Anion-anion proton transfer in hydrogen bonded complexes

Article abstract of DOI:10.1002/asia.200900230

Complexation of dihydrogen phosphate by an anion receptor containing six hydrogen bond donor groups has been shown to reduce the pK_a of the bound anionic species to such an extent that addition of further aliquots of dihydrogen phosphate result

Full text of DOI:10.1002/asia.200900230

DOI: 10.1002/asia.200900230
Anion–Anion Proton Transfer in Hydrogen Bonded Complexes
Philip A. Gale,*[a] Jennifer R. Hiscock,[a] Stephen J. Moore,[a] Claudia Caltagirone,[b]
Michael B. Hursthouse,[a] and Mark E. Light[a]
Dedicated to the 150th Anniversary of Japan–UK Diplomatic Relations
Abstract: Complexation of dihydrogen
phosphate by an anion receptor con-
taining six hydrogen bond donor
groups has been shown to reduce the
pKa of the bound anionic species to
such an extent that addition of further
aliquots of dihydrogen phosphate
result in deprotonation of the bound
species with the resultant formation of
a monohydrogen phosphate receptor
complex. X-ray crystallographic studies
confirm monohydrogen phosphate
complex formation in the solid state. In
this way, this study explains the forma-
tion of complexes with unusual stoi-
chiometries when investigating the
binding of dihydrogenphosphate anion
to hydrogen-bonding receptors.
Keywords: anions · crystallography ·
hydrogen bonds · NMR spectrosco-
py · supramolecular chemistry
Introduction
with the bound oxo-anions but that the amide group in the
2-position did not interact significantly with the guest spe-
cies. This was also observed in X-ray crystal structures of
the anion complexes of these systems. The design of the
second generation diindolylurea compounds built on these
findings by removing the amide group in the 2-position and
adding an extra indole moiety to produce a symmetrical re-
ceptor containing four hydrogen bond donor groups. These
compounds were found to be selective receptors for dihy-
drogen phosphate anions in [D6]DMSO/water mixtures over
carboxylates and chloride. Single crystal X-ray diffraction of
crystals obtained from a [D6]DMSO/water solution of the
receptor in the presence of excess tetrabutylammonium di-
hydrogenphosphate showed that three of these receptors
Proton transfer processes from acidic hydrogen bond donor
receptors to basic anions, such as fluoride and dihydrogen
phosphate, have been shown to compete with anion com-
plexation processes in a variety of hydrogen bond donor sys-
tems by our group,[1] Gunnlaugsson and co-workers,[2] Fab-
brizzi and co-workers,[3] and others.[4] We recently reported
that 1,3-diindolylureas form particularly stable complexes
with oxo-anions in [D6]DMSO/water mixtures.[5] This work
led from an initial collaborative project with Albrecht and
Triyanti on 2,7-disubstituted indoles containing urea sub-
stituents in the 7-position and amide substituents in the 2-
position that were found to bind oxo-anions strongly.[6]
Proton NMR titration studies on these compounds in
[D6]DMSO/0.5% water showed that the indole and urea
groups were participating in hydrogen bonding interactions
3À
could assemble around a single phosphate PO4 anion in
the solid state binding it by means of twelve hydrogen
bonds.[5b] Similarly crystallizations with tetraethylammonium
bicarbonate and a diindolylurea resulted in the crystalliza-
tion of deprotonated carbonate bound by two diindolylureas
through eight hydrogen bonds. Thus whilst 1:1 complexation
was apparently observed in solution, in the case of dihydro-
gen phosphate and bicarbonate, proton transfer was taking
place at some point in the crystallization process from the
bound anion to a more basic species. It occurred to us that
the receptors in this case may be reducing the pKa of the
bound anionic species (by forming 12 and 8 hydrogen bonds
to phosphate and carbonate, respectively) resulting in
proton transfer from the bound anion to further added ali-
quots of the same anion free in solution. Thus this is a relat-
ed process to those observed previously,[1–4] but in this case,
[a] Prof. P. A. Gale, J. R. Hiscock, S. J. Moore, Prof. M. B. Hursthouse,
Dr. M. E. Light
School of Chemistry
University of Southampton
Southampton, SO17 1BJ (UK)
Fax : (+44)23-8059-6805
E-mail: philip.gale@soton.ac.uk
[b] Dr. C. Caltagirone
Dipartimento di Chimica Inorganica ed Analitica
Universitꢀ degli Studi di Cagliari
S.S. 554 Bivio per Sestu, 09042, Monserrato, CA (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900230.
Chem. Asian J. 2010, 5, 555 – 561
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
555

FULL PAPERS
it is the bound anion that is deprotonated by the free anion
in solution, not the receptor. Multiple hydrogen bonds in
these complexes presumably act in concert to lower the pKa.
Hence we designed new receptors containing 6 rather than 4
NH hydrogen bond donor groups (by attaching amides to
the 2-positions of a diindolylurea) in order to see whether
this deprotonation process could be observed directly in so-
lution.
Results and Discussion
Scheme 1. Synthesis of receptors 1–4.
Compounds 1–4 were synthesized by a simple three-step
synthesis (Figure 1). Commercially available 7-nitroindole-2-
carboxylic acid was coupled to an amine (benzylamine or
Table 1. Apparent stability constants determined by 1H NMR titration
techniques with compound 1 in [D6]DMSO/water mixtures at 298 K fol-
lowing urea NH and indole CH (6-position) groups. Errors <15% except
where noted.
Anion[a] CH
(0.5% water) (0.5% water) (10% water) (10% water)
Urea NH
CH
Urea NH
ClÀ
166
22
n.d.
1020
462
n.d.
BzOÀ
AcOÀ
H2PO4
>104
>104
>104
>104
1100
[b]
–
À
[c]
[c]
–
–
>104
809
2310
395
À
HCO3
>104
2468
[a] Anions added as tetrabutylammonium salts except bicarbonate which
was added as the tetraethylammonium salt. [b] NMR spectrum indicates
conformational changes during the titration (see the Supporting Informa-
tion). [c] Fast and slow exchange. n.d.=not determined.
Table 2. Apparent stability constants determined by 1H NMR titration
techniques with compound 2 in [D6]DMSO/water mixtures at 298 K fol-
lowing urea NH and indole CH (6-position) groups. Errors <15% except
where noted.
Figure 1. Chemical structures for 1–4.
Anion[a] CH
(0.5% water)
Urea NH
CH
Urea NH
(0.5% water) (10% water) (10% water)
pyridin-2-ylmethanamine) using CDI to afford 2-carboxami-
do-7-nitroindole derivatives in 90 and 80% yields, respec-
tively. Coupling with n-butylamine or aniline was performed
using our previously published procedures.[6] The nitro-de-
rivatives were reduced using H2/Pd/C 10% affording the
amines which were coupled with triphosgene in a two phase
CH2Cl2/sat NaHCO3(aq) mixture to afford the urea deriva-
tives 1–4 in 49, 30, 56, and 55% yields, respectively
(Scheme 1).
ClÀ
79
<10
n.d.
639
n.d.
481
BzOÀ
AcOÀ
H2PO4
>104
–
[d]
>104
107
2250 (Æ17%)
8460
–
–
1422
[c]
À
[d]
[b]
[b]
–
–
–
–
À
[d]
[d]
HCO3
728
[a] Anions added as tetrabutylammonium salts except bicarbonate which
was added as the tetraethylammonium salt. [b] Isotherm could not be
fitted to a 1:1 or 1:2 binding model. [c] A shoulder appears a urea NH
resonance possibly indicating the formation of an unsymmetrical com-
plex. [d] Peak broadening prevented a stability constant from being ob-
tained in these cases. n.d.=not determined.
Apparent stability constants of compounds 1–4 with a
1
range of anionic guests were determined by H NMR titra-
tion techniques in [D6]DMSO/0.5% water or [D6]DMSO/
10% water. The results are shown in Tables 1–4. The stabili-
ty constants for carboxylates generally show good agree-
ment between those determined by the shift of the urea NH
protons and those determined by the shift of the indole CH
protons in the 6-position of the indole ring (the indole NH
broadens upon addition of anions in many cases). The re-
ceptors were found to have a low affinity for chloride but to
strongly bind the oxo-anions studied. Whilst the binding iso-
therms for carboxylates fit to a 1:1 binding model, the bind-
ing of dihydrogen phosphate is more complex and in many
cases could not be adequately fitted (possibly indicative of a
deprotonation process occurring). In the case of compound
1, the NMR titration with dihydrogen phosphate shows both
fast and slow exchange processes (vide infra). Examination
of the shifts of the urea NH, amide NH, and indole C6 CH
protons show that across the series of compounds, upon ad-
dition of carboxylates, the amide NH and indole CHs shift
downfield, and in 0.5% water solution, reach a plateau at
one equivalent of anion indicating strong binding. However,
the amide NH groups either do not shift at all or shift down-
field continuously and do not reach a plateau (see Figure 2
for compound 1 and benzoate). These results are evidence
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Chem. Asian J. 2010, 5, 555 – 561

Proton Transfer in Hydrogen Bonded Complexes
Table 3. Apparent stability constants determined by 1H NMR titration
techniques with compound 3 in [D6]DMSO/water mixtures at 298 K fol-
lowing urea NH and indole CH (6-position) groups. Errors <15% except
where noted.
Anion[a] CH
(0.5% water) (0.5% water) (10% water) (10% water)
Urea NH
CH
Urea NH
[b]
[d]
ClÀ
–
–
n.d.
303
278
2960
319
n.d.
284
293
812
BzOÀ
AcOÀ
H2PO4
1490
1580
>104
>104
À
[c]
[d]
–
–
–
À
[d]
[d]
HCO3
1420
–
[a] Anions added as tetrabutylammonium salts except bicarbonate which
was added as the tetraethylammonium salt. [b] No shift. [c] Isotherm
could not be fitted to a 1:1 or 1:2 binding model. [d] Peak broadening.
n.d.=not determined.
Figure 3. Proposed binding modes of bicarbonate, dihydrogen phosphate,
and a carboxylate with a bis-amide functionalized diindolylurea.
Table 4. Apparent stability constants determined by 1H NMR titration
techniques with compound 4 in [D6]DMSO/water mixtures at 298 K fol-
lowing urea NH and indole CH (6-position) groups. Errors <15% except
where noted.
bond as was observed with the 2,7-disubstituted indoles
studied previously.[6]
However, in contradistinction to the results with carboxy-
lates, addition of bicarbonate or dihydrogen phosphate
caused downfield shifts of the amide NH groups (see
Figure 4 for compound 1 and bicarbonate) in addition to the
Anion[a] CH
(0.5% water)
Urea NH
CH
Urea NH
(0.5% water) (10% water) (10% water)
[b]
ClÀ
–
<10
n.d.
298
485
256
149
n.d.
304
544
245
BzOÀ
AcOÀ
H2PO4
2430 (Æ19%) 4760
>104
>104
À
[c]
[d]
–
–
–
À
[d]
[d]
HCO3
7660
–
[a] Anions added as tetrabutylammonium salts except bicarbonate which
was added as the tetraethylammonium salt. [b] No shift. [c] Isotherm
could not be fitted to a 1:1 or 1:2 binding model. [d] Peak broadening.
n.d.=not determined.
Figure 4. 1H NMR titration of compound 1 with tetraethylammonium bi-
carbonate following amide NH, urea NH, and the aromatic CH in the 6-
position of the indole ring.
urea NH, C6 indole CH groups. These results are evidence
to support the binding modes proposed for bicarbonate and
dihydrogen phosphate shown in Figure 3a and b, in that
these oxo-anions can bind to all the NH groups in the recep-
tor. However, the extra hydrogen bonding interaction to bi-
carbonate versus carboxylates is not reflected in a higher af-
Figure 2. 1H NMR titration of compound 1 with tetrabutylammonium
benzoate following amide NH, urea NH, and the aromatic CH in the 6-
position of the indole ring.
À
that supports the hypothesis that carboxylates bind strongly
to the receptors, as shown in Figure 3c. The amide NH
groups do not interact with the bound carboxylate. The con-
tinuous downfield shift of the amide NH group in some
cases may be a result of the amide NH pointing out of the
binding cavity of the receptor and weakly binding further
aliquots of carboxylates weakly through a single hydrogen
finity of these receptors for HCO3 .
We further investigated the apparent slow exchange pro-
cess observed upon addition of dihydrogen phosphate to re-
ceptor 1 in [D6]DMSO/0.5% water. We observed shifts of
the amide NH groups up to 1.0 equivalent of added anion,
followed by the emergence of new peaks in the 1H NMR
spectrum as further aliquots of dihydrogen phosphate were
Chem. Asian J. 2010, 5, 555 – 561
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557

P. A. Gale et al.
FULL PAPERS
added. One possible explanation for this behavior is the for-
mation of a 1:1 complex at low anion concentrations which
is fast on the NMR timescale and at higher concentrations
of dihydrogen phosphate, the formation of a 2:1 anion/re-
ceptor complex which is slow on the NMR timescale. How-
ever, we noted that the new proton resonances which ap-
dihydrogen phosphate to solutions of compounds 2, 3, or 4.
It is possible that steric interactions in these complexes
reduce the degree of stabilization of monohydrogen phos-
phate as compared to that in the complex with receptor 1.
However, the fact that either broadening of the NH reso-
nances upon addition of dihydrogen phosphate or a binding
isotherm that could not be fitted to either 1:1 or 2:1 anion/
receptor binding models, in these cases, suggests that proton
transfer processes may also be occurring but that the equi-
librium between the mono- and dihydrogen phosphate com-
plexes is fast on the NMR timescale. For example, a titra-
tion with dihydrogen phosphate followed by addition of hy-
droxide with compound 4 in [D6]DMSO/10% water shows
that hydroxide causes further downfield shifts of the NH
proton resonances rather than the evolution of new resonan-
ces (see the Supporting Information). Discrepancies be-
tween stability constants determined using 1:1 binding
models following different proton resonances in the cases of
dihydrogen phosphate and bicarbonate complexation may
be a result of proton transfer processes occurring in these
systems, in addition to anion complexation.
Further evidence for proton transfer comes from solid-
state single crystal X-ray diffraction studies. Crystals of re-
ceptor 2 were grown by slow evaporation of a DMSO solu-
tion of the receptor in the presence of excess tetrabutylam-
monium dihydrogen phosphate. Interestingly, the receptor
crystallized as the hydrogen phosphate (HPO42À) complex as
shown in Figure 6 with three of the phosphate oxygen atoms
hydrogen bonded to the six NH groups with bonds N1···O5
2.734(5) ꢂ, N2···O5 2.668(5) ꢂ, N3···O7 2.804(4) ꢂ, N4···O7
2.842(5) ꢂ, N5···O6 2.660(5), and N6···O6 2.763(4) ꢂ see
Scheme 2.
1
peared in the H NMR spectrum were shifted downfield by
a considerable margin to those present in the presumed 1:1
complex (in one case by over 2 ppm). This led us to consider
other possible processes and in particular deprotonation of
the bound anion. Compound 1 contains six hydrogen bond
donors and thus potentially has a greater ability to modulate
the pKa of a bound anionic guest species than simple diindo-
lylureas if all six hydrogen bond donors complex an anionic
guest. Consequently, we considered whether the new peaks
À
that appear after addition of 1.0 equivalent of H2PO4 could
arise from a proton transfer between the bound dihydrogen
phosphate and the more basic free dihydrogen phosphate,
resulting in the formation of a monohydrogen phosphate
complex in solution. The double negative charge on this
anion would result in the formation of a stronger complex
and in a greater downfield shift of the NH groups as com-
pared to the dihydrogen phosphate complex. In order to
2À
confirm that the new peaks corresponded to the HPO4
complex, tetrabutylammonium hydroxide was titrated into a
solution of the receptor in the presence of 1.4 equivalents of
dihydrogen phosphate (Figure 5). The new peaks were
Conclusions
Compounds 1–4 form stable complexes with oxo-anions
such as carboxylates, but with dihydrogen phosphate and
compound 1, a proton transfer process takes place between
bound and free dihydrogen phosphate in solution resulting
in the formation of a monohydrogen phosphate complex
that is slow on the NMR timescale. Crystallization of com-
pound 2 with tetrabutylammonium dihydrogen phosphate
results in the formation of the monohydrogen phosphate
complex of the receptor with the anion bound by six NH···O
hydrogen bonds. Presumably the fact that these receptors
are able to form multiple hydrogen bonding interactions
with the bound guest reduces the pKa of the oxo-anion re-
sulting in proton transfer to the unbound anion in solution.
We propose that deprotonation of protonated oxo-anions
bound by multiple hydrogen bonds by further addition of
the same anion to the complex in solution may be a general
Figure 5. 1H NMR titration with compound 1 in [D6]DMSO/0.5% water.
a) Free receptor; b) 0.6 equivalents TBA H2PO4; c) 1.0 equivalent TBA
H2PO4; d) 1.4 equivalents TBA H2PO4; e) 1.4 equivalents TBA
H2PO4+0.7 equivalents
TBA
OH;
f) 1.4 equivalents
TBA
H2PO4+1.4 equivalents TBA OH.
found to increase in intensity, a finding consistent with the
formation of a greater proportion of the monohydrogen
phosphate complex in solution. This was also observed in
[D6]DMSO/10% water. A model experiment conducted in
the absence of dihydrogen phosphate did not result in the
formation of these NH resonances (see the Supporting In-
formation). New peaks were not observed upon addition of
1
process that cannot easily be observed using H NMR titra-
tion techniques unless there is slow exchange between the
different protonation states of the bound guest as we ob-
À
served with compound 1 and H2PO4 /HPO42À. We found
that dihydrogen phosphate binding often cannot be easily
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Proton Transfer in Hydrogen Bonded Complexes
Experimental Section
General
All reactions were performed using oven-dried glassware under slight
positive pressure of nitrogen/argon (as specified). 1H NMR (300 MHz)
and 13C{1H} NMR (75 MHz) spectra were determined on a Bruker
AV300 spectrometer. 1H NMR (400 MHz) and 13C{1H} NMR (100 MHz)
spectra were determined on a Bruker AV400 spectrometer. Chemical
shifts for 1H NMR are reported in parts per million (ppm), calibrated to
the solvent peak set. The following abbreviations are used for spin multi-
plicity: s=singlet, d=doublet, t=triplet, m=multiplet. Chemical shifts
for 13C{1H} NMR are reported in ppm, relative to the central line of a
septet at d=39.52 ppm for deuterio-dimethylsulfoxide. Infrared (IR)
spectra were recorded on a Matterson Satellite (ATR). FTIR are report-
ed in wavenumbers (cmÀ1). All solvents and starting materials were pur-
chased from chemical sources where available. NMR titrations were per-
formed by adding aliquots of the putative anionic guest (as the TBA or
TEA) salt (0.15m) in a solution of the receptor (0.01m) in [D6]DMSO to
a solution of the receptor (0.01m).
1H NMR Spectroscopic Titrations
A Bruker AV300 NMR spectrometer was used to measure the 1H NMR
shifts of the NH protons of the receptors. NMR titrations were per-
formed by adding aliquots of the putative anionic guest (as the TBA salt,
or TEA salt in the case of bicarbonate) salt (0.15m) in a solution of the
receptor (0.01m) in [D6]DMSO to a solution of the receptor (0.01m). The
titration data was plotted as Dppm versus concentration of guest and
fitted to a binding model using the EQNMR computer program.[7]
N-benzyl-7-nitro-1H-indole-2-carboxamide:
7-nitroindole-2-carboxylic
acid (0.410 g, 1.99 mm) and CDI (0.405 g, 2.50 mm) were dissolved in
chloroform (50 mL). The reaction mixture was heated at reflux for 3 h
under argon. Benzylamine (0.10 mL, 1.90 mm) was dissolved in dry
chloroform (20 mL) and then added dropwise to the stirring reaction
mixture. The reaction mixture was heated at reflux for 72 h under argon.
The reaction mixture was diluted with DCM (30 mL), washed with water
(2ꢄ15 mL), and then dried with magnesium sulphate. The reaction mix-
ture was reduced in vacuo and then purified by column chromatography
(5% ethyl acetate/DCM) to yield a yellow solid (0.511 g). Yield: 90%;
m.p.: 1738C; 1H NMR (300 MHz, [D6]DMSO): d=4.55 (d, J=5.6 Hz,
2H), 7.24–7.40 (m, Ar CH, 6H), 7.44 (s, 1H), 8.22 (t, J=8.4 Hz, 2H),
9.50 (t, J=5.7 Hz, NH, 1H), 11.38 ppm (s, NH, 1H); 13C NMR (75 MHz,
[D6]DMSO): d=42.5 (CH2), 106.6 (ArCH), 119.9 (ArCH), 121.1
(ArCH), 127.0 (ArCH), 127.5 (ArCH), 128.4 (Ar CH), 128.8 (ArC),
130.6 (ArCH), 130.9 (ArC), 133.1 (ArC), 134.5 (ArC), 139.0 (ArC),
159.5 ppm (CO); IR (film): n˜ =3457, 3380, 3085, 2963, 1650 cmÀ1; LRMS
(ESÀ): m/z: 294.2 [MÀH]À; HRMS (ES+): m/z: exp: 318.0855 [M+Na]+;
calcd: 318.0848 [M+Na]+
Figure 6. Top and side views of the hydrogen phosphate complex of com-
pound 2. Tetrabutylammonium counter cations, water and non-acidic hy-
drogen atoms have been omitted for clarity.
N-(2-pyridin-2-yl)-7-nitro-1H-indole-2-carboxamide: 7-nitroindole-2-car-
boxylic acid (0.200 g, 0.970 mm) was dissolved in dry chloroform. CDI
(0.193 g, 1.19 mm) was added to the stirring reaction mixture. The reac-
tion mixture was heated at reflux for 2 h under argon. A solution of 2-
aminopyridine (0.092 g, 0.967 mm) in chloroform (5 mL) was added drop-
wise to the stirring reaction mixture. The reaction mixture was heated at
reflux for 22 h. The reaction mixture was washed with water (2ꢄ15 mL)
and then dried with magnesium sulphate. The reaction mixture was then
reduced in vacuo and purified by column chromatography (10% ethyl
Scheme 2. Addition of dihydrogen phosphate to the dihydrogen phos-
phate complex of receptor 1 causes deprotonation of the bound anion
and the formation of a monohydrogen phosphate complex.
fitted to a 1:1 binding model and it may be that similar
proton transfer processes occur in other dihydrogen phos-
phate–receptor complexation processes.[8] Hence care must
be taken when interpreting stability constant data with this
class of common oxo-anionic species in organic solution.
Additionally, the demonstration that non-covalent binding
can modify the acidity/basicity of an anion might also indi-
cate that the anionꢃs reactivity can change significantly on
binding—this may be useful in the development of new cat-
alysts (to enhance the reactivity of both anionic and neutral
substrates based on phosphates) or other technological pro-
cesses.
1
acetate/DCM) to yield a yellow solid. Yield: 80%; m.p.: 1948C; H NMR
(300 MHz, [D6]DMSO): d=7.20 (ddd, J=7.3 Hz, 4.74 Hz, 0.92 Hz, 1H),
7.35 (t, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.88 (dt, J=7.3 Hz, 1.8 Hz, 1H),
8.20–8.31 (m, 3H), 8.43 (dd, J=2.4 Hz, 1.1 Hz), 11.57 (s, NH, 1H),
11.97 ppm (s, NH, 1H); 13C NMR (75 MHz, [D6]DMSO): d=109.2
(ArCH), 114.7 (Ar CH), 120.0 (2 ArCH), 121.7 (ArCH), 129.3 (ArC),
130.7 (ArCH), 130.8 (ArC), 133.2 (ArC), 134.1 (ArC), 138.3 (ArCH),
148.0 (ArCH), 151.9 (ArC), 158.4 ppm (CO); IR (film): n˜ =3382, 3345,
1671 cmÀ1; LRMS (ESÀ): m/z: 281.2 [MÀH]À; HRMS (ES+): m/z: exp:
283.0831 [M+H]+ calcd: 283.0831 [M+H]+
7,7’-carbonylbis(azanediyl)bis(N-butyl-1H-indole-2-carboxamide)
(1):
The synthesis of 7-nitro-N-butyl-1H-indole-2-carboxamide is taken from
Chem. Asian J. 2010, 5, 555 – 561
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559

P. A. Gale et al.
FULL PAPERS
a method described by Bates et al.[7] N-butyl-7-nitro-1H-indole-2-carbox-
amide (0.25 g, 0.96 mm) and a Pd/C 10% catalyst (0.03 g) were suspended
in ethanol (25 mL). The flask was evacuated and the mixture placed
under a hydrogen atmosphere and stirred vigorously for 3 h. After this
time the palladium catalyst was removed by filtration through celite and
the filtrate taken to dryness and placed under reduced pressure. This
gave a white solid. Assumed yield: 100%. The white solid was dissolved
in a two-phase solution of sat. NaHCO3 (20 mL) and DCM (20 mL). This
solution was stirred vigorously under nitrogen at room temperature and
triphosgene (0.30 g, 1.00 mm) added in two equal aliquots. The solution
was allowed to stir overnight. The two-phase solution was then filtered
and the white solid was sonicated in water (250 mL) for 30 mins. A white
solid was then collected by filtration and washed with DCM (20 mL) and
diethyl ether (20 mL). Yield: 49%; m.p.: 1388C; 1H NMR (300 MHz,
[D6]DMSO): d=0.92 (t, J=7.3 Hz, 3H), 1.36 (dd, J1 =6.93 Hz, J2 =
13.5 Hz, 2H), 1.54 (t, J=7.0 Hz, 2H), 3.33 (m, 2H), 7.01 (t, J=7.7 Hz,
1H), 7.16 (s, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.3 Hz, 2H), 8.51
(s, NH, 1H), 8.88 (s, NH, 1H), 11.37 ppm (s, NH, 1H); 13C{1H} NMR
(75 MHz, [D6]DMSO): d=13.7 (CH3), 19.6 (CH2), 31.3 (CH2), 38.4
(CH2), 102.8 (ArCH), 113.7 (ArCH), 116.0 (ArCH), 120.2 (ArCH), 124.9
(ArC), 128.0 (ArC), 128.6 (ArC), 131.7 (ArC), 153.1 (CO), 160.8 ppm
(CO); IR (film): n˜ =3340, 3270, 1640, 1560 cmÀ1; LRMS (ESÀ): m/z:
487.4 [MÀH]À; HRMS (ES+): m/z: exp: 489.2604 [M+H]+; calcd:
489.2609 [M+H]+.
161.0 ppm (CO); IR (film): n˜ =3290, 1635, 1575 cmÀ1; LRMS (ESÀ): m/z:
555.3 [MÀH]À; HRMS (ES+): m/z: exp: 557.2294 [M+H]+; calcd:
557.2301 [M+H]+
Bis((2-pyridin-2-yl)-7-nitro-1H-indole-2-carboxamine)-urea (4): (2-pyri-
dinyl-2-yl)-7-nitroindole-2-carboxamide (0.179 g, 0.635 mm) was dissolved
in ethanol (50 mL). Palladium on carbon 10% (0.030 g) was added. The
reaction vessel was evacuated and then supplied with hydrogen and
stirred at room temperature for 6 h. The reaction mixture was then fil-
tered through celite and reduced in vacuo to yield a white solid. As-
sumed yield: 100%. The white solid and triphosgene (0.037 g, 0.125 mm)
were dissolved in DCM (50 mL) and saturated sodium bicarbonate solu-
tion (50 mL) and stirred at room temperature for 2 h. The organic phase
was separated and reduced in vacuo. The resulting brown solid was soni-
cated in water (500 mL) for 1 h. The solid was filtered and washed with
water (2ꢄ25 mL) and diethyl ether (2ꢄ25 mL). This yielded a white
solid. Yield: 55%; m.p.: 2198C; 1H NMR (300 MHz, [D6]DMSO): d=
7.06 (t, J=7.7 Hz, 2H), 7.17 (dd, J=6.6 Hz, 4.8 Hz, 2H), 7.38 (d, J=
8.0 Hz, 2H), 7.59 (d, J=7.7 Hz, 2H), 7.70 (s, 2H), 8.25 (d, J=8.4 Hz,
2H), 8.41 (d, J=3.7 Hz, 2H), 8.97 (s, NH, 2H), 10.95 (s, NH, 2H),
11.65 ppm (s , NH, 2H); 13C{1H} NMR (75 MHz, [D6]DMSO): d=105.8
(ArCH), 114.6 (ArCH), 116.6 (ArCH), 119.5 (ArCH), 119.7 (ArCH),
120.5 (ArCH), 125.0 (ArC), 128.6 (ArC), 129.0 (ArC), 130.6 (ArC), 138.2
(ArCH), 148.0 (ArCH), 152.0 (ArC), 153.1 (CO), 160.0 ppm (CO); IR
(film): n˜ =3269, 1644, 1539 cmÀ1; LRMS (ESÀ): m/z: 529.2 [MÀH]À;
HRMS (ES+): m/z: exp: 531.1879 [M+H]+; calcd: 531.1893 [M+H]+.
7,7’-carbonylbis(azanediyl)bis(N-phenyl-1H-indole-2-carboxamide
(2):
The synthesis of 7-nitro-N-phenyl-1H-indole-2-carboxamide is taken
from a method described by Bates et al.[7] 7-Nitro-N-phenyl-1H-indole-2-
carboxamide (0.20 g, 0.71 mm) and a Pd/C 10% catalyst (0.02 g) were
suspended in ethanol (25 mL). The flask was then evacuated and the mix-
ture placed under a hydrogen atmosphere and stirred vigorously for 3 h.
After this time the palladium catalyst was removed by filtration through
celite and the filtrate taken to dryness and placed under reduced pressure
Crystallization
Crystallizations were performed by dissolving ca. 0.05 mmol of receptor 2
in 2 mL of DMSO followed by addition of approximately 0.25 mmol tet-
rabutylammonium dihydrogen phosphate and allowing the solution to
stand.
X-ray Structure Determination
affording
a white solid. 7-Amino-N-phenyl-1H-indole-2 carboxamide
(0.18 g, 0.71 mm) was dissolved in a mixture of DCM (20 mL) and a satu-
rated aqueous solution of NaHCO3 (20 mL). Triphosgene (0.28 g,
0.95 mm) was added in portions to the two-phase solution and the mix-
ture was left stirring under a nitrogen atmosphere overnight. The organic
layer was diluted with DCM (100 mL), washed with water, dried over
MgSO4, filtered, and concentrated in vacuo. The pure product was isolat-
ed by sonication in MeOH (5 mL) for 3 mins and removed by filtration.
The product was isolated as a white solid. Yield: 30%; m.p.: 1748C;
1H NMR (300 MHz, [D6]DMSO): d=7.05–7.15 (m, 4H), 7.36–7.43 (m,
6H), 7.51 (d, J=1.8 Hz, 2H), 7.60 (d, J=7.7 Hz, 2H), 7.84 (d, J=7.7 Hz,
4H), 8.97 (s, urea NH, 2H), 10.30 (s, amide NH, 2H), 11.62 ppm (s,
indole NH, 2H); 13C{1H} NMR (75 MHz, [D6]DMSO): d=104.5 (ArCH),
114.3 (ArCH), 116.3 (ArCH), 120.3 (ArCH), 120.5 (ArCH), 123.7
(ArCH), 125.0 (ArC), 128.6 (ArC), 128.8 (ArCH), 131.3 (ArC), 138.9
Data were collected on a Bruker Nonius KappaCCD with a Mo rotating
anode generator (l=0.71073) employing phi and omega scans; standard
procedures were followed. Lorentz and polarization corrections were ap-
plied during data reduction with DENZO[9] and multi-scan absorption
corrections were applied using SADABS.[10] The structure was solved and
refined using the SHELX suite of programs.[11]
Crystal data for the monohydrogen phosphate complex of compound
2.TBA2HPO4.2H2O: C63H101N8O9P, 0.18ꢄ0.05ꢄ0.02 mm3, Mr =1145.49,
T=120(2) K, Triclinic, space group P-1, a=13.9084(5), b=16.5116(5),
c=16.5971(4) ꢂ, a=65.864(2)8, b=72.349(2)8, g=71.014(2)8, V=
3224.48(17) ꢂ3, 1calc =1.180 MgmÀ3, m=0.102 mmÀ1, Tmin =0.9818 Tmax
=
0.9980, Z=2, reflections collected: 48032, independent reflections: 11275
(Rint =0.0900), 2qmax =25.008, Parameters=768, largest difference peak
and hole=0.748 and À0.753 eꢂÀ3, final R indices [I>2sI]: R1=0.0931,
(ArC), 153.2 (CO), 159.7 ppm (CO); IR (film): n˜ =3289, 1661 cmÀ1
;
wR2=0.1597,
R
indices (all data): R1=0.1586, wR2=0.1914.
LRMS (ESÀ): m/z: 527.5 [MÀH]À; HRMS (ES+): m/z: exp: 551.1794
CCDC 734479 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre at www.ccdc.cam.ac.uk/data_request/cif.
[M+Na]+; calcd: 551.1802 [M+Na]+
Bis(benzyl-7-nitro-1H-indole-2-carboxamine)-urea (3): N-benzyl-7-nitro-
indole-2-carboxamide (0.243 g, 0.824 mm) was dissolved in ethanol
(20 mL). Palladium on carbon 10% (0.025 g) was added. The reaction
vessel was evacuated and placed under a hydrogen atmosphere and
stirred at room temperature for 6 h. The reaction mixture was then fil-
tered through celite and reduced in vacuo to yield a white solid. As-
sumed yield: 100%. The white solid and triphosgene (0.051 g, 0.171 mm)
were dissolved in a two-phase solution of DCM (50 mL) and saturated
sodium bicarbonate solution (50 mL) and stirred at room temperature
for 2 h. The two-phase solution was then filtered. The resulting grey solid
was sonicated in water (500 mL) for 1 hr. A white solid was collected by
filtration and washed with water (2ꢄ25 mL), DCM (10 mL), and diethyl
ether (2ꢄ25 mL). Yield: 56%; m.p.: 1628C; 1H NMR (300 MHz,
[D6]DMSO): d=4.53 (d, J=5.85 Hz, 4H), 7.02 (t, J=7.9 Hz, 2H), 7.20–
7.38 (m, J=7.7 Hz, 14H), 7.52 (d, J=7.7 Hz, 2H), 8.89 (s, NH, 2H), 9.13
(t, J=5.9 Hz, NH, 2H), 11.46 ppm (s, NH, 2H); 13C{1H} NMR (75 MHz,
[D6]DMSO): d=42.2 (CH2), 103.4 (ArCH), 113.3 (ArCH), 115.9
(ArCH), 120.3 (ArCH), 125.2 (ArCH), 126.8 (ArC), 127.3 (ArCH), 128.1
Acknowledgements
P.A.G. thanks the EPSRC for funding and for access to the crystallo-
graphic facilities at the University of Southampton. C.C. would like to
thank Italian Ministero dell’Istruzione, dell’Universitꢀ e della Ricerca
Scientifica (MIUR) for financial support (Project PRIN-2007C8RW53).
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Received: June 29, 2009
Published online: September 3, 2009
Chem. Asian J. 2010, 5, 555 – 561
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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