Mapping the Binding Motifs of Deprotonated Monounsaturated Fatty Acids and Their Corresponding Methyl Esters within Supramolecular Capsules

Article abstract of DOI:10.1021/acs.joc.7b00264

A suite of NMR techniques revealed that a cavitand (1) formed 2:1 host-guest complexes with a range of monounsaturated fatty carboxylates and their corresponding methyl esters. All of the carboxylates bound to the capsule in a J-shaped motif with the carboxylate at the equatorial region of the dimeric capsule, and the reverse turn of the chain and the methyl terminal in each polar region of the host. Guest exchange was slow on the NMR time scale, while tumbling was slow or close to the NMR time scale depending on the position and stereochemistry of the double bond. In contrast, the methyl esters were found to bind in three motifs depending on the position and stereochemistry of the double bond. Thus, the esters were observed to bind in a J-shaped, U-shaped (the turn in the guest occupying a polar region and the two termini competing for occupancy of the other pole), or a reverse J-shaped motif (ester moiety and turn each occupying a pole and the methyl terminal located near the equator). Relative binding constant (K_rel) determinations revealed that the affinity for the capsule was dependent on the position and stereochemistry of the double bond.

Full text of DOI:10.1021/acs.joc.7b00264

Article
pubs.acs.org/joc
Mapping the Binding Motifs of Deprotonated Monounsaturated
Fatty Acids and Their Corresponding Methyl Esters within
Supramolecular Capsules
Kaiya Wang and Bruce C. Gibb*
Department of Chemistry, Tulane University, New Orleans, Louisiana 70118, United States
S
* Supporting Information
ABSTRACT: A suite of NMR techniques revealed that a cavitand
(1) formed 2:1 host−guest complexes with a range of mono-
unsaturated fatty carboxylates and their corresponding methyl esters.
All of the carboxylates bound to the capsule in a J-shaped motif with
the carboxylate at the equatorial region of the dimeric capsule, and
the reverse turn of the chain and the methyl terminal in each polar
region of the host. Guest exchange was slow on the NMR time scale,
while tumbling was slow or close to the NMR time scale depending
on the position and stereochemistry of the double bond. In contrast,
the methyl esters were found to bind in three motifs depending on
the position and stereochemistry of the double bond. Thus, the
esters were observed to bind in a J-shaped, U-shaped (the turn in
the guest occupying a polar region and the two termini competing
for occupancy of the other pole), or a reverse J-shaped motif (ester moiety and turn each occupying a pole and the methyl
terminal located near the equator). Relative binding constant (Krel) determinations revealed that the affinity for the capsule was
dependent on the position and stereochemistry of the double bond.
INTRODUCTION
■
Understanding molecular behavior within yocto-liter compart-
ments can offer new perspectives on biological phenomena in
Nature and open the way to highly unusual and selective forms
of catalysis,1−9 as well as molecular protection10−13 and
separation strategies.14,15
We have previously reported on the kinetic resolution of
constitutionally isomeric esters using the dimeric capsule
formed by octa-acid 1 in basic media.15 In the absence of the
host the selected guests revealed the expected relationship
between their hydrolysis rates and the size of their alkoxy R
group. However, in the presence of the host these intrinsic
reaction rates were strongly modulated by the affinity that each
conformations along the chain are found to predominate. This
ester had for the dry yocto-liter environment of the capsule.
is an unlikely conformation within free solution, but the
Hence by this type of selective molecular protection it was
opportunity to make more contacts with the walls of the
possible to bring about the kinetic resolution of pairs of esters
capsule more than compensates. As the alkane or alkyl chain is
that otherwise could not be separated by selective hydrolysis in
increased in length further relative to the capsule length, this
free solution.
motif becomes untenable. Instead guests adopt U-shaped or J-
Key to all of these applications within yocto-liter compart-
shaped motifs with a reverse turn located within the chain.20−22
ments is the preferred conformation and orientation of the
Similar higher-energy U- or J-shaped motifs have also been
bound guest (its packing motif). In the aforementioned case of
observed in fatty acids bound to their proteinaceous trans-
ester resolution the guests were relatively small compared to
porters,23,24 and with bolaamphiphiles bound to bowl-shaped
the overall capacity of the host, and these and other studies
hosts25,26 and more open cucurbiturils.27 Building on these
findings, very recent results have shown how controlling such
coefficients highly flexible molecules adopt principally extended
using fully capsular hosts have revealed that at such low packing
motifs with anti dihedral angles down the length of the main
chain of the guest.16−19 These same studies also revealed that
Received: February 2, 2017
when packing is more constrained helical motifs with gauche
© XXXX American Chemical Society
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Figure 1. Chemical structures of esters and carboxylates used in this study: methyl esters 2a−12a (R = Me) and sodium carboxylates 2b−12b (R =
Na). Atom numbering used in this study is shown in structure 2a/b.
Scheme 1. Synthesis of Guests 3a and 4a
Scheme 2. Synthesis of Guests 11a and 12a
conformations can be used to template cyclization reac-
tions.26,28,29
influence the affinity, packing motif, and mobility of a guest
within the capsule.
Considering our early successes with the kinetic resolution of
carboxylic esters using octa-acid 1, we wished to examine
analogous kinetic resolutions of long-chain fatty acid esters
(Figure 1).30−33 There are three principal reasons for this. First,
as structural components of bilayers, as energy sources, and as
signaling molecules,34 fatty acids and their esters play vital roles
in biology and health.35 Second, the separation of fatty acids
and esters differing only in the location or stereochemistry of a
sole double bond is frequently problematic.36 Third, we
envisaged that the position and stereochemistry of the CC
double bonds in these molecules would significantly influence
their packing motif within the confines of the dimer of 1, and
hence the outcome of corresponding kinetic resolution
experiments.
As a first step toward examining the kinetic resolution of
these fatty acid esters, we report here on the binding of esters
2a−12a (Figure 1) and their corresponding free carboxylates
(2b−12b) to the dimer formed by 1. Our results show that
changes to the headgroup (carboxylate or ester) and the
position and stereochemistry of the double bond all greatly
RESULTS AND DISCUSSION
■
The host central to this study is octa-acid deep-cavity cavitand
1.37,38 Under basic conditions octa-acid is capable of binding a
broad range of amphiphilic39,40 and anionic41,42 guests as 1:1
host−guest complexes, or forming capsular 2:1 (or 2:2) host−
guest complexes with more nonpolar guests.43 Driven by the
Hydrophobic Effect,44,45 host 1 forms capsular complexes with
guests as large as those possessing 27 non-hydrogen atoms,37
and consequently it was expected that it would readily form 2:1
complexes with the methyl esters used in this study. This was
also suggested by recent work that included the 2:1 capsular
complex between 1 and stearic acid/stearate 2b.46
Guest Synthesis. Among the esters studied here, saturated
ester 2a and six of the monounsaturated derivatives (5a−10a)
were commercially available. Esters 3a, 4a, 11a, and 12a, were
synthesized by Wittig chemistry (Schemes 1 and 2).47
Specifically, compounds 3a and 4a were accessed by forming
the triphenyl phosphonium salt of 1-bromohexadecane and
reacting its ylide (formed with sodium bis(trimethylsilyl)amide)
with methyl 2-oxoacetate (Scheme 1). This gave a 60:40 ratio
B
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of the two stereoisomers that were separated by column
chromatography.
The addition of a slight excess of guest revealed that in these
complexes exchange between the free and the bound state is
close to the NMR time scale; however, this fact cannot account
for the splitting of host signals such as in the case of the
complex with 6b. Consequently, this splitting of the host signals
was attributed to relatively slow tumbling of the guest within
the capsule (vide infra).
Ester 11a was obtained (Scheme 2) by converting 15-
hydroxypentadecanoic acid to its methyl ester, oxidation of the
terminal hydroxy group to the corresponding aldehyde, and
treatment of this with the ylide formed by reacting propyl-
triphenylphosphonium bromide and sodium bis(trimethylsilyl)-
amide. This process led to only trace amounts of ester 12a, and
as a result this trans-isomer was obtained via a two-step
epoxidation/elimination interconversion of 11a.48
Except where specifically required (vide infra), the different
acids were synthesized as their complexes within the octa-acid 1
dimer by simply treating the corresponding ester complex with
excess NaOH.
The upfield shifting of the bound guest signals relative to the
free state arises because of the shielding properties of the
aromatic walls of the container. It has been previously shown by
1
both H NMR, and molecular simulation and guest proton
chemical shift evaluation using Gauge Invariant Atomic Orbital
calculations, that in these types of capsular complexes, the
deeper a guest atom is on average located in one of the
hemispheres the greater the peak shift (Δδ) between the free
and the bound state.22,49 To understand the packing motifs of
these guests we therefore used COSY NMR to reveal the
coupling between the bound guest signals, identify them, and
calculate the corresponding Δδ value for each group
(Supporting Information). Figure 3 shows the Δδ values for
all of the methylene and methyl signals of guests 3b−12b.
En masse this data landscape reveals ridges for methylenes
C2−C3 and C12−C13 corresponding to limited upfield
shifting of these signals, a valley centered on methylenes
C7−C9 corresponding to strongly upfield shifted signals, and
very large upfield shifts for the C18 terminus of each guest.
Hence these data reveal that all carboxylates 3b−12b primarily
adopt a J-shaped motif within 12, with the terminal methyl
group deeply buried at one pole forming strong C−H···π
interactions with the host, a turn at C7−C9 located at the
other, and the carboxylate group at the equatorial region of the
capsule (Figure 4). The near uniformity of the data landscape
also shows that the location and stereochemistry of the bond
has little effect on the preferred motif of a guest. We attribute
this singular packing motif for all the guests to two factors, the
first being the solvation requirements of the polar carboxylate
group; if this headgroup is located at the equatorial region of
the host, small-scale opening of the capsule (its breathing)50
can allow partial solvation. The packing of these carboxylates
and the corresponding esters (vide infra) therefore reveal the
first evidence of heterogeneity in the polarity of the inner space
of the container 12. To our knowledge this type of guest
anchoring has not been identified in other, all-encapsulating
supramolecular hosts. Second, the sharpness of the methyl
group, the flexibility of its attendant chain, and the overall low
polarity of these moieties make the alkyl chain an efficient
packer of the nonpolar and relatively narrow polar region of the
capsule.22 In combination, these factors dominate packing and
ensure a singular type of binding. It is illustrative to compare
this J-shaped motif with comparably long alkane guests such as
n-octadecane, n-nonadecane, and n-eicosane, which due to
symmetry reasons adopt U-shaped motifs.22
Sodium Carboxylates 3b−12b Binding to Octa-acid 1.
The binding of stearic acid/stearate 2b (Figure 1) and five
other saturated acids to the dimer capsule 12 has been reported
previously.46 This study revealed that the acid guests formed a
stable 2:1 host−guest complex but that shorter chained guests
formed weaker, faster-exchanging complexes. Furthermore,
these capsular entities also possessed an ionization event
attributed to the deprotonation of a carboxylic acid with a shift
of 4 pKa units relative to free solution. We attributed this to the
bound guest and the nonpolar interior of the capsule greatly
reducing its acidity. This deprotonation was found to decap
smaller guest acids/carboxylates to form the corresponding 1:1
complex, but stearic acid/stearate 2b was shown to always form
the 2:1 host−guest complex irrespective of the pH of the
external medium. In all cases discussed here, because of the
high pH (∼12) these guests exist predominately as their
conjugate bases.
Figure 2 shows the 1H NMR spectra for the resulting
complexes with carboxylates 3b−12b at a host−guest ratio of
1
Figure 2. H NMR spectra of encapsulated guest 3b−12b within 1
mM host 1 in D2O buffered with NaOD to pH ∼12.
Upon further analysis of the Δδ landscape, Figure 3 also
shows (right) the corresponding plan perspective, with the
position of the double bonds in each isomer indicated as a blue
line. Assuming that the maximal Δδ values in the midsection of
the guest corresponds to the position of the turn, its precise
position is slightly different for each guest; in general for guests
3b−6b the double bond is located on the shorter (carboxylate-
terminated) arm of the J-motif, while for guests 7b−12b the
double bond is located in the longer (methyl terminated) arm
of the motif (Figure 4). In the case of cis-6 5b and trans-9 8b
(elaidic acid) the reverse turn is relatively early in the chain
2:1. DOSY NMR analysis confirmed that all these were 2:1 host
guest complexes (Supporting Information). Each guest binding
region in the spectra showed wide signal anisotropy, with an
envelope of signals amounting to a distinct, unique signature
for that complex. In all cases, however, the position of the
terminal C18 signal was remarkably consistent: −3.17 ( 0.14)
ppm. Also evident from Figure 2 was splitting of the host
signals in some of the complexes. For example the Hd signal
(see structure 1) at ∼6.7 ppm is sharp in the case of 12b, broad
in the case of 9b, and split into two singlets in the case of 6b.
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Figure 3. 3D plot of Δδ values for groups C2−C18 of encapsulated guest 3b−12b. (Left) Perspective highlighting: C2−C3 and C12−C13 ridges,
the C7−C9 valley corresponding to the turn of the J-motif, and the extreme upfield shifts for the C18 termini. (Right) Plan perspective looking
down on the same Δδ landscape for encapsulated guest 3b−12b. The location of the double bonds in the different guests is highlighted using blue
lines. Indicated values are the ΔΔδ for the alkene methine signals (see main discussion).
corresponding methine groups of guest 5b reside on average in
very different surroundings (ΔΔδ = 1.45 ppm). In this latter
case the C7 is bound near the very base of the pocket whereas
the adjacent C6 methine is located above it (Figure 4). It is
interesting to consider the possibility that these different
magnetic environments may indicate the possibility of
controlling the regioselectivity of addition reactions to such
guests.
The J-shaped motif for these guests represents a time-average
sum of the different conformations weighed according to their
relative energies. Thus, in the case of 6b the desymmetrization
of the host capsule (e.g., Hd, Figure 2) arises because the
tumbling of the guest (Figure 4 left) is slow on the NMR time
scale. However, this tumbling is evidently close to the NMR
time scale; the complex with 9b has very broad host signals,
Figure 4. Schematic representations of the complexes involving guests
5b and 12b as representative examples of the J-shaped packing motif
of acid guests 3b−12b.
whereas binding 12b results in an apparently symmetric
(Figure 3 right). We interpret these findings to the cis-6 double
capsule. To confirm this hypothesis a VT 1H NMR experiment
bond of 5b being more predisposed for the turn and promoting
was carried out with guest 6b (Figure 5). At room temperature,
the early reversal of direction, while the incongruity of a trans-9
the Hc and Hd signals are split into two singlets, but as the
double bond in 8b for the narrow polar region of the capsule
does likewise. Between these two isomers is cis-9 7b (oleic acid)
where the ideal geometry of the double bond results in it being
part of the turn. The C7−C9 turn of trans-15 guest 11b also
stands out from the average. Thus, although the double bond is
temperature was raised these signals coalesced and ultimately at
70 °C each appear as a sharp singlet.
To ascertain how the position and stereochemistry of the
double bond affects the coalescence temperature (Tcoal) we
carried out VT NMR studies of all of the complexes of
carboxylates 3b−12b. This revealed an order of increasing Tcoal
values for this series of guests as follows (°C): 12b (10), 8b
(12), 11b (14), 3b = 4b (30), 9b (31), 7b = 10b (34), 5b (41),
6b (44). Thus, although the location of the double bond in
these guests is not reflected in significant changes in their
packing motif, the kinetics of tumbling is more significantly
affected (Figure 6). The guests can be roughly grouped into
two families. The kinetically most stable motifs consist of either
cis double bonds located at the center of the main chain near
the reverse turn (e.g., 5b), or trans double bonds located away
from the turn and in the arms of the J-shaped motif (e.g., 10b).
The other guests have much lower Tcoal values. These include
those with double bonds near the termini (11b and 12b) or a
well removed from the turn, the upfield shifting of the turn is
relatively small. This suggests that on average the turn is not
deeply located in one polar region of the capsule.
The labels for each blue line indicating the position of the
double bond in Figure 3 are the attendant ΔΔδ values for the
alkene methine signals, i.e., the difference in the extent that
each vinylic proton is shifted upfield when in the bound state.
As the alkene group has limited flexibility and its methines
possess very similar chemical shifts in the free state, a
comparison of the magnetic environment of the two signals
in each guest gives a report of the heterogeneity of the
electronic environment around the double bond. For example,
in the case of 12b these two protons are in very similar
electronic environments (ΔΔδ = 0.23 ppm), whereas the
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clear from these data, but evidently their preferred motif is
relatively high in energy and the resulting Tcoal values are much
lower. One possibility is that the attenuated upfield shift of their
turns and low Tcoal values are a reflection of the difficulties with
storing a relatively rigid C15−C18 moiety in the narrowest
polar region of the capsule. In contrast, the low Tcoal for the
complex with 8b seems evident; the situation of having a trans
double bond near the reverse turn of the bound guest is far
from ideal.
In summary, the position and the stereochemistry of the C
C double bond in carboxylates 3b−12b do not influence the
gross overall conformation or motif of the different guests; the
J-shaped motif is controlled by the anchoring effect of the
terminal methyl group and the carboxylate binding to the polar
and equatorial regions of the capsule, respectively. However,
there are subtle differences between the motifs of the guests,
and the position and stereochemistry of the double bond do
influence the movement of the guest within the capsule.
Methyl Esters 2a−12a Binding to Octa-acid 1. To
investigate the binding motifs of the fatty acid methyl esters
inside the capsule formed by octa-acid (12), we performed the
same suite of analytical techniques utilized for studying the
carboxylate complexes. Namely 1H NMR was used to confirm a
2:1 host−guest stoichiometry and DOSY NMR was used to
confirm a dimeric capsule structure, while a combination of
COSY and NOESY NMR experiments allowed guest peak
assignment and revealed the Δδ values for the bound guest
signals. Figure 7 shows the Δδ values for all of the main-chain
methylene and methyl signals of guests 3a−12a and reveals a
more complex Δδ landscape than that seen for the carboxylate
complexes (Figure 3).
Figure 5. VT 1H NMR spectra of encapsulated guest 6b within 1 mM
host 1 in 100 mM NaOH/D2O.
There are several key, gross topological differences between
the Δδ landscapes of these two sets of guests. In particular, the
major ridges at C2−C3 and C12−C13 for esters 3a−12a are
generally more varied than the corresponding carboxylates. For
example, the upfield shifting of the C2 signal varies from −0.02
to −1.93 ppm for the esters (3a and 12a respectively), whereas
the same signals from the carboxylate guests range from −0.21
to −0.39 ppm (for 4b and 9b respectively). Relatedly, the Δδ
Figure 6. Influence on the position/stereochemistry of the double
bond upon Tcoal for the carboxylate guests 3b−12b.
trans-9 double bond (8b) near the turn in the molecule. As
Figure 3 shows, guests 11b and 12b have relatively small
upfield-shifted reverse turns at C8−C9 indicative of a far from
ideal packing of the polar region by the reverse turn. Precisely
how the packing of 11b and 12b differs from the others is not
Figure 7. 3D plot Δδ values for groups C2−C18 of encapsulated guest 3a−12a. (Left) Perspective highlighting: the strong, but variable upfield shifts
for the C18 methyl, and in particular the small shift in the C18 methyl signal for 12a. Also highlighted are saddles for guests 8a and 11a that cut
across the C7−C9 valley. (Right) Plan perspective looking down on the same Δδ landscape for encapsulated guest 3a−12a. The location of the
double bonds in the different guests is highlighted using blue lines. Indicated values are the ΔΔδ for the alkene methine signals.
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values for the terminal C18 signal for the esters vary from
−1.38 ppm in the case of 12a to −3.95 ppm in the case of 4a,
whereas the C18 signals for the bound carboxylates were spread
over a narrow range from −3.76 to −4.14 ppm (11b and 3b
respectively). Equally as significant, the C7−C9 valley of the
ester guest Δδ landscape is punctuated by two saddles
corresponding to minimally upfield-shifted turns for guests
8a, 11a, and 12a. Evidently, the decreased polarity of the ester
group relative to the carboxylate reduces the influence that this
terminus has on guest packing and hence allows for more
variety in the different possible guest motifs. Analysis of the
series of complexes reveals three different motifs exemplified by
ppm). The reverse turn in bound 5a was indicated by the
significant upfield shifts of the C7, C8, and C9 methylene group
signals which possess Δδ values of −2.42, − 2.15, and −2.22
ppm, respectively. In contrast, the C2 and methoxy (C0)
groups were shifted upfield only by respectively −0.46 and
−0.79 ppm. Additionally, the alkene methine signals of 5a
possessed a relatively large ΔΔδ value (the difference between
how much each methine is shifted upfield when moved from
the free to the bound state) indicating that on average each
methine resides in quite different electronic environments
(Figure 7). Thus, in combination these NMR shift results
demonstrate that 5a adopts a J-shaped motif in which the cis-6
double bond is located on the short (ester terminated) arm and
at the turn of the motif (Figure 9).
1
guests 5a, 8a, 11a, and 12a. The H NMR spectra of these
complexes are shown in Figure 8.
The guest binding region of the complex with trans-9 guest
8a shows the largest signal anisotropy with a spread of over 7
ppm (Figures 7 and 8). Nevertheless, at room temperature
many of the guest signals were broad and overlapping. To fully
characterize the signals from this guest a VT NMR experiment
was performed which gave improved signal resolution at 50 °C
(Supporting Information). Integration of the peaks at this
elevated temperature, combined with a COSY NMR experi-
ment, led to the assignment shown in Figures 7 and 8. In this
particular case the uncoupled methoxy group signal overlapped
with those from C2 and C11 and did not apparently integrate
for three protons. Extended delay times in the NMR
experiment did not resolve this issue, so we sought to confirm
this assignment using 2H NMR. Thus, the corresponding
deuterated methyl ester was synthesized by treating 8b with
HCl in d4-MeOH and the deuterium NMR of its corresponding
complex recorded in H2O (Supporting Information). The
Figure 8. 1H NMR spectra of encapsulated guests 5a, 8a, 11a, and 12a
within 1 mM host 1 in 10 mM Na2B4O7/D2O. Bound guest signals are
labeled as per Figure 1.
2
lower resolution of H NMR and the restricted movement of
the guest was evident in the broadness of the CD3− signal, but
accounting for the isotope effect on chemical shift these
experiments confirmed the location of the methoxy signal in
1
the H NMR spectrum of the complex. Thus, the methoxy
The complex formed by cis-6 isomer 5a is typical of a J-
shaped guest binding motif analogous to the carboxylate guests.
Of all the moieties in this guest it is the C-18 terminal methyl
that was shifted upfield to the greatest extent (Δδ = −3.82
(C0) and the C2 signals, as well as the C18 signal, were
considerably upfield shifted: Δδ = −2.32, −1.21, and −3.96
ppm, respectively. In contrast to the J-shaped guest 5a, the
Figure 9. Summary of approximate packing motifs of guests 3a−12a. Shown numerals are the Δδ values for the methoxy (C0), C2 (if the methoxy
signal was not observed), and C18.
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most upfield shifted methylene in the midsection of 8a, C9, was
only shifted by −1.79 ppm. This smaller shift in the signals
from the midsection of 8a, coupled with the much larger shift
in the signal from the methoxy (C0) group, suggests that rather
than adopting primarily a J-shaped motif, the trans-9 double
bond of guest 8a shifts the preferred motif to one that is more
U-shaped. In other words there is little energetic preference as
to which of the termini binds to the polar region. NOESY
NMR of the complex supports this idea with cross peaks
between the C-2 and C3 methylene signals and the Hb signals
from the host (Supporting Information). As with the
carboxylate guest 8b, the trans-9 double bond of 8a is located
after the turn in the guest, and the small difference between its
two methine signal shifts indicates that both carbons are at
similar depths in the pocket. We interpret these findings to the
poor fit of the trans double bond in the turn and at the narrow,
polar region of the capsule. This misfit prevents the turn fully
occupying the base of the host, leads to relatively small upfield
shifting of the signals at this point in the guest, and forces the
ester group more deeply into the opposing pole of the capsule
(Figure 9, cf. 6a). These factors were also evident in the
complex of 8b, but are not so pronounced because of the
stronger anchoring properties of the carboxylate for the
equatorial region of the capsule. In other words when the
carboxylate headgroup is replaced by the methyl ester the
reduced polarity of the group allows the guest to readjust to a
U-shaped motif to relieve the misfit of the double bond.
typically large amount: Δδ = −2.49 ppm. These observations
are consistent with a reverse J-shaped binding motif whereby
the ester group is located deep in one of the poles of the
capsule, and the terminal methyl group is located near the
equator (Figure 9). NOESY NMR confirmed this (Supporting
Information), with the only evident through-space interactions
between the guest and the Hb protons of the host involving the
methoxy (C0) and the C9−C11 methylenes. We attribute this
change in binding motif to the inflexibility and narrower profile
of the trans-butene terminal group making it an even poorer
packer of the narrow, polar region of the capsule than the
terminus of its cis-counterpart 11a.
Figure 9 shows a summary of the different binding motifs for
each guest 3a−12a. Most of the guests adopt J-motifs in which
the ester group is located near the equator of the capsule.
However, within this group of seven guests, 9a and 10a possess
relatively large Δδ values for the C2 methylene and relatively
small Δδ values for the C18 groups. This suggests that their
preferred motif is somewhat between a J-shape and a U-shape,
but we classify them as the former owing to the relatively large
difference between the Δδ values of the two termini.
Comparisons between the different complexes reveal the
importance of the position and the stereochemistry of the
singular double bond in this guest family. For example there is
little motif change between stereoisomers 3a and 4a, 5a and 6a,
or 9a and 10a. However, there are motif switches between 7a
and 8a, and between 11a and 12a. On the other hand, within
the cis isomers there are four J- and one U-motif, while within
the trans isomers there are three J-, one U-, and one reverse J-
motif.
Having determined the binding motif of each guest within
the dimer formed by octa-acid 1, we performed a cross-checked
network of paired competition experiments to determine the
relative binding constants for the five pairs of guests
(Supporting Information). For these determinations integration
of either the bound Hc or Hd peak from the host or the bound
guest methyl peaks could be utilized. By this approach the
relative binding constants for the guests were found to increase
in the following series (Krel): 3a (1), 12a (3), 4a (5), 11a (10),
8a (17), 10a (20), 6a (27), 9a (41), 5a (56), and 7a (67).
Figure 10 plots these data as a function of the position and
stereochemistry of the double bond. For all but one
stereoisomeric pair, the cis isomers have stronger binding
1
Considerable clustering of signals was evident in the H
NMR spectrum of the complex with 11a (Figure 8). Moreover,
the overall anisotropy for the bound guest signals was relatively
low, covering a range of 6.00 ppm. The overlap of signals was
improved at 40 °C (Supporting Information), and this allowed
complete assignment of the guest signals (Figure 7) and the
determination of the packing motif inside the capsule formed
by 1. The C-18 terminal signal was the most upfield shifted, but
only to a relatively small extent (Δδ = −3.76 ppm). Likewise,
compared to other guests the midsection of 11a also underwent
the least upfield shifting, by only Δδ = −1.40 ppm in the case of
C8. Finally, much like 8a, the methoxy (C0) and C2 signals of
11a were also shifted considerably upfield, by Δδ = 2.20 and
−1.01 ppm, respectively. This is again consistent with a U-
shaped binding motif. A re-examination of the Δδ landscape for
the complex with carboxylate 11b (Figures 3) highlights a spur
that rises in the C7−C9 valley that, in the case of 11a, is
exacerbated to the point of forming a saddle between the two
main ridges. Moreover, 11b possessed one of the lowest
recorded Tcoal values of the carboxylate guests. These results
therefore highlight that a cis-double bond is not well
accommodated near the terminus of the long chain of the
guest, presumably because it is too inflexible to efficiently fill
the narrow polar region of the capsule. Consequently, a
reduction of the polarity of the headgroup by methylation
allows guest 11a to adopt a more relaxed U-motif.
The NMR spectrum for the complex with guest 12a (Figure
8) is instantly distinctive with its lack of highfield methyl signal;
the absence of this signal leads to the narrowest anisotropy for
the series, ∼5 ppm. Full characterization of the bound guest
signals revealed that the terminal C18 and the methoxy (C0)
group had Δδ values of −1.38 and −4.21 ppm respectively;
uniquely, the methoxy (C0) is considerably more upfield
shifted than the C18 terminus. Correspondingly, the C2
methylene signal shifted upfield an exceptional −1.93 ppm. In
contrast, the midsection of the guest (C10) was shifted a
Figure 10. Krel values: as a function of the position and stereo-
chemistry of the double bond in guests 3a−12a.
G
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The Journal of Organic Chemistry
Article
affinities with 12 than the trans isomer. We ascribed this
observation to the overall more compact shape of the cis-
isomers conforming to the confining space of the capsule. In
addition, Figure 10 demonstrates that the closer a double bond
is to one of the termini, the weaker the complex. Evidently,
restricted conformations for groups that must reside at the
narrower polar regions of the capsule weakens affinity. Another
way of stating these two observations is that the most stable
complexes are formed by cis-monounsaturated esters where the
double bond is ideally placed for promoting the turn in the J-
shaped binding motif, e.g., in the cis-6, cis-9, and cis-11 guests
5a, 7a, and 9a. Interestingly, within experimental error these
bind as strongly or more strongly than the corresponding
saturated ester 2a (Krel = 42).
Although the double bond strongly influences the relative
affinity of the guests, we were not able to confirm that its
position or stereochemistry affect the Tcoal of the guest. Thus, of
all the esters examined only the complex with trans-2 4a
showed any signs of broadening of the Hc and Hd signals at
room temperature (Supporting Information). We carried out a
VT NMR study on this complex and ascertained that its Tcoal
was 12 °C. Hence the esters clearly tumble much more rapidly
within the capsule than the considerably more polar carboxylate
guestsa reflection of the weaker anchoring effect of the ester
groupsand only with the trans-2 double bond of 4a can this
motion be inhibited such that desymmetrization of the capsule
is apparent.
the trans double bond of 8aalso shifts the packing motif away
from the typical J-shaped motif, in this instance to a U-shaped
motif.
The lower polarity of the ester guests relative to the
carboxylates result in the former being more mobile within the
container, but this lower polarity also leads to slow exchange
between the free and the bound state. This latter fact allowed
the relative binding constants (Krel) of the ester guests to be
determined and revealed that the affinity for the capsule was
highly dependent on the position and stereochemistry of the
double bond. At the most general level, guests with cis-double
bonds in the middle of the main chain possess the highest
affinity, while unsaturation near one of the termini of the guest
leads to lower stabilities.
To our knowledge, these results represent an unprecedented
level of guest motif mapping and demonstrate how such
mapping can identify heterogeneities with the inner space of
molecular and supramolecular containers. These results also
demonstrate the potential for yocto-liter containers to bring
about exquisitely selective reactions upon bound guests. On
that topic, on the expectation that these varied binding motifs
considerably affect the rates of hydrolysis of encapsulated esters
3a−12a, we are currently investigating kinetic resolutions using
these complexes. These results will be reported in due course.
EXPERIMENTAL SECTION
■
1. Materials and Instrumentation. Host 1 was synthesized
following the previously reported procedure.37,38 All NMR spectra
were recorded on a Bruker 500 MHz spectrometer at 25 °C unless
otherwise stated. Spectral processing was carried out using Mnova
software (Mestrelab Research S.L). All reagents and guests 2a and 5a−
10a (Figure 1) were purchased from Aldrich and were used without
purification. The remaining (known) guests 3a, 4a, 11a, and 12a were
synthesized by using Wittig chemistry. Known acid guests 2b−12b
were generated as complexes in situ by adding NaOH solution to the
corresponding ester guest complexes.
CONCLUSIONS
■
Our previous studies with relatively small constitutionally
isomeric, unbranched esters (C11H22O2) revealed a straightfor-
ward pole-to-pole binding motif for all guests.15 However, the
C18 guests studied here reveal a much more complex picture
with larger guests. The binding motif of the carboxylate guests
is dominated by the propensity for the terminal methyl group
to anchor to the narrow walls of the poles of the capsule via C−
H···π interactions, and for the carboxylate group to be anchored
at the equatorial region of the host. To our knowledge, this
latter concept of guest anchoring because continual breathing
of the capsule leads to a more polar environment around the
equatorial region of the host is unique to encapsulating
supramolecular hosts. The result of this twin anchoring is a near
uniform J-shaped motif for guests 3b−12b. However, the
position and stereochemistry of the double bond do have a
significant impact on the kinetics of guest movement within the
capsule. In contrast, when the polarity of the headgroup is
diminished by methylation, this equatorial anchoring by the
headgroup is attenuated. As a result the methyl esters were
found to bind in three different binding motifs; depending on
the position and stereochemistry of the CC double bond, the
guests were found to adopt either a J-shaped, U-shaped, or
reverse J-shaped motif. The fact that the J-shaped motif also
predominates suggests that although ester groups are weaker
equatorial anchors than carboxylates, in most cases the alkyl
chain is a better packer of the polar regions of the capsule than
the ester moiety. The exceptions to this are when the sole C
C double bond is near the terminus of the main chain, in which
case the reduced flexibility of the tail of the main chain reduces
its ability to pack the polar regions of the capsule relative to the
ester group. In that regard the trans double bond geometry of
12a is the poorest packer of the guests examined here, and a
reverse J- shaped motif of this guest is preferred. A double bond
highly incongruous with the reverse turn of the bound guest
2. Synthesis of Guests 3a and 4a. The synthesis of guests 3a and
4a (Scheme 1) followed procedures described previously.51
Synthesis of Hexadecyltriphenylphosphonium Bromide. 1-
Bromohexadecane (10 mmol, 3.05 g) and triphenylphosphine (5
mmol, 1.30 g) were added to toluene (40 mL), and the solution was
heated to 90 °C. After 2 days, the reaction was cooled and
concentrated under reduced pressure to afford the crude phosphonium
salt that was washed with 50 mL of diethyl ether. 2.2 g (79% yield) of
precipitated phosphonium salts were collected and dried under
vacuum. 31P NMR (162 MHz, Chloroform-d, ppm): δ = 25.66 (s,
+
R-PPh3 , ref = −4.42 (s, PPh3).
Synthesis of Guests 3a and 4a. To a suspension of hexadecyl-
triphenylphosphonium bromide (7.0 mmol, 4.0 g) in anhydrous THF
(10 mL) at 0 °C under nitrogen was added NaN(TMS)2 (1.0 M in
THF, 6.43 mmol). The resulting orange mixture was stirred for 40 min
at rt. Methyl 2-oxoacetate (3.5 mmol 300 mg) in THF (5 mL) was
then added dropwise by syringe. After 3 h, the reaction was quenched
with saturated aqueous NH4Cl (20 mL) and extracted with DCM (3 ×
50 mL). The combined extracts were dried over anhydrous Na2SO4,
and DCM was removed under reduced pressure. The residue was
purified on silica gel by stepwise gradient elution with dichloro-
methane/hexane (20:80 to 50:50). Guests 3a and 4a were isolated in a
1
60:40 ratio (500 mg, 48% and 331 mg, 32% respectively). 3a: H
NMR (500 MHz, Chloroform-d, ppm): δ 6.25 (dt, J = 11.5, 7.5 Hz,
1H), 5.79 (d, J = 11.5, 1H), 3.73 (s, 3H), 2.67 (m, 2H), 1.46 (p, J = 7.3
1
Hz, 2H), 1.28 (m, 24H), 0.91 (t, J = 6.9 Hz, 3H). 4a: H NMR (500
MHz, Chloroform-d, ppm): δ 7.05−6.95 (dt, J = 15.7, 7.0 Hz, 1H),
5.84 (d, J = 15.7 Hz, 1H), 3.75 (s, 3H), 2.22 (m, 2H), 1.47 (p, J = 7.1
Hz, 2H), 1.29 (m, 24H), 0.91 (t, J = 6.9 Hz, 3H).
3. Synthesis of Guests 11a and 12a. Guests 11a and 12a were
synthesized (Scheme 2) by a similar procedure to that outlined by
H
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Article
Rawling et al.47 and were distinguished using FT-IR and 13C NMR.
Thus, as has been previously reported,52 guest 12a showed an
absorbed band at 967 cm−1, whereas for 11a this band was absent but
an absorption at 3001 cm−1 was evident. Again consistent with a
previous report,53 in the 13C NMR spectrum the allylic carbons
resonances of 11a were evident at 27.10 ppm (C14) and 20.51 ppm
(C17)m while those of 12a were observed at 32.59 and 25.60 ppm.
Synthesis of Methyl 15-Hydroxypentadecanoate. To a solution of
the hydroxy fatty acid (7.00 mmol) in acetone (120 mL) was added
water (8 mL), potassium carbonate (20.00 mmol), and iodomethane
(35.00 mmol). The resulting mixture was refluxed for 4 h and then
concentrated under reduced pressure. The residue was dissolved in
water (60 mL), and the solution was acidified with 1 M HCl. The
aqueous phase was extracted with DCM (3 × 60 mL), and the
combined extracts were washed with brine (100 mL), dried over
Na2SO4, and concentrated under reduced pressure to afford 1.80 g of
using a 600 μL sample of 1.0 mM host 1 in 10 mM Na2B4O7/D2O
buffer at 25 °C. To form the host−guest complexes the guests were
first dissolved in acetone-d6 to give a 30 mM stock solution.
Subsequently, 10 μL of each guest solution were added to the vial and
the acetone was removed with a stream of nitrogen. The vial was then
dried at rt under reduced pressure for 5 min. The host solution was
then added to the vial, and the resulting solution was stirred for 30 min
to give the corresponding 2:1 host−guest complex.
For all COSY and NOESY NMR experiments, a 10 μL volume of
150 mM stock solution of guest in acetone-d6 was combined with a
600 μL volume of a 5 mM host solution in 50 mM Na2B4O7/D2O
buffer.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00264.
the methyl ester (95% yield). H NMR (400 MHz, Chloroform-d): δ
3.64 (s, 3H), 3.61 (m, 2H), 2.28 (t, J = 7.6 Hz, 2H), 1.59 (m, 2H),
1.24−1.33 (m, 22H).
Materials and instrumentation information, details of
NMR studies including Δδ value calculations for
encapsulated guests, diffusion coefficient data, and
coalescence temperature measurements (PDF)
Synthesis of Methyl 15-Oxopentadecanoate. Under nitrogen,
methyl 15-hydroxypentadecanoate (4.00 mmol) in anhydrous DCM
(6 mL) was added to a suspension of pyridinium chlorochromate
(PCC, 6.68 mmol) and Celite (1.440 g) in 20 mL of anhydrous DCM.
The mixture was stirred for 2 h, after which time diethyl ether (50 mL)
was slowly added. The resulting mixture was stirred for 10 min and
then filtered over Celite. The Celite was washed with ether (2 × 20
mL), and the filtrate was concentrated under reduced pressure. The
residue was purified on silica gel by stepwise gradient elution with
dichloromethane/hexane (40:60 to 100:0) to give 0.90 g of the
aldehyde (84% yield). 1H NMR (500 MHz, Chloroform-d): δ 9.79 (t,
J = 1.9 Hz, 1H), 3.69 (s, 3H), 2.43 (td, J = 7.3 Hz, 1.9 Hz, 2H), 2.32
(t, J = 7.5 Hz, 2H), 1.56 (m, 4H), 1.40−1.24 (m, 18H).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bgibb@tulane.edu.
ORCID
Bruce C. Gibb: 0000-0002-4478-4084
Notes
Synthesis of Guest 11a. Under nitrogen, NaN(TMS)2 (1.0 M in
THF, 6.43 mmol) was added to a suspension of n-propyltriphenyl-
phosphonium bromide (7.00 mmol) in 10 mL of anhydrous THF at 0
°C. The resulting orange mixture was stirred for 1 h at rt. The solution
was then cooled to −78 °C, and methyl 15-oxopentadecanoate (3.21
mmol) in 5 mL of anhydrous THF was added dropwise by syringe.
The mixture was stirred at −78 °C for 30 min after which time the
reaction mixture was allowed to warm to rt. After further stirring for 2
h the reaction was quenched with 20 mL of saturated aqueous NH4Cl
and extracted with DCM (3 × 50 mL). The combined extracts were
dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. The residue was purified on silica gel by stepwise
gradient elution with dichloromethane/hexane (20:80 to 50:50) to
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the National Science
Foundation (CHE-1507344) for financial assistance and
Matthew B Hillyer and J. Wes Barnett for technical assistance.
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