An alternative synthesis of benziporphyrins starting from isophthaloyl chloride

Article abstract of DOI:10.1142/S1088424617500493

An alternative route to benziporphyrins has been developed. Reaction of an α-unsubstituted pyrrole ethyl ester with isophthaloyl chloride in the presence of aluminum chloride afforded a diketone that underwent selective reduction with diborane to give a b

Full text of DOI:10.1142/S1088424617500493

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2017; 21: 1–7
DOI: 10.1142/S1088424617500493
Published at http://www.worldscinet.com/jpp/
An alternative synthesis of benziporphyrins starting
from isophthaloyl chloride
William T. Darrow and Timothy D. Lash*◊
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160, U.S.A.
Received 2 April 2017
Accepted 17 May 2017
ABSTRACT:An alternative route to benziporphyrins has been developed. Reaction of an α-unsubstituted
pyrrole ethyl ester with isophthaloyl chloride in the presence of aluminum chloride afforded a diketone
that underwent selective reduction with diborane to give a benzitripyrrane. Cleavage of the ethyl
esters with sodium hydroxide in refluxing ethylene glycol, followed by acid catalyzed condensation
with a pyrrole dialdehyde and oxidation with DDQ, generated the targeted benziporphyrin product.
Spectrophotometric titration of the benziporphyrin with trifluoroacetic acid (TFA) demonstrated the
sequential formation of mono- and dicationic species. At lower dilutions, the free base benziporphyrin
5
showed unusually strong JHH coupling between two adjacent methyl substituents, indicating that the
connecting unit has substantial olefinic characteristics.
KEYWORDS: carbaporphyrinoids, benziporphyrins, “3 + 1” syntheses, aromaticity, protonation.
undergo selective oxidation reactions with silver(I)
INTRODUCTION
acetate [12, 17], and rhodium(III) derivatives can undergo
Carbaporphyrinoid systems [1, 2], including true
ring contraction reactions to afford metalated carbapor-
carbaporphyrins (e.g. 1a and 1b) [3, 4], azuliporphy-
rins (e.g. 2) [5], tropiporphyrins (e.g. 3) [6] and benzi-
porphyrins (e.g. 4) [7], have been widely investigated
over the last 20 years (Chart 1). Benziporphyrins 4 have
emerged as an important class of porphyrin analogs with
unique spectroscopic and chemical properties [7]. The
benziporphyrin system essentially differs from regular
porphyrins by having a benzene unit in place of one of
the pyrrole moieties. This results in cross-conjugated
structures that are devoid of macrocyclic aromatic prop-
erties [8]. However, electron-donating substituents such
as methoxy groups introduce a degree of diatropic char-
phyrins [21]. Furthermore, dihydrobenziporphyrins have
been utilized as components of nanomolecular arrays
[22] and have shown promise as fluorescent zinc cation
detectors [23].
Several routes to benziporphyrins have been described.
Acid catalyzed “3 + 1” MacDonald condensation of isoph-
thalaldehyde with tripyrranes 5, followed by oxidation
with DDQ, affords meso-unsubstituted benziporphyrins
4 (Scheme 1) [10, 14]. Alternatively, benzene dicarbinols
6 react with 3 equivalents of pyrrole and 2 equivalents
of an aromatic dialdehyde in the presence of boron tri-
fluoride etherate to give meso-tetraarylbenziporphyrins 7
acter [9] and protonated benziporphyrins also appear to
(Scheme 1) [11, 17]. These strategies have been adapted
possess significant diamagnetic ring currents [9–15].
for the synthesis of heterobenziporphyrins [13,15], naph-
Benziporphyrins act as dianionic organometallic ligands,
forming stable derivatives with Ni(II), Pd(II), Pt(II), etc.
[13–20]. In addition, meso-tetraarylbenziporphyrins
thiporphyrins [14] and fully aromatic oxybenziporphyrins
[10, 14, 24, 25]. In order to further extend our inquiries
into these types of porphyrinoid analogs, we have inves-
tigated the development of new synthetic routes to ben-
ziporphyrins and related systems. Herein, we report an
◊ SPP Full member in good standing.
alternative strategy for preparing benziporphyrins using
isophthaloyl chloride as the key precursor.
*Correspondence to: Timothy D. Lash, tel. +1 309-438-8554,
fax: +1 309-438-5538; email: tdlash@ilstu.edu
Copyright © 2017 World Scientific Publishing Company

2
W. T. DARROW AND T. D. LASH
Scheme 1. Earlier syntheses of benziporphyrins
and brine. The organic layer was dried over sodium sul-
fate and the solvent removed under reduced pressure.
The residue was purified by column chromatography on
silica gel eluting with dichloromethane and then recrys-
tallized from 95% ethanol to give the diketone (1.05 g,
2.26 mmol, 50%) as a yellow crystalline solid, mp 146–
147°C. 1H NMR (500 MHz, CDCl3): δH, ppm 1.38 (6H, t,
J = 7.2 Hz, 2 × CH2CH3), 1.99 (6H, s, 2 × pyrrole 3-Me),
2.28 (6H, s, 2 × pyrrole 4-Me), 4.36 (4H, q, J = 7.2 Hz,
2 × OCH2), 7.62 (1H, t, J = 7.7 Hz, 5-H), 7.88 (2H, dd,
J = 1.7, 7.7 Hz, 4,6-H), 8.01 (1H, t, J = 1.7 Hz, 2-H), 9.42
(2H, br s, 2 × NH). 13C NMR (125 MHz, CDCl3): δC, ppm
10.2 (2 × pyrrole 3-Me), 11.6 (2 × pyrrole 4-Me), 14.6
(2 × CH2CH3), 61.0 (2 × OCH2), 123.7, 127.91, 127.94,
129.08 (5-CH), 129.15 (2-CH), 129.6, 132.0 (4,6-CH),
139.6, 161.2 (2 × ester C=O), 186.4 (2 × bridge C=O).
HR-MS (EI) m/z 464.19445 (calcd. for C26H28N2O6 [M]+
464.19474).
1,3-Bis(5-ethoxycarbonyl-3,4-dimethyl-2-pyrrolyl-
methyl)benzene (17). Boron trifluoride etherate (3.5 mL)
in THF (8 mL) was added dropwise to a stirred solution
of diketone 16 (500 mg, 1.08 mmol) and sodium boro-
hydride (409 mg, 10.8 mmol) in THF (11 mL) under a
nitrogen atmosphere. After the mixture was stirred for
1.5 h at room temperature, the solvent was removed under
reduced pressure, methanol was added and the resulting
mixture stirred under reflux for 1 h. The methanol was
removed on a rotary evaporator and the residue dispersed
between ether and water. The ether layer was separated
and washed with 10% sodium bicarbonate solution and
then with water. The ether solution was dried over magne-
sium sulfate and the solvent removed under reduced pres-
sure. The residue was purified on a silica column eluting
with dichloromethane. The product fraction was evapo-
rated under reduced pressure to give the benzitripyrrane
Chart 1. Selected carbaporphyrinoid structures
EXPERIMENTAL
Melting points are uncorrected. NMR spectra were
recorded using a 500 MHz NMR spectrometer and were
run at 300 K unless otherwise indicated. 1H NMR values
are reported as chemical shifts δ, relative integral, mul-
tiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad peak) and coupling constant (J).
Chemical shifts are reported in parts per million (ppm)
relative to CDCl3 (1H residual CHCl3 δ 7.26, 13C CDCl3
triplet δ 77.23) and coupling constants were taken directly
from the spectra. NMR assignments were made with the
1
aid of H–1H COSY, HSQC, DEPT-135 and nOe differ-
ence proton NMR spectroscopy. 2D experiments were
performed by using standard software. High-resolution
mass spectra (HRMS) were carried out by using a double
focusing magnetic sector instrument.
1,3-Bis(5-ethoxycarbonyl-3,4-dimethyl-2-pyrroloyl)
benzene (16). Aluminum chloride (3.00 g, 22.5 mmol)
was added to a solution of ethyl 3,4-dimethylpyrrole-2-
carboxylate (1.50 g, 8.97 mmol) and isophthaloyl chloride
(1.00 g, 4.93 mmol) in carbon disulfide (50 mL) and the
resulting mixture was stirred under reflux overnight.
The solvent was removed under reduced pressure, water
(100 mL) was cautiously added, and the mixture was
allowed to stand overnight. The mixture was extracted
withdichloromethaneandwashedsequentiallywithwater,
10% hydrochloric acid, 10% sodium bicarbonate solution,
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 2–7

AN ALTERNATIVE SYNTHESIS OF BENZIPORPHYRINS STARTING FROM ISOPHTHALOYL CHLORIDE
3
(240 mg, 0.55 mmol, 51%) as a pale reddish solid, mp
8,9,13,14,18,19-Hexamethylbenziporphyrin (20).
Benzitripyrrane diethyl ester 17 (100 mg, 0.215 mmol)
was refluxed with sodium hydroxide (40 mg) in ethylene
glycol under nitrogen for 1 h. The mixture was cooled to
room temperature, diluted with water, and extracted with
hexanes. The hexane solution was washed with water,
dried over sodium sulfate and the solvent removed under
reduced pressure. The resulting intermediate was used
immediately for the next step in the synthesis.
184–185°C. 1H NMR (500 MHz, CDCl3): δH, ppm 1.32
(6H, t, J = 7.1 Hz), 1.94 (6H, s, 2 × pyrrole 3-Me), 2.27
(6H, s, 2 × pyrrole 4-Me), 3.87 (2 × bridge-CH2), 4.26
(4H, q, J = 7.1 Hz, 2 × OCH2), 6.92 (1H, br, 2-H), 6.9 (2H,
br dd, J = 1.6, 7.6 Hz, 4,6-H), 7.22 (1H, t, J = 7.6 Hz, 5-H),
8.38 (2H, br s, 2 × NH). 13C NMR (125 MHz, CDCl3): δC,
ppm 9.1 (2 × pyrrole 3-Me), 10.8 (2 × pyrrole 4-Me), 14.8
(2 × CH2CH3), 32.5 (2 × bridge-CH2), 59.9 (2 × OCH2),
117.7, 117.8, 126.9 (4,6-CH), 127.6, 128.8 (2-CH), 129.4
(5-CH), 131.7, 139.2, 161.9 (2 × ester C=O). HR-MS (EI)
m/z 436.23534 (calcd. for C26H32N2O4 [M]+ 436.23621).
1,3-Dihydroxymethylbenzene dimethylsulfonate
(12) [26]. Methanesulfonyl chloride (1.7 mL, 22 mmol)
was added dropwise over a period of 5 min to a stirred
mixture of 1,3-benzenedimethanol (1.38 g, 10.0 mmol)
and triethylamine (2.8 mL, 20 mmol) in dichloromethane
(40 mL) while maintaining the temperature below 5oC
with the aid of a salt-ice bath. The resulting mixture was
stirred at room temperature for 1 h. The solution was
sequentially washed with water, 2 M hydrochloric acid
and brine, and then dried over sodium sulfate. The sol-
vent was removed on a rotary evaporator and the resi-
due treated with ether, suction filtered and then washed
with additional ether to give the dimesylate (2.218 g,
7.54 mmol, 75%) as a white solid, mp 91–92°C. The
product was used in the next step without further purifi-
The deprotected benzitripyrrane was dissolved in
dichloromethane, 3,4-dimethylpyrrole-2,5-dicarbalde-
hyde [27, 28] (36.6 mg, 0.229 mmol) was added, and
nitrogen was bubbled through the mixture for 5 min.
TFA (1 mL) was added and the resulting solution was
stirred for 2 h in the dark. DDQ (51 mg, 0.22 mmol) was
then added and the mixture stirred for a further 1 h. The
solution was washed with 5% sodium bicarbonate solu-
tion and water, and then dried over sodium sulfate. The
solvent was removed under reduced pressure and the
residue purified by column chromatography on grade 3
alumina eluting with dichloromethane. Recrystalliza-
tion from chloroform-methanol gave the benziporphyrin
(21 mg, 0.052 mmol, 24%) as dark blue crystals, mp
>300°C. UV-vis (1% Et3N-CH2Cl2, free base): lmax, nm
(log ε) 309 (4.71), 379 (4.80), 610 (sh, 3.69), 658 (3.79),
714 (3.63). UV-vis (5 equivalents TFA-CH2Cl2, monoca-
tion 20H+): lmax, nm (log ε) 395 (4.84), 486 (3.29), 522
(3.59), 562 (3.70), 684 (sh, 3.45), 756 (3.93), 837 (4.22).
UV-vis(1%TFA-CH2Cl2, dication20H22+):lmax, nm(logε)
308 (4.56), 398 (4.84), 529 (3.36), 571 (3.34), 723 (3.86),
1
cation. H NMR (400 MHz, CDCl3): δH, ppm 2.98 (6H,
s), 5.25 (4H, s), 7.45–7.48 (4H, m). 13C NMR (125 MHz,
CDCl3): δC, ppm 38.5, 70.8, 129.0, 129.7, 134.6. 13C
NMR (125 MHz, d6-DMSO): δC, ppm 37.2, 71.2, 128.8,
129.20, 129.26, 134.8. HR-MS (EI) m/z 294.0233 (calcd.
for C10H14O6S2 [M]+ 294.0232).
1
779 (3.87). H NMR (500 MHz, CDCl3): δH, ppm 2.32
(6H, q, J = 1.0 Hz, 9,18-CH3), 2.39 (6H, s, 13,14-CH3),
2.41 (6H, q, J = 1.0 Hz, 8,19-CH3), 6.52 (6H, s, 11,16-H),
7.25 (2H, s, 6,21-H), 7.74 (1H, t, J = 7.6 Hz, 3-H), 7.90
(1H, br t, 22-H), 7.96 (2H, dd, J = 1.6, 7.6 Hz, 2,4-H), 8.93
(1H, br s, 2 × NH). 1H NMR (500 MHz, TFA-CDCl3, dica-
tion 20H22+): δH, ppm 2.476 (6H, br s, 9,18-CH3), 2.485
(6H, s, 13,14-CH3), 2.63 (6H, br s, 8,19-CH3), 5.22 (1H,
br s, 22-H), 6.98 (6H, s, 11,16-H), 7.95 (1H, t, J = 7.7 Hz,
3-H), 8.00 (2H, s, 6,21-H), 8.24 (2H, dd, J = 1.2, 7.7 Hz,
2,4-H), 9.52 (1H, br s, 2 × NH). 13C NMR (125 MHz,
CDCl3): δC, ppm 10.2 (2 × CH3), 10.5 (2 × CH3), 10.7 (2 ×
CH3), 92.8 (11,16-CH), 122.4 (6,21-CH), 125.0 (22-CH),
128.9 (3-CH), 134.2, 134.90, 134.96, 137.4 (2,4-CH),
141.9, 149.0, 157.2, 169.7. 13C NMR (125 MHz, TFA-
CDCl3, dication 20H22+): δC, ppm 9.5 (2 × CH3), 10.0 (2 ×
CH3), 10.6 (8,19-CH3), 94.2 (11,16-CH), 109.8 (22-CH),
127.6 (6,21-CH), 131.7, 133.5 (3-CH), 135.9, 139.8 (2,4-
CH), 141.5, 143.4, 148.7, 155.2, 163.0. HR-MS (EI) m/z
405.22113 (calcd. for C28H27N3 [M]+ 405.22050).
1,3-Bis(2-pyrrolylmethyl)benzene (11). Dimesylate
12 (612 mg, 2.08 mmol) was dissolved in a mixture of
pyrrole (10 mL) and dichloromethane (20 mL) and the
mixture stirred at room temperature under nitrogen over-
night. The solvent was removed on a rotary evapora-
tor, initially using a water aspirator and then a vacuum
pump. The residue was purified on a silica gel column
eluting with a mixture of dichloromethane, hexanes and
triethylamine in a ratio of 60:40:1. The product frac-
tion consisted of a mixture of benzitripyrranes. Further
column chromatography enabled the separation of the
desired isomer and following removal of the solvent
under reduced pressure the benzitripyrrane (20.7 mg,
0.088 mmol, 4.2%) was isolated as an off-white solid,
mp 74–76°C. 1H NMR (500 MHz, CDCl3): δH, ppm 3.94
(4H, s, 2 × bridge-CH2), 5.98–6.00 (2H, m, 2 × pyrrole
3-H), 6.14–6.16 (4H, m, 2 × pyrrole 4-H), 6.65–6.67 (2H,
m, 2 × pyrrole 5-H), 7.06–7.09 (3H, m, 2,4,6-H), 7.23–
7.26 (1H, m, 5-H), 7.79 (2H, br s, 2 × NH). 13C NMR
(500 MHz, CDCl3): δC, ppm 34.2 (2 × bridge-CH2), 106.7
(2 × pyrrole 3-CH), 108.6 (2 × pyrrole 4-CH), 117.2
(2 × pyrrole 5-CH), 127.0 (2-CH or 4,6-CH), 129.1
(5-CH), 129.2 (2-CH or 4,6-CH), 130.8, 140.1. HR-MS
(EI) m/z 236.1313 (calcd. for C16H14N2 [M]+ 236.1315).
RESULTS AND DISCUSSION
In an earlier study, good yields of benzitripyrranes
8 were prepared by reacting benzene dicarbinols 6 or
9 with pyrrole in the presence of a catalytic amount of
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 3–7

4
W. T. DARROW AND T. D. LASH
Scheme 4. Preparation of a 2-benzoylpyrrole
Scheme 2. Synthesis of aryl-substituted benzitripyrranes
Scheme 3. Synthesis of an unsubstituted benzitripyrrane
boron trifluoride etherate in refluxing 1,2-dichloroethane
(Scheme 2). However, attempts to carry out similar
condensations with 1,3-benzenedicarbinol 10 failed to give
unsubstituted benzitripyrrane 11 (Scheme 3). In order to
increase the reactivity of the benzene precursor, 10 was
converted into the corresponding dimesylate 12. Further
condensation was carried out by reacting 12 with excess
pyrrole in dichloromethane at room temperature overnight.
This resulted in a mixture of products including the targeted
benzitripyrrane 11 and an isomeric N-confused benzitripyr-
rane 13. Separation of these mixtures could be achieved
by column chromatography on silica gel. However, 11 was
only isolated in 4.2% yield, in part due to the difficulties
encountered in separating the benzitripyrrane from its iso-
mer 13. In principle, the formation of N-confused isomers
could be prevented by using β-substituted pyrroles in place
of pyrrole. However, a large excess of pyrrole is needed to
circumvent further reaction to give oligomeric species and
this makes such a strategy impractical.
In order to overcome these difficulties and generate a
benzitripyrrane intermediate, isophthaloyl chloride was
utilized to generate key carbon–carbon linkages. It had
previously been demonstrated that α-unsubstituted pyr-
role ester 14 could be reacted with benzoyl chloride in
the presence of aluminum chloride to form benzoylpyr-
role 15 (Scheme 4) [29]. This approach was adapted for
the reaction of isophthaloyl chloride with 2 equivalents
of pyrrole ethyl ester 14a. The reactants were refluxed
with aluminum chloride in carbon disulfide to afford
the dipyrrolyl diketone 16 in 50% yield (Scheme 5). In
Scheme 5. Synthesis of a benzitripyrrane from isophthaloyl
chloride
order to utilize this dipyrrolic derivative in the synthe-
sis of benziporphyrins, it was necessary to selectively
reduce the bridging carbonyl groups to methylene units
while retaining the integrity of the terminal ester pro-
tective groups. This was achieved using diborane [30],
which was generated in situ by reacting boron trifluoride
etherate with sodium borohydride. The resulting benzitri-
pyrrane 17 was isolated in 51% yield. Cleavage of the
terminal ester groups with sodium hydroxide in refluxing
ethylene glycol afforded the terminally unsubstituted
tripyrrane analog 18 and this was immediately reacted
with pyrrole dialdehyde 19 in the presence of trifluoro-
acetic acid (TFA) (Scheme 6). Following neutralization
of the solution with triethylamine, the intermediates were
oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ). Purification by column chromatography on
grade 3 alumina and recrystallization from chloroform-
methanol gave benziporphyrin 20 in 24% yield.
Benziporphyrin 20 produced blue colored solutions
and the UV-vis spectrum gave a Soret-like band at 379 nm
together with broad absorptions at higher wavelengths.
Addition of TFA to solutions of 20 in dichloromethane
showed the sequential formation of mono- and dicationic
species 20H+ and 20H22+ (Scheme 6, Figs 1–3). Titra-
tion with TFA showed the formation of a species with a
slightly intensified Soret-like band at 395 nm and weaker
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 4–7

AN ALTERNATIVE SYNTHESIS OF BENZIPORPHYRINS STARTING FROM ISOPHTHALOYL CHLORIDE
5
Me
Me
Me
Me
Me
1. TFA
N
N
HN
2. DDQ
H
18
24%
N
NH
CHO
Me
Me
Me
HN
OHC
19
Me
TFA
Me
20
Me
Me
Me
Me
Me
Me
Me
Me
N
N
N
N
TFA
H
H
H
H
H
N
N
Me
Me
Fig. 2. Benziporphyrin 20 in dichloromethane with 0, 0.5, 1, 2
and 3 equivalents of TFA showing the formation of a monopro-
tonated species. Even though the dichloromethane was deacidi-
fied with basic alumina, some protonation is evident even
before addition of TFA
Me
Me
Me
Me
Me
2+
20H+
20H2
Me
Me
Me
Me
Me
N
N
N
N
H
H
H
H
N
H
N
H
Me
Me
Me
2+
Me
Me
Me
2+
20'H2
20''H2
Scheme 6. Synthesis and protonation of a hexamethyl-
benziporphyrin
Fig. 3. Benziporphyrin 20 in dichloromethane with 50, 100,
200 and 300 equivalents of TFA and with 1% TFA in CH2Cl2
showing the formation of the diprotonated species 20H22+
the emergence of a new peak at 779 nm. The Soret-like
band underwent a small bathochromic shift to 398 nm.
As expected, the proton NMR spectrum for 20 in
CDCl3 demonstrated the absence of any global aromatic
characteristics. The precise chemical shifts for the arene
protons varied slightly with concentration but the exter-
nal and internal protons all showed up between 7.7
and 8.0 ppm (Fig. 4). The meso-protons gave rise to
two 2H singlets at 6.52 and 7.25 ppm, while the NH
appeared at 8.93 ppm, values that are consistent with the
absence of a macrocyclic ring current. Unexpectedly,
in relatively dilute solutions the 8,19- and 9,18-methyl
substituents appeared as two weakly coupled quartets
Fig. 1. UV-vis spectra of benziporphyrin 20 in 1% triethylamine
(TEA)-dichloromethane (red line, free base), with 5 equivalents
of TFA in dichloromethane (blue line, monocation 20H+) and in
1% TFA-dichloromethane (purple line, dication 20H22+)
broad absorptions that extended well above 800 nm
(Fig. 2). The formation of the monocation was complete
after the addition of 3 equivalents of TFA and no further
protonation was observed with 50 equivalents of TFA.
However, at higher concentrations of acid a new species
developed that was attributed to dication 20H22+ (Fig. 3).
This resulted in the loss of the absorption at 837 nm and
5
(Fig. 5). This is due to JHH or homoallylic coupling
between the inequivalent methyl groups. The coupling
constant of 1.0 Hz is relatively large for systems of this
type and suggests that the 8,9- and 18,19-carbon–carbon
bonds have substantial olefinic character. At higher
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 5–7

6
W. T. DARROW AND T. D. LASH
Fig. 4. Partial 500 MHz proton NMR spectra of benziporphyrin 20 and the related dication 20H22+ in CDCl3 and TFA-CDCl3, respec-
tively, showing the upfield shift to the internal CH proton and the downfield shifts of the external protons upon protonation. * = 13C
satellites for the CHCl3 peak
spectrometry. As had been noted previously [10], the
mass spectrum shows abnormally large [M + 1] and
[M + 2] peaks in addition to the molecular ion. Addition
of TFA to 20 resulted in the formation of dication 20H22+
and the proton NMR spectrum for this species showed
the emergence of a diamagnetic ring current (Fig. 4). The
internal 22-H shifted upfield from 7.90 ppm to 5.22 ppm,
while the meso-protons were further deshielded to give
2H singlets at 6.98 and 8.00 ppm. Although the presence
of positive charges could account for some of the down-
field shift, the pronounced shielding for the internal CH
must be due to the macrocycle taking on significant
aromatic properties. This analysis has been confirmed
by DFT calculations [31]. The aromatic properties of
Fig. 5. Partial 500 MHz proton NMR spectrum of benzipor-
phyrin 20 showing long range JHH coupling (1.0 Hz) between
adjacent methyl substituents
20H22+ can be rationalized by resonance contributors
such as 20′H22+ that introduce 18π electron delocaliza-
tion pathways, although computational analysis is more
consistent with contributions from the delocalized
hybrid structure 20′′H22+ (Scheme 6) [31]. The signals
for the methyl substituents are also shifted downfield
by approximately 0.1–0.2 ppm. Two of the methyl reso-
nances are broadened due to 5JHH coupling but in this case
they do not resolve into quartets. In the carbon-13 NMR
spectrum, the inner CH shifted upfield to 109.8 ppm,
while the meso-protons appeared at 94.2 (11,16-CH)
and 127.6 ppm (6,21-CH).
5
concentrations the methyl resonances were broadened
but did not fully resolve into quartets. The carbon-13
NMR spectrum of 20 confirmed the presence of a plane of
symmetry. The internal CH was identified at 125.0 ppm,
while the meso-protons appeared at 92.8 (11,16-CH)
and 122.4 ppm (6,21-CH). The identity of 20 was
confirmed by high resolution electron impact mass
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 6–7

AN ALTERNATIVE SYNTHESIS OF BENZIPORPHYRINS STARTING FROM ISOPHTHALOYL CHLORIDE
7
8. Lash TD. J. Porphyrins Phthalocyanines 2011; 15:
CONCLUSIONS
1093–1115.
An alternative route to benziporphyrins has been
developed. Reaction of an α-unsubstituted pyrrole ester
with isophthaloyl chloride in the presence of aluminum
chloride afforded a diketone and subsequent reduction
with diborane gave a benzitripyrrane. Cleavage of the
terminal ester functionalities with sodium hydroxide in
refluxing ethylene glycol, followed by acid catalyzed
condensation with a pyrrole dialdehyde and oxidation
with DDQ gave a hexamethyl substituted benziporphy-
rin in 24% yield. Inequivalent methyl substituents exhib-
ited relatively unusual homoallylic coupling, indicating
that the pyrrole bonds have significant olefinic character.
Addition of acid afforded a weakly diatropic dicationic
species that showed the presence of a global aromatic
ring current. The new synthetic strategy shows promise
for applications in the synthesis of novel benziporphyrin
analogs.
9. Richter DT and Lash TD. Tetrahedron 2001; 57:
3659–3673.
10. Lash TD, Chaney ST and Richter DT. J. Org. Chem.
1998; 63: 9076–9088.
11. Lash TD and Yant VR. Tetrahedron 2009; 65:
9527–9535.
12. Lash TD, Szymanski JT and Ferrence GM. J. Org.
Chem. 2007; 72: 6481–6492.
13. Fosu SC, Ferrence GM and Lash TD. J. Org. Chem.
2014; 79: 11061–11074.
14. Lash TD, Young AM, Rasmussen JM and Ferrence
GM. J. Org. Chem. 2011; 76: 5636–5651.
15. Lash TD, Toney AM, Castans KM and Ferrence
GM. J. Org. Chem. 2013; 78: 9143–9152.
16. Lash TD. Chem. Asian J. 2014; 9: 682–705.
17. Stepien M and Latos-Gražynśki L. Chem.-Eur. J.
2001; 7: 5113−5117.
18. Stepien M and Latos- Gražynśki L. Acc. Chem. Res.
2005; 38: 88–98.
Acknowledgements
19. Stepien M, Latos-Gražynśki L, Szterenberg L,
Panek J and Latajka Z. J. Am. Chem. Soc. 2004;
126: 4566–4580.
20. Hung CH, Chang FC, Lin CY, Rachlewicz K,
Stepien M, Latos-Gražynśki L, Lee GH and Peng
SM. Inorg. Chem. 2004; 43: 4118–4120.
21. Hurej K, Pawlicki M, Szterenberg L and Latos-
Gražynśki L. Angew. Chem. Int. Ed. 2016; 55:
1427–1431.
22. Huang C, Li Y, Yang J, Cheng N, Liu H and Li Y.
Chem. Commun. 2010; 46: 3161–3163.
23. Hung CH, Chang GF, Kumar A, Lin GF, Luo LY,
Ching WM and Diau EWG. Chem. Commun. 2008;
44: 978–980.
24. Lash TD. Angew. Chem. Int. Ed. Engl. 1995; 34:
2533–2535.
25. El-Beck JA and Lash TD. Org. Lett. 2006; 8:
5263–5266.
26. Fox BW, Hadfield JA and O’Connor PM. Anti-
Cancer Drug Design 1991; 6: 71–82.
27. Tardieux C, Bolze F, Gros CP and Guilard R.
Synthesis 1998: 267–268.
28. Li R, Lammer AD, Ferrence GM and Lash TD.
J. Org. Chem. 2014; 79: 4078–4093.
This work was supported by the National Science
Foundation under grants CHE-1212691 and CHE-
1465049, and the Petroleum Research Fund, adminis-
tered by the American Chemical Society.
Supporting information
1
1
Selected EI-MS, H NMR, H–1H COSY, HSQC,
DEPT-135, 13C NMR, and UV-Vis spectra are provided
as supplementary materials. This material is available
free of change via the Internet at http://worldscinet.com/
jpp/jpp.shtml.
REFERENCES
1. Lash TD. In Handbook of Porphyrin Science —
With Applications to Chemistry, Physics, Mate-
rial Science, Engineering, Biology and Medicine,
Vol. 16, Kadish KM, Smith KM and Guilard R.
(Eds.), World Scientific Publishing: Singapore,
2012; Chap. 74, pp. 1–329.
2. Lash TD. Chem. Rev. 2017; 117: 2313–2446.
3. Lash TD and Hayes MJ. Angew. Chem. Int. Ed.
Engl. 1997; 36: 840–842.
4. Li D and Lash TD. J. Org. Chem. 2014; 79:
7112–7121.
29. Badger GM and Ward AD. Aust. J. Chem. 1964; 17:
649–660.
5. Lash TD. Acc. Chem. Res. 2016; 49: 471–482.
6. Bergman KM, Ferrence GM and Lash TD. J. Org.
Chem. 2004; 69: 7888–7897.
30. Biswas KM. Houghton LE and Jackson AH. Tetra-
hedron 1966; 22: Supplement 7, 261–270.
31. AbuSalim DI and Lash TD. Org. Biomol. Chem.
2014; 12: 8719–8736.
7. Lash TD. Org. Biomol. Chem. 2015; 13: 7846–7878.
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 7–7