Metal catalyst-free amination of meso-bromoporphyrins: an entry to supramolecular porphyrinoid frameworks

Article abstract of DOI:10.1016/j.tet.2009.02.039

meso-Bromoporphyrins can be conveniently substituted by primary and secondary amines in a metal catalyst-free reaction which gives access to a large variety of meso-N-substituted derivatives. In some cases, considerable acceleration of this amination can

Full text of DOI:10.1016/j.tet.2009.02.039

Tetrahedron 65 (2009) 3733–3739
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Tetrahedron
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Metal catalyst-free amination of meso-bromoporphyrins: an entry to
supramolecular porphyrinoid frameworks
,
,b
Mihaela Carmen Balaban a b, Cyril Chappaz-Gillot c, Gabriel Canard c, Olaf Fuhr a
,
Christian Roussel c, Teodor Silviu Balaban a
,b,c,
*
a Karlsruhe Institute of Technology, Forschungszentrum Karlsruhe, Institute for Nanotechnology, Postfach 3640, D-76021 Karlsruhe, Germany
b Center for Functional Nanostructures at the Universita¨t Karlsruhe (TH), Germany
c Universite´ Paul Ce´zanne Aix-Marseille III, UMR 6263 - ISM2-Chirosciences, Faculte´ des Sciences de Saint-Je´roˆme Case A 62, Avenue Escadrille Normandie-Niemen,
F-13397 Marseille Cedex 20, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 January 2009
Received in revised form 15 February 2009
Accepted 18 February 2009
Available online 25 February 2009
meso-Bromoporphyrins can be conveniently substituted by primary and secondary amines in a metal
catalyst-free reaction which gives access to a large variety of meso-N-substituted derivatives. In some
cases, considerable acceleration of this amination can be effected under microwave irradiation. The
amino anchor on the porphyrin skeleton is useful for constructing novel self-assembling porphyrinoids
as demonstrated by a single crystal X-ray analysis as well as stationary absorption and fluorescence
spectroscopies.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
biomimetic light-harvesting systems.8 Self-assembly is used by
green photosynthetic bacteria to fabricate a peculiar antenna sys-
The Buchwald–Hartwig palladium catalysed aminations have
had an enormous impact on modern synthetic methodologies
allowing the preparation in high yields of almost any secondary or
sterically unhindered tertiary amines from aryl or hetaryl halo-
genides.1,2 However for pharmaceutical applications, where amine
functionalities abound, even at low catalyst loadings, a complete
removal of the transition (or noble) metal catalysts still remains
a challenge and drastically augments the costs, if large scale chro-
matographic separations have to be performed. Very recently,
scavenging of palladium to 100 ppm was demonstrated by means
of a simple sodium bisulfite wash at 60 ꢀC,3 however other func-
tionalities in the final coupled molecules must resist this reductive
treatment. Porphyrins can be easily reduced to chlorins or even
bacteriochlorins under these conditions.4 In the present article we
report a catalyst-free direct amination of meso-bromo-substituted
porphyrins. Porphyrinoids are currently an active field of research
for third generation photodynamic therapy (PDT) agents5 and due
to their rich coordination chemistry, magnetic resonance imaging
(MRI) contrast agents6 can be relatively easily developed. Other
potential applications relate to dye-sensitized solar cells.7 We have
been interested in self-assembling porphyrins, which are
tem, the so-called chlorosome (green sac), which agglomerates
bacteriochlorophyll (BChl) c, d, or e molecules. We have been suc-
cessful in engineering the same groups as in BChl’s,9 or other rec-
ognition groups,10 onto desired positions of porphyrins and
chlorins. As such, a preparatively useful method for directly linking
a substituted amine onto a porphyrin skeleton, by circumventing
the use of any transition metal catalyst and which can be easily up-
scaled for obtaining a pure active pharmaceutical ingredient (API),
or other novel self-assembling porphyrins, is of timely interest.
2. Results and discussion
2.1. Syntheses
Scheme 1 presents the title reaction which we encountered
serendipitously while trying to synthesize push–pull porphyrins
substituted by 5-amino and 15-cyano groups.11 In an experiment
with 5-bromo-15-cyanoporphyrin, in order to test its stability to-
wards weak bases and heating and to check for the formation of
secondary products, we heated it to reflux in morpholine in the
absence of any metal catalyst. We were surprised by the high yield
of direct amination product and in subsequent trials we could
definitely exclude that this reaction could be due to trace amounts
of metal catalyst adsorbed on the walls of glass vessels. This metal-
free nucleophilic substitution of an aromatic bromide by amines is
not unprecedented as shown by Imahori and co-workers for
* Corresponding author. Tel.: þ49 724 782 6415; fax: þ49 724 782 9030.
E-mail addresses: silviu.balaban@int.fzk.de, ts.balaban@univ-cezanne.fr (T.S.
Balaban).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.039

3734
M.C. Balaban et al. / Tetrahedron 65 (2009) 3733–3739
Br
Br
R
R
R
R
R
N
R
R
N
N
N
H
H
H
H
N
N
N
N
R
1
R = C(CH3)3
R = H
3 R = C(CH3)3
Br
O
2
+
HN
+
O
R'-NH2
h
a-g
NH-R'
N
R
R
R
R
N
R
R
N
N
N
H
H
H
H
N
N
N
N
R
R
N
R = C(CH3)3
1a-1g
2b-2g
R = C(CH3)3
R = H
4h
Zn(OAc)2
4h-Zn
O
Scheme 1. See Table 1 for reaction conditions and yields.
a bromoperylene tetracarboxylic acid diimide.12 Two other sub-
stitutions at sp2 carbon atoms have been described recently.13
Another earlier example includes the substitution of 2- and
4-chloronitrobenzene by piperidine.14 The herein described bro-
mine replacement is however novel to porphyrin chemistry
allowing direct coupling of primary and secondary amines to the
meso-positions. The bromine atoms substituting a b-pyrrolic posi-
tion in meso-tetraphenylporphyrin do not react even upon pro-
longed heating or microwave irradiation. In the presence of
palladium catalysts the b-bromine atoms can be substituted but
were obtained by Pd or Ni catalysis have been described before.16
Senge has pioneered other nucleophilic substitutions at the meso-
positions of porphyrins,17 which in our case, do not require an ox-
idant for rearomatization of the intermediate phlorin.
Table 1 presents the herein explored direct aminations with
reaction conditions and yields. It is advantageous if a liquid (or
molten) amine is used in great excess as solvent that can be easily
recovered at the end of the reaction by vacuum stripping, leaving
a solid residue, which can be then conveniently purified by column
chromatography. Alternatively, a solvent such as tetrahydrofuran
can be used. Yields increase with reaction time and excess of amine
on the order of 400 equiv. Primary alkyl amines generally gave
may also lead to cyclized products onto the neighbouring meso-
phenyl group.15 Examples of amino-substituted porphyrins, which
Table 1
Isolated yields and reaction times of meso-bromoporphyrins 1 and 2 at room temperature
Entry
Porphyrin
Amine
R0NH2
Equiv of amine
Product
Time (min)
THF (mL/mmol)
76
Yielda (%)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
a
a
b
b
c
c
d
d
e
e
f
g
h
a
b
c
c
CH3CH2CH2NH2
400
200
400
200
400
200
400
200
400
200
200
400
130
200
200
200
200
200
200
200
200
1a
1b
1b
1b
1c
1c
1d
1d
1e
1e
1f
1g
1h
2a
2b
2c
2c
2f
1440
40
120
40
90
3
180
3
90
72*
75
91*
95
36**
99
46**
77
12**
89
78**
40*/30**
36**
52**
50**
40**
89
1 MW
2
2 MW
3
3 MW
4
4 MW
5
5 MW
6
7
8
9
10
11
11 MW
12
CH3CH2CH2CH2NH2
C6H5CH2NH2
(4-H3CO-C6H4)-CH2NH2
(4-F-C6H4)-CH2NH2
6
H2NCH2CH2NH2
HOCH2CH2NH2
4-CH3-C6H4-NH2
CH3CH2CH2NH2
CH3CH2CH2CH2NH2
C6H5CH2NH2
1440
1440
840
1200
120
90
3
300
13
96
96
11
f
f
g
g
H2NCH2CH2NH2
HOCH2CH2NH2
11
11
53**
47
48**
10
12 MW
13
13 MW
2f
2g
2g
480
3
a
The yields denoted by ** are isolated yields after column chromatography and recrystallization; yields denoted by * are isolated yields after column chromatography. All
other yields are based on 1H NMR integrals from the crude reaction mixtures. Microwave experiments are italicized and details such as power and ramping settings can be
found in Supplementary data.

M.C. Balaban et al. / Tetrahedron 65 (2009) 3733–3739
3735
higher yields than variously substituted benzyl amines while ani-
A
lines reacted more sluggishly.
426
4
3
2
1
0
The meso-bromoporphyrins 1 and 2 also did not react directly
with alcohols, alkoxides, or sulfides. The substitution reactions with
ethylenediamine and ethanolamine provide synthons, which can
be readily derivatized to various porphyrin conjugates.
It is interesting to note a considerable acceleration of the re-
action in some cases by using microwaves. While benzylamine
reacts quantitatively after 3 min, propylamine and butylamine, due
to their low boiling points, needed longer microwave irradiation
times under pressure (5–10 bar). On the contrary, even after pro-
longed irradiation and heating up to 180 ꢀC, p-toluidine did not
react at ambient pressure. Palladium catalysed aminations under
microwave irradiation have been extensively studied by Maes and
co-workers,18 while microwave-assisted uncatalysed amination of
(hetero)aryl halides or triflates have been recently described,19 and
reviewed.20 Details of the microwave experiments are given in
Supplementary data.
420
567
604
455
540
300
400
500
Wavelength (nm)
600
700
800
The advantage of a metal catalyst-free reaction, besides of
considerably lowering the costs, resides mainly in the easier puri-
fication of the products. Especially Pd-catalysts although very ver-
satile, lead to tailing in chromatographic separations, which thus
often need to be repeated with different eluents and/or stationary
phases.
In the case where the amine is solid or when the solubility of the
porphyrins in the amine is low (for instance in the cases a, f, and g)
use of a cosolvent such as THF is recommended. Table 2 (in the
Experimental section) lists the solubilities of porphyrins 1 and 2 in
the various amines employed here.
B
645
140
120
100
80
696
666
The potential for further functionalization of N-substituted
porphyrins is illustrated by the 5,15-dimorpholinyl-porphyrin 4,
which was obtained from the corresponding 5,15-dibromopor-
phyrin (3) in 49% yield.11 In a similar reaction of porphyrin 1 with
morpholine (h) the monomorpholinyl-porphyrin 1h (not depicted
in Scheme 1) was obtained in 61% yield.11 The free bases 1h and 4h
could be easily metallated with zinc acetate to give the corre-
sponding new compounds 1h-Zn and 4h-Zn in good yields.
60
40
655
623
20
0
500
600
700
800
Wavelength (nm)
2.2. Self-assembly in nonpolar solvents of 4h-Zn
Figure 1. (A) Full trace: 50
(1.4 mg in 500 L) of 4h-Zn in dry methylene chloride is injected into 3 mL of dry
n-heptane (to give a final concentration of 25 M) and shaken vigorously. The baseline
shift is due to light scattering by the greenish-red suspension. Dotted trace: absorption
spectrum of the same cuvette after addition of 100 L methanol, threefold dilution
with n-heptane and 250 L methylene chloride to ensure a homogeneous solution. (B)
Corresponding fluorescence spectra: intense full trace upon 420 nm excitation;
quenched full trace upon 458 nm excitation; dotted trace after methanol addition and
dilution (426 nm excitation). Pathlength of the quartz cuvette was 1 cm and the
fluorescence spectra are uncorrected.
mL of a 1.5 mM concentrated homogeneous dispersion
In nonpolar solvents the dimorpholinyl zinc porphyrin 4h-Zn
self-assembles giving broad and redshifted peaks similar to other
synthetic bacteriochlorophyll mimics.8–10 Figure 1A presents the
absorption spectra in dry n-heptane while Figure 1B shows the
stationary fluorescence spectra upon excitation of the Soret band of
the monomer (at 420 nm) or of the aggregated species (at
w455 nm). Upon methanol addition the aggregate bands disappear
giving rise to the monomeric spectrum of the 4h-Zn$MeOH adduct
(dotted traces).
m
m
m
m
The fluorescence of the aggregates is self-quenched by a factor
of ten in comparison to the monomers. However, the fact that it is
not entirely quenched, as is the case with most chromophores in
the solid state, speaks for an orderly arrangement within the self-
assembled species.
Self-assembly of 4h-Zn occurs also in dry methylene chloride at
high concentrations. Upon dilution the aggregate maxima (at
453 nm and 613 nm) gradually decrease (Fig. 2).
The monomorpholino compound 1h-Zn stays under the same
conditions monomeric as no changes in the absorption spectra ei-
ther in dry dichloromethane or in n-heptane are encountered. In
the MALDI-TOF mass spectra however a dimer peak cluster could
be reproducibly observed.
Table 2
Solubilities of porphyrins 1 and 2 in different amines at 25 ꢀC or upon heating under
reflux of the amine or of THF, which can be added as a cosolventa
Amine
R0NH2
25 ꢀ
C
D
a
b
c
d
e
f
CH3CH2CH2NH2
CH3CH2CH2CH2NH2
C6H5CH2NH2
(4-H3CO-C6H4)-CH2NH2
(4-F-C6H4)-CH2NH2
H2NCH2CH2NH2
HOCH2CH2NH2
ꢁ
þ þ
þ
þ þ
þ þ
þ þ
þ þ
þ
þ
2.3. Self-assembly in the crystal of 4h-Zn
þ
ꢁ
g
ꢁ ꢁ
ꢁ
Upon zinc metallation the metal core becomes a coordination
center for morpholinyl oxygens of neighbouring porphyrins. This
strong 2.20 Å Zn–O ligation in the crystal of 4h-Zn leads to
a
þþ signifies complete solubility; þ signifies good solubility; ꢁ signifies poor
solubility; and ꢁ ꢁ signifies insoluble.

3736
M.C. Balaban et al. / Tetrahedron 65 (2009) 3733–3739
a framework of stacked porphyrins with an interesting nano-
422
4.5
architecture. Figure 3 shows the monomeric unit as well as the
supramolecular assembly where beside the Zn–O ligations, mul-
tiple hydrophobic interactions between the di-tert-butylphenyl
groups assure a dense packing, which does not include the
crystallization solvents chloroform and cyclohexane. The zinc
atoms are 5-coordinate and only one morpholinyl oxygen in each
porphyrin binds to a zinc atom in an adjacent porphyrin while
again only one of its two morpholinyl groups ligates the next
porphyrin in the stack. The spectator morpholinyl groups are
more than 4.5 Å away from any bonding atom. It is indeed in-
triguing that only one morpholinyl group participates in the or-
chestration of the network. This could be due to the preference of
the zinc atom for a fivefold coordination in spite of the extra free
ligand, which could enable a sixfold coordinated zinc atom. At
present it is still challenging to predict crystal structure packings,
especially with porphyrins where several weak interactions
abound. The stacking axes passing through the zinc atoms are
parallel and the slightly domed porphyrin planes are inclined
with 55ꢀ to these axes. The two porphyrin planes are inclined
with 70ꢀ to each other.
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
453
545
573
613
300
400
500
Wavelength (nm)
600
700
800
Figure 2. Dilution of a concentrated dispersion of 4h-Zn in dry dichloromethane. The
concentrations from the top trace to the bottom trace were (mM): 1.5, 1.0, 0.6, 0.48,
0.36, 0.3, 0.2, 0.15. The strongly light scattering suspension of the more concentrated
dispersion lead to a baseline shift, which was not corrected in the spectra (raw data are
presented). The topmost trace slightly saturates the detector at the Soret band
(422 nm) of the monomeric form.
The encountered stacking of the porphyrin macrocycles has
a spacing, which is much increased in comparison with the usual
3.45 Å
p–p stacking distance. As such the p–p interaction is
Figure 3. Top: monomeric 4h-Zn. Bottom the porphyrinoid network assembled by Zn–O ligations. Colour coding: carbon-black, nitrogen-blue, hydrogen-red and zinc-cyan.
Hydrogen atoms were omitted for clarity.

M.C. Balaban et al. / Tetrahedron 65 (2009) 3733–3739
3737
recessive the crystal structure being dominated by the strong Zn–O
ligations. This weak coupling of the chromophore with a Zn–Zn
distance of 10.0 Å within a stack and 9.19 Å in between adjacent
stacks can lead to efficient exciton diffusion. Architectures of
stacked bacteriochlorophylls are encountered in light-harvesting
systems of green photosynthetic bacteria,8–10,21 which we are try-
ing to mimic with fully synthetic and more robust porphyrinoid
pigments.
In conclusion we have developed a new and facile direct
amination of meso-bromo-substituted porphyrins. With ethyl-
enediamine or ethanolamine a second functionality can be easily
introduced, which may be used for further coupling in por-
phyrinic conjugates. The Zn-metalated bis-morpholinyl porphy-
rin 4h-Zn self-assembles both in nonpolar solvents and in the
crystal.
4.37 (CH2NH, 2H, t, 3J¼7.2 Hz), 2.08 (CH2CH3, 2H, m),1.56 (C(CH3)3, 36H,
s),1.03 (CH2CH3, 3H, t, 3J¼7.4 Hz), ꢁ1.69 (NH, 2H, s). UV–vis [CHCl3, lmax
(log 3max), nm]: 423 (5.05), 459 (3.75), 524 (3.63), 574 (3.76), 669 (3.64).
3.2.2. 5-Butylamino-10,20-bis(3,5-di-tert-butylphenyl)
porphyrin (1b)
Following the general solvent-free procedure, after 2 h of reflux
and chromatography (dichloromethane, Rf¼0.20), the porphyrin 1b
was obtained as a dark green solid (45 mg, 91% yield). 1H NMR
(200 MHz, CDCl3; d, ppm): 9.64 (H-meso, 1H, s), 9.25 (H-b, 2H, d,
3J¼4.6 Hz), 9.03 (H-
b
, 2H, d, 3J¼4.6 Hz), 8.83 (H-
b
, 2H, d, 3J¼4.6 Hz),
8.71 (H-
b
, 2H, d, 3J¼4.6 Hz), 8.05 (Ar–H, 4H, d, 4J¼1.8 Hz), 7.79 (Ar–H,
2H, t, 4J¼1.8 Hz), 4.40 (CH2NH, 2H, t, 3J¼7.2 Hz), 2.05 (CH2CH2CH2,
2H, m),1.67(CH2CH3, 2H, m),1.56 (C(CH3)3, 36H, s),1.03 (CH2CH3, 3H,
t, 3J¼7.4 Hz), ꢁ1.69 (NH, 2H, s). UV–vis [CHCl3, lmax (log 3max), nm]:
421 (5.00), 457 (3.95), 517 (3.65), 576 (3.65), 670 (3.52).
3. Experimental part
3.1. General methods
3.2.3. 5-Benzylamino-10,20-bis(3,5-di-tert-butylphenyl)-
porphyrin (1c)
Following the general solvent-free procedure, after 1.5 h of
reflux, chromatography (dichloromethane/hexane 7:3, Rf¼0.30)
and slow recrystallization from diethyl ether, porphyrin 1c was
obtained as a purple powder (19 mg, 36% yield). 1H NMR (200 MHz,
1H NMR (300 MHz or 200 MHz) spectra were recorded on Bruker
Avance 300 or Avance 200 spectrometers and are referenced with
respect to the residual solvent peaks, e.g., 7.26 ppm for the proton of
CHCl3. Mass spectra were routinely performed as MALDI-TOF on
a Voyager, Applied Biosystems instrument using as the matrix 1,8,9-
anthracenetriol (dithranol). High resolution mass spectra were
recorded either as FAB on a Finnigan MAT 90 instrument with
3-nitrobenzyl alcohol as the matrix, or as electrospray on a QStar Elite
spectrometer from Applied Biosystems SCIEX using in both cases PEG
oligomers as internal standard. UV–vis spectra were measured either
with a Shimadzu UV-2401 (PC) instrument or for the self-assembly
experiments on a Varian Cary 500 equipped with a Peltier tempera-
ture controller. Stationary fluorescence spectra were recorded on
a Varian Eclipse fluorimeter in 1ꢂ1 cm quartz cuvettes. Porphyrins 1
and 2 were synthesized and purified according to procedures in the
literature.22 Dichloromethane was distilled from calcium hydride
while cyclohexane and n-heptane were freshly distilled from sodium
metal. The other reagents and solvents were commercially bought
and used as received. Reactions were monitored by thin layer chro-
matography (Merck, silica gel 60). Column flash chromatography was
CDCl3;
9.09 (H-
d
, ppm): 9.73 (H-meso, 1H, s), 9.21 (H-
b
, 2H, d, 3J¼4.8 Hz),
b
, 2H, d, 3J¼4.7 Hz), 8.90 (H-
b
, 2H, d, 3J¼4.7 Hz), 8.74 (H-
b,
2H, d, 3J¼4.8 Hz), 8.09 (Ar–H, 4H, d, 4J¼1.8 Hz), 7.82 (Ar–H, 2H, t,
4J¼1.8 Hz), 7.39–7.60 (Bz–H, 5H, m), 5.57 (CH2, 2H, s), 1.57 (C(CH3)3,
36H, s), ꢁ1.81 (NH, 2H, s). HRMS-ESI ([MþH]þ): found 792.4999,
calcd 792.5000 for C55H61N5. UV–vis [CHCl3, lmax (log 3max), nm]:
423 (5.29), 524 (3.77), 571 (3.89), 668 (3.76).
3.2.4. 5-(4-Methoxybenzylamino)-10,20-bis(3,5-di-tert-
butylphenyl)porphyrin (1d)
Following the general solvent-free procedure, after 3 h of reflux,
chromatography (dichloromethane, Rf¼0.33) and recrystallization
from ethanol, porphyrin 1d was obtained as a dark purple powder
(25 mg, 46% yield).1H NMR (300 MHz, CDCl3;
d, ppm): 9.72 (H-meso,
1H, s), 9.20 (H-
b
, 2H, d, 3J¼4.5 Hz), 9.09 (H-
b
, 2H, d, 3J¼4.5 Hz), 8.92
(H-
b
, 2H, d, 3J¼4.8 Hz), 8.75 (H-
b
, 2H, d, 3J¼4.8 Hz), 8.11 (Ar–H, 4H, d,
4J¼1.8 Hz), 7.85 (Ar–H, 2H, t, 4J¼1.8 Hz), 7.46 (Bz–H, 2H, d, 3J¼8.6 Hz),
6.92 (Bz–H, 2H, d, 3J¼8.6 Hz), 5.52 (CH2, 2H, s), 3.81 (CH3, 3H, s),1.56
(C(CH3)3, 36H, s), ꢁ1.78 (NH, 2H, s). HRMS-ESI ([MþH]þ): found
822.5102, calcd 822.5105 for C56H63N5O. UV–vis [CHCl3, lmax
(log 3max), nm]: 423 (5.25), 525 (3.68), 573 (3.87), 670 (3.73).
performed on silica gel (SDS, 35–70 mm). Microwave experiments
were performed in 10 mL sealed tubes within the cavity of a pro-
fessional focused Discover microwave oven from CEM. Colourchanges
or precipitation could be followed during the irradiation period with
an external video camera connected via fiber optics.
3.2.5. 5-(4-Fluorobenzylamino)-10,20-bis(3,5-di-tert-
butylphenyl)porphyrin (1e)
3.2. General procedure for the amination of 5-bromo-
10,20-bis(3,5-di-tert-butylphenyl)porphyrin
Following the general solvent-free procedure, after 1.5 h of
reflux, chromatography (dichloromethane/hexane 7:3, Rf¼0.49)
and recrystallization from ethanol, porphyrin 1e was obtained as
a dark purple powder (6 mg, 12% yield). 1H NMR (300 MHz, CDCl3;
A solution of the porphyrin 1 (50 mg, 65 mmol, 1 equiv) in excess
amine (400 equiv) and eventually tetrahydrofuran (90 mL/mmol of
porphyrin) for the insoluble porphyrins (see Table 2) was heated at
reflux under argon. The mixture was evaporated and the residue was
deposited onto silica gel by vacuum evaporation. Column chroma-
tography on silica gel eluted with the appropriate eluent affords the
product, which was, if possible, recrystallized to get the pure product.
d
, ppm): 9.76 (H-meso, 1H, s), 9.18 (H-
b
, 2H, d, 3J¼4.5 Hz), 9.10 (H-
b,
2H, d, 3J¼4.6 Hz), 8.90 (H-
b
, 2H, d, 3J¼4.8 Hz), 8.75 (H-
b, 2H, d,
3J¼4.5 Hz), 8.07 (Ar–H, 4H, d, 4J¼1.8 Hz), 7.81 (Ar–H, 2H, t,
4J¼1.8 Hz), 7.47–7.51 (Bz–H, 2H, m), 7.05 (Bz–H, 2H, t, 3J¼8.4 Hz),
5.50 (CH2, 2H, s), 1.56 (C(CH3)3, 36H, s), ꢁ1.91 (NH, 2H, s). 19F NMR
(282 MHz, CDCl3;
d
, ppm): ꢁ115.1. HRMS-ESI ([MþH]þ): found
3.2.1. 5-Propylamino-10,20-bis(3,5-di-tert-butylphenyl)
porphyrin (1a)
810.4901, calcd 810.4906 for C55H60N5F. UV–vis [CHCl3, lmax
(log 3max), nm]: 421 (5.22), 522 (3.69), 569 (3.80), 667 (3.60).
Following the general procedure with tetrahydrofuran, after 24 h of
reflux (note that the boiling point of propylamine is 48 ꢀC) and chro-
matography (dichloromethane, Rf¼0.32), the porphyrin 1a was
obtained as a dark green solid (35 mg, 72% yield). 1H NMR (200 MHz,
3.2.6. 5-(2-Aminoethylamino)-10,20-bis(3,5-di-tert-
butylphenyl)porphyrin (1f)
Following the general procedure with tetrahydrofuran, after 24 h of
reflux, chromatography (dichloromethane/methanol 10:1, Rf¼0.32)
and recrystallization from diethyl ether, porphyrin 1f was obtained as
CDCl3;
d
, ppm): 9.64 (H-meso, 1H, s), 9.26 (H-
b
, 2H, d, 3J¼4.7 Hz), 9.03
(H-b
, 2H, d, 3J¼4.7 Hz), 8.83 (H-
b
, 2H, d, 3J¼4.7 Hz), 8.71 (H-
b, 2H, d,
3J¼4.7 Hz), 8.06 (Ar–H, 4H, d, 4J¼1.8 Hz), 7.80 (Ar–H, 2H, t, 4J¼1.8 Hz),
a dark purple powder (38 mg, 78% yield). 1H NMR (200 MHz, CDCl3;
d,

3738
M.C. Balaban et al. / Tetrahedron 65 (2009) 3733–3739
ppm): 9.65 (H-meso,1H, s), 9.38 (H-
b
, 2H, d, 3J¼4.7 Hz), 9.03 (H-
b
, 2H, d,
(CH2NH, 2H, t, 3J¼7.2 Hz), 2.05 (CH2CH2CH2, 2H, m), 1.00
(CH2CH3, 3H, t, 3J¼7.5 Hz), ꢁ1.72 (NH, 2H, s). HRMS-ESI
([MþH]þ): found 520.2508, calcd 520.2496 for C35H29N5. UV–
vis [CHCl3, lmax (log 3max), nm]: 421 (5.23), 523 (3.73), 573
(3.84), 670 (3.70).
3J¼4.7 Hz), 8.84 (H-
b
, 2H, d, 3J¼4.7 Hz), 8.71 (H-
b
, 2H, d, 3J¼4.7 Hz),
8.06(Ar–H, 4H, d, 4J¼1.8 Hz), 7.80(Ar–H, 2H, t, 4J¼1.8 Hz), 4.43 (CH2NH,
2H, t, J¼5.6 Hz), 3.29 (CH2NH2, 2H, t, J¼5.6 Hz), 1.56 (C(CH3)3, 36H, s),
ꢁ1.69 (NH, 2H, s). HRMS-ESI ([MþH]þ): found 745.4943, calcd
745.4952 for C50H60N6. UV–vis [CHCl3, lmax (log 3max), nm]: 422 (5.31),
523 (3.83), 572 (3.93), 668 (3.81).
3.3.2. 5-Butylamino-10,20-diphenylporphyrin (2b)
Following the general solvent-free procedure, after 2 h of reflux,
chromatography (dichloromethane, Rf¼0.15) and recrystallization,
porphyrin 2b was obtained as a dark purple powder (25 mg, 50%
3.2.7. 5-(2-Hydroxyethylamino)-10,20-bis(3,5-di-tert-
butylphenyl)porphyrin (1g)
Following the general procedure with tetrahydrofuran, after
24 h of reflux and chromatography (dichloromethane/methanol
100:2.5, Rf¼0.23), the porphyrin 1g was obtained as a dark purple
yield). 1H NMR (200 MHz, CDCl3;
d, ppm): 9.61 (H-meso, 1H, s), 9.19
(H-
b
, 2H, d, 3J¼4.6 Hz), 9.00 (H-
b
, 2H, d, 3J¼4.6 Hz), 8.78 (H-
b, 2H, d,
3J¼4.6 Hz), 8.64 (H-
b
, 2H, d, 3J¼4.6 Hz), 8.19 (Ph–H, 4H, m), 7.77
oil (15 mg, 30% yield). 1H NMR (200 MHz, CDCl3;
d
, ppm): 9.76 (H-
(Ph–H, 6H, m), 4.35 (CH2NH, 2H, t, 3J¼7.1 Hz), 1.95–2.03
(CH2CH2CH2, 2H, m),1.57–1.64 (CH2CH3, 2H, m),1.00 (CH2CH3, 3H, t,
3J¼7.3 Hz), ꢁ1.64 (NH, 2H, s). HRMS-ESI ([MþH]þ): found 534.2648,
calcd 534.2652 for C36H31N5. UV–vis [CHCl3, lmax (log 3max), nm]:
421 (5.22), 523 (3.68), 574 (3.84), 670 (3.71).
meso, 1H, s), 9.41 (H-
b
, 2H, d, 3J¼4.7 Hz), 9.09 (H-
b
, 2H, d,
2H, d,
3J¼4.7 Hz), 8.89 (H-
b
,
2H, d, 3J¼4.7 Hz), 8.78 (H-
b
,
3J¼4.7 Hz), 8.07 (Ar–H, 4H, d, 4J¼1.8 Hz), 7.80 (Ar–H, 2H, t,
4J¼1.8 Hz), 4.53 (CH2NH, 2H, t, 3J¼5.2 Hz), 4.11 (CH2OH, 2H, t,
3J¼5.2 Hz), 1.56 (C(CH3)3, 36H, s), ꢁ2.01 (NH, 2H, s). UV–vis
[CHCl3, lmax (log 3max), nm]: 421 (5.26), 523 (3.80), 567 (3.91), 664
(3.76).
3.3.3. 5-Benzylamino-10,20-diphenylporphyrin (2c)
Following the general solvent-free procedure, after 1.5 h of
reflux, chromatography (dichloromethane/hexane 8:2, Rf¼0.14)
and recrystallization, porphyrin 2c was obtained as a dark purple
3.2.8. 5-(4-Toluidin-1yl)-10,20-bis(3,5-di-tert-butylphenyl)
porphyrin (1h)
5-Bromo-10,20-bis(3,5-di-tert-butylphenyl)21H,23H-porphine (1,
50 mg, 0.065 mmol) was heated overnight with 3.0 g p-toluidine at
140 ꢀC under nitrogen. Then the reaction mixture was cooled at room
temperature and extracted in the minimal quantity of dichloro-
powder (21 mg, 40% yield). 1H NMR (200 MHz, CDCl3;
d, ppm):
9.70 (H-meso, 1H, s), 9.15 (H-
b
, 2H, d, 3J¼4.5 Hz), 9.05 (H-
b
, 2H, d,
3J¼4.8 Hz), 8.82 (H-
b
,
2H, d, 3J¼4.5 Hz), 8.65 (H-
b, 2H, d,
3J¼4.8 Hz), 8.19 (Ph–H, 4H, m), 7.76 (Ph–H, 6H, m), 7.52 (Bz–H, 2H,
m), 7.37 (Bz–H, 3H, m), 5.54 (CH2, 2H, s), ꢁ1.82 (NH, 2H, s). HRMS-
ESI ([MþH]þ): found 568.2493, calcd 568.2496 for C39H29N5. UV–
vis [CHCl3, lmax (log 3max), nm]: 420 (5.28), 516 (3.82), 571 (3.84),
672 (3.76).
methane. Column chromatography (L¼25 cm, ¼3 cm) after elution
F
with dichloromethane gave a first intensely coloured fraction,
which after evaporation of the solvent gave a brick red powder. Re-
crystallization from hot chloroform to which methanol was added
until a cloudy suspension was formed, afforded after cooling to
ꢁ20 ꢀC, 18.7 mg of pure 1h (36% yield).
3.3.4. 5-(2-Aminoethylamino)-10,20-diphenylporphyrin (2f)
Following the general procedure with tetrahydrofuran, after 5 h
of reflux, chromatography (dichloromethane/methanol 9:1,
Rf¼0.10) and recrystallization, porphyrin 2f was obtained as a dark
Rf (CH2Cl2)¼0.82. 1H NMR (300 MHz, CDCl3;
d, ppm): 10.10 (H-5,
1H, s), 9.35 (H-13 and H-17, 2H, d, 3J¼4.8 Hz), 9.27 (H-3 and H-7, 2H,
d, 3J¼4.5 Hz), 9.01 (H-2 and H-8, 2H, d, 3J¼4.5 Hz), 8.86 (H-12 and
H-18, 2H, d, 3J¼4.8 Hz), 8.09 (200,600-Ar–H, 4H, d, 4J¼1.8 Hz), 7.81 (400-
Ar–H, 2H, t, 4J¼1.8 Hz), 6.98 (30,50-C6H4CH3, 2H, d, 3J¼8.4 Hz), 6.80
(20,60-C6H4CH3, 2H, d, 3J¼8.4 Hz), 2.26 (–C6H4CH3, 3H, s), 1.57, 1.55,
1.53 (C(CH3)3, 36H, three s with intensities 1:2:1), ꢁ2.60 (NH, 2H, s).
Assignments are based on COSY and NOESY spectra. HRMS-FAB
([MþH]þ): found 792.5010, calcd 792.5005 for C55H62N5. UV–vis
[CH2Cl2, lmax (log 3max), nm]: 415.5 (5.20, FWHM¼39 nm), 515
(4.06), 590 (3.70), 656 (3.50).
purple powder (49 mg, 53% yield). 1H NMR (200 MHz, CDCl3;
d
,
,
ppm): 9.61 (H-meso, 1H, s), 9.33 (H-
b
, 2H, d, 3J¼4.5 Hz), 9.00 (H-
b
2H, d, 3J¼4.8 Hz), 8.77 (H-
b
, 2H, d, 3J¼4.8 Hz), 8.63 (H-
b, 2H, d,
3J¼4.5 Hz), 8.18 (Ph–H, 4H, m), 7.76 (Ph–H, 6H, m), 4.38 (CH2NH, 2H,
t, 3J¼5.6 Hz), 3.24 (CH2NH2, 2H, t, 3J¼5.6 Hz), ꢁ1.63 (NH, 2H, s).
HRMS-ESI ([MþH]þ): found 521.2448, calcd 521.2448 for C34H28N6.
UV–vis [CHCl3, lmax (log 3max), nm]: 420 (5.19), 517 (3.84), 572
(3.84), 668 (3.67).
3.3.5. 5-(2-Hydroxyethylamino)-10,20-diphenylporphyrin (2g)
Following the general procedure with tetrahydrofuran, after 8 h
of reflux, chromatography (dichloromethane, Rf¼0.47 in dichloro-
methane/methanol 100:8) and recrystallization, porphyrin 2g was
obtained as a dark purple powder (23 mg, 48% yield). 1H NMR
3.3. General procedure for the amination of 5-bromo-
10,20-diphenylporphyrin (2)
A solution of the porphyrin 2 (50 mg, 92 mmol, 1 equiv) in excess
amine (200 equiv) and eventually tetrahydrofuran (11 mL/mmol of
porphyrin) for the insoluble porphyrins was heated at reflux under
argon. The mixture was evaporated and the residue was deposited
onto silica gel by vacuum evaporation. Column chromatography on
silica gel eluted with the appropriate eluent affords the product,
which was recrystallized from n-heptane to get the pure products
2b–2g.
(200 MHz, CDCl3; d, ppm): 9.74 (H-meso, 1H, s), 9.36 (H-b, 2H, d,
3J¼4.7 Hz), 9.08 (H-
b
, 2H, d, 3J¼4.7 Hz), 8.82 (H-
b
, 2H, d, 3J¼4.7 Hz),
8.68 (H-
b
, 2H, d, 3J¼4.7 Hz), 8.19 (Ph–H, 4H, m), 7.77 (Ph–H, 6H, m),
4.48 (CH2NH, 2H, t, 3J¼5.2 Hz), 4.03 (CH2OH, 2H, t, 3J¼5.0 Hz),
ꢁ2.00 (NH, 2H, s). HRMS-ESI ([MþH]þ): found 522.2284, calcd
522.2288 for C34H27N5O. UV–vis [CHCl3, lmax (log 3max), nm]: 420
(5.24), 520 (3.83), 566 (3.83), 664 (3.65).
3.3.1. 5-Propylamino-10,20-diphenylporphyrin (2a)
3.3.6. 5,15-Dimorpholino-10,20-bis(3,5-di-tert-butylphenyl)-
Following the general procedure with tetrahydrofuran, after
20 h of reflux and chromatography (dichloromethane/hexane
7:3, Rf¼0.10), the porphyrin 2a was obtained as a dark green
porphyrinato zinc(II) (4h-Zn)
To
a solution of 5,15-dimorpholino-10,20-bis (3,5-di-tert-
butylphenyl)porphyrin11 (4h) (45 mg, 0.053 mmol) in chloroform
(8 mL), zinc acetate (48 mg, 0.26 mmol) in methanol (1.6 mL) was
added. The mixture was deaerated with nitrogen and then stirred
for 1.5 h (monitoring by UV–vis) under nitrogen atmosphere. The
reaction mixture was washed with distilled water (4ꢂ150 mL) until
solid (25 mg, 52% yield). 1H NMR (200 MHz, CDCl3;
d, ppm):
9.61 (H-meso, 1H, s), 9.19 (H-
b
, 2H, d, 3J¼4.8 Hz), 9.00 (H-
b, 2H,
b, 2H, d,
d, 3J¼4.8 Hz), 8.77 (H-
b
, 2H, d, 3J¼4.8 Hz), 8.62 (H-
3J¼4.8 Hz), 8.18 (Ph–H, 4H, m), 7.77 (Ph–H, 6H, m), 4.34

M.C. Balaban et al. / Tetrahedron 65 (2009) 3733–3739
3739
neutral pH. The organic layer was concentrated by rotary evapo-
Supplementary data
ration. After column chromatography on silica gel, 33.1 mg of the
reddish compound 4h-Zn was obtained (68% yield). A CDCl3 con-
centrated solution (w0.6 mL) was layered in a 20 cm tall glass tube
with an internal diameter of 7 mm with an intermediate layer of
a 1:1 (v/v) solution of nondeuterated chloroform and cyclohexane
(w0.5 mL). Then cyclohexane was added until filling the tube,
which was sealed by a rubber septum. After nine months micro-
crystals were formed, which in the same tube were grinded with
dry nondeuterated chloroform, which was layered with dry, freshly
distilled cyclohexane from sodium metal. After another six months
a ruby-red needle like crystal was collected and mounted on a STOE
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.02.039.
References and notes
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IPDS II at the ANKA Synchrotron
(
l
¼0.8 Å) at the For-
schungszentrum Karlsruhe (beamline for small crystal diffraction)
at 140 K. The structure solutions and full matrix least square re-
finements based on F2 were performed with SHELX-97 program
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a¼22.9743(7), b¼10.0085(3), c¼25.3334(8) Å,
b
¼107.936(2)ꢀ,
V¼5542.0(3) Å3, Z¼4, Dc¼1.204 g cmꢁ3
,
m
(
l
¼0.8 Å)¼0.772 mmꢁ1
giving a final R1 value of 0.0752 for 647 parameters and 6399
unique reflections with Iꢃ2s(I) and wR2 of 0.1895 for all 7195 re-
flections. A disorder has been modelled for two symmetry equiv-
alent tert-butyl groups. CCDC 704397 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from
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1H NMR (300 MHz, CDCl3;
d
, ppm): 9.72 (H-
b
, 4H, d, 3J¼4.5 Hz),
8.99 (H-
b
, 4H, d, 3J¼4.8 Hz), 8.06 (Ar–H, 4H, d, 4J¼1.8 Hz), 7.82 (40-
Ar–H, 2H, d, 4J¼1.8 Hz), 4.28 and 4.25 (morpholinyl-H, 16H, two br
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present in equilibrium with the monomeric form. Upon increasing
the temperature the equilibrium is shifted towards the monomer.
HRMS-FAB ([MþH]þ): found 917.4453, calcd 917.4460 for
C56H65N6O625Zn; ([Mþ2H]þ): found 918.4543, calcd 918.4539 for
C56H66N6O625Zn. UV–vis [CH2Cl2, lmax (log 3max), nm]: 306 (4.06),
422.5 (5.22), 549 (4.1), 600 (3.1). For other UV–vis and fluorescence
spectra see Figures 1 and 2.
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3.3.7. 5-Morpholino-10,20-bis(3,5-di-tert-butylphenyl)-
porphyrinato zinc(II) (1h-Zn)
Metallation with Zn(OAc)2 of the free base 1h11 (28 mg,
0.036 mmol) was performed as described above for 4h affording
after column chromatography on silica gel eluted with CH2Cl2/n-
hexane (1:1, v:v) 1h-Zn as a violet-raspberry powder (20 mg, 66%
yield). 1H NMR (300 MHz, CDCl3;
d, ppm): 10.19 (15-H, 1H, s), 9.69
(H-
b
, 2H, d, 3J¼4.5 Hz), 9.36 (H-
b
, 2H, d, 3J¼4.5 Hz), 9.10 (H-
b, 2H, d,
3J¼4.5 Hz), 9.06 (H-
b
,
4H, d, 3J¼4.5 Hz), 8.10 (Ar–H, 4H, d,
4J¼1.8 Hz), 7.82 (40-Ar–H, 2H, d, 4J¼1.8 Hz), 4.02 and 3.91 (mor-
pholinyl-H, 8H, two br s), 1.55 (C(CH3)3, 36H, s). MALDI-TOF MS:
832.9 [MþH]þ (100%), 1668.1 [DimerþH]þ (4%). UV–vis [n-heptane/
CH2Cl2, 25:1, v/v, lmax (relative intensity), nm]: 303 (0.14), 412.5
(3.5), 541 (0.2).
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We thank the Deutsche Forschungsgemeinschaft for partial
financial support through project C3.5 of the Centre for Functional
Nanostructures at the Universita¨t Karlsruhe (S.T.B. and M.C.B.). The
CNRS has made possible the collaborative work between Marseille
and Karlsruhe through PICS Nr. 3777. We gratefully acknowledge
beamline time at the ANKA Synchrotron and the assistance for data
collection from Dr. Gernot Buth.
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