Self-assembly of ureido-pyrimidinone dimers into one-dimensional stacks by lateral hydrogen bonding

Article abstract of DOI:10.1002/chem.200902107

Ureido-pyrimidinone (UPy) dimers substituted with an additional urea functionality self-assemble into one-dimensional stacks in various solvents through lateral non-covalent interactions. ¹HNMR and DOSY studies in CDCl₃ suggest the formation of short stacks (< 10), whereas temperature-dependent circular dichroism (CD) studies on chiral UPy dimers in heptane show the formation of much larger helical stacks. Analysis of the concentration-dependent evolution of chemical shift in CDCl₃ and the temperature-dependent CD effect in heptane suggest that this self-assembly process follows an isodesmic pathway in both solvents. The length of the ag-gregates is influenced by substituents attached to the urea functionality. In sharp contrast, UPy dimers carrying an additional urethane group do not selfassemble into ordered stacks, as is evident from the absence of a CD effect in heptane and the concentration-independent chemical shift of the alkylidene proton of the pyrimidinone ring in CDCl₃.

Full text of DOI:10.1002/chem.200902107

FULL PAPER
DOI: 10.1002/chem.200902107
Self-Assembly of Ureido-Pyrimidinone Dimers into One-Dimensional Stacks
by Lateral Hydrogen Bonding
Marko M. L. Nieuwenhuizen, Tom F. A. de Greef, Rob L. J. van der Bruggen,
Jos M. J. Paulusse, Wilco P. J. Appel, Maarten M. J. Smulders, Rint P. Sijbesma,* and
E. W. Meijer*[a]
Abstract: Ureido-pyrimidinone (UPy)
dimers substituted with an additional
urea functionality self-assemble into
one-dimensional stacks in various sol-
vents through lateral non-covalent in-
teractions. H NMR and DOSY studies
in CDCl3 suggest the formation of
short stacks (<10), whereas tempera-
concentration-dependent evolution of
chemical shift in CDCl3 and the tem-
perature-dependent CD effect in hep-
tane suggest that this self-assembly
process follows an isodesmic pathway
in both solvents. The length of the ag-
gregates is influenced by substituents
attached to the urea functionality. In
sharp contrast, UPy dimers carrying an
additional urethane group do not self-
assemble into ordered stacks, as is evi-
dent from the absence of a CD effect
in heptane and the concentration-inde-
pendent chemical shift of the alkyli-
dene proton of the pyrimidinone ring
in CDCl3.
1
Keywords:
helical structures · self-assembly ·
stacking interactions
supramolecular chemistry
hydrogen bonds
·
ture-dependent
circular
dichroism
(CD) studies on chiral UPy dimers in
heptane show the formation of much
larger helical stacks. Analysis of the
·
Introduction
result of polarization of the urea function during dimeriza-
tion.[9]
The N,N’-disubstituted urea moiety is often used in the con-
struction of hydrogen-bonded supramolecular polymers,[1]
organogelators,[2] foldamers[3] and novel crystalline frame-
works.[4] Urea groups are known to associate strongly
through bifurcated hydrogen bonds,[5] the strength of which
exceeds that of amide and urethane hydrogen bonds.[6] The
aggregation of N,N’-disubstituted urea groups leads to the
formation of linear chains in the solid state[7] and in solu-
tion.[7] FTIR measurements in CCl4 have shown that the
self-assembly of N,N’-dialkyl-substituted urea groups into
linear chains in solution is a cooperative process[8] as a
Due to the aggregation of urea groups into linear chains,
incorporation of these groups in covalent polymers has lead
to the formation of thermoplastic elastomers in which cross-
linking between the chains occurs through non-covalent in-
teractions.[10] Due to the combination of strongly interacting
segments alternating with weakly interacting segments, mi-
crophase-separated materials with a soft block/hard block
morphology are obtained. When the hard blocks contain
urethane and/or urea groups, strong and specific hydrogen-
bonding interactions lead to useful properties, such as a high
modulus for a given hard-block content.[6,11] In addition,
these groups enable molecular recognition and allow for a
modular approach in the development of functional (bio)-
materials.[12]
Recently, Kautz et al. investigated the effect of a combi-
nation of lateral hydrogen bonding between polymeric
chains induced by urea and urethane groups and chain ex-
tension due to strong end-to-end bonding by the quadruply
hydrogen bonding 2-ureido-pyrimidinone (UPy) motif (see
Figure 1).[13]
[a] M. M. L. Nieuwenhuizen, Dr. T. F. A. de Greef,
R. L. J. van der Bruggen, Dr. J. M. J. Paulusse, W. P. J. Appel,
M. M. J. Smulders, Prof. Dr. R. P. Sijbesma, Prof. Dr. E. W. Meijer
Institute for Complex Molecular Systems and
Laboratory of Macromolecular and Organic Chemistry
Eindhoven University of Technology
PO Box 513, 5600 MB Eindhoven (The Netherlands)
Fax : (+31)40-245-1036
E-mail: e.w.meijer@tue.nl
A series of telechelic UPy-, UPy-urea- and UPy-ure-
thane-substituted poly(ethylene butylene) polymers was
studied, and it was shown that directional lateral aggrega-
r.p.sijbesma@tue.nl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902107.
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Scheme 1. Design and structure of UPy monomers bearing additional lat-
erally interacting urea or urethane substituents.
Figure 1. Chain extension and lateral aggregation in UPy-urea- and UPy-
urethane-functionalized polymers.
tion in these supramolecular polymers results in one-dimen-
sional aggregation of the dimerized UPy end groups into
long fibres. Atomic force microscopy (AFM) on these poly-
mers revealed marked differences between the urea- and
urethane-substituted UPy polymers. Whereas lateral hydro-
gen bonding through the urea moiety resulted in the forma-
tion of micrometre-long fibres, lateral hydrogen bonding
through the urethane moiety resulted in a much smaller and
less densely packed morphology compared to the urea-sub-
stituted polymers indicating that aggregation is not com-
plete. Furthermore, tensile testing showed that the material
properties of these polymers are superior to those of the
same supramolecular polymer lacking additional lateral hy-
drogen bonding. Interestingly, differential scanning calorim-
etry (DSC) showed that the fibres display a first-order melt-
ing transition at high temperatures, while temperature-de-
pendent FTIR measurements have shown that this first-
order phase transition is directly associated with the break-
up of the UPy-urea aggregates.[13]
Figure 2. One-dimensional self-assembly and network formation of UPy-
urea and UPy-urethane dimers.
Here we aim to further elucidate the aggregation behav-
iour of UPy-urea and UPy-urethane aggregates. The synthe-
sis of several discrete UPy monomers bearing urea and ure-
thane groups, and their self-assembly in solution, studied by
tions have shown that the UPy dimers stack in an offset
fashion, inducing formation of a helical aggregate.
2) Chiral groups attached to the C6 position of the pyrimidi-
none group: By attaching chiral groups to this position,
possible formation of helical aggregates can be biased by
perturbation of the equilibrium between P- and M-type
helical aggregates.[16] As a result of this perturbation, the
self-assembly of the UPy dimers into ordered aggregates
can be conveniently followed by temperature-dependent
circular dichroism (CD) spectroscopy.
3) A urea or urethane functionality to induce lateral hydro-
gen bonding between UPy dimers. Because hydrogen
bonding through the urea group is much stronger than
hydrogen bonding through the urethane group, variation
at this position will greatly influence the lateral associa-
tion of UPy dimers into one-dimensional aggregates.
4) Additional solubilizing groups attached to urea or ure-
thane moiety: By variation of the R substituent, the self-
assembly of UPy dimers equipped with lateral interact-
ing groups can be studied in a wide range of solvents.
1
concentration-dependent H NMR and temperature-depen-
dent circular dichroism spectroscopy, will be discussed. The
design of the UPy monomers is shown in Scheme 1.
Each UPy monomer consists of the following parts:
1) A UPy group capable of quadruple hydrogen bonding:
By dimerization of the two pyrimidinone rings (Kdim =6ꢁ
107 mꢀ1 in CHCl3),[14] a flat surface is created which en-
hances p–p interactions between two hydrogen-bonded
dimers. Previous DFT calculations using an implicit sol-
vent model have shown that p-stacking of the 4[1H]-pyr-
imidinone dimer is an energetically favourable process.[15]
This additional interaction is important because it results
in the preference for ordered one-dimensional self-as-
sembly over unordered network formation of the UPy-
urea dimers (see Figure 2). Furthermore, these calcula-
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Self-Assembly of Ureido-Pyrimidinone Dimers
FULL PAPER
Moreover, by introducing an electron-withdrawing aro-
matic substituent at this position the intermolecular asso-
ciation between the urea groups is expected to strength-
en.[17]
Results and Discussion
The synthesis of chiral isocytosines 6a and 6b is depicted in
Scheme 2. The synthetic route towards isocytosines 6a and
6b was adapted from a previously established route for con-
Scheme 3. Synthetic route towards chiral UPy-urea monomers 10a and
10b bearing a chiral gallic wedge at the urea functionality. a) 1,1’-Carbon-
yldiimidazole, CHCl3, 4–12 h, 508C; b) mono-Boc-protected 1,6-hexanedi-
amine, CHCl3, 17 h, 508C; c) trifluoroacetic acid, dichloromethane, 4–
13 h, RT; d) 3,4,5-tris[3(S),7-dimethyloctyloxy]phenyl isocyanate (11), tri-
ethylamine, CHCl3, 48 h, 508C. Boc=tert-butoxycarbonyl.
Scheme 2. Synthetic route towards chiral isocytosines 6a and 6b. a) Pd/C,
H2, ethyl acetate, 24 h, RT, 98%; b) periodic acid, 2% pyridinium chloro-
chromate, acetonitrile, 3 h, 0–258C, 81%; c) oxalyl chloride, dimethylfor-
mamide (cat.), dichloromethane, 3–12 h, 0-258C, 90%; d) ethyl potassium
malonate, MgCl2, triethylamine, acetonitrile, 25 h, 0–258C, 61%; e) gua-
nidinium carbonate, potassium tert-butoxide, ethanol, 43–65 h, reflux,
70%.
R-Chiral UPy-urea monomer 13 bearing an aliphatic sub-
stituent was synthesized in two steps from 9a (Scheme 4).
The solubility of 13 in apolar solvents such as heptane and
cyclohexane is extremely low, but in CDCl3 chiral UPy-urea
13 was found to be soluble up to a concentration of 20 mm.
A more soluble UPy-urea 14 carrying a triethylene glycol
substituent at the urea position was also synthesized in two
steps from 9a.
Finally, (S,S,S,S)-chiral UPy-urethane 16 was synthesized
in two steps from isocytosine 6b (Scheme 5) by reaction
with 6-isocyanato-1-hexanol at elevated temperatures in di-
methyl formamide. Reaction of UPy 15 with 3,4,5-
tris[3(S),7-dimethyloctyloxy]phenyl isocyanate resulted in
chiral UPy-urethane 16.
verting acyl chlorides to isocytosines.[18] The corresponding
chiral acyl chlorides were synthesized from commercially
available[19] (R)-3,7-dimethyl-6-octen-1-ol (1a, 100% ee) and
(S)-3,7-dimethyl-6-octen-1-ol (1b, 98.4% ee) by reduction of
the double bond with Pd/C and hydrogen and subsequent
oxidation of alcohols 2a and 2b in the presence of periodic
acid and a catalytic amount of pyridinium chlorochromate[20]
to the corresponding carboxylic acids 3a and 3b, which
were then converted to acyl chlorides 4a and 4b with oxalyl
chloride.
Isocytosines 6a and 6b were activated with 1,1’-carbonyl-
diimidazole[21] and further treated with mono-Boc-protected
1,6-hexanediamine in CHCl3. Removal of the Boc group
with trifluoroacetic acid resulted in chiral ammonium salts
9a and 9b (Scheme 3). Chiral synthons 9a and 9b serve as
convenient intermediates in the synthesis of various chiral
UPy-urea monomers. A chiral 3,4,5-tris[3(S),7-dimethyloctyl-
oxy]phenyl group was introduced at this position to ensure
solubility in apolar solvents. By introduction of this substitu-
ent, two different diastereomers were created: (R,S,S,S)-10a
and (S,S,S,S)-10b.
Concentration-dependent 1H NMR studies: Concentration-
dependent 1H NMR measurements in CDCl3 were per-
formed on UPy-urea 10a in the concentration range of 0–
100 mm, in which all 10a is present as dimers.[22] These meas-
urements show a downfield shift of both urea NH protons at
higher concentrations (Figure 3) accompanied by an upfield
shift of the alkylidene proton located at the pyrimidinone
ring and significant line broadening. The upfield shift of the
proton located on the pyrimidinone ring is typical for self-
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E. W. Meijer, R. P. Sijbesma et al.
both urea NH protons involved
in hydrogen bonds and the pyri-
midinone rings of two UPy
dimers are in close contact.
To gain further proof for the
aggregation of these molecules,
concentration-dependent
DOSY measurements were per-
formed on solutions of 10a in
CDCl3 (Figure 4). They show
that the viscosity-corrected[26]
diffusion constant becomes
smaller at higher concentra-
tions, indicative of the forma-
tion of an aggregate consisting
of multiple dimers of 10a. The
concentration-dependent chem-
ical shift of all protons was sub-
jected to
squares analysis according to a
three-parameter
a nonlinear least-
Scheme 4. Synthetic route towards R-chiral UPy-urea monomer 13 bearing an aliphatic substituent and 14
bearing a triethylene glycol (TEG) substituent at the urea functionality. a) 1,1’-Carbonyldiimidazole, CHCl3,
4 h, 508C, 95%; b) n-dodecylamine, CHCl3, 48 h, 558C, 73%; c) 2-[2-(2-methoxyethoxy)ethoxy]ethyl amine,
CHCl3, 48 h, 558C, 83%.
isodesmic
(equal
K)
self-association
model[27] (see the Supporting
Scheme 5. Synthetic route towards S-chiral UPy-urethane monomer 16
bearing a chiral gallic wedge at the urethane functionality: a) Di-tert-
butyl tricarbonate, 6-amino-1-hexanol, dichloromethane, 0.5 h, RT fol-
lowed by 6b, dimethylformamide, 4.5 h, 908C, 56%; b) tris[3(S),7-dime-
thyloctyloxy]phenyl isocyanate 11, dibutyltin dilaurate, CHCl3, 48 h,
608C, 34%.
assembled structures resulting from close contact of aromat-
ics.[23]
Figure 3. Concentration-dependent 1H NMR spectra of UPy-urea dimer
10a·10a in CDCl3 at 258C.
Calculations on stacked cytosine assemblies have shown
that ring-current effects due to intermolecular interactions
result in a small upfield shift (between 0.1 and 0.3 ppm).[24]
Moreover, the downfield shift of both urea NH protons indi-
cate that these protons are involved in hydrogen bonds[25] at
higher concentrations. The downfield shift of both NH pro-
tons and the concomitant upfield shift of the alkylidene
proton suggest formation of a larger aggregate in which
Information) using the Levenberg–Marquardt algorithm to
gain additional insight into the self-assembly process of
UPy-urea dimer 10a·10a. In this way, the isodesmic equilib-
rium constant K, the chemical shift of protons in the non-ag-
gregated UPy-urea dimer and the limiting value of the
chemical shift of the protons within the stack were obtained.
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Self-Assembly of Ureido-Pyrimidinone Dimers
FULL PAPER
mic self-assembly model. Fitting of the concentration-depen-
dent chemical shift evolution of the second urea NH proton
&
^
( ) and the aromatic proton located on the gallic wedge ( )
to the same isodesmic self-assembly model showed that the
chemical shift evolution of these protons is also well de-
scribed by this model. The isodesmic equilibrium constants
K of these three protons, as determined by nonlinear least-
Table 1. Isodesmic equilibrium constants determined by 1H NMR spec-
troscopy with dilution from 10ꢀ1 to 10ꢀ4 m in CDCl3 at 258C for UPy-urea
dimers 10a·10a, 13·13 and 14·14 and for UPy-urethane dimer 16·16. The
protons are marked according to the symbols used in Figure 3.
Figure 4. Concentration dependence of the viscosity-corrected[26] average
diffusion constant for 10a·10a in CDCl3 at 258C, calculated from the
measured diffusion constants of the signals depicted in Figure 3. The
solid line represents the best fit of the data to the isodesmic model of in-
definite association.
~
&
*
UPy dimer
NH
NH
Gallic aryl
Alkylidene
10a·10a
13·13[a]
14·14
329ꢁ40
14.9ꢁ1.3
2.4ꢁ1.3
322ꢁ38
14.6ꢁ1.9
2.5ꢁ0.5
4.2ꢁ0.5
387ꢁ41
254ꢁ40
5.1ꢁ2.1
[b]
–
[c]
[c]
–
–
[a]
[b]
[c]
16·16
–
–
–
[a] Compound 13 precipitates at a concentration of 30 mm. Dilution ex-
periments were carried out between 30 mm and 0.1 mm. [b] Signal not
present. [c] The observed changes in chemical shift were too small to be
fitted in a reliable way.
Figure 5 displays concentration-dependent chemical shift
data of UPy-urea dimer 10a·10a as well as the best-fit
curves according to the isodesmic indefinite self-assembly
model. As can be observed from Figure 5a, the concentra-
tion-dependent chemical shift evolution of the urea NH
square fitting, are in the range of 322–387mꢀ1 (Table 1).
However, fitting of the concentration-dependent chemical
shift evolution of the alkylidene proton (Figure 5b) shows
that the isodesmic self-assembly model is inappropriate to
describe the experimental data, especially in the high con-
centration regime. The isodesmic equilibrium constant of
this proton was determined to be 254mꢀ1.
*
proton ( ) is accurately described by the indefinite isodes-
The differences between the isodesmic equilibrium con-
stants of the urea NH protons and the alkylidene proton can
be attributed to one of the two following effects. Firstly, the
error in the determination of the exact chemical shift is
much higher for the alkylidene proton than for the urea NH
protons, as the former only shifts by 0.1 ppm but the latter
by almost 1 ppm. Secondly, the difference in isodesmic equi-
librium constant between the two protons can be the result
of the fact that self-assembly of UPy-urea dimer 10a·10a is
hierarchical: At low concentrations, hydrogen bonding of
the urea NH protons results in formation of a hydrogen-
bonded aggregate in which the pyrimidinone rings are not
stacked on top of each other. Only at higher concentrations
does additional stabilization of the aggregate due to p–p in-
teractions occur.
Nevertheless, the equations that describe the concentra-
tion-dependent evolution of chemical shift as a result of di-
merization and isodesmic aggregation are algebraically iden-
tical apart from a factor of two.[27] Therefore, the quality of
the fits alone cannot be used to distinguish between the two
mechanisms. It has been shown that either the osmotic coef-
ficient or the concentration dependence of the diffusion co-
efficient can be used to distinguish between the two possible
mechanisms.[28] Fitting of the concentration-dependent diffu-
sion data of UPy-urea dimer 10a·10a, obtained by PGSE
NMR, to a monomer–dimer model and assuming spherical
aggregates clearly shows that this model is inappropriate to
describe the concentration dependence of the diffusion con-
Figure 5. Concentration-dependent chemical shift of UPy-urea dimer
10a·10a: a) Concentration-dependent chemical shift of the urea NH
&
proton ( ); b) concentration-dependent chemical shift of the alkylidene
~
proton ( ). The curves represent the best fit of the data to the isodesmic
model of indefinite association.
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E. W. Meijer, R. P. Sijbesma et al.
stant, whereas the isodesmic self-assembly model does show
good correspondence (see the Supporting Information).
Dilution of UPy-urea dimer 13·13, bearing linear aliphatic
substituents, resulted in concentration-dependent chemical
shifts of both urea NH protons and the alkylidene proton
(see the Supporting Information) in CDCl3. Fitting of the
concentration-dependent data to a three-parameter isodes-
mic self-assembly model resulted in isodesmic equilibrium
constants for all three protons (Table 1) The average isodes-
mic equilibrium constant of 13·13 is an order of a magnitude
lower than that value of UPy dimer 10a·10a. As already
mentioned, this lower value is most probably the result of
decreased acidity of the urea NH protons in 13 compared to
those in 10a, or possibly due to the absence of attractive p–
p interactions between aromatic rings at the urea group. In
the case of UPy-urea dimer 13·13, the isodesmic equilibrium
constant obtained from the concentration-dependent chemi-
cal shifts of the alkylidene proton was also found to be
lower than that found for the urea NH protons. Even
weaker association was observed for UPy-urea dimer 14·14,
substituted with triethylene glycol chains at the urea posi-
tions (Table 1). This decrease, compared to the association
constant that was found for UPy-urea dimer 13·13, is most
probably caused by competitive hydrogen bonding from the
oxygen atoms in the ethylene glycol chain with the urea NH
protons.[29,1c]
Finally, dilution studies were performed on UPy-urethane
dimer 16·16 in CDCl3. In sharp contrast to the urea-func-
tionalized ureido-pyrimidinones, no concentration-depen-
dent chemical shift was observed for the alkylidene proton,
that is, aromatic stacking interactions are absent even at
high concentrations. Fitting of the concentration-dependent
chemical shift of the urethane NH proton to a four-parame-
ter[30] indefinite isodesmic self-assembly model resulted in
an isodesmic equilibrium constant of only 4.2mꢀ1.
Temperature-dependent circular dichroism studies: Because
UPy-urea dimers 10a·10a and 10b·10b are chiral, their self-
assembly could be studied by circular dichroism (CD).
Indeed, CD spectroscopy performed on solutions of 10a and
10b at a concentration of 3.5ꢁ10ꢀ5 m (corresponding to a
UPy-dimer concentration of 1.75ꢁ10ꢀ5 m) in heptane at
room temperature showed the appearance of a Cotton
effect indicating formation of an aggregate with supramolec-
ular chirality (Figure 6a and b).[31] The reversibility of the
aggregation process was further elucidated by temperature-
dependent CD spectroscopy. At high temperatures, disap-
pearance of the Cotton effect indicated formation of non-ag-
Figure 6. CD spectra of 10a (a) and 10b (b) in heptane (3.5ꢁ10ꢀ5 m) at temperatures between 0 and 908C with 108C intervals (arrow indicates decreasing
temperature). Insets show the molar ellipticity at 220 nm as a function of temperature for the same solution. Normalized degree of aggregation (fn) for
10a (c) and 10b (d). The solid lines in c) and d) are the best-fit curves for a temperature-dependent isodesmic self-assembly model.
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Self-Assembly of Ureido-Pyrimidinone Dimers
FULL PAPER
gregated UPy-urea monomers or dimers, while the Cotton
effect reappeared at lower temperatures. At 208C, the
Cotton effects of 10a and 10b at 220 nm are opposite in
sign, while the absolute value of the Cotton effects are
15.35 mdeg for UPy-urea 10a (R,S,S,S) and 14.63 mdeg for
UPy-urea 10b (S,S,S,S). As this small difference can be ex-
plained by the chiral purity[19] of the starting material, it can
be concluded that the chirality of the aliphatic chain directly
attached to the pyrimidinone ring determines the helicity of
the aggregates formed by UPy-urea dimers 10a·10a and
10b·10b.
mers reveal that a nucleated first-order phase transition is
possible when a single supramolecular polymer condenses
into a fibril consisting of multiple polymeric chains.[33]
Hence, the first-order melting transition of UPy-urea-substi-
tuted polymers in the bulk is most probably the result of
melting of fibres consisting of multiple UPy-urea aggregates
associating through weak interactions, whereas initial forma-
tion of the one-dimensional aggregates is a non-cooperative
process.
The cooling curves obtained from the temperature-depen-
dent changes of the Cotton effect at 220 nm for UPy-urea
10a and 10b are clearly sigmoidal (Figure 6a and b, insets),
that is, the self-assembly of the UPy-urea dimers into helical
aggregates occurs by an isodesmic (equal K) self-assembly
mechanism. Fitting of the normalized degree of aggregation
fn by using a temperature-dependent isodesmic self-assem-
bly model[32] showed good correlation with the experimental
data (Figure 6c and d). This model was used to obtain the
“melting” temperature of the stack (defined as the tempera-
ture at which fn =0.5) and the molecular enthalpy release
due to noncovalent interactions DHm. From the calculated
fraction of aggregated material, an isodesmic equilibrium
constant of 4.5ꢁ105 mꢀ1 at T=258C for UPy-urea dimer
10a·10a in heptane was calculated (see the Supporting In-
formation).
In contrast with the behaviour observed in heptane, a so-
lution of 10a in the more polar solvent 2-propanol with the
same concentration at which a solution of 10a in heptane
showed the appearence of a Cotton effect did not show a
Cotton effect, that is, an ordered aggregate is not present in
this solvent. As 2-propanol can be expected to compete with
the intermolecular hydrogen bonds between UPy-urea
dimers, it can be concluded that intermolecular hydrogen
bonding of the urea functionality plays an important role in
stabilization of the helical aggregate formed by UPy-urea
dimer 10a·10a.
This notion was further confirmed by temperature-depen-
dent CD measurements on UPy-urethane dimer 16·16 in
heptane at an analytical concentration of 16 (S,S,S,S) of
2.5ꢁ10ꢀ5 m. For UPy-urethane dimer 16·16, a Cotton effect
was absent, while UPy-urea dimer 10a·10a does display a
Cotton effect at approximately the same concentration. This
clearly shows the necessity of strong intermolecular hydro-
gen bonding for formation of ordered aggregates consisting
of stacked UPy dimers.
The isodesmic self-assembly of UPy-urea aggregates in so-
lution raises an interesting question regarding the melting
behaviour of UPy-urea-substituted polymers in the bulk. In
the bulk, a first-order melting transition has been measured
at high temperatures, and it has been shown that this first-
order phase transition is directly associated with the break-
down of the UPy-urea aggregates.[12] How is it then possible
that a non-cooperative growth process in dilute solution re-
sults in a first-order phase transition in the bulk? Recent
Monte Carlo simulations on isodesmic supramolecular poly-
Conclusions
The self-assembly of UPy dimers substituted with additional
urea and urethane functionality has been studied in various
solvents. H NMR dilution experiments on UPy-urea dimer
1
10a·10a in CDCl3 showed concentration-dependent chemi-
cal shifts for both urea protons and the alkylidene proton on
the pyrimidinone ring. At high concentrations, the chemical
shift of the two NH protons of the urea functionality shifts
downfield, indicative of formation of a hydrogen-bonded ag-
gregate, while that of the alkylidene proton shifts upfield, in-
dicative of close contact between aromatic surfaces at high
concentrations. The concentration dependence of the chemi-
cal shifts and the diffusion coefficient showed good corre-
spondence with an isodesmic self-assembly model. Based on
these observations, it can be concluded that self-assembly of
the UPy-urea dimer 10a·10a occurs by an isodesmic mecha-
nism.
This notion is further confirmed by CD measurements in
the less polar solvent heptane. In heptane, 10a displays a
temperature-dependent Cotton effect, indicative of forma-
tion of an ordered helical aggregate. From the temperature
dependence of the Cotton effect, the fraction of aggregated
material at each temperature could be determined, and the
isodesmic equilibrium constant at room temperature calcu-
lated (4.5ꢁ105 mꢀ1). Good agreement between the tempera-
ture-dependent isodesmic self-assembly model and the frac-
tion of aggregated molecules was found, that is, also in hep-
tane the self-assembly of UPy-urea dimer 10a·10a occurs in
a stepwise manner.
The isodesmic equilibrium constant in heptane is more
than three orders of magnitude higher than in CDCl3, as a
result of stronger hydrogen bonds and stronger p–p interac-
tions. In contrast to CDCl3, heptane is unable to disrupt the
proposed one-dimensional hydrogen-bond array formed by
the urea protons of aggregated 10a·10a.[34] Furthermore, ar-
omatic–aromatic interactions between UPy-urea dimers
10a·10a are stronger in apolar solvents than in halogenated
solvents such as chloroform, as these compete with the p
electrons of the aromatic group.[35]
In contrast to the urea-substituted UPy dimers, urethane-
substituted UPy dimer 16·16 displays only a small downfield
shift of the NH proton and no upfield shift of the alkylidene
proton in CDCl3. This behaviour is translated to the more
apolar solvent heptane, as no Cotton effect is observed for
16·16 even at the lowest temperature. The lack of a Cotton
Chem. Eur. J. 2010, 16, 1601 – 1612
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1607

E. W. Meijer, R. P. Sijbesma et al.
through the solution for 15 min. Pd/C (0.5 g) was added, the solution was
catalytically hydrogenated in a Parr apparatus and after 24 h no more H2
was taken up. The suspension was filtered over Celite and washed with
ethyl acetate (20 mL). After evaporation in vacuo pure 2a was obtained
as an colourless oil (9.71 g, 61.43 mmol, 92%). 1H NMR (CDCl3): d=
3.67–3.58 (m, 2H, CH2OH), 1.62–1.47 (m, 3H, CH2, (CH2)2CHCH3),
effect for UPy-urethane dimer 16·16 in heptane shows that
strong lateral hydrogen bonding between the UPy dimers is
necessary to form an ordered aggregate consisting of several
UPy dimers.
1.39–1.06 (m, 7H, CH2, (CH2)2CH
0.87 ppm (d, 6H, CH
(CH3)2); 13C NMR (CDCl3): d=60.0 (COH), 39.9,
39.2, 37.3, 29.5, 27.9, 24.6, 22.6 (CH2), 22.5 (CHCH3), 19.6 ppm (CH-
ACHTNUGTRNEN(NUG CH3)2), 0.89 (d, 3H, CHCH3),
AHCTUNGTRENNUNG
Experimental Section
~
AHCTUNGTRENNUNG
General: All chemicals were purchased from Aldrich or Acros and were
used as received unless otherwise noted. Dichloromethane was distilled
over P2O5. Triethylamine was dried over KOH. Tetrahydrofuran was dis-
tilled over molecular sieves. CDCl3 and ethyl acetate were dried over 4 ꢂ
molecular sieves for at least two days. All reactions were carried out
under a protective atmosphere of nitrogen or argon and were followed
by thin-layer chromatography (precoated 0.25 mm silica gel plates from
Merck), and column chromatography was carried out with silica gel 60
(70–230 mesh). 1H NMR and 13C NMR spectra were recorded on
400 MHz (Varian Mercury, 400 MHz for 1H NMR and 100 MHz for
3(R),7-Dimethyloctanoic acid (3a): Periodic acid (31.15 g, 136.8 mmol)
was dissolved in acetonitrile (500 mL) and the mixture was vigorously
stirred at room temperature for 40 min. The solution was cooled on an
ice bath and a solution of 3(R),7-dimethyloctanol (2a, 9.71 g, 61.3 mmol)
and acetonitrile (125 mL) was added dropwise. Pyridinium chlorochro-
mate (0.272 g, 1.27 mmol) was added and the solution was stirred for an
additional 15 min. The reaction mixture was stirred for 3 h at room tem-
perature, after which the acetonitrile was evaporated in vacuo, ethyl ace-
tate (1000 mL) was added and the mixture extracted with H2O:brine (1:1
v/v, 600 mL), saturated NaHSO3 (1000 mL) and brine (1000 mL). The or-
ganic layer was dried over anhydrous MgSO4, filtered and evaporated in
vacuo. Kugelrohr distillation (1 mbar, 1208C) yielded the pure acid as
yellow oil (8.54 g, 49.57 mmol, 81%). ½aꢂ2D5 =+4.61 (neat); 1H NMR
(CDCl3): d=12.0 (s, 1H, COH), 2.36–2.31 (dd, 1H, CH2COOH), 2.15–
2.10 (dd, 1H, CH2COOH), 1.97–1.93 (m, 1H, (CH2)2CHCH3), 1.55–1.48
1
13C NMR), 300 MHz (Varian Gemini, 300 MHz for H NMR and 75 MHz
for 13C NMR) or 500 MHz NMR spectrometers (Varian Unity Inova, 500
MHZ for 1H NMR and 125 MHZ for 13C NMR). Proton chemical shifts
are reported in parts per million downfield from TMS. Carbon chemical
shifts are reported downfield from TMS by using the resonance of the
deuterated solvent as the internal standard. FTIR spectra were recorded
on a Perkin-Elmer Spectrum One FTIR spectrometer with a Universal
ATR sampling accessory. Matrix-assisted laser desorption/ionization time
of flight (MALDI-TOF) mass spectra were obtained on a PerSeptive
Biosystems Voyager-DE PRO spectrometer by using an acidic [a-cyano-
hydroxycinnamic acid (CHCA)] or a neutral 2-[(2E)-3-(4-tert-butylphen-
yl)-2-methylprop-2-enylidene]malononitrile (DCTB)] matrix. Elemental
analysis was performed on a Perkin-Elmer 2400 series II CHNS/O Ana-
lyzer. Melting points were determined on a Bꢃchi Melting Point B-540
apparatus. Optical rotations were measured on a Jasco DIP-370 digital
polarimeter at a wavelength of 589 nm (Na D line) and a temperature of
258C. 3(S),7-dimethyloctanol (2b) was prepared as reported by Schouten
et al.[36] 2-[2-(2-methoxyethoxy)ethoxy]ethyl amine was prepared as re-
ported by Scherman et al.[37] 3,4,5-Tris[(S)-3,7-dimethyloctyloxy]aniline
was prepared as reported by Van Gorp et al.[3a]
(m, 1H, CH2CH
0.86 ppm (d, 6H, CH
((C=O)CH2), 39.0, 36.9, 30.1, 27.9, 24.6, 22.6 (CH2), 22.5 (CHCH3),
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
~
ACTHUNGTRNEUNG(CH3)2); IR (ATR): n=2956, 2928, 2870, 2678, 1705, 1463,
19.6 ppm (CH
1410, 1293, 1220, 936 cmꢀ1
.
3(R),7-Dimethyloctanoic acid chloride (4a): Under an argon atmosphere
3(R),7-dimethyloctanoic acid (3a; 8.54 g, 49.51 mmol) was dissolved in
distilled dichloromethane (100 mL). The solution was cooled on an ice
bath and a drop of dimethylformamide was added. A solution of oxalyl
chloride (5.3 mL, 59.41 mmol) in dry dichloromethane (60 mL) was
added dropwise and the solution was stirred at room temperature over-
night. Evaporation of the solvent and excess oxalyl chloride followed by
flushing with toluene yielded the product as
a yellow oil (8.50 g,
44.57 mmol, 90%). 1H NMR (CDCl3): d=2.90–2.85 (dd, 1H,
(COOH)CH2), 2.70–2.64 (dd, 1H, (COOH)CH2), 2.16–2.07 (m, 1H,
1H NMR titrations: H NMR dilution experiments on 10a in CDCl3 were
1
performed on a 500 MHz Varian Unity Inova equipped with a 5 mm 1H/
X inverse detection probe with gradient capability at 258C. Typical pro-
cedure: Compound 10a (56.9 mg) was dissolved in CDCl3 (1 mL) to give
a 100 mm solution, of which 0.6 mL was injected into an NMR tube. This
was then diluted to a final concentration of 0.1 mm.
(CH2)2CHCH3), 1.56–1.50 (m, 1H, CH2CH
CH2), 0.98 (d, 3H, CHCH3), 0.88 ppm ((d, 6H, CH
(CDCl3): d=173.0 (COOH), 54.2 ((COOH)CH2), 38.8, 36.3, 30.7, 27.8,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
~
ACHTNUGTRNEUNG(CH3)2); IR (ATR): n=
24.5, 22.6 (CH2), 22.5 (CHCH3), 19.2 ppm (CH
2957, 2930, 2871, 1798, 1464, 1385, 985, 967, 929, 724 cmꢀ1
.
DOSY-NMR titrations: Compound 10a (135 mg) was dissolved in dry
CDCl3 (1.0 mL) to give a 140 mm solution (70 mm in 10a·10a). This was
then diluted to a final concentration of 0.5 mm. At each concentration, a
2D DOSY spectrum was recorded using the DOSY bipolar pulse pair
stimulated echo with convection compensation[38] (Dbppste_cc in the
Varian DOSY package) sequence for the determination of the self-diffu-
sion of the different components at a temperature of 258C. The self-diffu-
sion constant was calculated as the average of the values obtained for the
signals of the protons located on the gallic wedge, the alkylidene proton
and the OCH2 protons of the citronellyl chains attached to the gallic
wedge and were corrected for changes in the viscosity.[26]
5(R),9-Dimethyl-3-oxodecanoic acid ethyl ester (5a): Potassium ethyl
malonate (11.8 g, 66.8 mmol) and dry ethyl acetate (100 mL) were trans-
ferred to a round bottom flask. The mixture was cooled on an ice bath
under an argon atmosphere. To this mixture triethylamine (12.1 g,
119.5 mmol) was added followed by dry MgCl2 (5.46 g, 57.4 mmol). The
mixture was heated at 358C for 6 h and subsequently cooled on an ice
bath, and a solution of 3(R),7-dimethyloctanoic acid chloride (4a; 8.3 g,
43,5 mmol) in dry ethyl acetate (35 mL) was added dropwise. The mix-
ture was allowed to stir at room temperature for 19 h and then cooled on
an ice bath while adding 13% HCl (120 mL) carefully while keeping the
temperature below 258C. The aqueous layer was separated and then
back-extracted with CHCl3:ethyl acetate (1:1 v/v, 65 mL). The combined
organic layers were washed with 13% HCl (2ꢁ65 mL), followed by H2O
(70 mL), brine (70 mL) and 5 wt% KHCO3 (150 mL). The organic layer
was dried over sodium sulfate, filtered and evaporated in vacuo. Column
chromatography (SiO2, CHCl3:methanol 100:0 to 98:2 v/v) yielded the
pure product as a yellow oil (7.4 g, 30.53 mmol, 70%). ½aꢂ2D5 =+2.332
(neat); 1H NMR (CDCl3): d=4.22–4.16 (d, 2H, OCH2CH3), 3.41 (s, 2H,
CD spectroscopy: CD measurements were performed on a Jasco J-815
spectropolarimeter at appropriate sensitivity, time constant and scan rate.
Corresponding temperature-dependent measurements were performed
with a PFD-425S/15 Peltier-type temperature controller with a tempera-
ture range of 263–383 K and adjustable temperature slope.
Synthesis: The synthesis of compounds 3b–10b (S enantiomers) is to a
large extent similar to that of the corresponding R enantiomers 3a–10a.
Synthesis and characterization of the former is described in the Support-
ing Information.
(C=O)CH
(dd, 1H, CH
1.48 (m, 1H, CH2CH
12H, CH3); 13C NMR (CDCl3): d=202.4 (COOH), 167.0 ((O=C)O),
2A
2ACHUTGTNRENN(GU C=O)ACHTUTGNREN(NUGN COOEt)), 2.36–2.30
C
ACHTUNGTRENNUNG
3(R),7-dimethyloctanol (2a): 3(R),7-Dimethyl-6-octen-1-ol (1a; 10.40 g,
66.6 mmol) was dissolved in ethyl acetate (75 mL) and argon bubbled
ACHTUNGTRENNUNG
1608
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1601 – 1612

Self-Assembly of Ureido-Pyrimidinone Dimers
FULL PAPER
61.1
G
E
vacuo and the remaining solid was flushed several times with toluene.
Trituration with diethyl ether (25 mL) yielded the product as a white
solid (1.96 g, 3.97 mmol, 88%). M.p. 123.4–130.38C; 1H NMR
28.8, 27.8, 24.5, 22.5, 22.4, 19.6 (CH2), 19.3 (CHCH3), 14.0 ppm (CH-
A
1367, 1315, 1232, 1150, 1096, 1030 cmꢀ1
([D6]DMSO): d=10.6–8.4 (brs, 2H, CNHACHTNGUTERNNU(G C=O), (C=O)NHCH2), 7.73 (s,
1H, CH2NH3+), 7.61 (s, 1H, C=CNHC), 5.76 (s, 1H, C=CH), 3.17–3.12
(q, 2H, NHCH2CH2), 2.80–2.75 (q, 2H, CH2CH2NH3+), 2.38–2.30 (dd,
2-Amino-6-(2(R),6-dimethylheptyl)-6[1H]-pyrimidinone (6a): 5(R),9-Di-
methyl-3-oxodecanoic acid ethyl ester (5a; 7.4 g, 30.53 mmol), guanidini-
um carbonate (3.364 g, 40.30 mmol, 1.3 equiv) and potassium tert-butox-
ide (3.43 g, 30.53 mmol) were dissolved in ethanol (120 mL) and the solu-
tion was stirred at reflux for 65 h. The solvent was evaporated in vacuo
and CHCl3 (400 mL) was added. The organic layer was extracted with
10% citric acid (2ꢁ200 mL), saturated KHCO3 (2ꢁ200 mL) and brine
(2ꢁ200 mL). The organic layer was dried over sodium sulfate. The prod-
uct was concentrated in vacuo and precipitated in pentane. Column chro-
matography (SiO2, CHCl3:EtOH 100:0 to 95:5 v/v) yielded the pure iso-
cytosine (4.45 g, 18.73 mmol, 61%) as a slightly yellow solid. M.p. 201.9–
208.78C; ½aꢂ2D5 =+0.031 (0.02 gmLꢀ1 in CHCl3); 1H NMR (CDCl3): d=
7.00 (brs, 3H, NH), 5.56 (s, 1H, C=CH), 2.42–2.37 (dd, 1H, (CH=
C)CH2CH
1.83 (m, 1H, (CH2)2CHCH3), 1.53–1.46 (m, 1H, CH2CH
1.10 (m, 6H, CH2), 0.89–0.84 ppm (m, 9H, CH3); 13C NMR (CDCl3): d=
38.9, 36.8, 27.7, 24.5, 22.5 (CH2), 22.3 (CHCH3), 19.1 ppm (CH(CH3)2);
IR (ATR): n=3320, 3104, 2953, 2926, 2869, 2742, 1645, 1612, 1520, 1467,
1384 cmꢀ1; MALDI-TOF MS: m/z: calcd: 237.18; found: 238.27 [M+H]+
; elemental analysis (%) calcd for C13H23N3O: C 65.79, H 9.77, N 17.70;
found: C 66.12, H 9.78, N 17.85.
1H, (CH=C)CH2CH
(CH3)(CH2)), 1.90–1.78 (m, 1H, (CH2)2CHCH3), 1.55–1.44 (m, 1H,
CH2CHACTHGUNRTNE(NGU CH3)2), 1.39–1.09 (m, 14H, CH2), 0.87–0.79 ppm (m, 9H, CH3);
ACHTUNGTRENNUG(CH3)ACHTUNGTRENN(GUN CH2)), 2.17–2.12 (dd, 1H, (CH=C)CH2CH-
A
ACHTUNGTRENNUNG
13C NMR ([D6]DMSO): d=167.6, 162.7, 155.7, 152.5, 106.1, 44.9, 39.7,
39.5, 37.3, 32.4, 29.9, 28.3, 27.9, 26.7, 26.4, 25.1, 23.5, 23.4, 20.2 ppm; IR
~
(ATR): n=2934, 2866, 1698, 1640, 1575, 1526, 1465, 1435, 1251, 1202,
1182, 1133, 835, 798, 722 cmꢀ1; MALDI-TOF MS: m/z: calcd: 379.29;
found: 380.41, 402.40 [M+Na]+; elemental analysis (%) calcd for
C22H39F3N5O4: C 53.54, H 7.76, N 14.19; found: C 52.50, H 7.40, N 13.75
(0.15 equiv TFA).
2-{6-(3,4,5-Tris[3(S),7-dimethyloctyloxy]phenylureido}hexylureido-6-
[2(R),6-dimethylheptyl]-4[1H]-pyrimidinone (10a): 2-(6-Aminohexylur-
eido)-6-(2(R),6-dimethylheptyl)-4[1H]-pyrimidinone
(9a;
0.50 g,
1.01 mmol) was dissolved in dry Et3N (0.11 g, 1.11 mmol, 1.1 equiv) and
distilled CHCl3 (20 mL). 3,4,5-Tris[3(S),7-dimethyloctyloxy]phenyl isocya-
nate (11; 0.71 g, 1.22 mmol, 1.2 equiv) was added and the mixture stirred
under argon atmosphere at 508C for 48 h. Afterwards, CHCl3 (15 mL)
was added and the organic layer was extracted with NaHCO3 (25 mL),
citric acid (25 mL, pH 3~4) and brine (25 mL). The organic layer was
dried over magnesium sulfate and evaporated in vacuo. The pure product
was obtained after column chromatography (SiO2, CHCl3:ethanol 98:2 to
95:5 v/v) and precipitation in cold acetonitrile (40 mL) as an off-white
solid (0.43 g, 0.44 mmol, 45%). M.p. 99.8–102.98C; ½aꢂ2D5 =+1.32
(25 mgmLꢀ1 in CHCl3); 1H NMR (CDCl3): d=13.32 (s, 1H, CNHC),
11.75 (s, 1H, CNHC=O), 10.03 (s, 1H, O=CNHCH2), 7.74 (s, 1H, O=
CNHCarom), 6.74 (s, 2H, CHarom), 5.78 (s, 1H, C=CH), 5.73 (s, 1H,
CH2NHC=O), 3.99–3.86 (m, 6H, OCH2), 3.25–3.17 (m, 4H,
2-(1-Imidazolylcarbonylamino)-6-[2(R),6-dimethylheptyl]-4[1H]-pyrimi-
dinone (7a): 2-Amino-6-(2(R),6-dimethylheptyl)-6[1H]-pyrimidinone
(6a; 1.5 g, 6.31 mmol) and 1,1’-carbonyldiimidazole (1.24 g, 7.58 mmol)
were dissolved in dry CHCl3 (20 mL) under an argon atmosphere at
508C and the solution stirred overnight. CHCl3 (50 mL) was added and
the organic layer was extracted with H2O (2ꢁ35 mL) and brine (2ꢁ
35 mL). The organic layer was dried over magnesium sulfate and evapo-
rated in vacuo. Trituration in diethyl ether (20 mL) yielded the product
as a white solid (1.62 g, 4.89 mmol, 77%). 1H NMR (CDCl3): d=12.01–
11.86 (brs, 2H, NH), 8.86 (s, 8.86, NCH=N), 7.64 (s, 1H, (C=O)NCH=
CH), 7.02 (s, 1H, (C=O)NCH=CH), 5.79 (s, 1H, C=CH), 2.63–2.60 (dd,
HNCH2CH2), 2.51–2.45 (dd, 1H, (CH=C)CH2CH
ACHTUGTNRENUNG(CH3)ACHTUNGTREN(NUNG CH2), 2.25–2.19
(dd, 1H, (CH=C)CH2CH(CH3)(CH2)), 1.85–1.11 (m, 46H, alkyl H),
A
ACHTUNGTRENNUNG
0.97–0.84 ppm (m, 36H, CH3); 1H NMR ([D7]DMF): d=12.08–11.72
(brs, 1H, CNHC), 10.04–9.63 (brs, 1H, CNHC=O), 8.53 (s, 1H, O=
CNHCarom), 8.03–7.81 (brs, 1H, O=CNHCH2), 7.07 (s, 2H, CHarom), 6.35
(s, 1H, CH2NHC=O), 5.96 (s, 1H, C=CH), 4.20–4.01 (m, 6H, OCH2),
3.44–3.32 (m, 4H, HNCH2CH2), 2.61–2.57 (dd, 1H, (CH=C)CH2CH-
1H, (CH=C)CH2CH
(CH3)(CH2)), 1.97–2.00 (m, 1H, (CH2)2CHCH3), 1.54–1.51 (m, 1H,
CH2CH(CH3)2), 1.44–1.15 (m, 6H, CH2), 1.00–0.86 ppm (m, 9H, CH3).
A
2-(6-[tert-Butoxycarbonylamino]hexylureido)-6-[2(R),6-dimethylheptyl]-
4[1H]-pyrimidinone (8a): 2-(1-Imidazolylcarbonylamino)-6-[2(R),6-dime-
thylheptyl]-4[1H]-pyrimidinone (7a; 1.60 g, 4.83 mmol) and mono-Boc-
protected 1,6-hexanediamine (1.25 g, 5.77 mmol) were dissolved in dry
CHCL3 (20 mL) under an argon atmosphere and the solution stirred at
508C for 17 h. CHCl3 (100 mL) was added and the solution was extracted
with 1m HCl (60 mL), saturated NaHCO3 (60 mL) and brine (60 mL).
The organic layer was dried over magnesium sulfate, filtered and evapo-
rated in vacuo to give the product as a white solid (2.17 g, 4.52 mmol,
94%). M.p. 122.0–123.18C; ½aꢂ2D5 =+0.48 (50 mgmLꢀ1 in CHCl3);
ACHTNUTGER(GUNNN CH3)CAHTUNGTREN(NGU CH2), 2.37–2.32 (dd, 1H, (CH=C)CH2CHAHCTUNGERTNGN(NU CH3)ACHTNUGTREN(GUNN CH2)), 2.03–1.26
(m, 46H, alkyl H), 1.21–1.01 ppm (m, 36H, CH3); 13C NMR (CDCl3): d=
173.5, 156.3, 156.2, 154.8, 153.3, 152.3, 135.5, 133.4, 106.4, 98.2, 71.8, 67.3,
40.4, 39.4, 39.4, 39.0, 37.6, 37.4, 37.3, 36.8, 36.4, 32.0, 29.8, 29.7, 29.4, 29.1,
28.0, 27.9, 25.8, 25.6, 24.7, 24.5, 22.7, 22.6, 22.6, 22.6, 22.5, 19.6, 19.5, 19.5,
~
19.2 ppm; IR (ATR): n=3333, 2954, 2927, 2869, 1656, 1583, 1504, 1464,
1423, 1250, 1227, 1114, 907 cmꢀ1; MALDI-TOF MS: m/z: calcd: 966.78;
found: 967.72; elemental analysis (%) calcd for C57H102N6O6: C 70.76, H
10.63, N 8.69; found: 70.97, H 10.67, N 8.73.
1H NMR (CDCl3): d=13.18 (s, 1H, C=CNHC), 11.87 (s, 1H, CNH
ACTHNUTRGNE(UNG C=
3,4,5-Tris[3(S),7-dimethyloctyloxy]phenyl isocyanate (11): Under argon
atmosphere,
a
solution of 3,4,5-tris(3(S),7-dimethyloctyloxy)aniline
O)), 10.17 (s, 1H, (C=O)NH-CH2), 5.82 (s, 1H, C=CH), 4.64 (s, 1H,
NHBoc), 3.32–3.19 (q, 2H, NHCH2CH2), 3.17–3.08 (q, 2H,
(0.69 g, 1.23 mmol) in distilled toluene (25 mL) was added to a solution
of phosgene (20% w/w in toluene, 2.43 g, 12.9 mL, 24.56 mmol, 20 equiv)
and the mixture stirred at room temperature. After 3 h the excess phos-
gene and solvent were evaporated in vacuo. This yielded the pure com-
pound as a brown oil. (0.71 g, 1.21 mmol, 98%). 1H NMR (CDCl3): d=
6.29 (s, 2H, C=CHC), 3.98–3.91 (m, 6H, OCH2), 1.86–1.13 (m, 30H,
CH2CH2NHBoc), 2.51–2.39 (dd, 1H, (CH=C)CH2CH
2.16 (dd, 1H, (CH=C)CH2CH(CH3)(CH2)), 1.82 (m, 1H, (CH2)2CHCH3),
1.61 (m, 1H, CH2CH(CH3)2), 1.60–1.03 (m, 23H, CH2, CH3), 0.99–
0.65 ppm (m, 9H, CH3); 13C NMR (CDCl3): d=173.1, 156.6, 155.9, 154.7,
151.5, 106.8, 78.9 (OC(CH3)3), 40.4, 39.7, 38.9, 16.6, 31.9, 29.8, 29.3, 28.4,
ACHTUGTNRNENUG(CH3)CAHTUNGTRENN(GUN CH2), 2.32–
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
~
alkyl H), 0.95–0.91 (d, 9H, CHCH3), 0.88–0.86 ppm (d, 18H, CHACHTUNGTRENNUNG(CH3)2);
27.8, 26.4, 26.2, 24.5, 22.6, 22.5, 19.2 ppm; IR (ATR): n=3217, 1954,
2929, 2868, 1698, 1659, 1585, 1525, 1462, 1390, 1365, 1251, 1172, 1140,
801 cmꢀ1; elemental analysis (%) calcd for C25H45N5O4: C 62.60, H 9.46,
N 14.60; found: C 62.37, H 9.44, N 14.66; MALDI-TOF MS: m/z: calcd:
479.35; found: 480.22, 502.21 [M+Na]+.
ꢀ1
~
IR (ATR): n=2954, 2927, 2870, 2264, 1588, 1436, 1384, 1227, 1117 cm
;
C
MALDI-TOF MS m/z: calcd: 587.49; found: 587.43 [M] .
2-(6-[1-Imidazolylcarbonylamino]hexylureido-6-[2(R),6-dimethylheptyl]-
4[1H]-pyrimidinone (12): A mixture of 9a (1.00 g, 2.0 mmol), 1,1’-carbon-
yldiimidazole (0.39 g, 2.4 mmol) and dry triethylamine (0.30 g, 3 mmol)
in 5 mL of dry CHCl3 was stirred for 4 h at 508C under an atmosphere of
argon, until the mixture became clear. After evaporation of the solvent
in vacuo, the residue was transferred to a glass filter with acetone (3ꢁ
5 mL), filtered, rinsed with acetone (3ꢁ5 mL) and diethyl ether (5 mL)
and dried in vacuo at 508C. The product was obtained as an off-white
2-(6-Aminohexylureido)-6-[2(R),6-dimethylheptyl]-4[1H]-pyrimidinone
(9a):
2-(6-[tert-Butoxycarbonylamino]hexylureido)-6-[2(R),6-dimethyl-
heptyl]-4[1H]-pyrimidinone 8a (2.17 g, 4.52 mmol) was stirred in distilled
dichloromethane (200 mL). Trifluoroacetic acid (TFA) (65 mL, 30 equiv)
was added at room temperature and the mixture was stirred for 13 h. Af-
terwards, trifluoroacetic acid and dichloromethane were evaporated in
Chem. Eur. J. 2010, 16, 1601 – 1612
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1609

E. W. Meijer, R. P. Sijbesma et al.
1
powder (0.9 g, 1.9 mmol, 95%). H NMR (CDCl3): d=13.33 (s, 1H, NH),
showed immediate gas evolution (CO2) indicating formation of the isocy-
anate. Stirring was continued for 1 h. This reaction mixture was slowly
added to a solution of 2-amino-6-[2(S)-dimethylheptyl]-4[1H]-pyrimidi-
none (6b, 1.04 g, 4.38 mmol) in dry dimethylformamide (20 mL) at 908C
under an argon atmosphere. The reaction mixture was stirred for 4.5 h,
after which it was cooled. The solvent was evaporated in vacuo and the
remaining solid was recrystallized from cold acetone (30 mL), filtered
and washed with cold diethyl ether. Column chromatography (SiO2,
CHCl3/ethanol 93:7 v/v), yielded the pure product as a white solid
(0.94 g, 2.47 mmol, 56%). M.p. 99.9–101.78C; 1H NMR (CDCl3): d=
11.85 (s, 1H, NH), 10.02 (s, 1H, NH), 8.20 (s, 1H, imidazole CH), 7.47 (s,
1H, imidazole CH), 7.05 (s, 1H, imidazole CH), 5.64 (s, 1H, O=CCH=
CCH2), 3.47–3.25 (m, 4H, NHCH2CH2), 2.46–2.36 (dd, 1H, CH=
CCH2CHACHTUNGTRENNUNG(CH3)CH2), 2.24–2.13 (dd, 1H, CH=CCH2CHAHCTUNGTREN(NUGN CH3)CH2), 1.69–
1.11 (m, 17H, CH2 and CH2-CH-(CH3)2), 0.90 (d, 3H, CH3), 0.86 ppm (d,
6H, CH3); 13C NMR (CDCl3): d=173.6, 156.4, 154.7, 152.3, 149.1, 136.0,
130.0, 116.1, 106.3, 40.4, 40.0, 38.9, 38.8, 36.6, 31.9, 29.1, 28.4, 27.8, 25.2,
~
25.1, 24.5, 22.6, 22.5, 19.1 ppm; IR (ATR): n=3219, 3029, 2929, 2867,
1743, 1698, 1656, 1581, 1523, 1479, 1466, 1381, 1365, 1315, 1284, 1249,
1138, 1101, 1062, 1017, 953, 913, 838, 735 cmꢀ1
.
13.20 (s, 1H, C=CNHC), 11.86 (s, 1H, CNH
O)NHCH2)), 5.84 (s, 1H, C=CH), 3.64–3.61 (q, 2H, CH2CH2OH), 3.30–
3.25 (q, 2H, NHCH2CH2), 2.49–2.44 (dd, 1H, (CH=C)CH2CH(CH3)-
(CH2), 2.27–2.21 (dd, 1H, (CH=C)CH2CH(CH3)(CH2)), 1.78–1.67 (m,
ACHTUNGERTN(NUNG C=O)), 10.11 (s, 1H, (C=
2-(6-[2-Dodecylureido]hexyl)ureido-6-[2(R),6-dimethylheptyl]-4[1H]-
pyrimidinone (13): Activated UPy 12 (0.20 g, 0.42 mmol) and n-dodecyla-
mine (0.12 g, 0.65 mmol) were added to dry CHCl3 (5 mL) and the mix-
ture stirred at 558C for 2 d under an atmosphere of argon. After the mix-
ture had been cooled to room temperature, CHCl3 (25 mL) was added,
and the mixture was extracted with 0.1m HCl (aq) (3ꢁ15 mL), neutral-
ized with saturated NaHCO3 (aq) (20 mL) and washed with brine
(20 mL). After drying with MgSO4 the solvent was removed by evapora-
tion in vacuo to give the crude 2-ureido-pyrimidinone. Further purifica-
tion by recrystallization from 2-propanol resulted in pure 13 as a white
powder (0.18 g, 0.30 mmol, 73%). M.p. 1558C; 1H NMR (CDCl3): d=
13.22 (s, 1H, NH), 11.85 (s, 1H, NH), 10.10 (s, 1H, NH), 5.82 (s, 1H, O=
CCH=CCH2), 4.64 (t, 1H, NH), 4.42 (t, 1H, NH), 3.25 (m, 2H,
NHCH2CH2), 3.18–3.11 (m, 4H, NHCH2CH2), 2.50–2.45 (dd, 1H, CH=
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
1H, (CH2)2CHCH3), 1.65–1.51 (m, 1H, CH2CHACTHUNGTRNEUNG(CH3)2), 1.48–1.11 (m,
14H, CH2), 0.96–0.84 ppm (m, 9H, CH3); 13C NMR (CDCl3): d=173.4,
156.6, 154.7, 151.7, 106.8, 62.0, 40.4, 39.3, 39.0, 36.7, 32.5, 31.9, 29.3, 27.9,
25.8, 24.6, 24.5, 22.6 (CHACHTGNUNERT(NNGU CH3)2)., 22.5 (CHAHCTNURTGE(GUNNN CH3)2), 19.2 (CHACHTUNGTRENNUNG(CH3)2),
~
19.1 ppm (CHCH3); IR (ATR): n=3021, 2955, 2929, 2855, 1702, 1655,
1562, 1527, 1463, 1251, 1055, 798, 750, 740 cmꢀ1; MALDI-TOF MS: m/z:
calcd: 380.28; found: 381.13, 403.12 [M+Na]+; elemental analysis (%)
calcd for C20H36N4O3: C 63.13, H 9.54, N 14.72; found: C 62.97, H 9.56, N
14.52.
2-{6-(3,4,5-Tris(3(S),7-dimethyloctyloxy)-phenylurethane}hexylureido-6-
[2(S),6-dimethylheptyl]-4[1H]-pyrimidinone (16): 2-(6-Hydroxyhexylurei-
do)-6-(2(S),6-dimethylheptyl)-4[1H]-pyrimidinone (15; 0.50 g, 1.31 mmol)
was dissolved in distilled CHCl3 (20 mL). 3,4,5-Tris[3(S),7-dimethylocty-
loxy]phenyl isocyanate (11, 0.93 g, 1.58 mmol, 1.2 equiv) and a drop of di-
butyltin dilaurate (cat.) were added to the solution and the mixture
stirred under argon atmosphere at 608C for 48 h. CHCl3 (20 mL) was
added and the organic layer was extracted with NaHCO3 (25 mL), citric
acid (25 mL, pH 3–4) and brine (25 mL). The organic layer was dried
over magnesium sulfate and evaporated in vacuo. The pure product was
obtained after column chromatography (SiO2, CHCl3:ethanol 98:2 v/v)
(SiO2, ethyl acetate:heptane 4:6 v/v) and precipitation in cold acetonitrile
(25 mL) as an off-white solid (0.42 g, 0.434 mmol, 34%). M.p. 79.9–
82.08C; 1H NMR (CDCl3): d=13.17 (s, 1H, CNHC), 11.88 (s, 1H,
CNHC=O), 10.20 (s, 1H, O=CNHCH2), 6.69 (s, 1H, O=CNHCarom), 6.66
(s, 2H, CHarom), 5.80 (s, 1H, C=CH), 4.15–4.12 (s, 2H, CH2CH2O), 4.00–
3.88 (m, 6H, OCH2), 3.28–3.23 (m, 4H, HNCH2CH2), 2.46–2.43 (dd, 1H,
CCH2CH
(m, 1H, CH=CCH2CH
ACHTUNGTRENNUNG
(CH3)2), 0.95–0.86 ppm (m, 12H, CH3); 13C NMR (CDCl3): d=173.3,
158.5, 156.5, 154.8, 151.8, 106.7, 40.54, 40.48, 40.1, 39.6, 39.0, 36.7, 32.0,
31.9, 30.3, 29.71–29.60 (m), 29.38, 29.34, 29.23, 27.9, 26.9, 26.2, 26.1, 24.5,
A
ACHTUGNTREN(UNNG CH3)CH2), 1.83
ACHTUNGTRENNUNG
~
22.67, 22.66, 22.5, 19.2, 14.1 ppm; IR (ATR): n=3317, 3222, 2954, 2923,
2853, 1699, 1655, 1627, 1575, 1527, 1482, 1462, 1378, 1366, 1320, 1307,
1294, 1256, 1179, 1135, 1098, 1019, 941, 907, 892, 860, 801, 769, 742 cmꢀ1
;
MALDI-TOF MS: m/z: calcd: 590.49; found: 591.54, 613.50 [M+Na]+,
629.47 [M+K]+; elemental analysis (%) calcd for C33H62N6O3: C 67.08, H
10.58, N 14.22; found: C 66.45, H 10.87, N 14.05.
2-(6-[2-{2-(2-Methoxyethoxy)ethoxy}ethylureido]hexyl)ureido-6-[2(R),6-
dimethylheptyl]-4[1H]-pyrimidinone (14): Activated UPy 12 (0.20 g,
0.42 mmol) and 2-{2-[2-methoxyethoxy]ethoxy}ethyl amine (1.06 g,
0.65 mmol) were added to dry CHCl3 (4 mL) and the mixture stirred at
558C for 2 days under an atmosphere of argon. After the mixture had
been cooled to room temperature, CHCl3 (20 mL) was added, and the
mixture was extracted with 0.1m HCl (aq) (3ꢁ10 mL), neutralized with
saturated NaHCO3 (aq) (15 mL) and washed with brine (15 mL). After
the mixture had been dried with MgSO4 the solvent was removed by
evaporation in vacuo to give the crude ureido-pyrimidinone. Further pu-
rification by recrystallization from 2-propanol resulted in pure 14 as a
white powder (0.20 g, 0.35 mmol, 83%). M.p. 135.58C; 1H NMR
(CDCl3): d=13.18 (s, 1H; NH), 11.87 (s, 1H, NH), 10.16 (s, 1H, NH),
5.81 (s, 1H, O=CCH=CCH2), 5.08 (t, 1H, NH), 4.98 (t, 1H, NH), 3.65–
3.54 (m, 10H, OCH2), 3.39–3.35 (m, 5H, OCH3 and NHCH2), 3.24 (m,
2H, NHCH2CH2), 3.14 (m, 2H, NHCH2CH2), 2.50–2.45 (dd, 1H, CH=
(CH=C)CH2CHACHTNUGRTEN(GUNN CH3)ACHTUNREGTGNN(UN CH2), 2.25–2.23 (dd, 1H, (CH=C)CH2CHACHTUNGTRENNUNG(CH3)-
AHCTUNGTRENNG(UN CH2)), 1.86–1.14 (m, 46H, alkyl-H), 0.93–0.84 ppm (m, 36H, CH3);
13C NMR (CDCl3): d=173.2, 156.6, 154.7, 153.7, 153.3, 151.6, 134.1,
133.7, 106.8, 97.6, 71.7, 67.3, 65.2, 40.4, 39.9, 39.4, 39.3, 39.0, 37.5, 37.4,
37.3, 36.7, 36.4, 31.9, 29.8, 29.7, 29.3, 28.6, 28.0, 27.9, 26.6, 25.6, 24.7, 24.5,
~
22.7, 22.6, 22.6, 22.6, 22.5, 19.6, 19.5, 19.2 ppm; IR (ATR): n=2954, 2927,
2869, 1699, 1657, 1581, 1525, 1506, 1463, 1428, 1247, 1216, 1116, 908,
730 cmꢀ1; elemental analysis (%) calcd for C57H101N5O7: C 70.69, H 10.51,
N 7.23; found: C 70.90, H 10.75, N 6.78; MALDI-TOF MS: m/z: calcd:
967.77; found: 968.78.
CCH2CH
(m, 1H, CH=CCH2CH
ACHTUNGTRENNUNG
(CH3)2), 0.94 (d, 3H, CH3), 0.87 ppm (d, 6H, CH3); 13C NMR (CDCl3):
G
ACHTUGNTREN(UNNG CH3)CH2), 1.83
ACHTUNGTRENNUNG
Acknowledgements
d=173.1, 158.6, 156.5, 154.7, 151.6, 106.7, 71.9, 70.6, 70.3, 70.1, 58.8, 40.4,
40.1, 39.8, 38.9, 36.6, 31.9, 30.1, 29.4, 27.8, 26.5, 26.4, 24.5, 22.6, 22.5,
The authors thank the Netherlands Organisation for Scientific Research
(NWO) for financial support.
~
19.2 ppm; FTIR (ATR, solid state): n=3340, 3220, 2929, 2958, 1700,
1655, 1624, 1572, 1527, 1483, 1463, 1382, 1366, 1351, 1294, 1255, 120,
1200, 1183, 1110, 1028, 1005, 941, 854, 801, 769, 743 cmꢀ1; MALDI-TOF
MS: m/z: calcd: 568.39; found: 569.46, 591.44 [M+Na]+, 607.42 [M+K]+;
elemental analysis (%) calcd for C28H52N6O6: C 59.13, H 9.22, N 14.78;
found: C 59.48, H 9.35, N 14.74.
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1610
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1601 – 1612

Self-Assembly of Ureido-Pyrimidinone Dimers
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N
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Received: July 29, 2009
Published online: December 28, 2009
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1601 – 1612