Synthesis and anion-selective complexation of homobenzylic tripodal thiourea derivatives

Article abstract of DOI:10.1002/ejoc.200600647

Cryptand- and tripod-type thiourea derivatives 4b and 5a-d, which have binding functionalities at the homobenzylic positions, were synthesized as possible neutral receptors toward anions with an expectation that the three binding sites work cooperatively to bind an anion selectively. ¹H NMR spectroscopic monitoring of the titration of cryptand 4b with CH ₃CO₂^-, Cl^-, and F^- in CDCl₂CDCl₂ at 100°C showed that the binding constants were considerably smaller than those of tripodal thiourea 5a, presumably owing to the presence of strong intramolecular hydrogen bonding in 4b. Complexation constants of tripodal receptors 5a-d with H₂PO₄ ^-, CH₃CO₂^-, Cl^-, and Br^- anions were evaluated by ¹H NMR and/or UV/Vis spectroscopic analysis of the titration in DMSO. Though tripodal receptors 5a,b undergo complexation with phosphate anion in a 1:1 stoichiometry, their association constants were not as large as simple reference compound 14 probably because of the steric hindrance around the binding sites and the large entropy cost for cooperative binding. Receptor 5c exhibits complexation in a 1:2 stoichiometry with H₂PO₄^- and CH ₃CO₂^-, whereas it forms 1:1 complexes with chloride and bromide anions because of the subtle balance between the steric hindrance and the binding ability. However, by increasing the acidity of the thiourea functionality, receptor 5d exhibited remarkably enhanced binding ability and selectivity toward H₂PO₄^- compared to those of reference compound 15 presumably through cooperative complexation of the three binding sites to the guest anion. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600647

FULL PAPER
DOI: 10.1002/ejoc.200600647
Synthesis and Anion-Selective Complexation of Homobenzylic Tripodal
Thiourea Derivatives
Ichiro Hisaki,[a][‡] Shin-ichi Sasaki,[a][‡‡] Keiji Hirose,[a] and Yoshito Tobe*[a]
Keywords: Anions / Cryptands / Host–guest systems / Hydrogen bonds / Receptors
Cryptand- and tripod-type thiourea derivatives 4b and 5a–
d, which have binding functionalities at the homobenzylic
positions, were synthesized as possible neutral receptors to-
ward anions with an expectation that the three binding sites
work cooperatively to bind an anion selectively. 1H NMR
spectroscopic monitoring of the titration of cryptand 4b with
CH3CO2–, Cl–, and F– in CDCl2CDCl2 at 100 °C showed that
the binding constants were considerably smaller than those
of tripodal thiourea 5a, presumably owing to the presence of
ciation constants were not as large as simple reference com-
pound 14 probably because of the steric hindrance around
the binding sites and the large entropy cost for cooperative
binding. Receptor 5c exhibits complexation in a 1:2 stoichi-
ometry with H2PO4– and CH3CO2–, whereas it forms 1:1 com-
plexes with chloride and bromide anions because of the sub-
tle balance between the steric hindrance and the binding
ability. However, by increasing the acidity of the thiourea
functionality, receptor 5d exhibited remarkably enhanced
–
strong intramolecular hydrogen bonding in 4b. Complex- binding ability and selectivity toward H2PO4 compared to
–
ation constants of tripodal receptors 5a–d with H2PO4
,
those of reference compound 15 presumably through cooper-
ative complexation of the three binding sites to the guest
anion.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
CH3CO2–, Cl–, and Br– anions were evaluated by 1H NMR
and/or UV/Vis spectroscopic analysis of the titration in
DMSO. Though tripodal receptors 5a,b undergo complex-
ation with phosphate anion in a 1:1 stoichiometry, their asso-
Introduction
of neutral receptors are weaker than the positively charged
receptors and they are sensitive to the circumstances, for
example polarity of solvents. One of the strategies used to
design receptors which recognize a guest anion strongly and
selectively is to increase dimensions of their structures in
order to arrange the binding sites in an appropriate position
for complexation (i.e. preorganization). Indeed, it is well-
known for cation receptors that the structural dimension of
host molecules plays a significant role in the recognition of
guest species; receptors with higher structural dimension
tend to exhibit larger binding ability and selectivity toward
cations. For example, cyclic 18-crown-6 exhibits an associa-
tion constant towards K+ that is 7,000-fold larger than that
of the corresponding acyclic polyether (i.e. pentaglyme),
and the corresponding cryptand binds with a strength that
is more than 600,000-fold stronger than 18-crown-6.[12]
According to this concept, we[13] and others[10,14] have
Elucidation of basic principles for anion recognition and
development of highly selective receptors toward anionic
species have been attracting much interest in supramo-
lecular chemistry during the last two decades from the view
point of chemical, biological, and environmental pro-
cesses.[1] A number of anion receptors have been reported
so far which have various functional groups as anion bind-
ing sites. These include positively charged functional groups
such as ammonium,[2] guanidinium,[3] pyridinium,[4] and
imidazolium[5] ions, as well as coordinatively unsaturated
metal ions.[6] For neutral hydrogen-bond donor groups,
amides,[7] sulfonamides,[8] ureas,[9] thioureas,[10] and pyr-
roles[11] are employed. Neutral anion receptors capable of
hydrogen bonding to anions have been extensively studied
because counterion interferences do not have to be consid-
ered and hydrogen bonding exerts directional interactions
with certain anions. On the other hand, the binding abilities been studying neutral receptors having thiourea moieties as
binding sites to develop new selective receptors for anions.
[a] Division of Frontier Materials Science, Graduate School of
Previously, we reported that two-dimensional cyclophane-
Engineering Science, Osaka University,
based receptors such as 1 and 2 (Scheme 1), in which bind-
ing sites are appropriately preorganized for complexation
with guest anions, showed much larger association con-
stants than those of the corresponding acyclic receptor. Es-
pecially, the association constant of lariat-type receptor 2
with a phosphate anion was more than 20 times larger than
that of the acyclic one.[13b]
1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
[‡] Current address: Department of Material and Life Science,
Graduate School of Engineering, Osaka University,
Yamadaoka, Suita, Osaka 565-0871, Japan
[‡‡] Current address: Department of Bioscience and Biotechnology,
Ritsumeikan University,
Kusatsu, Shiga 525-8577, Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 607–615
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
607

I. Hisaki, S.-i. Sasaki, K. Hirose, Y. Tobe
FULL PAPER
interesting to see whether the cooperative effect of multiple
binding sites would work even in the more flexible homo-
benzylic systems. In this context, we describe here the syn-
thesis of cryptand- and tripod-type thiourea derivatives 4b
and 5a–d and their anion binding abilities.
Scheme 2. Tripodal receptors having benzylic thiourea groups.
Results and Discussion
Preparation of the Receptors
First, synthesis of cryptand-type receptor 4a having
methyl groups at the 2,4,6-positions of the benzene ring was
attempted as shown in Scheme 3 and Scheme 4. Substitu-
tion of tribromide 7[23] with KCN followed by reduction
with LiAlH4 in the presence of AlCl3 gave triamine 8a in
44% yield over two steps. After conversion of 8a to isothio-
cyanate 9a by treatment with DCC and CS2 (50% yield),
Scheme 1. Anion receptors with thiourea groups.
Molecular designs along the above line led to cage cyclization between 8a and 9a was carried out in CHCl3
(“cryptand”) structure 3. However, molecular modeling ex- under dilute conditions (Scheme 4). As a result, white solid
amination revealed that the thiourea linkages of 3 are so precipitated from the solution, which turned out to include
rigid that all of the N–H groups could not orient inside the 4a and higher oligomers, as judged from the FAB mass
cage. In this respect, we designed “homobenzylic” cryp- spectra of the solid. However, it was not possible to sepa-
tands 4a,b in which the thiourea group can rotate freely. We rate cyptand 4a from the oligomers owing to their low solu-
also designed tripod-type host molecules 5a–d. Although bilities in common organic solvents. In order to solve this
these do not have a three-dimensional structure, all three solubility problem, receptor 4b carrying isopentyl groups
binding sites attached to the 1,3,5-positions on the benzene instead of methyl groups was prepared. Thus, the cross
ring of 5a–d are expected to orient to one of the faces of coupling reaction of 1,3,5-trichlorobenzene (10) with iso-
the ring because of steric repulsion between the neighboring pentylmagnesium bromide with NiCl2(DPPP) as the cata-
substituents,[15] which thereby creates a three-dimensional lyst[24] gave 1,3,5-tris(3-methylbutyl)benzene (11) in 75%
binding site like that in cryptand-like 4. Indeed, a number yield.[25] Chloromethylation of 11 with chloromethyl methyl
of tripodal receptors possessing binding functionalities at ether catalyzed by conc. H2SO4 gave trichloride 12 in 12%
the benzylic positions have already been synthesized and yield. Cyanation of 12 by NaCN in DMSO followed by
their binding ability toward ammonium cations,[16] (spheri- reduction of the cyanide by hydrogenation with catalytic
cal) anions,[10f,17] carboxylates,[18] sugar-based anions,[19] platinum oxide gave corresponding triamine 8b in 94%
sugar derivatives,[20] and others[21] have been investigated.[22] yield over the two steps. Triamine 8b was converted to iso-
Moreover, in regard to tripodal receptors having thiourea thiocyanate 9b by treatment with DCC and CS2 in 51%
groups, Suzuki et al. reported that compounds 6a and 6b, yield. Finally, cyclization of 8b and 9b was carried out un-
which have benzylic thiourea groups and fluorescent chro- der dilute conditions to give cryptand-type receptor 4b in
mophores bind H2PO4– selectively (Scheme 2).[10f] However, 61% yield. Tripodal receptors 5a–d were prepared by the
there is no report of the receptors having any binding func- reactions of triamine 8b with corresponding commercially
tionalities at the “homobenzylic” positions. It would be available isothiocyanates 13a–d (a: R = n-butyl, b: R = ben-
608
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 607–615

Synthesis of Homobenzylic Tripodal Thiourea Derivatives
FULL PAPER
Scheme 3. Synthesis of hexasubstituted benzene derivatives 8a,b and 9a,b.
zyl, c: R = phenyl, d: R = p-nitrophenyl) in 40%, 57%, probably because of its slow conformational change on the
80%, and 80% yields, respectively (Scheme 5). Model com- NMR timescale owing to the relatively rigid three-dimen-
pounds 14[26] and 15[27] were also prepared by reaction of sional cyclophane structure and intramolecular hydrogen
appropriate amines and isothiocyanates (88% and 73% bonds between the thiourea functionalities. In less polar
yields, respectively)
solvents such as CDCl3 and CDCl2CDCl2, the signals of 4b
were barely sharp enough to determine exact chemical
shifts. Moreover, because the thiourea binding site of 4b is
not electronically conjugated with an aromatic chromo-
phore, spectral changes in the UV spectrum of 4b were not
expected to be sufficient to determine complexation con-
stants with the anions. For these reasons, titration experi-
ments of 4b toward anionic species were carried out at
100 °C in CDCl2CDCl2 by using NMR spectroscopy and
the binding constants were compared with those of tripodal
thiourea 5a (vide infra). Prior to the titration, the absence
of concentration dependence on the chemical shifts of 4b
and 5a was checked, and the possibility of intermolecular
hydrogen bonding between their thiourea groups was thus
excluded. Because the NH proton signal became signifi-
cantly broad upon addition of a guest anion, the titration
was carried out following the chemical shift change of the
methylene protons adjacent to the NH group. Though the
chemical shift change with bromide, nitrate, hydrogensul-
fate, and perchlorate anions was too small to determine the
binding constants, reliable results were obtained with ace-
tate, chloride, and fluoride.[28] The association constants
that were determined assuming a 1:1 binding stoichiometry
are listed in Table 1.[29] In spite of our expectation, the bind-
ing constants of 4b were much smaller than those of 5a,
which suggests the absence of cooperative anion binding.
Moreover, neither 4b nor 5a exhibits binding selectivity to-
ward the anions, except for the small selectivity of 5a to-
ward chloride anion. The lower binding ability of 4b than
that of acyclic 5a is attributed to the presence of strong intra-
molecular hydrogen bonding in the nonpolar solvent which
hinders the competitive anion binding.
Scheme 4. Synthesis of cryptands 4a,b.
Scheme 5. Synthesis of tripods 5a–d and the structures of model
compounds 14 and 15.
Complexation with Guest Anions
On the other hand, tripodal thiourea derivatives 5a–d are
1
To investigate complexation of cryptand-type receptor 4b readily soluble and gave unambiguous H NMR signals in
with anionic species, 1H NMR spectroscopic monitoring of [D6]DMSO solution, which allowed for the determination
1
the titration experiment of 4b was carried out in [D6]- of the complexation constants by H NMR spectroscopy.
DMSO. However, the observed H NMR signals of 4b in For host 5d, UV/Vis spectra can also be used because the
1
[D6]DMSO were very broad even at high temperatures, thiourea group is directly linked to the p-nitrophenyl chro-
Eur. J. Org. Chem. 2007, 607–615
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
609

I. Hisaki, S.-i. Sasaki, K. Hirose, Y. Tobe
FULL PAPER
Table 1. Association constants (–1) of cryptand-type receptor 4b
Table 2. Association constants (–1) of tripodal receptors 5a–c and
model compound 14.[a]
and tripodal receptor 5a.[a]
Anion[b]
4b
5a
Anion[b]
5a
5b
5c
14
–
–
CH3CO2
Cl–
116Ϯ9
112Ϯ3
93Ϯ10
3030Ϯ330
3700Ϯ430
1770Ϯ89
H2PO4
87Ϯ4
90Ϯ5
52Ϯ4
56000Ϯ23000[c] 128Ϯ14
–
CH3CO2 44Ϯ3
52000Ϯ5000[c]
9.5Ϯ0.7
351Ϯ28
F–
Cl–
Br–
6.8Ϯ0.4 11Ϯ1
2.2Ϯ0.1 1.4Ϯ0.1
ND[d]
1.80Ϯ0.07
ND[d]
[a] Determined by 1H NMR spectroscopy in CDCl2CDCl2 at
373 K. [b] Used as a tetrabutylammonium salt.
1
[a] Determined by H NMR spectroscopy in [D6]DMSO at 303 K.
[b] Used as a tetrabutylammonium salt. [c] Assuming the complex-
ation of the host and guest in a 1:2 stoichiometry. The unit is given
in –2. [d] Not determined.
mophore. First, the stoichiometry of the complexations of
–
5a,b with Bu4N+H2PO4 was investigated by the Job’s plot
1
by using H NMR spectra as shown in Figure 1 for 5b. It
is revealed that both 5a and 5b bind H2PO4 with a 1:1
stoichiometry, which indicates that three thiourea moieties
in these host molecules cooperatively bind one guest anion.
To determine the association constants of hosts 5a and 5b
with anions, titration experiments by 1H NMR spec-
–
other hand, the Job’s plot revealed that receptor 5c binds
spherical anions, Cl– and Br–, in a 1:1 stoichiometry. These
results indicate that the bulky phenyl groups directly at-
tached to the binding sites interfere with the cooperative
complexation of a nonspherical anion for steric reasons; ac-
cordingly the binding sites interact with the anions indepen-
dently. Such a subtle balance between steric hindrance and
binding ability of the host, and the geometry of the guests
is not fully understood. The association constants toward
H2PO4 and CH3CO2 were estimated assuming a 1:2 com-
plexation [Ka = (56000Ϯ23000) –2, and (52000Ϯ5000)
–2, respectively], while those toward Cl– and Br– with a 1:1
complexation [Ka = (9.5Ϯ0.7) –1, (1.80Ϯ0.07) –1,
respectively].
–
troscopy were undertaken with the use of H2PO4 ,
–
CH3CO2 , Cl–, and Br– as the corresponding Bu4N+
salts.[30] The chemical shift change of the NH proton in the
thiourea group was used for determination of the binding
constants. The results are shown in Table 2. Receptors 5a
–
–
–
–
and 5b bind H2PO4 most strongly, followed by CH3CO2 ,
Cl–, and Br–. The binding constants of receptor 5b are al-
most identical to those of 5a, which indicates little effect of
the terminal benzyl group upon complexation. Moreover,
the binding constants of 5a and 5b toward H2PO4 and
CH3CO2 are obviously smaller than those of reference re-
–
–
ceptor 14 which has only one binding site. These facts indi-
cate that even though the three thiourea moieties that are
bonded to the 1,3,5-positions of the benzene ring partici-
pate in the complexation to a guest anion cooperatively, the
binding ability was not enhanced unlike benzylic thiourea
6b. This is probably due to the steric hindrance around the
binding site and the large entropy cost for cooperative bind-
ing.
Figure 2. Job’s plot for complexation of receptor 5c with acetate
anion.
In order for further investigation on the cooperative ef-
fect due to the homobenzylic tripod structure, the acidity
of NH in the thiourea group[31] was increased further by
introducing p-nitrophenyl groups.[14j,14f,32] In contrast to the
structurally similar tripodal receptor 5c, the Job’s plot (not
shown) using UV/Vis spectroscopy showed that 5d bound
H2PO4– and CH3CO2– with a 1:1 stoichiometry, which indi-
cates cooperative anion binding. The association constants
Figure 1. Job’s plot for complexation of receptor 5b with phosphate
anion.
To investigate if the cooperative effect due to the homo- of 5d as well as model compound 15 were determined by
benzylic tripod structure would elicit large and/or selective UV/Vis spectra[33] for H2PO4– and CH3CO2– in DMSO and
1
binding ability toward a specific anion when the interaction by H NMR spectra for Cl– and Br– in [D6]DMSO. The
between a host and a guest is strengthened, the acidity of results are summarized in Table 3. As we expected, the asso-
NH in the thiourea group was increased by introducing ciation constants of 5d became significantly larger than
–
phenyl groups. Contrary to our expectation, however, recep- those of 5a and 5b, particularly so for H2PO4 and
–
–
–
tor 5c formed complexes with H2PO4 and CH3CO2 in a CH3CO2 . The increase in the binding constants for Cl– and
1
1:2 stoichiometry, as indicated by the Job’s plot using H Br– was not as remarkable. As a result, 5d exhibits highly
NMR spectra as shown in Figure 2 for CH3CO2 . On the selective anion binding in the order CH3CO2
–
–
≈
610
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 607–615

Synthesis of Homobenzylic Tripodal Thiourea Derivatives
FULL PAPER
H2PO4– ϾϾCl– Ͼ Br–. It should be pointed out, however, tration of the guest anion (Figure 3a). On the other hand,
–
that model compound 15 also exhibits larger binding con- when CH3CO2 was used, the growth of a new band at
–
–
stants for H2PO4 and CH3CO2 compared with corre- 488 nm, much more redshifted than the new band observed
–
sponding model compound 14.
in the case of H2PO4 , was observed together with the decay
of the band at 361 nm (Figure 3b). The same behavior was
observed in the case of complexation of model compound
Table 3. Association constants (–1) of tripodal receptor 5d and
model compound 15.
–
–
15 with both H2PO4 (Figure 4a) and CH3CO2 (Fig-
ure 4b). These remarkably redshifted bands indicate the for-
mation of a thioureido anion arising from proton transfer
Anion[a]
5d
15
–
H2PO4
41000Ϯ8000[b]
51000Ϯ4000[b]
23.5Ϯ0.6[c]
3100Ϯ400[b]
40000Ϯ8000[b]
41.9Ϯ0.5[c]
4.5Ϯ0.1[c]
–
–
from the relatively acidic NH group in 5d and 15 to H2PO4
CH3CO2
Cl–
–
or CH3CO2 as shown in Figure 5.[32a,34] To confirm this
Br–
4.2Ϯ0.2[c]
possibility, we examined the UV/Vis spectral change of 5d
and 15 in the presence of a strong base such as NaOH. As
a result, upon addition of an equimolar amount of NaOH,
5d and 15 exhibited absorptions at 490 and 483 nm (Figures
S28 and S29 in Supporting Information), respectively,
which indicates that the complexation between 5d and
CH3CO2 and between 15 and both H2PO4 and CH3CO2
take place between the corresponding thioureido anion and
the neutral acids in a manner shown in Figure 5. The re-
markable larger binding constant of 5d with H2PO4 than
that of 15 is therefore ascribed to the cooperative hydrogen
bonding of the three binding sites of 5d. In contrast, the
binding constant of 5d with more basic CH3CO2 is in the
same order of magnitude as that of 15, presumably because
cooperative hydrogen bonding of the thiourea groups is not
possible owing to the formation of the thioureido anion.
Further design of suitable thiourea-based, anion-binding
host molecules with high structural dimension is currently
undertaken in our laboratories.
[a] Used as a tetrabutylammonium salt. [b] Determined by UV/
Vis spectroscopy in DMSO at 303 K. [c] Determined by H NMR
spectroscopy in [D6]DMSO at 303 K.
1
It should be pointed out that benzylic thioureas 6a and
6b are reported to a show slight preference for H2PO4– com-
–
–
–
–
pared with CH3CO2 , whereas their acyclic reference com-
pounds exhibit selectivity toward the latter anion,[10f] as ob-
served for 14 and 15. Even though 5d binds CH3CO2– more
strongly in contrast to 6a and 6b, the difference is negligible
when the experimental errors are taken into account. These
results suggest that the three thiourea groups of 5d bind an
anion cooperatively like 6a and 6b in spite of the larger
conformational flexibility of 5d.
–
–
In Figure 3 and Figure 4, the UV/Vis spectral changes of
–
–
5d and 15 upon complexation with H2PO4 and CH3CO2
–
are shown. When H2PO4 was used, the intensity of the
absorption band of 5d at 361 nm decreased, while the band
at around 382 nm increased with an increase in the concen-
Figure 3. UV/Vis spectral change of receptor 5d upon complexation with (a) tetrabutylammonium phosphate ([host] = 1.43ϫ10–5 –1,
0Յ[guest]Յ8.74ϫ10–5 –1) and (b) tetrabutylammonium acetate ([host] = 1.55ϫ10–5 –1, 0Յ[guest]Յ4.16ϫ10–5 –1).
Figure 4. UV/Vis spectral change of receptor 15 upon complexation with (a) tetrabutylammonium phosphate ([host] = 5.19ϫ10–5 –1,
0Յ[guest]Յ8.99ϫ10–4 –1) and (b) tetrabutylammonium acetate ([host] = 5.40ϫ10–5 –1, 0Յ[guest]Յ1.44ϫ10–4 –1).
Eur. J. Org. Chem. 2007, 607–615
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
611

I. Hisaki, S.-i. Sasaki, K. Hirose, Y. Tobe
FULL PAPER
1,3,5-Tris(2-aminoethyl)-2,4,6-trimethylbenzene (8a): A mixture of
tribromide 7[22] (21.5 g, 54.0 mmol) and potassium cyanide (17.6 g,
270 mmol) in DMSO (150 mL) was warmed to 60 °C and stirred
for 20 h at this temperature. The mixture was then poured into
water to give a precipitate, which was filtered, washed with water,
and dried. The product was purified by column chromatography
(silica gel, 50% AcOEt in benzene) to afford 10.4 g (81%) of 1,3,5-
tris(cyanomethyl)-2,4,6-trimethylbenzene as a white solid. M.p.
Figure 5. A complex of the thioureido anion of 15 with acetic acid.
212–214 °C. IR (KBr): ν = 2249, 803 cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 2.46 (s, 9 H), 3.73 (s, 6 H) ppm. To a suspension of
LiAlH4 (3.80 g, 100 mmol) in THF (250 mL) was added dropwise
a solution of AlCl3 (13.3 g, 100 mmol) in THF (200 mL), and the
mixture was stirred for 5 min at room temperature. A solution of
1,3,5-tris(cyanomethyl)-2,4,6-trimethylbenzene (2.37 g, 9.99 mmol)
in THF (150 mL) was added dropwise, and the mixture was heated
at reflux for 12 h. Water was added dropwise with cooling in an ice
bath and then 10% aqueous HCl was added. The mixture was
washed with diethyl ether, and the aqueous layer was made alkaline
Conclusions
In summary, we have prepared cryptand- and tripod-
shaped neutral receptors having thiourea groups as anion-
binding sites and examined their binding ability toward
–
guest anions. The binding constants of 4b with CH3CO2 ,
Cl–, and F– were considerably smaller than those of tripodal
thiourea 5a, presumably owing to the presence of strong
intramolecular hydrogen bonds in 4b. Although the three with 2  aqueous NaOH. To this solution was added CHCl3, and
the mixture was shaken vigorously. The resulting emulsion was
passed through a pad of Celite and the organic phase was sepa-
rated, washed with brine, dried with anhydrous MgSO4, filtered,
and concentrated to leave 1.35 g (54%) of 8a as a white solid, which
was used for the subsequent reaction without further purification.
binding sites of tripodal receptors 5a and 5b bind an anion
cooperatively, they showed unexpectedly small association
constants toward the anions, presumably owing to the steric
hindrance and the entropy cost for cooperative binding. On
the other hand, 5c exhibits complexation in a 1:2 stoichiom-
M.p. 109–111 °C. IR (KBr): ν = 3354, 878, 748 cm–1. 1H NMR
˜
–
–
etry with H2PO4 and CH3CO2 , whereas it binds in a 1:1
stoichiometry with chloride and bromide because of the
subtle balance between the steric hindrance and the binding
ability. Finally, as a result of enhanced acidity of the bind-
ing moieties, tripodal receptor 5d exhibits a 10-fold increase
in the association constant in the complexation with
H2PO4– than that of model compound 15 through coopera-
tive binding.
(300 MHz, CDCl3): δ = 1.26 (br. s, 6 H), 2.32 (s, 9 H), 2.83 (m, 12
H) ppm.
1,3,5-Tris(2-aminoethyl)-2,4,6-tris(3-methylbutyl)benzene (8b):
A
mixture of trichloride 12 (670 mg, 1.5 mmol) and sodium cyanide
(0.74 g, 15 mmol) in DMSO (10 mL) was warmed to 80 °C and
stirred for 1 h at this temperature. Water was added, and the reac-
tion mixture was extracted with ethyl acetate. The organic layer
was washed with water and brine, dried with anhydrous MgSO4,
filtered, and concentrated. The product was purified by column
chromatography (silica gel, benzene) to afford 615 mg (98%) of
1,3,5-tris(cyanomethyl)-2,4,6-tris(3-methylbutyl)benzene as a white
Experimental Section
solid. M.p. 193–194 °C. IR (KBr): ν = 2275, 920, 758 cm–1. 1H
˜
1
General: H NMR spectra were recorded with a JEOL JNM-AL-
NMR (300 MHz, CDCl3): δ = 1.05 (d, J = 6.6 Hz, 18 H), 1.40–
1.48 (m, 6 H), 1.73–1.83 (m, 3 H), 2.72–2.78 (m, 6 H), 3.68 (s, 6
H) ppm. MS (CI): m/z = 406 [M]+. C27H39N3 (405.62): calcd. C
79.95, H 9.69, N 10.36; found C 79.76, H 9.82, N 10.17. To a
suspension of 1,3,5-tris(cyanomethyl)-2,4,6-tris(3-methylbutyl)ben-
zene (100 mg, 0.25 mmol) in ethanol (30 mL) was added plati-
num(IV) oxide dehydrate (30 mg, 0.11 mmol) and concentrated
aqueous HCl (1 mL), and the reaction mixture was stirred for 60 h
at room temperature under an atmosphere of hydrogen. The mix-
ture was passed through a pad of Celite and the filtrate was concen-
trated. To the residue was added 10% aqueous HCl, and the solu-
tion was washed with diethyl ether. The aqueous phase was made
alkaline with 2  aqueous NaOH and extracted with CHCl3. The
extract was washed with water and brine, dried with anhydrous
MgSO4, filtered and concentrated to leave 100 mg (96%) of 8b as
a white solid, which was used for the subsequent reaction without
400 or a JEOL JNM-GSX-270 spectrometer in CDCl3, [D6]-
DMSO, or CDCl2CDCl2 with Me4Si as an internal standard. IR
spectra were recorded as a KBr disk or a neat film with a JASCO
FTIR-410 instrument. Mass spectral analysis was preformed with
a JEOL JMS-DX303HF instrument. Elemental analyses were per-
formed with a Perkin–Elmer 2400 II analyzer. Column chromatog-
raphy and TLC were performed using Merck silica gel 60 (70–
230 mesh ASTM) and Merck silica gel 60 F254, respectively. Prepar-
ative HPLC separation was undertaken with a JAI LC-908 chroma-
tograph by using 600-mmϫ20-mm JAIGEL-1H and 2H GPC col-
umns with CHCl3 as the eluent.
1,3,5-Tris(chloromethyl)-2,4,6-tris(3-methylbutyl)benzene (12): To a
solution of 1,3,5-tris(3-methylbutyl)benzene (11)[25] (6.40 g,
22.0 mmol) in chloromethyl methyl ether (50 mL) was added con-
centrated sulfuric acid (4 mL), and the reaction mixture was heated
at reflux for 10 h. Water was added with cooling in an ice bath,
and the mixture was extracted with diethyl ether. The organic layer
was washed with saturated aqueous NaHCO3 and brine, dried with
anhydrous MgSO4, filtered, and concentrated. The product was
purified by column chromatography (silica gel, hexane) to afford
further purification. M.p. 78–80 °C. IR (KBr): ν = 3371, 818,
˜
745 cm–1. 1H NMR (270 MHz, CDCl3): δ = 0.99 (d, J = 6.6 Hz,
18 H), 1.31 (br. s, 6 H), 1.35–1.44 (m, 6 H), 1.62–1.77 (m, 3 H),
2.52–2.58 (m, 6 H), 2.67–2.75 (m, 6 H), 2.79–2.87 (m, 6 H) ppm.
HRMS (EI): calcd. for C27H51N3 [M]+ 417.4083; found 417.4106.
1.16 g (12%) of 12 as a white solid. M.p. 98–100 °C. IR (KBr): ν
1,3,5-Tris(2-isothiocyanatoethyl)-2,4,6-trimethylbenzene (9a): To a
˜
= 722, 663 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.03 (d, J = solution of DCC (1.24 g, 6.01 mmol) in THF (20 mL) and CS2
6.6 Hz, 18 H), 1.45–1.53 (m, 6 H), 1.71–1.84 (m, 3 H), 2.83–2.88
(m, 6 H), 4.64 (s, 6 H) ppm. MS (EI): m/z = 432 [M]+. C24H39Cl3
(432.21): calcd. C 66.43, H 9.06; found C 66.59, H 9.28.
(1.52 g, 20.0 mmol), 8a (500 mg, 2.00 mmol) was added. The reac-
tion mixture was stirred for 3 h, and the solvent was removed in
vacuo. The product was purified by column chromatography (silica
612
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 607–615

Synthesis of Homobenzylic Tripodal Thiourea Derivatives
FULL PAPER
gel, 50% benzene in hexane) to afford 373 mg (50%) of 9a as a
(br. s, 3 H), 9.47 (br. s, 3 H) ppm. MS (FAB): m/z = 823
1
white solid. M.p. 107–108 °C. IR (KBr): ν = 2191, 2108 cm–1. H [M + 1]+. C48H66N6S3 (822.45): calcd. C 70.03, H 8.08, N 10.21;
˜
NMR (270 MHz, CDCl3): δ = 2.34 (s, 9 H), 3.15 (t, J = 7.6 Hz, 6
H), 3.61 (t, J = 7.6 Hz, 6 H) ppm.
found C 69.79, H 8.26, N 10.10.
Tripod-Type Receptor 5d: The coupling reaction of p-nitrophenyl
isothiocyanate (13d) (1.86 g, 10.3 mmol) and triamine 8b (1.12 g,
2.68 mmol) was carried out as described for the preparation of 5a.
The resulting precipitate was washed with CHCl3 to afford 2.07 g
1,3,5-Tris(2-isothiocyanatoethyl)-2,4,6-tris(3-methylbutyl)benzene
(9b): Isothiocyanate 9b was prepared by the same procedure as de-
scribed for the preparation of 9a in 51% yield. M.p. 124–126 °C.
IR (KBr): ν = 2188, 2110, 704 cm–1. 1H NMR (300 MHz, CDCl ):
˜
(80%) of pure 5d as a yellow solid. M.p. 132 °C (dec). IR (KBr): ν
˜
3
= 3110, 1532, 1330 cm–1. 1H NMR (400 MHz, [D6]DMSO, 30 °C):
δ = 0.98 (d, J = 6.4 Hz, 18 H), 8.19 (d, J = 8.8 Hz, 6 H), 8.62 (br.
s, 3 H), 10.20 (br. s, 3 H) ppm. HRMS (FAB): calcd. for
C48H64N9O6S3 [M + H]+ 958.4142; found 958.4129.
δ = 1.02 (d, J = 6.6 Hz, 18 H), 1.29–1.37 (m, 6 H), 1.68–1.77 (m,
3 H), 2.51–2.57 (m, 6 H), 3.01 (t, J = 7.6 Hz, 6 H), 3.63 (t, J =
7.6 Hz, 6 H) ppm. MS (FAB): m/z = 544 [M + 1]+. C30H45N3S3
(543.90): calcd. C 66.25, H 8.34, N 7.73; found C 66.55, H 8.61, N
7.65.
Model compound 14: The coupling reaction of benzyl isothiocya-
nate (13b) (801 mg, 5.37 mmol) and benzylamine (1.06 g,
9.95 mmol) was carried out as described for the preparation of 5a.
The resulting precipitate was washed with diethyl ether to afford
1.22 g (88%) of pure 14 as a white solid. M.p. 145.5–146.0 °C. IR
Cryptand-Type Receptor 4b: A solution of amine 8b (75 mg,
0.18 mmol) in CHCl3 (50 mL) and a solution of isothiocyanate 9b
(98 mg, 0.18 mmol) in CHCl3 (50 mL) were added dropwise simul-
taneously to CHCl3 (50 mL) at 60 °C over 1 h. The reaction mix-
ture was heated at reflux for 0.5 h and cooled to room temperature.
The crude product was purified by column chromatography (silica
(KBr): ν = 3324, 3290, 1556 cm–1. 1H NMR (270 MHz, CDCl3,
˜
30 °C): δ = 4.63 (d, J = 5.4 Hz, 4 H), 6.00 (br. s, 2 H), 7.36–7.22
(m, 10 H) ppm. MS (FAB): m/z = 257 [M + 1]+. C13H12N2S
(256.10): calcd. C 70.27, H 6.29, N 10.93; found C 69.98, H 6.28,
N 10.89.
gel, CHCl3) to afford 105 mg (61%) of 4b as a white solid. M.p.
1
270 °C (dec). IR (KBr): ν = 3425, 3385, 1545, 886 cm–1. H NMR
˜
(400 MHz, CDCl2CDCl2, 100 °C): δ = 0.94 (d, J = 6.6 Hz, 36 H),
1.20–1.26 (m, 12 H), 1.60–1.66 (m, 6 H), 1.60–1.66 (m, 12 H), 2.46
(t, J = 7.1 Hz, 12 H), 3.35 (br. s, 12 H), 5.36 (br. s, 6 H) ppm. MS
(FAB): m/z = 961 [M]+. C57H96N6S3 (961.61): calcd. C 71.20, H
10.06, N 8.74; found C 71.34, H 10.01, N 8.48.
Model Compound 15: The coupling reaction of p-nitrophenyl iso-
thiocyanate (13d) (311 mg, 1.73 mmol) and 2-(phenylethyl)amine
(560 mg, 4.62 mmol) was carried out as described for the prepara-
tion of 5a. The reaction mixture was extracted with CHCl3, washed
with 10% HCl, saturated aqueous NaHCO3, and brine, dried with
anhydrous MgSO4, filtered, and concentrated. The product was
purified by recrystallization from CHCl3 to give 380 mg (73%) of
Tripod-Type Receptor 5a: A solution of butyl isothiocyanate (13a)
(346 mg, 3.00 mmol) in CHCl3 (5 mL) was added to a solution of
triamine 8b (418 mg, 1.00 mmol) in CHCl3 (5 mL). The reaction
mixture was heated at reflux for 0.5 h, and the solvent was removed
in vacuo. The product was purified by column chromatography (sil-
ica gel, AcOEt and CHCl3) followed by preparative HPLC to af-
ford 305 mg (40%) of 5a as a white solid. M.p. 100 °C (dec). IR
pure 15 as a pale yellow solid. M.p. 145.0–145.5 °C. IR (KBr): ν =
˜
3169, 1520, 1347 cm–1. 1H NMR (270 MHz, CDCl3, 30 °C): δ =
3.00 (t, J = 6.7 Hz, 2 H), 4.00–3.93 (m, 2 H), 6.15 (br. s, 2 H),
7.06–7.03 (m, 2 H), 7.66–7.21 (m, 5 H), 8.14–8.10 (m, 2 H) ppm.
MS (FAB): m/z = 302 [M + 1]+. C15H15N3O2S (301.09): calcd. C
59.78, H 5.02, N 13.84; found C 59.67, H 4.70, N 13.84.
(KBr):
ν =
˜
3268, 1553, 753 cm–1. 1H NMR (270 MHz,
CDCl2CDCl2, 100 °C): δ = 0.90 (t, J = 7.3 Hz, 9 H), 0.97 (d, J =
6.6 Hz, 18 H), 1.27–1.73 (m, 27 H), 2.10–2.64 (m, 6 H), 2.92 (br. s,
6 H), 3.36 (t, J = 6.9 Hz, 6 H), 3.64 (br. s, 6 H), 5.92 (br. s, 6 H)
ppm. MS (FAB): m/z = 764 [M + 1]+. C42H78N6S3 (763.31): calcd.
C 66.09, H 10.30, N 11.01; found C 66.06, H 10.55, N 10.79.
General Procedure for Determination of Association Constants (Ka):
[D6]DMSO and DMSO were dried with molecular sieves (4 Å).
CDCl2CDCl2 was passed through a column of activated alumina
prior to use. All guest anions are commercially available as tetrabu-
tylammonium salts and were recrystallized from the following sol-
Tripod-Type Receptor 5b: The coupling reaction of benzyl isothio-
cyanate (13b) (131 mg, 0.878 mmol) and triamine 8b (107 mg,
0.256 mmol) was carried out as described for the preparation of
5a. The product was purified by column chromatography (silica
gel, 20% AcOEt in hexane) followed by recrystallization from etha-
nol to afford 127 mg (57%) of 5b as a white solid. M.p. 166–169 °C.
–
–
vents: for Bu4N+H2PO4 and Bu4N+HSO4 from EtOAc/acetone,
for Bu4N+Cl– and Bu4N+Br– from EtOAc/hexane, and for
–
Bu4N+CH3CO2 from EtOAc. Bu4N+F– was obtained as a tri-
hydrate and used without purification.
IR (KBr): ν = 3428, 3226, 1557, 753 cm–1. 1H NMR (300 MHz,
Titration Experiments Using NMR Spectroscopy: As an example,
˜
–
titration experiment of tripodal receptor 5a with a Bu4N+H2PO4
CDCl3): δ = 0.93 (d, J = 6.6 Hz, 18 H), 1.19–1.23 (m, 6 H), 1.56–
1.69 (m, 3 H), 2.50–2.55 (m, 6 H), 2.82 (t, J = 6.3 Hz, 6 H), 3.57
(br. s, 6 H), 4.58 (d, J = 4.4 Hz, 6 H), 6.17 (br. s, 3 H), 6.46 (br. s,
3 H), 7.23–7.33 (m, 15 H) ppm. MS (FAB): m/z = 865 [M + 1]+.
C51H72N6S3 (865.36): calcd. C 70.79, H 8.38, N 9.71; found C
70.49, H 8.46, N 9.66.
using 1H NMR spectroscopy is described here. A 6.18 m solution
of 5a in [D6]DMSO was prepared in a volumetric flask, and the
initial NMR spectrum was recorded. Alternatively, a 103 m solu-
tion of the guest anion in [D6]DMSO was prepared in a volumetric
flask. Into a 600 µL solution of the host compound, 40, 55, 5, 10,
20, 20, 30, 30, 40, 40, 40, and 50 µL aliquots of the above solution
of the guest was added in this order (a total of 380 µL), and the
chemical shifts of the NH and the aromatic protons were recorded
each time. Relatively broad peaks were treated by a curve-fitting
program implemented in the NMR spectroscopic data system (EX-
calibur for Windows 95 ver. 2.02). The association constants were
calculated by the nonlinear least-squares technique. The curve fit-
ting data are given in the Supporting Information.
Tripod-Type Receptor 5c: The coupling reaction of phenyl isothio-
cyanate (13c) (988 mg, 7.31 mmol) and triamine 8b (781 mg,
1.87 mmol) was carried out as described for the preparation of 5a.
The product was purified by column chromatography (silica gel,
20% AcOEt in hexane) followed by recrystallization from ethanol
to afford 1.23 g (80%) of 5c as a white solid. M.p. 102–105 °C. IR
1
(KBr): ν = 3398, 3243, 1536, 747 cm–1. H NMR (270 MHz, [D ]-
˜
6
DMSO): δ = 0.98 (d, J = 6.4 Hz, 18 H), 1.24 (br. s, 6 H), 1.72–1.79
(m, 3 H), 2.81 (br. s, 12 H), 3.53 (br. s, 6 H), 7.11 (t, J = 7.3 Hz, 3
H), 7.32 (dd, J = 8.1, 7.3 Hz, 6 H), 7.40 (d, J = 8.1 Hz, 6 H), 8.02
Titration Experiments Using UV/Vis Spectroscopy: As an example,
titration experiment of tripodal receptor 5d with Bu4N+H2PO4
–
Eur. J. Org. Chem. 2007, 607–615
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
613

I. Hisaki, S.-i. Sasaki, K. Hirose, Y. Tobe
FULL PAPER
using UV/Vis spectroscopy is described here. A 7.14ϫ10–5  solu-
tion of 5d in [D6]DMSO was prepared in a volumetric flask. Alter-
natively, a 1.09ϫ10–4  solution of the guest anion in [D6]DMSO
was prepared in a volumetric flask. By using the stock solutions,
14 different solutions containing 5d (1.43ϫ10–5 ) and the guest
(ranging from 0 to 8.74ϫ10–5 –1) were prepared. The absorbance
at 382 nm was used for calculation of the association constant.
S. Nishizawa, T. Yokobori, N. Teramae, Tetrahedron Lett. 2004,
45, 4273–4276; e) Z.-Y. Zeng, Y.-B. He, J.-L. Wu, L.-H. Wei,
X. Liu, L.-Z. Meng, X. Yang, Eur. J. Org. Chem. 2004, 2888–
2893; f) J.-L. Wu, Y.-B. He, Z.-Y. Zeng, L.-H. Wei, L.-Z. Meng,
T.-X. Yang, Tetrahedron 2004, 60, 4309–4314; g) J. P. Clare,
A. J. Ayling, J.-B. Joos, A. L. Sisson, G. Magro, M. N. Pérez-
Payán, T. N. Lambert, R. Shukla, B. D. Smith, A. P. Davis, J.
Am. Chem. Soc. 2005, 127, 10739–10746; h) L. Fang, W.-H.
Chan, Y.-B. He, D. W. J. Kwong, A. W. M. Lee, J. Org. Chem.
2005, 70, 7640–7646; i) D. A. Jose, D. K. Kumar, B. Ganguly,
A. Das, Tetrahedron Lett. 2005, 46, 5343–5346; j) F. M. Pfeffer,
T. Gunnlaugsson, P. Jensen, P. E. Kruger, Org. Lett. 2005, 7,
5357–5360.
Supporting Information (see footnote on the first page of this arti-
cle): Titration plots of 4b with anions, titration plots of 5a–d, ti-
tration plots of 14 and 15, UV spectral changes of 5d and 15 upon
addition of NaOH.
[15]
[16]
a) D. J. Iverson, G. Hunter, J. F. Blount, J. R. Damewood Jr,
K. Mislow, J. Am. Chem. Soc. 1981, 103, 6073–6083; b) J. Sie-
gel, A. Gutiérrez, W. B. Schweizer, O. Ermer, K. Mislow, J. Am.
Chem. Soc. 1986, 108, 1569–1575.
a) K. H. Ahn, S.-G. Kim, J. Jung, K.-H. Kim, J. Kim, J. Chin,
K. Kim, Chem. Lett. 2000, 170–171; b) J. Chin, J. Oh, S. Y.
Jon, S. H. Park, C. Walsdorff, B. Stranix, A. Ghoussoub, S. J.
Lee, H. J. Chung, S.-M. Park, K. Kim, J. Am. Chem. Soc. 2002,
124, 5374–5379; c) J. Kim, S.-G. Kim, H. R. Seong, K. H. Ahn,
J. Org. Chem. 2005, 70, 7227–7231; d) J. Kim, B. Raman, K. H.
Ahn, J. Org. Chem. 2006, 71, 38–45.
a) K. Sato, S. Arai, T. Yamagishi, Tetrahedron Lett. 1999, 40,
5219–5222; b) H. Ihm, S. Yun, H. G. Kim, J. K. Kim, K. S.
Kim, Org. Lett. 2002, 4, 2897–2900; c) K. J. Wallace, W. J. Bel-
cher, D. R. Turner, K. F. Syed, J. W. Steed, J. Am. Chem. Soc.
2003, 125, 9699–9715; d) V. Amendola, M. Boiocchi, L. Fab-
brizzi, A. Palchetti, Chem. Eur. J. 2005, 11, 5648–5660; e) D. R.
Turner, M. J. Paterson, J. W. Steed, J. Org. Chem. 2006, 71,
1598–1608.
a) P. J. Garratt, A. J. Ibbett, J. E. Ladbury, R. O’Brien, M. B.
Hursthouse, K. M. Abdul Malik, Tetrahedron 1998, 54, 949–
968; b) S. L. Wiskur, P. N. Floriano, E. V. Anslyn, J. T. McDev-
itt, Angew. Chem. 2003, 42, 2070–2072; Angew. Chem. Int. Ed.
2003, 42, 2070–2072; c) S. L. Wiskur, J. J. Lavigne, A. Metzger,
S. L. Tobey, V. Lynch, E. V. Anslyn, Chem. Eur. J. 2004, 10,
3792–3804; d) C. Schmuck, M. Schwegmann, J. Am. Chem.
Soc. 2005, 127, 3373–3379; e) L. Fabbrizzi, F. Foti, A. Taglietti,
Org. Lett. 2005, 7, 2603–2606.
a) Z. Zhong, E. V. Anslyn, J. Am. Chem. Soc. 2002, 124, 9014–
9015; b) C. Schmuck, M. Schwegmann, Org. Lett. 2005, 7,
3517–3520.
a) M. Mazik, W. Radunz, W. Sicking, Org. Lett. 2002, 4, 4579–
4582; b) M. Mazik, W. Radunz, R. Boese, J. Org. Chem. 2004,
69, 7448–7462; c) M. Mazik, H. Cavga, P. G. Jones, J. Am.
Chem. Soc. 2005, 127, 9045–9052.
a) T. Szabo, B. M. O’Leary, J. Rebek Jr, Angew. Chem. 1998,
110, 3606–3609; Angew. Chem. Int. Ed. 1998, 37, 3410–3413;
b) K. Kavallieratos, R. A. Sachleben, G. J. Van Berkel, B. A.
Moyer, Chem. Commun. 2000, 187–188; c) B. M. O’Leary, T.
Szabo, N. Svenstrup, C. A. Schalley, A. Lu1tzen, M. Scha1fer,
J. Rebek Jr, J. Am. Chem. Soc. 2001, 123, 11519–11533; d) M.
Komiyama, S. Kina, K. Matsumura, J. Sumaoka, S. Tobey,
V. M. Lynch, E. Anslyn, J. Am. Chem. Soc. 2002, 124, 13731–
13736; e) S. Sasaki, A. Hashizume, D. Citterio, E. Fujii, K.
Suzuki, Angew. Chem. 2002, 114, 3131–3133; Angew. Chem.
Int. Ed. 2002, 41, 3005–3006; f) W. W. H. Wong, D. E. Phipps,
P. D. Beer, Polyhedron 2004, 23, 2821–2829; g) L. Han, D.
Yuan, Y. Xu, M. Wu, Y. Gong, B. Wu, M. Hong, Inorg. Chem.
Commun. 2005, 8, 529–532; h) Y. Tang, J. Zhang, W.-S. Liu,
M.-Y. Tan, K.-B. Yu, Polyhedron 2005, 24, 1160–1166.
[1] For recent reviews on anion receptor, see: a) F. P. Schmidtchen,
M. Berger, Chem. Rev. 1997, 97, 1609–1646; b) S. Aoki, E.
Kimura, Rev. Mol. Biotechnol. 2002, 90, 129–155; c) R. Martí-
nez-Máñez, F. Sancenón, Chem. Rev. 2003, 103, 4419–4476; d)
C. Suksai, T. Tuntulani, Chem. Soc. Rev. 2003, 32, 192–202; e)
J. L. Sessler, S. Camiolo, P. A. Gale, Coord. Chem. Rev. 2003,
240, 17–55; f) C. R. Bondy, S. J. Loeb, Coord. Chem. Rev. 2003,
240, 77–99; g) P. A. Gale, Coord. Chem. Rev. 2003, 240, 191–
221; h) P. D. Beer, E. J. Hayes, Coord. Chem. Rev. 2003, 240,
167–189; i) L. Fabbrizzi, M. Licchelli, A. Taglietti, Dalton
Trans. 2003, 3471–3479.
[17]
[18]
[2] a) F. P. Schmidtchen, Angew. Chem. 1977, 89, 751 –752; Angew.
Chem. Int. Ed. Engl. 1977, 16, 720–721; b) T. Clifford, A.
Danby, J. M. Llinares, S. Mason, N. W. Alcock, D. Powell, J. A.
Aguilar, E. Garcia-Espana, K. Bowman-James, Inorg. Chem.
2001, 40, 4710–4720.
[3] M. Berger, F. P. Schmidtchen, J. Am. Chem. Soc. 1996, 118,
8947–8948.
[4] V. Amendola, L. Fabbrizzi, E. Monzani, Chem. Eur. J. 2004,
10, 76–82.
[5] S. Yun, H. Ihm, H. G. Kim, C.-W. Lee, B. Indrajit, K. S. Oh,
Y. J. Gong, J. W. Lee, J. Yoon, H. C. Lee, K. S. Kim, J. Org.
Chem. 2003, 68, 2467–2470.
[6] M. Boiocchi, M. Bonizzoni, L. Fabbrizzi, G. Piovani, A. Tagli-
etti, Angew. Chem. 2004, 116, 3935–3940; Angew. Chem. Int.
Ed. 2004, 43, 3847–3852.
[7] K. Kavallieratos, C. M. Bertao, R. H. Crabtree, J. Org. Chem.
1999, 64, 1675–1683.
[19]
[20]
[8] S. Kondo, T. Suzuki, Y. Yano, Tetrahedron Lett. 2002, 43,
7059–7061.
[9] P. J. Smith, M. V. Reddington, C. S. Wilcox, Tetrahedron Lett.
1992, 33, 6085–6088.
[10] a) E. Fan, S. A. Van Arman, S. Kincaid, A. D. Hamilton, J.
Am. Chem. Soc. 1993, 115, 369–370; b) J. Scheerder, M. Fochi,
J. F. J. Engbersen, D. N. Reinhoudt, J. Org. Chem. 1994, 59,
7815–7820; c) C. Raposo, M. Almaraz, M. Martín, V. Wein-
rich, M. L. Mussóns, V. Alcazar, M. C. Caballero, J. R. Moran,
Chem. Lett. 1995, 759–760; d) P. Bühlmann, S. Nishizawa,
K. P. Xiao, Y. Umezawa, Tetrahedron 1997, 53, 1647–1654; e)
R. C. Jagessar, M. Shang, W. R. Scheidt, D. H. Burns, J. Am.
Chem. Soc. 1998, 120, 11684–11692; f) S. Sasaki, D. Citterio,
S. Ozawa, K. Suzuki, J. Chem. Soc., Perkin Trans. 2 2001,
2309–2313.
[11] J. L. Sessler, M. J. Cyr, V. Lynch, E. McGhee, J. A. Ibers, J.
Am. Chem. Soc. 1990, 112, 2810–2813.
[12] a) H. K. Frensdorff, J. Am. Chem. Soc. 1971, 93, 600–606; b)
R. M. Izatt, K. Pawlak, J. S. Bradshaw, R. L. Bruening, Chem.
Rev. 1991, 91, 1721–2085.
[13] a) Y. Tobe, S. Sasaki, M. Mizuno, K. Naemura, Chem. Lett.
1998, 835–836; b) S. Sasaki, M. Mizuno, K. Naemura, Y. Tobe,
J. Org. Chem. 2000, 65, 275–283.
[14] Examples of thiourea receptors with spacers capable of fixing
the binding sites, see: a) K. H. Lee, J.-I. Hong, Tetrahedron
Lett. 2000, 41, 6083–6087; b) D. H. Lee, K. H. Lee, J.-I. Hong,
Org. Lett. 2001, 3, 5–8; c) S. Kondo, M. Nagamine, Y. Yano,
Tetrahedron Lett. 2003, 44, 8801–8804; d) R. Kato, Y.-Y. Cui,
[21]
[22]
[23]
[24]
For a recent review: J. W. Steed, Chem. Commun. 2006, 2637–
2649.
A. W. van der Made, R. H. van der Made, J. Org. Chem. 1993,
58, 1262–1263.
K. Kumada, K. Tamao, K. Sumitani, Org. Synth., Coll. Vol.
1998, 6, 407–411 .
614
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 607–615

Synthesis of Homobenzylic Tripodal Thiourea Derivatives
FULL PAPER
[25] K. G. Estep, K. A. Josef, E. R. Bacon, C. R. Illig, J. L. Toner,
D. Mishra, W. F. Blazak, D. M. Miller, D. K. Johnson, J. M.
Allen, A. Spencer, S. A. Wilson, J. Med. Chem. 2000, 43, 1940–
1948.
D. Romano, L. H. Kuo, A. L. Burt, D. P. Curran, Tetrahedron
1995, 51, 621–634.
[32] Examples of complexation of p-nitrophenyl thiourea with an-
ionic species, see: a) R. Kato, S. Nishizawa, T. Hayashita, N.
Teramae, Tetrahedron Lett. 2001; 42, 5053–5056; b) S. Nishiz-
awa, T. Yokobori, R. Kato, T. Shioya, N. Teramae, Bull. Chem.
Soc. Jpn. 2001, 74, 2343–2347.
[26] L. E. Weller, C. D. Ball, H. M. Sell, J. Am. Chem. Soc. 1952,
74, 1104.
[27] D. S. Dhanoa, R. M. Soll, N. Subasinghe, Z. Wu, J. Rinker, J.
Hoffman, S. Eisennagel, T. Graybill, R. Bone, A. Radzicka, L.
Murphy, F. R. Salemme, Med. Chem. Res. 1998, 8, 187–205.
–
–
[33] Association constants of 5d with H2PO4 and CH3CO2 could
1
not be determined by H NMR analysis because of extensive
–
[28] Because Bu4N+H2PO4 decomposed under the titration condi-
overlap of the signals.
–
tions, the binding constant with H2PO4 was not determined.
[34] For the formation of thioureido anions in the complexation of
(benzylideneamino)thiourea derivatives with a fluoride anion,
see: M. Bonizzoni, L. Fabbrizzi, A. Taglietti, F. Tiengo, Eur. J.
Org. Chem. 2006, 3567–3574.
[29] The 1:1 stoichiometry was confirmed by the Job’s plot for com-
plexation between 4b and Bu4N+Cl–.
–
[30] Other anions such as I–, HSO4 , and NO3– were also examined.
However, association constants were too small to determine
exactly.
Received: July 26, 2006
Published Online: November 23, 2006
[31] For the effect of electron-withdrawing substituents of arylureas
on complexation with a sulfonate, see: C. S. Wilcox, E.-i. Kim,
Eur. J. Org. Chem. 2007, 607–615
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
615