Synthesis of Two 2,2′-Bipyridine Containing Macrocycles for the Preparation of Interlocked Architectures

Article abstract of DOI:10.1071/CH16710

The synthesis and characterisation of two 28-membered, 2,2′-bipyridine-containing macrocycles in high yield is reported. The first imine-containing macrocycle was formed via a Williamson ether synthesis and showed no evidence of higher oligomer formation.

Full text of DOI:10.1071/CH16710

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH16710
Synthesis of Two 2,29-Bipyridine Containing Macrocycles
for the Preparation of Interlocked Architectures*
A
A
B
Jacob Whittaker, Suresh Moorthy, Jonathan Cremers,
C
D
A E
,
Jason R. Price, John C. McMurtrie, and Jack K. Clegg
A
School of Chemistry and Molecular Biosciences, The University of Queensland,
St Lucia, Qld 4072, Australia.
B
Department of Chemistry, The University of Oxford, Chemistry Research Laboratory
Mansfield Road, Oxford OX1 3TA, UK.
C
The Australian Synchrotron, 800 Blackburn Rd, Clayton, Vic. 3168, Australia.
D
School of Chemistry, Physics and Mechanical Engineering, Faculty of Science and
Engineering, Queensland University of Technology, GPO Box 2434, Brisbane,
Qld 4001, Australia.
E
Corresponding author. Email: j.clegg@uq.edu.au
The synthesis and characterisation of two 28-membered, 2,20-bipyridine-containing macrocycles in high yield is reported.
The first imine-containing macrocycle was formed via a Williamson ether synthesis and showed no evidence of higher
oligomer formation. Reduction of the imines with sodium borohydride produced the second macrocycle quantitatively.
Manuscript received: 13 December 2016.
Manuscript accepted: 20 January 2017.
Published online: 13 February 2017.
Introduction
Treatment with potassium cyanide produced the metal-free
[2]catenane. The individual non-interlocked 28-membered
macrocyclic components of 1 and 2 (3 and 4, respectively) were
not reported. These macrocycles, which contain a 2,20-bipyridine
unit would be useful components for the formation of a wide
variety of interlocked architectures including further catenanes,
rotaxanes, and molecular machines. The present study reports the
preparation of macrocycle 3 in 82% yield and its quantitative
reduction to macrocycle 4 on the NMR scale (Chart 1).
The 2016 Nobel Prize for Chemistry was awarded to Sauvage,
Stoddart, and Feringa for the design and synthesis of molecular
machines.[1] Sauvage[2] and Stoddart,[3] in particular, have
based their design strategies for these machines around the use
of interlocked and topologically complex architectures such as
catenanes and rotaxanes.[4] Building on their early work, Leigh
and others have extended this approach producing a wide variety
of increasingly complex molecules and machines[5] including
rotors,[6] walkers,[7] peptide synthesisers,[8] ratchets,[9] and an
extended series of knots and links.[10] Learning from the low
yielding statistical approach to the first [2]catenane, which was
isolated in 1 ꢀ 10ꢁ4 % yield over 50 years ago,[11] higher-
yielding templated (pre-organised) designs have now been
established; however, macrocyclisation reactions are generally
still yield limiting.[12] In addition to high-dilution and/or syringe
pump additions of reagents, several groups have also employed
click reactions,[13] alkene-metathesis,[14] and coordination
bonds[15] in order to enhance the yields of the target macrocyclic
products. For example, Lindoy and colleagues[16] reported the
quantitative formation a [2]catenane 1 in solution through the
use of a reversible imine-condensation reaction and a copper(I)
template. The macrocycle employed was designed to have more
flexibility that the 1,10-phenanthroline-containing macrocycles
employed by Sauvage.[17] In situ reduction with borohydride led
to the isolation of the tetraamine-analogue 2 in more modest
yield, which was characterised by X-ray crystallography.
Results and Discussion
Lindoy and coworker’s high-yielding synthetic strategy[16] to
produce the [2]catenane 1 involved the pre-organisation of two
diadelhyde-2,20-bipyridine derivatives 5 around a copper(I) ion
followed by a Schiff base condensation reaction (Scheme 1).
The tetrahedral copper(I) template served to arrange the dia-
ldehyde groups to promote the formation of the target
[2]catenane rather than a non-interlocked [2þ2] macrocyclic
isomer, while the reversibility of the imine-formation reaction
allowed for self-correction during the high-dilution reaction.
Our first attempt to prepare 3 followed a similar approach
(Scheme 2).
We prepared dialdehyde 5 following Lindoy and cowor-
kers’s method and added one equivalent of commercially
available 1,6-diaminohexane in methanol. We monitored the
1
reaction using a combination of H NMR spectroscopy and
*Dedicated to Mrs Fay Lindoy on the occasion of Len’s 80th birthday.
Journal compilation ꢀ CSIRO 2017
www.publish.csiro.au/journals/ajc

B
J. Whittaker et al.
ϩ
ϩ
N
HN
N
NH
O
O
O
O
N
N
N
N
N
N
Cu
Cu
N
N
O
O
O
O
NH
N
N
HN
1
2
N
N
N
N
O
O
O
N
O
NH
HN
N
3
4
Chart 1.
ϩ
ϩ
O
N
O
N
O
O
O
O
N
N
2 eq. 1,6-diaminohexane
N
N
N
Cu
Cu
N
MeOH
4 Å sieves
N
N
O
O
O
O
O
N
O
N
[Cu52]
Scheme 1. Lindoy’s synthetic route to [2]-catenane 1 via CuI templation and imine condensation.
1
electrospray ionisation mass spectrometry (ESI-MS). Even after
72 h of reflux no imine formation was observed. This reaction
was performed numerous times with the addition of a variety of
imine to the corresponding diamine-containing diphenol 7 by
treatment with sodium borohydride.
The dropwise addition (over 12 h) of diphenol 6 to dibromide
4 under dilute conditions (0.1 mmoL) in N,N-dimethylforma-
mide (DMF) in the presence of excess caesium carbonate
followed by reflux for three days yielded the desired [1þ1]
macrocycle 3 in 82 % isolated yield after a sodium hydroxide
work-up. High-resolution mass spectrometry (HR-MS) (Fig. S1,
Supplementary Material) and 1H NMR spectroscopy in CDCl3
(Fig. 1) confirmed the formation of the desired product. The 1H
NMR spectrum of 3 in CDCl3 produced a spectrum consisting of
10 signals, confirming the 2-fold symmetry of the macrocycle.
The imine peak (Hg in Scheme 2) appears at 8.19 ppm. The
breadth of the peaks suggests that intramolecular rotations are
restricted to some extent, also consistent with a cyclised product.
˚
water sequestering agents (4A molecular sieves, magnesium
sulfate, sodium sulfate) or catalytic amounts of acetic acid. In
each case 1H NMR spectroscopy and ESI-MS indicated only the
dialdehyde and diamine starting materials were present.
We then explored the possibility of macrocyclisation via
ether formation from the previously reported 6,60-bis-(bromo-
methyl)-2,20-bipyridine 4 and the corresponding diphenol 6 in
the presence of base (Scheme 2). First we prepared 5 in 95 %
yield from the Schiff base condensation of 4-hydroxybenzalde-
hyde and 1,6-diaminohexane. Compound 6 shows a character-
istic 1H NMR pattern with a sharp singlet corresponding to the
imine proton at 8.14 ppm. We also successfully reduced the

Two 2,20-Bipyridine Containing Macrocycles
C
a
b
c
OH
N
N
d
Br
O
O
e
f
Base
DMF
N
ϩ
N
N
N
g
N
N
Br
i
h
OH
j
4
6
3
Scheme 2. Preparation of macrocycle 3.
Hd
Hh
Hf
He
Hj
Hi
Hg
#
Ha
Hb
Hc
∗
10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
0
δ [ppm]
Fig. 1. The 1H NMR spectrum of 3 (500 MHz, CDCl3). Proton assignments correspond to the lettering shown in
Scheme 2. Peaks marked with # correspond to residual CHCl3 (7.26 ppm) and with * to residual water (1.5 ppm).
A 13C NMR spectrum in CDCl3 further supported the synthesis
of macrocycle 3. The dominant peak at m/z 505.26 in the HR-MS
has a close match to the predicted isotropic distribution for
[M þ H]þ (Fig. S1), while both low- and high-resolution mass
spectra of the crude and purified products gave no evidence of
the formation of higher oligomers or by-products (Fig. S2,
Supplementary Material).
Conclusions
We have successfully prepared two new 2,20-bipyridine-
containing macrocycles in high-yield. No-evidence for higher
oligomer formation was observed during the macrocyclisation
reaction. Future studies will investigate the metal-complexation
properties of these ligands and their use in the formation of
interlocked architectures.
We then investigated the reduction of the imine groups of 3
to produce tetraamine 4 on the NMR scale. Treatment of 3 with
two equivalents of NaBH4 in methanol followed by filtration
produced the desired product quantitatively. The 1H NMR
spectrum of the sample in CDCl3 (Fig. 2) shows complete loss
of the imine peak at 8.19 ppm (Hg in top of Fig. 2) and a new
peak corresponding to the new methylene group at 3.33 ppm
(Hg in bottom of Fig. 2). These peaks and their chemical shifts
correspond closely to those of the previously reported [2]
catenane, 2.
Experimental
6,60-Dimethyl-2,20-bipyridine,[18] 6,60-bis-(bromomethyl)-2,20-
bipyridine,[19] and 4,40-(([2,20-bipyridine]-6,60-diylbis(methy-
lene))bis(oxy))dibenzaldehyde[16] were synthesised and purified
according to the literature methods. All other reagents were
purchased from commercial suppliers and used without further
purification unless otherwise stated. DMF was dried and dis-
pensed using an Innovative Technologies Pure Solv solvent

D
J. Whittaker et al.
Hd
Hh
He
Hf
Hj
Hi
Hg
Ha
#
Hb Hc
∗
Hk
Hg
Hh
#
Hi
Hj
Hd
Hb
He
Ha
c Hf
H
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
δ [ppm]
Fig. 2. 1H NMR spectra of 3 (above) and the reduced macrocycle of 4 (below). The proton assignments correspond to the
lettering shown in Scheme 2. Peaks marked with # correspond to residual CHCl3 (7.26 ppm) and with * to residual water
(1.5 ppm).
purification system, all other chemicals were used without puri-
fication. Bruker Avance 300 and 500 MHz spectrometers were
used to collect NMR spectra. All manipulations were performed
under an N2 atmosphere. Elemental analyses were completed by
The University of Queensland’s School of Chemistry and
Molecular Bioscience using a Thermo Scientific Flash 2000
Organic Elemental Analyser. All samples were dried under
vacuum over P2O5 for a minimum of 12 h before elemental
analysis submission. Mass spectrometry analyses were per-
formed on either a Bruker MicrOTOF-Q 70 or an Applied Bio-
systems Voyager-DESTR instrument used for ESI-MS and
matrix-assisted laser desorption–ionisation time-of-flight mass
spectrometry (MALDI-TOF MS), respectively.
solution was concentrated to 5 mL and a red solid was precipi-
tated upon the addition of diethyl ether. The red solid was
washed with diethyl ether (2 ꢀ 50 mL) and air-dried which
afforded the pure imine product (2.51 g, 95 % yield). Anal. Calc.
for C20H24N2O2: C 74.05, H 7.46, N 8.63. Found: C 73.90,
H 7.77, N 8.58 %. dH (DMSO, 300 MHz, 300 K) 1.32 (m, br,
4H), 1.55 (m, br, 4H), 3.46 (t, J 6.75, 6.65, 4H), 6.76 (d, J 8.6,
4H, Ar-H), 7.51 (d, J 8.81, 4H, Ar-H), 8.14 (s, 2H). dC (DMSO,
125 MHz, 300 K) 27.0, 31.2, 60.7, 115.9, 127.9, 129.9, 160.2. m/
z (ESI) 325 (M þ H)þ.
Synthesis of 4,40-((Hexane-1,6-diylbis(azanediyl))bis
(methylene))diphenol (7) (Chart 3)
Compound 1 (250 mg, 0.772 mmol) and sodium borohydride
(120 mg, 3.16 mmol) were dissolved in MeOH (50 mL) and
stirred at room temperature for 16 h. The solvent was concen-
trated to 20 mL, excess diethyl ether was added, and a white
solid precipitated. It was collected and washed with diethyl ether
(2 ꢀ 50 mL) to produce 2 (yield 241 mg, 95 %). Anal. Calc. for
Synthesis of 4,40-(Hexane-1,6-diylbis(azaneylylidene))bis
(methaneylylidine)diphenol (6) (Chart 2)
4-Hydroxybenzaldehyde (2.0 g, 0.0164 mol) and 1,6-hex-
anediamine (0.95 g, 0.0082 mol) were dissolved in MeOH
(100 mL) and the mixture stirred at 808C for 16 h. The red
OH
OH
H
N
N
N
H
N
6
7
OH
OH
Chart 2.
Chart 3.

Two 2,20-Bipyridine Containing Macrocycles
E
C20H28N2O2: C 73.14, H 8.59, N 8.53. Found: C 73.2, H 8.87,
N 8.32 %. dH (DMSO, 300 MHz, 300 K) 1.22 (m, br, 4H), 1.35
(m, br, 4H), 2.42 (t, J 6.80, 6.60, 4H), 3.52 (s, 4H), 6.67 (d, J
8.10, 4H, Ar-H), 7.08 (d, J 7.86, 4H, Ar-H), 9.20 (s, 2H, Ar-OH).
dH (DMSO, 125 MHz, 300 K) 27.4, 29.9, 49.1, 53.1, 115.2,
129.4, 131.6, 156.3. m/z (ESI) 329 (M þ H)þ.
brown powder of 4. dH (CDCl3, 500 MHz, 300 K) 8.32 (d, 2H,
HA), 8.01 (s, 2H, HB), 7.82 (d, 2H, HC), 7.52 (d, 4H, HF), 6.95
(d, 4H, HE), 5.27 (s, 4H, HD), 3.33 (s, 4H, HG), 2.88 (s, 2H, HH),
2.62 (s, 4H, HI), 1.54 (s, 4H, HJ), 1.20 (t, 4H, HK).
Crystallographic Data
The crystallographic data in CIF format has been deposited at
the Cambridge Crystallographic Data Centre with CCDC
1519162–1519167. It is available free of charge from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1 EZ, UK; fax: (þ44) 1223-336-033; or email:
deposit@ccdc.cam.ac.uk.
Synthesis of Macrocycle 3 (Chart 4)
Compound 1 (140 mg, 0.41 mmol) and caesium carbonate
(550 mg, 1.64 mmol) were added to DMF (150 mL) and heated
to 708C. Compound 3 (135 mg, 0.42 mmol) dissolved in DMF
(100 mL) was added dropwise over 12 h. The light brown mix-
ture was stirred at 1258C for 3 days. After cooling, the solvent
was concentrated to 20 mL and a fine solid precipitated upon the
addition of diethyl ether. The brown solid was collected and
suspended in NaOH (1 M, 10 mL) while stirring at 858C for
15 min and the resulting solid collected to yield 3 as a light
brown powder (yield 185 mg, 82 %). dH (CDCl3, 500 MHz,
300 K) 1.39 (br m, 4H, HJ), 1.69 (br m, 4H, HI), 3.56 (br m, 4H,
HH), 5.32 (s, 4H, HD), 7.04 (d, 4H, J 8.03, HE), 7.52 (d, 2H,
J 7.22, HC), 7.66 (m, 6H, J 8.03, HF), 7.84 (m, 2H, J 7.22, 7.30,
HB), 8.19 (s, 2H, HG), 8.35 (d, 2H, J 7.02, HA). dC (CDCl3,
125 MHz, 300 K) 27.3, 30.9, 61.6, 70.8, 114.9, 120.1, 121.3,
129.6, 137.7, 155.4, 156.4, 159.9, 160.3. m/z (ESI) 505.2
(M þ H)þ.
Supplementary Material
PXRD patterns of the bulk phases and the patterns predicted
from the single crystal experiments are available on the Jour-
nal’s website.
Acknowledgements
The authors thank the Australian Research Council for financial support.
References
[1] D. A. Leigh, Angew. Chem. Int. Ed. 2016, 55, 14506. doi:10.1002/
ANIE.201609841
[2] (a) J. P. Sauvage, Acc. Chem. Res. 1990, 23, 319. doi:10.1021/
AR00178A001
Preliminary Synthesis of Reduced Macrocycle 4 (Chart 5)
(b) J.-P. Sauvage, Acc. Chem. Res. 1998, 31, 611. doi:10.1021/
AR960263R
(c) C. O. Dietrich-Buchecker, J. P. Sauvage, Chem. Rev. 1987, 87, 795.
doi:10.1021/CR00080A007
(d) J.-P. Collin, C. Dietrich-Buchecker, P. Gavin˜a, M. C. Jimenez-
Molero, J.-P. Sauvage, Acc. Chem. Res. 2001, 34, 477. doi:10.1021/
AR0001766
The brown powder of 1 (10 mg, 0.02 mmol) was dissolved in
MeOD, NaBH4 added (1.5 mg, 0.04 mmol), and the mixture
heated to 508C for 3 h. The solvent was removed under vacuum
and CDCl3 was added and sonicated to aid in dissolving 4. The
precipitate was filtered and solvent removed to produce the light
[3] (a) R. A. Bissell, E. Cordova, A. E. Kaifer, J. F. Stoddart, Nature 1994,
369, 133. doi:10.1038/369133A0
(b) V. Balzani, M. Go´mez-Lo´pez, J. F. Stoddart, Acc. Chem. Res. 1998,
31, 405. doi:10.1021/AR970340Y
N
N
(c) V. Balzani, A. Credi, F. M. Raymo, J. F. Stoddart, Angew. Chem.
Int. Ed. 2000, 39, 3348. doi:10.1002/1521-3773(20001002)
39:19,3348::AID-ANIE3348.3.0.CO;2-X
O
O
(d) D. B. Amabilino, J. F. Stoddart, Chem. Rev. 1995, 95, 2725.
doi:10.1021/CR00040A005
[4] (a) J. E. Beves, B. A. Blight, C. J. Campbell, D. A. Leigh, R. T.
McBurney, Angew. Chem. Int. Ed. 2011, 50, 9260. doi:10.1002/ANIE.
201007963
N
N
(b) J.-P. Sauvage, C. Dietrich-Buchecker, Molecular Catenanes,
Rotaxanes and Knots 1999 (Wiley-VCH: Weinheim).
[5] M. R. Wilson, J. Sola`, A. Carlone, S. M. Goldup, N. Lebrasseur, D. A.
Leigh, Nature 2016, 534, 235. doi:10.1038/NATURE18013
[6] D. A. Leigh, J. K. Y. Wong, F. Dehez, F. Zerbetto, Nature 2003, 424,
174. doi:10.1038/NATURE01758
3
Chart 4.
[7] M. von Delius, D. A. Leigh, Chem. Soc. Rev. 2011, 40, 3656.
doi:10.1039/C1CS15005G
[8] B. Lewandowski, G. De Bo, J. W. Ward, M. Papmeyer, S. Kuschel,
M. J. Aldegunde, P. M. E. Gramlich, D. Heckmann, S. M. Goldup,
D. M. D’Souza, A. E. Fernandes, D. A. Leigh, Science 2013, 339, 189.
doi:10.1126/SCIENCE.1229753
N
N
O
O
[9] V. Serreli, L. Chin-Fa, E. R. Kay, D. A. Leigh, Nature 2007, 445, 523.
doi:10.1038/NATURE05452
[10] (a) J.-F. Ayme, J. E. Beves, D. A. Leigh, R. T. McBurney, K. Rissanen,
D. Schultz, Nat. Chem. 2012, 4, 15. doi:10.1038/NCHEM.1193
(b) J.-F. Ayme, J. E. Beves, D. A. Leigh, R. T. McBurney, K. Rissanen,
D. Schultz, J. Am. Chem. Soc. 2012, 134, 9488. doi:10.1021/
JA303355V
NH
HN
4
(c) J.-F. Ayme, J. E. Beves, C. J. Campbell, D. A. Leigh, Chem. Soc.
Chart 5.
Rev. 2013, 42, 1700. doi:10.1039/C2CS35229J

F
J. Whittaker et al.
(d) J. E. Beves, C. J. Campbell, D. A. Leigh, R. G. Pritchard, Angew.
Chem. Int. Ed. 2013, 52, 6464. doi:10.1002/ANIE.201302634
(e) D. A. Leigh, R. G. Pritchard, A. J. Stephens, Nat. Chem. 2014, 6,
978. doi:10.1038/NCHEM.2056
(f) V. Marcos, A. J. Stephens, J. Jaramillo-Garcia, A. L. Nussbaumer,
S. L. Woltering, A. Valero, J.-F. Lemonnier, I. J. Vitorica-Yrezabal, D.
A. Leigh, Science 2016, 352, 1555. doi:10.1126/SCIENCE.AAF3673
(g) F. Li, J. K. Clegg, L. F. Lindoy, R. B. MacQuart, G. V. Meehan,
Nat. Commun. 2011, 2, 205. doi:10.1038/NCOMMS1208
(b) S. L. Mangold, D. J. O’Leary, R. H. Grubbs, J. Am. Chem. Soc.
2014, 136, 12469. doi:10.1021/JA507166G
[15] (a) P. Mal, D. Schultz, K. Beyeh, K. Rissanen, J. R. Nitschke, Angew.
Chem. Int. Ed. 2008, 47, 8297. doi:10.1002/ANIE.200803066
´
(b) A. Gonza´lez-Alvarez, A. Frontera, P. Ballester, J. Phys. Chem. B
2009, 113, 11479. doi:10.1021/JP9053742
(c) J.-F. Ayme, J. E. Beves, D. A. Leigh, R. T. McBurney, K. Rissanen,
D. Schultz, Nat. Chem. 2012, 4, 15. doi:10.1038/NCHEM.1193
[16] J. R. Price, J. K. Clegg, R. R. Fenton, L. F. Lindoy, J. C. McMurtrie,
G. V. Meehan, A. Parkin, D. Perkins, P. Turner, Aust. J. Chem. 2009,
62, 1014. doi:10.1071/CH09253
[11] E. Wasserman, J. Am. Chem. Soc. 1960, 82, 4433. doi:10.1021/
JA01501A082
[12] L. F. Lindoy, The Chemistry of Macrocyclic Ligand Complexes 1989
[17] A. Livoreil, C. O. Dietrich-Buchecker, J.-P. Sauvage, J. Am. Chem.
(Cambridge University Press: Cambridge).
Soc. 1994, 116, 9399. doi:10.1021/JA00099A095
[13] R. A. Turner, A. G. Oliver, R. S. Lokey, Org. Lett. 2007, 9, 5011.
doi:10.1021/OL702228U
[14] (a) H. Zhang, E. C. Yu, S. Torker, R. R. Schrock, A. H. Hoveyda, J. Am.
[18] T. M. Cassol, F. W. J. Demnitz, M. Navarro, E. A. d. Neves, Tetra-
hedron Lett. 2000, 41, 8203. doi:10.1016/S0040-4039(00)01310-1
[19] Z. Wang, J. Reibenspies, R. J. Motekaitis, A. E. Martell, J. Chem. Soc.
1995, 1511.
Chem. Soc. 2014, 136, 16493. doi:10.1021/JA510768C