Covalent linkage of melamine and cyanurate improves the thermodynamic stability of hydrogen-bonded double rosettes in polar solvents

Article abstract of DOI:10.1002/ejoc.200390205

This paper describes studies on the synthesis, self-assembly behavior, and thermodynamic stabilities of eight different calix[4]arene di(melamine-cyanurate) or di(melamine-barbiturate) conjugates. The successful synthetic strategy comprises the preparation of amino-n-alkyl-functionalized calix[4]arene dimelamines coupled with a carboxyl-functionalized cyanurate or barbiturate by an amide bond-forming reaction. ¹H NMR experiments show that three of the eight conjugates form well-defined double rosette assemblies. DMSO titration experiments illustrate that the covalent linkage between the cyanurate and dimelamine moieties produces a significant increase in the thermodynamic stabilities of these conjugates. The relative stability of the assemblies seems to be primarily governed by the structure of the component connecting the melamine and cyanurate units. The highest stability (χ_DMSO = 70%) was observed for the di(melamine-cyanurate) assembly in which the components are connected through an n-heptylamidomethyl linker. Increasing the linker size from n-heptylamidomethyl to n-decylamidomethyl slightly reduced the thermodynamic stability (Δχ_DMSO ≈ 10%) of the corresponding double rosette assembly. The thermodynamic stability of the double rosette structure decreases drastically, however, on introduction of substituents at the position α to the methylcarbonyl group. With benzyl substituents (based on D-phenylalanine), neither the n-heptyl- nor the n-decylamidomethyl-linked compounds any longer form the double rosette structure in solution. For the conjugates with a methyl substituent at this position (based on L-alanine), only the heptyl-linked compound still forms the double rosette structure, the χ_DMSO value being reduced in this case by 15%. Neither of the di(melaminebarbiturate) conjugates form double rosette structures at all. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390205

FULL PAPER
Covalent Linkage of Melamine and Cyanurate Improves the Thermodynamic
Stability of Hydrogen-Bonded Double Rosettes in Polar Solvents
[a]
[a]
[b]
[a]
´
Olivier Felix, Mercedes Crego-Calama, Ingrid Luyten, Peter Timmerman,* and
David N. Reinhoudt*[a]
Keywords: Hydrogen bonds / Noncovalent interactions / Self-assembly / Solvent effects / Thermodynamics
This paper describes studies on the synthesis, self-assembly
behavior, and thermodynamic stabilities of eight different
calix[4]arene di(melamine-cyanurate) or di(melamine-barbit-
urate) conjugates. The successful synthetic strategy com-
ents are connected through an n-heptylamidomethyl linker.
Increasing the linker size from n-heptylamidomethyl to n-de-
cylamidomethyl slightly reduced the thermodynamic
stability (∆χDMSO ഠ 10%) of the corresponding double rosette
prises the preparation of amino-n-alkyl-functionalized ca- assembly. The thermodynamic stability of the double rosette
lix[4]arene dimelamines coupled with carboxyl-func- structure decreases drastically, however, on introduction of
tionalized cyanurate or barbiturate by an amide bond-for- substituents at the position α to the methylcarbonyl group.
a
ming reaction. 1H NMR experiments show that three of the
eight conjugates form well-defined double rosette assem-
blies. DMSO titration experiments illustrate that the covalent
linkage between the cyanurate and dimelamine moieties
With benzyl substituents (based on D-phenylalanine), neither
the n-heptyl- nor the n-decylamidomethyl-linked com-
pounds any longer form the double rosette structure in solu-
tion. For the conjugates with a methyl substituent at this po-
produces
a
significant increase in the thermodynamic
sition (based on L-alanine), only the heptyl-linked compound
stabilities of these conjugates. The relative stability of the
assemblies seems to be primarily governed by the structure
of the component connecting the melamine and cyanurate
units. The highest stability (χDMSO = 70%) was observed for
still forms the double rosette structure, the χDMSO value being
reduced in this case by 15%. Neither of the di(melamine-
barbiturate) conjugates form double rosette structures at all.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
the di(melamine-cyanurate) assembly in which the compon- Germany, 2003)
Introduction
sette assemblies 13·(DEB)6 or 13·(CYA)6 (see Figure 1) in
polar solvents.[34] These strategies have in common that
they stabilize the hydrogen-bonded assemblies by increasing
the ITm value (ITm ϭ HB/N Ϫ 1): the number of hydrogen
bonds (HB) per components (N).[24] Previous studies in our
group have shown that these assemblies are stable in apolar
solvents such as chloroform, benzene, and toluene,[4,35] but
tend to dissociate in the presence of small amounts of polar
solvent such as DMSO.[36] The first strategy, which is de-
scribed elsewhere,[37] is based on the covalent linkage of
multiple melamines, resulting in the synthesis of tetra-
(ITm ϭ 5.1) and hexamelamines (ITm ϭ 5.4). The resulting
tetra- and hexarosette assemblies, possessing 72 and 108 hy-
drogen bonds, respectively, express much higher stabilities
than the corresponding double rosettes in the presence of
polar solvents, in particular MeOH. In this paper we de-
scribe a slightly different approach, based on reducing the
total number of particles (N) in the assembly while keeping
the number of hydrogen bonds (HB) constant. Our ap-
proach has produced a new type of hydrogen-bonded as-
semblies, achieved practically through covalent connection
of the cyanuric or barbituric acid residues to the melamine
units by means of a flexible linker (Figure 1). We have used
linkers of variable size and rigidity and studied their influ-
During the last decade, the self-assembly of small molec-
ular entities into larger, well-defined structures[1Ϫ4] has been
intensively studied for the design of artificial receptors[5Ϫ8]
and novel materials.[9Ϫ11] Apart from metal-coordinated as-
semblies,[12,13] the majority of self-assembled structures are
held together by relatively weak interactions,[14] such as hy-
drogen bonding,[15Ϫ18] van der Waals interactions,[19,20] and
electrostatic interactions.[21] One major drawback of supra-
molecular architectures based on hydrogen bonding is their
inherently low stability in polar solvents.[22,23] However, ex-
amples of supramolecular structures stable in more polar
solvents such as DMSO and water have been
reported,[24Ϫ29] but most of them involve a combination of
hydrogen bonding with electrostatic interactions.[30Ϫ33]
We are currently exploring different strategies to increase
the thermodynamic stabilities of calix[4]arene double ro-
[a]
Laboratory of Supramolecular Chemistry and Technology,
MESAϩResearch Institute, University of Twente,
P. O. Box 217, 7500 AE, Enschede, The Netherlands
E-mail: D.N.Reinhoudt@ct.utwente.nl
[b]
Laboratory of Organic Synthesis, Department of Chemistry, K.
U. Leuven, University of Leuven, Leuven, Belgium
Celestijnenlaan 200F, 3001 Heverlee, Belgium
1463
Eur. J. Org. Chem. 2003, 1463Ϫ1474  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1463 $ 20.00ϩ.50/0

´
O. Felix, M. Crego-Calama, I. Luyten, P. Timmerman, D. N. Reinhoudt
FULL PAPER
Figure 1. Molecular structure and schematic representations of the nine-component double rosette assemblies 13·(DEB)6 and 13·(BuCYA)6
and the three-component assemblies 23 and 33, together with all possible isomeric conformations
ence on the thermodynamic stabilities of the corresponding first step involves the conversion of the amino function into
assemblies by DMSO titrations monitored by 1H NMR and a cyanurate unit by treatment with N-chlorocarbonyl isocy-
CD spectroscopy.
anate in THF according to the procedure reported by Kuni-
take (42 and 62% yields, respectively).[39] Subsequent hy-
drolysis of the resulting methyl esters 6b and 6c with NaOH
gave the corresponding carboxylic acid derivatives 6e and
6f in 100% yields. Barbiturate 7c was prepared from 5-ethyl-
barbituric acid (7a)[40,41] by treatment with methyl bromo-
acetate and triethanolamine in H2O (45% yield).[42] The re-
sulting ester 7b was saponified by treatment with NaOH to
give 7c in 100% yield.
Results and Discussion
Synthesis of Di(melamine-cyanurate) and Di(melamine-
barbiturate) Conjugates 2 and 3
Three different synthetic strategies for the covalent con-
nection of cyanuric or barbituric acids to calix[4]arene di-
melamines were investigated (Scheme 1). The most general
and successful strategy (I) is an amide coupling reaction
between the diamino dimelamines 5 and the carboxyl-func-
tionalized cyanurates 6dϪf or the barbiturate 7c (Scheme 1).
The diamino dimelamines 5a and 5b were obtained in good
yields (85Ϫ90%) from bis(chlorotriazine) 4[35] by treatment
with excess 1,7-diaminoheptane or 1,10-diaminodecane
in THF. Cyanurate 6d was synthesized by treatment of
cyanuric acid with benzyl 2-bromoacetate and DBU in
DMF to give the benzyl ester 6a in 33% yield.[38] Saponifi-
cation of 6a with NaOH gave the corresponding acid 6d in
Finally, the amide coupling reactions between 5 and 6dϪf
or 7c were performed with the aid of O-benzotriazol-
1-yl-N,N,NЈ,NЈ-tetramethyluronium hexafluorophosphate
(HBTU) and triethylamine in DMF/THF to give the di-
(melamine-cyanurates) 2 and di(melamine-barbiturates) 3,
all of which were fully characterized, in excellent yields
(87Ϫ100%).
Two other strategies for the coupling of cyanurates to ca-
lix[4]arene dimelamines were also investigated (Scheme 1).
100% yield. Cyanurates 6e and 6f were prepared from - Strategy II involves treatment of bis(chlorotriazine) 4 with
alanine methyl ester and -phenylalanine methyl ester. The amino-functionalized cyanurates 9aϪd.[35] The cyan-
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Hydrogen-Bonded Double Rosettes
FULL PAPER
urates were prepared in two steps starting from cyanuric
acid. Treatment of cyanuric acid with the corresponding
bromophthalimides in the presence of DBU in DMF gave
the phthalimido-substituted cyanurates 8aϪd in 15Ϫ31%
yields.[39] Removal of the phthalimide groups by treatment
with CH3NH2 in EtOH (33%) gave the amino-func-
tionalized cyanurates 9aϪd in 85Ϫ100% yields. The coup-
ling reactions between 4 and 9aϪd proved to be very diffi-
cult because compounds 9aϪd are not very soluble even in
DMSO or DMPU at elevated temperatures. Only in the
case of the aminohexyl-substituted cyanurate 9b was the de-
sired product 10 obtained, in 22% yield. The very low solu-
bilities and reactivities of these derivatives are most prob-
ably due to the formation of zwitterions (pKa,cyanurate ϭ 6.2
and pKa,amine ϭ 10.0),[43] in combination with the intrin-
sically low solubilities of cyanurate derivatives. To overcome
this solubility problem, a different strategy (III) was investi-
gated, starting from amino-functionalized dimelamine 5b.
Introduction of the cyanurate function was attempted by
the procedure developed by Whitesides.[18,44] The first step
involves treatment of 5b with nitrobiuret to give biuret de-
Scheme 1. Different synthetic strategies (IϪIII) for the preparation
of di(melamine-cyanurate) and di(melamine-barbiturate) conju-
gates
place at the amino functionalities present in the two mela-
mine units in 5b.
Noncovalent Synthesis of Stabilized Double Rosette
Assemblies 23 and 33
We first investigated the assembly behavior of di(mela-
rivative 11 (n ϭ 10) in 92% yield. Attempted ring closure mine-cyanurate) conjugates 2a and 2b, in which the mela-
of this compound by treatment with diethyl carbonate, mine and cyanurate units are linked either through an n-
either with NaH2PO4 or with NaOEt as a base, did not heptylamidomethyl (n ϭ 7) or through a n-decylamidome-
1
result in the formation of the desired compound 10 (n ϭ thyl (n ϭ 10) spacer, by H NMR spectroscopy. The conju-
10). We attribute this failure to secondary reactions taking gates are scarcely soluble in neat CDCl3, which prevented
Eur. J. Org. Chem. 2003, 1463Ϫ1474
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O. Felix, M. Crego-Calama, I. Luyten, P. Timmerman, D. N. Reinhoudt
FULL PAPER
1H NMR measurements in this solvent, but the formation fore measured the ratio of free and assembled conjugate 2
of double rosette assemblies 2a3 and 2b3 was clearly ob- as a function of the percentage of DMSO in the sample
served in CDCl3/[D6]DMSO (9:1, v/v). Two sharp signals by CHCl3/DMSO titration experiments. From the titration
were observed at δ ϭ 13.97 and 14.85 ppm for 2a3 and at curves, we can extrapolate the so-called χDMSO values (the
δ ϭ 14.08 and 14.62 ppm for 2b3 (Figure 2a,b), which is mol fraction of [D6]DMSO in CDCl3 at which 50% of the
highly characteristic of double rosette formation.[35] The assembly has decomposed into the free components[24]) for
presence of only two peaks in the δ ϭ 13Ϫ16 ppm region each assembly and use them to compare the thermo-
clearly indicates that the chiral D3 isomer (see Figure 1) is dynamic stabilities. The percentage of assembly formation
formed exclusively. Previous work in our group has shown was determined by comparison of the integrals for various
1
that the D3 isomer is the only one formed with barbiturates characteristic H NMR signals (for details see Exp. Sect.).
and alkyl-substituted cyanurates.[45] If all three isomers (D3, The results are depicted in Figures 3 and 4 and summarized
C3h, Cs, see Figure 1) had been formed, at least 10 separate in Table 1.
signals should have been observed in this region.
Figure 3. DMSO titration for assembly 2b3 in CDCl3: a) 50%, b)
60%, and c) 70% [D6]DMSO in CDCl3; the disassembly of 2b3 is
characterized by the disappearance of the NH proton signals at
δ ϭ 14.08 and 14.62 ppm and the appearance of the broad signal
around δ ϭ 11.5 ppm
Figure 4. Graphical representation of the results of 1H NMR
DMSO titration experiments for double rosette assemblies 2a3, 2b3,
and 13·(BuCYA)6
Table 1. χDMSO values for three- and nine-component hydrogen-
bonded assemblies
1
χDMSO values (%)
13·(CYA)6
2a3
2b3
2e3
Figure 2. H NMR spectra of double rosette assemblies: a) 2a3 (at
thermodynamic equilibrium), b) 2b3, c) 2a3 at t ϭ 0 s; all spectra
were recorded in CDCl3/[D6]DMSO (9:1, v/v)
NMR
CD
40
Ϫ
70
Ϫ
60
Ϫ
55
57
To evaluate the effect of covalently linking the melamine
and cyanurate units we compared the thermodynamic sta-
As would be expected, the three-component di(mela-
bilities of the three-component assemblies 2a3 and 2b3 with mine-cyanurate) assemblies 2a3 (χDMSO ϭ 70%) and 2b3
that of the 9-component assembly 13·(BuCYA)6. We there- (χDMSO ϭ 60%) exhibit thermodynamic stabilities signifi-
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Hydrogen-Bonded Double Rosettes
FULL PAPER
cantly higher than that of the nine-component assembly
13·(BuCYA)6 (χDMSO ϭ 40%). The observed increase in sta-
bility is reasonable (30 and 20% for 2a3 and 2b3) but does
not follow the predicted fourfold increase in the ITm value
[18 for 2a3 and 2b3 versus 4.5 for 13·(BuCYA)6], which em-
phasizes the fact that the ITm value is a qualitative rather
than a quantitative predictor. Nevertheless, some confor-
mation penalties should also be expected, because the
chains linking the rosette components cannot diverge out-
ward to adopt the preferred all-anti arrangement. Further-
more, there is a clearcut influence of spacer flexibility. On
an increase in the spacer length from heptyl to decyl the
assembly stability decreases by about 10%. This suggests
Scheme 2. Formation of two different isomers (A and B) for the
self-assembly of the 3-component double-rosette assemblies 23
and 33
that shortening of the spacer should make the assembly for assembly 2b3 (ca. 15 h at room temperature) than for
even more stable. However, molecular models suggest that assembly 2a3 (ca. 4 d at room temperature), which reflects
assembly formation with very short spacers is sterically im- the lower rate of dissociation and the higher thermo-
1
possible. The H NMR spectrum of conjugate 10 (n-hexyl dynamic stability of 2b3. Assemblies 2a3 and 2b3 are per-
spacer, n ϭ 6), for example, did not show any kind of evi- fectly stable over time in CHCl3/DMSO (9:1) (100% as-
dence of formation of the proposed double rosette structure sembly after heating the samples at 55 °C for 5 d).
either in CDCl3 or CDCl3/[D8]THF mixtures, most prob-
ably due to the very short spacer.
The two isomers are most probably energetically differ-
ent, but it is hard to predict a priori which one should be
In order to confirm the improved stabilities of aggregates the more stable. Molecular simulations for assembly 2a3
2a3 and 2b3 with respect to that of assembly 13·(BuCYA)6 show that both topologies (isomers A and B, see Figure 5)
we studied whether BuCYA has the ability to compete in can be adopted by the spacer without destroying the rosette
assembly formation. BuCYA was added both before (direct motif. However, the calculated energy difference for the
method) and after (indirect method) the formation of as- minimized structure in the gas phase is significant (15 kcal/
semblies 2a3 and 2b3 in order to rule out any favorable kine- mol), with isomer B being the more stable structure. This
tic factors in this experiment. It was found that addition of may suggest that isomer B represents the thermodynamic
2 equiv. of BuCYA to either assembly in CDCl3/[D6]DMSO product, but it should be borne in mind that these studies
(9:1) did not result in the formation of mixed rosette as- were performed in vacuo. The presence of solvent mol-
semblies. This experiment clearly shows that intramolecular ecules, particularly in the first solvation shell, can drasti-
complexation of the cyanurates that are linked to the mela- cally alter the energetics of the system. It was also exper-
mines is energetically by far the more favorable.
During our studies we found that the H NMR spectra the more stable isomer in solution.
of assemblies 2a3 and 2b3 are strongly dependent on the
imentally shown by different experiments that isomer B was
1
The 1D 1H NMR spectra (Figure 3a,b) each clearly show
mode of preparation of the NMR samples (see Figure 2a one set of peaks, indicating one isomer. Since the two iso-
1
and c for comparison). When the conjugate 2a or 2b is dis- mers have exactly the same symmetry (D3), the H NMR
solved in CDCl3/[D6]DMSO (9:1, v/v) and subsequently spectrum would display the same number of signals in the
heated for 5Ϫ10 min, the spectrum shows only one set of 1D 1H NMR spectrum for either isomer A or B. The ident-
signals (i.e., only two peaks in the δ ϭ 13Ϫ16 ppm region). ity of the isomer cannot therefore be determined by simple
1
However, when the H NMR spectrum is run without prior 1D NMR spectroscopy, and so 2D NMR spectroscopy was
heating of the sample, two additional signals are observed applied. With the aid of some measured distances for iso-
at δ ϭ 13.77 and 15.05 ppm for 2a3 and at δ ϭ 13.85 and mers A and B in the minimized structures (see Figure 5),
14.85 ppm for 2b3 (see Figure 2c). The presence of these we were able to use some key NOE cross-peaks in the 2D
additional signals corresponds to the initial formation of 1H-1H NOESY spectrum to rule out the existence of iso-
two different isomeric assemblies (isomers A and B, see mer A: (i) a strong NOE connectivity between Hg and
Scheme 2), the result of the fact that the cyanurate frag- NCH2CH2 for 2a3 is consistent with the corresponding sig-
˚
ments connected to the melamines can participate either in nificantly shorter distance in isomer B (2.5 A) than in iso-
˚
the same or in the opposite rosette layer. The isomers are mer A (3.8 A), and (ii) the absence of NOE cross-peaks
formed in almost equal amounts, which shows that they are between Hg and NCH2C(ϭO) and between the chain CH2
formed equally rapidly under these conditions. However, protons (δ ϭ 1.3Ϫ1.7 ppm) and the aromatic protons at
evolution of the isomer mixture over time at room tempera- δ ϭ 7.0 ppm also corresponds much better with the meas-
˚
˚
ture (or by heating the sample at 55 °C for a short time) ured distances in isomer B (Ͼ 5 A and Ͼ 4.5 A) than with
˚
˚
results in complete conversion into one single isomer (Fig- those in isomer A (2.5Ϫ3.5 A and 3Ϫ4 A). Finally, the ob-
ure 2a and b). This clearly shows that the assemblies are servation that the thermodynamic stabilities of assemblies
kinetically not inert and that they still form in a reversible 23 are very sensitive to the presence of R substituents at the
manner through breaking and reforming of multiple hydro- α-carbon atom of the cyanurate moiety (vide infra) is fully
gen bonds. The isomerization process is significantly faster in accordance with the formation of isomer B, as these sub-
Eur. J. Org. Chem. 2003, 1463Ϫ1474
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O. Felix, M. Crego-Calama, I. Luyten, P. Timmerman, D. N. Reinhoudt
FULL PAPER
Figure 5. Gas-phase-minimized structures of both isomers (A and B) of assemblies 2a3, and 2e3; these structures clearly illustrate the
very different environments that the methyl (2e) substituents experience in the two isomers
stituents are located in a sterically congested part of the that no hydrogen bonding takes place, or whether there is
assembly in this isomer. The gas-phase-minimized structure extensive exchange between different protons.
for assembly 2e3 clearly shows that these substituents are
The thermodynamic stability of chiral assembly 2e3 was
located on the outside of the assembly in the case of isomer determined by DMSO titration experiments monitored
1
A (see Figure 5), unlikely to cause any steric clutter, while both by H NMR and by CD spectroscopy (Figures 6 and
in the case of isomer B they are located in a more shielded 7). The latter technique makes use of the fact that chiral
region of the assembly and are likely to cause severe steric double rosette assemblies are strongly active in circular
hindrance.
dichroism (∆εmax ഠ 100 cm2·mmolϪ1), while the individual
We next studied the self-assembly behavior of the -phe- components are CD-inactive.[46] The observed CD signal is
nylalanine derivatives 2c (n ϭ 7) and 2d (n ϭ 10) and the therefore a direct measure of assembly formation and can
-alanine derivatives 2e (n ϭ 7) and 2f (n ϭ 10). Each of be used to study the thermodynamic stabilities of these as-
these conjugates has an R substituent at the α-carbon atom semblies. The CD spectrum of assembly 2e3 shows a posi-
of the cyanurate moiety, differing in size from R ϭ methyl tive curve, which is fully in accordance with earlier obser-
(2e and 2f) to R ϭ benzyl (2c and 2d). To our surprise it vations that (S)-cyanurates induce (M) helicity in the as-
was found that only the H NMR spectrum of the conju- sembly. The titration curves obtained by 1H NMR and CD
1
gate 2e in CDCl3/[D6]DMSO (9:1) clearly indicated forma- spectroscopy are very similar in shape, and both techniques
tion of a well-defined assembly 2e3, characterized by two give almost identical χDMSO values (55 vs. 57%, see Fig-
peaks at δ ϭ 13.88 and 14.63 ppm (Figure 6a). No forma- ure 7b). Comparison of these values with that found for as-
tion of two different isomers (A and B) was observed for sembly 2a3 (χDMSO ϭ 70%) made us conclude that the in-
assembly 2e3, most probably the result of chiral induction troduction of a methyl group at the α-position of the cyan-
by the alanine groups (vide infra). In sharp contrast to this, urate reduces the stability by 13Ϫ15%.
the 1H NMR spectrum of 2f in CDCl3/[D6]DMSO (9:1,
Finally, we investigated the assembly behavior of the di-
v/v) exhibited broad signals in the δ ϭ 13Ϫ16 ppm region (melamine-barbiturate) conjugates 3a and 3b, possessing
even after the sample had been heated at 55 °C for 24 h, either an n-heptylamidomethyl (n ϭ 7) or an n-decylamido-
which is most probably due to the formation of oligomeric methyl (n ϭ 10) linker unit. The very low solubility of these
assemblies. The broad 1H NMR spectra observed for conju- compounds in pure CDCl3 prevented a detailed NMR
gates 2c and 2d did not show any kind of signal in the δ ϭ study in this solvent. The 1H NMR spectrum of 3a in
13Ϫ16 ppm region. It is not clear whether this indicates CDCl3/[D6]DMSO (9:1) is broad and shows no proton sig-
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Hydrogen-Bonded Double Rosettes
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1
Figure 6. H NMR spectra for double rosette assemblies 2e3 in: a)
CDCl3/[D6]DMSO (9:1), b) CDCl3/[D6]DMSO (45:55); the latter
shows the coexistence of assembly 2e3 and of free 2e, shown by two
separate peaks for the α-CH2 of the cyanurate
nals in the region between δ ϭ 13 and 16 ppm. Compound
3b, however, showed broad signals corresponding to
complete [CDCl3/[D6]DMSO (9:1)] or partial ([D8]THF)
assembly both in a mixture of CDCl3/[D6]DMSO (9:1) and
in [D8]THF. The broadness of the spectra most probably Figure 7. a) CD titration curve for assembly 2e3; b) thermodynamic
stability measurement for assembly 2e3 as obtained by 1H NMR
indicates that oligomeric structures are also being formed
in this case, in accordance with the increased steric
crowding in the linker unit.
and CD titration experiments; both methods give similar χDMSO
values
Conclusions
semblies, however. With methyl substituents (based on -
alanine) the heptyl-linked conjugate is still formed, but the
stability is significantly lower than that of the unsubstituted
analogue (χDMSO ϭ 55Ϫ57%). In contrast to this, the decyl-
linked conjugate does not form well-defined assemblies at
all, but oligomeric structures are formed instead. In the case
of benzyl substituents (based on -phenylalanine) neither
the heptyl- nor the decyl-linked conjugate double rosette
assemblies can be detected any longer in solution. Similarly,
the dimelamine-barbiturate conjugates 3a and 3b also show
no sign of assembly formation, again most probably as the
The results described in this paper show that the thermo-
dynamic stabilities of double rosette hydrogen-bonded as-
semblies can be significantly increased by covalently linking
the dimelamine and cyanurate units. The relative stabilities
of the assemblies seem to be strongly influenced by the
length and structure of the linker unit. The shortest spacer
(heptyl) gives the highest thermodynamic stability
(χDMSO ϭ 70%), whereas an increase to a decyl spacer
slightly reduces the stability of the corresponding assembly
(χDMSO ϭ 60%). Introduction of substituents at the α-posi-
tion of the cyanurate unit strongly affects the thermo-
dynamic stability of the corresponding double rosette as- result of steric interactions.
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FULL PAPER
1H NMR (300 MHz, CDCl3): δ ϭ 7.10Ϫ6.70 (br. m, 6 H, ArH),
6.60Ϫ5.90 (br. m, 4 H, ArH), 4.84 (br. s, 4 H, NH2 melamine), 4.36
and 3.04 (ABq, 8 H, J ϭ 13.4 Hz, ArCH2Ar), 3.90 (t, J ϭ 7.7 Hz,
4 H, OCH2), 3.62 (t, J ϭ 6.6 Hz, 4 H, OCH2), 3.23 (q, J ϭ 6.5 Hz,
4 H, CH2NH), 2.60 (t, J ϭ 6.8 Hz, 4 H, CH2NH2), 1.85 (m, 8
H, OCH2CH2CH3), 1.48 (m, 4 H, CH2CH2NH), 1.35 (m, 4 H,
CH2CH2NH2), 1.21 (m, 24 H, other CH2 chain), 0.99 (t, J ϭ
Experimental Section
General: THF was freshly distilled from Na/benzophenone and
DMF was dried with molecular sieves. All chemicals were of re-
agent grade and were used without further purification. NMR
spectra were recorded with a Varian Unity 300 (1H NMR
300 MHz) spectrometer at room temperature. Residual solvent pro-
tons were used as internal standard, and chemical shifts are given
relative to tetramethylsilane (TMS). The 2D 1H-1H NOESY spec-
tra were recorded at 400 MHz with a Bruker AMX 400 instrument
in CDCl3 solutions with TMS as internal reference with a mixing
time of 150 ms, 1024 data points in t2, and 512 increments in t1.
FAB-MS data were recorded with a Finningan MAT 90 spec-
trometer with m-nitrobenzyl alcohol (NBA), m-nitrobenzyl alcohol/
o-nitrophenyloctyl ether (NBA/NPOE), or glycerol (Gly) as matrix.
Elemental analyses were performed with a Carlo Erba EA1160.
The presence of solvents in the analytical samples was confirmed
by 1H NMR spectroscopy. Column chromatography was per-
formed on silica gel (SiO2, E. Merck, 0.040Ϫ0.063 mm, 230Ϫ240
mesh). Melting points were determined with a Reichert melting
point apparatus and are uncorrected. 1,7-Diaminoheptane, 1,10-
diaminodecane, methyl 2-bromoacetate, triethanolamine, cyanuric
acid, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), benzyl 2-bromo-
acetate, N-chlorocarbonyl isocyanate, -alanine methyl ester hydro-
chloride, -phenylalanine methyl ester hydrochloride, O-benzotri-
7.5 Hz,
6 H, OCH2CH2CH3), 0.84 (t, J ϭ 7.2 Hz, 6 H,
OCH2CH2CH3) ppm. MS (FAB): m/z ϭ 1151.8 ([M ϩ Hϩ], calcd.
1151.8). C66H98N14O4·1.5H2O: calcd. C 67.26, H 8.64, N 16.64;
found C 67.32, H 8.25, N 16.29.
Benzyl (2,4,6-Trioxo-1,3,5-triazin-1-yl)acetate (6a): DBU (1.15 mL,
7.8 mmol) and benzyl 2-bromoacetate (1.2 mL, 7.8 mmol) were ad-
ded to a solution of cyanuric acid (5.0 g, 38.7 mmol) in dry DMF
(80 mL). The mixture was stirred under Ar at room temperature
for 1 h and heated overnight at 70 °C. After the reaction mixture
had cooled, DMF was removed under vacuum to give a precipitate
that was filtered and washed with THF. The filtrate was concen-
trated and poured into cold water. The obtained precipitate was
filtered and dried. After purification of the combined solid frac-
tions by flash column chromatography (SiO2, CH2Cl2/MeOH,
96:4), cyanuric acid derivative 6a was obtained as a white solid
(708 mg, 33%); m.p. 237Ϫ240 °C. 1H NMR (300 MHz,
[D6]DMSO): δ ϭ 11.69 (s, 2 H, NH), 7.34 (m, 5 H, ArH), 5.15 (s,
2 H, PheCH2O), 4.46 (s, 2 H, CH2N) ppm. MS (FAB): m/z ϭ 276.1
([M Ϫ Hϩ], calcd. 276.1). C12H11N3O5: calcd. C 51.99, H 4.00, N
15.16; found C 51.77, H 4.09, N 15.15.
azol-1-yl-N,N,NЈ,NЈ-tetramethyluronium
hexafluorophosphate
(HBTU), triethylamine, N-(4-bromobutyl)phthalimide, N-(6-
bromohexyl)phthalimide, N-(10-bromodecyl)phthalimide, methyl-
amine solution (33% in ethanol), diisopropylethylamine (DIPEA),
and N,NЈ-dimethylpropyleneurea (DMPU) were commercially
available and were used without further purification. Bis(chlorotri-
azine) 4,[47] 5-ethylbarbituratic acid (7a),[16,25,45] 1-(bromomethyl)-
3-(phthalimidomethyl)benzene, and nitrobiuret[36,48] were prepared
according to literature procedures.
(2,4,6-Trioxo-1,3,5-triazin-1-yl)acetic Acid (6d): Benzyl ester 6a
(661 mg, 2.4 mmol) was added to a solution of NaOH (477 mg,
11.9 mmol) in H2O (15 mL), and the mixture was stirred at room
temperature overnight. The reaction mixture was then acidified
(36% HCl, pH ϭ 1) and the water was removed under vacuum.
The remaining white residue was extracted several times with THF,
and the solution recovered after filtration was concentrated, giving
carboxylic derivative 6d as a white solid (414 mg, 92%); m.p.
249Ϫ251 °C. 1H NMR (300 MHz, [D8]THF): δ 11.60 (br, 1 H,
CO2H), 10.72 (br. s, 2 H, NH), 4.55 (s, 2 H, CH2N) ppm. MS
(FAB): m/z ϭ 186.0 ([M Ϫ Hϩ], calcd. 186.0). C5H5N3O5·0.8H2O:
calcd. C 29.80, H 3.30, N 20.85; found C 29.73, H 3.38, N 19.28.
5,17-Bis({4-amino-6-[(7-aminoheptyl)amino]-1,3,5-triazine-2-yl}-
amino)-25,26,27,28-tetrapropoxycalix[4]arene (5a): Bis(chlorotriaz-
ine) 4 (1.0 g, 1.1 mmol) and 1,7-diaminoheptane (3.0 g, 22.7 mmol)
were dissolved in dry THF (10 mL) under Ar and the mixture was
heated at 95 °C overnight. After the mixture had cooled, H2O
(70 mL) was added and the resulting precipitate was filtered off.
The solid was recrystallized from THF (10 mL) and H2O (80 mL).
Compound 5a was obtained as a yellowish solid (1.0 g, 85%); m.p.
N-(2,4,6-Trioxo-1,3,5-triazin-1-yl)-L-alanine Methyl Ester (6b): This
compound was prepared by a literature procedure.[38] Crude 6b was
purified by flash column chromatography (SiO2, CH2Cl2/MeOH/
NH4OH, 95:5:1) (321 mg, 42%); m.p. 185Ϫ187 °C. 1H NMR
(300 MHz, [D6]DMSO): δ ϭ 11.61 (br, 2 H, NH), 5.18 (q, J ϭ
6.9 Hz, 1 H, CHCH3), 3.61 (s, 3 H, CO2CH3), 1.40 (d, J ϭ 6.9 Hz,
3 H, CHCH3) ppm. MS (FAB): m/z ϭ 216.0 ([M ϩ Hϩ], calcd.
216.1). C7H9N3O5: calcd. C 39.08, H 4.22, N 19.53; found C 39.10,
H 4.24, N 19.64.
1
125Ϫ132 °C. H NMR (300 MHz, CDCl3): δ ϭ 7.10Ϫ6.60 (br. m,
6 H, ArH), 6.60Ϫ5.90 (br. m, 4 H, ArH), 5.10 (br. m, 4 H, NH2
melamine), 4.36 and 3.03 (ABq, 8 H, J ϭ 13.2 Hz, ArCH2Ar), 3.92
(br. s, 4 H, OCH2), 3.60 (br. s, 4 H, OCH2), 3.20 (br. s, 4 H,
CH2NH), 2.63 (br. s,
4 H, CH2NH2), 1.83 (m, 8 H,
OCH2CH2CH3), 1.60Ϫ1.10 (m, 20 H, other CH2 chain), 1.00 (t,
J ϭ 7.4 Hz, 6 H, OCH2CH2CH3), 0.82 (t, J ϭ 7.2 Hz, 6 H,
OCH2CH2CH3) ppm. MS (FAB): m/z ϭ 1067.8 ([M ϩ Hϩ], calcd.
1067.7). C60H86N14O4·3.13H2O: calcd. C 64.13, H 8.27, N 17.45;
found C 64.13, H 7.65, N 17.10.
N-(2,4,6-Trioxo-1,3,5-triazin-1-yl)-L-alanine (6e): Methyl ester 6b
(150 mg, 0.7 mmol) was added to a solution of NaOH (111 mg,
2.8 mmol) in H2O (4 mL), and the mixture was stirred at room
5,17-Bis({4-amino-6-[(10-aminodecyl)amino]-1,3,5-triazin-2-yl}- temperature overnight. The solution was then acidified (36% HCl,
amino)-25,26,27,28-tetrapropoxycalix[4]arene (5b): Bis(chlorotriaz- pH ϭ 1) and the water was removed under vacuum. The white
ine) 4 (1.0 g, 1.1 mmol) and 1,10-diaminodecane (11.0 g, 64 mmol) residue was extracted several times with THF, and the solution re-
were dissolved in dry THF (15 mL) under Ar and the mixture was
heated at 90 °C overnight. H2O (70 mL) was added to the warm
(not boiling) reaction mixture. After the mixture had cooled, a pre-
cipitate had formed. This was filtered off and redissolved in re-
fluxing THF (15 mL). H2O (70 mL) was added to the clear solu-
tion, and the precipitate was filtered off. After drying, di(melamine)
5b was obtained as a white solid (977 mg, 77%); m.p. 125Ϫ128 °C.
covered after filtration was concentrated to give carboxylic deriva-
tive 6e as a white solid (138 mg, 98%); m.p. 203Ϫ205 °C. 1H NMR
(300 MHz, [D6]DMSO): δ ϭ 12.76 (br, 1 H, CO2H), 11.58 (br, 2
H, NH), 5.07 (m, 1 H, CHCH3), 1.40 (d, J ϭ 6.9 Hz, 3 H, CHCH3)
ppm. MS (FAB): m/z
C6H7N3O5·0.03THF: calcd. C 36.16, H 3.59, N 20.67; found C
ϭ 200.0 ([M Ϫ
Hϩ], calcd. 200.0).
36.08, H 3.58, N 20.58.
1470
Eur. J. Org. Chem. 2003, 1463Ϫ1474

Hydrogen-Bonded Double Rosettes
FULL PAPER
N-(2,4,6-Trioxo-1,3,5-triazin-1-yl)-
D
-phenylalanine Methyl Ester
NH cyan), 8.70Ϫ8.30 (br. m, 2 H, NH calix), 7.99 (br, 2 H, NH-
CO), 7.48 (br. m, 4 H, ArH), 6.90Ϫ6.40 (br. m, 2 H, NH calix),
6.22 (br. m, 10 H, NH calix ϩ ArH), 4.32 (d, J ϭ 11.4 Hz, 4 H,
(6c): This compound was prepared by a literature procedure.[38]
Crude 6c was purified by flash column chromatography (SiO2,
CH2Cl2/MeOH/NH4OH, 90:9.5:0.5) (450 mg, 62%); m.p. 188Ϫ191 ArCH2Ar), 4.17 (s, 4 H, CH2CO), 3.89 (t, J ϭ 7.8 Hz, 4 H, OCH2),
°C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.64 (br, 2 H, NH),
3.60 (br. t, 4 H, OCH2), 3.10Ϫ2.90 (m, 8 H, CH2NHCO ϩ Ar-
7.30Ϫ7.10 (m, 5 H, ArH), 5.45 (q, J ϭ 5.6 Hz, 1 H, CHCH2Phe), CH2Ar), 2.00Ϫ1.74 (m, 8 H, OCH2CH2CH3), 1.60Ϫ1.10 (br. m,
3.66 (s, 3 H, CO2CH3), 3.44Ϫ3.12 (m, 2 H, CHCH2Phe) ppm. MS 20 H, other CH2 chain), 1.06 (t, J ϭ 7.5 Hz, 3 H, OCH2CH2CH3),
(FAB): m/z ϭ 292.2 ([M ϩ Hϩ], calcd. 292.1). C13H13N3O5: calcd.
C 53.61, H 4.50, N 14.43; found C 53.45, H 4.45, N 14.39.
0.87 (t, J ϭ 7.5 Hz, 3 H, OCH2CH2CH3) ppm. MS (FAB): m/z ϭ
1406.2 ([M ϩ Hϩ], calcd. 1405.7). C70H92N20O12·3.3H2O: calcd. C
57.39, H 6.78, N 19.12; found C 57.06, H 6.28, N 18.77.
N-(2,4,6-Trioxo-1,3,5-triazin-1-yl)-D-phenylalanine (6f): Methyl es-
ter 6c (100 mg, 0.3 mmol) was added to a solution of NaOH
(55 mg, 1.4 mmol) in H2O (3 mL), and the mixture was stirred at
room temperature overnight. The solution was then acidified (36%
HCl, pH ϭ 1) and the water was removed under vacuum. The white
residue was extracted several times with THF, and the solution re-
covered after filtration was concentrated to give carboxylic deriva-
Di(melamine-C10-GlyCyan) (2b): This compound was prepared
from dimelamine 5b and cyanurate 6d. Yield: 127 mg (98%). M.p.
278Ϫ280 °C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.59 (br, 2
H, NH cyan), 8.80Ϫ8.30 (br. m, 2 H, NH calix), 8.01 (t, J ϭ 5.1 Hz,
2 H, NH-CO), 7.48 (br. m, 4 H, ArH), 6.90Ϫ6.40 (br. m, 2 H, NH
calix), 6.21 (br. m, 6 H, ArH), 6.11 (br, 4 H, NH2), 4.32 (d, J ϭ
12.3 Hz, 4 H, ArCH2Ar), 4.17 (s, 4 H, CH2CO), 3.89 (t, J ϭ 7.7 Hz,
4 H, OCH2), 3.59 (br. t, 4 H, OCH2), 3.26 (br. m, 4 H, CH2NH
mela), 3.10Ϫ2.90 (m, 8 H, CH2NHCO ϩ ArCH2Ar), 2.00Ϫ1.74
(m, 8 H, OCH2CH2CH3), 1.60Ϫ1.08 (br. m, 32 H, other CH2
chain), 1.06 (t, J ϭ 7.5 Hz, 3 H, OCH2CH2CH3), 0.87 (t, J ϭ
7.5 Hz, 3 H, OCH2CH2CH3) ppm. MS (FAB): m/z ϭ 1490.9 ([M
ϩ Hϩ], calcd. 1491.8). C76H106N20O12·1.9H2O: calcd. C 59.82, H
7.25, N 18.36; found C 59.72, H 6.81, N 17.85.
1
tive 6f as a white solid (93 mg, 98%); m.p. 285Ϫ287 °C. H NMR
(300 MHz, [D6]DMSO): δ ϭ 13.05 (br, 1 H, CO2H), 11.58 (br, 2
H, NH), 7.30Ϫ7.10 (m, 5 H, ArH), 5.30 (q, J ϭ 5.6 Hz, 1 H,
CHCH2Phe), 3.44Ϫ3.12 (m, 2 H, CHCH2Phe) ppm. MS (FAB):
m/z ϭ 276.1 ([M Ϫ Hϩ], calcd. 276.1). C12H11N3O5·0.20H2O:
calcd. C 51.32, H 4.09, N 14.96; found C 51.33, H 4.13, N 15.07.
Methyl (5-Ethyl-2,4,6-trioxo-hexahydropyrimidin-5-yl)acetate (7b):
5-Ethylbarbituric acid 7a (1.0 g, 6.4 mmol) was suspended in H2O
(50 mL), and triethanolamine (0.85 mL, 6.4 mmol) was added.
Methyl 2-bromoacetate (0.6 mL, 7.0 mmol, 1.1 equiv.) was then ad-
ded dropwise over 10 min, giving a clear solution. After the solu-
tion had been stirred at room temperature for 4 d, a white precipi-
tate had formed, and this was isolated by filtration. After drying
under vacuum, ester 7b was obtained as a white solid (0.66 g, 45%);
Di(melamine-C7-D-PheCyan) (2c): This compound was prepared
from dimelamine 5a and cyanurate 6f. Yield: 97 mg (83%). M.p.
214Ϫ220 °C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.42 (br. s, 2
H, NH cyan), 8.80Ϫ8.30 (br. m, 2 H, NH calix), 7.91 (br. s, 2 H,
NH-CO), 7.49 (br. m, 4 H, ArH calix), 7.15 (m, 10 H, ArH benzyl),
6.90Ϫ6.50 (br. m, 2 H, NH calix), 6.21 (br. m, 6 H, ArH), 6.10 (br,
4 H, NH2), 5.16 (q, J ϭ 5.1 Hz, 2 H, CHbenzyl), 4.32 (d, J ϭ
12.6 Hz, 4 H, ArCH2Ar), 3.89 (t, J ϭ 7.8 Hz, 4 H, OCH2), 3.59 (br.
t, 4 H, OCH2), 3.45Ϫ2.95 (m, 16 H, CH2NH mela ϩ CH2benzyl ϩ
CH2NHCO ϩ ArCH2Ar), 2.06Ϫ1.72 (m, 8 H, OCH2CH2CH3),
1.60Ϫ1.08 (m, 20 H, other CH2 chain), 1.06 (t, J ϭ 7.5 Hz, 3 H,
OCH2CH2CH3), 0.87 (t, J ϭ 7.5 Hz, 3 H, OCH2CH2CH3) ppm.
1
m.p. 195Ϫ198 °C. H NMR (300 MHz, [D6]DMSO): δ ϭ 11.49 (s,
2 H, NH), 3.57 (s, 3 H, CO2CH3), 3.00 (s, 2 H, CH2CO2CH3), 1.61
(q, J ϭ 7.5 Hz, 2 H, CH2CH3), 0.81 (t, J ϭ 7.5 Hz, 3 H, CH2CH3)
ppm. MS (FAB): m/z ϭ 229.1 ([M
ϩ
Hϩ], calcd. 229.1).
C9H12N2O5: calcd. C 47.37, H 5.30, N 12.28; found C 47.38, H
5.20, N 12.02.
MS (FAB): m/z
ϭ 1586.6 ([M ϩ
Hϩ], calcd. 1585.8).
(5-Ethyl-2,4,6-trioxo-hexahydropyrimidin-5-yl)acetic Acid (7c):
Methyl ester 7b (400 mg, 1.8 mmol) was added to a solution of
NaOH (210 mg, 5.3 mmol) in H2O (6 mL), and the mixture was
stirred at room temperature overnight. The solution was then acidi-
fied (36% HCl, pH ϭ 1), giving the carboxylic acid derivative 7c
as a white precipitate that was separated by filtration. Subsequently,
the filtrate was concentrated and the white residue was extracted
several times with dry THF. After filtration and removal of THF,
a second crop of white solid was obtained. Both solid fractions
were combined to give pure 7c (365 mg, 97%); m.p. 274Ϫ276 °C.
1H NMR (300 MHz, [D6]DMSO): δ ϭ 12.70 (br, 1 H, CO2H),
11.40 (s, 2 H, NH), 2.90 (s, 2 H, CH2CO2H), 1.74 (q, J ϭ 7.5 Hz,
2 H, CH2CH3), 0.80 (t, J ϭ 7.5 Hz, 3 H, CH2CH3) ppm. MS
(FAB): m/z ϭ 213.0 ([M Ϫ Hϩ], calcd. 213.1).
C84H104N20O12·3.5H2O: calcd. C 61.19, H 6.79, N 16.99; found. C
60.99, H 6.43, N 16.33.
Di(melamine-C10-D-PheCyan) (2d): This compound was prepared
from dimelamine 5b and cyanurate 6f. Yield: 79 mg (90%). M.p.
210Ϫ214 °C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.42 (br, 2
H, NH cyan), 8.80Ϫ8.30 (br. m, 2 H, NH calix), 7.91 (t, J ϭ 5.4 Hz,
2 H, NH-CO), 7.49 (br. m, 4 H, ArH calix), 7.15 (m, 10 H, ArH
benzyl), 6.90Ϫ6.50 (br. m, 2 H, NH calix), 6.21 (br. m, 6 H, ArH),
6.10 (br, 4 H, NH2), 5.16 (q, J ϭ 5.1 Hz, 2 H, CHbenzyl), 4.32 (d,
J ϭ 12.6 Hz, 4 H, ArCH2Ar), 3.89 (t, J ϭ 7.8 Hz, 4 H, OCH2),
3.59 (br. t, 4 H, OCH2), 3.45Ϫ2.95 (m, 16 H, CH2NH mela ϩ CH2
benzyl
ϩ CH2NHCO ϩ ArCH2Ar), 2.06Ϫ1.72 (m, 8 H,
OCH2CH2CH3), 1.60Ϫ1.08 (m, 32 H, other CH2 chain), 1.06 (t,
J ϭ 7.5 Hz, 3 H, OCH2CH2CH3), 0.87 (t, J ϭ 7.5 Hz, 3 H,
OCH2CH2CH3) ppm. MS (FAB): m/z ϭ 1670.6 ([M ϩ Hϩ], calcd.
1669.9). C90H116N20O12·4.0H2O: calcd. C 62.05, H 7.17, N 16.08;
found C 62.08, H 6.73, N 15.86.
General Procedure for the Preparation of Di(melamine-cyanurate)
2aϪf and Di(melamine-barbiturate) 3aϪb: The appropriate cyanur-
ate 6 or barbiturate 7 (2.1 equiv.), triethylamine (4.0 equiv.), and
HBTU (2.1 equiv.) were added to a solution of dimelamine 5aϪb
in dry THF/DMF (2:1). The solution was stirred under Ar at room
temperature for 4 h and then poured into cold H2O (100 mL). The
obtained precipitate was filtered off and dried to give the desired
product as a white solid.
Di(melamine-C7-L-AlaCyan) (2e): This compound was prepared
from dimelamine 5a and cyanurate 6e. Yield: 120 mg (89%). M.p.
251Ϫ253 °C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.50 (br, 2
H, NH cyan), 8.80Ϫ8.30 (br. m, 2 H, NH calix), 7.81 (br, 2 H,
NH-CO), 7.48 (br. m, 4 H, ArH), 6.90Ϫ6.50 (br. m, 2 H, NH calix),
6.23 (br. m, 6 H, ArH), 6.13 (br, 4 H, NH2), 4.91 (m, 2 H, CHCO),
Di(melamine؊C7؊GlyCyan) (2a): This compound was prepared
from dimelamine 5a and cyanurate 6d. Yield: 128 mg (94%). M.p.
1
Ͼ 300 °C. H NMR (300 MHz, [D6]DMSO): δ ϭ 11.56 (br, 2 H, 4.32 (d, J ϭ 12.3 Hz, 4 H, ArCH2Ar), 3.89 (t, J ϭ 7.7 Hz, 4 H,
Eur. J. Org. Chem. 2003, 1463Ϫ1474
1471

´
O. Felix, M. Crego-Calama, I. Luyten, P. Timmerman, D. N. Reinhoudt
FULL PAPER
OCH2), 3.61 (br. t, 4 H, OCH2), 3.10Ϫ2.90 (m, 8 H, CH2NHCO
ϩ ArCH2Ar), 2.10Ϫ1.74 (m, 8 H, OCH2CH2CH3), 1.60Ϫ1.08 (br.
(16%). 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.32 (br. s, 2 H,
NH), 7.83 (m, 4 H, ArH), 3.63 (t, J ϭ 6.6 Hz, 2 H, CH2Ncyan),
m, 26 H, other CH2 chain ϩ CHCH3), 1.06 (t, J ϭ 7.5 Hz, 3 H, 3.56 (t,
OCH2CH2CH3), 0.88 (t, J ϭ 7.5 Hz, 3 H, OCH2CH2CH3) ppm. NCH2CH2CH2CH2N) ppm. MS (FAB): m/z ϭ 329.0 ([M Ϫ Hϩ],
MS (FAB): m/z 1433.8 ([M
Hϩ], calcd. 1433.8). calcd. 329.1).
J ϭ 6.5 Hz, 2 H, CH2NPht), 1.53 (br. s, 4 H,
ϭ
ϩ
C72H96N20O12·3H2O: calcd. C 58.13, H 6.91, N 18.83; found C
58.28, H 6.66, N 18.35.
1-(6-Phthalimidohexyl)-1,3,5-triazine-2,4,6-trione (8b): Flash col-
umn chromatography: SiO2, CH2Cl2/MeOH, 99:1. Yield: 175 mg
1
Di(melamine-C10-L-AlaCyan) (2f): This compound was prepared
(15%). H NMR (300 MHz, [D6]DMSO): δ ϭ 11.35 (s, 2 H, NH),
from dimelamine 5b and cyanurate 6e. Yield: 125 mg (95%). M.p.
233Ϫ236 °C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.51 (br, 2
H, NH cyan), 8.80Ϫ8.30 (br. m, 2 H, NH calix), 7.81 (br, 2 H,
NH-CO), 7.47 (br. m, 4 H, ArH), 6.90Ϫ6.50 (br. m, 2 H, NH calix),
6.21 (br. m, 6 H, ArH), 6.12 (br, 4 H, NH2), 4.92 (q, J ϭ 6.9 Hz,
2 H, CHCO), 4.32 (d, J ϭ 12.3 Hz, 4 H, ArCH2Ar), 3.89 (t, J ϭ
7.7 Hz, 4 H, OCH2), 3.59 (br. t, 4 H, OCH2), 3.10Ϫ2.90 (m, 8 H,
CH2NHCO ϩ ArCH2Ar), 2.10Ϫ1.72 (m, 8 H, OCH2CH2CH3),
7.83 (m, 4 H, ArH), 3.59 (t, J ϭ 6.9 Hz, 2 H, CH2Ncyan), 3.54 (t,
J ϭ 6.9 Hz, 2 H, CH2NPht), 1.56Ϫ1.47 (m, 4 H, CH2CH2N), 1.26
(br. s, 4 H, CH2CH2CH2N) ppm. MS (FAB): m/z ϭ 359.0 ([M ϩ
Hϩ], calcd. 359.1).
1-(10-Phthalimidodecyl)-1,3,5-triazine-2,4,6-trione (8c): Flash col-
umn chromatography: SiO2, CH2Cl2/MeOH, 95:5. Yield: 991 mg
1
(31%). M.p. 211Ϫ213 °C. H NMR (300 MHz, [D6]DMSO): δ ϭ
11.36 (s, 2 H, NH), 7.83 (m, 4 H, ArH), 3.58 (t, J ϭ 7.2 Hz, 2 H,
CH2Ncyan), 3.54 (t, J ϭ 7.2 Hz, 2 H, CH2NPht), 1.56Ϫ1.46 (m, 4
H, CH2CH2N), 1.21 (br. s, 12 H, other CH2) ppm. MS (FAB):
m/z ϭ 415.1 ([M ϩ Hϩ], calcd. 415.2). C21H26N4O5·0.21H2O:
calcd. C 60.31, H 6.37, N 13.40; found C 60.27, H 6.18, N 13.03.
1.68Ϫ0.98 (m, 44 H, other CH2 chain
OCH2CH2CH3), 0.87 (t, J ϭ 7.5 Hz, 3 H, OCH2CH2CH3) ppm.
MS (FAB): m/z 1518.1 ([M
Hϩ], calcd. 1517.9).
ϩ
CHCH3
ϩ
ϭ
ϩ
C78H108N20O12·2.7H2O: calcd. C 59.81, H 7.30, N 17.88; found C
59.75, H 7.03, N 17.33.
1-(Phthalimidomethyl)-3-{[(2,4,6-trioxo-1,3,5-triazin-1-yl)amino]-
methyl}benzene (8d): Flash column chromatography: SiO2, CH2Cl2/
MeOH, 95:5. Yield: 0.50 g (17%). M.p. Ͼ 300 °C. 1H NMR
(300 MHz, [D6]DMSO): δ ϭ 11.52 (s, 2 H, NH), 7.87 (m, 4 H,
ArH Pht), 7.21 (m, 4 H, ArH m-xylene) 4.78 (s, 2 H, CH2Ncyan),
4.74 (s, 2 H, CH2NPht) ppm. MS (FAB): m/z ϭ 379.0 ([M ϩ Hϩ],
calcd. 379.1). C19H14N4O5: calcd. C 60.32, H 3.73, N 14.81; found
C 60.66, H 3.78, N 14.36.
Di(melamine؊C7؊GlyBarb) (3a): This compound was prepared
from dimelamine 5a and barbiturate 7c. Yield: 127 mg (92%). M.p.
197Ϫ200 °C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.27 (br, 2
H, NH barb), 8.80Ϫ8.40 (br. m, 2 H, NH calix), 7.89 (br, 2 H,
NH-CO), 7.47 (br. m, 4 H, ArH), 7.00Ϫ6.60 (br. m, 2 H, NH calix),
6.23 (br. m, 10 H, NH calix ϩ ArH), 4.32 and 3.04 (ABq, 8 H,
J ϭ 12.9 Hz, ArCH2Ar), 3.89 (t, J ϭ 7.8 Hz, 4 H, OCH2), 3.60 (br.
t, 4 H, OCH2), 2.90 (br. m, 4 H, CH2NHCO), 2.81 (s, 4 H,
CH2CO), 2.00Ϫ1.76 (m, 8 H, OCH2CH2CH3), 1.69 (q, J ϭ 7.4 Hz,
2 H, CH2CH3 barb), 1.60Ϫ1.10 (br. m, 20 H, other CH2 chain),
1.06 (t, J ϭ 7.6 Hz, 3 H, OCH2CH2CH3), 0.87 (t, J ϭ 7.5 Hz, 3 H,
OCH2CH2CH3), 0.78 (t, J ϭ 7.4 Hz, 3 H, CH2CH3 barb) ppm.
General Procedure for the Synthesis of Amino-Substituted Cyanur-
ates 9a؊d: A solution of methylamine (33% in EtOH, 40 equiv.)
was added to a solution of phthalimide 8aϪd (1.0 equiv.) in EtOH
(10 mL), and the mixture was heated at 70 °C under Ar for
150 min. After the mixture had cooled, the resulting white precipi-
tate was filtered off, washed with EtOH (3 ϫ), and dried under
vacuum. Cyanuric acids 9aϪd were obtained as white solids.
MS (FAB): m/z
C76H102N18O12·4.5H2O: calcd. C 59.24, H 7.26, N 16.36; found C
58.85, H 6.66, N 16.35.
ϭ 1459.4 ([M ϩ
Hϩ], calcd. 1459.8).
Di(melamine-C10-GlyBarb) (3b): This compound was prepared
from dimelamine 5b and barbiturate 7c. Yield: 178 mg (85%). M.p.
185Ϫ190 °C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 11.26 (br, 2 H,
NH barb), 8.80Ϫ8.40 (br. m, 2 H, NH calix), 7.91 (t, J ϭ 5.1 Hz, 2
H, NH-CO), 7.31 (br. m, 4 H, ArH), 7.05Ϫ6.60 (br. m, 2 H, NH
calix), 6.37 (br, 4 H, NH2 calix), 6.22 (br. m, 6 H, ArH), 4.32 and
3.03 (ABq, 8 H, J ϭ 12.6 Hz, ArCH2Ar), 3.89 (t, J ϭ 7.8 Hz, 4 H,
OCH2), 3.60 (br. t, 4 H, OCH2), 2.89 (br. m, 4 H, CH2NHCO),
2.82 (s, 4 H, CH2CO), 2.00Ϫ1.76 (m, 8 H, OCH2CH2CH3), 1.69
(q, J ϭ 7.5 Hz, 2 H, CH2CH3 barb), 1.60Ϫ1.08 (br. m, 32 H, other
CH2 chain), 1.06 (t, J ϭ 7.4 Hz, 3 H, OCH2CH2CH3), 0.87 (t, J ϭ
7.5 Hz, 3 H, OCH2CH2CH3), 0.78 (t, J ϭ 7.5 Hz, 3 H, CH2CH3
barb) ppm. MS (FAB): m/z ϭ 1544.3 ([M ϩ Hϩ], calcd. 1543.9).
C82H114N18O12·5.9H2O: calcd. C 59.68, H 7.68, N 15.28; found C
59.59, H 7.05, N 15.63.
1-(4-Aminobutyl)-1,3,5-triazine-2,4,6-trione (9a): Yield: 105 mg
(91%). 1H NMR (300 MHz, D2O): δ ϭ 3.66 (br. s, 2 H,
CH2Ncyan), 2.88 (br. s, 2 H, CH2NH2), 1.54 (br. s, 4 H,
NCH2CH2CH2CH2N) ppm. MS (EI): m/z ϭ 200.0 ([Mϩ], calcd.
200.1).
1-(6-Aminohexyl)-1,3,5-triazine-2,4,6-trione (9b): Yield: 175 mg
1
(88%). H NMR (300 MHz, D2O): δ ϭ 3.62 (t, J ϭ 6.9 Hz, 2 H,
CH2Ncyan), 2.83 (t, J ϭ 6.9 Hz, 2 H, CH2NH2), 1.49 (m, 4 H,
CH2CH2N), 1.24 (m, 4 H, CH2CH2CH2N) ppm. MS (FAB):
m/z ϭ 229.2 ([M ϩ Hϩ], calcd. 229.1).
1-(10-Aminodecyl)-1,3,5-triazine-2,4,6-trione (9c): Yield: 132 mg
(96%). M.p. 255Ϫ257 °C. 1H NMR (300 MHz, [D6]DMSO ϩ 1
drop HCl): δ ϭ 11.37 (s, 2 H, NH), 8.01 (br. s, 3 H, NH3ϩ), 3.58
(t, J ϭ 7.2 Hz, 2 H, CH2Ncyan), 2.70 (t, J ϭ 6.0 Hz, 2 H,
CH2NH2), 1.51 (m, 4 H, CH2CH2N), 1.21 (br. s, 12 H, other CH2)
General Procedure for the Synthesis of Phthalimide-Protected Cyan-
urates 8a؊d: A solution of cyanuric acid (1.0 equiv.), N-(bromo-
alkyl)phthalimide (1.0 equiv.), and DBU (1.0 equiv.) in dry DMF
(40 mL) was heated at 70 °C under Ar for 7 h. After cooling, the
yellow solution was poured into cold H2O (300 mL), and the re-
sulting white precipitate was filtered off and dried under vacuum.
The obtained white solid was purified by flash column chro-
matography.
ppm. MS (FAB): m/z ϭ 285.1 ([M
ϩ
Hϩ], calcd. 285.2).
C13H24N4O3·0.53H2O: calcd. C 53.13, H 8.59, N 19.06; found C
53.13, H 8.06, N 18.45.
1-(Aminomethyl)-3-{[(2,4,6-trioxo-1,3,5-triazin-1-yl)amino]-
methyl}benzene (9d): Yield: 111 mg (85%). M.p. 278Ϫ281 °C. 1H
NMR (300 MHz, [D6]DMSO ϩ 1 drop HCl): δ ϭ 11.53 (s, 2 H,
NH), 8.48 (br. s, 3 H, NH3ϩ), 7.32 (m, 4 H, ArH m-xylene) 4.80
(s, 2 H, CH2Ncyan), 3.93 (s, 2 H, CH2NH2) ppm. MS (FAB):
m/z ϭ 249.1 ([M ϩ Hϩ], calcd. 249.1).
1-(4-Phthalimidobutyl)-1,3,5-triazine-2,4,6-trione (8a): Flash col-
umn chromatography: SiO2, CH2Cl2/MeOH, 9:1. Yield: 400 mg
1472
Eur. J. Org. Chem. 2003, 1463Ϫ1474

Hydrogen-Bonded Double Rosettes
FULL PAPER
5,17-Bis{[4-amino-6-({6-[(2,4,6-trioxo-1,3,5-triazin-1-yl)amino]- Molecular Simulation Studies: Initial structures were generated by
hexyl}amino)-1,3,5-triazin-2-yl]amino}-25,26,27,28-tetra- manual modification of the X-ray crystal structure of 13·(DEB)6 by
propoxycalix[4]arene (10): Bis(chlorotriazine)
0.12 mmol), 9b (58 mg, 0.25 mmol), and DIPEA (0.13 mL,
0.76 mmol) were dissolved in a 1:1 mixture of N,N-dimethylaceta-
4
(105.5 mg,
use of Quanta97.[49] Molecular simulations were run with
CHARMm, version 24.0.[9,10,50] Parameters were taken from
Quanta97, and point charges were assigned with the charge tem-
mide (DMA) and 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)- plate option in Quanta/CHARMm.
one (DMPU) (5 mL). The mixture was heated at 90 °C under Ar
for 3 d. After the mixture had cooled, H2O was added and the
formed precipitate was filtered. Impurities were removed by re-
Acknowledgments
peated washing with hot THF to give 10 as an off-white solid
(32 mg, 21%); m.p. 282Ϫ285 °C. 1H NMR (300 MHz, [D6]DMSO):
δ ϭ 11.31 (br. s, 2 H, NH cyan), 8.55Ϫ8.35 (2br. s, 2 H, NH calix),
7.43 (m, 4 H, ArH), 6.68Ϫ6.55 (2br. s, 2 H, NH calix), 6.17 (s, 6
H, ArH), 6.04 (br. s, 4 H, NH2 calix), 4.25 and 3.00 (ABq, 8 H,
J ϭ 12.9 Hz, ArCH2Ar), 3.82 (t, J ϭ 7.8 Hz, 4 H, OCH2), 3.54 (m,
8 H, OCH2 ϩ CH2Ncyan), 1.85Ϫ1.75 (m, 8 H, OCH2CH2CH3),
1.44 (m, 8 H, CH2CH2CH2N), 1.20 (m, 8 H, CH2CH2CH2N), 1.00
(t, J ϭ 7.4 Hz, 6 H, OCH2CH2CH3), 0.81 (t, J ϭ 7.4 Hz, 6 H,
OCH2CH2CH3) ppm. MS (FAB): m/z ϭ 1264.1 ([M ϩ Hϩ],
calcd. 1263.7).
We thank Dr. P. Lipkowski, Dr. V. Paraschiv, and Dr. Ir. L. Prins
for providing several intermediate compounds, and the FWO
Vlaanderen for financial support.
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