Factors influencing anion binding stoichiometry: The subtle influence of electronic effects

Article abstract of DOI:10.1002/ejoc.200701015

Six new, charge-neutral norbornene-based receptors 1a,1b-3a,3b were prepared, and their ability to interact with simple anions in DMSO was investigated using ¹H NMR and UV/Vis spectroscopy. Binding of dihydrogenphosphate by the six receptors ap

Full text of DOI:10.1002/ejoc.200701015

FULL PAPER
DOI: 10.1002/ejoc.200701015
Factors Influencing Anion Binding Stoichiometry: The Subtle Influence of
Electronic Effects
Adam J. Lowe,[a] Gail A. Dyson,[a] and Frederick M. Pfeffer*[a]
Keywords: Anion recognition / Hydrogen bonding / Norbornene / Preorganisation / Supramolecular chemistry
Six new, charge-neutral norbornene-based receptors 1a,1b–
3a,3b were prepared, and their ability to interact with simple
anions in DMSO was investigated using 1H NMR and UV/
Vis spectroscopy. Binding of dihydrogenphosphate by the six
receptors appeared to be based solely on steric constraints.
In contrast, the binding stoichiometry of 3a and 3b to acetate
was controlled by subtle electronic factors.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
roles,[20] calixarenes,[21] indoles,[22] cholic acid,[23] azophen-
ols,[24] and various other macrocycles.[14,25] In most cases
the predefined cavity geometry allows these hosts to dis-
criminate between guests of differing shape and overall size.
Norbornenes have only sparingly been utilised as scaf-
folds for supramolecular applications,[10,26] which is surpris-
ing considering they boast an inherent high degree of rigid-
ity, are readily synthesised through well-known Diels–
Alder cycloadditions[27,28] and can be tailored to contain
multiple points that can be functionalised with relative ease.
Furthermore, established cycloaddition methodologies[29]
can also be exploited to create fused [n]polynorbornane
frameworks for the purpose of encapsulating larger anionic,
and possibly neutral, guests.[30,31]
Introduction
Hosts for the selective recognition of anionic species are
highly sought after as anions are essential to many bio-
logical, chemical and environmental processes.[1] As such,
there is great current interest in the development of strong
and selective artificial anion receptors for use as enzyme
mimics, catalysts, extractants and molecular probes for
medicinal diagnostics and monitoring of anionic pol-
lutants.[2–4]
Neutral receptors are of great importance in anion re-
cognition as they are the most abundant in nature, and can
be designed to have high selectivity for a specific target.[5,6]
Charge-neutral receptors use hydrogen bonding as their pri-
mary mode of interaction; examples of neutral receptors
include thiourea, urea, amide, sulfonamide and/or pyrrole
groups.[7] Among these, the urea and thiourea functional
groups have proven to be particularly useful and are
amongst the most commonly employed.[8–10]
Herein the full synthesis of a family[10] of norbornene-
based receptors 1–3 is presented, followed by the results of
1
anion-binding studies using H NMR and UV/Vis titration
techniques.
Ideally, exceptionally strong complexation is achieved
through the active cooperation of multiple, prepositioned,
hydrogen bonds in a preorganised binding cavity.[11–13] Spe-
cific geometries can be exploited by arranging the hydro-
gen-bond donors around the acceptors in three-dimen-
sional space.[14] If the host’s preorganised binding cavity
complements the guest’s geometry, then high selectivity can
be achieved.[13]
Attaching hydrogen-bond donor units to a suitable mo-
lecular scaffold is a common method for achieving preor-
ganisation of the binding cavity.[15] A diverse number of
scaffolds have previously been employed for this purpose,
including naphthalenes,[16–18] benzene rings,[19] calixpyr-
Results and Discussion
Design
A family of six receptors 1a–3b (Figure 1) were designed;
all receptors contained two thiourea-functionalised ethylene
“arms”. The ethylene spacers introduced an element of flex-
ibility in the anionophoric “arms” to allow optimum bind-
ing through induced fit. In order to study the influence of
receptor-site prepositioning, receptor 1 was designed with
two endo “arms”, receptor 2 with the “arms” oriented by
the alkene and 3 with an endo/exo combination. As such,
each host has a unique degree of preorganisation imparted
by the rigid norbornene. The design offers the possibility of
binding an anionic guest within the preorganised cleft
through the cooperation of all six hydrogen-bond donors.
[a] School of Life and Environmental Sciences, Deakin University,
Geelong, VIC, Australia
Fax: +61-3-5227-1040
E-mail: thefef@deakin.edu.au
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1559–1567
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A. J. Lowe, G. A. Dyson, F. M. Pfeffer
FULL PAPER
Scheme 2. Synthesis of host 2 from precursor 5. Reagents and con-
ditions: (i) 12% TFA/DCM, room temp., 3 h, 100%; (ii) 4-fluo-
rophenyl isothiocyanate (for 2a)/4-nitrophenyl isothiocyanate (for
2b), DIPEA, CHCl3, room temp., 18 h, 76% (for 2a)/76% (for 2b).
Figure 1. Structures of the new norbornene-based receptors 1–3.
Three synthetic steps were required to accomplish the
synthesis of receptor 3 (Scheme 3). The Diels–Alder cyclo-
addition of neat cyclopentadiene with dimethyl maleate af-
forded dimethyl norborn-5-ene-2,3-endo-dicarboxylate (9)
in quantitative yield. Diester 9 was directly converted into
the diamine 10, and the conditions required to convert the
methyl ester to the amide (100 °C, neat ethylenediamine,
19 h) resulted in epimerisation of the bis(endo-carbonyl)
compound, and the thermodynamically more stable
endo/exo adduct was isolated.[34] After reaction of the bis-
(amine) 10 with either 4-fluorophenyl isothiocyanate or 4-
nitrophenyl isothiocyanate, receptors 3a and 3b were ob-
tained in 69% and 48% yield, respectively, after chromato-
graphic purification.
Synthesis
To accomplish the synthesis of 1, five steps were required
(Scheme 1) commencing with the Diels–Alder cycloaddition
of cyclopentadiene with acetylenedicarboxylic acid[32] to
produce norborna-2,5-diene-2,3-dicarboxylic acid[27] 4 in
quantitative yield. The diacid 4 was then coupled with tert-
butyl (2-aminoethyl)carbamate[33] using 1-[3-(dimeth-
ylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC).
The resulting alkene 5 was subsequently hydrogenated in
the presence of palladium hydroxide, producing the norbor-
nane endo-bis(amide) 6. The deprotection of 6 was sensitive
to TFA concentration but the optimum conditions (12%
TFA in DCM) provided quantitative yields of the free pri-
mary bis(amine) 7 which was used directly in the final step.
Nucleophilic attack by the primary amino groups of 7 on
either 4-fluorophenyl isothiocyanate or 4-nitrophenyl iso-
thiocyanate produced receptors 1a and 1b in 93%, and 88%
yield, respectively, after chromatographic purification.
Scheme 3. Synthesis of host 3. Reagents and conditions: (i) ethyl-
enediamine, 100 °C, 19 h, 98%; (ii) 4-fluorophenyl isothiocyanate
(for 3a)/4-nitrophenyl isothiocyanate (for 3b), CHCl3, room temp.,
24 h, 69% (for 3a)/48% (for 3b).
1H NMR Titration Studies
When examining hydrogen-bonding interactions 1H
NMR spectroscopy is an extremely powerful tool as it pro-
vides a means of monitoring the electron density surround-
ing each potential hydrogen-bond donor present in the
host. Conclusions can then be drawn as to which individual
protons are involved in the interaction, as well as the extent
to which they participate.[18,35]
Scheme 1. Synthesis of host 1. Reagents and conditions: (i) tert-
butyl (2-aminoethyl)carbamate, EDC, CHCl3, room temp., 17 h,
44%; (ii) Pd–OH/C, EtOH, room temp., 12 h, 99%; (iii) 12% TFA/
DCM, room temp., 3 h, 100%; (iv) 4-fluorophenyl isothiocyanate
(for 1a)/4-nitrophenyl isothiocyanate (for 1b), DIPEA, CHCl3,
room temp., 18 h, 93% (for 1a)/88% (for 1b).
To assess the ability of the new hosts to bind anions, [D6]-
–
DMSO solutions of Br–, Cl–, F–, HSO4 , H2PO4– and AcO–
[as their tetrabutylammonium (TBA) salts] were titrated
Starting with bis(amide) 5, only two steps were necessary against [D6]DMSO solutions of each host (ca. 1.2ϫ10–2 )
to synthesise receptor 2 (Scheme 2). The first of which was while recording any observed migration of the relevant N–
deprotection utilising 12% TFA/DCM to form bis(amine) H resonances.
8, followed by coupling with either 4-fluorophenyl isothio-
Initially, the spherical halides were evaluated; however,
cyanate or 4-nitrophenyl isothiocyanate, resulting in recep- the addition of both Br– and Cl– elicited only minor
tors 2a and 2b (both in 76% yield) after chromatographic changes in the H NMR spectrum (Table 1). For Br–, an
1
purification.
average downfield shift (∆δ) value of 0.10 ppm was ob-
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Factors Influencing Anion Binding Stoichiometry
Table 1. Maximum observed chemical shifts [ppm] and calculated binding constants[a]
.
–
–
Br–
Cl–
F–
HSO4
H2PO4
AcO– (NMR)
AcO– (UV/Vis)
1a
1b
2a
2b
3a
3b
max ∆δ[b]
logK1
0.10
–
–
0.11
–
–
0.09
–
–
0.14
–
–
0.09
–
–
0.04
–
–
0.51
–
–
0.53
–
–
0.48
–
–
0.84
–
–
0.44
–
–
0.53
–
–
1.51[c]
–
0.08
–
–
0.12
–
–
0.08
–
–
0.06
–
–
0.09
–
–
0.04
–
–
1.67
3.66
3.00
1.74
3.73
2.60
1.83
3.94
2.24
1.74
3.16
2.53
1.94
3.63
2.65
1.84
3.73
2.46
3.15
3.15
2.24
3.31
3.82
2.95
2.89
4.18
2.51
3.27
3.40
3.19
3.24
3.92
2.78
3.14
3.27
–
–
–
–
–
logK2
–
max ∆δ[b]
logK1
1.54[c]
–
3.67[d]
logK2
–
3.63[d]
max ∆δ[b]
logK1
1.24[c]
–
–
–
–
–
logK2
–
max ∆δ[b]
logK1
1.34[c]
–
3.70[d]
logK2
–
3.75[d]
max ∆δ[b]
logK1
1.62[c]
–
–
–
–
logK2
–
max ∆δ[b]
logK1
1.35[c]
–
3.95[d]
–
–
–
logK2
1
[a] Binding constants were determined from H NMR titration data using WinEQNMR software,[37] with calculated errors of Ͻ14.0%.
All 1H NMR titrations were carried out with initial host concentrations of approximately 1.2ϫ10–2 . [b] Maximum chemical shift
observed for Hc after addition of 6.0 equiv. of anion. [c] Values after addition of 1.6 equiv. of anion. [d] Binding constants determined
from UV/Vis titrations using non-linear least-squares curve fitting,[38] with calculated std. dev. σ Ͻ 1.3%. All UV/Vis titrations were
carried out with initial host concentrations of approximately 5.0ϫ10–5 .
served for all hosts (after 6.0 equiv. of anion). Although the = 0.39 ppm, Ha2-exo: ∆δ = 1.03 ppm; Figure 3). Although
shifts for Cl– were more significant, a lack of a consistent a 1:1 host/guest binding stoichiometry might have been ex-
trend in the data meant calculating binding constants was pected, given the capability of the more flexible two-“arm”
not viable. These results suggested that very weak, if any, system to encompass the larger multiple hydrogen-bond ac-
–
binding occurred between Br– or Cl– and any of the new ceptor anion H2PO4 , job plot data[13,38] showed a clear 1:2
hosts.
host/guest binding stoichiometry in all cases (Figure 4).
In contrast, upon addition of F– significant broadening
and considerable downfield migration of the N–H reso-
nances occurred immediately, with maximum ∆δ values
ranging from 1.24 to 1.62 ppm (Table 1). Again, stoichio-
metries and binding constants could not be calculated, as
saturation of the hosts had not been achieved before the
resonances became indistinguishable from the baseline (af-
ter 1.6 equiv.). A distinct, successive colour change from
pale yellow to deep red was observed during the titrations
of the nitro-substituted hosts. This colour change, which
was clearly visible to the naked eye and due to deproton-
ation (FHF– triplet observed at δ = 16.12 ppm),[8] provided
evidence that these norbornene-based receptors could func-
tion as colorimetric sensors.[30,36]
Figure 2. Changes in the chemical shift of relevant N–H protons
–
within 1a (1.25ϫ10–2 ) upon addition of H2PO4 in [D6]DMSO
(also representative of receptors 1b, 2a and 2b, see Supporting In-
formation for individual binding isotherms).
–
After the spherical halides, the tetrahedral anions HSO4
–
–
and H2PO4 were investigated; however, adding HSO4 re-
sulted in insignificant changes in chemical shift (Table 1),
–
suggesting weak, if any, binding of HSO4 . On the other
hand, upon addition of H2PO4 , considerable ∆δ values
–
were observed for the entire family of receptors 1–3
(Table 1) with a maximum ∆δ value of 1.94 ppm recorded
–
for 3a, which indicated that strong binding of H2PO4 was
occurring. As anticipated, the four thiourea protons of each
receptor experienced the largest shifts, but there were also
significant migrations associated with the two amide pro-
tons of each receptor (Figure 2). It was of great interest that
in the case of the endo/exo host 3 the ∆δ value of the two
Figure 3. Changes in the chemical shift of relevant N–H protons
–
within 3a (1.24ϫ10–2 ) upon addition of H2PO4 in [D6]DMSO
(also representative of receptor 3b, see Supporting Information for
amide proton resonances was not equal (3a: Ha1-endo: ∆δ binding isotherm).
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A. J. Lowe, G. A. Dyson, F. M. Pfeffer
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This implied that the two anionophoric “arms” act inde-
The final anion to be evaluated was the trigonal-planar
pendently to bind one guest each, and that the preorganised AcO– anion. It was immediately apparent that the receptors
cleft of the host was inappropriate to accommodate the were binding AcO– strongly due to the large ∆δ values re-
–
larger H2PO4 anion. The considerable thiourea proton corded for 1–3 (max ∆δ = 3.31 ppm for 1b after 6.0 equiv.
shifts suggest the guests were primarily bound by the thio- of added anion; Table 1). As was noted when titrating F–
urea protons; however, a definite contribution from the against the nitro-substituted receptors, a distinct visible col-
amide protons was evidenced by their significant ∆δ value. our change accompanied the significant downfield shifts,
Binding constants for the two-step binding process [H + G yet each N–H resonance was still clearly visible in the spec-
Ǟ HG (K1), HG + G Ǟ HG2 (K2)] were determined by trum after 9 equiv. of the anion had been added, ruling out
1
fitting the H NMR titration data using WinEQNMR[37] complete deprotonation as a cause for the colorimetric re-
and are reported as log K1 and log K2 (Table 1).
sponse. For all six receptors, the expected trend of larger
shifts for the thiourea proton resonances was observed;
however, the amide proton resonances remained unchanged
(Figure 6). This indicated strong hydrogen bonding between
the thiourea protons of the anionophoric “arms” and the
geometrically complementary acetate anions, with no con-
tribution from the amide protons.
Figure 4. Job plots for the complexation of receptors 1–3 with
H2PO4– atatotalconcentrationofapproximately1.2ϫ10–2 in[D6]-
DMSO.
It was established by multiple 1D and 2D ROESY ex-
periments (see Supporting Information) that a through-
space interaction was occurring between the amide N–Ha1
of the endo “arm” of 3 and H1 of the norbornene scaffold
(Figure 5). This interaction suggests that the lack of cooper-
–
ation of N–Ha1 when binding H2PO4 to the endo “arm” is
Figure 6. Changes in the chemical shift of relevant N–H protons
within 2b (top, 1.24ϫ10–2 ) and 3b (bottom, 1.16ϫ10–2 ) upon
addition of AcO– in [D6]DMSO (2b is also representative of recep-
tors 1a, 1b, 2a and 3a, see Supporting Information for individual
binding isotherms).
likely due to steric reasons. In kinetic studies examining en-
do- versus exo-norbornene substituents, the endo position
was found to be less reactive than the exo position, and this
difference was justified by steric constraints;[40] such conclu-
sions support our findings.
The job-plot data for receptors 1, 2 and 3a (Figure 7) are
consistent with a 1:2 host/guest arrangement, and again a
scenario where the two “arms” are acting independently to
bind a single anion each was proposed (Figure 8). It was
therefore surprising that for receptor 3b the titration iso-
therm (Figure 6) and the job-plot data (Figure 7) clearly
suggested a 1:1 host/guest stoichiometry where the anion
was bound within the receptor cavity through the coopera-
tion of all four thiourea hydrogen-bond donors (Figure 8).
The trigonal-planar AcO– anion complements the thiourea
hydrogen-bond donor system very well,[3,6] and, as such,
there are numerous examples of a single thiourea recogni-
tion unit binding a single AcO– anion.[41] On the other
hand, examples of two thiourea units binding a single AcO–
anion, as observed for receptor 3b, are less common, and
preorganisation arguments are usually invoked to explain
such instances.[16,42]
Figure 5. Energy-minimised molecular models[39] of receptors 1 or
–
2 with 2 equiv. of H2PO4 (top), and receptor 3 with 2 equiv. of
–
H2PO4 (bottom).
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Factors Influencing Anion Binding Stoichiometry
opposite is true for activating groups. Indeed, the pKa of 4-
nitrobenzoic acid and 4-fluorobenzoic acid are 3.43 and
4.15, respectively,[43] and this same concept can be used to
explain the increased acidity of the thiourea N–Hc protons
of receptor 3b.
Although the hydrogen-bonding ability of hosts 3a and
3b depends on a number of contributing factors, such as
electrostatic interactions, bond geometries and solvent po-
larity, this study suggests that increased hydrogen-bond do-
nor strength through substituent effects can prove signifi-
cant when considering host/guest binding stoichiometry. As
the experimental evidence supports receptor 3b binding a
single AcO– guest through all four thiourea hydrogen-bond
donors (Figure 8), it genuinely appears that the combina-
tion of steric and electronic properties of this host make 3b
unique within this closely related family.
Figure 7. Job plots for the complexation of receptors 1–3 with
AcO– at a total concentration of approximately 1.2ϫ10–2  in [D6]
DMSO.
UV/Vis Study
UV/Vis absorption spectroscopy is another important
tool when examining host/guest interactions; this technique
can be employed whenever the coordination of a guest is
accompanied by a spectral change of the host. Although
information regarding individual hydrogen-bond donors is
not provided, this method does enable a “global picture” of
the binding event to be established. As such, UV/Vis spec-
troscopy is often used for determining host/guest binding
stoichiometries and association constants.[4,44]
1
During the H NMR studies, addition of AcO– to the
nitro-substituted hosts (1b, 2b and 3b) resulted in a pro-
gressive colour change from pale yellow to a deep red.
When these titrations were monitored using UV/Vis absorp-
tion spectrometry [the AcO– anion was added to DMSO
solutions of the b series of receptors (5ϫ10–5 ) as a TBA
salt] a new absorption band at 480 nm was gradually en-
hanced, while the intensity of the absorption band at
362 nm correspondingly decreased (Figure 9). The origin of
the colour change could be ascribed to the charge-transfer
Figure 8. Energy-minimised molecular models[39] of receptors 1 or
2, and 3a with 2 equiv. of AcO– (top), and receptor 3b with 1 equiv.
of AcO– (bottom).
The contradicting host/guest binding stoichiometries de-
termined for receptors 3a and 3b with AcO– requires justifi-
cation. Preorganisation cannot be the sole factor influenc-
ing host/guest stoichiometry as the cleft-like binding site for
both receptors is essentially identical given that they have
the same rigid norbornene scaffold. Indeed, they are effec-
tively identical except for one feature – the phenyl substitu-
ent: F for 3a and NO2 for 3b. Therefore, electronic factors
are likely to play a role when accounting for the observed
results. By using the acidity of p-substituted benzoic acids
as an example, deactivating (electron-withdrawing) groups
Figure 9. Job plots (inset) and UV/Vis absorption spectra of recep-
tor 3b (DMSO, 5.0ϫ10–5 ) upon the addition of 6.0 equiv. of
AcO– anion in 0.2-equiv. increments (also representative of the
spectra obtained for both 1b and 2b under the same conditions, see
increase the acidity by stabilizing the carboxylate anion; the Supporting Information for individual spectra).
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A. J. Lowe, G. A. Dyson, F. M. Pfeffer
FULL PAPER
selgel 60 (70–230 mesh). General reagents were analytical grade
and used as supplied unless otherwise stated. Peptide coupling
agents and isothiocyanates were supplied by Aldrich Chemical Co.
interactions between the electron-rich donor nitrogen atoms
of the thiourea units and the electron-deficient p-ni-
trophenyl moieties.[17,18,45] A clear isosbestic point was ob-
served at 383 nm indicating the reversible formation of a
complex between the host and guest was occurring.[46]
Job plots (Figure 9) confirmed the unusual 1:1 host/guest
binding stoichiometry of receptor 3b with AcO–, while still
supporting the 1:2 host/guest binding stoichiometries deter-
mined for both receptors 1b and 2b with AcO–. Binding
constants were also calculated from the UV/Vis data
(Table 1).[38,43,45] Overall, these values were slightly larger
than those calculated from 1H NMR spectroscopic data,
this could be due to a number of factors including self-
aggregration and oligomerisation, which are less prominent
in the more dilute solutions employed in UV/Vis titration
experiments. As expected, 3b had the largest calculated
binding constant of the b series of receptors, indicating that
AcO– was bound most strongly by this receptor. The strong
Norborna-2,5-diene-2,3-dicarboxylic Acid (4):[32] Freshly cracked
cyclopentadiene (0.923 g, 13.96 mmol) was added dropwise with
stirring to a solution of acetylenedicarboxylic acid (1.592 g,
13.96 mmol) in 1,4-dioxane (5 mL). This reaction mixture was
stirred under nitrogen for 12 h, a water bath was used to maintain
room temperature throughout the exothermic reaction. TLC analy-
sis indicated complete consumption of the starting materials and
the formation of a single pure product 4 (Rf = 0.54, 25% methanol/
ethyl acetate) as a white crystalline solid in a quantitative yield
(2.516 g, 100%). No further purification was required for subse-
quent steps; m.p. 158.2–159.2 °C. 1H NMR (270 MHz; CDCl3,
TMS): δ = 2.16 (d, J = 6.9 Hz, 1 H, CH2), 2.28 (d, J = 7.4 Hz, 1
H, CH2), 4.19 (s, 2 H, CHCH2), 6.92 (s, 2 H, CH=CH) ppm. 13C
NMR (270 MHz; CDCl3, TMS): δ = 54.37, 73.17, 142.32, 157.84,
166.84 ppm. HRMS: m/z = 203.0268 [M + Na]+; C9H8NaO4 re-
quires 203.0320.
binding was likely due to the cooperation of all four thio- tert-Butyl (2-Aminoethyl)carbamate:[33] A solution of di-tert-butyl
dicarbonate (5.154 g, 23.62 mmol) in 1,4-dioxane (5 mL) was pre-
pared and added dropwise over 30 min to a solution of ethylenedi-
amine (5.0 mL, 74.6 mmol) in 1,4-dioxane (45 mL). This reaction
mixture was then stirred at room temperature for 4 h during which
time a white precipitate formed. The suspension was filtered and
the filtrate concentrated under reduced pressure to afford a clear
urea hydrogen-bond donors stabilising the host/guest com-
plex as depicted in Figure 8.
Conclusions
1
oil (3.675 g, 97.1%). H NMR (270 MHz; CDCl3, TMS): δ = 1.35
We have designed, synthesised and evaluated the anion
binding ability of six new, conformationally preorganised
norbornene-based receptors 1a,1b–3a,3b. Receptors 1 and 2
bind both H2PO4– and AcO– in a 1:2 host/guest stoichiome-
try regardless of preorganisation and electronic factors. Re-
ceptor 3 also binds H2PO4– in the 1:2 fashion, however each
“arm” adopts an independent conformation due to the ste-
ric constraints imparted by the norbornene scaffold. The
unexpected 1:1 binding of 3b with AcO– provides further
insight as to how subtle electronic factors can have a major
impact on overall host/guest binding stoichiometries.
These subtle electronic factors showcase the prospect
that deliberately “tuning” the acidity of the hydrogen-bond
donors can markedly influence the selectivity. Investigations
into [n]polynorbornane frameworks employing these simple
receptors as building blocks are currently underway, and
the results of these studies will be reported in due course.
[s, 9 H, C(CH3)3], 2.69 (q, J = 5.5 Hz, 2 H, CH2NH2), 3.08 (q, J
= 5.8 Hz, 2 H, CH2NH), 5.12 (br. s, 1 H, NH) ppm. 13C NMR
(270 MHz; CDCl3, TMS):
δ = 28.42, 41.89, 43.43, 44.85,
156.30 ppm. HRMS: m/z = 161.1155 [M + H]+; C7H17N2O2 re-
quires 161.1290.
Di-tert-butyl [Norborna-2,5-diene-2,3-diylbis(carbonyliminoethane-
2,1-diyl)]biscarbamate (5): A solution of norborna-2,5-diene-2,3-di-
carboxylic acid (4) (0.400 g, 2.220 mmol) and EDC (0.851 g,
4.439 mmol) was prepared in dry CHCl3 (5 mL), 2-(tert-butoxycar-
bonylamino)ethylamine (0.711 g, 4.438 mmol) was then added and
the mixture stirred for 48 h. The reaction mixture was further di-
luted with CHCl3 (10 mL) then transferred to a separating funnel.
The organic phase was washed with water (3ϫ30 mL), dried
(MgSO4), filtered, then concentrated to dryness under reduced
pressure. The crude product was purified using flash chromatog-
raphy with gradient elution (0–10% methanol/ethyl acetate,
Rf(prod.) = 0.64; ethyl acetate) to afford 5 as a white powder
(0.452 g, 43.8%); m.p. 196.1–197.2 °C. 1H NMR (270 MHz;
CDCl3, TMS): δ = 1.37 [s, 18 H, 2ϫ C(CH3)3], 1.86 (d, J = 6.2 Hz,
1 H, CHCH2), 1.98 (d, J = 4.7 Hz, 1 H, CHCH2), 3.05 (t, J =
5.7 Hz, 4 H, 2ϫ CH2NHCO), 3.17 (t, J = 5.7 Hz, 4 H, 2ϫ
CH2NHCOO), 4.01 (s, 2 H, 2ϫ CHCH2), 6.88 (s, 2 H, 2ϫ
NHCOO), 6.89 (s, 2 H, CH=CH), 9.25 (s, 2 H, 2ϫ NHCO) ppm.
13C NMR (270 MHz; CDCl3, TMS): δ = 28.76, 39.84, 47.54, 54.08,
71.08, 78.27, 142.88, 153.38, 156.30, 164.68 ppm. HRMS: m/z =
465.2713 [M + H]+; C23H37N4O6 requires 465.2713.
Experimental Section
General: NMR spectra were collected with either a JEOL EX
270 MHz FT-NMR spectrometer (Tokyo, Japan), or a JEOL EX
400 MHz FT-NMR spectrometer (Tokyo, Japan), where indicated.
UV/Vis spectra were measured using a Varian Cary Eclipse 300 Bio
UV/Vis spectrophotometer. HRMS was performed with an Agilent
6210 LC/MSDTOF instrument using CH3CN as the mobile phase.
Melting points were determined with a digital Electrothermal®
9200 (UK) heated-block melting point apparatus and are uncor-
rected. Microanalysis was performed by Chemical and Microana-
lytical Services Pty Ltd, Belmont, Geelong, 3216. TLC was per-
formed using Merck 60 F254 aluminium-backed silica plates. Visu-
alisation employed a UVP Mineralight 254 NM UV lamp or an
oxidising dip containing KMnO4 (1.0 g), K2CO3 (1.0 g) and H2O
(100 mL). Flash chromatography was performed using Merck Kie-
Di-tert-butyl
[Norbornane-2,3-endo-diylbis(carbonyliminoethane-
2,1-diyl)]biscarbamate (6): To a solution of the diene 5 (0.170 g,
0.366 mmol) in ethanol (20 mL), a catalytic amount of palladium
hydroxide on activated carbon was added. A gas bladder was used
to provide and maintain a hydrogen blanket over the reaction mix-
ture which was subsequently stirred at room temperature for 12 h.
The reaction mixture was filtered through Celite atop a Büchner
funnel, then the solvent removed under reduced pressure to yield 6
as a white powder (0.170 g, 99.2%); m.p. 209.8–211.4 °C. 1H NMR
1564
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1559–1567

Factors Influencing Anion Binding Stoichiometry
(270 MHz; CDCl3, TMS): δ = 1.21 (d, J = 8.1 Hz, 2 H, 2ϫ exo- N,NЈ-Bis[2-({[(4-fluorophenyl)amino]carbonothioyl}amino)ethyl]-
CHCH2CH2), 1.35 (s, 2 H, CHCH2), 1.37 [s, 18 H, 2ϫ C(CH3)3],
1.76 (d, J = 6.9 Hz, 2 H, 2ϫ endo-CHCH2CH2), 2.33 (s, 2 H, 2ϫ
CH2CHCH2), 2.69 (s, 2 H, 2ϫ exo-CH), 2.91–3.10 (m, 8 H, 2ϫ
norborna-2,5-diene-2,3-dicarboxamide (2a): The bis(amine) 8
(0.057 g, 0.237 mmol) was added to a solution of 4-fluorophenyl
isothiocyanate (0.091 g, 0.594 mmol) and ethyldiisopropylamine
CH2CH2), 6.64 (s, 2 H, 2ϫ NHCOO), 7.54 (s, 2 H, 2ϫ NHCO) (0.25 mL, 1.44 mmol) in CHCl3 (3 mL). This reaction mixture was
ppm. 13C NMR (270 MHz; CDCl3, TMS): δ = 24.61, 28.78, 39.12,
41.89, 47.39, 78.13, 156.10, 172.49 ppm. HRMS: m/z = 469.3151
[M + H]+; C23H41N4O6 requires 469.3026.
stirred at room temperature for 18 h before being concentrated to
dryness under reduced pressure. The crude product was purified
using column chromatography (ethyl acetate, Rf = 0.45) to afford
2a as a white powder (0.102 g, 75.6 %); m.p. 165.4–167.9 °C.
C27H28F2N6O2S2 (570.17): calcd. C 56.83, H 4.95, N 14.73; found
C 56.78, H 4.99, N 14.69. 1H NMR (400 MHz; [D6]DMSO, TMS):
δ = 1.90 (d, J = 6.2 Hz, 1 H, CHCH2), 2.01 (d, J = 5.8 Hz, 1 H,
CHCH2), 3.38 (d, J = 3.1 Hz, 4 H, 2ϫ CH2NHCO), 3.59 (br. s, 4
H, 2 ϫ CH2NHCS), 4.06 (s, 2 H, 2 ϫ CHCH2), 6.92 (s, 2 H,
CH=CH), 7.14 (t, J = 8.8 Hz, 4 H, 4ϫ Ar-CHCF), 7.36 (t, J =
5.3 Hz, 4 H, 4ϫ Ar-CHCNH), 7.77 (br. s, 2 H, 2ϫ NHCS), 9.42
(s, 2 H, 2ϫ CONH), and 9.57 (s, 2 H, 2ϫ Ph-NH) ppm. 13C NMR
(400 MHz; [D6]DMSO, TMS): δ = 43.62, 71.10, 115.71, 115.94,
126.58, 135.70, 142.92, 153.53, 158.49, 160.89, 164.83, 181.45 ppm.
HRMS: m/z = 571.1705 [M + H]+; C27H29F2N6O2S2 requires
571.1761.
N,NЈ-Bis(2-aminoethyl)norbornane-2,3-endo-dicarboxamide (7): A
mixture of 12% TFA/DCM (5 mL) was added to the bis(amide) 6
(0.220 g, 0.469 mmol), then stirred at room temperature for 3 h,
while being monitored by TLC. Complete consumption of 6 was
apparent by this time, and excess solvent and TFA were removed
under reduced pressure to yield 7 as an off-white solid (0.113 g,
100%). This material was used directly in subsequent steps.
N,NЈ-Bis[2-({[(4-fluorophenyl)amino]carbonothioyl}amino)ethyl]-
norbornane-2,3-endo-dicarboxamide (1a): The bis(amine) 7 (0.220 g,
0.469 mmol) was added to a solution of 4-fluorophenyl isothiocya-
nate (0.144 g, 0.940 mmol) and ethyldiisopropylamine (0.49 mL,
2.79 mmol) in CHCl3 (5 mL). This reaction mixture was stirred at
room temperature for 18 h before being concentrated to dryness
under reduced pressure. The crude product was purified using flash
chromatography (5% methanol/ethyl acetate; Rf = 0.51) to afford
1a as a white powder (0.252 g, 93.4 %); m.p. 130.1–132.9 °C.
C27H32F2N6O2S2 (574.20): calcd. C 56.43, H 5.61, N 14.62; found
C 56.36, H 5.72, N 14.56. 1H NMR (400 MHz; [D6]DMSO, TMS):
δ = 1.24 (d, J = 4.1 Hz, 2 H, 2ϫ endo-CHCH2CH2), 1.24 (d, J =
4.9 Hz, 1 H, CHCH2), 1.39 (d, J = 5.7 Hz, 1 H, CHCH2), 1.71 (d,
J = 4.2 Hz, 2 H, 2ϫ exo-CHCH2CH2), 2.36 (s, 2 H, 2ϫ CH2CH),
2.75 (s, 2 H, 2 ϫ exo-CHCH), 3.18 (d, J = 5.5 Hz, 4 H, 2 ϫ
CH2NHCO), 3.46–3.54 (m, 4 H, 2 ϫ CH2NHCS), 7.13 (t, J =
8.8 Hz, 4 H, 4ϫ Ar-CHCF), 7.37 (t, J = 6.8 Hz, 4 H, 4ϫ Ar-
CHCNH), 7.65 (br. s, 2 H, 2ϫ Ph-NH), 7.75 (s, 2 H, 2ϫ NHCS),
9.56 (s, 2 H, 2ϫ CONH) ppm. 13C NMR (400 MHz; [D6]DMSO,
TMS): δ = 24.64, 39.67, 42.18, 48.98, 115.66, 115.88, 126.31,
135.86, 158.38, 160.78, 173.03, 181.35 ppm. HRMS: m/z =
575.2048 [M + H]+; C27H33F2N6O2S2 requires 575.2074.
N,NЈ-Bis[2-({[(4-nitrophenyl)amino]carbonothioyl}amino)ethyl]-
norborna-2,5-diene-2,3-dicarboxamide (2b): As for 2a, using bis(am-
ine) 8 (0.178 g, 0.741 mmol), 4-nitrophenyl isothiocyanate (0.334 g,
1.854 mmol), and ethyldiisopropylamine (0.78 mL, 4.48 mmol) in
CHCl3 (5 mL) afforded 1a as a yellow powder (0.353 g, 76.3%);
ethyl acetate, Rf = 0.40; m.p. 181.1–184.2 °C. 1H NMR (400 MHz;
[D6]DMSO, TMS): δ = 1.91 (d, J = 6.1 Hz, 1 H, CHCH2), 2.03 (d,
J = 6.3 Hz, 1 H, CHCH2 ), 3.41 (d, J = 4.1 Hz, 4 H, 2 ϫ
CH2NHCO), 3.64 (d, J = 5.0 Hz, 4 H, 2ϫ CH2NHCS), 4.15 (s, 2
H, 2ϫ CHCH2), 6.93 (s, 2 H, CH=CH), 7.80 (d, J = 9.1 Hz, 4 H,
4ϫ Ar-CHCNH), 8.16 (d, J = 9.4 Hz, 4 H, 4ϫ Ar-CHCNO2), 8.43
(s, 2 H, 2ϫ NHCS), 9.44 (s, 2 H, 2ϫ CONH), and 10.29 (s, 2 H,
2ϫ Ph-NH) ppm. 13C NMR (400 MHz; [D6]DMSO, TMS): δ =
38.52, 43.96, 54.18, 71.24, 121.17, 125.03, 142.13, 142.93, 146.69,
153.58, 164.92, 180.92 ppm. HRMS: m/z = 625.1623 [M + H]+;
C27H29N8O6S2 requires 625.1651.
Dimethyl Norborn-5-ene-2,3-endo-dicarboxylate (9): Freshly
N,NЈ-Bis[2-({[(4-nitrophenyl)amino]carbonothioyl}amino)ethyl]- cracked cyclopentadiene (1.837 g, 27.79 mmol) was added dropwise
norbornane-2,3-endo-dicarboxamide (1b): As for 1a, using bis(am-
ine) 7 (0.200 g, 0.427 mmol), 4-nitrophenyl isothiocyanate (0.154 g,
0.855 mmol), and ethyldiisopropylamine (0.45 mL, 2.58 mmol) in
CHCl3 (5 mL) afforded 1b as a yellow crystalline solid (0.235 g,
87.6%); 5% methanol/ethyl acetate, Rf = 0.39; m.p. 151.9–154.2 °C.
C27H32N8O6S2 (628.19): calcd. C 51.58, H 5.13, N 17.82; found C
51.61, H 5.16, N 17.71. 1H NMR (400 MHz; [D6]DMSO, TMS): δ
= 1.23 (d, J = 4.2 Hz, 2 H, 2ϫ endo-CHCH2CH2), 1.24 (d, J =
with stirring to dimethyl maleate (4.006 g, 27.79 mmol). This reac-
tion mixture was stirred under nitrogen for 8 h, a water bath was
used to maintain room temperature throughout the exothermic re-
action. TLC indicated complete consumption of the starting mate-
rials and the formation of a single pure product [35% ethyl acetate/
petroleum ether (boiling range 40–60 °C), Rf = 0.41] as a clear oil
in a quantitative yield (5.842 g, 100%). No further purification was
required for subsequent steps. 1H NMR (270 MHz; CDCl3, TMS):
6.1 Hz, 1 H, CHCH2), 1.39 (d, J = 5.8 Hz, 1 H, CHCH2), 1.73 (d, δ = 1.33 (d, J = 6.8 Hz, 1 H, CHCH2), 1.44 (d, J = 6.9 Hz, 1 H,
J = 4.4 Hz, 2 H, 2ϫ exo-CHCH2CH2), 2.38 (s, 2 H, 2ϫ CH2CH), CHCH2), 3.12 (s, 2 H, 2ϫ exo-CHCO), 3.26 (s, 2 H, 2ϫ CH2CH),
2.78 (s, 2 H, 2 ϫ exo-CHCH), 3.24 (d, J = 5.7 Hz, 4 H, 2 ϫ
CH2NHCO), 3.47–3.58 (m, 4 H, 2 ϫ CH2NHCS), 7.78 (d, J =
8.7 Hz, 4 H, 4ϫ Ar-CHCNH), 7.83 (s, 2 H, 2ϫ CONH), 8.15 (d,
J = 7.2 Hz, 4 H, 4ϫ Ar-CHCNO2), 8.16 (s, 2 H, 2ϫ NHCS), and
10.22 (s, 2 H, 2ϫ Ph-NH) ppm. 13C NMR (400 MHz; [D6]DMSO,
TMS): δ = 24.62, 37.89, 44.70, 47.84, 121.08, 125.07, 142.35,
144.86, 146.72, 162.35, 173.24, 180.71 ppm. HRMS: m/z =
629.1941 [M + H]+; C27H33N8O6S2 requires 629.1964.
3.58 (s, 6 H, 2ϫ CH3) and 6.23 (s, 2 H, CH=CH) ppm. 13C NMR
(270 MHz; [D6]DMSO, TMS): δ = 46.32, 48.12, 51.59, 134.97,
138.02, 172.98 ppm. HRMS: m/z = 233.0812 [M + Na]+;
C11H14NaO4 requires 233.0790.
N,NЈ-Bis(2-aminoethyl)norborna-2,5-diene-2,3-dicarboxamide (10):
A solution of the diester 9 (550 mg, 2.62 mmol) in neat ethylenedi-
amine (3.0 mL, 45 mmol) was prepared in a 25-mL round-bot-
tomed flask equipped with a reflux condenser. After stirring at
100 °C for 18 h, excess ethylenediamine was removed under re-
duced pressure to yield an extremely viscous orange/brown oil
(682 mg, 97.9%). This material was used directly in the following
steps.
N,NЈ-Bis(2-aminoethyl)norborna-2,5-diene-2,3-dicarboxamide (8):
As for diamine 7, using diene 5 (0.321 g, 0.691 mmol) yielded 8 as
an off-white solid (0.165 g, 99.6%). This material was used directly
in subsequent steps.
Eur. J. Org. Chem. 2008, 1559–1567
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1565

A. J. Lowe, G. A. Dyson, F. M. Pfeffer
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N,NЈ-Bis[2-({[(4-fluorophenyl)amino]carbonothioyl}amino)ethyl]-
norborn-5-ene-2-endo,3-exo-dicarboxamide (3a): To a solution of
the endo/exo-bis(amine) 10 (500 mg, 1.88 mmol) in dry CHCl3
(3.0 mL), 4-fluorophenyl isothiocyanate (719 mg, 4.69 mmol) was
added in a single portion. This reaction mixture was stirred under
nitrogen at room temperature for 24 h before removal of excess
solvent under reduced pressure resulted in a crude yellow solid.
The crude product was purified by flash chromatography (10% 2-
propanol/ethyl acetate, Rf = 0.61) to yield a white powder (665 mg,
68.7 %); m.p. 93.2–95.3 °C. 1H NMR (400 MHz; [D6]DMSO,
TMS): δ = 1.21 (d, J = 7.9 Hz, 1 H, CHCH2), 1.68 (d, J = 7.6 Hz,
1 H, CHCH2), 2.51 (s, 1 H, exo-CH2CHCH), 2.84 (s, 1 H, exo-
CH2CH), 3.16 (s, 1 H, endo-CH2CHCH), 3.17 (s, 1 H, endo-
CH2CH), 3.22 (m, 2 H, exo-CONHCH2), 3.34 (m, 2 H, endo-
CONHCH2), 3.51–3.62 (br. m, 4 H, 2ϫ CSNHCH2), 5.95 (t, J =
3.5 Hz, 1 H, endo-CH=CH), 6.18 (t, J = 3.2 Hz, 1 H, exo-
CH=CH), 7.15 (t, J = 8.8 Hz, 4 H, Ar-CHCNH), 7.36 (t, J =
5.0 Hz, 4 H, Ar-CHCF), 7.68 (br. s, 2 H, 2ϫ NHCS), 7.87 (s, 1 H,
endo-CONH), 8.07 (s, 1 H, exo-CONH), 9.57 (s, 2 H, 2ϫ Ph-NH)
ppm. 13C NMR (400 MHz; [D6]DMSO, TMS): δ = 44.08, 46.02,
47.26, 47.75, 48.05, 49.21, 115.24, 115.67, 116.01, 126.46, 135.20,
135.78, 137.79, 157.87, 161.43, 173.10, 174.54, 181.35 ppm.
HRMS: m/z = 573.2015 [M + H]+; C27H31F2N6O2S2 requires
573.1918.
[2]
[3]
[4]
[5]
[6]
N,NЈ-Bis[2-({[(4-nitrophenyl)amino]carbonothioyl}amino)ethyl]-
norborn-5-ene-2-endo,3-exo-dicarboxamide (3b): As for 3a, using
endo/exo-bis(amine) 10 (701 mg, 2.63 mmol) and 4-nitrophenyl iso-
thiocyanate (1.008 g, 5.59 mmol) in dry CHCl3 (5.0 mL) yielded a
yellow powder (786 mg, 47.7%); 10% methanol/ethyl acetate, Rf =
0.35; m.p. 127.6–129.4 °C. 1H NMR (400 MHz; [D6]DMSO,
TMS): δ = 1.21 (d, J = 7.8 Hz, 1 H, CHCH2), 1.69 (d, J = 7.5 Hz,
1 H, CHCH2), 2.53 (s, 1 H, exo-CH2CHCH), 2.87 (s, 1 H, exo-
CH2CH), 3.17 (s, 1 H, endo-CH2CHCH), 3.18 (s, 1 H, endo-
CH2CH), 3.25 (m, 2 H, exo-CONHCH2), 3.35 (m, 2 H, endo-
CONHCH2), 3.55–3.68 (br. m, 4 H, 2ϫ CSNHCH2), 5.98 (t, J =
4.1 Hz, 1 H, endo-CH=CH), 6.19 (t, J = 2.2 Hz, 1 H, exo-
CH=CH), 7.78 (t, J = 8.0 Hz, 4 H, Ar-CHCNH), 7.94 (s, 1 H,
endo-CONH), 8.13 (s, 1 H, exo-CONH), 8.19 (t, J = 9.2 Hz, 4 H,
Ar-CHCNO2), 8.28 (br. s, 2 H, 2ϫ NHCS), 10.25 (s, 2 H, 2ϫ Ph-
NH) ppm. 13C NMR (400 MHz; [D6]DMSO, TMS): δ = 38.45,
38.67, 44.20, 46.61, 47.34, 47.58, 48.15, 49.32, 60.64, 121.79,
125.78, 135.89, 138.56, 143.19, 147.48, 174.08, 175.47, 181.82 ppm.
HRMS: m/z = 627.1807 [M + H]+; C27H31N8O6S2 requires
627.1808.
[7]
[8]
[9]
[10]
Part of this work has previously been published as a communi-
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[11]
[12]
[13]
[14]
[15]
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR binding isotherms, job plots and fit plots
(WinEQNMR) of hosts 1–3 when titrated against both H2PO4– and
AcO–, as well as the UV/Vis spectra, job plots and fit plots of hosts
1b, 2b, and 3b when titrated against AcO–; a ROESY spectrum and
an articulated description of the simulations conducted to obtain
the energy-minimised molecular models.
[16]
[17]
[18]
[19]
J.-L. Wu, Y.-B. He, Z.-Y. Zeng, L.-H. Wei, L.-Z. Meng, T.-X.
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The authors would like to thank Xavier Conlon for performing
high-resolution mass spectrometry and Deakin University for fi-
nancing this project in the form of a start-up grant for F. P. and a
scholarship for A. L.
[20]
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1566
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1559–1567

Factors Influencing Anion Binding Stoichiometry
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Received: October 26, 2007
Published Online: January 29, 2008
Eur. J. Org. Chem. 2008, 1559–1567
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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