Rational construction of macrocycles consisting of methylene bridged ureas

Article abstract of DOI:10.1016/j.tet.2016.04.009

Synthesis of two macrocycles formed by urea functions connected solely by methylene bridges is described. This is the first example of isolated and fully characterized macrocyclic compounds in which NH-containing urea units are separated by methylene bridges. X-ray diffractometry revealed formation of multiple intramolecular hydrogen bonds between acidic NH and oxygen atoms of urea within the macrocycles.

Full text of DOI:10.1016/j.tet.2016.04.009

Accepted Manuscript
Rational construction of macrocycles consisting of methylene bridged ureas
Mirza Arfan Yawer, Marek Necas, Vladimir Sindelar
PII:
S0040-4020(16)30263-0
10.1016/j.tet.2016.04.009
TET 27652
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 February 2016
Revised Date: 24 March 2016
Accepted Date: 5 April 2016
Please cite this article as: Yawer MA, Necas M, Sindelar V, Rational construction of macrocycles
consisting of methylene bridged ureas, Tetrahedron (2016), doi: 10.1016/j.tet.2016.04.009.
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Rational construction of macrocycles
consisting of methylene bridged ureas
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ab
a
ab
Mirza Arfan Yawer , Marek Necas , Vladimir Sindelar *
a
Department of Chemistry, Kamenice 5, 625 00 Brno, Czech Republic
b
RECETOX, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
E-mail: sindelar@chemi.muni.cz

1
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Tetrahedron
journal homepage: www.elsevier.com
Rational construction of macrocycles consisting of methylene bridged ureas
ab
a
ab
Mirza Arfan Yawer , Marek Necas , Vladimir Sindelar *
a
Department of Chemistry, Kamenice 5, 625 00 Brno, Czech Republic
RECETOX, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
b
E-mail: sindelar@chemi.muni.cz
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis of two macrocycles formed by urea functions connected solely by methylene bridges
is described. This is the first example of isolated and fully characterized macrocyclic compounds
in which NH-containing urea units are separated by methylene bridges. X-ray diffractometry
revealed formation of multiple intramolecular hydrogen bonds between acidic NH and oxygen
atoms of urea within the macrocycles.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords: macrocycles, ureas, triazinanones ,
hydrogen bonding, condensation
1
. Introduction
based on the same starting materials is difficult to drive towards
the formation of desired macrocycle as the polymerization, open
chain reactions and degradation predominate. Here we present
synthesis of two new macrocycles consisting of deprotected urea
units connected by methylene bridges.
Urea represents one of the most popular building blocks used
in supramolecular chemistry. Two nitrogen atoms of urea act as
donor of hydrogen atoms allowing the urea to interact with
hydrogen acceptors through intermolecular hydrogen bonding
1,2
interactions. Thus, urea containing compounds can act as
neutral anion receptors. Affinity of these receptors can be
enhanced by number of ways including attachment of electron
withdrawing substituents, incorporation of two or more urea units
into one receptor molecule, and arrangement of urea units into
2. Results and discussion
2.1. Macrocycle 2
Our approach is based on the acid catalyzed reaction of
protected urea, 5-tert-butylperhydro-1,3,5-triazin-2-one with
paraformaldehyde. Starting material 5-tert-butylperhydro-1,3,5-
triazin-2-one 1 was synthesized affording a slightly modified
3,4
linear, branched or cyclic structures. Urea and its derivatives
can self-associate through the hydrogen bonding between acidic
NH protons and oxygen atom of neighboring molecule. This
enable design and formation of three-dimensional structures in
the solid state usually represented by hollow tubes closely
21
reported procedure. The condensation of urea and tert-
butylamine in boiling methanol was performed using
paraformaldehyde instead formalin to achieve better yield.
5,6
connected within a crystal. The channels formed by urea
framework are able to include organic molecules. Therefore,
these nano-porous materials are used as the host matrixes for the
hydrocarbon separation, nanoreactors for organic reactions, and
Initially we tested reaction of 1 with paraformaldehyde in toluene
in the presence of p-toluenesulfonic acid at reflux for 24 h
(Scheme 1). This reaction leads to the formation of several
oligomers that are difficult to isolate. We have demonstrated
previously, that the formation of urea-based macrocycles such as
bambusurils can be enhanced by the presence of
tetrabutylammonium (TBA) salt of chloride, bromide and
7–9
X-ray dichroic filters.
We decided to investigate synthetic approaches leading to
macrocyclic compounds in which urea units are in close
proximity connected only by methylene bridges. Several
macrocycles containing this structural motives have been
synthesized in past including cucurbiturils, hemicucurbiturils,
14–16
iodide
. Therefore, we repeated the macrocyclization reaction
in the presence of TBAI. Slightly pink precipitate was obtained
after 24 h of reflux and was collected by filtration. Pure
macrocycle (2) was obtained after washing of the precipitate with
methanol and recrystallizing from diluted HCl. We also
succeeded to obtain single crystals of 2 suitable for X-ray
10–17
bambusurils, and biotinurils.
However, all these macrocycles
are composed of disubstituted urea units which do not contain
NH protons enabling the formation of hydrogen bonds with
guests. To the best of our knowledge, there has not been a single
example of macrocycle based on alternating NH-containing urea
and methylene units only. The required structural sequence can
be found in urea based resins which are prepared by the direct
22
diffraction analysis, which revealed true composition of the
macrocycle (Figure 1). The macrocycle 2 is composed of four
urea units connected by four methylene bridges. Two of these
urea units remained protected as triazinanones. Surprisingly, a
urea ring within the macrocycle is overbridged via urea dimer
18–20
reaction of urea and formaldehyde.
However, the reaction

2
Tetrahedron
using triazone cycles as a bridging point. The mechanism of the
data). Another set of C–H···O bonds (H···O distance 2.56 Å) is
ACCEPTED MANUSCRIPT
macrocycle formation is not yet clear. We propose that initially
six units of 5-tert-butylperhydro-1,3,5-triazin-2-one (1) surround
iodide in similar arrangement which can be found for building
responsible for stacking in the third dimension.
2.2. Deprotection
13
blocks in hemicucurbit[6]urils. Four of these units undergo
deprotection while two of them remain in the form of
triazinanones. Subsequent rearrangement of urea units during
condensation with paraformaldehyde result in the macrocycle 2.
Bridge of the macrocycle through two triazinanones further
stabilizes the structure. The generation of a small three-
dimensional cavity is most likely caused by formation of multiple
N–H···O hydrogen bonds within macrocycle. It is also possible
that four membered ring is thermodynamically more stable
compared to six-membered one as it is described for some
All tested approaches for the deprotection of remaining
two urea units in triazone rings of macrocycle 2 failed. For
example, heating in an acidic aqueous/methanol (1:1 v/v)
solution of diethanol amine leads to the decomposition of the
6
macrocycle, even the macrocycle is not stable in boiling conc.
HCl. Macrocycle 2 is comparatively stable in weaker acids and in
dilute hydrochloric acid. This environment is not sufficient to
achieve the deprotection of triazone moiety.
2.3. Macrocycle 3
22
bambusuril macrocycles.
After successful development of strategy for the synthesis of
macrocycle 2 in nonpolar solvent toluene, we worked more to
advance the macrocyclization using polar protic solvents.
Therefore the compound 1 was treated with paraformaldehyde in
methanol in the presence of catalytic amount of HCl, which did
not give the desired result. Succeeding macrocyclization trials in
pure methanol and mixtures of methanol and water at different
ratios, in the presence of various concentrations of aq. HCl also
leads to the formation of acyclic oligomers instead of fruitful
macrocyclization. After a number of unsuccessful attempts
eventually the condensation of 1 with paraformaldehyde in 4N
aq. hydrochloric acid solution in pure water was performed.
Turbid suspension initially formed which dissolved upon heating
N N
N
O
O
N
NH
O
Paraformaldehyde
HN
HN
O
NH
HN
NH
NH
NH
O
PTSA,Toluene
TBAI, reflux, 24 h
O
N
O
NN
50%
2
1
Scheme 1. Synthesis of macrocycle 2.
The macrocycle 2 shows a two-fold rotational symmetry which is
consistent with its positioning in a monoclinic cell; the
asymmetric unit of the cell thus contains only a half of the
molecule (Figure 1). Two intramolecular N–H···O hydrogen
bonds are observed between the two symmetry related parts of
the macrocycle. It is interesting to note an unusual anti
N4(H)···N5(H) conformation in substituted urea moiety, which
may be explained by a tendency to keep the O1 and O2 atoms
apart.
⁰
at 80 C for 2 h (Scheme 2). The reaction mixture was evaporated
to dryness. Resulting white solid was obtained by slow
crystallization from 2N aq. HCl. Particularly, the reaction was
performed at 0.1M concentrations of protected urea and
paraformaldehyde as further dilution leads to the failure of
macrocyclization. he Higher concentrations of the reactants were
avoided toreduce undesirable polymerization. X-ray diffraction
analysis unveils the exact arrangement of eight urea units and ten
22
methylenes bridges in macrocycle 3 (Figure 2). Macrocycle 3 is
constituted by two identical macrocycles, each macrocycle
contains 4 urea and 4
O
O
NH
NH
NH
N
N
NH
N
Paraformaldehyde
aq. HCl
NH
NH
4N
NH
O
O
HN
NH
O
80 °C , 2h
O
NH
O
NH
N
N
1
3
NH
18%
NH
NH
O
O
Figure 1. The structure of 2 showing intramolecular hydrogen
bonds. Note a rotational symmetry about a C2 axis passing
through C8.
Scheme 2. Synthesis of macrocycle 3.
methylene units attached alternately. Both macrocycles are
further connected by two methylene bridges. In this way a
symmetric macrocycle dimer is formed which, in contrast to
macrocycle 2, does not contain any triazinone units but only
solely deprotected ureas. Because of the presence of numerous
N–H and C=O groups and a spherical nature of the macrocycle,
several moderate N–H···O contacts are allowed, showing an
average donor-acceptor distance of 2.86 Å (Table S2 in
Supplementary data). In contrast to the crystal structure of 2, the
The molecules of 2 are tightly packed in the crystal without the
presence of any solvent molecules or ions. Four pairs of N–H···O
hydrogen bonds around each macrocycle are responsible for the
formation of 1D supramolecular chains which propagate parallel
to the c axis. In the bc plane, the hydrogen bonded chains are
locked together via pairs of three-center C–H···O bonds with
H···O distances of 2.61 and 2.63 Å (Figure S3 in Supplementary

3
structure of 3 contains four molecules of water
A
p
C
er
C
fo
E
rm
P
u
T
la
E
un
D
it, MAin
N
dic
U
at
S
ed
C
w
R
er
I
e
P
u
T
sed. Calibration of spectra was carried out on
which form several intermolecular hydrogen bonds with the
macrocycle. Overall, two double-hydrogen acceptors N–
H···O···H–N, one C=O···H–O–H···O=C, and three C=O···H–O
hydrogen bonding patterns are found (Figure 2). Such a solid-
state “hydration shell” mediates a 3D crystal packing of which an
arbitrary 2D section is shown in Figure S4 in Supplementary
data.
the solvent signals (CF COOD and CD OD). NMR spectra were
recorded on a Bruker Avance III 300 spectrometer with working
frequency 300.15 MHz for H and 75.47 MHz for C, or a
Bruker Avance III 500 spectrometer with working frequency
500.11 MHz for H and 125.75 for C. Both spectrometers were
equipped with a BBFO probe. X-ray Diffraction data were
collected at 120 K on a Kuma KM-4 CCD diffractometer for 2
and on a Rigaku MicroMax-007 HF rotating anode CCD
diffractometer for 3. HRMS data were obtained on a APCI+/MS-
TOF apparatus equipped with an ESI interface.
3
3
1
13
1
13
4
4
0
.2. General procedures
.2.1. 5-tert-Butylperhydro-1,3,5-triazin-2-one (1). Urea (12.0 g,
.2 mol), tert-butylamine (14.6 g, 21 mL, 0.2 mol), and
paraformaldehyde (12.0 g, 0.4 mol) were boiled in methanol (40
ml) for 5 h, reaction mixture was cooled down to room
temperature and precipitate was separated by filtration. The
filtrate was concentrated on rotavap to about 1/3 of the initial
volume and left at room temperature for 3 h to yield a white
precipitate. Pure compound was obtained by recrystallization of
the precipitate from ethanol. Yield 12.0 g (38%); mp 197-199 °C.
1
H NMR (300 MHz, CD OD) δ = 4.3 (4H, s, 2CH ), 1.2 (9H, s,
3
2
13
C(CH3)3). C NMR (125 MHz, CD OD) δ = 158.5, 57.0, 55.1,
3
2
7.7).
4
.2.2. Macrocycle (2). 5-tert-Butylperhydro-1,3,5-triazin-2-one
Figure 2. Hydrogen bonding between the macrocycle 3 and the
(6.45 mmol 1.00 g), p-toluenesulfonic acid (3.25 mmol, 0.613
molecules of water in 3·4H O. Symmetry codes: (i) −x+1, −y+1,
2
g), paraformaldehyde (9.67 mmol, 0.290 mg) and TBAI (0.16
mmol, 0.228 g) were suspended in toluene (40 mL) and refluxed
for 24 h. After that reaction mixture was cooled down to room
temperature, precipitate was collected by filtration and washed
with excess of methanol to give white powder. Recrystallized
−
z+1; (ii) x+1/2, −y+3/2, z+1/2.
2
.4. Ion binding
A thorough study of physical properties and complexations of
from 2N aq. HCl gave pure macrocycle 2. Yield (0.250 g, 50 %).
both macrocycles are not straightforward due to the lack of
solubility in common organic solvents and in pure water. X-ray
structure analysis shows strong intramolecular and intermolecular
hydrogen bonding between C-H···O and N-H···O within the
macrocycle and among the neighboring molecules in crystal
packing. The studies on the solubility of macrocycles 2 and 3
show that both macrocycles require strong acidic condition of pH
1
H NMR (500 MHz, CF COOD) δ = 2.82-2.89 (2H, m, CH ),
3
2
1
3
3
.02-3.50 (14H, mbr, 7CH ), 3.84-3.86 (2H, m, CH ). C NMR
2
2
(
125 MHz, CF COOD) δ = 160.7, 157.8, 157.4, 80.5, 75.1, 74.9,
3
6
2
4.6, 64.5, 53.8, 53.6, 53.5, 53.2. IR (KBr): 3283 (w), 2966 (w),
874 (w), 1707 (s), 1628 (s), 1497 (m), 1365 (w), 1291 (s), 1177
(
s), 1120 (s), 1008 (w), 980 (w), 936 (w), 848 (w), 680 (m).
+
1
HRMS (APCI+): m/z calcd for [C H N O ] : 469.2014, found:
below 1 in order to be dissolved. We used H NMR spectrometry
15 25 12
6
4
69.2015.
to investigate binding of ions such as halides, nitrate, alkyl metal
cations, with the macrocycles. Trifluoroacetic acid and 2N HCl
were used as a solvent enabling dissolution of the macrocycle.
However, no supramolecular interaction between the
macrocycles and both anions and cations was detected. This is
probably caused by net of hydrogen bonding interactions which
successfully compete with possible anion binding site.
4
.2.3. Macrocycle (3). Paraformaldehyde (6.45 mmol, 193 mg)
was added to a stirred suspension of 5-tert-butylperhydro-1,3,5-
triazin-2-one (6.45 mmol, 1.00 g) in 4N aq. HCl 65 mL and
⁰
mixture was heated at 80 C for 2 h. Reaction mixture was
evaporated under vacuo to give white powder. Pure macrocycle 3
was obtained by slow recrystallization from 2N HCl. after 6
1
weeks. Yield (90 mg, 18 %). H NMR (500 MHz, CF COOD) δ
= 2.66-3.38 (18H, mbr, CH
3
. Conclusions
3
1
3
In conclusion we have explicated simple and inexpensive one
), 3.63-3.66 (2H, m, CH ). C NMR
2 2
pot synthetic methodologies for the synthesis of two novel
(125 MHz, CF COOD) δ = 160.5, 155.9, 80.5, 52.1, 51.6. IR
3
macrocycles based on condensation of 5-tert-butylperhydro-
(KBr): 3302 (w), 3277 (w), 1673 (s), 1634 (s), 1546 (s), 1508
(m), 1468 (w), 1373 (s), 1233 (s), 1212 (s), 1105 (w), 984 (w),
1
,3,5-triazin-2-one with paraformadehyde in polar and in
nonpolar solvents. We demonstrated that this approach can be
used for the synthesis macrocyclic compounds 2 and 3 in which
urea units are connected by methylene bridges. Moreover,
prepared compounds are first examples of macrocycles in which
urea units bearing acidic NH protons are in close distance
separated just by one methylene bridge.
831 (w), 790 (w), 670 (m). HRMS (APCI+): m/z calcd for
+
[C18
H
33
N
16
O
8
] : 601.2661, found: 601.2662.
Acknowledgement
This work was supported by the Czech Science Foundation
(13-15576S) and the Czech Ministry of Education (projects
LM2011028 and LO1214). The X-ray part of the work was
carried out with the support of X-ray diffraction and Bio-SAXS
Core Facility of CEITEC.
4
4
. Experimental
.1. General information
All solvents were dried and purified by standard methods for
1
13
all reactions. For H and C NMR, the deuterated solvents

4
Tetrahedron
ACCEPTED MANUSCRIPT
Supplementary Material
1
13
H, C NMR, IR, and MS spectra of compounds 2 and 3 and X-
ray crystal data and refinement parameters of 2 and 3.
Supplementary data associated with this article can be found, in
the online version…
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Crystallographic data (excluding structure factors) for the structures
in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 1451138 and 1451139. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.UK).