An Inhospitable Cryptand: The Importance of Conformational Freedom in Host-Guest Complexation

Article abstract of DOI:10.1002/ejoc.201900038

Two new cryptands were synthesized from bis(5-bromomethyl-1,3-phenylene)-32-crown-10 (4). The third arms, containing 19 or 21 atoms, were installed via Williamson ether syntheses with bisphenols containing 2,6-disubstituted pyridines. 2,6-Diaminopyridine

Full text of DOI:10.1002/ejoc.201900038

A Journal of
Accepted Article
Title: An Inhospitable Cryptand: the Importance of Conformational
Freedom in Host-Guest Complexation
Authors: Harry W. Gibson, Feihe Huang, Run Zhao, Li Shao, Lev N.
Zhakharov, Carla Slebodnick, and Arnold L. Rheingold
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900038
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10.1002/ejoc.201900038
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An Inhospitable Cryptand: the Importance of Conformational Freedom in
Host-Guest Complexation
Harry W. Gibson,[a]* Feihe Huang,[a,b] Run Zhao,[b] Li Shao,[b] Lev N. Zakharov,[c,d] Carla
Slebodnick,[a] Arnold L. Rheingold [c]
Dedication. To the creative pioneers of supramolecular chemistry: Wasserman, Schill, Zollenkopf, Harrison and Zilkha and co-
workers.
Abstract: Two new cryptands were synthesized from bis(5-
bromomethyl-1,3-phenylene)-32-crown-10 (4). The third arms,
The cryptands we investigated earlier displayed very strong
binding with viologens, forming pseudorotaxanes; these hosts
contained pyridine rings in the third arms, prepared from
pyridine-2,6-dicarboxylic acid and the crown ether diols. In the
belief that a similar design using Williamson ether ring closures
but incorporating a diamino pyridine as a binding site would
result in even more powerful viologen binding, i. e., dilactams
instead of dilactones, cryptand 5 was prepared according to
Scheme 1. 2,6-Diaminopyridine was reacted with p-
benzyloxybenzoyl chloride (1)4 to afford the new protected
bisphenol 2; deprotection via hydrogenolysis afforded new
bisphenol 3 essentially quantitatively. Cyclization via Williamson
ether condensation of bis(5-bromomethyl-1,3-phenylene)-32-
crown-10 (4)5 with 3 produced the desired cryptand 5 in modest
untemplated yield.
containing 19 or 21 atoms, were installed via Williamson ether
syntheses with bisphenols containing 2,6-disubstituted pyridines.
2,6-Diaminopyridine was converted to the bis(p-hydroxybenzoyl)
derivative 3 for the first cryptand (5) and 2,6-dicarboxypyridine was
converted to the bis(p-hydroxybenzylamide)
9 for the second
cryptand (10). Cryptand 5 did not complex viologen derivatives
1
11−13 to an extent detectable by H NMR. We attribute the lack of
complexation between viologen derivatives and 5 to its lack of
conformational flexibility that prevents π-stacking,
a necessary
component for complexation of viologens. In contrast longer and
more flexible cryptand 10 did complex dimethyl paraquat (11) with Ka
3
1
o
−
= 1.6 (± 0.2) x 10 M in acetone at 23 C, probably by π-stacking
with the p-oxybenzyl moieties of the host, made available by its
enhanced flexibility.
O
O
COCl
HN
N
HN
N
b
a
Introduction
O
OH
O
OBn
HN
In our quest to find hosts that bind viologens (N,N’-dialkyl-
4,4’-bipyridinium salts) and/or diquats (N,N’-ethylene-2,2’-
bipyridinium salts) very strongly, over the last two decades we
developed cryptands from crown ethers,1 the best of which
provide binding constants in the range from 105 to > 106 M-1 at
HN
OBn
1
2
3
OH
OBn
O
O
O
4
O
O
O
o
25 C.1c,1d,1f,1h,1j,1m-1p We also developed templated, high-yielding
Br
Br
1i,2
+ 3
syntheses of dibenzo crown ethers
as well as a templated
method for converting dibenzo and bis(m-phenylene) crown
ethers to dilactone cryptands whose third arms contain 2,6-
dicarboxypyridine units as effective additional binding sites.3
However, not all cryptands provide strong binding with viologens.
Here we report two such cryptands designed along these lines.
c
1 a
3
O
O
O
O
O
HN
N
O
Results and Discussion
5
O
O
NH
O
a. Sytheses of New Cryptands
O
O
O
O
O
[a]
[b]
Department of Chemistry, Virginia Tech, Blacksburg, VA 24060
USA. hwgibson@vt.edu. http://www.gibson.chem.vt.edu/
State Key Laboratory of Chemical Engineering, Center for
Chemistry of High-Performance & Novel Materials, Department of
Chemistry, Zhejiang University, Hangzhou, P R China
Department of Chemistry, University of California, San Diego, La
Jolla, CA 92093-0358, USA
[c]
[d]
Scheme 1. Synthesis of cryptand 5. a. 2,6-diaminopyridine/Et3N, DCM, RT,
60%. b. H2/Pd/C, EtOH, RT, 98%. c. K2CO3/n-Bu4NI, DMF, RT-110 oC, 41%.
Present address: Department of Chemistry, University of Oregon,
Eugene, OR 97403, USA
Supporting information for this article is given via a link at the end of
the document.
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As an alternative we also prepared cryptand 10 via the route
indicated in Scheme 2. Here p-benzyloxybenzylamine (7), a
known compound,6 was prepared from the corresponding nitrile
6.7 The amine 7 was reacted with 2,6-pyridinedicarbonyl
chloride to produce new protected bisphenol 8, which upon
hydrogenolysis afforded the new bisphenol 9. Williamson ether
cyclization of 4 and 9 yielded the new cryptand 10, again in
modest untemplated yield.
thought was that instead of being a cryptand, 5 is really a
[1]rotaxane or a pseudo[1]catenane, as shown schematically in
Figure 2.
The intermediates and both cryptands were characterized
satisfactorily via NMR and mass spectrometry.
CH2NH2
CN
O
O
O
N
O
a
b
N
c
NH
NH
NH
NH
OBn
7
OBn
6
OBn
OBn
OH
OH
8
9
Figure 1. 1H NMR spectra (400 MHz, 2.5:1 v:v CD3COCD3:CDCl3, 22 °C) of
2.29 mM 5 (top), 2.29 mM 5 and 2.22 mM 11 (second from top), 2.29 mM 5
and 2.22 mM 12 (third from top), and 2.29 mM 5 and 2.22 mM 13 (bottom).
O
O
O
4
O
O
Br
Br
+ 9
1 a
O
d
3
O
O
O
O
O
HN
O
O
O
10
1
N
4
O
O
Figure 2. Schematic representation of a) left, a cryptand and b) right, its
isomer, a [1]rotaxane or a pseudo[1]catenane.
O
2
13
HN
6
5
9
O
3
O
7
12
8
O
11
10
[1]Rotaxanes have been reported, but they all consist of
cyclic hosts bearing a long linear substituent with a bulky
terminal group,11 so the structure shown in Figure 2 is better
called a pseudo[1]catenane. Pseudo[1]catenanes have also
been reported; these consist of in-out isomerization of fused or
nearly fused ring systems;11a,12 nearly fused means that the ring
Scheme 2. Synthesis of cryptand 10. a. LAH/AlCl3, Et2O, RT,
91%. b. pyridine-2,6-dicarbonyl chloride/Et3N, THF, RT, 82%. c.
H2/Pd/C, EtOH, RT, 99%. d. K2CO3/KCl/n-Bu4NI, DMF, RT-110
oC, 41%.
b. Studies of Complexation of Cryptand 5 with Viologens
To probe the abilities of the cryptand to complex viologens,
juncture on the initial macrocyclic is rather short, ca. four atoms.
three compounds were selected;
11, 12 and 13 were prepared as
13
2 PF6
Some systems called quasi[1]catenanes
have also been
reported; these consist of two rings sharing a spiro linkage
constructed by step-wise chemistry a la Schill.14 It seems that no
pseudo[1]catenane of the sort shown in Figure 2 formed by
hydrogen bond induced self-threading across the width of the
initial macrocycle has been reported. Therefore, we believe such
a structure would be unique at this time.
previously reported.8,9
R
N
N R
The proton NMR spectra of
cryptand 5 and its solutions with
the three viologen derivatives are
shown in Figure 1; a mixed solvent
11: R = CH3
12: R = CH2CH2OH
13: R = CH2CH2OOCNHC6H5
system was used because the viologens are not sufficiently
soluble in CDCl3. Strikingly, it can be seen that no change of
chemical shifts corresponding to hydrogen atoms of host 5 can
be observed, indicating that the expected complexations did not
occur! This was confirmed by the lack of color in the solutions;
usually hosts with aromatic rings form charge transfer
complexes with viologens, leading to colors varying from yellow
to dark orange or red.1,10 Moreover, attempts to grow crystals
from the solutions yielded only mixtures of the cryptand and the
guest; no complexes resulted. The question is: why? Our first
In comparison to the previous cryptands1 we examined, the
third arms in 5 and 10 differ in two important ways: 1) the arm is
longer, in 5 containing 19 atoms and in 10 21 atoms, as
opposed to 9-13 atoms in previous cryptands and 2) the
presence of the amide groups in place of ether or ester moieties.
These two factors could allow the third arm to thread through the
cavity of the crown ether simply by inverting one of the
phenylene rings in a process driven by hydrogen bonding of the
amide NH moieties with the ether oxygen atoms as shown in
Figure 3,
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1
2
O
N
N
H
N
H
O
d. Crystal Structure of Cryptand 5
3
With great anticipation a suitable crystal of the cryptand
was grown from a chloroform:acetone (2.5:1.0 v:v) solution and
subjected to X-ray diffraction. In the event, as shown in Figure 6,
we were disappointed to find that in the solid state there was no
evidence of self-threading of the type depicted in Figure 3.
Instead, from the single molecule perspective (Figure 6a) the
structure was open as initially expected from the CPK modeling.
However, a look at the packing (Figure 6b, 6c, 6d) reveals
that the molecules are inter-nested in infinite chains oriented
antiparallel to each other, consistent with the open clam-shell-
like structure of the individual molecule. The closely packed
molecules are held together by hydrogen bonds (α and β) to
adventitious bridging water molecules between the amide NHs
and ether oxygen atoms, in addition to dispersion forces.
4
5
O
O
O
O
1a
O
O
O
O
O
O
8
6
7
O
O
9
11
10
5h
O
O
O
O
1a
O
O
O
O
O
N
H
N
HN
O
O
O
O
5c
O
Figure 3. Possible equilibration of cryptand 5h (h for host) to isomeric 5c (c
for pseudo[1]catenane via inversion of one of the m-phenylene rings of the
crown ether driven by hydrogen bonding of the amide moieties to the ether
oxygen atoms.
c. The Influence of Solvent Polarity on Purported
Equilibration of Cryptand 5
To provide evidence for the putative formation of the
pseudo[1]catenane isomer 5c, 1H NMR spectra were recorded in
solvents of varying polarity as shown in Figure 4. Note that in
chloroform the N-H protons (labeled 3) yield two distinct and
sharp, but unequal signals, while in the mixed solvent and
DMSO only one broader signal is observed. In the latter two
cases hydrogen bonding of 5 with the solvents is possible.
Correspondingly the signals for the ethyleneoxy protons (labeled
9 – 11) are shifted downfield in CDCl3 as expected for hydrogen
bonding of the amide NHs to the ether oxygen atoms. In CDCl3
the hydrogen bonding could either be inter- or intra-molecular,
the latter corresponding the 5c. This result is not conclusive,
however. The NOESY spectrum (see SI) did not reveal any
through-space interactions indicative of 5c.
Figure 4. 1H NMR spectra (400 MHz, 22 °C) of 5 in CDCl3 (top), in 2.5:1 v:v
CD3COCD3/CDCl3 (middle), and DMSO-d6 (bottom). For numbering see Figure
3. Peak assignments made via COSY; see SI.
Turning to Corey-Pauling-Kortun (CPK) models we sought
confirmation of the ability of 5 to self-thread. However, they
showed that self-threading is not possible for cryptand 5
because the linkages in the third arm are too rigid to allow this.
As shown in Figure 5 the rigidity forces the cavity to be open
and apparently receptive to guests. Therefore, the reason for the
lack of complexation of viologens is not self-threading. What
then is the reason for this unexpected inhospitality??
Figure 5. Photographs of a CPK model of cryptand 5 showing its open cavity.
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Figure 6. X-ray crystal structure of cryptand 5 (CCDC no. pending): a) top,
stick and space filling representations of the individual molecule; b) middle,
stick representation of the truncated infinite chain of inter-nested cryptand
molecules (with non-interacting hydrogen atoms deleted); distance (angle) N--
O 2.93 Å, (N)H—O (α) 2.11 Å (155.67 o), O—O 2.84 Å, (O)H—O (β) 1.95 Å
(172.15 o); c) second from bottom, space filling representation (with non-
interacting hydrogen atoms deleted) of the truncated infinite chain of inter-
nested cryptand molecules; d) bottom, cartoon representation of inter-nested
cryptand molecules. Disordered solvent molecules are not shown.
α
α
α
β
β
β
H10 on the host 10 move upfield strongly upon complexation, as
do protons Hb and Hc of the guest paraquat; protons H4 and H5
move downfield and the ethylenexy protons merge into one
signal. These chemical shift changes are consistent with
previous observations of viologen complexes of cryptands based
on bis(m-phenylene)-32-crown-10.1a 1d,1l
−
!
Inasmuch as self-threading of 5 is impossible, its lack of
complexation with viologens must be attributed to something
else.
We initially suggested that aggregation in solution
analogous to that observed in the crystal structure, leading to
dimers, trimmers etc., prevented viologen complexation; the lack
of complexation of 5 with viologens at 2.00 mM concentrations
would thus imply that the dimerization constant is quite high, i. e.,
> 8 x 104 M-1, to consume ≥ 91% of the cryptand.
However, an astute and dutiful reviewer suggested a more
plausible explanation. As shown in Figure 6a and confirmed by
CPK models, the rigidity of the pyridyl-containing arm places the
1,3,5-phenylene rings of the cryptand 10.40 Å apart (centroid to
Figure 7. Photograph of a CPK model of viologen 11 in the flattened cavity of
cryptand 5.
centroid) and maintains them in
a
nearly orthogonal
o
arrangement (80.19 ). Complexation of viologens is primarily
driven by π-stacking of the electron poor pyridinium rings with
the electron rich aromatic rings of the host, which requires a
parallel arrangement and separation of the latter by ca. 7 Å; here
the conformational rigidity of 5 prevents this interaction. This is
shown in Figure 7; guest 11 is easily accommodated in the
large cavity of crypand 5, but the 1,3,5-phenylene rings of the
cryptand cannot π-stack with it nor can the aromatic rings of the
p-oxybenzoyl moiety, which lie 10.69 Å apart at a 56.36 o angle.
Hence there are no non-covalent binding forces to form a
complex between 5 and 11.
e. Studies of Complexation of Cryptand 10 with a Viologen
At this juncture we did not hold much hope that cryptand 10
would be receptive to viologen guests. However, to our surprise,
in fact, dimethyl paraquat (11) did form a 1:1 complex with 10 in
acetone as shown in Figure 8. Note that protons H7, H8, H9 and
Figure 8. Partial 1H NMR spectra (400 MHz, acetone-d6, 23 oC): a) 1.00 mM
cryptand 10, b) 1.00 mM 10 + 1.00 mM paraquat (11), c) 1.00 mM paraquat
(11). For numbering of the cryptand, see Scheme 2.
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By the Job plot (Figure 9) the stoichiometry of the complex
was established to be 1:1. The chemical shift of the fully
complexed cryptand (Δo) was determined and this value was
then used to calculate the binding constant of 10:11, Ka = 1.6 (±
for complexation is not sufficient; achieving the proper geometric
orentations through conformational flexibility is also necessary.
3
1
0.2) x 10 M at 23 oC.15 This value, however, is 1000-fold lower
that similar cryptands with shorter third arms.1d This Ka is 3–fold
higher than that of bis(m-phenylene)-32-crown-10 itself, which
displays Ka = 0.55 x 103 M-1 with paraquat 11 under these
conditions.1b
−
Figure 10. Photograph of a CPK model of cryptand 10 showing its open cavity
and nearly parallel p-oxybenzyl aromatic rings.
Experimental Section
Measurements, Materials: 1H NMR spectra were obtained on JEOL
Eclipse-500, Bruker 500 and Agilent NMR vnmrs400 spectrometers; 13C
NMR spectra were collected on these instruments at 126, 126 and 101
MHz, respectively. 1H NMR splitting abbreviations: s (singlet), d (doublet),
t (triplet), q (quartet), quin (quintet), sex (sextet), h (heptet); coupling
constants, J, are in Hz. High resolution mass spectra (HR MS) were
obtained on a JEOL Model HX 110. Melting points were determined on a
Mel-Temp II apparatus and are uncorrected. Reagents were purchased
Figure 9. Job plot for interaction of cryptand 10 with dimethyl paraquat (11) in
acetone-d6 at 23 oC. Total concentration = 1.00 mM.
A new question is raised: why do 5 and 10 behave so
differently in complexation experiments with viologens? We
conclude that the longer third arm of 10 relative to that in 5
renders it more flexible, consistent with CPK models and with
the fact that 10 is not a crystalline material; the addition of the
two benzylic methylene groups in 10 relieves the rigidity induced
through conjugation of the doubly aromatic amide linkages of 5.
The lower Ka of cryptand 10 with 11 relative to earlier cryptands
probably reflects the remaining rigidity of the third arm, which as
with host 5 probably prevents π-stacking of the 1,3,5-phenylene
rings of the cryptand with the guest as indicated in Figure 10.
However, this model also reveals that the two p-oxybenzyl
moieties are nearly parallel and able to sandwich guest 11 by π-
stacking. Unfortunately we were unable to obtain crystals of the
host−guest complex 10:11 suitable for X-ray diffraction to assess
this hypothesis.
and used as received unless otherwise noted. p-Benzyloxybenzoyl
5
chloride,4 bis(5-bromomethyl-1,3-phenylene)-32-crown-10 (4)
benzyloxybenzonitrile 6 were prepared via literature procedures.
and p-
2,6-Bis(p-benzyloxybenzoylamino)pyridine (2). Before the reaction,
dichloromethane (DCM) was dried over molecular sieves and
triethylamine was dried over KOH. A solution of p-benzyloxybenzoyl
chloride4 (1, 9.87 g, 40 mmol) in dry DCM (40 mL) was added dropwise
to an ice-cooled mixture of 2,6-diaminopyridine (2.19 g, 20 mmol) and dry
triethylamine (5.60 mL, 40 mmol) in dry DCM (120 mL). The mixture was
stirred for 12 h at room temperature (RT); then the reaction was
quenched with 20 mL of water, the organic layer was separated, washed
with water, dried with magnesium sulfate, and concentrated under
reduced pressure. The crude product was recrystallized from ethanol to
give pure 2 (5.01 g, 60%), mp 226.1−227.0 °C. 1H NMR (400 MHz,
CD3SOCD3, 22 °C) δ (ppm): 5.22 (4H, s), 7.14 (4H, d, J = 9 Hz), 7.42
(10H, m), 7.86 (3H, m), 8.02 (4H, d, J = 9 Hz), and 10.31 (2H, s). HR MS
FAB+ m/z: calcd. for [M+H]+, (C33H28N3O4)+: 530.20743; found:
530.20868 (error 0.43 ppm).
Conclusions
Two new dilactam cryptands, 5 and 10, based on bis(m-
phenylene)-32-crown-10 and containing long third arms were
prepared. NMR experiments showed that 5 did not complex any
of the three viologens tested. X-ray crystallography revealed that
the 1,3,5-phenylene rings of 5 in the solid state were nearly
orthogonal with each other and were too far apart to π-stack with
viologens, CPK models indicated the conformational rigidity of
the structure, which disallowed reorganization to accommodate
2,6-Bis(p-hydroxybenzoylamino)pyridine (3). A positive pressure (~ 40
psi) of H2 was maintained for 48 h over a vigorously shaken suspension
of 1.20 g (2.27 mmol) of benzyl ether 2 and 0.10 g Pd/C in 50 mL of
anhydrous ethanol. After removal of the catalyst by filtration, the solvent
was rotoevaporated to afford 3, 0.77 g (98%), mp 285.8−286.5 °C. 1H
NMR (400 MHz, CD3SOCD3, 22 °C) δ (ppm): 4.34 (2H, s), 6.83 (4H, d, J
= 9 Hz), 7.81 (3H, s), 7.88 (4H, d, J = 9 Hz), and 10.10 (2H, s). HR MS
FAB+ m/z: calcd. for [M+H]+, (C19H16N3O4)+: 350.11353; found:
350.11371 (error 0.51 ppm).
the guest. In contrast cryptand 10 did complex dimethyl
3
paraquat (11), with Ka = 1.6 (± 0.2) x 10 M 1 in acetone at 23 oC;
−
the more flexible third arm of 10 allows the two p-oxybenzyl
aromatic rings to be parallel and we propose that they interact
with the guest via π-stacking to stabilize the complex. These
results re-emphasize the fact that having the right components
Cryptand 5. A solution of 1.50 g (2.08 mmol) of crown ether dibromide 4
in 40 mL of DMF and a solution of 0.725 g (2.08 mmol) of bisphenol 3 in
40 mL of DMF were made. On the first day 10 mL of each solution were
added into a stirred suspension containing potassium carbonate (2.87 g,
20.8 mmol) and tetrabutylammonium iodide (5 mg) in 1600 mL of DMF at
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RT. After that, 5 mL of each were added every two days. After complete
addition, the reaction mixture was stirred at 110 °C for 7 days. The
cooled mixture was evaporated to remove DMF, treated with chloroform,
and filtered. Removal of chloroform afforded a crude product which was
purified by flash column chromatography (silica), eluting with 1:1 v:v
hexane/ethanol and gradually increasing to ethyl acetate to give 0.77 g
(41%) of 5, mp 213.4-214.9 °C. 1H NMR (400 MHz, CDCl3, 22 °C) δ
(ppm): 8.05 and 8.02 (2H, s), 7.97 (2H, d, J = 8 Hz), 7.77 (1H, t, J = 8 Hz),
7.70 (4H, d, J = 9 Hz), 6.87 (4H, d, J = 9 Hz), 6.46 (2H, d, J = 2 Hz), 6.41
(4H, t, J = 2 Hz), 5.21 (4H, s), 4.06 (8H, t, J = 5 Hz), 3.83 (8H, t, J = 5 Hz),
and 3.70 (16H, m). 1H NMR (400 MHz, 2.5:1 v:v CD3COCD3:CDCl3,
22 °C) δ (ppm): 9.05 (2H, s), 7.92 (2H, d, J = 8 Hz), 7.78 (1H, t, J = 8 Hz),
7.70 (4H, d, J = 9 Hz), 6.92 (4H, d, J = 9 Hz), 6.52 (2H, d, J = 2 Hz), 6.46
(4H, t, J = 2 Hz), 5.27 (4H, s), 4.09 (8H, t, J = 5 Hz), 3.80 (8H, t, J = 5 Hz),
and 3.63 (16H, m). 1H NMR (400 MHz, CD3SOCD3, 22 °C) δ (ppm):
10.00 (2H, s), 7.82 (1H, m), 7.77 (4H, d, J = 8 Hz), 7.74 (1H, br), 7.72
(1H, m), 6.96 (4H, d, J = 8 Hz), 6.47 (4H, d, J = 4 Hz), 6.46 (2H, d, J = 4
chromatography (silica), eluting with ethyl acetate and gradually
increasing to 1:1 ethyl acetate:methanol to afford 10 as a viscous oil,
0.26 g (40%), which did not crystallize. 1H NMR (400 MHz, CDCl3, 22 °C)
δ (ppm): 8.42 (2H, d, J = 8 Hz), 8.10 (1H, t, J = 8 Hz), 7.81 (2H, t, J = 6
Hz), 7.24 (4H, d, J = 9 Hz), 6.93 (4H, d, J = 9 Hz), 6.51 (4H, d, J = 2 Hz),
6.38 (2H, t, J = 2 Hz), 4.93 (4H, s), 4.63 (4H, d, J = 6 Hz), 3.98 (8H, t, J =
5 Hz), 3.85 (8H, t, J = 5 Hz), and 3.68−3.75 (16H, m). LR MS FAB+ (NBA)
m/z: calcd. for [M]+, (C51H59O14N3)+ 937.4; found 937.3. HR MS FAB+
(NBA/PEG) m/z: calcd. for [M + H]+, (C51H60O14N3)+, 938.40698; found
938.41180 (error 5.5 ppm).
Acknowledgments
Hz), 5.30 (4H, s), 4.04 (8H, t, J = 4 Hz), 3.70 (8H, t, J = 6 Hz), and 3.52
We thank the National Science Foundation for supporting this
work through Grant DMR0097126. We are very grateful to an
incisive and thoughtful reviewer who suggested a more plausible
explanation of our results based on the conformational
properties of the new cryptands.
(16H, m). HR MS FAB+: calcd. for [M+H]+, (C49H56N3O14
found 910.37579 (error 0.12 ppm).
)
910.37568;
+
4-Benzyloxybenzylamine (7). First 2.4 g (18 mmol) of AlCl3 was added
to a 250 mL three-necked round bottom flask with 35 mL of Et2O and
equipped with a magnetic stirrer. The resultant solution was added
dropwise into another 500 mL three-necked round bottom flask filled with
a mixture of 0.69 g (18 mmol) of LiAlH4, 3.15 g (15 mmol) of 4-
benzyloxybenzonitrile (6)6 and 30 mL of Et2O and equipped with a
magnetic stirrer. The reaction mixture was kept at RT for 3 h. Water (100
mL) was added dropwise to the flask. The organic and water layers were
separated. The aqueous layer was extracted with Et2O (100 mL × 2). The
combined organic layer was dried over Na2SO4 and concentrated under
reduced pressure to yield the product (2.91 g, 91%), mp 116.2−117.5 °C;
lit. mp 117 °C.6 1H NMR (400 MHz, CD3SOCD3, 22 °C) δ (ppm): 3.95 (2H,
s), 5.14 (2H, s), 7.06 (2H, d, J = 9 Hz), 7.39 (7H, m), and 8.16 (2H, br, s).
Keywords: cryptand, inhospitable non-host cryptand, viologen,
pseudorotaxane complex, conformational flexibility
1.
a. W. S. Bryant, J. W. Jones, P. E. Mason, I. Guzei, A. L. Rheingold, F.
R. Fronczek, D. S. Nagvekar, H. W. Gibson, Org. Lett. 1999, 1, 1001-
1004;
b. F. Huang, H. W. Gibson, W. S. Bryant, D. S. Nagvekar, F. R.
Fronczek, J. Am. Chem. Soc. 2003, 125, 9367-9371;
c. F. Huang, L. Zhou, J. W. Jones, H. W. Gibson, M. Ashraf-
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d. F. Huang, K. A. Switek, L. N. Zakharov, F. Fronczek, C. Slebodnick
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e. F. Huang, K. A. Switek, H. W. Gibson, Chem. Commun. 2005, 3655-
3657;
2,6-Bis(p-benzyloxybenzylaminocarbonyl)pyridine (8). To a solution
of 4-benzyloxybenzylamine (7, 2.13 g, 10 mmol) and Et3N (2.5 mL, 18
mmol) in THF (50 mL) was added 2,6-pyridinedicarbonyl dichloride (0.98
g, 4.8 mmol) in THF (30 mL) dropwise at RT. The resulting mixture was
allowed to stir at RT for 12 h and poured into 150 mL of water. Solvents
were removed with a rotoevaporator. The resultant solid mixture was
recrystallized from ethanol to afford a colorless solid, 2.19 g (82%), mp
204.8−205.3 °C. 1H NMR (400 MHz, CD3SOCD3, 22 °C) δ (ppm): 9.82
(2H, t, J = 7 Hz), 8.22 (3H, m), 7.36 (10H, m), 7.24 (4H, d, J = 9 Hz), 6.97
(4H, d, J = 9 Hz), 5.08 (4H, s), and 4.53 (4H, d, J = 7 Hz). LR MS FAB+
(NBA) m/z 558.1 [M + H]+; HR MS FAB+ (NBA/PEG): m/z calcd. for [M]+,
(C35H31O4N3)+, 557.23146; found 557.23187 (error 0.7 ppm).
f. F. Huang, C. Slebodnick, K. A. Switek, H. W. Gibson, Chem.
Commun. 2006, 1929-1931;
g. H. W. Gibson, H. Wang, C. Slebodnick, J. Merola, S. Kassel, A. L.
Rheingold, J. Org. Chem. 2007, 72, 3381-3393;
h. X. Zhang, C. Zhai, N. Li, M. Liu, S. Li, K. Zhu, J. Zhang, F. Huang, ,
H. W. GibsonTetrahedron Lett. 2007, 48, 7537-7541;
i. A. M.-P. Pederson, R. C. Vetor, M. A. Rouser, F. Huang, C.
Slebodnick, D. V. Schoonover, H. W. Gibson, J. Org. Chem. 2008, 73,
5570-5573;
2,6-Bis(p-hydroxybenzylaminocarbonyl)pyridine (9).
A
positive
j. A. M.-P. Pederson, E. Ward, D. S. Schoonover, C. Slebodnick, H. W.
Gibson, J. Org. Chem. 2008, 73, 9094-9101;
pressure (40 psi) of H2 was maintained for 48 h over a vigorously shaken
suspension of 1.60 g (2.87 mmol) of 8 and 0.10 g of Pd/C in 50 mL of
anhydrous ethanol. After the removal of catalyst by filtration, the solvent
was rotoevaporated to afford 9 as a colorless solid, 1.07 g (99%), mp
172.2−173.8 °C. 1H NMR (400 MHz, CD3SOCD3, 22 °C) δ (ppm): 9.80
(1H, t, J = 7 Hz), 9.19 (2H, s), 8.22 (4H, m), 7.13 (4H, d, J = 9 Hz), 6.72
(4H, d, J = 9 Hz), and 4.49 (4H, d, J = 7 Hz). LR MS FAB+ (NBA) m/z:
378.1 [M + H]+; HR MS FAB+ (NBA/PEG) m/z: calcd. for [M + H]+,
(C21H20O4N3)+, 378.14483; found 378.14517 (error −0.90 ppm).
k. Z. Niu, F. Huang, H. W. Gibson, J. Am. Chem. Soc. 2011, 133,
2836-2839;
l. M. Zhang, X. Yan, F. Huang, Z. Niu, H. W. Gibson, Acc. Chem. Res.
2014, 47, 1995-2005;
m. A. M.-P. Pederson, T. L. Price, Jr., C. Slebodnick, D. V. Schoonover,
H. W. Gibson, J. Org. Chem. 2017, 82, 8489-8496;
n. T. L. Price, Jr., C. Slebodnick, H. W. Gibson, Heteroatom Chem.
2017, 28, e21406;
o. A. M.-P. Pederson, T. L. Price, Jr., D. V. Schoonover, C. Slebodnick,
H. W. Gibson, Heteroatom Chem. 2018, 29, e21422;
p. T. L. Price, Jr., H. W. Gibson, J. Am. Chem. Soc. 2018, 140, 4455-
4465.
Cryptand 10. A solution of 0.500 g (0.690 mmol) of crown ether
dibromide 4 and 0.234 g (0.690 mmol) of bisphenol 9 in 40 mL of DMF
was added via a syringe pump at 0.50 mL/h to a suspension containing
0.960 g (6.90 mmol) of potassium carbonate, 0.520 g (6.90 mmol)) of
potassium chloride, and 5.00 mg of tetrabutylammonium iodide in 500
mL of DMF at 110 °C. After complete addition, the reaction mixture was
stirred at 110 °C for 6 days. The cooled mixture was evaporated to
remove DMF, extracted with chloroform, and filtered. Removal of
chloroform afforded a crude product, which was purified by flash column
2.
3.
a. H. W. Gibson, H. Wang, K. Bonrad, J. W. Jones, C. Slebodnick, B.
Habenicht, P. Lobue, Org. Biomol. Chem. 2005, 3, 2114-2121;
b. H. R. Wessels, H. W. Gibson, Tetrahedron 2016, 72, 396-399.
T. L. Price, Jr., H. R. Wessels, C. Slebodnick, H. W. Gibson, J. Org.
Chem. 2017, 82, 8117-8122.
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10.1002/ejoc.201900038
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from Ka = p/{(1 − p)([11]0 − p[10]0)} using the Δ value of a 1.00 mM 10
and 11 acetone solution.
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14.
15.
1H NMR characterizations were done on solutions with constant [10]0
=
0.250 mM and varied [11]0 (0.500, 0.750, 1.00, 3.00, 5.00, and 15.0
mM). Based on these NMR data, Δ0, the difference in δ values for
aromatic proton H9 of 10 in the uncomplexed and fully complexed
species, was determined to be 0.3259 ppm as the y-intercept of a plot
of Δ = δ - δu vs. 1/[11]0. Then p = Δ/Δ0; Δ = observed chemical shift
change relative to uncomplexed species. The Ka value was calculated
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10.1002/ejoc.201900038
European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
An Inhospitable Cryptand: the
Importance of Conformational
Freedom in Host-Guest Complexation
Prof. Dr. Harry W. Gibson,* Prof. Dr.
Feihe Huang, Run Zhao, Li Shao, Dr.
Lev N. Zakharov, Dr. Carla Slebodnick,
Prof. Dr. Arnold L. Rheingold
A conformationally rigid pyridyl cryptand
does not bind viologens! The rigidity of
the third arm of this cryptand causes the
1,3,5-phenylene rings (shown in pink) of the host to be nearly orthogonal and too
far apart to π-stack with viologen guests. An analogous cryptand with a slightly
longer and more flexible third arm does complex dimethyl paraquat.
Page No. – Page No.
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