A synthetic receptor for hydrogen-bonding to fluorines of trifluoroborates

Article abstract of DOI:10.1039/b914171e

A tripodal receptor featuring three inwardly-directed hydrogen-bond donors binds covalently bound fluorine atoms of trifluoroborates through hydrogen-bonding.

Full text of DOI:10.1039/b914171e

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A synthetic receptor for hydrogen-bonding to fluorines
of trifluoroboratesw
Per Restorp, Orion B. Berryman, Aaron C. Sather, Dariush Ajami and Julius Rebek, Jr.*
Received (in Austin, TX, USA) 15th July 2009, Accepted 19th August 2009
First published as an Advance Article on the web 4th September 2009
DOI: 10.1039/b914171e
A tripodal receptor featuring three inwardly-directed hydrogen-
bond donors binds covalently bound fluorine atoms of
trifluoroborates through hydrogen-bonding.
NMR-titration experiments9 of 1 with trifluorotoluene (3) in
CDCl3 : CD3CN (97 : 3) showed no downfield shift of the NH
signals (Table 1, entry 1); the covalently bound fluorines in
PhCF3 (3) do not hydrogen-bond to 1 under these conditions.
This result provides additional support for the observation
that covalently bound organic fluorines rarely engage in
hydrogen-bonding.5 Fluorines covalently bound to boron
should be stronger acceptors than those involving C–F
bonds.5c However, a survey of the literature showed few
examples of short-range contacts between B–F fluorines and
typical proton donors.10
The introduction of a fluorine atom in an organic molecule can
dramatically change its reactivity and properties.1 In medicinal
chemistry the incorporation of fluorine in drug lead
compounds is especially popular since the organofluorine
can affect nearly all relevant molecular properties for the drug
discovery process including adsorption, distribution,
metabolic stability and sometimes even the binding affinity
for its target.2 As a consequence, understanding the nature
and strength of the non-covalent interactions of covalently
bound fluorine atoms is desirable for drug development.3
The fluorine atom is the most electronegative element and
roughly isosteric to oxygen,4 and this raises the question
whether covalent fluorine atoms can mimic the hydrogen-
bonding acceptor ability of oxygen.5 While inorganic fluorides
are notoriously powerful proton-acceptors,6 a survey of the
Cambridge Structural Database (CSD) as well as the Protein
Data Bank (PDB) by Dunitz and Taylor revealed very few
examples of short-range contacts between covalently bound
fluorines and typical proton donors.5a To examine whether or
not such fluorines can act as hydrogen-bond acceptors in
solution we took a supramolecular approach7 using the
synthetic receptor molecule 1 (Scheme 1) and here we report
its binding to covalently bound trifluoroborates.
The tetrafluoroborate anion is a commonly used weakly
coordinating counterion and hydrogen-bonding interactions
between such fluorines and proton donors in the solid state11
and by the fastest of IR methods in aqueous media12 have been
reported. To determine whether our synthetic receptor 1 can
bind fluoroborates through hydrogen-bonding we performed
NMR-titration experiments of 1 with tetra-n-butylammonium
tetrafluoroborate (4). However, these experiments show no
detectable binding of the tetrafluoroborate anion with 1
(entry 2). In contrast, titration experiments with the tetra-n-
butylammonium phenylfluoroborate (5) resulted in a down-
field shift of the NH signals in 1 of about 0.5 ppm (Fig. 1).13
The association constant for 5 was determined to be 75 MÀ1
by taking the average value of three NMR titration
experiments (entry 3).9
It should be noted that the association constant between 1
and fluoroborate 5 is measured in competition with the
electrostatic interactions of the ion-pair of 5 in solution and
the binding event involves breaking of this ion-pair. We
suggest that the enhanced binding affinity of phenylfluoro-
borate 5 over tetrafluoroborate 4 is, in part, due to the dipole
moment of 5 not present in the symmetrically substituted 4
and results in stronger hydrogen-bonding interactions with 1.
To probe the steric and electron effects of binding with
receptor 1 we investigated a series of fluoroborates. The
similar binding constants of phenylfluoroborate 5 and methyl-
fluoroborate 6 suggest that secondary stabilizing interactions
The 1,3,5-trisubstituted 2,4,6-triethylbenzene scaffold 2 is an
appealing building block for supramolecular systems.8 To
avoid unfavorable steric clashes alternating substituents are
oriented on one face of the phenyl ring and different functional
groups can be incorporated that complement the surface and
geometry of the targeted molecule. Receptor 1 can readily
adopt a conformation where the three acylhydrazide NH’s are
projected into the cavity above the plane of the phenyl ring
and poised to hydrogen-bond to a guest. The spatial orientation
of the NH’s in 1 presents hydrogen-bonding interactions to
acceptors of appropriate size and C3V symmetry. The electron-
rich pyrroles on the rim of 1 provide the possibility for
additional stabilizing interactions with the bound guest, e.g.,
through CH–p or p–p interactions as well as shielding the
guest from approaching solvent molecules.
The Skaggs Institute for Chemical Biology and Department of Chemistry,
The Scripps Research Institute, 10550 North Torrey Pines Rd,
La Jolla, CA 92037, USA. E-mail: jrebek@scripps.edu
w Electronic supplementary information (ESI) available: Synthesis of
1, spectral data characterizations, details of computational studies and
NMR titration data for the binding constant determinations. See DOI:
10.1039/b914171e
Scheme 1 Synthesis of 1.
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This journal is The Royal Society of Chemistry 2009
5692 | Chem. Commun., 2009, 5692–5694

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Table 1 Average Ka (MÀ1) for receptor 1 with guests 3–6ab
Entry
Guest
Ka/MÀ1
1
2
3
4
5
6
PhCF3 (3)
—
—
75
70
25
80
À
NBu4+BF4 (4)
NBu4+PhBF3À(5)
NBu4+MeBF3 (6)
À
NBu4+4-NO2-PhBF3 (7)
À
À
NBu4+4-Me-PhBF3 (8)
a
b
Average Ka reported for 2–3 titration experiments. All titrations
were performed in CDCl3 : CD3CN (97 : 3) with receptor concentra-
tions of B0.5 mM; experimental errors are estimated at Æ10%.
Fig. 2 Minimized representation (B3LYP/6-311+G(2d,p)//B3LYP/
6-31G(d)) of fluoroborate 5 bound in receptor 1. Carbon colored gray,
nitrogen blue, oxygen red, fluorine light blue, boron pink and
hydrogen white.
through convergent15 hydrogen-bond donors in a shallow
cavitand.16 This study confirms that organofluorines and
tetrafluoroborates rarely engage in hydrogen-bonding.5
Organic trifluoroborates showed binding to the receptor. To
the best of our knowledge, this represents the first example of a
supramolecular receptor for trifluoroborates and illustrates
that covalenty bound fluorines can function as hydrogen-bond
acceptors.
Fig. 1 1H NMR spectra from titrations of receptor 1 (0.45 mM) with
NBu4+PhBF3À (5) highlighting the NH proton chemical shift changes
in receptor 1 (red circle) in the presence of 0 (A), 4 (B), 15 (C), 56 (D)
equiv. of 5, respectively. The aromatic signals from fluoroborate 5 are
marked with blue squares.
We are grateful to the Skaggs Institute and the National
Institute of Health (GM 50174) for support, and we thank
Prof. G. Molander for samples of trifluoroborates. P. R. is a
Swedish Knut and Alice Wallenberg Post-doctoral Fellow.
O.B.B and A.C.S are Skaggs Post-doctoral and Skaggs
Pre-doctoral Fellows, respectively. We are indebted to
Dr Laura Pasternak for invaluable NMR support. The
reviewers are thanked for insightful comments.
between the electron-rich pyrroles in the rim of 1 (CH–p or
p–p interactions) and the bound guest have negligible impact
on the binding constant (compare entry 3 and 4). The
electronic effects of the binding to 1 were examined with
arylfluoroborates 7 and 8 (entries 5 and 6). The p-nitro-
phenylfluoroborate (7) showed significantly weaker binding
Notes and references
to
1 (entry 5) whereas p-methyl-phenylfluoroborate (8)
1 (a) D. O’Hagan, Chem. Soc. Rev., 2008, 37, 308; (b) J. C. Biffinger,
H. W. Kim and S. G. DiMagno, ChemBioChem, 2004, 5, 622.
2 (a) K. Mueller, C. Faeh and F. Diederich, Science, 2007, 317, 1881;
exhibited stronger binding (entry 6). This observation supports
the notion that electron-poor arylfluoroborates drain the
fluoroborate fluorines of electron-density making them less
potent hydrogen-bond acceptors whereas the opposite holds
true for electron-rich arylfluoroborates. Additional support of
the binding mode for these fluoroborates to receptor 1 was
provided by DFT calculations.14 The 1 : 1 complex between
fluoroborate 5 and receptor 1 obtained in this way is shown in
Fig. 2.
(b) H. C. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn,
¨
K. Mueller, U. Obst-Sander and M. Stahl, ChemBioChem, 2004, 5,
637; (c) B.-S. Park, W. Widgerb and H. Kohn, Bioorg. Med.
Chem., 2006, 13, 1; (d) J. A. Olsen, D. W. Banner, D. W. Seiler,
U. Obst-Sander, A. D’Arcy, M. Stihle, K. Mueller and
K. Diederich, Angew. Chem., Int. Ed., 2003, 42, 2507.
3 (a) F. Hof, D. M. Scofield, W. B. Schweizer and F. Diederich,
Angew. Chem., Int. Ed., 2004, 43, 5056; (b) F. R. Fischer,
W. B. Schweizer and F. Diederich, Angew. Chem., Int. Ed., 2007,
46, 8270.
The minimized representation shows that 1 adopts an
averaged C3V symmetry (C3 symmetry shown in Fig. 2) and
binds to 5 through three bifurcated hydrogen-bonds between the
fluorines and the acylhydrazide NH’s in 1 (NÁ Á ÁF = 2.8 A).
Additionally, the distances between the CH’s of the phenyl
ring in 5 and the electron-rich pyrrole subunits in 1 are
approximately 3.2 A, which suggests that some CH–p
interactions are involved in the binding.
4 A. Bondi, J. Phys. Chem., 1964, 68, 441.
5 (a) J. D. Dunitz and R. Taylor, Chem.–Eur. J., 1997, 3, 89; (b) J. A.
K. Howard, V. J. Hoy, D. O’Hagan and G. T. Smith, Tetrahedron,
1996, 52, 12613; (c) J. D. Dunitz, ChemBioChem, 2004, 5, 614.
6 The hydrogen-bonding energy of the bifluoride anion [HF2]À is
approximately 37 kcal molÀ1. S. A. Harrell and D. H. McDaniel,
J. Am. Chem. Soc., 1964, 86, 4497.
7 For extensive reviews on anion binding in synthetic receptors, see:
(a) V. Amendola, D. Esteban-Gomez, L. Fabbrizzi and
M. Licchelli, Acc. Chem. Res., 2006, 39, 343; (b) K. Bowman-
James, Acc. Chem. Res., 2005, 38, 671; (c) F. Hof, S. L. Craig,
C. Nuckolls and J. Rebek, Jr, Angew. Chem., Int. Ed., 2002, 41,
1488; (d) K. S. Jeong, A. V. Muehldorf and J. Rebek, Jr, Molecular
Recognition. Asymmetric Complexation of Diketopiperazines,
J. Am. Chem. Soc., 1990, 112, 6144–6145; (e) J. L. Sessler,
In conclusion, we have fashioned a neutral receptor
molecule based on the 1,3,5-trisubstituted 2,4,6-triethylbenzene
scaffold that offers three convergent NH’s. These acyl
hydrazides feature perpendicular arrangement between the
amide and pyrrole planes that can interact with a bound guest
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Chem. Commun., 2009, 5692–5694 | 5693

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P. A. Gale and W.-S. Cho, Anion Coordination Chemistry, Royal
Society of Chemistry, Cambridge, 2006; (f) J. L. Sessler,
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9 K. Hirose, J. Inclusion Phenom. Macrocycl. Chem., 2001, 39, 193.
10 For an example of intermolecular hydrogen-bonding involving
B–FÁÁÁH–C bonds in the solid state, see: C. M. Clarke, M. K. Das,
E. Henecker, J. F. Mariategui, K. Niedenzu, P. M. Niedenzu,
H. Noth and K. R. Warner, Inorg. Chem., 1987, 26, 2310.
11 (a) W. L. Driessen, R. A. G. De Graaf and W. G. R. Wiesmeijer,
Acta Crystallogr.,Sect. C, 1987, 43, 2319; (b) T. W. Hudnall,
J. F. Bondi and F. P. Gabbai, Main Group Chem., 2006, 5, 319.
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13 Receptor 1 had low solubility in CDCl3. When receptor 1 was
titrated with 5 in CDCl3 a lower concentration of guest was
required to reach saturation conditions, suggesting a larger Ka in
this solvent. However, the low solubility and complex speciation
present in CDCl3 prohibited accurate Ka determination. We also
performed titration experiments on the 19F resonance of 5. The 19
F
signal shifts slightly upon addition of receptor 1 but the broad
character of this peak due to coupling of 19F to 10B and 11B
prevented accurate analysis.
14 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., T. Vreven,
K. N. Kudin and J. C. Burant, et al., Gaussian 03, Gaussian, Inc.,
Pittsburgh, PA, 2003, for complete list of authors see ESIw.
15 B. Verdejo, G. Gil-Ramrez and P. Ballester, J. Am. Chem. Soc.,
2009, 131, 3178.
16 F. C. Tucci, D. M. Rudkevich and J. Rebek Jr., J. Org. Chem.,
1999, 64, 4555.
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This journal is The Royal Society of Chemistry 2009
5694 | Chem. Commun., 2009, 5692–5694