Remarkable stability of imino macrocycles in water

Article abstract of DOI:10.1002/ejoc.200800462

Imines 3, 5 and 7 generated from 4-methoxypyridine-2,6-dicarbaldehyde (1) and several amines 2, 4 and 6 show a remarkable stability in water. The 18-membered macrocyclic diimine 5 is stable and could be synthesized in good yield by using 2 equiv. of calcium ions as template in pure water, and even the non-macrocyclic diimine 3 survives in water/methanol (50:50) without any template effect. In a mixture of pyridinedicarbaldehyde 1 and two glycol-derived diamines 4 and 6, a calcium template ion selects the 18-membered macrocycle 5 over the 20-membered one (7). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800462

FULL PAPER
DOI: 10.1002/ejoc.200800462
Remarkable Stability of Imino Macrocycles in Water[‡]
Vittorio Saggiomo[a] and Ulrich Lüning*[a]
Keywords: Combinatorial chemistry / Imines / Macrocycles / Pyridine / Templates
Imines 3, 5 and 7 generated from 4-methoxypyridine-2,6-di-
carbaldehyde (1) and several amines 2, 4 and 6 show a re-
markable stability in water. The 18-membered macrocyclic
diimine 5 is stable and could be synthesized in good yield by
using 2 equiv. of calcium ions as template in pure water, and
even the non-macrocyclic diimine 3 survives in water/meth-
anol (50:50) without any template effect. In a mixture of pyr-
idinedicarbaldehyde 1 and two glycol-derived diamines 4
and 6, a calcium template ion selects the 18-membered
macrocycle 5 over the 20-membered one (7).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
leads to an increased stability of the imines even in water.[15]
But in general, imines are rather unstable and are hy-
drolyzed quickly if water is present.[16–18] However, converse
results have also been reported.[19] In the DCC synthesis of
macrocyclic imines, too, the sensitivity against water has to
be investigated for several reasons: (i) every formation of an
imine from an aldehyde and an amine forms a water mole-
cule, (ii) the template salts often contain water,[14,20] (iii) the
reactions are usually not carried out under strict exclusion
of moisture and (iv) the hydrolysis plays an important rule
in the reversibility of the imine bond formation.[21]
Introduction
Macrocyclic structures have gained enormous attention
over the past decades.[1] However, macrocycles are not as
easily prepared as five- or six-membered rings,[2] and thus
special approaches have been developed for better synthe-
ses. For kinetically controlled macrocyclizations, the use of
the high-dilution technique[3] often increases yields con-
siderably, whereas in thermodynamically controlled reac-
tions, the template effect has proven to be the proper tool
to shift the equilibrium to the desired product.[4–6] Many
applications of macrocycles including the metal-ion-com-
plexing abilities of crown ethers make use of endo function-
alities. Therefore, it is self-evident that these functionalities
can be exploited in the macrocyclic assembly process.[7] Un-
like in a kinetically controlled reaction, the products of a
thermodynamically controlled reaction are interconverted
into one another constantly. The composition of the prod-
uct mixture is depending on the relative thermodynamic
stability of the products. The mixture is dynamic. If poly-
functional molecules or several starting materials are used,
numerous different combinations are conceivable, and usu-
ally mixtures are formed. For these situations, the term
dynamic combinatorial chemistry (DCC) has been
coined.[8–11] Since decades,[4] the imine formation has been
used to synthesize macrocycles, and templates have been
found to shift the equilibria of the dynamic combinatorial
libraries towards one product in good yield. Dynamic com-
binatorial libraries have been investigated by starting from
a dialdehyde and one[12,13] or several[14] diamines. The coor-
dinative bond between a transition-metal ion and an imine
Results and Discussion
Due to the instability of imines under the conditions of
many standard purification techniques, the analysis of an
imine library is rarely[22] performed on the imine mixture
itself but usually done by investigating the amine mixture
obtained by reduction of the imines.[14] Besides HPLC-
MS,[22] one other direct method to monitor the equilibrium
is the observation of the imines by NMR spectroscopy. In
this work, dynamic combinatorial libraries (DCL) derived
from pyridine-2,6-dicarbaldehyde 1 and various diamines
1
such as 2, 4 or 6 have been investigated by H NMR spec-
troscopy. One prerequisite for the analysis is the use of a 4-
substituted pyridine-2,6-dicarbaldehyde such as 4-methoxy-
pyridine-2,6-dicarbaldehyde (1) because the pyridine hydro-
gen atoms of 2,4,6-trisubstituted pyridines show a sharp
singlet in the NMR spectra. If the dynamic combinatorial
library gives a manageable number of products, their rela-
tive ratio can be determined by integration of these pyridine
3,5-H peaks. Quantitative measurements are possible if an
internal standard (for instance dimethyl terephthalate,
DMT) is added. Many components of a library can also be
detected by ESI mass spectrometry, although no quantita-
tive analysis is possible by this analytic technique. In the
[‡] Dynamic Combinatorial Chemistry, 2. Part 1: Ref.[14]
[a] Otto-Diels-Institut für Organische Chemie,
Christian-Albrechts-Universität zu Kiel,
Olshausenstr. 40, 24098 Kiel, Germany
Fax: +49-431-880-1558
E-mail: luening@oc.uni-kiel.de
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V. Saggiomo, U. Lüning
FULL PAPER
present study, three different amines [n-butylamine (2), a be detected. With 50% of water, still 90% of macrocycle 5
triethylene glycol derived diamine 4 and a bis(homo) ana- exists. This surprising stability led us to an experiment in
logue 6] have been used. From the resulting imines 3, 5 and pure water by using various amounts of templating calcium
7, only the largest macrocycle 7 was well detected by ESI ions. In pure water, the quantitative analysis of the NMR
[M + H+], whereas the smaller macrocycle 5 appeared as signals against the standard DMT cannot be carried out
an [M + Ca2+]/2 signal, and the butyl compounds could anymore due to DMT’s insolubility, but, to calculate the
not be detected at all (Figure 1).
yield, the intensities of the imine peak and the aldehyde
peak can be compared according to literature.[16] With 1 or
less equiv. of calcium ions, the reaction mixture was not a
solution, but a suspension, due to the fact that aldehyde 1
does not have sufficient solubility in water.
1
Figure 2. H NMR spectrum (500 MHz, 298 K) of imine 3 in: (a)
CD3OD, (b) CD3OD/D2O, 98:2, (c) CD3OD/D2O, 90:10, (d)
CD3OD/D2O, 50:50. All ratios are expressed in v/v. Capital letters
indicate prominent resonances: I = imine, S = DMT, P = pyridine,
A = free amine chain.
Figure 1. (a) CD3OD/D2O in various ratios, 12 h, room temp.; (b)
CD3OD/D2O in various ratios with 1 equiv. of CaCl2, 12 h, room
temp., and pure D2O with various equiv. of CaCl2, 12 h, room
temp.; (c) CD3OD/D2O in various ratios with 1 equiv. of CaCl2
12 h, room temp.
However, with 2 equiv. of calcium ions, the solution be-
came clear, and only one product 5, as the calcium complex,
was detected (Figure 3). Thus, even in water, a calcium ion
stabilizes the macrocyclic diimine 5 to such an extent that
it becomes the only product! In contrast to the stabilization
However, all three compounds gave nice and clear signals of a macrocycle by transition-metal ions, which bind donor
in the NMR spectra, well distinguishable from each other atoms by coordinative bonds, here, the interactions between
or from oligomer signals. The individual imine synthesis, the calcium ion and the donor atoms of the macrocycle are
as well the imine-based libraries, usually is carried out in predominantly dipol–ion interactions. But these interac-
methanol,[6,20,14] and consequently the reaction of 4-meth- tions are strong enough to withstand the competing sol-
oxypyridine-2,6-dicarbaldehyde (1) with n-butylamine (2) vation by 55  water, and macrocycle 5 is found exclusively.
gave the respective diimine 3 in good yield. Increasing per-
The reaction with the longest diamine 6, which contains
centages of water reduced the yield of 3 as could be deduced two aminopropylene groups instead of aminoethylene ones,
from the integrations of the respective signals in the NMR gave less clear results. Also in methanol, the macrocyclic
spectrum (Figure 2, for instance NH2CH2 of the free butyl diimine 7 was formed in good yield (Figure 4a) and could
chains at δ = 2.7 ppm, and CH of the aldehyde in its hydrate be analyzed by ESI mass spectrometry or NMR spec-
or hemiacetal form at δ ≈ 5.5 ppm). If more than 50% of troscopy. However, in contrast to the macrocycle formation
water was added, the solvent became too polar to dissolve of 5, the addition of water disturbs the formation of the
the starting materials completely. However, the diimine 3 macrocyclic diimine
7 (Figure 4). The NMR signals
proved to be rather stable, and 68% of it was still detected broaden, and increasing amounts of free diamine 6 appear.
when the solvent contained 50% of water. Next, the forma- But also in this case, the addition of templating calcium
tion of macrocyclic diimine 5 was investigated in the pres- ions favors the formation of the macrocycle, and for in-
ence of 1 equiv. of calcium ions. In methanol with various stance with 10 equiv. of CaCl2 in CD3OD/D2O (50:50), only
percentages of water, no change in the composition could the signals of the macrocycle 7 were observed again.
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Eur. J. Org. Chem. 2008, 4329–4333

Remarkable Stability of Imino Macrocycles in Water
Figure 3. 1H NMR spectrum (500 MHz, D2O, 298 K). Synthesis of
imine 5 in pure D2O with: (a) no CaCl2, (b) 1 equiv. of CaCl2, (c)
2 equiv. of CaCl2. Capital letters indicate prominent resonances: I
= imine, P = pyridine.
Figure 5. Exchange experiment. (a) 1 equiv. of dialdehyde 1,
1 equiv. of diamine 6, and 1 equiv. of CaCl2 in CD3OD give the
macrocyclic diimine 7; (b) addition of 5% of D2O interfers with
the exclusive formation of 7; (c) after addition of diamine 4 and
equilibration for 12 h, the most stable diimine complex 5 is exclu-
sively formed on the cost of the larger macrocycle 7 with liberation
of diamine 6. Capital letters indicate prominent resonances: I =
imine, S = DMT, P = pyridine, A = free amine chain.
Conclusions
Even in water, the macrocyclic diimine 5 can be formed
in excellent yields, provided that enough calcium ions are
present. These have two functions: they stabilize this prod-
uct by their template effect and they solubilize the complex
by the introduction of charge. But not only the templating
of the macrocycle contributes to the remarkable stability of
diimine 5 in water. Even the non-macrocyclic diimine 3 is
still formed in good yield in a solvent mixture containing
50% of water and 50% of methanol. This stability is proba-
bly caused by the pyridine unit and its conjugation with the
imine groups.[23]
1
Figure 4. H NMR (500 MHz, 298 K) of imine 7 in: (a) CD3OD,
(b) CD3OD/D2O, 98:2, (c) CD3OD/D2O, 90:10, (d) CD3OD/D2O,
50:50, (e) CD3OD/D2O, 50:50, and 10 equiv. of CaCl2. All ratios
are expressed in v/v. Capital letters indicate prominent resonances:
I = imine, S = DMT, P = pyridine.
Experimental Section
General Remarks: n-Butylamine (2), 4,7,10-trioxa-1,13-tridecanedi-
amine (6), and sodium cyanoborohydride were obtained commer-
cially from Fluka and used without further purification. 4-Meth-
oxypyridine-2,6-dicarbaldehyde (1)[20] and 3,6,9-trioxa-1,11-unde-
canediamine (4)[20] were synthesized according to literature pro-
cedures. NMR spectra were recorded with Bruker DRX 500 or AV
600 instruments. Assignments are supported by COSY, HSQC and
HMBC. All chemical shifts were referenced to the residual proton
(1H) or carbon (13C) signal of the solvent [CD3OD, δ = 3.35 (1H),
49.0 (13C) ppm]. Mass spectra were recorded with a Finnigan MAT
8200 or MAT 8230. ESI mass spectra were recorded with an Ap-
plied Biosystems Mariner Spectrometry Workstation.
Finally, we investigated a dynamic combinatorial library
derived from the dialdehyde 1 and both diamines 4 and 6.
In the first experiment, a mixture of CaCl2, dialdehyde 1
and the propylenediamine 6 was prepared, and the respec-
tive imines were allowed to form. Then, 5% of water and
1 equiv. of ethylenediamine 4 were added one after the
other, and each mixture was analyzed by NMR spec-
troscopy (Figure 5). First, the typical broadening of the sig-
nals of the propylenemacrocycle 7 appeared (see Figures 4
and 5b), and after addition of 4, the most stable macro-
cyclic diimine 5 was formed exclusively (shift of imine peak
from δ = 8.60 to 8.64 ppm), and free propylenediamine 6
was detected (see for instance CH2CH2CH2 of the free
amine chain: δ = 1.75 ppm), proving the formation of the
more stable 18-membered macrocycle in this dynamic com-
binatorial library.
General Procedure for the Preparation of Stock Solutions: To solu-
tions of 4-methoxypyridine-2,6-dicarbaldehyde (1, 9.6 mg,
0.058 mmol), dimethyl terephthalate (DMT, 5.6 mg, 0.029 mmol)
and CaCl2 (6.4 mg, 0.058 mmol) in CD3OD (5 mL), various di-
amines 2, 4 or 6 (1.05 to 1.5 equiv.) were added. The solutions were
stirred at room temp. for 12 h and were then transferred into NMR
tubes with various percentages of D2O. These solutions were al-
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V. Saggiomo, U. Lüning
FULL PAPER
lowed to stand for at least 4 h in order to equilibrate. In another
set of experiments, water was added before the amines to start the
reaction in aqueous media. The final volume for all NMR experi-
ments was 600 µL, the tube’s atmosphere was replaced with nitro-
gen, and the tubes were capped with Teflon caps.
DMT [δ = 8.15 (s, 4 H), 3.97 (s, 6 H) ppm] and imine protons: pure
CD3OD: 88%. 1H NMR (600 MHz, 298 K, CD3OD) of 7 in the
mixture: δ = 8.60 (t, J = 1.2 Hz, 2 H, CH=N), 7.58 (s, 2 H, Py),
4.11 (s,
3 H, OMe), 4.01–3.92 [overlapping signals, 16 H,
CH2(CH2OCH2)3CH2, CH=NCH2], 2.19 (quint, J = 6.6 Hz, 4 H,
CH2CH2CH2) ppm. 13C NMR (150 MHz, 298 K, CD3OD): δ =
171.58 [C-2,6 (Py)], 165.41 (CH=N), 154.59 [C-4 (Py)], 115.49
[C-3,6 (Py)], 71.54, 71.21, 70.92, 70.45, 69.64, 68.94, 58.14
2,6-Bis(n-butyliminomethyl)4-methoxypyridine (3): A stock solution
was prepared as follows: 4-methoxypyridine-2,6-dicarbaldehyde (1,
5 mg, 0.03 mmol) and DMT (2.15 mg, 0.011 mmol) were dissolved
in CD3OD (2.5 mL). n-Butylamine (2, 6.2 µL, 0.063 mmol) was
added, and the solution was stirred at room temp. for 12 h. Then,
various percentages of water (2%, 10%, 50% v/v) were added, and
1H NMR spectra were recorded after 4 h. Yields calcd. from the
ratio between signals of aromatic protons of DMT [δ = 8.15 (s, 4
H), 3.97 (s, 6 H) ppm] and imine protons: pure CD3OD: 91%, 2%
D2O: 88%, 10% D2O: 71%, 50% D2O: 68%. 1H NMR (600 MHz,
298 K, CD3OD) of 3 in the mixture: δ = 8.40 (t, J = 1.2 Hz, 2 H,
CH=N), 7.62 (s, 2 H, Py), 4.00 (s, 3 H, OMe), 3.77 (m, 4 H,
CH=NCH2), 1.76 (quint, J = 6 Hz, 4 H, N=CH2CH2CH2CH3),
1.45 (m, 4 H, N=CH2CH2CH2CH3), 0.98 (t, J = 7.8 Hz, 6 H, CH3)
ppm. 13C NMR (150 MHz, 298 K, CD3OD): δ = 168.79 [C-2,6
(Py)], 163.09 (CH=N), 157.04 [C-4 (Py)], 109.43 [C-3,5 (Py)], 61.88
(N=CH2), 56.38 (OMe), 33.77 (CH2CH2CH2), 21.38 (CH2CH3),
14.12 (CH2CH3) ppm. HRMS: calcd. for C16H25N3O 275.19977,
found 275.19992; calcd. for C1513CH25N3O 276.20313, found
176.20323.
[CH2(CH2OCH2)3CH2,
N=CH2],
57.39
(OMe),
29.04
(CH2CH2CH2) ppm. ESI-MS (positive ions) of the solution with
10% of water: calcd. for C18H27N3O4 349.42, found 350.29 [M +
H+]. HRMS: calcd. for C18H27N3O4 349.20016, found 349.20015;
calcd. for C1713CH27N3O4 350.20352, found 350.20405.
Exchange Reaction between the Macrocyclic Diimines 7 and 5: A
stock solution was prepared as follows: 4-methoxypyridine-2,6-di-
carbaldehyde (1, 8.7 mg, 0.052 mmol), DMT (6.6 mg, 0.034 mmol),
and CaCl2 (5.7 mg, 0.052 mmol) were dissolved in CD3OD (5 mL).
4,7,10-Trioxa-1,13-tridecanediamine (6, 17.1 µL, 0.078 mmol) was
added, and the solution was stirred for 12 h. Then, the solution
was transferred into an NMR tube with 5% of water and left at
room temperature for 4 h. Next, 3,6,9-trioxa-1,11-undecanedi-
amine (4, 1 equiv.) was added into the tube, and the reaction was
left to equilibrate for 12 h. 1H NMR spectra were recorded in each
step.
14-Methoxy-6,9,12-trioxa-3,15-diaza-1(2,6)-pyridinahexadecacyclo-
phan-2,15-diene (5). (a): A stock solution was prepared as follows:
4-methoxypyridine-2,6-dicarbaldehyde (1, 8.7 mg, 0.052 mmol),
DMT (6.2 mg, 0.032 mmol), and CaCl2 (5.7 mg, 0.052 mmol) were
dissolved in CD3OD (5 mL). 3,6,9-Trioxa-1,11-undecanediamine
(4, 10.9 mg, 0.057 mmol) was added, and the solution was stirred
for 12 h. Various percentages of water (2%, 10%, 50%) were added
to different tubes, and 1H NMR spectra were recorded after 5 h.
Yields calcd. from the ratio between signals of aromatic protons of
DMT [δ = 8.15 (s, 4 H), 3.97 (s, 6 H) ppm] and imine protons:
CD3OD: 92%, 2% D2O: 90%, 10% D2O: 90%, 50% D2O: 90%.
1H NMR (600 MHz, 298 K, CD3OD) of 5 in the mixture: δ = 8.64
(t, J = 1.2 Hz, 2 H, CH=N), 7.58 (s, 2 H, Py), 4.11 (s, 3 H, OMe),
4.05 (t, J = 4 Hz, 4 H, CH=NCH2), 3.96–3.91 [overlapping signals,
12 H, (CH2OCH2)3] ppm. 13C NMR (150 MHz, 298 K, CD3OD):
δ = 169.87 [C-2,6 (Py)], 163.45 (CH=N), 153.05 [C-4 (Py)], 113.82
[C-3,5 (Py)], 70.92, 70.04, 69.74, 69.36, 69.05, 68.72 [(CH2OCH2)3],
56.90 (N=CH2), 55.92 (OMe) ppm. HRMS: calcd. for C16H23N3O4
321.16885, found 321.16899; calcd. for C1513CH23N3O4 322.17221,
found 322.17218. (b): A stock solution was prepared as follows:
3,6,9-trioxa-1,11-undecanediamine (4, 10.9 mg, 0.057 mmol) was
added to a solution of 4-methoxypyridine-2,6-dicarbaldehyde (1,
8.7 mg, 0.052 mmol) in D2O (5 mL). Then various equivalents of
CaCl2 were added to the solution in different NMR tubes, and the
solutions were left to equilibrate for 12 h. Then the 1H NMR spec-
tra were recorded. ESI-MS (positive ions) of the water solution
with 2 equiv. of CaCl2: calcd. for C16H23CaN3O4 361.13, found
180.554 [M + Ca2+]/2.
Acknowledgments
We are grateful for the support by the Marie Curie Research Train-
ing Network (MRTN-CT-2006-035614), Dynamic Combinatorial
Chemistry (DCC).
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Remarkable Stability of Imino Macrocycles in Water
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signals can also be detected, and the amount of imine formed
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the imines 3, 5 and 7.
Received: May 9, 2008
Published Online: July 15, 2008
Eur. J. Org. Chem. 2008, 4329–4333
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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