A flavin-based [2]catenane

Article abstract of DOI:10.1039/b813779j

We report the synthesis, solid-state and preliminary solution properties of a flavin-based [2]catenane. The Royal Society of Chemistry.

Full text of DOI:10.1039/b813779j

Chemical Communications
www.rsc.org/chemcomm
Number 45 | 7 December 2008 | Pages 5857–6060
ISSN 1359-7345
FEATURE ARTICLE
Peter J. Stang et al.
COMMUNICATION
Coordination-driven self-assembly
of functionalized supramolecular
metallacycles
Graeme Cooke et al.
A flavin-based [2]catenane

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
A flavin-based [2]catenanew
Stuart T. Caldwell,a Graeme Cooke,*a Brian Fitzpatrick,a De-Liang Long,a
Gouher Rabania and Vincent M. Rotellob
Received (in Cambridge, UK) 7th August 2008, Accepted 3rd October 2008
First published as an Advance Article on the web 14th October 2008
DOI: 10.1039/b813779j
We report the synthesis, solid-state and preliminary solution
properties of a flavin-based [2]catenane.
Controlled molecular motion processes are ubiquitous in
nature and have inspired chemists to create synthetic analo-
gues in the form of molecular machines.1 By virtue of their
topology, molecular machines fabricated from catenanes
(mechanically interlocked macrocycles) can undergo con-
trolled rotational motion under the influence of an external
stimulus (e.g. electrochemistry).2 As a consequence catenane-
like architectures are attractive systems for the development of
biomimetic and synthetic rotary motors3 and components for
molecular electronics.4
Molecular machines fabricated from hydrogen bonded in-
terlocked structures have emerged as important systems for
the development of chemically, photochemically and electro-
chemically controllable assemblies.5 Although a range of
moieties have been incorporated into these architectures to
facilitate controlled molecular motion, there still remains
scope for the development of systems containing new mole-
cular components. Flavin units, in view of their interesting
electrochemically controllable hydrogen bonding properties,6
and their ability to have their recognition, redox7 and optical
properties tuned by synthetic manipulation, nominate these
units as excellent building blocks for the formation of func-
tional interlocked structures.8 In this communication, we
report the synthesis, solid-state structure and preliminary
solution properties of flavin-based [2]catenane 1.
Scheme 1 Synthesis of catenane 1.
Catenane 1 was synthesized as described in Scheme 1 and the
ESI.w Compound 2 was readily N-alkylated with 4-nitrobenzyl
chloride to yield compound 3 in 68% yield. The hydroxyl
group was protected with tert-butyldimethylsilyl chloride to
afford derivative 4 in 96% yield. The nitro group was then
reduced using ammonium formate and palladium on carbon to
yield derivative 5. This compound was then reacted with
succinic anhydride to yield compound 6. Compound 7 was
readily synthesised from 6 by reaction with 10-undecenamine
in the presence of EDCI–HOBt. Deprotection of the silyl
group of 7 to yield alcohol 8 was readily achieved under
standard conditions. Compound 8 was subsequently converted
to alkene derivative 9 in good yield by esterification with 10-
undecenoic acid. Macrocycle 10 was conveniently synthesized
using a ring-closing metathesis reaction catalysed by Grubbs’
second generation catalyst. A remarkably high yield of 50%
was obtained for the formation of the 43-atom macrocycle. 1H
NMR spectroscopy indicated that the ratio of the cis : trans
isomers was approximately 1 : 4. Catenane 1 was conveniently
synthesized from 10 using a standard clipping methodology in
26% yield.
a Glasgow Centre for Physical Organic Chemistry, WestCHEM,
Department of Chemistry, Joseph Black Building, University of
Glasgow, Glasgow, UK G12 8QQ
Low resolution fast-atom bombardment mass spectrometry
confirmed the [2]catenane structure for 1 ([M+] = 1409) (see
ESIw). Slow crystallization of 1 from ethanol/chloroform
provided crystals of sufficient quality for X-ray structure
determination (Fig. 1).z The data clearly proves the inter-
locked nature of the proposed catenane structure. The smaller
macrocycle forms hydrogen bonds to the carbonyl oxygen
b Department of Chemistry, University of Massachusetts at Amherst,
Amherst, MA 01002, USA
w Electronic supplementary information (ESI) available: Full syn-
thetic details for the preparation of 1–10, NMR spectra of 1 and 10,
crystallographic methods and electrochemistry details. CCDC 697887.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/b813779j
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5912 | Chem. Commun., 2008, 5912–5914

Fig. 2 Partial 1H NMR spectra of 1 and 10 showing: (a) spectrum of
10 in CDCl3; (b) spectrum of 1 in CDCl3; (c) spectrum of 10 in
DMSO-d6 (one methylene signal overlaps with the solvent peak); (d)
spectrum of 1 in DMSO-d6. Succinamide methylene protons are
highlighted in red.
which is a competitive solvent for hydrogen bonding interac-
tions, large shifts for the succinamide methylene protons were
not observed suggesting that the DMSO actively competes for
the succinamide binding site of the flavin-based macrocycle
(Fig. 2). The 1H and 2D COSY NMR spectra suggest that the
smaller macrocycle resides over the alkyl chain adjacent to the
N(10) of the flavin unit of the larger macrocycle in this solvent
(see ESIw).
Fig. 1 X-Ray crystal structure of catenane 1 depicted using: (a) a
stick representation (hydrogen bonding interactions are highlighted in
light green) and; (b) a spacefill model. The structures are visualised
using Mercury 1.4.2.15
atoms of the succinamide group of the larger flavin-based
macrocycle. Interestingly, only two hydrogen bonds were
indicated between two of the NH groups of the smaller
macrocycle and the succinamide carbonyl groups of the
flavin-based macrocycle. The remaining NH moieties of the
smaller macrocycle participate in inter-catenane hydrogen
bonding.
It is well established in the literature that three-point
hydrogen bonding between the imide moiety of the flavin
and diaminopyridine (DAP) derivatives results in significant
stabilisation (typically ꢁ150 mV) of the flavin radical anion
(Flꢂꢁ) state. Therefore, DAP-based hosts are attractive sys-
tems to model the role hydrogen bonding interactions have in
modulating the redox properties of flavin moieties in flavo-
enzymes.6,11 However, DAP systems do not adequately repli-
cate the geometry of the enzyme–cofactor interactions as the
enzyme spatially distributes the complementary hydrogen
bonding units in a semicircular array, while DAP constrains
the hydrogen bonding donor (D) and acceptor (A) moieties of
its DAD array to one face of the ADA hydrogen bonding
motif of the imide moiety of flavin. The unfavourable second-
ary interactions, inherent in the geometrically constrained
DAD–ADA arrays of this type, greatly diminish the efficiency
of the recognition process.12 More significantly, the increase in
electron density of O(2) and O(4) of the flavin unit upon
reduction accentuates these unfavourable interactions by in-
creasing negative charge density on the heteroatoms, and
hence the repulsive forces between these atoms and the
complementary DAD sites of DAP. This diminishment of
recognition between reduced flavin and DAP limits the ability
In order to gain insight into the structure of catenane 1 in
1
solution, the H NMR spectra of 1 and precursor macrocycle
10 were recorded. It has been previously been shown that this
technique offers a useful tool for studying the positional
integrity of interlocked structures of this type, as aromatic
ring currents in the p-xylylene rings result in significant upfield
shifts in the resonances of the portion if the axle/wheel covered
by this macrocycle.9 Catenane 1 displayed sufficient solubility
in chloroform and DMSO to allow us to compare the solution-
based structure in a non-polar (CDCl3) and relatively polar
(DMSO-d6) solvent. In CDCl3 the chemical shifts of the
succinamide methylene protons of 1 were positioned signifi-
cantly more upfield than the corresponding protons of macro-
cycle 10 (Fig. 2).10 Furthermore, 1H NMR spectroscopy
suggests that no other co-conformers exist, suggesting good
positional integrity of the smaller macrocyle over the succin-
amide station of catenane 1 in CDCl3. However, in DMSO-d6,
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 5912–5914 | 5913

GC gratefully acknowledges the EPSRC, RSE and the
University of Glasgow for funding this work. GC thanks
David Cooke for the design of a prototype syringe pump.
Notes and references
z Selected crystal data for 1. C84H107F3N10O14, M = 1537.80, mono-
clinic, a = 13.9514(5), b = 29.1721(10), c = 20.3132(7) A, b =
102.463(3)1. U = 8072.5(5) A3, T = 150 K, space group P21/c (no. 14),
Z = 4, 33 859 reflections measured, 10 751 unique (Rint = 0.0482)
which were used in all calculations. The final R1 was 0.065 and wR2
was 0.189 (all data).w
1 For recent reviews see: (a) E. R. Kay, D. A. Leigh and F. Zerbetto,
Angew. Chem., Int. Ed., 2007, 46, 72; (b) M. Venturi, A. Credi and
V. Balzani, Molecular Devices and Machines—A Journey into the
Nanoworld, Wiley-VCH, Weinheim, 2003; (c) V. Balzani, A. Credi,
F. M. Raymo and J. F. Stoddart, Angew. Chem., Int. Ed., 2000, 39,
3348; (d) B. Champin, P. Mobian and J.-P. Sauvage, Chem. Soc.
Rev., 2007, 36, 358.
2 For recent examples of electrochemically controllable catenanes see:
(a) B. Korybut-Daszkeiwicz, A. Wieckowska, R. Ilewicz, S.
Domagala and K. Wozniak, Angew. Chem., Int. Ed., 2004, 43,
1668; (b) V. Balzani, A. Credi, G. Mattersteig, O. A. Matthews, F.
M. Raymo, J. F. Stoddart, M. Venturi, A. J. P. White and D. J.
Williams, J. Org. Chem., 2000, 65, 1924; (c) C. Hamann, J.-M. Kern
and J.-P. Sauvage, Inorg. Chem., 2003, 42, 1877; (d) T. Ikeda, S. Saha,
I. Aprahamian, C.-F. Leung, A. Williams, W.-Q. Deng, A. H. Flood,
W. A. Goddard, III and J. F. Stoddart, Chem.–Asian J., 2007, 2, 76.
3 For recent examples of prototype catenane-based rotary motors
see: (a) D. A. Leigh, J. K. Y. Wong, F. Dehez and F. Zerbetto,
Fig. 3 Cyclic voltammograms of 1 (blue) and 10 (red) (B7 ꢃ 10ꢁ4 M)
recorded in CH2Cl2 (0.1 M Bu4NPF6). Scan rate 50 mV sꢁ1
.
of DAP hosts to efficiently modulate flavin redox potentials,
and hence to effectively model flavoenzyme behaviour.
Thus, there remains considerable scope for the development
of biomimetic flavin-based host–guest systems that
more accurately replicate the ability of the apoenzyme of
flavoenzymes to modulate the redox potential of the flavin
cofactor.
´
Nature, 2003, 424, 174; (b) J. V. Hernandez, E. R. Kay and D. A.
Leigh, Science, 2004, 306, 1532.
In catenane 1, reduction of the flavin moiety to the corres-
ꢁ
ponding Flꢂ state should increase the electronegativity of
4 For examples see: (a) C. P. Collier, G. Mattersteig, E. W. Wong, Y.
Luo, K. Beverly, J. Sampaio, F. M. Raymo, J. F. Stoddart and J.
R. Heath, Science, 2000, 289, 1172; (b) D. W. Steuerman, H.-S.
Teng, A. J. Peters, A. H. Flood, J. O. Jeppersen, K. A. Nielsen, J.
F. Stoddart and J. R. Heath, Angew. Chem., Int. Ed., 2004, 43,
6486.
5 E. R. Kay and D. A. Leigh, Top. Curr. Chem., 2005, 262, 133.
6 E. Breinlinger, A. Niemz and V. M. Rotello, J. Am. Chem. Soc.,
1995, 117, 5379.
O(2) and O(4), and therefore could provide an effective
hydrogen bonding site for complementary moieties within
the catenane architecture.13 Therefore, for catenane 1, wꢁe
anticipated that the electrochemical generation of the Flꢂ
species should occur at a significantly lower potential than
10.6,11 To test this hypothesis, we have investigated the solu-
tion electrochemistry of 1 and 10 using cyclic voltammetry
(CV) in CH2Cl2 (Fig. 3 and ESI). Macrocycle 10 gave a single
reversible redox wave (E1/2 = ꢁ0.62 V) corresponding to the
formation of the Flꢂꢁ species. When the CV of catenane 1 was
recorded, a reversible redox wave was observed at a signifi-
cantly lower potential (E1/2 = ꢁ0.35 V) than that obtained for
10. This +270 mV stabilisation of the Flꢂꢁ state suggests that
the flavin moiety becomes hydrogen bonded to a complemen-
tary moiety of the catenane upon reduction of the flavin unit
of 1.14
7 Y.-M. Legrand, M. Gray, G. Cooke and V. M. Rotello, J. Am.
Chem. Soc., 2003, 125, 15789.
8 G. Cooke, J. F. Garety, B. Jordan, N. Kryvokhyzha, A. Parkin, G.
Rabani and V. M. Rotello, Org. Lett., 2006, 8, 2297.
9 D. A. Leigh, K. Moody, J. P. Smart, K. J. Watson and A. M. Z.
Slawin, Angew. Chem., Int. Ed. Engl., 1996, 35, 306.
10 Examination of the 2D NOESY and COSY spectra indicate that
the succinamide methylene protons of 1 in CDCl3 appear at 1.8
and 1.1 ppm.
11 A. Niemz and V. M. Rotello, Acc. Chem. Res., 1999, 32, 44.
12 (a) W. L. Jorgensen and J. Pranata, J. Am. Chem. Soc., 1990, 112,
2008; (b) J. Pranata, S. G. Wierschke and W. L. Jorgensen, J. Am.
Chem. Soc., 1991, 113, 2810.
13 For examples of redox controllable hydrogen bonded rotaxanes
see: (a) A. Altieri, F. G. Gatti, E. R. Kay, D. A. Leigh, D. Martel,
F. Paolucci, A. M. Z. Slawin and J. K. Y. Wong, J. Am. Chem.
Soc., 2003, 125, 8644; (b) A. M. Brouwer, C. Frochot, F. G. Gatti,
D. A. Leigh, L. Mottier, F. Paolucci, S. Roffia and G. W. H.
Wurpel, Science, 2001, 291, 2124.
14 Experiments are underway in our laboratory on these and related
compounds to investigate whether redox-induced rotational mo-
tion occurs in catenanes of this type. The results from these
investigations will be reported in due course.
In conclusion, we have devised effective methodology for
synthesising a flavin-based [2]catenane. In the solid state and
chloroform solution, the smaller macrocycle is positioned over
the succinamide station of the flavin containing macrocycle.
Cyclic voltammetry studies indicate that the catenane archi-
ꢁ
tecture of 1 results in a significant stabilisation of the Flꢂ
,
presumably due to intra-catenane hydrogen bonding interac-
tions. A detailed study of the molecular machine and device
properties of derivative 1 and its analogues is underway in our
laboratory, and results from these investigations will be pub-
lished in due course.
15 Mercury: Visualization and analysis of crystal structures: C. F.
Macrae, P. R. Edgington, P. McCabe, E. Pidcock, G. P. Shields, R.
Taylor, M. Towler and J. van de Streek, J. Appl. Crystallogr., 2006,
39, 453.
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5914 | Chem. Commun., 2008, 5912–5914