Dimerization of aromatic ureido pyrimidinedione derivatives: Observation of an unexpected tautomer in the solid state

Article abstract of DOI:10.1039/b717285k

Ureido pyrimidinedione derivatives with phenyl, 1-naphthyl and 2-naphthyl substituents form stable dimers via quadruple hydrogen bonding, but the 1-naphthyl derivative presents an unexpected tautomer in the solid state. The Royal Society of Chemistry.

Full text of DOI:10.1039/b717285k

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Dimerization of aromatic ureido pyrimidinedione derivatives: observation
of an unexpected tautomer in the solid statew
Lu Cui,a Suresh Gadde,a Atindra D. Shukla,a Hao Sun,a Joel T. Mague*b and
Angel E. Kaifer*a
Received (in Cambridge, UK) 8th November 2007, Accepted 7th January 2008
First published as an Advance Article on the web 25th January 2008
DOI: 10.1039/b717285k
Ureido pyrimidinedione derivatives with phenyl, 1-naphthyl and
2-naphthyl substituents form stable dimers via quadruple hydro-
gen bonding, but the 1-naphthyl derivative presents an
unexpected tautomer in the solid state.
matic products, containing a DDAA hydrogen bonding array,
were obtained in modest yields, as a result of the low reactivity
of heterocyclic amines, such as 1, with isocyanates.4 Full
synthetic details and characterization data are given in the
1
ESI.w The H NMR spectra of all these compounds is con-
sistent with the presence of dimeric assemblies in CDCl3
solution, as evidenced by the three downfield-shifted NH
proton resonances, reflecting their engagement in hydrogen
bonds. Fig. 1 shows the spectrum of the phenyl derivative
(compound 2) in which the hydrogen-bonded NH protons
appear at 12.7, 11.3 and 10.5 ppm. Similar spectra were
obtained with 3 and 4 in CDCl3 as well as for 2–4 in CD2Cl2
solution.
The design and characterization of hydrogen bonding arrays is
an important research topic within supramolecular chemis-
try.1,2 A single hydrogen bond is usually too weak to provide a
stable connection between two molecules and, thus, it is
commonplace to design residues in which several hydrogen
bonding donor or acceptor sites are arranged side by side to
increase the enthalpic release upon association, as several,
parallel hydrogen bonds form simultaneously.3,4 In this regard
the self-complementary ureidopyrimidine motif, developed by
Meijer and co-workers5 has attracted considerable attention.
Its keto form presents a donor–donor–acceptor–acceptor
(DDAA) array, which gives rise to highly stable dimers. A
complication usually observed with this hydrogen bonding
motif is the presence of its tautomeric enol form (DADA),
which, as expected, gives rise to weaker dimers. Corbin and
Zimmerman have reported structural variations to improve on
this problem.6 In 2005, Sanjayan and co-workers proposed a
ureido pyrimidinedione motif (DDAA),7 capable of forming
stable dimers without complications derived from the exis-
tence of tautomeric forms. We recently prepared a ferrocenyl
ureido pyrimidinedione derivative that has interesting electro-
chemical properties.8 Intrigued by these results, we started a
systematic investigation of aromatic ureido pyrimidinedione
derivatives. Here, we report on the properties of pyrimidine-
dione compounds with phenyl, 1-naphthyl and 2-naphthyl
groups directly attached via a ureido linkage (Scheme 1). All
three compounds form stable dimers, although one of them
exhibits an unexpected tautomeric form in the solid state.
The preparation of the aromatic pyrimidinedione deriva-
tives (2–4) is shown in Scheme 1. Each of the commercially
available isocyanates were reacted with amine 1, which was
prepared as reported before.7 The self-complementary aro-
In order to assess the stability of these dimers we monitored
the chemical shifts of the three NH protons as a function of
temperature with samples of 22 in CDCl3 solution. We found
that the chemical shift of the lowest field NH proton is not
very sensitive to temperature in the range 25–50 1C [d(ppm) =
12.73 ꢀ 0.006T (1C)]. In clear contrast to this, the other two
NH protons exhibit greater temperature sensitivity: d(ppm) =
11.74 ꢀ 0.025T(1C) and d(ppm) = 10.88 ꢀ 0.023T (1C). The
displacement of all the NH resonances to higher field with
increasing temperature is consistent with a decreasing propor-
tion of dimer in the equilibrium mixture. However, the small
temperature sensitivity of the lowest field NH proton reveals
that this peak corresponds to the intramolecular hydrogen
bond, while the remaining two NH peaks correspond to the
intermolecular hydrogen bonds primarily responsible for the
formation of the dimer. Similar data were obtained in dilution
experiments with 2–4 in CDCl3 solution. In this case, lowering
a Center for Supramolecular Science and Department of Chemistry,
University of Miami, Coral Gables, FL 33124-0431, USA. E-mail:
akaifer@miami.edu; Fax: 1-305-284-4571; Tel: 1-305-284-3468
b Department of Chemistry, Tulane University, New Orleans, LA
70118, USA. E-mail: joelt@tulane.edu
w Electronic supplementary information (ESI) available: Synthetic
details and spectroscopic characterization data for compounds 2, 3
and 4. X-Ray experimental details. Plots of chemical shift for the NH
protons of 3 and 4 vs. temperature and concentration. See DOI:
10.1039/b717285k
Scheme 1 Synthesis of the self-complementary compounds surveyed
in this work. The DDAA hydrogen bonding array on the product is
indicated by arrows.
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Fig. 1 1H NMR (400 MHz, RT) spectrum of compound 2 (12 mM)
in CDCl3 solution. The symbol ‘*’ denotes residual solvent peaks.
the analytical concentration of the DDAA compound should
increase the [monomer]/[dimer] ratio and shift the NH proton
resonances to higher field. We did observe upfield shifts for all
the NH proton signals on dilution, but the magnitude of the
shift was very small in the case of the lowest field NH proton
(confirming its engagement in an intramolecular hydrogen
bond) and more pronounced in the case of the other two
NH protons. Since the chemical shift (dobs) of the latter
protons can be expressed as
Fig. 2 X-Ray crystal structures of (A) compound 2, (B) compound 3,
and (C) compound 4.
DADA dimers, due to repulsive secondary interactions9,10
between the four parallel hydrogen bonds in the latter case.
Despite final wR2 being somewhat larger in 3 (0.144) than in 2
(0.097) and 4 (0.117), hydrogen atoms attached to nitrogen
atoms were clearly visible in difference maps for all three
structures and their positional and isotropic displacements
were satisfactorily refined. Furthermore, both endocyclic
C–N bond distances in 3 were identical within experimental
error [average: 1.365(2) A] while the exocyclic C–N distance
was much shorter [1.304(2) A]. In 4, one of the endocyclic C–N
distances was identical to the exocyclic C–N distance [average:
1.356(2) A], while the other endocyclic C–N distance was
shorter [1.319(2) A]. A similar situation was seen in 2. All
these data strongly support the hydrogen atom positions
shown in Fig. 2. Additionally, it can be noted that, for
compounds 2 and 4, the aromatic residues align themselves
almost perfectly with the plane formed by the four hydrogen
bonds. Again compound 3 is the exception, as the naphthyl
groups are clearly twisted away from the hydrogen bonding
plane (see ESIw). The two naphthyl derivatives (3 and 4)
crystallize in the same space group but the unit cell of the 1-
naphthyl compound (3) is smaller by ca. 200 A3. Therefore, in
the solid state, the degree of packing and the density are higher
in 3 as compared to 4. Some representative atomic distances in
these crystals are listed in Table 2. The intermolecular H–O
hydrogen bonding distance is larger in the 32 dimer than in the
other two dimers, in agreement with the weaker binding
energy expected for DADA dimers compared to DDAA
dimers. However, these differences are attenuated in the inter-
molecular N–H distances, whereas the intramolecular O–H
hydrogen bond, which rigidifies these structures and facilitates
the formation of the four intermolecular hydrogen bonds, is in
fact shorter in 32 than in the other two dimers.
dobs = dmxm + ddxd
(1)
where the subscripts ‘m’ and ‘d’ refer to monomer and dimer,
respectively, we fitted the experimental data using regression
analysis (see ESIw for illustrative examples) to obtain the
equilibrium constants for the dimerization process (Kdim).
The resulting values are given in Table 1. Vapor pressure
osmometry (VPO) measurements were also utilized to deter-
mine the effective molecular weights of the solutes in CHCl3
solution. The results (Table 1) also indicate that the predomi-
nant solution species is the dimer in all cases.
Compounds 2–4 formed single crystals of sufficient quality
for X-ray diffraction studies.z All three compounds were
found to crystallize as hydrogen-bound dimers, and represen-
tative dimer structures are shown in Fig. 2. Interestingly
compound 2 and 4 self-recognize in the solid state, forming
dimers through DDAA hydrogen bonding arrays, but com-
pound 3 dimerizes as a tautomeric DADA array. This is a
surprising result, not only because these pyrimidinedione
derivatives were designed to avoid tautomerization, but also
because DDAA dimers are known to be more stable than
Table 1 Dimerization data for compounds 2–4 in chloroform solu-
tion at 25 1C
Compound
Kdim/Mꢀ1
MWa (exptl.)
MWb (calc.)
2
3
4
a
2.0 ꢂ 104
7.4 ꢂ 103
2.1 ꢂ 105
652
762
674
656
752
752
Measured in VPO experiments. Calibration curves were obtained
b
using biphenyl as a MW standard. Calculated for the dimer.
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Table 2 Representative distances (A) and angles in the crystal
structures of compounds 2–4
are consistent with the already mentioned greater stability of
dimers formed by self-recognition of DDAA hydrogen bond-
ing arrays vs. those formed by DADA arrays. In contrast to
this, our DFT computations suggest that the intramolecular
hydrogen bond, which rigidifies the monomers favoring the
formation of four intermolecular hydrogen bonds, is in fact
slightly shorter in the case of DADA tautomeric arrays, in
agreement with the experimental X-ray data.
a
b
c
Compound
dHꢀO
dHꢀN
dHꢀO
Angled/1
2
3
4
1.889(17)
2.05(2)
1.881(18)
2.153(16)
2.16(3)
2.147(18)
1.842(17)
1.74(3)
1.76(2)
178.4(1)
143.2(1)
179.8(1)
a
b
H–O intermolecular hydrogen bond distance. H–N intermolecular
c
hydrogen bond distance. H–O intramolecular hydrogen bond dis-
d
tance. Dihedral angle between the aromatic residue and the H-
Table 3 also lists the formation energies obtained from the
optimization of these structures. For each of the monomers,
more energy is released in the formation of the DADA
tautomer than in the formation of the corresponding DDAA
form. This is again expected, due to the minimization of electro-
static repulsions in the DADA forms. However, upon dimeriza-
tion, DDAA dimers are generally found to be slightly more
stable than their DADA counterparts. However, the calculated
energy of dimerization is clearly smaller in the case of compound
3 (1-naphthyl derivative) than for the other two compounds.
Since in the crystal structure of dimer 32 the naphthyl groups are
twisted out of the hydrogen bonding plane we also run a number
of computations exploring the effect of variable dihedral angles.
The results showed minimal variations compared to the data
given in Table 2. At this point the observed DADA tautomer in
the crystal structure of the 32 dimer can only be justified partially
by the results of these DFT calculations, which lead us to suggest
that crystal packing factors should play an important role in this
particular crystal structure.
bonding plane.
We also performed DFT calculations (using the B3LYP
method with a 3-21G* basis set11) on the monomeric and
dimeric forms of compounds 3 and 4 in an attempt to
rationalize the observation of the DADA tautomer in the
crystal structure of 32. These calculations were done for all
compounds in their DDAA and DADA tautomers. Starting
geometries for the computational work were taken from the X-
ray crystal structural data. A summary of the results is
collected in Table 3.
A comparison between the hydrogen bonding distances
determined experimentally from the X-ray crystal data
(Table 2) and those obtained computationally (Table 3) re-
veals that the latter are uniformly shorter. This finding is easily
rationalized by considering that the computational work does
not take into account the presence of solvent molecules and,
thus, electrostatic attractive interactions, such as hydrogen
bonding, are expected to be overemphasized. However, the
data set in Table 3 is self-consistent and we can draw useful
conclusions from its examination. For instance, in all cases,
the H–O intermolecular hydrogen bond distances are shorter
in dimers formed between DDAA tautomers than in those
formed by DADA tautomers. The same trend, although the
bond length differences are less pronounced, holds for the
H–N intermolecular hydrogen bond distances. These findings
In conclusion, we have shown that aromatic ureido pyrimi-
dinedione derivatives 2–4 self-recognize, forming stable di-
mers, assisted by the formation of two intramolecular
hydrogen bonds, which increase the structural rigidity of each
monomer and facilitate the formation of four parallel inter-
molecular hydrogen bonds. Surprisingly, one of the dimers
(32) crystallizes in the DADA tautomeric form, while the other
two crystallize in their DDAA forms. The |DdimE| value for 32
was found to be significantly smaller than those for 22 and 42.
This fact combined with the higher degree of crystal packing
found in the solid-state structure of 32 are probably the most
important factors behind the observation of the unexpected
tautomeric form.
Table 3 Representative distances (A), angles and energies of forma-
tion (kcal molꢀ1) calculated for dimers formed by compounds 2–4
using DFT methods
Comp. (tautomer)
dHꢀO
dHꢀN
dHꢀO
Angled
a
b
c
2 (DDAA)
2 (DADA)
3 (DDAA)
3 (DADA)
4 (DDAA)
4 (DADA)
1.644
1.712
1.662
1.720
1.642
1.707
1.826
1.870
1.813
1.856
1.831
1.880
1.658
1.642
1.637
1.633
1.659
1.641
179
179
154
153
180
180
Notes and references
z CCDC 670607–670609. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b717285k
1 L. J. Prins, D. N. Reinhoudt and P. Timmerman, Angew. Chem.,
Int. Ed., 2001, 40, 2382.
Comp. (tautomer)
DfE (monomer) DfE (dimer)
D
dimEe
2 J. L. Sessler and J. Jayawickramarajah, Chem. Commun., 2005, 1939.
3 R. P. Sijbesma and E. W. Meijer, Chem. Commun., 2003, 5.
4 T. Park, E. M. Todd, S. Nakashima and S. C. Zimmerman, J. Am.
Chem. Soc., 2005, 127, 18133.
5 F. H. Beijer, R. P. Sijbesma, H. Kooijman, A. L. Spek and E. W.
Meijer, J. Am. Chem. Soc., 1998, 120, 6761.
6 P. S. Corbin and S. C. Zimmerman, J. Am. Chem. Soc., 1998, 120, 9710.
7 P. K. Baruah, R. Gonnade, U. D. Phalgune and G. J. Sanjayan, J.
Org. Chem., 2005, 70, 6461.
8 H. Sun, J. Steeb and A. E. Kaifer, J. Am. Chem. Soc., 2006, 128, 2820.
9 W. L. Jorgenson and J. Pranata, J. Am. Chem. Soc., 1990, 112, 2008.
10 J. Pranata, S. G. Wierschke and W. L. Jorgenson, J. Am. Chem.
Soc., 1991, 113, 2810.
2 (DDAA)
2 (DADA)
3 (DDAA)
3 (DADA)
4 (DDAA)
4 (DADA)
a
ꢀ688 551.6
ꢀ688 564.1
ꢀ784 430.4
ꢀ784 443.1
ꢀ784 431.8
ꢀ784 444.7
ꢀ1 377 173.8
ꢀ1 377 174.0
ꢀ1 568 925.8
ꢀ1 568 925.5
ꢀ1 568 935.9
ꢀ1 568 935.1
b
ꢀ45.8
ꢀ39.6
ꢀ46.5
H–O intermolecular hydrogen bond distance. H–N intermolecular
c
hydrogen bond distance. H–O intramolecular hydrogen bond dis-
d
tance. Dihedral angle between the aromatic residue and the hydro-
e
gen bonding plane. Calculated as
DdimE
=
DfE(dimer)
ꢀ
2DfE(monomer) using the most stable dimer/monomer forms for each
compound.
11 M. E. Zandler and F. D’Souza, C. R. Chim., 2006, 9, 960.
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1448 | Chem. Commun., 2008, 1446–1448