Size matters - Strong binding of the terephthalate dianion by thiourea functionalised fused [n]polynorbornane hosts

Article abstract of DOI:10.1039/b801798k

Remarkably strong binding of the new [5]polynorbornane based host 2b to the terephthalate dianion is based on size complementarity of the preorganised binding cleft with the rigid dicarboxylate guest. The Royal Society of Chemistry.

Full text of DOI:10.1039/b801798k

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Size matters—strong binding of the terephthalate dianion by thiourea
functionalised fused [n]polynorbornane hostsw
Adam J. Lowe and Frederick M. Pfeffer*
Received (in Cambridge, UK) 31st January 2008, Accepted 26th February 2008
First published as an Advance Article on the web 18th March 2008
DOI: 10.1039/b801798k
Remarkably strong binding of the new [5]polynorbornane based host
2b to the terephthalate dianion is based on size complementarity of
the preorganised binding cleft with the rigid dicarboxylate guest.
Abundant in nature, anions are critical to life; indeed the
recognition, transport and transformation of anionic species is
involved at some level in almost every conceivable biochemical
1
operation. More specifically, dicarboxylates are involved in
the generation of high-energy phosphate bonds and numerous
metabolic processes including the citric acid and glyoxalate
2
cycles. As such, the construction of selective receptors for
these dianionic species is a worthy endeavour.
3
Size complementarity, as pioneered by Cram, plays a key role
Fig. 1 Structures of the polynorbornane based hosts 1 and 2.
when attempting to selectively bind anionic guests as they exist in
a wide range of geometries when compared to their simple
4
cationic counterparts. Crystal structures of enzyme–anionic sub-
13
tion of alkene 4 with dimethyl acetylenedicarboxylate (DMAD),
the resultant alkene diester was subjected to Weitz–Scheffer
14
epoxidation using tert-butyl hydroperoxide (TBHP) to yield
strate complexes (e.g. sulfate/phosphate binding proteins, DNA
epoxide 5. The [3]polynorbornane framework 6 was formed using
a 1,3-dipolar cycloaddition between epoxide 5 (which ring opens
to form a carbonyl ylide) and alkene 4. Removal of the Boc
groups with dilute TFA produced the free diamine 7 which was
reacted with 4-fluorophenyl isothiocyanate, or 4-nitrophenyl
isothiocyanate, to produce 1a and 1b, respectively.
helicase Rep A) clearly illustrate the importance of preorganisa-
1
tion and size complementarity for selective recognition.
,5
Examples of synthetic hosts exhibiting such specific host:guest
complementarity are less common, however, highly selective
anion recognition has been achieved using a variety of macro-
6
7
8
cyclic frameworks, calix[4]arenes, and cholic acid derivatives.
The design of the hosts employed herein relies on rigid
Synthesis of hosts 2 (Scheme 2) required a total of five steps,
and employed similar chemistry. Mitsudo reaction of norbor-
nadiene with two equivalents of DMAD afforded the bis
[
n]polynorbornane frameworks that can, through well estab-
9
lished methodologies, be tailored to different sizes. Such scaf-
folds are therefore ideally suited for constructing hosts to
complement a guest of a specific size or shape. Hosts 1 and 2
(Fig. 1) were designed with [3]- and [5]polynorbornane scaffolds,
respectively, and contain two thiourea groups for anion recogni-
tion. The short ethylene spacers allow a degree of flexibility for
induced fit, potentially optimising binding interactions. Previous
studies have indicated that electronic properties can have a
10
significant impact on host:guest binding stoichiometry, there-
fore 4-fluorophenyl and the more electron withdrawing 4-nitro-
phenyl substituents were included in the design. Herein, the full
synthesis of 1 and 2 is presented, followed by the results of anion
1
binding assays performed by means of H NMR spectroscopy.
The synthesis of 1z (Scheme 1) required six steps in total.
1
1
Heating anhydride 3 with tert-butyl (2-aminoethyl)carbamate
12
afforded the Boc protected imide 4. Following Mitsudo reac-
Scheme 1 Synthesis of hosts 1a and 1b from endo-norborn-5-ene-2,3-
anhydride and tert-butyl (2-aminoethyl)carbamate. Reagents and condi-
School of Life and Environmental Sciences, Deakin University,
Geelong, VIC, Australia. E-mail: thefef@deakin.edu.au; Fax: +61 3
tions: (i) tert-butyl (2-aminoethyl)carbamate, CHCl
DMAD, RuH (CO)(PPh , THF, 70 1C, 72 h, 86%; (iii) TBHP, KO Bu,
THF, 0 1C, 28 h, 69%; (iv) 1.1 equiv. 4, CH Cl , 140 1C, 24 h, 58%; (v)
20% TFA–CH Cl , 4 h, 100%; (vi) DIPEA, CHCl , RT, 23 h, 1a 4-
3
, 120 1C, 12 h, 81%; (ii)
t
5227 1040; Tel: +61 3 5227 1439
3 3
)
2
w Electronic supplementary information (ESI) available: Full syn-
thetic details for receptors 1 and 2, binding isotherms and fit plots
for binding studies. See DOI: 10.1039/b801798k
2
2
2
2
3
fluorophenyl isothiocyanate, 84%, 1b 4-nitrophenyl isothiocyanate, 68%.
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Chem. Commun., 2008, 1871–1873 | 1871

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Scheme 2 Synthesis of hosts 2a and 2b from norborna-2,5-diene and dimethyl acetylenedicarboxylate. Reagents and conditions: (i) DMAD,
t
RuH (CO)(PPh
2
3
)
Cl , 4 h, 100%; (v) DIPEA, CHCl
3
, THF, 70 1C, 24 h, 33%; (ii) TBHP, KO Bu, THF, 0 1C, 15 h, 54%; (iii) 2.2 equiv. 4, THF, 140 1C, 41 h, 64%; (iv) 20%
TFA–CH
2
2
3
, RT, 24 h, 2a 4-fluorophenyl isothiocyanate, 92%, 2b 4-nitrophenyl isothiocyanate, 95%.
1
5
alkene diester, which on epoxidation gave the bis epoxide 8.
Again, alkene 4 was used in the cycloaddition; this time two
equivalents were heated with bis epoxide 8, to form the
[
5]polynorbornane framework 9. Deprotection followed by
reaction with 4-fluorophenyl isothiocyanate, or 4-nitrophenyl
isothiocyanate resulted in hosts 2a and 2b, respectively.
The ability of the four hosts to recognise the rigid dicarboxy-
1
late, terephthalate, was investigated using H NMR by titrating
solutions of the terephthalate dianion [prepared as a tetrabuty-
1
6
6 6
lammonium (TBA) salt] in DMSO-d against DMSO-d solu-
ꢂ2
ꢂ3
tions of each host (B 1.3 ꢁ 10 M and also 1.0 ꢁ 10 My)
while recording any change of the thiourea N–H resonances.
For each of the hosts 1a–2b it was immediately apparent that
binding was occurring as all thiourea N–H resonances experienced
large downfield shifts (Table 1). Migration approaching 4 ppm with
no sign of deprotonation was observed and indicated strong binding
between the hosts and the terephthalate dianion. It was noted that
2
during titrations of 1b and 2b (Ar–NO substituent) an incremental
colour change from pale yellow through to red occurred; this was
1
anticipated and had been observed in previous studies.
0
1
Fig. 2 Stack plots of H NMR titrations of hosts 1a (top) and 2b
1
Stack plots of the H NMR data (Fig. 2) clearly show
strongly bound 1:1 host:guest complexes. For host 2b satura-
tion occurred after 1 equiv. of terephthalate had been added,
and once saturated the signals became sharper, indicating high
complex stability. It was also noteworthy that the 1:1 stoi-
chiometry beomes ‘locked-in’, and no further downfield mi-
gration of the N–H resonances was observed despite the
continued addition of guest. Such a stable state is suggestive
of strong binding and the corresponding isotherm (Fig. 3) also
depicts this ‘quantitative’ binding. When the results for 1a are
compared to those for host 2b it is clear that the titration ‘end-
point’ is significantly sharper for host 2b than for 1a, again
indicating a very stable host:guest complex.
(
bottom) upon addition of terephthalate dianion in DMSO-d
see ESIw for 1b and 2a stack plots).
6
(
the single step binding of terephthalate [H + G - HG (K)]
17
calculated using WinEQNMR (Table 1) range from host 1a
(
log K = 3.5) through to 2b (log K = 6.0).
Job plot data (see ESIw) confirmed the 1:1 host:guest
stoichiometry for all four hosts and binding constants for
a
Table 1 Observed chemical shifts and calculated binding constants
ꢂ2
ꢂ3
M
[
Host] B 1.3 ꢁ 10
M
[Host] B 1.0 ꢁ 10
b
b
Host max. dD (ppm) log K
max. dD (ppm) log K
1
1
2
2
a
a
b
a
b
3.38
3.51
3.64
3.74
2.7 (ꢃ0.19) 2.22
3.5 (ꢃ0.23)
3.8 (ꢃ0.52)
4.4 (ꢃ0.34)
6.0 (ꢃ0.49)
17
3.7 (ꢃ0.74) 3.02
4.0 (ꢃ1.15) 3.26
5.7 (ꢃ1.68) 3.61
Binding constants were determined using WinEQNMR software.
y
b
Fig. 3 Titration isotherms for N–H protons within 1a (top) and 2b
b
Maximum observed chemical shift observed for H after 6.0 equiv. of
(
bottom) upon addition of terephthalate dianion in DMSO-d
see ESIw for 1b and 2a binding isotherms).
6
anion.
(
1
872 | Chem. Commun., 2008, 1871–1873
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Notes and references
12
z Host 1b has been synthesised previously, however binding assays
involving dicarboxylates were not performed.
y There was no appreciable dissociation of the complex at or near the
ꢂ2
stoichiometric point (at a concentration of 1.3 ꢁ 10 M, Fig. 3)
despite the competitive solvent DMSO being used. As such large errors
2
0
(
o30%) accompanied the calculated binding constants, repeating
ꢂ3
titrations at lower concentration (1.0 ꢁ 10
reliable binding constants (error o8.1%).
M) provided more
1
2
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He, Z.-Y. Zeng, L.-H. Wei, L.-Z. Meng and T.-X. Yang, Tetra-
hedron, 2004, 60, 4309–4314.
Fig. 4 Energy minimised molecular models of receptors 1a (left) and
b (right) bound to 1 equiv. of terephthalate dianion (see ESIw for
molecular models of 1b and 2a).
2
3
4
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6
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norbornane based hosts 1a and 1b are too small to encompass
the large, rigid terephthalate guest. In order to achieve a 1:1
complex, host 1 must undergo significant backbone stretching.
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7
´
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larger [5]polynorbornane frameworks 2a, 2b accommodate the
terephthalate guest neatly—clearly showing excellent host:guest
8
9
´
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2
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2
(
see Fig. 4). Although the change in chemical shift was relatively
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19
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1
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1
1
In conclusion, we have designed and synthesised new poly-
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2
b efficiently binds the large, rigid, terephthalate dianion. The
results are a clear illustration of how size complementarity
plays a critical role when designing receptors for guests of
known dimensions and show that fused polynorbornane based
hosts are ideally suited for this task.
1
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This journal is ꢀc The Royal Society of Chemistry 2008
Chem. Commun., 2008, 1871–1873 | 1873