Helianthus-like cucurbit[4]uril and cucurbit[5]uril analogues

Article abstract of DOI:10.1039/c7nj01595j

A new glycoluril-like molecule, cyclopentanopropanediurea (CyP-TD), was prepared by malonic ester synthesis. Its condensation with paraformaldehyde resulted in two Helianthus-like cucurbituril analogues, CyP₄TD[4] and CyP₅TD[5], with cyclopentano groups evenly distributed on the equators. The structures of the two macrocycles were confirmed by ¹H-NMR, HRMS-ES and single-crystal X-ray diffraction. CyP₄TD[4] and CyP₅TD[5] both exhibit excellent thermal stability, and CyP₅TD[5] has better solubility in water and organic solvents, while CyP₄TD[4] can hardly dissolve in them.

Full text of DOI:10.1039/c7nj01595j

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Helianthus-like Cucurbit[4]uril and Cucurbit[5]uril analogues
Yufan Wua, Lixi Xua, Yenan Shena, Yang Wanga, Qiaochun Wang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new glycoluril-like molecule, cyclopentanopropanediurea (CyP-
TD), was prepared from malonic ester synthesis. Its condensation
with paraformaldehyde resulted in two Helianthus-like
cucurbituril analogues, CyP4TD[4] and CyP5TD[5], with
cyclopentano groups evenly decorated on the equators. The
1
structures of the two macrocycles were confirmed by by H NMR,
HRMS-ES and single crystal X-ray diffraction. CyP4TD[4] and
CyP5TD[5] both exhibits excellent thermal stability, and CyP5TD[5]
has better solubility in water and organic solvents while CyP4TD[4]
could hardly dissolve.
Scheme 1. The synthesis of CyP-TD[n]s. Reaction condition: (i) CH3COOH, H2SO4,
90°C. (ii) concd HCl, 90°C. CaCl2 was added in the case of CyP4TD[4].
Cucurbit[n]urils (CB[n]), macrocyclic hosts obtained from
glycoluril-formaldehyde condensation,[1] are of high binding
affinity and selectivity towards charged guest species[2], and
have been widely used in the fields of such as molecular
machines,[3] drug carriers,[4] supramolecular polymers[5] and
sensing ensembles.[6] The exploration of new cucurbituril
homologues and analogues has been being the hot topic in the
area of cucurbituril chemistry.[7] These new hosts have greatly
enlarged the cucurbituril family and aroused further interest
on their modification, so as to endow them aditional
functions[8-11] or to improve their solubility.[12,13] However,
glycoluril derivatives with too large substituents stretching
away on both sides of the glycoluril at the waist methine
bridge positions would be unfavourable to the cyclization upon
the condensation with formaldehyde, and as a result, few
glycolurils, except dimethyl,[14] cyclopentano[15] and
cyclohexano[16] glycoluril have been reported to produce
cucurbiturils. In comparison, when substituents are introduced
on the central methylene position of a propanediurea (2,4,6,8-
tetraazabicyclo[3.3.1]nonane-3,7-dione, TD), which possesses
the similar structure characteristics of glycoluril, they might
have less influence upon the cucurbituril-forming cyclization.
For example, we has been able to use dimethylpropanediurea
Me2-TD to synthesize decamethyl-decorated cucurbit[5]uril
analogue (Me10TD[5]),[17] so does Sindelar’s group[18]. More
recently, we also reported the synthesis of the smallest
[19]
cucurbituril analogue Me8TD[4]
,
which binds selectively
towards Ag+ with high K constant, basing on the same building
block. With the above works done, we naturally expected to
see 1) whether TD with larger substituents on the equator
could conduct the cyclization reaction with formaldehyde, and
2) if the above cyclization undergoes, whether the formed
Figure.1 Top and side view of X-ray crystal structures of CyP4TD[4] and
CyP5TD[5]. Color codes: carbon, black; nitrogen, blue; oxygen, red (the Ca2+, Cl-
and H2O are omitted for clarity).
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cucurbituril analogues could have better solubility.
The yield of CyP5TD[5] was 8%.
When calcium chloride was added to the reaction of CyP-
Herein we report a facile strategy to obtain glycoluril-like
cyclopentanopropanediurea (CyP-TD) and its condensation TD with formaldehyde, the same template-directed strategy as
1
with formaldehyde to form two helianthus-like cucurbituril used in the preparation of Me8TD[4], the H NMR spectra of
analogues, CyP4TD[4] and CyP5TD[5], as shown in Scheme 1. the precipitated solid gave one set of peaks, as shown in Figure
Owning to the introduction of the five hydrophobic 2b. The chemical shifts of the two ethylene protons move from
cyclopentano groups, CyP5TD[5] has better solubility in organic 6.26 & 4.19ppm to 6.44 & 4.11ppm, respectively, when
solvents such as CH3OH and DMSO, but poorer solubility in compared with CyP5TD[5]+CaCl2. The NMR result again
H2O, when compared with Me10TD[5]. But for CyP4TD[4], its suggested the formation of a new symmetrical homologue.
solubility in these common solvents is extremely low instead of Further MALDI-TOF measurement (Figure S10) gave an intense
being improved.
peak at m/z=959.4362, which corresponds to the [M+Na]+
The preparation of CyP-TD was started from the cyclic (calcd. 959.4365) of CyP4TD[4]. The X-ray crystallography
alkylation of malonic ester, followed by the reduction to diol (Figure 1 & Figure S12) confirmed the tetrameric structure of
using
cyclopentanedicarbaldehyde (
information), and the final condensation with urea. This
LiAlH4,
then
the
oxidation
to
(Scheme S1, supporting linkers.
The X-ray crystallography and Atomic Absorption
1,1- four propanediurea units doubly bridged by 8 methylene
[20]
1)
strategy allows the preparation of other substituted TDs by Spectroscopy (Figure S13) measurements indicated that the
simply changing the alkylating agent. The condensation of CyP- product at this stage was the complex of CyP4TD[4] with CaCl2
TD with formaldehyde was then carried out in concentrated in a ratio of 1:2. The calcium was then removed by treating
HCl at 95°C for 24 h, the same procedure as used in the CyP4TD[4]•
2CaCl2 solution with EDTA and (CH3)4N+OH- (see
preparation of Me10TD[5]. White precipitate appeared after supporting information for details). The validity of this method
cooling and was collected by filtration. After being washed was confirmed by elemental analysis (Figure S15). The yield of
with dilute HCl solution, a pure substance was obtained. The CyP4TD[4]•2CaCl2 was 5% and the final yield of CyP4TD[4] was
1H NMR spectra of this solid in D2O shows 3 groups of proton 2%.
resonances (Figure S4, supporting information), with the
It can be seen that the yields of CyP4TD[4] and CyP5TD[5]
propanediurea CH proton signal covered by the solvent peak were both low, so we turned to study the composition of the
of D2O. After the addition of CaCl2, the CH proton signal moves filtrates. Acetone was then added to filtrates respectively and
1
out and the H NMR spectra (Figure 2a) shows four groups of the resulting precipitates were collected by filtration. The 1H
proton resonances with the integration ratio of 1: 1: 1: 4. The NMR spectrum of the solid from the CyP4TD[4] filtrate (Figure
NMR result indicates a structure of typical symmetrical CB[n] S16) indicated that no CyP5TD[5] formed during the Ca2+
analogue. The HRMS-ES measurement (Figure S7) revealed the template-directed CyP4TD[4] synthesis, because the typical
formation of the cyclic pentamer CyP5TD[5], giving an intense peak at 4.88 ppm (Hb of CyP5TD[5] in the presence of Ca2+) was
peak at m/z 1193.5486 that corresponds to [M+Na]+ (calcd. not found. And the 1H NMR spectrum of the solid from the
1193.5481). The final structural confirmation was conducted CyP5TD[5] filtrate (Figure S17) showed it might contain
by X-ray crystallography, as shown in Figure 1. CyP5TD[5] homologues or acyclic oligomers. However, further MS
consists of five CyP-TD units linked by 10 methylene bridges, measurements (Figure S18) showed no sign of other
bearing a hydrophobic cavity and two identical carbonyl homologues, such as TD[6] (m/z 1404.6701) or TD[7] (m/z
portals, and shows the same structural characteristic as
Table 1 Cavity dimensions of CyP-TD[n][a]
cucurbituril, and the top view of which looks like a sunflower.
Portal diameter
(Å) (a) [b]
Cavity width (Å)
(b) [b]
height (Å) (h) [b]
CyP5TD[5]
CyP4TD[4]
2.2
1.2
4.8
3.4
8.2
8.6
[a] Based on X-ray crystal structures of CyP-TD[n]/Ca2+ complexes.
[b] The values quoted for a, b, and h take into account the van der Waals radii
of the relevant atoms.
Table 2 The solubility and thermostability of CyP-TD[n]
SH2O [mM]
SCH3OH [mM]
SDMSO [mM]
Stability[℃]
490
CyP5TD[5]
CyP4TD[4]
CyP4TD[4]c
6.3
＜0.1
24.2
10
14
＜0.1
2.1
＜0.1
490
12.5
560
Figure 2. The 1H NMR spectra (400 MHz, 25 °C, D2O) of a) CyP5TD[5] and b)
CyP4TD[4], both in the presence of CaCl2.
[c] The solubility and stability in this case was measured in the form of Ca2+
complex at 25°C.
2 | J. Name., 2012, 00, 1-3
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1638.7817). Many efforts had been made to isolate any pure
species from the above two filtrate, but all failed.
The structural dimensions of CyP4TD[4] and CyP5TD[5]
basing on the X-ray crystal structures are listed in table 1. The
portal size, cavity width, and the height of CyP4TD[4] are 1.2Å,
3.4Å and 8.6Å, respectively, while those of CyP5TD[5] are 2.2Å,
4.8Å and 8.2Å, respectively. The cavity volume of CyP4TD[4]
and CyP5TD[5] were then calculated as 38Å3 and 82Å3
respectively. The structural dimensions of CyP4TD[4] is
essentially the same as those of Me8TD[4], just like the fact
2
3
that the cavity of CyP5TD[5] equals to that of Me10TD[5]
.
The solubility of CyP4TD[4] and CyP5TD[5] in water and
organic solvents was determined by 1H NMR spectroscopy
with an internal standard[6a] at 25°C (see Supporting
Information for details), as illustrated in Table 2. It can be seen
that CyP5TD[5] has better oil solubility (10mM in methanol and
14mM in DMSO), but poorer solubility in H2O (6.3mM), when
compared with Me10TD[5] (5.6mM in methanol, 9.6mM in
DMSO, and 11.5mM in H2O), mainly due to the introduction of
the five hydrophobic cyclopentano groups. In comparison,
CyP4TD[4] does not show the solubility enhancement as
expected, it could hardly dissoveled among these solvents.
4
5
However, it should be noted that CyP4TD[4]•2CaCl2 shows
remarkable solubility in water (24.2mM), moderate one in
methanol (12.5mM), though relatively poor in DMSO (2.1mM).
Thermogravimetric analysis revealed that CyP4TD[4] and
CyP5TD[5] have good thermal stability. We did not detect any
mass loss connected with the decomposition of CyP5TD[5] and
CyP4TD[4] samples under nitrogen atmosphere up to 490°C
(Figure S11), which is comparable with cucurbituril
homologues.
6
In summary, we have successfully prepared two new
cucurbituril-like macrocycle, CyP4TD[4] and CyP5TD[5], by acid-
catalyzed condensation of cyclopentanopropanediurea and
formaldehyde, in the presence and absence of CaCl2 template,
respectively. Compared to CyP4TD[4] which has poor solubility
in common solvents, CyP5TD[5] has better solubility in organic
solvents than Me10TD[5] as expected. It should be emphasized
that other substituted propanediurea could be conveniently
obtained using the malonic ester synthetic strategy in this
work, and other functionalized TD[n] might consequently be
accessible.
7
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This work was financially supported by the NSFC/China
(21572063, 21372076, and 21072058), the Science Fund for
Creative Research Groups (21421004), the Programme of
Introducing Talents of Discipline to Universities (B16017), and
the Fundamental Research Funds for the Central Universities
222201717003.
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Two cucurbituril-like macrocycles were synthesized by condensing cyclopentano-subsituted
propanediurea with formaldehyde in the presence or absence of Ca2+ respectively.