Selective formation of either Tr?ger's base or spiro Tr?ger's base derivatives from [2-aminoporphyrinato(2-)]nickel by choice of reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2012.08.097

The article reports on the unique manipulation of the acid-catalyzed reaction of [2-aminoporphyrinato(2-)]nickel with formaldehyde to form selectively either the symmetric Tr?ger's base or the asymmetric spiro Tr?ger's base bis(metalloporphyrin) derivativ

Full text of DOI:10.1016/j.tetlet.2012.08.097

Tetrahedron Letters 53 (2012) 6015–6017
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Tetrahedron Letters
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Selective formation of either Tröger’s base or spiro Tröger’s base
derivatives from [2-aminoporphyrinato(2-)]nickel by choice of reaction
conditions
a
a,
⇑
b
a
´
ˇ
Ameneh Tatar , Bohumil Dolensky , Hana Dvoráková , Vladimír Král
a Institute of Chemical Technology, Department of Analytical Chemistry, Technická 5, 16628 Praha, Czech Republic
b Institute of Chemical Technology, Laboratory of NMR Spectroscopy, Technická 5, 16628 Praha, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
The article reports on the unique manipulation of the acid-catalyzed reaction of [2-aminoporphyrinato
(2-)]nickel with formaldehyde to form selectively either the symmetric Tröger’s base or the asymmetric
spiro Tröger’s base bis(metalloporphyrin) derivative. The reaction is driven by the choice of acid catalyst,
formaldehyde source, and particularly, solvent, to give a mixture of both derivatives in preparative yields
of about 90%, or to give selectively one of the derivatives in a yield of about 60%.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 17 May 2012
Revised 9 August 2012
Accepted 24 August 2012
Available online 7 September 2012
Keywords:
Bis(metalloporphyrin)
Tröger’s base derivative
Spiro Tröger’s base derivative
Solvent effect
Selectivity
2 (M = 2H, R = NH2)
3 (M = Zn, R = H)
4 (M = Pd, R = NH2)
6 (M = Ni, R = NH2)
10 (M = Ni, R = H)
Ph
Ph
N
M
N
Metalloporphyrins are essential for the vitality of bacteria, fun-
gi, plants, and animals, and they have been the subject of many
studies over several decades.1 In addition, there have been numer-
ous attempts by chemists to utilize the properties of metallopor-
phyrins in artificial systems.2 An important area of research and
development involves molecules possessing two metalloporphyrin
units in a specific spatial position, which enables their coopera-
tion.1–3
Crossley’s research group has recently shown that two metallo-
porphyrin units can be connected by a Tröger’s base (TB) structural
skeleton4 to form rigid V-shaped molecules, for example, metallo-
porphyrin TB 1 (Fig. 1).5 The metalloporphyrin units in a TB deriv-
ative are held in a rigid position, which enables their cooperation
that results in the selective binding of bidentate molecules, such
as diamines.5,6 Optically pure enantiomers of metalloporphyrin
TB exhibit excellent stereoselective binding of histidine and lysine
esters.7,8 With extended porphyrins, the metal–metal distance is
extended, and thus, the selectivity.9
R
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
N
M
N
N
M
N
N
N
N
N
Ph
Ph
Ph
Ph
1 (M = Pd)
5 (M = 2H)
7 (M = Ni)
Ph
Ph
73
N
8
N
N
Ph
51
172
N
Ni
N
The current methods for preparing TB 1 are not perfect. As the
initial aminoporphyrin 2 is prepared by the nitration of metallo-
porphyrin 3, followed by demetalation and reduction,10 it is
obvious that direct conversion of aminometalloporphyrin 4 into
TB 1 would save two reaction steps. Unfortunately, while amino-
porphyrin 2 yielded the corresponding TB 5 in a 73% yield, the
50
Ph 34
Ph
N
N
N
Ph
decisive chemical
shifts (ppm) of carbon
atoms are inscribed
Ni
N
Ph
N
Ph
⇑
Corresponding author. Tel.: +420 2 2044 4352; fax: +420 2 2044 4110.
E-mail address: Bohumil.Dolensky@vscht.cz (B. Dolensky´).
Figure 1. Structures of discussed porphyrin derivatives.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.097

6016
A. Tatar et al. / Tetrahedron Letters 53 (2012) 6015–6017
Table 1
Preparative yields of TB 7 and spiroTB 8 at various conditions
Reaction solvent
Source of formaldehyde
Acid
Reaction temperature (°C)
Reaction time (h)
Yield of TB 7 (%)
Yield of spiroTB 8 (%)
a
b
c
d
e
THF
THF
THF
THF
THF
Formalin
Formalin
Formalin
Formalin
Formalin
HCl
HCl
HCl
HCl
HCl
60
25
25
20
1
20
2
16
32
29
16
15
Trace
Trace
Trace
Trace
Trace
À20
À20
9
f
THF/CHCl3 99:1
THF/CHCl3 1:1
THF/CHCl3 1:99
CHCl3
CHCl3
CHCl3
Formalin
Formalin
Formalin
Formalin
Formalin
Formalin
HCl
HCl
HCl
HCl
HCl
HCl
25
25
25
25
25
20
20
20
20
1
39
43
13
19
13
14
Trace
16
77
70
69
g
h
i
j
k
À20
2
61
l
m
1,4-Dioxane
CH2Cl2
Formalin
Formalin
HCl
HCl
25
25
20
20
56
17
Trace
50
n
o
p
q
CHCl3
CHCl3
TFA
Formalin
HMTA
HMTA
TFA
TFA
TFA
HCl
25
25
25
25
20
20
20
20
32
43
Trace
Not observed
67
Not observed
Not observed
Not observed
CHCl3
HMTA
direct conversion of the aminometalloporphyrin 4 into TB 1 gave
only a 29% yield.5
was performed in CHCl3, the yields of TB 7 and spiroTB 8 were
barely affected by temperatures (rows i–k).
As we intend to utilize metalloporphyrins as the binding units
of molecular tweezers, based on bis-Tröger’s base derivatives,11,12
we performed a brief study of the direct conversion of the amin-
ometalloporphyrin 6 into TB 7 (Fig. 1). We found that the conver-
sion of 6 into TB 7 is followed by the formation of the more polar
spiroTB 8 (the only recently reported type13 of constitutional iso-
mer of TB), where the yields of TB 7 and spiroTB 8 are highly influ-
enced by the reaction conditions (Table 1). Demetalation was not
observed in any case because neither signals near À3 ppm in the
1H NMR spectra nor extra spots of expected polarity on TLC were
observed.
First, we applied conditions that were similar to those pub-
lished by Crossley.5 Specifically, nickelporphyrin 6 was treated
with formalin and hydrochloric acid in THF at 60 °C for 20 h to give
a 16% yield of TB 7 (row a). Lowering the reaction temperature to
25 °C doubled the yield; however, further reducing the reaction
temperature to À20 °C still produced only a 16% yield. In both
cases with a reduced reaction temperature, extending the reaction
duration did not affect the yields (rows b-e). In all cases, TB 7 was
accompanied by traces of spiroTB 8.
Next, we discovered that similar solvents behave similarly. The
replacement of THF by 1,4-dioxane significantly increased the yield
of TB 7 to 56%, while spiroTB 8 remained a trace byproduct (row l).
The replacement of CHCl3 with CH2Cl2 did not affect the yield of TB
7; however, the use of CH2Cl2 notably decreased the yield of spi-
roTB 8 to 50% (row m).
Finally, we evaluated the influence of the acid catalyst and the
formaldehyde source. The use of TFA instead of hydrochloric acid
decreased the total yield, although the yield of TB 7 notably in-
creased (rows n vs. i). Surprisingly, using hexamethylenetetramine
(HMTA) and TFA, which are the standard conditions that are used
for TB preparation,4,12 yielded only complex mixtures, even when
TFA was used as the solvent (rows o–p). Conversely, when HMTA
and hydrochloric acid were used, the formation of TB 7 was com-
pletely suppressed, and the yield of spiroTB 8 remained high (rows
q vs. i).
To determine whether the effect of the solvent is specific to por-
phyrins, we used naphth-2-ylamine, which is known to form both
a TB and a spiroTB,13 and aminopyrrole 9 (Scheme 1), which is clo-
sely related (in structure) to porphyrins and known to form TB.14
These amines were treated with formalin and hydrochloric acid
at 25 °C for 20 h in THF or CHCl3. The treatment of naphth-2-yla-
mine yielded only the corresponding TB, regardless of the solvent
used (71% in THF, 73% in CHCl3); the formation of the correspond-
ing spiroTB was not observed. In contrast, aminopyrrole 9 pro-
duced the corresponding TB in high yield (84%) with minor
We explored how a solvent affects the reaction yield. When a
99:1 volume ratio of THF/CHCl3 was used, the yield of TB 7 in-
creased, and spiroTB 8 was still present in trace amounts (row f).
However, when a higher content of CHCl3 was used, the yield of
spiroTB 8 increased dramatically to approximately 70% (rows g–
i). In contrast to the reaction in THF (rows a–e), when the reaction
CO2CH2Ph
9
formalin, 35% HCl
THF or CHCl3
N
H2N
CH3
25 °C, 20 h
CO2CH2Ph
H3C
N
CO2CH2Ph
N
N
N
N
+
CH3
N
N
N
CH3
CO2CH2Ph
CH3
CO2CH2Ph
Scheme 1. The expected products of aminopyrrole 9.
Figure 2. UV–Vis spectra in CH2Cl2: 6 (green), 7 (blue), 8 (red), and 10 (black).

A. Tatar et al. / Tetrahedron Letters 53 (2012) 6015–6017
6017
byproducts generated when THF was used; however, the treatment
in CHCl3 yielded TB in a 34% yield with many byproducts. Unfortu-
nately, we were unable to resolve the structures of these byprod-
ucts; however, none of the byproducts exhibited 1H or 13C NMR
features that are characteristic of spiroTB derivatives.
In spite of making many attempts, we were unsuccessful in
preparing single-crystals that were suitable for X-ray diffraction.
Fortunately, the NMR characteristics are known for both metallo-
porphyrin TBs15 and spiroTB structural motifs.13 Thus, detailed
analyses of 1D and 2D NMR spectra were sufficient to confirm
the structures.
In addition, we have prepared a new type of metalloporphyrin
dimer, spiroTB, which can alter the unique properties of metallo-
porphyrin TBs.5–9 Particularly, the different behaviors of TB 7 and
spiroTB 8 on a chiral HPLC column suggest that the two molecules
will behave differently in chiral applications. Another use of spi-
roTB can arise from the presence of two metalloporphyrin cores
with different spectral properties that are rigidly anchored in a
molecule.
Acknowledgments
Both porphyrin TB 7 and spiroTB 8 have m/z values for the
molecular ion and isotope cluster that correspond to the summary
formula C91H59N10Ni2 (MH+); however, because TB 7 has C2 sym-
metry, only half of the signals are distinguished in its 1H and 13C
NMR spectra, in contrast to the asymmetry observed in spiroTB
8. Consequently, TB 7 has only one AB system for the porph-CH2-
This work was supported by the Grant Agency of the Czech
Republic (203/08/1445).
Supplementary data
Supplementary data (Detailed preparations, analyses of NMR
spectra, UV–vis spectra and chiral separations are provided as sup-
plementary material) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
097.
2
N groups (3.80 and 3.66 ppm, JHH = 17.4 Hz) and a singlet for N-
CH2-N group (4.66 ppm), where the corresponding carbon atoms
are at 54.6 and 67.3 ppm, ‘respectively’. Conversely, spiroTB 8
has NMR spectral features typical of a spiroTB structural motif:13
(a) three AB systems at 4.22 and 4.10 ppm (2JHH = 18.2 Hz), 3.65
and 2.92 ppm (2JHH = 12.1 Hz), and 3.07 and 2.92 ppm (2JHH
=
References and notes
17.7 Hz), whereas the corresponding carbon atoms are at 72.9,
50.9, and 33.8 ppm; and (b) characteristic signals of 13C at
49.5 ppm (spiro carbon) and 172.0 ppm (imine carbon).
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An investigation of the UV–vis spectra (Fig. 2) revealed that TB 7
has a Soret band at 414 nm (similar to that of the initial porphyr-
inatonickel 10 and aminoporphyrinatonickel 6) but with a small
shoulder at a higher wavelength. In contrast, spiroTB 8 has a Soret
band at a higher wavelength (429 nm) with a distinct shoulder at a
lower wavelength. The Soret band of dimer 8 with a shoulder can
be attributed to the presence of two types of porphyrin units, as
well as to the exciton coupling between them. The Q-band of TB
7 at 536 nm is accompanied by a shoulder at approximately
576 nm, which is similar to aminoporphyrinatonickel 6. These
two Q-bands are also found in spiroTB 8 at similar wavelengths.
SpiroTB 8 also has an extra Q-band at 622 nm, which could be
attributed to the metalloporphyrin unit containing the spiro sp3
carbon.
´
4. The recent reviews on Tröger’s bases (a) Dolensky, B.; Elguero, J.; Král, V.;
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As is characteristic for porphyrinatonickel derivatives,16 we did
not observe fluorescence of either 7 or 8.
To resolve the enantiomers of TB 7 and spiroTB 8 on an analyt-
ical scale, we used an HPLC column Reprosil Chiral NR with a
Whelk O1 type chiral phase, which is generally efficient in resolv-
ing TB derivatives.17 Surprisingly, we found no conditions that
could resolve TB 7. Conversely, spiroTB 8 was resolved under al-
most any conditions we applied, with the best conditions giving
11. Bis-Tröger’s bases were independently introduced by (a) Pardo, C.; Sesmilo, E.;
Gutiérrez-Puebla, E.; Monge, A.; Elguero, J.; Fruchier, A. J. Org. Chem. 2001, 66,
´
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selectivity, a, of 1.77 and a resolution, RS, of 2.35.
In summary, we have discovered a unique way to manipulate
the reaction of aminoporphyrinatonickel 6 with formaldehyde
and an acid to form selectively either metalloporphyrin TB 7
(56% yield) or spiroTB 8 (67% yield) or to form a mixture of both
with 90% yields. Such manipulation of this reaction is unique; how-
ever, as the experiment with a pyrrole derivative 9 suggests, the
reaction is not limited to metalloporphyrin substrates, though we
believe that coordination of the solvent to the metal center could
be an important factor. Additional research is needed to under-
stand better the mechanisms underlying the reaction.
´
12. Dolensky, B.; Havlík, M.; Král, V. Chem. Soc. Rev. 2012, 41, 3839.
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Collas, A.; Sergeyev, S. Tetrahedron 2008, 64, 6252; (b) Sergeyev, S.; Stas, S.;
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´
ˇ
ˇ