Dynamic combinatorial libraries of metalloporphyrins: Templated amplification of disulfide-linked oligomers

Article abstract of DOI:10.1039/b310438a

Disulfide-linked cyclic porphyrin oligomers from dimer to tetramer can be selected and amplified virtually quantitatively from a dynamic combinatorial library using bis-thiol substituted zinc(II) porphyrin units with appropriate amine donor templates.

Full text of DOI:10.1039/b310438a

Dynamic combinatorial libraries of metalloporphyrins: templated
amplification of disulfide-linked oligomers
Amy L. Kieran, Andrew D. Bond†, Ana M. Belenguer and Jeremy K. M. Sanders*
Cambridge Centre for Molecular Recognition, University Chemical Laboratory, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: jkms@cam.ac.uk
Received (in Cambridge, UK) 29th August 2003, Accepted 17th September 2003
First published as an Advance Article on the web 30th September 2003
Disulfide-linked cyclic porphyrin oligomers from dimer to
tetramer can be selected and amplified virtually quantita-
tively from a dynamic combinatorial library using bis-thiol
substituted zinc(II) porphyrin units with appropriate amine
donor templates.
Previous work has shown the efficacy of templating the
formation of a butadiyne-linked porphyrin dimer with 4,4A-
bipyridine (Bipy; Scheme 1), in up to 70% yield.5 Initiation of
exchange in the dithiol porphyrin system in the presence of
Bipy, however, resulted in a dramatically different equilibrium
library composition, with a significant reduction in the amount
of cyclic dimer present; so that the final mixture consisted
mainly of trimer (50%) and higher oligomers (20%) at
equilibrium. In fact, species up to cyclic decamer were detected
by LC MS.
When cyclisation occurred in the presence of 0.5 equiv.
1,4-diazabicyclo(2.2.2)octane (DABCO) per porphyrin, there
was a shift in the equilibrium composition of the library. An
enhancement of the amount of dimer present, up to 99%, with a
concomitant reduction in the amount of higher oligomers
present, was seen. This contrasts with the Glaser coupling
results, and is indicative of the geometric requirements of the
hosts. The bis-disulfide dimer has a much smaller cavity than
the butadiyne-linked dimer, and hence Bipy is too large to be
encapsulated. When the linear intermediate binds to Bipy, it
cannot achieve the optimum geometry for cyclisation and so the
reactive thiols are held apart. By contrast, upon binding to
DABCO, the smaller ligand, there is an excellent geometrical
fit, leading to the exclusive formation of dimer (see X-ray
crystal structure below).
Dynamic combinatorial chemistry (DCC) provides access to
new host–guest systems with the potential for catalysis and drug
discovery that may be difficult to synthesise using traditional
design approaches.1 The salient feature of DCC is the dynamic
combinatorial library (DCL) in which each library member is
assembled from building blocks which are connected through
reversible bonds. As a result of this reversibility, all library
members are interconverting to give a distribution that is under
thermodynamic control. Thus addition of a guest molecule that
can selectively bind to one receptor in the library will serve to
increase the concentration of that host at the expense of others
in the DCL.
We, and others, have been developing thiol–disulfide
exchange chemistry for use in DCLs.2 Thiols can be readily
oxidised to disulfides in the presence of air. Exchange between
disulfides can be easily initiated and is rapid in the presence of
a catalytic amount of thiol under neutral or mildly basic
conditions. Disulfides are also stable towards many other
functional groups. We have recently reported the first example
of a catalyst obtained from a DCL using a Transition State
Analogue as a template.3
Cyclisation in the presence of a saturated solution of 4-s-
tripyridyltriazine (TPyT) promotes the formation of porphyrin
Previously, we have described the use of template-directed
synthesis to create porphyrin oligomers ranging in size from
cyclic dimer to linear octamer.4 The butadiyne-linked species
were synthesised by the removal of trimethylsilyl protecting
groups from alkynyl substituents on the meso-diarylporphyrins,
followed by zinc metallation and irreversible Glaser coupling.
Coupling in the presence of amines such as bipyridine was
found to significantly alter the final product distribution
obtained by kinetic templating.5 Here we present the initial
results from the unification of these two approaches.
Bis-benzylthiol substituted porphyrin Zn-2 was obtained by
the hydrazine mediated deprotection of bis-thioacetate ap-
pended porphyrin Zn-1 (Fig. 1), which was synthesized by
standard routes in good yield.6 When a 5 mM CHCl3 solution of
Zn-2 was treated with DBU in the presence of air, oxidative
cyclisation of the monomer occurred, as illustrated schemat-
ically in Fig. 2. At thermodynamic equilibrium, achieved after
3 to 4 days, MALDI TOF mass spectrometry of fractions
isolated from analytical runs of HPLC‡ showed that the major
constituent of the library was porphyrin dimer (87%), with
small amounts of cyclic trimer (11%) and higher oligomers
(2%) present (Fig. 3).§
Fig. 2 Oxidation and cyclisation of dithiol monomer Zn-2.
Fig. 1 Deprotection of thioacetate protected monomer Zn-1.
Fig. 3 HPLC traces of the porphyrin DCL in the a) absence of a template,
b) presence of DABCO, c) presence of TPyT, d) presence of TPyP, and e)
presence of Bipy.
† Present address: University of Southern Denmark, Department of
Chemistry, Campusvej 55, 5230 Odense M, Denmark.
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CHEM. COMMUN., 2003 2674–2675
This journal is © The Royal Society of Chemistry 2003

Scheme 1 Templates used in the disulfide porphyrin library: (a) 1,4-diazabi-
cyclo(2.2.2)octane (DABCO), (b) 4,4A-bipyridine (Bipy), (c) 4-s-tripyridyl
triazine (TPyT), (d) tetrapyridylporphyrin (TPyP).
Fig. 4 Ball and stick representation of the crystal structure of DABCO
encapsulated bis-disulfide dimer Zn-3·2CHCl3 with hexyl side chains
replaced by methyls, hydrogen atoms and solvent molecules omitted for
clarity. (Zn atoms pink, N atoms blue, S atoms yellow.)
tris-disulfide trimer to near quantitative yield, with again less
than 1% of the equilibrium mixture consisting of other
molecules. The same result was obtained when an isolated
sample of dimer was re-equilibrated in the presence of TPyT.
Initiation of exchange in this instance required the addition of
dithiothreitol to reduce a proportion of the disulfide bonds to
thiols. This experiment neatly demonstrated that the library is
indeed under thermodynamic control, and hence the ability of
the system to proof-read.
Use of tetrapyridylporphyrin (TPyP) as template in the
disulfide library results in the formation of tetramer, which
contrasts with earlier work. The direct synthesis of cyclic
tetramer from monomer using TPyP was also attempted using
Glaser coupling but proved unsuccessful.5 Although some
cyclic tetramer did form in the Glaser conditions, its separation
from cyclic pentamer and cyclic trimer was very difficult, and
so none was isolated in this way. Under the reversible
conditions employed a tetrameric disulfide oligomer was
formed in essentially quantitative conversion from monomer in
the presence of up to 1 equiv. of TPyP, as judged by HPLC
analysis.
The thermodynamically-controlled cyclisation of the bis-
thiol porphyrin monomer was also carried out on the preparative
scale in the presence of the DABCO template. After an HPLC
check of the reaction, removal of solvent and purification by a
flash alumina column, the bis-disulfide dimer Zn-3 was
obtained. The dimer was isolated with DABCO encapsulated
within its cavity as indicated by the presence of a single
DABCO CH2 resonance at 25.1 ppm in the 1H NMR spectrum.
This represents an upfield shift of almost 8 ppm relative to
unbound DABCO, which resonates at 2.8 ppm, and is due to the
double ring current effect of the two co-facially arranged
porphyrins. Furthermore, the relative simplicity of the NMR
spectrum is suggestive of a highly symmetrical structure for the
dimer. The ligand is in slow exchange with the host on the NMR
timescale and just one equivalent remains fully bound within
the cavity even in the presence of a 500-fold excess of free
DABCO, indicative of the complementarity of the host cavity to
the guest.
At the porphyrin concentration used for UV/vis titrations
(1027 M), binding of DABCO to monomer Zn-1 results in a
shift of the Soret band from 412 nm to 426 nm, typical of a 1 :
1 porphyrin–DABCO complex.7 By contrast, Zn-3–DABCO
complex has a Soret maximum at 418 nm. This blue shift, of 8
nm, is characteristic of a 2 : 1 porphyrin–DABCO complex, and
is due to exciton coupling between the co-facial porphyrin
units.8
distance of 7.053(1) Å confirms that Bipy is geometrically
precluded from the dimer cavity.9
In conclusion, we have extended the use of disulfide DCLs to
non-polar solvents and demonstrated proof-reading in a library
of disulfide porphyrin oligomers to selectively form a cyclic
dimer. Current work is being undertaken to isolate larger
porphyrin macrocycles.
We thank Dr E. Stulz for help with MALDI TOF mass
spectrometry, and EPSRC and the Newton Trust for financial
support.
Notes and references
‡ HPLC analysis was carried out on the unquenched reaction mixtures using
a Hewlett-Packard 1050 instrument, coupled to a HP 1050 DAD; data were
analysed using an HP ChemStation. Chromatographic separations were
achieved in the reverse phase, using a 25 cm 3 4.6 mm Phenomenex Jupiter
C18 column with a MeOH : THF solvent gradient. Exchange is slow on the
HPLC time scale.
§ ES-MS allowed distinction between linear and cyclic species.
¶ Crystal data for Zn-3. C130H168N10S4Zn2·2CHCl3, M = 2368.46, Z = 2,
monoclinic, space group P21/c, a = 13.6594(3), b = 21.1379(5), c =
21.4513(7) Å, a = 90, b = 96.534(1), g = 90°, U = 6153.4(3) Å3, T =
220(2) K, m(Mo-Ka) = 0.641 mm21. Data were collected on a Nonius
KappaCCD diffractometer. Of 28071 reflections measured, 7955 were
independent (Rint = 0.0975). The structure was solved by direct methods
(SIR92) and refined by full-matrix least-squares on F2 (SHEXLTL v.6.12).
Final R1 = 0.0767 (5512 reflections with I > 2s(I)) and wR2(F2) = 0.2132
(all data). The DABCO moiety is disordered and was modelled in two
orientations related by ca. 60° rotation about the Zn–N…N–Zn axis. One n-
hexyl chain (C25–C30) was also modelled in two orientations. CCDC
218740. See http://www.rsc.org/suppdata/cc/b3/b310438a/ for crystallo-
graphic data in CIF or other electronic format.
1 (a) S. Otto, R. L. E. Furlan and J. K. M. Sanders, Drug Disc. Today, 2000,
7, 117; (b) S. Otto, R. L. E. Furlan and J. K. M. Sanders, Curr. Opin.
Chem. Biol., 2002, 6, 321; (c) J. M. Lehn and A. V. Eliseev, Science,
2001, 291, 2331; (d) O. Ramström and J. M. Lehn, Nat. Rev. Drug Disc.
Today, 2002, 1, 26; (e) E. Stulz, Y. F. Ng, S. M. Scott and J. K. M.
Sanders, Chem. Commun., 2002, 524.
2 (a) H. Hioki and W. C. Still, J. Org. Chem., 1998, 63, 904; (b) S. Otto, R.
L. E. Furlan and J. K. M. Sanders, J. Am. Chem. Soc., 2002, 122, 8876;
(c) Y. Krishnan-Ghosh and S. Balasubramanian, Angew. Chem., Int. Ed.,
2003, 42, 2171.
3 B. Brisig, J. K. M. Sanders and S. Otto, Angew. Chem., Int. Ed., 2003, 42,
1270.
4 H. L. Anderson and J. K. M. Sanders, J. Chem. Soc., Perkin Trans. 1,
1995, 2223 and following 4 papers.
5 S. Anderson, H. L. Anderson and J. K. M. Sanders, J. Chem. Soc., Perkin
Trans. 1, 1995, 2247.
6 L. J. Twyman and J. K. M. Sanders, Tetrahedron Lett., 1999, 40,
6681.
7 C. A. Hunter, M. N. Meah and J. K. M. Sanders, J. Am. Chem. Soc., 1990,
112, 5773.
8 C. A. Hunter, J. K. M. Sanders and A. J. Stone, Chem. Phys., 1989, 133,
395.
9 In the crystal structure of a ternary Rh(III) Bipy complex reported
previously, the Bipy N…N distance is 7.06(2) Å, and a perpendicular
separation of ca. 11 Å exists between the porphyrin planes: H.-J. Kim, J.
E. Redman, M. Nakash, N. Feeder, S. J. Teat and J. K. M. Sanders, Inorg.
Chem., 1999, 38, 5178.
Crystals suitable for structure determination were obtained
by layering a CHCl3 solution of dimer with MeOH. The highly
symmetrical structure determined is in agreement with the
proposed solution state structure.¶ Zn-3 crystallises with the
DABCO ligand complexed in the cavity, between the two
porphyrins (see Fig. 4), sited across a crystallographic centre of
symmetry. The DABCO moiety is disordered about the Zn–
N…N–Zn axis, suggesting that it is able to rotate within the
cavity without decomplexation occurring. The Zn atoms are
displaced towards the N atoms of DABCO by ca. 0.29 Å from
the least-squares planes through the four N atoms of the
porphyrins, and the Zn–N DABCO bond distance of 2.227(5) Å
is typical of that in similar structures. The cross-cavity Zn…Zn
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