Synthesis and Properties of Carbaporphyrin and Carbachlorin Dimethyl Esters Derived from Cyclopentanedialdehydes

Article abstract of DOI:10.1021/acs.joc.7b01831

Norbornenes with two ester substituents were prepared by Diels-Alder cycloadditions of cyclopentadiene with dimethyl fumarate and dimethyl 1,1-ethylenedicarboxylate. Oxidation with potassium permanganate gave good yields of related diols that were oxidatively ring-opened to afford cyclopentane dialdehydes. MacDonald-type "3 + 1" condensations with a tripyrrane, followed by oxidation with DDQ in refluxing toluene, gave carbaporphyrin or carbachlorin products in good yields. The macrocyclic products were highly diatropic and produced porphyrin-like UV-vis spectra. The carbaporphyrin was converted into silver(III) and gold(III) organometallic derivatives. Reaction with methyl iodide in the presence of potassium carbonate gave mono- and dialkylation products, and treatment of the former with Ni(OAc)₂ or Pd(OAc)₂ afforded nickel(II) and palladium(II) complexes. The free base carbaporphyrin and carbachlorin, and the nickel and palladium complexes, were characterized by X-ray crystallography. The carbachlorin also reacted with silver(I) acetate to give a silver(III) derivative. Carbaporphyrins and carbachlorins underwent deuterium exchange at the meso-positions with deuteriated TFA, and this observation indicates that protonation is occurring at the bridging carbons. The new route to carbaporphyrins and carbachlorins has enabled detailed studies on the properties of these systems and provides the foundations for future investigations.

Full text of DOI:10.1021/acs.joc.7b01831

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Article
Synthesis and properties of carbaporphyrin and carbachlorin
dimethyl esters derived from cyclopentanedialdehydes
Navneet Sahota, Gregory M. Ferrence, and Timothy D. Lash
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01831 • Publication Date (Web): 29 Aug 2017
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Synthesis and properties of carbaporphyrin and carbachlorin dimethyl esters
derived from cyclopentanedialdehydes
Navneet Sahota, Gregory M. Ferrence and Timothy D. Lash*
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Department of Chemistry, Illinois State University, Normal, Illinois 61790ꢀ4160
Abstract
Norbornenes with two ester substituents were prepared by DielsꢀAlder cycloadditions of
cyclopentadiene with dimethyl fumarate and dimethyl 1,1ꢀethylenedicarboxylate. Oxidation with
potassium permanganate gave good yields of related diols that were oxidatively ring opened to
afford cyclopentane dialdehydes. MacDonaldꢀtype “3 + 1” condensations with a tripyrrane,
followed by oxidation with DDQ in refluxing toluene, gave carbaporphyrin or carbachlorin
products in good yields. The macrocyclic products were highly diatropic and produced
porphyrinꢀlike UVꢀVis spectra. The carbaporphyrin was converted into silver(III) and gold(III)
organometallic derivatives. Reaction with methyl iodide in the presence of potassium carbonate
gave monoꢀ and dialkylation products, and treatment of the former with Ni(OAc) or Pd(OAc)
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afforded nickel(II) and palladium(II) complexes. The free base carbaporphyrin and carbachlorin,
and the nickel and palladium complexes, were characterized by Xꢀray crystallography. The
carbachlorin also reacted with silver(I) acetate to give a silver(III) derivative. Carbaporphyrins
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and carbachlorins underwent deuterium exchange at the mesoꢀpositions with deuteriated TFA
and this observation indicates that protonation is occurring at the bridging carbons. The new
route to carbaporphyrins and carbachlorins has enabled detailed studies on the properties of these
systems and provides the foundations for future investigations.
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Introduction
Chart 1. Chlorin and medicinally active derivatives
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Chlorins 1 are 2,3ꢀdihydroporphyrins that are widespread in nature. In particular, many of
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the chlorophylls are magnesium chlorins and these play crucial roles in photosynthesis. In
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addition, certain bacteria produce the iron(II) chlorin heme d, while the marine echiuran worm
Bonellia viridis produces a chlorin derivative called bonellin that is responsible for
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masculinization of the larvae and also exhibits antitumor activity. Chlorophyllꢀderived chlorins
that possess antioxidant properties have been isolated from marine sponges, diatoms, tunicates
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and molusks. Chlorins also have medicinal applications as photosensitizers in photodynamic
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®
therapy (PDT) (Chart 1). Verteporfin (Visudyne , 2) has been approved for the treatment of ageꢀ
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related macular degeneration and has shown promise in atheroschlerotic plaque therapy.
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Temoporfin (3) is being used for the PDT treatment of squamous cell carcinomas, while
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talaporfin (4) has been approved for lung cancer. Chlorins commonly have electronic
absorptions above 650 nm and this feature is beneficial in PDT applications as light penetration
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in bodily tissues is more effective at longer wavelengths.
Unfortunately chlorin analogues
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have received very little attention, although structures of this type could potentially be equally
effective.
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Chart 2. Carbaporphyrinoid systems
Investigations into carbaporphyrinoid systems continue to extend the structural diversity of
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porphyrin analogues. Carbaporphyrinoids possess a porphyrinꢀlike framework where one or
more of the core nitrogen atoms have been replaced with carbons. Of these, NꢀConfused
porphyrins 5a (Chart 2) are the best studied and many examples of metalated derivatives for this
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system (e.g., 5b,c and 6) have been reported. Structurally diverse carbaporphyrinoids have
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been synthesized, including azuliporphyrins 7a and benziporphyrins 8a. Macrocycles 7a and
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reported (Chart 2).
True carbaporphyrins such as 9a and 10 (Chart 3) contain
cyclopentadiene subunits in place of one or more pyrrolic moiety and are commonly prepared as
benzoꢀfused structures. Benzocarbaporphyrins can be prepared in excellent yields using the “3 +
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” variant on the MacDonald condensation. However, only moderate yields were obtained in
the synthesis of carbaporphyrins with unsubstituted cyclopentadiene subunits. Carbaporphyrins
act as trianionic ligands and form silver(III), gold(III), rhodium(III) and iridium(III) complexes
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9b-e.
Reaction of carbaporphyrin 9a with methyl iodide and potassium carbonate in refluxing
acetone gave Nꢀmethylcarbaporphyrin 11a as the major product together with Cꢀmethyl
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derivative 11b. Similarly 9a reacted with ethyl iodide to afford 11c (major) and 11d (minor).
NꢀAlkylcarbaporphyrins 11a and 11c could be metalated with palladium(II) acetate in refluxing
acetonitrile to produce palladium(II) complexes 12a and 12b, respectively, where an unexpected
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alkyl group migration had also taken place. Related metallocarbaporphyrins have been obtained
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indirectly by the ring contraction of metalated benziporphyrins.
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Chart 3. True carbaporphyrins and their metalated derivatives
Carbachlorins have also been prepared by the MacDonaldꢀtype “3 + 1” strategy, although
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much lower yields were obtained.
In an early study, bicyclic dialdehydes 13, derived in two
steps from the dimer of cyclopentadiene, were reacted with tripyrrane 14 in the presence of
trifluoroacetic acid (TFA), and subsequent oxidation with DDQ in refluxing toluene afforded
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carbachlorins 15 in 11ꢀ15% yield (Scheme 1). Attempts to oxidize 15a or 15b to the
corresponding carbaporphyrins were unsuccessful even though most chlorins are readily
converted to porphyrins under mild oxidative conditions. In a more recent investigation,
ethoxymethylenecyclopentene carbaldehyde 16 was reacted with 14 under similar conditions and
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following oxidation with aqueous ferric chloride, carbachlorin 17 was isolated in 11ꢀ16% yield.
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A dicarbachlorin was prepared in 5ꢀ7% yield from dicyclopentadienylmethane, while a
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thiacarbachlorin was obtained in 5% yield by reacting a carbatripyrrene with a thiophene
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dicarbinol. Unlike 15a and 15b, carbachlorin 17 was easily dehydrogenated with DDQ to give
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carbaporphyrin 10. Reaction of 17 with silver(I) acetate afforded silver(III) complex 18, while
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alkylation with methyl iodide afforded the Nꢀmethyl derivative 19. Treatment with
palladium(II) acetate in acetonitrile led to a metalationꢀoxidationꢀalkyl group migration cascade
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to generate the palladium(II) complex 20. It is notable that the UVꢀvis spectra for 15a, 15b and
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7 all gave moderately strong absorptions at 650ꢀ651 nm.
Scheme 1. Examples of earlier syntheses and metalations of carbaporphyrins.
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Although carbachlorins possess potentially useful spectroscopic properties and display
interesting chemical reactivity, further studies have been limited due to the mediocre yields
obtained for previously reported syntheses. In this work, we set out to develop a superior
methodology for preparing carbachlorins and carbaporphyrins without fused aromatic units. This
work has resulted in the generation of new carbachlorins and carbaporphyrins and has enabled
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the formation and structural characterization of novel organometallic derivatives.
Results and discussion
Scheme 2. Retrosynthetic analysis of carbachlorin 21.
Scheme 3. Synthesis of a cyclopentane dialdehyde from dimethyl fumarate.
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Benzocarbaporphyrins such as 9a are robust compounds with intriguing reactivity.
However, although carbaporphyrin 10 is quite stable in solution, it appears to be far more prone
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to degradation reactions. In the case of a related thiacarbaporphyrin, this reactivity was applied to
the synthesis of an unusual dimer linked via the inner carbon atoms of the carbaporphyrinoid
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rings. However, for most purposes these properties are counterproductive and limit the studies
that can be conducted on these systems. With this in mind, the synthesis of carbachlorins and
carbaporphyrins with ester groups attached to the carbocyclic rings were targeted for synthesis as
it was anticipated that the presence of electronꢀwithdrawing groups would greatly improve the
stability of these structures. The synthesis of carbachlorin diester 21 was considered as this could
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conceivably be derived from cyclopentane dialdehyde 22 (Scheme 2). The required dialdehyde
can be prepared from the known DielsꢀAlder adduct 23 of dimethyl fumarate and
cyclopentadiene (Scheme 3). Several different procedures were attempted to prepare norbornene
23, and superior results were achieved using the method described by Beare et al. where freshly
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cracked cyclopentadiene was gradually added to an aqueous suspension of dimethyl fumarate.
Göksu et al. had reported that seven bicyclo[2.2.1]heptenes, including 23, were cleaved to cyclic
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dialdehydes in good yields by oxidation with KMnO ꢀCuSO .5H O. However, in our hands all
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attempts to reproduce this procedure with 23 failed to generate any dialdehyde. Hence, an
alternative synthetic method for preparing the required dicarbaldehyde was investigated. The
best results were obtained by carrying out a twoꢀstep procedure that was adapted from a
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literature report by Donohoe and coworkers. In this approach, a solution of norbornene 23 in
tertꢀbutyl alcohol was oxidized with potassium permanganate and sodium hydroxide in tertꢀbutyl
o
alcohol and water at 0 C to give the exoꢀdiol 24 in 73% yield (Scheme 3). Oxidative ring
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opening of the diol with potassium periodate gave the required dialdehyde 22 in 50% yield.
Dialdehyde 22 proved to be very unstable and for this reason was immediately reacted with
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tripyrrane dicarboxylic acid 14 in the presence of trifluoroacetic acid (Scheme 4). The solution
was neutralized with triethylamine and the solvent removed under reduced pressure. At this
stage, a hexahydrocarbaporphyrin intermediate such as 25 may have been generated. The crude
product was dissolved in toluene and refluxed with 2ꢀ3 equivalents of DDQ in an attempt to form
carbachlorin 21. However, in small scale reactions the only isolatable porphyrinoid product was
the related carbaporphyrin 26. In large scale reactions, carbachlorin 21 could be isolated as a
byproduct in up to 10% yield but carbaporphyrin 26 was always observed as the major product in
approximately 40% yield. In this respect, the reaction differs from condensations of bicyclic
dialdehydes 13 with tripyrrane 14, as the earlier study only gave carbachlorin products 15 in
moderate yields. The presence of a fused fiveꢀmembered ring in carbachlorins 15 is likely to
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disfavor oxidation to carbaporphyrin because increased angle strain would result if sp carbons
were introduced. Milder conditions for the oxidation were investigated but these experiments
either resulted in the formation of little or no isolatable porphyrinoid products, or the
predominance of carbaporphyrin 26. Porphyrinoids 21 and 26 were easily separated by column
chromatography on grade 3 alumina. Initially, it had been intended that a related cisꢀcarbachlorin
isomer would be prepared starting with the DielsꢀAlder adduct of dimethyl maleate, but as the
same carbaporphyrin would be formed and chlorin is only obtained as a minor product, this
synthetic variant was not pursued. Although the new methodology does not furnish carbachlorins
in acceptable yields, this approach provides a convenient and vastly superior route to a
carbaporphyrin that has no ring fused subunits. This has allowed the spectroscopic properties,
structural analysis and reactivity of 26 to be explored in detail.
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Scheme 4. “3 + 1” synthesis of a carbaporphyrin and a related carbachlorin.
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Figure 1. 500 MHz proton NMR spectrum of carbaporphyrin 26 in CDCl3.
As expected, carbaporphyrin 26 proved to be a fully aromatic compound. The proton NMR
spectrum in CDCl (Figure 1) showed the presence of a strong diatropic ring current, and the
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internal CH proton was found at ꢀ6.27 ppm while the mesoꢀprotons were shifted downfield to
give two 2H singlets at 9.51 and 10.24 ppm. Hence, the difference between the chemical shifts
for the internal and external protons (ꢀδ), which is a useful indicator of diatropic character, was
just over 16.5 ppm. The 7,18ꢀmethyl substituents gave a 6H singlet at 3.51 ppm, showing strong
deshielding due to their proximity to the macrocyclic ring current. The carbonꢀ13 NMR spectrum
of 26 demonstrated that the macrocycle possesses a plane of symmetry. The mesoꢀcarbons gave
rise to peaks at 94.6 and 107.2 ppm, while the internal carbon afforded a resonance at 100.7 ppm.
The UVꢀVis spectrum for 26 gave a strong absorption in the Soret region at 436 nm, followed by
a series of four weaker Q bands between 520 and 720 nm (Figure 2). These results are typical of
aromatic porphyrinoids such as true porphyrins and benzocarbaporphyrins 9a. High resolution
ESI mass spectrometry also supported the identity of 26. In addition, the structure of
carbaporphyrin 26 was confirmed by Xꢀray crystallography (Figure 3). The molecular structure
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shows that the macrocycle is reasonably planar as evidenced by the minimal pyrrole to mean
macrocycle plane tilts of 2.24(2)°, 1.13(2)°, and 1.26(2)°. The cyclopentadienyl subunit,
however, is significantly tilted 13.63(2)° out of the mean macrocyclic plane. This presumably
relieves steric crowding in the central cavity due to the presence of three hydrogen atoms. The
three hydrogen atoms, H21, H22 and H24, located in the carbaporphyrin cavity are attached to
the parent atoms C(21), and N(22) and N(24), and the pyrrole nitrogen atoms are cis to C(21).
Both solution NMR data and solidꢀstate diffraction data are consistent with tautomer 26, which
has two NHs flanking the pyrrolenine nitrogen. With the exception of the unusually short, yet
reasonable, C2ꢀC3 bond length, a Mogul geometry check validated all bond distances, angles and
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Wavelength (nm)
Figure 2. UVꢀvis spectra of carbaporphyrin 26 in dichloromethane (red line, free base), CH Cl2
2
with 100 equiv TFA (green line, monocation), 50% TFAꢀCH Cl (blue line, dication) and 5%
DBUꢀCH Cl (purple line, monoanion).
2
2
2
2
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52
53
54
55
56
57
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60
Figure 3 Color POVꢀRay rendered ORTEP III drawing (50% probability level, hydrogen atoms
rendered arbitrarily small for clarity) of carbaporphyrin 26.
MeO C
Me
2
MeO C
Et
Et
2
HN
N
NH
Me
Et
Et
26
2
MeO C
Me
MeO
2
C
Me
MeO
2
C
Me
MeO
2
C
Et
Et
MeO
2
C
Et
Et
MeO
2
C
Et
Et
N
N
N
N
N
N
H
H
H
H
H
N
H
H
N
N
Me
Me
Me
Et
Et
Et
Et
Et
Et
6’H+
26H+
26’’H+
2
MeO C
Me
2
MeO
2
C
Et
Et
N
N
H
H
H
N
Me
Et
Et
6H22+
2
Scheme 5. Protonation and proton exchange for carbaporphyrin 26.
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6
Upon addition of acid, carbaporphyrin 26 underwent two sequential protonations (Scheme 5).
+
Titration with TFA led to the formation of a new species that was attributed to monocation 26H .
Full conversion required the addition of 50 equiv TFA. The UVꢀVis spectrum showed multiple
weakened Soret bands at 315, 392 and 446 nm and a weaker absorption at 549 nm (Figure 2). In
0
1
2
3
4
5
6
7
8
9
0
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5
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9
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2
+
the presence of a large excess of TFA, a Cꢀprotonated dication 26H2 was generated, and the
UVꢀVis spectrum for this species in 50% TFAꢀdichloromethane showed a strong split Soret band
at 407 and 425 nm and Q bands at 549, 597 and 656 nm (Figure 2). Addition of one drop of TFA
to a NMR tube containing a solution of 26 in CDCl resulted in the formation of a mixture of
3
monoꢀ and dicationic species. However, when only 2 ꢁL of TFA was added to the solution, the
+
proton NMR spectrum of the monocation 26H could be obtained. The mesoꢀprotons were
shifted slightly further downfield to give two 2H singlets at 9.74 and 10.40 ppm. The NH protons
gave rise to two broad peaks at ꢀ1.97 (2H) and ꢀ3.14 (1H) ppm, while the internal CH appeared
at ꢀ5.95 ppm (ꢀδ 16.35 ppm). The proton NMR spectrum of the dication in 50% TFAꢀCDCl3
demonstrated that this species was highly diatropic (ꢀδ 19.5 ppm) as the internal CH gave an
2
upfield singlet at ꢀ7.65 ppm, while the mesoꢀprotons produced two 2H singlets at 11.10 and
1
1.86 ppm. The indirect effect of the ring current on the methyl substituents produced 6H
+
2+
singlets for 26H and 26H2 at 3.44 and 3.79 ppm, respectively, a result that further
demonstrates the highly diatropic nature of the dicationic species. Proton and carbonꢀ13 NMR
spectra for the monoꢀ and dications confirmed that these structures retain a plane of symmetry.
Addition of dꢀTFA to an NMR solution of 26 in CDCl showed rapid exchange of the 21ꢀH
3
resonance and slow exchange of the mesoꢀprotons. As the solutions consisted of a mixture of
protonated species, it was necessary to extract the sample before NMR analysis could be
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9
conducted. Two drops of dꢀTFA were added to the NMR tube and after 10 min the solution was
neutralized by addition of NaOD in D O. The mixture was diluted with water, extracted with
2
dichloromethane and the organic solutions dried over sodium sulfate. Following removal of the
solvent, the residue was analyzed by proton NMR spectroscopy. The results showed that the
internal CH had undergone exchange but no other resonances were affected. When the solution
was exposed to dꢀTFA for 24 h, and the solution neutralized and extracted as before, significant
reductions in the intensities of the mesoꢀproton resonances were observed. The peak
corresponding to the 5,20ꢀprotons was reduced by approximately 15%, while the 10,15ꢀproton
resonance was diminished by >40%. The results indicate that mesoꢀprotonated species such as
10
11
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26
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+
+
+
monocations 26aH and 26bH are energetically accessible and in equilibrium with 26, 26H and
2
+
21b
26H2 (Scheme 5). Similar results have previously been noted for benzocarbaporphyrins.
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8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Alkylation and metalation of carbaporphyrins.
Carbaporphyrinoids, including Nꢀconfused porphyrins 5a and benzocarbaporphyrins 9a, have
2
3,39
previously been shown to form stable silver(III) derivatives.
Hence, carbaporphyrin diester
2
6 was treated with silver(I) acetate in methanolꢀdichloromethane in an attempt to generate the
silver(III) complex 27a. After column chromatography, a red fraction was collected and
recrystallized from chloroformꢀmethanol to afford the organometallic complex 27a as a dark red
powder in 60% yield (Scheme 6). Proton NMR spectroscopy demonstrated that silver(III)
complex 27a retained strongly aromatic characteristics as the mesoꢀprotons showed up as two 2H
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singlets at 8.79 and 9.90 ppm. The proton and carbonꢀ13 NMR spectra were also consistent with
symmetrical structures. The carbonꢀ13 NMR results showed the mesoꢀcarbons at 96.1 and 110.1
ppm. The UVꢀvis spectrum for 27a produced a Soretꢀlike band at 449 nm together with weaker
absorptions at higher and lower wavelength (Figure 4). High resolution ESI MS also confirmed
that this species has the molecular formula C H AgN O .
10
11
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27
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3
5
36
3
4
5
4
3
2
1
0
ε
ε
300
400
500
600
700
Wavelength (nm)
Figure 4. UVꢀVis spectra of silver(III) carbaporphyrin 27a (red line) and gold(III)
carbaporphyrin 27b (blue line) in chloroform.
Gold(III) complexes have previously been prepared by reacting benzocarbaporphyrins
such as 9a with gold(III) acetate, although poor yields were obtained for mesoꢀunsubstituted
2
3b
structures. Attempts to react 26 with gold(III) acetate under the conditions used to prepare the
silver(III) complex were unsuccessful and no metalated product could be isolated. However,
when 26 was refluxed with gold(III) acetate in pyridine, the solution rapidly changed color from
brown to dark red. Following purification by column chromatography and recrystallization from
chloroformꢀmethanol, gold(III) complex 27b was isolated in 44% yield (Scheme 6). Although a
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6
moderate yield was obtained, the electronꢀwithdrawing ester groups do appear to stabilize the
carbaporphyrin system to a significant extent and reduce losses due to oxidative decomposition.
The gold complex gave a similar UVꢀvis spectrum (Figure 4) to the silver complex, although the
strongest of the Soret bands was significantly reduced in intensity for 27b. The proton NMR
spectrum of 27b showed significant downfield shifts compared to 27a. The mesoꢀprotons
appeared 0.09ꢀ0.23 ppm further downfield for 27b, and even the methyl substituents gave a
resonance 3.36 ppm for 27b compared to 3.31 ppm for 27a.
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8
9
0
Figure 5. 500 MHz proton NMR spectra of 21ꢀmethylcarbaporphyrin 28 (A) and the related
palladium(II) complex 30 (B) in CDCl3.
Benzocarbaporphyrin 9a (R = Et) has previously been shown to react with methyl or ethyl
iodide and potassium carbonate in refluxing acetone to afford Nꢀ and Cꢀalkylation products 11a-
25
d. When carbaporphyrin 26 was reacted with methyl iodide and potassium carbonate in
refluxing acetone for 30 min, a single monoalkylation product 28 was obtained in up to 75%
yield following purification by column chromatography and recrystallization from chloroformꢀ
methanol (Scheme 6). Unexpectedly, the reaction favored substitution at the internal carbon
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rather than on the nitrogen atom. Benzocarbaporphyrin 9a afforded Nꢀalkyl derivatives as the
2
5
major products in these reactions. Although the presence of an internal methyl substituent is
likely to reduce the planarity of the macrocycle, the proton NMR spectrum of 28 (Figure 5)
showed that the system is highly diatropic and the internal methyl group gave rise to an upfield
singlet at ꢀ4.68 ppm, while the mesoꢀprotons were strongly deshielded giving two 2H singlets at
10
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9
.28 and 9.90 ppm. Nevertheless, the downfield shifts for the external protons are reduced
compared to carbaporphyrin 26 and the methyl resonance shifted upfield by 0.08 ppm The
presence of a plane of symmetry was evident from the proton and carbonꢀ13 NMR spectra. In the
UVꢀvis spectrum for the free base, the Soret band was substantially broadened and diminished in
intensity giving rise to a peak at 428 nm (Figure 6). A series of Q bands were still present but
again these were broadened compared to those observed for 26. In our studies, UVꢀvis spectra
are commonly run in 1% triethylamineꢀchloroform, as the additive can scavenge the trace
amounts of acid that are commonly associated with chlorinated solvents. However, when 28 was
run under these conditions substantial changes in the UVꢀvis spectrum were observed indicating
ꢀ
the formation of a new species that was attributed to monoanion [28 – H] (Scheme 7). It should
be noted that the position of the internal NH is not known. In 5% DBUꢀCH Cl , full conversion
2
2
to the monoanion was observed (Figure 6). This spectrum showed three Soretꢀlike bands
between 400 and 500 nm and Q bands at 564, 648 and 700 nm. The proton NMR spectrum for
28 in DBUꢀCDCl showed the mesoꢀprotons downfield at 9.22 and 9.83 ppm, while the internal
3
methyl substituent gave a 3H singlet at ꢀ4.78 ppm. Naturally, the aliphatic region was completely
obscured by the DBU. The anion is clearly still aromatic and this may be due to the 17ꢀatom 18π
electron delocalization pathway shown in structure A (Scheme 7). Carbaporphyrin 26 did not
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5
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6
appear to deprotonate with triethylamine but a new species was observed upon addition of DBU
Figure 2).
(
1
1
1
4
2
0
8
6
4
2
0
0
1
2
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0
1
2
3
4
5
6
7
8
9
0
ε
ε
3
00
400
500
600
700
800
Wavelength (nm)
Figure 6. UVꢀvis spectra of 21ꢀmethylcarbaporphyrin 28 in dichloromethane (red line, free base),
CH Cl with 5 equiv TFA (green line, monocation 28H ), 25% TFAꢀCH Cl (blue line, dication
+
2
2
2
2
2
+
2
8H2 ) and 5% DBUꢀCH Cl (purple line, monoanion).
2 2
Scheme 7. Deprotonation of carbaporphyrin 28.
Addition of 5 equiv. of TFA to a solution of Cꢀmethylcarbaporphyrin 28 led to the formation
ꢀ
of monocation 28H (Scheme 8). The UVꢀVis spectrum showed a Soret band at 411 nm and
+
broad Q bands between 500 and 650 nm (Figure 6). The proton NMR spectrum for 28H
indicated that this species is slightly more diatropic than the free base form, as the internal
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methyl resonance was shifted upfield to ꢀ5.41 ppm while the mesoꢀprotons moved downfield to
give two 2H singlets at 9.49 and 10.03 ppm. Further addition of TFA led to the formation of a
2+
diprotonated dication 28H2 . In 25% TFAꢀCH Cl , the UVꢀVis spectrum gave an intense Soret
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
27
28
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band at 414 nm, with a shoulder at 430 nm, and two broad Q bands at 550 and 606 nm. The
proton NMR spectrum for this species in TFAꢀCDCl gave a quartet at ꢀ8.67 ppm and a doublet
3
at ꢀ6.55 ppm for the 21ꢀH and inner methyl substituent, respectively, while the mesoꢀprotons
showed up at 11.16 and 11.80 ppm. As would be expected, the proton and carbonꢀ13 NMR
spectra were both consistent with the monoꢀ and diprotonated structures possessing a plane of
symmetry.
When benzocarbaporphyrin 9 was reacted with methyl or ethyl iodide for 16 h, no more than
2
5
trace amounts of related dialkylation products were observed. However, overnight reactions of
2
6 with MeIꢀK CO in refluxing acetone afforded a dimethylated derivative 29 as the major
2
3
product. Following column chromatography and recrystallization from chloroformꢀmethanol, the
dialkylated carbaporphyrin 29 was isolated as shiny purple crystals in 69% yield (Scheme 6).
The proton NMR spectrum for 29 demonstrated that the methyl groups had been introduced on
the inner carbon atom and at an adjacent nitrogen. Crowding due to the presence of two methyl
groups within the porphyrinoid core is likely to lead to distortion of the macrocycle but the
diamagnetic ring current is only slightly reduced. The internal methyl groups were strongly
shifted upfield to give two 3H singlets at ꢀ5.27 and ꢀ3.91 ppm, while the external mesoꢀprotons
appeared as four 1H singlets at 8.90, 9.05, 9.52 and 9.54 ppm. The external methyl substituents
in 29 were not as deshielded as the corresponding resonances for 26 or 28, and gave rise to two
3H singlets at 2.95 and 3.32 ppm. The duplication of peaks seen in this spectrum demonstrated
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2
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5
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5
5
6
that there is no longer a plane of symmetry, and this observation was confirmed by carbonꢀ13
NMR spectroscopy. In addition, as the methyl groups are too large to fit within the cavity, they
will both be placed to one side of the structure. It is also likely that the two methyl groups are
placed on opposite sides of the macrocycle, and the structure is therefore chiral and exists as a
pair of enantiomers. The UVꢀVis spectrum for 29 gave broad Soret bands at 376 and 441 nm,
two Q bands at 545 and 589 nm, and a broad absorption at 736 nm (Figure 7). The weakened and
broadened absorptions again suggest that the system has become somewhat distorted.
0
1
2
3
4
5
6
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9
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7
8
9
0
7
6
5
4
3
ε
ε
2
1
0
300
500
700
900
Wavelength (nm)
Figure 7. UVꢀvis spectra of dimethylcarbaporphyrin 29 in 1% Et NꢀCH Cl (red line, free base)
3
2
2
+
and in CH Cl with 50 equiv. TFA (blue line, monocation 29H ).
2
2
Scheme 8. Protonation of carbaporphyrin 28.
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+
Addition of trace amounts of TFA led to the formation of monocation 29H , and the UVꢀVis
spectrum showed a relatively weak Soret band at 412 nm and two broad Q bands at 567 and 607
nm (Figure 7). However, further addition of acid did not generate the related dication and the
UVꢀvis spectrum remained unaltered. Presumably, the steric crowding in the carbaporphyrin
10
11
12
13
14
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+
cavity inhibits the second protonation. The proton NMR spectrum for monocation 29H showed
the internal methyl resonances at ꢀ4.91 and ꢀ3.54 ppm, while the mesoꢀprotons gave four singlets
at 9.45, 9.46, 9.86 and 9.92 ppm. The external methyl resonances appeared at 3.03 and 3.37 ppm.
The results indicate that the protonated species has a slightly stronger diatropic ring current than
the free base form, although the shifts are substantially reduced compared to the original
carbaporphyrin 26.
Metalation of Nꢀalkyl benzocarbaporphyrins 9a,c with palladium(II) acetate in refluxing
2
5
acetonitrile have previously been shown to give palladium(II) organometallic derivatives 12.
The metalation reaction is associated with an alkyl group migration from the nitrogen to the
inner carbon atom. It is noteworthy that the methyl group in 28 is already attached to the internal
carbon, and therefore no rearrangement would be necessary to form an analogous palladium
complex. In fact, reaction of 28 with palladium(II) acetate in refluxing acetonitrile gave
palladium(II) derivative 30 in 63% yield (Scheme 6). Although, the conjugation pathway in the
metal complex has been altered, the macrocycle still remains fully aromatic. The proton NMR
spectrum of 30 (Figure 5) gave two 2H singlets at 9.85 and 10.81 ppm in the downfield region
for the four mesoꢀprotons, confirming that the complex has a plane of symmetry. Moreover, the
presence of a singlet at ꢀ4.12 (3H) indicates that the internal methyl group is strongly shielded.
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5
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5
5
5
6
The NMR results show larger upfield and downfield shifts for the palladium complex compared
to the free base form of 28 (Figure 5), indicating an enhancement of the diamagnetic ring current.
In the carbonꢀ13 NMR spectrum, the internal methyl substituent showed up at 21.8 ppm, while
the mesoꢀprotons gave resonances at 101.7 and 113.0 ppm. The UVꢀVis spectrum for 30 gave
Soretꢀlike bands at 410 and 460 nm, and a weaker absorption at 602 nm (Figure 8). The structure
of palladium complex of carbaporphyrin 30 was also confirmed using Xꢀray crystallography
0
1
2
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9
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0
(
Figure 9). The metrics of the framework bond distances are consistent with an overall aromatic
3
carbaporphyrin with an sp hybridized C21. The palladium(II) center resides in a typical square
planar coordination environment with 2.054(2) Å PdꢀC21, 2.040(2) Å PdꢀN22, 2.066(2) Å Pdꢀ
N23, and 2.028(1) Å PdꢀN24 bond lengths. The framework and metal coordination environment
2
6
are similar to that of (tetraphenylꢀ21ꢀformylꢀ21ꢀcarbaporphyrinato)palladium(II) and like this
1
complex, 30 has the palladium(II) ion coordinating η to C21, which being alkylated leads to the
3
2
distended 1.491(2) Å and 1.495(2) Å sp ꢀ sp C21ꢀC1 and C21ꢀC bond distances. Unlike the
2
3
relatively short metal to sp formyl carbon atom distance observed in the formyl complex, the sp
hybridized C25 methyl group in 30 is not available to interact with the palladium(II) metal
center, as illustrated by the over 2.7 Å Pd…C(methyl) separation.
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ε
ε
300
500
700
900
Wavelength (nm)
Figure 8. UVꢀvis spectra of nickel(II) carbaporphyrin 31 (red line) and palladium(II)
carbaporphyrin 30 (blue line) in chloroform.
Figure 9. Color POVꢀRay rendered ORTEP III drawing (50% probability level, hydrogen atoms
rendered arbitrarily small for clarity) of palladium complex 30
Attempts to react 28 with nickel(II) acetate under the same conditions failed to give the
related nickel(II) complex 31 (Scheme 6). However, when the reaction was conducted in
refluxing DMF for 30 min, the nickel(II) derivative could be isolated in 70% yield. The proton
NMR spectrum of 31 showed two singlets at 9.59 and 10.56 ppm in the downfield region for the
four mesoꢀprotons, and a 3H singlet at ꢀ3.89 ppm (3H) for the internal methyl group. Clearly, the
macrocycle still retains fully aromatic characteristics and a plane of symmetry. However, the
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upfield and downfield shifts for 31 are reduced compared to palladium(II) complex 30,
indicating that 30 can support a slightly larger diamagnetic ring current. The carbonꢀ13 NMR
spectrum confirmed the symmetry of this complex and the internal methyl substituent could be
identified at 19.8 ppm. The mesoꢀcarbons gave resonances 2ꢀ3 ppm upfield from the values
observed for the palladium complex at 99.8 and 111.0 ppm. The identity of the nickel complex,
which is the first reported example of a nickel carbaporphyrin, was supported by high resolution
ESI MS. The structure was also confirmed by Xꢀray crystallography (Figure 10). The structure of
31 includes two crystallographically independent residues, the relative bond lengths and angles
of which are essentially indistinguishable. The metrics of the framework bond distances are
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consistent with an overall aromatic carbaporphyrin with an sp hybridized C21. The nickel(II)
center resides in a typical square planar coordination environment with 2.02(1) Å NiꢀC21,
1
.962(2) Å NiꢀN22, 1.961(2) Å NiꢀN23, and 1.957(2) Å NiꢀN24 bond lengths. In fact, the
framework and metal coordination environment are very similar to that of (2ꢀazaꢀtetraphenylꢀ21ꢀ
4
0
methylꢀ21ꢀcarbaporphyrinato)nickel(II)
and
(2ꢀazaꢀtetraphenylꢀ21ꢀtrifluoromethylꢀ21ꢀ
41
carbaporphyrinato)ꢀnickel(II). As is the case for these Nꢀconfused porphyrin complexes, 31 has
1
the nickel(II) ion coordinating η to C21, which being methylated leads to the distended 1.48(1)
3
2
Å sp ꢀ sp C21ꢀC1 and C21ꢀC bond distances.
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Figure 10. Color POVꢀRay rendered ORTEP III drawing (50% probability level, hydrogen atoms
rendered arbitrarily small for clarity) of nickel(II) carbaporphyrin 31.
2
CO Me
Me
MeO C
2
CO
2
Me
CHO
MeO C
Et
Et
2
1
. TFA
. DDQ
HN
N
2
OHC
NH
33
Me
Et
Et
32
AgOAc
Et
+ H+
CO Me
- H+
2
Me
2
MeO C
CO Me
2
Me
N
N
2
MeO C
Ag
N
Et
N
N
H
Me
Et
H
H
Et
Et
N
38
Me
Et
Et
Et
3
2H+
Scheme 9. Synthesis and metalation of carbachlorin 32.
The reported synthetic strategy provides straightforward access to carbaporphyrins with
electronꢀwithdrawing ester groups and has enabled investigations into the spectroscopic
properties, protonation, structural characterization and metalation of this important porphyrinoid
system. However, the formation of carbachlorin products in respectable yields was thwarted by
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the ease with which they were converted to carbaporphyrins. In order to overcome this problem,
carbachlorin 32 with geminal diester substituents was targeted for synthesis (Scheme 9). The
ester moieties are placed in a fashion that would block further oxidation to carbaporphyrin and
thereby open up carbachlorins for more detailed studies. The plan necessitated access to
cyclopentane dialdehyde 33, and this intermediate was obtained from norbornene 34 using a
similar strategy to the one used to prepare dialdehyde 22. The required norbornene diester 34
could be generated by a DielsꢀAlder cycloaddition reaction using dienophile 35 (Scheme 10).
Dimethyl 1,1ꢀethylenedicarboxylate (35) was prepared by a literature procedure reported by
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42
Takayama and coworkers by reacting copper(II) acetate in glacial acetic acid with
paraformaldehyde and dimethyl malonate. Due to the high reactivity of 35, it was immediately
diluted with dichloromethane and reacted with cyclopentadiene to give the bicyclic adduct 34.
Following purification by column chromatography on silica gel, norbornene 34 was isolated as a
colorless oil in 80% yield (Scheme 10). Oxidation with potassium permanganate and sodium
hydroxide in water and tertꢀbutyl alcohol afforded the required exoꢀdialcohol 36 as a white
crystalline solid in 61% yield. Oxidative ringꢀopening with potassium periodate gave the
unstable dialdehyde 33 in 60% yield (Scheme 10). Due to its instability, 33 was immediately
condensed with tripyrrane dicarboxylic acid 14 in the presence of TFA in dichloromethane.
Subsequent oxidation with DDQ in refluxing toluene afforded carbachlorin 32 in 30% yield
(Scheme 9).
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CO Me
MeO C
2
2
MeO CCH CO Me
2
2
2
Cu(OAc)
AcOH
2
C
(CH O)n
2
CH2
35
CO
2
Me
CO Me
2
HO
HO
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KMnO
4
CO Me
2
2
CO Me
3
6
34
KIO
4
CO Me
2
2
MeO C
CHO
OHC
33
Scheme 10. Synthesis of a cyclopentane dialdehyde with two geminal ester substituents.
Figure 11. 500 MHz proton NMR spectrum of carbachlorin 32 in CDCl3.
Carbachlorin 32, like other chlorin analogues, proved to be a fully aromatic system. The
proton NMR spectrum for 32 in CDCl (Figure 11) showed the presence of a strong diamagnetic
3
ring current and the internal CH proton was found at ꢀ7.08 ppm, while the mesoꢀprotons shifted
downfield to give four 1H singlets at 9.25, 9.58, 9.84 and 9.86 ppm (ꢀδ 16.94 ppm). The methyl
substituents were also significantly deshielded by the ring current effect, giving rise to two 3H
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