Azulichlorins and Benzocarbachlorins Derived Therefrom

Article abstract of DOI:10.1021/acs.joc.9b01578

Acid-catalyzed condensation of azulidipyrrane aldehydes with a dihydrodipyrrin carbaldehyde afforded the first examples of azulichlorins. These macrocyclic products were isolated in a monoprotonated form, and the free bases proved to be somewhat unstable. The monocations were strongly diatropic, and proton NMR spectroscopy showed the internal C-H at ca. -2 ppm. Addition of TFA gave the related dications, but these exhibited significantly reduced aromatic ring currents. Reaction of an azulichlorin with tert-butyl hydroperoxide and KOH in dichloromethane/methanol gave a benzocarbachlorin and two related aldehydes. The UV-vis spectrum for the benzocarbachlorin showed a split Soret band at 414 and 430 nm, together with a strong chlorin-like absorption at 684 nm. The proton NMR spectrum indicated that the carbachlorin is strongly aromatic and the internal C-H was observed at -4.64 ppm. Addition of TFA afforded a C-protonated dication with a significantly increased diatropic ring current. The proton NMR spectrum, NICS calculations, and AICD plots indicated that the system favors a 22πelectron delocalization pathway that runs through the fused benzo unit. Addition of TFA to the benzocarbachlorin aldehydes primarily led to the formation of monocations, and the generation of C-protonated dications was no longer favored due to the presence of electron-withdrawing formyl moieties.

Full text of DOI:10.1021/acs.joc.9b01578

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Article
Azulichlorins and Benzocarbachlorins Derived Therefrom
Mario A Noboa, Deyaa I. AbuSalim, and Timothy D. Lash
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01578 • Publication Date (Web): 20 Aug 2019
Downloaded from pubs.acs.org on August 23, 2019
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Azulichlorins and Benzocarbachlorins Derived Therefrom
Mario A. Noboa, Deyaa I. AbuSalim and Timothy D. Lash*
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160
E-mail: tdlash@ilstu.edu
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Abstract
X
R
Et
Et
Y
Me
Me
N
N
N
N
H
H
H
H
H
N
N
Me
Me
Me
Me
Me
Me
Et
R = H or t-Bu
Et
X,Y = H or CHO
Acid-catalyzed condensation of azulidipyrrane aldehydes with a dihydrodipyrrin carbaldehyde
afforded the first examples of azulichlorins. These macrocyclic products were isolated in a
monoprotonated form, and the free bases proved to be somewhat unstable. The monocations were
strongly diatropic and proton NMR spectroscopy showed the internal C-H at ca. -2 ppm. Addition
of TFA gave the related dications, but these exhibited significantly reduced aromatic ring currents.
Reaction of an azulichlorin with tert-butyl hydroperoxide and KOH in dichloromethane-methanol
gave a benzocarbachlorin and two related aldehydes. The UV-vis spectrum for the
benzocarbachlorin showed a split Soret band at 414 and 430 nm, together with a strong chlorin-
like absorption at 684 nm. The proton NMR spectrum indicated that the carbachlorin is strongly
aromatic and the internal C-H was observed at -4.64 ppm. Addition of TFA afforded a C-
protonated dication with a significantly increased diatropic ring current. The proton NMR
spectrum, NICS calculations and AICD plots indicated that the system favors a 22 electron
delocalization pathway that runs through the fused benzo-unit. Addition of TFA to the
benzocarbachlorin aldehydes primarily led to the formation of monocations, and the generation of
C-protonated dications was no longer favored due to the presence of electron-withdrawing formyl
moieties.
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Introduction
N
HN
N
N
HN
N
N
HN
N
0
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0
1
2
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5
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8
9
0
NH
NH
NH
Porphyrin
Chlorin
Bacteriochlorin
Figure 1. Structures of porphyrin, chlorin and bacteriochlorin.
Hydroporphyrins such as chlorins and bacteriochlorins (Figure 1) are widespread in nature
and fulfill many important functions.1-3 Most of the chlorophylls are magnesium chlorins,3 while
many bacteria utilize the iron(II) chlorin heme d (1, Figure 2) in the reduction of molecular oxygen
4
5
to water. Bacteriochlorophylls a and b are magnesium bacteriochlorins, and tolyporphin, heme
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7
d , and siroheme are examples of isobacterichlorins. In addition, the marine worm Bonellia
1
viridis generates the gem-dimethylchlorin bonellin (2) and this green pigment directs
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masculization of the larvae. Bonellin also exhibits antitumor activity and chlorophyll-derived
chlorins isolated from diatoms, sponges, tunicates and mollusks have been shown to have
1
0
antioxidant properties. Chlorins have comparatively long wavelength absorptions near 650 nm,
an attribute that is valued in the development of superior photosensitizers for applications in
photodynamic therapy (PDT). For instance, Verteporfin (Visudyne, 3) is a photosensitizer that has
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been used to treat age-related macular degeneration and has also been shown to have potential in
atheroschlerotic plaque therapy.12 meso-Tetrakis(3-hydroxyphenyl)chlorin (Temoporfin) is
1
3
similarly being used to treat squamous cell carcinomas, and Talaporfin (4) is being applied to the
treatment of lung cancer.14 Unsurprisingly, chlorins have been widely investigated and many
synthetic routes to this system have been developed.1,2,15 However, closely related chlorin-like
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systems have not been well studied even though these have the potential to possess equally
valuable properties.16
Me
Me
1
1
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Me
Me
NH
N
N
N
N
N
N
Fe
HN
Me
Me
Me
OH
Me
Me
O
O
CO H
HO C
2
HO C
2
2
1
Heme d
2 Bonellin
Me
Me
MeO C
2
Et
Et Me
Me Me
MeO C
2
N
Me
N
HN
N
NH
N
NH
HN
Me
Me
CO H
2
NH
MeO C
CO H
HO C
O
2
2
2
CO H
2
3
Verteporfin
4 Talaporfin
CO H
2
Figure 2. Examples of biologically active chlorins.
Carbaporphyrinoid systems, where one or more of the core nitrogens within the porphyrin
macrocycle have been replaced by carbon atoms, have diverse structural and spectroscopic
1
7
properties and display unusual reactivity such as the capacity to generate stable organometallic
derivatives.18 Examples of 2,3-dihydrocarbaporphyrins such as 5-8 (Figure 3) have been
reported19-22 and these chlorin analogues all have strongly aromatic properties. In common with
true chlorins, carbachlorins 5-8 show moderately strong absorptions near 650 nm, but are relatively
stable compounds compared to the tetrapyrrolic structures. Carbachlorins 5 and 8 only undergo
oxidation to carbaporphyrins when heated with DDQ in toluene,20,21 while the five-membered ring
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fused carbachlorins 6 resisted oxidation under any of the conditions examined. This process is
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blocked altogether in the gem-diester 7. It is noteworthy that these structures only represent a
single category of carbachlorin where the carbocyclic ring has been reduced. Carbachlorins CC-c
and CC-b with reductions of pyrrole rings c and b, respectively, represent currently unknown
examples of chlorin analogues, and the related benzocarbachlorins BCC-c and BCC-b have also
hitherto not been explored (Figure 4). In addition, dihydroazuliporphyrins AzC-c and AzC-b are
examples of previously unknown azulichlorin structures.
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Me
Et
Et
Et
Et
HN
N
HN
N
NH
NH
Me
Me
Et
Et
Et
Et
single or
6
5
=
double bond
CO Me Me
MeO C
2
Me
2
MeO C
2
Et
Et
Et
MeO C
2
HN
HN
N
NH
N
NH
Me
Me
Et
Et
Et
Et
Et
7
8
Figure 3. Previously reported carbachlorins.
a
d
b
c
HN
N
N
HN
N
NH
NH
HN
NH
CC-c
CC-b
BCC-c
HN
N
N
N
NH HN
N
N
HN
AzC-c
AzC-b
BCC-b
Figure 4. Proposed carbachlorin and azulichlorin systems.
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Azuliporphyrins 9 are porphyrin analogues that have an azulene unit instead of one of the
pyrrole rings (Figure 5).23 This system acts as a dianionic ligand and affords organometallic
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24
25
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derivatives with Ni(II), Pd(II), Pt(II), Ru(II), Rh(III) and Ir(III). The first example of an
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azuliporphyrin was reported in 1997, and this system was shown to have significantly reduced
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diatropic properties compared to porphyrins or carbaporphyrins. The intriguing reactivity and
spectroscopic properties of azuliporphyrins has led to the investigation of related porphyrinoid
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0
31
structures, including azulicorrole 10, azulisapphyrin 11, and the azulene-fused aza-coronene
analogue 12.32 Hence, the development of syntheses for azulichlorins and new classes of
carbachlorins was considered to be desirable for the development of this field. In this paper,
syntheses of azulichlorins belonging to the AzC-c class and related benzocarbachlorins belonging
to category BCC-c, are reported and detailed spectroscopic and computational studies have been
performed.33
N
N
Ar
Ar
NH HN
N
HN
Ar
Azulicorrole
9
Azuliporphyrin
1
0 (Ar = p-CF C H -)
3
6
4
t-Bu
Et
Et
Me
Et
Me
Et
N
N
Et
Et
Et
H
H
N
N
N
N
H H
N
N
Et
N
Et
Et
Et
Et
Me
Me
Et
Et
11
12
Figure 5. Examples of azulene-containing porphyrin analogues.
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Results and Discussion
Me
t-BuO2C
Me
t-BuO C
H
2
Et
N
N
HN
Me
Me
Me
t-BuO C
2
0
1
2
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0
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0
1
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8
9
0
Et
NH
N
Me
Me
Me
14
Et
13
The ‘3 + 1’ version of the MacDonald condensation is a versatile method for preparing diverse
3
4
porphyrinoid structures. Initially, dihydrotripyrrene 13 was targeted as a potential intermediate
in the synthesis of carbachlorin analogues. In principle, cleavage of the tert-butyl ester protective
groups, followed by condensation with monocyclic dialdehydes, would afford the desired
macrocyclic products. Convenient syntheses of dihydrodipyrrins related to structure 14 have been
reported by Jacobi and coworkers,35-38 and these useful intermediates have been used to prepare a
variety of chlorin37,38 and bacteriochlorin products. It was anticipated that functionalization of
the terminal methyl unit in 14, followed by condensation with an -unsubstitued pyrrole, would
afford the required dihydrotripyrrene.
39
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O
Et
O
HO
Me
O
Pd(PPh3)4
Et N
1
6
NH
17
Et
3
t-BuO C
Me
2
Me
CH CN 
I
3
Me
CO t-Bu
N
Cp2TiCl2 MeLi
1
1
1
1
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9
0
H
2
1
5
Et
O
HCl-DMF
Me
t-BuO C
CH2
Me
NH
2
Et
Me
18
Me
Me
Me
NH
O
O
Et N-NH OAc
3
t-BuO C
4
2
Me
19
Et
Me
Me
Me
SeO2
Me
NH
14
N
t-BuO C
Me
2
Et
Me
Me
NH
N
t-BuO C
2
CHO
20
Scheme 1. Synthesis of dihydrodipyrrin intermediates.
Heck coupling of iodopyrrole 15 with pentynoic acid 16 and catalytic Pd(PPh ) in refluxing
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triethylamine-acetonitrile gave lactone 17 in 87% yield (Scheme 1). The formation of Z-isomer 17
was confirmed by NOE difference proton NMR spectroscopy. These studies showed interactions
between the N-H resonance and the lactone CH unit that would only be observed in the Z-isomer.
2
Furthermore, the bridge C-H weakly interacted with the CH resonance for the ethyl substituent.
2
Reaction of 17 with the Petasis reagent (dimethyl titanocene) in refluxing toluene afforded the
related enol ether 18 in 76% yield. NOE difference proton NMR spectroscopy again confirmed
that the Z-isomer had been obtained. The two protons attached to the exocyclic double bond gave
1
H doublets at 4.02 and 4.40 ppm, and the upfield resonance was shown to correspond to the
hydrogen atom that was orientated towards the gem-dimethyl unit. In a one-pot procedure, enol
ether 18 was dissolved in DMF and hydrolyzed with 6 M hydrochloric acid to generate diketone
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2
2
2
2
2
2
2
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5
6
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9. This intermediate underwent a Paal-Knorr cyclization in situ with excess ammonium acetate
and triethylamine at 55 °C, and following purification by flash chromatography on silica gel,
dihydrodipyrrin 14 was isolated in 70% yield (Scheme 1). This product was shown to take on the
desired E-geometry by NOE difference proton NMR spectroscopy as the resonance for the bridge
C-H at 5.82 ppm correlated with the pyrrolene methylene unit at 2.58 ppm.
0
1
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9
0
Attempts to functionalize the terminal methyl group of 14 with lead tetraacetate, N-
bromosuccinimide, N-iodosuccinimide, or N-chlorosuccinimide led to decomposition. Jacobi had
reported that related dihydrodipyrrins could be selectively oxidized with selenium dioxide to give
aldehydes 20 and this transformation proved to be successful for 14 as well. Reaction of 14 with
one equivalent of selenium dioxide in DMF-pyridine, followed by purification using flash
chromatography (silica gel, eluting with toluene) gave aldehyde 20 in 46% yield (Scheme 1).
However, the formyl unit could not be reduced without destroying the dihydrodipyrrin,
presumably due to the presence of a reactive imine unit.
Et
AcOCH2
Me
R
R
N
Et
H
CO t-Bu
2
22
Me
AcOH-iPrOH 
N
H
2
3
CO t-Bu
2
POCl -DMF
3
K CO
2
R
3
Et
R
Et
Me
N
Me
H
CO t-Bu
2
N
H
H
N
OHC
CO2t-Bu
21
Me
CO t-Bu
2
a. R = H; b. R = t-Bu
Et
2
4
Scheme 2. Synthesis of azulidipyrrane carbaldehydes.
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Given the difficulties that had been encountered, it was necessary to develop an alternative
strategy for the synthesis of carbachlorin-type structures such as azulichlorins AzC-c. As
dihydropyrrin monoaldehyde was readily available, an alternative ‘2 + 2’ strategy was designed
that made use of this intermediate. This necessitated the use of complementary azulidipyrrane
aldehydes 21. (Scheme 2). Azulene was reacted with one equivalent of acetoxymethylpyrrole 22
and acetic acid in refluxing isopropyl alcohol. Following column chromatography, azulidipyrrane
23a was obtained as the major product, together with the related azulitripyrrane 24a.40,41
Condensation of 6-tert-butylazulene with 22 similarly gave azulidipyrrane 23b, together with
azulitripyrrane 24b (Scheme 2). Initially, formylation of 23a or 23b using the Vilsmeier-Haack
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reaction (POCl -DMF) gave poor results because the acidic conditions cleaved the tert-butyl ester
3
protective groups. However, when the reaction of 23a was carried out in the presence of potassium
carbonate, azulidipyrrane aldehyde 21a was generated in 69% yield. Azulidipyrrane 23b reacted
similarly to afford the related aldehyde 21b (Scheme 2).
R
Et
R
Et
Me
Me
N
H
N
N
OHC
CO2t-Bu
H
2
1
HI
TFA
I
H
CHO
Me
N
t-BuO C
2
Me
NH
N
Me
Me
Me
Et
Me
Et
25 a. R = H (17%)
b. R = t-Bu (15%)
2
0
Scheme 3. Synthesis of azulichlorins.
Aldehydes 20 and 21a were treated with TFA to cleave the tert-butyl ester protective groups,
and the solutions were then diluted with acetic acid and further acidified with hydroiodic acid
(Scheme 3). Although self-condensation of 20 or 21a could potentially occur, only one
macrocyclic product was identified resulting from the desired cross-condensation reaction. The
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction mixture was stirred at room temperature overnight, and the product purified on a silica
gel column. A green band was collected and further purified on a basic alumina column to give
+
the monoprotonated azulichlorin 25a.HI in 17% yield. The proton NMR spectrum for 25aH in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl (Figure 6) shows the internal C-H proton at -2.11 ppm, and this result indicates that the
3
monocation has a similar diamagnetic ring current to protonated azuliporphyrins. The meso-
protons were shifted downfield to give four singlets at 7.51 (10-H), 7.58 (15-H), 9.22 (20-H) and
9.28 (5-H) ppm.
Figure 6. Proton NMR spectrum of azulichlorin 25a.HI in CDCl3.
+
The UV-Vis spectrum of azulichlorin 25aH gave a strong Soret band at 445 nm along with two
+
weaker broad bands at 620 and 670 nm (Figure 7). When 25aH was exposed to triethylamine, a
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yellow solution corresponding to the free base azulichlorin 25a was generated (Scheme 4). The
UV-vis spectrum of 25a in 1% Et N-chloroform (Figure 7) showed substantial changes and the
3
Soret band was lost, suggesting a decrease in aromaticity. The free-base form is somewhat unstable
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and slowly air oxidized to give impure carbachlorins. The proton NMR spectra of 25a in Et N-
3
CDCl or d -pyridine gave broad poorly resolved peaks. Addition of TFA afforded a diprotonated
3
5
species 25aH22+ and the resulting UV-vis spectrum in 5% TFA-chloroform showed a strong Soret
band at 457 nm and weaker absorptions at 345, 505, 605 and 645 nm (Figure 7). Interestingly, the
proton NMR spectrum of 25aH 2+ showed a decrease in diatropic ring current compared to the
2
mono-protonated species as the internal C-H proton was only shifted upfield to 2.24 ppm, while
the NH protons gave broad peaks at 1.26, 5.40 and 5.41 ppm. The meso-protons, however, were
less affected, showing only a minor shifts compared to 25aH+.
1
1
0
9
8
7
6
5
4
3
2
1
0
1

300
400
500
600
700
800
Wavelength (nm)
Figure 7. UV-vis spectra of azulichlorin 25a in 1% Et N-CHCl (free base, red line), CHCl
3
3
3
+
2+
(
monocation 25aH , green line) and 5% TFA-CHCl (dication 25aH , purple line).
3
2
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2
2
2
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3
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5
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R
R
R
Et
Et
Et
Me
Me
Me
Me
Me
+ H+
H+
+ H+
N
N
N
N
N
H
H
H
H
H H
- H+
-
N
N
N
N
Me
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
Me
Me
Me
Me
Et
Et
25
5H+
Et
2
5H22+
2
a. R = H, b. R = t-Bu
t-BuOOH
KOH
R = H
N
H
N
CHO
Et
Et
Et
H
Et
OHC
Me
Me
Me
Me
Me
HN
HN
N
HN
N
HN
NH
N
NH
NH
NH
N
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Benzocarbachlorins
Et
Et
2
6
27a
27b
27c
Scheme 4. Protonation of azulichlorins and ring contraction to give benzocarbachlorins.
tert-Butylazulichlorin 25b was synthesized under the same conditions from azulidipyrrane
aldehyde 21b and dihydrodipyrrin aldehyde 20. As expected, azulichlorin 25b was isolated as the
monoprotonated species and gave a similar UV-vis spectrum to 25a. The proton NMR spectrum
+
for 25bH showed substantial diatropic character, although the internal C-H proton was slightly
+
less shielded than the equivalent peak for 25aH and appeared at -1.46 ppm. However, the meso-
protons were significantly deshielded compared to 25aH, giving rise to four 1H singlets at 7.72,
7
.83, 9.60 and 9.65 ppm. On balance, the presence of the tert-butyl substituent appears to enhance
the diatropicity of the macrocycle. Similar observations were previously reported for tert-butyl
substituted azuliporphyrins.41
Azuliporphyrins are susceptible to nucleophilic attack on the seven-membered ring and addition
of pyrrolidine results in the reversible formation of aromatic carbaporphyrin adducts.23,42 Addition
of pyrrolidine to a solution of 25a.HI gave a UV-vis spectrum that resembled an aromatic
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9
porphyrinoid structure. Specifically, a strong Soret band was observed at 408 nm and a moderately
strong chlorin-like absorption appeared at 677 nm (Figure 8). The proton NMR spectrum of 25a
with pyrrolidine in CDCl showed the formation of a strongly aromatic species. The internal C-H
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was shifted upfied to -4.59 ppm and two broad NH resonances were observed at -2.16 and -2.12
ppm. The meso-protons were shifted downfield to give four 1H singlets at 8.34, 8.45, 9.49 and
9
.52 ppm, and the resonances for the methyl substituents were also further deshielded giving rise
to two 3H singlets at 3.27 and 3.36 ppm. The cycloheptatriene unit gave a 2H doublet at 7.70 and
a 2H multiplet at 5.92-5.96 ppm. The results are consistent with the formation of the pyrrolidine
3
adduct 26 where nucleophilic attack is favored at position 2 (Scheme 4). The reduced 13-CH unit
2
afforded an AB quartet (2JHH = 16.3 Hz) for 2H at 4.39-4.47 ppm. This arises because the presence
of the pyrrolidine unit differentiates the two faces of the macrocycle, and this leads to geminal
coupling between the two protons.
1
2
0
8
6
4
2
0
1
300
400
500
600
700
Wavelength (nm)
Figure 8. UV-vis spectrum of azulichlorin 25a in 1% pyrrolidine-CHCl showing the formation
3
of carbachlorin adduct 26.
In earlier work, azuliporphyrins had been reported to undergo oxidative ring contractions to
generate benzocarbaporphyrins42,43 and it was proposed that this transformation was triggered by
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
initial nucleophilic attack onto the seven-membered ring. In a typical procedure, azuliporphyrins
were reacted with tert-butyl hydroperoxide and KOH at room temperature. The same synthetic
methodology was used to convert azulichlorin 25a into the first examples of benzocarbachlorins
(Scheme 4). Azulichlorin 25a was reacted with potassium hydroxide and tert-butyl hydroperoxide
in dichloromethane-methanol at room temperature. Following work up, the residue was
chromatographed on a grade 3 alumina column, eluting initially with 30% dichloromethane-
hexanes, and an orange band was collected. Following recrystallization from chloroform-hexanes,
benzocarbachlorin 27a was obtained in 24% yield as a yellow-brown powder. A second major
orange band was collected corresponding to a mixture of two isomeric benzocarbachlorin
aldehydes 27b and 27c in 37-46% yield (Scheme 4).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 9. Proton NMR spectrum of benzocarbachlorin 27a in CDCl3.
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The proton NMR spectrum for benzocarbachlorin 27a in CDCl showed the presence of a strong
3
diamagnetic ring current (Figure 9). The internal C-H proton was observed at -4.64 ppm and the
N-H protons gave broad peaks at -2.63 and -2.58 ppm. The external meso-protons were shifted
downfield to give four 1H singlets at 8.47 (10-H), 8.59 (15-H), 9.72 (20-H) and 9.76 (5-H) ppm.
The carbon-13 NMR spectrum showed the internal CH at 111.4 ppm, while the meso-carbons
appeared at 90.2 (C-10), 92.1 (C-15), 101.3 (C-20) and 101.6 (C-5) ppm. The UV-vis spectrum of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
benzocarbachlorin 27a in 1% Et N-chloroform produced a split Soret band at 414 and 430 nm,
3
together with a strong absorption at 684 nm that is characteristic of chlorin-type structures (Figure
1
0).
7
6
5
4
3
2
1
0

300
400
500
600
700
800
Wavelength (nm)
Figure 10. UV-vis spectra of benzocarbachlorin in CHCl (free base, red line), 0.1% TFA-CHCl
3
3
(orange line), 0.2% TFA-CHCl (green line), 0.5% TFA-CHCl (blue line), and 5% TFA-CHCl
3
3
3
2
+
(dication 27aH , purple line).
2
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1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
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5
5
5
5
5
5
5
6
27
H+
+ H+
Me
-
X
X
Et
Et
Y
Y
Me
+ H+
N
H
N
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H H
H
H
H+
-
N
N
N
Me
Me
Me
Me
Me
Me
Et
Et
27H22+
2
7H+
a. X = Y = H; b. X = CHO, Y = H; c. X = H, Y = CHO
Scheme 5. Protonation of benzocarbachlorins.
+
Addition of small amounts of TFA generated a monocationic species 27aH (Scheme 5). The
UV-spectrum for a solution of 27a with 0.1% TFA/CHCl showed that a new species had been
3
partially formed as a new absorption band had emerged at 717 nm. In 0.2% TFA-chloroform, this
species predominated but a new band started to emerge at 800 nm. In 5% TFA-chloroform, the
carbachlorin was completely converted into the latter form, and this was assigned to the dicationic
2+
structure 27aH . The dication gave a strong Soret band at 404 nm, in addition to the long
2
wavelength absorption at 800 nm (Figure 10). The proton NMR spectrum for dication 27aH22+ in
TFA-CDCl confirmed that C-protonation had occurred, and indicated that the diatropicity of the
3
carbachlorin system had been increased. The internal CH resonance was observed upfield at -6.77
2
ppm, while the meso-protons were shifted downfield to give singlets at 9.47, 9.64, 11.120 and
11.126 ppm. The chemical shifts for the methyl substituents were also shifted downfield by ca.
0
.26 ppm, which also implies that a larger macrocyclic ring current is present. Major changes were
1
1
observed for the chemical shifts of the benzo-protons. In the free base form, the 2 ,3 -protons gave
2
2
a multiplet at 8.68-8.73 ppm and the 2 ,3 -protons appeared at 7.65-7.68 ppm, but these resonances
were shifted downfield for 27aH22+ to give multiplets at 10.09-10.12 ppm and 8.74-8.78 ppm,
respectively. These shifts indicate that the global ring current passes through the benzene ring and
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indicates that a 22 electron pathway plays a significant role (see computational results below).
Similar conjugation pathways have been postulated for protonated benzocarbaporphyrins and
naphthocarbaporphyrins.44,45 The carbon-13 NMR spectrum for 27aH22+ showed the internal CH2
at 32.0 ppm, while the meso-carbons appeared at 101.2, 103.2 and 105.8 ppm (the latter resonance
corresponds to both the 5- and 20-CHs).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
8
6
4
2
0

300
500
700
900
Wavelength (nm)
Figure 11. UV-vis spectra of benzocarbachlorincarbaldehydes 27b,c in CHCl (free bases, red
line), 1% TFA- CHCl (monocations 27b,cH , blue line), and 50% TFA-CHCl (mixture of
monocations 27b,cH and dications 27b,cH , purple line).
3
+
3
3
+
2+
2
Attempts to separate benzocarbachlorin aldehydes 27b and 27c were unsuccessful, and
spectroscopic characterization was performed on the isomeric mixture. The proton NMR spectrum
of 27b,c in CDCl showed that the two isomers were present in a 50/50 mixture, and both forms
3
showed the presence of strong diamagnetic ring currents. The internal C-H protons were observed
at -4.70 and -4.69 ppm, while the meso-protons gave rise to a series of singlets between 8.43 and
9
.55 ppm. The aldehyde protons gave a singlet at 10.28 ppm. The UV-vis spectrum of 27b,c gave
a strong Soret band at 442 nm, together with small Q bands at 530, 557 and 616 nm and a stronger
chlorin-type absorption at 676 nm (Figure 11). In 0.1% TFA-CHCl a new species was formed
3
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4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
that afforded a Soret band at 450 nm and a strong absorption at 707 nm, and this was assigned to
+
monocation 27b,cH (Scheme 5). However, further addition of TFA did not initially show any
significant changes. Benzocarbachlorin 27a was completely converted into the dicationic species
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
27aH22+ in 5% TFA-CHCl , but benzocarbachlorins 27a,b only showed trace amounts of the
3
related dications in 10% TFA-chloroform (Figure 11). Even in 50% TFA-chloroform solutions,
conversion to 27b,cH22+ was incomplete. The presence of electron-withdrawing groups on the
benzene ring apparently inhibits the second protonation step, indicating that there must be a
significant electronic interaction between the benzo-unit and the porphyrinoid macrocycle in these
dicationic structures. This differs from the free base and monocationic forms, where the benzo-
units appear to be effectively disconnected from the macrocyclic -system. The proton NMR
+
spectrum of 27b,cH in CDCl containing a trace amount of TFA showed a downfield shift to the
3
internal C-H protons from -4.7 ppm to -2.0 ppm, and the meso-protons gave rise to singlets
between 7.96 and 9.67 ppm. These results indicate that the macrocyclic ring current for the free
base and monoprotonated porphyrinoids are very similar. The aldehyde moiety afforded a singlet
at 10.20 ppm.
Computational studies were also conducted on unsubstituted azulichlorins AzC-c and
benzocarbachlorins BCC-c and these provide further insights into these novel chlorin analogues.
A series of tautomers were examined for the free base and protonated forms for each system. The
structures were optimized using B3LYP with the triple- basis set 6-311++G(d,p).46 Four
tautomers for the free base forms of AzC-c were considered and these are designated according to
the position of the proton as AzC-c-22H, AzC-c-23H, AzC-c-5H and AzC-c-10H (Table 1). All
four structures are essentially planar. The relative energies were assessed using three different
functionals, B3LYP, M06-2X, and B3LYP-D3,47,48 and the relative Gibbs free energy was
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determined using B3LYP. The relative G values were consistently very similar to the relative E
values, demonstrating that entropic factors are not significant. The calculations showed that AzC-
c-22H is the most stable, yet AzC-c-23H is only slightly higher in energy. Although the
conjugation pathway in AzC-c-22H, which passes through an imine unit within the reduced ring,
would be expected to be favored over the alternative pathway in AzC-c-23H which passes through
an amine-type nitrogen, the former species has more steric congestion because the two internal
hydrogens are adjacent to one another. The other two tautomers, which have interrupted
conjugation pathways due to the presence of methylene bridges, are much higher in energy (Table
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
9
1
). Nucleus independent chemical shift (NICS) calculations were carried out using CAM-B3LYP
to assess the aromatic properties of these structures. Large negative values correspond to highly
shielded regions that result from aromatic ring currents, while positive values correspond to
deshielded regions. In this study, NICS(0) and NICS (1) calculations were conducted. Standard
zz
NICS calculations consider the effects due to  and  electrons and may not always reliably assess
aromatic properties, but NICS primarily measures the effects due to the  system. NICS
zz
zz
calculations were performed 1 Å above the ring. It should be noted that the numerical values
obtained using NICS (1) are much larger than those obtained using NICS(0), but the
zz
porphyrinoids examined in these studies showed similar trends using both techniques. To avoid
confusion, only the NICS(0) values will be discussed. AzC-c-22H exhibits moderate global
diatropicity, giving a NICS(0) value of -4.07 ppm. The NICS values for rings a and b are strongly
negative, demonstrating that the ring current primarily runs through the outside of these rings, but
rings c and d give low negative or positive results showing that the pathway runs through the inside
of these subunits. In addition to the NICS calculations, anisotropy of induced current density
50
(
AICD) was used to assess all of the calculated structures, and the plot for AzC-c-22H showed
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0
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
that bifurcated pathways were present that exclude the cycloheptratriene moiety (Figure 12). The
global ring current in AzC-c-23H is virtually absent, presumably due to the necessity for this
conjugation pathway to pass through the amine-type nitrogen.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 1. Calculated Relative Energies (kcal/mol) and NICS Values (ppm) for Free Base
Unsubstituted Azulichlorin Tautomers.
e
e
e
e
a
b
a
d
b
a
b
a
d
b
N
N
N
N
H
N
N c
N
HN c
N
N c
N
N c
d
d
Molecule
AzC-c-22H
0.00
AzC-23H
+0.12
(-1.27/
-3.53/
-1.38)
AzC-c-5H
+28.36
(+30.23/
+27.89/
+30.83)
AzC-10H
+25.50
(+27.00/
+23.01/
+27.74)

G (298 K)
 B3LYP/
M06-2X/

(0.00/
0.00/
0.00)
B3LYP-D3)
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
-4.07/-9.38
-14.07/-39.27
-6.59/-16.49
+3.57/+4.22
-0.08/-6.88
-0.92/-9.27
-1.69/-2.95
+0.35/+3.27
-14.10/-40.59
+1.78/-3.74
+1.62/+0.02
-1.50/-9.66
+1.72/+6.53
-13.15/-38.11
-1.36/-9.45
+1.23/-1.54
-0.61/-47.51
-3.44/-15.57
-13.46/-38.37
-1.36/-9.27
+0.54/+4.22
-1.36/-9.27
-1.90/-11.89
-3.71/-16.09
Figure 12. AICD plots (isovalues = 0.05) of azulichlorin AzC-c-22H and monocation AzC-c-
+
2
2,24H .
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2
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6
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Table 2. Calculated Relative Energies (kcal/mol) and NICS Values (ppm) for Tautomers of
Monoprotonated Azulichlorins.
e
e
e
e
a
b
a
b
a
b
a
b
HN
N
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NH N c
NH HN c
NH N c
N
HN c
d
d
d
d
Molecule
AzC-c-22,24H+
0.00
AzC-c-22,23H+
+10.92
AzC-c-5,24H+
+22.55
AzC-c-5,23H+
+31.60

G (298 K)
 B3LYP/
M06-2X/
B3LYP-D3)
(0.00/
0.00/
0.00)
(+10.56/
+9.54/
+10.73)
-4.17/-9.82
-9.24/-25.74
-1.56/-10.51
+1.82/+5.52
-8.97/-19.50
-3.10/-16.43
(+24.00/
+22.20/
+24.92)
+0.10/+2.09
-9.60/-28.13
+2.88/-1.23
+1.92/+0.21
-7.44/-17.93
-4.83/-19.38
(+33.96/
+34.68/
+34.76)
-1.92/-3.31
-9.48/-28.48
+4.00/+0.92
+1.93/+5.92
-3.16/-13.11
-4.00/-17.44
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
-6.85/-17.25
-10.76/-28.83
-8.30/-20.72
+5.00/+5.81
-8.31/-20.73
-2.91/-16.14
e
e
e
e
a
b
a
d
b
a
b
a
b
HN
N
N
HN
N
N c
NH N c
N
HN c
N
N c
d
d
d
AzC-c-5,22H+
AzC-c-10,24H+
AzC-c-10,23H+
AzC-c-5,22H+
Molecule

G (298 K)
+32.35
(+34.34/
+37.70/
+35.27)
-3.29/-6.87
-8.49/-26.04
-8.89/-21.34
+3.74/+4.74
-1.19/-9.73
-3.78/-17.53
+20.34
(+22.65/
+20.05/
+23.68)
+1.03/+4.47
-9.23/-26.98
-0.67/-7.73
+1.65/-0.92
-6.47/-15.59
-4.44/-18.53
+31.99
(+33.27/
+30.38/
+34.26)
+0.94/+4.26
-9.49/-28.15
-3.22/-12.88
+0.37/+2.02
-2.71/-11.63
-4.28/-18.26
+24.75
(+26.91/
+24.38/
+28.02)
+1.20/+4.86
-7.83/-23.79
-8.32/-19.82
+1.59/-0.48
+0.83/-4.26
-4.45/-18.61

 B3LYP/
M06-2X/
B3LYP-D3)
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
Protonation gives rise to monocationic and dicationic species. Eight possible monocationic
+
tautomers were considered (Table 2), and AzC-c-22,24H was calculated to be by far the most
+
favored form. AzC-c-22,23H was ca. 10 kcal/mol higher in energy, while the remaining meso-
+
protonated structures were 22-38 kcal/mol higher in energy. AzP-c-22,23H is less favored due to
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4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
steric crowding and the necessity for the -conjugation pathways to pass through the amine-type
nitrogen. Nevertheless, this tautomer has a significant NICS(0) value of -4.17 ppm and therefore
+
would have diatropic character. The favored tautomer, AzC-c-22,24H , gave a larger NICS(0)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
value of -6.85 ppm and rings a, b and d all gave large negative values, demonstrating that the
favored aromatic delocalization pathways run through the outside of these rings. This suggests that
the pathway shown in structure 28a (Figure 13) is favored, although the small negative values
calculated for the seven-membered ring (ring e) is rather small and therefore not consistent with
tropylium character. However, the AICD plot for this tautomer (Figure 12) indicates that -
conjugation extended through the seven-membered ring and instead is suggestive of contributions
from 23-atom delocalized structure 28b. In fact, computational studies on azuliporphyrins also
5
1
suggest that tropylium character is not favored in the free base and monoprotonated forms, even
4
2
though this interpretation is generally used to explain the properties of azuliporphyrins. Attempts
to rationalize the conjugation pathways in terms of resonance led to the proposal of similar
somewhat unlikely canonical forms, and it was concluded that azuliporphyrins cannot be
5
1
satisfactorily assessed in this fashion. The calculated bond lengths for the favored free base and
+
monocations AzC-c-22H and AzC-c-22,24H showed very little variation for the individual bonds
in the seven-membered ring apart from the position for ring fusion. In fact, this bond (C2-C3) was
0
.078 Å or 0.067 Å longer, respectively, for these two species. A series of diprotonated dications
2
+
were also considered (Table 3) and AzC-c-22,23,24H was unambiguously favored over the C-
protonated tautomers. The system retained substantial global diatropicity (NICS(0) = -5.47 ppm),
+
but this is reduced compared to monocation AzC-22,24H in agreement with the proton NMR
spectra obtained for azulichlorins 25a and 25b. Rings a, b and d all gave significant negative NICS
values, suggesting that the ring current passes through the periphery of these rings. The seven-
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membered ring also gives a substantial negative NICS value, potentially indicating that this species
possesses tropylium character, and the results are consistent with the conjugation pathway shown
2
+
in structure 29a (Figure 13). However, the AICD plot for AzC-c-22,23,24H (Figure 14) indicates
that the global conjugation pathway extends around the periphery of the seven-membered ring.
The calculated bond length for C2-C3 is 1.449 Å, which also indicates that this bond has substantial
single bond character, although it is slightly shorter than the equivalent bond in AzC-c-22H.
Again, it is only possible to postulate a rather unconventional resonance contributor 29b for this
species.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
H
H
+
H
H
2
N
N
2
8a
28b
N
N
N
N
H
H H
H
H
H
N
N
2+
2
9a
29b
N
N
N
N
N
H
H
H
N
N
N
N
30
31a
31b
N
N
N
H
H
NH H
H
N
HN
32
33
Figure 13. Potential conjugation pathways in selected azulichlorin and benzocarbachlorin
structures.
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4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Calculated Relative Energies (kcal/mol) and NICS Values (ppm) for Azulichlorin
Dications.
e
e
e
e
a
b
a
b
a
b
a
b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HN
N
HN
HN
NH HN c
NH HN c
N
HN c
NH N c
d
d
d
d
Molecule
G (298 K)
 B3LYP/
M06-2X/
B3LYP-D3)
AzC-c-22,23,24H2+
0.00
AzC-c-5,23,24H2+
+18.21
AzC-c-5,22,23H2+
+24.61
AzC-c-5,22,24H2+
+10.32

(0.00/
0.00/
0.00)
(+19.54/
+18.91/
+20.50)
(+25.99/
+30.04/
+27.01)
(+11.70/
+14.08/
+12.59)
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
-5.47/-8.26
-5.58/-16.18
-9.48/-18.99
+2.85/+4.91
-9.48/-18.98
-4.12/-19.29
-0.78/-0.07
-5.40/-15.85
+5.17/+3.94
+0.71/+2.90
-9.39/-20.02
-4.92/-20.83
-3.19/-5.87
-0.91/-8.85
-10.54/-19.40
+2.39/+6.03
+1.32/+23.57
-4.27/-19.09
-2.71/-4.88
-7.05/-19.78
-6.15/-15.04
+3.22/+3.16
-8.54/-20.85
-4.80/-20.15
e
e
e
a
b
a
b
a
b
N
HN
HN
NH HN c
N
HN c
NH N c
d
d
d
Molecule
AzC-c-10,23,24H2+ AzC-c-10,22,23H2+ AzC-c-10,22,24H2+

G (298 K)
+17.72
(+19.09/
+17.19/
+20.30)
+21.29
(+22.57/
+20.04/
+23.76)
+2.66
(+4.04/
+2.75/
+5.00)

 B3LYP/
M06-2X/
B3LYP-D3)
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
+0.76/+3.87
-5.19/-14.52
-2.21/-11.00
+0.10/+1.28
-8.60/-18.83
-5.00/-20.95
+2.51/+9.20
-5.06/-14.59
-8.92/-17.83
-1.12/-1.27
-0.77/-7.34
-5.40/-21.97
+0.60/+3.37
-7.05/-17.80
-5.13/-12.88
+1.88/0.00
-7.81/-18.45
-5.13/-21.35
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
+
Figure 14. AICD plot (isovalue = 0.05) of azulichlorin dication AzC-c-22,23,24H .
Eight tautomers of free base benzocarbachlorin BCC-c were considered and unsurprisingly
BCC-c-22,24H was the most favored (Table 4). This tautomer is highly diatropic (NICS(0) = -
1
1.70 ppm) and the rings b and c give large negative NICS values that demonstrate that the
macrocyclic ring current runs around the outside of these rings taking the inside track for rings a
and c. This interpretation is confirmed by the AICD plot for this tautomer (Figure 15).
Nonaromatic tautomers with CH bridges were 21.46-32.32 kcal/mol higher in energy. BCC-c-
2
2
2,23H is approx. 10-12 kcal/mol less stable due to the presence of a less favorable conjugation
pathway that runs through an amine-type nitrogen, and because the two NHs are adjacent to one
another. Tautomers BCC-c-21,22H and BCC-c-21,23H have internal methylene units and -
conjugation can occur through the exterior of ring a (18 electron pathway) or through the fused
benzo-unit (22 electron pathway). Both forms are much higher in energy but nevertheless are
strongly aromatic species. BCC-c-21,22H has a NICS(0) value of -8.92 ppm and shows an
increased NICS value for the benzo-unit, indicating that the 22 conjugation circuit (structure 30)
is an important contributor. This pathway is also evident in the AICD plot (Figure 15). The
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
structure of BCC-c-21,23H disrupts the 6 electron arene structure and while an 18 electron
circuit is still possible in this tautomer, this route (31a) appears to be overwhelmed by the 22
electron pathway 31b. Both of these pathways must pass through an amine-type nitrogen for BCC-
c-21,23H, so it is remarkable that the global aromatic character (NICS(0) = -11.90 ppm) is
substantially larger than is seen for BCC-c-21,22H. Nevertheless, the proposed -circuit is evident
in the AICD plot for this species (Figure 15).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
BCC-c-22,24H
BCC-c-21,2H
BCC-c-21,22,24H+
BCC-c-21,23H
Figure 15. AICD plots (isovalues = 0.05) for benzocarbachlorin tautomers BCC-c-22,24H, BCC-
c-21,22H and BCC-c-21,23H and for monocation BCC-c-21,22,24H . BCC-c-22,24H shows a
porphyrin-like 18 electron delocalization pathway that bypasses the benzo-unit. However, the
remaining structures favor 22 electron pathways that run around the benzo-moiety.
+
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Table 4. Calculated Relative Energies (kcal/mol) and NICS Values (ppm) for Benzocarbachlorin
Tautomers.
e
e
e
e
a
b
a
b
b
b
a
a
HN
N
N
N
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H
NH N c
NH HN c
N
N
d
d
d
c
d
c
Molecule
BCC-c-22,24H
0.00
BCC-c-22,23H
+12.15
BCC-c-21,22H
+15.83
BCC-c-21,23H
+21.70

G (298 K)
 B3LYP/
M06-2X/

(0.00/
0.00/
0.00)
(+11.62/
+9.71/
+11.80)
(+16.73/
+16.49/
+16.90)
(+21.79/
+23.49/
+21.70)
B3LYP-D3)
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
-11.70/-30.07
+2.46/+1.18
-13.28/-31.95
+6.98/+10.71
-13.30/-31.61
-6.27/-22.41
-6.48/-15.84
+2.79/+3.19
-3.57/-15.03
+2.64/+7.90
-13.70/-28.54
-6.51/-22.92
-8.92/-20.93
-9.89/-30.30
+0.20/-7.88
+5.85/+9.54
-14.39/-35.05
-9.49/-30.60
-11.90/-29.35
-13.62/-40.75
-2.45/-13.68
+6.91/+16.99
-2.45/-13.68
-8.86/-29.52
e
e
e
e
a
b
b
a
b
a
b
a
N
N
N
N
HN
H
NH N c
N
NH N c
N
N c
d
d
d
d
c
Molecule
BCC-c-5,24H
+25.27
BCC-c-5,22H
+29.23
BCC-c-10,24H
+22.87
BCC-c-10,22H
+25.48

G (298 K)

 B3LYP/
M06-2X/
B3LYP-D3)
(+26.97/
+24.59/
+27.98)
(+31.36/
+29.81/
+32.32)
(+24.98/
+21.46/
+26.02)
(+27.65/
+23.89/
+28.74)
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
-0.97/-0.47
+2.49/+2.64
+0.13/-7.45
+2.03/+1.76
-10.75/-24.58
-6.94/-23.43
-1.25/-1.28
+5.65/+9.31
-12.11/-26.27
+2.12/+2.27
-0.15/-7.46
-6.22/-21.74
+0.17/+2.40
+1.06/-0.50
-2.62/-12.18
+1.73/+0.64
-10.09/-22.69
-7.42/-24.43
+0.58/+3.47
+1.14/-0.36
-11.38/-25.07
+1.62/-0.08
-1.36/-9.04
-7.46/-24.65
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 5. Calculated Relative Energies (kcal/mol) and NICS Values (ppm) for Tautomers of
Benzocarbachlorin Monocations.
e
e
e
e
a
d
b
a
d
b
a
b
a
d
b
HN
N
HN
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NH N c
NH HN c
NH N c
NH HN c
d
BCC-c-
21,22,24H
BCC-c-
22,23,24H
+8.97
(+8.27/
+4.78/
BCC-c-
21,22,23H
+12.61
(+12.82/
+12.11/
+12.88)
BCC-c-
5,23,24H
+28.75
(+29.76/
+27.51/
+30.64)
Molecule
BCC-c-5,22,24H+
+
+
+
+

G (298 K)
 B3LYP/
M06-2X/
0.00
(0.00/
0.00/
+15.61
(+16.74/
+16.08/

B3LYP-D3)
0.00)
+8.07)
+17.44)
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
-13.08/-31.57
-15.48/-44.07
-13.18/-33.69
+8.24/+14.84
-13.18/-33.71
-10.45/-33.60
-7.91/-18.54
+3.51/+4.30
-12.61/-24.82
+3.71/+6.12
-12.65/-24.85
-6.63/-23.18
-10.14/-23.83
-11.80/-34.73
+1.21/-5.10
+5.65/+13.51
-14.79/-31.13
-9.10/-30.50
-3.37/-6.46
+6.41/+10.44
-10.48/-23.24
+3.27/+4,21
-8.37/-19.99
-5.83/-20.19
-2.76/-5.29
+5.65/+10.09
+1.88/-3.33
+1.81/+5.34
-10.82/-22.27
-6.15/-21.35
e
e
e
e
a
b
a
b
a
b
a
b
c
N
N
N
HN
HN
H
H
N
NH HN c
NH N c
N
HN c
d
d
d
d
BCC-c-
5,22,23H
+27.45
(+28.29/
+25.25/
+29.12)
BCC-c-
10,23,24H
+29.72
(+30.53/
+25.23/
BCC-c-
10,22,24H
+11.70
(+12.54/
+7.99/
BCC-c-
10,22,23H
+32.52
(+33.76/
+27.37/
Molecule
+
+
+
+
G (298 K)
 B3LYP/
M06-2X/
B3LYP-D3)
+31.59)
+13.30)
+34.83)
NICS(0)/NICS(1)zz
NICS(a)/NICS(1a)zz
NICS(b)/NICS(1b)zz
NICS(c)/NICS(1c)zz
NICS(d)/NICS(1d)zz
NICS(e)/NICS(1e)zz
-1.30/-0.22
+10.80/+19.78
-12.00/-29.35
+0.29/+4.80
+3.47/-0.17
-0.10/+1.60
+2.95/+4.86
-4.01/-14.99
+0.47/+2.34
-10.60/-22.08
-6.97/-23.61
+0.19/+2.30
+0.41/-0.24
-10.11/-21.82
+1.88/+0.78
-7.50/-17.73
-7.72/-25.43
+2.76/+10.03
+0.92/-3.65
-10.33/-20.92
-8.64/-4.91
-2.95/-11.17
-7.77/-24.94
-4.39/-16.32
Nine tautomers of monoprotonated BCC were analyzed and the most stable form proved to be
C-protonated BCC-c-21,22,24H+ rather than the expect N-protonated structure BCC-c-
+
22,23,24H (Table 5). The more stable tautomer is highly diatropic with a NICS(0) value of -13.08
ppm and rings a, b, d and e all gave large negative NICS values. These results were consistent with
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the 23-atom 22 electron delocalization pathway shown in structure 32, an outcome that is also
supported by AICD calculations (Figure 15). The C1-C2 and C3-C4 bonds, which connect the
benzo-unit to the rest of the macrocycle, are ca. 0.04 Å shorter than in the free base demonstrating
increases conjugative connectivity, although more pronounced bond length alternation emerges in
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
the arene unit. The NICS(0) value for BCC-c-22,23,24H , while substantial, is less than -8 ppm
indicating reduced aromaticity and the results suggest that a porphyrin-like 18 electron pathway
is favored for this species. It was not possible to obtain the proton NMR spectrum for
monoprotonated benzocarbachlorin 27a but the related aldehydes 27b,c gave conventional N-
+
protonated monocations 27b,cH (Scheme 5) in contradiction to the computational results. In
+
tautomer BCC-c-22,23,24H , the benzo-unit is effectively disconnected from the global
conjugation pathways and the presence of an electron-withdrawing formyl moiety would not
significantly affect the stability of the monocation. However, the presence of an aldehyde
+
substituent on the benzo-fragment of BCC-c-21,22,24H would directly interact with the 22
electron delocalization pathway and would thereby destabilize the structure. Hence, the N-
protonated tautomer is more favored under these circumstances. The alternative C-protonated
+
monocation BCC-c-21,22,23H was calculated to be >12 kcal/mol higher in energy, presumably
due to unfavorable steric interactions between the adjacent NHs. In addition, the core arrangement
+
in BCC-c-21,22,24H is set up for much more favorable hydrogen bonding interactions. The
remaining tautomers are protonated onto one of the meso-carbon bridges and four of the six
structures show increases in the relative energies that were close to 30 kcal/mol. However, BCC-
+
+
c-22,23,24H and BCC-c-22,23,24H were far more accessible species (relative energies between
7.99 and 17.44 kcal/mol) because these have macrocyclic cores that are arranged to maximize
intramolecular hydrogen bonding interactions. Three dications were also considered (Table 6) but
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