Template-directed synthesis of kinetically and thermodynamically stable molecular necklace using ring closing metathesis

Article abstract of DOI:10.1039/c0ob01034k

We report the template-directed synthesis of a well-defined, kinetically stable [5]molecular necklace with dialkylammonium ion (R₂NH ₂⁺) as recognition site and DB24C8 as macrocycle. A thread containing four dialkylammonium ions with olefin at both ends was first synthesized and then subjected to threading with an excess amount of DB24C8 to form pseudo[5]rotaxane, which in situ undergoes ring closing metathesis at the termini with second generation Grubbs catalyst to yield the desired [5]molecular necklace. The successful synthesis of [5]molecular necklace is mainly attributed to the self-assembly and dynamic covalent chemistry which allows the formation of thermodynamically most stable product. The self-assembly of the DB24C8 ring onto the recognition site known as templating effect was driven by noncovalent stabilizing interactions like [N⁺-H...O], [C-H...O] hydrogen bonds as well as [π...π] interactions which is facilitated in non-polar solvents. The reversible nature of olefin metathesis reaction makes it suitable for dynamic covalent chemistry since proof-reading and error-checking operates until it generates thermodynamically the most stable interlocked molecule. Riding on the success of [5]molecular necklace, we went a step further and attempted to synthesize [7]molecular necklace using the same protocol. This led to the synthesis of another thread with olefin at both ends but having six dibenzylammonium ions along the thread. However, the extremely poor solubility of this thread containing six secondary ammonium ions limits the self-assembly process even after we replaced the typical PF₆ ^- counter anion with a more lipophilic BPh₄^- anion. Although the poor solubility of the thread remains the bottleneck for making higher order molecular necklaces yet this approach of "threading-followed-by-ring-closing-metathesis" for the first time produces kinetically and thermodynamically stable, well-defined, homogeneous molecular necklace which was well characterized by one-dimensional, two-dimensional, variable temperature proton NMR spectroscopy and ESI mass spectroscopy.

Full text of DOI:10.1039/c0ob01034k

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PAPER
Template-directed synthesis of kinetically and thermodynamically stable
molecular necklace using ring closing metathesis†
Suvankar Dasgupta and Jishan Wu*
Received 16th November 2010, Accepted 10th February 2011
DOI: 10.1039/c0ob01034k
We report the template-directed synthesis of a well-defined, kinetically stable [5]molecular necklace
+
with dialkylammonium ion (R2NH2 ) as recognition site and DB24C8 as macrocycle. A thread
containing four dialkylammonium ions with olefin at both ends was first synthesized and then
subjected to threading with an excess amount of DB24C8 to form pseudo[5]rotaxane, which in situ
undergoes ring closing metathesis at the termini with second generation Grubbs catalyst to yield the
desired [5]molecular necklace. The successful synthesis of [5]molecular necklace is mainly attributed to
the self-assembly and dynamic covalent chemistry which allows the formation of thermodynamically
most stable product. The self-assembly of the DB24C8 ring onto the recognition site known as
templating effect was driven by noncovalent stabilizing interactions like [N+–H ◊ ◊ ◊ O], [C–H ◊ ◊ ◊ O]
hydrogen bonds as well as [p ◊ ◊ ◊ p] interactions which is facilitated in non-polar solvents. The reversible
nature of olefin metathesis reaction makes it suitable for dynamic covalent chemistry since
proof-reading and error-checking operates until it generates thermodynamically the most stable
interlocked molecule. Riding on the success of [5]molecular necklace, we went a step further and
attempted to synthesize [7]molecular necklace using the same protocol. This led to the synthesis of
another thread with olefin at both ends but having six dibenzylammonium ions along the thread.
However, the extremely poor solubility of this thread containing six secondary ammonium ions limits
-
the self-assembly process even after we replaced the typical PF6 counter anion with a more lipophilic
-
BPh4 anion. Although the poor solubility of the thread remains the bottleneck for making higher
order molecular necklaces yet this approach of “threading-followed-by-ring-closing-metathesis” for the
first time produces kinetically and thermodynamically stable, well-defined, homogeneous molecular
necklace which was well characterized by one-dimensional, two-dimensional, variable temperature
proton NMR spectroscopy and ESI mass spectroscopy.
but need to disrupt a covalent bond to separate the molecules.
The various kinds of mechanically interlocked molecules include
Introduction
The practical limitation of the “engineering down” approach1
in the field of nanotechnology and the realization of the cu-
mulative effects of weak noncovalent interactions existing in
nature2 gave chemists the impetus to emulate these interactions
in chemical systems, giving rise to a new field of chemistry,
known as supramolecular chemistry.3 Molecular recognition and
self-assembly4 has remained the key to the development of
supramolecular chemistry over years. Starting from simple host–
guest chemistry,5 supramolecular chemistry came a long way
and made possible the synthesis of various kinds of mechani-
cally interlocked molecules.6 Mechanically interlocked molecule
involves two or more molecules not connected by covalent bond
rotaxanes,7 catenanes,8 knots,9 molecular necklaces,10 suitane,11
and Borromean ring12 etc. The synthesis of such unorthodox
molecule utilizes template-directed strategy13 which functions
on molecular recognition and self-assembly. Conventionally the
molecular recognition and self-assembly process operating during
the synthesis of interlocked molecules are thermodynamically
controlled whereas the final and crucial step for the interlocking
remains kinetically controlled which leads to the formation of
undesirable unlocked oligomeric by-product. To address this acute
problem dynamic covalent chemistry (DCC)14 has been exploited.
DCC refers to the reversible chemical reactions involving
making and breaking of chemical bonds under thermodynamic
control. The reversibility aspect of DCC makes it suitable for
the synthesis of interlocked molecules as there lays the scope for
“error checking” and “proof-reading” which will eventually result
in the formation of thermodynamically most stable and desirable
interlocked molecules. Hence the template-directed approach is
Department of Chemistry, National University of Singapore, 3 Science Drive
3, Singapore, 117543. E-mail: chmwuj@nus.edu.sg; Fax: (+ 65) 6779-1691
† Electronic supplementary information (ESI) available: NMR and mass
spectra. See DOI: 10.1039/c0ob01034k
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used in conjunction with DCC for the synthesis of various
mechanically interlocked molecules. Reversible reactions like
imine formation,15 ester formation,16 disulfide formation,17 and
olefin metathesis18 have been particularly used for the synthesis of
interlocked molecules.
motivated us to develop a new synthetic strategy to construct
molecular necklaces, in particular, both thermodynamically and
kinetically stable molecular necklaces. In this paper, we introduce
“threading-followed-by-ring-closing-metathesis” approach to suc-
cessfully synthesize molecular necklace. Our strategy utilizes a
well-known self-assembly process between macrocycle dibenzo-
24-crown-8 (DB24C8) and dibenzylammonium ion20 followed by
reversible ring closing metathesis with Grubbs’s 2nd generation
catalyst. Although similar strategy has been utilised for making
[n]catenanes (n = 2, 3),8b but for molecular necklace synthesis our
strategy still remains unique.
Herein, we describe the attempt to make [5]MN and [7]MN
from the two threads 1·(PF6)4 and 2·(PF6)6 (Fig. 1) respectively,
which are having well defined dibenzylammonium ions along
the thread and long alkyl chains with olefin at their termini.
The major challenge for the synthesis of MN is to curb the
formation of undesirable oligomeric/interlocked molecules which
beckons for careful design of the thread. Therefore each segment
of the thread was designed in a way to facilitate the formation of
desired MN. meta-Substituted benzene moieties have been used for
macrocyclization21 and thus herein, the meta-substituted phenyl
group is used as core to facilitate intramolecular cyclization.
The polyethoxy backbone imparts flexibility to the thread in a
manner that post self-assembly process there is not much strain
involved in the system for the terminal olefinic bonds to remain
in close proximity. In addition, the polyethoxy group increases
the solubility of the thread overall. The well known self-assembly
process of DB24C8 and dibenzylammonium ions influenced the
inclusion of linearly attached dibenzylammonium ions next to
each other along the thread. The long alkyl chain relieves the
possible strain generated during ring closing metathesis of the self-
assembled molecule. Solubility of the thread in non-polar solvent
is also expected to be enhanced due to long alkoxy chains.
Although there are ample literatures citing synthesis of
rotaxane,7 polyrotaxane19 and catenane8 yet there remains few
limited literature10 on molecular necklace which underlines the
synthetic difficulty in making molecular necklace. A molecular
necklace consists of three or more rings mechanically locked
(threaded) onto a large ring. Molecular necklace are topological
isomers of catenanes and uniquely defined for a given number
of rings. It is denoted as [n]MN which means (n -1) rings are
threaded onto a large ring. The smallest molecular necklace
remains [4]MN having three rings threaded onto a large ring.
[2]MN and [3]MN are essentially [2]catenane and [3]catenane.
The molecular necklace happens to be a serendipitous scientific
discovery. The first molecular necklace being accidently discovered
by Sauvage and co-workers during the synthesis of [3]catenane.10a
A mixture of [n]MN (n = 4–7) were observed and characterized
by ESI mass spectroscopy. Stoddart and co-workers obtained
[4]MN as a by-product during the synthesis of oligocatenanes10b
and polyrotaxanes.10e Since then Kim and co-workers contributed
immensely towards the synthesis of molecular necklaces. Using the
metal coordination chemistry of copper(II) and platinum(II) along
with self-assembly of macrocycle cucurbit[6]uril, they have suc-
cessfully synthesized and characterized [4]MN10c,f and [5]MN.10d,f
The striking difference between the accidental discoveries and
intended synthesis of molecular necklaces lies in the crucial final
step which takes place under kinetic control and thermodynamic
control, respectively. The metal coordination driven synthesis
provides two advantages over conventional synthesis, the first
being the coordination geometry of the metal ion which can be
suitably manoeuvred according to the MN of interest and the
second being the involvement of reversible metal–ligand exchange
process which gives the scope for “error checking” and “proof-
reading”, thus generating the most stable desired MN. Later Kim
and co-workers report the synthesis of even higher molecular
necklace [6]MN10h utilizing only self-assembly. This commendable
work was facilitated by strong intermolecular charge-transfer
interactions between identical guest molecules (having an electron
donor and an electron acceptor connected by a rigid linker
with a proper angle) inside the cavity of host cucurbit[8]uril.
Harada and co-workers reported the formation of poly(catenane)
(Molecular necklace)10g and poly(polyrotaxane) by photoreaction
of 9-anthracene-capped polyrotaxane. Very recently Grubbs and
co-workers reported the synthesis of [4]MN10i using self-assembly
of diolefin crown ether-type fragment around dialkylammonium
ion followed by olefin metathesis with Hoveyda–Grubbs 2nd
generation catalyst.
Fig. 1 Molecular structure of threads 1·(PF6)4 and 2·(PF6)6.
Results and discussion
Synthesis of key intermediates 5, 13 and 19
The synthetic route for key intermediates 5, 13 and 19 is shown
in Scheme 1. Resorcinol is reacted with 2-(2-chloroethoxy)ethanol
to give dihydroxy compound 3 which is then ditosylated to yield
compound 4 in 55% yield for two steps. 4-Hydroxybenzaldehyde
undergoes O-alkylation with 4 to give the key intermediate 5
in a low yield (30%) mainly due to its poor solubility which
made purification very difficult. Compound 6 is then obtained
in 79% yield from 4- hydroxybenzaldehyde by O-alkylation with
11-bromoundec-1-ene. Methyl-4-(aminomethyl)-benzoate (7) is
condensed with compound 6 in toluene to give the corresponding
Although the reported literatures on the synthesis of molecular
necklace are appreciable yet there is a lack of general synthetic
strategy to construct well-defined, homogeneous molecular neck-
lace. The idiosyncratic coordination geometry of a particular
metal ion limits the versatility of metal coordination chemistry
in the synthesis of molecular necklace. Moreover, the obtained
[n]MN by coordination chemistry is not kinetically stable as
external stimuli (temperature, pH, and competitive ligand) can
destroy the thermodynamically stable interlocked structures. This
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Scheme 1 Synthetic route to key intermediates 5, 13, and 19.
imine in quantitative yield which is then reduced by sodium
borohydride in a mixture of THF and methanol to give the
amine 8 in nearly quantitative yield. The secondary amine 8 is
then converted in 92% yield to its tert-butyloxycarbonyl (Boc)
protected form 9 which is then reduced with lithium aluminium
hydride (LAH) to give the corresponding benzyl alcohol 10 in 84%
yield. The alcohol is then transformed into the key intermediate 13
via high yielding steps, bromination (11), azidation (12), followed
by the reduction of azide 12 in moderate yield. Following a
similar synthetic approach, the key intermediate 19 which has
two additional benzyl N-Boc unit compared with 13 can be
prepared by similar sequential processes such as condensation,
reduction by sodium borohydride, Boc-protection, reduction by
LAH, bromination, azidation and reduction by PPh3.
with aqueous NH4PF6 to yield the threads 1·(PF6)4 and 2·(PF6)6,
respectively, both in quantitative yield. Counter ion exchange is
done to ensure that the solubility of the salts increase in organic
solvents.
Synthesis of [5]molecular necklace 23·(PF6)4
The thread 1·(PF6)4 exhibits good solubility in acetonitrile how-
ever the solubility remains poor in chlorinated solvents such
as chloroform and dichloromethane (DCM). The solubility of
DB24C8 is just the other way. For the self-assembly process, the
thread 1·(PF6)4 and the macrocycle DB24C8 or their mixture needs
to be soluble in a common medium. Even the mixture of 1·(PF6)4
and DB24C8 was found to exhibit poor solubility in either of the
solvents implying absence of self-assembly. To resolve this issue,
a mixture of chloroform and acetonitrile solvents in 3 : 1 ratio22
(henceforth will be referred as mixed solvent) was tried (Scheme 3).
Interestingly the mixture of 1·(PF6)4 and DB24C8 was soluble in
the mixed solvent indicating self-assembly.23 Therefore this mixed
solvent was chosen for carrying out self-assembly process.
Synthesis of threads 1·(PF6)4 and 2·(PF6)6
As shown in Scheme 2, the intermediate 5 is condensed with 2
equivalents of 13 to give the corresponding imine in quantitative
yield which is subsequently reduced to 20 by sodium borohy-
dride in 65% yield. Similar reactions between 5 and 19 provide
analogous 21 with two additional benzyl N-Boc units in 81%
yield. Compounds 20 and 21 are subjected to Boc deprotection
with trifluoroacetic acid (TFA) followed by counter ion exchange
To ensure complete threading, we used 20 equivalents of
DB24C8 for 1 equivalent of 1·(PF6)4, making it 5 equivalent of
DB24C8 for each dibenzylammonium ion. In the mixed solvent,
a mixture of DB24C8 and 1·(PF6)4, in the above mentioned ratio
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expected to have predominantly 22·(PF6)4 and excess DB24C8.
Although there exists a dynamic equilibrium between the threaded
and dethreaded species yet equilibrium is expected to be shifted
towards the threaded species in non-polar solvents given that
threaded species is thermodynamically more stable in non-polar
solvents. 1H NMR spectrum of the residue in CDCl3 clearly shows
up-field resonance shift of the aromatic protons of the benzyl
units on the thread 1·(PF6)4, indicating a successful threading
of the DB24C8 onto the dibenzylammonium sites under this
mixed solvent condition. This was further supported by the fact
that a clear solution was obtained by dissolving the residue in
dichloromethane. In the final step, the clear dichloromethane
solution suggesting only the presence of pseudorotaxane 22·(PF6)4
was treated with Grubbs’s 2nd generation catalyst under refluxing
condition to obtain the desired [5]MN 23·(PF6)4 in 20% yield
(Scheme 3). Although the desired [5]MN 23·(PF6)4 dominated
the reaction mixture, yet there were trace amounts of [4]MN
and [3]catenane, which could only be detected by ESI mass
spectrometry of the crude reaction mixture. To ascertain the
complete reversibility, successful ring closing metathesis and
generation of thermodynamically most stable desired product, we
performed the final ring closing metathesis reaction under strictly
dry and extremely dilute condition (0.0003 M) with excess (20
equivalent) DB24C8 for 60 h so that we could exclusively get
[5]MN 23·(PF6)4 by eliminating the possibility for the formation of
less stable interlocked molecules ([4]MN, [3]catenane, [2]rotaxane)
and non-interlocked olefin oligomers. However even after 7 days
the presence of [4]MN and [3]catenane could be traced. But the fact
that [4]MN and [3]catenane were always present in trace amount
could be testified by TLC progress. The [4]MN and [3]catenane
never showed up in the TLC plate even when the TLC was
run with high polarity eluent like 1 : 4 MeOH–CHCl3 and 1 : 4
CH3CN–CHCl3. Therefore the crude reaction mixture mainly had
the [5]MN 23·(PF6)4 and excess unused DB24C8.
Scheme 2 Synthetic route to threads 1·(PF6)4 and 2·(PF6)6.
The purification of interlocked molecules is generally chal-
lenging due to high polarity, presence of side products and
limited solubility. In our case we utilised dynamic covalent
chemistry, the olefin metathesis as the final interlocking step to
eliminate the undesirable side products. Although the [4]MN and
[3]catenane formation could not be avoided however the amount
is so little that effectively their presence can be ignored. So the
trace amounts of [4]MN and [3]catenane did not complicate
the purification and isolation of [5]MN 23·(PF6)4. The column
chromatographic purification however remained challenging due
to the presence of excess amount of DB24C8 in the system
which could not be eluted out with ease due to its poor solu-
bility in both methanol–chloroform and acetonitrile–chloroform
solvent system. The methanol–chloroform system was chosen
over acetonitrile–chloroform system for purification of [5]MN
23·(PF6)4 because the solubilising capability of the first system
is better. The isolation of pure [5]MN 23·(PF6)4 was rendered
difficult due to the difficulty in removing the less polar DB24C8
from the system which is corroborated by the fact that during the
purification, a large fraction containing the mixture of DB24C8
and the desired product [5]MN 23·(PF6)4 is always obtained, which
accounts for the low isolated yield (20%) of pure [5]MN 23·(PF6)4
(Scheme 3). However the conversion ratio of pseudo [5]rotaxane
22·(PF6)4 to [5]MN 23·(PF6)4 is much higher than the isolated
yield, which could also be perceived from the TLC plate.
Scheme 3 Synthetic route to [5]MN 23·(PF6)4.
was stirred. The clear solution indicated the completion of self-
assembly process and formation of pseudorotaxane 22·(PF6)4.23
The clear solution was evaporated (under reduced pressure
without heating avoiding any risk of disassembly) leaving a residue
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Characterization of [5]molecular necklace 23·(PF6)4
(Fig. 2), briefly 2D NOESY (Figure S2†), variable temperature
NMR (Fig. 3) and ESI mass spectroscopy (Fig. 4).
In Fig. 2, the 1H NMR spectra of 1·(PF6)4 and 23·(PF6)4,
recorded in CD3CN at an operating frequency of 500 MHz
are compiled into a stacked form to appreciate the shift in
resonance peaks affected due to the threading of DB24C8 rings
onto the dibenzylammonium ions of 1·(PF6)4. The threading of
The formation of [5]MN 23·(PF6)4 is well supported by one-
dimensional (1D), two-dimensional (2D), variable temperature
proton NMR spectroscopy and ESI mass spectroscopy. The 2D
COSY, NOESY NMR spectral data are discussed in details in
the Supporting Information. Herein, we discuss the 1D NMR
Fig. 2 1H NMR spectra of A) 1·(PF6)4 (500 MHz, CD3CN), B) [5]MN 23·(PF6)4 (500 MHz, CD3CN).
Fig. 3 1H NMR spectra (500 MHz, C2D2Cl4) of [5]MN 23·(PF6)4 at various temperatures.
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to 350 K, the resonance peak for aromatic protons (Hl, Hm) show
a significant downfield shift from ~6.9 ppm to ~7.1 ppm with
notable downfield shift for other aromatic protons of the system
(Hi, Hp, HDB). The downfield shift for the benzyl protons (Hk,
Hn, Hj, Ho) of the system could also be observed. Increasing the
temperature to 370 K caused further downfield shift for both
the aromatic and the benzyl protons (Hl, Hm, Hi, Hp, HDB, Hk,
Hn, Hj, Ho) to varying extent. On cooling the system to 320 K,
the protons (Hl, Hm, Hi, Hp, HDB, Hk, Hn, Hj, Ho) displayed
upfield shift in resonance peaks which shifted further upfield
on lowering the temperature to 300 K. The observed shifts can
only be explained for the structure proposed for 23·(PF6)4. The
toughness of mechanical bond holding the macrocycle DB24C8
to the dibenzylammonium ion in 23·(PF6)4 relies on the strength
of H-Bond formed which could be perturbed by the supply of
energy. As we increase the temperature, the thermal energy of
the system increases, causing disruption of H-bonds and shuttling
of the freed macrocycle along the thread. The downfield shift
observed is due to an increase in percentage of freed macrocycle
making more of the dibenzylammonium ions deshielded. However
even at 370 K the resonance peak for aromatic protons (Hl,
Hm, Hi, Hp, supposedly the most affected due to heating) of
23·(PF6)4 (Fig. 3) remain shifted to high field by a significant
margin when compared with the corresponding resonance peak
for open thread 1·(PF6)4 aromatic protons (Fig. 2). This observed
difference in resonance peak value accounts for the absence of
dethreading process, excluding the possibility of 23·(PF6)4 being
a pseudorotaxane. Therefore the downfield shifts observed during
heating process indicate temporal dislodgement of macrocycles
from the recognition sites (causing deshielding) and shuttling of
macrocycles along the thread. However, during the cooling process
the resonance peak keeps shifting to high field and eventually
returns to the initial state when cooled to 300 K which can only
be explained by the H-bond driven regrouping of macrocycles
(scattered along the thread) onto the dibenzylammonium ions.
Thus both heating and cooling experiment confirms the formation
of [5]MN.
The role of ESI mass spectroscopy in elucidating structure is
always prominent in the field of supramolecular chemistry. The
observation of m/z peaks corresponding to the charged molecular
fragment of supramolecular species is typically observed by
ESI technique. We employed LCMS-IT-TOF technology for our
compound 23·(PF6)4which detects mass in ESI mode. The LC-
ESI-MS for [5]MN 23·(PF6)4 in acetonitrile clearly showed two
peaks 755.6145 and 1007.1636 that can be assigned to the [M-
4PF6]4 + and [M-3PF6-HPF6]3 + species respectively in which M is
[5]MN 23·(PF6)4 (Fig. 4). The absence of peak corresponding to
the thread 1·(PF6)4 ruled out the presence of any pseudorotaxane
species. The lack of peaks corresponding to any undesirable
interlocked/supramolecular species confirms the presence of only
[5]molecular necklace whose molecular fragments are observed.
Isotopic distribution of mass further proved the existence of
species for the peaks assigned.
Fig. 4 ESI mass spectrum for [5]MN 23·(PF6)4 (A) and the isotope
distribution of the major peaks (B and C).
DB24C8 onto the dibenzylammonium ions shields the aromatic
protons in its proximity due to which there will be an upfield
shift in the resonance value for the shielded protons. For the
thread 1·(PF6)4, the aromatic protons (Hl, Hm) are expected to
be most shielded due to threading. Other aromatic protons (Hi,
Hp, Hh, Hq) will experience lesser shielding effect. The observed
upfield shift for aromatic protons (Hl, Hm, Hi, Hp, Hh, Hq) and
downfield shift for benzyl (methylene) protons (Hk, Hn, Hj, Ho)
in 23·(PF6)4 (compared with 1·(PF6)4) accounts for the complete
threading of DB24C820,22 onto all the four dibenzylammonium
ions. Furthermore, the strong NOE cross-peaks (Figure S2†)
observed for 23·(PF6)4 indicates spatial interactions between
the thread and DB24C8. DB24C8 (referred as DB in spectral
assignment) show intramolecular NOE cross-peaks with the
aromatic protons (Hl, Hm, Hi, Hp, Hh, Hq), benzyl (methylene)
protons (Hk, Hn, Hj, Ho) and ammonium protons as expected
from the structure elucidated for [5]MN 23·(PF6)4. In addition,
the absence of terminal olefin protons (Hv and Hw), presence
of disubstituted olefin protons (Hz) and a distinct set of peaks
observed for aromatic protons (Hl, Hm, Hi, Hp, Hh, Hq) indicate
the compound 23·(PF6)4 to be a molecular necklace resembling
the structure proposed. The integration ratios of all the aromatic
protons, olefin protons and benzyl protons agree well with this
structure. Had it been a pseudorotaxane, signals corresponding to
uncomplexed thread, eight possible partially complexed threads
(2 isomeric pseudo[2]rotaxane, 4 isomeric pseudo[3]rotaxane and
2 isomeric pseudo[4]rotaxane) and uncomplexed crown ether
would have been observed in addition to those attributed to the
complexed species.23 This is because for dibenzylammonium ion
motif the threading and dethreading of DB24C8 are both slow
on 1H NMR time scale at room temperature24 and we could have
never observed a distinct set of peaks for the protons of interest.
Moreover, the absence of peaks corresponding to uncomplexed
DB24C8 eliminates the possibility for the exclusive formation of
only pseudo[5]rotaxane in the presence of excess DB24C8.23
To further confirm the proposed structure of 23·(PF6)4 and
eliminate any possibility of this being a pseudorotaxane, we
recorded the 1H NMR spectra of 23·(PF6)4 in C2D2Cl4 at
increasing and decreasing temperatures. Fig. 3 compares the shift
in resonance peak value of 23·(PF6)4 with temperature variations.
As the temperature is increased from 300 K (room temperature)
Attempted synthesis of [7]molecular necklace
The successful synthesis of [5]MN spurred us to make the higher
homologue [7]MN utilising the same protocol. Accordingly the
thread 2·(PF6)6 was designed and synthesized using conventional
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organic synthesis as shown above. The solubility of 2·(PF6)6 is
extremely poor in almost all organic solvents and it gets no better
with excess DB24C8 in the mixed solvent. The six ammonium
ion containing thread 2·(PF6)6 seems to be extremely polar and
hence to make it less polar, counter ion exchange was done with
a more lipophilic salt NH4BPh4 to generate 2·(BPh4)6 (Scheme 4).
However, the solubility increases to an extent that it could only
be soluble in methanol and not in acetonitrile or nitromethane.
Keeping in mind about the limited solubility, we stirred 2·(BPh4)6
along with excess DB24C8 in mixed solvent for a long time with
occasional heating, but the solution never becomes clear which
indicates threading does not take place to provide the desired
pseudo [7]rotaxane 24·(BPh4)6. Thus, the limited solubility of the
six ammonium ion containing thread 2·(PF6)6/2·(BPh4)6 impedes
the threading of DB24C8, eluding the synthesis of [7]MN.
tion chemistry. Therefore, we attempted the synthesis of just the
higher homologue [7]molecular necklace. Unfortunately we failed
to get the desired [7]molecular necklace. The failure however is
attributed to the poor solubility of the ammonium ion containing
thread. Since this approach is not substrate specific, this idea can
be extended to construct a variety of molecular necklaces based on
different kind of recognition sites, lipophilic counteranions, and
macrocycles.
Experimental
Materials and methods
All reagents and starting materials including DB24C8 were
bought from commercial suppliers and used without further pu-
rification. Anhydrous solvents, N,N-dimethylformamide (DMF),
dichloromethane were obtained from dry distillation of their
analytical grade by CaH2. Anhydrous tetrahydrofuran (THF)
was obtained by distilling its analytical grade with sodium-
benzophenone. Always freshly distilled dry solvents were used.
Column chromatography was performed on silica gel 60 (Merck
40–60 nm, 230–400 mesh). Deuterated solvents (Cambridge
Isotope Laboratories) for NMR spectroscopic analyses were used
as received. All NMR spectra were recorded on Bruker AMX500
at 500 MHz and Bruker ACF300 at 300 MHz spectrometers with
tetramethylsilane (TMS) as the internal standard. The 2D COSY,
NOESY NMR spectral data were recorded on Bruker AMX500 at
500 MHz. All chemical shifts are quoted in ppm with multiplicities
being denoted by s (singlet), d (doublet), t (triplet), m (multiplet),
and br (broad). Mass spectra were recorded on Finnigan LCQ
quadrapole ion trap mass spectrometer and Shimadzu LCMS-IT-
TOF, in ESI mode.
2,2¢-(2,2¢-(1,3-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy)-
diethanol (3). A mixture of resorcinol (2 g, 18.1 mmol), 2-
(2-chloroethoxy)ethanol (11.36 g, 90.8 mmol), K2CO3 (15 g,
◦
109 mmol), KI (0.15 g, 0.9 mmol) was heated to 80 C in DMF
(50 mL) under nitrogen atmosphere for 2 days. The mixture was
filtered to remove undissolved excess K2CO3. The solvent was
removed in vacuum to leave a residue which was extracted with
CHCl3. The organic layer was washed with water, dried over anhy-
drous Na2SO4, and the solvent was then removed under vacuum.
The crude residue was purified by column chromatography (silica
gel, acetone/hexane = 1 : 1) to give compound 3 (3.1 g, 60%). 1H
NMR (500 MHz, CDCl3): d = 7.16 (1 H, t, J = 8.2 Hz, Ar), 6.54
(2 H, br, Ar), 6.52 (1 H, d, J = 2.55 Hz, Ar), 4.12 (4 H, t, J =
4.4 Hz, CH2), 3.85 (4 H, t, J = 5.05 Hz, CH2), 3.75 (4 H, br, CH2),
3.67 (4 H, m, CH2), 2.20 (2 H, br, -OH). 13C NMR (125 MHz,
CDCl3): d = 159.9, 129.9, 107.3, 102.0, 72.6, 69.7, 67.5, 61.8. ESI
MS: m/z = 309.1 ([M + Na+]); calculated exact mass: 286.14. HR
ESI MS: m/z = 309.1323 ([M + Na+]); calculated exact mass for
C14H22NaO6: 309.1309.
Scheme 4 Attempted threading of 2·(BPh4)6.
Conclusion
In this paper, we report a new approach “threading-followed-by-
ring-closing-metathesis” for the synthesis of molecular necklaces.
This approach exploits the known self-assembly of DB24C8 with
dibenzylammonium ion and the dynamic covalent chemistry in the
form of olefin metathesis which is carried out by 2nd generation
Grubbs catalyst. Utilizing the above mentioned approach, we
could successfully synthesize a well-defined, well-characterized
homogeneous [5]molecular necklace, which is both kinetically
and thermodynamically stable. The “threading-followed-by-ring-
closing-metathesis” approach could be generalised for synthesiz-
ing molecular necklaces since it does not involve metal coordina-
2,2¢-(2,2¢-(1,3-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy)-
bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) (4). Com-
pound 3 (2.45 g, 8.5 mmol) was dissolved in dry DCM (22 mL)
under nitrogen atmosphere. To this was added triethylamine
(3.47 g, 34.3 mmol) and the mixture was stirred under nitrogen
◦
atmosphere. The reaction mixture was cooled to 0 C, and then
toluene-4-sulfonyl chloride (4.9 g, 25.7 mmol) was added. The
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reaction mixture was stirred for 36 h. The solvent was removed
under vacuum leaving the crude residue which was purified by
column chromatography (silica gel, acetone/hexane = 1 : 2) to give
compound 4 (4.68 g, 92%). 1H NMR (500 MHz, CDCl3): d = 7.78
(4 H, d, J = 8.2 Hz, Ar), 7.30 (4 H, d, J = 8.2 Hz, Ar), 7.15 (1
H, t, J = 8.2 Hz, Ar), 6.49 (2 H, dd, J = 8.2 Hz, J = 1.9 Hz,
Ar), 6.44 (1 H, t, J = 2.55 Hz, Ar), 4.18 (4 H, t, J = 4.4 Hz, CH2),
4.01 (4 H, t, J = 4.4 Hz, CH2), 3.77 (8 H, m, CH2), 2.40 (6 H, s,
PhCH3). 13C NMR (125 MHz, CDCl3): d = 159.8, 144.8, 132.9,
129.9, 129.8, 127.9, 107.1, 101.8, 69.8, 69.2, 68.9, 67.4, 21.6. ESI
MS: m/z = 617.0 ([M + Na+]); calculated exact mass: 594.16. HR
ESI MS: m/z = 617.1487 ([M + Na+]); calculated exact mass for
C28H34NaO10S2: 617.1486.
a Dean–Stark apparatus under nitrogen atmosphere. The solvent
was removed under vacuum, and the imine obtained was dissolved
in THF (150 mL) and MeOH (150 mL) to which NaBH4 (5.62 g,
148.6 mmol) was added in portions. After stirring for overnight,
the solvent was removed under vacuum leaving a residue which
was extracted by CHCl3. The organic layer was washed by brine,
dried over anhydrous Na2SO4, and the solvent was then removed
under vacuum leaving the crude product 8 in quantitative yield
which was used for the next step without further purification. 1H
NMR (500 MHz, CDCl3): d = 8.0 (2 H, d, J = 8.2 Hz, Ar), 7.43 (2
H, d, J = 8.2 Hz, Ar), 7.23 (2 H, d, J = 8.8 Hz, Ar), 6.86 (2 H, d,
J = 8.2 Hz, Ar), 5.81 (1 H, m, C(H) = CH2), 4.96 (2 H, m, CH =
C(H2)), 3.94 (2 H, t, J = 6.3 Hz, CH2), 3.91 (3 H, s, OCH3), 3.84
(2 H, s, CH2), 3.73 (2 H, s, CH2), 2.06 (2 H, m, CH2), 1.80 (2 H,
m, CH2), 1.47 (12 H, br, CH2). 13C NMR (125 MHz, CDCl3): d =
167.0, 158.3, 145.8, 139.2, 131.9, 129.7, 129.3, 128.8, 127.9, 114.5,
114.1, 68.0, 52.63, 52.61, 52.0, 33.8, 29.5, 29.39, 29.36, 29.3, 29.1,
28.9, 26.0. ESI MS: m/z = 423.9 ([M + H+]); calculated exact mass:
423.28. HR ESI MS: m/z = 424.2858 ([M + H+]); calculated exact
mass for C27H38NO3: 424.2846.
3
4
4,4¢-(2,2¢-(2,2¢-(1,3-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis-
(oxy)bis(ethane-2,1-diyl))bis(oxy)dibenzaldehyde (5). A mixture
of compound 4 (4.4 g, 7.4 mmol), 4- hydroxybenzaldehyde (1.98
g, 16.2 mmol) and K2CO3 (4.49 g, 32.5 mmol) was heated to
100 ◦C in dry DMF (25 mL) under nitrogen atmosphere for 3 days.
The mixture was filtered to remove undissolved excess K2CO3.
The solvent was removed in vacuum to leave a residue which was
extracted with ethyl acetate. The organic layer was washed with
water, dried over anhydrous Na2SO4, and the solvent was then
removed under vacuum. The crude residue was purified by column
chromatography (silica gel, EA/hexane = 1 : 1) to give compound
5 (1.09 g, 30%). M.p.: 97–98 ◦C. 1H NMR (500 MHz, CDCl3): d =
9.87 (1 H, s, CHO), 7.82 (4 H, d, J = 8.8 Hz, Ar), 7.15 (1 H, t,
J = 8.2 Hz, Ar), 7.02 (4 H, d, J = 8.2 Hz, Ar), 6.51 (2 H, dd, 3J =
8.2 Hz, 4J = 1.9 Hz, Ar), 4.23 (4 H, t, J = 4.4 Hz, CH2), 4.12 (4 H,
t, J = 4.4 Hz, CH2), 3.95 (4 H, t, J = 5.0 Hz, CH2), 3.91 (4 H, t,
J = 5.0 Hz, CH2). 13C NMR (125 MHz, CDCl3): d = 190.7, 163.8,
159.9, 131.9, 130.1, 129.9, 114.9, 107.2, 101.9, 70.0, 69.7, 67.8,
67.5. ESI MS: m/z = 517.1 ([M + Na+]); calculated exact mass:
494.19. HR ESI MS: m/z = 517.1842 ([M + Na+]); calculated exact
mass for C28H30NaO8 517.1833.
Methyl 4-((tert-butoxycarbonyl(4-(undec-10-enyloxy)benzyl)-
amino)methyl)benzoate (9). Compound 8 (12.5 g, 29.5 mmol)
was dissolved in CHCl3 (250 mL) under nitrogen atmosphere.
To this was added triethylamine (6.57 g, 64.9 mmol) and stirred
for 5 min. This was followed by addition of Boc2O (12.88 g,
59.0 mmol) and stirring of the reaction mixture for 24 h. The
solvent was removed under vacuum leaving the crude residue
which was purified by column chromatography (silica gel,
1
EA/hexane = 1 : 9) to give compound 9 (14.2 g, 92%). H NMR
(300 MHz, CDCl3): d = 8.0 (2 H, d, J = 8.2 Hz, Ar), 7.11 (8 H, br,
Ar), 6.85 (2 H, d, J = 8.4 Hz, Ar), 5.81 (1 H, m, C(H) = CH2), 4.96
(2 H, m, CH C(H2)), 4.35 (4 H, br, CH2), 3.96 (2 H, br, CH2),
3.91 (3 H, s, OCH3), 2.07 (2 H, m, CH2), 1.82 (2 H, m, CH2) 1.52
(21 H, br, CH2 & Boc). 13C NMR (125 MHz, CDCl3): d = 166.9,
158.5, 155.9, 139.1, 129.8, 129.4, 129.0, 128.8, 127.7, 127.0, 114.5,
114.1, 80.2, 68.0, 52.0, 49.0, 48.6, 33.7, 29.5, 29.4, 29.3, 29.2,
29.1, 28.9, 28.4, 27.4, 26.0. ESI MS: m/z = 546.1 ([M + Na+]);
calculated exact mass: 523.33. HR ESI MS: m/z = 546.3201 ([M +
Na+]); calculated exact mass for C32H45NNaO5: 546.3190.
4-(Undec-10-enyloxy)benzaldehyde (6).
A mixture of 4-
hydroxybenzaldehyde (5 g, 40.9 mmol), 11-bromoundec-1-ene
(11.45 g, 49.1 mmol) and K2CO3 (16.97 g, 122.8 mmol) was
refluxed in acetone (275 mL) for 2 days under nitrogen atmosphere.
The mixture was filtered to remove undissolved excess K2CO3.
The solvent was removed in vacuum to leave a residue which
was extracted with CHCl3. The organic layer was washed with
water, dried over anhydrous Na2SO4, and the solvent was then
removed under vacuum. The crude residue was purified by column
chromatography (silica gel, EA/hexane = 1 : 4) to give compound
6 (8.8 g, 79%). 1H NMR (300 MHz, CDCl3): d = 7.83 (2 H, d, J =
8.7 Hz, Ar), 7.00 (2 H, d, J = 8.7 Hz, Ar), 5.81 (1 H, m, C(H) =
CH2), 4.96 (2 H, m, CH C(H2)), 4.03 (2 H, t, J = 6.57 Hz, CH2),
Tert-butyl 4-(hydroxymethyl)benzyl(4-(undec-10-enyloxy)ben-
zyl)carbamate (10). Compound 9 (13.53 g, 25.8 mmol) was
dissolved in dry THF (260 mL) under nitrogen atmosphere. The
solution was cooled to 0 ◦C followed by addition of LAH (1.96 g,
51.6 mmol) in portions. The resulting suspension was gradually
allowed to warm to room temperature and was stirred overnight.
The excess LAH was quenched by slow addition of ground
powder of Na2SO4·10H2O and celite (1 : 1, w/w). The mixture
was stirred for 30 min and filtered. The filtrate containing the
desired compound was concentrated in vacuum, extracted with
CHCl3, washed with water, dried over anhydrous Na2SO4, and the
solvent was then removed under vacuum leaving a residue which
was purified by column chromatography (silica gel, EA/hexane =
2.07 (2 H, m, CH2), 1.85 (2 H, m, CH2), 1.48 (12 H, br, CH2). 13
C
NMR (125 MHz, CDCl3): d = 190.7, 164.2, 139.0, 132.2, 131.9,
129.7, 114.7, 114.1, 68.3, 33.7, 29.4, 29.3, 29.2, 29.0, 28.9, 28.8,
25.9. ESI MS: m/z = 275.1 ([M + H+]); calculated exact mass:
274.19. HR ESI MS: m/z = 297.1831 ([M + Na+]); calculated
exact mass for C18H26NaO2: 297.1825.
1
3 : 7) to give compound 10 (7.9 g, 84%). H NMR (500 MHz,
CDCl3): d = 7.33 (2 H, d, J = 7.5 Hz, Ar), 7.18 (4 H, br, Ar), 6.85
(2 H, d, J = 8.8 Hz, Ar), 5.81 (1 H, m, C(H) = CH2), 4.96 (2 H, m,
CH C(H2)), 4.67 (2 H, s, CH2), 4.37 (4 H, br, CH2), 3.94 (2 H, t,
J = 6.95 Hz, CH2), 2.06 (2 H, m, CH2), 1.97 (1 H, br, OH), 1.80
(2 H, m, CH2), 1.49 (21 H, br, CH2 & Boc). 13C NMR (125 MHz,
Methyl 4-((4-(undec-10-enyloxy)benzylamino)methyl)benzoate
(8). A mixture of compound 6 (8.16 g, 29.7 mmol) and methyl
4-(aminomethyl)benzoate (4.91 g, 29.7 mmol) in 1 : 1 molar ratio
was heated in dry toluene (300 mL) to 140 ◦C for 16 h using
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CDCl3): d = 158.4, 155.9, 139.9, 139.2, 137.5, 129.7, 129.3, 128.7,
128.1, 127.6, 127.2, 114.5, 114.1, 79.9, 68.0, 65.0, 48.6, 48.3, 33.7,
29.5, 29.4, 29.3, 29.2, 29.1, 28.9, 28.4, 26.0. ESI MS: m/z = 518.2
([M + Na+]); calculated exact mass: 495.33. HR ESI MS: m/z =
518.3254 ([M + Na+]); calculated exact mass for C31H45NNaO4:
518.3241.
CH2), 4.96 (2 H, m, CH = C(H2)), 4.31 (4 H, br, CH2), 3.94 (2 H,
t, J = 6.57 Hz, CH2), 3.86 (2H, s, CH2), 2.08 (2 H, m, CH2), 1.82
(2 H, m, CH2), 1.50 (21 H, br, CH2 & Boc). 13C NMR (125 MHz,
CDCl3): d = 158.4, 155.9, 142.2, 139.1, 136.6, 129.7, 128.7, 127.6,
127.2, 114.4, 114.1, 79.8, 67.9, 48.5, 46.1, 33.7, 29.4, 29.34, 29.3,
29.2, 29.0, 28.8, 28.4, 25.9. ESI MS: m/z = 495.0 ([M + H+]);
calculated exact mass: 494.35. HR ESI MS: m/z = 495.3590 ([M +
H+]); calculated exact mass for C31H47N2O3: 495.3581.
Tert-butyl
4-(bromomethyl)benzyl(4-(undec-10-enyloxy)ben-
zyl)carbamate (11). Compound 10 (8.72 g, 17.6 mmol) was
dissolved in dry THF (118 mL) under nitrogen atmosphere.
Triphenylphosphine (6.92 g, 26.3 mmol) was added and the
solution was stirred for 5 min followed by addition of carbon
tetrabromide (8.75 g, 26.3 mmol). After a while a white precipitate
indicating the formation of triphenylphosphine oxide could be
observed. The resulting mixture was stirred overnight under
nitrogen atmosphere. The suspension was filtered and the filtrate
was concentrated under vacuum. The crude residue was purified
by column chromatography (silica gel, EA/hexane = 1 : 9) to give
Methyl 4-((4-((tert-butoxycarbonyl(4-(undec-10-enyloxy)ben-
zyl)amino)methyl)benzylamino)methyl)benzoate (14). Using the
procedure for synthesizing compound 8, compound 14 was
obtained (4.25 g, 82%) from condensation of compound 13 (3.9
g, 8.0 mmol) with methyl 4-formylbenzoate (1.32 g, 8.0 mmol)
followed by reduction with NaBH4 (1.53 g, 40.4 mmol).
Chromatographic purification was not done at this stage. 1H
NMR (500 MHz, CDCl3): d = 8.01 (2 H, d, J = 8.2 Hz, Ar), 7.43
(2 H, d, J = 8.2 Hz, Ar), 7.30 (2 H, d, J = 7.5 Hz, Ar), 7.15 (4
H, br, Ar), 6.85 (2 H, d, J = 8.8 Hz, Ar), 5.81 (1 H, m, C(H) =
CH2), 4.97 (2 H, m, CH = C(H2)), 4.34 (4 H, br, CH2), 3.94 (2
H, t, J = 6.3 Hz, CH2), 3.90 (3 H, s, OCH3), 3.86 (2 H, s, CH2),
3.79 (2 H, s, CH2), 2.06 (2 H, m, CH2), 1.80 (2 H, m, CH2), 1.50
(21 H, br, CH2 & Boc). 13C NMR (125 MHz, CDCl3): d = 166.9,
158.4, 155.9, 145.7, 139.1, 138.9, 136.9, 129.8, 129.7, 129.3, 128.8,
128.3, 127.9, 127.6, 114.5, 114.1, 79.9, 67.9, 52.9, 52.7, 51.9,
48.6, 48.3, 33.7, 29.5, 29.4, 29.3, 29.2, 29.1, 28.9, 28.4, 26.0. ESI
MS: m/z = 643.3 ([M + H+]); calculated exact mass: 642.4. HR
ESI MS: m/z = 643.4084 ([M + H+]); calculated exact mass for
C40H55N2O5: 643.4105.
1
compound 11 (8.8 g, 90%). H NMR (500 MHz, CDCl3): d =
7.35 (2 H, d, J = 7.5 Hz, Ar), 7.14 (4 H, br, Ar), 6.85 (2 H, d,
J = 8.2 Hz, Ar), 5.81 (1 H, m, C(H) = CH2), 4.96 (2 H, m, CH =
C(H2)), 4.49 (2 H, s, CH2), 4.34 (4 H, br, CH2), 3.94 (2 H, t, J =
6.3 Hz, CH2), 2.05 (2 H, m, CH2) 1.79 (2 H, m, CH2), 1.49 (21 H,
br, CH2 & Boc). 13C NMR (125 MHz, CDCl3): d = 158.5, 155.9,
139.2, 136.6, 129.6, 129.3, 129.2, 128.7, 128.3, 127.7, 114.5, 114.1,
80.0, 68.0, 48.7, 48.5, 33.8, 33.3, 29.5, 29.4, 29.34, 29.26, 29.1,
28.9, 28.4, 26.0. ESI MS: m/z = 580.1 ([M + Na+]); calculated
exact mass: 557.25. HR ESI MS: m/z = 580.2411 ([M + Na+]);
calculated exact mass for C31H44BrNNaO3: 580.2397.
Tert-butyl
4-(azidomethyl)benzyl(4-(undec-10-enyloxy)ben-
Methyl
4-((tert-butoxycarbonyl(4-((tert-butoxycarbonyl(4-
zyl)carbamate (12). A mixture of compound 11 (8.15 g,
14.6 mmol) and sodium azide (1.9 g, 29.2 mmol) was heated to
55 ◦C in DMF (90 mL). After heating overnight, the solvent
was removed under vacuum and the residue was extracted with
CHCl3. The organic layer was washed with water, dried over
anhydrous Na2SO4, and the excess of solvent was then removed
under vacuum to give crude compound 12 (6.3 g, 83%), which
was used for the next step without further purification. 1H NMR
(500 MHz, CDCl3): d = 7.28 (2 H, d, J = 8.2 Hz, Ar), 7.22 (4 H, br,
Ar), 6.86 (2 H, d, J = 8.2 Hz, Ar), 5.81 (1 H, m, C(H) = CH2), 4.97
(2 H, m, C(H) = C(H2)), 4.35 (4 H, br, CH2), 4.33 (2 H, s, CH2),
3.94 (2 H, t, J = 6.9 Hz, CH2), 2.07 (2 H, m, CH2), 1.80 (2 H, m,
CH2), 1.49 (21 H, br, CH2 & Boc). 13C NMR (125 MHz, CDCl3):
d = 158.5, 155.9, 139.1, 138.4, 134.2, 129.6, 129.4, 128.7, 128.4,
127.8, 114.5, 114.1, 80.0, 68.0, 54.5, 48.8, 33.7, 29.5, 29.4, 29.3,
29.2, 29.0, 28.9, 28.4, 26.0. ESI MS: m/z = 543.2 ([M + Na+]);
calculated exact mass: 520.34. HR ESI MS: m/z = 543.3324 ([M +
Na+]); calculated exact mass for C31H44N4NaO3: 543.3306.
(undec-10-enyloxy)benzyl)amino)methyl)benzyl)amino)methyl)be-
nzoate (15). Using the procedure for synthesizing compound
9, compound 14 (4.13 g, 6.4 mmol) was reacted with Boc2O
(2.8 g, 12.8 mmol) and triethylamine (1.43 g, 14.1 mmol) to
give compound 15 (4.1 g, 87%) after purification by column
chromatography (silica gel, EA/hexane = 1 : 4). 1H NMR
(500 MHz, CDCl3): d = 8.00 (2 H, d, J = 7.5 Hz, Ar), 7.14 (8 H,
br, Ar), 6.85 (2 H, d, J = 8.2 Hz, Ar), 5.81 (1 H, m, C(H) = CH2),
4.96 (2 H, m, CH = C(H2)), 4.44 (8 H, br, CH2), 3.94 (2 H, t, J =
6.95 Hz, CH2), 3.90 (3 H, s, OCH3), 2.06 (2 H, m, CH2), 1.79 (2
H, m, CH2), 1.50 (30 H, br, CH2 & Boc). 13C NMR (125 MHz,
CDCl3): d = 166.8, 158.4, 155.9, 155.8, 139.1, 137.3, 136.6, 129.8,
129.7, 129.3, 129.1, 128.7, 128.1, 127.7, 127.0, 114.4, 114.1, 80.3,
79.9, 67.9, 51.9, 49.4, 48.7, 48.4, 33.7, 29.4, 29.35, 29.31, 29.2,
29.0, 28.9, 28.4, 28.3, 25.9. ESI MS: m/z = 765.1 ([M + Na+]);
calculated exact mass: 742.46. HR ESI MS: m/z = 765.4468 ([M +
Na+]); calculated exact mass for C45H62N2NaO7: 765.4449.
Compound 16. Using the procedure for synthesizing com-
pound 10, compound 15 (4.13 g, 5.5 mmol) was reduced by LAH
(0.42 g, 11.1 mmol) to give compound 16 (2.49 g, 63%) after
purification by column chromatography (silica gel, EA/hexane =
3 : 7). 1H NMR (500 MHz, CDCl3): d = 7.32 (2 H, d, J = 7.5 Hz,
Ar), 7.15 (8 H, br, Ar), 6.86 (2 H, d, J = 8.2 Hz, Ar), 5.81 (1 H,
m, C(H) = CH2), 4.97 (2 H, m, CH = C(H2)), 4.67 (2 H, s, CH2),
4.40 (8 H, br, CH2), 3.94 (2 H, t, J = 6.3 Hz, CH2), 2.06 (2 H, m,
CH2), 1.80 (2 H, m, CH2), 1.50 (30 H, br, CH2 & Boc). 13C NMR
(125 MHz, CDCl3): d = 158.4, 155.9, 140.0, 139.1, 137.3, 137.2,
137.0, 136.9, 129.7, 129.3, 128.8, 128.1, 127.6, 127.1, 114.5, 114.1,
Tert-butyl
4-(aminomethyl)benzyl(4-(undec-10-enyloxy)ben-
zyl)carbamate (13). Triphenylphosphine (6 g, 22.9 mmol) and
deionised water (0.6 mL, 33.3 mmol) was added to the RBF
containing compound 12 (5.97 g, 11.5 mmol). THF (55 mL) was
added to dissolve the mixture which was stirred overnight under
nitrogen atmosphere. The solvent was removed under vacuum
to give a residue which was purified by column chromatography
(silica gel, MeOH/CHCl3 = 1 : 20) to give compound 13 (2.9 g,
1
52%). H NMR (300 MHz, CDCl3): d = 7.28 (2 H, br, Ar), 7.18
(4 H, br, Ar), 6.86 (2 H, d, J = 8.5 Hz, Ar), 5.81 (1 H, m, C(H) =
3512 | Org. Biomol. Chem., 2011, 9, 3504–3515
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80.1, 80.0, 68.0, 64.9, 49.1, 48.8, 48.4, 33.7, 29.5, 29.4, 29.3, 29.2,
29.1, 28.9, 28.44, 28.42, 26.0. ESI MS: m/z = 737.2 ([M + Na+]);
calculated exact mass: 714.46. HR ESI MS: m/z = 737.4502 ([M +
Na+]); calculated exact mass for C44H62N2NaO6: 737.4500.
in dry toluene (100 mL) to 140 ◦C for 16 h using a Dean–
Stark apparatus under nitrogen atmosphere. The solvent was
removed under vacuum, and the imine obtained was dissolved
in THF (20 mL) and MeOH (20 mL) to which NaBH4 (0.27 g,
7.3 mmol) was added in portions. After stirring for overnight,
the solvent was removed under vacuum leaving a residue which
was extracted by CHCl3. The organic layer was washed by
brine, dried over anhydrous Na2SO4, and the solvent was then
removed under vacuum leaving a residue which was purified by
column chromatography (silica gel, MeOH/CHCl3 = 1 : 19) to
Compound 17. Using the procedure for synthesizing com-
pound 11, compound 16 (2.48 g, 3.4 mmol) was brominated by
CBr4 (1.72 g, 5.2 mmol) and PPh3 (1.36 g, 5.2 mmol) to give
compound 17 (2.27 g, 86%) after purification by column chro-
matography (silica gel, EA/hexane = 1 : 4). 1H NMR (500 MHz,
CDCl3): d = 7.35 (2 H, d, J = 7.8 Hz, Ar), 7.17 (8 H, br, Ar),
6.87 (2 H, d, J = 8.2 Hz, Ar), 5.81 (1 H, m, C(H) = CH2), 4.97
(2 H, m, CH = C(H2)), 4.47 (2 H, s, CH2), 4.41 (8 H, br, CH2),
3.95 (2 H, t, J = 6.3 Hz, CH2), 2.07 (2 H, m, CH2), 1.81 (2 H, m,
CH2) 1.51 (30 H, br, CH2 & Boc). 13C NMR (125 MHz, CDCl3):
d = 158.3, 155.75, 155.73, 138.9, 138.3, 137.0, 136.6, 129.6, 129.2,
129.1, 128.6, 128.2, 127.9, 127.6, 127.5, 114.3, 114.0, 79.9, 79.7,
67.8, 48.6, 48.3, 33.6, 33.0 29.3, 29.23, 29.19, 29.12, 28.9, 28.7,
28.33, 28.28, 25.9. ESI MS: m/z = 799.0 ([M + Na+]); calculated
exact mass: 776.38. HR ESI MS: m/z = 799.3663 ([M + Na+]);
calculated exact mass for C44H61BrN2NaO5: 799.3656.
1
give compound 20 (1.37 g, 65%). H NMR (500 MHz, CDCl3):
d = 7.21 (4 H, d, J = 8.2 Hz, Ar), 7.16 (4 H, d, J = 8.2 Hz, Ar),
7.08 (9 H, br, Ar), 6.81 (2 H, d, J = 8.8 Hz, Ar), 6.77 (4 H, d, J =
8.2 Hz, Ar), 6.44 (3 H, br, Ar), 5.73 (2 H, m, C(H) = CH2), 4.88
(4 H, m, CH = C(H2)), 4.29 (8 H, br, CH2), 4.05 (8 H, m, CH2),
3.86 (12 H, br, CH2), 3.69 (4 H, s, CH2), 3.65 (4 H, s, CH2), 1.98
(4 H, m, CH2), 1.75 (2 H, br, NH), 1.71 (4 H, m, CH2), 1.41 (42
H, br, CH2 & Boc). 13C NMR (125 MHz, CDCl3): d = 159.9,
158.4, 157.8, 155.9, 139.16, 139.13, 136.7, 132.5, 129.8, 129.3,
128.7, 128.3, 128.0, 127.5, 114.5, 114.4, 114.1, 107.1, 101.8, 79.9,
69.9, 69.8, 67.9, 67.5, 67.4, 52.7, 52.5, 48.5, 48.3, 33.7, 29.4, 29.34,
29.31, 29.2, 29.0, 28.8, 28.4, 25.9. ESI MS: m/z = 1451.4 ([M +
H+]), 726.5 ([M + 2H+]); calculated exact mass: 1450.91. HR
ESI MS: m/z = 1451.9158 ([M + H+]); calculated exact mass for
C90H123N4O12: 1451.9132.
Compound 18. Using the procedure for synthesizing com-
pound 12, compound 17 (0.56 g, 0.72 mmol) was treated with
sodium azide (0.09 g, 1.44 mmol) to give compound 18 (0.47 g,
88%). Chromatographic purification was not done at this stage.
1H NMR (500 MHz, CDCl3): d = 7.28 (2 H, d, J = 7.5 Hz, Ar),
7.15 (8 H, br, Ar), 6.85 (2 H, d, J = 8.2 Hz, Ar), 5.81 (1 H, m,
C(H) = CH2), 4.97 (2 H, m, CH = C(H2)), 4.41 (8 H, br, CH2),
4.33 (2 H, s, CH2), 3.94 (2 H, t, J = 6.95 Hz, CH2), 2.06 (2 H,
m, CH2), 1.80 (2 H, m, CH2), 1.49 (30 H, br, CH2 & Boc). 13C
NMR (125 MHz, CDCl3): d = 158.4, 155.9, 139.2, 136.8, 134.3,
129.7, 129.3, 128.8, 128.4, 128.1, 127.6, 114.5, 114.1, 80.2, 79.9,
68.0, 54.5, 49.0, 48.7, 33.8, 29.5, 29.4, 29.35, 29.27, 29.1, 28.9,
28.5, 28.4, 26.0. ESI MS: m/z = 762.2 ([M + Na+]); calculated
exact mass: 739.47. HR ESI MS: m/z = 762.4581 ([M + Na+]);
calculated exact mass for C44H61N5NaO5: 762.4565.
Compound 21. A mixture of compound 5 (0.1 g, 0.21 mmol)
and compound 19 (0.3 g, 0.42 mmol) in 1 : 2 molar ratio was
◦
heated in dry toluene (70 mL) to 140 C for 16 h using a Dean–
Stark apparatus under nitrogen atmosphere. The solvent was
removed under vacuum, and the imine obtained was dissolved
in THF (6 mL) and MeOH (6 mL) to which NaBH4 (0.04 g,
1.06 mmol) was added in portions. After stirring for overnight,
the solvent was removed under vacuum leaving a residue which
was extracted by CHCl3. The organic layer was washed by
brine, dried over anhydrous Na2SO4, and the solvent was then
removed under vacuum leaving a residue which was purified by
column chromatography (silica gel, MeOH/CHCl3 = 1 : 15) to
Compound 19. Using the procedure for synthesizing com-
pound 13, compound 18 (0.47 g, 0.63 mmol) was reduced by
H2O (0.029 g, 1.58 mmol) and PPh3 (0.34 g, 1.27 mmol) to
give compound 19 (0.32 g, 72%) after purification by column
chromatography (silica gel, MeOH/CHCl3 = 1 : 9). 1H NMR
(500 MHz, CDCl3): d = 7.28 (2 H, d, J = 8.2 Hz, Ar), 7.15 (8 H, br,
Ar), 6.85 (2 H, d, J = 8.2 Hz, Ar), 5.81 (1 H, m, C(H) = CH2), 4.96
(2 H, m, CH = C(H2)), 4.39 (8 H, br, CH2), 3.94 (2 H, t, J = 6.95 Hz,
CH2), 3.87 (2 H, s, CH2), 2.06 (2 H, m, CH2), 1.80 (4 H, br, CH2 &
NH2), 1.50 (30 H, br, CH2 & Boc). 13C NMR (125 MHz, CDCl3):
d = 158.4, 155.96, 155.95, 142.0, 139.2, 137.1, 136.9, 136.6, 129.7,
129.3, 128.72, 128.67, 128.4, 128.1, 127.6, 127.3, 114.5, 114.1, 80.0,
79.9, 68.0, 48.9, 48.7, 48.4, 46.1, 33.8, 29.5, 29.38, 29.35, 29.27,
29.1, 28.9, 28.5, 28.4, 26.0. ESI MS: m/z = 714.1 ([M + H+]);
calculated exact mass: 713.48. HR ESI MS: m/z = 714.4848 ([M +
H+]); calculated exact mass for C44H64N3O5: 714.4840.
1
give compound 21 (0.32 g, 81%). H NMR (500 MHz, CDCl3):
d = 7.32 (4 H, d, J = 7.6 Hz, Ar), 7.26 (4 H, d, J = 8.2 Hz, Ar),
7.18 (17 H, br, Ar), 6.91 (4 H, d, J = 8.8 Hz, Ar), 6.87 (4 H, d,
J = 8.2 Hz, Ar), 6.54 (3 H, br, Ar), 5.82 (2 H, m, C(H) = CH2),
4.97 (4 H, m, CH = C(H2)), 4.42 (16 H, br, CH2), 4.14 (8 H, m,
CH2), 3.95 (4 H, t, J = 6.3 Hz, CH2), 3.92 (8 H, m, CH2), 3.79
(4 H, s, CH2), 3.75 (4 H, s, CH2), 2.08 (4 H, m, CH2), 1.96 (2 H,
br, NH), 1.81 (4 H, m, CH2), 1.52 (60 H, br, CH2 & Boc). 13C
NMR (125 MHz, CDCl3): d = 159.8, 158.3, 157.7, 155.82, 155.79,
139.2, 138.9, 136.9, 136.5, 132.4, 129.7, 129.1, 128.6, 128.3, 128.2,
127.9, 127.5, 114.44, 114.36, 114.0, 107.0, 101.7, 79.9, 79.8, 69.8,
69.7, 67.9, 67.4, 67.3, 52.6, 52.4, 48.8, 48.6, 48.3, 33.6, 29.3, 29.24,
29.21, 29.1, 28.9, 28.8, 28.33, 28.32, 25.9. ESI MS: m/z = 1890.5
([M + H+]), 946.3 ([M + 2H+]); calculated exact mass: 1889.16.
HR ESI MS: m/z = 945.5885 ([M + 2H+]); calculated exact mass
for C116H158N6O16: 945.5862.
Tert-butyl
(4,4¢-(4,4¢-(2,2¢-(2,2¢-(1,3-phenylenebis(oxy))bis-
(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(4,1-phe-
nylene))bis(methylene)bis(azanediyl)bis(methylene)bis(4,1-pheny-
lene))bis(methylene)bis(4-(undec-10-enyloxy)benzylcarbamate)
(20). A mixture of compound 5 (0.71 g, 1.45 mmol) and
compound 13 (1.44 g, 2.9 mmol) in 1 : 2 molar ratio was heated
Compound 1·(PF6)4. Compound 20 (1.3 g, 0.9 mmol) was
dissolved in dry DCM (50 mL) under nitrogen atmosphere.
Trifluoroacetic acid (2.04 g, 17.9 mmol) was added to this solution
and stirred overnight. The solvent was removed in vacuum and the
residue was dissolved in minimum amount of methanol-acetone
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(2 : 1, v/v) mixture. To this was added a saturated aqueous NH4PF6
solution to yield compound 1·(PF6)4 as a white precipitate. The
solution was filtered through Buchner funnel and the residue
collected was washed with water, dried in vacuum and used for
next step. Compound 1·(PF6)4 was obtained in quantitative yield.
6.98 (8 H, br, Ar), 6.50 (3 H, br, Ar), 4.09 (br, -OCH2 peaks overlap
with broad solvent peak), 1.66 (4 H, br, CH2), 1.27 (24 H, br, CH2).
13C NMR (125 MHz, CD3SOCD3): could not be observed even
after scanning for long time, because of poor solubility. ESI MS
obtained after neutralization of 2·(PF6)6 with NaOH (aq), found:
m/z = 1489.7 ([M + H+]); calculated exact mass: 1488.95. EA: for
neutral compound, C96H124N6O8 requires C 77.38, H 8.39, N 5.64;
found C 77.24, H 8.51, N 5.95.
1
M.p.: Decomposed. H NMR (500 MHz, CD3CN): d = 7.49 (8
+
H, br, Ar), 7.42 (8 H, br, NH2 ), 7.38 (8 H, br, Ar), 7.15 (1 H,
t, J = 8.2 Hz, Ar), 6.98 (4 H, d, J = 8.8 Hz, Ar), 6.95 (4 H, d,
3
4
J = 8.8 Hz, Ar), 6.51 (2 H, dd, J = 8.2 Hz, J = 2.5 Hz, Ar),
6.46 (1 H, t, J = 1.9 Hz, Ar), 5.82 (2 H, m, C(H) = CH2), 4.95
(4 H, m, CH = C(H2)), 4.20 (8 H, br, CH2), 4.16 (12 H, br, CH2),
4.08 (4 H, t, J = 4.4 Hz, CH2), 3.97 (4 H, t, J = 6.9 Hz, CH2),
3.84 (8 H, m, CH2), 2.04 (4 H, m, CH2), 1.76 (4 H, m, CH2),
1.42 (24 H, br, CH2). 13C NMR (125 MHz, CD3CN): d = 161.3,
161.1, 160.9, 140.3, 133.0, 132.9, 132.8, 131.7, 131.1, 123.4, 122.9,
115.99, 115.92, 114.7, 108.1, 102.3, 70.5, 70.4, 69.1, 68.7, 68.5,
52.12, 52.08, 51.5, 51.4, 34.4, 30.2, 30.1, 30.0, 29.9, 29.8, 29.7,
26.7. ESI MS: m/z = 1688.3 ([M-PF6]+), 1543.2 ([M-HPF6-PF6]+),
1397.5 ([M-2HPF6-PF6]+), 1251.3 ([M-3HPF6-PF6]+), 722.1 ([M-
2PF6]2 +), 699.0 ([M-HPF6-2PF6]2 +), 626.5 ([M-2HPF6-2PF6]2 +);
calculated exact mass: 1834.69. HR ESI MS: m/z = 626.4084 ([M-
2HPF6-2PF6]2 +); calculated exact mass for C80H108N4O8: 626.4078.
Compound 2·(BPh4)6. Compound 2·(PF6)6 was neutralised
with NaOH (aq) and extracted with CHCl3. The solvent was
removed and the residue obtained was dissolved in minimum
amount of trifluoroacetic acid. To this was added equivalent
amount of NH4BPh4 (in aqueous acetone) to yield 2·(BPh4)6 as
a white precipitate. The solution was filtered through Buchner
funnel and the residue collected was dried in vacuum. Compound
2·(BPh4)6 was obtained in quantitative yield. M.p.: Decomposed.
1H NMR (500 MHz, CD3OD): d = 7.55 (br, BPh4 peaks overlap
with aromatic protons of thread), 7.38 (br, BPh4 peaks overlap
with aromatic protons of thread), 7.12 (1 H, br, Ar), 6.91 (8 H,
br, Ar), 6.61 (3 H, br, Ar), 4.23 (44 H, br, CH2), 1.70 (4 H, br,
CH2), 1.40 (24 H, br, CH2). 13C NMR (125 MHz, CD3OD): d =
163.4, 163.3, 163.2, 163.1, 163.0, 162.9, 161.6, 134.8, 134.4, 134.0,
133.8, 132.6, 131.85, 131.77, 131.1, 130.7, 130.4, 129.9, 129.8,
128.6, 120.5, 116.8, 116.5, 116.2, 116.1, 71.1, 70.9, 70.8, 69.1, 68.7,
68.6, 51.7, 51.6, 51.1, 40.2, 33.0, 30.7, 30.4, 30.2, 27.0, 26.8. ESI
MS obtained after neutralization of 2·(BPh4)6 with NaOH (aq),
found: m/z = 1489.7 ([M + H+]); calculated exact mass: 1488.95.
EA: for neutral compound, C96H124N6O8 requires C 77.38, H 8.39,
N 5.64; found C 77.24, H 8.51, N 5.95.
Compound 23·(PF6)4 ([5]MN). Compound 1·(PF6)4 (0.1 g,
0.056 mmol) and DB24C8 (0.5 g, 1.12 mmol) are dissolved in
the mixed solvent (40 mL, CHCl3/CH3CN = 3 : 1 (v/v)). The
solution was stirred for 24 h and the solvent was then removed
under vacuum without heating and then the residue was dissolved
in dry DCM (200 mL, 0.0003 M) under nitrogen atmosphere.
2nd Generation Grubbs catalyst (0.02 g, 0.02 mmol) was added
and the resulting mixture was refluxed for 3 days. The reaction
mixture was cooled followed by quenching with ethyl vinyl ether.
The excess solvent was removed in vacuum and the residue was
subjected to column chromatography (silica gel, MeOH–CHCl3 =
1 : 4 (v/v)) to give the desired product 23·(PF6)4 (0.04 g, 20%).
M.p.: Decomposed. 1H NMR (300 MHz, CDCl3): d = 7.37 (8 H,
Acknowledgements
This work was financially supported by the AcRF Tier 1 grant
(R-143-000-328-133) and the NUS Young Investigator Award (R-
143-000-356-101).
+
br, NH2 ), 7.24 (8 H, d, J = 8.0 Hz, Ar), 7.13 (1 H, t, J = 8.0 Hz,
Ar), 6.94 (8 H, br, Ar), 6.77 (40 H, br, DB & Ar), 6.52 (2 H, br,
Ar), 6.49 (1 H, br, Ar), 5.37 (2 H, br, C(H) = C(H)), 4.54 (8 H,
Notes and references
+
+
br, C(H2)NH2 ), 4.36 (8 H, br, C(H2)NH2 ), 4.12–3.46 (116 H, br,
DB & CH2), 1.96 (4 H, br, CH2), 1.76 (4 H, m, CH2), 1.29 (24 H,
br, CH2). 13C NMR (125 MHz, CDCl3): d = 159.9, 159.6, 159.3,
147.4, 132.3, 130.64, 130.58, 130.3, 129.8, 129.6, 124.1, 123.6,
121.3, 114.6, 114.4, 112.49, 112.46, 107.1, 101.9, 70.8, 70.2, 69.8,
69.7, 67.9, 67.5, 67.4, 52.0, 51.7, 32.5, 29.7, 29.5, 29.4, 29.3, 29.1,
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