DESolution of CD and CB Macrocycles

Article abstract of DOI:10.1002/chem.201701275

Supramolecular chemistry utilizing the macrocyclic hosts cyclodextrins (CDs) and cucurbit[n]urils (CB[n]s) is traditionally performed in aqueous media; however, their solubility is typically poor, especially for the family of CB[n]s. Through derivatization of these macrocycles their solubility can be augmented to enable enhanced solubility in water and in some organic solvents. The increase in solubility of these derivatized macrocycles allows for their use in a wider range of chemical environments and giving rise to myriad potential applications. The dissolution of parent CDs (α-, β- and γ-) and CB[n]s (n=6–8) in deep eutectic solvents (DES) is reported, showing dramatic enhanced solubility of the larger species in both families, CB[7] and CB[8] as well as β- and γ-CD, respectively. Furthermore, the host–guest properties are maintained in this new solvation medium.

Full text of DOI:10.1002/chem.201701275

A Journal of
Accepted Article
Title: DESolution of CD and CB macrocycles
Authors: Jade A. McCune, Susanna Kunz, Magdalena Olesińska, and
Oren A. Scherman
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To be cited as: Chem. Eur. J. 10.1002/chem.201701275
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10.1002/chem.201701275
Chemistry - A European Journal
DESolution of CD and CB macrocycles ∗∗
Jade A. McCune, Susanna Kunz, Magdalena Olesin´ska and Oren A. Scherman ∗
Abstract: Supramolecular chemistry utilizing the macro- from ChCl and a hydrogen bond donor.[4] As a result of
cyclic hosts cyclodextrins (CDs) and cucurbit[n]urils the wide scope of compounds that fall within each type of
(CB[n]s) is traditionally carried out in aqueous media, how- DES, a broad range of solvents exists with tuneable physical
ever, their solubility is typically poor, especially the family and chemical properties. Type III DES, specifically those
of cucurbit[n]urils. Through derivitization of these macro- based upon ChCl-urea, Figure 1 (top), have shown the most
cycles their solubility can be augmented to enable enhanced promise in the solvation of a wide range of chemical enti-
solubility in water and in some organic solvents. The in- ties including metal oxides,[1,2] biopolymers[6,7] and in the
crease in solubility of these derivitized macrocycles allows synthesis of materials for gas adsorption.[8,9]
for their use in a wider range of chemical environments and
Cyclodextrins (CDs) and cucurbit[n]urils (CB[n]s) are
giving rise to myriad potential applications. We report the two families of macrocyclic host molecules, Figure 1 (bot-
dissolution of parent CDs (α-, β- and γ-) and CB[n]s (n tom). CDs are formed from cyclized glucopyranose units
= 6–8) in a in deep eutectic solvents (DES) showing dra- and are produced from the enzymatic degradation of starch
matic enhanced solubility of the larger species in both fam- whereas CB[n]s are formed from the cyclization of n gly-
ilies, CB[7] and CB[8] as well as β- and γ- CD, respec- coluril (n = 5–8, 10) units joined by methylene bridges un-
tively. Furthermore, we show that the host–guest properties der acidic conditions.[10,11] Despite having different chem-
are maintained in this new solvation medium.
ical compositions they share many of the same properties,
namely, they both act as host molecules capable of binding
guest moieties inside their hydrophobic cavities. This bind-
ing event is driven, in part, by the release of conformation-
ally restricted water molecules from the cavity. Both fami-
lies are comprised of three main homologues, which increase
in cavity diameter α-, β- and γ-CD and CB[6], CB[7] and
CB[8]. The homologues of CD and CB[n] are approximately
analogous in size and the nature of the guest molecules they
can encapsulate. Within both families the cavity dimensions
of the homologues vary, however, they all have a uniform
D
eep eutectic solvents (DES) are a relatively new
class of solvents first reported in 2002 by Abbot and co-
workers.[1,2] They share many similarities in their physico-
chemical properties with ionic liquids (ILs), however, have
several notable differences.[3–5] Made of biodegradable,
cheap and non-toxic components, DES are an environmen-
tally, economically and industrially more attractive alterna-
tive to ILs. In addition, their synthesis does not require an
inert atmosphere and is considerably more straightforward.
Typically, DES contain bulky ions that, on account of having
a low lattice energy, form liquids at room temperature as a
result of a decreased melting point. Delocalization of charge
throughout the bulk liquid structure of the DES through the
hydrogen bond network formed between the hydrogen bond
donor and acceptor that causes this suppression in melting
point.[4]
˚
˚
height (CDs 7.8 A and CB[n]s 9.1 A). Similarly, the aque-
ous solubility of each homologue differs in both families, as
detailed in Table 1.
O
N
ChCl-urea
DES
+
:
OH
H2N
NH2
There are three main classes of DES, Type I are formed
through MClx and a quaternary ammonium salt (where M is
a metal), Type II through complexation of a hydrated metal
halide and choline chloride (ChCl) and Type III are formed
1
2
O
OH
O
N
CH2
H
N CH2
N
∗∗ This research was supported by the European Union (European Research
Council Starting Grants ASPiRe 240629 (OAS), EPSRC departmental
PhD studentship (EP/K503009/1 (JAM)) and Marie Curie FP7 SASSY-
POL ITN (607602) programme (OAS & MO).
H
O
HO
N
OH
n
O
n
∗
Jade A. McCune, Susanna Kunz, Magdalena Olesin´ska and
Prof. O.A. Scherman
Figure 1 Top: Synthesis of ChCl-urea (1:2) DES. Bottom: Struc-
ture of CB[n]s (left) and CDs (right).
Melville Laboratory for Polymer Synthesis
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW, UK
E-mail: oas23@cam.ac.uk
CDs have, in general, much higher aqueous solubility
compared to CB[n]. CB[n] homologues where n is odd, i.e.
Supporting information for this article is available on the WWW under
or from the author.
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Table 1 Summary of aqueous solubility values of CD and CB[n]
macrocycles.
readily included within the bulk liquid structure at such high
concentrations.
Water solubility
Macrocycle
Table 2 Top: Table detailing the maximum solubility (mg/mL) of
α-, β- and γ-CD and CB[n] (n = 6–8) in ChCl-urea DES and the
enhancement factor relative to aqueous solution. Bottom: Vials
showing (L to R) 1g/mL of α-, β- and γ-CD and CB[6] (1mg/mL),
CB[7] (17mg/mL) and CB[8] (2mg/mL) dissolved in 1mL ChCl
urea DES.
mg/mL
α-CD
β-CD
γ-CD
CB[6]
CB[7]
CB[8]
129.5[12]
18.4[12]
249.2[12]
<0.1
4.4
<0.2
DES solubility Enhancement
Macrocycle
mg/mL
>500
>1000
>1000
1.0
factor
>3.5
>55
>4
10
3.9
α-CD
β-CD
γ-CD
CB[6]
CB[7]
CB[8]
CB[5] and CB[7] share similar solubilities as do the even ho-
mologues, i.e. CB[6] and CB[8]. Both CDs and CB[n]s are
generally insoluble in organic solvents and thus far have only
been reported to be soluble in water. While CDs have been
shown to be stable in alkaline media, they are readily hy-
drolyzed in acidic conditions, whereas CB[n]s are reported
to be stable in strong acidic environments.
17
2.0
10
To date, strategies to enhance the solubility of both
macrocycles have been either through functionalization on
their periphery, encapsulation of a guest molecule inside the
cavity or through dissolution in an aqueous solution with an-
other component such as NaCl for CB[n]. The poor solu-
bility of both CDs and CB[n]s is a longstanding issue and
Based on cavity size, price and (regulatory body) ap-
enhancing the solubility in a solvent other than water whilst proval status β-CD is the most widely used CD,[14] however,
retaining host-guest properties has been a significant aim for it has the poorest water solubility, Table 1. The solubility
many years. One rational for enhancing the solubility of a enhancement in DES is greatest for β-CD at >55x, a sub-
macrocycle is to increase the number of solvent–macrocycle stantial increase that will undoubtably have an impact on the
interactions. Therefore, our strategy was based on increas- industrial applications of β-CD.
ing the number of solvent-macrocycle interactions through
Unlike CDs, values related to the solubility of CB[n]s in
selection of a solvent, which not only had excellent solu- different solvation environments is not as well documented
bilization properties but was also likely to interact with the in the literature. Therefore, the solubility of each CB[n] (n =
macrocycle directly and thus achieve an enhancement of the 6–8) homologue was initially studied in a variety of com-
overall solubility.
monly used media, Table S1 (supporting information), as
On account of many reports detailing their excellent sol- well as in ChCl-urea DES, Table 2. All CB[n] homologues
ubilization properties, DES were considered as a potential showed a significant solubility enhancement at room temper-
alternative solvent.[3–5] Moreover, the binding of ChCl to ature in the ChCl-urea DES than in water: CB[7] by almost
CB[7] has been reported in the literature by Macartney and a factor of 4 (4.4 vs 15 mg/mL) and CB[6] and CB[8] by
co-workers.[13] If the CDs and CB[n] were soluble in a DES a factor of 10 (<0.1 vs 1.0 mg/mL and <0.2 vs 2 mg/mL,
in which in one component (ChCl) is able to act as a weakly respectively) in ChCl-urea. It should be noted that the ChCl-
◦
bound guest, we believed the number of solvent–macrocycle urea DES is slightly basic (pH 10 at 20 C[15]) and CB[n]
interactions would increase and CDs and CB[n]s would ex- have not been reported previously to exhibit any solubility
hibit enhanced solubility in DES compared to an aqueous in basic environments. Considering the enhanced solubility
environment.
of CB[n] in acidic media, we also studied the solubility in
First, we studied the solubility of α-, β- and γ-CDs. In an acidic DES, ChCl-TsOH and found that the solubility of
all cases we found that CDs were soluble in ChCl-urea DES CB[7] and CB[8] was even further enhanced (see supporting
and the solubilities of each CD were significantly enhanced, information Table S1).
Table 2. For α-CD the solubility was >500 mg CD/mL
The ability to dissolve both CDs and CB[n] homologues
DES, however, in the cases of β and γ-CD, the solubility in a new medium with significant enhancement opens up a
was found to be >1 g/mL, which equates to a ≈ 50wt% so- plethora of new and exciting opportunities. The poor solubil-
lution of these CDs in the DES, a solubility that has never ity of both CD and CB[n] in water, and insolubility in most
before been achieved. We postulate that this huge enhance- organic solvents, limits many applications either on account
ment of solubility comes from the hydroxyl groups on the of low concentrations or poor solvent compatibility. From
exterior of the CD being able to interact with the hydrogen the solubilization of enhancements observed in Table 2 it
bonded network of the DES, which results in the CDs being was clear that the solvation environment of ChCl-urea DES
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is unique. DES have a highly ordered liquid structure com- ogous experiment with γ-CD was also conducted, Figure S7,
prising many hydrogen bonding interactions,[1] the enhanced and γ-CD showed the same homoternary binding behavior as
solubility of CB[n] and especially CDs is likely due to the CB[8].
ability of this network to include the macrocycles within the
liquid structure and stabilize such high amounts through fur-
ther hydrogen bonding interactions. For the solvation and
enhanced solubility of CDs and CB[n] in DES to be useful
within the field, the host–guest properties of the macrocycles
should ideally be preserved in this new solvation medium.
However, probing the binding properties of macrocycles in
DES is not as straightforward as in aqueous environments or
traditional organic solvents.
On account of the highly ionic nature of the solvent,
1H NMR cannot be utilized, similarly, the viscosity of
ChCl-urea is higher than water and thus isothermal titration
calorimetry (ITC) cannot be readily conducted at room tem-
perature. Cyclic voltammetry (CV) was attempted and in-
dicated that some binding event occurred with both CB[7]
and CB[8], Figures S8 and S9, respectively. Considering
these limitations, we decided to probe binding further us-
ing UV/vis spectroscopy. To do so, we needed to identify a
guest that had a characteristic UV/vis profile and would bind
to both CDs and CB[n]. The interaction of alkylviologens
with both CDs and CB[n] is widely reported in the litera-
ture, therefore we chose methylviologen, the simplest and
most studied alkylviologen.
In its dicationic form MV2+ is reported to bind 1:1 to
both CB[7][16,17] and CB[8][18,19] but does not show any in-
teraction with either β- or γ-CD.[18] However, methylviolo-
gen is a redox active molecule that can reversibly undergo
two consecutive one electron reductions to form a monoca-
tionic radical species, MV·+ or a fully reduced MV0 species.
In aqueous environments the monocationic radical species
MV·+ is reported to bind 1:1 with CB[7][16,17] and β-CD[20]
and 2:1 with CB[8][19] and γ-CD.[21] Therefore, we decided
to study the behavior of MV·+ in the presence of both CDs
(β- and γ) and CB[n] (n = 7 & 8) using UV/vis spectroscopy.
Initially, we studied the 1:1 complexes of MV·+ with
CB[7] and β-CD. For CB[7] we saw that there was a su-
pression of the absorbance at 609 nm upon the addition of
CB[7], Figure S6 (supporting information) which indicates
that binding of MV·+ is occurring.[17] Unfortunately, we
were not able to observe this with β-CD as the required
concentration was too high to allow us to obtain a UV/vis
spectrum. Shown in Figure 2, the introduction of CB[8] to a
MV·+ solution resulted in a color change from blue to purple
and a pronounced change in the UV/vis spectra. This color
change is a result of the formation of the MV·+ dimer inside
the CB[8] cavity. The MV·+ peak at 609 nm decreases in
intensity and shifts to 605 nm upon addition of CB[8] with
concomitant appearance of a peak at 557 nm corresponding
to the formation of the dimer. Furthermore, the addition of
a competitive guest for CB[8], 1-adamantylamine (Ada), to
the solution results in a shift back to a blue solution as the
MV·+ species have been displaced from the CB[8] cavity
and the CB[8]·(MV·+)2 complex no longer exists. An anal-
Figure 2 UV/vis spectra of MV·+ in ChCl-urea DES (blue line), in
the presence of CB[8] (purple line) and upon the addition of Ada
(green line).
In conclusion, we have reported the dissolution of CD
and CB[n] macrocycles in a novel class of deep eutectic
solvents. The solubility of CDs (α-, β- and γ) and CB[n]
(n = 6 – 8) are found to be significantly enhanced in ChCl-
urea compared to aqueous environments. The ability to dis-
solve both CD and CB[n] macrocycles in this new solvent
at higher concentrations opens up many exciting possibili-
ties as well as significantly enhancing the current industrial
use of CDs (especially β-CD) and future use of CB[n]s. Fi-
nally, we demonstrate that CD and CB[n] retain their host-
guest chemistry in the new solvation environment as shown
through UV/vis spectroscopy with a model guest, MV·+.
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Significantly high solubilities of CDs
(α, β & γ) and CB[n] (n = 6, 7, &
8) are exhibited in a choline chloride
(ChCl)-urea DES. β & γ CDs were
soluble at > 1 g/mL DES resulting
in 50 wt% solutions, additionally, the
solubility of CB[n] were also found
to be significantly enhanced extending
the range of CB solubility into alka-
line media for the first time. The host-
guest chemistry of these macrocycles
is maintained upon dissolution in these
highly ordered solvents.
Supramolecular DESolution
Jade A. McCune, Susanna Kunz, Mag-
dalena Olesin´ska and Oren A. Scher-
man
DESolution of CD and CB macrocy-
cles
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