Pseudocryptand Hosts for Paraquats and Diquats

Article abstract of DOI:10.1021/acs.joc.7b02812

H-bonding interaction of acidic moieties (CH₂OH, COOH) at the 5- and 5′-positions of bis(1,3-phenylene)-32-crown-10 (1) with di- or tritopic anions leads to enhanced formation of inclusion complexes with N,N′-dialkyl-4,4′-bipyridinium salts ("paraquats", 2); the enforced folding of the crown ethers into pseudocryptands thus leads to pseudo-pseudorotaxanes. Strikingly, in the presence of the most effective anion (trifluoroacetate, TFA), the apparent bimolecular association constants for crown-paraquat complexation increase by more than an order of magnitude and approach those for covalent cryptands derived from the crown ether. Even though they may form pseudocryptands, the picolinate, nicotinate, and isonicotinate diesters 6 of cis-(4,4')-bis(hydroxymethyl)dibenzo-30-crown-10 do not exhibit enhanced binding of either diquat or paraquat relative to the starting diol in contrast to the picolinate ester of isomeric 5,5′-bis(hydroxymethyl)bis(m-phenylene)-32-crown-10, which displayed a higher binding constant than the starting diol. The results for the analogous reverse esters 7 derived from cis-(4,4')-dicarboxydibenzo-30-crown-10 and pyridylmethanols reveal weaker complexes with diquat than the normal esters 6; however, surprisingly, two reverse esters 7 complex paraquat more strongly than isomers 6.

Full text of DOI:10.1021/acs.joc.7b02812

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Article
PSEUDOCRYPTAND HOSTS FOR PARAQUATS & DIQUATS
Jason W Jones, Terry Leon Price, Feihe Huang, Lev N. Zakharov,
Arnold L. Rheingold, Carla Slebodnick, and Harry William Gibson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02812 • Publication Date (Web): 22 Dec 2017
Downloaded from http://pubs.acs.org on December 22, 2017
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PSEUDOCRYPTAND HOSTS FOR PARAQUATS & DIQUATS
a,¶
a,�
a,§
b,£
Jason W. Jones, Terry L. Price, Jr., Feihe Huang, Lev Zakharov, Arnold L.
b
a
a
Rheingold, Carla Slebodnick and Harry W. Gibson
a
b
Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech,
Blacksburg VA 24060
Department of Chemistry, University of California, San Diego, La Jolla, CA 92093-
0358
ABSTRACT
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H-bonding interaction of acidic moieties (CH OH, COOH) at the 5- and 5’-
2
positions of bis(1,3-phenylene)-32-crown-10 (1) with di- or tri-topic anions leads to
enhanced formation of inclusion complexes with N,N’-dialkyl-4,4’-bipyridinium salts
(
“paraquats”, 2); the enforced folding of the crown ethers into pseudocryptands thus
leads to pseudo-pseudorotaxanes. Strikingly, in the presence of the most effective
anion (trifluoroacetate, TFA) the apparent bimolecular association constants for crown-
paraquat complexation increase by more than an order of magnitude and approach
those for covalent cryptands derived from the crown ether.
Even though they may form pseudocryptands the picolinate, nicotinate and
isonicotinate diesters 6 of cis-(4,4’)-bis(hydroxymethyl)dibenzo-30-crown-10 do not
exhibit enhanced binding of either diquat or paraquat relative to the starting diol in
contrast to the picolinate ester of isomeric 5,5’-bis(hydroxymethyl)bis(m-phenylene)-32-
crown-10, which displayed a higher binding constant than the starting diol. The results
for the analogous reverse esters 7 derived from cis-(4,4’)-dicarboxydibenzo-30-crown-
1
0 and pyridylmethanols reveal weaker complexes with diquat than the normal esters
6; however, surprisingly two reverse esters 7 complex paraquat more strongly than
isomers 6.
¶
Present address: The Chemours Company, Wilmington, DE 19899
Present address: Zestron Corporation, 11285 Assett Loop, Manassas, VA 20109
Present address: Department of Chemistry, Zhejiang University, Hangzhou, P. R. China
Present address: Department of Chemistry, University of Oregon, Eugene, OR, 97403
�
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INTRODUCTION
In the field of host-guest chemistry there is an ongoing quest to find new higher
1
binding systems, more facile syntheses, and new molecular recognition motifs. This
opens the door to the production of new materials which may be accessed more easily
and/or possess unique properties. Our work initially focused on improved syntheses of
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1g,2,3
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dibenzo crown ethers,
and then the much higher binding cryptands.
With each
change the host synthesis was improved and/or higher binding was achieved, leading to
more efficient host-guest combinations. As an illustration of the importance of this
progression, if the goal is the production of supramolecular polymers, with every
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increase in binding, higher molecular weights are achieved. Since the synthesis of the
pyridyl dibenzo-30-crown-10 cryptands and the recent introduction of pseudocryptands
achieving association constants close to those of the corresponding cryptands with
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paraquat, effort has been put into exploring other pseudocryptands. Pseudocryptands
are cyclic host compounds which contain one or two unconnected arms that non-
covalently yield a cryptand-like structure upon guest binding; these compounds are an
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extension of the class of pseudomacrobicyclic compounds
that earlier were called
11a,11b
11c-11e
lariat ethers
and now rigid U-shaped hosts called “tweezers”;
however, the
arms of the lariat ethers were designed to interact with the guests, while in the present
work some arms were designed to close the encapsulating host by interacting with each
other or counter-anions of guests. Figure 1 provides cartoon examples of
pseudocryptands.
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Figure 1. Pseudocryptand complexes formed from one- and two-armed hosts by interaction of the arms
with either the guest and/or another part of the host.
+
Useful crown ether derivatives are now available in high yields via K templated
1g,2,3,12
syntheses [the Wang-Pederson-Wessels (WPW) protocol].
Here we explore two
types of crown ether derivatives: in the first studies we examined use of counterions to
bring about pseudocryptand formation through chelation of substituents on bis(m-
phenylene)-32-crown-10 and the second series investigated the effects of the
attachment of pyridyl ester moieties to dibenzo-30-crown-10.
RESULTS AND DISCUSSION
A. Anion Chelation of Derivatives of Bis(m-phenylene)-32-crown-10 (BMP32C10)
In the solid-state, one of the complexes formed between bis(5-hydroxymethyl-
1
,3-phenylene)-32-crown-10 (1b) and dimethyl paraquat 2a was not a pseudorotaxane,
4a
but an exo- or taco-complex. The required folding of the host to adopt the taco-
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complex suggested a favorable effect of constraining the flexible host molecule to the
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requisite folded shape,
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Scheme 1. Hosts and guest used in this study.
thereby minimizing the entropic penalty of reorganization. Indeed, when a covalent
linker was used to do so in forming bicyclic host 3, a 100-fold improvement in
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-1
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-
association constant (K ) resulted, increasing from 5.5 x 10 M in 1b•2a to 6.0 x 10 M
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results which were supported by X-ray structural analyses as nearly identical
geometries and interactions were noted for 1b•2a and 3•2a.
Encouraged by these exciting results, we explored other methods to drive
pseudorotaxane formation by enforcing the folding of BMP32C10 necessary for
formation of taco complexes, thus reducing the entropic penalty for complexation,
through hydrogen bonding of suitable 5- and 5’-substitutents with di- and tri-topic
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anions, i. e., formation of “pseudocryptands” in a non-covalent or truly supramolecular
manner. The anions were introduced as tetraalkylammonium salts.
As a control experiment, an acetone-d solution of crown ether diol 1b with two
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equivalents of tetra(n-butyl)ammonium hexaflurophosphate (n-Bu NPF ) was studied.
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Neither H (see SI, Figure S1) nor F NMR resonances shifted for either of the two
components, indicating that n-Bu NPF does not form a complex with 1b. Under similar
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conditions, H (see SI, Figure S2) and F NMR indicated that no interaction occurs
between paraquat diol 2b and n-Bu NPF .
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In a second control experiment, we observed complexation of paraquat diol 2b by
14,15
crown ether diol 1b in acetone-d . As discussed elsewhere,
a bright orange solution
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resulted upon mixing the host and guest components, indicative of a charge transfer
event from the electron rich host to the electron deficient viologen. We then titrated n-
1
Bu NPF into the solution and noted that the time averaged H NMR resonances of the
4
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crown ether shift towards their uncomplexed positions, qualitatively signaling a
decrease in association (Figure 2). In light of a report that suggests 2a to be fully ion
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paired in acetone-d , this finding was unexpected: if the complex truly were 100% ion
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paired, one would predict K not to vary. To explain this anomaly, we consider two
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possibilities.
First, it may be the case that ∆ changes for the system upon addition of n-
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qualitative meaning. We tested this possibility by studying a solution 0.9 mM in host 1b
and 100 mM in paraquat 2b both before and after addition of 100 mM n-Bu NPF . The
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00-fold excess of guest relative to host ensured near quantitative complexation of 1b,
enabling one to determine δbound, and thus ∆ , by simple observation of the host
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resonances. As can be seen in Figure 3, the δbound signals do not change upon addition
of n-Bu NPF . We conclude that ꢀ is therefore unaffected by addition of n-Bu NPF .
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Figure 2. H NMR spectra (400 MHz, 295 K, acetone-d ) of a) crown diol 1b; b)
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2.00 mM 1b + 2.00 mM paraquat diol 2b; c) 2.00 mM 1b + 2.00 mM 2b + 4.63
mM n-Bu NPF .
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Figure 3. H NMR spectra (400 MHz, 295 K, acetone-d ) of a) 0.9 mM crown diol
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b + 100 mM paraquat diol 2b and b) 0.9 mM 1b + 100 mM 2b + 100 mM n-
Bu NPF .
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Because the result of Figure 2 is reminiscent of a similar experiments with
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dibenzo-24-crown-8 and dibenzylammonium PF6,
we considered the only remaining
possibility: the complex 1bꢀ2b may not be fully ion paired. As a result of the ion pair
-2
19a,19b
dissociation constants (K ) of n-Bu NPF (1 to 5 x 10 M)
and analog 2a (≈ 1 ×
ipd
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-
1
0 M) in acetone, the paraquat under the influence of a large excess of PF would
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become more ion paired, thereby driving the complexation equilibrium towards starting
materials, as observed in Figure 2. We believe this to be the reality, and speculate that
minor percentages in the extent of complex ion pairing would otherwise be difficult to
discern in this fast exchange system.
Therefore, we concluded that the reduction in binding was due to enhanced ion
-
pairing of the paraquat diol (2b) by the added PF . The spectra were analyzed to
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estimate K . Because addition of n-Bu NPF was shown not to influence δ
, ꢀ was
a
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bound
0
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taken from earlier studies to be 0.472 ppm for H . Based on this value, we calculated
b
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K = 8.3 (� 1.3) x 10 M for 1bꢀ2b alone and K = 5.2 (� 0.8) x 10 M for 1bꢀ2b in
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the presence of n-Bu NPF , representing a significant 40% reduction in K .
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with the host (Figure S1). Similarly, no interaction occurs between paraquat diol 2b and
n-Bu N PF (Figure S2). However, addition of n-Bu NPF to a solution of 1b/2b caused
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signals to shift toward the uncomplexed state. Contrary to this result, as we previously
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reported the H NMR resonances of the crown signals in a solution of crown diol 1b
and paraquat diol 2b all shifted towards their fully complexed positions upon addition of
tetraethylammonium trifluoroacetate (Et NTFA), signaling an increase in association.
4
Indeed, at 2.35 equivalents of added salt the apparent K value increased an impressive
a
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4-fold. The observed upfield chemical shift upon addition of Et NTFA is especially
4
-
- 17,18,19c
noteworthy given the tendency of TFA to form a much tighter ion pair than PF ,
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which, as demonstrated by Figure 2, would otherwise result in a downfield chemical
shift of the complex. Indeed, in the absence of host 1b, counterion exchange between
2
a or 2b and Et NTFA results in the precipitation of 2c or 2d, respectively. Furthermore,
4
parent crown ether 1a without the hydroxymethyl groups complexed guest 2a 43% more
weakly in the presence of Et NTFA through increased ion pairing of the guest, indicating
4
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the critical importance of the hydroxyl moieties. An X-ray crystal structure of the
pseudocryptand complex 1bꢀ2e clearly showed the hydrogen bonding of the ditopic
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trifluoroacetate (TFA) anion with the hydroxyl groups of 1b. Later this motif was re-
confirmed via X-ray crystallography of an analogous complex comprising the
pseudocryptand formed from crown ether bisphenol 1c and TFA anion and a
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bisparaquat.
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Figure 4.
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H NMR spectra (400 MHz, 295 K, acetone-d ) of a) 2.00 mM crown diol
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b + 2.00 mM paraquat diol 2b and b) 2.00 mM 1b + 2.00 mM 2b + 2.50 mM n-
Bu NOTs.
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In the case of dol 1b, since no changes occurred in the H NMR spectrum upon
addition of ET NTFA we concluded that formation of the pseudocryptand structure is a
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cooperative process requiring the presence of both the guest and the anion, leading to
complex 1bꢀ2e.
Based on these encouraging results we moved on to study the influence of other
tetrabutylammonium salts on the complexation of host 1b with guest 2b. Using the
-
same approach the tridentate tosylate anion (OTs ) increased K
1.6 fold (to K = 920
a,exp
a
-1
M , Figure 4, Table 1). Again in view of the fact that tetra(n-butyl)ammonium tosylate
-3
19d
(
n-Bu NOTs) is more ion paired (K = 2.5 x 10 M)
than n-Bu NPF it might have
4
ipd
4
6
been expected that complexation would be retarded. A single crystal of the resultant
mixed anion complex 1bꢀ2f was grown and the X-ray diffraction structure (Figure 5)
shows that in this solid state structure only two oxygen atoms of the tosylate anion
interact with one of the hydroxyl groups of host 1b at O--H distances of 2.70 and 1.96 Å
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a and h in Figure 5); one of the oxygen atoms of the TsO interacts strongly with the 2-
and 3-protons of one pyridyl ring of the paraquat guest (b and c In Figure 5).
Presumably in solution, however, the anion does bind both OH groups of the host to
form a pseudocryptand, but the solid state structure does not comprise a
0
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pseudocryptand. Notably the remaining PF anion interacts with both � � hydrogens of
6
the paraquat; that is, the complex is ion paired. Other details of the structure are similar
to analogous complexes: π-stacking of the aromatic rings at 3.6 Å and multiple
interactions of the protons of the guest with oxygen atoms of the host.
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h
l
i
k
j
n
B
m
o
C
p
Figure 5. X-ray crystallography of 1b•2f grown by liquid diffusion of pentane into an acetone solution of
the components. A) Space filling representation, showing the interaction of the tosylate with one hydroxyl
group of the host and the 2- and 3-protons of the guest; the host is shown in red and the guest in blue;
the hydrogens of the tosylate anion are white, the sulfur is yellow and the oxygens are red. B) Stick
representation showing interactions of one tosylate oxygen with a hydroxyl proton of the host and the 2-
and 3-protons of the guest and other interactions between host and guest as well as with the PF6
counteranion. C) Stick representation showing interactions of another tosylate oxygen with the same
hydroxyl proton of the host and other host-guest interactions. In B and C hydrogen atoms on the host and
tosylate have been removed for clarity. Hydrogen-bond parameters: C---O(X) distances (Å), C-H---O(X)
distances (Å), C-H ---O(X) angles (deg) a:----, 2.70, ---; b: ---, 2.49, ---; c: ---, 2.57, ---; d: 3.23, 2.26, 175.0;
e: 3.62, 2.84, 140.2; f: 3.29, 2.58, 131.7; g: 2.92, 2.31, 122.0; h: ---, 1.96, ---; i: 3.64, 2.71, 157.4; j: 3.12,
.45, 127.8; k: 3.37, 2.51, 151.0; l: 3.40, 2.53, 147.1; m: 3.03, 2.51, 115.2; n: 3.53, 2.64, 157.4; o: ---,
.21,---; p: ---, 1.93, ---. Centroid to centroid distance between phenyl rings: 7.08 Å; distance between
centroids of top phenyl ring and that of paraquat: 3.57 Å; distance between centroids of bottom phenyl
ring and that of paraquat: 3.58 Å. Angle between phenyl planes of the host: 1.60 . Angle between top
phenyl plane and PQ plane: 3.45 . Angle between bottom phenyl plane and PQ plane: 5.05 . Torsion
2
2
o
o
o
o
angle of bipyridinium rings: 1.81 .
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The interaction of crown diol 1b with dimethyl paraquat 2a and n-Bu NOTs led to
4
7
a 1.5-fold increase in K (Table 1). The resulting complex 1b•2g is superficially similar
a
to 1b•2f as shown in Figure 6. However, the torsion angle of the paraquat is quite
o
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different from that in Figure 5: 20.7 vs. 1.8 !! Again the tosylate anion interacts with
only one of the hydroxy groups of the crown diol (a In Figure 6). But now instead of the
other oxygen atom of the tosylate interacting with the 2- and 3-protons of one of the
paraquat rings as in Figure 5, it now interacts with the 3-protons of both paraquat rings
(
b and c In Figure 6).
Interestingly, there is an element of unpredictability in use of chelating anions.
This is demonstrated by enhanced complexation of crown ether diol 1b with diquat (4a)
26a
in the presence of Et NTFA, yielding 1bꢀ4b, as previously reported. Contrary to the
4
above results (Figures 5 and 6) the two hydroxyl groups of the host crown ether in
1bꢀ4b are linked not by one of the anions, but rather by an adventitious water molecule
(
f and g in Figure 7); the TFA anions do interact with the methylene protons of the
paraquat guest (b and c in Figure 7). The water in this case is the hydrogen bond donor
and the diol the acceptor, as opposed to the case of 1bꢀ2e, in which the TFA anion is
7
the hydrogen bond acceptor and the diol is the donor. However, the oxygen atom of
the water molecule interacts with the 3- and 3’-hyrdrogen atoms of the diquat (i and j in
Figure 7). In this case the water closes the pseudocryptand (f and g in Figure 7) and
not the TFA anion.
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A
f
l
g
b
e
d
h
c
i
j
a
k
C
B
Figure 6. X-ray crystallography of 1b•2g grown by liquid diffusion of pentane into an acetone solution of
the components. A) Space filling representation, showing the interaction of the tosylate with one hydroxyl
group of the host and the 3- and 3’-protons of the guest; the host is shown in red and the guest in blue;
the hydrogens of the tosylate anion are white, the sulfur is yellow and the oxygens are red. B) Stick
representation showing interactions of one tosylate oxygen with a hydroxyl proton of the host and the 3-
and 3’-protons of the guest and other interactions between host and guest. C) Stick representation
showing other host-guest interactions and interactions with the PF anion. In B and C hydrogen atoms on
6
the host and tosylate have been removed for clarity. Hydrogen-bond parameters: C---O(X) distances (Å),
C-H---O(X) distances (Å), C-H ---O(X) angles (deg) a:----, 2.06, ---; b: 3.13, 2.31, 144.8; c: 3.64, 2.82,
1
1
69.6; d: 3.57, 2.62, 164.9; e: 3.49, 2.79, 129.6; f: 3.28, 2.44, 139.8; g: 3.38, 2.51, 153.6; h: 3.23, 2.46,
38.7; i: 3.62, 2.77, 151.1; j: 3.48, 2.54, 173.3; k: 3.46, 2.72, 135.6; l: 3.400, 2.84, 117.7. Centroid to
centroid distance between phenyl rings: 7.17 Å; distance between centroids of top phenyl ring and that of
paraquat: 3.55 Å; distance between centroids of bottom phenyl ring and that of paraquat: 3.52 Å. Angle
o
o
between phenyl planes of the host: 15.35 . Angle between top phenyl plane and PQ plane: 8.60 . Angle
o
o
between bottom phenyl plane and PQ plane: 6.90 . Torsion angle of bipyridinium rings: 20.69 .
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7
8
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A
e
f
a
b
i
k
j
g
c
d
h
B
C
Figure 7. X-ray crystallography of 1b•4b grown by vapor diffusion of pentane into acetone at room
temperature. A) Space filling representation with counterions removed, showing the pseudocryptand
structure resulting from water chelation; the host is shown in red and the guest in blue; the hydrogens of
water are white and the oxygen is red. B) Stick representation showing interactions of the counterions
with the methylene protons and other interactions. Hydrogen atoms on the host have been removed for
clarity. Carbons are gray, hydrogens are white, nitrogens are blue, oxygens are red and fluorines are
yellow-green. C) Stick representation showing interactions of the guest with water and the host.
Counterions and hydrogen atoms on the host have been removed for clarity. Carbons are gray,
hydrogens are white, nitrogens are blue and oxygens are red. Hydrogen-bond parameters: C---O(X)
distances (Å), C-H---O(X) distances (Å), C-H ---O(X) angles (deg) a: 2.80, 3.66, 151.9; b: 2.41, 3.13,
128.4; c: 2.89, 3.22, 100.4; d: 2.52, 3.39, 146.6; e: 2.63, 3.78, 132.2; f: 2.00, 2.81, 166.0; g: 2.00, 2.84,
1
67.0; h: 2.59, 3.45, 150.9; i: 2.46, 3.39, 166.9; j: 2.45, 3.36, 162.2; k: 2.62, 3.22, 120.9. Centroid to
centroid distance between phenyl rings: 6.98 Å. Angle between phenyl planes of the host: 1.16 . Angle
between top phenyl plane and DQ plane: 0.48 . Angle between bottom phenyl plane and DQ plane: 1.49
Torsion angle of bipyridinium rings: 17.6 .
o
o
o
o
.
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Incremental addition of teta(n-butyl)ammonium nitrate (n-Bu NO ) to an acetone-
4
3
d solution 2.00 mM in both BMP32C10 diol (1b) and paraquat diol PF (2b) caused
6
6
diminution in the extent of complexation initially, as noted both by chemical shift
changes and lessening of the intense yellow-orange color of the initial solution, and then
precipitation and finally total loss of the guest from solution. This experimental result
indicates that nitrate salt 2g is insoluble in acetone. Indeed precipitation of 2g was
observed upon addition of n-Bu NNO to 2b in acetone.
1
1
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4
3
-
As expected, the non-chelating tetrafluoroborate (BF ) anion of tetra(n-
4
butyl)ammonium tetrafluroborate (n-Bu NBF ) reduced association of paraquat diol 2b
4
4
with crown diol 1b. (Figure S3, SI). Likewise, addition of tetra(n-butyl)ammonium
trifluoromethanesulfonate (n-Bu NCF SO ) also diminished apparent K values, a result
4
3
3
a
of the reduced basicity of trifluoromethanesulfonate (triflate) anion relative to TFA
-
(Figure S4, SI). At the other extreme, addition of the more basic acetate (CH COO )
3
anion via tetra(n-butyl)ammonium acetate (n-Bu NCH CO ) to 1b/2b resulted in
4
3
2
25
electron transfer reactions, which destroyed the guest ligand.
Noting that the dicarboxylic acid host 1d should more readily H-bond to di- and
tri-topic anions than host 1b due to its higher acidity, we explored its complexation with
4
paraquat 2a in the presence of Et NTFA and found a 47-fold increase in K to 3.4 x 10
4
a
-
1
M (Table 1). This finding is significant, especially considering that this value is within a
4
-1
factor of two of that determined for the covalent cryptand analog 3 (6.1 x 10 M , Table
1
1
). In the case of diacid 1d H NMR spectra (see SI, Figure S8) show definite
interactions with Et NTFA, suggesting that a pseudocryptand is in dynamic equilibrium
4
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with its components in the absence of the guest species. Thus, this system contrasts
with 1bꢀ2e, in which pseudocryptand formation requires the guest.
Table 1.
Comparison of binding constants (Ka) of various
o
pseudocryptand and cryptand systems in acetone-d at 22 C. Values
6
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2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
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9
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determined from the chemical shift of H for each host.
b
Host
.00 mM
Guest
2.00 mM
2b
Additive
(Equiv.)
0
App. K
(M )
61
48 (± 19)
35 (± 17)
Change in
Ka
a
-
1
2
2
3
1a
1a
---
0.79 x
2b
Et NTFA
4
1
.25
1
a
2b
Et NTFA
0.57 x
4
3
.75
0
4
a
1b
1b
2a
2a
570
920
---
1.6 x
7
n-Bu NOTs
4
(1.00)
0
7
1
1
b
b
2b
2b
830
520
---
0.63 x
7
n-Bu NPF
4
6
(
2.32)
3
4
7
7
1
b
2b
2b
2b
Et NTFA
5.63 x 10
1.20 x 10
6.8 x
14 x
2.2 x
4
(1.18)
1b
Et NTFA
4
(
2.35)
4
1
b
n-Bu NOTs
1.86 (± 0.35)
3
(1.00)
x 10
390
1
4
1
1b
1
1
a
4a
4a
2a
2a
0
0
0
---
---
---
3
26a
4
2.8 x10
a
d
d
70
Et NTFA
3.4 x 10
47 x
4
(
1.00)
0
0
4
a, 4a
3
2a
4a
6.1 x 10
---
---
4
26b
3
2.0 x 10
a
o
At 21 C.
The results with addition of tetralkylammonium salts to solutions of hosts and
guests are summarized in Table 1. With non-chelating hosts such as 1a addition of any
salt results in diminution of the binding constant, because the guest becomes more ion
paired. With chelating hosts such as 1b and 1d addition of PF salts decreases K for
6
a
the same reason; however, anions that interact to form pseudocryptands, i. e., TFA and
OTs, increase K as a result, offsetting the ion pairing effect.
a
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B. Pyridyl Esters of cis-Dibenzo-30-crown-10 Diol
Previously the syntheses of cryptands such as 3 were low yielding; this has been
4b
remedied now in the case of the dibenzocrown ether-based pyridyl cryptands.
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
2
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0
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5
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7
8
9
0
However, we previously showed that easily prepared diesters 1e – 1g displayed
6
significanltly enhanced binding constants with paraquats. That naturally begged the
question: would corresponding pyridyl diesters of dibenzo-30-crown-10 similarly be
elevated? A series of three isomeric dibenzo-30-crown-10 diol pyridyl esters (6) was
synthesized (Scheme 2) and association constants with paraquat and diquat were
determined by isothermal titration calorimetry (Tables 2 and 3; see SI Figures S19 and
1
S20 for examples); in all cases 1:1 stoichiometry was observed. An H NMR-based Job
plot (Figure 8) confirmed the expected 1:1 stoichiometry for 6a with diquat.
Scheme 2. Synthesis of pyridyl esters of 6a – 6c of dibenzo-30-crown-10 diol (5a).
Table 2. Association constants and thermodynamic parameters for complexation of
hosts 5a, 5b, 6a-6c with diquat (4a, acetone, 25 °C via ITC).
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6
-3
10 K (M )
-1
HOST
∆G (kcal/mol)
∆H (kcal/mol)
∆S (eu)
a
a
5
5
b
a
17
50
---
---
-6.28
(± 0.29)
-4.96
(± 0.11)
-4.83
(± 0.13)
---
---
---
---
b
6a
40.6
± 1.9)
-17.4
(± 0.1)
-17.3
(± 0.2)
-17.7
(± 0.2)
-37.3
(± 1.8)
-41.4
(± 1.1)
-43.2
(± 1.3)
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
b
c
4.36
± 0.10)
3.50
(
6
(± 0.09)
a
b
Byuv/vis: ref. 27.
Byuv/vis: ref. 28.
Table 3. Association constants and thermodynamic parameters for complexation of
hosts 5a, 6a-6c with paraquat 2a (acetone, 25 °C via ITC).
-1
HOST
K (M )
a
∆G (kcal/mol)
∆H (kcal/mol)
∆S (eu)
3
a
5a
6a
1.1 x 10
---
-3.16
(± 0.08)
-3.95
(± 0.06)
-3.95
---
-4.31
(± 0.04)
-10.2
(± 0.1)
-5.60
---
-3.86
(± 0.10)
-21.0
(± 0.35)
-8.66
207
(± 5)
6
b
c
785
± 12)
162
(
6
(± 11)
(± 0.20)
(± 0.08)
(± 0.60)
a
Byuv/vis: ref. 29.
The ITC data indicate that association constants for esters 6 with diquat PF (4a)
6
were lower than those with starting diol 5a; this is presumed to be due to a combination
of electronic and steric effects. Likewise with paraquat PF (2a), binding with esters 6 is
6
weaker than that with the starting diol 5a, presumably for similar reasons. Interestingly
however, the dipicolinate, 6a, gave the highest association constant with diquat, while
the dinicotinate, 6b, is advantageous for binding paraquat. Looking first at the diquat
series (Table 1), as the pyridyl ring’s attachment is moved from the 2- position to 4-
position, ∆H remains the same within experimental error, while ∆S becomes more
negative due to a more extensive rearrangement for binding the guest. With 6b and
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paraquat the higher association constant (Table 2) results from a much larger enthalpy
change than the other isomers.
0
0
0
.25
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.2
.15
0.1
.05
0
0
0.2
0.4
0.6
0.8
1
mole fraction H
1
Figure 8. 500 MHz H NMR Job Plot titration of 6a with diquat 4a in acetone-d at room
6
temperature ([6a] + [4a] = 0.97 mM); H used for analysis.
a
There is a correlation between enthalpy and entropy changes for the
complexation of complexes 6 with the two bpyridinium guests as shown in Figure 9.
30
Others have reported similar results and rationalized them.
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 4 lists
association constants
for similar bis(m-
phenylene)-32-crown-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0 pseudocryptands
we
reported
6,10
previously;
compound
6a
is
analogous to 32-
crown-10 version 1e,
while compounds 1f
ꢀH (kcal / mol)
Figure 9. Correlation of ꢀH and ꢀS for complexes 6 with
paraquat 2a and diquat 4a (Tables 2 and 3). Error bars: 5 %.
and 1g were strategically evolved to increase π–stacking of the aroyl groups and thus
cooperative binding with paraquat. The paraquat binding of 1e is an order of magnitude
higher than 6a, but the diquat binding of 6a is nearly two orders of magnitude higher
than 1e. It is worth pointing out that 6a bound diquat better than host 1g.
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10
Table 4. Association constants (K ) Hosts 1e–1g with paraquat 2a and diquat 4a.
a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-3
10 K (M )
-1
Complex
e•2a
1f•2a
a
a
1
3.1
a
12.4
b
1
g•2a
e•4a
250
c
1
0.77
d
1f•4a
g•4a
value obtained in CDCl /CDCN (1/1, v/v) via H NMR.
0.56
d
1
32
a.
b.
c.
d.
1
3
value obtained in CHCl /CHCN (1/1, v/v) via ITC.
3
1
value obtained in acetone-d at 25 °C via H NMR.
6
value obtained in acetone at 25 °C via ITC.
Both 2D NOESY and X-ray crystallography were employed to probe the 3D
structures of the complexes. 2D NOESY spectra were taken in acetone-d at room
6
temperature for DQ PF (4a) with all three esters 6. The X-ray crystal structure of 6b•4a
6
is shown in Figure 10.
2
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9
1
1
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1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
A)
B)
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3
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1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
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9
0
C)
D)
E)
F)
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Figure 10. X-ray crystallography of 6b•4a grown by slow vapor diffusion of ether into acetone (crystal
structure contains a reasonable amount of disorder; counter ions, solvent, artifacts, and non-guest
hydrogens have been removed for clarity; carbons are gray, hydrogens are white, nitrogens are blue, and
oxygens are red. A) side view; B) top down view; C) hydrogen bonding to the m-ethyleneoxy chain; D)
hydrogen bonding to the p-ethyleneoxy chain; E) hydrogen bonding at the ester. Hydrogen-bond
parameters: C---O distances (Å), C-H---O distances (Å), C-H ---O angles (deg) A: 3.455, 2.887, 117.29;
B: 3.088, 2.405, 128.55; C: 3.605, 2.843, 137.98; D: 3.072, 2.093, 170.35; E: 3.031, 2.541, 110.42; F:
3.117, 2.458, 123.64; G: 3.320, 2.451, 146.20; H: 3.340, 2.447, 149.74; I: 3.421, 2.739, 126.35; J: 3.278,
2.808, 109.76; K: 3.619, 2.722, 150.96; L: 3.281, 2.399, 154.19; M: 2.954, 2.230, 132.31; N: 3.679, 3.170,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
113.52; O: 3.445, 2.470, 173.75; P: 3.265, 2.470, 141.24. F) Space-filling representation with the host in
red and the guest in blue showing closure of the pseudocryptand by the embracing pyridine moieties; the
pyridyl nitrogen of one ester group is 3.34 Å from the carbonyl carbon of the other ester moiety while the
o
adjacent pyridyl 2-H interacts with the carbonyl oxygen at 3.26 / 2.52 Å / 134.6 . Angle between phenyl
o
o
planes of the host: 1.86 . Angle between top phenyl plane and DQ plane: 1.38 . Angle between bottom
4
o
o
phenyl plane and DQ plane: 1.53 . Torsion angle of bipyridinium rings: 17.5 .
NOESY experiments (see SI, Figures S16-S18) with complexes of 6a–c with
diquat 4a indicate no detectable interactions between the pyridine rings and the diquat
cation, suggesting that in solution diquat sits in a cupped pocket formed by the crown
3,28,29
(similar to other taco structures observed for dibenzo-30-crown-10 systems).
However, it is suspected that in complex 6a•4a, the pyridyl rings are π-stacked on the
basis of a NOESY correlation between protons A (6-H) and D (3-H) on opposite sides of
the pyridyl ring. In the complexes of 6b and 6c, this correlation was not observed,
suggesting that the pyridyl units point outwards and are not π –stacked; this explains
the higher K observed for 6a vs. 6b and 6c.
a
In the X-ray crystallographic structure of 6b•4a, Figure 10, most of the hydrogen
bonding occurs between the ethyleneoxy units and diquat, while the pyridyl nitrogen
atoms sit too far away to play an active role with the guest. However, the interaction of
one pyridyl nitrogen with th carbonyl carbon of the other ester moiety coupled with its 2-
proton interacting with the ester ether oxygen effectively seals the pseudocryptand.
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4
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5
5
5
5
5
5
5
6
C. cis-Dibenzo-30-crown-10 Dicarboxylic Esters of Pyridyl Alcohols
By use of the crown ether diacid chloride and the corresponding
pyridylmethanols we envisioned a stronger interaction of the more basic nitrogen atom
with paraquat and diquat guests. Hence, the “reverse esters” 7a – 7c were prepared
from the acid chloride 5f and the isomeric pyridylmethanols (Scheme 3). These hosts
were then examined with diquat (Table 5) and paraquat (Table 6) by ITC (see SI
Figures S39-S44).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Synthesis of dibenzo-30-crown-10 dicarboxylic esters 7a-7c of
pyridylmethanols.
Table 5. Association constants and thermodynamic parameters for complexation of
hosts 7a-7c with diquat (4a, acetone, 25 °C via ITC).
-1
K (M )
HOST
∆G (kcal/mol)
∆H (kcal/mol)
∆S (eu)
a
7
a
556
± 90)
696
± 30)
636
-3.74
(± 0.10)
-3.88
(± 0.03)
-3.82
-3.83
(± 1.97)
-6.42
(± 0.12)
-4.46
-0.30
(± 6.96)
-8.52
(± 0.51)
-2.15
(
(
(
7b
7
c
± 23)
(± 0.02)
(± 0.08)
(± 0.34)
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The complexations of reverse esters 7 with diquat PF (4a) are one to two orders
6
of magnitude weaker in terms of K than “normal esters” 6 (Table 2). Such a reduction
a
in binding strength is consistent with the electronic effect of reversing the ester moiety,
since in 7 the electron withdrawing effect supposedly weakens the ability of the aromatic
rings to participate in charge transfer interactions with the cationic guest.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 6. Association constants and thermodynamic parameters for complexation of
hosts 7a-7c with paraquat 2a (acetone, 25 °C via ITC).
-1
K (M )
HOST
∆G (kcal/mol)
∆H (kcal/mol)
∆S (eu)
a
7
a
427
± 29)
633
-3.59
(± 0.05)
-3.82
-4.41
(± 0.15)
-4.98
-2.75
(± 0.67)
-3.89
(
7b
(± 47)
423
(± 0.05)
-3.58
(± 0.04)
(± 0.17)
-6.20
(± 0.21)
(± 0.78)
-8.79
(± 0.84)
7
c
(± 28)
Surprisingly,
however, the binding
of paraquat PF6 by
reverse esters 7 is
stronger in two cases
by factors of ca. two-
fold in K (Table 6)
a
than the isomeric
ꢀH (kcal / mol)
normal
Table 3. The reasons
for this generally
esters
of
Figure 11. Correlation of ꢀH and ꢀS for complexes 7 with
paraquat 2a and diquat 4a (Tables 2 and 3). Error bars: 10 %.
enhanced binding of esters 7 are not clear in the absence of crystal structural
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
information. However, we speculate that perhaps in this case the increased electron
density on the pyridyl nitrogen atoms offsets the decreased electron density of the
aromatic rings of the hosts.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
As observed in series 6 (Figure 9) the data for interaction of reverse esters 7
with diquat and paraquat reveal a linear correlation of the enthalpy and entropy changes
associated with complex formation (Figure 11).
CONCLUSIONS
The use of counter-anions to link acidic moieties at the 5- and 5’-positions of
bis(m-phenylene-32-crown-10) is a simple means of enhancing the binding of the host
with paraquat derivatives by more than an order of magnitude in apparent Ka.
The placement of the 2-pyridyl carboxylate group in the dibenzo-30-crown-10 diol
diester provided the best overall binding constant, 6a●4a (diquat), in this series of
diesters. However, all of these hosts (6a–6c) were worse in terms of the binding
28,29
strength than the parent crown diol 5a both with diquat and paraquat.
These results
are in contrast to those obtained with the analogous bis(m-phenylene)-32-crown-10
pyridyl derivatives (1e-1g, Table 4), all of which possessed higher binding constants
than parent diol 1b. The results for reverse esters 7 reveal weaker complexes with
diquat than normal esters 6; however, surprisingly, reverse esters 7a and 7c complex
paraquat more strongly than isomers 6a and 6c.
EXPERIMENTAL
33
34
34
31
32
4a
3
3
General Information: 1a, 1b, 1c, 2a, 2b, 3, 5a and 5d were prepared as
described in the literature. All other reagents were purchased from commercial
1
suppliers and used without further purification except where noted. H NMR spectra
2
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were obtained on JEOL ECLIPSE-500, BRUKER-500, and AGILENT-NMR-vnmrs400
13
spectrometers.
C NMR spectra were collected at 125 MHz and 101 MHz on these
instruments, respectively. HR MS were obtained using an Agilent LC ESI TOF system
and acetonitrile solvent. Reagents were purchased and used as received without
further purification, except for DCM, which was dried by distillation over CaH. ITC
results were obtained using an MCS system from Microcal, Inc.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR Studies of Complexation: For all complexation studies, precisely weighed
amounts of each component were added to a 5.00 mL volumetric flask (±0.02 mL)
equipped with a ground glass stopper to make a moderately concentrated (nominally 16
mM) master solution. This solution was then sequentially diluted (no more than four
sequential dilutions per master solution) as needed by transferring exactly half of the
higher concentration solution to a clean volumetric flask by means of to-deliver
volumetric pipettes (±0.006 mL) and diluting to the 5.00 mL mark. The fresh solutions
were passed through a filter before 0.500 mL of each solution component (both host
and guest) at a specified concentration was transferred via a to-deliver pipette to a 5
1
mm NMR tube. H NMR data were collected on a temperature controlled spectrometer
(
400 MHz). Errors are reported by assuming a 5% variation in ꢀ/ꢀ values.
0
Determination of Ka for Bis(5-carboxy-m-phenylene)-32-crown-10 (1d) with
Parquat Diol Bis(hexafluorophosphate)(2b): The following data were collected in
o
acetone-d at 21.4 ± 0.1 C with constant [1d] = 8.484 mM. Analysis using the
6
[2b]
δb
δb
(mM)
(ppm)
(ppm)
2
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
.00
4.64
28.54
6.757
6.520
6.428
6.370
6.344
6.325
6.297
6.279
7.152
6.967
6.895
6.846
6.829
6.811
6.792
6.777
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
5
7.11
8.28
71.70
4.95
21.40
9
1
21,35
iterative Cresswell-Allred method
afforded the following values from the data for Ha
-1
and H , respectively: K = 70 ± 6 and 70 ± 5 M .
b
a
Example of ITC Titration Method: Two different ITC titration methods were used for
this work; in each the first data point was ignored to avoid preimixing error. Low gain
titrations with paraquat PF (2a) employed 25 aliquots using host in the cell (5.00 mM)
6
and guest in the syringe (75.0 mM). High gain titrations with diquat PF (4a) employed
6
1
00 aliquots using host in the cell (0.990 mM) and guest in the syringe (15.0 mM). For
both methods acetone was used as the solvent and experiments were conducted at
5°C. The following is a detailed description of titration of crown ether 6a with diquat
2
PF (4a); the other systems were done similarly with slightly different concentrations.
6
Host 6a was loaded into the cell of the instrument at a concentration of 0.994 mM, while
a 250 µL ITC syringe was loaded with diquat PF (4a) at a concentration of 15.00 mM.
6
The instrument was set to high gain (high sensitivity). The titration was achieved
through 100 injections of 2.50 µL every 180 s; a primary filter period of 2 s and a
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secondary filter period of 4 s were applied (filter period switch time was set to 120 s). A
background titration used exactly the same titration conditions with the exception that
the solution of 6a in the cell was replaced with acetone. The heats for the dilution
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
experiment were subtracted from the heats for the titration of diquat PF (4a) with 6a.
6
Analysis of the data was carried out using software provided by the manufacturer. A
“One Set of Sites” model was used; stoichiometries other than 1:1 provided
unsatisfactory fits and the “One Set of Sites” model was justified by an NMR-based Job
Plot.
1
H NMR Job Plot Titration: A diquat solution was made at 0.968 mM and 6a at 0.987
mM, both in deuterated acetone. NMR solutions were made at ratios of host/guest:
9
.00/1.00, 7.00/3.00, 6.00/4.00, 5.00/5.00, 4.00/6.00, 3.00/7.00, and 1.00/9.00.
Aromatic hydrogen H (Scheme 2) of the crown was observed for the titration due to its
a
large chemical shift change.
General procedure 1, acid chlorides. Picolinoyl Chloride: Thionyl chloride (18.0
mL, 247 mmol) was added to a flask containing picolinic acid (4.35 g, 35.4 mmol) with
magnetic stirring under nitrogen. The reaction mixture was allowed to stir at room
temperature for 48 h, followed by removal of the excess thionyl chloride using
evaporation to provide the desired product, 5.00 g (100%). No further purification was
performed; the product was used directly.
General procedure 2. Dipicolinate Ester of cis(4,4’)-Bis(hydroxymethyl)dibenzo-
3
0-crown-10 (6a). Picolinoyl chloride (3.21 g, 22.7 mmol) was added to a flask with
magnetic stirring, freshly distilled DCM (125 mL), and pyridine (2.9 mL, 36 mmol). The
mixture was stirred briefly and crown diol 5a (0.38 g, 0.64 mmol) was added and the
2
9
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