Synthesis and modulation of bis(triazine) hydrogen-bonding receptors

Article abstract of DOI:10.1002/ejoc.200500628

The synthesis of bis(triazine) molecules capable of acting as synthetic receptors for barbiturate guest molecules is described. The binding properties are also reported illustrating the modulation of the binding properties of these species by the modifica

Full text of DOI:10.1002/ejoc.200500628

FULL PAPER
DOI: 10.1002/ejoc.200500628
Synthesis and Modulation of Bis(triazine) Hydrogen-Bonding Receptors
Pamela V. Mason,[a] Neil R. Champness,*[a] Simon R. Collinson,[a] Matthew G. Fisher,[a] and
Gudrun Goretzki[a]
Keywords: Hydrogen-bonding receptors / Triazines / Host–guest chemistry / Supramolecular chemistry / Barbiturates
The synthesis of bis(triazine) molecules capable of acting as
synthetic receptors for barbiturate guest molecules is de-
scribed. The binding properties are also reported illustrating
the modulation of the binding properties of these species by
3 and 5 the hydrogen-bonding secondary amines at the apex
of the receptor 1 are substituted by non-hydrogen-bonding
ether links. The hydrogen-bonding ability is further modified
in the case of 5 by the removal of all hydrogen-bond donors
the modification of the hydrogen-bonding patterns of the re- from the receptor site, replacing secondary amines by terti-
ceptor molecule, namely 1,3-N,NЈ-bis[4-(dibenzylamino)-6-
(butylamino)-1,3,5-triazin-2-yl]xylylenediamine (1). Thus
1,3-O,OЈ-bis[4-(dibenzylamino)-6-(butylamino)-1,3,5-triazin-
2-yl]benzenedimethanol (3) and 1,3-O,OЈ-bis[4-(diben-
zylamino)-6-(diethylamino)-1,3,5-triazin-2-yl]benzenedime-
thanol (5) have been prepared, and their binding constants
compared to those observed for 1. In the case of compounds
ary amines. NMR binding studies illustrate how these simple
modifications of the hydrogen-bonding patterns of these re-
ceptors influences the overall strength of binding demon-
strating a simple mechanism for controlling host-guest com-
plex formation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
In this study, we have developed methods for the synthe-
sis of a number of symmetric receptor molecules capable of
Introduction
The design and synthesis of receptor molecules that act
as hosts for barbiturate molecules is perhaps one of the
most widely studied areas of supramolecular chemistry and
builds on the wider research field studying the interactions
between melamine and cyanuric acid and their deriva-
tives.[1–4] Indeed, the concerted hydrogen bonding observed
between diaminopyridine and diimide moieties has been
widely used in a range of applications from synthetic recep-
tors[3,5] to surface self-assembly and templating.[6]
Key studies have developed barbiturate receptors using
either diamidopyridines[7–9] or amino-substituted triazine
molecules.[10–12] Both systems offer the pre-organised se-
quence of hydrogen-bond acceptors and donors in the form
of N–H moieties, either as amines or as amides, coupled
with aromatic nitrogen hydrogen-bond acceptors in a do-
nor–acceptor–donor sequence. The designed coupling of
two such moieties provides a highly pre-organised receptor
for a guest barbiturate group that show strong binding con-
stants of up to 106 –1.[7] More advanced systems show the
development of this area towards sensing systems[13] and
the use of the strong interactions between barbiturates and
the host molecules for the construction of self-assembled
arrays.[3,4,14]
[a] School of Chemistry, The University of Nottingham, University
Park,
Nottingham NG7 2RD, UK
Scheme 1. Illustration of the target bis(triazine) receptor–barbital in-
teractions, appropriate substitution of the triazine allows modulation
of the number of hydrogen-bonding acceptor and donor sites allowing
a degree of control over the strength of the host–guest interaction.
Fax: +44-115-9513563
E-mail: Neil.Champness@nottingham.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Synthesis and Modulation of Bis(triazine) Hydrogen-Bonding Receptors
FULL PAPER
forming multiple hydrogen bonds to guest molecules such and higher reaction temperatures, and that the alcoholic
as barbital, a generic barbiturate. The pocket systems are substituent needs to be added first.[15] In our experience,
composed of two identical triazine derivatives linked by one mono-substitution of cyanuric chloride with an amine re-
of two linker groups, either m-xylylenediamine or 1,3- sults in the deactivation of the triazine ring with respect to
benzenedimethanol (Scheme 1). Through the variation of further substitution, and thus harsher conditions are re-
not only the linking unit but also the triazine substituents quired to add additional substituents. Thus, it was found
we show that the pattern of hydrogen-bonding donors and that attempts to add alkoxy substituents to mono- or di-
acceptors can be readily modified allowing controlled varia- amino-substituted chlorotriazines were unsuccessful. But
tion in the binding ability of the receptor species. This in the reverse approach of adding amines to alkoxy-substi-
turn shows that such receptors can be modulated allowing tuted triazines was successful.[15] Compound 2 was ob-
tuning of this host–guest interaction, indicating their poten- tained as a brown sticky oil, which was used without further
tial application in self-assembled devices where such modu- purification, as attempts at separation were unsuccessful,
lation is required.
but reaction of 2 with dibenzylamine afforded 3 as a colour-
less solid in 32% yield following purification by column
chromatography (2% MeOH/CH2Cl2 on silica).
Results and Discussion
A range of hydrogen-bonding systems has been prepared,
based on the Reinhoudt systems,[10,11] by the use of cyanuric
chloride as the basis for the subsequent preparation. This
approach is extremely attractive as it allows a high degree
of variation in the substituents added to the triazine ap-
pendages of the hydrogen-bonding receptor molecule. By
simple adaptations the ability of a hydrogen-bonding
pocket to effectively bind to the barbiturate guest can be
significantly altered. This has been achieved by preparing
receptors with simple ether analogues or tertiary amines re-
placing secondary amine N–H hydrogen-bond donors. By
this simple approach, changing the nature of the hydrogen-
bonding sites within the receptor, the binding of barbitu-
rates has been modulated.
In the first instance, the hydrogen-bonding receptor bis-
(melamine) species 1,3-N,NЈ-bis[4-(dibenzylamino)-6-(bu-
tylamino)-1,3,5-triazin-2-yl]xylylenediamine (1) (Scheme 1)
was prepared following an adaptation of the route de-
scribed by Reinhoudt et al.[10] This species was prepared to
Scheme 2. i. 1,3-Benzenedimethanol, 2,6-lutidine, room temp.
CH2Cl2; ii. butylamine, 2,6-lutidine, room temp. CH2Cl2; iii.
(PhCH2)2NH, refluxing THF.
The hydrogen-bonding ability of the receptor can be fur-
act as a standard for comparison of barbiturate binding ther modulated by additional adaptation of the hydrogen-
ability. bonding potential presented by the pocket, by replacement
The hydrogen-bonding ability, and thus the barbiturate of the remaining hydrogen-bond donors with comparatively
binding ability, was then modulated by replacing the di- hydrogen-bond inactive groups (in this context) such as ter-
amine bridge between the triazine substituents by a simple tiary amines, for example in compound 5 (Scheme 1).
diether linkage. Thus, in the case of 1 the triazine molecules
Compound 5, 1,3-O,OЈ-bis[4-(dibenzylamino)-6-(dieth-
are bridged by the introduction of 1,3-xylylenediamine, so ylamino)-1,3,5-triazin-2-yl]benzenedimethanol, was pre-
simple replacement of this species by 1,3-benzenedime- pared according to the procedure outlined in Scheme 3. The
thanol in the preparation of 3, 1,3-O,OЈ-bis[4-(diben- first step was the preparation of 1,3-O,OЈ-bis[4-chloro-6-
zylamino)-6-(butylamino)-1,3,5-triazin-2-yl]benzenedime- (diethylamino)-1,3,5-triazin-2-yl]benzenedimethanol
(4),
thanol (Scheme 1) resulted in a hydrogen-bonding receptor which was prepared as a sticky brown oil that was used
with only two hydrogen-bond donors (N–H groups) and without further purification, as in the case of compound 2.
with two hydrogen-bond acceptors (triazine N sites). Al- Reaction of 4 with dibenzylamine gave the bis(triazine) 5 in
though the ether linkages can in principal act as hydrogen- 22% yield as a colourless solid following purification by
bonding acceptor sites, they are relatively poor in doing so, column chromatography (CH2Cl2 on silica).
and the arrangement of donors and acceptors around the
pocket are less compatible with those presented by the bar- gen-bonding receptor bis(melamine) compounds in which
biturate guest species. both triazines were substituted exclusively by tertiary amine
A variety of attempts were made to prepare the hydro-
The synthesis of compound 3 follows the procedure out- moieties (Scheme 4). Thus, each triazine appendage would
lined in Scheme 2. Firstly it is important to note that when be substituted by 1,3-xylylenediamine and dibenzylamine
adding an alcohol rather than an amine to cyanuric chlo- and one further amine moiety, either dibenzylamino, dibu-
ride, slightly stronger conditions are required, stronger base tylamino or diethylamino. This final series of compounds
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P. V. Mason, N. R. Champness, S. R. Collinson, M. G. Fisher, G. Goretzki
FULL PAPER
NMR and mass spectrometry analysis. Further attempts to
fully substitute the triazine under conditions using stronger
bases such as 2,6-lutidine and solvents with higher reflux
temperatures such as toluene were also unsuccessful.
Scheme 3. i. 1,3-Benzenedimethanol, 2,6-lutidine, room temp.
CH2Cl2; ii. diethylamine, 2,6-lutidine, room temp. CH2Cl2; iii.
(PhCH2)2NH, DIPEA, refluxing THF.
would have yielded host molecules with each triazine ap-
pendage offering two hydrogen-bond donors to the guest.
Scheme 5. i. 1,3-Xylylenediamine, DIPEA, THF, 0 °C; ii. dieth-
ylamine, DIPEA, THF, room temp.; iii. (PhCH2)2NH, DIPEA, re-
fluxing THF.
Binding Studies
The ability of compounds 1, 3 and 5 to bind barbital
through hydrogen-bonding interactions has been studied by
NMR titrations in dry [D]chloroform at 25 °C using the
method of continuous variation.[16] Where possible binding
modes were established from Job plots of the NMR spec-
Scheme 4. Targeted-amine-substituted bis(triazine) receptor mole-
cules, R = Bz, Bu, Et.
In all three cases (R = NBz2, NBu2, NEt2) 1,3-xylylenedi- troscopic data and the binding energies of complex forma-
amine was treated with an excess of the appropriate triazine tion between the receptors and barbital have been calcu-
[R = NBz2, 2-chloro-4,6-bis(dibenzylamino)-1,3,5-triazine lated.
(6);
R
=
NBu2, 2-chloro-4-(dibenzylamino)-6-(dibu-
In order to standardise the results observed, the interac-
tylamino)-1,3,5-triazine (7); R = NEt2; 2-chloro-4-(diben- tion between 1 and barbital was assessed. The Job plot of
zylamino)-6-(diethylamino)-1,3,5-triazine (8)]. However, in the NMR results confirmed the formation of a 1:1 1/barbi-
each case the reaction was found to produce only mono- tal complex with a binding energy of (1.8 1)·105 –1 or
substituted 1,3-xylylenediamine even following prolonged 30 kJmol–1. This results is consistent with those previously
reflux and none of the desired product was identified.
reported[10] for systems that adopt six cooperative hydrogen
An alternative strategy was then employed in an attempt bonds between the receptor (1 in the current case) and the
to prepare 1,3-N,NЈ-bis[4-(dibenzylamino)-6-(diethylami- guest barbital. Attempts to measure the binding energy of
no)-1,3,5-triazin-2-yl]xylylenediamine (10) proceeding via this system, and those below, by UV/Vis spectroscopy were
1,3-N,NЈ-bis[4-chloro-6-(diethylamino)-1,3,5-triazin-2-yl]- hampered by the absence of appropriate reporter groups in
xylylenediamine (9) (Scheme 5). Compound 9 was prepared compounds 1, 3, 5.
by addition of m-xylylenediamine to a solution of cyanuric
Receptor 3 is capable of adopting four hydrogen-bonding
chloride in THF at 0 °C, followed by addition of dieth- interactions with barbital (Scheme 1). The replacement of
ylamine at room temperature. The product was purified by the bridging 1,3-xylenediamine bridge by a non-hydrogen-
column chromatography (2% MeOH/CH2Cl2 silica) and bonding diether link in this case was anticipated to signifi-
isolated as a colourless solid. Attempts were made to pre- cantly alter the mode and strength of binding with barbital.
pare compound 10 by heating compound 9 with an excess The overall shape of the Job plot is indicative of a 1:1 com-
of dibenzylamine in THF at reflux for 6 days. The resulting plex; small variations in the overall shape observed are a
mixture of products was separated by column chromatog- result of experimental error (Figure 1). Clearly the less dis-
raphy (n-hexane/ethyl acetate, 3:1, silica) and the major tinct maximum in this case supports the smaller binding
product purified and identified as 1-N-[4-(dibenzylamino)- constant as has been noted previously.[17] The possibility
6-(diethylamino)-1,3,5-triazin-2-yl]-3-NЈ-[4-chloro-6-(dieth-
that the small variations in the Job plot were due to the
ylamino)-1,3,5-triazin-2-yl]xylylenediamine (11), by 1H formation of a variety of dynamic structures, which are ini-
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Synthesis and Modulation of Bis(triazine) Hydrogen-Bonding Receptors
FULL PAPER
tially formed as kinetic products,[3] was precluded by heat- been demonstrated, depending on the nature of the linker
ing samples to 40 °C in CDCl3 (over periods of 30 min, 1 h group between the two triazine rings. Whereas when the
or 5 h) prior to cooling to room temperature and collection linker used is m-xylylenediamine, the di-substituted triazine
1
of H NMR spectra.
can be prepared before the linking step, when the linker
used is 1,3-benzenedimethanol, the two triazines must be
linked in the first step by the diether bridge prior to subse-
quent substitutions of the triazine rings.
By examining the hydrogen-bonding interaction between
hydrogen-bonding pocket systems and barbital it has been
shown that the number of hydrogen-bonding sites capable
of binding a guest such as barbital has a significant effect
on the overall strength of binding. This study illustrates the
capability to modulate the hydrogen-bonding strength of
such receptors indicating that the host–guest interaction of
such receptors with barbiturate may be tuned potentially
for subsequent use in devices where a reversible self-as-
sembly process may be required.
Figure 1. Job plot of [Complex] vs. [Host]/([Host] + [Guest]) for
barbital and 3.
The association constant for this system was calculated
using EQNMR,[18] on the basis of a 1:1 complex being the
only species present, giving 140 3 –1, significantly lower
than that of 1/barbital. This confirms that the interaction
between the xylylenediamine NH of 1 and barbital is par-
ticularly significant in the binding of barbiturates by pock-
ets of this design. The smoothing of the Job plot curve is a
reflection of the weaker binding of this pocket in compari-
son to that observed for 1, caused by both reduced numbers
of hydrogen-bonding interactions and by repulsive electro-
static interactions between the ether linkers and one of the
barbiturate oxygen atoms in the case of 3.
Experimental Section
1
General: H and 13C NMR spectra were measured with a Bruker
300 MHz spectrometer. Infra-red spectra were measured as KBr
disks with a Nicolet Avatar 380 FT-IR spectrometer over the range
400–4000 cm–1. Microanalyses were performed by the University of
Nottingham Chemistry Department microanalytical service with a
Perkin–Elmer 240B analyser. All chemicals were purchased from
Aldrich Chemicals, Lancaster Chemicals or Acros Chemicals and
used without further purification. Compound 1 was prepared ac-
The receptor 5 is capable of adopting two hydrogen- cording to the procedures described by Reinhoudt et al.,[10] except
that instead of refluxing 2-chloro-4-(dibenzylamino)-6-(bu-
tylamino)-1,3,5-triazine in neat m-xylylenediamine, THF solvent
was used with an excess of the triazine starting material.
bonding interactions with barbital (Scheme 1) and, thus, is
expected to exhibit weak host–guest interactions. As in the
case of 3, this system suffers the absence of the well-defined
hydrogen-bonding position between barbital and the xylyl-
1,3-O,OЈ-Bis[6-(butylamino)-4-chloro-1,3,5-triazin-2-yl]benzenedi-
methanol (2): To a solution of cyanuric chloride (3.68 g, 20 mmol)
and 2,6-lutidine (5 mL) in CH2Cl2 (50 mL) was added a solution
of 1,3-benzenedimethanol (1.38 g, 10 mmol) in CH2Cl2 (10 mL).
The mixture was stirred at room temperature for ca. 20 h resulting
in a dark red mixture. Butylamine (1.46 g, 20 mmol) in CH2Cl2
(5 mL) was added and the mixture stirred at room temperature for
a further 20 h. The mixture was washed with 1  HCl (50 mL),
water (50 mL) and brine (50 mL) and the organic layers dried with
MgSO4. The solvent was evaporated under reduced pressure to give
a brown sticky foam, which was used without further purification.
ES-MS: m/z = 507 [M+ + H].
1
enediamine NH seen in 1. The H NMR titration experi-
ments indicate a small shift in the baribital NH shift, poten-
tially indicating an interaction between barbital and 5.
However, because of the much smaller chemical shifts in-
volved in this system it was decided to investigate further
the nature of the interaction in which the barbital is taking
1
part. It was established that the H NMR shifts observed
for the barbital NH were also found in the absence of com-
pound 5, and therefore it can be concluded that the shifts
observed in the 1H NMR spectrum are due to barbital self-
association (a binding constant of 14 4 moldm–3 was
found for this species; which compares well with a pre-
viously reported values[11]). This is perhaps to be expected
considering that barbital self-association will take place via
the formation of double N–H···O hydrogen bonds; which
are likely to be stronger than any hypothetical hydrogen-
bonding interactions between barbital and 5.
1,3-O,OЈ-Bis[6-(butylamino)-4-(dibenzylamino)-1,3,5-triazin-2-yl]-
benzenedimethanol (3): A solution of 1,3-O,OЈ-bis[6-(butylamino)-
4-chloro-1,3,5-triazin-2-yl]benzenedimethanol (2) (ca. 2 g, 4 mmol),
dibenzylamine (2.0 g, 10 mmol), and DIPEA (5 mL) in THF
(100 mL) was heated at reflux for 3 days. The solvent was evapo-
rated under reduced pressure and the residue dissolved in dichloro-
methane (100 mL), washed with 1  HCl (50 mL), water (50 mL)
and brine (50 mL). The solvent was evaporated under reduced pres-
sure to give the crude product as a brown sticky foam. The filtrate
was purified by column chromatography (CH2Cl2 on silica) to give
the product as a white foamy solid (1.04 g, 32 %). 1H NMR
(CDCl3): δ = 7.40–7.19 (m, 24 H), 5.25 (s, 4 H), 4.75 (s, 8 H), 3.35
(m, 4 H), 1.49 (m, 4 H), 1.30 (m, 4 H), 0.86 (t, 6 H) ppm. 13C
NMR (CDCl3): δ = 171.6, 167.6, 167.2, 166.7, 138.1, 137.9, 137.0,
128.5, 127.9, 127.1, 67.8, 48.5, 40.6, 31.8, 20.0, 13.8 ppm. ES-MS:
m/z = 829 [M + H]. C50H56N10O2 (829.05): calcd. C 72.44, H 6.81,
Conclusions
A range of hydrogen-bonding receptor systems has been
prepared and the synthetic routes thoroughly investigated.
It has been shown that the number of hydrogen-bonding
sites available to interact with a guest such as a barbiturate
can be modulated. Two distinct routes to the receptors have N 16.89; found C 72.04, H 6.83, N 16.76.
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1,3-O,OЈ-Bis[4-chloro-6-(diethylamino)-1,3,5-triazin-2-yl]benzenedi-
methanol (4): To a solution of cyanuric chloride (3.68 g, 20 mmol)
and 2,6-lutidine (5 mL) in CH2Cl2 (50 mL) was added a solution
of 1,3-benzenedimethanol (1.38 g, 10 mmol) in CH2Cl2 (10 mL).
The mixture was stirred at room temperature for ca. 20 h resulting
in a dark red mixture. Diethylamine (1.46 g, 20 mmol) in CH2Cl2
(5 mL) was added and the mixture stirred at room temperature for
a further 20 h. The mixture was washed with 1  HCl (50 mL),
water (50 mL) and brine (50 mL) and the organic layers dried with
MgSO4. The solvent was evaporated under reduced pressure to give
a brown sticky foam which was used without further purification.
ES-MS: m/z = 507, 509 [M+ + H].
167, 165.5, 137.9, 128.9, 128.5, 127.8, 127.5, 49.4, 49.2, 48.0, 47.5,
30.5, 31.5, 20.6, 20.5, 14.4, 14.2 ppm. ES-MS: m/z = 438 [M+].
C25H32ClN5 (438.01): calcd. C 68.55, H 7.36, N 15.99; found C
68.49, H 7.34, N 15.76.
2-Chloro-4-(dibenzylamino)-6-(diethylamino)-1,3,5-triazine (8): To a
solution of cyanuric chloride (1.84 g, 10 mmol) and DIPEA (4 mL)
in THF (50 mL) at 0 °C, was added dibenzylamine (1.97 g,
10 mmol) in THF (10 mL) dropwise. The resulting slurry was
stirred at 0 °C for 2 h. The reaction mixture was warmed to room
temperature and diethylamine (0.73 g, 10 mmol) in THF (10 mL)
was added dropwise. The reaction was stirred at room temperature
for ca. 20 h. The solvent was evaporated under reduced pressure
and the residue dissolved in dichloromethane (150 mL) which was
washed with water (50 mL), 1  HCl (2 × 50 mL) and brine
(50 mL). The organic layers were combined and dried with MgSO4
and the solvent evaporated under reduced pressure to give the
crude product as a sticky yellow solid. Recrystallisation from hot
ethanol gave 2-chloro-4-(dibenzylamino)-6-(diethylamino)-1,3,5-
triazine (5) as a colourless solid (2.9 g, 76%). 1H NMR (CDCl3): δ
= 7.35–7.21 (m, 10 H), 4.79 (s, 2 H), 4.71 (s, 2 H), 3.59 (q, 2 H),
3.47 (q, 2 H), 1.19 (t, 3 H), 1.04 (t, 3 H) ppm. 13C NMR [CDCl3];
δ = 169.4, 165.6, 164.2, 137.6, 137.5, 128.9, 128.5, 128.1, 127.5,
127.3, 127.2, 48.7, 48.6, 41.6, 41.5, 13.3, 12.6 ppm. C21H25ClN5
(382.91): calcd. C 66.04, H 6.33, N 18.34; found C 65.60, H 6.32,
N 18.00. ES-MS: m/z = 382 [M + H].
1,3-O,OЈ-Bis[4-(dibenzylamino)-6-(diethylamino)-1,3,5-triazin-2-yl]-
benzenedimethanol (5): A solution of 1,3-O,OЈ-bis[4-chloro-6-(di-
ethylamino)-1,3,5-triazin-2-yl]benzenedimethanol (ca. 5 g,
10 mmol), dibenzylamine (3.94 g, 20 mmol), and 2,6-lutidine
(5 mL) in THF (100 mL) was heated at reflux for 3 days. The sol-
vent was evaporated under reduced pressure and the residue dis-
solved in dichloromethane (100 mL), washed with 1  HCl
(50 mL), water (50 mL) and brine (50 mL). The solvent was evapo-
rated under reduced pressure to give a brown sticky residue which
was purified by column chromatography (2% MeOH in CH2Cl2 on
1
silica) to give the product as a white foam (1.8 g, 22%). H NMR
[CDCl3]: δ = 7.34–7.20 (m, 24 H), 5.31 (s, 4 H), 4.80 (s, 4 H), 4.75
(s, 4 H), 3.59 (q, 4 H), 3.51 (q, 4 H), 1.18 (t, 6 H), 1.06 (t, 6 H)
ppm. 13C NMR (CDCl3): δ = 170.7, 167.0, 165.7, 138.5, 138.2,
137.4, 128.4, 127.9, 127.7, 127.5, 127.0, 67.9, 48.5, 41.5, 41.3, 13.4,
13.0 ppm. ES-MS: m/z = 829 [M + H]. C50H58N10O3 (5·0.5H2O,
847.06): calcd. C 71.66, H 6.86, N 16.71; found C 71.67, H 6.66,
N 16.52.
1,3-N,NЈ-Bis[4-chloro-6-(diethylamino)-1,3,5-triazin-2-yl]xylylenedi-
amine (9): To a solution of cyanuric chloride (1.84 g, 10 mmol) and
DIPEA (8 mL) in THF (50 mL) at 0 °C was slowly added a solu-
tion of m-xylylene diamine (0.68 g, 5 mmol) in THF (5 mL). The
resulting slurry was stirred at 0 °C for ca. 4 h. The mixture was
warmed to room temperature and a solution of diethylamine
(0.73 g, 10 mmol) in THF (5 mL) was slowly added. The resulting
mixture was stirred at room temperature for ca. 20 h. The solvent
was evaporated under reduced pressure and the residue dissolved
in dichloromethane (150 mL) which was washed with water
(50 mL), 1  HCl (2×50 mL) and brine (50 mL). The organic lay-
ers were combined and dried with MgSO4 and the solvent evapo-
rated under reduced pressure to give the crude product as a yellow
oil. Column chromatography (2% MeOH in CH2Cl2) yielded com-
2-Chloro-4,6-bis(dibenzylamino)-1,3,5-triazine (6): To a solution of
cyanuric chloride (1.84 g, 10 mmol) and DIPEA (5 mL) in THF
(50 mL) was added dibenzylamine (3.94 g, 20 mmol) in THF
(20 mL) dropwise. The reaction mixture was stirred at room tem-
perature for ca. 20 h during which time a white precipitate formed.
The solvent was evaporated under reduced pressure and the residue
dissolved in CH2Cl2. The solution was washed with 1  HCl
(50 mL) and brine (50 mL), the organic layer dried with MgSO4
and the solvent evaporated under reduced pressure. The residue
was recrystallised from diethyl ether to give 2-chloro-4,6-bis(diben-
zylamino)-1,3,5-triazine as a white solid (3.36 g, 66%). 1H NMR
CDCl3]; δ = 7.38–7.10 (m, 20 H), 4.83 (s, 4 H), 4.68 (s, 4 H). 13C
NMR (CDCl3). δ = 169.93, 165.82, 137.24, 137.08, 128.58, 128.52,
128.18, 127.64, 127.46, 127.25, 48.76, 48.60 ppm. ES-MS: m/z =
506 [M + H+]. C31H28ClN5 (506.03): calcd: C 73.58, H 5.58, N
13.84; Found C 73.10, H 5.60, N 13.70.
1
pound 6 as a colourless solid (2.4 g, 47%). H NMR (CDCl3): δ =
7.29–7.17 (m, 4 H), 4.58 (s, 2 H), 4.56 (s, 2 H), 3.56 (q, 4 H), 3.48
(q, 4 H), 1.17 (t, 6 H), 1.05 (t, 6 H) ppm. ES-MS: m/z = 506 [M+].
C22H30Cl2N10 (505.46): calcd. C 52.28, H 5.98, N 27.72; Found C
52.70, H 6.04, N 27.33.
3-NЈ-[4-Chloro-6-(diethylamino)-1,3,5-triazin-2-yl]-1-N-[4-(dibenzyl-
amino)-6-(diethylamino)-1,3,5-triazin-2-yl]xylylenediamine, (11): To
a solution of 1,3-N,NЈ-bis[4-chloro-6-(diethylamino)-1,3,5-triazin-
2-yl]xylylenediamine (6, 2.0 g, 4 mmol) in THF (50 mL) was added
dibenzylamine (1.58 g, 8 mmol) in THF (5 mL) and the mixture
heated at reflux for 6 days. The solvent was evaporated under re-
duced pressure and the residue dissolved in dichloromethane
(150 mL) which was washed with water (50 mL), 1  HCl
(2×50 mL) and brine (50 mL). The organic layers were combined
and dried with MgSO4 and the solvent evaporated under reduced
pressure to give the crude product as a brown sticky foam. Column
chromatography (n-hexane/ethyl acetate, 3:1 on silica) yielded the
product 7 as a white solid (1.7 g, 64%). 1H NMR (CDCl3): δ =
7.34–7.18 (m, 24 H), 6.29 (s, 2 H, NH), 4.78 (s, 4 H), 4.60 (s, 2 H),
4.58 (s, 2 H), 3.59 (m, 8 H), 1.15 (m, 12 H) ppm. ES-MS: m/z =
666 [M+].
2-Chloro-6-(dibenzylamino)-4-(dibutylamino)-1,3,5-triazine (7): To a
solution of cyanuric chloride (1.84 g, 10 mmol) and DIPEA (5 mL)
in THF (50 mL) at 0 °C, was added dibutylamine (1.29 g, 10 mmol)
in THF (10 mL) dropwise. The resulting slurry was stirred at 0 °C
for 2 h. The reaction mixture was warmed to room temperature;
and dibenzylamine (1.98 g, 10 mmol) in THF (10 mL) was added
dropwise. The reaction was stirred at room temperature for ca.
20 h. The solvent was evaporated under reduced pressure and the
residue dissolved in dichloromethane (100 mL), washed with water
(50 mL), 1  HCl (2×50 mL) and brine (50 mL) and the organic
layer dried with MgSO4. The solvent was evaporated under reduced
pressure and the residue recrystallised from hot ethanol to give
1
compound 7 as a white solid (2.45 g, 56%). H NMR (CDCl3): δ
= 7.36–7.18 (m, 10 H), 4.79 (s, 2 H), 4.70 (s, 2 H), 3.51 (t, 2 H),
3.38 (t, 2 H), 1.57 (m, 2 H), 1.43 (m, 2 H), 1.35 (m, 2 H), 1.14 (m, 4-(Butylamino)-2-chloro-6-(dibenzylamino)-1,3,5-triazine: To a solu-
2 H), 0.95 (t, 3 H), 0.75 (t, 3 H) ppm. 13C NMR (CDCl3): δ = 170, tion of cyanuric chloride (9.2 g, 50 mmol) and DIPEA (12 mL) in
1448
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Eur. J. Org. Chem. 2006, 1444–1449

Synthesis and Modulation of Bis(triazine) Hydrogen-Bonding Receptors
FULL PAPER
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the organic layer dried with MgSO4. The solvent was removed and
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the residue recrystallised from hot ethanol to give 1 as a white solid
(14.0 g, 73%). 1H NMR (CDCl3): δ = 7.35–7.18 (m, 10 H), 5.95 (t,
1 H, NH), 4.79 (s, 2 H), 4.75 (s, 2 H), 3.34 (m, 2 H), 1.51 (m, 2
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165.8, 165.6, 137.2, 137.1, 128.5, 128.1, 127.7, 127.5, 127.4, 127.3,
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1
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We would like to thank the EPSRC for support (P. V. M., G. G.).
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Received: August 18, 2005
Published Online: January 17, 2006
Eur. J. Org. Chem. 2006, 1444–1449
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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