Synthesis of 2-bromo-and 2-phenyl-neo-confused porphyrins

Article abstract of DOI:10.1039/d0ob01642j

Neo-confused porphyrins (neo-CPs), porphyrin isomers with a 1,3-connected pyrrolic subunit, are aromatic structures with a CNNN coordination core. Previously, examples of neo-CPs with fused benzo units or electron-withdrawing ester substituents have been

Full text of DOI:10.1039/d0ob01642j

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Synthesis of 2-bromo- and 2-phenyl-neo-confused porphyrins
Arwa S. Almejbel and Timothy D. Lash*
ABSTRACT
Neo-confused porphyrins (neo-CPs), porphyrin isomers with a 1,3-connected pyrrolic subunit, are aromatic
structures with a CNNN coordination core. Previously, examples of neo-CPs with fused benzo units or
electron-withdrawing ester substituents have been described. In this paper, two new examples of neo-CPs
are reported that lack a fused aromatic unit or an ester moiety, but instead have a bromo or phenyl
substituent on the neo-confused ring. Acid-catalyzed condensation of suitably substituted 1,2’-
dipyrrylmethane dialdehydes with a 2,2’-dipyrrylmethane, followed by oxidation with aqueous ferric
chloride solutions, afforded the neo-CPs in 40-45% yield. These porphyrin analogues had slightly reduced
diatropic ring currents and slowly decomposed in solution. The related palladium(II) and nickel(II)
complexes proved to be very unstable, even though the diatropicity of the macrocycle was enhanced. This
study shows that stabilizing substituents are necessary for investigations into this class of porphyrinoids.
Attempts to prepare imidazole versions of neo-CPs were unsuccessful.
_
__________________________________________________________________________
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160, USA
E-mail: tdlash@ilstu.edu
1
1
1
†
Electronic supplementary information (ESI) available: selected UV-Vis, H NMR, H- H COSY, HSQC,
1
3
DEPT-135, C NMR, and mass spectra.

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INTRODUCTION
NH
N
N
NH
N
N
HN
HN
1
(Porphyrin)
2 (Porphycene)
H
N
N
HN
N
N
NH
N
HN
3b
3
a
N-Confused Porphyrin
22
21
R
2
20
18
32
31
1
N
19
2
20
18
1
N
19
3
5
17
16
15
14
Me
Me
3
17
16
15
4
6
N
21
24
4
6
N
24
21
5
2
2
23
22
23
N
HN
14
N
HN
7
13
Me 7
13
9
11
12
8
9
11
12
8
10
10
Et
Et
4
(Neo-Confused
Porphyrin)
5 (Benzo-Neo-Confused Porphyrins)
22
21
Me
18
32
31
MeO2C
R
2
20
1
19
Et
Me
Me
N
3
17
16
15
14
4
HN
N
2
1
24
5
22
23
6
NH
N
N
HN
Me
7
13 Et
Me
Et
9
11
12
8
1
0
Et
Et
Et
7
6
(Benzocarbaporphyrin)
a. R = Et; b. R = Me
Figure 1. Porphyrin isomers and analogues.
Porphyrins 1 are one of the most studied families of organic compounds and have many important
1
biological functions. Synthetic porphyrins are being investigated for numerous applications that include
2
3
4
the development of sensors, optical materials, catalysts and photosensitizers in photodynamic therapy
5
(
PDT). The importance of this macrocyclic system has led to investigations into related structures,
6
7
8
9
including expanded porphyrins, contracted porphyrins, core modified porphyrins and porphyrin isomers.

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The first example of a porphyrin isomer, porphycene 2 (Figure 1), was reported in 1986 by Vogel and
1
0
11
coworkers. In porphycene, the four pyrrolic subunits are linked by two ethylene bridges and two direct
connections rather than the four single carbon bridges found in true porphyrins. Nevertheless, both
porphyrin and porphycene use a total of four methine carbons and four pyrrole units to construct these
macrocyclic systems. Porphycenes retain strongly aromatic characteristics and readily form metalated
derivatives, but also show comparatively strong absorptions at longer wavelengths.11,12 Several other
1
2
examples of porphyrin isomers were subsequently discovered with inward facing nitrogen atoms. An
alternative class of porphyrin isomers, the so-called N-confused porphyrins (NCPs, 3), were reported in
994,13,14 although structures of this type had been proposed at a far earlier point in time. NCPs have a
15
1
“
confused” pyrrolic subunit that places its nitrogen atom on the macrocyclic periphery. This results in a
carbon atom being placed within the macrocyclic core, and NCPs can be considered to be
carbaporphyrinoid systems.16 There are two thermodynamically accessible NCP tautomers, 3a and 3b,
1
7
although the more aromatic form 3a is favored in relatively nonpolar solvents such as chloroform. NCPs
exhibit long wavelength absorptions and have been investigated as potential photosensitizers for PDT
1
8
19
applications. In addition, NCPs readily form metalated derivatives, including organometallic complexes.
Examples of porphyrin isomers with two inverted pyrrole subunits, doubly N-confused porphyrins or
2
0
N CPs, have also been reported.
2
Another category of porphyrin isomer was discovered more recently in which the nitrogen atom of a
pyrrole subunit is directly attached to a methine bridge.21-23 Porphyrin isomers of this type were termed
“
neo-confused porphyrins”, or neo-CPs (4, Figure 1), and were initially prepared as benzo-fused derivatives
such as 5.21,23 Benzo-neo-confused porphyrins have electronic absorption spectra that are surprisingly
similar to regular porphyrins, showing a strong Soret band at 407 nm and four smaller Q bands between
5
03 and 615 nm. Nevertheless, the diatropic ring current in benzo-neo-CPs is significantly reduced21,23,24
2
5
compared to porphyrins or benzocarbaporphyrins (e.g. 6). The NMR spectrum for 6 in CDCl showed the
3
internal CH and NH protons at highly upfield values of -6.74 and -4.0 ppm, respectively, while the external
meso-protons were strongly deshielded giving rise to two 2H singlets at 9.82 and 10.10 ppm.25 In contrast,

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the internal CH and NH resonances for 5 were observed at -0.74 and -0.33 ppm, while the meso-protons
gave rise to four 1H singlets at 8.91, 8.96, 9.68 and 9.99.21,24 It is worth noting that the most downfield
meso-proton is deshielded, in part, because it is connected to a nitrogen atom. Even so, the difference in
chemical shifts between the most upfield and downfield proton resonances () is 10.73 ppm, while 6 had
a  value of almost 17 ppm ( values can be quite diagnostic in assessing global aromaticity in
macrocyclic systems of this type).21,23,24 NICS calculations were used to confirm these observations26,27 and
while the NICS(0) value for benzo-neo-confused porphyrin of -12.21 ppm showed that the system has a
significant degree of magnetic aromaticity, benzocarbaporphyrin gave a larger negative value of -14.43
ppm. Neo-confused porphyrin 5 gave a slightly reduced negative NICS(0) value of -11.41 ppm.26
Following the initial report, examples of neo-confused porphyrins 7 with an electron-withdrawing
methyl ester unit attached to the neo-confused ring were reported.24,28 These porphyrinoids were also stable
aromatic compounds with porphyrin-like characteristics. The  value for methyl ester 7a was 9.34 ppm,
although this result is slightly exaggerated because one of the meso-protons is deshielded by its proximity
to the ester moiety, but the results still indicated that neo-confused porphyrin esters 7 have reduced
diatropicity compared to 5. Both neo-CPs 7 and benzo-neo-CPs 5 acted as dianionic ligands and afforded
stable nickel(II) and palladium(II) derivatives.21,24 In an attempt to prepare a neo-confused porphyrin 8a
2
4
without any substituents on the neo-confused ring, 1,2’-dipyrrylmethane dialdehyde 9a was condensed
with a dipyrrylmethane dicarboxylic acid 10 under MacDonald “2 + 2” reaction conditions (Scheme 1).29
2
4
However, no porphyrin-like products could be isolated. It was unclear whether the expected neo-confused
porphyrin product was too unstable to isolate or whether the unsubstituted pyrrole ring failed to facilitate
cyclization. In order to extend these observations, the synthesis of related neo-CPs lacking fused benzo-
units or electron-withdrawing substituents was investigated. Two new examples of neo-NCPs are described
but these compounds proved to be less stable than the previously described structures. Nevertheless, these
neo-CPs continued to exhibit significant macrocyclic diatropicity.

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R
Me
R
Me
N
Me
N
Me
Me
HN
CHO
H+
HN
N
OHC
9
HO C
CO2H
2
NH
NH HN
Me
Me
Me
a. R = H
b. R = Br
c. R = Ph
Et
R
Et
1
3
Et
Et
1
0
[
O]
Me
R
Me
N
Me
Me
N
Me
Me
N
N
N
M(OAc)2
M
N
HN
N
Me
Me
Et
Et
Et
Et
8
1
8 M = Ni 19 M = Pd
Scheme 1. Synthesis and metalation of neo-confused porphyrins.
RESULTS AND DISCUSSION
CHO
CHO
N
Br
N
H
N
H
Si(i-Pr)3
11a
11b
Me
Me
PhB(OH)2
Pd(PPh3)4
AcOCH2
CHO
N
NaH
H
12
CHO
R
Me
NaH
12
N
Me
CHO
Ph
N
H
HN
11c
OHC
9
b. R = Br; c. R = Ph
Scheme 2. Synthesis of pyrrole-3-carbaldehydes and 1,2’dipyrrylmethane dialdehydes.
Initially, 2-bromo-neo-CP 8b was targeted for synthesis. The required precursor to the neo-confused
ring, 5-bromopyrrole-3-carbaldehyde (11b), was prepared from N-tri-isopropylsilylpyrrole (Scheme 2).30

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Vilsmeier formylation, followed by cleavage of the silyl group with aqueous sodium hydroxide, gave
pyrrole-3-carbaldehyde (11a) and subsequent bromination with N-bromosuccinimide afforded the required
bromopyrrole (Scheme 2).31 Treatment with sodium hydride and subsequent reaction with
acetoxymethylpyrrole aldehyde 12 gave dipyrrylmethane 9b. Initially, THF was used as the solvent for this
chemistry, but very poor yields of 9b were obtained. However, after numerous trials, a 74% yield of the
o
dipyrrolic product was obtained when the reaction was performed in DMF at 30 C. Acid catalyzed
condensation of dialdehyde 9b with dipyrrylmethane 10, followed by oxidation of the intermediary phlorin
1
3b with ferric chloride, gave neo-confused porphyrin 8b in 45% yield (Scheme 1).
OH
O
N
N
CO Et
2
CO Et
2
Me
DABCO
7%
Me
1
5
7
14
microwave
78%
o
175 C, 2 h
CHO
CO Et
2
o
1
. DIBAL-H -70 C
Ph
+
-
N
2. Pr N RuO
Ph
4
4
N
H
H
51%
11c
16
Scheme 3. Synthesis of 5-phenylpyrrole-3-carbaldehyde.
In parallel work, 5-phenylpyrrole-3-carbaldehyde (9c) was required as a precursor to 2-phenyl-neo-CP
8
c. This pyrrole can be obtained by Pd(Ph ) -catalyzed Suzuki-Miyaura coupling of 8b with phenylboronic
3 4
3
1
acid. Alternatively, 9c can be prepared in 4 steps from oxime 14 by adapting procedures reported by
3
2
32
Ngwerume and Camp (Scheme 3). Reaction of E-acetophenone oxime 14 with ethyl propiolate and 1,4-
diazabicyclo[2.2.2]octane (DABCO) afforded a 9:1 mixture of E and Z-isomers of acrylate 15. Thermal
rearrangement and cyclization was accomplished under microwave conditions to give ethyl 5-
phenylpyrrole-3-carboxylate (16). This chemistry was very sensitive to temperature. In our hands, no
o
o
significant reaction was observed after 45 min at 170 C. However, at 180 C extensive decomposition took
o
place. The best results were obtained when the reaction was carried out at 175 C for 2 h and 16 was isolated

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o
in 78% yield. Reduction of the ester moiety with DIBAL-H at -70 C, followed by oxidation of the resulting
3
1
carbinol with tetrapropylammonium perruthenate, furnished the required aldehyde 9c. Treatment of 9c
2
4
o
with sodium hydride and reaction with acetoxymethylpyrrole 12 in DMF at 30 C, gave dipyrrylmethane
dialdehyde 9c in 75% yield (Scheme 2). Condensation of 9c with dipyrrylmethane 10 in the presence of p-
toluenesulfonic acid, followed by oxidation with aqueous ferric chloride, afforded 2-phenyl-neo-CP 8c in
4
0% yield (Scheme 1).
Figure 2. Partial 500 MHz proton NMR spectrum of bromo-neo-confused porphyrin 8b in
CDCl3.
The proton NMR spectra of 8b and 8c demonstrated that these porphyrin analogues possessed significant
diatropic character (Figure 2). Neo-confused porphyrin 8b in CDCl gave four 1H singlets for the meso-
3
protons at 8.46, 8.54, 8.90 and 9.45 ppm (the latter corresponding to the methine unit connected to the
nitrogen atom). In addition, the internal CH was shifted upfield to between 0.21 and 0.32 ppm. The outer
pyrrolic CH gave a resonance at 7.92 ppm; in some spectra, a poorly resolved doublet was observed due to
transannular coupling with the internal CH. Phenyl-neo-CP 8c gave the meso-resonances at 8.55, 8.65, 9.12
and 9.42 ppm, while the external 3-H and internal 21-H peaks appeared at 7.96 and 0.88 ppm, respectively.
The results suggest that 8b and 8c have comparable aromatic ring currents, although the diatropicity is

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slightly reduced compared to neo-CPs 5 and 7. In the carbon-13 NMR spectrum for 8b, the meso-protons
appeared at 93.5 (15-CH), 94.1 (10-CH), 110.3 (20-CH) and 113.0 (20-CH), and the internal CH resonance
showed up at 118.7 ppm. Addition of TFA to solutions of 8b or 8c resulted in the formation of the
2
+
corresponding dications 8H , and these showed enhanced diamagnetic ring currents. For instance, the
2
proton NMR spectrum of 8bH22+ in CDCl (Figure 3) gave four downfield 1H singlets for the meso-protons
3
at 9.09 (15-H), 9.17 (10-H), 9.73 (20-H) and 10.12 (5-H) ppm, while the external pyrrolic proton (3-H)
produced a resonance at 7.77 ppm and the internal 21-H peak shifted upfield to -2.20 ppm. Hence, the 
value for 8bH22+ increased to 12.32 ppm, compared to  = 9.2 ppm for the free base form. 2-Phenyl-neo-
CP dication 8cH22+ gave a similar  value of 12.77 ppm.
Figure 3. Partial 500 MHz proton NMR spectrum of neo-confused porphyrin dication 8bH 2 in
+
2
TFA-CDCl3.
The UV-vis spectra for 8b and 8c were porphyrin-like in appearance. Bromo-neo-confused porphyrin
8
b gave a Soret band at 394 nm and smaller Q bands at 509, 544, 564 and 614 nm (Figure 4). The equivalent
absorptions in 8c appeared at 398, 510, 544, 565 and 614 nm. The corresponding dications 8H22+ in 1%
2
+
TFA-CHCl produced modified chromophores. 8bH gave a broad split Soret band near 400 nm, together
3
2
with a broad absorption at 665 nm (Figure 4).

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9
9
8
7
6
5
4
3
2
1
0

300
400
500
600
700
800
Wavelength (nm)
Figure 4. UV-vis spectra of bromo-neo-CP 8b in 1% Et N-CHCl (red line) and 1% TFA-CHCl
3
3
3
2
+
(
dication 8bH , blue line).
2
Although good yields of 8b and 8c were obtained, the stability of these derivatives appeared to be
substantially reduced compared to 5 and 7. In the dark, solutions of 8b and 8c showed little sign of
degradation after several hours. However, when dilute solutions were exposed to ambient levels of light in
the laboratory (fluorescent lights, not sunlight) the samples underwent substantial decomposition. This is
illustrated for phenyl-neo-CP in Figure 5. After 20 minutes exposure to light, the intensity of the Soret band
was reduced by nearly 50% and the Q bands become less well defined. Bromo-neo-CP did not decompose
as quickly but significant changes to the UV-vis spectra were still observed over a similar time frame (see
ESI section).
1
.4
.2
1
1
0.8
0.6
0.4
0.2
0
A
300
400
500
600
700
800
Wavelength (nm)
Figure 5. UV-vis spectrum of phenyl-neo-CP 8c in 1% Et N-CHCl after 0 min (red), 20 min (green), 40
3
3
min (blue) and 60 min (purple) exposure to ambient lighting in the laboratory.

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1
0
Ph
Ph
N
Br
Br
HN
N HN
Ph
pyridine
Br
NH
Ph
Ph
Ph
N
N
N
17
Ph
Ph
N-Fused Porphyrin
16
Scheme 4. Conversion of a dibromo-NCP into an N-fused porphyrin.
Bromo-N-confused porphyrins such as 16 undergo inversion of the confused pyrrolic subunit and
3
3
cyclization in the presence of pyridine to produce N-fused porphyrins 17 (Scheme 4). We contemplated
that a similar transformation might also be possible for neo-confused porphyrins. However, all attempts to
further brominate 8b at position 21 lead to decomposition and this prevented any further investigations into
the preparation of neo-fused porphyrins. Attempts to prepare organometallic derivatives of 8b and 8c were
also problematic. Both of the neo-confused porphyrins reacted with nickel(II) acetate or palladium(II)
acetate to afford the related metalated porphyrinoids 18 and 19 (Scheme 1). However, unlike the metal
complexes of 5 and 7, these species proved to be very unstable in solution. The nickel and palladium
complexes of 8b were isolated in reasonably pure form but decomposed before carbon-13 NMR data could
be obtained. The proton NMR spectrum of nickel(II) complex 18b in CDCl showed the meso-protons at
3
8
.56, 8.88, 8.97 and 9.48 ppm, while the equivalent resonances for palladium(II) derivative 19b appeared
at 8.65, 8.94, 9.08 and 9.58 ppm. The results suggest that the diatropic ring current for 19b is slightly larger
than for 18b, and that both metalloporphyrinoids are more diatropic than neo-CP 8b. Nevertheless, the
increased diatropicity coincides with drastically reduced stability for these complexes. The UV-vis spectra
for 18b and 19b (Figure 6) show similarities to previously described nickel(II) and palladium(II) complexes
2
4
of neo-confused porphyrins. Nickel complex 18b gave Soret band at 383 nm and several broad poorly
resolved absorptions that extended up to 700 nm. Palladium derivative 19b afforded several absorptions in
the Soret region (i.e. near 400 nm) and a series of Q-like bands at 499, 532, 603 and 644 nm.

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1
1
6
5
4
3
2
1
0

300
500
700
900
Wavelength (nm)
Figure 6. UV-vis spectra of metalated neo-confused porphyrins in chloroform: Ni(II) complex
1
8b (red line) and Pd(II) complex 19b (blue line).
R
H
N
N
a. R = H
b. R = Me
OHC 21
NaH
12
R
Me
R
Me
N
Me
Me
N
10
H+
N
N
Me
CHO
N
HN
OHC
[O]
N
HN
2
2
Me
Et
Et
H+
a. R = H; b. R = Me
+
2
0 3-aza-neo-CP
R
Me
R
Me
H
N
Me
N
CH2
H
N
Me
HN
N
HN
OHC
CHO
OHC
decomposition
CHO
Scheme 5. Attempted synthesis of 3-aza-neo-confused porphyrins.
The formation of related macrocyclic ring systems was also considered. Specifically, the synthesis of
imidazole analogues of neo-CPs 20 was attempted (Scheme 5). Imidazole-4-carbaldehyde (21a) was
reacted with sodium hydride and condensed with acetoxymethylpyrrole 12 in THF to give 1-(2-

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1
2
3
4
pyrrolylmethyl)imidazole 22a in 60% yield. 2-Methylimidazole carbaldehyde 19b similarly afforded the
related pyrrolylmethylimidazole 22b in 51% yield. However, all attempts to react these intermediates with
dipyrrylmethane 10 failed to give any macrocyclic products. It may be that aza-neo-CPs 20 are too unstable
to isolate. However, another possibility is that 22a and 22b fragment rapidly under the acid-catalyzed
conditions that are required for MacDonald-type condensations and this circumvents macrocycle formation.
Alternative routes to 3-aza-neo-CPs will be investigated in the future.
CONCLUSIONS
Neo-confused porphyrins are an interesting class of porphyrin isomers that exhibit reduced stability
compared to porphyrins and N-confused porphyrins. Structures with fused benzo-units or electron-
withdrawing ester moieties are robust compounds that easily form organometallic derivatives. However, in
the absence of these structural units, neo-CPs have more limited stability and while the formation of
organometallic species can still be accomplished, the nickel(II) and palladium(II) complexes are very
unstable in solution. Neo-confused porphyrins of this type, together with their metalated derivatives, exhibit
global aromatic properties, and have strong diamagnetic ring currents, even though the stability of the
system has been undermined. These observations suggest that further exploration of neo-confused
porphyrins should be directed towards structures with fused aromatic rings and/or electron-withdrawing
substituents.
Experimental Section
Melting points are uncorrected. NMR spectra were recorded using a 400 or 500 MHz NMR
1
spectrometer and were run at 302 K unless otherwise indicated. H NMR values are reported as
chemical shifts δ, relative integral, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad peak) and coupling constant (J). Chemical shifts are reported in parts per

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1
3
1
13
million (ppm) relative to CDCl ( H residual CHCl δ 7.26, C CDCl triplet δ 77.23) or DMSO-
3
3
3
1
13
d ( H residual DMSO-d pentet δ 2.49, C DMSO-d heptet δ 39.7), and coupling constants were
6
5
6
1
1
taken directly from the spectra. NMR assignments were made with the aid of H- H COSY, HSQC,
DEPT-135, and NOE difference proton NMR spectroscopy. 2D experiments were performed by
using standard software. High-resolution mass spectra (HRMS) were obtained by using a double
1
13
focusing magnetic sector instrument. H and C NMR spectra for all new compounds are reported
in Supporting Information.
Ethyl 5-phenylpyrrole-3-carboxylate (16). Acetophenone oxime 14 (2.00 g, 14.8 mmol) and 1,4-
diazabicyclo[2.2.2]octane (180 mg) were dissolved in dichloromethane (40 mL) and cooled to -10
°
C. A mixture of ethyl propiolate (1.4 mL, 1.35 g, 1.38 mmol) in dichloromethane (15 mL) was
o
added dropwise over 10 min while maintaining the temperature at -10 C. The reaction was
warmed to room temperature and stirred for 20 h. The solvent was evaporated under reduced
pressure and the residue purified by flash chromatography on silica gel eluting with 10% ethyl
acetate-petroleum ether (60-90) to give a mixture of E- and Z-isomers of ethyl 3-(1-
phenylethylideneamino-oxy)acrylate in a ratio of 9:1 (2.449 g, 10.7 mmol, 77%) as a colorless oil.
1
E-isomer (major): H NMR (500 MHz, CDCl )  1.29 (3H, t, J = 7.1 Hz), 2.36 (3H, s), 4.20 (2H,
3
q, J = 7.1 Hz), 5.68 (1H, d, J = 12.5 Hz), 7.38-7.44 (3H, m), 7.68-7.71 (2H, m),   d, J =
1
1
4
7
2.5 Hz). Z-isomer (minor): H NMR (500 MHz, CDCl )  1.32 (3H, t, J = 7.2 Hz), 2.47 (3H, s),
3
.21 (2H, q, J = 7.2 Hz), 4.93 (1H, d, J = 7.4 Hz), 7.39-7.45 (3H, m),   d, J = 7.4 Hz),
.67-7.70 (2H, m). A solution of the foregoing oil (300 mg, 1.30 mmol) in toluene (7.5 mL) was
heated to 175 °C for 2 h under microwave irradiation. The solvent was evaporated under reduced
pressure and the residue purified on silica gel, eluting with 25% ethyl acetate-petroleum ether (60-

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9
0), to give the pyrrole ester (216 mg, 1.00 mmol, 78%) as a pale orange oil. A sample crystallized
o
35
o
1
from chloroform-hexanes to give an off-white solid, mp 152-153 C (lit. mp 149-151 C). H
NMR (500 MHz, CDCl )  1.36 (3H, t, J = 7.1 Hz, CH CH ), 4.32 (2H, q, J = 7.1 Hz, OCH ),
3
2
3
2
6
.92 (1H, dd, J = 1.6, 2.7 Hz, 4-H), 7.24-7.27 (1H, m, p-H), 7.37-7.40 (2H, m, 2 x m-H), 7.47 (1H,
1
3
dd, J = 1.6, 3.0 Hz, 2-H), 7.48-7.50 (2H, m, 2 x o-H), 8.87 (1H, br s, NH). C NMR (125 MHz,
CDCl )  14.7 (CH ), 60.1 (OCH ), 106.9 (4-CH), 118.4, 124.31, 124.33 (2 x o-CH and 2-CH),
3
3
2
1
27.3 (p-CH), 129.2 (m-CH), 132.0, 133.2, 165.2 (C=O).
2
-Bromo-3’,4’-dimethyl-1,2’-dipyrrylmethane-4,5’-dicarbaldehyde (9b). Sodium hydride
(
60% in mineral oil, 48 mg, 1.2 mmol) was added to a solution of 5-bromopyrrole-3-carbaldehyde
144 mg, 0.827 mmol) in DMF (30 mL) and the mixture was stirred for 30 min at room
(
temperature. A solution of acetoxymethylpyrrole aldehyde 12 (171 mg, 0.875 mmol) in DMF (15
mL) was added dropwise over 10 min, and the mixture stirred for 18 h at 30 ˚C. The mixture was
then diluted with ether and washed with water. The aqueous phase was back extracted with ether
(x3) and the combined organic layers dried over sodium sulfate. After suction filtration, the solvent
was evaporated down under reduced pressure. Recrystallization from ethanol gave the
1
dipyrrylmethane (190 mg, 0.615 mmol, 74%) as a pale brown solid, mp 196-198˚ C. H NMR (500
MHz, CDCl ) δ 1.99 (3H, s, 3’-Me), 2.28 (3H, s, 4’-Me), 5.10 (2H, s, bridge-CH ), 6.68 (1H, d, J
3
2
=
2.0 Hz, 4-H), 7.24 (1H, d, J = 2.0 Hz, 2-H), 9.57 (1H, s), 9.59 (1H, s) (2 x CHO), 9.83 (1H, br
1
3
s, NH). C NMR (125 MHz, CDCl ): δ 8.7 (3’Me), 9.0 (4’-Me), 44.1 (bridge-CH ), 105.9, 111.1
3
2
(4-CH), 120.6, 127.1, 129.1 (2-CH), 129.6, 130.4, 132.3, 177.8 (CHO), 184.4 (CHO). HRMS (EI)
+
m/z: M calcd for C H BrN O 308.0160, found 308.0168.
1
3
13
2
2
2
-Phenyl-3’,4’-dimethyl-1,2’-dipyrrylmethane-4,5’-dicarbaldehyde (9c). Sodium hydride
(60% in mineral oil, 44 mg, 1.1 mmol) was added to a solution of 5-phenyl-3-pyrrolecarbaldehyde

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(147 mg, 0.858 mmol) in DMF (27.5 mL) and the mixture stirred for 30 min at room temperature.
A solution of acetoxymethylpyrrole aldehyde 12 (156 mg, 0.80 mmol) in DMF (13.8 mL) was
added dropwise over 10 min, and the mixture was stirred for 18 h at 30 ˚C. The mixture was then
diluted with ether and washed with water. The aqueous phase was back extracted with ether (x3)
and the combined organic layers dried over sodium sulfate. After suction filtration, the solvent was
evaporated down under reduced pressure. Recrystallization from ethanol gave the dipyrrylmethane
1
o
(
185 mg, 0.604 mmol, 75%) as a brown solid, mp 202-204 ˚C. H NMR (500 MHz, CDCl , 50 C)
3
δ 1.81 (3H, s, 3’-Me), 2.23 (3H, s, 4’-Me), 5.05 (2H, s, bridge-CH ), 6.67 (1H, d, J = 1.85 Hz, 4-
2
H), 7.28 (1H, d, J = 1.85 Hz, 2-H), 7.31-7.34 (2H, m, 2 x o-H), 7.41-7.45 (3H, m, m- & p-H), 8.67
1
3
(
1H, br s, NH), 9.55 (1H, s), 9.76 (1H, s) (2 x CHO). C NMR (125 MHz, CDCl ): δ 8.3 (3’Me),
3
8
1
.8 (4’-Me), 43.6 (CH ), 109.0 (4-CH), 126.9, 128.8 (2 x o-CH), 129.1 (2-CH), 129.3, 129.5,
2
+
29.6, 130.9, 131.5, 131.7, 137.2, 177.4 (CHO), 185.4 (CHO). HRMS (ESI) m/z: M calcd for
C H N O 306.1368, found 306.1378.
1
9
18
2
2
1
(5-Formyl-3’,4’-dimethyl-2-pyrrolylmethyl)imidazole-4-carbaldehyde
(22a).
Sodium
hydride (60% in mineral oil, 26 mg, 0.65 mmol) was added to a solution of formyl imidazole (87
mg, 0.90 mmol) in THF (16 mL) and the mixture was stirred for 30 min at room temperature. A
solution of acetoxymethylpyrrole aldehyde 12 (92 mg, 0.47 mmol) in THF (8 mL) was added
dropwise over 10 min, and the mixture was stirred for 18 h at 30 ˚C. The mixture was then diluted
with ether and washed with water. The aqueous phase was back extracted with ether (x3) and the
combined organic layers dried over sodium sulfate. After suction filtration, the solvent was
evaporated under reduced pressure. Recrystallization from ethanol gave the dialdehyde (66 mg,
1
0
.28 mmol, 60%) as a brown solid, mp 198-200 ˚C. H NMR (500 MHz, DMSO-d ) δ 1.96 (3H,
6
s, 3-Me), 2.18 (3H, s, 4-Me), 5.21 (2H, s, bridge-CH ), 7.90 (1H, d, J = 1.2 Hz, imidazole-2-H),
2

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1
1
.99 (1H, d, J = 1.2 Hz, imidazole-5-H), 9.57 (1H, s, imidazole-CHO), 9.67 (1H, s, pyrrole-CHO),
1
3
1.83 (1H, br s, NH). C NMR (125 MHz, DMSO-d ): δ 8.1 (3’-Me), 8.8 (4’-Me), 41.3 (CH ),
6
2
19.0, 127.3 (imidazole-5-CH), 129.1, 131.3, 139.6 (imidazole-2-CH), 141.7, 178.1 (pyrrole-
+
CHO), 185.4 (imidazole-CHO). HRMS (ESI) m/z: [M + H] calcd for C H N O 232.1086,
1
2
14
3
2
found 232.1081.
(5-Formyl-3’,4’-dimethyl-2-pyrrolylmethyl)-2-methylimidazole-4-carbaldehyde
1
(22b).
Sodium hydride (60% in mineral oil, 48 mg, 1.2 mmol) was added to a solution of 4(5)-formyl-2-
methylimidazole (104 mg, 0.944 mmol) in THF (21.5 mL) and the mixture was stirred for 30 min
at room temperature. A solution of acetoxymethylpyrrole aldehyde 12 (122 mg, 0.625 mmol) in
THF (11 mL) was added dropwise over 10 min, and the mixture was stirred for 18 h at 30˚C. The
mixture was then diluted with ether and washed with water. The aqueous phase was back extracted
with ether (x3) and the combined organic layers dried over sodium sulfate. After suction filtration,
the solvent was evaporated under reduced pressure. Recrystallization from ethanol gave the
1
dialdehyde (78 mg, 0.32 mmol, 52%) as a brown solid, mp 200-202 ˚C. H NMR (500 MHz,
CDCl ) δ 1.96 (3H, s, 3’-Me), 2.26 (3H, s, 4’-Me), 2.43 (3H, s, imidazole-Me), 5.11 (2H, s, bridge-
3
CH ), 7.46 (1H, s), 9.49 (1H, s, pyrrole-CHO), 9.66 (1H, s, imidazole-CHO), 11.19 (1H, br s, NH).
2
1
3
C NMR (125 MHz, CDCl ): δ 8.7 (3’-Me), 9.1 (4’-Me), 13.4 (imidazole-Me), 42.0 (CH ), 120.5,
3
2
1
26.3 (imidazole-5-CH), 129.8, 130.4, 140.4, 147.2, 178.1 (pyrrole-CHO), 185.6 (imidazole-
+
CHO). HRMS (ESI) m/z: [M + Na] calcd for C H N O Na 268.1062, found 268.1065.
1
3
15
3
2
2
-Bromo-8,12-diethyl-7,13,17,18-tetramethyl-1-aza-21-carba-1H,23H-porphyrin (8b). p-
Toluenesulfonic acid (56 mg) in methanol (6 mL) was added dropwise to a stirred mixture of
dialdehyde 9b (31 mg, 0.10 mmol) and dipyrrylmethane dicarboxylic acid 10 (32 mg, 0.10 mmol)
in dichloromethane (50 mL) and methanol (6 mL). The resulting mixture was stirred for 16 h at

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room temperature. The solution was stirred vigorously with a 0.2% aqueous ferric chloride solution
for 1 h to oxidize the phlorin intermediate. The organic phase was separated, and the aqueous
solution back extracted with dichloromethane. The combined organic solutions were washed with
water and 5% aqueous sodium bicarbonate solution, and the solvent was removed under reduced
pressure. The residue was purified by column chromatography on grade 3 alumina eluting with
3
:1 hexanes-dichloromethane. The product was collected as a pink-purple fraction.
Recrystallization from chloroform-hexanes gave the neo-confused porphyrin 8b (20.4 mg, 0.0407
mmol, 41%) as a purple powder, mp >300 ˚C. UV-vis (1% Et N-CHCl ): max/nm (log ) 337
3
3
(4.64), 394 (4.92), 476 (sh, 3.70), 509 (3.94), 544 (4.14), 564 (3.86), 614 (3.78). UV-vis (1% TFA-
CHCl ): max/nm (log ) 368 (4.74), 405 (4.80), 422 (sh, 4.78), 538 (3.78), 581 (3.83), 665 (3.87).
3
1
H NMR (500 MHz, CDCl ) δ 0.21 (1H, br s, 21-H), 1.58 (3H, t, J = 7.7 Hz), 1.65 (3H, t, J = 7.7
3
Hz) (2 x CH CH ), 2.97 (3H, s, 17 -Me), 3.009 (3H, s), 3.014 (3H, s) (7,18-Me), 3.15 (3H, s, 13-
2
3
3
4
Me), 3.45 (2H, q, J = 7.7 Hz, 8-CH ), 3.61 (2H, q, J = 7.7 Hz, 12-CH ), 7.92 (1H, s, 3-H), 8.46
2
2
1
3
(
1H, s, 15-H), 8.54 (1H, s, 10-H), 8.90 (1H, s, 5-H), 9.45 (1H, s, 20-H). C NMR (125 MHz,
CDCl ) δ 11.01, 11.02, 11.04, 11.1 (7,13,17,18-Me), 16.7, 16.8 (2 x CH CH ), 19.3 (2 x CH ),
3
2
3
2
9
1
3.5 (15-CH), 94.1 (10-CH), 109.1, 110.3 (20-CH), 113.0 (5-CH), 118.7 (21-CH), 119.8 (3-CH),
1
22.9, 135.0, 135.6, 140.2, 141.0, 141.8, 141.9, 143.3, 144.5. H NMR (500 MHz, TFA-CDCl ,
3
2
+
dication 8bH ) δ -2.20 (1H, s, 21-H), 1.55 (3H, t, J = 7.7 Hz), 1.59 (3H, t, J = 7.7 Hz) (2 x
2
CH CH ), 3.17 (3H, s), 3.20 (3H, s) (17,18-Me), 3.24 (3H, s, 13-Me), 3.29 (3H, s, 7-Me), 3.61-
2
3
3
.69 (4H, overlapping quartets, 8,12-CH ), 7.77 (1H, s, 3-H), 9.09 (1H, s, 15-H), 9.17 (1H, s, 10-
2
1
3
2+
H), 9.73 (1H, s, 20-H), 10.12 (1H, s, 5-H). C NMR (125 MHz, TFA-CDCl , dication 36aH ) δ
3
2
1
9
1.0, 11.3, 11.4, 11.8 (7,13,17,18-Me), 15.7 (2 x CH CH ), 19.4 (CH ), 19.7 (CH ), 94.8 (15-CH),
2 3 2 2
6.4 (10-CH), 109.0 (21-CH), 111.1, 113.7 (5-CH), 117.7 (3-CH), 119.0 (20-CH), 126.3, 133.1,

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1
37.0, 140.2, 142.4, 142.7, 144.4, 146.3, 147.8, 148.0, 151.0, 154.7. HRMS (ESI) m/z: [M + H]+
calcd for C H BrN 501.1654, found 501.1652.
2
8
30
4
2
-Phenyl-8,12-diethyl-7,13,17,18-tetramethyl-1-aza-21-carba-1H,23H-porphyrin (8c). p-
Toluenesulfonic acid (56 mg) in methanol (6 mL) was added dropwise to a stirred mixture of
dialdehyde 9c (29 mg, 0.94 mmol) and dipyrrylmethane dicarboxylic acid 10 (30 mg, 0.94 mmol)
in dichloromethane (50 mL) and methanol (6 mL). The mixture was stirred for 16 h at room
temperature, a 0.2% aqueous ferric chloride solution was added, and the resulting biphasic mixture
was vigorously stirred for 1 h. The organic phase was separated, and the aqueous solution back
extracted with dichloromethane. The combined organic solutions were washed with water and 5%
aqueous sodium bicarbonate solution, and the solvent was removed under reduced pressure. The
residue was purified by column chromatography on grade 3 alumina eluting with 3:1 hexanes-
dichloromethane, and the product was collected as a pink-purple fraction. Recrystallization from
chloroform-hexane gave the neo-confused porphyrin 8c (19.5 mg, 0.039 mmol, 41%) as a purple
powder, mp >300 ˚C. UV-vis (1% Et N-CHCl ): max/nm (log ) 348 (4.64), 398 (4.91), 478 (sh,
3
3
3
.72), 510 (3.92), 544 (4.09), 565 (4.64), 614 (3.81). UV-vis (1% TFA-CHCl ): max/nm (log )
3
1
3
82 (4.88), 415 (4.78), 538 (3.84), 582 (3.84), 671 (3.84). H NMR (500 MHz, CDCl ) δ 0.73 (1H,
3
br s, NH), 0.88 (1H, br s, 21-CH), 1.62 (3H, t, J = 7.7 Hz), 1.68 (3H, t, J = 7.7 Hz) (2 x CH CH ),
2
3
2
.89 (3H, s, 18-Me), 2.99 (3H, s, 17-Me), 3.07 (3H, s, 7-Me), 3.19 (3H, s, 13-Me), 3.51 (2H, q, J
7.7 Hz, 8-CH ), 3.66 (2H, q, J = 7.7 Hz, 12-CH ), 7.64 (1H, t, J = 7.4 Hz, p-H), 7.73 (2H, t, J =
=
2
2
7
.5 Hz, 2 x m-H), 7.96 (1H, s, 3-H), 7.99 (2H, d, J = 7.5 Hz, 2 x o-H), 8.55 (1H, s, 15-H), 8.65
1
3
(
1H, s, 10-H), 9.12 (1H, s, 5-H), 9.42 (1H, s, 20-H). C NMR (125 MHz, CDCl ): δ 11.0 (13-Me),
3
1
1.1 (7,18-Me), 11.2 (17-Me), 16.8 (CH CH ), 17.1 (CH CH ), 19.4 (12-CH ), 19.5 (8-CH ), 92.8
2 3 2 3 2 2
(15-CH), 93.9 (10-CH), 111.6 (20-CH), 114.2 (5-CH), 117.8 (3-CH), 120.1 (21-CH), 122.9, 128.5

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(p-CH), 129.1 (2 x m-CH), 131.5 (2 x o-CH), 132.5, 133.8, 135.4, 139.5, 139.9, 140.7, 141.2,
1
1
3
3
41.7, 142.4, 143.3, 144.2, 154.0, 160.1, 161.5. H NMR (500 MHz, TFA-CDCl , dication
3
2
+
6aH ) δ -2.78 (1H, s, 21-H), 1.59 (3H, t, J = 7.7 Hz), 1.64 (3H, t, J = 7.7 Hz) (2 x CH CH ),
2
2
3
.15 (3H, s, 18-Me), 3.20 (3H, s, 17-Me), 3.28 (3H, s, 13-Me), 3.33 (3H, s, 7-Me), 3.67-3.77 (4H,
m, 2 x CH CH ), 7.75-7.80 (5H, m, Ph), 7.84 (1H, s, 3-H), 9.26 (1H, s, 15-H), 9.34 (1H, s, 10-H),
2
3
1
3
2+
9
.93 (1H, s, 20-H), 9.99 (1H, s, 5-H). C NMR (125 MHz, TFA-CDCl , dication 36aH ): δ 10.9
3 2
(
17-Me), 11.3 (13-Me), 11.4 (7-Me), 11.7 (18-Me), 15.7 (2 x CH CH ), 19.5 (CH ), 19.8 (CH ),
2 3 2 2
9
4.6 (15-CH), 96.1 (10-CH), 108.1 (21-CH), 114.6 (20-CH), 115.2 (3-CH), 119.9, 126.3, 128.7,
1
29.8 (2 x m-CH), 130.7 (p-CH), 132.1 (2 x o-CH), 133.0, 136.8, 140.2, 141.04, 142.4, 142.8,
+
1
46.1, 147.0, 147.7, 149.8, 149.9, 153.6. HRMS (ESI) m/z: [M + H] calcd for C H N 499.2862,
3
4
35
4
found 499.2857.
[2-Bromo-8,12-diethyl-7,13,17,18-tetramethyl-1-aza-21-carba-1H,23H-
porphyrinato]nickel(II) (18b). Neo-confused porphyrin 8b (15.0 mg, 0.030 mmol) was dissolved
in pyridine (15 mL) along with nickel(II) acetate (15.0 mg) and the mixture was stirred under
reflux for 1 h. The mixture was diluted with dichloromethane, washed with water and the aqueous
solution back extracted with dichloromethane. The combined organic solutions were evaporated
under reduced pressure. The residue was purified by column chromatography on grade 3 alumina
eluting with 3:1 hexanes-dichloromethane to give the nickel neo-confused porphyrin (10.0 mg,
0
.0179 mmol, 60%) as a brown powder, mp >300 ˚C. UV-vis (CHCl ): max/nm (log ) 334 (4.32),
3
1
3
83 (4.74), 432 (sh, 4.13), 523 (3.66), 631 (3.31), 675 (3.30). H NMR (500 MHz, CDCl ) δ 1.62
3
(
3H, t, J = 7.7 Hz), 1.65 (3H, t, J = 7.7 Hz) (2 x CH CH ), 2.88 (3H, s), 2.92 (3H, s), 3.00 (3H, s),
2 3
3
.09 (3H, s) (7,13,17,18-Me), 3.53-3.59 (4H, m, 2 x CH CH ), 7.92 (1H, s, 3-H), 8.56 (1H, s, 15-
2 3
1
3
H), 8.88 (1H, s, 10-H), 8.97 (1H, s, 5-H), 9.48 (1H, s, 20-H). C NMR (partial data derived from

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HSQC and DEPT-135 spectra)  10.7, 10.8, 10.90, 10.95, 16.9, 17.0, 19.2 (CH ), 19.3 (CH ), 94.4
2
2
+
(
15-CH), 96.9 (10-CH), 109.7 (20-CH), 112.4 (5-CH), 123.4 (3-CH). HRMS (ESI) m/z: M calcd
for C H BrN Ni 556.0773, found 556.0772.
2
8
27
4
[2-Bromo-8,12-diethyl-7,13,17,18-tetramethyl-1-aza-21-carba-1H,23H-
porphyrinato]palladium(II) (19b). Neo-confused porphyrin 8b (10.0 mg, 0.019 mmol) was
dissolved in acetonitrile (10 mL) along with palladium(II) acetate (10.0 mg) under reflux
conditions for 1 h. The mixture was diluted with dichloromethane and washed with water. The
organic solution was evaporated under reduced pressure and the residue was purified by column
chromatography on grade 3 alumina eluting with 3:1 hexanes-dichloromethane to give the
palladium neo-confused porphyrin (4.8 mg, 0.0079 mmol, 40%) as a green solid, mp >300 ˚C.
UV-vis (CHCl ): max/nm (log ) 336 (4.45), 377 (4.66), 426 (sh, 4.40), 499 (3.78), 532 (3.82),
3
1
6
03 (3.61), 644 (3.62). H NMR (500 MHz, CDCl ) δ 1.66 (3H, t, J = 7.7 Hz), 1.68 (3H, t, J = 7.7
3
Hz) (2 x CH CH ), 2.98 (3H, s, 17-Me), 3.00 (3H, s, 18-Me), 3.09 (3H, s, 13-Me), 3.14 (3H, s, 7-
2
3
Me) 3.57-3.65 (4H, m, 2 x CH CH ), 7.90 (1H, s, 3-H), 8.65 (1H, s, 15-H), 8.94 (1H, s, 10-H),
2
3
1
3
9
.08 (1H, s, 5-H), 9.52 (1H, s, 20-H). C NMR (partial data derived from the HSQC spectrum) 
9
5.1 (15-CH), 97.9 (10.CH), 111.4 (20-CH), 114.8 (5-CH), 123.0 (3-CH). HRMS (ESI) m/z: M+
calcd for C H2779BrN4108Pd 606.0458, found 606.0480.
2
8
Conflicts of Interest
There are no conflicts to declare.
Acknowledgements

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This work was supported by the National Science Foundation under grants CHE-1465049 and
CHE-1855240.
References and Notes
1
.
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3
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Nardis, D. Monti, M. Stefanelli and C. Di Natale, Chem. Rev., 2017, 117, 2517–2583.
(a) M. Brunel, F. Chaput, S. A. Vinogradov, B. Campagne, M. Canva and J. P. Boilot,
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Fleitz, J. Phys. Chem. A, 2003, 107, 11331-11339.
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.
(a) E. Rose, B. Andrioletti, S. Zrig and M. Quelquejen-Etheve, Chem. Soc. Rev., 2005, 34,
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Graphical Abstract
R
Me
R
Me
N
Me
N
Me
Me
HN
H+
N
OHC
CHO
[
O]
HO C
CO2H
N
HN
2
NH HN
Me
Me
Me
Et
Et
Et
Et
R = Br or Ph
New examples of neo-confused porphyrins are reported. These retain global diatropic
characteristics but are relatively unstable in solution.