Towards the synthesis of Schiff base macrocycles under supercritical CO2 conditions

Article abstract of DOI:10.1039/c0cc00077a

The synthesis of Schiff base macrocycles was achieved using supercritical CO₂ as both solvent and acid catalyst.

Full text of DOI:10.1039/c0cc00077a

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Towards the synthesis of Schiff base macrocycles under supercritical
CO2 conditionsw
´ ´ ´
´
Ana M. Lopez-Periago,* Carlos A. Garcıa-Gonzalez and Concepcion Domingo
Received 1st March 2010, Accepted 22nd April 2010
First published as an Advance Article on the web 18th May 2010
DOI: 10.1039/c0cc00077a
The synthesis of Schiff base macrocycles was achieved using
supercritical CO2 as both solvent and acid catalyst.
(1R,2R)-diaminocyclohexane is hygroscopic, and it is the
adsorbed water that, when in contact with CO2, produces
the acid medium necessary for the catalysis.
As a major disadvantage of using the scCO2 synthesis
procedure, it must be mentioned that CO2 can react directly
with primary and secondary amines to produce carbamates
through the formation of zwitterion intermediates.13 In an
aqueous amine environment, as the one employed for CO2
capture, the base that deprotonates the zwitterion can be
another amine, H2O or OHꢀ. In dry conditions, the deproto-
nation occurs with another amine. In the studied process, this
side reaction can slow down the rate of the intended reaction.
Hence, before proceeding to the preparation of the studied
compounds, we first examined the behaviour of the reagent 1a
in a scCO2 atmosphere at a pressure of 15–20 MPa and a
temperature of 35.5 1C (Table 1, entry A). This preliminary
test was performed to evaluate the extension of the possible
reaction between the CO2 and the amine under used experi-
mental conditions.
The nuclear magnetic resonance (1H-NMR) spectrum of the
recovered sample after scCO2 treatment of 1a displayed only
the signals of the diamine that remained unreacted (Fig. S1a,
ESIw). However, the attenuated total reflectance Fourier
transform infrared (ATR-FTIR) spectrum of the solid sample
showed, together with the bands of the diamine, the set
of bands of the amide group (N–CQO) at 1625ꢀ1510 cmꢀ1
Over the past few years, the investigation of the synthesis of
chiral imine macrocycles has become of growing interest.1
These Schiff based symmetric macrocyclic compounds offer
an enormous potential in host–guest chemistry and molecular
recognition, besides their additional potential applications as
ligands and organocatalysts in asymmetric synthesis.2–3 The
preparation of large polyimine meta- and para-macrocycles,
also called trianglimines, has been successfully achieved using
a classic synthetic strategy based on a [3+3] cyclocondensation
(Scheme 1),4–7 where 3 units of (1R,2R)-diaminocyclohexane
(1a) react with 3 units of an aromatic dialdehyde, either 1,3-
(2) or 1,4-diformylbenzene (3), in a standard 0.4 M concentra-
tion in dichloromethane (DCM), yielding species 4a or 5a,
respectively.
The preparation of these macrocyles required the use of
organic solvents during their synthesis and, in most cases, also
in the purification step (ethyl acetate), which difficulted the
design of sustainable synthetic routes.
Supercritical carbon dioxide (scCO2) has been proved as an
environmentally benign medium for the substitution of
organic solvents in processes related with preparative chemistry8
and materials modification.9–11 In this work, we report on the
possibilities of using scCO2 as a green solvent for the preparation
of Schiff base macrocycles following the classical reaction.4z
scCO2 has a number of characteristics that are expected to
facilitate the synthesis of these macrocycles. First, the solvating
properties of this fluid can be continuously varied from gas-
like to liquid-like values with small changes in the pressure
and/or temperature, which can be used to control the thermo-
dynamics and kinetics of the process. The additional degree of
freedom related to the density of scCO2, allows simultaneous
control of the composition and the structure of the produced
materials, and, thus, the design of one-stage processes.
Moreover, the fact that scCO2 is an aprotic solvent is also
an advantage in the studied process, because it cannot protonate
the amine and there are not labile protons interfering in the
reaction. On the other hand, compressed CO2 acts as a
Lewis acid,12 which favours the formation of the acid
catalysed imine bond. It should be taken into account that
Instituto de Ciencia de Materiales de Barcelona (ICMAB-CSIC),
Campus de la UAB s/n, Bellaterra, Spain.
E-mail: amlopez@icmab.es; Fax: +34935805729;
Tel: +34935801853
w Electronic supplementary information (ESI) available: 1H-NMR,
13C-NMR, ATR-FTIR and MS spectra. See DOI: 10.1039/c0cc00077a
Scheme 1 Cyclocondensation reaction and structure of polyimine
para- (4a) and meta- (5a) macrocycles
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Table 1 Experimental conditions: pressure (P), temperature (T) and time (t); and characterization of prepared compounds
Reaction
Conditions
1H- and 13C-NMR in CDCl3
(d ppm)
ATR-FTIR
(n/cmꢀ1
Entry
A
Product
MS m/z CI
1625–1510
N–CQO
1a 115 (M + H)+
(100%)
1H: 2.22 d (2H)
1.81 d (2H)
P = 15–20 MPa
1b 157 (M+) (o5%)
1c 229 (M + H)+
(10%)
T = 35.5 1C
1.66 d (2H)
t = 4 h
1.18 m (4H)
3300 NH2
2900ꢀ2800 CH2
1a in scCO2
cyclohexane
4b 327 (M + H)+
(55%)
B(i)
1H: 8.14 s (1H,NQCH)
1638 CQN
P = 15 MPa
T = 35.5 1C
7.53 s (2H,Ar)
3.76 b (2H,CH–N)
1a + 2 in
scCO2
t = 1.5 h
1.59 b (10H,–CH2–)
4a 637 (M + H)+
(100%)
B(ii)
1H: 8.14 s (6H,NQCH)
1641 CQN
1645 CQN
P = 20 MPa
T = 35.5 1C
t = 2 h
7.52 s (12H,Ar)
3.36 b (6H,CH–N)
1.80 b (18H,–CH2–)
1.48 b (6H,–CH2–)
13C: 160.1, 137.7, 128.0, 74.4,
32.7, 24.4
Macrocycle 4a
1a + 2 in
scCO2
Macrocycle 5a &
5a 637 (M + H)+
(45%)
C
1H: 8.18 s (6H,NQCH)
5b 425 (M + H)+
(100%)
P = 20 MPa
7.91 s (3H,Ar)
T = 35.5 1C
t = 2 h
7.52 b (6H,Ar)
7.26 b (3H,Ar)
3.38 b (6H,CH–N)
1.70 b (30H,–CH2–)
1H: 8.31 s (4H,NQCH)
7.98 b (2H,Ar)
1a + 3 in
scCO2
7.53 b (4H,Ar)
7.27 b (2H,Ar)
3.40 b (4H,CH–N)
1.70 b (16H,–CH2–)
(Fig. S2a, ESIw) that indicated the formation of carbamate
(1b). Moreover, the intensity of the peaks at 800–925 cmꢀ1
amine group is attached to a tertiary carbon atom. It has been
shown that introducing steric hindrance by a bulky substituent
adjacent to the amino group lowers the stability of the
carbamate formed by CO2-amine reaction.15
,
attributed to the wagging and twisting of the –NH2 group in
the specie 1a, was considerably reduced in the obtained
sample. Mass spectrometry (MS) analysis (Fig. S3a, ESIw)
revealed the presence of unreacted diamine at m/z 115 (M + H)+,
and two extra minor peaks that were used two quantified the
produced reactions. The first minor peak with a 10% of
intensity at m/z 229 (M + H)+, was attributed to the formation
of the diamine dimer (1c) produced by short contact interactions.14
Carbamate formation was evidenced by a second minor peak
(o5%) at m/z 157 (M+). Hence, under used experimental
conditions, the reaction between the amine group and the CO2
did not occurred with a high conversion. The used amine is
defined as an sterically hindered amine, since the primary
Next, reagents 1a and 2 were reacted under scCO2 at two
different conditions (Table 1, entry B(i) and (ii)). At 15 MPa
and 35.5 1C (conditions B(i)), the obtained reaction product
was mainly compound 4b, and not the expected [3+3]-cyclo-
condensation product 4a, as demonstrated by 1H-NMR
(Table 1), ATR-FTIR (Table 1) and MS (Fig. S3b, ESIw)
characterization. The isolated product 4b was an intermediate
of the trianglimine 4a, in which the two –NH2 groups activated
the molecule towards an intermolecular reaction with the
incoming reagent 2. The detection of this intermediate compound
is in good agreement with the computational mechanism
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proposed for trianglimine macrocycle formation operating
under kinetic control and having the transition state with the
lowest energy.4 Likely, the solvent power of scCO2 at the
working conditions was not sufficient to allow the complete
macrocyclation. Hence, in a further trial, both the system
pressure and the reaction time were raised up to 20 MPa and
2 h, respectively (Table 1, entry B(ii)). Under those experi-
mental conditions, [3+3]-cyclocondensation took place and
the highly symmetric (D3h) macrocycle 4a was formed with a
high yield. The isolated 4a specie was analyzed by both
1H- (Fig. S1b, ESIw) and 13C-NMR (Fig. S1c, ESIw) spectro-
scopies, showing the set of signals corresponding to the 4a
repeating unit, as quoted by Gawronski et al.4 The ATR-
FTIR spectrum indicated the formation of the bond CQN4
with a band at ca. 1641 cmꢀ1 (Fig. S2b, ESIw). Further, MS
analysis (Fig. S3c, ESIw) revealed the formation of the
molecular ion at m/z 637 (M + H)+, indicating the presence
of the trimeric structure ((C14H16N2)3) of the 4a macrocycle
The major divergence with the data published in the
literature in regard of the characteristics of the prepared
macrocycle was related with the solubility of the precipitated
compound. The 4a trianglimine synthesized by the classical
route has been described to be very soluble in chloroform,
ethyl acetate or even methanol.4 However, the macrocyle
synthesised following the scCO2 method was highly insoluble
in those organic solvents. This difference in solubility was
thought to be caused by the effect of the solvent used in the
reaction. Solubility is very dependent on crystal structure and
habit, which are influenced by the used solvent.16–17 Hence,
using scCO2 instead of and organic solvent could give place to
a different crystal structure or crystal habit. Indeed, the crystal
structure of specie 4a reported in the literature showed the
inclusion of ethyl acetate within the macrocyclic cavity, which
could be responsible for the fast dissolution of the trianglimine
in organic solvents.4
is not only a greener and safer method than the classical
procedure, but also a one-stage process that would lead to
high yield values, thus, allowing a sustainable use of resources.
The synthesized Schiff bases had an empty core, not filled with
solvent molecules, since the scCO2 was eliminated as a gas
during depressurization. Hence, the supercritically as-synthesized
compounds are ready to participate in host–guest chemistry or
to act as selective probe materials. These results open a new
vision on the use of scCO2 for the preparation of imine
containing materials.
This work was financially supported by the MICIN Spanish
Projects CTQ-2008-05370/PPQ and MAT-2007-63355. We
also acknowledge the Barcelona University and Dr J. Saurina
for the use of the Mass Spectrometry service.
Notes and References
z Experimental procedure: Cyclocondensation reaction under super-
critical conditions was performed using a high pressure apparatus
described elsewhere.18 Typically, a 100 mL autoclave was charged with
500 mg (4.4 mmol) of 1a and 587 mg (4.4 mmol) of the aromatic
dialdehyde (either 2 or 3). Compressed CO2 was then added to the
reactor already heated at the working temperature. The system was
stirred at 300 rpm. At the end of each experiment, the system was
depressurized and let to cool down to room temperature before sample
collection.
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Finally, the reaction between 1a and 3 (Table 1, entry C)
performed under scCO2 at 20 MPa and 35.5 1C gave a mixture
of [3+3]- (compound 5a with symmetry C3) and [2+2]-
(compound 5b) cyclocondensation products in a ca. 28 : 71
molar ratio estimated by 1H-NMR spectroscopy and MS
(Fig. S3d, ESIw). ATR-FTIR spectroscopy indicated the
formation of the CQN bond at ca. 1645 cmꢀ1 (Fig. S2c,
ESIw). In this case, the appearance of 5b formed by [2+2]-
cyclocondensation as a major product indicated that the thermo-
dynamic control, where the formation of the intermediate
proceed via the less activated form, might be responsible of
the reaction performed under scCO2 conditions. Hence, the
precipitation of the compound with the lowest molecular
weight 5b, occurred in preference to the [3+3]-condensation
product 5a.
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To conclude, in this work it was proven that large polyimine
macrocycles, with molecular weights ranging from 425 to
637 gmolꢀ1, were formed under scCO2 conditions in the
absence or organic solvents. The designed supercritical route
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This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4315–4317 | 4317