Cavity effect amplification in the recognition of dicarboxylic acids by initial ditopic H-bond formation followed by kinetic trapping

Article abstract of DOI:10.1039/b614575b

Di[dihydroxotin(iv)] Troeger's base bis-porphyrin 1, a host molecule with two internal and two external guest interaction sites, binds ≤ 1 equivalent of dicarboxylic acid quantitatively within the chiral cavity, a regioselectivity amplified by initial dit

Full text of DOI:10.1039/b614575b

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Cavity effect amplification in the recognition of dicarboxylic acids by
initial ditopic H-bond formation followed by kinetic trapping{
Peter R. Brotherhood, Richard A.-S. Wu, Peter Turner and Maxwell J. Crossley*
Received (in Cambridge, UK) 6th October 2006, Accepted 10th November 2006
First published as an Advance Article on the web 29th November 2006
DOI: 10.1039/b614575b
Host 15 possesses a relatively rigid chiral cleft and the
Di[dihydroxotin(IV)] Tro¨ger’s base bis-porphyrin 1, a host
orientation of the internal metal binding sites makes it appropriate
for the ditopic association of bridging guest ligands in the interior
of the cavity.6 The cavity also possesses two external binding sites
that are more sterically accessible. X-ray crystal structure analysis
of host 1 (Fig. 1a,b){ confirms these design features. Products of
ligand exchange at host 1 can be identified and characterised by
NMR. Summation of the porphyrin ring current effects results in
significant shifts for internally bound ligands which resonate 1.5 to
3.5 ppm upfield of those bound at the exterior.
molecule with two internal and two external guest interaction
sites, binds ¡ 1 equivalent of dicarboxylic acid quantitatively
within the chiral cavity, a regioselectivity amplified by initial
ditopic H-bond formation, followed by kinetic trapping.
Dihydroxotin(IV) porphyrins have been used extensively as
building blocks in the formation of supramolecular complexes1
and in molecular recognition.2 Ligand exchange with protic
oxygen molecules occurs at these systems to form strong six-
coordinate O-bound complexes, with the elimination of water, that
are readily studied by NMR.3 It is proposed that the first step in
the ligand exchange process is a H-bond equilibrium complex
between the in situ hydroxo ligand and the incoming guest ligand.4
Observations in the current study can only be rationalised by such
a process. A mechanism of this nature offers the possibility for
guests to organise to a thermodynamic interaction with the host
prior to formation of the ester-like RO–Sn bond. There is scope
for application of this binding phenomenon to the formation of
intricate self-assembled complexes with stability constants far in
excess of those available through the use of more labile assembly
Regioselective binding of dicarboxylic acids ditopically at the
interior of the cavity extends to malonic acid, succinic acid 3,
glutaric acid and adipic acid. When introduced to host 1 at ¡ 1
mole equivalent,7 each of these dicarboxylic acids binds mono-
topically within the cavity in under 10 min and subsequently no
free dicarboxylic acid is detected. Times for complete ditopic
interactions. Herein we report
a strategy that combines
dihydroxotin(IV) porphyrin carboxylate binding chemistry with
rigid cavity host morphology and elucidate a mechanism that leads
to the quantitative, ditopic, internal cavity binding of dicarboxylic
acids.
Fig. 1 X-ray crystal structures. Eight meso-3,5-But2C6H3 groups
removed for clarity. (a) Host 1 view into cavity, (b) side-on view. (c)
Host 1?succinate complex 6 view into cavity, 70% occupancy succinate
shown, (d) side-on view. Complex 6 resides on a 2-fold axis passing
through the centre of the succinate ligand and the bis-porphyrin
bridgehead.
School of Chemistry, The University of Sydney, NSW 2006, Australia.
E-mail: m.crossley@chem.usyd.edu.au; Fax: +61 2 9351 3329;
Tel: +61 2 9351 2751
{ Electronic supplementary information (ESI) available: Synthetic details,
1H NMR titration spectra and X-ray crystallographic data. See DOI:
10.1039/b614575b
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Chem. Commun., 2007, 225–227 | 225

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17 results in interaction first at the interior of the cavity in the form
binding, however, increase markedly with the length of the
dicarboxylic acid from , 2 min for malonic acid, 15 min for
succinic acid 3, 30 min for glutaric acid, to 30 h for adipic acid. The
X-ray crystal structure of one of these products, host 1?succinate 6
is given in Fig. 1.
of a ditopic H-bonded complex. Protonation of one hydroxo
ligand, its dissociation as water, and condensation of the
carboxylate anion with the tin(IV) centre occurs rapidly to yield
the monotopically bound complex 5 (Fig. 2b, inset). The ditopic
H-bond complex precursor is not detected by 1H NMR. Pre-
organisation of the dicarboxylic acid in the cavity renders the first
ligand exchange process effectively intramolecular, resulting in rate
enhancement. Ligand exchange rates for monodentate acids at
monomeric tin(IV) porphyrin systems can be much slower,
allowing observation of the initial H-bonded complex.4 Ligand
exchange at the second internal tin(IV) binding site then occurs to
afford the ditopic complex 6 in under 15 min (Fig. 2c,d). Although
two distinct conformations of bound succinate are seen in the solid
state structure, the sharp resonances for bound succinate (Fig. 2)
indicate fast conformational changes on the NMR timescale and
therefore that interconversion of these binding modes does not
require Sn–O bond breakage. When internal cavity binding
is complete exchange of external hydroxo ligands commences.
At ¡ 2.0 equivalents of succinic acid 3 a mixture of the 1 : 1
Of particular interest in the crystal structure of complex 6 is the
orientation of the succinate ligand when bound in the cavity.
Succinate is bound in two conformations in a 70 : 30 ratio. The
70% occupancy is shown in Fig. 1c,d. This conformation shows
gauche interactions and projection of the succinate carbonyl
oxygens into the rear of the cavity. The 30% occupancy succinate
adopts antiperiplanar geometry and the carbonyl oxygens project
to the mouth of the cavity, leaving what appears as void space at
the interior. Apparently favourable interaction between the
carbonyl oxygen and the interior of the cavity is sufficient to
counter the energy penalty due to eclipsing interactions in the
guest. Structural changes are also evident in the host molecule on
binding of succinic acid 3. The porphyrin macrocycles in complex
6 are distorted from planarity compared with those of the host 1
˚
and the Sn…Sn distance is reduced from 8.60 A to 8.48 A.
˚
1
Examination by H NMR of the binding to host 1 of succinic
acid 3 provides a basis for understanding the origins of the high
regioselectivity seen in the binding of this series of dicarboxylic
acids. The mechanism of succinate binding to host 1 is summarised
in Scheme 1. Addition of ¡ 1 equivalent of succinic acid 3 to host
Fig. 2 1H NMR (400 MHz, CDCl3) spectra showing the titration of
succinic acid 3 with host 1.7 0.7 to 21.0 ppm, external succinate ligands,
21.5 to 24.5 ppm, internal succinate ligands, 26.8 to 28.2 ppm, hydroxo
ligands. (a) Host 1, (b) host 1 + 0.5 equiv. 3, 3 min. Inset shows
expansion of signals for 3 bound monotopically inside the cavity, complex
5. (c) Host 1 + 0.5 equiv. 3, 15 min. Complete internal ditopic binding,
complex 6 and residual 1. (d) + 0.5 equiv. 3, 1.0 equiv. total, 15 min,
complex 6. (e) + 0.5 equiv. 3, 1.5 equiv. total, 10 min, predominantly
complexes 6 and 7. (f) + 0.5 equiv. 3, 2.0 equiv. total, 10 min, complexes 6,
7 and 8. (g) + 1.0 equiv. 3, 3.0 equiv. total, 10 min, complex 8.
Scheme 1 Mechanism of succinic acid 3 binding to host 1, representative
of binding mechanism for malonic, glutaric and adipic acids. Porphyrin
macrocycles and methanodiazocine bridge represented by the bold lines.
226 | Chem. Commun., 2007, 225–227
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complex 6, the 2 : 1 complex 7 and the 3 : 1 complex 8 is formed
(Fig. 2e,f). Addition of a third equivalent results in ligand exchange
at the remaining external binding sites and quantitative formation
of the 3 : 1 complex 8 (Fig. 2g). Hydroxo ligand resonances are
included in Fig. 2 and changes in these are easily rationalised by
the proposed binding mechanism. At the completion of ditopic
binding at the interior of the cavity (Fig. 2d) the resonance for the
exterior hydroxo ligands becomes broadened by exchange with
water expelled from the cavity during the binding process.
Satellites to the central 119Sn(IV) and 117Sn(IV) nuclei are clear
dicarboxylic acid guest and the host, a ditopic H-bond complex in
the interior of the cavity. This complex is subsequently removed
from pre-equilibrium by formation of one ester-like tin(IV)–
carboxylate bond and the dissociation of a molecule of water,4
thereby syphoning material towards quantitative intra-cavity
binding. Formation of the second tin(IV)–carboxylate bond in
the cavity is then an intramolecular reaction, the rate of which is
determined by the degree of organisation required of both host
and guest to facilitate binding. As the degree of conformational
freedom of the dicarboxylic acid increases with chain length a
greater period of time is required for adoption of a bound
conformation.
2
(host 2 27.65 ppm (2 H, s, satellites JSn–H 35 Hz), complex 6
27.21 ppm (2 H, s, satellites 2JSn–H 34 Hz)).
The chirality of host 1 delivers additional information about
binding modes. When subjected to the chiral environment of the
cavity the diastereotopicity of the succinate methylene protons is
evident in the complex splitting of their NMR resonances.
External succinate ligands are also bound in a chiral environment,
however, with less constraint on their conformation, and as a
result the signals for diastereotopic protons on these groups
average to a- and b-methylene. The asymmetric environment of
the cavity is especially evident when the C2 symmetry of the
complex is broken, as in the monotopically bound succinic acid
complex 5 (inset, Fig. 2b) and in the 2 : 1 complex 7. In these
instances each of the four succinate methylene protons gives rise to
a multiplet reflecting the complexity of their spin system. These
signals for the 2 : 1 complex 7 are almost coincident with those for
the 1 : 1 complex 6 and the 3 : 1 complex 8 (Fig. 2e,f). The obvious
diastereotopicity of the methylene protons for the first equivalent
of bound succinate confirms the chemical shift data, that initial
binding is in the interior of the cavity.
In ongoing studies we have found that this phenomenon, a
labile pre-equilibrium interaction followed by kinetic trapping by
tin(IV)–carboxylate bond formation, also leads to amplification of
the cavity effect in a zinc(II)-dihydroxotin(IV) Tro¨ger’s base bis-
porphyrin5 host system, leading to enantioselective intra-cavity
binding of a-amino acids. These studies will be reported shortly.
We thank the Australian Research Council for a Discovery
Grant to MJC, an Australian Postgraduate Award to RASW and
The University of Sydney for an H. B. and F. M. Gritton
postgraduate award to PRB.
Notes and references
{ Crystal structure data for host 1: model formula
¯
C157.50H194ClN11O10.25Sn2, M 2678.07, triclinic, P 1 (#2), a 16.468(9), b
˚
21.274(12), c 23.587(13) A, a 90.583(9), b 94.483(9), c 95.907(9)u,
3
23
˚
˚
V 8193(8) A , Dc 1.086 g cm , Z 2, T = 150(2) K, l(MoKa) 0.71073 A,
m(MoKa) 0.376 mm21, Nind 37404 (Rmerge 0.0656), Nobs 29063 (I . 2s(I)),
R1(F) 0.1848, wR2(F2) 0.4521. Crystal structure data for complex 6: model
formula C175.20H200.40N10O11.40Sn2, M 2866.04, monoclinic, C2/c (#15), a
3
Control experiments were performed to determine the detail of
the mechanism that leads to the quantitative internal cavity
binding exhibited by succinic acid 3 to host 1. (see ESI{) Acetic
acid 4 was bound to di[dihydroxotin(IV)] host 1 to determine the
importance of the second H-bond donor site on the succinate
guest, and acetic acid 4 and succinic acid 3 were bound to
dihydroxotin(IV)-free-base host 2 to determine the importance of
the second internal H-bond acceptor site in the interior of the
cavity. Both these features of the host–guest system were identified
as essential to quantitative internal cavity binding. Acetic acid 4
(1 equivalent) binds to host 1 with only a 1.5-fold preference for
internal cavity positions at 3 min, the time required for quantitative
association of succinic acid 3 in the interior of the cavity.
Equilibration occurs over 100 min to give a 4.5 : 1 ratio of acetates
bound at the interior. Dihydroxotin(IV)-free-base host 2 binds the
first equivalent of acetic acid 4 or succinic acid 3 predominantly at
the exterior of the cavity, with only trace ligand substitution at the
internal position and trace formation of the dicarboxylatotin(IV)-
free-base complex. This indicates that contributors to the above
cavity effect such as desolvation of guest and cavity are
unimportant compared to the facility to form H-bonding
interactions. For host 2 the free-base porphyrin macrocycle
appears simply to pose a steric barrier to H-bond complexation
in the interior of its cavity, resulting in ligand exchange at the
exterior.
˚
˚
31.236(5), b 27.384(7), c 21.366(5) A, b 115.594(10)u, V 16482(6) A , Dc
1.155 g cm23, Z 4, T = 123(2) K, l(synchrotron) 0.56356 A, m(synchrotron)
˚
0.199 mm21, Nind 20278 (Rmerge 0.0786), Nobs 16684 (I . 2s(I)), R1(F)
0.0415, wR2(F2) 0.1177. CCDC 623698–623699. For crystallographic data
in CIF format see DOI: 10.1039/b614575b
1 Y. Kim, M. F. Mayer and S. C. Zimmerman, Angew. Chem., Int. Ed.,
2003, 42, 1121; J. E. Redman, N. Feeder, S. J. Teat and J. K. M. Sanders,
Inorg. Chem., 2001, 40, 2486. Review: J. K. M. Sanders, in The Porphyrin
Handbook, ed. K. M. Kadish, K. M. Smith and R. Guilard, Academic
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2 J. C. Hawley, N. Bampos and J. K. M. Sanders, Chem.–Eur. J., 2003, 9,
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Commun., 1998, 661.
5 M. J. Crossley, P. Thordarson and R. A.-S. Wu, J. Chem. Soc., Perkin
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Commun., 1995, 1925; M. J. Crossley, T. W. Hambley, L. G. Mackay,
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Asymmetry, 1997, 8, 1161.
7 Host 1 (3.10 mg, 1.24 mmol) was dissolved in CDCl3 (600 mL) in an
NMR tube and dicarboxylic acid solution in d6-DMSO–CDCl3 (10 : 90,
0.100 M) was added by microlitre syringe in successive 0.5 mole
equivalent aliquots to a total of 2.0 equivalents and subsequently a
1.0 mole equivalent aliquot was added to a total of 3.0 mole equivalents.
After each addition 1H NMR spectra were recorded at regular intervals
until no further spectral changes indicated binding processes were
complete. For titration experiments with acetic acid 4, stock solutions
were prepared in d6-DMSO–CDCl3 (5 : 95, 0.100 M).
From these studies, a mechanism that accounts for the high
selectivity of binding of dicarboxylic acids in host 1 emerges. A
pre-equilibrium H-bond step in this binding process results in the
formation of a thermodynamic product in the interaction of the
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Chem. Commun., 2007, 225–227 | 227