Extending mechanochemical porphyrin synthesis to bulkier aromatics: Tetramesitylporphyrin

Article abstract of DOI:10.3762/bjoc.15.111

Aldehydes with bulky substituents in the ortho-positions have been historically difficult in porphyrin synthesis, presumably owing to steric hindrance around the reactive site. We have used mechanochemistry for the simple, room-temperature synthesis of te

Full text of DOI:10.3762/bjoc.15.111

Extending mechanochemical porphyrin synthesis to bulkier
aromatics: tetramesitylporphyrin
Qiwen Su1,2 and Tamara D. Hamilton*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1149–1153.
1Department of Physical Sciences, Barry University, 11300 NE 2nd
doi:10.3762/bjoc.15.111
Ave., Miami Shores, FL 33161, USA and 2Department of Chemistry,
Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467, USA
Received: 27 February 2019
Accepted: 17 May 2019
Published: 22 May 2019
Email:
Tamara D. Hamilton* - thamilton@barry.edu
This article is part of the thematic issue "Mechanochemistry II".
Guest Editor: J. G. Hernández
*
Corresponding author
Keywords:
condensation; grinding; mechanochemistry; milling; porphyrin;
sterically-hindered
© 2019 Su and Hamilton; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Aldehydes with bulky substituents in the ortho-positions have been historically difficult in porphyrin synthesis, presumably owing
to steric hindrance around the reactive site. We have used mechanochemistry for the simple, room-temperature synthesis of tetra-
meso-substituted porphyrins. In the present study, mesitaldehyde undergoes acid-catalyzed mechanochemical condensation with
pyrrole to give meso-tetrakis[2,4,6-(trimethyl)phenyl]porphyrin (TMP) after oxidation in solution. Yields are similar to those ob-
tained using high-temperature porphyrin synthesis, although they remain significantly lower than some optimized room-tempera-
ture, solution-based methods. Yields of the mechanochemical synthesis were found to increase slightly upon longer exposure to an
organic oxidizing agent in solution. This indicates that the mechanochemical condensation step may be more successful than
initially realized. This work shows that mechanochemistry is a successful, simple, room-temperature method for producing tetra-
meso-substituted porphyrins with bulky substituents.
Introduction
Porphyrins and related macrocycles such as chlorins, corroles, in the meso or β-positions (Figure 1A). Tetra-meso-substituted
and bacteriochlorins carry out important functions in nature in- porphyrins are usually synthesized from simple starting materi-
cluding light harvesting (i.e., chlorophyll), oxygen transport als, namely: pyrrole and an aldehyde (Scheme 1). Porphyrin
(
i.e., heme), biocatalysis, and electron transfer. The ability to synthesis is interesting to study as a mechanochemical reaction
synthesize porphyrins bearing a variety of chemical and steric because it involves the combination of reactive molecules under
functionalities on the periphery is important in fields as diverse appropriate conditions to give a very stable, aromatic product.
as catalysis [1], photovoltaics [2], photodynamic therapy [3,4], Furthermore, depending on the nature of the substituents, the
environmental remediation [5,6], biomimetic modelling [7] and porphyrin product can be labor-intensive to produce and purify
metal-organic self-assembly [8]. Porphyrins may be substituted in good yield and large quantities using other methods. The
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Beilstein J. Org. Chem. 2019, 15, 1149–1153.
process involves multiple condensations, together with oxida- the premise that the cyclized condensation product (called a
tion that may happen in one pot or as separate steps. Other porphyrinogen) should be thermodynamically favored over
no-solvent-added methods of porphyrin synthesis have been re- linear alternatives (Scheme 1), Lindsey et al. sought to maxi-
ported [9,10], while optimization of solvent, dilution and cataly- mize yields under milder conditions by promoting the establish-
sis conditions using solvent-based approaches have been inves- ment of an equilibrium for the cyclization step, then adding a
tigated for the synthesis of many porphyrins [11-14].
gentle oxidizer (p-chloranil or 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ)) in a second step to obtain irreversibly the
aromatized porphyrin [11]. The symmetrical tetra-meso-substi-
tuted porphyrins are synthesized through a four-fold acid-cata-
lyzed condensation to form a porphyrinogen which is then
oxidized (− 6H) to form the conjugated porphyrin product.
Lindsey’s reaction takes place at room temperature and utilizes
chlorinated solvents under optimized dilution conditions
(
10−2 M reactant concentration). The cyclization step necessi-
tates an oxygen-free environment, in order to allow the equilib-
rium to be fully established before any oxidation takes place.
Tar-like byproducts are avoided under these conditions, and
purification is achieved using only a short chromatography
column.
Figure 1: A) Porphyrin structure and labelling system. B) Substituents
in the ortho-position of the group attached to the methane bridge
create steric hindrance around the meso-position, above and below
the plane of the porphyrin ring.
Our previous work on mechanochemical porphyrin synthesis
Tetraphenylporphyrin (TPP) synthesis, as first reported in 1935 has demonstrated that it is possible to synthesize tetraphenyl-
by Rothemund [15-17], involved placing reactants in a sealed porphyrin (TPP) by grinding benzaldehyde and pyrrole (two
tube at high temperatures (150 °C or higher) for 24 to 48 hours liquids) in the presence of an acid catalyst, followed by oxida-
in the absence of air or any oxidant. Not every substituted tion with DDQ in minimal amounts of solvent [19]. TPP was
benzaldehyde could survive this process and yield the porphy- produced in a yield similar to that obtained from the Lindsey
rin. Adler and Longo later introduced refluxing propionic acid synthesis. Additionally, several monosubstituted benzalde-
(
141 °C) open to air as a reaction medium [18]. This widened hydes, as well as two isomers of naphthaldehyde, were shown
the variety of substituted aldehydes successfully converted to to undergo successful mechanochemical reaction in reasonable
porphyrins, but employment of a caustic solvent at high temper- yields.
ature is a drawback. These conditions also proved inappropriate
for several substituted benzaldehydes, and the best yields have Mesitaldehyde has been considered a representative “sterically-
been in the order of 20% with many porphyrins needing exten- hindered” reagent, serving as a touchstone for the wider appli-
sive work-up to isolate from tar-like byproducts. Working from cability of porphyrin reaction conditions [12]. Porphyrins with
Scheme 1: Steps leading to the formation of a porphyrin.
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Beilstein J. Org. Chem. 2019, 15, 1149–1153.
bulky groups in the meso-positions, especially aromatics with mixer mill for 10 minutes (Scheme 2), a pink powder is formed.
bulky substituents in the position ortho to the methine bridge, As in the case of benzaldehyde, the powder is found to contain
have been used for biological modelling. The large groups no porphyrin, evidenced by the lack of a Soret band at
become oriented above and below the plane of the porphyrin 410–420 nm in the electronic spectrum. Our work with
ring, forming a protective shroud around the reactive center, benzaldehyde showed that even when grinding is carried out
much like some protein systems (Figure 1B) [12,20-22]. The manually and open to air using a mortar and pestle, no Soret
corresponding substituted benzaldehydes, however, have not band is observed in the spectrum of the freshly-ground powder
easily yielded results upon reaction with pyrrole under any [19]. Also in the case of benzaldehyde, it was found that
traditional synthetic method. High-temperature (>170 °C) allowing the mechanochemically-generated powder to sit on a
sealed-bomb reactions in the presence of metal salts will, after benchtop open to air for several weeks brought about the ap-
2
–3 days, yield 1–6% of meso-tetrakis[2,4,6-(trimethyl)phen- pearance of TPP in small amounts. More immediate oxidation
yl]porphyrin (TMP) [20,21,23,24], and a gas-phase synthesis in of this power, by dissolving in chloroform and stirring with
the presence of TFA yielded 7% TMP [9]. Under the first-re- DDQ for 2 hours, allowed isolation of TPP in 28% yield [19].
ported conditions of the Lindsey synthesis, mesitaldehyde Appearance of TPP upon oxidation confirms that mechano-
“failed to give good yields” of TMP [11]. Later studies of modi- chemistry successfully brought about the condensation step.
fied reaction conditions employing boron trifluoride as the acid The freshly-ground “pink powder” must contain cyclized prod-
catalyst, and small amounts of ethanol as a co-catalyst, were ucts, perhaps including porphyrinogen (colorless) and various
successful in producing TMP with yields around 30% at room other reduced-porphyrin intermediates having one to five more
temperature [13,25,26]. Optimized conditions still required hydrogens than TPP. Many of these intermediates have absor-
reactant concentrations of 10−2 M. Increasing or decreasing the bance in the visible region.
concentration lowered the yield, as did increasing the tempera-
ture. In the present study we set out to test whether our Other no-solvent-added routes to porphyrins, including high-
mechanochemical porphyrin synthesis could accommodate a temperature sealed-bomb methods [15-17], gas-phase synthesis
sterically-hindered aldehyde, and produce TMP at room temper- [9], and microwave irradiation [10] do not employ a second oxi-
ature and in the absence of added solvent for the condensation dation step. Presumably for the latter two methods open to air,
step, using relatively simple reaction conditions. The use of dioxygen serves as a rapid oxidizer under high-temperature
mechanochemistry to bring about a no-solvent-added acid-cata- conditions, while the sealed-bomb reaction products are heavily
lyzed condensation between aldehydes and pyrrole enables the contaminated with chlorins [27-29], byproducts that contain two
reduction of solvent and elimination of high temperatures from more hydrogens than the porphyrin, and which easily undergo
the synthesis of these important compounds, representing a sig- chemical oxidation to yield porphyrin.
nificant reduction in environmental impact.
In contrast, since the no-solvent-added mechanochemical syn-
Results and Discussion
thesis takes place at room temperature, like the Lindsey synthe-
When mesitaldehyde and pyrrole, both colorless liquids, are sis, it may be that the equilibrium is reached between starting
combined in the presence of an acid catalyst and ground using a materials and cyclocondensation products before conditions are
Scheme 2: Mechanochemical synthesis of tetramesitylporphyrin.
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Beilstein J. Org. Chem. 2019, 15, 1149–1153.
introduced to trigger the irreversible oxidation of porphyrinogen these advantages even further [30]. Further studies aimed at
to porphyrin. Optimization of conditions could maximize the understanding the mechanism of the mechanochemical porphy-
porphyrinogen yield by adjusting the equilibrium, even though rin synthesis and its differences and similarities compared to the
the absence of added solvent means the concentration of solvent-based methods will be important advances for the field
reagents is at a maximum, and high concentrations are usually of mechanochemistry.
thought to favour linear over cyclic products.
Experimental
In the present work for the mesitaldehyde reaction, the pink Materials and methods
powder obtained upon grinding was immediately combined All chemicals used were purchased from Sigma-Aldrich and
with DDQ, dissolved in a small amount (ca. 50 mL) of chloro- used without further purification. Mesitaldehyde (98%), p-tolu-
form, and left to stir for one week. This is the same oxidation enesulfonic acid monohydrate (p-TSA, 98.5%), chloroform
method as used by Lindsey et al. and is presumed in their case (99.8%), alumina (99.9%), triethylamine (99.5%), silica gel
to convert any porphyrinogen or partially-oxidized intermedi- (technical grade, pore size 60 Å, 200–425 mesh particle size),
ate present into porphyrin instantaneously [11]. In the case of ethyl acetate (anhydrous, 99.8%), hexane (mixture of isomers,
the mechanochemical synthesis, the results show that a longer 98.5%), deuterated chloroform (99.8 atom % D) were used. 2,3-
oxidation time results reproducibly in a somewhat higher yield Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 97.0%) was
(
Table 1), although the isolated yield remains around 5%. Iden- purchased from TCI America and used without further purifica-
tity and purity of TMP was confirmed by UV–vis and 1H NMR tion. Pyrrole (98%) was purchased from Sigma-Aldrich and
spectroscopy (see Supporting Information File 1). Although we purified by distillation once per week after discoloration
are not certain of the identity of intermediates or side products appeared. The electronic spectra were recorded on a Perkin
from the mechanochemical reaction, it may be possible that via Elmer Lambda 850 UV–vis spectrophotometer, measured from
milling they are activated enough so that mechanical stirring 200–800 nm at 1 nm intervals. The samples were placed in
during the oxidation with DDQ in solution continues to promote quartz cuvettes with a 1 cm path length. 1H NMR spectra were
the formation of porphyrinogen. Throughout the oxidation recorded on a Varian 300 MHz nuclear magnetic resonance
process, the porphyrinogen immediately gets irreversibly spectrometer.
oxidized to porphyrin. It is clear that further work is needed to
elucidate differences between the mechanochemical and the sol- Mechanochemical synthesis
vent-based porphyrin syntheses.
meso-Tetrakis[2,4,6-(trimethyl)phenyl]porphyrin. Equimolar
amounts of pyrrole (0.259 g, 3.75 mmol) and 2,4,6-trimethyl-
benzaldehyde (0.556 g, 3.75 mmol) were placed in a 10 mL
stainless steel grinding jar along with acid catalyst p-toluene-
sulfonic acid (0.026 g, 0.151 mmol, 4%) and two stainless steel
balls of 5 mm diameter (0.52 g/ball; 0.81 mass-to-balls ratio).
The mixture was ground using the Retsch Mixer Mill MM200
for 10 minutes at a frequency of 25 Hz, resulting in formation
of a dark pink-colored powder. The powder was then dissolved
in 50 mL chloroform and 3 molar equivalents of DDQ (2.554 g,
Table 1: Tetramesitylporphyrin yields.
Milling time
minutes)
Oxidation timea
Average isolated
yield (%)b
(
1
0
0
1 week
1.82
5.10
1
1 month
aStirring in chloroform with DDQ; bAverage based on isolated, purified
mass from three replicates.
1
1.20 mmol) were added. The mixture was stirred to undergo
oxidation for a period of one week. The mixture was then
passed through a 1 cm alumina plug and 3–5 drops of triethyl-
Conclusion
Mechanochemical milling has successfully led to cycloconden- amine were added to the filtrate. The filtrate was passed through
sation of pyrrole with a sterically-hindered aldehyde. After oxi- a silica gel column using 1:3 ethyl acetate/hexanes as the
dation to give a porphyrin with bulky substituents, isolated mobile phase. Fractions containing porphyrin, as determined by
yields are comparable to those obtained from high-temperature thin-layer chromatography and UV–vis spectroscopy were
syntheses (though still lower than the 30% obtainable with combined and the solvent was removed using a rotary evapo-
added solvent at room temperature). The mechanochemical syn- rator. meso-Tetrakis[2,4,6-(trimethyl)phenyl]porphyrin was iso-
thesis is carried out at room temperature with no added solvent lated as a purple-red crystalline powder in 1.8% average yield,
during the condensation step, simplifying and reducing the which could be increased to 5.1% if oxidation time was length-
environmental impact for the synthesis of this important class of ened to one month. 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 8H),
molecules. Notably, James et al. have reported the simple and 6.91 (s, 8H), 2.62 (s, 12H), 1.85 (s, 24H), −2.52 (s, 2H);
clean mechanochemical metalation of porphyrins, extending 13C NMR (300 MHz, CDCl3) δ 138.4, 137.2, 136.6, 126.7,
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Beilstein J. Org. Chem. 2019, 15, 1149–1153.
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