Self-association of an indole based guanidinium-carboxylate-zwitterion: Formation of stable dimers in solution and the solid state

Article abstract of DOI:10.3762/bjoc.6.3

The indole based zwitterion 2 forms stable dimers held together by H-bond assisted ion pairs. Dimerisation was confirmed in the solid state and studied in solution using dilution NMR experiments. Even though zwitterion 2 forms very stable dimers even in D

Full text of DOI:10.3762/bjoc.6.3

Self-association of an indole based guanidinium-
carboxylate-zwitterion: formation of stable dimers in
solution and the solid state
Carolin Rether1, Wilhelm Sicking1, Roland Boese2 and Carsten Schmuck*1
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 3.
1Institute of Organic Chemistry, Faculty of Chemistry, University of
Duisburg-Essen, Universitätsstraße 7, 45141 Essen, Germany and
2Institute of Inorganic Chemistry, Faculty of Chemistry, University of
Duisburg-Essen, Universitätsstraße 7, 45141 Essen, Germany
doi:10.3762/bjoc.6.3
Received: 28 October 2009
Accepted: 04 January 2010
Published: 14 January 2010
Email:
Carsten Schmuck* - carsten.schmuck@uni-due.de
Guest Editor: C. A. Schalley
* Corresponding author
© 2010 Rether et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
dimerisation; molecular recognition; self-assembly; supramolecular
chemistry; zwitterions
Abstract
The indole based zwitterion 2 forms stable dimers held together by H-bond assisted ion pairs. Dimerisation was confirmed in the
solid state and studied in solution using dilution NMR experiments. Even though zwitterion 2 forms very stable dimers even in
DMSO, their stability is lower than of an analogous pyrrole based zwitterion 1. As revealed by the X-ray crystal structure the two
binding sites in 2 cannot be planar due to steric interactions between the guanidinium group and a neighbouring aromatic CH.
Hence the guanidinium moiety is twisted out of planarity from the rest of the molecule forcing the two monomers in dimer 2·2 to
interact in a non-ideal orientation. Furthermore, the acidity of the NHs is lower than in 1 (as determined by UV-pH-titration) also
leading to less efficient binding interactions.
Introduction
The vast majority of supramolecular self-assembling systems ested in developing self-complementary zwitterions that from
known so far form stable assemblies only in non polar solvents stable aggregates in polar solution based on H-bond assisted ion
such as chloroform, as they mainly rely on hydrogen bonds pair formation. A few years ago we introduced the guanidinio-
[1-4]. The design of self-complementary molecules that carbonyl pyrrole carboxylate zwitterion 1 which forms extreme-
assemble even in polar solvents is still a challenging task ly stable dimers not only in the solid state but also in polar solu-
despite all the progress made in this field in recent years. The tion [12]. In DMSO the stability is too large to evaluate with an
use of metal-ligand coordination and hydrophobic interactions estimated association constant of Kass> 1010 M−1. Even in water
has proven especially useful in this context [5-11]. We are inter- dimerisation still takes place (Kass = 170 M−1) [13]. The
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Beilstein Journal of Organic Chemistry 2010, 6, No. 3.
stability of the dimer 1·1 is significantly larger than the simple Results and Discussion
Coulomb-interactions of point charges, suggesting that indeed The indole zwitterion 2 was prepared by a four-step synthesis
the formation of directed, H-bond assisted salt-bridges is (Scheme 1). Commercially available 7-nitro-1H-indole-2-
crucial. Zwitterion 1 combines in a near perfect fit geometrical carboxylate 3 was reduced by reaction with hydrogen in the
self-complementarity with the possibility to form two salt- presence of Pd/C to provide the amine 4 in a yield of 98%. For
bridges assisted by a network of six H-bonds. The superior the next stept, first, thiourea was N-Boc-protected at both
stability of 1·1 compared to analogous zwitterions based on amino-functions following a literature procedure [20]. Thiourea
other aromatic scaffolds such as benzene or furan instead of was deprotonated with sodium hydride and afterwards reacted
pyrrole or with an amidinium cation instead of a guanidinium with di-tert-butyl dicarbonate to give the di-Boc-protected
cation was also confirmed by DFT calculations [14]. Zwitterion thiourea 5 in 79% yield. The di-Boc-protected thiourea 5 was
1 has thus found widespread application in the formation of then reacted with the amine 4 in the presence of Mukaiyama’s
self-assembled nanostructures such as vesicles or supramolecu- reagent [21] and triethylamine as a base, which provided 6 in a
lar polymers [15-17].
yield of 71% [22]. Deprotection of the two Boc-groups was
achieved by treatment with TFA and the guanidinium salt 7 was
We have now synthesized and studied the indole based zwit- obtained quantitatively. In the last reaction step the ethyl ester
terion 2, a close analogue of 1. In 2 the guanidinium group is in 7 was hydrolysed with lithium hydroxide in a THF/water
not acylated as in 1 but conjugated to an aromatic ring. mixture (THF/water = 4/1). Zwitterion 2 was then obtained after
Compared to the parent guanidinium cation, in both cases the adjustment of the pH to 6 with 1M HCl in a yield of 84% as a
acidity of the NHs is significantly increased due to the −M light brown crystalline solid.
effect of the carbonyl group or the aromatic ring, respectively,
thus facilitating the formation of H-bond assisted ion pairs [18,
19]. Apart from the increased acidity of the NHs in 1 and 2, also
the geometric shape of 2 is very similar to 1 at least based on
the inspection of simple models. It was therefore expected that
the new zwitterion 2 might form dimers with similar stability to
1, increasing our repertoire of self-complementary binding
motifs that efficiently self-assemble in polar solution. And
indeed we could show that zwitterion 2 is able to form highly
stable dimers in polar solution and in the solid state as well.
However, dimer 2·2 is significantly less stable than dimer 1·1.
Possible reasons for this decreased stability are discussed.
Scheme 1: Synthesis of zwitterion 2.
For the spectroscopic characterisation and as a reference
compound also the picrate salt of 2 was prepared by treating a
methanolic solution of 2 with picric acid (Scheme 2). The
picrate salt 2·H+ was isolated in form of a yellow, crystalline
solid in 89% yield.
Figure 1: Self-assembly of zwitterion 1 to give dimer 1·1 and self-
assembly of zwitterion 2 to give dimer 2·2 – both using the same inter-
molecular interactions: a pattern of six H-bonds and two salt bridges.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 3.
Hence, the downfield shifts in the spectrum of zwitterion 2
relative to the protonated form 2·H+ are most likely also due to
the formation of a H-bonded ion pair which can only take place
intermolecularly due to the rigidity of 2. The similarity of the
shift changes with those of zwitterion 1 suggests that dimerisa-
tion takes place.
The stability of these dimers was determined by an NMR dilu-
tion experiment. To obtain the binding constant for the dimer-
isation, we studied the concentration dependence of the 1H
NMR spectrum of 2 in a concentration range from 0.25 to 100
mM in [D6]DMSO. The 1H NMR shifts are concentration-
Scheme 2: Synthesis of compound 2·H+.
While the picrate salt 2·H+ is moderately soluble in methanol dependent as expected for a dimerisation (Figure 3).
and water, the zwitterionic form of 2 is virtually insoluble in all
solvents except DMSO and DMSO-containing solvent As the binding isotherms show (Figure 4), even at concentra-
mixtures, such as DMSO–MeOH or DMSO–CHCl3, so that the tions > 10 mM dimerisation is mostly complete. This suggests
dimerisation studies in solution were limited to DMSO. The 1H very large stability of the dimers even in DMSO. In agreement
NMR spectrum (Figure 2) of the protonated zwitterion 2·H+ with this, a quantitative data analysis provided a dimerisation
(picrate salt in [D6]DMSO) shows the signals expected for an constant Kass > 105 M−1, too large to be measured accurately by
aromatic guanidinium cation [23]. The four guanidinium NH2 NMR techniques. Similar observations were made earlier for
protons have a chemical shift of δ = 7.19, whereas the NH of zwitterion 1. However, for 1 the estimated stability in DMSO
the guanidinium group shows up at δ = 9.21 and the indole NH was even higher. Interestingly, at higher concentrations the
at δ = 12.06. The signals were assigned based on 2D NMR formation of larger aggregates also seems to occur. For
experiments.
example, the signal for the guanidinium NH2 protons shows a
second shift change at concentrations > 20 mM. First, the signal
The 1H NMR spectrum of zwitterion 2 is significantly different. is shifted to lower field due to the dimerisation, and then a
Especially the NH signals are shifted downfield. The indole NH smaller upfield shift is observed (Figure 5). This could be indic-
is shifted downfield by 0.2 ppm and appears at δ = 12.26 and ative of a second association process in which the dimers 2·2
the four guanidinium NH2 are shifted to δ = 8.00 ppm. Most start to interact at concentration > ca. 15 mM. However, the
significantly the NH of the guanidinium group is shifted down- exact nature of these larger aggregates is unclear at the moment.
field by nearly 4 ppm from δ = 9.21 to δ = 13.07 pm. A similar
dramatic downfield shift was observed for the guanidinium We were able to determine the solid state structure of 2. X-ray
amide NH of zwitterion 1 upon dimer formation [12,13].
quality crystals of compound 2 were obtained by slow evapora-
Figure 2: 1H NMR spectra of zwitterion 2 (bottom) and its protonated form 2·H+ (top).
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Beilstein Journal of Organic Chemistry 2010, 6, No. 3.
Figure 3: Part of the 1H NMR spectrum of 2 in [D6]DMSO showing the complexation-induced shifts of the indole CH protons (concentration from
bottom to top: 0.4, 1, 6, 12, 25 and 50 mM).
Figure 4: Representative binding isotherm of the aromatic proton d (left) and the indole NH proton (right).
tion of a dimethyl sulfoxide solution. X-ray crystallography
confirmed the formation of head-to-tail dimers, which are held
together by the formation of two salt bridges assisted by a
network of six hydrogen bonds (Figure 6). The hydrogen bond
distances between the aromatic N...O (2.703 Å), the guan-
idinium N...O (2.942 Å) and the indole N...O (2.935 Å) are all
rather short.
However, the distances are larger than the corresponding
distances in dimer 1·1: the amide N...O (2.679 Å), the guan-
idinium N...O (2.854 Å), and the pyrrole N...O (2.731 Å)
distances in dimer 1·1 are even shorter than in dimer 2·2. The
main difference between 1·1 and 2·2 is however that the dimers
2·2 are not completely planar. Zwitterion 2 itself is not planar,
but the guanidinium group is twisted out of planarity by 48.75°
(Figure 7). Also the two molecules within the dimer are not
within the same plane but slightly offset (by 1.050 pm). This is
Figure 5: Binding isotherm of the guanidinium NH2 protons.
a consequence of the twisted guanidinium group. To allow
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Beilstein Journal of Organic Chemistry 2010, 6, No. 3.
Figure 8: Part of the crystal lattice of zwitterion 2.
the latter. This is most likely due to steric interactions with the
neighboring aromatic C-H bond (Scheme 3). In the pyrrole
zwitterion 1 this position is occupied by the carbonyl oxygen
which forms an H-bond to the guanidinium moiety and thus
actually helps to keep the molecule planar. This amide group in
1 is replaced by the aromatic benzene ring in 2, thereby repla-
cing an attractive H-bond with a repulsive steric interaction.
Figure 6: Crystal structure of dimer 2·2 with hydrogen bond distances
(Å) and dihedral angles.
Scheme 3: An attractive H-bond in 1 (left) is replaced by a repulsive
steric interaction in 2 (right).
Figure 7: Side view of dimer 2·2 in the solid state.
This twisted, non-planar structure of dimer 2·2 is also repro-
optimal interaction of the carboxylate with the NHs of the guan- duced by DFT calculations. Geometry optimizations were
idinium group the second molecule has to be a little bit out of performed with the Gaussian03 program package using the
plane of the first, which results in longer hydrogen bond M05-2X/6-311+G** basis set [24]. In all calculations DMSO as
distances for the guanidinium N...O and the indole N...O a solvent was included (CPCM, = 48) [25,26]. The optimiza-
(Figure 7) and less favorable H-bond angles within the dimer tion revealed the twisted dimer, which fits quite well to the
(164.78° for the outer and 148.97° for the inner guanidinium X-ray structure. Though the calculated structure of dimer 2·2 is
NH-bonds and 141.37° for the indole NH-bond).
not completely symmetric like the X-ray structure, all the
hydrogen bond distances, as well as the torsion angle match
Within the crystal lattice the molecules of 2 are arranged in pretty well (Figure 9). In the solid state structure, the hydrogen
parallel planes held together most likely by aromatic stacking bond distances between the aromatic N...O (2.703 Å), the guan-
interactions: The centroid-centroid distance of two indoles is idinium N...O (2.942 Å) and the indole N...O (2.935 Å) are quite
3.636 Å. Furthermore, the “backside” of the out of plane short, as mentioned above. The torsion angle between the
twisted guanidinium cation also interacts with the carboxylate aromatic scaffold and the guanidinium group is 48.75°. The
group one plane below (Figure 8). The corresponding hydrogen DFT calculation give an average dihedral angle of 53.57° and
bond distances are 2.790 Å and 2.922 Å, respectively, and are lead to the following averaged hydrogen bond distances: 2.738
therefore similar to the hydrogen bond distances within the Å (aromatic N...O), 2.931 Å (guanidinium N...O) and 2.850
dimer.
(indole N...O).
The main difference between the pyrrole zwitterion 1 and the Hence, the good agreement of the observed structure in the
indole zwitterion 2 is hence the non-planar, twisted structure of solid state and the calculated structure obtained from DFT
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Beilstein Journal of Organic Chemistry 2010, 6, No. 3.
the pKa of the guanidinium group in 2 also obtained from a
UV-pH-titration is significantly larger with pKa = 10.6 ± 0.1.
Hence, the lower acidity of the NHs in 2 is a second important
factor leading to the overall reduced stability of dimer 2·2.
Conclusion
In conclusion, we have presented the synthesis of a new indole
based zwitterion 2, a close analogue of the 5-(guanidinio-
carbonyl)-1H-pyrrole-2-carboxylate (1) which we recently
introduced as one of the most stable self-complementary simple
molecules known so far. Both dimers rely on the same inter-
molecular interactions, two salt-bridges assisted by a very
similar network of six H-bonds. We could show here that zwit-
terion 2 also self-assembles into stable dimers in the solid state
and also solution (Kass > 105 M−1 in DMSO). However, DFT
calculations suggest that the dimers are significantly less stable
than dimer 1·1 despite the overall similarity of the binding inter-
actions. The calculated dimerisation enthalpy for dimer 2·2 is
only 66% of that for dimer 1·1. This is most likely due to two
reasons. As the solid state structure shows, the two binding sites
in 2·2 are not coplanar, but the guanidinium moiety is twisted
Figure 9: Energy-minimized structure for dimer 2·2 with hydrogen
bond distances (Å) and dihedral angles.
calculations suggests that the level of theory used in these out of plane of the aromatic ring. This forces the two zwit-
calculations describes the dimer with sufficient accuracy. We terions in the dimer also to be out of plane leading to less effi-
therefore also calculated the enthalpy values for the dimerisa- cient interactions between them. Furthermore, the NHs in 2 are
tion process of zwitterion 2 and of 1, respectively, as the experi- significantly less acidic than in 1 which also reduces the
mental values were too large to measure them accurately in stability of H-bonded ion pairs. Hence, geometric as well as
DMSO (as mentioned above). The calculated stability of dimer electronic fit is the important factor controlling the stability of
2·2 is significantly lower than for the pyrrole zwitterion 1: ΔH aggregates obtained from such self-complementary molecules.
−54 kJ/mol and −85 kJ/mol, respectively. Hence, even though Nevertheless, zwitterion 2 is an efficient self-assembling
the bonding interactions in dimer 1·1 and 2·2 are temptingly molecule. This indole guanidinium cation might also be an
similar the latter is only two third as stable as the former.
interesting binding motif for the recognition of oxoanions by
indole based receptors [27-29], similar to our guanidinio-
This difference in stability is most likely due to the non-ideal carbonyl pyrrole cation [30-32].
geometry of the H-bonded ion pairs and reflects the importance
of planarity in zwitterion 1 for an effective dimerisation. Due to Experimental
the twisted guanidinium groups in 2 the two monomers in dimer General Remarks: Solvents were dried and distilled before
2·2 are not in-plane, which leads to less efficient interactions. use. The starting materials and reagents were used as obtained
Also as mentioned above, the guanidinium group in zwitterion 2 from Aldrich or Fluka. 1H and 13C NMR spectra were recorded
is directly attached to the aromatic indole scaffold, whereas it is with a Bruker Avance 400 spectrometer. The chemical shifts are
acylated in 1. Though the overall structure looks similar, this reported relative to the deuterated solvents. The ESI-mass
replaces an attractive H-bond which also help to planarize zwit- spectra were recorded with a Finnigan MAT 900 S spectro-
terion 1 by a repulsive steric interaction in 2, which is respons- meter. IR spectra were recorded by measuring the Attenuated
ible for its non-planar structure.
Total Reflectance (ATR). Melting points are not corrected. The
pH values were measured with a Knick pH meter 766 Calimatic
Furthermore, the pKa value of the two guanidinium groups as at 25 °C. UV spectra were measured in 10 mm rectangular cells
well is an important factor for the stability of the dimers. While with a Jasco V660 spectrometer.
simple guanidinium cations as in arginine have a pKa of 13.5,
the pKa of the acylguanidinium group in 1 was measured by Ethyl 7-amino-1H-indole-2-carboxylate (4): A mixture of
UV-pH-titration to be 6.3 ± 0.1. Analysis of the pH dependent ethyl 7-nitro-1H-indole-2-carboxylate (3; 200 mg, 0.85 mmol)
UV spectral changes was performed using the Specfit/32 soft- and Pd/C (20 mg) in methanol (40 mL) was hydrogenated at
ware program from Spectrum Software Associates. However, ambient temperature for 1.5 h. The mixture was filtered over
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Beilstein Journal of Organic Chemistry 2010, 6, No. 3.
Celite to remove Pd/C, and the solvent was evaporated to give 27.8, 27.8, 60.5, 78.4, 82.9, 108.4, 120.2, 120.9, 121.8, 122.8,
the desired product 4 (170 mg, 0.83 mmol, 98%) as a colour- 127.8, 128.3, 133.5, 152.0, 155.0, 161.2, 162.8; IR (KBr): ν =
less solid: mp 146 °C; 1H NMR (400 MHz, [D6]DMSO, 25 °C): 3136 (w), 2974 (w), 2930 (w), 1717 (m), 1636 (m), 1360 (m)
δ = 1.34 (t, 3H), 4.34 (q, 2H), 5.38 (s, 2H), 6.41 (dd, 1H), 6.78- cm−1; HR-MS (ESI) calcd for [M+Na]+: 469.2058; found
6.86 (m, 2H), 7.02 (d, 1H), 11.40 (bs, 1H) ppm; 13C NMR 469.2096.
(100 MHz, [D6]DMSO, 25 °C): δ = 14.3, 60.3, 106.5, 108.1,
109.5, 121.5, 126.2, 127.3, 127.6, 134.6, 161.5; IR (KBr): ν = 2-(Ethoxycarbonyl)-1H-indole-7-guanidinium trifluoro-
3329 (s), 2996 (w), 2939 (w), 1668 (s), 1250 (s), 1215(s) cm−1; acetate (7): Trifluoroacetic acid (3 mL) was added to the ethyl
HR-MS (ESI) calcd for [M+H]+: 205.0972; found 205.0979.
7-[N,N’-bis-(tert-butoxycarbonyl)guanidino]-1H-indole-2-
carboxylate (6, 170 mg, 0.39 mmol), and the reaction mixture
N,N’-Di-(tert-butoxycarbonyl)thiourea (5): To a stirred solu- was stirred at room temperature for 2 h. The excess trifluoro-
tion of thiourea (570 mg, 7.50 mmol) in dry tetrahydrofuran acetic acid was removed in vacuo to give 7 as a colourless solid
(150 mL) sodium hydride (1.35 g, 33.80 mmol, 60% in mineral (140 mg, 0.39 mmol, 100%): mp > 240 °C; 1H NMR
oil) was added under argon atmosphere at 0 °C (ice bath). After (400 MHz, [D6]DMSO, 25 °C): δ = 1.35 (t, 3H), 4.36 (q, 2H),
5 min the ice bath was removed and the mixture was stirred for 7.13-7.26 (m, 7H), 7.69 (d, 1H), 9.29 (s, 1H), 12.11 (s, 1H)
additional 10 min at ambient temperature. The mixture was ppm; 13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 14.3, 60.6,
cooled to 0 °C again and di-tert-butyl dicarbonate (3.60 g, 16.50 108.7, 112.0, 120.7, 121.8, 122.8, 128.3, 128.9, 133.5, 156.4,
mmol) was added. After 40 min of stirring at 0 °C the ice bath 161.1; IR (KBr): ν = 3298 (w), 3193 (w), 3101 (w), 2955 (w),
was removed and the mixture was stirred for additional 3 h at 1699 (m), 1671 (s), 1255 (s) cm−1; HR-MS (ESI) calcd for
ambient temperature. The reaction was quenched by adding an [M+H]+: 247.1190; found 247.1215.
aqueous saturated solution of NaHCO3 (10 mL). Water
(200 mL) was added and the reaction mixture was extracted 7-Guanidinio-1H-indole-2-carboxylate (2): To a solution of
with ethyl acetate (3 × 75 mL). The collected organic layers the trifluoroacetate salt 7 (130 mg, 0.53 mmol) in water/THF
were dried over MgSO4, filtered and evaporated to dryness. The (1/4; 15 mL) LiOH·H2O (223 mg, 5.30 mmol) was added. The
white solid was purified by flash column chromatography on reaction mixture was heated to 40 °C and stirred for 8 h. The
silica gel (hexane/ethyl acetate = 1 : 1 + 0.5% triethylamine) to solvent was removed under reduced pressure and the residue
give N,N’-di-(tert-butoxycarbonyl)thiourea (5, 1.63 g, was dissolved in water (20 mL). The solution was acidified
5.92 mmol, 79%) as a colourless solid: mp 130 °C; 1H NMR dropwise with hydrochloric acid (0.1 molar) until a yellow solid
(400 MHz, [D6]DMSO, 25 °C): δ = 1.44 (s, 9H), 1.45 (s, 9H), precipitated at a pH = 6. The solid was filtered and to remove
8.96 (s, 1H), 9.14 (s, 1H) ppm; 13C NMR (100 MHz, inorganic salts again suspended in water (25 mL), some dioxane
[D6]DMSO, 25 °C): δ = 27.6, 82.5, 150.5, 178.7; IR (KBr): ν = (5 mL) was added. The mixture was heated to reflux for 40 min.
3160 (s), 2987 (m), 2933 (m), 1767 (m), 1718 (m), 1128 (s) The residue was filtered, and washed with water and afterwards
cm−1; HR-MS (ESI) calcd for [M+H]+: 277.1217; found with diethyl ether. The residue was dried in vacuo to give 2 as a
277.1056.
light brown solid (98 mg, 0.44 mmol, 84%): mp > 240 °C; 1H
NMR (400 MHz, [D6]DMSO, 25 °C): δ = 6.82 (s, 1H), 7.05 (t,
Ethyl 7-{N,N’-bis-[tert-(butoxycarbonyl)guanidino]}-1H- 1H), 7.15 (d, 1H), 7.43 (d, 1H), 7.99 (bs, 4H), 12.26 (bs, 1H),
indole-2-carboxylate (6): To a solution of ethyl 7-amino-1H- 13.07 (bs, 1H) ppm; 13C NMR (100 MHz, [D6]DMSO, 25 °C):
indole-2-carboxylate (4, 130 mg, 0.65 mmol), N,N’-di-(tert- δ = 103.4, 113.0, 118.1, 119.7, 122.0, 128.1, 129.6, 135.9,
butoxycarbonyl)thiourea (5, 185 mg, 0.65 mmol) and triethyl- 155.9, 166.4; IR (KBr): ν = 3327 (m), 3086 (m), 3724 (m),
amine (0.35 mL, 2.44 mmol) in dry dichloromethane (30 mL) 1397 (s), 737 (s) cm−1; HR-MS (ESI) calcd for [M+H]+:
was added 2-chloro-1-methyl-pyridinium iodide (297 mg, 219.0877; found 219.0884.
1.14 mmol) at 0° C and the mixture was stirred for 30 min. The
ice bath was removed and the reaction mixture was stirred at (2-Carboxy-1H-indole-7-yl)guanidinium picrate (2·H+): To a
ambient temperature for 24 h. The solvent was removed under suspension of the zwitterion 2 (20 mg, 0.09 mmol) in methanol
reduced pressure, and the residue was purified by flash column (4 mL) a saturated solution of picric acid in water (6 mL) was
chromatography on silica gel (ethyl acetate/hexane = 2:3) to added and the mixture was stirred for 24 h at ambient tempera-
give 6 (206 mg, 0.46 mmol, 71%) as a colourless solid: mp ture. The picrate salt crystallized and was filtered, washed
144 °C; 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 1.28 (s, several times with methanol, and dried to provide the yellow
9H), 1.34 (t, 3H), 1.54 (s, 9H), 4.36 (q, 2H), 7.09 (t, 1H), 7.20 solid 2·H+ (35 mg, 0.08 mmol, 89%): mp > 240 °C; 1H NMR
(d, 2H), 7.60 (d, 1H), 9.73 (s, 1H), 11.56 (bs, 1H), 11.95 (bs, (400 MHz, [D6]DMSO, 25 °C): δ = 7.11-7.20 (m, 8H), 7.67 (d,
1H) ppm; 13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 14.3, 1H), 8.58 (s, 2H), 9.21 (s, 1H), 12.02 (s, 1H), 13.23 (bs, 1H)
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Beilstein Journal of Organic Chemistry 2010, 6, No. 3.
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ppm; 13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 120.5,
124.1, 125.2, 129.1, 129.2, 141.9, 156.3, 160.9; IR (KBr): ν =
3200(w), 1674 (w), 1554 (m), 1336 (m) cm−1; HR-MS (ESI)
calcd for [M+H]+: 219.0877; found 219.0884.
X-ray Crystallographic Data
Crystal structure of 2: C10H10N4O2, colourless crystals,
dimensions 0.16 × 0.13 × 0.10 mm3, measured with a Bruker
D8 KAPPA series II with APEX II area detector system at
100 K; a = 12.1695 (5) Å, b = 7.1061 (3) Å, c = 12.3061 (4) Å,
V = 985.45 (7) Å3, Z = 4, ρ = 1.471 g/cm3, space group P21/n,
7030 intensities measured (θmax = 28.33°), 2458 independent
(R(int) = 0.0279), 2061 observed, structure solution by direct
methods and refinement of 145 parameters on F2 with the
Bruker software package SHELXTL Vers. 2008/4/(c) 2008, R1
= 0.0485, ωR2 (all data) = 0.1111, Gof = 1.053, max electron
density 0.407 e Å−3.
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