Synthesis of quinoxaline cavitand baskets

Article abstract of DOI:10.1080/10610278.2021.1917768

The unique temperature, solvent and pH drivenvase?to?kite?equilibrium in quinoxaline cavitands allows the reversible uptake and release of guests. However, the cavity breathing associated with this conformational switch reduces the strength of complexatio

Full text of DOI:10.1080/10610278.2021.1917768

Supramolecular Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gsch20
Synthesis of quinoxaline cavitand baskets
Alessia Favero, Andrea Rozzi, Chiara Massera, Alessandro Pedrini, Roberta
Pinalli & Enrico Dalcanale
To cite this article: Alessia Favero, Andrea Rozzi, Chiara Massera, Alessandro Pedrini, Roberta
Pinalli & Enrico Dalcanale (2021): Synthesis of quinoxaline cavitand baskets, Supramolecular
Chemistry, DOI: 10.1080/10610278.2021.1917768
To link to this article: https://doi.org/10.1080/10610278.2021.1917768
Published online: 02 May 2021.
Submit your article to this journal
Article views: 77
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gsch20

SUPRAMOLECULAR CHEMISTRY
https://doi.org/10.1080/10610278.2021.1917768
ARTICLE
Synthesis of quinoxaline cavitand baskets
Alessia Favero , Andrea Rozzi , Chiara Massera , Alessandro Pedrini , Roberta Pinalli
and Enrico Dalcanale
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy and INSTM Parma Research Unit,
Italy
ABSTRACT
ARTICLE HISTORY
Received 16 March 2021
Accepted 9 April 2021
The unique temperature, solvent and pH drivenvase to kite equilibrium in quinoxaline cavitands
allows the reversible uptake and release of guests. However, the cavity breathing associated with
this conformational switch reduces the strength of complexation. A limited number of solutions
have been proposed for the cavity rigidification, using either H-bonding, metal coordination or
covalent connections. Here we report the synthesis and structural characterisation of quinoxaline-
based cavitand baskets, which present two distal quinoxaline walls linked together. Baskets A and
B were obtained through a bridging reaction starting from an AC di-quinoxaline bridged cavitand
using two different di-quinoxaline moieties. In both cases, two isomers were obtained:
isomer C2, with the linking unit crossing the cavity mouth, and isomer Cs, having the linker
sideways. The isomers were identified through 1H NMR analysis. In the case of basket A-Cs, the
resolved molecular structure confirmed the Cs symmetry of the basket.
KEYWORDS
Quinoxaline cavitands; cavity
partial rigidification; X-ray
crystal structure; upper rim
bridging
linking the four quinoxaline walls (Chart 1a). This rigidi-
fication has further sharpened the molecular recognition
properties of the resulting cavitands, leading to a sensor
for the detection of benzene at ppb levels in air [17]. An
intermediate level of rigidification has been reported by
Diederich’s group by replacing two distal quinoxaline
walls with diazaphthalimide walls, connected via diace-
tylenic or p-xylylene bridges (Chart 1(b,c)) [18,19]. In this
way, the upper mouth of the cavity is partially sealed,
leaving the other two quinoxaline walls as gates for the
opening and closing of the cavity. In this case, the resi-
dual vase-kite conformational switch is also pH driven.
These molecular baskets have shown enhanced molecu-
lar recognition properties compared to the parent flex-
ible cavitand, coupled with the ability to open the lateral
portals for guest release.
1 Introduction
The unique temperature, solvent and pH driven vase-
kite equilibrium in quinoxaline cavitands [1] has
attracted the attention of several researchers [2–4],
since this conformational switch allows the reversible
uptake and release of candidate guests [5] (Figure 1).
Quinoxaline cavitands in the vase form have shown
peculiar molecular recognition properties in the gas-
phase [6,7], in solution [8,9] and at the solid-gas interface
[10,11], leading to their use in sensors for the detection
of aromatic volatile organic compounds [12–14]. The
vase-kite equilibrium can be suppressed in favour of
the vase form via H-bonding [15], metal coordination
[16] or covalent connections. Covalent rigidification
was obtained by introducing four lateral bridging units
CONTACT Enrico Dalcanale
enrico.dalcanale@unipr.it
Parco Area delle Scienze 17/A, Parma 43124, Italy
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma,
Dedicated to the memory of David Gutsche
© 2021 Informa UK Limited, trading as Taylor & Francis Group

2
A. FAVERO ET AL.
Figure 1. Vase-kite switching by controlling temperature, pH and solvent polarity.
Intrigued by the possibility to use quinoxaline cavi-
tand baskets as selective preconcentration units in sen-
sors, we explored different synthetic pathways for the
synthesis of molecular baskets featuring exclusively qui-
noxaline walls. Here we report the results of this study.
was removed and water was added to the solid crude.
The crude was sonicated for 15 min and filtered through
a Büchner funnel to afford a red solid. The target com-
pound was obtained after recrystallisation from dichlor-
omethane (DCM) as a dark red powder (374 mg, 69%).
1H NMR (CDCl3, 300 MHz): δ ppm = 7.63 (d, 2H, J = 2.8
Hz), 7.13 (dd, 2H, Jo = 6.0 Hz, Jm = 3.0 Hz), 6.77 (d, 2H,
2 Materials and methods
J
=
9.0
Hz),
4.29
(s,
4
H).
2.1 Chemicals
ESI-MS: m/z 357.19 [M+ Na]+; m/z 373.26 [M + K]+.
Unless stated otherwise, reactions were conducted in
flame-dried glassware under an atmosphere of argon
using anhydrous solvents (either freshly distiled, passed
through activated alumina columns or stored on molecular
sieves for at least 48 h). All commercially obtained reagents
were used as received unless otherwise specified. Silica
column chromatography was performed using silica gel
60 (Fluka 230–400 mesh or Merck 70–230 mesh).
Automatic purification was performed on COMBIFLASH
NextGen 300. Silica cartridges (Purezza-Daily Open-Load
Flash Cartridge Silica 60A 50um-Size 40) were purchased
from SEPACHROM.
2.3 Synthesis of 4,4ʹ-(ethane-1,2-diylbis(oxy))bis
(benzene-1,2-diamine) (2)
To a solution of compound 1 (374 mg, 1.12 mmol) in
EtOH (40 mL), SnCl2*2H2O (2.52 g, 11.16 mmol) was
added in one portion and the solution was stirred at
80°C for 17 h. The eluent was evaporated under vacuum
to give a dark solid, which was maintained under inert
atmosphere and carried to the next step without further
purification (307 mg, quantitative yield).
1H and 13C NMR spectra were obtained using a Bruker
AVANCE 300 (300 MHz) and a Bruker AVANCE 400
(400 MHz) spectrometer at 298 K. All the chemical shifts
(δ) were reported in ppm relative to the proton reso-
nances resulting from incomplete deuteration of the
NMR solvents. High-resolution MALDI-TOF was per-
formed on an AB SCIEX MALDI TOF-TOF 4800 Plus
(matrix: α-cyano-4-hydroxycinnamic acid).
4-hydroxy-2-nitroaniline and 1,3-diphenylpropane
were purchased by Fluorochem. Products 5 and 6 were
obtained following a literature procedure [20], as well as
AB-2QxCav and AC-2QxCav [21].
2.4 Synthesis of 6,6ʹ-(ethane-1,2-diylbis(oxy))bis
(quinoxaline-2,3-diol) (3)
To a solution of compound 2 (307 mg, 1.12 mmol) in HCl
4 N (18 mL), oxalic acid (242 mg, 2.69 mmol) was added and
the mixture was stirred at 110°C for 16 h. The reaction
mixture was filtered through a Büchner funnel. The
obtained solid was washed with water and subsequently
dried under vacuum to give
(394 mg, 92%).
a dark purple solid
1H NMR (DMSO-d6, 300 MHz): δ ppm = 11.83 (d, 2H,
OH, J = 16 Hz), 7.05 (d, 2 H, J = 8.7 Hz), 6.78 (dd, 2 H, Jo
= 11.3 Hz, Jm = 2.6 Hz), 6.72 (s, 2 H, J = 2.5 Hz), 4.25 (s, 4 H).
2.2 Synthesis of 4,4ʹ-(ethane-1,2-diylbis(oxy))bis
(2-nitroaniline) (1)
2.5 Synthesis of 1,2-bis((2,3-dichloroquinoxalin-
6-yl)oxy)ethane (4)
To a solution of 4-hydroxy-2-nitroaniline (500 mg,
3.24 mmol) in dry ACN (15 mL), K2CO3 (1.345 g,
9.73 mmol) was added. After 5 min, ethylene di(p-tolue-
nesulfonate) was added (1.803 g, 4.87 mmol) and the
reaction mixture was stirred at 80°C for 24 h. The solvent
To a solution of 3 (200 mg, 0.52 mmol) in dry 1,2-dichlor-
oethane (30 mL), dry DMF (5 drops) and POCl3 (1.95 mL,
20.90 mmol) were added. The mixture was stirred at 80°C

SUPRAMOLECULAR CHEMISTRY
3
Chart 1. Possible rigidification of the quinoxaline cavitand. (a) Connection of all the quinoxaline moieties with ethoxy bridges; partial
rigidification connecting two distal diazaphthalimide walls via (b) diacetylenic and (c) p-xylylene bridges.
for 16 h, then cooled to room temperature and the
solvent removed under vacuum. The crude was sus-
pended in MeOH and filtered through a Büchner funnel
to give a brownish solid (490 mg, 96%).
MALDI-TOF: m/z 1387.6232 calculated for C86H83N8
O10 [M + H]+, found 1387.6268; m/z 1409.6052 calculated
for C86H82N8NaO10 [M+ Na]+, found 1409.6017.
A-C2 1H NMR (CDCl3, 400 MHz): δ ppm = 8.27 (s, 2 H,
ArHup), 8.25 (m, 2 H, QxH), 8.00 (m, 2 H, QxH), 7.98 (s, 2 H,
ArHup), 7.87 (t, 2 H, QxH, J = 7.03 Hz), 7.77 (t, 2 H, QxH,
J = 6.90 Hz), 7.46 (d, 2 H, QxH, J = 9.12 Hz), 7.36 (d, 2 H,
QxH, J = 8.07 Hz), 7.22 (s, 2 H, ArHdown), 7.01 (s, 2 H,
ArHdown), 6.65 (dd, 2 H, QxH, J = 6.78), 6.32 (d, 2 H, QxH,
J = 2.55 Hz), 5.65 (t, 2 H, J = 8.11 Hz), 5.57 (t, 2 H,
J = 8.20 Hz), 3.99 (m, 2 H), 3.40 (m, 2 H), 2.33 (m, 4 H),
2.18 (m, 4 H), 1.35 (m, 32 H), 0.94 (m, 12 H).
1H NMR (CDCl3, 300 MHz): δ ppm = 7.93 (d, 2 H,
J = 9.2 Hz), 7.49 (dd, 2 H, Jo = 9.3 Hz, Jm = 2.7 Hz), 7.38
(d,
2
H,
J
=
2.8 Hz), 4.55 (s,
4
H).
ESI-MS: m/z 456.97 [M + H]+.
2.6 Synthesis of baskets A
In a Schlenk flask, AC-2QxCav (53 mg, 0.05 mmol) was
dissolved in 70 mL of dry DMF in an inert atmosphere.
After the addition of K2CO3 (41 mg, 0.3 mmol) and
13C NMR (CDCl3, 100 MHz): δ ppm = 154.11, 153.63,
152.85, 152.70, 152.57, 152.53, 151.59, 150.74, 140.50,
140.19, 139.45, 135.71, 135.53, 135.42, 135.11, 129.47,
129.13, 128.77, 128.48, 128.25, 124.06, 123.21, 122.84,
119.67, 109.24, 65.03, 34.41, 34.14, 33.99, 33.58, 32.00,
31.95, 31.84, 31.55, 30.72, 29.43, 29.37, 28.09, 27.94,
22.73, 22.68, 14.12, 14.07.
MALDI-TOF: m/z 1387.6232 calculated for C86H83N8O10
[M + H]+, found 1387.6254 [M + H]+; m/z 1409.6052
calculated for C86H82N8NaO10 [M+ Na]+, found 1409.6063.
ethylenedioxy bis-dichloroquinoxaline
4
(23 mg,
0.05 mmol), the reaction was stirred at 80°C for 16 h.
The solvent was removed under vacuum, H2O was
added to the crude, and the suspension was sonicated
and filtered. Purification by flash column chromatogra-
phy over silica gel and subsequent preparative TLCs
using DCM/MeOH 98:2 as eluent in both cases, afforded
pure A-Cs (3 mg, 12%) followed by A-C2 (1.3 mg, 5%).
1
A-Cs. H NMR (CDCl3, 400 MHz): δ ppm = 8.38 (s, 2 H,
ArHup), 8.33 (m, 2 H, QxH), 8.12 (s, 2 H, ArHup), 8.03 (m, 2 H,
QxH), 7.87 (m, 2 H, QxH), 7.73 (m, 2 H, QxH), 7.40 (d, 2 H,
2.7 Synthesis of N,N’-(propane-1,3-diylbis(2-nitro-
4,1-phenylene))diacetamide (7)
QxH, J = 9.21 Hz), 7.20 (s, 2 H, ArHdown), 7.08 (s, 2 H, ArHdown
)
, 6.65 (dd, 2 H, QxH, J1 = 9.21 Hz, J2 = 2.58), 5.96 (d, 2 H, QxH,
J = 2.58 Hz), 5.86 (t, 1 H, J = 8.25 Hz), 5.64 (t, 1 H, J = 8.32 Hz),
5.58 (t, 2 H, J = 8.32 Hz), 3.69 (m, 2 H), 3.30 (m, 2 H), 2.39 (m,
2 H), 2.27 (m, 2 H), 2.15 (m, 4 H), 1.41 (m, 32 H), 0.99
(m, 12 H).
Compound 6 (360 mg, 1.59 mmol) was suspended in
15 mL of acetic anhydride, and the suspension was
cooled down in an ice bath. p-Toluenesulfonic acid
(665 mg, 3.5 mmol) and KNO3 (353 mg, 3.5 mmol) were
added and the mixture was stirred overnight at room
temperature. The reaction was quenched with 200 mL of
water and the formed precipitate was sonicated, filtered
off on a frit glass (G4), recovered with 20 mL of ethyl
acetate, sonicated and filtered again. The obtained crude
was purified with an automatic flash column in a linear
gradient Hex = > AcOEt in 20 minutes. 475 mg of pro-
duct 7 were obtained with an overall yield of 74%.
13C NMR (CDCl3, 100 MHz): δ ppm = 154.06, 153.60,
152.87, 152.66, 152.54, 152.52, 151.56, 150.72, 140.48,
140.16, 139.47, 135.78, 135.59, 135.49, 135.02, 129.47,
129.10, 128.76, 128.46, 128.26, 124.00, 123.20, 122.82,
119.64, 109.20, 64.98, 34.46, 34.12, 33.96, 33.57, 31.98,
31.93, 31.81, 31.52, 30.69, 29.41, 29.34, 28.04, 27.90,
22.69, 22.65, 14.10, 14.06.

4
A. FAVERO ET AL.
1H NMR (400 MHz, CDCl3) δ (ppm) = 10.26 (s, 2 H), 8.69
2.10 Synthesis of 1,3-bis(2,3-dichloroquinoxalin-
6-yl)propane (11)
(d, J = 8.7 Hz, 2 H), 8.02 (d, J = 2.0 Hz, 2 H), 7.48 (dd,
J = 8.7, 2.0 Hz, 2 H), 2.79–2.65 (m, 4 H), 2.31 (s, 6 H), 1.99
(t, J = 7.7 Hz, 2 H).
To a solution of 10 (280 mg, 768 μmol) in 20 mL of dry
dichloroethane thionyl chloride (280 μL, 3.84 mmol) was
added together with three drops of dry DMF as catalyst.
The temperature was risen to 80°C and the inert atmo-
sphere maintained. The reaction was stirred overnight
and then quenched by adding 20 mL of methanol. The
solvent was evaporated at reduced pressure, and the
crude was suspended in methanol and filtered off. The
product was obtained as white solid (252 mg, 75% yield).
1H NMR (400 MHz, CDCl3) δ (ppm) = 7.96 (d, J = 8.6 Hz,
2 H), 7.82 (d, J = 1.4 Hz, 2 H), 7.65 (dd, J = 8.6, 1.9 Hz, 2 H),
2.99–2.86 (m, 4 H), 2.19 (t, m, 2 H).
ESI-MS: m/z 271.13 [M-NO2−]+, 317.15 [M + H]+.
2.8 Synthesis of 4,4ʹ-(propane-1,3-diyl)bis
(2-nitroaniline) (8)
Product 7 (425 mg, 1.06 mmol) was suspended in 20 mL
of ethanol and 2 mL of water. An excess of sodium
hydroxide was added (400 mg, 10 mmol) and the reac-
tion was stirred at 80°C for 5 h. The solvent was evapo-
rated at reduced pressure and the crude extracted with
3 × 20 mL of AcOEt. The organic phase was dried over
anhydrous sodium sulphate and filtered. The crude was
purified by flash chromatography using Hex:AcOEt as
eluent in a linear gradient from 7:3 to 1:1 mixture in
20 min. The desired product was obtained as yellow
solid (302 mg, 90% yield).
MALDI-TOF, m/z 438,9606 calculated for C19H13Cl4N4
[M + H]+, found 438,9637.
2.11 Synthesis of baskets B
In a Schlenk flask, AC-2QxCav (27.4 mg, 25.4 µmol) was
dissolved in 40 mL of dry DMF. After the addiction of K2
CO3 (10.5 mg, 76.3 µmol) and 3-bis(2,3-dichloroquinox-
alin-6-yl)propane (11) (12.2 mg, 28 µmol), the reaction
was stirred at 80°C for 16 h. The solvent was removed
under vacuum and the crude was purified by preparative
TLC in DCM as eluent, affording pure B-Cs (1.7 mg, 5%)
followed by B-C2 (0.7 mg, 2%). The low amount of B-C2
obtained hampered the possibility of clean 1H-NMR
spectrum. However, all the diagnostic peaks were clearly
present for the univocal identification of the compound.
1H NMR (400 MHz, CDCl3) δ (ppm) = 7.91 (d, J = 2.0 Hz,
2 H), 7.19 (dd, J = 8.5, 2.1 Hz, 2 H), 6.75 (d, J = 8.5 Hz, 2 H),
2.60–2.52 (m, 4 H), 1.88 (tt, J = 8.9, 6.9 Hz, 2 H).
ESI-MS: m/z 339.17 [M+ Na]+.
2.9 Synthesis of 4,4ʹ-(propane-1,3-diyl)bis
(benzene-1,2-diamine) (intermediate 9) and 6,6ʹ-
(propane-1,3-diyl)bis(quinoxaline-2,3-diol) (10)
Product 8 (302 mg, 955 μmol) was dissolved in 20 ml of
THF, obtaining a clear yellow solution. The temperature
was risen to 60°C under nitrogen. Hydrazine 80%
(300 μL, 7.64 mmol) was added, followed by a catalytic
amount of Nickel Raney. After 30 minutes the reaction
1
B-Cs. H NMR (CDCl3, 400 MHz): δ ppm = 8.43 (s, 2 H,
ArHup), 8.37 (m, 2 H, QxH), 8.07 (s, 2 H, ArHup), 8.03 (m,
2 H, QxH), 7.97 (m, 2 H, QxH), 7.74 (m, 2 H, QxH), 7.40 (d,
2 H, QxH, J = 8.7 Hz), 7.17 (s, 2 H, ArHdown), 7.06 (s, 2 H,
ArHdown), 6.76 (dd, 2 H, QxH, J1 = 8.6 Hz, J2 = 2.0), 6.57
(dd, 2 H, J1 = 11.8, J2 = 1.9 Hz, QxH), 5.86 (t, 1 H,
J = 8.2 Hz), 5.69 (t, 1 H, J = 8.2 Hz), 5.57 (d, 2 H,
J = 8.4 Hz). 2.40 (m, 2 H), 2.28 (m, 8 H), 2.16 (m, 4 H),
1.35 (m, 32 H), 0.94 (m, 12 H).
was quenched. The unstable intermediate
9 was
obtained after filtration of the catalyst on a glass filter
under an inert atmosphere. The immediate addition of
10 mL of HCl 4 M to the filtrate preserved the intermedi-
ate from degradation. THF was removed under reduced
pressure and the aqueous phase became pale yellow.
The solution was immediately poured into a 100 mL
round-bottom flask and oxalic acid (198 mg,
2.20 mmol) was added. The temperature was raised to
100°C and the reaction was left stirring overnight. The
white precipitate formed was filtered on a glass filter
(G4), obtaining 282 mg of 10 (81% yield).
MALDI-TOF: m/z 1386.6750 calculated for C87H88N9O8
[M+ NH4]+, found 1386.6932 [M+ NH4]+.
B-C2 1H NMR (CDCl3, 400 MHz): δ ppm = 8.43 (s, 2 H,
ArHup), 8.37z (m, 2 H, QxH), 8.07 (s, 2 H, QArHup), 8.04 (m,
2 H, QxH), 7.96 (m, 2 H, QxH), 7.75 (m, 2 H, QxH), 7.47 (s,
2 H, ArHdown, J = 9.12 Hz), 7.17 (s, 2 H, QxH), 7.06 (s, 2 H,
ArHdown), 6.76 (dd, 2 H, QxH, J1 = 8.6, J2 = 2.0 Hz), 6.57
(m, 2 H, QxH), 5.86 (t, 1 H, J = 8.2 Hz), 5.69 (t, 2 H,
J = 8.2 Hz), 5.58 (t, 2 H, J = 8.2 Hz), 2.40 (m, 2 H), 2.29
(m, 8 H), 2.16 (m, 4 H), 1.38 (m, 32 H), 1.25 (m, 12 H).
MALDI-TOF: m/z 1386.6750 calculated for C87H88N9O8
[M+ NH4]+, found 1386.6876 [M+ NH4]+.
1H NMR (400 MHz, DMSO-d6) δ (ppm) = 11.88 (2s, 4 H),
7.05 (d, J = 8.6 Hz, 2 H), 6.96–6.90 (m, 4 H), 2.56 (t,
J = 7.5 Hz, 4 H), 1.87–1.73 (m, 2 H).
MALDI-TOF: m/z 365,1250 calculated for C19H17N4O4
[M + H]+, found 365,0837.

SUPRAMOLECULAR CHEMISTRY
5
Compound 5 was obtained in low yields since differ-
ent isomers were formed during the nitration reaction,
and several recrystallisation steps were necessary to iso-
late the desired isomer. The reduction of the two nitro
groups on 5 required Ni Raney as catalyst and hydrazine
as reducing agent, to give 6 in high yield. Subsequently,
the amino groups of 6 were protected using acetic
anhydride, followed by in situ nitration using KNO3 as
nitrating agent to give 7 [22]. Removal of the acetyl
groups under basic conditions afforded compound 8 in
good yield. The subsequent reduction of the two nitro
groups was performed following the same conditions
used in step b), except for the use of THF as solvent,
selected to favour the solubility of 8. Compound 9 was
not isolated but directly converted into 10 via conden-
sation with oxalic acid. The desired compound 11 was
obtained in the last step by chlorination with SOCl2 in
1,2-dichloroethane followed by precipitation and filtra-
tion. The overall yield of the synthetic procedure is 9%.
3 Results and discussion
All cavitand baskets reported so far have a bridging con-
nection between distal walls (AC mode, Figure 2a). We
were interested in assessing whether the introduction of
the basket bridge in a single step would have been suita-
ble for the vicinal mode connection (AB mode, Figure 2b).
Out of the two synthetic routes to cavitand baskets,
namely the introduction of functionalised quinoxaline
walls followed by basket bridging (11a) and the single-
step introduction of the two connected walls (11b) we
opted for the latter. For this purpose, two bis-
dichloroquinoxalines were prepared connected via ethy-
lenedioxy and propyl chains, respectively (Schemes 1, 2).
Synthesis of bis-quinoxaline bridging moieties
1,2-bis((2,3-dichloroquinoxalin-6-yl)oxy)ethane building
block 4 was synthesised via a four-step synthesis, with
an overall yield of 61% (Scheme 1).
The first step involved the link of two 3-amino-2-nitro
phenol moieties with ethylene di(p-toluenesulfonate) to
give the diamino-dinitro intermediate 1. The two nitro
groups of 1 were reduced in the presence of SnCl2,
obtaining the tetraamino compound 2. Due to the
high propensity of the amino groups to undergo oxida-
tion, 2 was directly condensed with oxalic acid to obtain
compound 3. Compound 3 was obtained in pure form
directly as precipitate from water. The final step was the
chlorination of 3 performed using POCl3 in 1,2-dichlor-
oethane to give the desired synthon 4.
1,3-bis(2,3-dichloroquinoxalin-6-yl)propane 11 pre-
senting a shorter all hydrocarbon C3 tether required
a longer, more elaborate synthetic sequence (Scheme
2). Both intermediates 5 and 6 were obtained by litera-
ture procedure (12).
Synthesis of baskets A and B
AB and AC dibridged quinoxaline cavitands were pre-
pared following a known procedure (21). All attempts to
form the AB connected basket with compounds 4 and
11 failed. These reactions led to the exclusive formation
of oligomeric material. A reasonable explanation of this
failure can be attributed to the conformational flexibility
of both di-bridging units, which disfavours the vicinal
connection.
In contrast, bridging AC di-quinoxaline cavitand AC-
2QxCav with 4 and 11 to give the corresponding bas-
kets A and B turned out to be successful under the same
conditions, as reported in Scheme 3. In both cases, the
reaction leads to two different isomers, one charac-
terised by a C2 symmetry (A-C2 and B-C2), and the
other one by a Cs symmetry (A-Cs and B-Cs). Baskets A-
Figure 2. (a) AC mode and (b) AB mode bridging connection.

6
A. FAVERO ET AL.
Scheme 1. Synthetic pathway to obtain the bridging moiety 4. Conditions: a) ACN, K2CO3, 80°C, o.n., 69%; b) SnCl2*H2O, EtOH, 80°C, o.
n., quantitative; c) oxalic acid, HCl 4 N, reflux, o.n., 92%; d) POCl3, DCE, DMF, 80°C, o.n., 96%.
Scheme 2. Synthetic pathway to obtain bridging moiety 11. Conditions: a) HNO3/H2SO4 in acetic anhydride, 95°C, 1 h, 23%; b)
Dioxane, hydrazine hydrated 80%, Ni Raney, 60°C, 1 h, 93%; c) Acetic anhydride, R. T., 1 h; p-Toluenesulfonic acid, KNO3, R. T., o.n., 74%;
d) EtOH, H2O, NaOH, 80°C, 5 h, 90%; e) THF, hydrazine hydrated 80%, Ni Raney, 60°C, 30 min, not isolated; f) Oxalic acid, 100°C, o.n.,
81%; g) DCE, DMF, SOCl2, 80°C, o.n., 75%.
C2 and B-C2 present one C2 axis, with the quinoxaline
linker crossing the cavity. Instead, baskets A-Cs and B-Cs
present only a σ plane, since the linker moiety is on the
same side of the scaffold. In both cases, the two isomers
form in a ratio of Cs/C2 ≈ 2.5:1, highlighting that the Cs
symmetry is favoured. In all cases, the yields are quite
low, being oligomers the major components of the
crude. Isolation of the baskets required in both cases
extensive column chromatography and several prepara-
tive TLCs.
the resorcinarene skeleton in the 1H NMR spectrum.
Cavitand A-C2 presents two methine resonances at
5.6–5.7 ppm (pink dot – Figure 1 upper part) in 1:1
ratio, in agreement with the symmetry of its structure,
while A-Cs shows three resonances in 1:1:2 ratio (pink
dot – Figure 3 lower part) in the same ppm range. The
chemical shift of these resonances is diagnostic of the
vase conformation for both cavitands in solution, as
confirmed in the solid state for A-Cs by its crystal
structure.
The different symmetry of the two isomers allowed
their identification through 1H NMR. In the case of basket
A-Cs, the NMR assignment was confirmed by single-
crystal X-ray diffraction analysis.
In both isomers, the ethylenedioxy bridge, indicated
by light blue dots, appears as a pair of multiplets
between 3.3 and 3.6 ppm (Figure 3). Its multiplicity and
broadening are caused by the protons slow motion on
the NMR timescale, which allows distinguishing between
proton pointing inward or outward to the cavity. The
quinoxaline resonances are between 6.0 and 7.5 ppm for
the linked ones, and 7.5–8.0 ppm for the others. The
resorcinarene aromatic protons are split into four
1H NMR analyses
The different symmetry of the two cavitands is reflected
in the number of resonances of the methine protons of

SUPRAMOLECULAR CHEMISTRY
7
Scheme 3. Synthesis of the four basket cavitands. Conditions: a) DMF, K2CO3, 80°C, o.n., A-C2 5%, A-Cs 12%. b) DMF, K2CO3, 80°C, o.n.,
B-C2 2%, B-Cs 5%.
singlets, as expected by symmetry considerations. Both
isomers are the result of a first attack of the dimeric
compound 4 on AC-2QxCav, followed by reaction of
the remaining portion either in a parallel or antiparallel
mode on the remaining OHs. The formation of the Cs
isomer is more favoured, as testified by the reaction
yield.
passing through the walls and the mean plane passing
through the eight O1/O2 oxygen atoms. By comparison,
the corresponding values for the other pair of quinoxa-
line walls are 10.377(4) Å for the C19A∙∙∙C20Ai distance
and 89.49(7)° for the inclination angle. Due to the geo-
metry of the ethylenedioxy bridge which leans more
towards one of the two lateral walls, the opening of
the cavity is asymmetric, as clearly shown by the space
filling view in Figure 2C,D.
Crystal structure of A-Cs
In the case of cavitand A-Cs, suitable crystals for X-Ray
diffraction analysis were grown from DMSO. The
obtained molecular structure is shown in Figure 4.
Isomer A-Cs crystallises in the space group C2/c and
the asymmetric unit comprises half of the molecule of
the cavitand and two half molecules of DMSO. The
whole molecules are generated by rotation around
a 2-fold axis. As a result, the ethylenedioxy bridge is
disordered over two equivalent positions, as are the
two DMSO molecules which are located in the cavity
and among the four alkyl feet. The quinoxaline walls
bridged by the ethylenedioxy moiety are bent towards
the inside of the cavity. This is evidenced by the
C19B∙∙∙C20Bi (and the equivalent C20B∙∙∙C19Bi) distances
of 4.714(5) Å (i = 1-x, y, 1/2-z) and by an inclination angle
of 67.60(8)°. This is the angle between the mean planes
Synthesis of baskets B-Cs and B-C2
The formation of basket B was performed similarly to
basket A, through a bridging reaction on AC-2QxCav in
presence of bis-dichloroquinoxaline 11. Also, in this
case, two isomers B-Cs and B-C2 were formed and sepa-
rated via preparative TLC. As in the previous case, the
distinction between the two isomers was performed
1
through H NMR. In the case of basket B, the presence
of a shorter link between the two quinoxaline moieties
led to a reduction of the yield reaction compared to
basket A. The main products are oligomeric species,
present in the final crude and insoluble residue. It is
interesting to note that, like basket A, the major product
is the Cs isomer. Working under high dilution conditions
did not affect the final yields.

8
A. FAVERO ET AL.
Figure 3. 1H NMR spectra of compounds A-C2 and A-Cs in CDCl3, 25°C, 400 MHz. Diagnostic peaks are highlighted with coloured dots.
1H NMR analyses
resonances are between 2.0 and 2.5 ppm, together
with the protons of the cavitand chain.
Similar considerations for cavitands A can be applied
1
As for isomer B-Cs, the H NMR shows for the methine
to cavitands B, namely the different symmetry of the
protons three resonances around 5.9, 5.7 and 5.6 ppm in
two isomers is reflected in the number of resonances
about 1:1:2 ratio (green dot – Supplemental material,
of the methine protons of the resorcinarene skeleton
1
Figure S1 lower part), respectively. In this case, the chemical
in the H NMR spectrum. Basket B-C2 was obtained in
shift of these resonances is also diagnostic of the vase
only 2% yield (0.7 mg) so the low S/N ratio of the
1H NMR spectrum (Supplemental material, Figure S1
conformation of the cavitand in solution. The quinoxaline
resonances can be seen between 7.7 and 8.3 ppm, while
upper part), made the aromatic peak assignment dif-
the bridging unit resonances are between 2.0 and 2.5 ppm,
ficult. In the spectrum reported in Figure S1 – upper
together with some protons of the cavitand chain.
part, it is possible to clearly distinguish two methine
resonances in the 5.6–5.7 ppm range (green dots) in
about 1:1 ratio, in agreement with the symmetry of
the structure. The low field shift of the methine pro-
Conclusions
tons confirms that the cavitand is in a vase conforma-
tion. The quinoxaline resonances can be seen
between 6.5 and 8.3 ppm, while the bridging unit
Four new quinoxaline-based cavitands, namely A-C2, A-
Cs, B-C2, and B-Cs, possessing a narrow and partially rigid
cavity have been designed and synthesised. The cavitands

SUPRAMOLECULAR CHEMISTRY
9
Figure 4. Molecular structure of cavitand A-Cs (A). Detail of the cavity with partial labelling scheme (B). H atoms and disorder have
been omitted for clarity. Labels coloured in red refers to atoms generated by symmetry (1-x, y, 1/2-z). (C) Side and (D) top view of the
cavity in space filling mode. H atoms, disorder and solvent molecules have been omitted for clarity. Colour code: Gray: carbon; red:
oxygen; blue: nitrogen.
rigidification on the uptake/release of VOCs in air.
were obtained through a bridging reaction on an AC di-
quinoxaline bridged cavitand, AC-2QxCav. Two different
bridging units were used, an ethylenedioxy bis-
dichloroquinoxaline synthon, obtaining baskets A, and
Acknowledgments
This work has benefitted from the equipment and framework
of the COMP-HUB Initiative, funded by the ‘Departments of
Excellence’ program of the Italian Ministry for Education,
University and Research (MIUR, 2018-2022). The authors
acknowledge MIUR through the PRIN project 20179BJNA2 for
financial support. The authors acknowledge the Centro
Interdipartimentale di Misure “G. Casnati” of the University of
Parma for the use of NMR facilities and Prof. D. Bonifazi of the
University of Vienna for MALDI-TOF analyses. Chiesi
Farmaceutici SpA is acknowledged for its support with the
D8Venture X-ray equipment.
a
propane bis-dichloroquinoxaline unit, presenting
a smaller linker between the two quinoxaline moieties,
that led to basket B. In both cases, two isomers were
obtained, differing in the symmetry of the cavity. In the
isomers A-C2 and B-C2, the linker unit crosses the cavity
providing a C2 symmetry, while in the isomers A-Cs and B-
Cs, the linker is on the same side of the resorcinarene
scaffold affording a Cs symmetry. The structure of the
1
isomers was assigned via H NMR and, in the case of A-
Cs, it was confirmed through X-Ray diffraction analysis.
Both reactions showed a preference for the formation of
the Cs isomer, probably due to the preferred orientation
of the linker in solution. The slightly higher yields
obtained for basket A with respect to basket B highlight
that the longer linker between the two quinoxaline units
allows a better insertion of the bridging unit. However,
reduction of the length of the linker does not lead to AB
bridging. These baskets will be tested as selective precon-
centration units to investigate the role of partial cavity
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the Ministero dell’Istruzione,
dell’Università e della Ricerca [PRIN project 20179BJNA2].

10
A. FAVERO ET AL.
ORCID
[11] Condorelli GG, Motta M, Favazza M, et al. Molecular
recognition of halogen-tagged aromatic VOCs at the
air–silicon interface. Chem Commun. 2010;46(2):288.
[12] Dalcanale E, Hartmann J. Selective detection of
organic compounds by means of cavitand-coated
QCM transducers. Sens Actuators B. 1995;24(1–3):39.
[13] Zampolli S, Betti P, Elmi I, et al. A supramolecular
approach to sub-ppb aromatic VOC detection in air.
Alessia Favero
Andrea Rozzi
Chiara Massera
Alessandro Pedrini
Roberta Pinalli
http://orcid.org/0000-0002-1106-9818
http://orcid.org/0000-0001-7674-264X
http://orcid.org/0000-0003-0230-1707
http://orcid.org/0000-0003-3949-7563
http://orcid.org/0000-0002-0000-8980
http://orcid.org/0000-0001-6964-788X
Enrico Dalcanale
Chem.
Commun.
2007;27:2790.
DOI:10.1039/
b703747c
[14] Clement P, Korom S, Struzzi C, et al. Deep cavitand
self-assembled on Au NPs-MWCNT as highly sensitive
benzene sensing interface. Adv. Funct. Mater. 2015;25
(26):4011.
[15] Rudkevich D, Hilmersson G, Rebek J Jr. Intramolecular
hydrogen bonding controls the exchange rates of
References
[1] Moran JR, Ericson JL, Dalcanale E, et al. Vases and kites as
cavitands. J. Am. Chem. Soc. 1991;113(15):5707.
[2] Pinalli R, Pedrini A, Dalcanale E. Chapter 5. In: George W.
Gokel, Jerry L.A, editors. Comprehensive supramol.
Chem. II. Vol. 3. Oxford: Elsevier; 2017. p. 87.
guests in
(41):9911.
a cavitand. J Am Chem Soc. 1997;119
[3] Gropp C, Quigley BL, Diederich F. Molecular recognition
with
resorcin[4]arene
cavitands:
switching,
[16] Rahman F-U, Li YS, Petsalakis ID, et al. Recognition with
metallo cavitands. Proc Natl Acad Sci USA. 2019;116
(36):17648.
[17] Trzcinski JW, Pinalli R, Riboni N, et al. In search of the
ultimate benzene sensor: the EtQxBox solution. ACS
Sens. 2017;2(4):590.
[18] Hornung J, Fankhaser D, Shirtcliff LD, et al. Cycloalkane
and alicyclic heterocycle complexation by new switch-
able resorcin[4]arene-based container molecules: NMR
and ITC binding studies. Chem. Eur. J. 2011;17
(44):12362.
halogen-bonded capsules, and enantioselective
complexation. J. Am. Chem. Soc. 2018;140(8):2705.
[4] Hooley RJ, Rebek Jr J. Chemistry and catalysis in func-
tional cavitands. Chem & Biol. 2009;16(3):255.
[5] Milic JV, Diederich F. The quest for molecular grippers:
photo-electric control of molecular gripping machinery.
Chem. Eur. J. 2019;25(36):8440.
[6] Vincenti M, Pelizzetti E, Dalcanale E, et al. Molecular
recognition in the gas phase. Pure Appl. Chem.
1993;65(7):1507.
[7] Vincenti M, Dalcanale E. Host–guest complexation in the
gas phase. Investigation of the mechanism of interaction
between cavitands and neutral guest molecules. J Chem
Soc Perkin Trans 2. 1995;6:1069. DOI:10.1039/
P29950001069
[19] Fankhauser D, Kolarski D, Gruning WR, et al. Resorcin[4]
arene-based molecular baskets and water-soluble con-
tainer molecules: synthesis and 1 H NMR host-guest
complexation studies. Eur. J. Org. Chem. 2014;2014
(17):3575.
[8] Soncini P, Bonsignore S, Dalcanale E, et al. Cavitands as
versatile molecular receptors. J. Org. Chem. 1992;57
(17):4608.
[20] Nagasawa HT, Gutmann HR. Notes—preparation and
properties of S-acetyl-N-benzoylcysteamine. J. Org.
Chem. 1958;23(3):487.
[9] Giannetto M, Pedrini A, Fortunati S, et al. Sensing of
halogenated aromatic hydrocarbons in water with
a cavitand coated piezoelectric device. Sensors and
Actuators B: Chemical. 2018;276:340.
[10] Condorelli GG, Motta A, Favazza M, et al. Grafting cavitands
on the Si(100) surface. Langmuir. 2006;22(26):11126.
[21] Castro PP, Zhao G, Masangkay GA, et al. Quinoxaline
excision: a novel approach to tri- and diquinoxaline
cavitands. Org. Lett. 2004;6(3):333.
[22] Chong JH, MacLachlan MJ. Robust non-interpenetrating
coordination frameworks from new shape-persistent
building blocks. Inorg. Chem. 2006;45(4):1442.