Cucurbit[7]uril host-guest complexes of cholines and phosphonium cholines in aqueous solution

Article abstract of DOI:10.1039/b917610a

The neutral host cucurbit[7]uril forms very stable complexes with a series of cationic cholines (R₃NCH₂CH₂OR'⁺) and their phosphonium analogues (R₃PCH₂CH ₂OR'⁺) (R₃ = Me₃, Et₃, or Me₂Bz, or R₃N = quinuclidinium, and R' = H, COCH ₃, CO(CH₂)₂CH₃, or PO₃H), and (±)-carnitine, in aqueous solution. The complexation behaviour has been investigated using ¹H and ³¹P NMR spectroscopies, and ESI mass spectrometry. The complexation-induced chemical shift changes of the guests clearly indicate the effects of replacing the N(CH₃) ₃⁺ end group by P(CH₃)₃⁺, and changing the nature of R on the position of the guest with respect to the CB[7] cavity and its polar portal-lining carbonyl groups. This study demonstrates that molecular recognition of cholines in aqueous solution is achievable with a neutral host without the need for aromatic walls for cation-π interactions. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b917610a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Cucurbit[7]uril host–guest complexes of cholines and phosphonium cholines
in aqueous solution†
Ian W. Wyman and Donal H. Macartney*
Received 26th August 2009, Accepted 13th October 2009
First published as an Advance Article on the web 24th November 2009
DOI: 10.1039/b917610a
The neutral host cucurbit[7]uril forms very stable complexes with a series of cationic cholines
+
+
(R3NCH2CH2OR¢ ) and their phosphonium analogues (R3PCH2CH2OR¢ ) (R3 = Me3, Et3, or Me2Bz,
or R3N = quinuclidinium, and R¢ = H, COCH3, CO(CH2)2CH3, or PO3H), and ( )-carnitine, in
aqueous solution. The complexation behaviour has been investigated using 1H and 31P NMR
spectroscopies, and ESI mass spectrometry. The complexation-induced chemical shift changes of the
+
+
guests clearly indicate the effects of replacing the N(CH3)3 end group by P(CH3)3 , and changing the
nature of R on the position of the guest with respect to the CB[7] cavity and its polar portal-lining
carbonyl groups. This study demonstrates that molecular recognition of cholines in aqueous solution is
achievable with a neutral host without the need for aromatic walls for cation–p interactions.
of amino acids and peptides by CB[7] and CB[8] has been
Introduction
reported by the groups of Urbach and Kim.8 The extremely stable
complexation of ferrocenes with CB[7] (1010–1015 dm3 mol-1)5
has led to the development of systems which behave like the
biotin–avidin system.5c We have recently reported studies of the
pH-dependent host–guest interactions of CB[7] with the drug
ranitidine9 and a series of local anaesthetics10 in aqueous solutions,
with stability constants considerably greater than those reported
for the analogous complexes with b-cyclodextrin. Nau and
coworkers have likewise shown that the proton-pump inhibitors
lansoprazole and omeprazole, and the fungicide thiabendazole
form stable complexes with CB[7],11 improving activation and
stabilization properties of the guests. We have observed that CB[7]
binds the a-axial 5,6-dimethylbenzimidazole ligands of vitamin
B12 and coenzyme B12 (stabilizing the ‘base-off’ form) and in the
latter compound exhibits a subsequent binding of the b-axial 5¢-
deoxyadenosyl group.12 With these and other guests which bear
nitrogen13 or carbon14 acid sites, the pKa values are observed to
increase upon encapsulation of the guests, as the protonated forms
bind more strongly through ion–dipole and hydrogen bonding
interactions with the carbonyl groups on the CB[7] portals.
The cucurbit[n]uril family (CB[n], n = 5–8, 10) of macrocyclic host
molecules1 have been of increasing interest since the development
of methods for improving the yields of the minor congeners (n =
5, 7, 8, and 10), in addition to the major CB[6] product, at the
beginning of the millennium.2 With a hydrophobic cavity compa-
rable in size to b-cyclodextrin or calix[4]arenes, and two restrictive
portals lined with ureido carbonyl groups, the cucurbit[7]uril host
(Scheme 1) has been shown to form remarkably stable complexes
with a variety of guest molecules,3 particularly cationic organic3,4
and organometallic species,5 in aqueous solution. In addition to
the hydrophobic effects of placing the guest within the cavity,
the carbonyl groups are capable of stabilizing the host–guest
complex through hydrogen bonding, ion–dipole, and dipole–
dipole interactions with appropriate guests.1
The choline family ((CH3)3NCH2CH2OR+) of important bio-
logical molecules have in common a trimethylammonium head
group, which in the case of acetylcholine (R = COCH3), is
used to bind the substrate to the active site of the acetyl-
cholinesterase enzyme.15 The binding site consists of aromatic
amino acid residues such as tryptophan, which employ cation–
p interactions to hold the substrate in place.16 The majority
of artificial macrocyclic host molecules which have previously
exhibited binding of choline guests have contained aromatic walls
and have been anionic in nature, thus employing electrostatic
as well as cation–p interactions.17-30 These host molecules in-
clude acyclic receptors,17 cryptands,18 cyclophanes,19 molecular
clefts,20 p-tert-butylcalix[n]arene dianions (n = 4, 6),21 p-sulfonated
calix[n]arenes22 and other calix[n]arenes,23 tetracyanoresorcin-
[4]arene24 and other resorcin[n]arenes,25 pyrogallol[4]arenes,26 and
other macrocycles.27 Kim and co-workers have reported that the
water-soluble hexa(cyclohexyl)cucurbit[6]uril binds acetylcholine,
Scheme 1 Cucurbit[7]uril.
There has been considerable recent interest in using cucur-
biturils to aid in the delivery of molecules of biological and
medicinal interest, through host–guest formation. Several po-
tential antitumour platinum(II)6 and titanocene complexes7 have
been shown to bind to CB[7] and CB[8]. Molecular recognition
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston,
ON, K7L 3N6, Canada. E-mail: donal@chem.queensu.ca; Fax: +1 613 533
6669; Tel: +1 613 533 2617
† Electronic supplementary information (ESI) available: Details of guest
syntheses and characterizations, ESI-MS spectra, and 1H NMR spectra of
competitive binding experiments. See DOI: 10.1039/b917610a
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with K*CB[6] = 1.3 ¥ 103 dm3 mol-1, but does not include choline
itself.28
Rebek and coworkers have designed deep, resorcarene-based
cavitands for the binding of choline cations29 and have carried out
catalytic formations of acetylcholine, and the aminolysis of the
acetylcholine mimic p-nitrophenyl choline carbonate (PNPCC).30
Cuevas et al. had previously prepared ditopic, guanidinium-
appended calix[6]arene receptors which act as an artificial acetyl-
cholinesterase in the methanolysis of PNPCC.31
The phosphonium analogues of choline, acetylcholine and other
related compounds have been known for some time and have been
studied in terms of their relative activity to the corresponding
nitrogen compounds.32 They have also been investigated as probes
of choline and phospholipid metabolism employing in situ 31P
NMR experiments.32a
We have recently shown that while simple cations, such as
protons and alkali metal and transition metal ions, as well as
the positive sites on organic cations, bind at the polar portals of
CB[7], more hydrophobic and charge-diffuse peralkylated onium
+
+
+
cations, such as NR4 , PR4 and SR3 , (R = methyl and ethyl)
bind within the cavity of the host molecule in aqueous solution.4h
+
+
With the larger NnPr4 and NnBu4 guests, energy-minimization
calculations and the complexation-induced chemical shift changes
in the two alkyl groups. In a related study we observed that the
depolarizing muscle relaxing agent succinylcholine, as well as 1,10-
bis(trimethylammonium)decane and its phosphonium analogue,
can bind with CB[7] to form very stable [2]pseudorotaxanes at
host : guest ratios up to 1 : 1.33 With additional CB[7], the migra-
tion of the host to encapsulate the ammonium or phosphonium
end groups forms 2 : 1 host–guest complexes of varying stability.
In conjunction with these studies, we have investigated the
binding of quaternary ammonium and phosphonium guests in-
cluding choline, acetylcholine, and their phosphonium analogues
(Scheme 2), with CB[7] in aqueous solution. In addition, we have
examined the binding of related guests, such as the zwitterionic ( )-
Scheme 2 Choline guests (X = N or P and R = methyl or ethyl) used in
this study.
choline, or slow exchange in which there are resonances for the
both free and bound guests, as in the case of the phosphonium
choline, for example.
1
In the H NMR spectra of cucurbituril host–guest complexes,
the complexation-induced shift changes (CIS = Ddlim = dbound
-
d
free) in the proton resonances of the guest molecule are very
+
carnitine and choline phosphate, and a series of R3X(CH2)4CH3
informative as to the average location of the guest with respect
to the CB[7] cavity.1,3 Upfield shifts (Ddlim < 0) are observed
for protons located within the hydrophobic cavity, while the
deshielding of the polar carbonyl groups results in downfield shifts
(Ddlim > 0) in the resonances of guest protons in the proximity of
the carbonyl oxygens. The Ddlim values for the proton resonances
of the choline guests are presented in Table 1.
(X = N or P and R = methyl or ethyl) cations, in which the
pentyl chain has the same backbone length as the acetylcholine
–CH2CH2OC(CO)CH3 group (Scheme 2). We have studied the
1
host–guest interactions using H and 31P NMR spectroscopy to
probe the nature of the complexes, and the stability constants,
1
which have been determined by means of competitive H NMR
spectral measurements, may be compared with reported values for
the complexes with other artificial receptors.
With choline and its phosphonium analogues, the Ddlim values
are < 0 for all of the proton resonances, indicating that the entire
guests are included in the cavity, including the trialkylonium head
group. With acetylcholine, on the other hand, replacement of
the N atom with P results in considerable changes in the Ddlim
values (Table 1), indicating a change in the position of the guest
relative to the CB[7] cavity. The Ddlim value for the onium methyl
resonance is much smaller for acetylcholine (-0.28 ppm) than that
of the phosphonium analogue (or choline itself), while the most
upfield chemical shift change switches from the methylene group
Results and discussion
NMR and ESI-MS spectra of host–guest complexes
The formation of host–guest complexes between cucurbit[7]uril
and the choline and phosphonium choline guests in aqueous
solution have been established by ESI mass spectrometry34 and
from 1H and 31P NMR spectroscopies. The titrations of the choline
guests with CB[7] resulted in changes in the chemical shifts of
the guest proton resonances, as illustrated in Fig. 1 for choline
and its phosphonium analogues. The guests generally exhibit
fast or intermediate exchange on the NMR timescale, with the
guest resonances representing an average chemical shift of the
resonances for the free and bound guest species, as seen with
+
next to NMe3 (Ha), to the proton next to the acetyl group (Hb)
with P. The acetyl methyl proton resonance exhibits a very slight
downfield shift with X = P and a significant upfield shift with
X = N. These differences clearly indicate that with the smaller
+
N(CH3)3 group, the acetyl group is included in the cavity, while
+
the more hydrophobic P(CH3)3 group is included in the case of
the phosphonium acetylcholine analogue.
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or outside of the portal. Similar behaviour is observed for the
trimethylphosphonium compounds (Table 1), with the exception
of the aforementioned comparison between acetylcholine and the
phosphonium analogue. The most upfield shifts are observed
for choline and other species with b-hydroxyl groups and/or
carboxylate or phosphate groups at the other end of the guest.
+
The values are similar to the those observed for N(CH3)4
(-0.72 ppm),4h which is fully encapsulated in the CB[7] cavity.
The 31P Ddlim values for the central P atom in the trimethyl- and
triethylphosphonium analogues of the choline compounds were
determined and are presented in Table 1. For the trimethylphos-
phonium compounds the Ddlim value is small and follows the trend
in the magnitude of Ddlim for the methyl proton resonance. Notably,
with the trimethylpentylphosphonium cation, very small upfield
shifts are observed for the proton and phosphorus resonances
of the trimethyl group, suggesting that it is located near the
portal, rather than closer to the center of the cavity. For the
triethylphosphonium guests, the 31P Ddlim values are considerably
larger, as we observed previously for tetraethylphosphonium
cation (Ddlim = -5.77 ppm),4h but follow a similar trend as observed
with the trimethylphosphonium analogues. In the case of the
phosphocholine, the phosphate P exhibits a small downfield shift,
as the anionic groups are located outside the CB[7] cavity.
The effect of the acetyl group on the strength and position
of the binding of acetylcholine to CB[7] was also probed by
+
studying a series of R3X(CH2)4CH3 (X = N or P and R =
methyl or ethyl) cations, in which the pentyl chain has the same
length as the acetylcholine –CH2CH2O2CCH3 group. In each case,
the trimethyl- or triethylonium proton resonances display small
upfield or downfield chemical shifts, while the pentyl methylene or
methyl protons exhibit considerable upfield shifting upon CB[7]
complexation (Table 1). With these guests, the more hydrophobic
pentyl group is preferred for binding, while for the acetylcholine
species, the trimethyl- or triethylonium centers are preferably
bound in the CB[7] cavity.
Fig. 1 1H NMR spectra of choline (1.44 mmol dm-3) in (a) the
absence of CB[7] and in the presence of (b) 0.25, (c) 0.65, and
(d) 1.41 equivalents of CB[7], and (e) (2-hydroxyethyl)trimethyl-
phosphonium bromide (1.50 mmol dm-3) in the absence of CB[7] and
in the presence of (f) 0.29, (g) 0.74, and (h) 1.30 equivalents of CB[7],
in D2O.
Host–guest stability constants
The magnitude of the stability constants for the host–guest
complexes formed between cucurbit[7]uril and the choline guests
in this study would be expected to be dependent on a number
of features of the guest structure including the nature of the
quaternary center (central atom (N vs. P) and alkyl substituent(s))
and the size, charge, and hydrophobicity of the substituents on the
hydroxyl/ester oxygen on the opposite side of the molecule, as well
as the nature of any substituent on the ethylene linker between the
quaternary center and the oxygen. While we have not examined
the effects of the counter ion (Br- vs. Cl-) of these salts on the
host–guest stability constants, it would be anticipated they would
be minimal in the presence of an excess of acetate ions from the
buffer employed. Biczo´k and co-workers have reported that there
is not a significant change in the stability constants for CB[7] with
the cationic berberine guest when the anion is varied from chloride
to iodide to hydrogen phosphate.4j
The complexation of acetylcholine is stabilized by ion–dipole
and dipole–dipole interactions of the protonated and polar head
groups of the guests with carbonyl laced portals. In addition, the
Ddlim values of the Ha, Hb, and acetyl methyl protons suggest
that the carbonyl oxygen atom of the guests are located in
the center of the CB[7] cavity. With the quadrupolar nature of
the cucurbituril cavity, the oxygen may be involved in dipolar–
quadrupolar interactions with the trimethylammonium group
much closer to the carbonyls of the portal. We have recently shown
that small polar molecules such as acetone and methyl acetate
bind reasonably strongly to CB[7] as a result of contributions
from dipole–quadrupole interactions, with the oxygen of the guest
directed towards the center of the cavity wall.36
For the trimethylammonium compounds in general, the methyl
protons all shift upfield, with the Ddlim values ranging from -0.07
to -0.82 ppm, indicating that on average the methyl protons are
spending more time within the cavity. The least upfield shifts are
for the most extended species, where the cavity is occupied by
the long alkyl or ester chains, placing the cationic head group at
With the zwitterionic ( )-carnitine and choline phosphate
guests, the smallest stability constants were observed, and de-
termined from least-squares fits to the 1 : 1 binding curves. The
carboxylic acid group of the ( )-carnitine guest, (CH3)3NCH2CH-
(OH)CH2CO2H+, has a pKa of 3.78.37 The titrations of carnitine
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Table 1 Complexation-induced chemical shift changes (Ddlim) and host–guest stability constants (KCB[7]) for cucurbit[7]uril with cholines, phosphonium
analogues, and related guests in D2O at 25 ◦
C
Ddlim, ppm
Guest
CH3
CH2
P
Ca
Cb
Cg
Cd
Ce
Cz
Ch
K
CB[7], dm3 mol-1
+
a
N(CH3)4
-0.72
-0.66
-0.28
-0.16
(1.2 0.4) ¥ 105
(6.5 1.2) ¥ 105
(7.0 1.3) ¥ 105
(4.9 0.9) ¥ 106
(CH3)3N(CH2)2OH+
(CH3)3N(CH2)2O2CCH3
(CH3)3NCH2CH(CH3)O2CCH3
-0.93 -0.73
-0.65 -0.85
-0.90 -0.97
-0.65f
b,c
b,d
e
+
-0.68
-0.20
+
+
b
e
(CH3)3N(CH2)2O2C(CH2)2CH3
-0.10
-0.36 -0.62
-0.82 -0.65 -0.76
(1.7 0.3) ¥ 107
(2.2 0.3) ¥ 107
-0.56 -0.71 -0.65 -0.65 -0.58 -0.58 -0.44 h (5.8 0.1) ¥ 104
(3.8 0.5) ¥ 102
g
(CH3)3N(CH2)11CH3
-0.07
-0.78
(CH3)3N+CH2CH(OH)CH2CO2
-
i
(CH3)3NCH2CH(OH)CH2CO2H+ -0.70
-0.91 -0.65 -0.14
-0.19
-0.43 -0.04
(8.0 1.1) ¥ 104
(2.8 0.4) ¥ 103
(1.2 0.2) ¥ 103
(2.5 0.2) ¥ 108
(4.1 1.2) ¥ 108
(1.0 0.2) ¥ 106
(1.8 0.3) ¥ 106
(8.3 1.9) ¥ 105
(1.3 0.3) ¥ 109
j
k
l
(CH3)3N+(CH2)2OP(O)(OH)O-
-0.82
-0.25
-0.23
-0.87
-0.46
-0.09
-0.76p
-0.46r
-0.71
-0.04
-0.68
-0.67
-0.72
+0.18
-0.32
-0.35
+
a
(PhCH2)N(CH3)3
-0.70m
-0.69n
-0.44
-0.83
-0.29
-0.90
(PhCH2)(CH3)2N(CH2)2OH+
-0.16 -0.22
e
+
a
N(CH2CH3)4
(CH3CH2)3N(CH2)2OH+
-0.87 -0.45
-0.51 -0.62 -0.56 -0.45 -0.46
-0.39 -0.07
e
o
q
+
(CH3CH2)3N(CH2)4CH3
Quin(CH2)2OH+
+
a
P(CH3)4
-0.38
-0.02
-0.13
-0.56
-5.77
-1.65
-4.75
-5.03
(2.2 0.4) ¥ 106
(1.4 0.3) ¥ 107
(6.9 1.8) ¥ 106
(8.9 1.7) ¥ 105
(1.3 0.3) ¥ 105
(1.6 0.3) ¥ 106
(1.3 0.3) ¥ 105
(8.6 1.6) ¥ 105
+
b
(CH3)3P(CH2)4CH3
-0.74 -0.69 -0.64 -0.55 -0.64
-0.95 -0.52
-0.90 -0.40
(CH3)3P(CH2)2OH+
o,s
b
+
+
(CH3)3P(CH2)2O2CCH3
P(CH2CH3)4
+0.02
+
a
-0.31
+0.04
-0.72
-0.66
e,t
o
(CH3CH2)3P(CH2)4CH3
-0.54 -0.74 -0.76 -0.68 -0.73
-0.69 -0.18
-0.66 -0.22
(CH3CH2)3P(CH2)2OH+
+
b,u
(CH3CH2)3P(CH2)2O2CCH3
-0.01
a Data from reference 4h. b Using 1,4-phenylenediamine as the competitor. c Values of (7.0 1.6) ¥ 105 and (1.1 0.3) ¥ 106 dm3 mol-1 determined with
PMe4 and PEt4+, respectively, as the competitors. d Values of (5.7 1.5) ¥ 105 and (1.3 0.4) ¥ 106 dm3 mol-1 determined with PMe4 and PEt4
,
+
+
+
respectively, as the competitors. e Using TMSP as the competitor. f Methyl protons on Cb. g Data from reference 35. h Dd for the next methylene group is
-0.23 ppm, while the remaining protons on the terminal end of the alkyl chain experience downfield shifts of 0.06 ppm or less upon complexation (ref.
35). i At pD 7.0. j In D2O with no added electrolyte. k At pD 2.0. l In D2O with 2.1 equiv of edta4- to complex Ca2+ m Methylene of benzyl group. Ddlim
.
for phenyl resonances are -0.47 (p), -0.78 (m), and -1.07 ppm (o). n Methylene of benzyl group. Ddlim for phenyl resonances are -0.54 (p), -0.84 (m), and
+
-1.04 (o). o Using NEt4 as the competitor. p H3 protons. q Using p-xylylenediamine as a competitor. r H4 proton. s Value of (1.7 0.2) ¥ 106 dm3 mol-1
determined using 1,4-phenylenediamine as the competitor. t Value of (5.6 1.3) ¥ 105 dm3 mol-1 determined using TMSP as the competitor. u Values of
(1.6 0.4) ¥ 106 and (3.0 0.5) ¥ 106 dm3 mol-1 determined using 1,4-phenylenediamine and NEt4+, respectively as the competitors.
with CB[7] were performed at pD 2.0 and 7.0, using 0.010 mol dm-3
DCl–0.050 mol dm-3 NaCl and 0.050 NaO2C(CD3)2 solutions,
respectively (Fig. 2). In the acidic solution, the stability constant
was determined to be (2.8 0.4) ¥ 103 dm3 mol-1, with an upfield
shift of the methyl protons of the NMe3 group of 0.66 ppm,
+
indicating that the trimethylammonium group was located in the
cavity, while the carboxylic acid group was outside near the portal.
In neutral solution, the deprotonation of the carboxylic acid
group resulted in a significant decrease in the stability constant
to (3.8 0.5) ¥ 102 dm3 mol-1, and an increase in the upfield shift
of the methyl protons to 0.78 ppm. The repulsions between the
carboxylate group and the polar portal-lining carbonyl groups
result in a movement of the zwitterionic form of the guest, with
respect to the cation form, with the NMe3+ head group now located
further into the cavity.
The choline phosphate guest was commercially available as its
calcium salt. The CB[7] complexation of the zwitterionic form of
the calcium salt of the choline phosphate, was examined by a 1H
NMR chemical shift titration at pD 3.7. The result was a sigmoidal
binding curve, due to competitive Ca2+ binding to the portals
of the CB[7]. The additions of edta4- to the solution provided
complexation of the Ca2+, allowing for uninhibited binding of the
guest to CB[7]. With an excess of edta4- (2.1 equivalents) a normal
1 : 1 host–guest titration curve was obtained, with the stability
constant of (1.2 0.2) ¥ 103 dm3 mol-1 being determined. At pD 7,
Fig. 2 1H NMR chemical shift titrations of carnitine with CB[7] in
D2O at (ꢀ) pD 2.0 (0.01 mol dm-3), (ꢀ) pD 4.8 (0.050 mol dm-3
NaOAc/0.025 mol dm-3 DCl) and (᭹) pD 7.0 (no added electrolytes).
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where the phosphate group is dianionic (pKa of the zwitterion
is 5.5),38 only small changes in chemical shifts of the guest were
observed (Dd = -0.07, -0.02, and 0.02 ppm for CH3, Ha and Hb,
respectively at [CB[7]/[guest] = 10), suggesting very weak binding
in which the strength of the binding to CB[7] is dictated by the
hydrophobic portion of the molecule attached to the trimethylam-
monium group, including ferrocene,5c adamantane,3 and methyl
viologen units.4i With these guests, as noted with quinuclidinium
and benzyl substituents, the CB[7] host–guest stability constants
are very similar in magnitude to those for other guests containing
these hydrophobic centers.
+
of the NMe3 head group.
The stability constants for the remainder of the CB[7] host–guest
complexes are too large to calculate directly and were determined
by 1H NMR competition experiments at pD 4.75 (acetate buffer)
using a variety of competitor guests whose stability constants have
been measured previously under these conditions.3,4h The values in
The CB[7] host has a reasonable selectivity between bu-
tyrylcholine (2.0 ¥ 107 mol dm-3) and acetylcholine (7.0 ¥
105 mol dm-3), the two natural substrates of butylcholinesterase
and acetylcholinesterase, respectively. There is also good se-
lectivity between acetylcholine (or choline) and ( )-carnitine
(3.8 ¥ 102 mol dm-3), which is also produced naturally through
biosynthesis. The complexations of choline, acetylcholine, and
related guests, such as carnitine, by a number of other artificial
macrocyclic host molecules have been reported,17–31 although most
of these have been measured in chloroform or other organic
solvents. In the majority of these hosts, the repeating subunits
contain aromatic rings and/or anionic substituents to provide for
non-covalent cation–p and ion–dipole interactions, respectively,
+
Table 1 may be compared with the corresponding NR4+ and PR4
cations determined previously.4h The magnitudes of the stability
constants for the monocationic choline and acetylcholine guests,
along with the NEt3 , PMe3 , and PEt3+ analogues may be related
to the natures of the cationic head groups and the hydroxyl or
acetyl end groups. For the choline series, the stability constants
follow the same trend as observed for the tetraalkylonium cations,
with PMe3 > NEt3 > PEt3 > NMe3 (choline). This trend
is consistent with the observation from the Ddlim values that the
trialkylonium head group is located within the cavity, along with
the remainder of the ‘ethanol’ moiety of the cholines.
+
+
+
+
+
+
+
with the N(CH3)3 head groups. There are several reports of the
With the acetylcholine series, the stability constants are very
similar, in the range of 7–9 ¥ 105 dm3 mol-1. With this guest
series, the location of the acetylcholines within the CB[7] is
clearly different than that for the phosphonium species, where the
Ddlim values (near zero) for the acetyl methyl protons indicated
interior binding of the phosphonium head group, compared
with the ammonium species, with a considerable upfield shift
for the acetyl Me protons. The similarity of stability constants
for the series is therefore likely coincidental. On comparing
the phosphonium acetylcholine guests with the corresponding
trialkylpentylphosphonium guests (same length backbone), the
latter guests exhibit greater stability constants and form a complex
with the CB[7] located over the pentyl group.
comparisons of stability constants for choline, acetylcholine, and
carnitine with water-soluble macrocyclic host molecules. With p-
sulfonated calix[4]arene, Nau and co-workers reported stability
constants (pD 7.4) for these guests are 7 ¥ 104, 1.0 ¥ 105, and
1.7 ¥ 103 dm3 mol-1, respectively, from a fluorescence displacement
assay.22i Using a deep cavitand, Rebek and co-workers measured
values of 2.6 ¥ 104, 1.5 ¥ 104, and 1.5 ¥ 102 dm3 mol-1, respectively,
utilizing isothermal calorimetry.29c Inoue and co-workers have
determined stability constants of 3.4 ¥ 103, 6.1 ¥ 103, and 4.4 ¥
103 dm3 mol-1 (1.8 ¥ 104 dm3 mol-1 for the zwitterion), respectively,
for these guests with a pyrogallol[4]arene in ethanol.26
These values show similar trends to those obtained with CB[7],
in that there is relatively little selectivity between choline and
acetylcholine, and significantly lower values, with the exception
of the pyrogallol[4]arene, for the zwitterionic carnitine. The
comparisons of magnitudes of the stability constants for neutral
CB[7] with the other host molecules indicate that the combination
of ion–dipole interactions and the hydrophobic effect with the
portals and cavity of the host, respectively, are sufficient to
provide for significant molecular recognition of the choline and
acetylcholine guests in aqueous solution.
+
Within the choline/acetylcholine series (with NMe3 head
groups), the order of KCB[7] is butyrylcholine > b-methylacetyl-
+
choline > acetylcholine > choline > NMe4 . This trend is
primarily related to the increased hydrophobicity of additional
alkyl groups at the neutral end of the guest, or to the ethylene linker
+
connecting the NMe3 group to the hydroxyl or acetyl terminals.
The trend in the stability constants is also paralleled by the
trend in the absolute value of the N-methyl Ddlim parameter, with
butyrylcholine (-0.10 ppm) < b-methylacetylcholine (-0.16) <
acetylcholine (-0.28) < choline (-0.66) < NMe4+ (-0.72). By pro-
viding more hydrophobic aliphatic substituents, that are further
from the quaternary ammonium center, the shielding cavity region
Experimental
Materials
+
of the CB[7] is drawn further away from the NMe3 group.
By replacing the methyl or ethyl groups on the ammonium end
of the choline guests with quinuclidinium or benzyl groups, the
stability constants are increased to the 108–1010 dm3 mol-1 range.
These end groups, whose protons experience large upfield shifts
(Table 1), are located in the CB[7] cavity, with the Ha and Hb
protons being shifted far less upfield than the parent choline guest.
The stability constants are similar in magnitude to those obtained
The cucurbit[7]uril was synthesized and characterized accord-
ing to the method of Day and coworkers.2b The choline,
acetylcholine, trimethylphosphine, triethylphosphine, trimethyl-
amine, triethylamine, 2-bromoethanol, 1-bromopentane, 2-
bromoethylacetate, and butyrylcholine (Sigma-Aldrich), and ben-
zyldimethylaminocholine bromide (Fluka) were used as received.
The yields of the novel compounds have not been optimized.
for other cationic guests containing the quinuclidinium (KCB[7]
=
(5.8 1.3) ¥ 109 dm3 mol-1 for N-methylquinuclidinium)33 and
Triethylpentylammonium bromide
benzyl (KCB[7] = (2.5 0.6) ¥ 108 dm3 mol-1 for (PhCH2)N(CH3)3 )4h
+
substituents on the quaternary nitrogen. There are several other
A solution of 7.82 g (51.8 mmol) 1-bromopentane and 5.79 g
(57.2 mmol) triethylamine in 8 mL CH3CN was refluxed for 48 h.
+
examples of guest molecules containing N(CH3)3 head groups
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Removal of the solvent gave a hygroscopic reddis◦h-orange ◦solid.
Yield 4.76 g (36%). mp. 155–159 ◦C (lit. 145–147 C,39 147 C40).
1H NMR (400 MHz, D2O) d 3.24 (q, 6H, J = 7.2 Hz, CH2), 3.12
(t, 2H, J = 7.8 Hz, Ha), 1.54 (qn, 2H, J = 7.8 Hz, Hb), 1.32 (m,
4H, Hg and Hd), 1.23 (tt, 9H, J = 7.2 Hz, 1.9 Hz, CH3), 0.87 (t,
3H, J = 7.0 Hz, He) ppm. 13C NMR (100 MHz, D2O) d 55.82
(t, J = 2.7 Hz, Ca), 51.96 (t, J = 2.7 Hz, N+-CH2CH3), 26.88
(Cd), 20.66 (Cg), 19.71 (Cb), 12.19 (Ce), 5.76 (N+-CH2CH3) ppm.
HR-ESI-MS: calcd. for C11H26N (M-Br+) m/z = 172.2060; found
172.2059.
argon in a pressure tube for 12 h, followed by a further 6 h at 60 ◦C.
The product was washed with ether and dried. Yield 0.244 g (17%).
mp. 176–178 ◦C. 1H NMR (400 MHz, D2O) d 2.20 (m, 2H, Ha),
2.19 (dq, 6H, CH2CH3, JP–H = 18.0 Hz, J = 7.8 Hz), 1.59 (m,
2H, Hb, JP–H = 23.2 Hz, J = 7.2 Hz), 1.44 (q, 2H, Hg, J =
7.2 Hz), 1.36 (sx, 2H, Hd, J = 7.2 Hz), 1.22 (dt, 9H, CH3, JP–H
=
18.0 Hz, J = 7.8 Hz), 0.89 (t, 3H, He, J = 7.2 Hz) ppm. 13C NMR
(100 MHz, D2O) d 32.39 (d, Cg, JP–C = 15 Hz), 21.54 (s, Cd),
20.47 (d, Cb, JP–C = 6 Hz), 16.90 (d, Ca, JP–C = 48 Hz), 13.28 (s,
Ce), 11.24 (d, P+-CH2CH3, JP–C = 50 Hz), 4.94 (d, P+-CH2CH3,
JP–C = 5 Hz) ppm. 31P NMR (133 MHz, D2O) d 38.56 ppm.
HR-ESI-MS: calcd. for C11H26P (M-Br)+ m/z = 189.1766; found
189.1766.
(2-Hydroxyethyl)triethylammonium bromide
A mixture of 0.724 g (5.79 mmol) of 2-bromoethanol and 0.665 g
(6.57 mmol) of triethylamine in 3 mL of ethanol was stirred at
room temperature for 4 days. The precipitate was washed with
(2-Hydroxyethyl)trimethylphosphonium bromide
◦
ether and dried. Yield 0.224 (17%). mp. 250–253 C (lit.41 256–
A solution of 0.618 g (5.95 mmol) of 2-bromoethanol and 5.00 mL
of 1.0 M trimethylphosphine (5.00 mmol) in THF was heated at
70 ◦C under argon in a pressure tube for 12 h. The precipitate
was washed with ether and dried. Yield 0.483 g (48%). mp.
290–292 ◦C. 1H NMR (400 MHz, D2O) d 3.97 (dt, 2H, Hb,
JP–H = 20.0 Hz, J = 6.2 Hz), 2.46 (dt, 2H, Ha, JP–H = 13.2 Hz,
J = 6.2 Hz), 1.87 (d, 9H, CH3, J = 14.8 Hz) ppm. 13C NMR
(100 MHz, D2O) d 54.88 (d, Cb, JP–C = 5 Hz), 26.20 (d, Ca,
JP–C = 49 Hz), 8.15 (d, P+-CH3, JP–C = 49 Hz), 5.00 (d, CH3
JP–C = 5 Hz) ppm. 31P NMR (133 MHz, D2O) d 26.33 ppm. HR-
ESI-MS: calcd. for C5H14OP (M - Br)+ m/z = 121.0776; found
121.0772.
◦
1
257 C). H NMR (400 MHz, D2O) d 3.92 (br t, 2H, Hb), 3.32
(q, 6H, J = 7.2 Hz, CH2), 3.31 (t, 2H, Ha), 1.22 (t, 9H, J =
7.2 Hz, CH3) ppm. 13C NMR (100 MHz, D2O) d 57.43 (Ca),
54.44 (Cb), 53.38 (N+-CH2CH3), 6.69 (N+-CH2CH3) ppm. HR-
ESI-MS: calcd. for C8H20O2N (M - Br+) m/z = 146.1534; found
146.1534.
(2-Hydroxyethyl)quinuclidinium bromide
The quinuclidine was prepared by placing 1.989 g (13.5 mmol) of
quinuclidine hydrochloride in 270 ml of 0.10 M NaOH (27 mmol).
The neutralized quinuclidine was extracted with chloroform and,
upon removing the solvent under reduced pressure, 0.981 g
(8.82 mmol, yield 65%) was obtained. A solution of 0.517 g
(4.14 mmol) of 2-bromoethanol and 0.391 g (3.52 mmol) of
quinuclidine in 5 mL of THF was heated under argon at 50 ◦C for
4 h. The product was washed with ether and dried. Yield 0.476 g
(2-Hydroxyethyl)triethylphosphonium bromide
A solution of 0.800 g (6.40 mmol) of 2-bromoethanol and 7.00 mL
of 1.0 M triethylphosphine (7.00 mmol) in THF was heated at
◦
70 C under argon in a pressure tube for 24 h. The product was
◦
1
(57%). mp 231–233 C. H NMR (400 MHz, D2O) d 3.95 (br
t, 2H, Hb), 3.44 (t, 6H, H2, J = 8.0 Hz), 3.24 (t, 2H, Ha, J =
washed with ether and dried. Yield 0.158 g (10%). mp. 221–225 ◦C
(lit.42 223 ◦C). 1H NMR (400 MHz, D2O) d 3.91 (dt, 2H, Hb, 3J =
5.2 Hz), 2.12 (hp, 1H, H4, J = 3.2 Hz), 1.93 (m, 6H, H3) ppm. 13
C
3
6.2 Hz, JP–H = 18 Hz), 2.42 (dt, 2H, Ha, J = 6.2 Hz, JP–H
=
NMR (100 MHz, D2O) d 65.31 (Ca), 55.50 (C2), 54.80 (Cb), 23.61
(C3), 19.01 (C4) ppm. HR-ESI-MS: calcd. for C9H18NO (M - Br+)
m/z = 156.1382; found 156.1382.
3
12 Hz), 2.22 (dq, 6H, CH2CH3, J = 7.8 Hz, JP–H = 13 Hz),
1.19 (dt, 9H, CH3CH2, J = 7.8 Hz, JP–H = 18 Hz) ppm. 13C
3
NMR (100 MHz, D2O) d 64.60 (d, J = 5.6 Hz, Cb), 20.48 (d,
J = 48.9 Hz, Ca), 11.60 (d, J = 49.4 Hz, P+-CH2CH3), 4.62 (d,
J = 5.4 Hz, P+-CH2CH3) ppm. 31P NMR (133 MHz, D2O) d
37.93 ppm. HR-ESI-MS: calcd. for C8H20OP (M - Br)+ m/z =
163.1246; found 163.1246.
Trimethylpentylphosphonium bromide
A solution of 0.755 g (5.00 mmol) of 1-bromopentane and 5.00 mL
of 1.0 M trimethylphosphine (5.00 mmol) in THF was heated
◦
under argon at 70 C for 12 h. The precipitate was◦washed with
ether and dried. Yield 0.0754 g (7%). mp. 174–176 C. 1H NMR
(2-Acetoxyethyl)trimethylphosphonium bromide
(400 MHz, D2O) d 2.18 (m, 2H, Ha), 1.84 (d, 9H, CH3, JP–H
=
A solution of 0.707 g (4.23 mmol) of 2-bromoethyl acetate and
5.10 mL of 1.0 M trimethylphosphine (5.10 mmol) in THF was
heated at 70 ◦C under argon for 72 h. The hygroscopic product was
washed with ether and dried. Yield 0.348 g (34%). mp. 59–62 ◦C.
1H NMR (400 MHz, D2O) d 4.42 (dt, 2H, CH2-O, JP–H = 19.9 Hz,
J = 6.2 Hz), 2.64 (dt, 2H, CH2-P+, JP–H = 13.2 Hz, J = 6.2 Hz),
2.09 (s, 3H, CH3C(O)), 1.90 (d, 9H, CH3, JP–H = 14.4 Hz) ppm.
15.6 Hz), 1.61 (m, 2H, Hb, J = 7.2 Hz), 1.44 (qn, 2H, Hg, J =
7.2 Hz), 1.35 (sx, 2H, Hd, J = 7.2 Hz), 0.89 (td, 3H, He, J = 7.2 Hz,
JP–H = 1.6 Hz) ppm. 13C NMR (100 MHz, D2O) d 32.14 (d, J =
15.5 Hz, Cg), 22.95 (d, J = 52.3 Hz, Ca), 21.55 (s, Cd), 20.66 (d,
J = 4.2 Hz, Cb), 13.26 (s, Ce), 7.53 (d, J = 54.9 Hz, CH3) ppm.
31P NMR (133 MHz, D2O) d 25.93 ppm. HR-ESI-MS: calcd. for
C8H20P (M - Br)+ m/z = 147.1298; found 147.1298.
13C NMR (100 MHz, D2O) d 173.32 (s, CO), 57.93 (d, Cb, JP–C
=
6 Hz), 23.04 (d, Ca, JP–C = 54 Hz), 20.19 (s, CH3), 7.89 (d, P+-CH3,
JP–C = 55 Hz) ppm. 31P NMR (133 MHz, D2O) d 25.84 ppm. HR-
ESI-MS: calcd. for C7H16O2P (M - Br)+ m/z = 163.0882; found
163.0888.
Triethylpentylphosphonium bromide
A solution of 0.801 g (5.30 mmol) of 1-bromopentane and 6.00 mL
of 1.0 M triethylphosphine (6.00 mmol) in THF were stirred under
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(2-Acetoxyethyl)triethylphosphonium bromide
Notes and references
A solution of 0.749 g (4.48 mmol) of 2-bromoethylacetate and
5.00 mL of 1.0 M triethylphosphine (5.00 mmol) in THF was
heated at 60 C under argon in a pressure tube for 6 h, followed
1 (a) W. L. Mock, Top. Curr. Chem., 1995, 175, 1; (b) K. Kim, Chem. Soc.
Rev., 2002, 31, 96; (c) O. A. Gerasko, D. G. Samsonenko and V. P. Fedin,
Russ. Chem. Rev., 2002, 71, 741; (d) J. W. Lee, S. Samal, N. Selvapalam,
H.-J. Kim and K. Kim, Acc. Chem. Res., 2003, 36, 621; (e) J. Lagona, P.
Mukhopadhyay, S. Chakrabarti and L. Isaacs, Angew. Chem., Int. Ed.,
2005, 44, 4844; (f) N. J. Wheate, Aust. J. Chem., 2006, 59, 354; (g) K.
Kim, N. Selvapalam, Y. H. Ko, K. M. Park, D. Kim and J. Kim, Chem.
Soc. Rev., 2007, 36, 267; (h) L. Isaacs, Chem. Commun., 2009, 619.
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Yamaguchi and K. Kim, J. Am. Chem. Soc., 2000, 122, 540; (b) A. Day,
A. P. Arnold, R. J. Blanch and B. Snushall, J. Org. Chem., 2001, 66,
8094.
◦
by a further 12 h at room temperature. The hygroscopic◦product
was washed with ether and dried. Yield ~2%. mp. 58–64 C (lit.42
◦
1
74.5 C). H NMR (400 MHz, D2O) d 4.41 (dt, 2H, Hb, JP–H
=
17.5 Hz, J = 6.5 Hz), 2.65 (dt, 2H, CH2-P+, JP–H = 12.5 Hz, J =
6.5 Hz), 2.27 (dq, 6H, CH2CH3, JP–H = 13.0 Hz, J = 7.6 Hz), 2.10
(s, 3H, CH3C(O)), 1.23 (dt, 9H, CH3CH2, JP–H = 18.5 Hz) ppm.
13C NMR (100 MHz, D2O) d 173.30 (s, CO), 57.75 (d, J = 5.4 Hz,
Cb), 20.17 (s, COCH3), 17.26 (d, J = 49.3 Hz, Ca), 11.51 (d, J =
48.8 Hz, P+-CH2CH3), 4.62 (d, J = 5.4 Hz, P+-CH2CH3) ppm.
31P NMR (133 MHz, D2O) d 38.34 ppm. HR-ESI-MS: calcd. for
C10H22O2P (M - Br)+ m/z = 205.1351; found 205.1352.
3 S. Liu, C. Ruspic, P. Mukhopadhyay, S. Chakrabarti, P. Y. Zavalij and
L. Isaacs, J. Am. Chem. Soc., 2005, 127, 15959.
4 See for example: (a) W. Ong, M. Gomez-Kaifer and A. E. Kaifer,
Org. Lett., 2002, 4, 1791; (b) H.-J. Kim, W. S. Keon, Y. H. Ko and K.
Kim, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 507; (c) Choi, S. H.
Park, A. Y. Ziganshina, Y. H. Ko, J. W. Lee and K. Kim, Chem.
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6, 185; (e) V. Sindelar, M. A. Cejas, F. M. Raymo and A. E. Kaifer,
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St-Jacques, I. W. Wyman and D. H. Macartney, Chem. Commun., 2008,
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681; (j) M. Megyesi, L. Biczo´k and I. Jablonkai, J. Phys. Chem. C, 2008,
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5 (a) W. S. Jeon, K. Moon, S. H. Park, H. Chun, Y. K. Ho, J. Y. Lee,
S. E. Lee, S. Samal, N. Selvapalam, M. V. Rekharsky, V. Sindelar,
D. Sobransingh, Y. Inoue, A. E. Kaifer and K. Kim, J. Am. Chem.
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Organometallics, 2006, 25, 1820; (c) M. V. Rekharsky, T. Mori, C. Yang,
Y. H. Ko, N. Selvapalam, H. Kim, D. Sobransingh, A. E. Kaifer, S.
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Methods
The 1H, 13C, and 31P NMR spectra were recorded on Bruker
Avance 400 or 500 spectrometers in D2O. The high-resolution
electrospray ionization time-of-flight mass spectra were recorded
on a QStar XL QqTOF instrument with an ESI source. The
host–guest stability constants for the cucurbit[7]uril complexes
with the cationic guests (KCB[7]) were determined by competitive
1H NMR binding studies at 298 K as described by Isaacs and
co-workers.3 The solutions were prepared in D2O containing
acetate buffer (0.050 mol dm-3 NaOAc-d3–0.025 mol dm-3 DCl)
at pD 4.75 with 3-trimethylsilylpropionic-2,2,3,3-d4 acid (KCB[7]
=
(1.82 0.22) ¥ 107 dm3 mol-1),3 tetraethylammonium bromide
((1.0 0.2) ¥ 106 dm3 mol-1),4h tetramethylphosphonium bromide
((2.2 0.4) ¥ 106 dm3 mol-1),4h tetraethylphosphonium chloride
6 (a) N. J. Wheate, A. I. Day, R. J. Blanch, A. P. Arnold, C. Cullinane
and J. G. Collins, Chem. Commun., 2004, 1424; (b) Y. J. Jeon, S. Y. Kim,
Y. H. Ko, S. Sakamoto, K. Yamaguchi and K. Kim, Org. Biomol. Chem.,
2005, 3, 2122; (c) N. J. Wheate, D. P. Buck, A. I. Day and J. G. Collins,
Dalton Trans., 2006, 451; (d) S. Kemp, N. J. Wheate, S. Wang, J. G.
Collins, S. F. Ralph, A. I. Day, V. J. Higgins and J. P. Aldrich-Wright,
J. Biol. Inorg. Chem., 2007, 12, 969.
((1.3
0.3) ¥ 105 dm3 mol-1),4h p-xylylenediamine ((1.84
0.34) ¥ 109 dm3 mol-1),3 or 1,2-phenylenediamine ((8.04 1.28) ¥
104 dm3 mol-1)3 (Sigma-Aldrich, used as received) as the competing
guests.
7 D. P. Buck, P. M. Abeysinghe, C. Cullinane, A. I. Day, J. C. Collins and
M. M. Harding, Dalton Trans., 2008, 2328.
8 (a) M. E. Bush, N. D. Bouley and A. R. Urbach, J. Am. Chem. Soc.,
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G. Ghale and W. M. Nau, Chem. Commun., 2007, 1614; (e) M. V.
Rekharsky, H. Yamahura, Y. H. Ko, N. Selvapalam, K. Kim and Y.
Inoue, Chem. Commun., 2008, 2236.
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10 I. W. Wyman and D. H. Macartney, Org. Biomol. Chem., accepted for
publication. 10.1039/b915694a.
Conclusions
The cucurbit[7]uril host molecule forms very stable complexes with
a variety of choline cations and their phosphonium analogues
in aqueous solution. The stability of the host–guest complexes
depends on the nature of the cationic head group as well as the size
and charge on the substituents on the opposite end of the guest and
on the ethylene linker. The neutral CB[7] host is able to recognize
the cholines in water without the use of aromatic or anionic
components in macrocycle subunits. We are currently investigating
the use of CB[7] in assisting the metal-catalyzed hydrolyses of
choline phosphate esters, such as 4-nitrophenylphosphocholine,
by binding the choline ester and helping to stabilize transition
states involving binding of the metal ion, such as zinc, at the
carbonyl-lined portal(s) of the cucurbit[7]uril host.
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Acknowledgements
The financial support of this work by the Natural Sciences and En-
gineering Research Council of Canada is gratefully acknowledged
(D.H.M.). The Ontario Government and the Walter C Sumner
Foundation are thanked for scholarship support (I.W.W.).
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