A novel type of hydrogen-bonded assemblies based on the melamine·cyanuric acid motif

Article abstract of DOI:10.1021/jo020610c

This paper reports the formation of novel hydrogen-bonded assemblies 1₃·CA obtained upon mixing cyanuric acid (CA) with melamine derivatives 1, in which two of the three possible H-bonding arrays have been blocked. The four components are held together by 9 hydrogen bonds and form a rigid planar structure in which a central CA (three ADA motifs: A = acceptor, D = donor) is hydrogen bonded to three peripheral melamine derivatives (DAD motif). Furthermore, the synthesis and assembly studies are described of hydrogen-bonded assemblies 2-4·CA, comprised of three melamine derivatives that are covalently connected, and CA. The overall thermodynamic stability of assemblies 2-4·CA is superior to 1₃·CA (I_Tm = 9 vs 3.6). The presence of the 2·CA complex in chloroform was confirmed by ¹H NMR spectroscopy and MALDI-TOF mass spectrometry. Substitution of the trimelamines with chiral or fluorescent groups (R³) enabled the study of the assemblies by CD and fluorescence spectroscopy. Titration experiments revealed strongly enhanced stabilities even in the presence of polar solvents, such as THF and CH₃OH. Depending on the polarity of the solvent, stacking between the planar assembly units was observed.

Full text of DOI:10.1021/jo020610c

A Novel Typ e of Hyd r ogen -Bon d ed Assem blies Ba sed on th e
Mela m in e‚Cya n u r ic Acid Motif
Maria Arduini, Mercedes Crego-Calama, Peter Timmerman,* and David N. Reinhoudt*
Laboratory of Supramolecular Chemistry and Technology, MESA+ Research Institute,
University of Twente, P.O. Box 217, 7500 AE, Enschede, The Netherlands
d.n.reinhoudt@ct.utwente.nl
Received August 29, 2002
This paper reports the formation of novel hydrogen-bonded assemblies 13‚CA obtained upon mixing
cyanuric acid (CA) with melamine derivatives 1, in which two of the three possible H-bonding arrays
have been blocked. The four components are held together by 9 hydrogen bonds and form a rigid
planar structure in which a central CA (three ADA motifs: A ) acceptor, D ) donor) is hydrogen
bonded to three peripheral melamine derivatives (DAD motif). Furthermore, the synthesis and
assembly studies are described of hydrogen-bonded assemblies 2-4‚CA, comprised of three melamine
derivatives that are covalently connected, and CA. The overall thermodynamic stability of assemblies
2-4‚CA is superior to 13‚CA (ITm ) 9 vs 3.6). The presence of the 2‚CA complex in chloroform was
confirmed by 1H NMR spectroscopy and MALDI-TOF mass spectrometry. Substitution of the
trimelamines with chiral or fluorescent groups (R3) enabled the study of the assemblies by CD and
fluorescence spectroscopy. Titration experiments revealed strongly enhanced stabilities even in
the presence of polar solvents, such as THF and CH3OH. Depending on the polarity of the solvent,
stacking between the planar assembly units was observed.
In tr od u ction
acid-melamine motif.11,12 Early work by Whitesides and
Lehn has shown that blocking one of the H-bonding
arrays of both the cyanuric acid and melamine compo-
nents leads to the formation of either infinite tapes or
cyclic rosette motifs.11,13 While tape-like structures have
been studied merely in the solid state14,15 and in mono-
layers,16,17 the rosette motif has been the major topic of
interest in solution-phase studies.18
The exclusive formation of a cyclic rosette structure
was achieved by covalently connecting three melamine
units on a synthetic scaffold.13,19 The resulting assemblies
with single cyanurates exhibit increased thermodynamic
stabilities (ITm ) 6) in comparison to conventional rosettes
(ITm ) 3.6) as a result of the reduced number of separate
components in the assemblies. The melting point index
(ITm ) HB/(N - 1)) was defined as a parameter that
qualitatively represents the stability of an assembly
comprised of N particles held together by HB hydrogen
Multiple noncovalent interactions, such as hydrogen-
bonding, hydrophobic interactions, metal coordination,
and ionic interactions, drive host-guest complexation
processes and control the spontaneous aggregation of
highly ordered structures in many natural and synthetic
systems. Because of the unique properties of hydrogen
bonds (directionality, specificity),1,2 considerable efforts
have focused on a complete understanding and full
control of this special type of weak interaction.3,4 Over
the years a wide variety of well-defined synthetic su-
pramolecular architectures has been developed.5-10 In
this respect many groups have studied the self-assembly
of multicomponent structures based on the cyanuric
* To whom correspondence should be addressed. Fax: +31-53-489-
4645.
(1) Prins, L. J .; Reinhoudt, D. N.; Timmerman, P. Angew. Chem.,
Int. Ed. 2001, 40, 2383-2426.
(2) Konrat, R.; Tollinger, M.; Kontaxis, G.; Kra¨utler, B. Monatsh.
Chem. 1999, 130, 961-982.
(11) Lehn, J .-M.; Mascal, M.; DeCian, A.; Fischer, J . J . Chem. Soc.,
Chem. Commun. 1990, 479-480.
(3) Schuster, P.; Zundel, G.; Sandorfy, C. The Hydrogen Bond:
Recent Developments in Theory and Experiments; North-Holland:
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(12) Simanek, E. E.; Mammen, M.; Gordon, D. M.; Chin, D. N.;
Mathias, J . P.; Seto, C. T.; Whitesides, G. M. Tetrahedron 1995, 51,
607-619.
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(5) Ghadiri, M. R.; Granja, J . R.; Milligan, R. A.; McRee, D. E.;
Khazanovich, N. Nature 1993, 366, 324-327.
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6409-6411.
(6) Whitesides, G. M.; Simanek, E. E.; Mathias, J . P.; Seto, C. T.;
Chin, D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28,
37-44.
(14) MacDonald, J . C.; Whitesides, G. M. Chem. Rev. 1994, 94,
2383-2420.
(15) Beijer, F. H.; Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer,
E. W. Angew. Chem., Int. Ed. 1998, 37, 75-78.
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(17) Ahuja, R.; Caruso, P.-L.; Mo¨bius, K.; Paulus, W.; Ringsdorf, H.;
Wildburg, G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1033-1036.
(18) Mathias, J . P.; Seto, C. T.; Simanek, E. E.; Whitesides, G. M.
J . Am. Chem. Soc. 1994, 116, 1725-1736.
(7) Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin, S.
V. Science 1996, 271, 1095-1098.
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burg, J . P. Angew. Chem., Int. Ed. Engl. 1996, 35, 2204-2206.
(9) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J . B.;
Hirschberg, J . H. K. K.; Lange, R. F. M.; Lowe, J . K. L.; Meijer, E. W.
Science 1997, 278, 1601-1604.
(19) Seto, C. T.; Mathias, J . P.; Whitesides, G. M. J . Am. Chem. Soc.
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10.1021/jo020610c CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/08/2003
J . Org. Chem. 2003, 68, 1097-1106
1097

Arduini et al.
SCHEME 1. F or m a tion of th e 13‚CA Assem blya
CHART 1
a
The four components are held together by nine hydrogen bonds
bonds.20 A different approach toward rosette structures
with improved thermodynamic stabilities involves the
sideways connection of two or more melamine units into
layer-by-layer double rosette (ITm ) 4.5),21,22 tetrarosette
(ITm ) 5.14),23 and octarosette (ITm ) 5.33) assemblies.24
In a similar fashion others have used the concepts of
cooperativity to improve the stability of different H-
bonded structures.25-30
In this paper we report on a hitherto unknown sub-
structure of the melamine‚cyanuric acid (M‚CA) lattice.
The structure (13‚CA) is obtained when neat cyanuric
acid is mixed with 3 equiv of an N,N′,N′′,N′′-tetraalkyl
melamine unit 1. Despite the complete insolubility of CA
in chloroform, formation of the 13‚CA assembly is readily
observed as the result of the very strong interaction
between cyanurate and melamine units.31 We further
describe the synthesis and formation of assemblies 2-4‚
CA, which exhibit improved thermodynamic stabilities
as the result of covalent preorganization of the melamine
units.
(ITm ) 3).
chloride with 1.0 equiv of either dibutylamine (a ), dibenz-
ylamine (b), or 3,3′-iminodipropionitrile (c) at 0 °C in the
presence of N,N-diisopropylethylamine (DIPEA) in THF.
Subsequent reaction with an excess of n-butylamine at
90 °C gave 1a -c in 80-90% yield. Compounds 1d and
1e were prepared in a two-step procedure. First, the
chlorotriazines 1f and 1g were synthesized by reaction
of cyanuric chloride with 2.0 equiv of either 1-amino-5-
hexene (f) or L-leucine methyl ester (g) at room temper-
ature. Conversion into the melamines 1d and 1e was
achieved by reaction with an excess of dibutylamine in
75-85% yield.
Preparation of trimelamines 2a , 3, and 4 was carried
out in a three-step procedure. In the first step the
chlorotriazines 5, 6, and 7 (Scheme 1) were synthesized
in 85% yield by reaction of cyanuric chloride with 1.0
equiv of the corresponding primary amine (n-butylamine,
(S)-2-methylbenzylamine, and pyrenemethylamine, re-
spectively) at 0 °C, followed by treatment with 2.0 equiv
of the secondary amine (dibutylamine, dibenzylamine,
and dibutylamine, respectively) at 30 °C. Subsequently,
the amino-functionalized melamines 8-10 were obtained
(80-98% yield) by refluxing the chlorotriazine 5 with a
large excess of the corresponding diamine (m-xylylene-
diamine, 1,7-diaminoheptane, and 1,10-diaminodecane,
respectively), while melamine 11 and 12 were obtained
by refluxing 6 and 7 with m-xylylediamine.
Resu lts a n d Discu ssion
Syn th esis of th e Mela m in e Der iva tives. Single
N,N′,N′′,N′′-tetraalkylmelamine derivatives 1a -e were
synthesized starting from cyanuric chloride by stepwise
substitution of the three chloro substituents for either a
primary or a secondary amine. Compounds 1a -c were
prepared in a one-pot procedure by reaction of cyanuric
In the final step (Scheme 2), the trimelamines 2a , 3,
and 4 were synthesized by reaction of 0.5 equiv of 2-(N,N-
dibenzylamino)-4,6-dichloro-1,3,5-triazine, obtained by
reaction of cyanuric chloride with 1.0 equiv of dibenzyl-
amine at 0 °C, with 8, 9, and 10 respectively, in 60-85%
yield. For the synthesis of trimelamines 2b and 2c a
slightly different procedure was followed. The strands 13
and 14 were obtained by a reaction of 2 equiv of the
corresponding external melamines 11 and 12 with cya-
nuric chloride at 30 °C (70% yield). The third chloride of
the central melamine was substituted by reaction with
an excess of dibutylamine in refluxing THF to give the
final compounds 2b and 2c in 90% and 80 yield, respec-
tively.
(20) Mammen, M.; Simanek, E. E.; Whitesides, G. M. J . Am. Chem.
Soc. 1996, 118, 12614-12623.
(21) Mathias, J . P.; Simanek, E. E.; Whitesides, G. M. J . Am. Chem.
Soc. 1994, 116, 4326-4340.
(22) Vreekamp, R. H.; Van Duynhoven, J . P. M.; Hubert, M.;
Verboom, W.; Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1996,
35, 1215-1218.
(23) J olliffe, K. A.; Crego-Calama, M.; Fokkens, R.; Nibbering, N.
M. M.; Timmerman, P.; Reinhoudt, D. N. Angew. Chem., Int. Ed. 1998,
37, 1247-1251.
(24) Paraschiv, V.; Crego-Calama M.; Fokkens, R. H.; Padberg, C.
J .; Timmerman, P.; Reinhoudt, D. N. J . Org. Chem. 2001, 66, 8297-
8301.
(25) Adams, H.; Carver, F. J .; Hunter, C. A.; Morales, J . C.; Seward,
E. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 1542-1544.
(26) Sessler, J . L.; Wang, R. J . Org. Chem. 1998, 63, 4079-4091.
(27) Folmer, B. J . B.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.;
Meijer, E. W. J . Am. Chem. Soc. 1999, 121, 9001-9007.
(28) Lipkowski, P.; Bielejewska, A.; Kooijman, H.; Spek, A. L.;
Timmerman, P.; Reinhoudt, D. N. J . Chem. Soc., Chem. Commun.
1999, 1311-1312.
For m ation of th e 4-Com pon en t Hydr ogen -Bon ded
Assem blies 13‚CA. First we studied the spontaneous
formation of the hydrogen-bonded assemblies 13‚CA that
are held together by 9 hydrogen bonds (Scheme 3). Initial
extraction experiments showed that the single melamine
1a (R1 ) R2 ) butyl) can solubilize up to 0.33 equiv of
CA in CDCl3, which by itself is completely insoluble in
(29) Gonza´lez, J . J .; Prados, P.; De Mendoza, J . Angew. Chem., Int.
Ed. 1999, 38, 525-528.
(30) Zeng, H.; Miller, R. S.; Flowers, R. A., II; Gong, B. J . Am. Chem.
Soc. 2000, 122, 2635-2644.
(31) Bielejewska, A. G.; Marjo, C. E.; Prins, L. J .; Timmerman, P.;
de J ong, F.; Reinhoudt, D. N. J . Am. Chem. Soc. 2001, 123, 7518-
7533.
1
this solvent. H NMR spectroscopy gives clear evidence
1098 J . Org. Chem., Vol. 68, No. 3, 2003

Novel Hydrogen-Bonded Assemblies
SCHEME 2. Syn th etic Sch em e for th e Mela m in e P r ecu r sor s 8-12
SCHEME 3. Syn th etic Sch em e for th e
Tr im ela m in es 2-4
for the formation of the anticipated assembly 1a 3‚CA.
Titration of 1a with CA causes a strong downfield shift
of the broad melamine NH signal at 4.8 ppm as a result
of H-bond formation (see Figure 1). With 0.33 equiv of
CA present, the melamine NH protons give rise to a
single resonance at 7.7 ppm. The signal for the NH
protons of CA within the assembly is broad and remains
invisible in CDCl3, even at -50 °C. To confirm the 3:1
stoichiometry of the 1a 3‚CA assembly, a chloroform
solution of 1a was saturated with CA and after sonication
for 2 h the remaining solid was removed via filtration.
Upon evaporation of the solvent the mixture was redis-
solved in DMSO-d6 and integration of the melamine
NHCH2 and the cyanurate NH proton resonances, clearly
visible in this solvent, confirmed the 3:1 ratio.
Formation of the 1a 3‚CA assembly in CDCl3 was also
observed by means of 13C NMR spectroscopy. The spec-
trum of free 1a shows two peaks at 165.3 and 164.6 ppm
for the carbons of the triazine ring. In the presence of
0.33 equiv of CA the two peaks shift to 161.7 and 158.0
ppm and an extra signal appears at 163.8 ppm, corre-
sponding to the carbonyl of the complexed CA.
Molecular modeling studies of the 1a 3‚CA assembly
clearly show that the three melamine units nicely sur-
round the CA unit while forming a well-defined flat
triangular structure (Figure 2). The arrangement of the
substituents of the three melamine units 1a is fully
compatible with the formation of nine strong hydrogen
bonds, without imposing steric hindrance that could
possibly destabilize the assembly.
F IGURE 1. 1H NMR titration of melamine 1a with CA
(CDCl3, 25 °C): (a) 1a /CA ) 3:0; (b) 1a /CA ) 3:0.5; (c) 1a /CA
) 3:1; (d) 1a /CA ) 3:2. The melamine NH signal is marked
with a square and shifts downfield upon the addition of CA.
mass spectrometry after Ag+-labeling.23 This technique
was developed in our group for the characterization of
neutral hydrogen-bonded assemblies by mass spectrom-
etry. It requires the presence of a (reasonably strong)
binding site for Ag+, like a cyano group or a cleft-like
aromatic pocket.32 Melamines such as 1b and 1c, carrying
either a dibenzylamino or a cyano group, should be able
to bind Ag+ thus providing the required ionization for
detection of the corresponding assemblies 13‚CA by
MALDI-TOF mass spectrometry. Samples of 1b3‚CA
treated with 1.5-2.0 equiv of AgCF3COO in chloroform
indeed showed a strong signal at m/z 1494.0 (calcd for
C78H105N21O3‚107Ag+: 1491.8) corresponding to the mono-
(32) Timmerman, P.; J olliffe, K. A.; Crego-Calama, M.; Weidmann,
J .-L.; Prins, L. J .; Cardullo, F.; Snellink-Ruel, B. H. M.; Fokkens, R.;
Nibbering, N. M. M.; Shinkai, S.; Reinhoudt, D. N. Chem. Eur. J . 2000,
6, 4104-4115.
Additional evidence for the formation of the hydrogen-
bonded assemblies 13‚CA was obtained by MALDI-TOF
J . Org. Chem, Vol. 68, No. 3, 2003 1099

Arduini et al.
F IGURE 3. Intramolecular H-bonding in melamine 1e.
ultimate objective to covalently link the three 1d units.34
In this way, the thermodynamic stability is expected to
increase significantly, since the number of individual
components changes from 4 to 2, and therefore the ITm
from 3 to 9. For this purpose, we used the Grubbs’ ring-
closing metathesis reaction (RCM) because it is usually
quantitative and can be performed under very mild
conditions (toluene/dichloromethane, room tempera-
ture).35 Previous work in our group has shown that the
RCM reaction is fully compatible with the formation of
hydrogen-bonded double rosette assemblies.36 However,
the RCM reaction by adding 0.6 equiv of Grubbs’ catalyst
to a 5 mM solution of assembly 1d 3‚CA in CD2Cl2 gave
neither the cyclic trimer nor the linear trimer or dimer.
This might indicate that assembly 1d 3‚CA is significantly
less stable and consequently much higher concentrations
of free melamine are available for binding to the catalyst
and concomitant deactivation.
F or m a tion of 2-Com p on en t Hyd r ogen -Bon d ed
Assem blies 2a ‚CA, 3‚CA, a n d 4‚CA. The results de-
scribed above clearly show that single melamines such
as 1 form well-defined complexes with CA but the
stability of these assemblies is sometimes too low. To
enhance the thermodynamic stability of these complexes,
we connected the three melamine units via linkers of
appropriate size. Thus, trimelamines 2-4 are designed
to form well-defined 1:1 assemblies with CA (Scheme 4).
These assemblies (2-4‚CA) are expected to exhibit
increased thermodynamic stabilities as a result of the
preorganization of the melamine units within the corre-
sponding complexes (ITm from 3 to 9).20
F IGURE 2. Molecular simulation (CHARMm 24.0) of as-
sembly 1a 3‚CA.
valent Ag+-complex of the assembly. Signals for as-
semblies with different stoichiometries were not detected.
Similarly, a sample of assembly 1c3‚CA gave a distinct
signal at m/z 1271.1 (calcd for C54H87N27O3‚107Ag+: 1269.5).
In this case an additional signal was observed at m/z
581.3 corresponding to the 1c‚CA‚Ag+-complex (calcd for
C20H31N11O3‚107Ag+: 580.5).
Formation of assemblies 1b3‚CA and 1c3‚CA in solution
was also studied by 1H NMR spectroscopy. The NH signal
of melamine 1b was shifted from 4.8 to 7.3 ppm upon
the addition of 0.33 equiv of CA, indicating the formation
of assembly 1b3‚CA. The spectra for assembly 1c were
more difficult to interpret. The spectrum of free 1c gives
several broad signals for the NH protons between 4.7 and
5.1 ppm, most likely due to the presence of different
conformers resulting from hindered rotation around the
C-NH bonds (the same phenomenon was observed for
melamine 1a and 1b at -50 °C).33 After the addition of
CA to compound 1c the melamine NH signal shifts
downfield to 7.2 ppm and other broad peaks remain
between 4.0 and 5.0 ppm. Unfortunately, the relatively
low solubility of both assemblies precluded further stud-
ies by 13C NMR spectroscopy.
As a logical next step, we studied the formation of 13‚
CA complexes carrying different functionalities, like
amino acid side chains as in 1e. However, 1H NMR
titration experiments of 1e with CA did not show the
expected complexation-induced shifts for the melamine-
NH signal, suggesting that the melamine does not
interact with CA. Furthermore, the cyanuric acid was not
solubilized into chloroform by complexation to the
melamine. The very low stability of assembly 1e3‚CA is
most likely due to intramolecular H-bond formation
between the melamine NH and the ester carbonyl group
(Figure 3). The downfield position of the NH proton
signals in free 1e (5.0 and 5.9 ppm) is fully consistent
with this hypothesis. CPK model inspections clearly show
that the observed low stability cannot be due to steric
hindrance between the branched alkyl side chains of the
amino acids.
The three melamine units in 2a are connected via two
relatively rigid m-xylylene linkers. Extraction experi-
ments clearly confirmed the formation of 1:1 complex 2a ‚
CA as up to 1.0 equiv of CA was solubilized in a solution
of 2a in CDCl3 (free CA is completely insoluble in
1
chloroform). H NMR titration of trimelamine 2a with
CA showed features characteristic for formation of as-
sembly 2a ‚CA. In the presence of 0.5 equiv of CA three
broad signals, assigned to the hydrogen-bonded NH
protons of melamine 2a in the assembly, become visible
at 8.1, 7.8, and 7.7 ppm in addition to the broad NH
signals for free 2a between 5.3 and 4.8 ppm. The intensity
of the three peaks corresponding to the complexed 2a
increases during the titration, while the intensity of the
peaks corresponding to the NH protons of free 2a
decreases, indicating that exchange between free 2a and
(34) Clark, T. D.; Ghadiri, M. R. J . Am. Chem. Soc. 1995, 117,
12364-12365.
(35) O’Leary, D. J .; Blackwell, H. E.; Washenfelder R. A.; Grubbs
R. H. Tetrahedron Lett. 1998, 39, 7427-7430.
(36) Cardullo, F.; Crego-Calama, M.; Snellink-Rue¨l, B. H. M.;
Weidmann, J .-L.; Bielejewska, A.; Fokkens, R.; Nibbering, N. M. M.;
Timmerman, P.; Reinhoudt, D. N. J . Chem. Soc., Chem. Commun.
2000, 367-368.
Subsequently, we studied the possibility for covalent
capture of the 4-component assembly 1d 3‚CA, with the
(33) Willner, I.; Rosengaus, J .; Biali, S. Tetrahedron Lett. 1992, 33,
3805-3808.
1100 J . Org. Chem., Vol. 68, No. 3, 2003

Novel Hydrogen-Bonded Assemblies
SCHEME 4. F or m a tion of th e 2-4‚CA Com p lexa
a
Nine hydrogen bonds are formed between the two species (ITm ) 9).
the [2a ‚CA‚Ag]+ complex. Signals corresponding to oli-
gomeric species were not observed.
To study the influence of the size and flexibility of the
linker on the assembly process, trimelamines 3 and 4,
with heptylene and decylene spacers connecting the
individual melamine moieties, were synthesized. 1H NMR
titration of free 3 with CA resulted in a gradual dis-
appearance of the broad signal between 4.5 and 4.8 ppm
for the NH melamine protons, while three new peaks
between 7.0 and 8.5 ppm appeared. With 1.0 equiv of CA,
only the three new peaks at 8.5, 7.9, and 7.4 ppm for the
three sets of NHmelamine protons corresponding to com-
plexed 3 were present. Additional CA was not solubilized
in agreement with the expected 1:1 stoichiometry of the
complex. Formation of the 1:1 assembly was also con-
firmed by MALDI-TOF mass spectrometry. Upon addi-
tion of 1.5 equiv of AgCF3COO to a 1:1 mixture of 3‚CA
in chloroform an intense signal was observed at m/z
1324.6 (calcd for C64H105N21O3‚107Ag+: 1323.7) corre-
sponding to the [3‚CA‚Ag]+ complex. Again, signals
corresponding to higher oligomers were not observed.
The same experiments were performed with tri-
melamine 4, having two decylene linkers connecting the
melamine units. Upon addition of CA to a CDCl3 solution
of 4, a white precipitate was formed and the 1H NMR
spectrum showed a decrease of the amount of tri-
melamine 4 in solution instead of the expected downfield
shift of the melamine NH proton signals. When 1.0 equiv
of CA was added the proton signals for trimelamine 4
had completely disappeared and no signals for the
complex could be seen. Also the MALDI-TOF spectrum
did not show any signal related to the 1:1 assembly.
The experiments described above clearly illustrate the
crucial role of the linkers in the assembly process.37 The
system should be sufficiently preorganized to form a well-
defined hydrogen-bonded structure, otherwise insoluble
oligomeric networks are formed.
F IGURE 4. 1H NMR titration of melamine 2a with CA
(CDCl3, 25 °C): (a) 2a /CA ) 1:0; (b) 2a /CA ) 1:1; (c) 2a /CA )
1:1 (at -50 °C). The melamine NH signals are marked with a
square and the cyanurate NH signals are marked with stars.
the complex is slow on the NMR time scale. With 1.0
equiv of CA present, the NH signals for free 2a have
completely disappeared and sharp signals for the as-
sembly indicate the exclusive formation of the 2a ‚CA
assembly (Figure 4). The 1H NMR spectrum of the
assembly at -50 °C shows two signals for the hydrogen-
bonded NH protons of CA (ratio 1:2). The relatively sharp
signal at 13.5 ppm corresponds to the cyanurate NH
proton that is hydrogen bonded to the central melamine
unit, while the broader signal at 14.5 ppm corresponds
to the cyanurate NH protons that are hydrogen bonded
to the outer melamine units. Obviously, the difference
in peak shape is largely due to differences in exchange
rates for these two protons. The cyanurate NH signals
are too broad to be observed at room temperature, while
all the other peaks remain sharp upon increasing the
temperature from -50 to 30 °C. Supporting Information
about the stoichiometry of the 2a ‚CA complex was
obtained by MALDI-TOF mass spectrometry after Ag+-
labeling. The presence of the dibenzyl side chains at the
central melamine unit in 2a allows coordination of Ag+
ions to this assembly. Consequently, the mass spectrum
of a chloroform solution of 2a ‚CA after addition with 1.5
equiv of AgCF3COO showed a strong signal at m/z 1335.9
(calcd for C66H93N21O3‚107Ag+: 1336.4) corresponding to
Subsequently, we investigated the assembly behavior
of trimelamines with different R3 substituents. The
functionalities at these positions (R3) are of particular
interest because their environment changes drastically
after complexation of CA. Molecular modeling studies
suggest that upon formation of assembly 2a ‚CA the two
R3 substituents are forced to bend out of the plane of the
assembly because of mutual steric hindrance. Therefore,
the two R3 groups are expected to arrange themselves
(37) Tjivikua, T.; Deslongchamps, G.; Rebek, J . J . Am. Chem. Soc.
1990, 112, 8408-8414.
J . Org. Chem, Vol. 68, No. 3, 2003 1101

Arduini et al.
F IGURE 5. Schematic representation of assemblies 2-4‚CA.
Different diastereoisomers may be formed: (a) the two R3
groups are on opposite sides of the plane of the assembly, (b)
enantiomer of (a), (c) the two R3 groups are on the same side
of the plane of the assembly.
F IGURE 7. CD spectra of (S,S)-2b and (R,R)-2b (dashed
lines) and the corresponding assemblies (S,S)-2b‚CA and
(R,R)-2b‚CA (solid line) in CHCl3.
F IGURE 6. 1H NMR spectra of assembly (S,S)-2b‚CA (CDCl3,
-50 °C). Cyanurate NH signals are observed between 14.5 and
16.5 ppm.
either on the same side of the assembly plane or in a
helical fashion (Figure 5). In the second case, the
hydrogen-bonded structure can be considered as a non-
covalent analogue of helicenes and should be present as
a racemic mixture of two enantiomers with either P- or
M-helicity. Introduction of chiral substituents at position
R3 can possibly induce the formation of diastereoisomeric
1
assemblies, exhibiting different H NMR and CD spectra.
F IGURE 8. CD dilution experiments of assembly (R,R)-2b‚
CA in CHCl3/THF ) 1:1.
Therefore, trimelamine (S,S)-2b containing two (S)-R-
methylbenzylamino substituents was synthesized. In
CDCl3 the H NMR spectrum of (S,S)-2b in the presence
1
2b with two (R)-R-methylbenzylamino substituents with
CA shows the mirror image CD spectrum.
of 1.0 equiv of CA exhibits sharp and well-defined proton
signals. Three signals at 7.3, 7.6, and 8.0 ppm are
observed for the melamine NH protons. At -50 °C, the
1H NMR spectrum clearly shows the presence of different
diastereomeric structures (Figure 6). The signals of the
melamine strand split in many small signals and the CA
units give rise to four peaks at 16.5, 15.7, 14.2, and 13.8
ppm instead of two as observed with achiral 2a . The ratio
of these peaks (0.9:1.5:4.0:1.1) is difficult to analyze and
suggests that all possible conformers are present in
solution. Moreover, at low temperatures rotation around
the C-N bond in the melamine becomes slow on the
NMR time scale, which increases the number of observed
signals further. The MALDI TOF mass spectrum mea-
sured after treatment of the 1:1 mixture with AgCF3COO
shows only a signal for the (S,S)-2b‚CA assembly at m/z
1500.7 (calcd for C80H89N21O3‚107Ag+: 1499.7), which
excludes the presence of higher-order assemblies.
As a result of the chirality of trimelamine (S,S)-2b,
assembly (S,S)-2b‚CA is CD active, which enables us to
study its formation and stability by CD spectroscopy. The
CD spectrum of free (S,S)-2b shows a weak absorption
between 255 and 280 nm with two maxima at 262 and
268 nm (∆ꢀ ) 2.0 and 1.53 L mol-1 cm-1, respectively).
However, the CD intensity of the hydrogen-bonded as-
sembly (S,S)-2b‚CA is about 10 times larger (Figure 7),
and λmax has shifted from 262 to 259 nm (∆ꢀ ) 12.5 L
mol-1 cm-1). As expected, assembly of trimelamine (R,R)-
CD Titr a tion Exp er im en ts: Th er m od yn a m ic Sta -
bility in P ola r Solven ts. Subsequently, we studied the
thermodynamic stability of assembly (R,R)-2b‚CA in
chloroform by means of CD titration experiments. A plot
of the CD intensity at 259 nm versus the amount of CA
added gives a straight line (see Supporting Information,
Figure S1), indicating the Kass > 106 M-1. This is not
surprising considering the fact that nine strong hydrogen
bonds are formed, while only two different components
are brought together (ITm ) 9).
An interesting behavior of assembly (R,R)-2b‚CA was
observed upon performing dilution experiments in two
different solvents. In pure chloroform dilution studies
showed a strictly linear relation (see Supporting Infor-
mation, Figure S2), between the assembly concentration
and CD intensity (at λ262). However, the same dilution
experiment performed in a 50% THF/CHCl3 solution
clearly showed a nonlinear relation, which might suggest
that hydrophobic interactions cause stacking of the
planar triangular (R,R)-2b‚CA assemblies (Figure 8).
This phenomenon is currently being studied in detail.
F lu or escen ce Stu d ies w ith Hyd r ogen -Bon d ed As-
sem bly 2c‚CA. Introduction of two pyrene moieties at
positions R3 of trimelamine 2c (Scheme 5) enabled us to
study the stability of the assembly by fluorescence
spectroscopy.38 As for the other trimelamines, formation
of the complex with CA was confirmed by 1H NMR
1102 J . Org. Chem., Vol. 68, No. 3, 2003

Novel Hydrogen-Bonded Assemblies
F IGURE 9. MALDI TOF mass spectrum of assembly 2c‚CA after treatment with AgCF3COO for 24 h at room temperature.
SCHEME 5. Sch em a tic Rep r esen ta tion of th e
Assem bly F or m ed u p on Mixin g CA a n d
Tr im ela m in e 2c
F IGURE 10. Fluorescence spectra of compound 2c (dashed
line) and the corresponding assembly 2c‚CA (solid line) in
chloroform (λexc ) 350 nm).
pyrene emission almost disappears and the excimer band
at 480 nm drastically increases, indicating that more of
the excimer is present in the complex. This is consistent
with the fact that upon formation of the assembly the
trimelamine is folded around the CA unit, which brings
the chromophores much closer together (Scheme 5).
To estimate the association constant for assembly
formation, a fluorescence titration experiment with tri-
melamine 2c and CA was carried out in a mixture of
chloroform and THF (4:1), (λexc ) 350 nm) (see Supporting
Information, Figure S3), which allows the addition of up
to 3.0 equiv of CA. Fitting of the data to a 1:1 binding
model gave an association constant of 105-107 M-1, which
represents a remarkably high stability considering the
large amount (20%) of THF, a solvent that competes with
hydrogen bond formation.
We also studied the stability of the 1:1 assembly via
addition of different amounts of CH3OH and THF to a
0.05 mM solution of 2c‚CA in chloroform.40,41 Since a
change in solvent polarity is also expected to influence
the molar absorption coefficient of the chromophores, it
is impossible to quantify the obtained results. Instead,
we calculated the ratio between excimer intensity (480
nm) and the intensity for free pyrene (400 nm), assuming
that both molar absorption coefficients are affected in a
similar manner by the solvent polarity change. This
spectroscopy. In the presence of 1.0 equiv of CA, all the
proton signals are sharp.39 Even though trimelamine 2c
does not carry dibenzyl groups, it was found to be able
to coordinate to Ag+, most likely via the two pyrene units.
An intense signal at m/z 1585.2 (calcd for C86H101N21O3‚
107Ag+: 1583.9) is present in the MALDI-TOF spectrum
(Figure 9), which corresponds to the 2c‚CA‚Ag+ complex.
Both free 2c and 2c‚CA give nearly identical UV
spectra; however, the fluorescence spectra are clearly
different (Figure 10, λexc ) 350 nm). The spectrum of free
2c shows two fluorescent emission bands, i.e., the pyrene
emission at about 375 and 400 nm, and the excimer band
at 480 nm. Upon the addition of CA to this solution, the
(38) Aoki, I.; Harada, T.; Sakaki, T.; Kawahara, Y.; Shinkai, S. J .
Chem. Soc., Chem. Commun. 1992, 1341-1345.
(39) Only one peak is observed for the melamine NH protons at 8.7
ppm, since the other two peaks are masked by the aromatic proton
signals between 8.1 and 7.5 ppm.
(40) Wuerthner, F.; Thalacker, C.; Sautter, A.; Schaertl, W.; Ibach,
W.; Hollricher, O. Chem. Eur. J . 2000, 6, 3871-3886.
(41) Sautter, A.; Thalacker, C.; Heise, B.; Wuerthner, F. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 4993-4996.
J . Org. Chem, Vol. 68, No. 3, 2003 1103

Arduini et al.
1.5 (m, 4H), 1.4-1.3 (m, 4H), 0.96 (t, 6H, J HH ) 7.2 Hz). 13C
NMR (75 MHz, CDCl3) δ 165.3, 164.2, 118.0, 44.9, 39.9, 31.4,
19.5, 16.5, 13.3. MS (FAB): m/z 345.4 ([M + H+], calcd 345.2).
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 1f
a n d 1g. To an ice-cold solution of cyanuric chloride (0.1 g, 0.56
mmol) and DIPEA (12.6 mL, 72 mmol) in THF (80 mL) was
added dropwise the appropriate primary amine (4.0 equiv).
After the solution was stirred for 24 h at room temperature
the solvent was removed under reduced pressure and the
residue was partitioned between CH2Cl2 and 1 N HCl. The
organic layer was washed with H2O and brine and the solvent
was removed under reduced pressure.
assumption was supported by the fact that for free 2c
both intensities were equally affected. A plot of the ratio
I
480/I400 versus the percentage of THF shows a clear
change in the stability of the complex (manifested as an
increase of the amount of the monomer) only at 50% THF/
chloroform (see Supporting Information, Figure S4). In
the presence of 90% of THF, a significant amount of
assembly 2c‚CA is still present, judging from the clear
spectral difference for free 2c and 2c‚CA complex. Similar
results were obtained with methanol, with the difference
that the spectra of the complex and the free melamine
become almost equal at 50% of CH3OH in chloroform.
2,4-Bis(N-(5-h exen yl)am in o)-6-ch lor o-1,3,5-tr iazin e (1f).
The resulting yellow solid was purified by column chromatog-
raphy (SiO2; CH2Cl2) to yield 1f as a white solid in 84% yield.
1
Con clu sion s
Mp 128-130. H NMR (300 MHz, CDCl3) δ 6.8-6.6 (m, 2H),
5.5 and 5.2 (br s, 2H), 5.2-5.0 (m, 4H), 3.4-3.2 (m, 4H), 2.1-
1.9 (m, 4H), 1.6-1.5 and 1.5-1.3 (2m, 8H). MS (FAB): m/z
310.1 ([M + H+], calcd 309.2.
Single N,N′,N′′,N′′-tetraalkylmelamines, in which two
of the three DAD H-bonding arrays have been crippled,
spontaneously form planar 3:1 hydrogen-bonded as-
semblies 13‚CA upon mixing with 0.33 equiv of cyanuric
acid (CA). The assemblies, consisting of 4 components
that are held together by 9 H-bonds, are stable in apolar
solvents such as chloroform and can be conveniently
characterized by MALDI-TOF MS. The thermodynamic
stability can be significantly improved when the three
melamines are covalently connected to give the 1:1
complex 2‚CA. Titration studies by NMR, CD, and
fluorescence spectroscopy confirm the much higher sta-
bility of the 1:1 complex, particularly in the presence of
the more polar solvent THF. Additionally, the planar
assemblies show a strong tendency to form larger ag-
gregates, presumably via stacking, upon increasing the
composition of the solvent from pure CHCl3 to CHCl3/
THF ) 1:1.
2,4-Bis(N-(3-m eth yl-1-(L)-(m eth oxyca r bon yl)bu tyl)a m i-
n o)-6-ch lor o-1,3,5-tr ia zin e (1g). The resulting solid was
purified by column chromatography (SiO2; CH2Cl2/MeOH/NH4-
OH 95/4.5/0.5) to yield 1g as a white solid in 75% yield. Mp
1
160-161 °C. H NMR (300 MHz, CDCl3) δ 5.9-5.6 (br s, 2H),
4.9-4.6 (m, 2H), 3.8 (s, 6H), 1.8-1.6 (m, 6H), 1.1-0.9 (m, 12H).
MS (FAB): m/z 402.1 ([M + H+], calcd 401.9).
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 1d
a n d 1e. An excess of dibutylamine (0.9 mL, 5 mmol) was added
dropwise to a solution of compound 1f or 1g (0.25 mmol) in
THF (5 mL) and the solution was refluxed for 20 h at 90 °C.
Then, the solvent was removed under reduced pressure and
the residue was partitioned between CH2Cl2 and 1 N HCl. The
organic layer was washed with water and brine and the solvent
was removed under reduced pressure.
2,4-Bis(N-(5-h exen yl)a m in o)-6-N,N-d ibu tyla m in o-1,3,5-
tr ia zin e (1d ). The resulting yellow oil was obtained from 1f
and dibutylamine and was purified by flash column chroma-
tography (SiO2; hexane/AcOEt 4/1). Compound 1d was ob-
1
tained as a white solid in 92% yield. Mp 92-95 °C. H NMR
Exp er im en ta l Section
(300 MHz, CDCl3) δ 5.9-5.8 (m, 2H), 5.02 (dd, 2H J HH ) 17.1
and 1.8 Hz), 4.96 (dd, 2H J HH ) 10.2 and 1.8 Hz), 4.85 (br s,
2H), 3.49 (t, 4H J HH ) 7.5 Hz), 3.4-3.3 (m, 4H), 1.6-1.3 (m,
20H), 1.98 (t, 6H J HH ) 7.5 Hz). MS (FAB): m/z 401.3 ([M -
H+], calcd 401.3.
Gen er a l. THF was freshly distilled from Na/benzophenone,
and CH2Cl2 from CaCl2. All chemicals were of reagent grade
and used without further purification. NMR spectra were
recorded at room temperature unless indicated otherwise.
Flash column chromatography was performed with silica gel
(SiO2, 0.040-0.063 mm, 230-240 mesh). Compound 1a was
synthesized according to a literature procedure.31
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 1b
a n d 1c. To an ice-cold solution of cyanuric chloride (1.9 g, 10
mmol) and DIPEA (6.6 mL, 50 mmol) in THF (50 mL) was
added dropwise the appropriate secondary amine (1.0 equiv)
and the solution was stirred for 2 h. Upon increasing the
temperature to 30 °C, butylamine (7.2 mL, 74.4 mmol) was
added and the solution was stirred for another 24 h at 90 °C.
Then, the solvent was removed under reduced pressure and
the residue was partitioned between CH2Cl2 and 1 N HCl. The
organic layer was washed with H2O and brine and the solvent
was removed under reduced pressure. The resulting yellow oil
was purified by column chromatography (SiO2; CH2Cl2/MeOH/
NH4OH 95/4.5/0.5).
2,4-Bis(N-(3-m eth yl-1-(L)-(m eth oxyca r bon yl)bu tyl)a m i-
n o)-6-N,N-d ibu tyla m in o-1,3,5-tr ia zin e (1e). The resulting
yellow oil was obtained from 1g and dibutylamine and was
purified by flash column chromatography (SiO2; CH2Cl2/
MeOH/NH4OH 95/4.5/0.5). Compound 1e was obtained as a
white solid in 95% yield. Mp 195-197 °C. 1H NMR (300 MHz,
CDCl3) δ 6.2 and 5.0 (br s, 2H), 4.7-4.6 (m, 2H), 3.69 (s, 6H),
3.42 (t, 4H J HH ) 7.5 Hz), 1.8-1.3 (m, 14H), 1.0-0.9 (m, 18H).
13C NMR (75 MHz, CDCl3) δ 174.8, 164.9, 164.1, 51.3, 46.3,
40.7, 29.6, 24.2, 22.4, 21.1, 19.7, 13.4. MS (FAB): m/z 495.3
([M - H+], calcd 495.4). Anal. Calcd for C25H46N6O4: C 60.70,
H 9.37, N 16.99. Found: C 60.80, H 9.28, N, 16.62.
2-N-Bu tyla m in o-4-ch lor o-6-N,N-d ibu tyla m in o-1,3,5-tr i-
a zin e (5). To an ice-cold solution of cyanuric chloride (3.7 g,
3.7 mmol) and DIPEA (12.6 mL, 72 mmol) in THF (80 mL)
was added dropwise n-butylamine (1.20 g, 12.1 mmol) and the
solution was stirred for 2 h at 0 °C. Upon increasing the
temperature to 30 °C dibutylamine was added (12.3 mL, 7.2
mmol) and the solution was stirred for another 5 h at room
temperature. The solvent was removed under reduced pressure
and the residue was partitioned between CH2Cl2 and 1 N HCl.
The organic layer was washed with H2O and brine and the
solvent was removed under reduced pressure. The resulting
yellow solid was purified by column chromatography (SiO2;
CH2Cl2) to yield 5 as a transparent oil in 83% yield (3.1 g). 1H
NMR (300 MHz, CDCl3) δ 5.4 (br s, 1H, NH), 3.6-3.5 (m, 4H,
CH2NCH2), 3.4-3.3 (m, 2H, HNCH2), 1.7-1.5 (m, 6H,
NCH2CH2), 1.4-1.2 (m, 6H, CH2CH3), 1.0-0.9 (m, 9H, CH3).
2,4-Bis(N-bu tyla m in o)-6-N,N-d iben zyla m in o-1,3,5-tr i-
a zin e (1b). Compound 1b was obtained as a transparent oil
1
in 72% yield. H NMR (300 MHz, CDCl3) δ 7.2-7.1 (m, 10H),
4.68 (br s, 6H), 3.3-3.2(m, 4H), 1.5-1.4 (m, 4H), 1.3-1.2 (m,
4H), 0.8-0.6 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 165.6, 138.3,
127.8, 127.3, 126.3, 47.5, 39.9, 31.5, 19.5, 13.3. MS (FAB): m/z
419.3 ([M + H+], calcd. 419.3). Anal. Calcd for C77H86N18: C
71.74, H 8.19, N 20.08. Found: C 71.87, H 8.25, N 20.06.
2,4-Bis(N-bu tyla m in o)-6-(N,N-bis(cya n oeth yl)a m in o)-
1,3,5-tr ia zin e (1c). Compound 1c was obtained as a transpar-
ent oil in 74% yield. 1H NMR (300 MHz, CDCl3) δ 4.86 (br,
2H), 3.87 (br s, 4H), 3.4-3.3 (m, 4H), 2.8-2.6 (m, 4H), 1.6-
1104 J . Org. Chem., Vol. 68, No. 3, 2003

Novel Hydrogen-Bonded Assemblies
MS (FAB): m/z 315.2 ([M + H+], calcd 314.2). Anal. Calcd for
2-N,N-Diben zylam in o-4,6-bis[N-(10-N-(4-N-bu tylam in o-
6-N,N-dibu tylam in o-1,3,5-tr iazin -2-yl)am in odecyl)am in o]-
1,3,5-tr ia zin e (4). Compound 4 was obtained from 10 as a
transparent oil in 60% yield. 1H NMR (300 MHz, CDCl3) δ 7.4-
7.2 (m, 10H), 4.9 (br s, 6H), 4.7 (s, 4H), 3.6-3.4 (m, 8H), 3.4-
3.3 (m, 12H), 1.7-1.2 (m, 56H), 1.0-0.9 (m, 18H). 13C NMR
(75 MHz, CDCl3) δ 138.2, 127.7, 127.3, 126.2, 47.4, 45.8, 40.1,
39.7, 31.4, 29.6, 29.3, 28.8, 28.7, 26.3, 19.6, 19.5, 13.4, 13.2.
MS (FAB): m/z 1171.9 ([M + H+], calcd 1172.0). Anal. Calcd
for C67H114N18: C 68.68, H 9.81, N 21.52. Found: C 68.34, H
9.60, N, 20.98.
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 6
a n d 7. To an ice-cold solution of cyanuric chloride (1.4 g, 7.5
mmol) and DIPEA (5.2 mL, 3.0 mmol) in THF (100 mL) was
added dropwise the appropriate primary amine (1.0 equiv) and
the solution was stirred for 2 h at 0 °C. Upon increasing the
temperature to 30 °C the secondary amine (dibenzylamine and
dibutylamine, respectively) was added (4.0 equiv) and the
solution was stirred for another 24 h at 90 °C. Then, the
solvent was removed under reduced pressure and the residue
was partitioned between CH2Cl2 and 1 N HCl. The organic
layer was washed with H2O and brine and the solvent was
removed under reduced pressure.
C
15H28N5Cl: C 57.40, H 8.99, N 22.31. Found: C 57.66, H 8.83,
N, 21.60.
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 8,
9, a n d 10. To a solution of compound 5 (833 mg, 2.6 mmol) in
THF (10 mL) was added dropwise an excess of the appropriate
diamine (30 equiv) and the solution was refluxed for 24 h at
90 °C. The solvent was removed under reduced pressure and
the residue was partitioned between CH2Cl2 and 1 N HCl. The
organic layer was washed with water, 1 N NaOH, and brine.
The solvent was removed under reduced pressure. The result-
ing yellow oil was purified by column chromatography (SiO2;
CH2Cl2/MeOH/NH4OH 90/8/2).
2-N-(3-(Am in om eth yl)p h en yl)a m in o-4-N-bu tyla m in o-
6-N,N-d ibu tyla m in o-1,3,5-tr ia zin e (8). Compound 8 was
obtained from 5 and m-xylylene diamine as a transparent oil
1
in 95% yield. H NMR (300 MHz, CDCl3) δ 7.3-7.1 (m, 4H),
5.1 (br s, 1H), 4.72 (br s, 1H), 4.50 (d, 2H, J HH ) 6.0 Hz), 3.78
(s, 2H), 3.4-3.3 (m, 4H), 3.3-3.2 (m, 2H), 1.5-1.4 (m, 6H),
1.3-1.2 (m, 6H), 0.9-0.8 (m, 9H). 13C NMR (75 MHz, CDCl3)
δ 128.1, 125.6, 125.5, 125.1, 45.9, 44.0, 39.9, 31.5, 29.6, 19.7,
19.6, 13.4, 13.3. MS (FAB): m/z 414.3 ([M + H+], calcd 414.3).
2-N-(7-Am in oh ep t yl)a m in o-4-N-b u t yla m in o-6-N,N-d i-
bu tyla m in o-1,3,5-tr ia zin e (9). Compound 9 was obtained
from 5 and 1,7-diaminoheptane as transparent oil in 90% yield.
1H NMR (300 MHz, CDCl3) δ 4.68 (br s, 2H), 3.48 (t, 2H, J HH
) 7.2 Hz), 3.4-3.3 (m, 4H), 2.7 (t, 2H, J HH ) 6.9 Hz), 1.6-1.3
(m, 22H), 1.0-0.9 (m, 9H). MS (FAB): m/z 408.5 ([M + H+],
calcd 408.4).
2-Ch lor o-4-N,N-d iben zyla m in e-6-N-((S)-r-m eth ylben z-
yl)a m in o-1,3,5-tr ia zin e (6). The resulting yellow solid was
purified by flash column chromatography (SiO2; CH2Cl2/
MeOH/NH4OH 98/1.7/0.3) to yield 6 as a yellow oil in 84%
yield. 1H NMR (300 MHz, CDCl3) δ 7.4-7.1 (m, 15H), 5.73 (d,
1H, J HH ) 6.9 Hz), 5.1-5.0 (m, 1H), 4.9-4.5 (m, 4H), 1.53 (d,
3H, J HH ) 6.9 Hz). MS (FAB): m/z 430.5 ([M + H+], calcd
430.2). Anal. Calcd for C25H24N5Cl: C 69.84, H 5.63, N 16.29.
Found: C 69.88, H 5.46, N, 15.89.
2-N-(10-Am in od ecyl)a m in o-4-N-bu tyla m in o-6-N,N-d i-
bu tyla m in o-1,3,5-tr ia zin e (10). Compound 10 was obtained
from 5 and 1,10-diaminodecane as a transparent oil in 99%
yield. 1H NMR (300 MHz, CDCl3) δ 4.71 (br s, 2H), 3.5-3.4
(m, 4H), 3.4-3.3 (m, 4H), 2.71 (t, 2H J HH ) 6.6 Hz), 1.7-1.3
(m, 28H), 1.0-0.9 (m, 9H). MS (FAB): m/z 450.4 ([M + H+],
calcd 450.4).
2-Ch lor o-4-N,N-d ibu tyla m in o-6-N-(p yr en em eth yl)a m i-
n o-1,3,5-tr ia zin e (7). The resulting yellow oil was purified
by flash column chromatography (SiO2; hexane/EtOAc 250/8)
1
to yield 7 as a white solid in 70% yield. H NMR (300 MHz,
CDCl3) δ 8.5-8.0 (m, 9H), 6.03 (br s, 1H), 5.31 (d, 2H, J HH
)
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 2a ,
3, a n d 4. To an ice-cold solution of cyanuric chloride (30 mg,
0.16 mmol) and DIPEA (0.27 mL, 1.0 mmol) in THF (10 mL)
was dropwise added dibenzylamine (0.031 mL, 0.16 mmol) and
the solution was stirred for 2 h at 0 °C. Upon increasing the
temperature to 30 °C the appropriate compound 8, 9, or 10
was added (4.0 equiv) and the solution was stirred for another
24 h at 90 °C. The solvent was removed under reduced
pressure and the residue was partitioned between CH2Cl2 and
1 N HCl. The organic layer was washed with H2O and brine
and the solvent was removed under reduced pressure. The
resulting yellow oil was purified by column chromatography
(SiO2; CH2Cl2/MeOH/NH4OH 98/1.7/0.3).
5.4 Hz), 3.6-3.4 (m, 4H), 1.6-0.9 (m, 8H), 1.0-0.7 (m, 6H).
MS (FAB): m/z 472.5 ([M + H+], calcd 472.5). Anal. Calcd for
C
28H30N5Cl: C 71.25, H 6.41, N 14.84. Found: C 71.36, H 6.26,
N 14.51.
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 11
a n d 12. An excess of m-xylylenediamine (30 equiv) was added
dropwise to a solution of the appropriate melamine (6 or 7) in
THF (10 mL) and the solution was refluxed for 24 h at 90 °C.
The solvent was removed under reduced pressure and the
residue was partitioned between CH2Cl2 and 1 N HCl. The
organic layer was washed with H2O, 1 N NaOH, and brine.
The solvent was removed under reduced pressure.
2-N -(3-(Am in om e t h yl)p h e n ylm e t h yl)a m in o-4-N ,N -
d iben zyla m in o-6-N-((S)-R-m eth ylben zyla m in o)-1,3,5-tr i-
a zin e (11). The resulting yellow oil was obtained from 6 and
m-xylylene diamine and was purified by flash column chro-
matography (SiO2; CH2Cl2/MeOH/NH4OH 92/6/2). Compound
11 was obtained as a transparent oil in 90% yield. 1H NMR
(300 MHz, CDCl3) δ 7.2-7.1 (m, 19H), 5.10 (br s, 3H), 4.8-
2-N ,N -D ib e n zy la m in o -4,6-b is [N -(3-(N -(4-N -b u t y l-
amino-4-N,N-dibutylamino-1,3,5-triazin-2-yl)aminomethyl)-
p h en ylm eth yl)a m in o]-1,3,5-tr ia zin e (2a ). Compound 2a
was obtained from 8 as a transparent oil in 74% yield. 1H NMR
(300 MHz, CDCl3) δ 7.4-7.1 (m, 18H), 5.5, 5.1, and 4.8 (3 br
s, 6H), 4.7 (s, 4H), 4.5 (br s, 8H), 3.5-3.4 and 3.4-3.3 (2m,
20H), 1.7-1.5 and 1.5-1.2 (2m, 24H), 1.0-0.9 (m, 18H). 13C
NMR (75 MHz, CDCl3) δ 166.0, 165.5, 165.4, 165.3, 164.4,
139.9, 138.5, 128.6, 128.3, 128.2, 127.9, 127.8, 126.9, 48.1, 46.6,
44.7, 44.5, 40.4, 32.0, 30.1, 20.2, 20.1, 14.0, 13.8. MS (FAB):
m/z 1099.8 ([M + H+], calcd 1099.8).
4.6 (br m, 2H), 4.8 (m, 4H), 3.74 (br s, 2H), 1.42 (d, 3H, J HH
)
5.7 Hz). 13C NMR (75 MHz, CDCl3) δ 165.7, 165.6, 164.8, 144.4,
142.9, 139.5, 138.0, 128.2, 127.9, 127.8, 127.4, 126.4, 126.2,
125.7, 125.5, 125.3, 49.6, 47.5, 45.8, 44.2, 22.4. MS (FAB): m/z
530.3 ([M + H+], calcd 530.3). Anal. Calcd for C33H35N7: C
74.83, H 6.66, N 18.51. Found: C 74.79, H 6.54, N 18.46.
2-N-(3-(Am in om et h yl)p h en ylm et h yl)a m in o-4-N,N-d i-
bu tyla m in o-6-N-(pyr en em eth yl)a m in o-1,3,5-tr ia zin e (12).
The resulting yellow oil was obtained from 7 and m-xylylene
diamine and was purified by column chromatography (SiO2;
hexane/EtOAc 250/8) to yield 12 as a white solid in 80% yield.
Mp 118-122 °C. 1H NMR (300 MHz, CDCl3) δ 8.35 (d, 1H,
J HH ) 9.8 Hz), 8.19 (d, 1H, J HH ) 10.0 Hz), 8.1-8.0 (m, 7H),
7.3-7.2 (m, 4H), 5.29 (br, 2H), 5.28 (br s, 2H), 5.31 (br s, 2H),
3.84 (s, 2H), 3.5-3.4 (m, 4H), 1.6-0.4 (br m, 4H), 1.3-1.1 (br
m, 4H), 0.9-0.7 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 165.5,
2-N,N-Diben zyla m in o-4,6-bis[N-(7-N-(4-N-bu tyla m in o-
6-N,N-d ibu tyla m in o-1,3,5-tr ia zin -2-yl)a m in oh ep tyl)a m i-
n o]-1,3,5-tr ia zin e (3). Compound 3 was obtained from 9 as
a white solid in 80% yield. Mp 202-203 °C. 1H NMR (300 MHz,
CDCl3) δ 7.3-7.2 (m, 10H), 4.78 (br s, 6H), 4.76 (s, 4H), 3.5-
3.4 (m, 8H), 3.3-3.1 (m, 12H), 1.6-1.5 (m, 20H), 1.3-1.2 (m,
24), 1.0-0.9 (m, 18H). 13C NMR (75 MHz, CDCl3) δ 166.0,
165.6, 165.4, 164.4, 138.3, 127.8, 127.3, 126.3, 47.5, 45.9, 40.2,
40.1, 39.8, 31.6, 29.7, 29.4, 29.3, 28.6, 26.4, 19.7, 13.5. MS
(FAB): m/z 1087.8 ([M + H+], calcd 1087.9). Anal. Calcd for
C
61H102N18: C 67.37, H 9.45, N 23.18. Found: C 66.91, H 9.26,
N, 22.84.
J . Org. Chem, Vol. 68, No. 3, 2003 1105

Arduini et al.
165.4, 164.6, 143.3, 139.7, 132.3, 130.8, 130.2, 128.3, 128.1,
127.2, 126.9, 126.6, 125.9, 125.6, 125.5, 125.3, 125.2, 124.5,
124.3, 124.2, 122.6, 46.1, 45.9, 44.1, 42.4, 29.7, 19.7, 13.4. MS
(FAB): m/z 573.0 ([M + H+], calcd 573.3). Anal. Calcd for
36H41N7: C 75.62, H 7.23, N 17.15. Found: C 75.80, H 7.06,
N 16.52.
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 13
a n d 14. To an ice-cold solution of cyanuric chloride (1.9 g, 10
mmol) and DIPEA (6.6 mL, 50 mmol) in THF (50 mL) was
added dropwise the appropriate amino-functionalized single
melamine (11 or 12) (3.0 equiv) and the solution was stirred
for 2 h at 0 °C. Upon increasing the temperature to 30 °C the
solution was stirred for another 24 h at room temperature.
Then the solvent was removed under reduced pressure and
the residue was partitioned between CH2Cl2 and 1 N HCl. The
organic layer was washed with H2O and brine and the solvent
was removed under reduced pressure.
2-Ch lor o-4,6-bis[N-(3-(N-(4-N,N-diben zylam in o-6-N-((S)-
r-m eth ylben zyl)a m in o-1,3,5-tr ia zin -2-yl)a m in om eth yl)-
p h en ylm eth yl)a m in o]-1,3,5-tr ia zin e (13). The resulting
yellow oil was obtained from 11 and cyanuric chloride and was
purified by column chromatography (SiO2; CH2Cl2/MeOH/NH4-
OH 95/4.5/0.5) to yield 13 as a transparent oil in 89% yield.
1H NMR (300 MHz, CDCl3) δ 7.2-6.9 (m, 38H), 5.2-4.2 (br
m, 18H), 5.1-5.0 (m, 1H), 4.9-4.5 (m, 8H), 1.29 (br s, 6H).
13C NMR (75 MHz, CDCl3) δ 165.5, 165.2, 164.9, 144.5, 139.7,
137.9, 128.2, 127.8, 127.5, 126.4, 126.2, 125.5, 49.5, 47.5, 44.2,
22.3. MS (FAB): m/z 1170.7 ([M + H+], calcd 1170.6).
2-Ch lor o-4,6-b is[N-(3-(N-(4-N,N-d ib u t yla m in o-6-N-(1-
p yr en em et h yl)a m in o-1,3,5-t r ia zin -2-yl)a m in om et h yl)-
p h en ylm eth yl)a m in o]-1,3,5-tr ia zin e (14). The resulting
yellow solid was obtained from 12 and cyanuric chloride and
was purified by column chromatography (SiO2; CH2Cl2/MeOH/
NH4OH 95/4.5/0.5) to yield 14 as a white solid in 65% yield.
Mp 196-198 °C. 1H NMR (300 MHz, CDCl3) δ 8.1-7.8 (m,
18H), 7.0-6.8 (m, 8H), 6.4, 5.9, 5.6, 5.2, and 4.9 (5 br s, 10H),
4.3 (br s, 8H), 3.3 (br s, 8H), 1.4-0.9 (br m, 16H), 0.7 and 0.5
(2 br s, 12H). MS (FAB): m/z 1254.6 ([M + H+], calcd 1254.7.
Gen er a l P r oced u r e for th e Syn th esis of Mela m in es 2b
a n d 2c. An excess of dibutylamine (0.9 mL, 5 mmol) was added
dropwise to a solution of the appropriate trimelamine (13 or
14) (0.5 mmol) in THF (5 mL) and the solution was refluxed
for 24 h at 90 °C. Then, the solvent was removed under
reduced pressure and the residue was partitioned between
CH2Cl2 and 1 N HCl. The organic layer was washed with H2O
and brine and the solvent was removed under reduced pres-
sure.
4H, J HH ) 6.7 Hz), 1.7-1.6 (m, 4H), 1.4-1.3 (m, 4H), 0.86 (t,
6H, J HH ) 7.8 Hz). MS (FAB): m/z 1263.4 ([M + H+], calcd
1261.7). Anal. Calcd for C77H86N18: C 73.19, H 6.86, N 19.95.
Found: C 73.19, H 6.82, N 19.87.
C
2-N,N-Dib u t yla m in o-4,6-b is[N-(3-(N-(4-N,N-d ib u t yl-
am in o-6-N-(pyr en em eth yl)am in o-1,3,5-tr iazin -2-yl)am in o-
m eth yl)p h en ylm eth yl)a m in o]-1,3,5-tr ia zin e (2c). The re-
sulting oil was obtained from 14 and dibutylamine and was
purified by column chromatography (SiO2; CH2Cl2/MeOH/NH4-
OH 98/1.7/0.3) to yield 2c as a white solid in 78% yield. 1H
NMR (300 MHz, CDCl3) δ 8.3-7.9 (m, 18H), 7.3-7.1 (m, 8H),
5.2 (br s, 10H), 4.5 (br s, 8H), 3.5 (br s, 12H), 1.6-1.2 (m, 24H),
1.0-0.8 (m, 6H). MS (FAB): m/z 1347.9 ([M + H+], calcd:
1347.8). Anal. Calcd for C83H98N18: C 73.97, H 7.33, N 18.71.
Found: C 73.21, H 7.79, N 19.04.
Assem bly P r ep a r a tion . Typically, 4.0 mM solutions of
assemblies were prepared by sonicating the melamine and
cyanuric acid (in excess) for 1 h in THF (5 mL). After
evaporation of the solvent and drying under high vacuum, the
assemblies were dissolved in CDCl3 (5 mL) and excess of CA
was removed by filtration.
Gen er a l P r oced u r e for MALDI-TOF Ch a r a cter iza tion .
The samples for the MALDI TOF were prepared adding 1.5-
2.0 equiv of AgCF3COO to a 5 mM solution of the assembly in
chloroform. Subsequently the suspension was stirred for a
couple of minutes. MALDI-TOF measurements were per-
formed according to literature procedures.32
Gen er a l P r oced u r e for CD Mea su r em en ts. All the
measurements were performed using a 0.1-mm cell, to mini-
mize solvent effects. The concentration of the melamines in
the samples was kept constant at 7 mM. The titration of
compound (R,R)-2b with CA was performed by mixing solu-
tions of melamine (R,R)-2b and assembly (R,R)-2b‚CA in
different ratios.
In the dilution experiments, the higher limit (14.2 mM) was
determined by the solubility of the assemblies, and the lowest
(2.1 mM) by the S/N ratio of the CD spectrum.
Gen er a l P r oced u r e for F lu or escen ce Stu d ies. The
emission spectra were recorded using a 1.0 mm cell with λexc
) 350 nm. The melamine concentration of the samples was
0.5 or 0.05 mM. Dilution experiments showed that in this
range the emission of the pyrene moieties was independent
from the concentration. The titration experiments were per-
formed maintaining a constant concentration of trimelamine
2c, applying the same procedure used for the CD measure-
ments.
2-N ,N -Dib u t yla m in o-4,6-b is[N -(3-(N -(4-N ,N -d ib e n z-
yla m in o-6-N-((S)-r-m et h ylb en zyl)a m in o-1,3,5-t r ia zin -2-
yl)am in om eth yl)ph en ylm eth yl)am in o]-1,3,5-tr iazin e (2b).
The resulting solid was obtained from 13 and dibutylamine
and was purified by flash column chromatography (SiO2; CH2-
Cl2/MeOH/NH4OH 98/1.7/0.3) to yield 2b as a white solid in
95% yield. Mp 215-216 °C. 1H NMR (300 MHz, CDCl3) δ 7.2-
7.0 (m, 38H), 5.2, 5.1, and 4.7 (3 br s, 8H), 4.4 (m, 8H), 3.32 (t,
Su p p or tin g In for m a tion Ava ila ble: CD titration of
(R,R)-2b with CA; CD dilution experiments of (R,R)-2b‚CA;
fluorescence titration of trimelamine 2c with CA; plot of the
ratio I480/I410 vs percent of THF for free 2c and 2c‚CA. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O020610C
1106 J . Org. Chem., Vol. 68, No. 3, 2003