Chain Entropy Beats Hydrogen Bonds to Unfold and Thread Dialcohol Phosphates inside Cyanostar Macrocycles to Form [3]Pseudorotaxanes

Article abstract of DOI:10.1021/acs.joc.0c02887

The recognition of substituted phosphates underpins many processes including DNA binding, enantioselective catalysis, and recently template-directed rotaxane synthesis. Beyond ATP and a few commercial substrates, however, little is known about how substituents effect organophosphate recognition. Here, we examined alcohol substituents and their impact on recognition by cyanostar macrocycles. The organophosphates were disubstituted by alcohols of various chain lengths, dipropanol, dihexanol, and didecanol phosphate, each accessed using modular solid-phases syntheses. Based on the known size-selective binding of phosphates by π-stacked dimers of cyanostars, threaded [3]pseudorotaxanes were anticipated. While seen with butyl substituents, pseudorotaxane formation was disrupted by competitive OH···O- hydrogen bonding between both terminal hydroxyls and the anionic phosphate unit. Crystallography also showed formation of a backfolded propanol conformation resulting in an 8-membered ring and a perched cyanostar assembly. Motivated by established entropic penalties accompanying ring formation, we reinstated [3]pseudorotaxanes by extending the size of the substituent to hexanol and decanol. Chain entropy overcomes the enthalpically favored OH···O- contacts to favor random-coil conformations required for seamless, high-fidelity threading of dihexanol and didecanol phosphates inside cyanostars. These studies highlight how chain length and functional groups on phosphate's substituents can be powerful design tools to regulate binding and control assembly formation during phosphate recognition.

Full text of DOI:10.1021/acs.joc.0c02887

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Article
Chain Entropy Beats Hydrogen Bonds to Unfold and Thread
Dialcohol Phosphates inside Cyanostar Macrocycles To Form
[3]Pseudorotaxanes
Rachel E. Fadler, Abdelaziz Al Ouahabi, Bo Qiao, Veronica Carta, Niklas F. König, Xinfeng Gao,
Wei Zhao, Yankai Zhang, Jean-Franco
̧
is Lutz, and Amar H. Flood*
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ABSTRACT: The recognition of substituted phosphates underpins many
processes including DNA binding, enantioselective catalysis, and recently
template-directed rotaxane synthesis. Beyond ATP and a few commercial
substrates, however, little is known about how substituents effect
organophosphate recognition. Here, we examined alcohol substituents
and their impact on recognition by cyanostar macrocycles. The organo-
phosphates were disubstituted by alcohols of various chain lengths,
dipropanol, dihexanol, and didecanol phosphate, each accessed using
modular solid-phases syntheses. Based on the known size-selective binding
of phosphates by π-stacked dimers of cyanostars, threaded [3]-
pseudorotaxanes were anticipated. While seen with butyl substituents,
pseudorotaxane formation was disrupted by competitive OH···O− hydrogen bonding between both terminal hydroxyls and the
anionic phosphate unit. Crystallography also showed formation of a backfolded propanol conformation resulting in an 8-membered
ring and a perched cyanostar assembly. Motivated by established entropic penalties accompanying ring formation, we reinstated
[3]pseudorotaxanes by extending the size of the substituent to hexanol and decanol. Chain entropy overcomes the enthalpically
favored OH···O− contacts to favor random-coil conformations required for seamless, high-fidelity threading of dihexanol and
didecanol phosphates inside cyanostars. These studies highlight how chain length and functional groups on phosphate’s substituents
can be powerful design tools to regulate binding and control assembly formation during phosphate recognition.
recognition is using modular, automated,56 solid-phase57
INTRODUCTION
■
syntheses derived from phosphoramidite chemistry.58 The
Substituent-mediated recognition of organophosphates under-
pins processes across biology1 and chemistry,2 yet the role of
resulting organophosphates possess terminal hydroxyl units
the substituents is poorly understood.3 The biorecognition of
(Figure 1a). While useful as functional groups for further
oligonucleotides,4,5 R1−PO4 −R1 (R1 = hydroxyl-substituted
−
functionalization, the role of hydroxyls and linking alkyl chains
ribose/deoxyribose sugars), and phospholipids,6,7 R3−PO4 −
−
on binding is unknown. We address the recognition of this
R4 (e.g., R3 = ester-linked fatty acids, R4 = 4° ammonium) are
class of organophosphates using macrocyclic cyanostars (CS,
Figure 1b),24−26 which are size-matched to phosphate anions
and enable programmed formation of threaded structures
(Figure 1c). We find, however, that hydroxyls (−OH)
hydrogen bond to and fold up the organophosphate (Figure
1d) to compete with pseudorotaxane formation, which can
only be overcome using synthetic control of chain length to
access the many conformations that turn on the entropy
penalty of ring formation59−61 (Figure 2).
critical for life8−11 and human health12 while chiral phosphates,
R5−R5*−PO4 , (e.g., R5−R5* = BINOL) enable organic
−
catalysis.13,14 Synthetic organophosphates15,16 are also func-
tional targets, such as designer polyphosphates for information
storage,17−19 self-assembly,20−23 and templates24 for rotaxane
synthesis.25 Despite this broad diversity of usage, and beyond
dihydrogen phosphate anions26−31 (H2PO4 ), most studies of
−
organophosphate recognition have focused on ATP.32−34
Recognition targets are growing with more aimed at
phosphorylated biomolecules,35−39 phosphate-rich phy-
tate,40−42 dyes,43 insecticides,44 herbicides,45 neurotoxins,46
and phosphoryl nerve agents.47−50 However, the binding of
Received: December 16, 2020
Published: February 26, 2021
disubstituted phosphates (R−PO4 −R),51,52 where R = alkyl,53
−
benzyl,54 phenyl,55 and propargyl,25 is rare, which is limited by
the synthetic difficulty for disubstituted organophosphate. One
strategy to diversify organophosphates to help understand their
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Figure 1. (a) Structures of dibutyl, dipropanol, dihexanol, and didecanol phosphate and (b) the cyanostar macrocycle. (c) Dibutyl phosphate
threads inside two π-stacked cyanostars to form a [3]pseudorotaxane stabilized by 20 CH···O− hydrogen bonds. (d) Representative folding
equilibria of alcohol-substituted phosphates involve a balance between formation of two OH···O− hydrogen bonds into folded cyclic structures
(anti/syn) and random-coil extended structures.
Figure 2. Models of the conformations of the dihexanol phosphate guest showing (a) many possible conformations, (b) one folded conformation,
and (c) one of many extended, random-coil conformations favored with longer chains.
26
−
Studies of the receptor-mediated binding and recognition of
disubstituted organophosphates is rare.51,52 The binding of
with H2PO4 alone, formation of divergent anti-electrostatic
hydrogen bonds (AEHBs)64 between multiple anions
produced a mixture in solution composed of higher-order
complexes with a range of cyanostar−anion ratios (4:3, 3:3,
3:2, 2:2, 2:1) depending on the conditions in solution.
Phosphates monosubstituted with bulky naphthyl groups63
simplified the behavior by forming only a 2:2 species with
convergent AEHBs. Disubstituted phosphates cannot support
AEHBs, and thus dibutyne and dipropyne substituted
phosphates formed [3]pseudorotaxanes with cyanostar macro-
cycles25 in a 2:1 stoichiometry consistent with size-selective
binding of aprotic anions.24 The bambusuril macrocycle also
has binding preferences for larger anions65 but was seen in the
solid state to bind 2 equivalents of diethyl phosphate66 in a
perched geometry with the anions bridged by water molecules.
−
dibenzyl phosphate (Bz−PO4 −Bz) by doubly charged
bis(alkylguanidinium) receptors54 was studied to establish
the effect of the phosphate’s charge relative to monophenyl
phosphate (Ph−PO42−), but differences between substituents
were not examined. The number of organic substituents on
organophosphates was shown to impact binding to cationic
sapphyrin macrocycles62 with H2PO4 preferring 1:1 stoi-
−
chiometry while the monobasic mono- and diphenyl
substituted phosphates favored 1:2 structures in the solid
state. These 1:2 assemblies had different packings, which were
attributed to differences in the number of hydrogen bond
donors, the overall shape of the anion, and crystal growing
effects. A variation in stoichiometry with substitution was also
seen in the binding to cyanostar macrocycles.26,63 Therein,
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These studies suggest that a substituent’s sterics play an
important role in the binding of organophosphates.
was reinstated. These findings show how organic substituents
can play significant roles in organophosphate recognition as
well as being subject to manipulation for guiding self-assembly
toward desirable products.
Despite the diverse roles of disubstituted phosphates,67−69
the introduction of hydroxyl functional groups has only been
explored when mimicking biocatalysis. The binding of
organophosphates was leveraged in studies70−72 on the
reactivity of the terminal hydroxyl groups toward trans-
esterification of phosphodiester. In those cases, most
receptors70−74 also contained basic sites, e.g., pyridines,
imidazoles, hydroxyls, for deprotonating the hydroxyl groups
in order to accelerate the hydrolysis of the organophosphates.
The role of terminal hydroxyl (−OH) groups on recognition
properties therefore remain untested.
RESULTS AND DISCUSSION
■
Dibutyl Phosphate-Cyanostar [3]Pseudorotaxanes. In
the simplest case, cyanostars form [3]pseudorotaxanes as
threaded 2:1 cyanostar−anion complexes with dialkyl sub-
1
stituted organophosphates. A H NMR titration monitoring
addition of cyanostar to dibutyl phosphate (4:1
CD2Cl2:CD3CN, Figure 3a) shows slow-exchange peaks.
Hydroxyl groups are known to be strong hydrogen bond
donors75 capable of anion binding,76−78 and while interactions
with phosphates are expected,79 their role has not been
studied. Similar interactions have been seen but between NH
hydrogen bond donors and phosphates in receptors.80 The
ability of phosphate to act as a base14,81 and deprotonate
phenol OH groups may have discouraged further study of
OH···O− motifs.82 Nevertheless, and not unsurprisingly,
evidence for hydrogen bonds between hydroxyl units and
phosphates is seen in other areas of chemistry83,84 and
biology.85,86 Putative intermolecular hydrogen bonds between
hydroxyl-substituted substrates and chiral phosphate ligands
−
(R*=PO4 ) were invoked in the enantioselective fluorination
of phenols.87 Intramolecular OH···O− hydrogen bonds
between hydroxyls and phosphates were observed in a crystal
structure of oligonucleotides88 between ribose and the
phosphate backbone. Interestingly, phosphorylation was used
as a switch to fold up an intrinsically disordered protein89 and
is shown with NMR spectroscopy to operate by a threonine
OH hydrogen bonding to the phosphoryl site. Based on these
precedents, hydroxyl groups would be expected to hydrogen
bond with anionic phosphates to impact their recognition by
regulating their structures (Figure 2).
Herein, we evaluate the role of hydroxyl end groups on the
binding of disubstituted organophosphates with cyanostar
macrocycles. We do not know if the competition for phosphate
posed by two (2) strong intramolecular OH···O− hydrogen
bonds will displace the many (20) weak CH···O− hydrogen
bonds formed inside the 2:1 intermolecular complex with a
cyanostar. In the latter, large anions24 with the same size as
disubstituted phosphates are usually bound as a 2:1 complex
with high affinities ∼1012 M−2. To help evaluate this
competition, we designed a series of organophosphates. As a
control, the binding of dibutyl phosphate bearing just alkyl
chains was confirmed to form a threaded [3]pseudorotaxane.
Isosteric introduction of hydroxyl groups in dipropanol
phosphate generated additional equilibria that competed with
[3]pseudorotaxane formation. A perched 2:2 assembly was
observed in the crystal structure with OH···O− hydrogen
bonding from the two hydroxyl groups to the phosphate.
Computational modeling revealed the strong enthalpic
preferences for the formation of the OH···O− hydrogen
bonds with concomitant generation of two 8-membered
intramolecular rings. Among the many conformations possible
(Figure 2a), the ones folded into a cycle (Figure 2b) regulated
the recognition. Thus, we leveraged the well-known impact of
entropy on ring formation by lengthening the alkyl chain
(Figure 2c) to lower the probability of forming the back-
folded90−92 conformations. Using dihexanol and didecanol
organophosphates, high-fidelity [3]pseudorotaxane formation
1
Figure 3. (a) H NMR titration of cyanostar into dibutyl phosphate
(1 mM, in 4:1 CD2Cl2/CD3CN, 298 K, 600 MHz). (b) Normalized
peak intensities of uncomplexed phosphate (Hf) and [3]-
pseudorotaxane (Hf).
Based on the α methylene protons (Hf) on the organo-
phosphate, we see conversion at just over 2 equivalents (Figure
3b) to a 2:1 cyanostar−phosphate assembly with characteristic
peaks.24,25 Specifically, diastereomeric pairs (e.g., Hb and Hb’)
only emerge when the bowl-shaped M- and P-handed
cyanostars (Figure S28) form a π-stacked dimer.24 We observe
83% of the meso (MP, Hb) and 17% of the chiral (MM plus PP,
Hb’) diastereomers (Figure 3a).25 These percentages are
similar to studies using dipropargyl phosphate (90% meso,
10% chiral).24
Formation of a threaded [3]pseudorotaxane structure was
further confirmed by 2D NMR studies. 1H−1H ROESY
(Figure 4, CD2Cl2) shows cross peaks between the cyanostar’s
CH hydrogen-bonding protons on the macrocycle’s interior,
Ha and Hd, and the phosphate’s α methylene protons, Hf. The
threaded architecture is also supported by the change in
chemical shift of the phosphate’s methylene, Hf (Figure 3a).
An ∼1 ppm downfield shift upon complexation with cyanostar
is consistent with being close to the plane of the cyanostar.24,25
Observation of a threaded [3]pseudorotaxane in dichloro-
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Figure 4. (a) 1H−1H ROESY of the [3]pseudorotaxane with
cyanostar (1 mM) and dibutyl phosphate (0.5 equiv) in CD2Cl2
(298 K, 600 MHz) and (b) model of the contacts.
methane provides us with a foundation for testing the effects of
the terminal hydroxyl groups on its recognition.
Intramolecular Hydrogen Bonds to Phosphate. An
examination of the recognition characteristics of dipropanol
phosphate was undertaken starting with a conformational
analysis (molecular mechanics, gas phase, Figure S1). As
expected, the most favored conformation shows both end
groups engaging in OH···O− hydrogen bonds with the
phosphate moiety. The folded conformation forms 8-
membered rings between the end groups and two different
oxygen atoms on the phosphate in an anti arrangement. There
are many anti conformations differing only in the local
arrangements of the alkyl chains. The next unique arrangement
shows hydrogen bonding from either end to the same oxygen
atom to form a syn geometry, which also generated a range of
alkyl conformers. All 235 conformations found by molecular
mechanics to be less than 40 kJ mol−1 had the two hydrogen
bonds. The anti and syn structures were further refined by
density functional theory (DFT, B3LYP/6-31+G*), and the
anti was found to be favored by +16 kJ mol−1 (Figure 5a−b).
We examined the experimental evidence for the folded
conformation in solution by NMR spectroscopy (Figures S23−
S25). First, the 3J coupling between phosphorus and Hf
protons on the organic backbone was used to examine the
conformational changes of the molecule in different solvents.
As known from the Karplus equation,93,94 specific conforma-
tions display specific coupling constants while random coils
display average values.95,96 Using dibutyl phosphate as a model
for a random coil, 31P−1Hf coupling was 6.5 Hz, which is the
average of a variety of low-lying conformations. Dipropanol
phosphate is anticipated from modeling to be in a compact
folded geometry with local conformations accessible. We
observe the coupling is 10.8 Hz indicative of a different average
geometry. When the solvent is changed to a methanol mixture
to disrupt OH···O− hydrogen bonds, we expect a random coil
(Figure 5c) and consistently see a coupling constant (6.3 Hz)
that matches dibutyl phosphate. This interpretation is further
confirmed by the appearance of the hydroxyl proton peak and
the 3J coupling between the hydroxyl proton and the Hf proton
observed in aprotic condition, but not in protic conditions
(Figures S23 and S24).
Figure 5. (a) Anti and (b) syn intramolecular hydrogen-bond
conformations of dipropanol phosphate obtained from molecular
mechanics compared with (c) a random-coil conformation that has no
hydrogen bonding. Calculated electrostatic potential maps for the
corresponding conformers are included. Equilibrium geometries were
optimized using density functional theory (B3LYP/6-31+G*, gas
phase).
mol−1 upon OH···O− hydrogen bonding (anti, Figure 5a) and
to a lesser degree to −550 kJ mol−1 for the syn conformation
(Figure 5b).
The conformational and electrostatic properties paint an
interesting picture for recognition of these organophosphates.
The favored anti structure may be too bulky to bind inside a π-
stacked pair of cyanostars and it has the lowest ESP, which
lowers binding energies. In the syn structure, the phosphate
moiety is both more exposed and has an ESP that is 17
kJ mol−1 greater than the anti. Both factors could offer higher
binding energies to help offset the energy cost (16 kJ mol−1) of
its formation from the anti. Finally, the conformational analysis
indicates that it will cost a large amount of energy (>40
kJ mol−1) to break even one of the OH···O− hydrogen bonds
and unfold the dipropanol phosphate into an extended
conformation. Once formed, its increased ESP (41 kJ mol−1)
would offer stronger binding. Toward [3]pseudorotaxane
formation, the 20 CH···O− hydrogen bonds in the 2:1
cyanostar complex with the phosphate would need to
compensate for the costs of breaking the OH···O− contacts.
One additional factor is the role of chain entropy on the
formation of closed rings,97−99 which would favor the random
coil form. Overall, this analysis shows that dipropanol
phosphate as a more interesting recognition partner than
expected, and it is still not clear if the OH···O− hydrogen
bonds will interfere with [3]pseudorotaxane formation.
The presence of intramolecular hydrogen bonds is shown
using computational chemistry to cause a change in the
electrostatic potential (ESP) on the phosphate moiety
calculated using DFT (B3LYP/6-31+G*, gas phase). In one
extended state, the maximum ESP of −574 kJ mol−1 located on
one of the oxygen atoms (Figure 5c) decreases to −533 kJ
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Intramolecular Hydrogen-Bonded Rings Interfere
with [3]Pseudorotaxane Formation. Clear evidence of
interference from the hydroxyl groups is seen in the serpentine
peak shifts (Figure 6a) in the NMR titration when the
Figure 7. (a) Crystal structure showing a 2:2:2:2 assembly with
cyanostar, dipropanol phosphate, tetrabutylammonium, and water,
respectively. (b) Syn conformation of dipropanol phosphate with O···
O− distances for dipropanol phosphate. Conditions: 1:1 cyanostar:di-
propanol phosphate, 4:1 CD2Cl2 to CD3CN with slow diffusion of
ethyl ether.
Figure 6. (a) Titration of cyanostar into dipropanol phosphate (1
mM, 4:1 CD2Cl2/CD3CN, 298 K, 600 MHz), and (b) normalized
peak shift change of Hf and Hc during titration.
pseudorotaxane formed from dibutyl phosphate. The water
produced new peaks (Figure S16) that show a correspondence
to the ones seen with dipropanol phosphate at 5.1 mM; e.g., Hc
and Hb grow in at the same positions as seen at 5.1 mM, while
Ha and Hd overlap but arise in slightly different positions in
this different solvent system. Nevertheless, we cannot exclude a
1:1 species. While the NMR signature does not match the
situation with an anion located centrally in the binding
cavity,101 a 1:1 species could also be composed of half the
perched 2:2 complex seen in the crystal (Figure 7). Similar
deviations in stoichiometry seen between solid state and
solution structures have been observed.66,102 Specifically,
cyanostar formed a 2:2 and water-bridged complex in the
solid state with the salicylate anion yet a 1:1 assembly in
solution.102 Similarly bambusuril formed a water-bridged 1:2
bambusuril−diethyl phosphate assembly in the solid state and
a 1:1 assembly in solution.66
At the end of the titration, all the peak shifts more closely
match those of a [3]pseudorotaxane. Specifically, Hf shifts to
4.74 ppm, which is consistent what was seen with dibutyl
phosphate at 4.62 ppm (Figure 3). The aromatic cyanostar
peaks represent an average of bound and unbound macro-
cycles, so they are less informative. Thus, the intermediate is
believed to be a complex between cyanostar and folded
dipropanol phosphate that competes with formation of the
[3]pseudorotaxane from the unfolded dipropanol phosphate.
Intramolecular Rings Stabilized by Hydroxyl-to-
Phosphate OH···O− Hydrogen Bonds. A crystal structure
grown from an equimolar mixture of cyanostar and dipropanol
phosphate in a dichloromethane and acetonitrile solvent
mixture reveals (Figure 7) a 2:2 stoichiometry and a perched
cyanostar is added to dipropanol phosphate (4:1 CD2Cl2/
CD3CN). This pattern differs from the end point seen after 2
equivalents of cyanostar is added to dibutyl phosphate (Figure
3). Another difference is the change from slow-exchange NMR
peaks to the fast-exchange peaks seen with dipropanol
phosphate (Figure 6a). The changes in chemical shift are a
weighted average of various species. Thus, the serpentine
binding patterns with multiple inflection points in the binding
curves (Figure 6b) are consistent with the presence of at least
two binding equilibria and the formation of three (or more)
species in solution.100
Serpentine shifts in the peaks for the protons on the alkyl
chain of the phosphate (Hf, Hg, Hh) and all the aromatic
protons on the cyanostar indicate that both of the self-
assembling components participate in the additional equilibria.
The cyanostar-based binding curves (Figure 6b) show an
inflection point at ∼1.0 equiv indicating an intermediate
around this ratio. Based on X-ray crystallography (Figure 7,
vide infra) this intermediate is expected to be a 2:2 species,
which is consistent with our solution data. We investigated this
intermediate further by serial dilution. At 40 μM, the signals
closely matched the free cyanostar and uncomplexed
dipropanol phosphate (Figure S15) while they saturated as
the intermediate species with a clear spectrum at 5.1 mM. We
were able to closely reproduce this signature in a separate
experiment designed to test the idea that the 2:2 species is
stabilized by bridging water molecules. Thus, we added water
to a dichloromethane solution containing the [3]-
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binding arrangement. The crystal structure is defined by a π-
stacked dimer of macrocycles, two dipropanol phosphates, two
bridging water molecules, and two TBA+ counter cations. The
dipropanol phosphate shows formation of two intramolecular
rings residing in the syn geometry despite being less stable by
16 kJ mol−1 relative to the preferred anti geometry. When we
repeated the DFT calculation to test for the role of solvent
using a solvation model for dichloromethane, the energy
difference between the syn and anti conformers is still sizable at
12 kJ mol−1. Thus, the syn geometry is likely formed when the
cost of conformational rearrangement is repaid by more
favorable cyanostar binding. This crystal structure verifies the
presence of folded conformations and that medium strength
OH···O− hydrogen bonds are important for the recognition of
alcohol-substituted phosphates.
preference is the existence of intermolecular OH···O− binding.
We tested this idea using methanol (MeOH) and expected to
disrupt the [3]pseudorotaxane formation. We undertook this
study using both the dialkyl and dialcohol phosphates.
1
Consistently, the H NMR titration with cyanostar in 20%
methanol in dichloromethane (Figures S21 and S22) is
different from the ones in aprotic conditions. Overall, we see
small NMR shifts under fast exchange that indicate poor-to-
weak binding.
We were fortunate to obtain a crystal structure of the
complex between cyanostar and dibutyl phosphate (Figure 8)
The crystal structure reveals more details about the
intramolecular hydrogen bonds in the syn dipropanol
phosphate. We see bifurcated hydrogen bonds with one O···
O distance at 2.7 Å, and the other showing disorder with O···O
distances of 2.7 Å (29%) and 2.9 Å (71%). The average
matches the computed distance of 2.8 Å in the syn conformer.
Both distances seen in the crystal structure are less than the
sum of the oxygens’ van der Waals radii of 3.04 Å103 and
consistent with Jeffrey’s structural classifications75 as moderate
strength hydrogen bonds.
Within the 2:2 structure, we expect electrostatic repulsions
to exist between the two negatively charged phosphates. The
two phosphorus atoms are 6.9 Å apart with the closest
approach of the oxygen atoms at 4 Å. Similar distances were
observed with 2:2 complexes between cyanostar and water-
bridged salicylate.102 Shorter P···P distances, ∼4 Å,26,63 can be
supported inside cyanostar assemblies104 when stabilized by
AEHBs64 as opposed to water bridges.102 The CH···O−
distances between cyanostar and phosphate are 4.4 Å on
average consistent with weak hydrogen bonding.75 The water-
to-phosphate Ow···O− distances are 2.7 and 2.9 Å correspond-
ing to moderate strength.75 Other examples of bridging waters
between complexed anions,105 while rare, have been seen with
bambusuril binding with diethyl phosphate66 with four
bridging waters. Ion pairing is also expected to offset
repulsions. To test this idea, we enhanced ion pairing by
conducting the titrations between dibutyl phosphate and
cyanostar in chloroform and saw the emergence of a new
species in addition to the [3]pseudorotaxane (Figure S17),
suggestive of competition from a perched structure. Con-
sistently, the [3]pseudorotaxane could be reinstated upon
addition of polar acetonitrile to break ion pairs (Figure S18).
Overall, repulsions between phosphates will be offset by ion
pairing, the summation of many weak CH hydrogen bonding
from inside the cyanostar, and the hydrogen bonding with
bridging water molecules.
Figure 8. Crystal structure of 2:2:2:2 assembly with cyanostar, dibutyl
phosphate, tetrabutylammonium, and water grown under protic
conditions of 5:1 CH2Cl2 to CD3OD with slow diffusion of ethyl
ether.
that was grown under protic conditions (5:1 dichloromethane/
methanol). The structure showed a perched 2:2:2:2
stoichiometry between cyanostar, dibutyl phosphate, tetrabu-
tylammonium, and water molecules that resembles the
structure observed with dipropanol phosphate (Figure 7).
No methanol was observed in the crystal structure. The water
molecules also serve to bridge the phosphates inside the
cyanostar cavity. This observation is consistent with the
production of the perched structure when water was added to a
dichloromethane solution of the [3]pseudorotaxane formed
between cyanostar and dibutyl phosphate (Figure S16). These
studies consistently show that OH hydrogen bonding regulates
the recognition of organophosphates.
Recovering [3]Pseudorotaxanes by Synthetic Control
over the Entropy of Ring Formation. Knowledge of how
OH···O− hydrogen bonding disrupts recognition of organo-
phosphates, we investigated a strategy to recover [3]-
pseudorotaxane formation in the presence of hydroxyl groups.
We drew inspiration from the entropic60 contributions to ring
formation.106 The entropic penalties of forming an 8-
membered ring with the propanol substituent are higher
relative to an 11-membered ring that forms with hexanol.107,108
Lengthening the alkyl linkers of the alcohol substituents should
disfavor the formation of folded conformations and their
intramolecular hydrogen bonds to recover strong binding and
high-fidelity [3]pseudorotaxane formation.
We see the anion is offset from the center of the cyanostar
cavity and is 1.7 Å out of the macrocycle plane. This nonideal
binding geometry helps explain the smaller changes in
chemical shift observed for the perched intermediate assembly
seen in solution (Figure 6). Similarly, bambusuril showed
1
moderate changes in chemical shifts in the H NMR titration
To test the entropic hypothesis, dihexanol and didecanol
phosphate threads were selected to probe the length threshold
needed to shut down folding. Both show the same formation of
intramolecular hydrogen bonds in the gas phase (Figures S2
and S3). Exactly as was observed with dipropanol phosphate,
all 500 conformations for each thread within 40 kJ mol−1 were
folded with OH···O− hydrogen bonds. This outcome is
(1:1 CDCl3/CD3OD), which suggests the formation of a
perched assembly in solution.66
Methanol Disrupts [3]Pseudorotaxane Formation.
Knowledge of the hydrogen bonding involving the terminal
hydroxyl groups helps refine our understanding of phosphate
recognition. One natural extension of this recognition
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expected when considering that the calculations do not include
entropy and thus more closely resemble the enthalpic stability
of these conformations.
phosphate formed meso and chiral [3]pseudorotaxanes with
cyanostar in solution (Figure 11), and the threaded
The large ring systems formed with dihexanol and didecanol
do not persist in solutions when subject to free energy.
Consistent with the behavior of dibutyl phosphate, the
31P−1Hf coupling constants of 6.4 and 6.5 Hz in aprotic
solvent conditions indicate that dihexanol and didecanol
phosphate, respectively, both exist in extended random-coil
conformations (Figure S26). Gratifyingly, longer linkers
recovered high-fidelity [3]pseudorotaxane formation in the
solid state (Figure 9). The terminal hydroxyls do not fold back
to point toward the phosphate in this structure.
Figure 11. Coincident NMR signatures of [3]pseudorotaxanes
formed in a 2:1 mixture of cyanostar (2 mM) and the dibutyl,
dihexanol, and didecanol phosphates (4:1 v/v CD2Cl2/CD3CN, 298
K, 600 MHz).
architecture was confirmed by a 1H−1H ROESY (Figure
S11). The meso and chiral [3]pseudorotaxanes formed with
didecanol phosphate are also consistent with the dibutyl and
dihexanol phosphate [3]pseudorotaxanes (Figure 11). Overall,
these studies show that we can alter the design of phosphate’s
organic substituent to control the supramolecular assemblies
that form.
Implications of OH···O− Hydrogen Bonding on
Organophosphate Recognition. Formation of intramolec-
ular OH···O− bonds to organophosphate molecules has the
potential to inform studies, observations, and uses of
phosphate recognition across chemistry and biology. The
OH···O− contact is sufficiently strong82 that it can be used as a
reliable and therefore programmable109 contact for phosphate
binding. The caveat is that water and alcohol based solvents110
are best avoided. Alternatively, solvent-excluded binding
pockets based on capsular foldamers offer a novel strategy to
circumvent this problem,111,112 which is consistent with
observations of these hydrogen bonding contacts in bio-
molecular recognition events even in aqueous solutions.86 In
addition, while phenol can be deprotonated (pKa = 18),113
alkyl alcohols have higher pKa values (29−32.2),114 which
might facilitate use of alkyl alcohols in organophosphate
recognition. It is also clear that the formation of OH···O−
Figure 9. Crystal structure of [3]pseudorotaxane between cyanostar
and dihexanol phosphate grown in 4:1 CD2Cl2 to CD3CN by vapor
diffusion of hexane.
The 1H NMR titration studies of cyanostar added to
dihexanol phosphate (4:1 CD2Cl2/CD3CN, Figure 10a)
showed the recovery of a tight-binding [3]pseudorotaxane
(Figure 10b). The cyanostar’s diastereomer peaks were also
present upon complexation with dihexanol phosphate (Figure
10a) indicative of π stacking. The 31P NMR spectra also show
diastereomer peaks with consistent meso-chiral peak intensities
(Figure S14). To illustrate the generality of the strategy to
increase the alkyl chains to recover [3]pseudorotaxane
formation, didecanol phosphate was also examined. Didecanol
Figure 10. (a) Titration of cyanostar into dihexanol phosphate (1 mM, 4:1 CD2Cl2/CD3CN, 298 K, 600 MHz). (b) Normalized peak intensities.
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a
Scheme 1. Synthesis of the Intermediates 4,4′-Dimethoxytrityl-diol and the Phosphoramidite Monomers
a
(i) DMTrCl, DIPEA, CH2Cl2; (ii) (iPr)2NP(Cl)OCH2CH2CN, DIPEA, CH2Cl2.
contacts could stabilize foldamers22,115 and now rotaxanes116
when this interaction is shut down. Our findings also strongly
support the role of OH···O− hydrogen bonding inferred in
enantioselective catalysis using chiral phosphates.87
Dibutyl phosphate was purchased from Sigma-Aldrich. The cyanostar
macrocycle was synthesized from 5-tert-butylisothalic acid using
reported methods.24
Thin-layer chromatography (TLC) was performed on precoated
silica-gel plates (0.25 mm thick, Silicycle), and the plates were
observed under long (248 nm) and short wavelength UV light.
Column chromatography was performed on silica gel (160−200
mesh, Sorbtech). NMR spectra were recorded on Varian Inova (400,
500, and 600 MHz) and Varian VXR (400 MHz) instruments at room
temperature (298 K) and a Bruker Advance (400 MHz)
spectrometer. Chemical shifts were referenced using residual solvent
peaks or 85% phosphoric acid. Spectroscopic grade solvents (CH2Cl2,
CH3CN, CH3OH, CHCl3, Omnisolve) were used as received to
prepare tetrabutylammonium salts and titration stock solutions.
Deuterated solvents (CD2Cl2, CD3CN, CD3OD, CDCl3, Sigma-
Aldrich and Cambridge Isotope Laboratories) were used as received.
High resolution electrospray ionization mass spectrometry (ESI-MS)
was performed on a Thermo Electron Corporation MAT 95XP-Trap
mass spectrometer and on a QStar Elite mass spectrometer (Applied
Biosystems SCIEX, Concord, ON, Canada).
General Synthesis of Phosphoramidite Monomers. The
disubstituted phosphates examined in this work were obtained by
solid-phase phosphoramidite chemistry. For that purpose, phosphor-
amidite reagents and modified resins were first prepared. The
phosphoramidite monomers employed in this work were synthesized
following the protocol depicted in Scheme 1. This protocol was
previously utilized for the synthesis of 6-(4,4′-dimethoxytriphenyl-
methyloxy)propyl 2-cyanoethyl N,N-diisopropylphosphoramidite and
the monoprotected intermediate 3-(4,4′-dimethoxytriphenyl-
methyloxy)propan-1-ol.17
CONCLUSION
■
We discovered that the recognition of organophosphates
depends on competitive OH···O− hydrogen bonding as well as
the conformations of the organic substituent, and that we can
control these factors to direct formation of cyanostar-based
[3]pseudorotaxanes. When using alkyl substituents, [3]-
pseudorotaxanes are formed with 2:1 cyanostar−phosphate
stoichiometries unless the reaction is undertaken in protic
solvent mixtures or where ion pairing is expressed. When
terminal hydroxyls are introduced using dipropanol phosphate,
favorable OH···O− hydrogen bonding drives formation of
eight-membered rings. These conformations lead to complexes
with the folded dipropanol phosphate merely perched on the
cyanostar cavity and competitively interfering with threaded
complexes. [3]Pseudorotaxanes could be recovered, even in
the presence of the enthalpically favored OH···O− hydrogen
bonds, simply by lengthening the intervening chain to increase
the entropic penalties associated with ring formation.
Dihexanol phosphate, with an extra three methylene groups,
was sufficient to ensure high-fidelity formation of [3]-
pseudorotaxanes in the solid state and in solution. This is
one of a few examples using entropy in noncovalent
synthesis.61 This study opens up the opportunity to use
alcohol-substituted threads in the formation of pseudorotax-
anes and lays a foundation for investigating the use of organic
substituents to regulate the recognition of organophosphates.
Synthesis of 6-(4,4′-Dimethoxytriphenylmethyloxy)hexan-1-ol.
1,6-Hexandiol (1.5 g, 12.6 mmol) was coevaporated with 8 mL of
anhydrous pyridine. Afterward, 8 mL of pyridine and 15 mL of
anhydrous THF were introduced and the diol was reacted with 4,4′-
dimethoxytrityl chloride (DMTCl) (4.3 g, 12.6 mmol). The DMTCl
was added in four equal portions at a rate of one portion every hour.
After the four additions, the mixture was stirred at room temperature
for 2 h. The reaction was stopped with the addition of 8 mL of
methanol, and the mixture was evaporated to dryness. The residue
was dissolved in ethyl acetate (50 mL) and washed with 5% sodium
bicarbonate ice-cold solution. The aqueous layer was extracted with
50 mL of ethyl acetate. The combined organic layers were washed
with water and brine, dried with anhydrous Na2SO4, and evaporated.
The resulting product was chromatographed on silica gel (30% ethyl
acetate in cyclohexane with a 1% triethylamine) yielding 3.09 g of 6-
(4,4′-dimethoxytriphenylmethyloxy)hexan-1-ol (58%) as a colorless
EXPERIMENTAL SECTION
■
General Methods. All reagents were obtained from commercial
suppliers and used as received unless otherwise noted. Succinic
anhydride (≥99%, Sigma-Aldrich), 1,3-propanediol (99%, Alfa
Aesar), 1,6-hexanediol (>97%, TCI), 1,10-decanediol (>97%, TCI),
2-cyanoethyl diisopropylchlorophosphoramidite (95%, Alfa Aesar),
4,4′-dimethoxytriphenylmethyl chloride (DMTrCl or DMTCl,
≥97.0%, Sigma-Aldrich), N,N-diisopropylethylamine (DIPEA, 99%,
Alfa Aesar), 4-(dimethylamino)pyridine (DMAP, 99%, Sigma-
Aldrich), N,N′-dicyclohexylcarbodiimide (99%, DCC, Alfa Aesar),
aminopolystyrene resin (1.4 mmol g−1, Novabiochem), trichloroacetic
acid (≥99%, Sigma-Aldrich), tetrabutylammonium hydroxide (1 M in
methanol, Sigma-Aldrich), 1,4-dioxane (≥99.5%, Alfa Aesar),
ammonium hydroxide (≥28% NH3 in H2O, VWR), iodine (>99%,
Prolabo), piperidine (99%, Alfa Aesar), and triethylamine (97%,
Acros Organics) were used as purchased. Anhydrous dichloro-
methane, pyridine, and acetonitrile were purchased from Aldrich.
Anhydrous THF was obtained using a dry solvent station GT S100.
1
oil. H NMR (400 MHz, CDCl3) δ 7.46−7.42 (m, 2H), 7.37−7.24
(m, 6 1H peak partially overlapping with residual solvent peak), 7.22−
7.18 (m, 1H), 6.85−6.80 (m, 4H), 3.79 (s, 6H), 3.65−3.59 (m, 2H),
3.05 (t, J = 6.6 Hz, 2H), 1.67−1.22 (m, 8H). 13C{1H} NMR (100
MHz, CDCl3) δ 158.4, 145.5, 136.8, 130.1, 128.3, 127.8, 126.7, 113.1,
85.8, 63.4, 63.1, 55.3, 32.9, 30.2, 26.3, 25.8. HRMS (ESI) m/z: [M +
Na]+ Calcd for C27H32O4Na+ 443.2193; Found 443.2183.
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a
Scheme 2. Synthesis of Intermediate Succinates and Resin Modification (Red Bead)
a
(i) Succinic anhydride, DMAP, pyridine; (ii) DCC, CH2Cl2.
a
Scheme 3. Synthesis of the Disubstituted Phosphates
a
(i) DMT deprotection: 3% CCl3COOH in CH2Cl2; (ii) coupling step: rt, phosphoramidite monomer, AcCN, tetrazole; (iii) oxidation: rt, I2,
H2O/Pyridine/THF; (iv) cyanoethyl deprotection: piperidine, AcCN; (v) cleavage: NH3, H2O, dioxane.
Synthesis of 10-(4,4′-Dimethoxytriphenylmethyloxy)decan-1-ol.
Following the procedure above 1,10-decandiol (2.34 g, 13.4 mmol)
was reacted with 4,4′-dimethoxytrityl chloride (DMTCl) (4.56 g, 13.4
mmol). The resulting product was chromatographed on silica gel
(30% ethyl acetate in cyclohexane with a 1% triethylamine) yielding
3.5 g of 10-(4,4′-dimethoxytriphenylmethyloxy)decan-1-ol (55%) as a
(m, 4H), 1.44−1.30 (m, 4H), 1.23−1.14 (m, 12H). 13C{1H} NMR
(100 MHz, CDCl3) δ 158.4, 145.5, 136.8, 130.1, 128.3, 127.8, 126.6,
117.8, 113.0, 85.7, 63.7 (d, J = 17.1 Hz), 63.5, 58.4 (d, J = 19.0 Hz),
55.3, 43.1 (d, J = 12.3 Hz), 31.3 (d, J = 7.2 Hz), 30.2, 26.2, 26.0,
24.9−24.5 (m), 20.4 (d, J = 6.8 Hz). 31P NMR (162 MHz, CDCl3) δ
147.20. HRMS (ESI) m/z: [M
C36H49N2O5PNa+643.3271; Found 643.3258.
+
Na]+ Calcd for
1
1
colorless oil. H NMR (400 MHz, CDCl3) δ H NMR (400 MHz,
1
Synthesis of 10-(4,4′-Dimethoxytriphenylmethyloxy)decyl 2-
Cyanoethyl N,N-Diisopropylphosphoramidite. 10-(4,4′-Dimethoxy-
triphenylmethyloxy)decan-1-ol (0.9 g, 1.88 mmol) was reacted with
O-2-cyanoethyl-N,N-diisopropyl-chlorophosphoramidite (0.49 g, 2.0
mmol) and DIPEA (1.75 mL, 10 mmol) as described above. The
resulting product was purified by chromatography on silica gel
(hexane/ethyl acetate (7:3) + 1% triethylamine) yielding 1.2 g of
CDCl3) δ 7.46−7.42 (m, 2H), 7.35−7.25 (m, six H peak partially
overlapping with residual solvent peak), 7.22−7.14 (m, 2H), 6.83
(ddd, J = 9.0, 4.9, 2.2 Hz, 4H), 3.79 (t, J = 3.9 Hz, 6H), 3.64 (td, J =
6.6, 2.6 Hz, 2H), 3.03 (td, J = 6.6, 1.7 Hz, 2H), 1.65−1.50 (m, 4H)
1
1.40−1.20 (m, 12 H peak partially overlapping with residual water).
13C{1H} NMR (100 MHz, CDCl3) δ 158.4, 145.6, 136.9, 130.2,
128.3, 127.8, 126.6, 113.1, 85.7, 63.6, 63.2, 55.3, 32.94, 32.92, 30.2,
29.7, 29.6, 29.5, 26.4, 25.9. HRMS (ESI) m/z: [M + Na]+ Cald for
C31H40O4Na+ 499.2819; Found 499.2830.
1
phosphoramidite (94%) as a colorless liquid foam. H NMR (400
MHz, CDCl3) δ 7.47−7.43 (m, 2H), 7.37−7.26 (m, 6H), 7.23−7.18
(m, 1H), 6.85−7.81 (m, 4H), 3.91−3.76 (m, 8H), 3.72−3.54 (m,
4H), 3.04 (t, J = 6.6 Hz, 2H), 2.63 (t, J = 6.6 Hz, 2H), 1.63 (dq, J =
14.3, 7.4, 6.7 Hz, 4H), 1.40−1.23 (m, 12H), 1.20 (dd, J = 6.8, 4.6 Hz,
12H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.4, 145.6, 136.9,
130.1, 128.3, 127.8, 126.6, 117.8, 113.0, 85.7, 63.8 (d, J = 17.2 Hz),
63.6, 58.4 (d, J = 18.9 Hz), 55.3 (two 13C peaks overlap), 43.1 (d, J =
12.3 Hz), 31.3 (d, J = 7.2 Hz), 30.2, 29.6, 29.4, 26.4, 26.0, 24.7 (dd, J
= 10.3, 7.2 Hz), 20.4 (d, J = 6.8 Hz). 31P NMR (162 MHz, CDCl3) δ
147.20. HRMS (ESI) m/z: [M + Na]+ Calcd for C40H57N2O5PNa+
699.3897; Found 699.3883.
Preparation of Modified Resins. Functional resins were synthe-
sized following the protocol shown in Scheme 2. It involves first the
synthesis of an intermediate succinate that is then coupled to a
commercial aminopolystyrene resin. This synthesis was already
reported for n = 1.17
Synthesis of 6-(4,4′-Dimethoxytriphenylmethyloxy)hexyl 2-Cya-
noethyl N,N-Diisopropylphosphoramidite. 6-(4,4′-Dimethoxy-
triphenylmethyloxy)hexan-1-ol (2.0 g, 4.75 mmol) was coevaporated
with 8 mL of anhydrous dichloromethane and dried under vacuum
over 30 min, and then 0.1 g of molecular sieves (3 Å) was added. A 12
mL aliquot of anhydrous dichloromethane and DIPEA (4.1 mL, 23.7
mmol) was added successively under argon, and the system was
cooled with an ice−water bath. O-2-Cyanoethyl-N,N-diisopropyl-
chlorophosphoramidite (1.2 g, 5.0 mmol) was added dropwise with
continuous stirring. The reaction flask was then allowed to warm to
room temperature and stirred for 1 h. The mixture was evaporated to
dryness, dissolved in ethyl acetate, and then chromatographed directly
on silica gel using hexane/ethyl acetate (3:2) + 1% trimethylamine as
eluent yielding 2.26 g of phosphoramidite (79%) as a foam. 1H NMR
(400 MHz, CDCl3) δ 7.48−7.40 (m, 2H), 7.38−7.24 (m, 6H), 7.23−
7.17 (m, 1H), 6.87−6.78 (m, 4H), 3.89−3.75 (m, 8H), 3.70−3.53
(m, 4H), 3.05 (t, J = 6.6 Hz, 2H), 2.62 (t, J = 6.5 Hz, 2H), 1.67−1.57
Synthesis of Succinate Intermediates. In a 25 mL round-bottom
flask, a monoprotected diol (either 6-(DMT)hexan-1-ol or 10-
(DMT)decan-1-ol) (1 mmol) was coevaporated with 4 mL of
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Scheme 4. Synthesis of Disubstituted Phosphate Tetrabutylammonium Salts
1
pyridine, dried under vacuum for 30 min, and then reacted with 1.5
equiv of succinic anhydride and 1.5 equiv of DMAP in 4 mL of
anhydrous pyridine at 35 °C for 5 h. The reactions were quenched
with methanol, and the solvent was concentrated. The resulting oils
were diluted with ethyl acetate (20 mL) and washed with water, 0.1
M sodium phosphate (pH 5.0), and again water. The organic phases
were dried with MgSO4, and the solvent was evaporated to dryness to
give colorless oils in quantitative yields which were used without any
further purification.
Resin Modification. The appropriate succinate (0.73 mmol) was
reacted with 0.4 g of amino-polystyrene resin (1.4 mmol g−1), 0.26
mmol of DMAP, and 2.26 mmol of DCC in 5 mL of anhydrous
dichloromethane following a previously reported procedure.17 The
unreacted amino groups were capped with acetic anhydride in
pyridine (1:5 v/v). The loading of the support was determined by the
removal of the DMT group of an aliquot and analyzing its absorbance
at 504 nm to find a loading of about 0.8 mmol g−1.
Bis(3-hydroxydecyl) Hydrogen Phosphate. H NMR (400 MHz,
CD3OD) δ 3.79 (q, J = 6.4 Hz, 4H), 3.50 (t, J = 6.8 Hz, 4H), 1.58 (p,
J = 7.1, 6.6 Hz, 4H), 1.49 (t, J = 6.5 Hz, 4H), 1.35−1.27 (m, 24H).
13C{1H} NMR (100 MHz, CD3OD): 66.4 (d, J = 5.9 Hz), 63.0, 33.7,
31.9 (d, J = 7.6 Hz), 30.7 (two carbon peaks are overlapping), 30.6,
30.5, 27.00, 26.96. 31P NMR (162 MHz, CD3OD) δ 0.97. HRMS
(ESI) m/z: [M−H]− Calcd for C20H42O6P− 409.2724; Found
409.2717.
General Procedure for Preparing Phosphate Salts. The
phosphate tetrabutylammonium salt was formed by titrating the
corresponding acid (1 mM) with aliquots of tetrabutylammonium
hydroxide solution (1 mM) until deprotonation (Scheme 4) was
complete as verified by NMR spectroscopy. The resulting
tetrabutylammonium salt was concentrated in vacuo under low heat
and was dried under vacuum pump overnight.
Preparation of the Bis(3-hydroxypropyl) Phosphate Tetrabutyl-
ammonium Salt. Dipropanol phosphate tetrabutylammonium salt
was prepared using the general procedure for phosphate salts from
dipropanol phosphoric acid (0.4 mg, 0.0019 mmol) and tetrabuty-
lammonium hydroxide solution (1.3 equiv, 1.1 M). Dipropanol
phosphate tetrabutylammonium salt was obtained as a yellow oil (0.9
mg, 0.0020 mmol, quantitative yield). 1H NMR (500 MHz, CD3OD)
δ 3.95 (q, J = 6.3 Hz, 4H), 3.68 (t, J = 6.3 Hz, 4H), 3.26−3.21 (m,
10H), 1.82 (p, J = 6.2 Hz, 4H), 1.66 (p, J = 7.8 Hz, 10H), 1.42 (m,
10H), 1.03 (t, J = 7.4 Hz, 15H). 13C{1H} NMR (100 MHz, CD3OD)
δ 63.2 (d, J = 5.7 Hz), 59.53, 59.50, 34.7 (d, J = 7.2 Hz), 24.8, 20.7,
13.9. 31P NMR (162 MHz, CD3OD) δ 1.23. HRMS (ESI) m/z: [M−
TBA+]− Calcd C6H14O6P− 213.0533; Found 213.0530.
Preparation of the Bis(3-hydroxyhexyl) Phosphate Tetrabutyl-
ammonium Salt. Dihexanol phosphate tetrabutylammonium salt was
prepared using the general procedure for phosphate salts from
dihexanol phosphoric acid (1.9 mg, 0.0064 mmol) and tetrabuty-
lammonium hydroxide solution (1.1 equiv, 1.1 M). Dihexanol
phosphate tetrabutylammonium salt was obtained as a yellow oil
(4.3 mg, 0.0080 mmol, quantitative yield). 1H NMR (500 MHz,
CD3OD) δ 3.84 (q, J = 6.4 Hz, 4H), 3.54 (t, J = 6.6 Hz, 4H), 3.27−
3.21 (m, 9H), 1.66 (m, 13H), 1.55 (p, J = 6.9 Hz, 4H), 1.42 (m,
17H), 1.03 (t, J = 7.4 Hz, 13H). 13C{1H} NMR (100 MHz, CD3OD)
δ 66.3 (d, J = 5.8 Hz), 62.9, 59.6−59.5 (m), 33.7, 31.9 (d, J = 7.6 Hz),
26.8, 26.7, 24.79, 20.7, 13.9. 31P NMR (162 MHz, CD2Cl2) δ −0.36.
HRMS (ESI) m/z: [M−TBA+]− Calcd for C12H26O6P− 297.1472;
Found 297.1469.
General Synthesis of the Disubstituted Phosphates. The
disubstituted phosphates were obtained by phosphoramidite coupling,
carried out under vacuum-argon in rigorously dry conditions using a
homemade peptide synthesis reaction vessel as shown in Scheme 3.
The general procedure is as follows: 1 mol equiv of polystyrene
support (0.8 mmol g−1) was introduced in the reaction vessel, treated
with a 3% trichloroacetic acid solution in dichloromethane, and
washed with a solution of 2% pyridine in acetonitrile and again with
pure acetonitrile. After a fast swelling in dichloromethane, the
appropriate phosphoramidite (1.5 equiv) dissolved in anhydrous
acetonitrile (0.1 M) and tetrazole (4 equiv, 0.45 M solution in
acetonitrile) were added under an argon atmosphere. The reactor was
shaken at room temperature for 15 min. Afterward, the solution was
removed and the polystyrene support was washed with acetonitrile;
the resulting phosphite-triester was oxidized for 2 min to phosphate-
triester with a 0.1 M iodine solution (I2 in water/pyridine/THF 2/
20/80). The excess iodine was removed by acetonitrile and
dichloromethane washes. Finally, deprotection of the cyanoethyl
phosphate protecting group was performed using a 10% piperidine
solution in acetonitrile (5 min), the terminal DMT-protecting group
was deprotected using the 3% trichloroacetic acid solution, and the
disubstituted phosphates were cleaved from the resins using 30%
aqueous ammonia solution/dioxane (1:1 v/v) during 12 h at 45 °C.
The ammonia mixture was filtered, and the flask was left for 5 min
under argon bubbling in order to eliminate the excess gaseous
ammonia. After solvent evaporation and drying under vacuum, the
resulting products obtained with almost quantitative yields were
Preparation of the Bis(3-Hydroxydecyl) Hydrogen Phosphate
Tetrabutylammonium Salt. Didecanol phosphate tetrabutylammo-
nium salt was prepared using the general procedure for phosphate
salts from didecanol phosphoric acid (1.2 mg, 0.0029 mmol) and
tetrabutylammonium hydroxide solution (1.6 equiv, 1.1 M).
Didecanol phosphate tetrabutylammonium salt was obtained as a
white, waxy solid (2.1 mg, 0.0080 mmol, quantitative yield). 1H NMR
(400 MHz, CD2Cl2) δ 3.70 (q, J = 6.7 Hz, 4H), 3.53 (td, J = 6.8, 2.0
Hz, 4H), 3.28−3.18 (m, 13H), 1.63 (p, J = 8.3 Hz, 16H), 1.53 (m,
12H), 1.42 (m, 18H), 1.29 (s, 12 1H partially overlapping with
residual water peak), 1.00 (td, J = 7.4, 1.9 Hz, 19H). 13C{1H} NMR
(100 MHz, CD2Cl2) δ 65.1, 62.7, 59.2, 33.3, 31.44, 31.38, 29.68,
29.66, 29.62, 26.2, 26.1, 24.4, 20.1, 13.8. 31P NMR (162 MHz,
CD2Cl2) δ −0.44. HRMS (ESI) m/z: [M−TBA+]− Calcd for
C20H42O6P− 409.2724; Found 409.2718.
1
characterized by H, 13C{1H}, and 31P NMR and ESI-MS.
Bis(3-hydroxypropyl) Hydrogen Phosphate. 1H NMR (400 MHz,
CD3OD) δ 3.95 (q, J = 6.3 Hz, 4H), 3.68 (t, J = 6.3 Hz, 4H), 1.82 (p,
J = 6.3 Hz, 4H). 13C{1H} NMR (100 MHz, CD3OD) δ 63.2 (d, J =
5.7 Hz), 59.5, 34.7 (d, J = 7.2 Hz). 31P NMR (162 MHz, CD3OD) δ
1.23. HRMS (ESI) m/z: [M−H]− Calcd for C6H14O6P− 213.0533;
Found 213.0531.
1
Bis(3-hydroxyhexyl) Hydrogen Phosphate. H NMR (400 MHz,
CD3OD) δ 3.84 (q, J = 6.4 Hz, 4H), 3.55 (t, J = 6.7 Hz, 4H), 1.64 (p,
J = 6.7 Hz, 4H), 1.55 (p, J = 6.7 Hz, 4H), 1.48−1.34 (m, 8H).
13C{1H} NMR (100 MHz, CD3OD): 66.3 (d, J = 6.0 Hz), 62.9, 33.7,
31.9 (d, J = 7.6 Hz), 26.8, 26.7. 31P NMR (162 MHz, CD3OD) δ
0.96. HRMS (ESI) m/z: [M−H]− Calcd for C12H26O6P− 297.1472;
Found 297.1468.
Preparation of the Bis(3-butyl) Phosphate Tetrabutylammo-
nium Salt. Dibutyl phosphate tetrabutylammonium salt was prepared
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using the general procedure for phosphate salts from dibutyl
phosphoric acid (75.1 mg, 0.357 mmol) and tetrabutylammonium
hydroxide solution (1.0 equiv, 1.1 M). Dibutyl phosphate
tetrabutylammonium salt was recovered as a colorless oil (0.1758 g,
(occupancies 0.56 and 0.44). Disorder was also modeled in the
tetrabuthyl ammonium and in the dipropanol phosphate. Restraints
and constraints (equal thermal displacement parameters and similar
distances) were applied to obtain a stable and chemically reasonable
model.
1
0.3892 mmol, quantitative yield). The H NMR, 13C{1H} NMR, and
31P NMR are consistent with previous reports.14 1H NMR (500 MHz,
CD2Cl2) δ 3.71 (q, J = 6.5 Hz, 4H), 3.28−3.22 (m, 8H), 1.62 (s, 8 1H
partially overlapping with residual water peak), 1.58−1.51 (m, 4H),
1.44 (p, J = 7.4 Hz, 8H), 1.40−1.33 (m, 4H), 1.01 (t, J = 7.3 Hz,
12H), 0.91 (t, J = 7.4 Hz, 6H). 13C{1H} NMR (126 MHz, CD2Cl2) δ
64.81 (d, J = 5.8 Hz), 59.16, 33.65 (d, J = 7.5 Hz), 24.37, 20.12,
19.61, 14.12, 13.81. 31P NMR (162 MHz, CD2Cl2) δ −0.36. HRMS
(ESI) m/z: [M−TBA+]− Calcd for C8H14O4P− 209.0948; Found
209.0946.
Dibutyl Phosphate and Cyanostar Crystal: Grown in the
Presence of Methanol (CCDC Deposition Number: 2034419). Single
crystals suitable for X-ray diffraction were grown by vapor diffusion of
diethyl ether into a dichloromethane and methanol solution. A
colorless crystal (Figure S35, plate, approximate dimensions 0.37 ×
0.12 × 0.09 mm3) was placed onto the tip of a MiTeGen pin and
mounted on a Bruker Venture D8 diffractometer equipped with a
Photon III detector at 100.0 K.
Data Collection. The data collection was carried out using Mo Kα
radiation (λ = 0.71073 Å, graphite monochromator) with a frame
time of 2 s and a detector distance of 40 mm. A collection strategy
was calculated, and complete data to a resolution of 0.77 Å with a
redundancy of 5 were collected. The total exposure time was 0.85 h.
The frames were integrated with the Bruker SAINT117 software
package using a narrow-frame algorithm. The integration of the data
using a triclinic unit cell yielded a total of 91 297 reflections to a
maximum θ angle of 27.49° (0.77 Å resolution), of which 19 782 were
independent (average redundancy 4.615, completeness = 99.7%, Rint
= 6.83%, Rsig = 5.38%) and 14 266 (72.12%) were greater than
2σ(F2). The final cell constants of a = 16.2873(4) Å, b = 17.9403(5)
Å, c = 18.2427(5) Å, α = 106.5390(10)°, β = 111.7860(10)°, γ =
105.1800(10)°, volume = 4321.7(2) Å3 are based upon the
refinement of the XYZ-centroids of 1114 reflections above 20 σ(I)
with 5.837° < 2θ < 51.47°. Data were corrected for absorption effects
using the Multi-Scan method (SADABS).118 The ratio of minimum to
maximum apparent transmission was 0.943. The calculated minimum
and maximum transmission coefficients (based on crystal size) are
0.9620 and 0.9900. Additional crystal and refinement information is
also included (Table S2).
General Procedure for Titrations. Titrations were monitored by
1H NMR spectroscopy using a Varian Inova (500 and 600 MHz).
Tetrabutylammonium (TBA) phosphate salts were prepared and
dried under vacuum for at least 12 h prior to use. Phosphate stock
solutions were prepared immediately prior to use, and Hamilton
gastight syringes (10, 100, 500, and 1000 μL) were used to transfer
solvents and perform titrations. NMR tubes, quartz cuvettes, and
1
screw-cap vials were fitted with PTFE/silicone septa. In a typical H
NMR titration, a 500 μL TBA phosphate solution (1 mM) was
prepared in an NMR tube and aliquots of a cyanostar solution (50
mM) were injected into the NMR tube.
X-ray Crystallography Methods. Dipropanol Phosphate and
Cyanostar in a Perched Structure (CCDC Deposition Number:
2034420). Single crystals suitable for X-ray diffraction were grown by
vapor diffusion of diethyl ether into a dichloromethane and
acetonitrile solution. A colorless crystal (Figure S29, block,
approximate dimensions 0.81 × 0.34 × 0.28 mm3) was placed onto
the tip of a MiTeGen pin and mounted on a Bruker Venture D8
diffractometer equipped with a Photon III detector at 100.0 K.
Data Collection. The data collection was carried out using Mo Kα
radiation (λ = 0.71073 Å, graphite monochromator) with a frame
time of 0.50 s for low angle frames (2 sets) and 15 s for high angle
frames (5 sets). The detector distance was 120 mm. A collection
strategy was calculated, and complete data to a resolution of 0.70 Å
with a redundancy of 6 were collected. A total of 2431 frames were
collected. The total exposure time was 7.18 h. The frames were
integrated with the Bruker SAINT117 software package using a
narrow-frame algorithm. The integration of the data using a
monoclinic unit cell yielded a total of 152 650 reflections to a
maximum θ angle of 30.63° (0.70 Å resolution), of which 24 964 were
independent (average redundancy 6.115, completeness = 99.4%, Rint
= 12.25%, Rsig = 6.65%) and 13 408 (53.71%) were greater than
2σ(F2). The final cell constants of a = 35.5547(15) Å, b = 19.4454(8)
Å, c = 25.5479(11) Å, β = 112.7990(10)°, volume = 16283.2(12) Å3
are based upon the refinement of the XYZ-centroids of reflections
above 20 σ(I). Data were corrected for absorption effects using the
Multi-Scan method (SADABS).118 The calculated minimum and
maximum transmission coefficients (based on crystal size) are 0.9300
and 0.9750. Additional crystal and refinement information is also
included (Table S1).
Structure Solution and Refinement. The space group P1 was
̅
determined based on intensity statistics and systematic absences. The
structure was solved using XT119,120 and refined using full-matrix
least-squares on F2 within the OLEX2 suite.121 An intrinsic phasing
solution was calculated, which provided most non-hydrogen atoms
from the E-map. Full-matrix least-squares/difference Fourier cycles
were performed, which located the remaining non-hydrogen atoms.
All non-hydrogen atoms were refined with anisotropic displacement
parameters. The hydrogen atoms were placed in ideal positions and
refined as riding atoms with relative isotropic displacement
parameters. The final full matrix least-squares refinement converged
to R1 = 0.0783 and wR2 = 0.2270 (F2, all data). The goodness-of-fit
was 1.017. On the basis of the final model, the calculated density was
1.125 g/cm3 and F(000), 1588 e−. Whole molecule disorder on the
macrocycle was modeled by dividing the occupancy into two parts
related by pseudo mirror symmetry (occupancies 0.75 and 0.25).
Disorder was also modeled in the tetrabutylammonium and in the
dibutyl phosphate. Restraints and constraints (equal thermal displace-
ment parameters and similar distances) were applied to obtain a stable
and chemically reasonable model.
Structure Solution and Refinement. The space group C 2/c was
determined based on intensity statistics and systematic absences. The
structure was solved using SHELXT 2014/5119,120 and refined using
full-matrix least-squares on F2 within the OLEX2 suite.121 An intrinsic
phasing solution was calculated, which provided most non-hydrogen
atoms from the E-map. Full-matrix least-squares/difference Fourier
cycles were performed, which located the remaining non-hydrogen
atoms. All non-hydrogen atoms were refined with anisotropic
displacement parameters. The hydrogen atoms were placed in ideal
positions and refined as riding atoms with relative isotropic
displacement parameters. The final full matrix least-squares refine-
ment converged to R1 = 0.1506 and wR2 = 0.4590 (F2, all data). The
goodness-of-fit was 1.519. On the basis of the final model, the
calculated density was 1.154 g/cm3 and F(000), 6124 e−. Whole
molecule disorder on the macrocycle was modeled by dividing the
occupancy into two parts related by pseudo mirror symmetry
Dihexanol Phosphate and Cyanostar Pseudorotaxane Crystal
Structure (CCDC Deposition Number: 2034421). Single crystals
suitable for X-ray diffraction were grown by vapor diffusion of hexane
into a 1:1 solution of dichloromethane and acetonitrile. A colorless
crystal (block, approximate dimensions 0.4 × 0.27 × 0.23 mm3) was
placed onto the tip of a MiTeGen pin and mounted on a Bruker
Venture D8 diffractometer equipped with a PhotonIII detector at
100.0 K.
Data Collection. The data collection was carried out using Mo Kα
radiation (λ = 0.71073 Å, graphite monochromator) with a frame
time of 1 s for low angle scans and 25 s for high angle scans. The
detector distance was 130 mm. The total exposure time was 18.99 h.
The frames were integrated with the Bruker SAINT117 software
package using a narrow-frame algorithm. The integration of the data
using a monoclinic unit cell yielded a total of 145 044 reflections to a
maximum θ angle of 25.05° (0.84 Å resolution), of which 13 926 were
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independent (average redundancy 10.415, completeness = 99.6%, Rint
= 12.23%, Rsig = 4.80%) and 8898 (63.89%) were greater than 2σ(F2).
The final cell constants of a = 40.3948(13) Å, b = 15.3986(5) Å, c =
25.9488(9) Å, β = 102.2010(10)°, volume = 15776.2(9) Å3 are based
upon the refinement of the XYZ-centroids of 9912 reflections above
20 σ(I) with 4.610° < 2θ < 46.34°. Data were corrected for absorption
effects using the Multi-Scan method (SADABS).118 The ratio of
minimum to maximum apparent transmission was 0.909. The
calculated minimum and maximum transmission coefficients (based
on crystal size) are 0.9720 and 0.9840. Additional crystal and
refinement information is also included (Table S3).
Structure Solution and Refinement. The space group C 2/c was
determined based on intensity statistics and systematic absences. The
structure was solved using the SHELX suite of programs119,120 and
refined using full-matrix least-squares on F2 within the OLEX2
suite.121 An intrinsic solution was calculated, which provided most
non-hydrogen atoms from the E-map. Full-matrix least-squares/
difference Fourier cycles were performed, which located the
remaining non-hydrogen atoms. All non-hydrogen atoms were refined
with anisotropic displacement parameters. The hydrogen atoms were
placed in ideal positions and refined as riding atoms with relative
isotropic displacement parameters. The final full matrix least-squares
refinement converged to R1 = 0.1384 and wR2 = 0.4236 (F2, all data).
The goodness-of-fit was 1.624. On the basis of the final model, the
calculated density was 1.035 g/cm3 and F(000), 5320 e−. Whole
molecule disorder on the macrocycle was modeled by dividing the
occupancy into two parts related by pseudo mirror symmetry
(occupancies 0.73 and 0.27). Disorder over a special position was
modeled for the tetrabutylammonium and the dihexanol phosphate.
Restraints and constraints (equal thermal displacement parameters
and similar distances) were applied to obtain a stable and chemically
reasonable model.
Bo Qiao − Department of Chemistry, Indiana University,
Bloomington, Indiana 47405, United States; orcid.org/
0000-0001-6137-3239
Veronica Carta − Department of Chemistry, Indiana
University, Bloomington, Indiana 47405, United States;
orcid.org/0000-0001-8089-8436
Niklas F. König − Université de Strasbourg, CNRS, Institut
Charles Sadron UPR22, Strasbourg 67034, France;
orcid.org/0000-0002-9293-3734
Xinfeng Gao − Department of Chemistry, Indiana University,
Bloomington, Indiana 47405, United States; orcid.org/
0000-0001-6821-5188
Wei Zhao − Department of Chemistry, Indiana University,
Bloomington, Indiana 47405, United States; orcid.org/
0000-0001-8941-3044
Yankai Zhang − Université de Strasbourg, CNRS, Institut
Charles Sadron UPR22, Strasbourg 67034, France
Jean-Franco̧ is Lutz − Université de Strasbourg, CNRS, Institut
Charles Sadron UPR22, Strasbourg 67034, France;
orcid.org/0000-0002-3893-2458
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02887
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.H.F. acknowledges support from the National Science
Foundation (CHE 1709909), and R.E.F. thanks the Raymond
Siedle Materials Fellowship for support and the National
Institutes of Health (T32 GM109825 and T32 GM131994)
for support through the training grant entitled “Graduate
Program in Quantitative and Chemical Biology at Indiana
University Bloomington”. Support for the acquisition of the
Bruker Venture D8 diffractometer through the Major Scientific
Research Equipment Fund from the President of Indiana
University and the Office of the Vice President for Research is
gratefully acknowledged. J.-F.L. acknowledges support from
the H2020 program of the European Union (project Euro-
Sequences, H2020-MSCA-ITN-2014, Grant Agreement No.
642083) and the CNRS. J.-F.L. also thanks Laurence Oswald
(Institut Charles Sadron) for the synthesis of phosphoramidite
monomers and Laurence Charles (Aix Marseille Université)
for the mass spectrometry characterization of the organo-
phosphates. R.E.F. thanks Alketa Lutolli for assistance with
some NMR on account of Covid-19.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02887.
1H NMR spectra, 13C{1H} NMR spectra, and 31P NMR
spectra, 2D NMR analysis, 1H NMR titrations,
computational analyses, crystallographic methods, and
characterizations (PDF)
Accession Codes
CCDC 2034419−2034421 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Rachel E. Fadler − Department of Chemistry, Indiana
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Abdelaziz Al Ouahabi − Université de Strasbourg, CNRS,
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