Substituent effects in the binding of bis(4-fluorobenzyl)ammonium ions by dianilino[24]crown-8

Article abstract of DOI:10.1016/j.tetlet.2003.10.132

A series of para-substituted dianilino[24]crown-8 (DA24C8) macrocycles were synthesized and their ability to form host-guest complexes with bis(4-fluorobenzyl)ammonium ions (DFA⁺) were investigated. Although these crown ethers contain weakly hy

Full text of DOI:10.1016/j.tetlet.2003.10.132

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 213–216
Substituent effects in the binding of bis(4-fluorobenzyl)ammonium
ions by dianilino[24]crown-8
Sheng-Hsien Chiu,* Kang-Shyang Liao and Jen-Kuan Su
Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan, ROC
Received 8 July 2003; revised 12 September 2003; accepted 16 October 2003
Abstract—A series of para-substituted dianilino[24]crown-8 (DA24C8) macrocycles were synthesized and their ability to form host–
guest complexes with bis(4-fluorobenzyl)ammonium ions (DFAþ) were investigated. Although these crown ethers contain weakly
hydrogen bonding aniline motifs, they do bind DFAþ in CDCl3/CD3NO2 solution, presumably in a pseudorotaxane-like manner. A
plot of the values of the relative binding strengths (log½KaðRÞ=KaðHފ) versus the Hammett substituent constants rþ of the groups at
the para-position of the aniline units suggests that a linear free energy correlation exists for this self-assembly process. The strength
of the binding between the crown ether and the thread-like ion can be fine-tuned over a narrow range by judicious choice of the
substituting groups.
Ó 2003 Elsevier Ltd. All rights reserved.
The binding between dibenzo[24]crown-8 (DB24C8) and
various dibenzylammonium ions (DBAþ) has been in-
vestigated extensively for almost a decade.1 The favor-
able [Nþ–HÁ Á ÁO] and [Nþ–C–HÁ Á ÁO] hydrogen bonding
interactions between the ammonium ion and the ether
motifs of the macrocycle result in the interpenetration of
the DBAþ ion into the cavity of the DB24C8 macroring
to form a 1:1 pseudorotaxane2 complex. To date, the
geometry of this inclusion complex and the strong
noncovalent interactions between DB24C8 and DBAþ
units have led to efficient syntheses of many interlocked
molecular compounds, such as catenanes and rotax-
anes.3 DB24C8 cannot be substituted simply in a sym-
metrical manner, however, and this feature is one that
complicates stereochemical matters when it comes to
building intricate interlocked molecules from mono- or
bifunctional DB24C8 macrocycles.4 To overcome this
problem, other symmetrical crown ethers, such as bis-m-
phenylene-[26]crown-8 (BMP26C8)5 and dipyrido[24]-
crown-8 (DP24C8),6 have been synthesized and investi-
gated as alternative host molecules (Fig. 1).
is that the strong binding interactions between the
components can results in high activation energies and
corresponding slow rates of switching,8 which could be
drawbacks for their eventual use in high-speed devices.
Using components that bind less strongly would over-
come this problem, albeit at the expense of low yields for
their molecular assembly. Thus, in making high-speed,
symmetrical, machine-like molecules it would be useful
to be able to adjust the strength of the hydrogen
bonding interactions after assembly of the interlocked
N
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
An additional issue to address in preparing molecular
shuttles and molecular switches7 based on these species
DB24C8
BMP26C8
DP24C8
DA24C8
+
N
_
H2
Keywords: crown ethers; pseudorotaxanes; linear free energy correla-
tion.
PF6
.
DBA
PF
6
* Corresponding author. Tel.: +886-2-23690152x150; fax: +886-2-
24980963; e-mail: shchiu@ntu.edu.tw
Figure 1. Some crown ethers that bind to the thread-like DBAþ ion.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.132

214
S.-H. Chiu et al. / Tetrahedron Letters 45 (2004) 213–216
molecules. From this point of view, using the crown
ether dianilino[24]crown-8 (DA24C8)9 and its D2h-sym-
metrical substituted derivatives in the synthesis of
interlocked molecules may be a solution to these prob-
lems. The binding behavior between DA24C8 and
DBAþ has not been reported so far, but we expected
that it would be reasonably strong because of the pres-
ence of six aliphatic ether oxygen atoms and two aniline
nitrogen atoms (cf. DB24C8, which has four aliphatic
(strong) and four aromatic (weak) ether oxygen atoms)
in the crown ether that are capable of accepting
hydrogen bonds. Although we expected the aniline
nitrogen atoms to be quite weak hydrogen bond accep-
tors, because their lone pairs of electrons are positioned
perpendicular to the mean plane of the macrocycle
rather than within it,10 their basicity can be increased by
positioning electron-donating groups at their para-
positions,11 which would enhance the strength of bind-
ing between the crown ether and DBAþ ions. Thus, a
crown ether with strongly electron-donating groups
could be used in the synthesis of an interlocked mole-
cule, which is then modified with electron-withdrawing
groups that decrease the energy barrier for translation of
the macrocyclic ring. As a first steptoward such con-
trollable molecular devices, in this paper we report the
syntheses of a series of para-substituted DA24C8 mac-
rocycles and investigate their binding to bis(4-fluoro-
benzyl)ammonium hexafluorophosphate (DFAÆPF6).
the signals in the spectrum relative to the spectra of the
individual components. This result suggests that the
degree of binding between crown ether 6a and thread-
like ion DBAþ is negligible in CD3CN at 298 K. To
enhance the hydrogen bonding strength, we changed the
14
solvent to a 2:1 mixture of CDCl3 and CD3NO2 and
replaced DBAÆPF6 with the more-soluble DFAÆPF6.
Thus, when DFAÆPF6 and the crown ether 6a were
mixed together (20 mM) in CDCl3/CD3NO2 (2:1), we
observed the appearance of additional broad signals in
1
the H NMR spectrum recorded at 298 K. To monitor
the complexation more conveniently, we cooled the
solution to 223 K. At this temperature, more than half
of the components in the solution were complexed
(Fig. 2).
Upon complexation, the signal of the methylenþe protons
of DFAÆPF6 that are adjacent to the NH2 unit is
shifted downfield by 0.49 ppm, relative to its signal when
uncomplexed, to 4.46 ppm. The broad signal at 3.25–
3.60 ppm, which represents the resonances of the ethyl-
ene protons of the crown ether 6a, is split upon
complexation into four signals at 3.16, 3.41, 3.50 and
Scheme 1 depicts the route we used to synthesize the
substituted DA24C8 macrocycles 6a–d. Reactions of
excess p-substituted anilines 1a–d with the bistosylate 2
afforded diamines 3a–d. The diamines 3a–d were then
reacted with tetraethyleneglycoyl dichloride12 in dry
toluene under conditions of high dilution to give the
macrocyclic lactams 5a–d, which were subsequently
reduced smoothly by borane in THF into the corre-
sponding substituted DA24C8 macrocycles 6a–d. The
overall yields of these synthetic procedures, from ani-
lines 1a–d to crown ethers 6a–d, are between 18% and
33%. Crown ether 6e was synthesized in 78% yield from
crown ether 6d by a palladium-catalyzed amination.13
1
Figure 2. Partial 1H NMR spectrum [400 MHz, CDCl3/CD3NO2 (2:1),
223 K] of an equimolar mixture (20 mM) of 6a and DFAÆPF6, which
demonstrates that uncomplexed (uc) and complexed (c) species equil-
ibrate with one another slowly on this NMR spectroscopy timescale.
When a H NMR spectrum was obtained from a solu-
tion (20 mM) of both the crown ether 6a and dibenzyl-
ammonium hexafluorophosphate (DBAÆPF6) in CD3CN
at 298 K, we observed no significant movement of any of
R
R
N
R
N
Crown Ether
6a
R
R
Cl
O
CH3
1a-d
O
O
NH
NH2
O
6b
6c
6d
H
OMe
Br
O
O
O
O
O
O
+
OTs
BH3-THF
O
O
O
O
O
O
4
O
O
O
O
O
O
O
Cl
NH
R
N
R
N
R
O
6e
N
O
2
O
morpholine
OTs
3a-d
5a-d
6d
6e
Pd(OAc)2 /P( t-Bu)3
/ t-BuONa
Scheme 1. Syntheses of the DA24C8 derivatives.

S.-H. Chiu et al. / Tetrahedron Letters 45 (2004) 213–216
215
3.56 ppm, respectively. In the mixture, the signals of the
aromatic protons of 6a exist in two distinct groups:
sharp complexed and broad uncomplexed signals. These
signals are consistent with the notion that 6a and
DFAÆPF6 form a pseudorotaxane-like complex in
CDCl3/CD3NO2, with possible [Nþ–HÁ Á ÁO] and [Nþ–
HÁ Á ÁN] hydrogen bonding interactions. The fast-atom
bombardment (FAB) mass spectrum recorded on an
equimolar mixture of 6a and DFAÆPF6 reveals a peak at
m=zÀ765 corresponding to the 1:1 complex having lost its
PF6 ion.
formation between DFAÆPF6 and 6a was calculated to
be 15 MÀ1 at 298 K. We used this method to determine
the association constants for the complexes formed be-
tween DFAÆPF6 and the other substituted DA24C8
crown ethers;17 Table 1 lists the values of the association
constants and their derived free energies of association.
We note that among these crown ethers, it is macrocycle
6e, which bears the most-strongly electron-donating
substituents (morpholine units) on its aniline rings, that
binds most strongly to DFAÆPF6; the crown ether with
the most-electron-withdrawing bromine substituents
(6d) is the weakest binder. The values of DH° and DS° of
each complexation process were obtained from the
intercept and slope, respectively, of the straight line in
the plot of DG° versus T, which was obtained from the
variable-temperature NMR spectroscopy experiments.
The negative values of DH° and DS° in each case suggest
that these complexation events are enthalpy-driven
processes. A linear free energy correlation has been
reported in the supramolecular complexation between
DB24C8 and variety of meta- and para-substituted
DBAþ ions.15b The electronic nature of the substituents
on the DBAþ unit affects the NHþ2 centerꢀs ability to
donate a hydrogen bond and the ability to form p–p
stacking interactions between the substituted benzyl unit
and the catechol ring of the DB24C8 macrocycle. From
Table 1, it is clear that the strength of the binding
between DA24C8 derivatives and DFAþ ions is related
to the electronic nature of the substituents on the aniline
units of the macrocycles. To examine whether a linear
free energy correlation exists in this case or not, the
relative association constants (log½KaðRÞ=KaðHފ) for
pseudorotaxane formation between the fluoro-substi-
tuted salt DFAÆPF6 and the substituted crown ethers
We could not accurately determine the association
1
constant for this assembly by H NMR spectroscopy
using the single-point method15 at either 223 or 298 K
because of difficulty in integrating the broad and, in
some cases, overlapping signals; instead, the binding
constant was elucidated at 298 K using 19F NMR spec-
troscopy.4b As expected, a solution (20 mM) of a mix-
ture of the salt DFAÆPF6 and the crown ether 6a gave an
19F NMR spectrum at 298 K having sharp and distin-
guishable signals (Fig. 3). The signals appearing at
)112.94 and )111.23 ppm were assigned to the uncom-
plexed and complexed DFAþ ions, respectively, based
on a literature precedent.4b;16 By integration of these
signals, the association constant for pseudorotaxane
were plotted against the substituent constant (rþ).18
A
straight line is the result (Fig. 4), which suggests that a
linear free energy correlation does exist for this supra-
molecular complexation event. The slope of the straight
line, which corresponds to the value of for the com-
plexation process, is ca. )0.28. The linear tendency
implies that the binding strength between DFAþ and
other substituted DA24C8 macrocycles may be closely
estimated simply by knowing the value of rþ of the
substitutents.
Figure 3. Partial variable-temperature 19F NMR spectra [376 MHz,
CDCl3/CD3NO2 (2:1)] of an equimolar mixture (20 mM) of 6a and
DFAÆPF6.
The negative value of q suggests that the fluoro-substi-
tuted salt DFAÆPF6 favors complexation with DA24C8
macrocycles
bearing
strongly
electron-donating
Table 1. Stability constantsa (Ka) and derived thermodynamic data for the complexation of substituted DA24C8 macrocycles and DFAÆPF6
a
b
c
c
Crown ether
Ka (MÀ1
)
ÀDG° (kcal molÀ1
)
DH° (kcal molÀ1
)
DS° (cal molÀ1 KÀ1
)
6a
6b
6c
6d
6e
15
11
16
8
1.60
1.42
1.64
1.23
2.02
)4.7 0.7
)4.3 0.5
)6.3 0.8
)4.0 0.4
)8.8 1.1
)10.7 2.8
)10.3 2.0
)15.5 2.8
)9.2 1.7
)22.7 4.0
30d
a Stability constants (Ka) were obtained as outlined in Ref. 15 based on the 19F NMR spectra in CDCl3/CD3NO2 (2:1) at 298 K (error 6 15%).
b The free energy of complexation (ÀDG°) was calculated from each value of Ka using the equation ÀDG° ¼ RT ln Ka.
c The values of DH° and DS° were obtained from the intercept and slope of the straight line in the plot of DG° versus T using the relationship
DG° ¼ DH° À TDS°.
d The samples were prepared by dissolving freshly prepared 6e in the degassed deuterated solvent: they were then kept in the dark to minimize any
possible photooxidation.

216
S.-H. Chiu et al. / Tetrahedron Letters 45 (2004) 213–216
4. (a) Ashton, P. R.; Baxter, I.; Cantrill, S. J.; Fyfe, M. C. T.;
log[K (R)/K (H)]
Glink, P. T.; Stoddart, J. F.; White, A. J. P.; Williams, D.
J. Angew. Chem., Int. Ed. 1998, 37, 1294–1297; (b)
Cantrill, S. J.; Youn, G. J.; Stoddart, J. F.; Williams, D.
J. J. Org. Chem. 2001, 66, 6857–6872.
a
a
N
O
0.5
CH3
OMe
ρ
= -0.28
5. (a) Bryant, W. S.; Guzei, I. A.; Rheingold, A. L.; Merola,
J. S.; Gibson, H. W. J. Org. Chem. 1998, 63, 7634–7639;
(b) Cantrill, S. J.; Fulton, D. A.; Heiss, A. M.; Pease, A.
R.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. Chem.
Eur. J. 2000, 6, 2274–2287.
H
σ+
-1.5
-1.0
-0.5
0.5
Br
-0.5
6. Chang, T.; Heiss, A. M.; Cantrill, S. J.; Fyfe, M. C. T.;
Pease, A. R.; Rowan, S. J.; Stoddart, J. F.; White, A. J. P.;
Williams, D. J. Org. Lett. 2000, 2, 2947–2950.
7. Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F.
Angew. Chem., Int. Ed. 2000, 39, 3348–3391.
8. Cao, J.; Fyfe, M. C. T.; Stoddart, J. F. J. Org. Chem.
2000, 65, 1937–1946.
Figure 4. Hammett correlation between log½KaðRÞ=KaðHފ and rþ in
CDCl3/CD3NO2 (2:1) at 298 K. The slope of the straight line obtained
corresponds to the supramolecular reaction constant (q).
9. Ghorbanian, S.; Mehta, L. K.; Parrick, J.; Robson, C. H.
Tetrahedron 1999, 55, 14467–14478.
10. There are [N–HÁ Á ÁN] hydrogen bonding interactions in
the solid-state structure of a [2]rotaxane comprised of a
DBAþ ion and a crown ether containing an aniline-like
unit. See: Glink, P. T.; Oliva, A. I.; Stoddart, J. F.; White,
A. J. P.; Williams, D. J. Angew. Chem., Int. Ed. 2001, 40,
1870–1875.
11. (a) Summerhays, K. D.; Pollack, S. K.; Taft, R. W.;
Hehre, W. J. J. Am. Chem. Soc. 1977, 99, 4585–4587; (b)
The Chemistry of the Amino Group; Patai, S., Ed.; VCH-
Wiley: London, 1968.
12. Lehn, J.-M. U.S. Patent 888,877, 1975; Chem. Abstr.
1976, 85, 160192x.
13. (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S.
L. Acc. Chem. Res. 1998, 31, 805–818; (b) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046–2067.
14. The binding constant between DB24C8 and DBAþ is
400 MÀ1 in CD3CN, but it is much higher in CDCl3
27,000 MÀ1; see: Ashton, P. R.; Campbell, P. J.; Chrystal,
E. J. T.; Glink, P. T.; Menzer, S.; Philp, D.; Spencer, N.;
Stoddart, J. F.; Tasker, P. A.; Williams, D. J. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1865–1869, and in
CD3NO2 (8000 MÀ1).
15. (a) Ashton, P. R.; Chrystal, E. J. T.; Glink, P. T.; Menzer,
S.; Schiavo, C.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.;
White, A. J. P.; Williams, D. J. Chem. Eur. J. 1996, 2,
709–728; (b) Ashton, P. R.; Fyfe, M. C. T.; Hicking-
bottom, S. K.; Stoddart, J. F.; White, A. J. P.; Williams,
D. J. J. Chem. Soc., Perkin Trans. 2 1998, 2117–
2124.
substitutents. The small value of q implies that it is
possible to modify the binding affinity between the
crown ether and the thread-like ion over a reasonable
range by controlling the electronic properties of the
substitutents on the aniline ring, but that the magnitude
of this change in the association constant is not dra-
matic. Since a simple oxidation reaction can readily
convert the electron-donating methyl groups of macro-
cycle 6a into more-electron-withdrawing formyl groups,
and that an amination reaction can translate the mac-
rocycle 6d into a fourfold stronger binder (6e), it seems
reasonable to expect that judicious choice of the sub-
stituent on the crown ether, coupled with a suitable
post-assembly modification, would allow the prepara-
tion of speed-controllable machine-like molecules.
We have synthesized a series of DA24C8 derivatives and
demonstrated that their affinity for binding with DFAþ
ions can be fine-tuned by judicious choice of substitu-
ents. We are now trying to assemble this recognition
system into a [2]rotaxane through dynamic imine for-
mation.19
Acknowledgements
16. 19F NMR spectra were recorded on a Varian Unity Plus
(376 MHz) spectrometer and are referenced to C6F6
()163.0 ppm) present as a CH2Cl2 solution in an internal
capillary tube.
We thank the National Science Council for financial
support (NSC 91-2113-M-002-055).
17. The values of Ka for the binding of DFAÆPF6 and 6d in
CDCl3/CD3NO2 (2:1) were determined at 273, 263, 253,
243, and 233 K from the recorded 19F NMR spectra using
a single-point method (see, i.e. Ref. 4b). Extrapolation of
the vanꢀt Hoff plot obtained using these data gives a value
References and Notes
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Jones, J. W. J. Am. Chem. Soc. 2003, 125, 3522–
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2. Asakawa, M.; Ashton, P. R.; Balzani, V.; Boyd, S. E.;
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Raymo, F. M.; Ruffilli, C.; Stoddart, J. F.; Venturi, M.;
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3. Molecular Catenanes, Rotaxanes and Knots; Sauvage,
J.-P., Dietrich-Buchecker, C., Eds.; VCH-Wiley: Wein-
heim, 1999.
for Ka at 298 K of about 8 MÀ1
.
18. Since the electron density of the para-substituents of the
aniline ring can interact both inductively and mesomer-
ically to the aniline N-atom (see, Ref. 11b)––the hydrogen
bonding interacting site––the substitution constant rþ
was applied instead of r values. See: (a) Okamoto, Y.;
Brown, H. C. J. Org. Chem. 1957, 22, 485–494; (b) Brown,
H. C.; Okamoto, Y. J. Am. Chem. Soc. 1958, 80, 4979–
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K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41,
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