Complexation of metals with piperazine containing azamacrocyclic fluorophores

Article abstract of DOI:10.1021/jo049465o

Azamacrocyclic fluorophores containing piperazine units were synthesized using sequential rhodium-catalyzed regioselective hydroformylation-reductive amination. A piperazine unit is introduced into the macrocycles to act simultaneously as electron donor a

Full text of DOI:10.1021/jo049465o

Com p lexa tion of Meta ls w ith P ip er a zin e-Con ta in in g
Aza m a cr ocyclic F lu or op h or es
Goran Angelovski,† Burkhard Costisella,‡ Branko Kolaric´,*,§ Martin Engelhard,§ and
Peter Eilbracht*,†
FB Chemie-Organische Chemie I and FB Chemie-Gemeinsame Einrichtungen-NMR-Spektroskopie,
Universita¨t Dortmund, Otto-Hahn-Str. 6, D-44227 Dortmund, Germany and Max-Planck-Institut fu¨r
Molekulare Physiologie, Abteilung III - Physikalische Biochemie, Otto-Hahn-Str. 11,
D-44227 Dortmund, Germany
peter.eilbracht@udo.edu; branko.kolaric@mpi-dortmund.mpg.de
Received April 1, 2004
Azamacrocyclic fluorophores containing piperazine units were synthesized using sequential rhodium-
catalyzed regioselective hydroformylation-reductive amination. A piperazine unit is introduced
into the macrocycles to act simultaneously as electron donor and binding site. The macrocycles
chelate divalent cations, either Zn2+ or Co2+, which considerably enhanced fluorescence. Complex-
ation with Zn2+ was additionally confirmed by NMR.
In tr od u ction
The design and construction of molecular scale sensors
is a challenging aspect of modern nanotechnology.1
Molecular sensors are devices that are used for the
sensitive and rapid detection of various organic com-
pounds and metals. The detection of toxic metals is
crucial not only for environmental protection but also in
medicine or pharmacology.2 Fluorescence spectroscopy,
because of its sensitivity, is often used as a tool for
detection. It is governed by three principal parameters:
lifetime of excited states, intensity, and quantum yields.3
Fluorescence techniques are used in combination with
imaging techniques in various biological and material
research areas.3
F IGURE 1. Scheme of the fluorescent sensor in which the
same group acts as a receptor and electron donor.
and simultaneously as a recognition moiety (Figure 1).
Motivation for chosing piperazine as a building block of
the macrocycle was to investigate the effect on the
fluorescence sensitivity during the metal complexation
of piperazine, since detectable changes should occur with
the same group acting as electron donor of the fluoro-
phore and also as the host for the complexation-
recognition moiety of the potential sensor.
Typical fluorescent sensors contain signaling and
recognition parts.4 The recognition moiety within mol-
ecules is responsible for the selectivity and efficiency of
binding with guests.5 To date, various sensors based on
signaling and recognition units have been synthesized
and investigated.6 In this manuscript, a new approach
to the design of sensors is presented. Piperazine was
introduced into the macrocycle to act as an electron donor
The synthesis of various azamacrocycles containing
piperazine has been reported, and their complexation
characteristics have been investigated.7 In this paper we
report a new and convenient method for incorporating
piperazine into a macrocycle, as well as fluorescence
investigations that, to our knowledge, have not previosly
been carried out with this type of compounds. The
* To whom correspondence should be addressed. For P.E.: Tel +49-
(0)231-755-3858. Fax +49(0)231-755-5363. For B.K.: Tel +49(0)231-
133-2311. Fax +49(0)231-133-2399.
† FB Chemie-Organische Chemie I.
‡ FB Chemie-Gemeinsame Einrichtungen.
§ Max-Planck-Institut fu¨r Molekulare Physiologie.
(1) (a) Niemeyer, C. M. Angew. Chem., Int. Ed. 2001, 40, 4128-
4158. (b) Nishimura, G.; Kinjo, M. J . Phys. Chem. B 2003, 107, 6012-
6017.
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J . J . Am. Chem. Soc. 2000, 122, 968-969. (c) Pearson, A. J .; Xiao, W.
J . Org. Chem. 2003, 68, 5361-5368. (d) Kimura, E.; Koike, T. Chem.
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10.1021/jo049465o CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/08/2004
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J . Org. Chem. 2004, 69, 5290-5294

Piperazine-Containing Azamacrocyclic Fluorophores
SCHEME 1. Syn th esis of Aza m a cr ocycle 4a
SCHEME 2. Syn th esis of Aza m a cr ocycle 9a
a
(a) 20 bar CO/H2 (1:1), [Rh(acac)(CO)2], XANTPHOS, 70 °C,
toluene; (b) Ti(O-iPr)4, NaBH3CN, EtOH; (c) TFA, CH2Cl2; (d) 40
bar H2, [Rh(acac)(CO)2], toluene.
a
(a) Ti(O-iPr)4, NaBH3CN, EtOH; (b) TFA, CH2Cl2; (c) 40 bar
H2, [Rh(acac)(CO)2], toluene.
piperazine unit proved to be a very good host for many
heavy metals. We chose to investigate two of them, cobalt
and zinc, since both form dications, with the former
strongly complexing many similar multidentate ligands,
while the latter is an important cation present in biologi-
cal systems.6d,8
Resu lts a n d Discu ssion
Syn t h esis. The macrocycles were synthesized by
improving our general method for the synthesis of such
compounds.9 Starting from aromatic diolefins, dialde-
hydes were synthesized via regioselective hydroformy-
lation. The piperazine unit was incorporated within the
macrocycles by a convergent strategy with dialdehydes,
employing a convenient reductive amination/deprotec-
tion/reductive amination sequence. Ring closure in the
rhodium-catalyzed last reductive amination step occurred
in relatively high yields (31-36%) for these types of
macrocycles.
The first step was the reductive amination of dialde-
hyde 19 with monoprotected Boc-piperazine10 using
Ti(O-iPr)4 and NaBH3CN. The reduction was performed
with 81% isolated yield of 2, which underwent TFA
cleavage of the Boc protecting groups to give 3 in 95%
yield. Finally, rhodium-catalyzed reductive amination of
1 with 3 gave macrocycle 4 in 36% yield. (Scheme 1).
Additionally, using the same methodology, azamacro-
cycle 9 was synthesized from diolefin 5.11,12 First, the
F IGURE 2. UV absorption spectra of 4 and 9 in CH3CN, c )
0.1 mM.
synthesis of dialdehyde 6 via regioselective Rh-catalyzed
n-hydroformylation using XANTPHOS ligand was ac-
complished in 71% yield. Compounds 7 and 8 were then
prepared analogously to 2 and 3 in 72% and 89% yields,
respectively. Finally, azamacrocycle 9 was synthesized
again by rhodium-catalyzed reductive amination from
aldehyde 6 and amine 8 in 31% yield (Scheme 2).
F lu or escen ce Exp er im en ts. To determine the best
emission wavelengths for 4 and 9, UV absorbance experi-
ments were performed (Figure 2). UV spectra show the
absorbance between 260 and 320 nm, which relates to
electronic transitions of the aromatic ring.13 A small peak
at higher wavelengths (around 370 nm) was not observed
for macrocycles that do not contain piperazine units, so
it can be assumed that this absorbance is caused by a
charge-transfer transition within the azamacrocycles.14
Different charge-transfer mechanisms via space or con-
jugate units or by intraanular interactions have been
addressed previously.15 In the present example the pos-
sible mechanism of this charge transfer is still under
investigation.
(7) (a) Krakowiak, K. E.; Bradshaw, J . S.; J iang, W.; Dalley, N. K.;
Wu, G.; Izatt, R. M. J . Org. Chem. 1991, 56, 2675-2680. (b) Fuji, K.;
Takasu, K.; Miyamoto, H.; Tanaka, K.; Taga, T. Tetrahedron Lett. 1996,
37, 7111-7114. (c) Seki, Y.; Miyake, H.; Kojima, Y. Chem. Lett. 1996,
153-154. (d) Hancock, R. D.; Dobson, S. M.; Evers, A.; Wade, P. W.;
Ngwenya, M. P.; Boeyens, J . C. A.; Wainwright, K. P. J . Am. Chem.
Soc. 1988, 110, 2788-2794. (e) Izatt, R. M.; Pawlak, K.; Bradshaw, J .
S.; Bruening R. L. Chem. Rev. 1991, 91, 1721-2085.
(8) (a) Creaser, I. I.; Geue, R. J .; Harrowfield, L. MacB.; Herlt, A.
J .; Sargeson, A. M.; Snow, M. R.; Springborg, J . J . Am. Chem. Soc.
1982, 104, 6016-6026. (b) Geue, R. J .; McCarthy, M. G.; Sargeson, A.
M. J . Am. Chem. Soc. 1984, 106, 8282-8291.
(9) Angelovski, G.; Eilbracht, P. Tetrahedron 2003, 59, 8265-8274.
(10) Boschi, D.; Di Stilo, A.; Fruttero, R.; Medana, C.; Sorba, G.;
Gasco, A. Arch. Pharm. (Weinheim) 1994, 327, 661-667.
(11) Brouwer. A. J .; Mulders, S. J . E.; Liskamp, R. M. J . Eur. J .
Org. Chem. 2001, 1903-1915.
(12) van Nunen, J . L. M.; Folmer, B. F. B.; Nolte, R. J . M. J . Am.
Chem. Soc. 1997, 119, 283-291.
(13) Hesse, M.; Meier, H.; Zeeh, B. Spectroscopic Methods in Organic
Chemistry; Georg Thieme Verlag: Stuttgart, New York, 1997; pp 1-17.
(14) Stimulating Concepts of Chemistry; Vo¨gtle, F., Stoddart, J . F.,
Shibasaki, M., Eds.; Wiley-VCH: Weinheim, 2000; pp 267-293.
J . Org. Chem, Vol. 69, No. 16, 2004 5291

Angelovski et al.
TABLE 1. F lu or escen ce En h a n cem en t Du e to
Com p lexa tion of 4 a n d 9 w ith Meta lsa
λex ) 280 nm
4
9
Co2+
Zn2+
100×
1.6×
2×
70×
a
c ) 20 µM, [macrocycle]/[cation] 1:1, CH3CN.
enhancement is 70 times (7,000%) and 2 times (100%)
higher for the macrocycles 4 and 9 respectively.
The fluorescence intensities at 280 nm and their
changes due to complexation with metals are sum-
marized in the Table 1.
From the presented data, it is possible to conclude that
both macrocycles 4 and 9 interact with the metals, and
these interactions are easily monitored by observing the
changes in fluorescence intensity. Taking into account
the concentrations used in the fluorescence experiments,
one estimates that the dissociation constants for com-
plexation of metals with macrocycles should be in the low
micromolar range.
F IGURE 3. Fluorescence spectra of 4, before and upon
addition of equimolar amounts of Co2+ and Zn2+ in CH3CN, c
) 20 µM, λex ) 280 nm.
It is also possible to conclude that macrocycle 4 is a
much better sensor for metals than 9 because of the
observed high changes in the intensity for 4. This might
be due to differences in the distance of the donor and
acceptor groups and/or due to different conformational
flexibilities of the macrocycles.
NMR Stu d ies. To confirm the complexation between
the macrocyclic ligand and the metal, NMR spectra of 9
were recorded with and without Zn2+ ions in solution.
The strongest changes in the NMR signals of macrocycles
were expected in the area of piperazine subunit, where
complexation with the metals should actually take place.
As the signals of all 16 protons within the piperazines
are not resolvable, 1H NMR could not be used for proving
complexation. Therefore, 13C NMR investigations were
performed. Several NMR techniques such as 1D-NOE,
g-COSY, and g-HSQC were used to assign the signals to
the macrocycle 9. The results indicate that the signal at
53.8 ppm belongs to the piperazine methylenes (position
a) and the signal at 58.4 ppm belongs to the methylenes
adjacent to the piperazine ring system (position b) (Figure
5, bottom).
F IGURE 4. Fluorescence spectra of 9, before and after the
addition of equimolar amounts of Co2+ and Zn2+ in CH3CN, c
) 20 µM, λex ) 280 nm.
For the fluorescence experiments, the macrocycles were
excited at 280 nm, and the corresponding emissions were
recorded. Using the same conditions, fluorescence of
macrocycles 4 and 9 was also recorded in the presence
of equimolar amounts of CoCl2 and ZnCl2. Figures 3 and
4 show the fluorescence spectra of 4 and 9 without the
cations and with equimolar amounts of Co2+ and Zn2+ at
the chosen excitation wavelength. The addition of metals
does not change the position of the maximum in the
emission spectrum, which is expected when taking into
account that only weak physical interactions take place
between the corresponding macrocycles 4 and 9 and
metal ions.6c However, strong changes of the fluorescence
intensity were observed, as in the case of previously
described chemosensors.6b,c
For the complexation studies, 13C NMR experiments
were performed on 9 alone and upon addition of 1 and 2
equiv of ZnCl2 (Figure 5, top). The shift differences are
summarized in Table 2.
The strongest shifting and broadening of signals occurs
for carbons inside the piperazine ring (position a, down-
field shift more than 2.0 ppm). Contrary to what was
expected, shifting does not decrease from position a to
d, since the resonance of position c (â to the nitrogen,
downfield shift around 1.2 ppm) shifts more than that of
position b (adjacent to the piperazine ring system,
downfield shift around 0.8 ppm). Finally, carbons at
position d (γ to the nitrogen) have a downfield shift of
around 0.6 ppm, while the ether methylenes (δ to the
nitrogen) have the smallest shift (downfield shift of 0.3
ppm). For all other carbon atoms no shift of signals was
observed.
The fluorescence was enhanced approximately 100
times (10,000%) for macrocycle 4 and 1.6 times (60%) for
the macrocycle 9 as a result of the complexation of
macrocycles with Co2+ at an excitation wavelength of 280
nm. At the same wavelength upon addition of Zn2+, the
(15) (a) Dietrich, B.; Viout, P.; Lehn, J .-M. Macrocyclic Chemistry;
VCH Verlagsgesellschaft mbH: Weinheim, 1993. (b) Balzani, V.;
Scandola, F. Supramolecular Photochemistry; Ellis Horwood Limited:
Chichester, 1991. (c) Kavarnos, G. J . Fundamentals of Photoinduced
Electron Transfer; VCH Publishers: New York, 1993; pp 185-234.
From these data, it can be concluded that the center
of the complexation of Zn2+ with 9 is in the area of
5292 J . Org. Chem., Vol. 69, No. 16, 2004

Piperazine-Containing Azamacrocyclic Fluorophores
Exp er im en ta l Section
4-(4-{4-[4-(4-ter t-Bu tylca r boxy-p ip er a zin -1-yl)-bu toxy]-
p h en oxy}-bu tyl)-p ip er a zin e-1-ca r boxylic Acid ter t-Bu tyl
Ester (2). A mixture of 1 (1.26 g, 5.03 mmol), mono-Boc-
piperazine (1.90 g, 10.20 mmol), and Ti(O-iPr)4 (3.59 g, 12.63
mmol) was stirred at room temperature. After 1 h, the viscous
solution was diluted with 10 mL of absolute EtOH. NaBH3CN
(423 mg, 6.73 mmol) was added, and the solution was stirred
for 20 h. Water (10 mL) was added with stirring, and the
resulting inorganic precipitate was filtered and washed with
EtOH. The solvent was removed with a rotary evaporator, and
the residue was purified by column chromatography (silica gel,
CH2Cl2/MeOH 95:5) to give 2.40 g (81%) of 2 as a colorless,
viscous oil. 1H NMR (400 MHz, CDCl3): δ 6.73 (s, 4H), 3.85
(t, J ) 6.3 Hz, 4H), 3.38 (t, J ) 4.8 Hz, 8H), 2.38-2.35 (m,
12H), 1.75-1.68 (m, 4H), 1.65-1.59 (m, 4H), 1.39 (s, 18H). 13
NMR (100 MHz, CDCl3): δ 154.6, 153.0, 115.3, 79.6, 68.1, 58.1,
C
52.9, 28.3, 27.2, 23.1. HRMS-FAB for
C32H54N4O6: calc
591.4122 [M + H]+, found 591.4125.
1-{4-[4-(4-P iper azin e-1-yl-bu toxy)-ph en oxy]-bu tyl}-pip-
er a zin e (3). TFA (5 mL) was added to a solution of 2 (1.95 g,
3.30 mmol) in CH2Cl2 (15 mL). The mixture was stirred at
room temperature for 30 min. After 30 min, the solvent was
removed with a rotary evaporator, and 30 mL of 1 N NaOH
was added to the residue. The aqueous layer was extracted
with CH2Cl2 (3 × 50 mL), and the organic phase was washed
with brine and dried over MgSO4. The solvent was removed
1
in vacuo to give 1.23 g (95%) of 3 as a colorless viscous oil. H
F IGURE 5. 13C NMR spectra before (bottom) and after (top)
addition of 2 equiv of Zn2+ to 9 and assignment of resonances
in compound 9. Solvent: CD3CN/CDCl3 (9:1).
NMR (400 MHz, CDCl3): δ 6.73 (s, 4H), 3.84 (t, J ) 6.3 Hz,
4H), 2.82 (t, J ) 4.8 Hz, 8H), 2.37-2.28 (m, 12H), 1.92-1.82
(m, 2H), 1.73-1.66 (m, 4H), 1.61-1.54 (m, 4H). 13C NMR (100
MHz, CDCl3): δ 152.8, 115.1, 68.0, 58.6, 54.1, 45.7, 27.1, 22.9.
HRMS-FAB for C22H38N4O2: calc 391.3073 [M + H]+, found
391.3085.
TABLE 2. Sh ifts, Sh ift Differ en ces (∆δ), a n d Sign a l
Br oa d en in g in 13C NMR of 9a
Ma cr ocycle 4. Compounds 1 (48 mg, 0.19 mmol) and 3 (75
mg, 0.19 mmol) and [Rh(acac)(CO)2] (4 mg, 16 µmol) were
mixed in 40 mL of toluene and stirred for 1 h. The solution
was placed in an autoclave, pressurized with 40 bar H2, and
heated at 50 °C for 18 h. The solvent was removed with a
rotary evaporator, and the crude product was purified by
column chromatography (silica gel, CH2Cl2/MeOH 95:5) to give
42 mg (36%) of 4 as a yellow viscous oil that solidifies upon
position and shift (ppm)
a
b
c
d
e
9
53.8
51.8 b
2.0
51.5 vb
2.3
58.4
57.6
0.8
23.5
22.4 b
0.9
27.5
26.9
0.6
68.9
68.6
0.3
68.6
0.3
9 + Zn2+
∆δ1
9 + 2Zn2+
∆δ2
57.8
0.6
22.3 b
1.2
26.7
0.8
1
standing. H NMR (400 MHz, CDCl3): δ 6.74 (s, 8H), 3.92 (t,
b ) broad, vb ) very broad; ∆δ1 ) (9 + 1 equiv of Zn2+) - 9;
∆δ2 ) (9 + 2 equiv of Zn2+) - 9.
a
J ) 6.0 Hz, 8H), 2.50-2.35 (m, 16H), 2.34 (t, J ) 7.3 Hz, 8H),
1.73-1.67 (m, 8H), 1.62-1.57 (m, 8H). 13C NMR (100 MHz,
CDCl3): δ 153.0, 115.6, 68.1, 57.8, 52.8, 27.1, 22.6. HRMS-
FAB for C36H56N4O4: calc 609.4380 [M + H]+, found 609.4402.
piperazine units. Upon complexation, part of the molecule
probably assumes a boat conformation where carbons in
position b and d are almost at the same distance from
Zn2+ while carbons between them are slightly closer.
Furthermore, upon addition of the second equivalent
of Zn2+ only slight additional downfield shifts are ob-
served, with an additional broadening of signals, which
indicates the formation of a 1:1 complex between the
macrocycle and Zn2+, with the cation inside the macro-
cyclic cavity.
3,5-Bis(4-oxo-bu toxy)-ben zoic Acid Meth yl Ester (6).
Compound 5 (226 mg, 0.91 mmol), [Rh(acac)(CO)2] (3 mg, 12
µmol), XANTPHOS (30 mg, 52 µmol), and toluene (15 mL)
were dissolved in the autoclave. The solution was pressurized
with 20 bar CO/H2 (1:1) and heated at 70 °C for 18 h. The
solvent was removed with a rotary evaporator, and the crude
mixture was purified by column chromatography (silica gel,
CH2Cl2) to give 200 mg (71%) of 6 as a colorless, viscous oil.
1H NMR (400 MHz, CDCl3): δ 9.76 (s, 2H), 7.07 (d, J ) 2.3
Hz, 2H), 6.52 (t, J ) 2.3 Hz, 1H), 3.94 (t, J ) 6.0 Hz, 4H), 3.62
(s, 3H), 2.59 (dt, J ) 5.8, 1.2 Hz, 4H), 2.08-2.01 (m, 4H). 13C
NMR (100 MHz, CDCl3): δ 201.6, 166.6, 159.6, 131.9, 107.7,
106.8, 66.9, 52.2, 40.4, 21.8. EA for C16H20O6 (308.33 g/mol):
calc C, 62.3; H, 6.5. Found: C, 62.4; H, 6.3. HRMS-FAB: calc
309.1338 [M + H]+, found 309.1346.
3,5-Bis[4-(4-ter t-bu tylca r boxy-p ip er a zin -1-yl)-bu toxy]-
ben zoic Acid Meth yl Ester (7). Following the procedure for
the synthesis of 2, starting from 6 and Boc-piperazine,
compound 7 was prepared in 72% yield as a colorless, viscous
oil.
3,5-Bis(4-p ip er a zin -1-yl-bu toxy)-ben zoic Acid Meth yl
Ester (8). Following the procedure for the synthesis of 3,
starting from 7, compound 8 was prepared in 89% yield as a
colorless, viscous oil.
Con clu sion
Azamacrocycles containing piperazine units are de-
signed as potential chemosensors for metal cations.
Complexation of cations was detected by fluorescence
spectroscopy and confirmed by NMR. Different sensitivi-
ties of macrocycles for different metals offer a variety of
applications of macrocycles in biological research. The
observed intramolecular charge transfer within noncon-
jugated macrocycles is an additional interesting property
of these compounds and is currently under further
investigation.
J . Org. Chem, Vol. 69, No. 16, 2004 5293

Angelovski et al.
Ma cr ocycle 9. Following the procedure for the synthesis
of 4, starting from 6 and 8, azamacrocycle 9 was prepared in
31% yield as a yellow, viscous oil that solidifies upon standing.
NMR Exp er im en ts for Com p lexa tion In vestiga tion s.
All experiments were run on a 600 MHz spectrometer. 2D
experiments (g-COSY and g-HSQC) and 1D-NOE were per-
formed at 40 °C in CDCl3, and 13C NMR experiments were
performed in CD3CN/CDCl3 (9:1) solution at 27 °C. Experi-
ments were performed on compound 9 before and after
addition on 1 and 2 equiv of ZnCl2. The chemical shift changes
on all carbons were monitored.
G.A.) and DFG (B.K.) for financial support. We also
thank Degussa AG Du¨sseldorf for donations of chemi-
cals and MPG for technical support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR
and HRMS-FAB data of 7, 8 and 9; UV spectra of 4 and 9
1
after addition of Co2+ and Zn2+; H and 13C NMR (APT) of 4
and 9; 1D-NOE, g-COSY, g-HQSC of 9 and 13C NMR complex-
ation experiments of 9 with Zn2+. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. Authors would like to acknowl-
edge Deutscher Akademischer Austauschdienst (DAAD,
J O049465O
5294 J . Org. Chem., Vol. 69, No. 16, 2004