Spontaneous Assembly of Rotaxanes from a Primary Amine, Crown Ether and Electrophile

Article abstract of DOI:10.1021/jacs.8b03394

We report the synthesis of crown ether-ammonium, amide and amine [2]rotaxanes via transition state stabilization of axle-forming reactions. In contrast to the two-step "clipping" and "capping" strategies generally used for rotaxane synthesis, here the components assemble into the interlocked molecule in a single, reagent-less, step under kinetic control. The crown ether accelerates the reaction of the axle-forming components through the cavity to give the threaded product in a form of metal-free active template synthesis. Rotaxane formation can proceed through the stabilization of different transition states featuring 5-coordinate (e.g., S_N2) or 4-coordinate (e.g., acylation, Michael addition) carbon. Examples prepared using the approach include crown-ether-peptide rotaxanes and switchable molecular shuttles.

Full text of DOI:10.1021/jacs.8b03394

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Communication
Spontaneous Assembly of Rotaxanes From a
Primary Amine, Crown Ether and Electrophile
Stephen D. P. Fielden, David A. Leigh, Charlie McTernan,
Borja Pérez-Saavedra, and Inigo J. Vitorica-Yrezabal
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03394 • Publication Date (Web): 02 May 2018
Downloaded from http://pubs.acs.org on May 2, 2018
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Spontaneous Assembly of Rotaxanes From a Primary Amine,
Crown Ether and Electrophile
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Stephen D. P. Fielden, David A. Leigh,* Charlie T. McTernan, Borja Pérez-Saavedra, and Iñigo J.
Vitorica-Yrezabal
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
Supporting Information Placeholder
would be expected based solely on binding thermodynamics;
unbound species tend to react faster than a pseudo-rotaxane
ABSTRACT: We report the synthesis of crown ether-
ammonium, amide and amine [2]rotaxanes via transition
(for steric, solvation and other reasons), and used in conjunc-
state stabilization of axle-forming reactions. In contrast to
tion with irreversible covalent capture reactions this leads to
significant amounts of non-interlocked products through Le
Chatelier’s principle. Here we report on the one-step synthe-
sis of rotaxanes from crown ethers and primary amines in
which, despite the macrocycle having a modest association
constant for the thread building blocks (<35 M-1), a covalent-
bond-forming reaction to form the axle is significantly accel-
erated by the macrocycle through its cavity so that it pro-
ceeds more quickly than that to form the non-interlocked
thread.2,3
the two-step ‘clipping’ and ‘capping’ strategies generally used
for rotaxane synthesis, here the components assemble into
the interlocked molecule in a single, reagent-less, step under
kinetic control. The crown ether accelerates the reaction of
the axle-forming components through the cavity to give the
threaded product in a form of metal-free active template
synthesis. Rotaxane formation can proceed through the sta-
bilization of different transition states featuring 5-coordinate
(e.g. SN2) or 4-coordinate (e.g. acylation, Michael addition)
carbon. Examples prepared using the approach include
crown-ether-peptide rotaxanes and switchable molecular
shuttles.
We recently described the synthesis of rotaxanes featuring
a bifunctional macrocycle, with amide groups at one end and
an oligo(ethylene glycol) chain at the other.4 The macrocycle
was designed to stabilize the charges that develop during the
addition of a primary amine to a cyclic sulfate, leading to
[2]rotaxane formation. A control reaction reported in that
paper (Entries 3 and 4 of Table 2 in Ref 4) showed that a
macrocycle missing the amide groups (which stabilize the
negative charge that develops on the sulfate during ring-
opening) unexpectedly still afforded rotaxane, albeit in mod-
est (5-25 %) yield. One of us (SDPF) was sufficiently in-
trigued by this result to try an unlikely looking experiment:
The most common strategy for making rotaxanes is the
covalent capture of a pre-formed threaded or entwined su-
pramolecular complex (typically by ‘clipping’ or ‘capping’).1
Molecular designs and reaction conditions are generally cho-
sen to maximize intercomponent binding so that as much as
possible of the pseudo-rotaxane intermediate is initially pre-
sent. Yet the rotaxane yield is often significantly lower than
Scheme 1. [2]Rotaxane Formation by Crown-Ether-Accelerated N-Alkylation of Primary Amines Showing Some
Potential Stabilizing Interactions in the Proposed Transition State.
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the synthesis of [2]rotaxane (1) by the reaction of a primary
Slow diffusion of hexane into an ethyl acetate solution of
rotaxane 6.HCl produced single crystals suitable for X-ray
diffraction. The solid-state structure (Figure 1a) confirmed
the interlocked architecture, showing two intercomponent
N+H…O and two N+CH…O hydrogen bonds (typical of crown-
ether-secondary-ammonium rotaxanes9), each of which like-
ly contributes to lowering the energy of the N-alkylation
transition state.10
amine (2) and an alkyl bromide (3) in the presence of 24-
crown-8 (4) (Scheme 1a). A priori such a reaction seems un-
likely because amines are poor hydrogen bond donors,5 bind-
ing only weakly to crown ethers,6 while the corresponding
primary ammonium salts (which could form by proton trans-
fer from secondary and tertiary ammonium N-alkylation
products) are excellent hydrogen bond donors7 but have no
lone pair available to act as a nucleophile. Nevertheless, the
reaction in chloroform using a 5:5:1 primary amine (2): alkyl
bromide (3): crown ether (4) ratio successfully afforded a
small amount (5 %) of [2]rotaxane 1.HBr after 24 h (Support-
ing Information, Table S1, entry 1). Mass spectrometry and 1H
NMR spectroscopy confirmed the interlocked architecture of
1 (Supporting Information).
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The conversion of macrocycle to 1.HBr could be improved
to 50 % (48 % isolated yield) by using toluene, a less polar
solvent. Higher temperatures increased the relative rate of
the thread-forming side reaction (to give 5) resulting in a
lower yield of 1.HBr. Reducing the relative amounts of the
axle-forming components, 2 and 3, or using more dilute con-
ditions also lowered the yield of [2]rotaxane (see Supporting
Information for details of the optimization studies).
We examined the influence of crown ether size and consti-
tution on the rotaxane-forming reaction (Supporting Infor-
mation, Table S2). Crown ethers with a 24-membered ring
gave higher yields of rotaxanes than the corresponding 21-
and 27- membered rings. Dibenzo-crown ethers afforded less
rotaxane than all-ethylene-glycol crown ethers. This may be
due to phenolic ethers being poorer hydrogen bond accep-
tors,5 or the conformation of the macrocycle being less well-
suited to stabilizing the reaction transition state.8
Figure 1. X-Ray crystal structures of rotaxanes formed by N-
alkylation (scheme 1) and aza-Michael addition (scheme 3).
(a) Hydrogen bond lengths [Å]: O5−H33N, 2.00; O23−H33N,
1.88; O11−H34C, 2.52; O17−H34C, 2.55. Hydrogen bond angles
(°): O5−H-N33, 169.0; O23−H−N33, 164.7; O11−H−C34, 153.7;
O17−H−C34, 143.4. (b) Hydrogen bond lengths [Å]: O10−H1N,
1.90; O16−H1N, 1.96; O12−H25C, 2.40; O15−H25C, 2.70. Hy-
drogen bond angles (°): O10−H-N1, 169.6; O16−H−N1, 164.3;
O12−H−C25, 172.2; O15−H−C25, 147.4. N+H…O and N+CH…O
hydrogen bonds shown in dark green. Solvate molecules,
counterions and other hydrogen atoms omitted for clarity.
We also investigated the influence of the axle-forming
components on rotaxane formation. Replacing alkyl amine 2
with the corresponding alcohol, thiol or ammonium salt did
not generate rotaxane (Supporting Information, Table S3).
Anilines were similarly unreactive. However, benzylamine 7
produced rotaxanes when using a benzylic electrophile bear-
ing various leaving groups (Scheme 1b), the yield of rotaxane
6 decreasing (at the expense of non-interlocked thread 8)
with increasing electrophile reactivity (Supporting Infor-
mation, Table S4).
Scheme 2. [2]Rotaxane Formation by Crown-Ether-Accelerated N-Acylation of Primary Amines Showing Some Poten-
tial Stabilizing Interactions in the Proposed Transition State.
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The experimental results obtained are consistent with the
mechanism of rotaxane formation being acceleration of the
SN2-alkylation reaction through the crown ether cavity:
jacent amino acid groups leaves little room for a convention-
al capping or clipping strategy. Pleasingly, treatment of gly-
cine derivative 13 with N-Boc-phenylalanine 4-nitrophenol
ester 14 in the presence of 24C8 (1:1:1 building block ratio)
afforded [2]rotaxane 12 in 56 % yield after 2.5 h (Scheme 2b).
There is clearly scope for synthesizing otherwise hard-to-
access structures if this transition-state-stabilization ap-
proach can be utilized with other types of macrocycle.14
(i) We measured the Ka of 24C8 for amine 2 to be 32±2 M-1 in
d8-toluene (which is roughly two orders of magnitude less
than the value for 24C8 and secondary ammonium ions used
in the synthesis of similar rotaxanes by ‘capping’11), while the
Ka of 24C8 for alkyl halide 3 was below the limits we could
1
detect by H NMR. Accordingly, the mechanism of rotaxane
Scheme 3. [2]Rotaxane Formation by Crown-Ether-
Accelerated Aza-Michael Addition Showing Some Po-
tential Stabilizing Interactions in the Proposed Transi-
tion State.
9
formation likely starts with a crown ether bound primary
amine. Hydrogen bonding to the crown ether would enhance
the nucleophilicity of the amine lone pair on electronic
grounds, although the environment will be more sterically
hindered than the free amine.
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(ii) Ethylene glycol oligomers and crown ethers have been
reported to accelerate amidation reactions,12 including in
Hirose’s synthesis of threaded structures from a covalently-
constructed ‘pre-rotaxane’,12c by the glycol units stabilizing
charges in the transition state. With a crown ether, primary
amine and alkyl halide, it appears that similar stabilization of
the charge developing in the SN2 transition state that forms
1H+ accelerates N-alkylation preferentially through the cavity
rather than by a less congested pathway (e.g. perched on the
surface of the macrocycle).
(iii) The yield of rotaxane is increased when the background
reaction to produce non-interlocked thread is slow but ob-
servable (i.e. by using relatively unreactive electrophiles,
Supporting Information Table S4, and/or less polar solvents,
Supporting Information Table S5), i.e. in a regime that lower-
ing the energy of the transition state (i.e. activation energy)
by even a few kJ mol-1 can have a pronounced effect on the
reaction rate.
Finally, we investigated the formation of rotaxanes through
aza-Michael addition. Reaction of amine
7 and α,β-
unsaturated anilide 17 in the presence of 24C8 (4) (5:5:1
building block ratio) afforded rotaxane 16 in 72 % yield after
16 days (Scheme 3). Once again the threaded structure of the
To corroborate the proposed mechanism, and to expand
the scope of the rotaxane-forming strategy, we investigated
other types of reactions featuring electrophiles capable of
reacting with a nucleophilic primary amine (Schemes 2 and
3). Reaction of amine 7 with nitro-phenol ester 10 in the
presence of 24C8 (5:5:1 building block ratio) afforded amide
[2]rotaxane 9 in 73 % yield (Scheme 2a). The threaded archi-
1
rotaxane was characterized by H NMR spectroscopy and
1
mass spectrometry (see Supporting Information). In the H
NMR spectrum of the crude reaction mixture the diagnostic
signal for rotaxane protons adjacent to an ammonium group
is not present (Figure 2a), indicating that the ammonium site
in the initially formed ammonium-enolate zwitterionic in-
termediate quickly rearranges to the amine-amide tautomer
despite stabilization of the ammonium group by the crown
ether. Slow diffusion of pentane into an ethyl acetate solu-
tion of an analog of rotaxane 16.HCl produced colorless crys-
tals suitable for single crystal X-ray diffraction (Figure 1b).
1
tecture was confirmed by H NMR spectroscopy and mass
spectrometry (see Supporting Information). In this rotaxane-
forming reaction the proposed transition state stabilized by
the crown ether centers on a tetrahedral carbon atom
(Scheme 2). Unlike the rotaxanes formed by stabilization of
SN2 N-alkylation, which are isolated as their ammonium
salts, rotaxane 9 was isolated as a neutral molecule, confirm-
ing that acid is unnecessary for rotaxane formation by this
strategy.
Reaction rate studies using a 1:1:1 ratio of 4:7:10 showed that
formation of rotaxane 9 is initially rapid: 26x faster (52 %
yield after 1 h) than formation of the non-interlocked axle 11
(2 % after 1 h) over the first hour of reaction (Supporting
Information, Section 6). The rate of rotaxane formation then
slows (65 % rotaxane 9 after 6 days), probably due to 7.H+
binding to the crown ether. This retardation can likely be
improved by judicious choice of leaving group or additives.
Lasso peptides such as microcin J25 feature a macrocyclic
section tightly locked between adjacent peptide residues on
the backbone.13 To date such structures have eluded total
synthesis, in part because the steric congestion between ad-
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Figure 2. Partial H NMR spectra (600 MHz, CD3CN, 298 K)
of a rotaxane assembled by aza-Michael addition. (a) Reac-
tion mixture following assembly of 16. (b) Rotaxane 16.HCl
isolated following acidic workup. (c) 16, formed by deproto-
nation of 16.HCl with 5 eq. DBU. The assignments corre-
spond to the lettering shown in Scheme 3. For full assign-
ment of 16.HCl see Supporting Information.
ty at Swansea University for high resolution mass spectrome-
try, Diamond Light Source for time on the I19 beamline, and
the Xunta de Galicia and European Social Fund for a pre-
doctoral fellowship to BP-S. DAL is a Royal Society Research
Professor.
REFERENCES
Rotaxane 16/16.HCl acts as a stimuli-responsive molecular
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From Molecules to Machines; John Wiley & Sons: Hoboken, NJ, 2017.
(2) Rotaxane formation through transition state stabilization is a
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active template synthesis, see: (d) Hoekman, S.; Kitching, M. O.;
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M.; Beer, P. D. Org. Biomol. Chem. 2017, 15, 4587−4594.
(3) Rotaxanes have been formed through complexation-driven effec-
tive molarity increases that accelerate axle-forming reactions within
the cavity. For selected examples, see: (a) Mock, W. L.; Irra, T. A.;
Wepsiec, J. P.; Adhya, M. J. Org. Chem. 1989, 54, 5302−5308. (b) Tun-
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A calixarene-based metal-free active template rotaxane-forming
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Zanichelli, V.; Secchi, A.; Silvi, S.; Venturi, M.; Arduini, A.; Credi, A.
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(10) In the N-alkylation reaction, stabilizing CH-O interactions in the
transition state could involve the -NCH2- group originating from the
electrophile (as depicted in Scheme 1) and/or the nucleophile. In the
N-acylation and aza-Michael addition reactions the only -NCH-
protons are derived from the nucleophile (as depicted in Schemes 2
and 3). Other stabilizing interactions of partial charge in the transi-
tion states are likely also involved.
shuttle (Supplementary Information, Section 6).1 In the am-
9
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monium form (16.HCl) the H NMR spectrum in CD3CN
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shows that the macrocycle binds to the ammonium group of
the thread (H2 δ4.5; H1 δ7.5; Figure 2b). In amine 16 the ring
resides primarily on the axle amide group (H2 δ3.8; H1 δ7.25;
Figure 2c). Switching between 16.HCl and 16 is achieved in
one direction with 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)
(16.HCl to 16) and in the other by addition of HCl (16 to
16.HCl).
In conclusion, crown-ether-dialkylammonium rotaxanes,
one of the most extensively studied rotaxane systems,1,15 can
be assembled directly from primary amines and alkyl or ben-
zyl halides (or other leaving groups). The approach circum-
vents the classic two-step clipping and capping strategies
used for rotaxane synthesis, and negates the need for addi-
tional reagents or the incorporation into the rotaxane design
of additional functionality for covalent capture. Rotaxane
formation is accomplished by transition state stabilization of
the axle-forming reaction by the macrocycle, a form of metal-
free active template2 synthesis. Other electrophiles can also
be used, demonstrating that different transition states can be
stabilized, leading to amide (through N-acylation) or 3-
aminopropanamide (through aza-Michael addition) rotax-
anes. Rotaxane formation by aza-Michael addition leads di-
rectly to pH-switchable molecular shuttles; N-acylation of
amino acids generates crown-ether-peptide rotaxanes. The
rotaxane yields in these first generation systems range from
modest-to-good (25-73 %) and, although in some cases ini-
tially rapid, require relatively long reaction times to go to
completion (typically >2 days). Both should improve with
macrocycle and leaving group designs specifically tailored4 to
suit the axle-forming reaction.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxxxxxxx. Detailed descrip-
tions of synthetic procedures; characterization of new com-
pounds; spectroscopic data (PDF).
(11) Ashton, P. R.; Bartsch, R. A.; Cantrill, S. J.; Hanes, R. E., Jr.; Hick-
ingbottom, S. K.; Lowe, J. N.; Preece, J. A.; Stoddart, J. F.; Talanov, V.
S.; Wang, Z.-H. Tetrahedron Lett. 1999, 40, 3661−3664.
AUTHOR INFORMATION
Corresponding Author
(12) (a) Hogan, J. C.; Gandour, R. D. J. Org. Chem. 1992, 57, 55−61. (b)
Basilio, N.; García-Río, L.; Mejuto, J. C.; Pérez-Lorenzo, M. J. Org.
Chem. 2006, 71, 4280−4285. (c) Hirose, K.; Nishihara, K.; Harada, N.;
Nakamura, Y.; Masuda, D.; Araki, M.; Tobe, Y. Org. Lett. 2007, 9,
2969−2972. (d) Hiratoni, K.; Suga, J.-i.; Nagawa, Y.; Houjou, H.; To-
kuhisa, H.; Numatab, M.; Watanabe, K. Tetrahedron Lett. 2002, 43,
5747–5750. (e) Kameta, N.; Hiratani, K.; Nagawa, Y. Chem. Commun.
2004, 466–467.
(13) Brayro, M. J.; Mukhopadhyay, J.; Swapna, G. V. T.; Huang, J. Y.;
Ma, L.-C.; Sineva, E.; Dawson, P. E.; Montelione, G. T.; Ebright, R. H.
J. Am. Chem. Soc. 2003, 125, 12382−12383.
(14) For rotaxanes with peptide macrocycles threaded onto an am-
monium axle by a standard ‘capping’ protocol, see: Aucagne, V.;
*david.leigh@manchester.ac.uk
ACKNOWLEDGMENT
This research was funded by the Engineering and Physical
Sciences Research Council (EP/P027067/1). We thank Dr
Simon Halstead for preliminary modeling studies on the
mechanism of rotaxane formation and Dr George Whitehead
for assistance with the X-ray crystallographic analysis. We
are grateful to the EPSRC National Mass Spectrometry Facili-
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Leigh, D. A.; Lock, J. S.; Thomson, A. R. J. Am. Chem. Soc. 2006, 128,
(15) Thibeault, D.; Morin, J.-F. Molecules 2010, 15, 3709−3730.
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