Anion receptors containing thiazine-1,1-dioxide heterocycles as hydrogen bond donors

Article abstract of DOI:10.3762/bjoc.6.50

The synthesis, X-ray crystal structures and anion recognition properties of two receptors containing thiazine-1,1-dioxide heterocycles as hydrogen bond donating subunits are reported. The newly synthesized receptors display much different anion selectivit

Full text of DOI:10.3762/bjoc.6.50

Anion receptors containing thiazine-1,1-dioxide
heterocycles as hydrogen bond donors
Hong-Bo Wang, James A. Wisner* and Michael C. Jennings
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 50.
Department of Chemistry, University of Western Ontario, 1151
Richmond St., London, Ontario N6A 5B7, Canada
doi:10.3762/bjoc.6.50
Received: 18 February 2010
Accepted: 22 April 2010
Published: 19 May 2010
Email:
James A. Wisner* - jwisner@uwo.ca
* Corresponding author
Guest Editor: C. A. Schalley
Keywords:
© 2010 Wang et al; licensee Beilstein-Institut.
License and terms: see end of document.
anions; hydrogen bonds; receptors; sulfonamides; supramolecular
chemistry
Abstract
The synthesis, X-ray crystal structures and anion recognition properties of two receptors containing thiazine-1,1-dioxide hetero-
cycles as hydrogen bond donating subunits are reported. The newly synthesized receptors display much different anion selectivities
in acetone-d6 than N,N′-diphenyl-1,3-disulfonamidobenzene that was used as a comparison. The selectivity exhibited by one of the
new receptors for chloride anions can be attributed to greater steric demand in the cleft formed, in part, by its terminal phenyl rings;
an effect that is absent in the comparison receptor.
Introduction
The synthesis of neutral hosts and study of their anion recogni- frameworks. The greater acidity of such a subunit can be an
tion properties is an area of research that has grown in interest advantage by providing greater potential hydrogen bond donor
over the past several years owing to the potential use of such strength with anionic guests. Alternatively, the possibility of
receptors in environmental, biomedical and materials applica- deprotonation in some specific systems by basic anions such as
tions [1,2]. The basic design methodology for these hosts has carboxylates or fluoride can be employed as an indicator for
largely focused on the use of nitrogen-based hydrogen bond these species. Regardless, the incorporation of sulfonamide
donor groups such as amides [3,4], ureas [5], pyrroles/indoles/ functional groups has typically been realized synthetically by
carbazoles [6,7] and sulfonamides [8-23] to complex the sulfonylation of an amine to form a sulfonamide product. This
anionic targets in a topologically complementary fashion. approach is somewhat limited, from a design perspective, in
Sulfonamides are an interesting case as the hydrogen bond that the majority of examples to date consist of sulfonamides
donor is often significantly more acidic (pKa approx. 11 for derived from a few commercially available starting materials
simple N-phenylaryl sulfonamides such as 3 (see below)) than such as benzenesulfonyl, toluenesulfonyl, dansyl, and benzene-
that presented by other groups typically incorporated in these disulfonyl chlorides [8-23]. We have recently investigated
Page 1 of 6
(page number not for citation purposes)

Beilstein J. Org. Chem. 2010, 6, No. 50.
thiazine-1,1-dioxide heterocycles (Figure 1A) as hydrogen bond cation of the potential versatility of the synthetic method
donor groups in the formation of double helical complexes [24]. described here that the elusive 2,6-disulfonamidopyridine host 4
The parent heterocycle can be viewed as a cyclic, vinylogous (Figure 2) that would provide a more direct comparison to 2 is
sulfonamide that presents a different spatial, conformational and at present unknown and likely synthesized only with some diffi-
electronic relationship between the sulfonyl and NH subunits culty.
than that of a typical sulfonamide function (Figure 1B). It is a
simple matter to access many such derivatives with this frame- The syntheses of receptors 1 and 2 are summarized in
work using straightforward synthetic methods and inexpensive Scheme 1. α,α′-Dibromo-1,3-diacetylbenzene (5) and α,α′-
materials and reagents. Herein, we describe an illustrative syn- dibromo-2,6-diacetylpyridine (6) are both simply generated by
thesis of two anion hosts incorporating these heterocycles and bromination of the corresponding diacylarenes. The reaction of
compare their binding affinities with some common anionic either dibromide with α-mercaptoacetophenone in the presence
guests to that of an analogous benzene disulfonamide anion of 2,6-lutidine yields dithioether intermediates 7 and 8. Oxida-
receptor.
tion of these dithioethers to the disulfones 9 and 10 with urea-
hydrogen peroxide (UHP) and trifluoroacetic anhydride
(TFAA) in acetonitrile at room temperature proceeds in high
yields. The final products 1 and 2 were obtained by the cycliza-
tion and dehydration of these intermediate disulfones with
ammonium acetate in refluxing glacial acetic acid. Overall, the
yields of receptors 1 and 2 are 62% and 72% respectively, from
the dibromides. The simplicity and mild nature of these trans-
formations make them easily applicable to the derivatization of
most α-bromoacyl functional groups should one desire the
installation of this subunit in a potential host.
Figure 1: Structures of thiazine-1,1-dioxide heterocycle (A) and sulfon-
amide function (B).
The solid-state structures of both newly synthesized receptors
were confirmed by X-ray diffraction analysis of single crystals
Results and Discussion
The two receptor structures 1 and 2 (Figure 2) were chosen with grown by the slow diffusion of isopropyl ether into concen-
the intent of evaluating their efficacy in comparison to the trated DMSO solutions of each (Figure 3). Unfortunately,
known anion host N,N′-diphenyl-1,3-disulfonamidobenzene 3 attempts to co-crystallize the receptors with anionic guests in a
(Figure 2) [21]. Originally investigated for anion recognition by number of organic solvents were unsuccessful. The conforma-
Crabtree and coworkers, 3 was considered a representative tions of the receptors in the solid state are surprisingly different
comparator given the similar stereochemical arrangement of the given the similarity in molecular structure; the two receptors
two NH donors and the 1,3-benzenediyl spacer. The incorpor- differ only in the replacement of an aryl CH in 1 for N in 2. The
ation of a pyridyl spacer in 2 was chosen to examine the structure of 1 is in an extended, approximately anti-anti
possible effect the ring nitrogen atom might have on the preor- conformation [27] where each of the NH groups is hydrogen
ganization and anion recognition properties of the resulting host bonded to a different DMSO solvent molecule in the lattice
in comparison to 1. It is well known that structurally related (N···O = 2.821(3) and 2.770(3) Å). In contrast, 2 crystallizes in
2,6-dicarboxamidopyridine containing hosts have markedly an approximately cleft-shaped syn-syn conformation where both
different properties compared to their analogous isophthal- NH groups are hydrogen bonded to a single DMSO solvent
amide derivatives in these regards as well [25,26]. It is an indi- molecule (N···O = 2.971(2) and 2.950(3) Å). The difference
Figure 2: Structures of anion receptors 1–4.
Page 2 of 6
(page number not for citation purposes)

Beilstein J. Org. Chem. 2010, 6, No. 50.
Scheme 1: Syntheses of 1 and 2. Reaction conditions: (a) (X = CH) NBS, TsOH, CH3CN, reflux or (X = N) Br2, AlCl3, Et2O, 0 °C; (b) 2,6-lutidine,
α-mercaptoacetophenone (2 equiv), CH2Cl2; (c) UHP/TFAA, CH3CN; (d) NH4OAc, AcOH, reflux.
may be rationalized by the presence of a weak intramolecular guests and the shifts of their 1H NMR resonances were
N-H···N hydrogen bond between the central pyridine ring and observed as a function of anion concentration. In the majority of
each of the two thiazine-1,1-dioxide rings in 2 that is necessar- cases the downfield shift of the NH protons of the receptors was
ily absent in 1. This conclusion is supported by the approxi- used to determine the stability constants. However, the addition
mate 0.5 ppm chemical shift difference of the two receptor NH of less than a half an equivalent of either acetate or dihydrogen
resonances in acetone-d6 (2 > 1) and similar shift differences phosphate anions to any of the three receptors resulted in the
observed in analogous hosts that are even larger when measured disappearance of the receptor NH proton resonances in their
in the less competitive solvent CDCl3 [28].
NMR spectra. In these cases, either the upfield shift of a CH
resonance on the thiazine-1,1-dioxide rings (1 and 2) or the
downfield shift of the 2-CH proton on the central phenyl ring of
the receptor (3) was used to determine the stability constants.
Non-linear least squares fitting of the data using the program
EQNMR [29] yielded the complex stability constants in all
cases. All of the titrations were fit to a 1:1 (receptor:anion)
binding model except for the titration of receptor 1 with TBA
chloride. In this case the data fit a 1:1 binding model that
included a much weaker 2:1 (receptor:anion) component. It
should also be noted that the data from titration of 3 with
acetate had a binding constant that was too large to be reliably
fit by this method. The titration results are summarized in
Table 1.
Receptor 1 exhibits a clear preference for a chloride anion guest
over the other anions tested. Chloride is likely an excellent
steric match to the cleft formed by the NH protons, the 2-CH
proton of the central aryl ring and two of the ortho-protons of
the terminal phenyl rings of 1 in a planar syn-syn binding
conformation similar to that observed in the solid state struc-
ture of 2 with DMSO (Figure 1B). This conclusion is supported
by the observation of significant downfield shifts of all three of
these protons (Figure 2) in the 1H NMR spectrum upon chloride
Figure 3: Stick representations of the X-ray crystal structures of (a)
receptor 1 and (b) receptor 2. Non-acidic hydrogen atoms omitted for
clarity. Red = oxygen, blue = nitrogen, yellow = sulfur, grey = carbon.
Hydrogen bonds denoted by dotted orange lines.
The three receptors were each titrated in acetone-d6 with a complexation (Δδmax = 0.15 (Ha), 1.91 (Hb), 0.17 (Hc) ppm).
number of TBA (tetrabutylammonium) salts of common anionic The progressively reduced affinity of 1 for bromide and iodide
Page 3 of 6
(page number not for citation purposes)

Beilstein J. Org. Chem. 2010, 6, No. 50.
an order of magnitude but is still preferred over bromide even
though the affinity of 3 for the latter guest has approximately
doubled in comparison to receptor 1. No change in the 1H NMR
spectrum of 3 is observed upon the addition of iodide. We
believe that the differences in anion binding between these two
receptors can be satisfactorily explained by the differences in
their cleft geometries. The central three atoms (NH and CHa)
that define the binding cleft in both 1 and 3 circumscribe a very
similar meridian. In fact, we manipulated the single crystal
molecular structures of 1 and the 4,4′-di-t-butyl derivative of 3
[30] (available from the Cambridge Crystallographic Database
#1003/6124) by rotating the two relevant dihedral angles to
bring the NH groups into plane with their central aryl rings in
an idealized syn-syn conformation. Measurement of these
“closest approach” N···N distances in the two models yields
Table 1: Stability constants (Ka) determined by 1H NMR in acetone-d6
solution at 298 K for receptors 1–3 with a variety of anionic guests.
Aniona
Receptor 1
Receptor 2
Receptor 3
(2:1) 300
(1:1) 59000
Cl−
300
4300
Br−
380
53
83
—b
740
86
I−
HSO4−
AcO−
H2PO4−
220
130
480
360
560
12500
540
>105
79000
aAdded as their tetrabutylammonium salts. Errors are estimated to be
<10%.
bNo change was observed in the 1H NMR of the receptor upon anion
addition.
can be attributed both to their inability to fit into this idealized values of 4.76 and 4.77 Å for 1 and the derivative of 3, respect-
cleft conformation and their respectively decreasing efficacies ively; a difference of 0.01 Å. The terminal phenyl rings of 3 do
as hydrogen bond acceptors. In fact, this observation is common not, however, occlude this central cleft like those of 1 and 2.
to 1 and 2 and mirrors the behaviour of similar acyclic iso- Rather, they form a divergent “V”-shaped geometry upon chela-
phthalamide hosts studied previously by Crabtree and tion of anionic species by the two NH groups of 3, regardless of
coworkers in CD2Cl2 [21]. Receptor 1 shows a preference for whether coplanarity is maintained with the central benzene ring.
the complexation of chloride over acetate (5:1) and a distinct The ortho-protons of these terminal rings (Hc) are certainly too
discrimination against the dihydrogen phosphate (>100:1 far away to contribute to the stability of the halide anion
Cl:H2PO4) guest. Presumably, the larger size of the dihydrogen complexes that presumably form in this manner. The general
phosphate anion prevents complexation by 1 in a coplanar syn- result of this relaxation of the steric requirements for anion
syn conformation. The distortion of the receptor from a low complexation by 3, in comparison to 1, is a marked increase in
energy coplanar binding geometry should reduce its affinity for binding strength for all of the larger anions. Thus, the binding
such guests, despite their greater basicity. This supposition is affinities of 3 for these larger anions follow the trend of their
supported in the case of dihydrogen phosphate by a very small aqueous basicities (pKa conj. acid): AcO− (4.75), H2PO4−
Δδmax for Ha observed when 1 is titrated with this anion (0.01 (2.12), HSO4− (−3), Br− (−9), I− (−10) [31].
ppm) though Δδmax of protons Hc remains significant (0.15
ppm) indicating their continued participation in the binding Conclusions
event. The titration of 1 with the less basic but similarly sized We have presented a simple synthetic route for the incorpor-
and shaped HSO4− anion displays an upfield shift of Ha (Δδmax ation of thiazine-1,1-dioxide heterocycles as hydrogen bond
= −0.05 ppm) and a reduced downfield shift of Hc (Δδmax = donating subunits in two new acyclic anion receptors. The two
0.07 ppm).
new receptors 1 and 2, were titrated with a number of anions
and displayed very different complexation behaviour to the
Replacement of the central phenyl ring spacer of 1 for pyridine known disulfonamide receptor 3 that was used as a comparison.
in 2 results in a significant reduction of the association The difference can be attributed to the differing steric demands
constants for all of the anions tested. This result was expected of the terminal phenyl rings in the two different receptor
as a consequence of repulsion of anionic guests by the lone pair geometries despite the similar character of their central binding
of the pyridine ring nitrogen atom upon binding in the cleft of clefts. The steric effect of these rings in receptor 1 generates
the receptor. The other outcome of this replacement is a loss of significant selectivity by the receptor for chloride versus the
any selectivity for chloride and, in fact, a slight preference by other, larger anions studied. The replacement of the central 1,3-
receptor 2 for acetate and dihydrogen phosphate.
benzenediyl spacer in 1 for 2,6-pyridinediyl in 2 greatly reduces
the affinity of the resulting receptor for all of the anions
The simple disulfonamide receptor 3 exhibits very different examined and eliminates any selectivity for chloride. The
complexation behaviour than 1 and 2 with the anions investi- synthetic approach described here can be easily adapted to the
gated. Receptor 3 displays a strong preference for acetate and synthesis of oligomeric analogues of these two receptors that
dihydrogen phosphate over all of the other anions investigated we expect will display an even greater selectivity for chloride
in this solvent. The binding constant for chloride is reduced by anions and operate in more competitive solvent environments.
Page 4 of 6
(page number not for citation purposes)

Beilstein J. Org. Chem. 2010, 6, No. 50.
12.Berryman, O. B.; Johnson, C. A., II; Zakharov, L. N.; Haley, M. M.;
Johnson, D. W. Angew. Chem., Int. Ed. 2008, 47, 117–120.
doi:10.1002/anie.200703971
Supporting Information
Details of synthetic procedures, characterization data for
intermediates and final products, and binding isotherms for
receptors 1 and 2 with TBA salts of anions.
13.Shang, X. F.; Lin, H.; Lin, H. K. J. Fluorine Chem. 2007, 128, 530–534.
doi:10.1016/j.jfluchem.2007.01.005
14.Wu, Y.; Peng, X.; Fan, J.; Gao, S.; Tian, M.; Zhao, J.; Sun, S.
J. Org. Chem. 2007, 72, 62–70. doi:10.1021/jo061634c
15.Kavallieratos, K.; Sabucedo, A. J.; Pau, A. T.; Rodriguez, J. M.
J. Am. Soc. Mass Spectrom. 2005, 16, 1377–1383.
doi:10.1016/j.jasms.2005.04.008
Supporting Information File 1
Experimental details.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-50-S1.pdf]
16.Kondo, S.-I.; Suzuki, T.; Toyama, T.; Yano, Y. Bull. Chem. Soc. Jpn.
2005, 78, 1348–1350. doi:10.1246/bcsj.78.1348
17.Smith, B. D.; Lambert, T. N. Chem. Commun. 2003, 2261–2268.
doi:10.1039/b303359g
Supporting Information File 2
X-ray crystal data for receptor 1.
18.Kondo, S.-I.; Suzuki, T.; Yano, Y. Tetrahedron Lett. 2002, 43,
7059–7061. doi:10.1016/S0040-4039(02)01543-5
19.Kavallieratos, K.; Moyer, B. A. Chem. Commun. 2001, 1620–1621.
doi:10.1039/b102152b
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-50-S2.cif]
20.Chrisstoffels, L. A. J.; de Jong, F.; Reinhoudt, D. N. Chem.–Eur. J.
2000, 6, 1376–1385.
Supporting Information File 3
X-ray crystal data for receptor 2.
doi:10.1002/(SICI)1521-3765(20000417)6:8<1376::AID-CHEM1376>3.
0.CO;2-I
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-50-S3.cif]
21.Kavallieratos, K.; Bertao, C. M.; Crabtree, R. H. J. Org. Chem. 1999,
64, 1675–1683. doi:10.1021/jo982382l
22.Davis, A. P.; Perry, J. J.; Williams, R. P. J. Am. Chem. Soc. 1997, 119,
1793–1794. doi:10.1021/ja9629930
23.Morzherin, Y.; Rudkevich, D. M.; Verboom, W.; Reinhoudt, D. N.
J. Org. Chem. 1993, 58, 7602–7605. doi:10.1021/jo00078a052
24.Li, J.; Wisner, J. A.; Jennings, M. C. Org. Lett. 2007, 9, 3267–3269.
doi:10.1021/ol071171c
Acknowledgements
We thank the Natural Sciences and Engineering Council of
Canada and the Ontario Ministry of Research and Innovation
for their generous financial support of this research.
25.Brooks, S. J.; Garcia-Garrido, S. E.; Light, M. E.; Cole, P. A.;
Gale, P. A. Chem.–Eur. J. 2007, 13, 3320–3329.
doi:10.1002/chem.200601647
References
26.Schmuck, C.; Machon, U. Chem.–Eur. J. 2005, 11, 1109–1118.
doi:10.1002/chem.200400652
1. Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor Chemistry;
Royal Society of Chemistry: Cambridge, U.K., 2006.
2. Katayev, E. A.; Kolesnikov, G. V.; Sessler, J. L. Chem. Soc. Rev. 2009,
38, 1572–1586. doi:10.1039/b806468g
27.Hunter, C. A.; Purvis, D. A. Angew. Chem., Int. Ed. Engl. 1992, 31,
792. doi:10.1002/anie.199207921
28.Wisner, J. A.; Li, J. unpublished results.
3. Kubik, S. Chem. Soc. Rev. 2009, 38, 585–605. doi:10.1039/b810531f
4. Kang, S. O.; Begum, R. A.; Bowman-James, K. Angew. Chem., Int. Ed.
2006, 45, 7882–7894. doi:10.1002/anie.200602006
5. Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198.
doi:10.1039/b801793j
29.Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311.
doi:10.1039/DT9930000311
30.Eagle, C. T.; Kavallieratos, K.; Bryan, J. C. J. Chem. Crystallogr. 2002,
32, 165. doi:10.1023/A:1020283701925
31.Brownstein, S.; Stillman, A. E. J. Phys. Chem. 1959, 63, 2061–2062.
doi:10.1021/j150582a022
6. Cho, W.-S.; Sessler, J. L. Artificial pyrrole-based anion receptors. In
Functional Synthetic Receptors; Schrader, T.; Hamilton, A. D., Eds.;
Wiley-VCH: Weinheim, Germany, 2005; pp 165–256.
doi:10.1002/352760572X.ch4
7. Gale, P. A. Chem. Commun. 2008, 4525–4540. doi:10.1039/b809508f
8. López, M. V.; Bermejo, M. R.; Vásquez, M. E.; Taglietti, A.;
Zaragoza, G.; Pedrido, R.; Martínez-Calvo, M. Org. Biomol. Chem.
2010, 8, 357–362. doi:10.1039/b916040j
9. Warr, R. J.; Westra, A. N.; Bell, K. J.; Chartres, J.; Ellis, R.; Tong, C.;
Simmance, T. G.; Gadzhieva, A.; Blake, A. J.; Tasker, P. A.;
Schröder, M. Chem.–Eur. J. 2009, 15, 4836–4850.
doi:10.1002/chem.200802377
10.Kakuchi, R.; Kodama, T.; Shimada, R.; Tago, Y.; Sakai, R.; Satoh, T.;
Kakuchi, T. Macromolecules 2009, 42, 3892–3897.
doi:10.1021/ma900409h
11.Caltagirone, C.; Bates, G. W.; Gale, P. A.; Light, M. A.
Chem. Commun. 2008, 61–63. doi:10.1039/b713431b
Page 5 of 6
(page number not for citation purposes)

Beilstein J. Org. Chem. 2010, 6, No. 50.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.6.50
Page 6 of 6
(page number not for citation purposes)