Daisy chain assembly formed from a cucurbit[6]uril derivative

Article abstract of DOI:10.1021/ol3011425

The building block synthesis of a derivative of CB[6] that bears a reactive propargyloxy group and its functionalization by click chemistry to yield 1 which contains a covalently attached isobutylammonium group is presented. Compound 1 undergoes self-assembly to yield a cyclic [c2] daisy chain assembly (1₂) in water. The behavior of 1₂ in response to various stimuli (e.g., guests and CB[n] receptors) is described.

Full text of DOI:10.1021/ol3011425

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3072–3075
Daisy Chain Assembly Formed from
a Cucurbit[6]uril Derivative
Liping Cao and Lyle Isaacs*
Department of Chemistry and Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
LIsaacs@umd.edu
Received April 27, 2012
ABSTRACT
The building block synthesis of a derivative of CB[6] that bears a reactive propargyloxy group and its functionalization by click chemistry to yield 1
which contains a covalently attached isobutylammonium group is presented. Compound 1 undergoes self-assembly to yield a cyclic [c2] daisy
chain assembly (12) in water. The behavior of 12 in response to various stimuli (e.g., guests and CB[n] receptors) is described.
The synthesis of cucurbit[n]uril (CB[n]) molecular con-
tainers proceeds by the condensation of glycoluril with
formaldehyde in hot concentrated acidic conditions.1 Con-
temporary interest in the supramolecular chemistry of
CB[n] molecular containers2 has been fueled by the com-
mercial availability of a homologous series of hosts (CB[n],
n = 5, 6, 7, 8, 10) that display exceptionally high affinity and
selectivity toward their guests in aqueous solution.3 These
high affinity and high selectivity CB[n]•guest interactions
have been used to create a number of functional CB[n] sys-
tems including molecular machines,4 biomimetic systems,5
sensing ensembles,6 stimuli responsive polymers,7 gas se-
questration and purification,8 and drug delivery systems.9
In order to further extend the supramolecular chemistry of
CB[n] it is necessary to develop efficient synthetic methods
to prepare functionalized CB[n] derivatives. A major step
in this direction was accomplished by the Kim group who
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r
10.1021/ol3011425
Published on Web 05/31/2012
2012 American Chemical Society

performed the direct perhydroxylation of CB[n] using
K2S2O8 asanoxidanttoyield (HO)2nCB[n].10 Themultiply
functionalized CB[n] derivatives prepared in this manner
have been used in numerous application areas including
ion channels, membrane protein fishing, and nanocapsules.11
Despite the demonstrated utility of these (per)functionalized
CB[n] derivatives, it would be useful to develop clickable
monofunctionalized CB[n] to ensure chemical homogeneity
of compounds and materials derived therefrom. Scherman’s
group recently tamed the persulfate oxidation of CB[6] which
allowed the isolation of (HO)1CB[6] (Figure 1) in 12% yield
after chromatography on a reversed-phase macroporous
resin.12 They transformed (HO)1CB[6] into propargyloxyCB-
[6] which undergoes azideꢀacetylene click reaction to gener-
ate a self-complexing CB[6] derivative.
Our group has been using our knowledge of the mechan-
ism of CB[n] formation13,14 to develop robust, scalable
procedures for the synthesis of monofunctionalized CB[n]
derivatives that bear reactive functional groups. Recently,
we reported the gram scale templated synthesis of methyl-
ene bridged glycoluril hexamer 2 and its conversion into
monofunctionalized CB[6] derivatives by the reaction with
substituted phthalaldehydes.14 In this paper we report the
synthesis of phenol substituted CB[6] (3), its transformation
into propargyloxy compound (4), and finally triazole 1. We
describe the self-assembly properties of 1 in water and its
response to various forms of chemical stimuli.
Figure 1. Chemical structures of CB[n] and (HO)1CB[6].
yield on the gram scale. Next, we reacted 3 with propargyl
bromide in N-methylpyrrolidinone (NMP) as solvent with
anhydrous K2CO3 as the base to yield CB[6] derivative 4 in
97% yield which contains a reactive propargyloxy sub-
stituent. Finally, we reacted 4 with azido amine 6
ꢀ
(Supporting Information) in the presence of Pericas’ cat-
alyst 716 to give compound 1 in 75% yield.
The chemical structure of 1 features a CB[6] sized cavity
covalently connected to an isobutylammonium group that
we anticipated would act as a guest for the substituted
1
CB[6] group. Accordingly, we measured the H NMR
spectrum of 1in D2O (Figure 2a) in the presence of spermine
(8) as a tight binding guest to eliminate the self-assembly of
1
1. The H NMR spectrum is fully consistent with the Cs-
symmetric structure of 1•8. Of particular note are the two
nonequivalent CH groups (Hk and Hl) of 1 which resonate
at 6.66 and 6.65 ppm, the triazole proton (Hf) at 8.21 ppm,
the glycoluril methine protons (Hm and Hn) which are
upfield shifted by the adjacent o-xylylene ring, and the free
nonbinding isobutylammonium group (Ha ꢀ Hc).
Scheme 1 shows the synthesis of compound 1. First, we
react hexamer 2 with 4-hydroxyphthalaldehyde (5,15 Sup-
porting Information) to give CB[6] derivative 3 in 52%
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Zavalij, P. Y.; Briken, V.; Isaacs, L. Nat. Chem. 2012, 4, 503–510.
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Nat. Chem. 2011, 3, 154–159. (b) Jeon, Y. J.; Kim, H.; Jon, S.;
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A priori, compound 1 could be expected to undergo
intramolecular self-complexation, form cyclic assemblies
(e.g., dimer, trimer, tetramer), or undergo supramolecular
polymerization. Based on the design of 1 we expected that
intramolecular self-complexation12 would be sterically
unfavorable. Furthermore, we did not expect the relatively
weak binding constant for the complexation with isobutyl-
ammonium groups (3.0 ꢁ 104 Mꢀ1 14
)
to support supra-
molecular polymerization over the experimentally acces-
sible concentration regime.17
Figure 2b shows the 1H NMR spectrum recorded for 1
on its own. Quite interestingly, we observe four resonances
in the 8.7ꢀ8.4 ppm region of the spectrum, two of which
are of equal intensity, which corresponds to the triazole
CH protons (Hf). In order to obtain information about the
constitution of the mixture of assemblies present in solution
we performed diffusion ordered spectroscopy (DOSY) on the
mixture.18 The diffusion coefficient measured for each of the
four peaks was in the range of (2.25ꢀ2.60) ꢁ 10ꢀ10 m2 sꢀ1
whereas the value for a monomeric analogue was 3.16 ꢁ
10ꢀ10 m2 sꢀ1 (Supporting Information). The ∼18ꢀ29%
€
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ꢀ
2009, 11, 6480–4683.
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Anzenbacher, P., Jr.; Isaacs, L. J. Am. Chem. Soc. 2011, 133, 17966–
17976.
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Org. Lett., Vol. 14, No. 12, 2012
3073

Scheme 1. Synthesis of Compound 1
Figure 2. 1H NMR spectra recorded for (a) 1•8 (1 mM) and excess 8 (1 mM) in D2O (500 MHz, rt), and (b) 12 (1 mM), (c) a mixture of
1 (0.45 mM) and CB[8] (0.675 mM), and (d) a mixture of 1 (0.4 mM), 8 (0.48 mM), and CB[8] (0.48 mM) in 50 mM NaO2CCD3 buffer
(pD 4.74, 600 MHz, rt). x = acetate buffer; CB = resonances from CB[6] group.
decrease in diffusion coefficient is consistent with the
formulation of all three assemblies as dimers. Furthermore,
we performed ESI-MS experiments and observed sizable
ions corresponding to (12)3þ and (12)2þ (Supporting
Information). The symmetry properties of monomeric 1
allow us to rationalize the formation of a mixture of cyclic
dimers (12). Because of the position of attachment of the
O-atom on the aromatic ring of 1, the two ureidyl carbonyl
portals are nonequivalent. Therefore, when an alkylam-
monium ion binds to 1 it can do so in two isomeric
orientations. Scheme 2 shows the three isomers of the
cyclic dimer daisy chain assembly 12 (inꢀin, inꢀout, and
outꢀout). Symmetry considerations dictate that the inꢀ
out isomer should display two singlets of equal intensity
for the symmetry nonequivalent triazole protons (Hf and
displayone singletfor the symmetryequivalent Hf protons.
On the basis of the diffusion measurements and molecular
models (Supporting Information) we believe that inꢀin 12
is the predominant isomer.
To try to bias the self-assembly of 1 toward larger cyclic
oligomers we studied the response toward changes in
concentration, temperature, and metal ion concentration.
Variable temperature 1H NMR experiments over the
277ꢀ333 K range do not show any changes indicative of
changes in oligomerization state (Supporting Information).
1
Similarly, the H NMR spectra recorded for 12 do not
change over the experimentally accessible range of con-
centration ([1] = 0.15 to 1.25 mM) and in the presence of
different metal ions (Naþ, Kþ, Csþ, Mg2þ, Cu2þ) which
suggests that the cyclic [c2] daisy chain assembly 12 is of
high thermodynamic stability. In order to gauge the
0
Hf ) whereas the outꢀout and inꢀin isomers should each
3074
Org. Lett., Vol. 14, No. 12, 2012

however, the addition of 1.5 equiv of CB[8] resulted in a
significant dissociation of 12 with concomitant formation
of a new complex 1•CB[8] (Figure 2c and Scheme 2).
Addition of 8 as a guest for the CB[6] sized cavity of 1
yields 8•1•CB[8] which simplifies the 1H NMR spectrum as
shown in Figure 2d. Complexation induced chemical shifts
that provide evidence for the geometry of 1•CB[8] and
8•1•CB[8] include the upfield shift observed for triazole
Hf and isobutylammonium Ha resonances. Based on this
evidence, we formulate the geometry of 1•CB[8] and
8•1•CB[8] as thebackfoldedform13g,19 depictedin Scheme 2.
As described above, we found that 8 causes dissociation of
12 to yield 1•8. Interestingly, we found that addition of
CB[6] to a solution of 1•8 results in the formation of CB[6]•8
and the reformation of 12 (Scheme 2). We believe this
process is driven by the higher affinity of 8 toward CB[6]
than 1.
Scheme 2. Depiction of the Three Isomers of 12 and Their
Response to Addition of 8, CB[8], and CB[6]
In conclusion, we have reported the synthesis of mono-
functionalized CB[6] derivative 4 which contains a propar-
gyloxy substitutent which undergoes a click reaction to
yield 1. Compound 1 undergoes self-assembly in water to
give the cyclic [c2] daisy chain 12. Assembly 12 is responsive
to chemical stimuli in the form of competing guests and
competing hosts. For example, the addition of 8 opens up
dimer 12 to give 1•8; subsequent addition of CB[6] reverses
this process to deliver cyclic [c2] daisy chain 12. The most
significant aspect of the work, however, is the gram scale
synthesis of monofunctionalized CB[6] derivative 3 and its
high yield transformation into 4 which contains a clickable
propargyloxy group. Accordingly, it is straightforward to
imagine merging the recognition properties of CB[6] with
other functional supramolecular and biomolecular systems
by simple click chemistry.
increase in affinity for the formation of cyclic dimer 12
relative to monomeric models14 we added 1 equiv of
guests of increasing affinity toward the CB[6] derivative
(butanediammonium (9), Ka = 4.9 ꢁ 105 Mꢀ1; pentane-
diammonium (10), Ka = 5.7 ꢁ 106 Mꢀ1; hexanediammo-
nium (11), Ka = 1.4 ꢁ 107 Mꢀ1).14 We found that 1 equiv
of 10 and 11, which bind 190ꢀ466-fold tighter than
isobutylammonium, cause significant dissociation (75ꢀ81%)
of 12 to give 1•10 and 1•11 which reflects the thermody-
namic advantage for cyclic dimer versus 1:1 complex for-
mation.
Acknowledgment. We thank the National Science
Foundation (CHE-1110911 to L.I.) for financial support.
We also probed the response of [c2] daisy chain 12
toward chemical stimuli in the form of added molecular
containers (CB[6], CB[7], CB[8], and HP-β-CD). We
hoped that the added molecular containers, in particular
HP-β-CD and CB[8], would bind to the substituted
o-xylylene and triazole rings of 1 and thereby rigidify the
linking group between the cavity and the isobutylammo-
nium ion arm which might result in a preference for
different sized cyclic daisy chains. In practice, the addition
of CB[6], CB[7], and HP-β-CD did not result in a significant
dissociation of 12 (Supporting Information). In contrast,
Supporting Information Available. Details of the synthe-
sis and characterization of 1 and 3ꢀ6, and results of variable
temperature, dilution experiments, diffusion ordered spec-
troscopy, chemical stimuli experiments, and molecular
modeling performed with 12. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Ko, Y. H.; Kim, E.; Hwang, I.; Kim, K. Chem. Commun. 2007,
1305–1315.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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