2,7,12,17-Tetra(p-butylphenyl)-3,6,13,16-tetraazaporphycene: The first example of a straightforward synthetic approach to a new class of photosensitizing macrocycles

Article abstract of DOI:10.1002/ejoc.200200684

Selected on the basis of computational studies and synthetic feasibility, the title compound 9c has been obtained by cross-coupling of 4,4′-bis(p-butylphenyl)-2,2′-biimidazole-5,5′- dicarbaldehyde (28c) followed by oxidative aromatization. The introduction of a Suzuki coupling protocol opens the way to 2,7,12,17-tetraryl-substituted 3,6,13,16-tetraazaporphycenes avoiding the development of a de novo synthesis whenever a new peripheral substituent is desired. As predicted by computational studies, oxidation of the non-aromatic precursor 33c to yield the azaporphycene macrocycle 9c is more favourable than in the case of porphycene itself. The absorption spectrum of 9c shows a substantial bathochromic shift relative to porphycene 1a, revealing a synergism between aza substitution in the macrocycle and phenyl substitution at its periphery. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200200684

FULL PAPER
2,7,12,17-Tetra(p-butylphenyl)-3,6,13,16-tetraazaporphycene: The First
Example of a Straightforward Synthetic Approach to a New Class of
Photosensitizing Macrocycles
[a]
[a]
[a]
[a]
[a]
´
´
Santi Nonell, Jose I. Borrell, Salvador Borros, Carles Colominas, Oscar Rey,
[a]
[a]
[a]
´
´
´
´
Noemı Rubio, David Sanchez-Garcıa, and Jordi Teixido*
Keywords: Macrocycles / Density functional calculations / Synthesis design / CϪC coupling / Photochemistry
Selected on the basis of computational studies and synthetic
feasibility, the title compound 9c has been obtained by cross-
coupling of 4,4Ј-bis(p-butylphenyl)-2,2Ј-biimidazole-5,5Ј-di-
carbaldehyde (28c) followed by oxidative aromatization. The
introduction of a Suzuki coupling protocol opens the way to
2,7,12,17-tetraryl-substituted 3,6,13,16-tetraazaporphycenes
avoiding the development of a de novo synthesis whenever
a new peripheral substituent is desired. As predicted by com-
putational studies, oxidation of the non-aromatic precursor
33c to yield the azaporphycene macrocycle 9c is more favour-
able than in the case of porphycene itself. The absorption
spectrum of 9c shows a substantial bathochromic shift rela-
tive to porphycene 1a, revealing a synergism between aza
substitution in the macrocycle and phenyl substitution at its
periphery.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
their lower symmetry. Porphycene 1a (G ϭ H, Po) was first
synthesised by Vogel and co-workers in 1986 (Figure 1).[10]
Tetrapyrrole macrocycles and related compounds con-
tinue to be the focus of intense research activity due to their
particular optical and electric properties, which find appli-
cations in fields ranging from materials science to biomedic-
ine. Specifically for the later applications, their photosensit-
izing ability is exploited in dermatology (treatment of pso-
riasis or acne),[1,2] ophthalmology (treatment of macular de-
generation in the elderly),[3] inactivation of bacteria,[4,5]
purification of blood to remove viruses such as HIV-1, her-
pes simplex, cytomegalovirus, and hepatitis-inducing vi-
rus,[6,7] as well as for cancer treatment.[8]
Figure 1. Porphycenes 1 and azaporphycenes 2Ϫ24 studied; R, S,
Photodynamic therapy (PDT) or photochemotherapy has
arisen as an attractive therapeutic approach to cancer treat-
ment based on the use of photosensitizing drugs that ac-
cumulate preferentially in tumour tissues. Thus, irradiation
of the tumour area with red light induces the formation of
T, U, V, W, X and Y are either CH or N (see text)
With perhaps the sole exception of symmetric phthalocy-
anines, the synthesis of most photosensitizers requires leng-
thy, multistep procedures. This is particularly true for aryl-
substituted porphycenes.[11,12] Moreover, whenever new
substituents need to be introduced — in order to modulate
properties such as solubility, absorption spectra or redox
potential — more often than not a de novo synthesis needs
to be developed. When taken together, these are the main
reasons precluding the use of combinatorial chemistry tech-
niques for the development of novel photosensitizers.
Consequently, we set out to develop a new class of photo-
sensitizing macrocycles that should be accessible by a syn-
thetic itinerary eventually prone to a combinatorial ap-
proach. As a starting point, taking into account our pre-
1
highly reactive oxygen species (mainly singlet oxygen, O2)
that ultimately lead to cell death.
Several families of compounds are currently being inves-
tigated as PDT drugs,[9] such as porphyrins, chlorins, bac-
teriochlorins, azaporphyrins, purpurins, phthalocyanines,
texaphyrins, and naphthalocyanines. Particularly relevant
for this work are porphycenes (1), porphyrin isomers with
much higher absorption coefficients above 600 nm, due to
[a]
´
`
Grup d’Enginyeria Molecular, Institut Quımic de Sarria,
Universitat Ramon Llull,
Via Augusta 390, 08017 Barcelona, Spain
Fax: (internat.) ϩ 34-93/205-6266
E-mail: j.teixido@iqs.url.edu
Eur. J. Org. Chem. 2003, 1635Ϫ1640
DOI: 10.1002/ejoc.200200684
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J. Teixido et al.
FULL PAPER
vious experience in the synthesis of 2,7,12,17-tetraphenyl-
porphycene 1b (G ϭ Ph, TPPo) and its palladium complex
([PdTPPo]),[11Ϫ15] both of which are efficient at inactivating
tumour cells in vitro, we studied which structural modifi-
cations would be required to allow for such an approach
and, at the same time, would shift the absorption spectrum
to the 700Ϫ800 nm region, where tissue is most trans-
parent. This paper reports on the theoretical and exper-
imental results obtained in that study.
Table 1. Gas-phase energies (Hartrees) and ∆λmax displacement dif-
ferences[b] (nm) of selected azaporphycene cores.
R
S
T
U
V
W
X
Y
Energy(H)[a] ∆λmax
0[b]
1a CH CH CH CH CH CH CH CH Ϫ989.5513
2
CH N CH CH CH N CH CH Ϫ1021.6696 19
CH CH N CH CH CH N CH Ϫ1021.6625
CH CH N CH CH N CH CH Ϫ1021.6659 12
CH CH CH N CH CH CH Ϫ1021.6680 14
CH CH CH N CH CH CH N Ϫ1021.6617 Ϫ1
3
9
4
5
N
6
7
N
N
CH N
CH CH CH CH CH CH N Ϫ1021.6648
CH CH N
3
8
N
CH CH N Ϫ1053.7388 28
9
N
CH CH N
N
CH Ϫ1053.7471 10
Results and Discussion
10
N
CH N CH N CH N CH Ϫ1053.7479 17
11 CH N CH N CH N CH N Ϫ1053.7476 15
Bearing in mind that the incorporation of nitrogen atoms
to a conjugated macrocycle produces a bathochromic shift
of the lowest energy band (often termed Q-band)[16] we in-
vestigated, by means of computational techniques, the effect
of aza substitution on the position of the lowest-energy ab-
sorption band for 23 porphycene-like systems (2Ϫ24).
Specifically, we calculated the Q-band shift ∆λmax relative
12
13
N
N
CH N CH CH N CH N Ϫ1053.7477 16
CH CH N CH CH Ϫ1053.6986 53
CH CH N
CH CH CH CH N
N
N
14 CH CH N
N
N
N
N
Ϫ1053.6866 36
Ϫ1053.6935 12
Ϫ1085.7676 34
15
16
17
18
19
N
N
N
N
N
N
CH N
CH N
CH N
N
N
N
N
CH N
N
N
N
N
CH N Ϫ1085.7731 44
CH N Ϫ1085.7707 21
N
N
N
N
N
N
N
N
N
N
N
CH N
N CH N
CH CH N
CH Ϫ1085.7646 54
to porphycene 1a (G ϭ H, Po) (Figure 1). Azaporphycenes 20 CH N
N
N
N
N
Ϫ1085.7589 43
Ϫ1085.7621 30
Ϫ1117.7794 120
Ϫ1053.7122 17
21
22
N
N
N
N
2Ϫ24 were constructed by the formal stepwise substitution
of the pyrrole units present in porphycene by imidazole and
triazole rings. This procedure includes tautomeric isomers
(cf. pairs 2Ϫ3, 5Ϫ6, 13Ϫ14, 16Ϫ17 and 19Ϫ20). Their geo-
metries were optimised at the B3LYP/6Ϫ31G** level of the-
ory,[17,18] followed by a TDDFT calculation at the same le-
vel in order to predict the UV/Vis spectra.[19]
N
N
N
23 CH CH N CH CH N
24
N
N
CH N
N
CH CH CH Ϫ1053.7181 32
[a]
All geometries and energies were calculated at the TDDFT-
[b]
B3LYP/6Ϫ31G** level. All values are relative to porphycene 1a
(λmax ϭ 553 nm), calculated at the TDDFT-B3LYP/6Ϫ31G** level.
The results obtained (Table 1) show that, as expected, the
introduction of nitrogen atoms in the porphycene structure
should cause a bathochromic shift (in the range 3Ϫ120 nm)
depending on the number and position of the nitrogen
atoms incorporated. The energy values of tautomeric aza-
porphycenes in turn reveals that the tautomers protonated
at the less nitrogenated rings are more stable and have
larger bathochromic shifts.
Azaporphycenes 2Ϫ24 could, in principle, be obtained by
a McMurry coupling of the corresponding dialdehydes 25
and 26 (equal or different depending on the nature of R, S,
T, U, V, W, X, and Y) followed by oxidative aromatization
(spontaneous or chemically induced) of the reduced inter-
mediate 27 (Scheme 1). Clearly, the most symmetrical aza-
Scheme 1. Synthetic itinerary for azaporphycenes 2Ϫ24 showing
the oxidized intermediate 27
porphycenes 9, 10, and 22 would be more easily accessible tetraazaporphycene 10 (ϩ0.2 kcal/mol energy difference),
through this approach. and clearly less feasible for 2,3,6,7,12,13,16,17-octaazapor-
Rendering the macrocycle aromatic occurs at the expense phycene 22 (by ϩ16.7 kcal/mol) in line with the aforemen-
of the aromaticity of three of the constitutive rings. This is tioned triazolehemiporphyrazine case.[20] These results
a delicate balance and in related macrocycles the aromatic pointed to 3,6,13,16-tetraazaporphycene 9 as the synthetic
structure is often less stable than its reduced precursor. For candidate with the highest chance of being obtained. This
instance, when two isoindole units were replaced by tri- is fortunate since, in addition, the synthesis of its precursor
azoles in the phthalocyanine macrocycle (formal introduc- 2,2Ј-biimidazole can be achieved in one step from ammonia
tion of four nitrogens) the triazolehemiporphyrazine ob- and glyoxal,[21] which is a significant advantage over the
tained could not be rendered aromatic.[20] We assessed the lengthy, multi-step synthesis of bipyrroles.[22]
feasibility of gas-phase oxidation of the annulenes 27 to
Although the bathochromic shift expected for 9 is modest
symmetrical azaporphycenes 9, 10, and 22 relative to por- (ca. 10 nm, cf. Table 1), such a structure allows the intro-
phycene 1a by means of calculations at the B3LYP/ duction of further red-shifting substituents at positions C2,
6Ϫ31G** level. We found the oxidation reaction to be more C7, C12, and C17, the ones with the least steric hindrance.
feasible for 3,6,13,16-tetraazaporphycene 9 than for por- Specifically, having observed previously that the presence of
phycene 1a (by Ϫ11.6 kcal/mol), comparable for 2,7,12,17- phenyl substituents in 2,7,12,17-tetraphenylporphycene (1b)
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Eur. J. Org. Chem. 2003, 1635Ϫ1640

A New Class of Photosensitizing Macrocycles
FULL PAPER
Scheme 2. Retrosynthetic analysis for 2,7,12,17-tetrasubstituted 3,6,13,16-tetraazaporphycenes 9
causes a bathochromic shift of 29 nm with respect to por-
phycene 1a, we calculated the UV/Vis spectrum of the
2,7,12,17-tetraphenyl-substituted 3,6,13,16-tetrazaporphy-
cene 9b (G ϭ Ph) at the TDDFT-B3LYP/3Ϫ21G level. Sur-
prisingly, this calculation predicted a bathochromic shift of
106 nm with respect to porphycene 1a, 80 nm with respect
to 2,7,12,17-tetraphenylporphycene (1b), and 96 nm with
respect to 3,6,13,16-tetraazaporphycene (9), i.e. a synergic
effect of aza-substitution in the macrocycle and phenyl sub-
stitution in the periphery.
The retro-synthetic analysis depicted in Scheme 2 points
to 4,4Ј-disubstituted 2,2Ј-biimidazole-5,5Ј-dicarbaldehydes
28 as the precursors needed to obtain 3,6,13,16-tetrazapor-
phycenes 9.
As mentioned above, a general drawback of most current
Scheme 3. Synthetic route for azaporphycenes 9 applied to 9c (G ϭ
p-BuPh): (i) BuLi/THF/Ϫ78 °C followed by DMF; (ii) p-butylphe-
nylboronic acid (31c)/[Pd(PPh3)4]/Na2CO3/toluene/EtOH; (iii) HCl/
EtOH/H2O; (iv) TiCl4/Zn(Cu)/THF; (v) O2 in the presence of I2
methods for the preparation of peripherally substituted
porphyrinoids is the need to carry out a de novo synthesis
whenever a new substituent is desired. In pursuing a syn-
thetic methodology that would overcome this problem, thus
allowing a combinatorial approach, we herewith propose aza[20]annulene 33c (G ϭ p-BuPh), which was oxidized by
4,4Ј-dibromo-1,1Ј-bis[(trimethylsilyl)ethoxymethyl]-2,2Ј- molecular oxygen to the corresponding 2,7,12,17-tetrasub-
biimidazole-5,5Ј-dicarbaldehyde (29) as the key intermedi- stituted 3,6,13,16-tetrazaporphycene 9c (G ϭ p-BuPh).
ate (Scheme 2).
Such oxidation could be accelerated by means of iodine
The SEM-protected 4,4Ј-dibromo-2,2Ј-biimidazole-5,5Ј- vapour
dicarbaldehyde 29 [SEM ϭ (trimethylsilyl)ethoxymethyl], (DDQ).
or
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
which should allow the introduction of almost any aryl and
In this context, a bibliographic search revealed that the
heteroaryl substituents at later stages of the synthesis by unsubstituted 3,6,13,16-tetraazaporphycene (9a) (G ϭ H)
using Suzuki[23] or Stille[24,25] protocols, was easily acces- was first cited in a communication to the 222nd ACS
sible from tetrabromo-2,2Ј-biimidazole[26] (30) by treatment National Meeting (Chicago, 2001) by Sargent.[31] However,
with BuLi in THF at Ϫ78 °C followed by addition of the synthesis of 9a has not been published so far to the best
DMF (Scheme 3).
of our knowledge. Other porphycene analogues containing
In order to incorporate G ϭ p-butylphenyl (p-butyl sub- external nitrogen atoms have been synthesised by Neidlein
stituent added to increase solubility in organic solvents) we and co-workers. Specifically, this group reported the syn-
treated 29 under Suzuki reaction conditions with the p-bu- thesis of the aromatic 21,23-dithia-3,13-diazaporphycenes
tylphenylboronic acid (31c) in toluene/ethanol/water in the (where two pyrrole rings of porphycene have been substi-
presence of [tetrakis(triphenylphosphane)palladium(0)] and tuted by thiazoles, i.e., two external nitrogen atoms).[16]
Na2CO3 to yield the corresponding 4,4Ј-bis(p-butylphenyl)- More significant for our work, the same group also de-
substituted SEM-protected dialdehyde 32c (G ϭ p-BuPh), scribed a macrocycle derived from 2,2Ј-bithiazole (i.e. con-
which was deprotected with ethanolic HCl or tetrabutylam- taining four external nitrogen atoms) which, interestingly,
monium fluoride (TBAF) in THF to afford dialdehyde 28c could not be rendered aromatic.[32] The tetraazaporphycene
(G ϭ p-BuPh) (Scheme 3).
Dialdehyde 28c was deoxygenatively cross-coupled in the analogue containing four additional external nitrogens.
presence of the McMurry reagent[27Ϫ30] (low-valent ti-
Consistent with our expectations, 9c (G ϭ p-BuPh)
tanium) to yield the corresponding 1,8,11,18-tetra- shows distinct absorption bands in the red (λmax ϭ 760 nm,
9c described in this work is the first aromatic porphycene
Eur. J. Org. Chem. 2003, 1635Ϫ1640
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FULL PAPER
ε ϭ 2.4 ϫ 104 Ϫ1cmϪ1), which represents a red shift of
about 130 nm relative to porphycene 1a, and about 100 nm
relative to 2,7,12,17-tetraphenylporphycene (1b)[13]. The po-
sition of this band is highly favourable for photodynamic
therapy applications. Taken together, the absorption spec-
trum and the NMR spectroscopic data confirm a highly
delocalised aromatic system. Compound 9c is fluorescent
(λmax ϭ 777 nm, quantum yield ΦF ϭ 0.03) (Figure 2),
forms a long-lived triplet state (τT ϭ 40 µs) and sensitizes
tra were recorded on a Nicolet Magna 560 FTIR spectrophoto-
meter. 1H and 13C NMR spectra were determined on a Varian
Gemini-300 operating at a field strength of 300 and 75.5 MHz,
respectively. Chemical shifts are reported in parts per million (δ)
and coupling constants (J) in Hz, using in the case of 1H NMR,
TMS as an internal standard at δ ϭ 0.00 ppm. All 13C NMR spec-
tra were referenced to the signal of the solvent (δ ϭ 77.00 ppm,
CDCl3). Mass spectra (EI, 70 eV) were obtained on a VG AutoSpec
while FAB(ϩ)-HRMS were recorded at the Servicio de Espectro-
´
´
metrıa de Masas (Universidad de Cordoba) using a VG AutoSpec
the production of singlet oxygen, albeit with a low quantum spectrometer (resolution 8000, 3-nitrobenzyl alcohol as matrix). El-
emental microanalyses were obtained on a CarloϪErba CHNS-O/
EA 1108 analyzer and gave results for the elements stated with
Ϯ0.4% of the theoretical values. Thin-layer chromatography (TLC)
was performed on precoated sheets of silica 60 Polygram SIL N-
HR/UV254 (MachereyϪNagel, # 804023). Column chromatogra-
phies were performed using the ‘‘dry-column’’ flash technique.[39]
THF was distilled from potassium/benzophenone immediately
prior to use. Reagents were used without purification. Absorption
spectra were recorded in a Varian Cary 4 spectrophotometer. Flu-
orescence spectra were recorded using a JobinϪYvon Spex Fluoro-
max 2 spectrofluorometer.
yield (Φ∆ ϭ 0.013). All these properties suggest that tetra-
azaporphycenes 9 may be a new valuable class of photo-
sensitizing compounds. A detailed photophysical character-
isation of this compound will be published elsewhere.
4,4Ј-Dibromo-1,1Ј-bis[(trimethylsilyl)ethoxymethyl]-2,2Ј-biimida-
zole-5,5Ј-dicarbaldehyde (29): 5.3 mL (8.6 mmol) of a 1.6  solution
of BuLi in hexane was added to a solution of tetrabromo-2,2Ј-
biimidazole (30; 2.8 g, 3.9 mmol)[26] in 120 mL of THF at Ϫ78 °C.
The resulting mixture was stirred for 30 min and 1 mL of DMF
was then added. The mixture was stirred for 2 h and allowed to
warm to room temp. for 12 h. The reaction mixture was poured
into 200 mL of a saturated solution of NH4Cl and extracted with
EtOAc. The organic layer was dried (MgSO4), concentrated in va-
cuo and the resulting residue was chromatographed with a gradient
of EtOAc/hexane as the eluent to yield 1.7 g (2.8 mmol, 71%) of 29
as slightly yellow needles; m.p. 66Ϫ67 °C. IR (KBr): ν˜ ϭ 3038,
2996, 2954, 2894, 2835, 1673, 1450, 1385, 1322, 1097, 864, 834,
Figure 2. The UV/Vis absorption (Ϫ) and fluorescence (---) spectra
of 9c (G ϭ p-BuPh)
771, 731 cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ 9.89 (s, 2 H,
.
CHO), 6.27 (s, 4 H, N-CH2), 3.57 (t, J ϭ 8.4 Hz, 4 H, OϪCH2),
0.87 (t, J ϭ 8.4 Hz, 4 H, SiϪCH2), Ϫ0.06 [s, 18 H, Si(CH3)3] ppm.
13C NMR (75.5 MHz, CDCl3): δ ϭ 179.4, 140.3, 130.1, 127.7, 74.3,
66.8, 17.8, Ϫ1.5 ppm. C20H32Br2N4O4Si2 (608.5): calcd. C 39.48,
H 5.30, N 9.21; found C 39.53, H 5.32, N 9.16.
Conclusion
In summary, by a combination of theoretical and exper-
imental techniques, we have designed and developed a feas-
ible synthetic route that opens the way to a new class of
porphycene-like aromatic macrocycles amenable to a com-
4,4Ј-Bis(p-butylphenyl)-1,1Ј-bis[(trimethylsilyl)ethoxymethyl]-2,2Ј-
binatorial approach. The approach followed may provide a biimidazole-5,5Ј-dicarbaldehyde (32c): p-Butylphenylboronic acid
(31c; 1.0 g, 5.6 mmol), 15 mL of a 2  aqueous solution of
Na2CO3, and 6 mL of EtOH were added to a solution of of 4,4Ј-
dibromo-1,1Ј-bis(trimethylsilylethoxymethyl)-2,2Ј-biimidazole-
5,5Ј-dicarbaldehyde (29; (1.7 g, 2.8 mmol). The resulting mixture
was degassed with a stream of dry nitrogen for 10 min. Then, 0.3 g
of [tetrakis(triphenylphosphane)palladium] was immediately added
and the resulting mixture was refluxed for 7 h under argon. The
resulting mixture was cooled, diluted with EtOAc, dried (MgSO4)
and concentrated in vacuo. The residue obtained was column chro-
matographed with a gradient of EtOAc/hexane as the eluent to
yield 1.1 g (1.54 mmol, 55%) of 32c as colourless needles; m.p.
92Ϫ93 °C. IR (KBr): ν˜ ϭ 3081, 2954, 2924, 2872, 2856, 1665, 1489,
cost-effective alternative for the development of new PDT
drugs. Furthermore, the presence of the four outer nitrogen
atoms opens the way to a new field of porphyrin chemistry
based on the external coordination of metal ions[33,34] in
addition to the conventional inner coordination. Work is
currently in progress in such directions.
Experimental Section
General Remarks
1339, 1250, 1087, 861, 833, 767, 730 cmϪ1 1H NMR (300 MHz,
.
Computational Details: Geometry optimisations and TDDFT[35Ϫ37]
computations were carried out with the standard GAUSSIAN-
98[38] quantum mechanical package. Calculations were performed
on SGI workstations.
CDCl3): δ ϭ 10.01 (s, 2 H, CHO), 7.64 (d, J ϭ 8.1 Hz, 4 H, Ph),
7.32 (d, J ϭ 8.1 Hz, 4 H, Ph), 6.45 (s, 4 H, NϪCH2), 3.61 (t, J ϭ
8.4 Hz, 4 H, OϪCH2), 2.69 (t, J ϭ 7.8 Hz, 4 H, CH2) 1.66 (q, J ϭ
7.8 Hz, 4 H, CH2) 1.39 (m, J ϭ 7.8 Hz, 4 H, CH2), 0.96 (t, J ϭ
7.8 Hz, 6 H, CH3), 0.87 (t, J ϭ 8.4 Hz, 4 H, SiϪCH2), Ϫ0.11 [s,
18 H, Si(CH3)3] ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ 181.1,
Experimental Details: All melting points were determined with a
Büchi 530 capillary apparatus and are uncorrected. Infrared spec-
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Eur. J. Org. Chem. 2003, 1635Ϫ1640

A New Class of Photosensitizing Macrocycles
FULL PAPER
154.5, 144.7, 141.2, 129.3, 129.2, 128.9, 128.7, 127.2, 74.5, 66.4,
؋ 104), 425 (3.31 ؋ 104), 698 (3.86 ؋ 104), 760 nm (2.37 ؋ 104).
35.5, 33.5, 22.3, 17.9, 13.9, Ϫ1.5 ppm. MS (70 eV): m/z (%) ϭ 715 HRMS calcd. for C56H59N8 [MHϩ] 843.4863; found 843.4843.
(100) [Mϩ], 671 (58), 583 (65), 527 (98), 469 (53). C40H58N4O4Si2
(715.1): calcd. C 67.19, H 8.18, N 7.83; found C 67.19, H 8.14,
N 7.79.
Acknowledgments
This work was supported by the Programa Sectorial de
4,4Ј-Bis(p-butylphenyl)-2,2Ј-biimidazole-5,5Ј-dicarbaldehyde (28c):
´
´
Promocion General del Conocimiento (Ministerio de Educacion y
A suspension of 4,4Ј-bis(p-butylphenyl)-1,1Ј-bis[(trimethylsilyl)e-
thoxymethyl]-2,2Ј-biimidazole-5,5Ј-dicarbaldehyde (32c; 1.96 g,
2.7 mmol) in 30 mL of a 1:1 mixture of 10% HCl and ethanol was
stirred at reflux for 1 h under argon. The resulting mixture was
cooled and carefully neutralised with a 10% aqueous solution of
Na2CO3. The resulting solid was filtered and washed with hexane
to yield 0.95 g (2.1 mmol, 76%) of 28c as a white solid (hexane/
CH2Cl2); m.p. Ͼ 250 °C. IR (KBr): ν˜ ϭ 3250, 3030, 2956, 2926,
2871, 2856, 1677, 1649, 1506, 1463, 1324, 1157, 938, 836, 775, 738
Cultura, PM98Ϫ0017ϪC02Ϫ02) and the Programa Nacional
´
Tecnologıa,
de Biomedicina (Ministerio de Ciencia
y
SAF2002Ϫ0434ϪC02Ϫ02). Fellowships by the IQS (O. R., N. R.,
D. S.-G.) are also acknowledged.
[1]
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cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 9.92 (s, 2 H, CHO), 7.59
2000, 19, 134Ϫ141.
M. Merchat, A. Villanueva, P. Giacomoni, G. Bertoloni, G.
(d, J ϭ 7.8 Hz, 4 H, Ph), 7.30 (d, J ϭ 7.8 Hz, 4 H, Ph), 2.68 (t,
J ϭ 7.5 Hz, 4 H, CH2) 1.64 (q, J ϭ 7.5 Hz, 4 H, CH2) 1.37 (m,
J ϭ 7.5 Hz, 4 H, CH2), 0.95 (t, J ϭ 7.5 Hz, 6 H, CH3) ppm. 13C
NMR (75.5 MHz, CDCl3): δ ϭ 182.7, 145.3, 139.8, 129.2, 129.0,
128.5, 128.3, 124.6, 35.4, 33.3, 22.3, 13.8 ppm. MS (70 eV): m/z
(%) ϭ 455 (89) [Mϩ], 454 (100), 411 (15), 231 (27). HRMS calcd.
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2,7,12,17-Tetra(p-butylphenyl)-3,20:6,9:10,13:16,19-tetraimino-
1,8,11,18-tetraaza[20]annulene (33c): TiCl4 (2.3 mL, 19 mmol) was
added dropwise to a suspension of Zn/Cu couple(5) (2.7 g,
41 mmol) in 500 mL of anhydrous THF cooled to 0 °C. Then, 1 mL
of anhydrous pyridine was added and the mixture was heated at
reflux for 2 h. A solution of 4,4Ј-bis(p-butylphenyl)-2,2Ј-biimid-
azole-5,5Ј-dicarbaldehyde (28c; 0.95 g, 2.1 mmol) in 250 mL of an-
hydrous THF was added dropwise to the resulting black suspen-
sion. The mixture was then heated at reflux for 1 h, allowed to
cool to room temp. and filtered through Celite. The filtrate was
hydrolysed with a 10% aqueous ammonia solution and extracted
with EtOAc (500 mL). The organic layer was dried (MgSO4), con-
centrated in vacuo and the resulting residue was chromatographed
with a gradient of EtOAc/hexane as the eluent to yield 0.06 g
(71 mmol, 7%) of 33c as a yellow powder (EtOEt/CH2Cl2). IR
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A. Gavalda, J. I. Borrell, J. Teixido, S. Nonell, O. Arad, R.
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.
´
J. Teixido, S. Nonell, A. Villanueva, Anti-Cancer Drug Des.
CDCl3): δ ϭ 7.31 (d, J ϭ 7.8 Hz, 8 H, Ph), 7.15 (d, J ϭ 7.8 Hz, 8
H, Ph), 6.28 (s, 4 H, 9,10,19,20-H), 2.63 (t, J ϭ 7.5 Hz, 8 H, CH2),
1.63 (q, J ϭ 7.5 Hz, 8 H, CH2) 1.38 (m, J ϭ 7.5 Hz, 8 H, CH2),
0.96 (t, J ϭ 7.5 Hz, 12 H, CH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ ϭ 142.3, 136.7, 131.5, 128.6, 128.5, 127.6, 127.5, 115.4,
35.5, 33.6, 22.5, 14.1 ppm. HRMS calcd. for C56H61N8 [MHϩ]
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2,7,12,17-Tetra(p-butylphenyl)-3,6,13,16-tetraazaporphycene (9c): A
solution of 2,7,12,17-tetra(p-butylphenyl)-3,20:6,9:10,13:16,19-
tetraimino-1,8,11,18-tetraaza[20]annulene (33c; 0.06 g, 71 mmol) in
10 mL of THF was stirred in a closed vessel saturated with I2 vap-
our for 48 h. The resulting dark green coloured solution was col-
umn chromatographed with a gradient of EtOAc/hexane as the elu-
ent to yield 0.04 g (43 mmol,60%) of 9c as a dark emerald green
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1414, 1249, 1133, 992, 945, 838 cmϪ1 1H NMR (300 MHz,
.
CDCl3): δ ϭ 9.62 (s, 4 H, 9,10,18,19-H), 7.53 (d, J ϭ 7.5 Hz, 8 H,
Ph), 7.57 (d, J ϭ 7.5 Hz, 8 H, Ph), 2.89 (t, J ϭ 7.8 Hz, 8 H, CH2)
1.85 (q, J ϭ 7.8 Hz, 8 H, CH2) 1.55 (m, J ϭ 7.8 Hz, 8 H, CH2),
1.09 (t, J ϭ 7.8 Hz, 12 H, CH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ ϭ 166.2, 145.2, 140.9, 138.6, 131.9, 131.2, 129.0, 116.7,
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Received December 5, 2002
1640
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 1635Ϫ1640