A tri-armed sulfonamide host for selective binding of chloride

Article abstract of DOI:10.1039/b206125m

An uncharged host 6 for selective binding of chloride is described. This host features a triazine-trione platform, three short side-arms which are conformationally preorganised relative to the platform, and p-nitrophenylsulfonamide groups for hydrogen-bonding to anions. Host 6 binds chloride with K ≈ 150 000 M^-1 in CHCl₃ and shows a chloride/nitrate selectivity of 10².

Full text of DOI:10.1039/b206125m

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A tri-armed sulfonamide host for selective binding of chloride
Frank Hettche and Reinhard W. Hoffmann*
Fachbereich Chemie der Philipps Universita¨t Marburg, Hans Meerwein Str., D-35032,
Marburg, Germany. E-mail: rwho@chemie.uni-marburg.de
Received (in Montpellier, France) 24th June 2002, Accepted 23rd September 2002
First published as an Advance Article on the web 27th November 2002
An uncharged host 6 for selective binding of chloride is described. This host features a triazine–trione
platform, three short side-arms which are conformationally preorganised relative to the platform, and
p-nitrophenylsulfonamide groups for hydrogen-bonding to anions. Host 6 binds chloride with K ꢀ 150 000 Mꢁ1
in CHCl3 and shows a chloride/nitrate selectivity of 102.
(4) compared to 16 for compound 3 and 4 for compound 2.
Introduction
While the set of hosts 2–4 gave us a first insight, the effects
were rather small. This led us to question our plan on two
points:
Conformational preorganisation is found in many flexible nat-
ural products.1 This feature may be advantageous for nature to
strike a balance between flexibility on the one side and optimi-
sation of binding free energy on the other side when a natural
product is interacting with whatever biological partner. Con-
formational preorganisation has been recognised2 ever since
the pioneering investigations of Cram,3 to affect binding con-
stants and binding selectivities.
Is a four-carbon length of the side-arms optimal? Long
spacers, in general, will have adverse effects on binding entro-
pies. We therefore wanted to evaluate an analogous system
with shorter side-arms. Second, urea groups are often prone
to self-association,8 an effect which counteracts the binding
of anions. Hence, we decided to evaluate another powerful
anion-coordinating group in addition and opted for a p-nitro-
phenylsulfonamide group.9,10
In our ongoing studies on conformation design1 we became
interested in directly assessing the effect of conformational pre-
organisation on binding constants and binding selectivities. As
a test system we used tripodal hosts, of the general type 1,
bearing urea functions to complex anions,4 such as chloride.
In a preceding investigation5 we studied a set of three tripodal
hosts 2–4 based on a triazine–trione platform,6 hosts which
have an identical binding topology but differ in the level of
conformational preorganisation, cf. Scheme 1.
As it is not wise to change two parameters in one stroke, we
projected first host 7 which, compared to 4, reflects only the
change from urea to the p-nitrophenylsulfonamide group. A
subsequent change to host 6 then maintains conformational
preorganisation with respect to the platform, but reduces the
length of the side-chain. This reduction in chain-length will
moreover position the anionic guests closer to the (partially)
positively charged centre of the triazine–trione platform,11
a
position which corresponds to a Burgi–Dunitz trajectory with
¨
respect to the carbonyl groups.12 Finally, host 5 has the same
binding topology as 6, but is devoid of any conformational
preorganisation; cf. Scheme 2.
Scheme 2
Scheme 1
We report here on the synthesis of these three new hosts and
on their ability to bind and differentiate between the anions
chloride, bromide and nitrate in solution in chloroform.
We found a 2.5-fold increase in the binding constant for
Bu4N+Cl in CDCl3 on going from host 2 to host 3. This can
be attributed to a distinct arrangement of the side arms relative
to the platform caused by the avoidance of A1,3-strain in com-
pound 3.7 Further conformational organisation within the
side-chains itself, i.e. going from host 3 to 4, did not lead to
an additional increase in the binding constant for chloride. It
did, however, increase the chloride/nitrate selectivity to 24
Synthesis and conformational analysis
The synthesis of host 5 started from the commercially available
cyanuric acid 8. The hydroxy functions were replaced by azido
172
New J. Chem., 2003, 27, 172–177
DOI: 10.1039/b206125m
This journal is # The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2003

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groups to give 88% of 9. The azido groups were subsequently
reduced13 followed by direct conversion of the amino functions
into sulfonamido groups (32%) as outlined in Scheme 3.
Scheme 5
Scheme 6
Scheme 3
2–4 we presumed that self-interaction between the sulfonamide
groups would be less than between the urea moieties.8 Whereas
the urea-based host 4 showed a self-association of about 20
Host 6 has a stereogenic centre in each of the side-chains.
The intended binding studies by NMR-titration require that
a single stereoisomer of the host is used, rather than a mixture
of diastereomeric hosts. Hence, the synthesis of 6 had to make
sure that the side-chains in 6 are homochiral to one another.
This was attained by a convergent synthesis starting from
the enantiomerically pure acid 10.
The carboxylic acid 10 was subjected to a Curtius degrada-
tion and the resulting isocyanate was immediately cyclotri-
merised14 to give the triazine–trione 11.15 After conversion of
11 into the tris-azide 13, further processing to the tris-sulfona-
mide 6 followed the steps outlined above in the preparation of
5; cf. Scheme 4.
1
Mꢁ1 which was determined by following the H-NMR chemi-
cal shift (CDCl3) of the NH protons on dilution,5 the NH
chemical shift of the sulfonamide-based host 6 in CDCl3
turned out to be concentration independent, suggesting
negligible self-association of the tris-sulfonamide 6. Such lack
of self-association should then be reflected in a cleaner confor-
mational preorganisation within the side-chains of host 7.
The anticipated18 preferred conformation is shown as 7a in
Scheme 7.
Scheme 7
The conformational preorganisation in the side arms of
compound 7 was monitored by determining JH,H and JC,H
3
3
3
coupling constants. JH,H coupling constants of almost 10
Hz from H-1 as well as from H-3 to protons H2a and H2b of
the methylene group indicated that there is indeed a strong
conformational preference. The nature of the preferred confor-
mation as 7a follows from the 3JC,H coupling constants, which
form a unique set of data: two small19 couplings between Me1
and the methylene protons indicated that the conformation
around the C-1/C-2 bond is as shown. A large and a small
3JC,H coupling of the methylene protons at C-2 to Me3 indi-
cates that the preferred conformation around the C-2/C-3
bond is also that shown in 7a. However, the values of 6.5
and 4.1 Hz suggest that the conformational preference at the
C-2/C-3 bond may not be as high as at the C-1/C-2 bond.
Scheme 4
Host 7 with two stereogenic centres in each of the side-
chains likewise had to be prepared as a single stereoisomer.
To this end we started as shown in Scheme 5 from the config-
urationally homogenous tris-azide 14, an intermediate in our
previous synthesis of the tris-urea 4.5 The conversion of 14 into
the tris-sulfonamide 7 followed again the steps outlined above
in the preparation of 5.
Finally, the simple conformationally non-preorganised tren-
derivative 15 was prepared as shown in Scheme 6. We wanted
15 for comparison, as tren-derived hosts frequently have been
used in anion complexation.16,17
Complexation studies
The binding of anions (tetrabutylammonium salts) to the hosts
5–8 was followed by monitoring the chemical shift of NH pro-
tons. Job plots (SigmaPlot200020) showed that in all cases 1:1
complexes were formed. Binding constants were estimated by
curve fitting with the program SigmaPlot2000.20 Initial binding
studies with the host 7 used CDCl3 as solvent, in order to relate
the measurements to those obtained previously5 with host 4.
The results are compiled in Table 1.
When choosing the p-nitrophenylsulfonamide moiety as the
anion complexing group instead of the urea groups in hosts
New J. Chem., 2003, 27, 172–177
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Table 1 Binding constants for tetrabutylammonium salts in CDCl3
(300 K) determined by NMR titration for the hosts 7 and 4
Table 3 Binding constants for tetrabutylammonium salts in CDCl3/
DMSO 95:5 (300 K)
Host
Host
Guest
7
4
Guest
7
5
6
15
Clꢁ
Brꢁ
151 000 ꢅ 34 200
16 200 ꢅ 1800
6100 ꢅ 140
19 500 ꢅ 2160
2260 ꢅ 100
800 ꢅ 10
Clꢁ
Brꢁ
4170 ꢅ 130
570 ꢅ 30
275 ꢅ 10
4870 ꢅ 170
1020 ꢅ 65
380 ꢅ 5
12 630 ꢅ 1100
425 ꢅ 10
174 ꢅ 5
35 ꢅ 5
< 10
ꢁ
ꢁ
NO3
NO3
120 ꢅ 10
The data in Table 1 show that host 7 with the sulfonamide
groups binds the anions (chloride, bromide, nitrate) about 8
times more strongly than host 4 featuring urea groups. The
selectivity of hosts 7 towards the different anions remains,
however, the same as that of host 4.
the data for host 7). The data for the full range of hosts in
the more polar mixed solvent are compiled in Table 3.
Consider first hosts 5 (no conformational preorganisation)
and 6 (conformationally preorganised) having the same bind-
ing topologies: conformational preorganisation leads to a
moderate increase (ꢂ2.6) in the binding of chloride, but to
decreases (ꢂ0.4) in the binding of bromide or of nitrate.
Hence, conformational preorganisation accentuates binding
selectivities, which becomes apparent when comparing the
Clꢁ/NO3ꢁ selectivity for 5, which is 13; with that for 6 ¼ 105!
The tren-derived conformationally non-preorganised host
15 has binding selectivities17 similar to those of host 5 with
conformationally non-preorganised side arms. But overall
binding constants are much smaller for 15 than for 5 showing
the benefits of having a rigid central platform.
The binding constants of host 7 extended into a range
( > 50 000 Mꢁ1) in which the curvature of the NMR titration
changes so sharply at the 1:1 point, that determination of the
binding constants becomes rather inaccurate. This prevented
a meaningful determination of the binding constant between
host 6 and chloride, which was even larger. Large binding con-
stants may, however, be determined by microcalorimetric titra-
tion.21 With this technique we obtained the binding parameters
of chloride to both hosts 7 and 6 (in CHCl3) cf. Table 2. A
direct comparison of the two methods was possible in the case
of chloride binding to host 7. The values for the binding con-
stant (Table 1 vs. Table 2) are of the same magnitude but differ
by a factor of about 2, which appears acceptable.22 Microca-
lorimetry then indicates that host 6 indeed binds chloride even
more strongly than host 7.
Host 7, with conformational preorganisation in the side
arms, comes out pretty similar to the fully flexible host 5
regarding binding constants and selectivities, something we
would not have expected. Thus, the unique position of host
6 regarding the selective binding of chloride becomes more
manifest.
With compound 6 we have prepared a neutral host which
complexes chloride strongly (K ꢀ 1.5 ꢂ 105 Mꢁ1 in chloroform)
and reaches a chloride/nitrate selectivity of 102. It compares
favourably with the highly chloride-selective sulfonamide host
described recently by Davis.10 The key features of host 6 are
the triazine–trione platform, short but conformationally preor-
ganised side-arms and p-nitrophenylsulfonamide hydrogen
bond donors.
Table 2 Microcalorimetrically determined parameters for complexa-
tion of tetrabutylammonium chloride by the tris-sulfonamides 6 and
7 in CHCl3 at 298 K
Host
Parameter
7
6
K/L molꢁ1
81 000 ꢅ 10 000
ꢁ28.1 ꢅ 0.35
ꢁ19.6 ꢅ 0.27
+29 ꢅ 2.1
155 000 ꢅ 11 000
ꢁ29.7 ꢅ 0.38
ꢁ9.4 ꢅ 0.05
+68 ꢅ 1.4
DG/kJ molꢁ1
DH/kJ molꢁ1
DS/J molꢁ1 Kꢁ1
Experimental
General remarks. All temperatures quoted are uncorrected. 1H
NMR, 13C NMR: Bruker ARX-200, AC-300, WH-400, AMX-
500. Boiling range of petroleum ether: 40–60 ꢃC. Flash chro-
matography: silica gel SI 60, E. Merck KGaA, Darmstadt,
40–63 mm. pH 7 buffer: NaH2PO4ꢄ2H2O (56.2 g) and Na2-
HPO4ꢄ4H2O (213.6 g) filled up to 1 L with water.
However, there are more subtle differences between the two
hosts as revealed by the binding enthalpy and entropy avail-
able through microcalorimetry.21 Complexation of chloride
by a tridentate host leads to a positive complexation entropy,
as solvent molecules are released from the solvation shells of
the chloride anion and the host. The entropy change on com-
plexation to the host 7 is, however, far less positive than for
complexation by host 6. This may be a consequence of redu-
cing the rotational freedom of the longer side arms of host 7
on complexation, in line with the NMR studies above which
indicated that there is still considerable rotational freedom
around bonds C-2/C-3 in host 7. Regarding enthalpy, the
binding of chloride by host 6 is clearly less exothermic than
binding by host 7. This invites the speculation that the more
flexible host 7 can adopt an optimal coordination geometry,
whereas the more rigid host 6 is less in a position to do so.
Moreover, a potential electrostatic attraction of chloride by
the triazine–trione platform11 is not reflected by the data.
Another aspect we wanted to focus on is the binding selec-
tivity between different anions. Before addressing this, we
noted that chloroform was not an optimal solvent to determine
binding constants for such strongly complexing hosts as 6. In
order to determine binding selectivities, we therefore moved
to a more polar solvent (CDCl3/DMSO ¼ 95:5) in which the
binding constants are numerically smaller23 (ca. ꢂ0.03, cf.
1. 1,3,5-Tris(2-azidoethyl)-1,3,5-triazine-2,4,6-trione
(9).
Triethylamine (2.30 mL, 16.6 mmol) was added at 0 ꢃC into
a solution of 1,3,5-tris(2-hydroxyethyl)-1,3,5-triazine-2,4,6-
trione (8) (1.0 g, 3.8 mmol) in DMF (100 mL). After stirring
for 10 min at 0 ꢃC methanesulfonyl chloride (1.11 mL, 14.4
mmol) was added. After continued stirring for 2.5 h the mix-
ture was allowed to reach room temperature. Sodium azide
(8.80 g, 13.5 mmol) was added and the mixture was heated
for 5 d to 70 ꢃC. Saturated aqueous NaHCO3 solution (250
ml) and water (200 mL) were added. The layers were separated
and the aqueous layer was extracted with ether (5 ꢂ 150 mL).
The combined organic layers were washed with brine (100
mL), dried (Na2SO4) and concentrated. Flash chromatography
of the residue with pentane/tert-butyl methyl ether ¼ 1:3 furn-
ished the tris-azide 9 (1.12 g, 88%) as a colourless resin. M.p.
1
83–84 ꢃC. H-NMR (500 MHz, CDCl3): d ¼ 3.56 (t, J ¼ 5.9
Hz, 6H), 4.14 (t, J ¼ 5.9 Hz, 6H). 13C-NMR (125 MHz,
CDCl3): d ¼ 41.7, 48.3, 148.6. C9H12N12O3 (336.3): Calcd.:
174
New J. Chem., 2003, 27, 172–177

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C, 32.15; H, 3.60; N 49.98; Found: C, 32.14; H, 3.57; N
49.88%.
the product 11 (470 mg, 67%) as a colourless oil. [a]2D0 ¼ +
1
4.9 (c ¼ 3.2, CHCl3). H-NMR (500 MHz, CDCl3): d ¼ 0.00
(s, 9H), 0.01 (s, 9H), 0.83 (s, 27H), 1.35 (d, J ¼ 6.7 Hz, 9H),
3.76 (dd, J ¼ 9.4, 6.8 Hz, 3H), 3.98 (pseudo t, J ¼ 8.9 Hz, 3H),
4.93 (pseudo sex, J ¼ 7.1 Hz, 3H). 13C-NMR (500 MHz,
CDCl3): d ¼ ꢁ5.5 (3C), ꢁ5.4 (3C), 14.3 (3C), 18.0 (3C), 25.8
(9C), 53.2 (3C), 63.4 (3C), 149.2 (3C). C30H63N3O6Si3
(645.4): Calcd.: C, 55.77; H, 9.83; N, 6.50; Found: C, 55.61;
H, 9.65; N, 6.80%.
2. 1,3,5-Tris[2-(4-nitrophenylsulfonylamido)ethyl]-1,3,5-tri-
azine-2,4,6-trione (5). A solution of trimethylphosphine (1.0 M
in THF, 2.4 mL, 2.4 mmol) was added at 0 ꢃC into a solution
of the tris-azide 9 (250 mg, 684 mmol) in THF (8.0 mL). After
stirring for 5 h at room temperature water (60.0 mL, 3.28
mmol) was added. After continued stirring for 3 d triethyla-
mine (430 mL, 3.19 mmol) and p-nitrophenylsulfonyl chloride
(672 mg, 3.03 mmol) were added and the mixture was heated to
80 ꢃC for 8 h. The solvents were removed in vacuo and the resi-
due was purified by flash chromatography with chloroform/
methanol/formic acid ¼ 20:1:0.1 to 15:1:0.1 giving the tris-sul-
fonamide 5 (180 mg, 32%) as a slightly yellowish resin. M.p.
193–194 ꢃC. 1H-NMR (500 MHz, acetone-D6): d ¼ 3.28
(t, J ¼ 6.0 Hz, 6H), 6.10 (t, J ¼ 6.1 Hz, 6H), 7.02 (broad s,
3H), 8.08 (d, J ¼ 8.1 Hz, 6H), 8.40 (d, J ¼ 8.2 Hz, 6H). 13C-
NMR (125 MHz, acetone-D6): d ¼ 41.0, 42.8, 125.2, 129.0,
147.3, 149.9, 150.9. HRMS (ESI) C27H27N9O15S3 + Na Calcd.:
836.0686; Found: 836.0716.
5. 1,3,5-Tris[(1S)-2-hydroxy-1-methylethyl]-1,3,5-triazine-
2,4,6-trione (12). HF (5% in acetonitrile, 3.2 mL) was added to
11 (426 mg, 659 mmol). After stirring for 2 h saturated aqueous
NaHCO3 solution (5 ml) was added dropwise. The layers were
separated and the aqueous layer was saturated with NaCl and
extracted with ethyl acetate (6 ꢂ 10 mL). The combined
organic layers were dried (Na2SO4) and concentrated. Flash
chromatography of the residue with ethyl acetate furnished
the triol 12 (193 mg, 96%) as a colourless solid. M.p. ¼ 192–
1
194 ꢃC. [a]2D0 ¼ ꢁ3.7 (c ¼ 1.4, acetone). H-NMR (500 MHz,
CDCl3): d ¼ 1.28 (d, J ¼ 6.9 Hz, 9H), 3.60 (dd, J ¼ 11.6,
5.6 Hz, 3H), 4.09 (pseudo t, J ¼ 11.6 Hz, 3H), 4.85–4.95 (m,
3H), OH signals not detected. 13C-NMR (125 MHz, CDCl3):
d ¼ 13.8 (3C), 52.0 (3C), 61.9 (3C), 149.1 (3C). C12H21N3O6
(303.1): Calcd.: C, 47.52; H, 6.98; N, 13.85; Found: C, 47.55;
H, 6.84; N, 13.90%.
3. (2S)-3-(tert-Butyldimethylsilyloxy)-2-methylpropionic
acid (10). Imidazole (1.03 g, 15.1 mmol), 4-dimethylaminopyr-
idine (160 mg, 1.31 mmol) and tert-butylchlorodimethylsilane
(50% in toluene, 4.50 g, 14.9 mmol) were added at 0 ꢃC into
a
solution of methyl (2S)-3-hydroxy-2-methylpropionate
6. 1,3,5-Tris[(1S)-2-azido-1-methylethyl]-1,3,5-triazine-
2,4,6-trione (13). Triethylamine (233 mL, 1.68 mmol) was
added at 0 ꢃC into a solution of the triol 12 (115 mg, 379 mmol)
in DMF (20 mL). After stirring for 10 min at 0 ꢃC methane-
sulfonyl chloride (111 mL, 1.44 mmol) was added. After con-
tinued stirring for 2.5 h the mixture was allowed to reach room
temperature and sodium azide (845 mg, 13.0 mmol) was
added. The mixture was heated to 65 ꢃC for 5 d. Saturated
aqueous NaHCO3 solution (50 mL) and water (40 mL) were
added. The layers were separated and the aqueous layer was
extracted with ether (5 ꢂ 30 mL). The combined organic layers
were washed with brine (40 mL), dried (Na2SO4) and concen-
trated. Flash chromatography of the residue with pentane/
tert-butyl methyl ether ¼ 4:1 furnished the tris-azide 13
(132 mg, 92%) as a colourless resin. [a]2D0 ¼ ꢁ2.1 (c ¼ 1.9,
CHCl3). 1H-NMR (500 MHz, CDCl3): d ¼ 1.43 (d, J ¼ 7.0
Hz, 9H), 3.46 (dd, J ¼ 12.5, 5.7 Hz, 3H), 3.97 (dd, J ¼ 12.5,
10.0 Hz, 3H), 4.94–5.03 (m, 3H). 13C-NMR (125 MHz,
CDCl3): d ¼ 15.5 (3C), 51.1 (3C), 52.5 (3C), 148.6 (3C).
C12H18N12O3 (378.4): Calcd.: C, 38.09; H, 4.80; N, 44.42;
Found: C, 37.91; H, 4.76; N, 44.63%.
(1.15 g, 9.74 mmol) in dichloromethane (40 mL). After stirring
for 1 h at room temperature methanol (2 mL) was added and
stirring was continued for 15 min. Water (50 mL) was added
and the layers were separated. The aqueous layer was extracted
with dichloromethane (4 ꢂ 20 mL). The combined organic
layers were dried (Na2SO4) and concentrated. The residue
was taken up in a THF/methanol/water ¼ 2:2:1 mixture.
After cooling to 0 ꢃC aqueous NaOH solution (5M, 2.80 mL,
14.0 mmol) was added. After stirring for 16 h at room tem-
perature saturated aqueous NH4Cl solution (20 mL) and water
(20 mL) were added. The layers were separated and the aqu-
eous layer was extracted with ether (5 ꢂ 25 mL). The combined
organic layers were washed with water (10 mL) and brine (30
mL). The combined aqueous layers were saturated with NaCl
and extracted with ethyl acetate (4 ꢂ 20 mL). The combined
organic extracts were dried (Na2SO4) and concentrated. Flash
chromatography of the residue with tert-butyl methyl ether
was followed by bulb to bulb distillation of the crude product
at p60 ꢃC in vacuo to give the acid 10 (1.39 g, 66%) as a col-
ourless oil. [a]2D0 ¼ +17.2 (c ¼ 3.08, CHCl3). 1H-NMR (500
MHz, CDCl3): d ¼ 0.04 (s, 6H), 0.87 (s, 9H), 1.16 (d,
J ¼ 7.2 Hz, 3H), 2.60–2.69 (m, 1H), 3.69 (dd, J ¼ 9.9, 5.8
Hz, 1H), 3.77 (dd, J ¼ 7.0, 9.9 Hz, 1H), OH signal not
detected. 13C-NMR (125 MHz, CDCl3): d ¼ ꢁ5.5 (2C), 13.1,
18.2, 25.8 (3C), 42.2, 64.9, 180.4. C10H22O3Si (218.4): Calcd.:
C, 55.00; H, 10.15; Found: C, 54.74; H, 10.38%.
7. 1,3,5-Tris[(1S)-2-(4-nitrophenylsulfonamido)-1-methy-
lethyl]-1,3,5-triazine-2,4,6-trione (6). The tris-azide 13 (47.0 mg,
124 mmol) was allowed to react as described in part 2 above.
Flash chromatography of the crude product with tert-butyl
methyl ether/dichloromethane ¼ 4:1 furnished the tris-sulfo-
namide 6 (31 mg, 29%) as a slightly yellowish solid. M.p.
118–120 ꢃC. [a]D20 ¼ ꢁ138 (c ¼ 2.55, CHCl3). 1H-NMR (500
MHz, CDCl3): d ¼ 1.46 (d, J ¼ 6.7 Hz, 9H), 3.13 (pseudo
dt, J ¼ 14.6, 5.3 Hz, 3H), 3.75 (ddd, J ¼ 14.6, 11.3, 6.7 Hz,
3H), 5.18–5.29 (m, 3H), 6.21 (broad s, 3H), 8.05 (d, J ¼ 8.9
Hz, 6H), 8.32 (d, J ¼ 8.9 Hz, 6H). 13C-NMR (125 MHz,
CDCl3): d ¼ 15.2 (3C), 44.4 (3C), 52.0 (3C), 124.5 (6C),
128.1 (6C), 145.6 (3C), 149.3 (3C), 150.2 (3C). HRMS (ESI)
C30H33N9O15S3 + Na Calcd.: 878.1156; Found: 878.1198.
4. 1,3,5-Tris[(1S)-2-(tert-butyldimethylsilyloxy)-1-methyl-
ethyl]-1,3,5-triazine-2,4,6-trione (11). Triethylamine (470 mL,
3.39 mmol) and diphenoxyphosphoryl azide (dppa, 780 mL,
3.65 mmol) were added at 0 ꢃC into a solution of the acid 10
(712 mg, 3.26 mmol) in pentane (18 mL). The mixture was stir-
red for 16 h at room temperature and then for 6.5 h at 65 ꢃC.
The solution was decanted and the residue was triturated with
pentane (4 ꢂ 7 mL). The combined solutions were concen-
trated and the residue was heated for 4 min to 70 ꢃC. The resi-
due was bulb to bulb distilled at p50 ꢃC in vacuo to give the
isocyanate (532 mg) as a colourless oil which was taken up
in THF (1.5 mL). KOEt (15 mg, 0.18 mmol) was added and
the mixture was stirred for 20 h. The solvents were removed
in vacuo and the residue was subjected to flash chromatogra-
phy with pentane/tert-butyl methyl ether ¼ 40:1 to furnish
8. 1,3,5-Tris[(1R,3S)-4-(4-nitrophenylsulfonamido)-1,3-
dimethylbutyl]-1,3,5-triazine-2,4,6-trione (7). The tris-azide 1424
(207 mg, 410 mmol) was allowed to react as described in part 2
above. Flash chromatography of the crude product with tert-
butyl methyl ether, saturated with NH3 , furnished the product
7 (195 mg, 48%) as a colourless solid. M.p. ¼ 91–93 ꢃC.
New J. Chem., 2003, 27, 172–177
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[a]2D0 ¼ ꢁ53.1 (c ¼ 1.64, CHCl3). 1H-NMR (CDCl3 , 500
MHz): d ¼ 0.96 (d, J ¼ 6.6 Hz, 9H), 1.27 (ddd, J ¼ 13.9,
9.7, 4.5 Hz, 3H), 1.41–1.51 (m, 3H), 1.46 (d, J ¼ 7.0 Hz,
9H), 2.37 (ddd, J ¼ 13.9, 9.9, 3.7 Hz, 3H), 2.70–2.88 (m,
6H), 4.89–5.00 (m, 3 H), 5.69 (broad s, 3H), 8.07 (d, J ¼ 8.9
Hz, 6H), 8.33 (d, J ¼ 9.0 Hz, 6H). 13C-NMR (125 MHz,
CDCl3): d ¼ 17.6 (3C), 18.7 (3C), 31.7 (3C), 37.5 (3C), 49.0
(3C), 49.3 (3C), 124.4 (6C), 128.3 (6C), 145.4 (3C), 148.9
(3C), 150.0 (3C). HRMS (ESI) C39H51N9O15S3 + Na, Calcd.:
1004.2564; Found: 1004.2543.
9. N,N,N-Tris[2-(4-nitrophenylsulfonamido)ethyl]amine
(15). Triethylamine (1.08 mL, 7.80 mmol) and p-nitrophenyl-
sulfonyl chloride (1.70 g, 7.67 mmol) were added into a solu-
tion of tris(2-aminoethyl)amine (317 mg, 2.16 mmol) in THF
(10 mL). After stirring for 6 h at 80 ꢃC and 12 h at room tem-
perature the solvent was removed in vacuo. The crude product
was purified by twofold flash chromatography with tert-butyl
methyl ether/acetone ¼ 9:1 ! acetone in each case to give
the tris-sulfonamide 15 (520 mg, 34%) as a slightly yellowish
1
solid. M.p. ¼ 180–181 ꢃC. H-NMR (500 MHz, DMSO-D6):
d ¼ 2.33 (t, J ¼ 6.4 Hz, 6H), 2.73 (d, J ¼ 6.4 Hz, 6H), 7.77
(broad s, 3H), 8.01 (d, J ¼ 9.0 Hz, 6H), 8.38 (d, J ¼ 9.0 Hz,
6H). 13C-NMR (125 MHz, DMSO-D6): d ¼ 40.4, 52.9,
124.6, 127.9, 146.1, 149.5. HRMS (ESI) C24H27N7O12S3 + H,
Calcd.: 702.0958; Found: 702.0999.
Fig. 2 Job plot for binding of tetrabutylammonium chloride to host
6 in CHCl3 .
SIGMA Plot 200020 with routines to determine complexation
constants for 1:1 complexes. The prevalence of 1:1 complexes
was secured by Job plot experiments, in which based on the
chemical shift of the free host (500 mL) Dd was determined
for the following host/guest combinations (host and guest hav-
ing the same stock concentration; host mL/guest mL: 450/50,
400/100, 350/150, 300/200, 250/250, 200/300, 150/350,
100/400, 50/450). A plot of the product Dd ꢂ mole fraction
(x) of the host against x led to a characteristic curvature, which
was fitted using again SIGMA plot 2000.20 Results from a
typical experiment are reproduced in Fig. 1: A representative
Job plot is reproduced in Fig. 2. Characteristic data for the
microcalorimetric titration are given in Fig. 3 and Fig. 4.
10. Complexation studies. Tetrabutylammonium salts were
of > 98% purity and were used as obtained from Aldrich or
Merck. CDCl3 and DMSO-D6 (Aldrich or Deutero GmbH;
deuterium content > 99.6%) were used as obtained. A solution
of the host (ca. 1 mM, 600 mL) was placed in an NMR tube.
Spectra were recorded after injection of increments of a solu-
tion of the guest (ca. 25 mM). The changes upon complexation
in the chemical shift (Dd) of either the NH-proton or of the
protons of the arene moieties (or both) were recorded. A plot
of Dd against the concentration of the guest showed a charac-
teristic curvature The curve was fitted with the program
11. Microcalorimetric titrations. The calorimetric titrations
were made at 298 K using a Thermometric1 titration calori-
metric system (Thermometric1, Sweden). The reproducibility
of the calorimeter was checked using the complexation of Ba2+
by 18-crown-6. A solution of tetrabutylammonium chloride
(40.03 mM) in chloroform was titrated into a 1.59 mM
Fig. 1 NMR titration for the association of tetrabutylammonium
chloride to host 6 in CDCl3 at 300 K.
Fig. 3 Calorimetric titration of tetrabutylammonium chloride/host 6
in CHCl3 .
176
New J. Chem., 2003, 27, 172–177

View Article Online
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Fig. 4 Resulting binding curve (corrected for enthalpy of dilution)
,
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Acknowledgements
We would like to thank the European Community (TMR
network ERBFMRXCT 960011) and the Fonds der Che-
mischen Industrie for support of this study. We are grateful
to Dipl.-Chem. Wolfgang Radunz and Dr. Monika Mazik,
Institut fur Organische Chemie der Universitaet Essen, for
¨
carrying out the microcalorimetric titrations, and to Professor
T. Schrader, Marburg, for many helpful suggestions.
19 P. E. Hansen, Progr. NMR Spectrosc., 1981, 14, 175.
20 SPSS Inc. 2000, We thank Prof. A. P. Davis (Bristol) and Prof.
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