n-BuLi, the deep
red solution of the free porphyrin Br4TPPH2 immediately turned
green. This was ascribed to the binding of two lithium ions to
the nitrogens of the porphyrin core which is characteristic for dian-
ionic porphyrins23 in non-polar solvents such as Et2O. The color
slowly changed to dark blue-green after the addition of DMF and
after hydrolysis with HCl returned to a red-brown solution reveal-
ing the presence of a free porphyrin which became red-purple after
neutralization by NH4OH and extraction with chloroform.
On the basis of UV–vis absorption spectrophotometry, presump-
tive structures for the intermediates were deduced (Scheme 1). The
green intermediate, showed four bands in the visible spectrum con-
sistent with the retention of the D2h symmetry attributed to
Li4TPPLi2. In contrast, the well-defined spectrum of the dark
blue-green intermediate reflected the higher D4h symmetry of the
molecule upon metallation, attributed to the symmetrically bound-
ing of the lithium ion with the four porphyrin nitrogen atoms sur-
rounded by symmetrical solvent molecules23,24 corresponding to
(DMFLi)4TPP(DMF)4Li2. The absorption spectra of the porphyrins
are summarized in Table 1 and represented in Figure 2.
Figure 2. UV–vis absorption spectra.
CHO
Hc
Hc
Hb
Hb
Ha
CHO
NH
N
N
OHC
HN
Ha
CHO
11.0
9.5
8.5
7.5
6.5
5.5
4.5
3.5
f1 (ppm)
2.5
1.5
0.5
-0.5
-2.0
Figure 3. 1H NMR spectrum of (CHO)4TPPH2 in CDCl3.

5160
E. Önal et al. / Tetrahedron Letters 56 (2015) 5157–5160
tetra-formylation had occurred on the meso-phenyl which was in
agreement with other characterization methods.
In summary, we have demonstrated that the formyl functional
group could be introduced in
a straightforward manner by
bromine–lithium exchange on the para position of the phenyl sub-
stituent present on the meso position of a porphyrin. This two-step,
one-pot reaction regioselective proceeds through two successive
lithium
intermediates
that
give
the
meso-tetrakis
(4-formylphenyl)porphyrin ((CHO)4TPPH2) in an excellent yield
of 80%. The overall yield of the (CHO)4TPPH2 synthetic pathway
is higher than previous attempts and is a promising synthon for
a vast variety of reactions which are currently being examined in
our group.
Acknowledgments
_
This work was supported by the TÜBITAK-CNRS project
113Z005 and the French Embassy in Turkey for the Co-tutelle
PhD of Emel Önal.
Supplementary data
Figure 4. View of the molecular structure of the zinc(II) complex fraction (0.17) as
Supplementary data (experimental section comprising informa-
tion on materials, synthetic procedures, HR-ESI Mass, NMR and
FT-IR spectroscopies and X-ray crystal structure determination of
determined X-ray diffraction of
a
single crystal of {[(CHO)4TPPZn]0.17
[(CHO)4TPPH2]0.83 (C5H12 The hydrogen atoms and the disordered atoms
}
)
0.5
.
found for one of the phenyl-CHO groups (O1) have been removed for clarity.
{[(CHO)4TPPZn]0.17[(CHO)4TPPH2]0.83} (C5H12 0.5. CIF files for the
)
crystal structure) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.021.
The structure of (CHO)4TPPH2 was unambiguously confirmed
by HR-ESI Mass Spectroscopy, UV–vis, FT-IR, and single crystal
X-ray diffraction. HR-ESI Mass spectroscopy displayed a parent
molecular peak at m/z = 727.2348 (calculated for C48H30N4O4
m/z = 726.230) which corresponded to [M+H] (ESI Fig. S7). In the
IR spectra, a sharp and intense peak at 1694 cmÀ1 which is charac-
teristic of formyl vibration was observed (ESI Fig. S8).
The UV–vis spectrum of meso-tetrakis(4-formylphenyl)por-
phyrin ((CHO)4TPPH2) measured in chloroform gave clear insights
into the corresponding porphyrin (Fig. 2) exhibiting a strong and
broad ill-defined Soret band around 420 nm and four weak
Q-bands in the visible region between 500 and 650 nm due to a
S0 ? S1 transition.
References and notes
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The 1H NMR spectrum of (CHO)4TPPH2 (Fig. 3) in CDCl3 exhib-
ited two doublets in the aromatic region at 8.32 and 8.40 ppm cor-
responding to the 8 protons of the ortho-CHAr (Hb) and the 8
protons of the meta-CHAr (Ha) on the meso-phenyl group. The b
hydrogen atom of the pyrrole fragment was found as a singlet peak
at 8.83 ppm and a characteristic singlet peak at 10.40 ppm corre-
sponding to the proton of the formyl groups was observed. The
shielded protons of the inner NH groups were observed at high
field, À2.79 ppm in agreement with the literature.
The molecular structure (Fig. 4) was further proved using X-ray
crystal structure determination from single crystals obtained dur-
ing the formylation reaction on the zinc metallated porphyrin (vide
infra).25 Refinement of the structure showed an occupancy rate of
0.17 for the central zinc(II) ions. This indicated that the crystals
were comprised of a mixture of free CHO)4TPPH2 (83%) and zinc
metallated CHO)4TPPZn (17%) which was in agreement with the
previously discussed partial demetallation. This may also be
viewed as a doping of the free porphyrin by zinc(II). As it can be
expected, this was accompanied by disorder of one of the phe-
nyl-CHO atoms, however the bond lengths and angle were normal.
Tiny and twinned single crystals of the pure form of the free
porphyrin (CHO)4TPPH2 were also obtained and were found to
be isomorphs, however all attempts to refine the structure were
unsuccessful. Irregardless, this un-ambiguously established that
19. Genady, A. R. Org. Biomol. Chem. 2005, 3, 2102.
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25. CDCC 1402793. Copies of the data can be obtained free of charge on application
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