CuAAC "click" active-template synthesis of functionalised [2]rotaxanes using small exo-substituted macrocycles: How small is too small?

Article abstract of DOI:10.1039/c4cc03077j

Two "small" 22- and 24-membered exo-alcohol functionalised pyridyl macrocycles are exploited in the CuAAC active-template synthesis of [2]rotaxanes. The 24-membered macrocycle forms [2]rotaxanes in good yields while the smaller 22-membered macrocycle does

Full text of DOI:10.1039/c4cc03077j

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CuAAC ‘‘click’’ active-template synthesis of
functionalised [2]rotaxanes using small exo-
substituted macrocycles: how small is too small?†
Cite this: Chem. Commun., 2014,
50, 7044
Received 25th April 2014,
Accepted 15th May 2014
Asif Noor, Warrick K. C. Lo, Stephen C. Moratti and James D. Crowley*
DOI: 10.1039/c4cc03077j
www.rsc.org/chemcomm
Two ‘‘small’’ 22- and 24-membered exo-alcohol functionalised chiral rotaxanes7 and to trap the Cu(I) triazolide intermediate of
pyridyl macrocycles are exploited in the CuAAC active-template the CuAAC reaction.8 It is a matter of some interest to discover
synthesis of [2]rotaxanes. The 24-membered macrocycle forms the smallest useful macrocycle that can be exploited in this
[2]rotaxanes in good yields while the smaller 22-membered macro- reaction, in terms of atom efficiency, to get away from traditionally
cycle does not lead to interlocked products.
bulky stoppers and to increase the potential functional diversity
of the MIAs.
The development of reliable template methods for the synthesis
We have been attempting to use the CuAAC-AMT strategy to
of mechanically interlocked architectures (MIAs)1 has meant generate functionalised MIAs for a variety of purposes.9 Here,
that these molecules have become important building blocks as part of work towards novel MIAs, we build on the efforts of
for a range of nanotechnologies. MIAs, particularly rotaxanes, Goldup and co-workers5 and examine the use of two smaller
generated using supramolecular forces (hydrogen bonding and 22- and 24-membered exo-alcohol functionalised pyridyl macro-
p–p interactions) have been extensively exploited to generate a cycles in the CuAAC-AMT synthesis of [2]rotaxanes. The
wide range of functional nanoscale systems.2 Conversely, metal 24-membered macrocycle forms alcohol functionalised
(both passive3 and active4) templated systems have not received [2]rotaxanes in good yields while the smaller 22-membered
as much attention in this regard. This is, in part, connected to macrocycle does not lead to interlocked products. Furthermore,
the fact that the macrocycles used to generate these systems are the presence of the reactive alcohol functionality potentially
often quite large (430-membered) and as such there is a need to allows the post-synthetic modification of the [2]rotaxanes and
use large stoppers, such as triphenylmethyl (trityl) units which should enable the generation more highly functionalised inter-
can be difficult to functionalise.
locked systems.
Recently, Goldup and co-workers5 have demonstrated, using
The small exo-alcohol functionalised macrocycles were
the highly efficient Cu(I)-catalysed Huisgen 1,3-dipolar cycload- prepared using Williamson ether reaction conditions (Scheme 1).
dition of terminal azides and alkynes (CuAAC) ‘‘click’’ ‘active’ Under pseudo high dilution conditions, equimolar solutions of
metal template (AMT) reaction6a–d developed by the Leigh group, 3,5-dihydroxybenzyl alcohol (1) and one of the dibromides (either 2
that the use of smaller bipyridine (bipy) macrocycles leads to very or 3) were heated at 55 1C with K2CO3 in acetone for 72 hours
high yields of [2]rotaxanes. Exploiting the functional group providing the macrocycles 4 (26%) and 5 (31%) in modest isolated
tolerance of the CuAAC they generated a family of [2]rotaxanes yields, respectively. The macrocycles have been characterized using
with a range of different small stoppers. A 26-membered bipy 1H and 13C NMR spectroscopies, high resolution electrospray
macrocycle5 proved the most efficient system but due synthetic ionisation mass spectrometry (HR-ESMS), elemental analyses
difficulties Goldup and co-workers were unable to test if smaller and the molecular structures of 4 and 5 were confirmed using
macrocycles were also competent in the CuAAC-AMT reaction. X-ray crystallography (Scheme 1 and ESI†).
However, they have gone on to shown that related 26-membered
Vapour diffusion of diethyl ether into a chloroform solution
bipy macrocycles can be used to generated mechanically planar of one of the macrocycles produced single crystals suitable
for X-ray diffraction. The molecular structures of 4 and 5
(Scheme 1a and b) were as expected with 22-membered system
displaying a smaller cavity (N1–C12 6.900(3) Å) than the
24-membered species (N1–C14 7.607(2) Å). In both structures
there are hydrogen bonding interactions between the pyridyl
nitrogen atom and the OH group of the neighbouring
Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand.
E-mail: jcrowley@chemistry.otago.ac.nz; Fax: +64 3 479 7906; Tel: +64 3 479 7731
† Electronic supplementary information (ESI) available: The experimental proce-
dures, 1H, 13C and DOSY NMR, HR-ESMS and crystallographic data. CCDC
997798–997802. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc03077j
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Scheme 1 Synthesis of the 22- and 24-membered exo-alcohol functio-
nalised macrocycles 4 and 5: (i) K2CO3, acetone, 55 1C, 72 h. Labelled
ball-and-stick diagrams of the macrocycles 4 (a) and 5 (b). Selected
distances (Å) for 4 N1–C12 6.900(3), C22–C10 4.671(3), C21–C9 4.615(3)
and 5 N1–C14 7.607(2), C23–C7 6.457(2), C22–C8 6.021(2).
macrocycle. For 4 this interaction generates a one dimensional
chain of macrocycles arranged in a head-to-tail fashion supported
by hydrogen bonds between the pyridyl nitrogen atom and the OH
group of the neighbouring macrocycle (N1ꢀꢀꢀO50 2.775(2) Å, O50–
H50ꢀꢀꢀN1 170.1(1)1, ESI†). In the larger system (5) the hydrogen
bonding (N1ꢀꢀꢀO50 2.841(2) Å, O50–H50ꢀꢀꢀN1 170.69(8)1) generates
a dimer of macrocycles (ESI†).
These hydrogen bonding interactions could potentially
interfere with the metal ion coordination required for the
AMT ‘‘click’’ reaction. As such we examined the coordination
chemistry of the new macrocyclic ligands with both Cu(I) and
the larger isoelectronic Ag(I) ions. 1H NMR and HR-ESMS
experiments on 1 : 1 mixtures of either [Cu(CH3CN)4](PF6)
(1 eq.) or AgOTf (1 eq.) and one of the macrocycles 4 or 5
(1 eq.) confirmed metal ion complexation. The mass spectra all
displayed prominent peaks due to [macrocycle (4 or 5) + M
(Cu or Ag)]+ ions while the 1H NMR spectra of the 1 : 1 mixtures
were also indicative of metal ion complexation with large
downfield shifts observed for the pyridyl protons Ha and Hb
in each case (ESI†). The solid state structures of the silver(I)-
macrocycle complexes for both 4 and 5 confirmed that coordi-
nation to the macrocycle is through the pyridyl nitrogen atoms
and that the alcohol oxygen does not interact with the metal
ions (ESI†).
Scheme 2 The CuAAC active metal template [2]rotaxane synthesis using
the exo-alcohol functionalised 2,6-bis[(alkyloxy)methyl]pyridine macro-
cycle 5: (i) [Cu(CH3CN)4](PF6) (1 eq.), azide stopper (5 eq.), alkyne stopper
(5 eq.), CH2Cl2, 40 1C, 48 h; (ii) [Cu(CH3CN)4](PF6) (1 eq.), azide stopper
(5 eq.), alkyne stopper (5 eq.), CH2Cl2, 80 1C, 72 h; (iii) AgOTf, methanol, RT,
1
h. Bottom, the molecular structure of the bis-([2]rotaxane) dimer
[Ag2(11)2](OTf)2. Selected distances (Å) and angles (1) for [Ag2(11)2](OTf)2:
Ag1–N1 2.216(3), Ag1–N2 2.191(3), Ag1–N3 2.278(2), N3–Ag1–N1
114.39(9), N2–Ag1–N1 132.1(1), N3–Ag1–N2 113.30(9). Symmetry codes
x, y, z and ꢁx, ꢁy, ꢁz.
and alkyne 7 (5 eq.) stoppers were added to a CH2Cl2 solution
containing [Cu(CH3CN)4](PF6) (1 eq.) and the resulting reaction
mixture was stirred at 40 1C (Scheme 2). The reactions were
monitored using thin-layer chromatography (TLC) and HR-ESMS
and were found to proceed to completion over 48 hours. TLC
analysis of the reaction mixture containing the smallest macrocycle
Having confirmed that 4 and 5 will coordinate to metal ions,
CuAAC-AMT reactions were attempted with both systems. Initi-
ally, one of the macrocycles 4 or 5 (1 eq.), and the azide 6 (5 eq.),
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4 only showed the presence of the ‘‘free’’ macrocycle and the non- corresponding to the macrocycle’s methylene groups protons
interlocked thread, no additional spots due to the [2]rotaxane (Hd and Hg) split into diastereotopic pairs due to the reduced
were observed. This was further supported by the mass spectrum symmetry within the [2]rotaxane.
of the reaction mixture which only displayed ions due to the
Next we examined if the large trityl stoppers 6 and 7 could be
macrocycle, and the non-interlocked thread, no interlocked replaced by smaller more readily accessible units in the same way
product could be detected. In contrast, TLC analysis of the reaction that Goldup and co-workers have already demonstrated with their
mixture containing the ‘‘larger’’ 24-membered macrocycle 5 larger 26-membered bipy macrocycle.5 Reaction of 5 (1 eq.) with
showed three species, macrocycle, thread and the [2]rotaxane 8. the smaller azide 9 (5 eq.) and alkyne 10 (5 eq.) stoppers in the
The formulation of 8 was confirmed using HR-ESMS. The presence of [Cu(CH3CN)4](PF6) (1 eq.) in CH2Cl2 solution at 80 1C
spectrum displayed a major peak at m/z = 1635 whose isotope (Scheme 2), resulted in the formation of the small [2]rotaxane
pattern was consistent with [8 + Na]+ ions (ESI†). After workup 8 11 (52%). The 1H and DOSY NMR spectra and HR-ESMS data
was isolated in 17% yield. The yield of the AMT reaction could be (m/z = 965 [11 + Na]+) of 11 were consistent with the formation of
further improved by exploiting the conditions used by Goldup the interlocked product (ESI†) and the molecular structure was
and co-workers,5 heating the reaction in a sealed tube at 80 1C confirmed using X-ray crystallography (vide infra).
for 72 hours generated 8 in 70% isolated yield.10
There has been considerable recent interest in the develop-
It is postulated the difference in reactivity, of the macro- ment of rotaxane ligands.2h,i The [2]rotaxane 11 contains both
cycles 4 and 5, in the CuAAC-AMT is connected to the size and pyridyl and 1,2,3-triazoyl11 ligating units as such we examined
conformation of the smaller macrocycle 4. If the conformation the silver(I) coordination chemistry of the MIA. Vapour diffu-
of 4 observed in the solid state is maintained in solution then sion of petroleum ether into a 1 : 1 mixture of the [2]rotaxane
the CuAAC-AMT reaction would occur around rather than ligand 11 and Ag(OTf) in methanol led to the formation of
through the macrocycle’s cavity. Additionally, the cavity size colourless X-ray quality crystals. The molecular structure of the
of 4 may be too small to accommodate the required bond silver(I) complex was determined using X-ray crystallography
formation process.
and revealed that a 2 : 2 silver(I)–[2]rotaxane dimer is generated
1
Consistent with the HR-ESMS data the H and DOSY NMR under these conditions (Scheme 2).
spectra of the isolated material were indicative of [2]rotaxane
The silver(I) ions are coordinated to three nitrogen atoms in a
formation. All the proton signals due to the macrocyclic and trigonal planar geometry. The pyridyl nitrogen of the macrocycle
thread components of
8 displayed the same diffusion and the less electron-rich nitrogen atom of the 1,2,3-triazoyl unit
co-efficient (D = 3.39 ꢂ 10ꢁ10 m2 sꢁ1) indicating that they are of the same rotaxane act as a bidentate chelate ligand for the
part of the same species. 1H NMR spectrum of 8 in CDCl3 silver(I) ions. The more electron-rich nitrogen of the 1,2,3-triazoyl
(Fig. 1b) was very similar to that of previously reported ‘‘click’’ unit on a second rotaxane ligand completes the coordination
AMT [2]rotaxanes.5,6c,d,7,8 Large upfield shifts, with respect to sphere of the silver ions generating the dimeric structure. The
its non-interlocked components (Fig. 1a and c, respectively) are 1,2,3-triazole units act as bridging ligands consistent with litera-
observed for several signals. This type of shielding is commonly ture reports on similar complexes.12 The 1H and DOSY NMR
observed in interlocked architectures which feature aromatic and HR-ESMS spectra of the isolated [Ag2(11)2](OTf)2 complex
units positioned face-on to the thread component of the rotaxane. suggest that the interesting bis-([2]rotaxane) structure is main-
The triazole protons (HI) on the thread was shifted downfield tained in solution (ESI†).
presumably due to a hydrogen bonding interaction (C–HꢀꢀꢀN)
In conclusion we have demonstrated that a ‘‘small’’ readily
between the nitrogen atom of the pyridine and the hydrogen synthesised 24-membered exo-alcohol functionalised 2,6-
atom on the 1,2,3-triazole.5,7,8 Additionally, the resonances bis[(alkyloxy)methyl]pyridine macrocycle can be exploited in
the CuAAC ‘‘click’’ active-template synthesis of [2]rotaxanes.
The related 22-membered macrocycle does not lead to inter-
locked products under the same condition, and thus it appears
that a 24-membered macrocycle represents the lower limit of
required macrocycle size for a successful CuAAC-AMT outcome.
The small macrocycle size enables the incorporation of much
smaller and more readily functionalised stopper units into the
MIAs.5 Furthermore, the presence of the reactive alcohol func-
tionality with the macrocyclic component opens up the possi-
bility for the post-synthetic modification of these [2]rotaxanes,
which could be exploited to generate additional molecular
complexity. The ready synthesis of multifunctional rotaxanes
has potential in a range of areas and efforts to exploit this
methodology to synthesise rotaxane ligands, poly-rotaxanes,
and molecular machines are currently underway.
Fig. 1 Partial stacked 1H NMR spectra (CDCl3, 298 K) of (a) macrocycle 5,
(b) [2]rotaxane 8 and (c) 1,2,3-triazole thread.
We thank the Department of Chemistry, University of Otago
and the NZ Ministry of Business, Innovation and Employment
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5 H. Lahlali, K. Jobe, M. Watkinson and S. M. Goldup, Angew. Chem.,
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¨
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