Modular Synthetic Route to Monofunctionalized Porphyrin Architectures

Article abstract of DOI:10.1021/acs.orglett.6b02507

The synthesis of a borylated Ni²⁺ porphyrin and its application as a versatile precursor for building up functional ortho-substituted tetraaryl porphyrin architectures is reported. This precursor porphyrin provides the basis for efficient modul

Full text of DOI:10.1021/acs.orglett.6b02507

Letter
pubs.acs.org/OrgLett
Modular Synthetic Route to Monofunctionalized Porphyrin
Architectures
Gernot Heitmann, Marcel Dommaschk, Roland Low, and Rainer Herges*
̈
Otto Diels-Institute for Organic Chemistry, University of Kiel, Otto-Hahn-Platz 4, Kiel D-24119, Germany
S
* Supporting Information
ABSTRACT: The synthesis of a borylated Ni2+ porphyrin and its application as
a versatile precursor for building up functional ortho-substituted tetraaryl
porphyrin architectures is reported. This precursor porphyrin provides the
basis for efficient modular syntheses of porphyrin compounds with covalently
attached axial ligands which are important as enzyme model complexes, electron
transfer dyads, and many other applications. In the present study, the precursor
porphyrin was used for the synthesis of molecular spin switches which previously
showed high potential as photoresponsive contrast agents for magnetic resonance imaging.
orphyrins and metalloporphyrins are an important class of
Pmacrocyclic compounds and are extensively studied. These
tetrapyrrolic macrocycles exhibit a high stability, a rigid
structure, interesting photophysical properties, a rich coordi-
nation chemistry, and redox activity. They are ubiquitous in
biological systems and have found technical applications in a
large number of fields, e.g., catalysis,1 solar energy harvesting,2
sensors, tracers,3 and triplet sensitizers in photodynamic
therapy.4−6 meso-Tetraarylporphyrins are the predominant
molecular structures in synthetic porphyrin chemistry. A
number of functionalized tetraaryl-substituted porphyrins are
commercially available. Furthermore, they are relatively easy to
synthesize, highly stable, and allow the introduction of a variety
of functionalities by the proper choice of starting components
or by postsynthetic derivatization of the meso-aryl substitu-
ents.7,8 In particular, the ortho position of the meso-aryl groups
is of great interest for the tethering of functional elements
because it provides the closest connecting point with respect to
the metal ion in the porphyrin center. Asymmetric tetraaryl
porphyrins with only a single functional substituent connected
in the ortho-position at one of the meso-aryl groups (see Figure
1) have been applied, e.g., for intramolecular axial coordina-
tion,9,10 photoinduced electron transfer in porphyrin−fullerene
dyads,11,12 or enzyme model complexes.13,14 We used this
porphyrin architecture for the intramolecular light-driven
coordination-induced spin-state switching (LD-CISSS)15 of
Ni2+ porphyrins.16−21
The covalently bound functional substituent in this case is an
azopyridine16−19 or azoimidazole20,21 that is reversibly
coordinated to the Ni2+ porphyrin upon cis/trans isomerization
of the azo function. The coordination and decoordination of
the axial ligand gives rise to a spin transition between a
diamagnetic (S = 0) state and a paramagnetic (S = 1) state. We
coined the above-mentioned porphyrins “record player”
molecules because the light-induced coordination of the
switchable azo unit (“tone arm”) to the metal center resembles
the movement of a needle that is put down on a vinyl record.
Light-driven spin transition in solution is highly promising for a
number of applications such as light-controlled magnetic
levitation,22−25 photoactivatable paramagnetic relaxation en-
hancement,26 and particularly responsive contrast agents for
magnetic resonance imaging (MRI).17,20,27−30 However, to
date, the low-yielding, multistep syntheses of the spin switches
(up to 14 individual steps)20 are the major bottlenecks toward
practical applications. Three key steps have to be performed
during the synthesis of every derivative (see Figure 2): the
formation of the switchable azo unit (yellow), the tethering of
the switching unit to the porphyrin’s meso substituent (blue),
and the porphyrin synthesis including the Ni2+ insertion (red).
Within the well-established linear approach (Figure 2a), these
key steps are performed consecutively.17−21 This route suffers
from the disadvantage that even slight variations in the
switching unit require each synthesis to be performed from
scratch. Moreover, the “mixed aldehyde” porphyrin synthesis,
though using cheap components, is known to give notoriously
low yields and many side products. Therefore, it should
preferentially be performed as the first step of the synthesis. In
our previous procedure, the porphyrin synthesis in the final
Figure 1. Asymmetric tetraaryl porphyrins with a functional
substituent in the ortho-position at one of the aromatic meso-
substituents are of interest for a number of applications.
Received: August 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02507
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Organic Letters
Letter
required for efficient spin switching, and it was obtained in
only very poor yields. Porphyrin 5 is easily accessible in high
purity, exhibits a high thermal stability, and can be stored at
ambient conditions for several months without any sign of
degradation. Therefore, it meets all requirements for an
efficient precursor for monosubstituted porphyrins.
With the key intermediate 5 in hand, we set out to evaluate
its scope in Suzuki cross-coupling reactions,34,35 particularly
with photoisomerizable azo compounds (see Scheme 2). For
this purpose, we synthesized the iodinated azobenzenes 636
with the azo substituent in the ortho (6a), meta (6b), and para
(6c) position with regard to the iodo substituent (for details,
see the Supporting Information). The azobenzenes 6 were
reacted with precursor 5 by applying a standard Suzuki cross-
coupling protocol we already used for the former linear
approach.17,19 By using tetrakis(triphenylphospine)-
palladium(0) as catalyst, potassium carbonate as the base, and
a toluene−ethanol−water solvent mixture, all azobenzenes 6
were coupled to precursor 5, giving the respective azo-
functionalized Ni2+ porphyrins 7 in excellent isolated yields
(7a, 94%; 7b, 97%; 7c, 93%, see Scheme 2, middle). Cross
coupling of 5 is also feasible with (3′-bromophenylazo)-
pyridines 8 and (3′-bromophenylazo)-N-methylimidazoles 9,
which provide a photoresponsive coordinating unit and
therefore are suitable ligands for molecular spin switches. The
azo heterocycles 8 and 9 were synthesized according to
convenient synthetic routes (for details, see the SI).37−39 The
Suzuki cross-coupling reactions of 5 with azopyridines 8 were
performed by applying the same synthetic protocol we used for
azobenzenes 6. The respective azopyridine-functionalized
porphyrins 10 were obtained in very high yields (10a, >99%;
10b, 95%; 10c, 90%; see Scheme 2, right). For the coupling
reactions with azoimidazoles 9, we had to adjust the synthetic
protocol and used [1,1′-bis(diphenylphosphino)ferrocene]-
dichloropalladium(II) as catalyst, cesium carbonate as base,
and a 1,4-dioxane−water solvent mixture, giving the derivatives
11 in satisfying yields as well (11a, 90%; 11b, 82%; 11c, 93%;
11d, 66%; see Scheme 2, left).
Figure 2. Schematic depiction of possible synthetic routes toward
“record player” molecules. Key steps are the formation of the
switchable azo unit (gray), tethering the switching unit to the
porphyrin’s meso substituent (blue), and the synthesis of the Ni2+
porphyrin (red). The key steps might be carried out (a) in a linear
fashion via the well-established “tone arm” approach or (b) in a
convergent fashion via a modular approach which requires the
synthesis of a suitable precursor porphyrin.
step gives rise to a significant loss of the valuable azo
compound. A modular approach with an appropriate precursor
porphyrin (Figure 2b) would certainly be much more efficient.
We previously reported a monoiodinated derivative of the
widely used Ni2+ porphyrin Ni−TPPF20 as a precursor
porphyrin. The porphyrin was obtained in nine synthetic
steps (five pots) and was coupled with borylated azopyridine to
give the perfluorinated “record player” derivative.16 To provide
an even more straightforward access to the porphyrin key
intermediate, we use the commercially available 2-formylphe-
nylboronic acid pinacol ester (1) pentafluorobenzaldehyde (2),
and pyrrole (3) for the porphyrin synthesis via the Lindsey
method (see Scheme 1).31,32 The monoborylated metal-free
Table 1 compares the yields of spin switches 10a,19 10b,17
and 11a20 obtained from both the linear and the convergent
synthesis. The formation and derivatization of the azo unit
(Figure 2, gray) is identical for both synthetic approaches.
Therefore, we only considered the respective linear sequence
which includes the Ni2+ porphyrin synthesis (Figure 2, red) and
the tethering of the switching unit to the porphyrin’s meso-
substituent (Figure 2, blue). The yields for the tethering step
via Suzuki cross-coupling reactions are almost identical (90% or
higher). However, the synthesis of the Ni2+ porphyrin is much
more efficient for the convergent route. Precursor porphyrin 5
was obtained in 22% yield, whereas the linear approach
provided only 2−5% yield for the porphyrin synthesis and
metalation. Consequently, the modular (convergent) route
improves the overall yields strikingly by a factor of 4−11.
Furthermore, porphyrin 5 is accessible from commercially
available starting materials. In the linear route, more than 95%
of the compounds synthesized in previous steps are lost
because the last step (porphyrin synthesis) proceeds only in 2−
5% yield.
Scheme 1. Synthesis of Precursor 5
porphyrin 4 was obtained in a fairly high yield, and the
following metalation with nickel(II) acetylacetonate gave
almost quantitative yields of the desired precursor porphyrin
5. The synthesis of a similar Zn(II)porphyrin has been
described previously.33 However, this porphyrin did not
contain the meso-pentafluorophenyl substituents that are
In summary, we present the synthesis of the boronic acid
pinacol ester functionalized Ni2+porphyrin 5 and its applica-
tions as a building block for the convergent syntheses of
functionalized porphyrins. The Ni2+porphyrin 5 is accessible in
pure form from commercially available compounds in only
B
DOI: 10.1021/acs.orglett.6b02507
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Organic Letters
Letter
Scheme 2. Suzuki Cross-Coupling Reactions of Precursor 5 with Azobenzenes 6, Azopyridines 8, and Azoimidazoles 9
Table 1. Yields (Suzuki Coupling and Porphyrin Synthesis)
for Spin Switches 10a, 10b, and 11a via the Linear Approach
and the New Modular Approach
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rherges@oc.uni-kiel.de.
Notes
overall yield (%)
derivative
linear approach
modular approach
The authors declare no competing financial interest.
10a
10b
11a
5.019
1.917
3.320
22
21
20
ACKNOWLEDGMENTS
■
Financial support from the “Deutsche Forschungsgemein-
schaft” (DFG) via CRC677 “Function by Switching” is
gratefully acknowledged.
three synthetic steps (two pots) and can be stored for several
months at ambient conditions without degradation. Subsequent
Suzuki cross-coupling reactions of 5 were successfully
demonstrated. Porphyrin 5 was coupled with 10 different
halogenated azo compounds in high isolated yields. The
reaction with photoswitchable azopyridines or azoimidazoles
provides efficient access to molecular spin switches that exhibit
intramolecular light-driven coordination-induced spin-state
switching (LD-CISSS). The modular synthetic approach via
the novel precursor porphyrin 5 is a considerable improvement
to previously applied routes. Our new synthetic concept
certainly will help us to further develop and optimize our spin
switches toward applications as smart MRI contrast agents. The
new precursor porphyrin should also be a versatile key
intermediate for other functional porphyrins. Ortho-substitution
in asymmetric tetraaryl porphyrins is a recurring structural
element and is found in many studies regarding different
applications. The pentafluorophenyl substituents at the
porphyrin’s meso-positions further increase the possibilities for
functionalization since they are highly reactive in nucleophilic
aromatic substitution reactions40−42 and allow, for example, the
introduction of solubilizing substituents.43
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02507.
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