Component exchange as a synthetically advantageous strategy for the preparation of bicyclic cage compounds

Article abstract of DOI:10.1039/b801299g

Macrobicyclic triphosphazides are able to reversibly exchange one of their tripodal components by means of a dynamic disassembly-reassembly process; surprisingly this strategy provides better yields of cage compounds than a direct tripod-tripod coupling.

Full text of DOI:10.1039/b801299g

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Component exchange as a synthetically advantageous strategy for the
preparation of bicyclic cage compoundsw
a
a
a
´
´ ´ ´
Mateo Alajarın,* Jose Berna,* Carmen Lopez-Leonardo
and Jonathan W. Steedb
Received (in Cambridge, UK) 23rd January 2008, Accepted 27th February 2008
First published as an Advance Article on the web 14th March 2008
DOI: 10.1039/b801299g
Macrobicyclic triphosphazides are able to reversibly exchange
one of their tripodal components by means of a dynamic
disassembly–reassembly process; surprisingly this strategy pro-
vides better yields of cage compounds than a direct tripod–tripod
coupling.
meta-azidobenzyl)amines and triphos (3a). No selectivity was
observed when the reaction is carried out in diethyl ether at
room temperature, giving rise to an equimolar mixture of the
triphosphazides 1 and 2a (Scheme 1, path A) which precipi-
tated in the reaction medium. Gratifyingly, by changing the
solvent to deuterated chloroform, in which both cages are
soluble, the ternary mixture of reactants led exclusively to the
less sterically congested triphosphazide 2a (Scheme 1, path B),
the thermodynamically most stable product.
Self-assembly1 is a key synthetic tool in both nature and
abiotic systems. The reversible self-assembly of structurally
complementary multifunctional building blocks to form large
cage-type structures can work at both the molecular and
supramolecular levels.1,2 Molecular architectures obtained in
this way are dynamic structures in which the reversible linkage
of their components3 enables structural reconfigurations by
disassembly–reassembly events.4 Recently, this particular
feature has been implemented, at the molecular level, in
component exchange processes aimed either at the generation
of dynamic constitutional diversity4b,c or the interconversion
of metallo–organic structures.5
We have previously described6 the direct tripod–tripod
coupling of tris(ortho- and meta-azidobenzyl)amines with
1,1,1-tris(diphenylphosphinomethyl)ethane (triphos) to give
macrobicyclic triphosphazides 16a and 2a6b by a molecular
self-assembly process7 involving a triple phosphane–imination
reaction which can be understood as the first mechanistic step
of a Staudinger PIII imination.8
In these reversible conditions, the extreme selectivity of that
dynamic process relies on the metastable nature of the phos-
phazide group at each arm of these bicycles, which is in a
relatively fast equilibrium with their phosphane and azide
precursors.9 This fact apparently allows a proof-reading me-
chanism to operate such that if the reactants come together in
an ‘‘incorrect’’, thermodynamically unfavorable manner then
the system can readjust itself to yield the thermodynamically
favored product.5 In order to verify if such an underlying
mechanism is working, we attempted a triazide exchange in 1.
In fact the addition of tris(meta-azidobenzyl)amine (1 equiv.)
to a solution of the triphosphazide 1 in deuterated chloroform
at room temperature quantitatively yielded a clean mixture of
triphosphazide 2a plus an equimolecular amount of the ejected
tris(ortho-azidobenzyl)amine (Scheme 2).
Herein we describe the dynamic behavior of these macro-
bicycles which are able to undergo exchange reactions of their
triazide and triphosphane fragments through dynamic dis-
assembly–reassembly processes which operate under very mild
reaction conditions and without recourse to any templating
agent. Interestingly, the preparation of macrobicyclic tri-l5-
phosphazenes by this unprecedented protocol improves the
yields obtained in their direct synthesis based on tripod–tripod
coupling strategies.
Based on the different thermodynamic stability6 of 1 and 2a
we first focused our attention on their selective assembly from
a ternary mixture of equimolar amounts of tris(ortho- and
a
´
´
´
Departamento de Quımica Organica, Facultad de Quımica,
Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain.
E-mail: alajarin@um.es. E-mail: ppberna@um.es; Fax: +34 968
364149; Tel: +34 968 367497
b Department of Chemistry, University of Durham, South Road,
Durham, UK DH1 3LE
w Electronic supplementary information (ESI) available: CCDC
671014. For crystallographic data in CIF or other electronic format,
and details of synthesis and structural characterization. See DOI:
10.1039/b801299g
Scheme 1 (a) Simultaneous self-assembly of triphosphazides 1 and 2a
(Path A). (b) Selective formation of the triphosphazide 2a from a
ternary mixture of tris(azidobenzyl)amines and triphos (Path B).
ꢀc
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Fig. 1 (a) Molecular structure of 5 (hydrogen atoms omitted for
clarity), (b) perspective view as projected along the threefold axis.
Scheme 2 Synthesis of triphosphazide 2a by triazide exchange.
ceeds much more cleanly than the direct combination of
triazide and triphosphane to give the tri-l5-phosphazene 5.
This surprising result led us to study if this trend is observed in
the synthesis of other similar cage compounds. We find that
the metastable cage 2b10c is able to eject the triphosphane 3b
when reacted with one equivalent of the triphosphane 4, or
with its nitrogenated analog 6, leading to the new macrobyclic
tri-l5-phosphazenes 7 and 8 in 60 and 76% yield, respectively
(Scheme 4). For comparison, the direct tripod–tripod coupling
approaches to 7 and 8 were also accomplished to afford these
macrobicycles in 23 and 40% yield, respectively. Surprisingly
again, in both cases a higher efficiency of the exchange
protocol vs. the tripodal coupling was observed, validating
the component exchange method as synthetically advanta-
geous.
We reasoned that exchange of the triphosphane fragment
should also be possible if the equilibrium between e.g. 1 and a
new triphosphane lies in favor of the new cage. This situation
should arise with the longer-branched triphosphane 4 (Scheme
3) which could give rise to a less sterically constrained macro-
bicycle in which the second step of the Staudinger reaction, the
extrusion of dinitrogen, might easily occur in each arm to give
phosphazene functions. Indeed, the reaction of the macro-
bicyclic triphosphazide 1 with an equimolar amount of 4 at
room temperature gave the new macrobyclic tri-l5-phospha-
zene 5 in 84% yield (Scheme 3, path A) by means of a
triphosphane exchange followed by a triple expulsion of
molecular N2. In this case, this disassembly–reassembly pro-
cess is kinetically trapped by the dinitrogen expulsion to give a
non-dynamic macrobicycle of the type tri-l5-phosphazene.
In contrast with the macrobicyclic tri-l5-phosphazenes
bearing a triphos-like phosphane moiety, which are rigid
compounds with a propeller-like shape in solution,10 macro-
bicycle 5 displays a time-averaged C3v symmetry as determined
by the magnetic equivalence of their CH2N methylenic pro-
We reasoned that the higher efficiency of the syntheses of 5,
7 and 8 by triphosphane exchange, when compared with their
tripod–tripod couplings, might only be possible if, first, a
stepwise disassembly11 of 1 takes place to yield equilibrium
species with one or two disassembled arms. Their free N3
functions then sequentially react with the P atoms of the new
triphosphane giving rise to a dynamic set of PN3 intermediates
in which both old and new triphosphane fragments become
simultaneously linked to the triazide scaffolding,12 which plays
the role of a preorganized skeleton for building up the new
cage compound.
1
tons observed by H NMR spectroscopy and also of the two
phenyl rings of the Ph2P groups observed in the 13C NMR
spectra.z The geometry of the compound in the solid state was
determined by X-ray analysisy (Fig. 1) which revealed an
approximate C3 symmetric conformation in which the two
propeller fragments, the upper tribenzylamine core and the
lower triphosphane moiety, adopt different helical senses
(Fig. 1b), a remarkable difference compared to other reported
macrobicyclic tri-l5-phosphazenes.10
The driving force for the selective formation of the tri-l5-
phosphazenes 5, 7 and 8 during the component exchange
Particularly striking is the fact that 5 was obtained in a
much lower yield, 37%, in the direct tripod–tripod coupling of
equimolar amounts of tris(2-azidobenzyl)amine and triphos-
phane 4 (Scheme 3, path B). For some reason, the triphos-
phane exchange in the macrobicyclic triphosphazide 1 pro-
Scheme 3 Synthesis of the macrobicyclic tri-l5-phosphazene 5 by (a)
triphosphane exchange (Path A) and (b) by tripod–tripod coupling
(Path B).
Scheme 4 Syntheses of the macrobicyclic tri-l5-phosphazenes 7 and 8
by (a) triphosphane exchange (Path A) and (b) by tripod–tripod
coupling (Path B).
ꢀc
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process is most probably the irreversible N2 extrusion in the
forming PN3 arms of the new cage.
Hickman, D. Sarazin and J.-M. Lehn, Chem.–Eur. J., 2006, 12,
8581–8588.
5 (a) J. R. Nitschke, D. Schultz, G. Bernardinelli and D. Gerard, J.
´
In summary, we have shown that macrobicyclic triphos-
phazides are able to exchange their tripodal components by
means of a dynamic disassembly–reassembly process which
clearly improves the conventional synthesis of flexible macro-
byclic tri-l5-phosphazenes by direct tripod–tripod coupling.
This work was supported by the MEC and FEDER (Project
Am. Chem. Soc., 2004, 126, 16538–16543; (b) J. R. Nitschke,
Angew. Chem., 2004, 116, 3135–3137; J. R. Nitschke, Angew.
Chem., Int. Ed., 2004, 43, 3073–3075; (c) D. Schultz and J. R.
Nitschke, Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 11191–11195;
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2513–2516; D. Schultz and J. R. Nitschke, Angew. Chem., Int.
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Chem.–Eur. J., 2007, 13, 3660–3665; (f) J. R. Nitschke, Acc. Chem.
Res., 2007, 40, 103–112.
CTQ2005-02323/BQU) and Fundacio
´
n
Seneca-CARM
´
(Project 00458/PI/04). J. B. also thanks the University of
Murcia for a postdoctoral fellowship.
6 (a) M. Alajarı
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n, P. Molina, A. Lo
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n, P. Molina, A.
´
´
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´
Notes and references
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1
z Selected spectral data for 5: H NMR (300 MHz, CDCl3, 298 K): d
´
2.40 (m, 6H, CH2PN), 3.00 (m, 6H, CH2PSe), 4.16 (s, 6H, CH2N), 6.27
(m, 3H, HAr), 6.71 (dd, J(H,H) = 5.9, 3.5 Hz, 6H, HAr), 7.23–7.65 (m,
33H, HAr). 13C NMR (75 MHz, CDCl3, 298 K): d 24.62 (br d, 1J(C,P)
= 94.5 Hz, CH2PSe); 25.98 (dd, 1J(C,P) = 40.0, 2J(C,P) = 7.2 Hz,
CH2PN), 53.97 (CH2N), 117.81 (C6), 120.72 (d, 3J(C,P) = 9.3 Hz, C3),
126.07 (C4), 128.95 (d, 2J(C,P) = 11.0 Hz, oC–PhP), 130.20 (d, 1J(C,P)
= 80.0 Hz, iC–PhP), 130.38 (C5), 131.87 (br s, pC–PhP), 131.93 (d,
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9 For other examples of phosphazides that equilibrate in solution
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2
3J(C,P) = 9.3 Hz, pC–PhP), 134.25 (d, J(C,P) = 22.0 Hz, C1–CH2),
149.18 (C2–NP). 31P NMR (121.4 MHz, CDCl3, 298 K): d 3.50 (d,
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y Crystal data for 5ꢁCHCl3ꢁ(C2H5)2O: M = 1269.48, monoclinic,
P21/n, a = 13.2007(4), b = 23.8974(6), c = 20.0702(6) A, b =
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12 See ESI for experimental evidence (NMR, ESI-MS) of species
containing both triphosphane moieties in the reaction mixturew.
ꢀc
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