Weinreb Amide as Secondary Station for the Dibenzo-24-crown-8 in a Molecular Shuttle

Article abstract of DOI:10.1002/ejoc.201900046

Here is reported the synthesis of a new molecular shuttle: it consists of a dibenzo-24-crown-8 (DB24C8) that surrounds a molecular axle containing an ammonium group and a newly considered Weinreb amide as stations. At the protonated state the DB24C8 is localized around the best ammonium station, while deprotonation-carbamoylation of the ammonium triggers the shuttling of the macrocycle around the Weinreb amide site. Further post-interlocking modification of the [2]rotaxane was attempted through the cleavage of the Weinreb amide bond using a Grignard reagent. While the non-interlocked molecular axle was cleaved after a short time in mild conditions, the Weinreb amide bond remained unaltered in the [2]rotaxane species over time, even in the presence of a larger amount of Grignard and at a higher temperature, highlighting the protection shield of the macrocycle around the encircled axle.

Full text of DOI:10.1002/ejoc.201900046

A Journal of
Accepted Article
Title: Weinreb Amide Bond as Secondary Station for the DB24C8 in a
Molecular Shuttle
Authors: Maxime Gauthier and Frédéric Coutrot
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900046
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900046
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10.1002/ejoc.201900046
European Journal of Organic Chemistry
COMMUNICATION
Weinreb Amide Bond as Secondary Station for the DB24C8 in a
Molecular Shuttle
Maxime Gauthier and Frédéric Coutrot*[a]
Dedication ((optional))
Abstract: Here is reported the synthesis of a new molecular shuttle:
it consists of a dibenzo-24-crown-8 (DB24C8) that surrounds a
molecular axle containing an ammonium and a newly considered
Weinreb amide stations. At the protonated state the DB24C8 is
localized around the best ammonium station, while deprotonation-
carbamoylation of the ammonium triggers the shuttling of the
macrocycle around the Weinreb amide site. Further post-interlocking
modification of the [2]rotaxane was attempted through the cleavage
of the Weinreb amide bond using a Grignard reagent. While the non-
interlocked molecular axle was cleaved after a short time in mild
conditions, the Weinreb amide bond remained unaltered in the
[2]rotaxane species over time, even in the presence of a larger
amount of Grignard and at higher temperature, highlighting the
protection shield of the macrocycle around the encircled axle.
physical and chemical properties of the encircled molecular
thread, thus conferring to this family of compounds a promising
research area. In this context, the synthesis of molecular shuttle
possessing novel molecular stations is of interest. In this paper,
we report on the synthesis of a new [2]rotaxane molecular shuttle
that holds a Weinreb[7] amide as a molecular station for the
DB24C8 macrocycle. While the DB24C8 is localized around the
ammonium moiety at the protonated state, it shuttles toward the
Weinreb amide site upon carbamoylation of the ammonium. In
addition, since post-interlocking modification of rotaxanes, with
preservation of the mechanical bond, looks attractive for the
synthesis of challenging interlocked compounds,[8] the cleavage
of
the
Weinreb
amide
bond
using
the
3,5-
dimethylphenylmagnesium bromide to afford a ketone-containing
[2]rotaxane was further investigated, then directly compared to
the same reaction on the non-interlocked analogue. The Weinreb
amide link proved to be inert in the interlocked compounds, while
very reactive in the absence of the macrocycle. This result
highlights the very efficient protection shield of the macrocycle
against the Grignard reagent.
Introduction
Mechanically interlocked molecules (MIMs),[1] especially
catenanes and rotaxanes, belong to a class of appealing
compounds, not only because of their aesthetic architecture but
also for their potential applications in a wide range of domains[2]
due to their topology-dependent properties. MIMs are interlaced
molecular assemblies trapped by a mechanical bond.[3] In the
[2]rotaxane series, a macrocycle is mechanically confined around
a molecular thread that is ended by bulky extremities, commonly
named stoppers, which sterically prevent the molecular
architecture from any disassembly. The most popular way to drive
the assembly of the elements in an interlocked architecture is to
use a site on the axle that is able to interact with the macrocycle
Results and Discussion
The targeted Weinreb amide-containing [2]rotaxane molecular
shuttle 6/7 was synthesized according to a multi-step sequence,
from the commercially available p-tert-butylbenzaldehyde and 3-
aminopropane-1,2-diol (Scheme 1). The reductive amination
using sodium triacetoxyborohydride (STAB) as the reducing
agent and the subsequent one pot N-carbamoylation of the
intermediary secondary amine using Boc2O were carried out in
the conditions of Petukhov[9] and afforded the pure corresponding
diol 1 in a 59% overall yield. The vicinal diol 1 was then easily
(i.e.
a
template[4] effect). When several sites of different
interactions for the macrocycle (i.e. molecular stations) are
present on the encircled axle, it can give rise to a multi-stable
molecular shuttle[5] if several co-conformations can be obtained
through the controlled displacement of the macrocycle along the
encircled axle upon stimuli.[6] In such interlocked molecular
structures, the presence and the localization of a macrocycle
around a molecular axle dramatically might affect both the
cleaved through Malaprade oxidation[10] using
a polymer-
supported ammonium periodate[11] that was anteriorly prepared
from the commercial hydroxide form Amberlyst A26. A second
reductive amination was carried out in methanol between the
aldehyde
2
and the commercial O-methylhydroxylamine
hydrochloride in the presence of triethylamine. Noteworthy, the
reduction of the O-methyloxime intermediate turned out to be
difficult, as already reported by Vanderesse et al..[12] Whereas
hydrogenation using palladium catalyst or reduction using sodium
borohydride (NaBH4) were inefficient, the use of an excess of
sodium cyanoborohydride (NaBH3CN, 15 equiv.) at pH 5-6 gave
satisfactory results and provided the methoxyamine compound 3
in a 71% overall yield. The ammonium template, which is
necessary to drive the threading of the DB24C8, was then
revealed by removing the Boc protective group using a solution of
hydrogen chloride in ether. The resulting chlorinated salt was
[a]
M. Gauthier, Dr. F. Coutrot*
Supramolecular Machines and ARchitectures Team, Institut des
Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS ; Université
de Montpellier ; ENSCM, case courrier 1706, Bâtiment Chimie (17),
3ème étage, Faculté des Sciences, Place Eugène Bataillon 34095
Montpellier cedex 5, France.
E-mail:frederic.coutrot@umontpellier.fr
Homepage: http://www.glycorotaxane.fr
Supporting information for this article is given via a link at the end of
the document.
subjected
to
anion
exchange
using
ammonium
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10.1002/ejoc.201900046
European Journal of Organic Chemistry
COMMUNICATION
hexafluorophosphate in order to obtain the ionic compound 4 as
interactions with the oxygen atoms of the DB24C8. On the other
hand, the hydrogen atom H10 is shielded in 5 (Δδ = -0.20 ppm),
due to its localization in the shielding region of the aromatic rings
of DB24C8. Finally, in 5, the ion-dipole interactions between the
cationic charge of the ammonium moiety and the crown ether
result in an upfield shift of H4-5 and in a lesser extent H1 (Δδ = -
0.27, -0.14 and -0.06 ppm, respectively). Noteworthy, contrary to
HA-B, the methylene hydrogen atoms HC, HD and HE corresponding
to the methylene signals of the DB24C8 of the semi[2]rotaxane 5
are not split at room temperature (Fig. 1 b, c). They are usually
split in rotaxane species because they are facing the two non-
symmetrical ends of the encircled thread. In this case, one might
suggest a fast conformational exchange on the NMR time scale
that provides an average value of the considered chemical shifts.
A slight upfield shift is nevertheless observed for the hydrogen
atoms HE (Δδ = -0.13 ppm) in the semi[2]rotaxane 5, due to their
localization in the shielding region of the aromatic ring of the
benzylammonium moiety belonging to the encircled molecular
axle. As expected, lowering the temperature until 213 K restored
the splitting of the signals of the crown ether because the
conformational exchange was lowered at this temperature (Fig. 1
d), which corroborated the formation of the supramolecular
assembly.
a
soluble salt in the hydrogen bond promoting solvent
dichloromethane.
The threading of compound 4 by the DB24C8 was then studied in
dichloromethane at room temperature. The semi[2]rotaxane
molecular architecture of compound 5 was first evidenced in
1
CD2Cl2 on a very small scale by comparing the H NMR spectra
of the free DB24C8 with both a mixture of the compound 4 at a
concentration of [3.10-2 M] in the presence of 1 equiv. of DB24C8
and the non-interlocked thread 4 (Fig. 1 a-c). The direct
comparison of the 1H NMR spectra of the non-interlocked thread
4
and the semi[2]rotaxane 5 demonstrates the rotaxane
architecture of 5 (Fig. 1 a, b). An average of 1H NMR signals was
observed for the encircled and uncomplexed thread, indicating a
fast exchange on the NMR time scale between the free
components and the semirotaxane. In the semirotaxane 5, at the
exception of the appearance of the signals corresponding to the
hydrogen atoms of the DB24C8, typical variations in chemical
shifts of the molecular thread are observed. Notably, the chemical
shifts of the methylene hydrogen atoms H7 and H9 (neighbouring
the ammonium station) are shifted downfield in the
semi[2]rotaxane (Δδ = 0.15 and 0.33 ppm, respectively), because
these hydrogen atoms are involved in hydrogen-bonding
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10.1002/ejoc.201900046
European Journal of Organic Chemistry
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Scheme 1. Synthesis of the Weinreb amide-containing molecular shuttle 6/7 and reactivity of the [2]rotaxane 7 vs its non-interlocked thread 7ut toward the 3,5-
dimethylphenylmagnesium bromide.
considered on 6 in order to evaluate the propensity for the
Weinreb amide to act as an efficient secondary molecular station.
The deprotonation of the ammonium necessitated the use of the
strong Schwesinger’s[14] base P1-tBuPhosphazene. This weak
acidity of the encircled ammonium is commonly observed in the
absence of a close and strong secondary site of interaction.[15] As
already mentioned by us with tertiary N,N-dialkylamide as
secondary station for the DB24C8,[16] no shuttling of the DB24C8
was observed upon deprotonation because the DB24C8 better
interacts with the amine moiety than with the Weinreb amide. The
shuttling of the macrocycle from the ammonium toward the
Weinreb amide site was nevertheless successfully achieved by
deprotonation-carbamoylation of the ammonium. It was
evidenced by the comparison between the 1H NMR spectra of the
protonated [2]rotaxane 6, its non-interlocked thread 6ut, the N-
carbamoylated [2]rotaxane 7 and its non-interlocked thread 7ut
(Fig. 2).
Figure 1. 1H NMR spectra (CD2Cl2, 400 MHz) of: a) the uncomplexed compound
4 at 298 K, b) a mixture of 4 at a concentration of [3.10-2M] with 1 equiv. of
DB24C8 at 298 K, c) the free DB24C8 at 298 K, d) a mixture of 4 at a
concentration of [3.10-2M] with 1 equiv. of DB24C8 at 213 K. The numbering
and coloring correspond to the hydrogen assignments indicated in Scheme 1.
To improve both the yield and rate of the threading step, the
concentrations of the thread 4 and the DB24C8 were increased.
Moreover, a growing amount of DB24C8 was added on the thread
4 until the maximum of chemical shift variations was reached
between the signals of the semirotaxane 5 and those of the non-
interlocked thread 4. The semi[2]rotaxane 5 was then prepared
by mixing for 15 minutes a 0.35 M solution of 4 in the hydrogen
bond promoting solvent dichloromethane, at 298 K and in the
presence of 1.5 equiv. of DB24C8.[13] The uninsulated
semi[2]rotaxane 5 was capped at its methoxyamine end through
the condensation of the freshly prepared acyl chloride 5’. The
Figure 2. 1H NMR spectra (CD2Cl2, 298 K, 400 MHz) of: a) the protonated
uncomplexed thread 6ut, b) the protonated [2]rotaxane molecular shuttle 6, c)
the N-carbamoylated [2]rotaxane molecular shuttle 7, d) the N-carbamoylated
uncomplexed thread 7ut. The numbering and coloring correspond to the
extended [2]rotaxane 6 was isolated in a 28% yield after flash
chromatography on a silica gel column. The low yield might be
explained by the weak nucleophilic nature of the methoxyamine,
due to the electron-withdrawing inductive effect of the methoxy
group, and by the steric hindrance brought by the macrocycle
around the reactive site. Molecular machinery was then
hydrogen assignments indicated in Scheme 1.
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COMMUNICATION
The direct comparison of the 1H NMR spectra of 6ut and 6
indicates the presence and the localization of DB24C8 around the
ammonium station in 6 (Fig. 2 a, b). Firstly, the signals
corresponding to the methylene hydrogen atoms HC-E of the
DB24C8 are split in 6, because these hydrogen atoms are facing
the two non-symmetrical ends of the thread. With respect to 6ut,
the chemical shifts of the hydrogen atoms H7 and H9 appeared
downfield in the [2]rotaxane 6 (Δδ = 0.38 and 0.26 ppm,
respectively) as a result of their hydrogen-bonding interactions
with the oxygen atoms of the DB24C8. At the same time, the
hydrogen atoms H10, H12 and H20 are all more or less shifted
upfield in 6 (Δδ = -0.16, -0.22 and -0.21 ppm, respectively), due
to their localization in the shielding cavity of the aromatic rings of
the DB24C8. The same trend of chemical shift variation is
observed for hydrogen atoms H1, H4, H5 (Δδ = -0.05, -0.16, -0.06
ppm, respectively), due to the stabilization of the cationic charge
of the ammonium moiety by the crown ether. The direct
comparison between the 1H NMR spectra of 6 and 7 indicates the
shuttling of the DB24C8 and its new localization around the
Weinreb amide site in the carbamoylated [2]rotaxane 7 (Fig. 2 b,
c). The hydrogen atoms H7 and H9 are logically shifted upfield in
7 (Δδ = -0.13 and -0.30 ppm, respectively) because of the N-
carbamoylation and the leaving of DB24C8. Simultaneously, the
hydrogen atoms neighbouring the Weinreb amide H12 and H13 are
shifted downfield in 7 (Δδ = 0.73 and 0.62 ppm, respectively),
because of their hydrogen-bonding interactions with the oxygen
atoms of the DB24C8. The hydrogen atoms H15, H17, H18 and H19
are all shifted upfield in 7 (Δδ = -0.28, -0.31, -0.31 and -0.27 ppm,
respectively) because they undergo the shielding effect of the
aromatic rings of DB24C8. The localization of the DB24C8 around
the Weinreb site in 7 is confirmed thanks to the comparison
between the 1H NMR spectra of the [2]rotaxane 7 and its
uncomplexed thread 7ut (Fig. 3 c, d). Indeed, the same trend of
chemical shift displacements is observed concerning the
hydrogen atoms that are implicated in hydrogen bonding (i.e. in 7,
H12 and H13 are shifted downfield with Δδ = 0.56 and 0.45 ppm,
respectively) or shielded by the aromatic rings of DB24C8 (i.e. in
7, H15, H17, H18 and H19 are shifted upfield with Δδ = -0.33, -0.31,
-0.21 and -0.21 ppm, respectively).
the use of a larger excess of Grignard reagent (up to 5 equiv.)
and/or at higher temperature (up to 50°C), did not yield to any
improvement even after 4 days. This demonstrates the high
efficacy of the protection of a Weinreb amide moiety by a
surrounding DB24C8.
Conclusions
In conclusion, we have reported the synthesis of a new molecular
shuttle that contains an ammonium and a Weinreb amide stations
for the DB24C8. The DB24C8 was localized around the best
ammonium station at the protonated state. The sole
deprotonation of the ammonium station did not trigger the
shuttling of the DB24C8 because of the too weak affinity of the
Weinreb amide for the macrocycle, this latter interacting better
with the amine site. Nevertheless, Weinreb amide proved to act
as an efficient secondary molecular station for the DB24C8 after
N-carbamoylation of the deprotonated ammonium. In this case,
the DB24C8 shuttles around the amide site, where it acts as a
protective shield that prevents the Weinreb amide from any attack
by Grignard reagent. Using a macrocycle as a temporary
protection of specific sites of an encircled axle might be valuable
for the post-interlocking multi-step modification of rotaxanes.
Acknowledgments
We thank the ”Agence Nationale de la Recherche” for funding this
research under the project ANR-17-CE07-0014-01.
Keywords: rotaxane • molecular shuttle • Weinreb amide •
dibenzo-24-crown-8 • protective group
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containing molecular shuttle, we envisaged the cleavage of the
encircled axle of 7 by a Grignard reagent (Scheme 1). Post-
interlocking modification of such amide-containing rotaxanes
could be of interest for the synthesis of challenging rotaxanes
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moiety to a methylene unit. As a model experiment, the dropwise
addition of 2 equiv. of the 3,5-dimethylphenylmagnesium bromide
(0.5 M solution in Me-THF) on a solution of the molecular thread
7ut in THF was achieved at 0°C and the mixture was allowed to
warm up until room temperature and stirred for 17h. The ketone-
containing molecular thread 8ut was obtained in a 70% yield after
silica gel flash chromatographic purification. Unfortunately, the
experiment in the same experimental conditions on the rotaxane
analogue 7 did not provide any expected ketone compound. In
the interlocked compound 7, the DB24C8 acts as a protective
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of the axle.[19] Operating in harder experimental conditions, like
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COMMUNICATION
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Entry for the Table of Contents (Please choose one layout)
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A [2]rotaxane molecular shuttle
containing an ammonium and a
Weinreb amide molecular station for
the DB24C8 is reported. The Weinreb
amide proved to be an efficient
secondary molecular station upon
carbamoylation of the ammonium.
Although the amide was easily
cleaved by a Grignard reagent in the
non-interlocked analogue, no
Molecular Shuttle
Maxime Gauthier and Frédéric Coutrot*
Page No. – Page No.
Weinreb Amide Bond as Secondary
Station for the DB24C8 in a Molecular
Shuttle
cleavage was possible in the rotaxane
species, due to the protective shield of
the surrounding DB24C8.
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