Highly stable self-association of 5-(guanidiniocarbonyl)-1H-pyrrole- 2carboxylate in DMSO - The importance of electrostatic interactions

Article abstract of DOI:10.1002/(sici)1099-0690(199909)1999:9<2397::aid-ejoc2397>3.0.co;2-3

The zwitteriomc compound 5-(guanidiniocarbonyl)-1H-pyrrole-2-carboxylate (1) self-assembles to form dimers, which are completely stable in DMSO even at 170 °C or at concentrations of 0.001 mM. This high stability stems from a combination of multiple weak interactions. NMR titrations of 1H-pyrrole-2- carboxylate (5) with (1H-pyrrole-2-carbonyl)-guanidinium (6) and [5- (methoxycarbonyl)-1H-pyrrole-2-carbonyl]guanidinium (8) led to binding constants of K ? 10⁶ mol^-1 in DMSO and K ? 10³ mol^-1 in 40% water/DMSO for carboxylate binding by the 2-(guanidiniocarbonyl)pyrrole moiety. The stability constant for the dimer 1₂ in DMSO could therefore be estimated as K ? 10¹² mol^-1. In solution, the self-association process of 1 can be completely disrupted by protonation of the carboxylate group. In the solid state, however, the hydrochloride salt 1⁺ also exists as a similar but only very weakly hydrogen-bonded dimer.

Full text of DOI:10.1002/(sici)1099-0690(199909)1999:9<2397::aid-ejoc2397>3.0.co;2-3

FULL PAPER
Highly Stable Self-Association of 5-(Guanidiniocarbonyl)-1H-pyrrole-2-
carboxylate in DMSO – The Importance of Electrostatic Interactions
Carsten Schmuck[a]
Keywords: Supramolecular chemistry / Self-assembly / Molecular recognition / Guanidinium cations
The zwitterionic compound 5-(guanidiniocarbonyl)-1H-
pyrrole-2-carboxylate (1) self-assembles to form dimers,
which are completely stable in DMSO even at 170 °C or at
mol–1 in DMSO and K ഠ 103 mol–1 in 40% water/DMSO for
carboxylate binding by the 2-(guanidiniocarbonyl)pyrrole
moiety. The stability constant for the dimer 12 in DMSO could
therefore be estimated as K ഠ 1012 mol–1. In solution, the self-
association process of 1 can be completely disrupted by
protonation of the carboxylate group. In the solid state,
however, the hydrochloride salt 1+ also exists as a similar but
only very weakly hydrogen-bonded dimer.
concentrations of 0.001 mM. This high stability stems from a
combination of multiple weak interactions. NMR titrations of
1H-pyrrole-2-carboxylate (5) with (1H-pyrrole-2-carbonyl)-
guanidinium (6) and [5-(methoxycarbonyl)-1H-pyrrole-2-car-
bonyl]guanidinium (8) led to binding constants of K ഠ 106
Introduction
Results and Discussion
It is known that the guanidinium group constitutes a
good binding group for oxo anions such as phosphates[12]
or carboxylates.[13] Due to the additional electrostatic inter-
action, such complexes are stronger than their neutral
counterparts (i.e. complexes between carboxylic acids and
aminopyridines).[14][15] Even so, complexes between guani-
dinium cations and carboxylates are normally very weak
in highly competitive solvents.[16] Only a few systems bind
carboxylates in DMSO, methanol, or even water.[13] To
achieve strong binding in such polar solvents, additional
binding interactions are therefore necessary. Following pre-
vious work in this laboratory, 2-(guanidiniocarbonyl)-1H-
pyrroles were introduced as a new class of receptors for
carboxylates (Figure 1), which indeed showed improved
binding properties compared to simple acylguanidines. The
binding of carboxylates can be increased by a factor of up
to 30 compared to the parent acetylguanidinium cation,
with binding constants of the order of K ഠ 103 molϪ1 even
in 50% water/DMSO.[17]
Molecular recognition and especially self-assembly[1] can
lead to the formation of highly complex and fascinating
structures, as exemplified in nature by the molecular archi-
tecture of the tobacco virus, the formation of protein pla-
ques in AlzheimerЈs disease, or the association of microtub-
uli during mitosis.[2] Over the past few years, intense re-
search has been directed towards gaining an understanding
of the concepts and principles that govern these processes.
Artificial self-assembling systems have also been devised,
which may prove useful in the design of novel materials
and nanostructures.[1c,3]
Besides metal coordination,[4] most of the work in this
field is concerned with weak interactions[5] such as hydro-
gen bonds, hydrophobic interactions, or π-π stacking inter-
actions, that lead to the assembly of one or more building
blocks into more complex structures.[6] Despite the useful-
ness of this approach, one major drawback of simple hydro-
gen-bonding interactions, for example, is that their strength
decreases rapidly as the polarity of the surrounding solvent
increases, owing to the competitive solvation of donor and
acceptor sites by the solvent.[7][8] Therefore, most systems
described to date show aggregation only in the solid state[9]
or in organic solvents such as chloroform.[10] However, it
would be very desirable to have access to self-assembling
systems that also function in more polar (i.e. more “natu-
ral”) solvents such as DMSO or water.[11] The present
paper deals with the synthesis of a very simple, yet ef-
ficiently self-associating molecule, which forms highly stable
dimers in DMSO, held together by multiple weak interac-
tions. Furthermore, the formation of this dimer can be
turned off and on by protonation or deprotonation of the
molecule.
Figure 1. Idealized hydrogen-bonding interactions in the complex
between carboxylates and 2-(guanidiniocarbonyl)-1H-pyrroles
It was reasoned that by attaching a carboxylate group at
the 5-position of the pyrrole ring, a 5-(guanidiniocarbonyl)-
1H-pyrrole-2-carboxylate (1) would be obtained, which
possesses a carboxylate and a complementary binding
group within the same molecule and should therefore rep-
resent a heteroditopic molecule capable of self-associ-
ation.[18][19] The pyrrole ring forms a rigid scaffold pre-
venting intramolecular association of the carboxylate and
acylguanidinium groups and at the same time places these
groups in a U-shaped geometrical arrangement that should
[a]
Institut für Organische Chemie, Universität zu Köln,
Greinstrasse 4, D-50939 Köln, Germany
Fax: (internat.) ϩ 49-(0)221/470-5102
E-mail: carsten.schmuck@uni-koeln.de
Eur. J. Org. Chem. 1999, 2397Ϫ2403
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0909Ϫ2397 $ 17.50ϩ.50/0
2397

C. Schmuck
FULL PAPER
favour intermolecular association (Figure 2). By virtue of of base gives the anion 1Ϫ, which again is freely soluble in
the strong binding interaction between 2-(guanidiniocar- methanol and water.
bonyl)pyrroles and carboxylates, such self-assembled struc-
tures should be stable even in DMSO or water.
The 1H-NMR spectrum (Figure 3) of the protonated cat-
ion 1ϩ (picrate salt in [D6]DMSO) shows the “normal” sig-
nals expected for an acylguanidinium cation,[25] i.e. a broad
signal at δ ϭ 8.2 for the 4 guanidinium NH2 protons, a sin-
glet for the pyrrole NH at δ ϭ 12.7, and broad signals for
the amide NH and the carboxyl proton at δ ϭ 11.1 and
13.2, respectively. The unsplit signal due to the 4 guanidin-
ium NH protons shows that in DMSO there is no intramol-
ecular hydrogen bonding between these protons and the ad-
jacent carbonyl group. Upon deprotonation, the signals are
markedly shifted downfield; the signal due to the guanidin-
ium NH2 protons splits into two signals (two protons each),
appearing at δ ϭ 8.1 and 9.8; the amide NH signal is shifted
downfield by nearly 4 ppm and appears at δ ϭ 14.8, and
the pyrrole NH signal is shifted by 0.4 ppm and appears at
δ ϭ 13.1. Of the pyrrole CH protons, only the 4-H signal
shows a minor upfield shift (< 0.2 ppm), probably due to
the increased electron density in the heterocycle compared
to the cation. Further deprotonation leads to the anion 1Ϫ,
which shows only very broad, unresolved signals in the
NMR spectrum, typical for an acylguanidine.
Figure 2. 5-(Guanidiniocarbonyl)-1H-pyrrole-2-carboxylate (1) as
a rigid heteroditopic molecule with complementary hydrogen-bond
donor (D) and acceptor (A) sites capable of self-assembly
The synthesis of 1 is outlined in Scheme 1. Pyrrole (2)
was first transformed into 2-(methoxycarbonyl)-1H-pyrrole
(3) by acylation with trichloroacetyl chloride and sub-
sequent cleavage of the trichloroacetyl group with sodium
methoxide.[20] VilsmeierϪHaack formylation,[21] followed
by oxidation with permanganate, gave 5-(methoxycar-
bonyl)-1H-pyrrole-2-carboxylic acid (4).[22] The guanidinyl-
ation of this compound was best achieved by refluxing the
ester and an excess of guanidinium chloride with sodium
methoxide in methanol.[23] Other attempts at carrying out
this reaction, e.g. by treating the ester with the free guani-
dine base, prepared by ion-exchange from the hydrochlo-
ride, or by treating activated acid derivatives with guani-
dine, either failed or gave only very low yields.[24]
These results are consistent with the formation of a zwit-
terion capable of self-association. Compound 1 can exist
1
both in a neutral and a zwitterionic form. The H-NMR
spectrum of 1 clearly shows that, as expected on the basis
of the pKa values,[26] only the zwitterion is present, as no
carboxyl proton but only 4 guanidinium NH2 proton sig-
nals can be seen. In this zwitterionic form, the carboxylate
clearly interacts with the 2-(guanidiniocarbonyl)pyrrole
group of another molecule as shown in Figure 4. The reso-
nance due to the two guanidinium protons that are not in-
volved in hydrogen bonding to the carboxylate hardly shifts
at all (< 0.1 ppm), whereas the signals due to the other two
guanidinium protons, the amide NH, and the pyrrole NH,
all of which are involved in the complexation process, show
significant downfield shifts (up to 3.6 ppm), indicative of
hydrogen-bonding interactions. Such a complexation can-
not occur intramolecularly due to the rigid nature of 1, thus
it has to be concluded that intermolecular self-association
takes place.
Molecular modelling (Macromodel V 6.0)[27] supports
the formation of discrete dimers. Two molecules of 1 can
easily form C2-symmetric dimers 12 in a head-to-tail orien-
tation. As can be seen in Figure 5, there is a near perfect
geometric fit between the complementary groups on each
molecule. The planes of the two molecules are slightly tilted
(dihedral angle 140°). The hydrogen bonds are all very short
Scheme 1. Synthesis of 5-(guanidiniocarbonyl)-1H-pyrrole-2-car-
boxylate (1); reagents and conditions: (i) Cl3CCOCl, Et2O, reflux,
30 min., 85%; (ii) 0.1 equiv. NaOMe, MeOH, r.t., 30 min, 63%; (iii)
POCl3/DMF, CH2Cl2, 0 °C Ǟ reflux, 63%; (iv) KMnO4, acetone/
water (1:1, v/v), 40 °C, 30 min, 75%; (v) 5 equiv. guanidinium chlo-
ride, 5 equiv. NaOMe, MeOH, reflux, 12 h, 72%
The free base of compound 1 can easily be protonated (between 169 and 172 pm for the NHϪO distances), re-
by picric or hydrochloric acid to give the corresponding cat- flecting the strong interaction between the two molecules.
ionic salts 1ϩ. These salts are readily soluble in methanol
Due to the apparent high stability of the dimer in DMSO
or DMSO and can be recrystallized from water. Addition (e.g. concentration and temperature invariance of the shift
of one equivalent of base, however, leads to deprotonation changes, vide infra) and the insolubility in all other solvents
and formation of the overall neutral compound 1, which is (1 even precipitates upon addition of 10% water to a 1 m
virtually insoluble in all solvents other than DMSO. Even solution in DMSO), no conditions were found under which
in DMSO, the maximum achievable concentration is only the dissociation of the dimer itself could be studied directly
around 5 m. Deprotonation of 1 by a second equivalent by NMR.[28]
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Highly Stable Self-Association of 5-(Guanidiniocarbonyl)-1H-pyrrole-2-carboxylate in DMSO
FULL PAPER
1
Figure 3. H-NMR spectra of the protonated form 1ϩ and the dimeric zwitterion 12 (300 MHz, [D6]DMSO)
However, the association constant for the dimer, with its
two equivalent binding sites, can be estimated if the binding
energy for one such interaction is known. NMR titrations
ϩ
of 1H-pyrrole-2-carboxylate (as the NMe4 salt) (5) with
2-(guanidiniocarbonyl)pyrrole picrate (6) and [5-(meth-
oxycarbonyl)-1H-pyrrole-2-carbonyl]guanidinium chloride
(8), obtained from 1 by esterification of the acyl chloride
with methanol (Scheme 2), were performed. The interac-
tions in the complex of 5 with 6 correspond to one of the
two binding sites in the dimer. In the complex between 5
and 8, there is an additional hydrogen-bonding interaction.
In both cases, the observed complexation-induced shift
changes are the same as those observed for the zwitterion
1. The binding constants for the complexes of 5 with 6 and
8 were calculated using a non-linear least-squares fitting
procedure with a 1:1 association model in each case (Table
1). In DMSO, there is a linear increase in the chemical shift
change until a molar ratio of 1:1 is reached (Figure 6),
Figure 4. Association of 1 to give the dimer 12, held together by a
network of multiple weak interactions; this dimerization is only
possible in the zwitterion 1; neither the cation 1ϩ nor the anion 1Ϫ
can form a similarly stable complex
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C. Schmuck
FULL PAPER
Figure 6. NMR titration curve of carboxylate 5 (1 m) with guani-
dinium cation 6 in [D6]DMSO
Figure 5. Calculated structure of the dimer 12 in water; energies
of two different conformers of the dimer 12 relative to two non-
interacting monomers 1 (according to molecular dynamics calcula-
tions; in kJ molϪ1
)
Figure 7. NMR titration curves of carboxylate 5 (1 m) with guani-
dinium cations 7 and 8 in 40% water/DMSO
as is suggested by the findings of molecular modelling stud-
ies (vide infra), the dimerization constant for 1 in DMSO
can be estimated as K ഠ 1012 molϪ1. Hence, it is not sur-
prising that under the conditions accessible by NMR, no
indications of any break-up of the dimer could be seen.
Even in 40% water/DMSO, the binding constant for the
complex of 5 with 8 is still K ϭ 4.1 ϫ 103 molϪ1 (Table 1).
In principle, the self-association could also lead to the
formation of oligomeric chain-like structures instead of dis-
crete dimers. Two such possible structures are shown in Fig-
ure 8, in which the zwitterions are either arranged in a zig-
zag (type B) or in a linear way (type C). However, the com-
plex of 5 with the unsubstituted acetylguanidinium cation 7
has a binding constant K ϭ 1.5 ϫ 102 molϪ1 (in 40% water/
DMSO), which is 30 times lower than that with 8. This
energetic disadvantage of simple 2-point binding makes the
formation of oligomers 1n of type C less likely than dimers
12. Formation of linear oligomers of type C would only
Scheme 2. Compounds which are not capable of self-assembly; re-
agents and conditions for the synthesis of [5-(methoxycarbonyl)-
1H-pyrrole-2-carbonyl]guanidinium (8): (i) 1.1 equiv. (COCl)2,
DMF (cat.), CH2Cl2, reflux 2 h; (ii) MeOH, r.t., 10 h, 44% over
both steps
Table 1. Binding constants of carboxylate 5 with cations 6, 7, and
8[a]
Cation
Solvent
K [molϪ1
]
6
7
8
8
DMSO
ca. 106
150
H2O/DMSO
DMSO
ca. 106
4140
H2O/DMSO
[a] Measured by NMR titration at 25 °C; [5] ϭ 1 m in [D6]DMSO
or 40% H2O/[D6]DMSO.
clearly indicating the 1:1 stoichiometry of the binding inter- allow the same 2-point interaction with the carboxylate as
action. The binding constants for both complexes 5/6 and seen in the complex with 7 (Figure 8). In comparison with
5/8 are K ഠ 106 molϪ1. Using this binding constant for the the formation of such oligomeric chains, the dimer would
complexation of a carboxylate group by an acylguanidin- therefore be expected to have a binding constant some 900
ium pyrrole group and assuming that the association ener- times higher. In the zigzag like oligomer of type B the same
gies for the two binding sites in the dimer 12 are identical, three point binding is present as in the dimer 12. In prin-
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Highly Stable Self-Association of 5-(Guanidiniocarbonyl)-1H-pyrrole-2-carboxylate in DMSO
FULL PAPER
1
ciple, the concentration dependence of the H-NMR spec-
trum should allow a distinction to be made between dimer-
ization and oligomerization. With decreasing concen-
tration, the formation of oligomers becomes more and more
unfavorable relative to the formation of discrete dimers. In
the concentration range from 5 m to as low as 0.001 m
1
in [D6]DMSO, the H-NMR spectrum of the zwitterion 1
does not change. Moreover, even at 170 °C, no indications
of any breaking-up of the aggregates were found, further
highlighting their very high stability. Taking all data into
account, it seems likely that in the self-association process
of the zwitterion 1 no oligomers but exclusively discrete di-
mers are formed.[29]
Figure 9. X-ray crystal structure of 1ϩ (chloride salt); above: sche-
matic representation; below: top view (left), and side view (right)
(chloride anions and water molecules have been omitted for the
sake of clarity)
compound 1 in water. A conformational docking study re-
vealed the proposed dimeric structure 12 to be the energy
minimum, with any other possible orientation of the two
molecules being at least 20 kJ molϪ1 less stable (Figure 5).
Also of interest was the structure B, in which the relative
orientation of the two molecules is such that only one of
the two carboxylates and acylguanidinium groups interact
while the others are pointing away from each other and are
solvated only by water. The binding site in this conformer
possesses a similar geometry to that in A (similar hydrogen-
bonding distances, though there is a more pronounced tilt).
The relative energy is more or less half-way between the
energies of the two non-interacting molecules and that of
the fully complexed dimer 12. As expected for a rigid mol-
ecule, the binding energies for the two binding sites are
identical. Figure 10 shows a superposition of complex
Figure 8. Three possible alternatives for the self-association of zwit-
terion 1: discrete dimers (A) and oligomer chains (B and C)
A major part of the binding energy of the dimer 12 is
probably associated with the ion pairing between the car-
boxylate group and the guanidinium moity; this is one rea-
son why protonation of the carboxylate groups disrupts the
dimer. Addition of the carboxylic acid 5 to guanidinium
cation 6 or 8 in DMSO at millimolar concentrations does
not lead to any shift changes in the NMR spectra, which
implies that the binding constant for this type of interaction
must be < 100 molϪ1. The carboxylate is therefore bound
with a binding constant at least three times higher than that
for binding of the acid.
The cation 1ϩ does not self-assemble in polar solution.
However, the X-ray crystal structure of the hydrochloride
salt 1ϩ (Figure 9)[30] shows the existence of a very weakly
bound dimer (1ϩ)2 in the solid state, held together by 4
intermolecular hydrogen-bonding interactions. These hy-
drogen bonds are all very long (OϪH distances 223 and
235 pm, respectively), reflecting the weak nature of the
complex. The protonation or deprotonation of the car-
boxylate group in the zwitterion 1 therefore provides a
means of turning the self-association off or on.
Figure 10. Superposition of 50 structures of the dimer 12 in water,
sampled from a molecular dynamics calculation over 100 ps at
To gain further insight into the stability of such struc-
tures, we performed molecular mechanics calculations on 300 K
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C. Schmuck
FULL PAPER
tion was acidified with hydrochloric acid. The white precipitate
formed was filtered off, washed with cold water, and redissolved in
aqueous sodium hydroxide. Upon addition of picric acid, the pic-
rate salt precipitated, which was filtered off and recrystallized from
ethanol to give orange needles (2.28 g, 52%). Ϫ 1H NMR (300
MHz, [D6]DMSO): δ ϭ 6.28 (dt, 1 H, pyrrole CH), 7.04 (m, 1 H,
pyrrole CH), 7.20 (m, 1 H, pyrrole CH), 8.11 (br. s, 4 H, guanidin-
ium NH2), 8.58 (s, 2 H, picrate), 10.71 (br. s, 1 H, amide NH),
12.20 (s, 1 H, pyrrole NH). Ϫ 13C NMR (75.5 MHz, [D6]DMSO):
δ ϭ 110.55 (CH), 115.22 (CH), 123.34 (quat. C), 125.41 (CH),
127.09 (CH), 142.04, 155.29, 159.83, 161.01 (all quat. C). Ϫ
C6H7N4O·picrate (381.1): calcd. C 37.79, H 2.91, N 25.72; found
C 37.72, H 3.01, N 25.82.
structures sampled over a period of 100 ps at 300 K in
water, as generated by a molecular dynamics calculation.
The complex barely changes its structure, with not one of
the binding interactions being even temporarily broken over
time. This again clearly reflects the high stability of the di-
mer. More detailed studies aimed at further elaborating the
importance of the various binding interactions are currently
in progress.
Conclusions
The design of systems that self-assemble in highly polar
solvents remains a difficult task, owing to the weak nature
of non-covalent intermolecular forces in such solvents. It
has been shown herein that by using multiple weak interac-
tions, a new self-associating molecule 1 can be constructed
that forms a highly stable dimer 12 in DMSO, with an esti-
mated stability constant K ഠ 1012 molϪ1. This hitherto un-
explored binding motif can also be used for the com-
plexation of other oxo anions in water/DMSO. This might
prove useful for the design of switchable molecular devices,
functional oxo anion receptors, or self-assembling poly-
mers. Relevant work is currently in progress.
[5-(Methoxycarbonyl)-1H-pyrrole-2-carbonyl]guanidinium (8): Com-
pound 1 (644 mg, 3.3 mmol) was suspended in dry THF (20 mL),
dry DMF (3 drops) and oxalyl chloride (835 mg, 6.6 mmol, 2
equiv.) were added, and the reaction mixture was refluxed for 4 h.
To the slightly yellow suspension, methanol (20 mL) was then ad-
ded dropwise at room temperature. After stirring for about 12 h,
the white precipitate formed was filtered off, washed with ice-cold
methanol, and dried over phosphorus(V) oxide. After recrystalliza-
tion from water, white needles were obtained (360 mg, 44%). Ϫ
1H NMR (300 MHz, [D6]DMSO): δ ϭ 3.82 (s, 3 H, Me), 6.88 (d,
1 H, pyrrole CH), 7.51 (s, 1 H, pyrrole CH), 8.30Ϫ8.70 (two broad
overlapping singlets, 4 H, guanidinium NH2), 12.19 (br. s, 1 H, am-
ide NH), 12.87 (s, 1 H, pyrrole NH). Ϫ 13C NMR (75.5 MHz,
[D6]DMSO): δ ϭ 52.03 (CH3), 115.69 (CH), 116.19 (CH), 128.09
(quat. C), 155.78, 159.84, 160.28 (all quat. C). Ϫ C8H11ClN4O3
(246.0): calcd. C 39.02, H 4.51, N 22.76; found C 38.69, H 4.48,
N 22.97.
Experimental Section
General Remarks: Solvents were dried and distilled under argon
prior to use according to standard procedures. All other reagents
were used as obtained from either Aldrich or Fluka. All experi-
ments were performed in oven-dried glassware under argon unless
otherwise stated. 1H- and 13C-NMR spectra were recorded with
a Bruker AM300 spectrometer. Shifts are reported relative to the
deuterated solvents. Elemental analysis was carried out with an
Elemtar Vario EL.
Molecular Modelling: All calculations described in this paper were
performed on an SGI O2 workstation using the software package
Macromodel 6.0.[27] Conformational searches were performed with
at least 1000 steps until the minimum structure had been found sev-
eral times. Molecular dynamics calculations were carried out using
a constant temperature bath at 300 K, with 1.5 fs time steps and 100
ps total time. The Amber* force field and the GB/SA water solvation
model implemented in Macromodel were used in all studies.
5-(Guanidiniocarbonyl)-1H-pyrrole-2-carboxylate (1): The ester 4[22]
(2.0 g, 12 mmol) and guanidinium hydrochloride (5.7 g, 60 mmol)
were added to a solution of sodium methoxide, prepared from so-
dium (1.3 g, 56 mmol) in methanol (50 mL). The reaction mixture
was refluxed for 12 h and then the solvent was evaporated. The
oily residue was dissolved in water (50 mL). Upon acidification
with concentrated hydrochloric acid, the crude product precipi-
tated, which was filtered off and washed thoroughly with methanol
to afford a white solid (1.7 g, 72%). In order to obtain the picrate
salt, 1 was dissolved in aqueous picric acid solution; after filtration
of the hot solution, the product crystallized as yellow needles. Ϫ
1H NMR (300 MHz, [D6]DMSO): δ ϭ 6.84 (d, 1 H, pyrrole CH),
7.01 (s, 1 H, pyrrole CH), 8.16 (br. s, 4 H, guanidinium NH2), 8.58
(s, 2 H, picrate), 11.07 (br. s, 1 H, amide NH), 12.74 (s, 1 H, pyrrole
NH), 13.16 (br. s, 1 H, acid NH). Ϫ 13C NMR (75.5 MHz,
[D6]DMSO): δ ϭ 115.26 (CH), 115.84 (CH), 124.36 (quat. C),
125.39 (CH), 127.05, 132.5, 142.06, 155.05, 159.53, 160.99 (all quat.
C). Ϫ C13H11N7O10·H2O (443.1): calcd. C 35.02, H 2.93, N 22.12;
found C 35.37, H 3.03, N 22.40.
X-ray Crystallographic Study of 1·HCl: Nonius KappaCCD dif-
fractometer (20 °C), Mo-Kα radiation, 2Θmax ϭ 56°; structure de-
termination by direct methods (SHELXS-86, SHELXL-93).
C7H9ClN4O3·2 H2O, monoclinic, space group P21/n, a ϭ 4.779(1),
3
˚
˚
b ϭ 27.868(1), c ϭ 10.654(1) A, β ϭ 112.39(1)°, V ϭ 1311.9(3) A ,
Z ϭ 4, ρcalcd. ϭ 1.360 g cmϪ3, µ ϭ 3.07 cmϪ1, 2268 independent re-
flections, of which 2113 with I > 0 were used; R ϭ 0.0813, Rw ϭ
Ϫ3
˚
0.1256. The final difference density was less than 0.309 eA
.
NMR Titrations: All NMR titrations were carried out by adding
aliquots of a 10 m solution of the guanidinium salt to a 1 m
solution of the carboxylate and recording the chemical shifts after
each addition. Dilution was taken into account when analyzing the
data. For each titration, 6Ϫ8 measurements were made. Where pos-
sible, different NMR signals of the carboxylate were used to calcu-
late the binding constants. For the titrations in water, presaturation
of the water signal was used.
(1H-Pyrrole-2-carbonyl)guanidinium (5): To a solution of sodium
methoxide, prepared from sodium (1.3 g, 56.5 mmol) and dry meth-
anol (50 mL), the ester 3[20] (1.4 g, 11.5 mmol) and guanidinium
hydrochloride (5.5 g, 57.6 mmol) were added and the reaction mix-
ture was refluxed for about 12 h. The solvent was then evaporated,
the residue was taken up in water (20 mL), and the resulting solu-
Acknowledgments
This work was supported by the Fonds der Chemischen Industrie
(Liebig fellowship). The author thanks Dr. Johann Lex, Köln, for
the crystal structure determination of 1ϩ and Professor Albrecht
Berkessel, Köln, for his generous support and helpful discussions.
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Eur. J. Org. Chem. 1999, 2397Ϫ2403

Highly Stable Self-Association of 5-(Guanidiniocarbonyl)-1H-pyrrole-2-carboxylate in DMSO
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