Effect of spacer geometry on oxoanion binding by bis- and tetrakis-thiourea hosts

Article abstract of DOI:10.1016/j.tet.2008.01.026

Hosts with thiourea groups bind anions by formation of multiple hydrogen bonds. This contribution discusses how spacers linking two or four thiourea groups affect the host affinity and selectivity. While most of the bis-thioureas bind H₂PO₄^- preferentially, the extent of selectivity over chloride, acetate, and H₂AsO₄^- is determined by the size of the binding cavity. A tetrakis-thiourea is shown to exhibit a unique H₂AsO₄^- selectivity, and the discrimination of chloride is enhanced by specific solvation in dimethyl sulfoxide.

Full text of DOI:10.1016/j.tet.2008.01.026

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2530e2536
www.elsevier.com/locate/tet
Effect of spacer geometry on oxoanion binding
by bis- and tetrakis-thiourea hosts
*
Annie N. Leung, Dave A. Degenhardt, Philippe Buhlmann
¨
University of Minnesota, Department of Chemistry, 207 Pleasant St. SE, Minneapolis, Minnesota, MN 55455, United States
Received 25 May 2007; received in revised form 7 January 2008; accepted 7 January 2008
Available online 11 January 2008
Abstract
Hosts with thiourea groups bind anions by formation of multiple hydrogen bonds. This contribution discusses how spacers linking two or four
thiourea groups affect the host affinity and selectivity. While most of the bis-thioureas bind H2POꢀ4 preferentially, the extent of selectivity over
chloride, acetate, and H2AsOꢀ4 is determined by the size of the binding cavity. A tetrakis-thiourea is shown to exhibit a unique H2AsOꢀ4 selec-
tivity, and the discrimination of chloride is enhanced by specific solvation in dimethyl sulfoxide.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
that appropriate host preorganization as in 2a and 2b can dras-
tically increase the affinity for H2POꢀ4 .7,8 The preferential
complexation of H2POꢀ4 by these hosts was interpreted in
terms of the hydrogen bond acceptor strength and geometry
of the anion guests. Initially, only binding motifs I and II
were considered,5,7 and experimental data seemed to suggest
that I is the better representation of the actual complex.
The development of synthetic hosts for anions is a very ac-
tive area of research.1 In view of their important biological and
environmental roles, oxoanions such as phosphate and sulfate
have attracted particular attention. The design of most electri-
cally neutral hosts for these anions is based on Lewis acid and/
or hydrogen bond donor groups.1 Encouraged by reports on
mono-urea compounds that bind organic phosphates,2 bis-
ureas3,4 that form complexes with dicarboxylates, disulfo-
nates, and diphosphonates, and a host with two thiourea
groups3 that binds a dicarboxylate, we previously investigated
hydrogen bond-mediated binding of inorganic phosphate by
a number of bis-urea and bis-thiourea hosts (e.g., 1a, 1b, 2a,
2b in Fig. 1).5e7 We showed that very simple hosts with
a m-xylenyl-bis-thiourea subunit (1a, 1b) are well suited for
recognition of H2POꢀ4 in non-aqueous solvents because they
dissolve better, self-associate much less, and bind H2PO4ꢀ
more strongly than corresponding bis-ureas.5 Using a xanthene
spacer (introduced by Rebek and co-workers)6 to separate the
two thiourea groups from one another, we also demonstrated
O
S
R
N
H
N
H
S
R
S
R
N
H
N
H
S
R
H
H
H
H
N
N
N
N
1a: R = Bu
2a: R = Bu
1b: R = Ph
2b: R = Ph
S
R
N
N
S
S
N
N
S
N
N
H
S
R
S
R
H
H
H
O
O
H
H
O
O
H
H
O
P
O
P
N
N
H
N
N
N
N
H
O
H
H
H
H
P
R
R
R
O
O
H
O
OH
OH
I
III
II
* Corresponding author.
E-mail address: buhlmann@chem.umn.edu (P. Buhlmann).
Figure 1. Bis-thiourea hosts with a meta-xylylene (1a, 1b) and a xanthene
(2a, 2b) spacer, along with motifs IeIII for H2POꢀ4 binding.
¨
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.026

A.N. Leung et al. / Tetrahedron 64 (2008) 2530e2536
2531
However, a recent computational study of bis-urea complexes
suggests that binding motif III should also be considered.9
Unfortunately, crystallographic evidence is not yet available.
Since the first report of phosphate binding by bis-thioureas,
a large number of new anion hosts with thiourea groups have
been developed. Effects of electron withdrawing and hydro-
gen-bonding substituents on the selectivity and spectroscopic
properties of a variety of mono-thioureas were reported, and
iminoyl- as well as N-benzamido-substituted mono-thioureas
with similar binding patterns were described.10 Complexation
of dicarboxylates with bis-ureas and bis-thioureas in dimethyl
sulfoxide (DMSO) was shown to be enthalpically driven,11
and ditopic carriers with two thiourea groups were shown to
permit spectroscopic phosphate detection and phosphate ester
binding in water.12 Moreover, anion binding properties of
macrocycles, resorcinarene cavitands, bis-crown ethers, and
tripodal benzene derivatives with three or four thiourea groups
were reported.13
S
N
S
N
N
N
H
H
H
H
3
S
N
S
N
N
N
H
H
4
H
H
S
N
N
S
H
H
N
N
H
F3C CF3
H
5
H3C
S
CH3
S
N
N
H
H
N
N
H
H
6
Interestingly, the m-xylenyl-bis-thiourea subunit was uti-
lized in several hosts. It was applied in several macrocyclic
bis- and tris-thioureas,14 and in linear tri-, tetra-, and hexa-
thiourea hosts.15 Bis-thiourea hosts with a m-xylenyl-bis-
thiourea subunit were used as ionophores for ion-selective
electrodes to facilitate ion transfer at the liquideliquid inter-
face and to promote helicity in carbohydrate-containing fol-
damers.16 Moreover, the m-xylenyl spacer was used in
closely related bis-isothiouronium hosts,17 and a geometrically
similar spacer based on indoaniline was used for colorimetric
detections.18 A bis-thiourea based on a 2,20-disubstituted bi-
phenyl spacer represents a rare departure from the m-xylenyl
spacer approach.19 Rotation around the single bond connecting
the two phenyl units permits the two thiourea groups to ap-
proach one another to the extent that steric repulsion may oc-
cur. Not surprisingly, this host was found to bind the small
fluoride ion very strongly.
Figure 2. New bis-thiourea hosts.
was obtained by dibromination of 2,7-dimethylnaphthalene,
conversion to the diazide, and reduction to the diamine.21
The linear tetrakis-thiourea 7 was synthesized by mono-pro-
tection of m-xylenediamine,22 conversion of the unprotected
amino group into a isothiocyanate, reaction with m-xylenedi-
amine to give 8, deprotection, and conversion to the tetrakis-
thiourea with phenyl isothiocyanate (Fig. 3).
The association of the new hosts with various anionic
1
guests in DMSO-d6 was studied by H NMR spectroscopy,
as described previously.5,7 This solvent was chosen because
it is a strong hydrogen bond acceptor itself, and thereby effec-
tively suppresses ionophore self-association. To diminish pos-
sible effects of ion-pair formation on the formation constants,
However, in view of the need for selective oxoanion hosts
and the rather extensive literature on anion hosts with thiourea
groups, it has surprised us and others9 how little experimental
effort has been spent in the past to systematically investigate
the relationship between the shape of the host cavity formed
by thiourea compounds and the resulting affinity and selectiv-
ity for different anions. A computational study suggests that
doubly charged oxoanions such as sulfate may bind up to
six urea groups at a time, and it appears likely that the same
would also be true for thiourea groups.20 Unfortunately,
spacers that connect the urea groups with an optimum geometry
were not proposed.20 Also, besides the above mentioned
xanthene and biphenyl spacer, little is known experimentally
about alternatives to the popular m-xylenyl-bis-thiourea spacer.
Therefore, we determined binding strengths and selectivities of
hosts with four new spacers linking two thiourea groups.
+
O
NH2
NH2
N
C
S
N
H
O·tBu
9
EtOH, rt, 10 h
1. CF3COOH, CH2Cl2,
rt,12 h
S
S
N
N
2. PhNCS, Et3N, THF,
H
H
rt, 20 h
N
N
H
H
H
H
8
N
N
O
O
tBu
O
tBu
O
S
S
N
N
H
H
H
H
N
N
H
H
7
2. Results and discussion
H
H
N
S
N
S
N
N
Bis-thiourea hosts 3e6 (see Fig. 2) were prepared from
phenyl isothiocyanate and the appropriate diamines. 2,7-Bis-
(aminomethyl)naphthalene required for the synthesis of 5
Ph Ph
Figure 3. Synthesis of tetrakis-thiourea 7.

2532
A.N. Leung et al. / Tetrahedron 64 (2008) 2530e2536
K11, of the 1:1 complexes, the bulky tetrabutylammonium ion
was chosen as counterion.
for different host hydrogens of any given hosteguest system
did not differ much from one another. This is reflected by
the relative standard deviation of the K11 values for the differ-
ent hydrogens of a given hosteguest system. Relative standard
deviations were obtained for each hosteguest system from the
standard deviation of the experimental log K11 values by divi-
sion with the average log K11 of the respective hosteguest sys-
tem. The relative standard deviation of the log K11 values was
thus found to be for all hosteguest systems within the range of
8ꢁ4%. Indeed, all fits were of high quality and showed no
evidence of 1:2 or 2:2 complex formation, as it was described
for other hosts previously.5
Table 1 shows K11 values for the new hosts and four previ-
ously described bis-thioureas.5,7 As reported earlier, the higher
acidity of the thiourea hydrogens correlates with stronger
anion binding.5,7 This explains the higher K11 values for the
more acidic phenyl-substituted hosts 1b and 2b in comparison
to the butyl-substituted 1a and 2a analogues, respectively.
Phenyl groups are well known to increase the acidity of the
thioureas (pKa of (H2N)2CS: 21.0; pKa of (PhNH)2CS: 13.5;
in DMSO at 25 ꢂC).23 To make a meaningful comparison pos-
sible, all other bis-thiourea hosts investigated in this study are
also phenyl-substituted.
Representative titration curves are shown in Figure 4 for the
naphthylene derivative 5. As for all other hosteguest systems,
binding of the anion guests to this host resulted in changes in
the chemical shifts of more than one hydrogen. For most hosts,
not only nitrogen-bound hydrogens of the thiourea groups but
also carbon-bound hydrogens exhibited chemical shift changes
upon anion binding. Even though the changes in the chemical
shifts of the carbon-bound hydrogens (e.g., bottom panel of
Fig. 4) were always significantly smaller than for nitrogen-
bound hydrogens (e.g., top panel, Fig. 4), the sharpness of
the signals provided for titration curves of high quality.
Figure 4 shows titration curves for only two hydrogens of
host 5, but for each of the three guest anions titration curves
could be obtained for four different host hydrogens. Due to
the different structures of the hosts and occasional signal over-
lap, the number of individual titration curves for each of the 23
newly investigated hosteguest systems varied. However, for
22 of the 23 systems, titration curves for at least three different
hydrogens could be obtained. The resulting data were fitted
with an appropriate binding isotherm model, as reported
previously.5,7
While the chemical shifts of different hydrogens of a given
host changed to a different extent upon addition of a given an-
ion, these changes are the result of the same macroscopic
binding event. Therefore, fitting of the titration curves of
different host hydrogens for any given hosteguest pair is
expected to give within error the same binding constant. In-
deed, experimentally determined binding constants obtained
Host 1b is a meta-substituted phenylene derivative, and host
4 is its para-substituted analogue. Binding of H2POꢀ4 to 4 is
weaker by two orders of magnitude than in the case of 1b.
Host 4 was tested with the expectation that it might discrimi-
nate better against smaller anions such as chloride. CPK
models24 suggested thatddespite the flexibility imparted by
the two methylene groupsdthe two thiourea groups could
not converge to bind small anions such as chloride. Indeed,
chloride binding is weak, but so is H2POꢀ4 , H2AsO4ꢀ, and
acetate binding. This may be the result not of geometric con-
straints but rather of electrostatic repulsion. In a complex in
which both thiourea groups interact with an oxoanion, the
latter has to be located in the electrostatically unfavorable
position above the phenyl ring.
The previously reported, less preorganized host 1b is found
to have a smaller affinity for H2POꢀ4 than the new hosts 3 and
5 with their cyclohexylene and naphthylene-based spacers,
Table 1
Association constants (K11, Mꢀ1, in DMSO-d6) of hosts 1e8 with various
anions
Host
H2POꢀ4
H2AsOꢀ4
CH3COOꢀ
Clꢀ
1aa
1ba
2aa
2ba
3
820
4600
55,000
195,000
5500
2600
47
dc
dc
dc
dc
640
240
47
470
2300
3800
840
9
10
dc
1000
68
1200
370
3b
4
6500
19
33
520
5
5800
330
1100
23
16
6
350
20
Figure 4. Representative 1H NMR titrations: observed chemical shifts of NH
hydrogens (top) and the phenyl hydrogens in meta position to the thiourea sub-
stituents (bottom) of bis-thiourea 5 (1 mM, in DMSO-d6) upon addition of
tetrabutylammonium salts of various anion guests. Data for chloride binding
are not included since binding constants for this weakly binding anion had
to be determined at higher host and guest concentrations.
7b
8
1700
440
2700
dc
1200
dc
dc
140
a
Refs. 5 and 7.
Solvent: THF-d8/DMSO-d6 90:10.
Not determined.
b
c

A.N. Leung et al. / Tetrahedron 64 (2008) 2530e2536
2533
respectively. Importantly, the selectivities of anion binding of
1b, 3, and 5 clearly show size selectivity. On the one hand, the
low discrimination of chloride by 3 is consistent with the abil-
ity to form a rather small binding cavity. On the other hand,
the naphthylene-based spacer of host 5 puts a larger distance
between the two thiourea groups, resulting in the highest
H2POꢀ4 vs acetate selectivity of 1b, 3, and 5.
Of all the bis-thioureas, the highly preorganized hosts 2a
and 2b with their xanthene spacers bind H2POꢀ4 most strongly.
Both compounds have a spacer between their thiourea groups
with similar atom connectivity as host 6, which binds this
oxoanion much more weakly. Steric repulsion between the hy-
drogens bound to the two methylsubstituted aromatic rings of
6 prevent the near coplanarity that is possible for the two C6
rings in the xanthene unit of 2a and 2b.
are well confirmed, it can be expected that H2AsOꢀ4 is also
a good hydrogen bond acceptor and will form stable com-
plexes with hydrogen bond donating hosts. Because H2PO4ꢀ
and H2AsOꢀ4 have very similar basicities, it appears that the
H2AsOꢀ4 selectivity evident from Table 1 is caused by the
larger size of this oxoanion. This is illustrated by the crystal
structures of Ca[H2AsO4]2 and Ca[H2PO4]2.26,27 In the former,
the average AseO bond is 169 pm long, while the average Pe
O bond in the latter is only 154 pm. Similarly, in H2AsO4ꢀ the
average distance between two hydrogen-bonded oxygens is
275 pm, while the corresponding average O/O distance in
H2PO4ꢀ is 251 pm. Interestingly, there is indication from crys-
tal structures that the AsOꢀ4 tetrahedron is more easily distorted
than the POꢀ4 tetrahedron.28 This suggests that size selectivity
may be used to prepare even more selective H2AsOꢀ4 hosts us-
ing a higher degree of host preorganization. This is particularly
interesting in view of the toxicity of arsenate and the fact that
even nature has not developed systems with a more than mar-
ginal H2AsOꢀ4 vs H2POꢀ4 binding selectivity.
Table 1 also shows a very distinct difference in the selectiv-
ities of host 3 in pure DMSO-d6 and in THF-d8/DMSO-d6 9:1.
While in DMSO-d6 chloride is discriminated by nearly two
orders of magnitude, chloride is the preferred ion in the solvent
mixture. Even though not anticipated to this extent, this effect
is expected. Strong ionedipole interactions between chloride
and DMSO are known (DG0 in the gas phase for
ClꢀþDMSO5Clꢀ$DMSO: 52.3 kJ/mol).29 Therefore, specific
solvation of chloride in DMSO lowers the observed affinity of
bis-thiourea hosts in DMSO-d6. Also, since pKa values are
biased by solvation effects, chloride is a better hydrogen bond
acceptor than its pKa of ꢀ6.1 might suggest. The free energies
of hydration DG00,1 in the gas phase (in kJ/mol; CH3COOꢀ: 39;
Clꢀ: 34; H2PO4ꢀ: 32)30 show that chloride is a very good hydro-
gen bond acceptor. This explains at least partly the high chlo-
ride selectivity of ion-selective electrodes based on host 2a.8
To test whether the introduction of two additional thiourea
groups can result in strong oxoanion binding without the need
for a highly rigid host structure, tetrakis-thiourea 7 was pre-
pared. This host was found to be rather insoluble in DMSO-
d6. Therefore, the stability of its complexes was determined
with THF-d8/DMSO-d6 9:1 as solvent. For comparative pur-
poses, the stabilities of complexes of 3 were determined in
the same solvent mixture. As Table 1 shows, the difference
between the stabilities of the H2POꢀ4 complexes of 3 in pure
DMSO-d6 and in THF-d8/DMSO-d6 9:1 is rather small. This
suggests that even if the experiment could be performed, tetra-
kis-thiourea 7 would not bind H2POꢀ4 in DMSO-d6 more
strongly than 2a or 2b do, and is more evidence for the impor-
tance of the high level of host preorganization in 2a and 2b.
However, this does not mean that the third and fourth thiourea
groups are not affected by H2POꢀ4 binding. In the NMR titra-
tions, the chemical shifts of their NH hydrogens clearly in-
creased by several parts per million with addition of anions.
Moreover, tetrakis-thiourea 7 has a notably larger H2PO4ꢀ
affinity than its synthetic precursor 8, which has an identical
structure around its two central thiourea groups but two ure-
thane groups replacing the two peripheral thiourea groups.
An explanation for these findings may be that 7 and 8 form in-
tramolecular hydrogen bonds that must be broken to permit
binding of H2POꢀ4 , thereby lowering the H2POꢀ4 affinity of
these hosts. The fact that the carbonyl group of 8 is a stronger
hydrogen bond acceptor than the thiocarbonyl group of 7
would be consistent with the weaker binding of H2POꢀ4 by
8. Indeed, even conformations of bis-thiourea hosts with intra-
molecular hydrogen bonds between the two thiourea groups
are conceivable. While they would not affect binding selectiv-
ities, they would lower anion binding affinities overall.
Tetrakis-thiourea 7 is remarkable in that it has a strong af-
finity for H2AsOꢀ4 , which it binds preferentially over H2POꢀ4 .
While the cis-1,2-cyclohexylene host 3 and naphthylene deriv-
ative 5 exhibit H2POꢀ4 vs H2AsOꢀ4 selectivity, these two bis-
thioureas also bind H2AsOꢀ4 quite strongly. The formation of
complexes between thiourea hosts and these oxoanions is
not surprising. H3AsO4 (pKa 2.26) and H3PO4 (pKa 2.16)
have very similar pKa values,25 suggesting similar properties
of the corresponding mono-anions as hydrogen bond accep-
tors. Since the hydrogen bond acceptor properties of H2PO4ꢀ
3. Conclusion
In conclusion, the results from this study put the popularity
of the meta-xylylene spacer into perspective. While the limited
added advantages of the naphthylene spacer may not justify the
extra synthetic effort, the cis-1,2-cyclohexylene spacer is read-
ily available and offers, in view of selectivity, an interesting al-
ternative. This study also confirms the exceptional advantages
of the highly preorganized xanthene spacer. Knowing the effect
of cavity size on the anion selectivities of these bis-thioureas
will be useful in the design of hosts with multiple thiourea
groups. Interestingly, tetrakis-thiourea 7 is uniquely H2AsO4ꢀ
selective. To the best of our knowledge, this is the first
synthetic host that preferentially binds H2AsOꢀ4 vs H2PO4ꢀ.
4. Experimental
4.1. Synthesis of bis-thiourea hosts 3e6
Bis-thiourea hosts 3e6 were prepared in good yields from
the appropriate diamines according to a procedure previously

2534
A.N. Leung et al. / Tetrahedron 64 (2008) 2530e2536
described for 1b.5,7 Specifically, solutions of the diamines in
EtOH (dried over molecular sieves) were cooled to 0 ꢂC. A so-
lution with 2 equiv of phenyl isothiocyanate was then added
slowly. The reaction solutions were stirred for at least another
12 h, at first for about 3 h at 0 ꢂC and subsequently at room
temperature. 2,7-Bis(aminomethyl)naphthalene required for
the synthesis of 5 was obtained by dibromination of 2,7-dime-
thylnaphthalene, conversion to the diazide, and reduction to
the diamine.21 The bis-thioureas were purified by chromatog-
raphy on silica gel using methylene chloride/ethyl acetate as
eluent.
4.2. tert-Butyl 3-(isothiocyanatomethyl)benzylcarbamate, 9
Isothiocyanate 9 was prepared in a modification of a litera-
ture procedure.22 The mono-protected diamine tert-butyl 3-
(aminomethyl)benzylcarbamate (0.99 g, 4.1 mmol) in ethyl
acetate (20 mL) was added dropwise to a solution of 1,10-thio-
carbonyldiimidazole (0.77 g, 4.3 mmol) in ethyl acetate
(20 mL). After stirring for 16 h at room temperature and dilu-
tion with ethyl acetate (50 mL), the reaction mixture was
washed with water and brine. The resulting solution was dried
over MgSO4, concentrated, and purified by column chroma-
tography with hexane/ethyl acetate (3:1) as eluent to yield
a white solid (0.79 g, 69% yield). 1H NMR (300 MHz,
CDCl3): d 7.39 (t, 1H, J¼7.8 Hz, ArCH), 7.28 (m, 3H,
ArCH), 4.98 (br, 1H, NH), 4.74 (s, 2H, CH2NCS), 4.35 (br,
2H, CH2NH), 1.49 (s, 9H, CH3).
4.1.1. N,N00-cis-1,2-Cyclohexanediylbis[N0-phenyl-
thiourea], 3
1H NMR (300 MHz, DMSO-d6): d 9.66 (br, 2H, NH), 7.57
(d, 2H, J¼4.2 Hz, NH), 7.50 (d, 4H, J¼4.5 Hz, Ph), 7.28 (t,
4H, J¼4.8 Hz, Ph), 7.06 (t, 2H, J¼4.5 Hz, Ph), 4.66 (br, 2H,
CHNH), 1.80e1.40 (m, 8, CH2). 13C NMR (75 MHz,
DMSO-d6): d 180.3, 139.7, 128.9, 124.3, 122.8, 52.8, 28.6,
22.2. ESI-MS, m/z calcd for C20H25N4S2, [MþH]þ:
385.1521; found: 385.1497.
4.3. [[1,3-Phenylenebis(methylene)]bis[thioureylene[1,3-
phenylenebis(methylene)]]]biscarbamic acid dibutyl ester, 8
A solution of m-xylylenediamine (0.137 g, 1.01 mmol) in
dried EtOH (70 mL) was chilled in an ice bath. A solution
of isothiocyanate 9 (0.531 g, 1.91 mmol) in dry EtOH
(10 mL) was added dropwise to the m-xylylenediamine solu-
tion. The reaction was allowed to reach room temperature
and stirred for 10 h. The cloudy white solution was concen-
trated by evaporation in vacuo at 45 ꢂC, and the compound
was purified by column chromatography with CH2Cl2/
EtOAc/EtOH (6:2:1) to yield a white solid (0.332 g, 50%).
1H NMR (300 MHz, DMSO-d6): d 7.95 (br, 4H, NH), 7.41
(t, H, J¼6.3 Hz, ArCH), 7.27 (m, 2H, ArCH), 7.16 (m, 9H,
ArCH), 4.68 (br, 10H, CH2 and NHCO), 4.11 (d, 4H,
J¼6.0 Hz, CH2NHCO), 1.41 (s, 18H, CH3). 13C NMR
(75 MHz, DMSO-d6): d 140.7, 139.7, 128.7, 126.7, 126.1,
125.9, 75.6, 43.8, 47.7, 28.7. ESI-MS, m/z calcd for
C36H49N6O4S2, [MþH]þ: 693.3257; found: 693.3292.
4.1.2. N,N00-[1,4-Phenylenebis(methylene)]bis[N0-
phenylthiourea], 4
1H NMR (300 MHz, DMSO-d6): d 9.66 (br, 2H, NH), 8.20
(br, 2H, NH), 7.44 (d, 4H, J¼7.5 Hz, Ph), 7.35 (t, 4H,
J¼7.5 Hz, Ph), 7.33 (s, 4H, phenylene), 7.11 (t, 2H,
J¼7.5 Hz), 4.72 (d, 4H, J¼5.1 Hz, CH2). 13C NMR
(75 MHz, DMSO-d6): d 181.0, 139.5, 138.0, 129.0, 127.7,
124.6, 123.7, 47.2. ESI-MS, m/z calcd for C22H23N4S2,
[MþH]þ: 407.1364; found: 407.1333.
4.1.3. N,N00-[2,7-Naphthalenediylbis(methylene)]bis[N0-
phenylthiourea], 5
1H NMR (300 MHz, DMSO-d6): d 9.71 (br, 2H, NH), 8.31
(br, 2H, NH), 7.90 (d, 2H, J¼8.5 Hz, naphthyl), 7.80 (s, 2H,
naphthyl), 7.51 (d, 2H, J¼8.5 Hz, naphthyl), 7.47 (d, 4H,
J¼7.8 Hz, Ph), 7.36 (t, 4H, J¼7.5 Hz, Ph), 7.14 (t, 2H,
7.5 Hz, Ph), 4.92 (d, 4H, J¼5.1 Hz, CH2). 13C NMR
(75 MHz, DMSO-d6): d 181.2, 139.5, 137.3, 133.1, 131.6,
129.0, 128.0, 126.0, 125.7, 124.7, 123.7, 47.6. ESI-MS, m/z
calcd for C26H25N4S2, [MþH]þ: 457.1521; found: 457.1495.
4.4. N,N00-[1,3-Phenylenebis(methylene)]bis[N0-[3-[N0-
phenylthioureylene]-1,3-phenylenebis(methylene)]-
thiourea], 7
Bis-thiourea 8 (0.189 g, 0.27 mmol) was suspended in
CH2Cl2 (20 mL) to form a cloudy white solution, and tri-
fluoroacetic acid (3.0 mL) was added dropwise. The reaction
solution was allowed to stir for 12 h before evaporation of
the solvent. To remove traces of trifluoroacetic acid, 10 mL al-
iquots of THF were added three times, which was each time
followed by complete evaporation of the solvent. The raw
product of the resulting diamine was used without further pu-
rification. It was dissolved in THF (20 mL), and triethylamine
(0.160 mL, 3.0 mmol, dried over molecular sieves) and phenyl
isothiocyanate (0.128 mL, 2.8 mmol) were added. After stir-
ring the reaction solution for 20 h, the solvent was evaporated
and the raw product was purified by column chromatography
with CH2Cl2/EtOAc/EtOH (18:4:1) to yield 7 as a white solid
4.1.4. 1,10-[[2,2,2-Trifluoro-1-(trifluoromethyl)-
ethylidene]bis(6-methyl-3,1-phenylene)]-
bis[N0-phenylthiourea], 6
1H NMR (300 MHz, DMSO-d6): d 9.84 (s, 2H, NH), 9.37
(s, 2H, NH), 7.45 (d, 4H, J¼7.8 Hz, Ph), 7.33 (m, 8H, overlap
of two signals from trisubstituted phenyl ring and one signal
from Ph), 7.15 (m, 4H, overlap of triplet from Ph and doublet
from trisubstituted phenyl ring), 2.28 (s, 6H, CH3). 13C NMR
(75 MHz, DMSO-d6): 180.1, 139.6, 138.3, 136.4, 130.8,
130.0, 129.6, 128.8, 127.8, 124.9, 124.1, 17.8. Due to
19Fe13C coupling, the signals for C(CF3)2 and CF3 are
expected to consist of 7 and 16 peaks, respectively, and
were too small to be observed. ESI-MS, m/z calcd for
C31H27F6N4S2, [MþH]þ: 633.1581; found: 633.1602.
1
(0.081 g, 64%). H NMR (300 MHz, DMSO-d6): d 9.66 (br,
2H, NH), 8.19 (br, 2H, NH), 7.99 (br, 4H, NH), 7.45 (d, 2H,

A.N. Leung et al. / Tetrahedron 64 (2008) 2530e2536
2535
2. Smith, P. J.; Reddington, M. V.; Wilcox, C. S. Tetrahedron Lett. 1992, 33,
6085.
J¼7.8 Hz, ArCH), 7.23 (m, 20H, ArCH), 4.71 (m, 12H, CH2).
13C NMR (75 MHz, DMSO-d6): d 181.1, 139.5, 139.2, 138.9,
128.7, 128.6, 126.7, 126.5, 126.4, 124.7, 123.7, 47.8. ESI-MS,
m/z calcd for C40H41N8S4, [MꢀH]ꢀ: 761.2337; found:
761.2356.
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53, 1647.
Tetrabutylammonium dihydrogen arsenate was prepared by
titration of an aqueous solution of arsenic(V) oxide with tetra-
butylammonium hydroxide to the first equivalence point,
washing of the resulting solution with chloroform, and freeze
drying of the aqueous phase.31 All other inorganic anions were
commercially available as tetrabutylammonium salts and were
thoroughly dried in vacuo prior to use. DMSO-d6 was dried
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˚
over molecular sieves (3 A).
4.5.2. Determination of complexation constants by 1H NMR
spectroscopy
1H NMR spectra were obtained on a Varian Inova 300 or
Varian Unity 300 spectrometer (300 MHz; Varian, Palo Alto
CA). All chemical shift values (d) are reported in parts per
1
million (ppm). For H NMR titrations, two stock solutions
were prepared in DMSO-d6, one of them containing host
only and the second one host of the same concentration and
an appropriate concentration of guest. Aliquots of the two so-
lutions were mixed directly in NMR tubes, minimizing exper-
imental error, and H2O contamination. Insufficient mixing
would be readily recognizable in the resulting titration curves
by broad signals and poor fits. It was carefully avoided, giving
data of the type shown in Figure 4 and in Ref. 5. All experi-
mental data obtained by these methods were analyzed using
MathematicaÒ 6.0 with an appropriate binding isotherm
model.32
13. Boerringer, H.; Grave, L.; Nissink, J. W. M.; Chrisstoffels, L. A. J.; van
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Acknowledgements
15. Benito, J. M.; Gomez-Garcia, M.; Blanco, J. L.; Mellet, C. O.; Fernandez,
J. M. G. J. Org. Chem. 2001, 66, 1366; Dahan, A.; Ashkenazi, T.; Kuznet-
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This work was partially supported by the National Institute
of Health (1R01 EB005225-01) and an NSF Research Experi-
ence for Undergraduates fellowship to A.N.L. Trevor Bieber
and Mary Messner are gratefully acknowledged for their assis-
tance with the preparation of host compounds.
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