Acyclic cucurbit[n]urils capped with alkylene linkers: synthesis and molecular recognition properties

SUPRAMOLECULAR CHEMISTRY

https://doi.org/10.1080/10610278.2018.1539228

ARTICLE

Acyclic cucurbit[n]urils capped with alkylene linkers: synthesis and molecular

recognition properties

Shweta Ganapati and Lyle Isaacs

Department of Chemistry & Biochemistry, University of Maryland, College Park, MD, USA

ABSTRACT

ARTICLE HISTORY

We report the synthesis and characterization of three new acyclic cucurbit[n]uril-type receptors that

feature a covalent capping group in the form of an alkylene linker (2a – 2c) that we hypothesized

would have higher binding aﬃnity toward alkylammonium ions in water. Hosts 2a – 2c have lower

aqueous solubility (≤2 mM) than the prototypical acyclic CB[n]-type host 1 (346 mM). Hosts 2a – 2c do

not undergo signiﬁcant intermolecular self-association over the experimentally accessible concen-

Received 15 August 2018

Accepted 5 October 2018

KEYWORDS

Cucurbit[n]uril (CB[n]); host-

guest chemistry;

preorganization; cation

receptors; ammonium ions

1

tration range. In contrast, the results of H NMR experiments shows that the alkylene linkers of 2b and

2

c undergo self-inclusion and that this process is reversed upon addition of ammonium ions 6–10 as

guests. The host•guest K values were determined for hosts 1 and 2a – 2c toward guests 6–10 by

isothermal titration calorimetry. We ﬁnd that 2a – 2c bind less strongly toward guests 6–10 than host

a

1

due to the energetic penalty associated with expulsion of the alkylene linker from its own cavity.

Introduction

can be used for a variety of applications including

chemical sensors, supramolecular catalysis, supramole-

cular polymers, drug solubilization, gold sequestration,

molecular machines, and the stabilization of reactive

species (3). We, and others, have been particularly inter-

ested in an alternative class of molecular containers

known as cucurbit[n]urils (CB[n], Figure 1) (4). CB[n]

are formed by the condensation of glycoluril with for-

maldehyde under strongly acidic conditions that gen-

erate a homologous series of compounds (n = 5, 6, 7, 8,

The preparation of new macrocyclic compounds that

function as hosts for complementary guest molecules in

organic and aqueous solution remains a core activity of

supramolecular chemistry (1). The purpose of these

studies is to discover new host systems and investigate

their host•guest recognition properties as a means to

improve our fundamental understanding of non-cova-

lent interactions (e.g. H-bonds, electrostatic interac-

tions, π-π interactions, hydrophobic eﬀect) and enable

new applications. Accordingly, much research has been

directed toward a variety of macrocyclic host systems

including cyclophanes, cyclodextrins, calixarenes, pillar-

arenes, bambusurils, and self-assembled hosts (2) which

1

0, 13–15) whose recognition properties are deﬁned by

two symmetry equivalent ureidyl carbonyl portals and a

central hydrophobic cavity (5). For example, CB[n] com-

pounds are well known to complex hydrophobic (di)

17

−1

cations with high aﬃnity (K up to 10 M ), high

a

CONTACT Lyle Isaacs

LIsaacs@umd.edu

Department of Chemistry & Biochemistry, University of Maryland, College Park, USA

©

2018 Informa UK Limited, trading as Taylor & Francis Group

2

S. GANAPATI AND L. ISAACS

selectivity, and to respond to appropriate environmen-

tal stimuli (e.g. chemical, pH, electrochemical, photo-

chemical) (4b , 6 ). Accordingly, CB[n] compounds have

been used in a wide range of applications, including

supramolecular materials for art conservation, drug

delivery, sensing ensembles, drug reversal, molecular

machines, and supramolecular organic frameworks (7).

Researchers have developed methods to prepare deri-

vatives of macrocyclic CB[n] (8) as a means to improve

their aqueous solubility and enable their attachment by

click chemistry to materials, polymers, assemblies, and

even DNA as a route to new applications including

materials for protein puriﬁcation, as supramolecular

Velcro, to monitor vesicle fusion, (targeted) drug deliv-

ery, and for theranostic applications (8b , 9).

aromatic walls, glycoluril oligomer length (e.g. monomer

– tetramer), and length of the alkyl chain connecting (e.g.

(CH ) , n = 2, 3, 4) the solubilizing group to the arom atic

2

n

wall on their molecular recognition properties (10b , 12 ).

From these studies, we found that hosts comprising a

longer glycoluril oligomer (e.g.: tetramer), larger aromatic

walls (e.g.: substituted naphthalene), and negatively

charged solubilizing groups (e.g.: sulfonate as compared

to neutral or positive groups) lead to more potent mole-

cular hosts with higher binding aﬃnities towards guests

such as hydrophobic diammonium cations. In this paper,

we explore the recognition properties of a series of hosts

(2a – 2c, Scheme 1 ) that are related to 1 but that feature a

covalent alkylene linker (e.g. (CH ) , n = 2, 4, 6) connection

2

n

between adjacent sidewalls (e.g. a capping group). We

hypothesized that such capped acyclic CB[n] would be

more eﬀectively preorganized, display higher aﬃnity and

selectivity toward its best guests, and therefore be better

suited for application as a sequestration agent. Herein, we

present the results of this study.

Previously, based on our synthetic and mechanistic

knowledge of the CB[n] forming reaction, our group

designed and synthesized acyclic CB[n]-type receptors

(e.g. 1, Figure 1 ) that are composed of a central glycoluril

tetramer, two aromatic sidewalls, and four sulfonate solu-

bilizing groups (10). Despite its acyclic nature, host 1 is

nicely preorganized into a C-shape by virtue of the sup-

porting polycyclic ring system and therefore retains the

essential molecular recognition properties of macrocyclic

CB[n] (10d). Host 1 has high aqueous solubility (346 mM)

and excellent biocompatibility. Accordingly, we investi-

gated the use of 1 and analogues in biomedical applica-

tions including as a solubilizing excipient for insoluble

drugs and as a reversal agent for neuromuscular blocking

agen ts (NM BAs) and drugs of abuse (methamphetamine)

Results and discussion

This results and discussion section is organized as fol-

lows. First, we describe the design and synthesis of

hosts 2a – 2c (Scheme 1) as well as their aqueous

solubility and self-association properties. Second, we

gleen aspects of the conformational properties of

1

uncomplexed 2 by H NMR spectroscopy and report

(

7d , 10a , 11 ). Because 1 is prepared by a building block

the results of qualitative host-guest binding studies.

Third, we perform quantitative binding studies by iso-

thermal titration calorimetry between hosts 2a – 2c and

guests 6–10 (Figure 2). Finally, we relate the trends in

the ITC binding data to structural changes induced by

the alkylene capping groups.

synthesis involving glycoluril oligomer and aromatic wall,

we have conducted several structure-recognition prop-

erty relationship studies. For example, the Isaacs and

Sindelar groups have studied the inﬂuence of the nature

–

+

of the solubilizing groups (e.g. SO₃vs NH₃vs OH),

Figure 1. Chemical structures of cucurbit[n]urils (CB[n]) and acyclic CB[n]-type container 1.

SUPRAMOLECULAR CHEMISTRY

3

Scheme 1. Synthesis of hosts 2a – 2c.

substitution reaction between glycoluril tetramer bis

cyclic ether) building block (5) and the corresponding

dialkoxybenzene sidewall in hot CF CO H (10a). The

(

3

2

high binding aﬃnity of 1 toward various hydrophobic

ammonium cations can be attributed to its electrosta-

tically negative ureidyl carbonyl portals which engage

in ion-dipole interactions, its hydrophobic cavity which

engages in π-π interactions and the hydrophobic eﬀect,

−

and its SO₃groups which impart high water solubility

and engage in ion-ion interactions with its guests. In

designing congeners of 1 we wanted to preserve the

carbonyl portals, aromatic walls, and sulfonate solubiliz-

ing groups to maintain the recognition properties and

aqueous solubility of 1, while improving the preorgani-

zation of the cavity size of the acyclic host by locking

the distance between sidewalls and providing addi-

tional binding surfaces to complement the guest. We

hypothesized that the binding aﬃnity of 1 toward

Figure 2. Chemical structures of guests used in this study.

Design and synthesis of hosts 2a – 2c

We have previously reported that the synthesis of 1

proceeds by the double electrophilic aromatic

4

S. GANAPATI AND L. ISAACS

hydrophobic cations could be increased by incorpora-

tion of a covalent alkylene capping group on one face

of the host as manifested in 2a – 2c (Scheme 1).

2a, 2b, and 2c as 1.8 mM, 1.5 mM, and 1.7 mM respec-

tively in 20 mM sodium phosphate buﬀered D O at pD

2

7.4 at room temperature. This large decrease in aqu-

eous solubility was unexpected, but can be attributed

to the loss of two solubilizing sulfonate groups per host

and the addition of the hydrophobic alkylene ((CH ) ,

The preparation of 2a – 2c required the synthesis of

a new series of aromatic wall building blocks that fea-

ture covalent alkylene connections. For this purpose,

we reacted hydroquinone with 1,n-dibromoalkanes

under basic conditions (CH CN, K CO ) to yield com-

2

n

n = 2, 6, 10) linkers into 2a – 2c. While this reduced

aqueous solubility makes 2a – 2c less attractive for use

in biological systems relative to 1, we nevertheless

decided to investigate the eﬀect of the alkyl linker on

the self-association properties and the molecular recog-

nition properties of these hosts toward some common

guests for CB[n].

3

2

3

pounds 3a – 3c in modest yields (13%, 50%, and 33%,

Scheme 1) (13). Subequently, 3a – 3c were separately

alkylated with 1,3-propanesultone under basic condi-

tions (NaOH) in aq. THF or dioxane to deliver the

required covalently connected sidewalls 4a – 4c in

8

7%, 77%, and 47% yields, respectively (Scheme 1 ).

With the required aromatic wall building blocks in

hand we proceeded to explore the double electrophilic

aromatic substitution reaction with glycoluril tetramer

Self-association properties of hosts 2a – 2c

In order for molecular containers to function as good

hosts in water they must not undergo strong self-asso-

ciation which would prevent host•guest binding. The

5

. When a mixture of tetramer 5 and aromatic wall 4

was heated in a 1:1 mixture of triﬂuoroacetic acid and

acetic anhydride at 70 °C, we obtained the targeted

alkylene capped containers 2a, 2b, and 2c in 33%,

−

1

self-association of 1 (K = 47 M ) has been previously

s

1

studied by dilution experiments monitored by H NMR

1

3%, and 26% yield, respectively. The puriﬁcation of

spectroscopy and ﬁtted to a 2-fold self-association

model (10a). When acyclic CB[n]-type containers aggre-

gate, typically the resonances for the aromatic rings

shift upﬁeld due to cavity inclusion. For 1 and analo-

hosts 2a – 2c proceeded by ion exchange chromato-

graphy on Dowex® 1 × 2 (chloride form, 200–400 mesh

ion exchange resin) which contains quaternary ammo-

nium ion functional groups that electrostatically bind to

the dianionic hosts. The new hosts were fully character-

ized by spectroscopic methods. For example, all three

containers show ions in the high resolution negative

ion mode electrospray ionization mass spectra that can

gues measured to date the K values are generally lower

s

−

1

than 1000 M which has been attributed to electro-

static repulsion between the tetraanionic molecules

upon putative aggregation processes (15). We per-

1

formed analogous H NMR dilution experiments over

2-

13

be assigned to the [M – 2Na] species. The C NMR

spectra display the number of resonances (2a: 26; 2b:

the accessible concentration range (1.0–0.1 mM) in

20 mM sodium phosphate buﬀered D O at pD 7.4 at

2

8; 2c: 30) expected given the top-bottom dissymmetry

room temperature (Supporting Information) for 2a – 2c

we did not observe any signiﬁcant changes in chemical

shift that would be indicative of self-association.

Accordingly, we conclude that 2a – 2c are monomeric

over this concentration range as required for the

detailed binding studies described below.

and overall C -symmetric nature of 2a – 2c. Similarly,

the H NMR spectra display resonances that can be

attributed to the six chemically distinct CH -groups

that connect two glycolurils and a glycoluril with a

sidewall as expected for the top-bottom dissymmetric

s

1

2

and overall C -symmetric structure of 2a – 2c

Although we conclude that the intermolecular asso-

ciation in 2a – 2c is low, we did note some concentra-

tion independent intramolecular features in the H NMR

s

(Supporting Information).

1

spectra of our hosts which suggest the partial inclusion

of the alkylene linker within the hydrophobic cavity of

each host molecule. For example, Figure 3(b) shows the

Solubility properties of hosts 2a – 2c

The use of molecular containers for biological applica-

tions such as drug reversal and drug solubilization

requires good inherent solubility in water of the

uncomplexed hosts and their host•guest complexes

1

H NMR spectrum of host 2b in which the resonances of

the methylene protons of the linker H , H , and H are

f

e’

e

shifted upﬁeld by 0.5 ppm relative to their resonances

in 4b (Supporting Information). This can be explained

by the alkylene linker of 2b being bound within the

magnetic shielding environment inside the cavity of 2b

driven by the hydrophobic eﬀect of the self-ﬁlling the

(3c , 7c, 10d, 14) Previously, we determined the inherent

solubility of 1 as 346 mM in H O and 105 mM (D O,

2

1

20 mM sodium phosphate buﬀer, RT, pD 7.4) by H

NMR integration of host resonances versus resonances

of an internal standard of known concentration. In

analogous manner we determined the solubilities of

cavity. The resonance for H is not signiﬁcantly diﬀerent

g

between 2b and 4b indicating that its magnetic

SUPRAMOLECULAR CHEMISTRY

5

1

Figure 3. H NMR spectra recorded (400 MHz, RT, 20 mM sodium phosphate buﬀered D O, pH 7.4) for: (a) 8 (1 mM), (b) 2b (1 mM),

2

(c) a mixture of 2b (0.5 mM) and 8 (0.5 mM), and (d) 2b (0.5 mM) and 8 (1.0 mM).

environment is unchanged and it does not enter the

cavity of 2b. A similar eﬀect is observed for host 2c, in

which the resonances of all the methylene protons of

uncomplexed 2b. Interestingly, 2b assumes a splayed

geometry in which one of the aromatic rings is dis-

placed downward and the other is displaced upward

creating a helical twist. As a result, the hexylene linker

of 2b partially threads through the cavity; at the same

time the downward displaced aromatic ring folds

inwards to partially ﬁll the cavity. As can be readily

the alkyl linker (except the ArO-CH resonances) are

2

upﬁeld shifted by 0.2–0.6 ppm relative to their reso-

nances in 4c (Supporting Information). Figure 4 shows a

stereoview of an MMFF minimized model of

Figure 4. Cross-eyed stereoviews of an MMFF minimized molecular model of uncomplexed host 2b. Color code: C, grey; H, white; N,

blue; O, red; S, yellow.

6

S. GANAPATI AND L. ISAACS

seen from Figure 4 , the central protons of the hexylene

linker are nearby the face of an aromatic sidewall.

Since the decyl linker is longer and has more degrees

of freedom than the hexyl linker we observed a broad-

with hosts containing alkyl linkers (2a – 2c) was generally

less than or equal to the upﬁeld shifting of the same

resonances in the complexes with host 1. This preliminary

observation suggests that in most cases the cavity of host

1 better accommodates or binds more strongly to guests

6–10 as compared to the cavities of 2a – 2c. All of the

host•guest complexes display fast kinetics of exchange

1

ening of the H NMR signals of the protons in the linker of

2c as compared to the sharper resonances of those in 2b.

The decyl linker also penetrates more fully into its own

cavity relative to the hexyl linker on account of its longer

length, as is evidenced by the larger upﬁeld shifts of its

methylene protons at the mid-point of the linker. In case

of host 2a, the linker is shortest (ethyl group) and the

methylene groups are both directly attached to the

O-atoms on the aromatic walls of the host. Two well-

resolved resonances are observed for the diasterotopic

linker protons in 2a at 4.47 ppm and 3.87 ppm respec-

tively. The resonance at 3.87 ppm is shifted upﬁeld by 0.5

1

on the H NMR timescale which suggests that these

complexes would be of moderate stability in water. As

additional evidence of cavity self-inclusion of the alkylene

linkers, we observe that the binding of guests 6–10 to

hosts 2a – 2c results in the downﬁeld shifting of the

resonances of the alkylene linker protons because cavity

binding of the guest displaces the alkylene linkers from

1

the cavity of the host. For example, the H NMR spectrum

of the 2b•8 complex is presented in Figure 3(c ). The

resonances of the aromatic protons H , H , H of 8

1

ppm relative its position in the H NMR spectrum of 4a

b

c

d

(

Supporting Information) which indicates that this set of

undergo upﬁeld shifting in its complex with 2b as a result

of the anisotropic environment of the aromatic walls of

the host when the host and guest are combined in a 1:1

ratio. Upon adding excess guest (2:1 ratio) we observe

that the peak corresponding to H , H , and H protons

protons is experiencing a diﬀerent magnetic environ-

ment, potentially from the anisotropic eﬀect of the aro-

matic walls of the host. The other set of protons is

probably downﬁeld shifted due to their orientation with

respect to the ureidyl C = O portals which constitute a

deshielding region (4a, 16). This phenomenon of the

alkylene linker of hosts 2a – 2c interacting with or

being partially included within their cavities is expected

to create an energetic penalty for guest molecules to be

included within their cavities. In the following sections

we investigate the binding properties of 2a – 2c toward a

series of ammonium ion guests and qualtitatively assess

the thermodynamic cost of this phenomenon.

b

c

d

(Figure 3(d )) shifts to a position which is the average

between the free (Figure 2(a )) and bound (Figure 3(c))

forms of the guest. This indicates a fast kinetics of

exchange between free guest 8 and the 2a·8 complex

1

relative to the H NMR chemical shift time scale. The

same trend is observed for the H methylene protons of

a

8 in free and bound form which experience the shielding

eﬀect of the cavity of the host when bound to 2b. The

resonances of the aromatic protons of host 2b, H and H

v

u

also undergo upﬁeld shifting in the 2b·8 complex. We

believe that this change reﬂects the change in orientation

of the two aromatic sidewalls with respect to one another

as the cavity that was previously ﬁlled with the linker

becomes ﬁlled with the guest; the presence of the aro-

matic ring of guest 8 may also play a role (10b).

1

H NMR investigation of the binding of 1 and 2a –

c toward guests 6–10

2

Initially, we tried to investigate the ability of hosts 2a – 2c

to bind typical dicationic guests known to bind to CB[n]

such as 1,6-hexanediammonium ion, trans-1,4-cyclohex-

anediammonium, and p-xylene diammonium ion. We

found that the complexes of these dicationic guests

with our dianionic hosts 2a – 2c precipitated from aqu-

eous solution which precluded detailed H NMR investi-

gations. We rationalize this precipitation as

consequence of the formation of a zwitterionic host-

guest complex which would have lower aqueous solubi-

lity. Therefore, we decided instead to study the water

soluble complexes of monocationic guests 6–10 with

Interestingly, H and H each appear as doublets

v u

(J = 9.0 Hz) in the 2b·8 complex. The other noteworthy

change in the spectrum of 2b occurs to the resonances of

the H , He’, and H protons of the linker. In the spectrum

f e

1

of the 2b·8 complex these protons are shifted downﬁeld

by 0.5 ppm relative to their positions in free 2b, at the

same positions where they were observed in the spec-

trum of 4b (Supporting Information). This downﬁeld shift

indicates that the presence of guest 8 in the cavity of

host 2b necessitates the displacement of the hexyl linker

from the cavity of 2b. Analogous phenomena were seen

a

1

hosts 1 and 2a – 2c by H NMR spectroscopy. In each

1

of these cases, upon host•guest complexation we

observe upﬁeld shifting of many guest resonances

which indicates that these protons on the gu est are

located in the cavity of the host molecule (4a , 5a , 16 ).

The upﬁeld shifting of guest resonances in the complexes

in the H NMR spectra recorded for the remaining host-

guest complexes.

One further aspect of the host•guest complexes

between 2a – 2c and guests 6–10 deserves comment.

Because the hosts are top-bottom dissymmetric and the

SUPRAMOLECULAR CHEMISTRY

7

SO ^-

SO₃^-

3

NH

3

H N

3

Alkylene

Linker

2

•8 (top diastereomer)

2•8 (bottom diastereomer)

Figure 5. Cartoon representation of the top and bottom diastereomers of the 2•8 complex.

guests are monoammonium ions and therefore have

two ends, two diﬀerent diastereomeric complexes are

possible as indicated in Figure 5 (17). In one diastereo-

mer, the ammonium ion resides at the portal contain-

ing the alkylene linker whereas in the other

diastereomer the ammonium ion resides at the sulfo-

nated portal and the hydrophobic residue points

toward the alkylene linker at the other portal. We

posit that the top diasteromer is preferred because it

would beneﬁt from sulfonate-ammonium electrostatic

interactions and also van der Waals interactions

between the guest hydrophobic residue and the alky-

1

lene linker. Unfortunately, because the H NMR spectra

indicate a fast exchange on the chemical shift time-

scale, we cannot diﬀerentiate between these diﬀerent

possibilities experimentally.

Measurement of binding aﬃnities of hosts 1 and

2a – 2c toward guests 6–10 by isothermal

calorimetry (ITC)

Given the high binding constants exhibited by CB[n]-

1

type containers toward their guests, direct H NMR

titrations to determine K are not generally reliable

a

(

5e , 16 ). To avoid the need to perform competition

1

Figure 6. (a) ITC thermogram recorded during the titration of

experiments (e.g. H NMR or UV/Vis) we decided to

turn to ITC for direct measurements of the thermody-

namic parameters of binding. For example, Figure 6

shows the thermogram recorded for the titration of

2

b (0.1 mM) in the cell with 8 (1.0 mM) in the syringe. (d)

Fitting of the data to 1:1 binding model with

a

6

−1

K = (1.6 ± 0.1) × 10 M .

a

2

b (100 μM) in the cell with 8 (0–200 μM) which was

Discussion of the thermodynamic parameters

ﬁtted with the MicroCal PEAQ-ITC analysis software to

deliver K_a= (1.6 ± 0.1) × 10 M and Δ H = –

6

−1

A perusal of the binding constant and ΔH values col-

lected in Table 1 reveal a number of trends that are

−1

9.5 ± 0.1 kcal mol for the 2b•8 complex. Table 1

presents the values of K and ΔH measured for the

worthy of comment. First, the K values measured for

a

remaining complexes between hosts 1 and 2a – 2c

and guests 6–10 that were determined analogously

the various hosts and guests in this study ranged from

6.2 × 10 to 6.2 × 10 M . Host 1 is the most potent

host in this series (low μM to high nM aﬃnity) and

3

6

−1

(Supporting Information).

8

S. GANAPATI AND L. ISAACS

Table 1. Thermodynamic parameters determined by ITC for the interaction between molecular containers 1, 2a – 2c and guests 6–10.

−1

K

a

(M ) and ΔH (kcal mol ) values

Hosts: 1

2a

2b

2c

6

3

5

6

5

4

Guests: 6

(2.4 ± 0.1) × 10

(6.2 ± 0.9) × 10

–3.9 ± 0.4

(2.3 ± 0.2) × 10

–8.7 ± 0.1

(2.1 ± 0.1) × 10

–11.3 ± 0.2

(2.7 ± 0.6) × 10

–4.5 ± 0.5

(1.3 ± 0.1) × 10

–5.5 ± 0.1

(7.9 ± 0.1) × 10

–8.6 ± 0.02

(1.6 ± 0.1) × 10

–9.5 ± 0.1

(7.2 ± 1.0) × 10

–3.9 ± 0.2

(2.3 ± 0.2) × 10

–5.0 ± 0.2

(3.2 ± 0.3) × 10

–6.0 ± 0.2

(7.1 ± 0.4) × 10

–8.5 ± 0.1

(1.5 ± 0.04) × 10

–6.5 ± 0.1

(2.7 ± 0.2) × 10

–5.7 ± 0.1

–

8.7 ± 0.1

(1.7 ± 0.1) × 10

8.2 ± 0.04

(3.9 ± 0.2) × 10

10.5 ± 0.03 ₅

(4.9 ± 0.2) × 10

7.1 ± 0.1

(6.2 ± 0.6) × 10

9.0 ± 0.1

4

7

8

9

–

4

–

6

5

10

(6.9 ± 0.3) × 10

–6.9 ± 0.1

(1.3 ± 0.03) × 10

–9.6 ± 0.04

–

displays higher K values toward virtually all of the

guests compared to the capped hosts 2a – 2c. Among

the capped hosts, 2b performs best and binds guests

aﬃnity, but low selectivity nature of host 1 was pre-

viously put to good use through the solubilization of

water insoluble anticancer agents (10b). We were some-

what surprised that we did not see a trend in binding

aﬃnity related to guest size across the series from

narrow guest 6 to bulky guest 10 for 2a – 2c as is

observed for macrocyclic CB[n] because we presumed

that the covalent caps would hold the aromatic walls in

a more well deﬁned and preorganized geometry.

Unfortunately, Nature had other ideas and the host

assumed the self-included geometry shown in

Figure 4. Despite the low selectivity of these hosts,

several trends in binding aﬃnity can still be gleaned.

First, guests 10 and 8 are the tightest binders toward

hosts 1 and 2a – 2c. This is perhaps unsurprising given

the well known complementarity between the methy-

lene bridged glycoluril oligomer backbone of CB[n] and

the roughly spherical surface of adamantanes that leads

to ultratight (up to 10 M ) binding toward CB[7] (4d,

6a ). Compound 8 with its aromatic ring is a preferred

guest presumably because it beneﬁts from enthalpically

favorable π-π in the host•guest complexes. This inter-

pretation is reinforced by the observation of largest

enthalpic driving forces for the host•8 complexes

(Table 1 ). A comparison of the binding aﬃnity of

guest 9 and 10 reveals that all four hosts prefer the

quaternary guest 10 by factors ranging from 2- to 18-

fold. Related diﬀerences have been observed in the

binding behavior of CB[7] and have been interpreted

to result from the ability of the quaternary ammonium

to engage in more and better ion dipole interactions

with the ureidyl C = O portals of the host (6b , 18 ).

Finally, we note that all of the complexation events

a

6

–8 and 10 only 2–18-fold weaker than 1; 2b even

binds guest 9 1.5-fold stronger than 1. Toward this

panel of guests, host 2c with a decylene linker performs

signiﬁcantly worse than 1 with K diﬀerences in the 20-

a

to 100-fold range. Finally, host 2a with an ethylene

linker is the least potent host with K values that are

a

generally 2 orders of magnitude weaker than 1. Clearly,

the inferiority of 2a – 2c compared to 1 is caused by the

introduction of the covalent alkylene caps. We suggest

the reasons are multifaceted. First, hosts 2a – 2c are

dianionic whereas host 1 is tetranionic which decreases

the electrostatic driving force for host•guest complexa-

tion with 2a – 2c. Second, as shown in Figure 4 , the

presence of the covalent capping group results in a

helical twist to the acyclic CB[n]-type receptor that

prompts the alkylene linker to thread through the cav-

ity rather than acting as a true capping group. A related

eﬀect has been previously identiﬁed crystallographically

for a naphthalene walled acyclic CB[n]-type receptor

15

−1

(12b). This intramolecular self-inclusion of the linker

for 2b and 2c is energetically favorable; the energetic

cost of explusion of the linker from the cavity must

therefore be paid during the host•guest complexation

step. The 5–48 fold higher binding aﬃnities of hexylene

capped 2b compared to 2c most likely reﬂects the

larger energetic penalty associated with expulsion of

the longer more hydrophobic decylene linker. The

very poor performance of 2a probably reﬂects that

the short ethylene linker deforms the cavity by sterically

preventing ammonium complexation at one portal and

splaying the ureidyl carbonyls at the other portal which

would reduce the potent ion-dipole driving force which

is well known for CB[n] hosts (4e, 16).

listed in Table

1

are enthalpically favorable.

Enthalpically favorable complexation is typically seen

with cyclophanes and with CB[n] where it is attributed

to a non-classical hydrophobic eﬀect involving the

release of intracavity waters that do not possess a full

complement of H-bonds (4e, 8g , 19 ). In the present

case, given that the cavities of 2a – 2c are partially

Individually, these hosts do not display high selectiv-

ity toward this series of guests (6–10) with the spread

of K values covering a relatively small range (Host 1: 13

a

fold; 2a: 11-fold; 2b: 12-fold; 2c: 18-fold). The high

SUPRAMOLECULAR CHEMISTRY

9

ﬁlled with their alkylene linkers the enthalpic driving

force also reﬂects the diﬀerence between the intramo-

lecular host-host contacts and the intermolecular host-

guest contacts in the complexes. Finally, the strain

energy associated with the helical distortion of uncom-

plexed host will be gained upon complexation.

Synthetic procedures and characterization data

Compound 3a. A mixture of hydroquinone (17.55 g,

1

3

59 mmol) and potassium carbonate (44.00 g,

18 mmol) in acetonitrile (123 mL) was heated to 85°C

under N . 1,2-dibromoethane (3.0 g, 1.4 mL, 15.9 mmol)

2

was added dropwise and the reaction was stirred for

1

2 h. The reaction mixture was cooled and ﬁltered and

the ﬁltrate was evaporated under reduced pressure to

obtain the crude solid product. This crude product was

washed with water (375 mL) and recrystallized from

ethanol (75 mL) to obtain 3a as an oﬀ white solid

(0.51 g, 2.1 mmol, 13%). M.p. = 212–214°C. IR (ATR,

Conclusions

Three new hosts 2a – 2c were synthesized with alkylene

linkers of diﬀerent lengths (ethyl, hexyl, and decyl) that

were designed to cap one portal of the acyclic CB[n]-

type skeleton and thereby preorganize the system.

These new hosts were less water soluble than 1 due

to the loss of two sulfonate groups and did not

undergo intermolecular self-association. However, the

intramolecular self-inclusion of the alkyl linkers inside

the cavity of these hosts thwarted our attempts at

increased preorganization and instead led to decreased

binding aﬃnities toward guests relative to 1. Future

work will try to overcome these disadvantages in the

solubility and molecular recognition properties of 2a –

−

1

cm ): 3365w(br), 2943 w, 1512s, 1452m, 1373w,

1268w, 1211s, 1109 m, 1081w, 1070m, 1011w, 954s,

1

943w, 831s, 813m, 756s. H NMR (600 MHz, DMSO):

8.91 (s, 2H), 6.78 (d, J = 8.9, 4H), 6.67 (d, J = 8.9, 4H),

13

4.14 (s, 4H). C NMR (150 MHz, DMSO, 1,4-dioxane as

internal reference): δ 151.4, 151.2, 115.8, 115.5, 67.0.

−

High-Res MS (ESI): m/z 245.0825 ([M – H] ), calculated

−

for C H O 245.0814.

1

4 13 4

Compound 3b. A mixture of hydroquinone (27.10 g,

246 mmol) and potassium carbonate (68.00 g,

492 mmol) in acetonitrile (190 mL) was heated to 85°C

2c by incorporating linkers with more rigidity and

hydrophilic groups that do not undergo self-inclusion

processes. Such linkers would lead to entropic gains

from the improved preorganization of the acyclic CB

under N . 1,6-dibromohexane (6.0 g, 3.8 mL, 24.6 mmol)

2

was added dropwise and the reaction was stirred for

12 h. The reaction mixture was cooled and ﬁltered and

the ﬁltrate was evaporated under reduced pressure to

obtain the crude solid product. This crude product was

washed with water (500 mL) and recrystallized from

ethanol (100 mL) to obtain 3b as an oﬀ white solid

[n] cavity and enthalpic gains from the favorable inter-

actions between the capping linker and encapsulated

guest; without the energetic penalty of self-inclusion or

loss in aqueous solubility.

(

3.66 g, 12.3 mmol, 50%). M.p. = 178–180°C. IR (ATR,

−

1

cm ): 3381w(br), 2944w, 2866w, 1506s, 1477m, 1452m,

Experimental section

1395w, 1374m, 1299m, 1221s, 1167m, 1104s, 1072w,

1

022s, 826s, 806m, 763s, 732m. H NMR (600 MHz,

General experimental details

DMSO): 8.85 (s, 2H), 6.72 (d, J = 8.9, 4H), 6.65 (d,

J = 8.9, 4H), 3.84 (t, J = 6.5, 4H), 1.72–1.63 (m, 4H),

Starting materials were purchased from commercial

suppliers and were used without further puriﬁcation.

Compound 1 and 5 were prepared according to litera-

ture procedures (10a). The synthesis of 3a, 3b, and 3c

from dibromoalkanes and hydroquinone were per-

formed by procedures similar to those reported in the

literature (13). The characterization data matches the

reported data. Melting points were measured on a

Meltemp apparatus in open capillary tubes and are

uncorrected. IR spectra were measured on a JASCO

FT/IR 4100 spectrometer and are reported in cm .

NMR spectra were measured on Bruker spectrometers

operating at 400 or 600 MHz for H and 200 MHz for

NMR. ITC data was collected on a Malvern Microcal

PEAQ-ITC instrument. Mass spectrometry was per-

formed using a JEOL AccuTOF electrospray instru-

ment (ESI).

13

1.48–1.38 (m, 4H). C NMR (150 MHz, DMSO): δ 151.5,

151.1, 115.7, 115.3, 67.8, 28.8, 25.4. High-Res MS (ESI):

−

m/z 301.1443 ([M – H] ), calculated for C H O

8 21 4

1

301.1440.

Compound 3c. A mixture of hydroquinone (11.00 g,

100 mmol) and potassium carbonate (27.64 g, 200 mmol)

in acetonitrile (160 mL) was heated to 85°C under N . 1,10-

2

dibromodecane (3 g, 2.2 mL, 10 mmol) was added drop-

wise and the reaction was stirred for 12 h. The reaction

mixture was cooled and ﬁltered and the ﬁltrate was eva-

porated under reduced pressure to obtain the crude solid

product. This crude product was washed with water

(500 mL) and recrystallized from ethanol (75 mL) to obtain

3c as an oﬀ white solid (1.18 g, 3.3 mmol, 33%). M.

−

1

13

C

−1

p. = 146–148°C. IR (ATR, cm ): 3420w(br), 2931w,

2917w, 2852w, 1509m, 1473w, 1451w, 1395w, 1371w,

1

0

S. GANAPATI AND L. ISAACS

1

(

299w, 1227s, 1168w, 1104w, 1048w, 822s, 767s. H NMR

600 MHz, DMSO): 8.84 (s, 2H), 6.72 (d, J = 8.9, 4H), 6.65 (d,

J = 8.9, 4H), 3.82 (t, J = 6.5, 4H), 1.64 (p, J = 7.0, 4H), 1.41–

1217s, 1115w, 1046s, 1029s, 827s, 768m, 731m. H NMR

(600 MHz, DMSO, 1, 4-dioxane as internal reference): 7.02–

7.00 (m, 4H), 7.00–6.98(m, 4H), 4.14 (t, J = 6.3, 4H), 4.05 (t,

J = 6.5 4H), 3.11–3.07 (m, 4H), 2.23–2.16 (m, 4H), 1.74 (p,

13

1

3

.34 (m, 4H), 1.34–1.22 (m, 8H). C NMR (150 MHz, DMSO,

, 4-dioxane as internal reference): δ 151.5, 151.0, 115.6,

15.3, 67.8, 28.9, 28.8, 28.7, 25.5. High-Res MS (ESI): m/z

57.2080 ([M – H] ), calculated for C H O 357.2066.

Compound 4a. A solution of 1,3-propanesultone

1.34 g, 11 mmol) in 1,4-dioxane (11 mL) was added to

13

J = 6.9, 4H), 1.44 (p J = 7.3, 4H), 1.39–1.30 (m, 8H). C NMR

(150 MHz, DMSO, 1, 4-dioxane as internal reference): δ

152.6, 152.6, 115.3, 115.2, 67.8, 67.1, 48.0, 29.0, 28.9, 28.8,

+

−

22 29 4

−

25.5, 25.4. High-Res MS (ESI): m/z 601.2131 ([M – 2Na +H] ),

−

(

calculated for C H NaO S 601.2141.

28

40

10 2

a solution of 3a (1.2 g, 4.1 mmol) in aqueous sodium

hydroxide solution (10 wt%, 9 mL). This mixture was

stirred at RT for 12 h and then ﬁltered to collect the

crude solid. The crude product was washed with acetone

Compound 2a. Compound 4a (1.8 g, 3.4 mmol) was

added to a solution of 5 (1.3 g, 1.7 mmol) in a mixture

of triﬂuoroacetic acid (130 mL) and acetic anhydride

(130 mL). This solution was stirred and heated at 70°C

for 3 h. The reaction mixture was cooled to room

temperature, treated with methanol (130 mL), and the

solvent was removed under reduced pressure to obtain

the crude product. The crude product was washed

three times with a mixture of water (50 mL) and acet-

one (100 mL). The dark orange colored solid obtained

was loaded onto a Dowex® 1 × 2 chloride form,

200–400 mesh ion exchange resin (50 g). The column

was eluted with increasing concentrations of hydro-

chloric acid (HCl) starting from plain water (750 mL) to

6M HCl (750 mL) to 12 M HCl (300 mL). The eluted

(

30 mL). The ﬁltered solid was dissolved in hot water

15 mL) and precipitated with ethanol (30 mL) to obtain

the oﬀ white solid 4a (1.91 g, 3.6 mmol, 87%). M.p. >300°

−1

C. IR (ATR, cm ): 3422w(br), 2942w, 2520w, 1512s,

1

450w, 1285w, 1201s, 1053s, 943m, 758m, 734m. H

NMR (600 MHz, D O): 7.06–7.04 (m, 4H), 7.04–7.02 (m,

2

4

2

H), 4.37 (s, 4H), 4.18 (t, J = 6.3, 4H), 3.13–3.09 (m, 4H),

13

.25–2.18 (m, 4H). C NMR (150 MHz, D O, 1, 4-dioxane

2

as internal reference): δ 152.3, 151.9, 115.9, 115.8, 67.0,

6

2

6.7, 47.3, 23.8. High-Res MS (ESI): m/z 489.0882 ([M –

−

Na +H] ), calculated for C H O S 489.0889.

20 25 10 2

1

Compound 4b. A solution of 1,3-propanesultone

7.7 g, 63 mmol) in tetrahydrofuran (152 mL) was

fractions were analyzed by H NMR and the almost

(

pure compound 2a was obtained in the fractions eluted

with 12 M HCl. This fraction was dried under reduced

pressure and washed with a mixture of water and

methanol (1:1, v/v, 100 mL). Finally, the solid obtained

was dissolved in water and the pH of the solution was

adjusted to 7 using aqueous sodium hydroxide (1M).

The solvent was removed under reduced pressure and

the solid was further dried under high vacuum to

obtain pure 2a as a light orange solid (0.72 g,

added to a solution of 3b (7.6 g, 25.2 mmol) in aqueous

sodium hydroxide solution (10 wt%, 76 mL). This mixture

was stirred at RT for 12 h and then ﬁltered to collect the

crude solid. The crude product was washed with acetone

(

200 mL). The ﬁltered solid was dissolved in hot water

100 mL) and precipitated with ethanol (200 mL) to

obtain the oﬀ white solid 4b (11.5 g, 9.4 mmol, 77%).

−1

M.p. >300°C. IR (ATR, cm ): 2941w, 2905w, 2870w,

−

1

1508s, 1475m, 1399w, 1289w, 1220s, 1188s, 1170s,

0.56 mmol, 33%). M.p. >300°C. IR (ATR, cm ): 3447w

(br), 1712s, 1466s, 1422m, 1377m, 1317s, 1228s, 1182s,

1

115m, 1050s, 1031s, 830s, 805m, 767s, 755m, 734m.

1

H NMR (600 MHz, D O): 7.03–7.00 (m, 4H), 7.00–6.98

1084m, 1036s, 974m, 926w, 794s, 760s, 731m. H NMR

2

(m, 4H), 4.16 (t, J = 6.3, 4H), 4.07 (t, J = 6.5, 4H), 3.13–

(600 MHz, D O): 7.17 (d, J = 9.0, 2H), 7.05 (d, J = 9.0, 2H),

2

3

1

.07 (m, 4H), 2.24–2.16 (m, 4H), 1.82–1.75 (m, 4H), 1.54–

.50 (m, 4H). C NMR (150 MHz, DMSO, 1,4-dioxane as

5.63 (d, J = 15.5, 2H), 5.54 (d, J = 15.5, 2H), 5.50–5.42 (m,

8H), 5.26 (d, J = 16.4, 2H), 4.47 (d of d, J = 5.4, 2H), 4.33

(d, J = 16.4, 2H), 4.31 (d, J = 15.7, 2H), 4.27–4.24 (m, 4H),

1

3

internal reference): δ 152.6, 115.3, 115.3, 67.8, 67.1, 48.0,

2

+

8.8, 25.4. High-Res MS (ESI): m/z 545.1519 ([M – 2Na

4.19–4.14 (m, 6H), 3.87 (d of d, J = 5.4, 2H), 3.29–3.13 (m,

−

13

H] ), calculated for C H O S 545.1515.

4H), 2.30 (p, J = 7.2, 4H), 1.76 (s, 6H), 1.75 (s, 6H).

C

24 33 10 2

Compound 4c. A solution of 1,3-propanesultone

1.00 g, 8.25 mmol) in tetrahydrofuran (20 mL) was added

NMR (125 MHz, D O, 1, 4-dioxane as internal reference):

2

(

δ 157.3, 156.2, 155.9, 154.5, 151.2, 149.0, 127.8, 127.7,

117.9, 113.9, 81.4, 78.9, 77.4, 71.1, 70.8, 70.6, 68.0, 51.8,

47.9, 47.7, 47.5, 35.4, 33.7, 24.2, 14.5, 13.7. High-Res MS

to a solution of 3c (1.2 g, 3.3 mmol) in aqueous sodium

hydroxide solution (10 wt%, 10 mL). This mixture was

stirred at RT for 12 h and then ﬁltered to collect the crude

solid. The crude product was washed with acetone (30 mL).

The ﬁltered solid was dissolved in hot water (15 mL) and

precipitated with ethanol (30 mL) to obtain the oﬀ white

2-

(ESI): m/z 616.1650 ([M – 2Na] ), calculated for

2-

C H N O S 616.1700.

5

0 56 16 18 2

Compound 2b. Compound 4b (2.0 g, 3.4 mmol) was

added to a solution of 5 (1.3 g, 1.7 mmol) in a mixture

of triﬂuoroacetic acid (130 mL) and acetic anhydride

(130 mL). This solution was stirred and heated at 70°C

−1

solid 4c (1.0 g, 1.6 mmol, 47%). M.p. >300°C. IR (ATR, cm ):

935w, 2924w, 2853w, 1508s, 1475m, 1396w, 1289w,

2

SUPRAMOLECULAR CHEMISTRY

11

for 3 h. The reaction mixture was cooled to room

temperature, treated with methanol (130 mL), and the

solvent was removed under reduced pressure to obtain

the crude product. The crude product was washed

three times with a mixture of water (50 mL) and acet-

one (100 mL). The dark orange colored solid obtained

was loaded onto a Dowex® 1 × 2 chloride form,

hydrochloric acid (HCl) starting from plain water

(750 mL) to 6M HCl (750 mL) to 12 M HCl (300 mL).

The eluted fractions were analyzed by H NMR and the

1

almost pure compound 2c was obtained in the frac-

tions eluted with 12 M HCl. This fraction was dried

under reduced pressure and washed with a mixture of

water and methanol (1:1, v/v, 100 mL). Finally, the solid

obtained was dissolved in water and the pH of the

solution was adjusted to 7 using aqueous sodium

hydroxide (1M). The solvent was removed under

reduced pressure and the solid was further dried

under high vacuum to obtain pure 2c as an oﬀ white

solid (0.47 g, 0.34 mmol, 26%). M.p. >300°C. IR (ATR,

2

00–400 mesh ion exchange resin (50 g). The column

was eluted with increasing concentrations of hydro-

chloric acid (HCl) starting from plain water (750 mL) to

6

M HCl (750 mL) to 12 M HCl (300 mL). The eluted

1

fractions were analyzed by H NMR and the almost

pure compound 2b was obtained in the fractions

eluted with 12 M HCl. This fraction was dried under

reduced pressure and washed with a mixture of water

and methanol (1:1, v/v, 100 mL). Finally, the solid

obtained was dissolved in water and the pH of the

solution was adjusted to 7 using aqueous sodium

hydroxide (1M). The solvent was removed under

reduced pressure and the solid was further dried

under high vacuum to obtain pure 2b as a light yellow

solid (0.30 g, 0.56 mmol, 13%). M.p. >300°C. IR (ATR,

−

1

cm ): 3435w (br), 2930w, 1721s, 1463s, 1425m, 1378m,

1313m, 1230s, 1181s, 1085m, 1037s, 972m, 924w, 823m,

1

797s, 757m, 731m. H NMR (600 MHz, D O): 7.10–6.98

2

(m, 4H), 5.72 (d, J = 15.2, 1H), 5.64 (d, J = 15.2, 1H), 5.59

(d, J = 15.7, 2H), 5.56 (d, J = 15.7, 2H),5.45 (d, J = 9.0,

2H), 5.45 (d, J = 16.5, 2H), 5.40 (d, J = 9.0, 2H), 5.31 (d,

J = 16.5, 2H), 4.31 (d, J = 15.7, 2H), 4.23 (d, J = 15.7, 2H),

4.20–4.08 (m, 11H), 4.06 (d, J = 15.2, 1H), 4.01–3.93 (m,

2H), 3.28–3.09 (m, 4H), 2.35–2.22 (m, 4H), 1.78 (s, 6H),

1.74 (s, 6H), 1.58–1.46 (m, 2H), 1.40–1.27 (m, 2H), 1.12–

−

1

cm ): 3449w (br), 2939w, 1719s, 1464m, 1425w, 1378w,

1

3

1

7

314m, 1230m, 1181m, 1084m, 1036s, 972m, 924w,

0.93 (m, 4H), 0.91–0.75 (m, 6H), 0.75–0.65 (m, 2H).

C

1

97s, 758m, 730w. H NMR (600 MHz, D O): 7.01–6.96

NMR (150 MHz, DMSO, 1, 4-dioxane as internal refer-

ence): δ 156.1, 155.2, 154.6, 154.0, 150.2, 150.1, 128.1,

114.0, 113.6, 113.5, 77.5, 76.4, 70.7, 70.4, 69.8, 68.6, 64.6,

59.2, 48.4, 48.3, 48.2, 34.7, 34.5, 28.5, 27.2, 27.1, 25.6,

24.2, 16.6, 15.7.High-Res MS (ESI): m/z 672.2341 ([M –

2

(

m, 4H), 5.72 (d, J = 15.4, 1H), 5.57 (d, J = 15.4, 1H), 5.56

d, J = 15.7, 2H), 5.53 (d, J = 15.7, 2H), 5.46 (d, J = 9.0,

2

H), 5.38 (d, J = 16.4, 2H), 5.37 (d, J = 9.1, 4H), 5.25 (d,

J = 16.4, 2H), 4.36 (d, J = 15.7, 2H), 4.32 (d, J = 16.4, 2H),

2-

4.24–4.12 (m, 4H), 4.22 (d, J = 15.7, 2H), 4.16 (d, J = 15.4,

1H), 4.13 (d, J = 16.4, 2H), 4.03 (d, J = 15.4, 1H), 3.90–

3.76 (m, 4H), 3.127–3.11 (m, 4H), 2.34–2.23 (m, 4H), 1.76

2Na] ), calculated for C H N O S 672.2326.

58 72 16 18 2

(

1

s, 6H), 1.75 (s, 6H), 1.39–1.26 (m, 4H), 1.18–1.09 (m, 2H),

.05–0.95 (m, 2H). C NMR (150 MHz, DMSO, 1, 4-

Acknowledgments

13

We thank the National Science Foundation (CHE-1404911 and

CHE-1807486 to L.I.) and the University of Maryland (Graduate

Deans Dissertation Fellowship to S. G.).

dioxane as internal reference): δ 156.0, 155.2, 154.8,

1

7

3

m/z 644.2016 ([M

C H N O S 644.2013.

54.1, 150.2, 150.0, 127.8, 126.6, 113.9, 113.5, 77.3,

6.9, 70.5, 70.2, 69.5, 68.5, 64.6, 59.2, 48.5, 48.3, 48.0,

5.7, 34.4, 28.0, 25.6, 24.0, 16.8, 15.0. High-Res MS (ESI):

2-

–

2Na] ), calculated for

Disclosure statement

2

-

5

4 64 16 18 2

L.I. holds and equity stake in Calabash Bioscience which aims

to develop acyclic CB[n] for biomedical application.

Compound 2c. Compound 4c (1.7 g, 2.6 mmol) was

added to a solution of 5 (1.0 g, 1.3 mmol) in a mixture

of triﬂuoroacetic acid (100 mL) and acetic anhydride

(

100 mL). This solution was stirred and heated at 70°C

Funding

for 3 h. The reaction mixture was cooled to room

temperature, treated with methanol (100 mL), and the

solvent was removed under reduced pressure to obtain

the crude product. The crude product was washed

three times with a mixture of water (50 mL) and acet-

one (100 mL). The dark orange colored solid obtained

was loaded onto a Dowex® 1 × 2 chloride form,

This work was supported by the National Science Foundation

[CHE-1404911 and CHE-1807486] and the University of

Maryland [Graduate Deans Dissertation Fellowship].

ORCID

200–400 mesh ion exchange resin (50 g). The column

Shweta Ganapati

http://orcid.org/0000-0003-1955-2772

was eluted with increasing concentrations of

Lyle Isaacs http://orcid.org/0000-0002-4079-332X

1

2

S. GANAPATI AND L. ISAACS

References

Angew. Chem., Int. Ed. 2012, 51, 11358–11362; e) Tian,

J.; Zhou, T.-Y.; Zhang, S.-C.; Aloni, S.; Altoe, M. V.; Xie, S.-

H.; Wang, H.; Zhang, D.-W.; Zhao, X.; Liu, Y.; Li, Z.-T., Nat.

Commun. 2014, 5, 5574; f) Walsh, Z.; Janecek, E.-R.;

Hodgkinson, J. T.; Sedlmair, J.; Koutsioubas, A.; Spring,

D. R. W., M.; Hirschmugl, C. J.; Toprakcioglu, C.; Nitschke,

J. R.; Jones, M.; Scherman, O. A., Proc. Natl. Acad. Sci.

USA 2014, 111, 17743–17748. DOI: 10.1021/ar500116d

8) a) Jon, S.Y.; Selvapalam, N.; Oh, D.H.; Kang, J.-K.; Kim, S.-

Y.; Jeon, Y.J.; Lee, J.W.; Kim, K. J. Am. Chem. Soc. 2003 ,

(

1) a) Cram, D.J. Angew. Chem. Int. Ed. 1988, 27, 1009–1020;

b) Lehn, J.-M., Angew. Chem. Int. Ed. 1988, 27, 89–112; c)

Pedersen, C. J., Angew. Chem. Int. Ed. 1988, 27,

1021–1027. DOI: 10.1002/anie.198810093

(2) a) Gutsche, C.D. Acc. Chem. Res. 1983, 16, 161–170; b)

Diederich, F., Angew. Chem., Intl. Ed. Engl. 1988, 27,

3

1

62–386; c) Rebek, J., Acc. Chem. Res. 2009, 42,

660–1668; d) Yoshizawa, M.; Klosterman, J. K.; Fujita,

(

M., Angew. Chem. Int. Ed. 2009, 48, 3418–3438; e) Zarra,

S.; Wood, D. M.; Roberts, D. A.; Nitschke, J. R., Chem. Soc.

Rev. 2015, 44, 419–432; f) Dale, E. J.; Vermeulen, N. A.;

Juricek, M.; Barnes, J. C.; Young, R. M.; Wasielewski, M.

R.; Stoddart, J. F., Acc. Chem. Res. 2016, 49, 262–273; g)

Rekharsky, M. V.; Inoue, Y., Chem. Rev. 1998, 98,

1

25, 10186–10187; b) Ahn, Y.; Jang, Y.; Selvapalam, N.;

Yun, G.; Kim, K., Angew. Chem. Int. Ed. 2013, 52,

140–3144; c) Vinciguerra, B.; Cao, L.; Cannon, J. R.;

Zavalij, P. Y.; Fenselau, C.; Isaacs, L., J. Am. Chem. Soc.

012, 134, 13133–13140; d) Lucas, D.; Minami, T.;

3

2

Iannuzzi, G.; Cao, L.; Wittenberg, J. B.; Anzenbacher, P.;

Isaacs, L., J. Am. Chem. Soc. 2011, 133, 17966–17976; e)

Gilberg, L.; Khan, M. S. A.; Enderesova, M.; Sindelar, V.,

Org. Lett. 2014, 16, 2446–2449; f) Zhao, N.; Lloyd, G.;

Scherman, O., Chem. Commun. 2012, 48, 3070–3072; g)

Assaf, K. I.; Nau, W. M., Chem. Soc. Rev. 2015, 44,

1875–1917. DOI: 10.1021/ar00089a003

(3) Stoddart, J.F. Angew. Chem. Int. Ed. 2017, 56, 11094–

11125; b) You, L.; Zha, D.; Anslyn, E. V., Chem. Rev. 2015,

1

15, 7840–7892; c) Stella, V. J.; Rajewski, R. A., Pharm.

Res. 1997, 14, 556–567; d) Brown, C. J.; Toste, F. D.;

Bergman, R. G.; Raymond, K. N., Chem. Rev. 2015, 115,

3

94–418; h) Ayhan, M. M.; Karoui, H.; Hardy, M.;

3012–3035; e) Mal, P.; Breiner, B.; Rissanen, K.; Nitschke,

Rockenbauer, A.; Charles, L.; Rosas, R.; Udachin, K.;

J. R., Science 2009, 324, 1697–1699; f) Lehn, J.-M., Chem.

Soc. Rev. 2007, 36, 151–160; g) Liu, Z.; Frasconi, M.; Lei,

J.; Brown, Z. J.; Zhu, Z.; Cao, D.; Lehl, J.; Liu, G.;

Fahrenbach, A. C.; Botros, Y. Y.; Farha, O. K.; Hupp, J.

T.; Mirkin, C. A.; Stoddart, J. F., Nature Commun. 2013, 4,

Tordo, P.; Bardelang, D.; Ouari, O., J. Am. Chem. Soc.

2015, 137, 10238–10245; i) Cong, H.; Ni, X. L.; Xiao, X.;

Huang, Y.; Zhu, Q.-J.; Xue, S.-F.; Tao, Z.; Lindoy, L. F.; Wei,

G., Org. Biomol. Chem. 2016, 14, 4335–4364; j) Day, A. I.;

Arnold, A. P.; Blanch, R. J., Molecules 2003, 8, 74–84; k)

Wu, F.; Wu, L.-H.; Xiao, X.; Zhang, Y.-Q.; Xue, S.-F.; Tao, Z.;

Day, A. I., J. Org. Chem. 2012, 77, 606–611; l) Zhao, Y.;

Mandadapu, V.; Iranmanesh, H.; Beves, J. E.; Day, A. I.,

Org. Lett. 2017, 19, 4034–4037. DOI: 10.1021/ja036536c

9) A) Kim, E.; Kim, D.; Jung, H.; Lee, J.; Paul, S.; Selvapalam,

N.; Yang, Y.; Lim, N.; Park, C.G.; Kim, K. Angew. Chem. Int.

Ed. 2010 , 49, 4405–4408; b) Jung, H.; Park, K. M.; Yang,

J.-A.; Oh, E. J.; Lee, D.-W.; Park, K.; Ryu, S. H.; Hahn, S. K.;

Kim, K., Biomaterials 2011, 32, 7687–7694; c) Lee, D.-W.;

Park, K.; Banerjee, M.; Ha, S.; Lee, T.; Suh, K.; Paul, S.;

Jung, H.; Kim, J.; Selvapalam, N.; Ryu, S.; Kim, K., Nat.

Chem. 2011, 3, 154–159; d) Jung, H.; Park, J. S.; Yeom, J.;

Selvapalam, N.; Park, K. M.; Oh, K.; Yang, J.-A.; Park, K. H.;

Hahn, S. K.; Kim, K., Biomacromolecules 2014, 15,

1855. DOI: 10.1002/anie.201703216

(

4) a) Masson, E.; Ling, X.; Joseph, R.; Kyeremeh-Mensah, L.;

Lu, X. RSC Adv. 2012, 2, 1213–1247; b) Isaacs, L., Acc.

Chem. Res. 2014, 47, 2052–2062; c) Barrow, S. J.; Kasera,

S.; Rowland, M. J.; del Barrio, J.; Scherman, O. A., Chem.

Rev. 2015, 115, 12320–12406; d) Shetty, D.; Khedkar, J.

K.; Park, K. M.; Kim, K., Chem. Soc. Rev. 2015, 44,

(

8747–8761; e) Nau, W. M.; Florea, M.; Assaf, K. I., Isr. J.

Chem. 2011, 51, 559–577. DOI: 10.1039/C1RA00768H

5) a) Freeman, W.A.; Mock, W.L.; Shih, N.-Y. J. Am. Chem.

Soc. 1981, 103, 7367–7368; b) Kim, J.; Jung, I.-S.; Kim, S.-

Y.; Lee, E.; Kang, J.-K.; Sakamoto, S.; Yamaguchi, K.; Kim,

K., J. Am. Chem. Soc. 2000, 122, 540–541; c) Day, A. I.;

Arnold, A. P.; Blanch, R. J.; Snushall, B., J. Org. Chem.

(

2

001, 66, 8094–8100; d) Day, A. I.; Blanch, R. J.; Arnold,

7

07–714; e) Gong, B.; Choi, B.-K.; Kim, J.-Y.; Shetty, D.;

A. P.; Lorenzo, S.; Lewis, G. R.; Dance, I., Angew. Chem.

Int. Ed. 2002, 41, 275–277; e) Liu, S.; Zavalij, P. Y.; Isaacs,

L., J. Am. Chem. Soc. 2005, 127, 16798–16799; f) Cheng,

X.-J.; Liang, L.-L.; Chen, K.; Ji, N.-N.; Xiao, X.; Zhang, J.-X.;

Zhang, Y.-Q.; Xue, S.-F.; Zhu, Q.-J.; Ni, X.-L.; Tao, Z.,

Angew. Chem. Int. Ed. 2013, 52, 7252–7255. DOI:

Ko, Y. H.; Selvapalam, N.; Lee, N. K.; Kim, K., J. Am. Chem.

Soc. 2015, 137, 8908–8911; f) Yeom, J.; Kim, S. J.; Jung,

H.; Namkoong, H.; Yang, J.; Hwang, B. W.; Oh, K.; Kim, K.;

Sung, Y. C.; Hahn, S. K., Adv. Healthcare Mater. 2015, 4,

2

37–244; g) Cao, L.; Hettiarachchi, G.; Briken, V.; Isaacs,

L., Angew. Chem., Int. Ed. 2013, 52, 12033–12037; h)

Bockus, A. T.; Smith, L. C.; Grice, A. G.; Ali, O. A.;

Young, C. C.; Mobley, W.; Leek, A.; Roberts, J. L.;

Vinciguerra, B.; Isaacs, L.; Urbach, A. R., J. Am. Chem.

Soc. 2016, 138, 16549–16552; i) Li, W.; Bockus, A. T.;

Vinciguerra, B.; Isaacs, L.; Urbach, A. R., Chem.

Commun. 2016, 52, 8537–8540; j) Webber, M. J.;

Appel, E. A.; Vinciguerra, B.; Cortinas, A. B.; Thapa, L. S.;

Jhunjhunwala, S.; Isaacs, L.; Langer, R.; Anderson, D. G.,

Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 14189–14194; k)

Samanta, S. K.; Quigley, J.; Vinciguerra, B.; Briken, V.;

Isaacs, L., J. Am. Chem. Soc. 2017, 139, 9066–9074; l)

Zhou, X.; Su, X.; Pathak, P.; Vik, R.; Vinciguerra, B.; Isaacs,

L.; Jayawickramarajah, J., J. Am. Chem. Soc. 2017, 139,

10.1021/ja00414a070

(

6) a) Liu, S.; Ruspic, C.; Mukhopadhyay, P.; Chakrabarti, S.;

Zavalij, P.Y.; Isaacs, L. J. Am. Chem. Soc. 2005, 127,

15959–15967; b) Cao, L.; Šekutor, M.; Zavalij, P. Y.;

Mlinarić-Majerski, K.; Glaser, R.; Isaacs, L., Angew.

Chem., Int. Ed. 2014, 53, 988–993. DOI: 10.1021/

ja055013x

7) a) Ghale, G.; Nau, W.M. Acc. Chem. Res. 2014, 47, 2150–

2159; b) Ko, Y. H.; Kim, E.; Hwang, I.; Kim, K., Chem.

Commun. 2007, 1305–1315; c) Chen, H.; Chan, J. Y.-W.;

Li, S.; Liu, J. J.; Wyman, I.; Lee, S. M.-Y.; Macartney, D. H.;

Wang, R., RSC Adv. 2015, 5, 63745; d) Ma, D.; Zhang, B.;

Hoﬀmann, U.; Sundrup, M. G.; Eikermann, M.; Isaacs, L.,

SUPRAMOLECULAR CHEMISTRY

13

1

3916–13921; m) Sun, C.; Zhang, H.; Li, S.; Zhang, X.;

Falcinelli, S.; Mandadapu, V.; Zavalij, P. Y.; Day, A.;

Briken, V.; Isaacs, L. Chem. Med. Chem. 2016, 11,

980–989. DOI: 10.1039/C3OB42603C

Cheng, Q.; Ding, Y.; Wang, L.-H.; Wang, R., ACS Appl.

Mater. Interfaces 2018, 10, 25090–25098; n) Chen, H.;

Ma, H.; Tan, Y., J. Polym. Sci., Part A Polym. Chem. 2015,

(13) a) Griﬃn, A.C.; Havens, S.J. J. Polym. Sci., Polym. Phys. Ed.

1981, 19, 951; b) Caruso, U.; Pragliola, S.; Rovielllo, A.;

Sirigu, A.; Iannelli, P. Macromolecules 1995, 28, 6089.

DOI: 10.1002/pol.1981.180190605

5

3, 1748–1752; o) Chen, H.; Hou, S.; Ma, H.; Li, X.; Tan, Y.,

Sci. Rep. 2016, 6, 20722pp; p) Shen, F.-F.; Chen, K.;

Zhang, Y.-Q.; Zhu, Q.-J.; Tao, Z.; Cong, H., Org. Lett.

2

016, 18, 5544–5547; q) Chen, H.; Huang, Z.; Wu, H.;

Xu, J.-F.; Zhang, X. Angew. Chem., Int. Ed. 2017, 56,

6575–16578. DOI: 10.1002/anie.201000818

(14) a) Bom, A.; Bradley, M.; Cameron, K.; Clark, J.K.; Van

Egmond, J.; Feilden, H.; MacLean, E.J.; Muir, A.W.; Palin,

R.; Rees, D.C.; Zhang, M.-Q. Angew. Chem. Int. Ed. 2002,

41, 265–270; b) Yin, H.; Wang, R., Isr. J. Chem. 2017, 58,

188–198; c) Yang, X.; Li, S.; Wang, Z.; Lee, S. M. Y.; Wang,

L.-H.; Wang, R. Chem. - Asian J . 2018 , 13 , 41–45. DOI:

10.1002/1521-3773(20020118)41:2<265::AID-

1

(

10) a) Ma, D.; Hettiarachchi, G.; Nguyen, D.; Zhang, B.;

Wittenberg, J.B.; Zavalij, P.Y.; Briken, V.; Isaacs, L. Nat.

Chem. 2012, 4, 503–510; b) Zhang, B.; Isaacs, L., J. Med.

Chem. 2014, 57, 9554–9563; c) Gilberg, L.; Zhang, B.;

Zavalij, P. Y.; Sindelar, V.; Isaacs, L., Org. Biomol. Chem.

ANIE265>3.0.CO;2-Q

2

015, 13, 4041–4050; d) Ganapati, S.; Isaacs, L., Isr. J.

(15) She, N.F.; Moncelet, D.; Gilberg, L.; Lu, X.Y.; Sindelar, V.;

Briken, V.; Isaacs, L. Chem. Eur. J. 2016 , 22, 15270–

15279. DOI: 10.1002/chem.201601796

(16) Mock, W.L.; Shih, N.-Y. J. Org. Chem. 1986 , 51, 4440–

4446. DOI: 10.1021/jo00373a018

(17) a) Huang, W.-H.; Liu, S.; Zavalij, P.Y.; Isaacs, L. J. Am.

Chem. Soc. 2006 , 128, 14744–14745; b) Huang, W.-H.;

Zavalij, P. Y.; Isaacs, L. Org. Lett. 2008, 10, 2577–2580.

DOI: 10.1021/ja064776x

(18) Masson, E.; Shaker, Y.M.; Masson, J.-P.; Kordesch, M.E.;

Yuwono, C. Org. Lett. 2011 , 13, 3872–3875. DOI:

10.1021/ol201403m

(19) a) Biedermann, F.; Uzunova, V.D.; Scherman, O.A.; Nau,

W.M.; A., D.S. J. Am. Chem. Soc. 2012 , 134, 15318–15323;

b) Biedermann, F.; Nau, W. M.; Schneider, H.-J. Angew.

Chem. Int. Ed. 2014, 53, 11158–11171. DOI: 10.1021/

ja303309e

Chem. 2018, 58, 250–263; e) Stancl, M.; Hodan, M.;

Sindelar, V., Org. Lett. 2009, 11, 4184–4187; f) Stancl, M.;

Gilberg, L.; Ustrnul, L.; Necas, M.; Sindelar, V. Supramol.

Chem. 2014, 26, 168–172. DOI: 10.1038/nchem.1326

11) a) Haerter, F.; Simons, J.C.P.; Foerster, U.; Duarte, I.M.;

Diaz-Gil, D.; Eikermann-Haerter, K.; Ayata, C.; Ganapati,

S.; Zhang, B.; Blobner, M.; Isaacs, L.; Eikermann, M.

Anesthesiology 2015 , 123, 1337–1349; b) Hettiarachchi,

G.; Samanta, S.; Falcinelli, S.; Zhang, B.; Moncelet, D.;

Isaacs, L.; Briken, V., Mol. Pharmaceut. 2016, 13,

809–818; c) Ganapati, S.; Grabitz, S. D.; Murkli, S.;

Scheﬀenbichler, F.; Rudolph, M. I.; Zavalij, P. Y.;

Eikermann, M.; Isaacs, L. Chembiochem 2017, 18,

1

583–1588. DOI: 10.1097/ALN.0000000000000868

12) a) Zhang, B.; Zavalij, P.Y.; Isaacs, L. Org. Biomol. Chem.

014 , 12, 2413–2422; b) Sigwalt, D.; Moncelet, D.;

2

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Acyclic cucurbit[n]urils capped with alkylene linkers: synthesis and molecular recognition properties

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