A new sulfonamide derivative as magnesium ion receptor: N-tosyl-2,6-diisopropyl-4-(2,3-dimethoxylbenzoylamide)aniline

Article abstract of DOI:10.1016/j.tetlet.2009.02.005

N-Tosyl-2,6-diisopropyl-4-(2,3-dimethoxylbenzoylamide)aniline (1) has been synthesized and its metal ion (Na⁺, K⁺, Ca²⁺, Mg²⁺) coordinating properties investigated by FT-IR, ESI-MS, and ¹H NMR methods

Full text of DOI:10.1016/j.tetlet.2009.02.005

Tetrahedron Letters 50 (2009) 1820–1824
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Tetrahedron Letters
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A new sulfonamide derivative as magnesium ion receptor:
N-tosyl-2,6-diisopropyl-4-(2,3-dimethoxylbenzoylamide)aniline
Zerong Long a,b, Peiju Yang a, Yana Xia a,b, Zaiwen Yang a,b, Biao Wu a,
*
a State Key Laboratory for Oxo Synthesis & Selective Oxidation, Lanzhou Institute of Chemical Physics, CAS, Lanzhou 730000, China
b Graduate School of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Tosyl-2,6-diisopropyl-4-(2,3-dimethoxylbenzoylamide)aniline (1) has been synthesized and its metal
ion (Na+, K+, Ca2+, Mg2+) coordinating properties investigated by FT-IR, ESI-MS, and 1H NMR methods.
Among the tested metal ions, the overall stability constant (log K) for Mg2+ (6.89) is the highest (Na+,
5.64; K+, 5.43; Ca2+, 5.51) in 10% water/THF at 25.0 0.5 °C determined by UV–vis spectroscopy, indicat-
ing that 1 is a potent ionophore for Mg2+ ion.
Received 17 October 2008
Revised 4 January 2009
Accepted 3 February 2009
Available online 10 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
N-Tosyl-2,6-diisopropyl-4-(2,3-
dimethoxylbenzoylamide)aniline
Sulfonamide
Magnesium
Metal ion binding
Magnesium is the dominant divalent intracellular cation and is
essential for a variety of cellular processes such as enzyme func-
tion, DNA and protein synthesis, and the regulation of ion chan-
nels.1 Despite the abundance and importance of magnesium,
little is known about the molecular nature of proteins involved
in cellular magnesium transport at the molecular level.1,2 The
amide group as a peptide linkage unit binds Ca2+ in Ca-selective
proteins, and is the donor in potassium ion channels and probably
also in Ca2+ and Na+ ion channels.3 At the same time, the amide do-
nors are of considerable importance in the acylamide oxidization
or metal cation coupling cases.4 Sulfonamide derivatives are the
most important class of drugs, displaying activities including anti-
bacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and anti-
thyroid effectiveness.5 In view of these facts, it should be
interesting to introduce the amide moiety with metallophilic prop-
erties6 into sulfonamide derivatives7a,8 to make use of both func-
tionalities in the potentiation of biological activities. Although a
few examples (e.g., coumarin 343 and nitrilotriacetamide)6
showed that amide donor could selectively bind and sense some
magnesium ion over alkali metal ions (Na+, K+) and other alkaline
earth metal ions (Ca2+).
Compound 1 was synthesized by the reaction of 2,3-dimethoxyl
benzoyl chloride with N-tosyl-4-amino-2,6-diisopropyl aniline9
under mild conditions in 78% yield (Scheme 1).10 Colorless crystals
of 1 were obtained from a dichloromethane solution.11 Structural
analysis shows that the central phenyl ring is nearly coplanar with
the dimethoxy-substituted phenyl group (dihedral angle: 6.22°).
There is an intramolecular N–Hꢀ ꢀ ꢀO hydrogen bond between the
amide N2H and a methoxy group (O1ꢀ ꢀ ꢀN2, 2.674(6) Å; N2–
H2Aꢀ ꢀ ꢀO1, 141°; Fig. 1). The extended solid-state structure of 1 is
derived mainly from intermolecular hydrogen bonding and
p–p
stacking interactions. A pair of symmetry-related N–Hꢀ ꢀ ꢀO hydro-
gen bonds in the R22ð8Þ motif between the sulfonamide N1H group
and one sulfonyl oxygen atom connects two molecules into a di-
mer, which is further linked by
p–p stacking interactions into a
one-dimensional chain along the a-axis (Fig. S1, see Supplementary
data).
In the infrared spectrum of 1 (Fig. 2A (a)), the bands at 3289 and
3250 cmꢁ1 are assigned to the N–H stretching vibration, and the
strongest band at 1660 cmꢁ1 is due to the stretching of the C@O
group. The N–H bending vibrations of amide groups are at 1596,
1577, and 1548 cmꢁ1, and the characteristic strong bands at
1267 and 1325–1303 cmꢁ1 can be attributed to C–O and O@S@O.
To examine its cation sensing properties, compound 1 was mixed
with equimolar alkali metal or alkaline earth metal chloride (NaCl,
KCl, CaCl2, or MgCl2ꢀ6H2O, respectively) in methanol and stirred
until complete dissolution, and then dried under vacuum at
metal ions, such as Ca2+, Mg2+, Cd2+, Pb2+, Ni2+, and La3+ 7,8
in fact,
;
very little attention has been paid to the sulfonamide analogues
containing acylamide moiety as an appropriate metal ionophore.
In this Letter, we present the structural and spectroscopic char-
acterization of a new sulfonamide compound 1 and its metal ion
affinities. The receptor 1 shows a relatively high selectivity to the
* Corresponding author. Tel./fax: +86 931 4968286.
E-mail address: wubiao@lzb.ac.cn (B. Wu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.005

Z. Long et al. / Tetrahedron Letters 50 (2009) 1820–1824
1821
Scheme 1. Synthesis of 1.
Figure 1. Molecular structure of 1, showing the intramolecular N–Hꢀ ꢀ ꢀO hydrogen bond (thermal ellipsoids at 50% probability level; noninteracting hydrogen atoms are
omitted for clarity.). Selected bond distance (Å): N2–C4, 1.409(3); N2–C13, 1.352(3); N1–C1, 1.444(3); S1–O4, 1.420(2); S1–O5, 1.434(2).
50 °C. There was no obvious change in their FT-IR spectra except
that of the Mg-loaded adduct, in which the vibration of carbonyl
at 1660 cmꢁ1 split into two bands (1660, 1631 cmꢁ1; Fig. 2A).
When the metal-to-receptor ratio was increased to 5:1, the C@O
stretching for the Ca2+ and Mg2+ adducts completely shifted to
1629 and 1634 cmꢁ1, respectively (Fig. 2B), indicating the transfer
of the lone pair electrons from oxygen to metal, which leads to the
relaxation and bathochromic shift of the C@O group.
bestic point was observed at 315 nm. Similar phenomena were also
observed in the titration of K+, Ca2+, or Mg2+ to 1, corresponding to
the formation of the 1:1 complex except for the magnesium ion
(Fig. S2). The stability constant (log K) of 1 with the three metal
ions, Na+ (5.64), K+ (5.43), and Ca2+ (5.51), is very close (error < 10%,
r2 0.98).
Xlim ꢁ X0
X ¼ X0 þ
2C0
In addition,
an approximate
aryl@C@O asymmetric stretching at 2107 and 2247 cmꢁ1 for the
p-electron delocalization of the aryl ring generated
h
i
2
1=2
ꢂ C0 þ CM þ 1=Ks ꢁ ½ðC0 þ CM þ 1=KsÞ ꢁ 4C0CMꢃ
ð1Þ
p–p
conjugation cumulative double bonds of
C
Mg2+ is usually thought to be ‘UV-silent’ for its stable electron
configuration (s2p6). However, intense absorption bands occur in
the range of 200–350 nm upon addition of 1. This may be attrib-
Ca2+- and Mg2+-treated samples.12 The wide and strong bands at
472 and 559 cmꢁ1 are ascribed to Mg–O and Ca–O bond formation,
respectively.13 In contrast, the alkali metals Na+ and K+ showed lit-
tle influence on the infrared absorption of 1, suggesting that the
binding ability of 1 with Na+ or K+ is much weaker than with
Ca2+ or Mg2+, which is probably due to the far lower charge density
uted to the charge transfer involving the ‘lone pair’ on the Mg2+
.
The variation of these bands with increasing concentration of 1 is
seen in Figure 3b. The free Mg2+ ion shows a band at about
of Na+ (1.05 q Åꢁ1) and K+ (0.75 q Åꢁ1) than of Mg2+ (2.32 q Åꢁ1
)
225 nm,
while
the
highest
intensity
occurs
for
3.7 ꢂ 10ꢁ3 mol dmꢁ3 of 1. The spectra represent two successive
equilibria. The lower intensity set at about 245 nm corresponds
to the formation of the mono-ligand complex, while the subse-
quent set (277 nm) with higher intensity corresponds to the for-
mation of the bis-ligand complex. Therefore the magnesium
complexation by 1 should consider both ML and ML2 stoichiome-
tries. The inset shows that the fit to the curve of the absorbance
intensity versus concentration of 1 can be fulfilled by the DYNAFIT
program, and the stepwise stability constants for magnesium
(log K1 = 4.50 for ML and log K2 = 2.39 for ML2) were calculated.
The results show that Mg2+ (the smallest cation among the series)
has unique chemical properties, and one to two receptor molecules
could be accommodated around it.
and Ca2+ (1.75 q Åꢁ1).6b The electronic delocalization may also af-
fect the N–H stretching, but the broad peak of water at 3200–
3500 cmꢁ1 caused by deliquescence of the Ca2+ or Mg2+ adducts
most probably shielded the stretching absorbance of N–H. The
vibration absorption of O@S@O in all samples remained un-
changed. These results indicate the preference of the amide group
to metal ions via formation of the M–O@C bond.8
Electronic spectral titrations were performed to study the affin-
ity of 1 to different metals. Binding constants for the 1:1 complex-
ation were obtained by
a nonlinear least-square fit of the
absorbance (X) versus the concentration of the metal ion added
(CM) according to Eq. 1.14 Stability constants for both 1:1 and 2:1
(L:M) complexes were calculated using the DYNAFIT program.15 Fig-
ure 3a shows the changes in the UV–vis spectrum of 1 upon addi-
tion of sodium ion. The band at 277 nm decreased gradually as the
concentration of sodium ion increased, and a well-defined isos-
Mass spectrometry measurements were performed for com-
plexes of 1 with equimolar amounts of K+, Na+, Ca2+, and Mg2+
(Fig. 4). In the case of the magnesium complex, the stoichiometry

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Z. Long et al. / Tetrahedron Letters 50 (2009) 1820–1824
Figure 4. ESI-MS spectrum of 1 with equimolar amounts of sodium, potassium,
calcium and magnesium ions in THF solution.
those of other metals ([L+Na]+, m/z: 533.7, 39.6%; [L+K]+, m/z:
549.7, 64.0%; and [L+Ca]2+, m/z: 275.6, 29.5%). The results also
demonstrate that compound 1 has high selectivity for magnesium
ion. Meanwhile, to further validate the abovementioned conclu-
sion, ion chromatographic analyses were performed on this system
(Fig. S3, see Supplementary data). According to the relation of ion
content corresponding to its peak area, the concentration of Na+,
K+, Ca2+, and Mg2+ extraction in deionized water was calculated
as 0.82, 0.50, 0.74, and 0.07 mg dmꢁ3, respectively. The concentra-
tion of Mg2+ is the lowest, indicating that its complex is the hardest
to hydrolyze among these alkali metal or alkaline earth complexes.
The results also revealed that the binding ability of 1 to Na+, K+, and
Ca2+ is quite close, as shown by the stability constants.
Figure 2. FT-IR spectra of (a) compound 1, (b) 1 + Na+, (c) 1 + K+, (d) 1 + Ca2+, and (e)
1 + Mg2+. The molar ratios of metal-to-receptor are 1:1 (A) and 5:1 (B) in the
experiments in (b)–(e).
To clarify the complexation environment of the metal ions with
the receptor 1, 1H NMR examination was carried out in acetone-d6
with a 1:1 molar ratio of magnesium chloride hexahydrate and 1.
Changes of the chemical shifts of ‘free’ ligand 1 and the corre-
sponding complex are shown in Figure 5. Regarding the complex-
ation of 1 with Mg2+, amide proton showed large magnetic shift
1:1 is the majority as indicated by signals at m/z 267.6 (100.0%,
[L+Mg]2+) and 569.7 (27.3%, [L+Mg+Cl]+). The minor peak at m/z
522.7 (33.0%, [2L+Mg]2+) is for the bis-ligand complex. The mass
spectra of other metal complexes show only the 1:1 complex.
The total content of the magnesium complex is much higher than
Figure 3. (a) Changes in the absorption spectra of ligand 1 (3.0 ꢂ 10ꢁ5 mol dmꢁ3) upon titration of sodium chloride in 10% water/THF (1/6 to 5 equiv); (b) absorption spectra
of magnesium chloride (1.3 ꢂ 10ꢁ4 mol dmꢁ3) upon titration of ligand 1 in 10% water/THF (up to 2.1 equiv). Inset: absorbance at 277 nm (j) as a function of [1] with
theoretical 1:1 and 1:2 (M:L) stoichiometry (–) fits using DYNAFIT program.

Z. Long et al. / Tetrahedron Letters 50 (2009) 1820–1824
1823
Figure 5. 1H NMR spectra (400 MHz, acetone-d6) of (a) free ‘ligand’ 1, and (b) 1 + MgCl2ꢀ6H2O.
Scheme 2. Proposed binding mode for the magnesium complex.
changes (
on the oxygen atom by coordinated cation. The methoxy proton
2 showed small shift tendency ( d = +0.89) due to the weak inter-
action of the oxygen atom with the metal ion. The aromatic proton
signals (a–f) shifted slightly up-field (
d = ꢁ0.56 to ꢁ0.11). In con-
trast to proton 2, a large up-field shift of proton 1 (
d = ꢁ2.38) was
Dd = +2.21) because of the reduction of electron density
Supplementary data
D
Crystallographic data for the structure reported in this Letter
have been deposited with the Cambridge Crystallographic Data
Center (CCDC 713841). Copies of this material can be obtained free
of charge on application to the Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: ++44 12 23 336 033; email: depos-
it@ccdc.cam.ac.uk). Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2009.02.005.
D
D
induced upon complexation. Interestingly, each peak of methyl
proton 3 corresponds to a different chemical environment, indicat-
ing the formation of a locally distorted structure. Furthermore, sul-
fonamide NH signals shifted up-field
(
D
d = ꢁ0.93) upon the
addition of metal ions. The result indicates that the contribution
of different oxygen-containing groups of the ‘ligand’ to the com-
plex formation is different. On the basis of FT-IR, UV–vis titration,
and 1H NMR studies, plausible structures of the magnesium com-
plexes are illustrated in Scheme 2. We adopt the term coordinative
unsaturation to describe the complex Mgꢀ1 that has more open
coordination sites where another ligand could be bonded in a sim-
ilar fashion.16
In summary, we report a new sulfonamide-amide moiety that
displays relatively high selectivity to magnesium ion over other al-
kali metals or alkaline earth metal ions (Na+, K+, and Ca2+). FT-IR
and 1H NMR spectroscopy showed that the magnesium ion has a
strong binding interaction with the carbonyl and the methoxy
group adjacent to the carbonyl moiety of 1. Absorption spectros-
copy and ESI-MS spectrometry also revealed the presence of 1:1
and 1:2 stoichiometries (M:L) for the magnesium complexation.
References and notes
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10. Preparation of N-tosyl-2,6-diisopropyl-4-(2,3-dimethoxyl benzoylamide)aniline:
To a solution of 2,3-dimethoxyl benzoyl chloride (3.8 g, 19 mmol) in THF
Acknowledgment
This work was supported by the ‘Bairen Jihua’ program of the
Chinese Academy of Sciences.

1824
Z. Long et al. / Tetrahedron Letters 50 (2009) 1820–1824
(30 mL) was added N-tosyl-4-amino-2,6-diisopropyl aniline (6.5 g, 19 mmol)
Z = 8, Dcalc = 1.236 g cmꢁ3, F(000) = 2176,
reflections collected, 6659 independent (Rint = 0.045), R1 = 0.0520,
wR2 = 0.1259 [I > 2 (I)].
l
= 0.16 mmꢁ1, T = 293(2) K, 16507
in three portions under stirring. Then NEt3 (2.6 mL) in dry THF (60 mL) was
added dropwise. The mixture was heated to 60 °C for 24 h under N2. The
solvent was removed and the residue was partitioned into a mixture of water
(50 mL) and dichloromethane (50 mL). The organic phase was then washed
successively with 1 M NaOH (100 mL), 1 M HCl (100 mL) and saline solution
(100 mL), and then dried over anhydrous MgSO4. The product was
r
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recrystallized from dichloromethane/diethyl ether as
a
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material. Yield 7.5 g (78%). Mp: 201–203 °C. Anal. Calcd for C28H34N2O5S: C,
65.86; H, 6.71; N, 5.49. Found: C, 65.85; H, 6.70; N, 5.35. See Supplementary
data for other characterization of 1 (1H NMR, 13C NMR, IR).
ˇ
15. Kuzmic, P. Anal. Biochem. 1996, 237, 260–273.
11. Crystal data for 1: C28H34N2O5S (510.64), monoclinic, space group C2/c,
16. Jeon, S.-J.; Li, H.; García, C.; LaRochelle, L. K.; Walsh, P. J. Org. Chem. 2005, 70,
a = 30.371(3), b = 10.981(1), c = 17.667(2), b = 111.326(3)°, V = 5488.7(10) Å3,
448–455.