A 'click' chemistry route to 'capped' porphyrins

Article abstract of DOI:10.1055/s-2008-1077899

Synthesis of a new 'capped' porphyrin 3 with rigid 1,2,3-triazole linkers between the porphyrin and 'capping' group has been achieved. A 'click' reaction, the copper(I)-catalysed variant of the Huisgen 1,3-dipolar cycloaddition, is used to create four linkages concomitantly under anhydrous conditions in N,N-dimethylformamide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1077899

LETTER
2147
A ‘Click’ Chemistry Route to ‘Capped’ Porphyrins
A
‘
Click C
a
hemistry’
m
P
e
orphyrins s E. A. Webb, Felicia Maharaj, Iain M. Blake, Maxwell J. Crossley*
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
Fax +61(2)93516650; E-mail: m.crossley@chem.usyd.edu.au
Received 23 March 2008
Dedicated to Professor Sir Jack Baldwin FRS on the occasion of his 70th birthday in appreciation for teaching one of us how to think at a
deeper level about molecules and what is happening on the molecular scale
tion conditions (2–28% yield), and the other involving
Abstract: Synthesis of a new ‘capped’ porphyrin 3 with rigid 1,2,3-
reaction of an isomeric mixture of the corresponding por-
triazole linkers between the porphyrin and ‘capping’ group has been
phyrin tetraalcohol with pyromellitic tetraacid chloride
achieved. A ‘click’ reaction, the copper(I)-catalysed variant of the
Huisgen 1,3-dipolar cycloaddition, is used to create four linkages
(15% yield).1 The convergent synthesis of 1 involved the
concomitantly under anhydrous conditions in N,N-dimethylforma- separation of various atropisomers,1 a consequence of the
restricted rotation of ortho substituted meso-aryl groups.5
mide.
Key words: porphyrin, alkyne, azide, 1,3-dipolar cycloaddition,
1,2,3-triazoles
Superstructures of ‘capped’ porphyrins provide a cavity
within which the selective binding of small molecules to
the chelated metal ion can occur. This is of great interest
given the potential of the metal centre to be catalytically
Baldwin’s ‘capped’ porphyrin 1 represents a landmark in
design and synthesis of functional molecules and estab-
lished the paradigm for ‘molecular engineering’.1 The
‘capped’ porphyrin has great beauty and its iron chelate
mimics aspects of the oxygen-carrying function of myo-
globin.2 A particularly elegant example from the Baldwin
group is the more elaborated ‘strapped’ ‘capped’ porphy-
rin 2 (Figure 1).3 These synthetic mimics revealed in-
sights not easily discerned by study of natural systems; for
example, the means by which carbon monoxide binding
can be reduced.2 These studies focused attention on the di-
verse and complex porphyrin-containing structures found
in nature like the light-harvesting complexes I and II, hae-
moglobin, myoglobin, and proteins such as cytochrome C
active. A measure of cavity size is the separation between
the centroid of the capping aryl group and the porphyrin
macrocycle. This distance is 3.96 Å in the crystal structure
of 1.6 Interestingly, the ‘C3-capped’ porphyrin, homolo-
gous to 1 but with an extra methylene group in each link-
ing rib, has a smaller cavity. Intuitively the extra
methylenes would be expected to lead to a larger cavity
than 1. The crystal structure, however, showed the separa-
tion of cap and porphyrin planes is only 3.49 Å,7 a result
of the ribs being less rigidifying.
We now report the synthesis of ‘capped’ porphyrin 3
through convergent regioselective Cu(I)-catalysed cy-
cloaddition of an azide and an alkyne ‘click’ chemistry,8
forming rigid 1,2,3-triazoles as linkers in the ‘capped’
porphyrin (Scheme 1). A key consideration was the need
to construct a ‘capped’ porphyrin with a cavity that will
not collapse onto the macrocycle.
and F430
.
Baldwin’s ‘capped’ porphyrin 1 was synthesised by two
synthetic paths, one utilising one-step Adler–Longo4 con-
densation of a tetraaldehyde and pyrrole under high dilu-
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
NH
N
Fe
N
O
O
N
N
N
HN
N
O
N
O
2
1
Figure 1 Baldwin’s ‘capped’ porphyrin 1 and ‘strapped’ ‘capped’ porphyrin 2
SYNLETT 2008, No. 14, pp 2147–2149
2
2
.0
8
.2
0
0
8
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1077899; Art ID: D10208ST
© Georg Thieme Verlag Stuttgart · New York

2148
J. E. A. Webb et al.
LETTER
N3
N3
O
O
O
O
O
O
N
O
N
O
O
N
N
N
O
O
O
O
O
N
N
N
Zn
N
N
N
N
Method A
Method B
N
+
N
N
N
N
N
Zn
N
N
O
O
4
5
N3
N3
3
Scheme 1 Reagents and conditions: Method A: 10% H2O in THF, CuSO4·5H2O, L-ascorbic acid, Et3N. Method B: DMF, Cu(MeCN)4PF6,
Et3N.
Capping group precursor 4 was obtained in 74% yield by CDCl3 the capping aryl protons of ‘capped’ porphyrin 3
reaction of propargyl alcohol with pyromellitic tetraacid resonate at d = 7.32 ppm, an upfield shift of 0.83 ppm
chloride in the presence of triethylamine.9 Tetraazide por- compared with the resonance of the corresponding pro-
phyrin 5 was obtained from [5,10,15,20-tetrakis-(3-bro- tons in 4. Both the Cross and Crossley14 ring current mod-
momethylphenyl)porphyrinato]zinc(II) in 86% yield by el and low-level UFF molecular modelling agree on a
treatment with NaN3 in DMF; the tetrabromoporphyrin distance of about 7.2 0.3Å between the aromatic plane
being obtained in 22% overall yield by Rothemund con- of the capping group and that of the porphyrin in 3. A
densation of 3-(bromomethyl)benzaldehyde and pyrrole, COESY experiment showed that the meso-aryl H2 pro-
followed by metalation using Zn(OAc)2.
tons are shifted upfield by 1.33 ppm, compared with the
H6 protons, consistent with them falling within the
deshielding zone of the 1,2,3-triazoles requiring that the
triazoles be orthogonally aligned to the meso-aryls, a con-
formation supported by the modelling. The relatively
large cavity that is formed can be attributed to the rigid tri-
azole linkers preventing collapse of the capping group
onto the porphyrin.
‘Capped’ porphyrin 3 was formed in moderate yields
through the reaction of tetraalkyne 4 with tetraazide 5
(Scheme 1). Two sets of conditions were explored.
Method A10 (Scheme 1) used standard conditions of cata-
lytic copper(II) sulfate with L-ascorbic acid in H2O–THF
(1:10) with four equivalents of triethylamine. The pres-
ence of a tertiary amine base has been previously shown11
to increase the rate of Cu(I)-catalysed cycloaddition reac-
tions. The reaction was heated at reflux for 30 hours and
chromatography of the product over silica, to remove
polymeric byproducts, gave the capped porphyrin 3 in
19% yield.12
In summary, we have applied ‘click’ chemistry to attach a
capping superstructure to a porphyrin. The concomitant
formation of four linkages between a porphyrin-tetraazide
and an arene-tetraalkyne was achieved in both hydrous
and anhydrous conditions, with similar yields. This meth-
odology allows the incorporation of a number of sensitive
functional groups and highlights the ease in which sophis-
ticated molecular architectures can be generated utilising
‘click’ chemistry in conjunction with a porphyrin sub-
structure.
The coupling was also carried out under anhydrous condi-
tions (Scheme 1, Method B) using anhydrous DMF as sol-
vent in conjunction with four equivalents of triethylamine
and catalytic copper(I) tetrakis(acetonitrile) hexafluoro-
phosphate. The use of a copper(I) salt avoids the depen-
dence upon a solvent system in which L-ascorbic acid is
necessary to reduce the copper(II) species. The reaction
was stirred at 70 °C for 16 hours, affording the ‘capped’
porphyrin 3 in 14% yield.13
Acknowledgment
We thank the Australian Research Council for funding for this re-
search.
An interesting point is the deshielding effect of the mag-
netic anisotropy of the porphyrin ring on the aryl protons
of the capping group. In CDCl3 the resonance of the cap-
ping aryl protons of ‘capped’ porphyrin 1 is shifted up-
field to d = 5.49 ppm, a shift of about 2.7 ppm compared
with the precursor tetraaldehyde. This upfield shift, ac-
cording to the multipole-expansion porphyrin ring current
model of Cross and Crossley,14 corresponds to a time-av-
eraged separation of about 4.2 Å between the centroids of
the capping aryl and the 24-atom porphyrin skeleton. In
References and Notes
(1) (a) Almog, J.; Baldwin, J. E.; Dyer, R. L.; Peters, M. J. Am.
Chem. Soc. 1975, 97, 226. (b) Almog, J.; Baldwin, J. E.;
Crossley, M. J.; Debernadis, J. F.; Dyer, R. L.; Huff, J. R.;
Peters, M. K. Tetrahedron 1981, 37, 3589.
(2) (a) Almog, J.; Baldwin, J. E.; Huff, J. R. J. Am. Chem. Soc.
1975, 97, 227. (b) Hashimoto, T.; Dyer, R. L.; Crossley, M.
J.; Baldwin, J. E.; Basolo, F. J. Am. Chem. Soc. 1982, 104,
2101.
Synlett 2008, No. 14, 2147–2149 © Thieme Stuttgart · New York

LETTER
‘Click’ Chemistry Route to ‘Capped’ Porphyrins
2149
(3) Baldwin, J. E.; Cameron, J. H.; Crossley, M. J.; Dagley, I. J.;
Hall, S. R.; Klose, T. J. Chem. Soc., Dalton Trans. 1984,
1739.
(4) Adler, A. D.; Longo, F. R.; Finarelli, J. D.; Golmacher, J.;
Assour, J.; Korsakoff, L. J. Org. Chem. 1967, 32, 476.
(5) Crossley, M. J.; Field, L. D.; Forster, A. J.; Harding, M. M.;
Sternhell, S. J. Am. Chem. Soc. 1987, 109, 341.
phase was collected and the aqueous phase was extracted
with a mixture of MeOH and H2O (1:1, 2 × 100 mL). This
was then dried over Na2SO4, filtered and evaporated.
Purification on silica with 4% MeOH in H2O yielded capped
porphyrin 3 in 19% yield.
(11) Lipshutz, B. H.; Taft, B. R. Angew. Chem. Int. Ed. 2006, 45,
8235.
(6) Jameson, G. B.; Ibers, J. A. J. Am. Chem. Soc. 1980, 102,
2823.
(7) Sparapany, J. W.; Crossley, M. J.; Baldwin, J. E.; Ibers, J. A.
J. Am. Chem. Soc. 1988, 110, 4559.
(12) Selected data for compound 3: mp >300 °C. 1H NMR (400
MHz, CDCl3): d = 8.72 (s, 4 H), 8.68 (s, 4 H), 8.41 (br d, J =
7.6 Hz, 4 H, meso-aryl H6), 7.85 (t, J = 7.6 Hz, 4 H, meso-
aryl H3), 7.77 (br d, J = 7.6 Hz, 4 H, meso-aryl H4), 7.64 (br
s, 4 H), 7.32 (s, 2 H), 7.08 (br s, 4 H, meso-aryl H2), 5.93 (A
of ABq, J = 16.1 Hz, 4 H), 5.79 (B of ABq, J = 16.1 Hz,
4 H), 5.13 (A of ABq, J = 13.0 Hz, 4 H), 5.03 (B of ABq,
J = 13.0 Hz, 4 H). MS (ESI): m/z [M + Na] calcd for
C70H46N16O8Zn: 1325.3; found: 1325.4.
(13) Dimethylformamide Method for the Cycloaddition: To a
stirred solution of 5 (45 mg), (NCCH3)4CuPF6 (4 mg) and
Et3N (28 mL) in DMF (100 mL) was added 4 (20 mg). This
was then put under nitrogen and stirred at 70 °C for 16 h.
This was then added to a mixture of CH2Cl2 and EtOAc (1:1,
200 mL), washed with H2O (2 × 100 mL), and the organic
phase was filtered and washed again with H2O (2 × 100 mL).
The organic phase was then dried over Na2SO4, filtered and
evaporated with the residue subjected to purification on
silica, eluting capped porphyrin 3 in 14% yield.
(8) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(9) Selected data for compound 4: mp 119–120 °C. 1H NMR
(200 MHz, CDCl3): d = 8.15 (s, 2 H), 4.95 (d, J = 2.45 Hz, 8
H), 2.57 (t, J = 2.45 Hz, 4 H). 13C NMR (75 MHz, CDCl3):
d = 164.9, 133.9, 130.1, 76.7, 76.0, 53.8.
(10) Tetrahydrofuran–H2O Method for the Cycloaddition:
To a stirred mixture of porphyrin 5 (65 mg) and Et3N (40 mL)
in THF (100 mL) were added CuSO4·5H2O (4 mg) and
ascorbic acid (5 mg) dissolved in H2O (15 mL). Then a
solution of tetraalkyne 4 in THF (35 mL) was added and the
mixture was heated at reflux for 24 h. An additional portion
of CuSO4·5H2O (4 mg) and L-ascorbic acid (5 mg) in H2O
(5 mL) was added and refluxed for a further 6 h. The reaction
was then filtered, evaporated to approximately 20 mL with
CH2Cl2 (100 mL) and H2O (100 mL) added. The organic
(14) Cross, K. J.; Crossley, M. J. Aust. J. Chem. 1992, 45, 991.
Synlett 2008, No. 14, 2147–2149 © Thieme Stuttgart · New York

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