Targeted Synthesis of Regioisomerically Pure Dodecasubstituted Type i Porphyrins through the Exploitation of Peri-interactions

Article abstract of DOI:10.1021/acs.joc.0c00798

A targeted synthesis of dodecasubstituted type I porphyrins that utilizes the reaction of unsymmetrical 3,4-difunctionalized pyrroles and sterically demanding aldehydes was developed. This way, type I porphyrins could be obtained as the only type isomers, likely due to a minimization of the steric strain arising from peri-interactions. Uniquely, this method does not depend on lengthy precursor syntheses, the separation of isomers, or impractical limitations of the scale. In addition, single-crystal X-ray analysis was used to elucidate the structural features of the macrocycles.

Full text of DOI:10.1021/acs.joc.0c00798

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Note
Targeted Synthesis of Regioisomerically Pure Dodecasubstituted
Type I Porphyrins Through the Exploitation of peri-Interactions
Marc Kielmann, Keith J. Flanagan, and Mathias O. Senge
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00798 • Publication Date (Web): 11 May 2020
Downloaded from pubs.acs.org on May 13, 2020
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Targeted synthesis of regioisomerically pure dodecasubstituted
type I porphyrins through the exploitation of peri-interactions
Marc Kielmann, Keith J. Flanagan, Mathias O. Senge*
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School of Chemistry, SFI Tetrapyrrole Laboratory, Trinity Biomedical Sciences
Institute, Trinity College Dublin, the University of Dublin, 152–160 Pearse St., Dublin
2, Ireland
Email: Mathias O. Senge - sengem@tcd.ie
* Corresponding author
ABSTRACT: A targeted synthesis of dodecasubstituted type I porphyrins that utilizes
the reaction of unsymmetrical 3,4-difunctionalized pyrroles and sterically demanding
aldehydes was developed. This way, type I porphyrins could be obtained as the only
type isomers, likely due to a minimization of the steric strain arising from peri-
interactions. Uniquely, this method does not depend on lengthy precursor syntheses,
the separation of isomers, or impractical limitations of the scale. In addition, single
crystal X-ray analysis elucidated the structural features of the macrocycles.
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Porphyrins are abundant in nature where they fulfill many important roles, for example,
in the functioning of pigment protein complexes and metalloproteins.1,2 Today, they
are frequently applied as model compounds to illustrate new achievements in multiple
scientific areas, including biology, chemistry, medicine, physics, including dye-
sensitized solar cells (DSSCs) and beyond.3 Conclusively, research aims to
synthesize complex porphyrin architectures with diverse substitution patterns that
show tailored functional properties, including organocatalytic activity,4 singlet oxygen
delivery,5 and innovative sensors.6 As such, short but efficient syntheses or new
functionalization reactions are highly sought after.7 However, the choice of which
synthetic route to use to synthesize any particular porphyrin depends upon the
symmetry features of the product itself.
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The synthesis of regioisomerically enriched or pure porphyrin type isomers usually
depends on the preparation of special pyrrolic precursors or the design of particular
condensation strategies. That is because conventional condensation reactions of, e.g.,
3,4-disubstituted pyrroles would result in the formation of statistical mixtures of all
possible type isomers. Moreover, due to the very similar physicochemical properties
of a set of type isomers, it is not trivial to separate these on a preparative scale. Thus,
for example, etioporphyrin I (1) and coproporphyrin I tetramethyl ester are accessible
by the tetramerization of -functionalized pyrroles,8 and so-called opp-porphyrins, in
which like pyrrole rings are regiochemically situated opposite to each other, were
prepared in a similar fashion.9 On the other hand, dipyrromethenes have been utilized
in the syntheses of 1 and coproporphyrin I (5) (Figure 1).10
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R1
R1
R2
R1
4
5
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7
8
9
R2
R2
R1
R2
NH
N
NH
N
N
N
HN
HN
R1
R2
R2
R2
R2
R1
R1
R1
R1
R1
R1
R1
type I
type II
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R2
R2
R2
R2
NH
N
NH
N
N
HN
HN
N
R2
R1
R1
R1
R1
R2
R2
R2
type III
type IV
e.g.,
1_4
R1 = Et
R2 = Me
: etioporphyrin
O
O
5_8
R1
=
: coproporphyrin
OH
R2 = Me
9_12
1
R
=
=
: uroporphyrin
OH
R2
O
OH
Figure 1: Examples of porphyrin type isomers: etioporphyrin I−IV (1−4) as well
as biologically relevant copro- and uroporphyrin I−IV (5−8 and 9−12,
respectively).
This methodology was later extended to the use of dipyrromethenes for the
preparation of isomers other than type I.11 At the same time, where the separation of
type isomers from statistical mixtures is attempted, time-consuming or small-scale
purification methods are required, such as HPLC. Naturally, this is more challenging
the more type isomers are present in a given sample. Type I and III isomers of penta-,
hexa-, and heptacarboxyporphyrin as well as those of uro- (9 and 11), copro- (5 and
7), and isocoproporphyrin were separated via HPLC.12 The authors stated that this
method would be suitable for the preparative isolation and for the detailed analysis of
such isomers in clinical materials, e.g., urine and feces of patients. More recently,
HPLC was also applied to separate coproporphyrin I and III (5 and 7) where
tetrapyrroles were extracted from various types of yeast and bacteria and then
analyzed by MS.13
Porphyrin type isomers14 are important for medicinal and synthetic studies: In one
report, tetrapyrroles excreted by patients with different types of porphyria were
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analyzed.15 Therein, the type isomer composition was disclosed with regards to, for
example, type I and III uro- (9 and 11) and coproporphyrin (5 and 7) presence
depending on the type of porphyria.
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This overview shows that methods for the facile synthesis of regioisomerically pure
porphyrin type isomers are scarce. Moreover, the synthetic approaches that were
shown are usually not broadly applicable and as such, a relatively small library of such
tetrapyrroles is at hand. This was taken as an occasion to elaborate a concept where
simple Lindsey condensation reactions16 would lead to the preferential formation of
type I porphyrins (Scheme 1).
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repulsive peri-interactions
ArCHO
+
N
= small substituent
= bulky substituent
H
i) BF3·OEt2
ii) DDQ
favored product:
least peri-interactions
Ar
Ar
NH
N
N
NH
N
N
Ar
Ar
Ar
Ar
HN
HN
Ar
Ar
type I
Ar
type II
Ar
NH
N
N
NH
N
N
Ar
Ar
Ar
Ar
HN
HN
Ar
type IV
Ar
type III
Scheme 1: Concept of the targeted synthesis of highly substituted type I
porphyrins, rather than a statistical mixture, from unsymmetrical 3,4-
difunctionalized pyrroles and sterically demanding aldehydes.
In this proposal, the pyrrolic precursors are designed in a way that a significant
difference in steric demand between the groups carried at the 3- vs the 4-position is
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generated (e.g., as in 14). When condensed with large aromatic aldehydes, type I
porphyrins should be formed as the major products due to a minimization of the peri-
interactions and the reduction of the overall steric strain. peri-Interactions are
conformational effects that occur when meso residues are flanked by β substituents.17
This creates a steric clash, resulting in high energy steric strain and deformation of the
molecule, which is particularly pronounced in dodecasubstituted porphyrins.18
For proof of principle, 3-ethyl-4-isopropylpyrrole (14) was prepared by the reduction of
3-acetyl-4-isopropylpyrrole (13) with lithium aluminium hydride in 84% yield. And
indeed, the following reaction of compound 14 with benzaldehyde in the presence of
the Lewis acidic BF3 catalyst yielded 15•2HCl as the only detectable porphyrin species
after the oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, Scheme 2).
Notably, 15 was obtained as a dihydrochloride salt, as indicated by the presence of
only two Q bands in the UV–vis absorption spectrum, likely due to the protonation by
residual hydrochloric acid present in the solvent. This can be associated with the
pronounced basicity of the neutral macrocycle 15 due to the high degree of
nonplanarity and electron-rich character.4c The protonation could not be prevented
even when the solvent was predried, neutralized over K2CO3, and filtered through
silica before use. And while the compound could initially be neutralized through the
addition of DCM:TFA (100:1, v/v), redissolving in DCM or chloroform resulted in anew
protonation. As such, for the purpose of this study, further neutralization attempts of
the complex (e.g., drying over CaH2, followed by distillation) were ultimately not
attempted.
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H
H
N
N
LiAlH4
O
THF, 66 °C, 16 h, 84%
13
14
i) PhCHO, BF3·OEt2
ii) DDQ
DCM, rt, 22 h, 9%
2Cl
Ph
Ph
NH
HN
HN
N
N
N
N
Ni(acac)2
Ph
Ph
Ph
Ni
Ph
DMF, 153 °C,
20 h, 86%
NH
Ph
Ph
16
15
·2HCl
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Scheme 2. Synthesis of type I porphyrin isomers 15•2HCl and 16 through
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condensation and metalation.
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The formation of the type I isomer 15⋅2HCl was confirmed with certainty by single
crystal X-ray analysis. Interestingly, the alternating ethyl–isopropyl type I substituent
pattern resulted in an overall molecular shape resembling a macroscopic propeller or
a Dutch windmill where the isopropyl groups are analogous to molecular-scale blades
attached at a precise 90° pitch angle. To investigate the features of the corresponding
metalloporphyrin 16, and for comparison with 15•2HCl, Ni(II) insertion was performed,
which occurred in a high yield of 86%. The crystal structures of both 15•2HCl and the
Ni(II) complex 16 revealed a severe saddle distortion of each macrocycle (Figure 2).
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Figure 2: Side and top views (stick models) of 15•2HCl (left) and 16•DCM
(right).19a One of the chloride ions has been omitted for clarity.
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In addition, the crystal lattice of 16 had a tunnel-like structure where DCM was
incorporated (Figure 3). Moreover, the isopropyl substituents extended well beyond
the porphyrin plane, with the result that the DCM guest molecules were fully engulfed
in hydrophobic binding pockets. The formation of this nonplanar metalloporphyrin
solvate complex is somewhat reminiscent of {2,3,7,8,12,13,17,18-octaethyl-
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5,10,15,20-tetraphenylporphyrinato}copper(II)
dichloromethane
solvate
(Cu(II)OETPP•2DCM) and points at possible receptor applications due to the
availability of solvent-accessible voids4a,20 or at enzyme-like catalytic properties due
to the presence of hydrophobic cavities.
Figure 3: Excerpt of the crystal structure lattice diagram (stick model) of
16•DCM.19a The blue circle marks a hydrophobic binding pocket.
The selective formation of 15•2HCl confirmed the initial hypothesis that the rational
choice of the pyrrole and aldehyde components would open a new avenue to
regioisomerically pure type I porphyrins via simple condensation pathways. In order to
expand the product library, 14 was also reacted with 4-methoxybenzaldehyde with a
similar outcome (Scheme 3).
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OMe
2Cl
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7
i) (4-MeO-C6H4)CHO,
BF3·OEt2
NH
NH
HN
HN
8
9
ii) DDQ
OMe
MeO
DCM, rt, 21 h
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H
N
OMe
17
·2HCl (3%)
17 _
+
2CH3 (<1%, side reaction)
14
OMe
side reaction:
decomposition
H
i) (4-MeO-C6H4)CHO,
BF3·OEt2
N
NH
N
N
ii) DDQ
OMe
14
+
MeO
HN
18
OMe
17 _
2CH3:
19
e.g.,
Scheme 3. Synthesis of the type I porphyrin 17•2HCl through a condensation
reaction.
While the only porphyrin type isomer that could be observed and isolated was 17•2HCl,
the presence of another species after the condensation reaction was noted. This
tetrapyrrole could be readily separated from 17•2HCl, but no structure was assigned
with certainty. However, HRMS analysis indicated that this porphyrin was devoid of
two CH3 fragments (17 − 2CH3) when compared to 17. One explanation is that a
fraction of 14 underwent a type of dealkylation prior to the condensation to form 3,4-
diethylpyrrole (18), which could then have reacted with unaltered 14 and 4-
methoxybenzaldehyde to form a tetrapyrrole like 19 or corresponding regioisomers
(Scheme 3). But at this stage, the actual molecular structure of, and the mechanism
for the formation of 17 − 2CH3, and whether this is a mixture of isomers is speculation.
In any case, this side product could be separated from 17•2HCl through conventional
column chromatography, and unambiguous assignment of the structure is currently
under investigation.
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In the following, it was attempted to extend this method to different types of pyrroles
and to investigate some of the limitations. For this, 3-methyl-4-phenylpyrrole (23) was
selected as a promising target in order to test whether it would be possible to introduce
aromatic functions into the β-positions of type I porphyrins. In practical terms, 23 was
synthesized from 20 and p-toluenesulfonylmethyl isocyanide (21) in a sequence of a
Van Leusen reaction21 and a reduction of the methyl ester function in 22 (Scheme 4).
Unfortunately, the condensation of 23 with benzaldehyde resulted in the formation of
an inseparable statistical mixture of all four porphyrin isomers. Apparently, the
difference in steric bulk between the methyl and phenyl group in 23 was not distinct
enough for selective type I porphyrin formation. While the 4-phenyl substituent in 23
may be considered as a large functional group, the flat geometry of this group may
account for an insufficient distinction from the 3-methyl unit in terms of bulkiness and,
consequently, the lack of regioselectivity. This was reflected by a high number of
methyl signals in the 1H NMR spectra of the free base products and the corresponding
Ni(II) complexes. The Ni(II) complexes were synthesized to investigate whether a
separation by chromatography could be accomplished. But unfortunately, the TLC
analysis indicated a very similar polarity of the products. However, this example did
not eliminate the option that in the future, 3,4-disubstituted pyrroles with more sterically
demanding aromatic substituents may eventually lead to type I porphyrin formations.
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H
N
NaH
CN
Ph
+
CO2Me
Ts
Et2O:DMSO, rt,
16 h, 44%
Ph
CO2Me
22
20
21
LiAlH4
THF, 66 °C,
16 h, 33%
i) PhCHO, BF3·OEt2
H
ii) DDQ
N
all four porphyrin
type isomers
DCM, rt, 19 h
Ph
Ni(acac)2
DMF, 153 °C, 18 h
23
Ni(II) complexes
of all four
type isomers
Scheme 4: Synthesis of 3-methyl-4-phenylpyrrole (23), acid-catalyzed
condensation with benzaldehyde, and metalation.
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Upon recrystallization of the pyrroles 14 and 23, samples that were suitable for single
crystal X-ray analysis could be obtained. The structural analysis revealed the
formation of intermolecular H-bonds in both species between the polarized carbonyl
functions and N−H groups (Figure 4). This was an interesting observation since H-
bonding of the nitrogenous hydrogen atoms in pyrroles is an important feature for the
application as catalysts4,22 and innovative sensors.23
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Figure 4: Excerpts of the crystal structure lattice diagrams (stick models) of 13
(top) and 22 (bottom), both revealing the formation of intermolecular H-bonds.19a
To conclude, a method for the selective preparation of type I porphyrins in
straightforward condensation reactions was developed, and the utility of the method
could be proven in a promising case study. Therein, dodecasubstituted type I
porphyrins formed as the only regioisomers, and it is likely that the presence of a
higher number of repulsive peri-interactions in the type II, III, and IV tetrapyrroles is
responsible for the high degree of regioselectivity. Notably, this innovative method
does not depend on tedious precursor syntheses, cumbersome purification steps (i.e.,
HPLC), or impractical limitations on the reaction scale that are usually associated with
this type of chemistry. While this strategy was initially investigated for 3,4-
dialkylpyrroles, an expansion to more diverse systems is currently under investigation.
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Moreover, the crystal structural analyses of 15•2HCl and 16 confirmed the type I
substitution pattern, likewise revealing a high degree of saddle distortion in both.
Interestingly, the Ni(II) complex 16 formed a tunnel-like structure in the solid state and
acted as a receptor for DCM, which could be exploited for the sensing of neutral
molecules in the future. Additionally, the crystal structures of the unsymmetrically 3,4-
difunctionalized pyrroles 14 and 23, which formed intermolecular H-bonds due to the
presence of carbonyl and N−H groups, were solved, pointing at a potential as sensors
and organocatalysts.24
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EXPERIMENTAL SECTION
Analytical Techniques. Analytical TLC was performed using sheets precoated with
silica gel to a depth of 0.2 mm or aluminum oxide plates, both impregnated with
fluorescence indicator F254. The visualization was accomplished with a UV lamp. Flash
column chromatography was carried out using aluminum oxide (neutral, activated with
6% H2O, Brockman Grade III). Mass spectrometry analysis was performed with a Q-
Tof Premier Waters MALDI quadrupole time-of-flight (Q-TOF) mass spectrometer
equipped with a matrix-assisted laser desorption ionization (MALDI) source and DCTB
(trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile) as the matrix.
APCI experiments were performed on a Bruker microTOF-Q III spectrometer
interfaced to a Dionex UltiMate 3000 LC. UV–vis absorption measurements were
performed in DCM as the solvent using a Shimadzu MultiSpec-1501. Melting points
are uncorrected and were measured with a Stuart SMP-50 melting point apparatus.
1H and 13C {1H} NMR spectra were recorded at 400.13 MHz and 100.61 MHz,
respectively, using Bruker DPX400, Bruker AV 600, and Bruker AV 400 devices,
respectively. All NMR experiments were performed at 25 °C. Resonances  are given
in ppm units and referenced to the deuterium peak in the NMR solvent CDCl3 (H =
7.26 ppm, C = 77.2 ppm). Signal multiplicities are abbreviated as follows: singlet = s,
doublet = d, quartet = q, septet = sept, multiplet = m. IR spectra were recorded on a
PerkinElmer Spectrum 100 FTIR spectrometer utilizing the ATR sampling technique.
General Information. To protect air and moisture sensitive compounds, the
corresponding reactions were carried out under “Schlenk” conditions using argon as
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an inert gas. Air and residual moisture were removed from the instruments by a hot air
gun under high vacuum, and the flasks were purged with argon subsequently. This
cycle was repeated up to three times as necessary.
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In the NMR spectra of the new highly substituted type I porphyrins, the signals
corresponding to the -ethyl and -isopropyl groups are broad. This is in accordance
with conformational studies by Medforth et al. on decaalkylporphyrins.25 Presumably,
the highly substituted products existed as a mixture of atropisomers in solution. The
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missing signals corresponding to the inner protons, as observed in most H NMR
spectra, have been reported previously, too.26
Materials. Most commercially available reagents were used as received unless
otherwise noted. For example, THF and DCM for air and moisture sensitive reactions
were obtained by passing the degassed solvents through an activated aluminium
oxide column. Alternatively, DCM for porphyrin syntheses was obtained via drying over
phosphorus pentoxide and distillation. The pyrroles 13,27 22,28 and 2329 have been
prepared following the literature.
3-Ethyl-4-isopropylpyrrole 14: 3-Acetyl-4-isopropylpyrrole 13 (4 g, 26.5 mmol, 1
equiv) in 70 mL THF was added dropwise to a suspension of LiAlH4 (3.14 g, 82.7
mmol, 3.1 equiv) in 20 mL THF at 0 °C. After that, the reaction mixture was left to stir
for 1 h at rt and heated to 66 °C for 17 h by an oil bath. Upon the careful hydrolysis
with ≈150 mL of a 2 M sodium hydroxide solution at 0 °C, Et2O was added, and the
layers were separated. The aqueous phase was extracted with Et2O, and the
combined organic layers were washed with water, dried with MgSO4, filtered, and the
solvent was removed in vacuo. The title compound was obtained as yellow oil (3.05 g,
22.26 mmol, 84%). Rf 0.55 (SiO2, hexane). 1H NMR (CDCl3, 400.13 MHz):  1.36–1.42
(m, 9H), 2.68 (q, J = 7.5 Hz, 2H), 3.02 (sept, J = 6.8 Hz, 1H), 6.65 (d, J = 2.7 Hz, 2H),
13
7.91 (s, 1H). C {1H} NMR (CDCl3, 100.61 MHz):  14.6, 18.5, 24.0, 25.2, 113.3,
114.6, 124.0, 129.8. HRMS−APCI (m/z): [M + H]+ calcd for C9H16N, 138.1277; found,
138.1281. MS–APCI m/z (% relative intensity, ion): 96.07 (100, M − C3H7 + 2H). IR
(ATR) ṽmax: 2959, 2931, 2870, 1670, 1640, 1462, 1379, 1076, 896, 776 cm−1.
2,7,12,17-Tetraethyl-3,8,13,18-tetraisopropyl-5,10,15,20-tetraphenyl-22H,24H-
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porphyrindiium dihydrochloride 15•2HCl: 3-Ethyl-4-isopropylpyrrole (14, 1 g, 7.29
mmol, 1 equiv) and benzaldehyde (0.77 g, 7.29 mmol, 1 equiv) were dissolved in dry
DCM (1 L) and boron trifluoride diethyl etherate (90 L, 0.73 mmol, 10 mol %) was
added. This was reacted for 22 h at rt, followed by the addition of DDQ (7.28 g, 32.1
mmol, 4.4 equiv). The solution became purple and was left to stir for another hour. The
solvent was removed at reduced pressure, the residue was dissolved in DCM and
filtered through a plug of Al2O3, Brockman grade III, using DCM, mixtures of DCM and
ethyl acetate, and eventually mixtures of ethyl acetate and methanol to partly separate
the relevant green fractions. These were evaporated to dryness and chromatographed
on Al2O3, Brockman grade III, using DCM:ethyl acetate, 2:1, v/v. A major green band
was isolated, which contained the title compound. After drying in vacuo, 15•2HCl was
obtained as green solid (172 mg, 0.66 mmol, 9%). mp > 300 °C. Rf 0.34 (Al2O3,
DCM:ethyl acetate, 10:1, v/v). 1H NMR (CDCl3, 400.13 MHz):  −0.34 (s, 4H), −0.17–
0.58 (m, 24H), 1.38–1.55 (m, 12H), 2.12–2.33 (m, 4H), 2.41–2.74 (m, 8H), 7.73–7.98
(m, 12H), 8.39–8.72 (m, 8H). 13C {1H} NMR (CDCl3, 100.61 MHz):  14.7, 15.9, 16.4,
16.5, 16.6, 16.7 (× 3), 19.6 (× 2), 19.8, 23.0, 23.1, 23.2 (× 2), 23.3 (× 2), 27.4, 27.5,
32.2, 118.1, 118.2, 118.5, 118.7 (× 2), 118.8, 119.1, 128.7, 128.8, 128.9 (× 2), 129.0
(× 2), 129.1, 130.0 (× 2), 130.1, 130.7, 134.3, 137.3, 137.4 (× 2), 137.6, 137.7, 137.8
(× 2), 137.9 (× 2), 138.4, 138.7, 138.9, 139.1 (× 2), 139.2, 139.3, 139.5, 139.7, 139.9,
140.2, 140.8, 140.9, 141.1, 141.2 (× 2), 141.5, 144.9, 145.0 (× 2), 145.1, 145.2, 145.4,
145.5, 145.6, 145.7 (× 2), 145.8, 145.9, 146.0, 146.2. UV–vis (DCM) max (log ): 484
(5.57), 646 (4.09), 703 nm (4.69). HRMS−MALDI (m/z): [M − 2HCl + H]+ calcd for
C64H71N4, 895.5673; found, 895.5670.
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2,7,12,17-Tetraethyl-3,8,13,18-tetraisopropyl-5,10,15,20-
tetraphenylporphyrinato}nickel(II) 16: Porphyrin 15•2HCl (60.3 mg, 62 mol, 1
equiv) and Ni(acac)2 (159 mg, 0.62 mmol, 10 equiv) were dissolved in 0.6 mL DMF,
and this was heated to 153 °C for 20 h by a heating mantle during which the reaction
mixture changed color from green to purple. After cooling to rt, water and DCM were
added, and the layers were separated. The aqueous phase was extracted with DCM
and the combined organic layers were washed with water, dried with MgSO4, filtered,
and the solvent was evaporated in vacuo. The purple crude product was purified by
column chromatography (Al2O3, Brockman grade III, using DCM:petroleum ether,
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1:10, v/v). The first fraction, a purple band, was isolated and upon evaporation of the
solvent, the title compound was obtained as purple solid (51 mg, 53.3 μmol, 86%). mp
> 300 °C. Rf 0.61 (SiO2, hexane:DCM, 5:1, v/v). 1H NMR (CDCl3, 400.13 MHz):  0.33–
0.49 (m, 12H), 0.54–0.77 (m, 12H), 1.26–1.45 (m, 12H), 1.79–2.09 (m, 4H), 2.52–2.83
(m, 8H), 7.53–7.70 (m, 12H), 7.94–8.21 (m, 8H). 13C {1H} NMR (CDCl3, 100.61 MHz):
 17.6, 20.4, 23.2, 26.7, 26.8, 26.9, 127.0, 127.3, 127.7, 127.8, 127.9, 128.1, 134.2,
134.7, 135.3, 140.7, 146.3, 146.5, 148.7, 148.9. UV–vis (DCM) max (log ε): 444 (5.33),
593 (4.15), 599 nm (4.01). HRMS−MALDI (m/z): [M]+ calcd for C64H68N4Ni, 950.4797;
found, 950.4785.
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2,7,12,17-Tetraethyl-3,8,13,18-tetraisopropyl-5,10,15,20-tetrakis(4-
methoxyphenyl)-22H,24H-porphyrindiium dihydrochloride 17•2HCl:
Similar to the synthesis of 15•2HCl, 3-ethyl-4-isopropylpyrrole (14, 0.5 g, 3.6 mmol,
1.1 equiv) and 4-methoxybenzaldehyde (0.4 mL, 3.3 mmol, 1 equiv) were dissolved in
500 mL of dry DCM and BF3•OEt2 (43 L, 0.33 mmol, 10 mol %) was added. This was
reacted at rt for 21 h during which the reaction mixture turned red, followed by DDQ
addition (3.3 g, 14.52 mmol, 4.4 equiv). After stirring for another 2 h, the solvent was
removed in vacuo and the residue dissolved in DCM and filtered through Al2O3,
Brockman grade IIII, using DCM and DCM:ethyl acetate mixtures up to pure ethyl
acetate to remove DDQ derivatives and other nonporphyrin material. Then,
DCM:methanol, 1:1, v/v was applied to isolate a green/brown fraction. The relevant
fractions, which had brown or green/brown colors, were combined upon TLC analysis,
and the solvent was evaporated. The crude product was then subjected to column
chromatography. Column chromatography (Al2O3, Brockman grade IIII) was
performed using DCM to remove brown impurities, then DCM:ethyl acetate, 10:1, v/v
to isolate a light green fraction of 17•2HCl, giving a green solid (27 mg, 0.1 mmol, 3%)
upon evaporation of the solvent. Second, a porphyrin (e.g., 19, see Scheme 3) that
was devoid of two CH3 fragments when compared to 17, as indicated by HRMS
analysis, was eluted as a dark green band, yielding a green solid (5 mg, <1%) after
evaporation of the solvent. 17•2HCl: mp 286–290 °C dec. Rf 0.67 (Al2O3, DCM:ethyl
1
acetate, 10:1, v/v). H NMR (CDCl3, 400.13 MHz):  0.02–0.24 (m, 12H), 0.25–0.38
(m, 12H), 1.44–1.54 (m, 12H), 2.21–2.39 (m, 4H), 2.44–2.71 (m, 8H), 4.09 (s, 3H),
4.11 (s, 6H), 4.12 (s, 3H), 7.35–7.44 (m, 8H) 8.31–8.55 (m, 8H). 13C {1H} NMR (CDCl3,
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100.61 MHz):  15.7, 15.8, 15.9 (× 2), 16.0, 19.1, 26.6, 26.7, 113.7, 114.1 (× 2), 116.6,
116.8, 117.2, 117.4, 117.7, 118.0, 130.4, 131.5, 131.8, 132.7, 133.0, 137.5, 137.8,
137.9, 138.0, 138.1, 138.4, 138.5 (× 2), 138.6, 139.6, 139.7, 140.0, 140.5, 144.8,
144.9, 145.0, 145.3, 145.4, 145.6, 145.7, 145.8, 146.0, 146.3, 146.5, 161.0, 161.1.
UV–vis (DCM) max (log ): 486 (5.63), 722 nm (4.87). HRMS−MALDI (m/z): [M − H −
2Cl]+ calcd for C68H79N4O4, 1015.6101; found, 1015.6074. 17 − 2CH3 (e.g., 19):
HRMS−MALDI (m/z): [M − 2HCl + H]+ calcd for C62H67N4, 867.5360; found, 867.5371.
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SUPPORTING INFORMATION
13
1H and C NMR spectra of the newly synthesized compounds, single crystal X-ray
1
structures, and H NMR spectra of statistical porphyrin type isomer mixtures. This
material is available free of charge via the Internet at http://pubs.acs.org. CCDC
1993404–1993407 contain the supplementary crystallographic data for this note.
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENTS
This work was supported by grants from Science Foundation Ireland (SFI IvP
13/IA/1894) and through funding from the European Union's Horizon 2020 research
and innovation program under the FET Open grant agreement no. 828779.
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