Tripodal Tris- N -oxides: Synthesis and Hydrogen Bonding Capabilities

Article abstract of DOI:10.1055/s-0035-1560533

A number of tripodal tris-N-oxide receptors were synthesized and their hydrogen-bonding capabilities were investigated. Particular success was seen with both the benzene- and mesitylene-linked trismorpholine N-oxide receptors, which exhibited significant hydrogen bonding to both water and urea, as well as the inclusion of a rare decameric water cluster, as demonstrated by X-ray crystallography.

Full text of DOI:10.1055/s-0035-1560533

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 141–145
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G. L. Nixon et al.
Letter
Synlett
Tripodal Tris-N-oxides: Synthesis and Hydrogen Bonding Capabili-
ties
Gemma L. Nixon
Helen Billington
S. Barret Kalindjian
Alexander Steiner
Ian A. O’Neil*
Robert Robinson Laboratories, Department of Chemistry,
University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK
ion@liverpool.ac.uk
Dedicated with respect to Professor Steve Ley FRS, mentor
and friend, on the occasion of his 70th birthday
Received: 01.10.2015
Accepted after revision: 24.10.2015
Published online: 08.12.2015
involving complexation of N-oxides to sulfonamides, phe-
nols, or 2-amino-3-hydroxypyridium ions have also been
described in the literature.5 The stabilization of proteins by
trimethylamine N-oxide and the ability of this compound
to counteract the effects of urea have recently been demon-
strated.6 Commercially, 4-methylmorpholine N-oxide has
been used as a solvent in spinning of cellulose fibers, and N-
oxides can be used to dissolve a wide range of natural and
synthetic polymers.7 Despite this interest and potential
there are only a few examples of hydrogen-bonding recep-
tors for small organic molecules in organic solvents and
none that work in an aqueous environment, so progress in
this area would be significant.8
DOI: 10.1055/s-0035-1560533; Art ID: st-2015-d0782-l
Abstract A number of tripodal tris-N-oxide receptors were synthesized
and their hydrogen-bonding capabilities were investigated. Particular
success was seen with both the benzene- and mesitylene-linked tris-
morpholine N-oxide receptors, which exhibited significant hydrogen
bonding to both water and urea, as well as the inclusion of a rare de-
cameric water cluster, as demonstrated by X-ray crystallography.
Key words tripodal receptors, amine oxides, hydrogen bonding, crys-
tal structure, water clusters
Recently, there has been great interest in the area of
synthetic hydrogen-bonding receptors that are capable of
binding to small organic molecules or to metal cations.1
This interest is due to the potential pharmaceutical applica-
tions of such compounds. Small molecules such as carbohy-
drates, ureas, or metal cations are involved in numerous bi-
ological processes in the body, such as inflammation, infec-
tion, and intercellular communication. Consequently,
synthetic receptors might be useful as biomimetics or as
prodrugs that transport active drugs to their sites of action
and are subsequently cleaved to release the active mole-
cule. Another potential application of hydrogen-bonding
receptors is their use as scavengers to bind unwanted mate-
rials in chemical or biological systems.2
Previous work by our group has shown that N-substitut-
ed proline derivatives that possess a hydrogen-bond donor
group in a carboxylate side chain undergo highly diastereo-
selective oxidations to give stable N-oxides in which the
N-oxide is hydrogen-bonded to the donor group(s) (Scheme
1).9 These observations led to the development of a wide
range of chiral proline-derived N-oxides for use in asym-
metric synthesis.10 The extensive hydration of these N-ox-
ides combined with evidence from the literature indicated
to us that similar compounds containing additional N-oxide
moieties might bind small hydrogen-bond-donor com-
pounds such as carbohydrates, amino acids, specific pep-
tide sequences, ureas, or metal cations (see below).11
The hydrogen-bonding capabilities of N-oxides are well
documented.3 Recently, N-oxides have been reported as the
first class of chemical reagents capable of stabilizing alde-
hyde hydrates (which are important but highly unstable
transient intermediates in biological and synthetic oxida-
tions to give carboxylic acids). This stabilizing affect has
been attributed to hydrogen bonding.4 Other examples of
m-CPBA
CH2Cl2, 96%
O
O
N
N
O
O
N
HN
O
t-Bu
H
t-Bu
N
H
H
NH2
Scheme 1 A proline-derived stabilized N-oxide
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G. L. Nixon et al.
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To this end, the synthesis of a related tris-N-oxide com-
pound was of great interest, as we surmised that a better
binding cavity would be created if the three N-oxide moi-
eties were on the same face of the aryl linker. It was also hy-
pothesized that by varying the amine groups it might be
possible to introduce chirality and, consequently, selectivity
into the tripodal receptor. Although there are several
reported examples of tripodal receptors, none contain an
N-oxide moiety.12 The effect of using a different aromatic
core unit, such as mesitylene, was also considered as a
means of introducing hindered rotation and securing the
positioning of the N-oxide moieties. As most N-oxides are
highly polar compounds, we were aware that the prepara-
tion of compounds possessing multiple N-oxides might
present significant problems in isolation and purification.
Our route for the synthesis of the tripodal tris-N-oxides
with a benzene linker (Scheme 2) began with the reduction
of commercially available trimethyl benzene-1,3,5-tricar-
boxylate with lithium aluminum hydride to give the triol 1
in 80% yield.12a
Table 1 Yields of Triamines 3a–e and the Corresponding N-Oxides 4a–e
Amine
Yield (%) of 3
Yield (%) of 4
K2CO3
DBU
a
72
61
98
50
40
81
88
0
>100a
>100a
>100a
79
b13
c
d
57
75
e
79
a The product was inseparable from 3-ClC6H4CO2H.
capability of these compounds to bind to metal cations.
Several other oxidants were tested, including hydrogen per-
oxide, tert-butyl hydroperoxide/vanadyl bis(acetylaceto-
nate), urea–hydrogen peroxide/phthalic anhydride, and so-
dium perborate. These methods either failed or gave the de-
sired product in an inseparable mixture with byproducts of
the reaction. We therefore decided that m-chloroperbenzo-
ic acid is the reagent of choice, because of its simple reac-
tion conditions, tolerance of a wide range of functional
groups, and simple workup procedure. We were unable to
perform an X-ray crystallographic analysis of any of these
compounds.
Our synthetic route to tripodal tris-N-oxides with a me-
sitylene linker (Scheme 3) began with commercially avail-
able mesitylene (5), which was treated with paraformalde-
hyde and 30% hydrogen bromide in acetic acid to give
tribromide 6 in 92% yield.14 Substitution of the tribromide
with three equivalents of the appropriate amine and three
equivalents of a base gave the corresponding triamines 7a–
d. The amine required for the synthesis of 7d was synthe-
sized by using the route previously reported by Prasad et
al.15
HO
OH
HBr/AcOH 30%
Br
Br
HO
Br
1
2
HNR2
base
O
O
R2N
NR2
R2N
NR2
mCPBA
K2CO3
R2N
R2N
4
3
O
HNR2 =
O
d HN(C10H21 2
)
N
H
e HN(C6H13 2
)
N
N
H
H
OH
In the case of these mesitylene-linked compounds, po-
tassium carbonate was the base of choice, giving much
higher yields (Table 2). The oxidation step of the reaction
was achieved by using m-chloroperbenzoic acid, giving
compounds 8a–d.
a
b
c
Scheme 2 Synthesis of phenyl-linked tripodal tris-N-oxides 4a–e
Triol 1 was then brominated by using 30% hydrogen
bromide in acetic acid to give tribromide 2 in 78% yield.8a
We then examined the displacement of the bromo groups
with a number of secondary amines; potassium carbonate
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were both
tested as bases in this step (Table 1).
Table 2 Yields of Mesitylene-Linked Triamines 7a–d and Their N-Ox-
ides 8a–d
DBU gave the highest yields, with the exception of tri-
amine 3c. The resulting tertiary amines 3a–e were oxidized
with m-chloroperbenzoic acid to give the corresponding
tris-N-oxides 4a–e in good yields; however, we encoun-
tered problems with 4a–c, which were inseparable from
m-chlorobenzoic acid, a byproduct of the reaction. The pro-
linol-derived tris-N-oxide 4c was found by mass spectrom-
etry to have bound to potassium from the potassium car-
bonate used in the oxidation reaction, demonstrating the
Amine
Yield (%) of 7
Yield (%) of 8
K2CO3
DBU
a
b
c
100
86
–
78
85
79
57
33
–
96
d
76
–
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G. L. Nixon et al.
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molecule is connected to three (H2O)10 clusters,17c which, in
return, bind six tris-N-oxides. The decameric water cluster
can be described as a polyhedral cage consisting of two
four-membered- and four five-membered-ring systems,
analogous to the C10 framework of the 1,4-bishomocubane
water cluster. Decameric and dodecameric water cages that
are part of molecular organic or metaloorganic crystals
have been reported,17 including one example that exhibits
the same cage topology as our structure.17a Structural data
for water clusters can provide useful models for the com-
plex structures of liquid water and aggregates in the gas
phase.18
Br
Br
HBr/AcOH 30%
paraformaldehyde
5
Br
6
HNR2
base
O
O
mCPBA
R2N
NR2
K2CO3
R2N
NR2
The most striking difference between the crystal struc-
tures of the benzene derivative 4b and the mesitylene de-
rivative 8b is the orientation of the three morpholine oxide
groups with respect to the central C6 ring. This all-cis con-
figuration might be the result of a templating effect facili-
tated by hydrogen bonding to hydrogen donors, which forc-
es all three N-oxide groups onto one side of the molecule.
These are then locked into place as a result of the presence
of the three methyl groups of the mesitylene ring, which in-
R2N
R2N
7
O
8
(C7H15
)
HNR2
=
O
N
H
N
N
H
N
H
H
OH
a
b
c
d
Scheme 3 Synthesis of the mesityl-linked tripodal tris-N-oxides 8a–d
We next attempted to grow crystals for X-ray structure
analysis of both the benzene derivatives 4 and the mesity-
lene derivatives 8, with the aim of studying the relative
conformations of the N-oxide groups and their potential
role as tripodal hydrogen-acceptors in supramolecular ag-
gregates. Suitable crystals containing 4b were obtained as
co-crystals with urea (4b·3urea·3H2O), whereas 8b crystal-
lized in the form of its heptahydrate (8b·7H2O).16
The crystal structure of 4b·3urea·3H2O shows that all
three N-oxide groups are axial with respect to the chair-
shaped morpholine rings. The overall conformation of the
three N-oxide groups with respect to the central C6 ring is
such that two of the N-oxide groups are situated on one
face with one N-oxide group on the other face (Figure 1). All
three N-oxides of 4b are engaged in intermolecular hydro-
gen bonds with urea molecules, confirming the strong hy-
drogen-acceptor properties of the partially negative oxygen
sites. One of the N-oxide groups forms a bifurcated hydro-
gen bond with two amino groups of urea, whereas the oth-
er two bind in a single fashion.
The X-ray crystal structure of 8b·7H2O also shows that
the N-oxide groups adopt an axial position relative to the
morpholine rings. However, in contrast to the benzene de-
rivative in 4b·3urea·3H2O, all the N-oxide groups in 8b·7H2O
are located on the same face of the central C6 ring, resulting
in a molecular symmetry that is close to C3 (Figure 2). The
three N-oxide groups form a coordination cavity that en-
capsulates a pair of water molecules. Each N-oxide group
interacts with two water molecules; one is part of the en-
capsulated pair, the other is part of a decameric cage-like
cluster of water molecules. The result is a three-dimension-
al supramolecular network in which every tris-N-oxide
Figure 1 Crystal structure of 4·3urea·3H2O. Top: View of 4 showing
the molecular confirmation. Bottom: Hydrogen-bonded aggregate of 4
and three urea molecules. The hydrogen atoms of the tris-N-oxide mol-
ecule have been omitted for clarity.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560533.
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We would like to thank the James Black Foundation for their generous
financial support.
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G. L. Nixon et al.
Letter
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H), 73.4 (6CH2 α to O), 63.1 (3ArCH2), 61.0 (6CH2 α to N). MS
(FAB): m/z = 424 (55) [M + H]+, 322 (43) [M + H]+ – C4H8NO2, 220
(25) [M + H]+ –2[C4H8NO2]. HRMS: m/z [M + H]+ calcd for
C
21H34N3O6: 424.24476; found: 424.24416.
Crystal data: C21H33N3O6·3CH4N2O·3 H2O: Stoe IPDS, T = 213 K,
monoclinic, space group P21/c, a = 10.166(2) Å, b = 21.823(4) Å,
c = 15.565(2) Å, β = 103.58(2)°, V = 3356.7(10) Å3, 2θmax = 45°;
4097 unique reflections, R1 [I
> 2σ(I)] 0.081, wR2 (all
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data) = 0.242. Crystals diffracted very weakly; therefore data
were truncated at 2θmax = 45°; all three water molecules are dis-
ordered. Crystal data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html. 4b·3CH4N2O·3H2O:
CCDC 1439355.
4,4′,4′′-[(2,4,6-Trimethylbenzene-1,3,5-triyl)tris(methylene)-
]tris(morpholine) 4,4′,4′′-Trioxide (8b)
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White solid; yield: 480 mg (85%); mp 128–130 °C. IR (nujol):
2924, (s, C–H), 1665 (s, C=C aryl), 1570 (s, C=C aryl), 1114 (s, C–
N), 858 (s, N+–O–) cm–1; 1H NMR (300 MHz, CD3OD): δ = 2.85 (s,
9 H, 3CH3), 3.05 (s, 6 H, 3 × ring C–CH2), 3.46 (m, 6 H, 6 CH α to O
and syn to N+–O–), 3.66 (m, 6 H, 6 CH α to O and anti to N+–O–),
4.35 (m, 6 H, 6 CH α to N and syn to N+–O–), 4.81 (m, 6 H, 6 CH α
to N and anti to N+–O–). 13C NMR (75 MHz, CD3OD): δ = 130.05
(3 × ring C–CH2), 129.65 (3 × ring C–CH3), 69.2 (3 × ring C–CH2),
62.6 (6 CH2 α to O), 61.4 (6 CH2 α to N), 21.8 (3 CH3). MS
(ES,+ve): m/z (%) 488 (100) [M + Na]+, 472 (35%) [M + Na – O]+.
HRMS: m/z [M + Na]+ calcd for C24H40N3NaO6: 488.2723; found:
488.2752.
Crystal data: C24H39N3O6·7 H2O: Bruker Smart Apex, T = 150 K,
orthorhombic, space group Pbca, a = 17.8733(11) Å,
b = 18.0114(11) Å, c = 18.6381(12) Å, V = 6000.0(6) Å3,
2θmax = 55°; 7125 unique reflections, R1 [I > 2σ(I)] = 0.050, wR2
(all data) = 0.130. H-atoms on water molecules were refined by
using restraints. Crystal data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html. 8b·7H2O: CCDC
1439354.
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(16) Tris-N-oxides 4a–e and 8a–d; General Procedure
mCPBA (2.20 mmol) was added to a stirred solution of triamine
3 or 7 (0.70 mmol) and K2CO3 (2.20 mmol) in CH2Cl2 (14 mL)
under N2 at –78 °C, and the reaction vessel was allowed to warm
to r.t. After 48 h, the mixture was filtered, the residue was
washed with CH2Cl2, and the solvent was removed in vacuo to
give the desired compound.
All other experimental procedures and characterization data
can be found in the Supporting Information.
4,4′,4′′-[Benzene-1,3,5-triyltris(methylene)]tris(morpho-
line) 4,4′,4′′-Trioxide (4b)
(17) (a) Ermer, O.; Neudörfl, J. Chem. Eur. J. 2001, 7, 4961.
(b) Barbour, L. G.; Orr, G. W.; Atwood, J. L. Nature 1998, 393,
671. (c) Yoshizawa, M.; Kusukawa, T.; Kawano, M.; Ohhara, T.;
Tanaka, I.; Kurihara, K.; Niimura, N.; Fujita, M. J. Am. Chem. Soc.
2005, 127, 2798. (d) Li, X.; Xu, X.; Yuan, D.; Weng, X. Chem.
Commun. 2012, 48, 9014.
White solid; yield: 201 mg (>100%). 1H NMR (300 MHz, CD3OD):
δ = 7.89 (s, 3 H, 3Ar–H), 4.56 (s, 6 H, 3CH2), 4.18 (t, J = 11.7 Hz, 6
H, 6CH α and syn to N+–O–), 3.83 (d, J = 11.7 Hz, 6 H, 6CH α to O
and syn to N+–O–), 3.63 (t, J = 11.7, 6 H, 6CH α to O and anti to
N+–O–), 3.05 (d, J = 11.7, 6 H, 6CH α and anti to N+–O–). 13C NMR
(75 MHz, CD3OD): δ = 138.7 (3 ring × C–CH2), 129.1 (3 × ring C–
(18) Fucke, K.; Steed, W. Water 2010, 2, 333.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 141–145