Anion binding vs. sulfonamide deprotonation in functionalised ureas

Article abstract of DOI:10.1039/b713431b

Sulfonamide groups, commonly used as neutral hydrogen bond donors in a wide variety of anion receptors, deprotonate upon addition of certain basic anionic guests in two simple functionalised ureas. The Royal Society of Chemistry.

Full text of DOI:10.1039/b713431b

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Anion binding vs. sulfonamide deprotonation in functionalised ureas{
Claudia Caltagirone, Gareth W. Bates, Philip A. Gale* and Mark E. Light
Received (in Austin, TX, USA) 31st August 2007, Accepted 15th October 2007
First published as an Advance Article on the web 25th October 2007
DOI: 10.1039/b713431b
Sulfonamide groups, commonly used as neutral hydrogen
bond donors in a wide variety of anion receptors, deprotonate
upon addition of certain basic anionic guests in two simple
functionalised ureas.
Anion recognition is an area of growing interest in supramolecular
chemistry due to its potential environmental, clinical and biological
applications.1 Many examples have been reported of anion
receptor systems that employ amide,2 urea3 and both amide and
urea groups to complex anionic guests.4 Sulfonamide-based
receptors for anions are also an important class of anion receptor
Fig. 1 The X-ray crystal structure of the DMSO solvate of 2. Non-acidic
that have been investigated by a number of groups due to their
hydrogen atoms have been omitted for clarity. (i) x, y + 1/2, z 2 1/2.
enhanced acidity relative to analogous secondary amides and
hence their potential to form stronger hydrogen bonds with
N-(2-(3-Phenylureido)phenyl)benzenesulfonamide (1) and N,N9-
anions.5 However, competing processes, that are not always
(2,29-carbonylbis(azanediyl)bis(2,1-phenylene))dibenzenesulfonamide
immediately recognised, can complicate apparently simple anion
(2) were synthesised from 1-(2-aminophenyl)-3-phenylurea and 1,3-
complexation processes. For example, over the last five years,
bis(2-aminophenyl)urea,11 respectively, and benzene sulfonylchloride
deprotonation of neutral hydrogen bond donor groups by basic
(see ESI{). The structure of receptor 2 was confirmed by single
anions such as fluoride and acetate has been reported by ourselves
crystal X-ray diffraction of crystals grown by slow evaporation of a
and others in a variety of systems including pyrroles,6 amines,7
DMSO solution of the receptor.{ (Fig. 1)
The interactions of receptors 1 and 2 with anions (fluoride,
amidoureas8 and ureas.9
Recently, we began to explore the anion complexation and
acetate, dihydrogen phosphate, benzoate, chloride, added as their
1
tetrabutylammonium salts) were studied using H NMR titration
fluorescence properties of a family of receptors containing urea
and dansyl groups as potential fluorescent sensors for anions.10
However, we noticed that NMR titrations of these receptors with
fluoride, acetate, dihydrogen phosphate and benzoate all gave
identical final shifts of the urea NH groups in DMSO-d6–5% water
solution in the presence of excess anion. This evidence led us to
explore the possibility that this type of receptor, rather than
forming complexes with these anions, may in fact be deprotonating
under these conditions and hence forming identical deprotonated
species in solution. We therefore synthesised simpler compounds 1
and 2 that contain a urea group and one or two sulfonamide
moieties respectively and studied their behaviour in organic
solution upon addition of a series of tetrabutylammonium anion
salts. We found that the sulfonamide group in these systems is
readily deprotonated by a number of different anions.
techniques in acetonitrile-d3. In all cases the sulfonamide NH
resonance would broaden or disappear during the titration
experiments and hence the urea NH proton resonances were
followed. Upon addition of chloride, formation of stable 1 : 1
complexes was observed in solution with stability constants Ka of
7550 M21 and .104 M21 for receptors 1 and 2, respectively.12 The
NMR titration curve of receptor 1 with tetrabutylammonium
chloride (Fig. 2) shows downfield shifts of both urea NH groups
that then reach a plateau.
However upon addition of acetate, a different titration profile
was observed (Fig. 3). The urea NH groups shifted downfield on
School of Chemistry, University of Southampton, Southampton, UK
SO17 1BJ. E-mail: philip.gale@soton.ac.uk; Fax: +44 (0)23 8059 6805;
Tel: +44 (0)23 8059 3332
Fig. 2 Shifts of the urea NH groups of compound 1 upon addition of
tetrabutylammonium chloride in CD3CN. Symbols correspond to the NH
groups labelled in the structure of 1.
{ Electronic supplementary information (ESI) available: Synthesis details,
NMR spectra and 1H NMR titration curves. See DOI: 10.1039/b713431b
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Chem. Commun., 2008, 61–63 | 61

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Fig. 3 Shifts of the urea NH groups of compound 1 upon addition of
tetrabutylammonium acetate in CD3CN. Symbols correspond to the NH
groups labelled in the structure of 1.
addition of one equivalent of acetate and then shifted upfield as
further aliquots of acetate were added. We interpret this behaviour
as the first equivalent of acetate binding to the receptor and
deshielding the urea NH groups. Further additions of acetate
trigger deprotonation and a shift of the urea NH protons upfield.
Presumably this shift is also indicative of decomplexation of the
Fig. 5 The X-ray crystal structure of the deprotonated sulfonamide 1
forming a dimer via hydrogen bond bridges through two water molecules.
(i) 2x + 2, 2y, 2z. Non-acidic hydrogen atoms and tetrabutylammonium
counter cation have been omitted for clarity.
Similar solution results were obtained with the bis-sulfonamide
2 but in this case four equivalents of fluoride were required to
deprotonate two NH groups in two separate deprotonation
processes (see ESI for more information{). Crystals of doubly
deprotonated 2 were obtained by slow evaporation of a CD3CN
2
bound acetate. Deprotonation driven by HX2 formation in
solution has been observed by ourselves and others previously.6,9
A similar result is obtained upon addition of fluoride anions
with two equivalents of fluoride required to deprotonate the
receptor.6 The urea NH adjacent to the sulfonamide (shown as a
red circle in Fig. 4) shifts downfield, then upfield and then reaches
a plateau upon addition of successive aliquots of fluoride.
Presumably this urea NH group can form an intramolecular
hydrogen bond to the deprotonated sulfonamide nitrogen atom
and is therefore not available to interact with additional added
fluoride anions. However the terminal urea NH group is not
involved in any putative intramolecular interactions and so is
solution of receptor
2 in the presence of an excess of
tetrabutylammonium acetate." The structure (Fig. 6) shows a
water molecule bound to the urea group in the dianion with
additional intramolecular hydrogen bonding interactions between
the urea NH groups and the adjacent deprotonated sulfonamide
…
…
˚
˚
nitrogen atoms (N1 N2 = 2.598(4) A; N3 N4 = 2.556(4) A).
Interestingly, the 1H NMR spectrum obtained by dissolving these
crystals in acetonitrile-d3 is identical to the 1H NMR spectrum of
the receptor in the presence of excess tetrabutylammonium acetate,
further evidence of deprotonation of these systems in solution.
However, it was possible to obtain crystals of the less basic
benzoate anion bound to receptor 1 by slow evaporation of a
DMSO solution of the receptor in the presence of tetrabutylam-
monium benzoate.I The structure (shown in Fig. 7) shows the
benzoate anion bound to all three NH groups in the receptor
2
capable of forming a single hydrogen bond to fluoride or HF2
present in solution, and hence this resonance continues to shift
downfield after two equivalents of fluoride have been added.
Crystals of the tetrabutylammonium salt of 1–(H+) were grown
by slow evaporation of an acetonitrile solution of the receptor in
the presence of excess tetrabutylammonium fluoride.§ The
structure shown in Fig. 5 reveals anion dimer formation in the
solid state with the deprotonated species bridged by two water
molecules and illustrates the urea nitrogen atom N2 forming a
hydrogen bond to the deprotonated sulfonamide nitrogen N3
…
…
…
˚
(N1 O5 = 2.765(4) A; N2 O4 = 2.972(4 ) A; N3 O4 =
˚
1
2.732(4) A). However, H NMR evidence leads us to conclude that
˚
…
(N2 N3 = 2.664(5) A) in the solid state.
˚
Fig. 6 The X-ray crystal structure of the doubly deprotonated
sulfonamide 2 bound to a water molecule. Non-acidic hydrogen atoms,
disordered water and tetrabutylammonium counter cations have been
omitted for clarity.
Fig. 4 Shifts of the urea NH groups of compound 1 upon addition of
tetrabutylammonium fluoride in CD3CN. Symbols correspond to the NH
groups labelled in the structure of 1.
62 | Chem. Commun., 2008, 61–63
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collected: 55113, independent reflections: 10342 (Rint = 0.0679), final R
indices [I . 2s(I)]: R1 = 0.0702, wR2 = 0.1283, R indices (all data): R1 =
0.1030, wR2 = 0.1435. Hydrogen atoms of the disordered water could not
be located from the difference map and were omitted from the refinement.
I Crystal data for the benzoate complex of 1: C42H58N4O5S, Mr = 730.98,
T = 120(2) K, monoclinic, space group P21/n, a = 10.0564(5), b =
3
˚
˚
24.5513(11), c = 16.6808(5)A, b = 96.544(3)u, V = 4091.6(3) A , rcalc
=
1.187 g cm23, m = 0.126 mm21, Z = 4, reflections collected: 35935,
independent reflections: 9245 (Rint = 0.0578), final R indices [I . 2s(I)]:
R1 = 0.0876, wR2 = 0.1560, R indices (all data): R1 = 0.1280, wR2 =
0.1280.
CCDC 659344–659347. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b713431b
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Cambridge, UK, 2006.
Fig. 7 The X-ray crystal structure of the benzoate complex of receptor 1.
Non-acidic hydrogen atoms and tetrabutylammonium counter cation have
been omitted for clarity.
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benzoate also triggers deprotonation in solution as we see a similar
titration profile to acetate (see ESI{). In solution an equilibrium
will exist between neutral, complexed and deprotonated forms of
the receptor and thus isolation of this complex should not be taken
as evidence that deprotonation is not occurring in this case.
We have shown that basic anions can deprotonate the
sulfonamide groups in compounds 1 and 2 in organic solution.
In these cases, the deprotonated sulfonamide anion is stabilised by
intramolecular hydrogen bonding interactions from the adjacent
urea NH group. This work shows that caution should be exercised
when interpreting NMR binding data of simple sulfonamide
containing anion receptors as deprotonation processes, that may
not be easily recognised at first, may compete with anion
complexation.
We would like to thank the EPSRC/Crystal Faraday for a
studentship (GWB) and the EPSRC together with Professor Mike
Hursthouse for access to the crystallographic facilities at the
University of Southampton. CC would like to thank Regione
Sardegna for a Master & Back grant.
Notes and references
{ Crystal data were collected on a Bruker Nonius KappaCCD with a Mo
rotating anode generator; standard procedures were followed. N–H
hydrogen atoms were located in the difference map in all the structures
and freely refined. Crystal data for compound 2: C29H34N4O7S4, Mr =
678.84, T = 120(2) K, monoclinic, space group P21/c, a = 12.5841(6),
3
˚
˚
b = 15.6088(4), c = 16.5762(7) A, b = 99.885(2)u, V = 3207.6(2) A , rcalc
=
1.406 g cm23, m = 0.348 mm21, Z = 4, reflections collected: 36921,
independent reflections: 5656 (Rint = 0.1052), final R indices [I . 2s(I)]:
R1 = 0.0487, wR2 = 0.1072, R indices (all data): R1 = 0.0821. wR2 =
0.1210.
§ Crystal data for tetrabutylammonium salt of 1–(H+) C35H54N4O4S, Mr =
626.88, T = 120(2) K, monoclinic, space group P21/c, a = 12.0833(4),
˚
3
˚
b = 17.0447(5), c = 18.2143(4) A, b = 108.808(1)u, V = 3551.04(18) A ,
r
calc = 1.173 g cm23, m = 0.133 mm21, Z = 4, reflections collected: 70013,
independent reflections: 7256 (Rint = 0.2143), final R indices [I . 2s(I)]:
R1 = 0.0808, wR2 = 0.1775, R indices (all data): R1 = 0.1737. wR2 =
0.2223. It is interesting to note that identical crystals could be grown by
evaporation of a DMSO solution of the receptor in the presence of excess
TBAF.
" Crystal data for tetrabutylammonium salt of 2–(2H+): C57H94N6O6S2,
Mr = 1023.50, T = 120(2) K, monoclinic, space group P21/n, a =
˚
17.9274(3), b = 14.1111(3), c = 24.2589(4) A, b = 106.918(1)u, V =
5871.31(19) A , rcalc = 1.158 g cm23, m = 0.142 mm21, Z = 4, reflections
12 M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311.
3
˚
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Chem. Commun., 2008, 61–63 | 63