Anion recognition by N,N′-diarylalkanediamides

Article abstract of DOI:10.1016/j.tetlet.2012.08.103

The preparation of N,N′-diarylalkanediamides from the respective aliphatic dicarboxylic acids and 4-nitroaniline via microwave-prompted reactions is presented. The most positive effect of microwave irradiation was observed for N,N′-bis(4-nitrophenyl)butanediamide. Anion binding studies on the obtained diamides were carried out in DMSO and acetonitrile using UV-vis and ¹H NMR spectroscopy. A mechanism for selective fluoride recognition by N,N′-bis(4-nitrophenyl)butanediamide in DMSO is proposed.

Full text of DOI:10.1016/j.tetlet.2012.08.103

Tetrahedron Letters 53 (2012) 6029–6034
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Anion recognition by N,N0-diarylalkanediamides
⇑
Ewa Wagner-Wysiecka , Natalia Łukasik
´
Chemical Faculty, Gdansk University of Technology, Narutowicza 11/12, 80 233 Gdansk, Poland
a r t i c l e i n f o
a b s t r a c t
The preparation of N,N0-diarylalkanediamides from the respective aliphatic dicarboxylic acids and 4-
nitroaniline via microwave-prompted reactions is presented. The most positive effect of microwave irra-
diation was observed for N,N0-bis(4-nitrophenyl)butanediamide. Anion binding studies on the obtained
diamides were carried out in DMSO and acetonitrile using UV–vis and 1H NMR spectroscopy. A mecha-
nism for selective fluoride recognition by N,N0-bis(4-nitrophenyl)butanediamide in DMSO is proposed.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 28 June 2012
Revised 1 August 2012
Accepted 24 August 2012
Available online 3 September 2012
Keywords:
N,N0-diarylalkanediamides
Microwave synthesis
Anion complexation
UV–vis spectroscopy
1H NMR spectroscopy
Amides occur widely in Nature (peptides, proteins), and many
synthetic amides are used in various fields of science. In medicinal
chemistry they attract attention due their antitumour activity,1
and they are also used as antibacterial agents2 and HIV inhibitors.3
The presence of the N–H residue makes amides interesting for
supramolecular chemists as potential artificial anion receptors.4
Investigations of synthetic receptors allows natural systems to be
copied and information on the mechanisms of biochemical pro-
cesses to be derived. Synthetic receptors are also useful analytical
tools. The incorporation of a chromophore into anion sensitive
molecules results in chromo-ionophores. Chromogenic receptors
enable the application of simple and inexpensive spectrophoto-
metric methods for anion detection and determination. Such com-
pounds may also work as ‘naked-eye’ anion sensors.5
In many cases, the main factor limiting the possible applications
of a receptor is its synthesis which can be complicated, for exam-
ple, by time and energy consumption, utilizing harmful reagents,
etc. Amides are among those compounds which can be obtained
relatively easily, in high yields using the corresponding acid chlo-
rides as substrates. Elimination of hazardous organic compounds
is one of the essential requirements of green chemistry. High yield-
ing and environmentally friendly synthetic methods can, among
the others, be based on microwave-assisted protocols.6 Micro-
waves (MWs) were found to be an effective tool in amide prepara-
tion. Loupy et al.7 synthesized amides by the direct irradiation of
an amine and monocarboxylic acid mixtures. The yields of the ob-
tained products were 2 to 10-fold higher in comparison to conven-
tional methods. Zare and co-workers8 proved that the presence of a
quaternary ammonium salt increases the microwave effect result-
ing in improved conversions into the desired amides. Khalafi-Nez-
had et al.9 applied microwaves for the preparation of primary
amides using imidazole as a base. It was found that the presence
of imidazole leads to the formation of polar salts with carboxylic
acids, which results in greater absorption of microwave energy.10
The low melting point of imidazolium carboxylates (they melt
even when low microwave power is applied) provides homogene-
ity to the reaction mixture.
Herein, we describe simple amides, being derivatives of ali-
phatic dicarboxylic acids and p-nitroaniline, their MW assisted
synthesis and ion complexation properties.
N,N0-diarylalkanediamides were previously obtained and stud-
ied as cytotoxic agents by Chacón-Gracía and Martínez.11 In this
work, amides of succinic (1, n = 2), glutaric (2, n = 3), adipic (3,
n = 4), pimelic (4, n = 5) and suberic (5, n = 6) acids (Fig. 1) were ob-
tained using a previously described method12 (see Supplementary
data). This method, although well proven in the case of 2,6-pyri-
dine dicarboxylic acid amides12 allowed amides of the above men-
tioned aliphatic acids to be obtained in rather moderate yields (15–
45%). A more efficient and less time-consuming method was pro-
posed by Martínez.11 However, both the above synthetic proce-
dures use acid chlorides as substrates, the preparation of which
required toxic and rather unpleasant reagents. Thus, investigations
on the preparation of amides of aliphatic dicarboxylic acids 1–5
(Fig. 1) in reactions promoted by microwave irradiation were per-
formed (for experimental details, see Supplementary data). The ef-
fect of solvent, type of base, microwave power, temperature, and
reaction time were investigated in order to obtain the highest yield
of the desired product with the least amount of by-product forma-
tion. Traces of amides were observed using DMF, acetonitrile, and
⇑
Corresponding author. Tel.: +48 58 3472359; fax: +48 58 3471949.
E-mail address: ewa.wagner-wysiecka@pg.gda.pl (E. Wagner-Wysiecka).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.103

6030
E. Wagner-Wysiecka, N. Łukasik / Tetrahedron Letters 53 (2012) 6029–6034
O
O
(CH2)n
NH2
NH
HN
1.n = 2
2.n = 3
3.n = 4
4.n = 5
5.n = 6
O
O
imidazole
(CH2)n
2
+
HO
OH
MW irridation
(no solvent)
NO2
NO2
NO2
Figure 1. Microwave-assisted preparation of amides 1-5.
The atomic arrangement and the presence of the chromophore
in the amides obtained make them possible ion complexing agents.
To our knowledge, their ion recognition ability has not been tested
using UV–vis spectrophotometry. Both metal cations (used as per-
chlorates) and anions (as tetra-n-butylammonium salts) of differ-
ent shapes and sizes in various organic solvents were used for
ion complexation studies. No color or spectral changes were ob-
served in the presence of alkali and alkaline earth metal cations
in DMSO. Among the studied anions were halides, oxygen-contain-
ing inorganic anions (hydrogen sulfate, dihydrogen phosphate, ni-
trate, nitrite, and perchlorate) and carboxylic acid anions (acetate,
benzoate). In DMSO, spectral changes were observed only in the
presence of fluorides and dihydrogen phosphates. Spectral changes
upon spectrophotometric titrations with tetra-n-butylammonium
dihydrogen phosphates (TBADHP) are exemplified with pimelic
acid diamide (4) in Figure 2a. Spectral changes in the presence of
TBADHP for all the investigated amides have the same trend, that
is, no particular selectivity in their colorimetric response to dihy-
drogen phosphate anion recognition was found. On the basis of
titration experiments the stability constant values of the diamide
complexes with dihydrogen phosphates were estimated. Calcula-
tions using the OPIUM13 program showed the best fit for 1:1 com-
plexes. The obtained values of the stability constants, shown in
Figure 2b, for the dihydrogen phosphate complexes did not differ
dramatically. From the obtained results it might be concluded that,
to some extent, the dihydrogen binding strength is dependent on
the number of carbon atoms in the amides aliphatic chain. In the
studied range of amide homologues, the stability constants were
higher for shorter analogs (ligands 1–4). The lowest stability con-
stant was obtained for suberic acid diamide (5). Moreover, there
was relationship between the stability constant value and the par-
ity of carbon atoms in the aliphatic chain. They were slightly higher
for amides with an even number of carbon atoms. This observed
trend might be explained by the flexibility of the diamide mole-
cules affecting the shape of the formed molecular ‘‘cavity’’ upon
Table 1
The conditions and yields of the direct MW-assisted synthesis of amides 1–5
Product Acid
Temperature
(°C)
Time
(min)
Power
(W)
MW Yielda
(%)
1
2
3
4
5
Succinic 90
(n = 2)
Glutaric 110
10
10
30
10
30
500
500
500
600
500
26
30
29
40
15
(n = 3)
Adipic
(n = 4)
Pimelic
(n = 5)
Suberic
(n = 6)
110
110
110
By bold the highest obtained yield is marked.
a
Estimated from the 1H NMR spectra.
water as the solvent. No beneficial effect of the kind of the used
base (anhydrous potassium carbonate, triethylamine, imidazole,
potassium tert-butanolate) was apparent. The best results were ob-
tained for reactions carried out under solvent-free conditions, as
schematically shown in Figure 1. The optimum reaction conditions
and the best obtained yields are collected in Table 1. For more de-
tails, see Supplementary data (Table S1).
The most beneficial effect of MW irridation was observed for
succinic acid diamide. The yield of succinic acid diamide is usually
low, due to preferential cyclic imide formation. Under conventional
conditions, the yield of N,N0-bis(4-nitrophenyl)butanediamide (1)
usually does not exceed 20%. The microwave-assisted reaction
gave the same amide within 10 min in 26% yield. In the cases of
amides with longer aliphatic chains, the yields were not spectacu-
lar, the highest being for pimelic acid diamide (4). However, signif-
icantly shorter reaction times and the avoidance of toxic reagents
(e.g., thionyl chloride) were the principal advantages of the de-
scribed method.
(b)
(a)
2.75
2.70
2.65
0.6
2.73
2.72
adipic
2.70
0.5
succinic
pimelic
2.67
0.4
0.3
0.2
0.1
0.0
glutaric
2.60
2.55
2.50
2.52
suberic
6
300
350
400
450
500
2
3
4
5
wavelength [nm]
n
Figure 2. (a) Spectral changes upon titration of 4 (2.08 ꢀ 10ꢁ5 M) with tetra-n-butylammonium dihydrogen phosphate (TBADHP) (cTBADHP = 0–2.52 ꢀ 10ꢁ3 M) in DMSO; (b)
The relationship between the stability constant value (logK) of TBADHP complexes (DMSO) and the number of carbon atoms (n) in the aliphatic chain of N,N0-
diarylalkanediamide 1–5.

E. Wagner-Wysiecka, N. Łukasik / Tetrahedron Letters 53 (2012) 6029–6034
6031
Table 2
acid residue to aliphatic chain seems to have beneficial effect for
anion recognition. In the series of chromogenic pyridine-2,6-dicar-
boxylic acid amides mentioned above selective phosphate binding
in DMSO was found for N,N’-bis(2-hydroxy-4-nitrophenyl)pyri-
dine-2,6-dicarboxamide. However the stability constant value,
logK = 2.51, is in this last case lower than that for investigated ali-
phatic acid diamides. Flexible aliphatic chains of various length,
besides aromatic acid residues, were building blocks in a series
of macrocyclic tetraamides obtained by Chmielewski and Jurc-
zak.4a–d The highest affinity toward anions was found for 20-mem-
bered compounds4b with binding constant for dihydrogen
phosphates logK ꢂ 3.9 (DMSO-d6). The anion affinity of their open
chain analogs was significantly lower.
To support our dihydrogen phosphate complexation theory, the
1H NMR spectra of the diamides 1, 3, and 4 in the presence of equi-
molar amounts of dihydrogen phosphate were recorded in DMSO-
d6. The chemical shifts [ppm] for the free ligands and their changes
in the presence of TBADHP are summarized in Table 2. The respec-
tive spectra are shown in Supplementary data (Fig. S1).
1
The chemical shift (d [ppm]) changes in the H NMR spectra of N,N0-diarylalkane-
diamides 1, 3, and 4 in the presence of an equimolar amount of tetra-n-butylam-
monium dihydrogen phosphate in DMSO-d6
O
O
C
C
A
A
NH
HN
B
B
A'
A'
O2N
NO2
B'
B'
Ligand
NH
AA0
BB0
LogKa
1
10.67
11.72
+1.05
10.53
11.72
+1.19
10.50
11.42
+0.92
7.82
7.92
+0.10
7.83
7.94
+0.11
7.82
7.89
+0.07
8.21
8.18
2.72 0.06
1 + H2POꢁ4
D
d [ppm]
ꢁ0.03
3
8.20
2.73 0.19
2.70 0.01
3 + H2POꢁ4
8.16
D
d [ppm]
ꢁ0.04
4
8.19
4 + H2POꢁ4
8.16
ꢁ0.03
D
d [ppm]
The chemical shift values of the NH signals for the free ligands
suggest the presence of intramolecular hydrogen bonds
(NHꢃ ꢃ ꢃO@C) of increasing strength, inversely proportional to the al-
kyl chain length. In the presence of dihydrogen phosphates, in all
cases, the NH signal was shifted downfield indicating stronger
intermolecular hydrogen bond formation, that is, between the li-
gand and anion. The most significant change in the chemical shift
By bold
Dd [ppm] are marked.
a
Determined from UV–vis measurements (DMSO).
anion complexation. A lower value of stability constant for simple
N-methylacetamide4e (logK = 1.41, chloroform-d3), proves a che-
late effect in phosphate binding by synthesized diamides 1–5.
Comparing to previously described12 N,N0-bis(4-nitrophenyl)pyri-
dine-2,6-dicarboxamide, where no spectrophotometric response
toward dihydrogen phosphate was found, the change of aromatic
of the NH signal (Dd = +1.19) was observed for adipic acid diamide
(3). Analysis of the chemical shift changes for the NH and aromatic
proton signals again showed the correlation between the length of
the alkyl chain and the strength of dihydrogen phosphate binding.
(a) 0.9
(b)
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0.8
0.7
0.6
0.5
24.5 eq OH-
0-14.5 eq OH-
0.4
to 14 eq F-
0.3
0.2
above 15 eq F-
0.1
0.0
300
350
400
450
500
550
600
300
350
400
450
500
550
600
wavelength [nm]
wavelength [nm]
(c)
0.5
380 nm (R2= 0.9960)
0.4
0.3
0.2
0.1
0.0
400 nm (R2= 0.9966)
1x10-4 2x10-4 3x10-4 4x10-4 5x10-4 6x10-4 7x10-4
0
c
F-
Figure 3. Comparison of the spectral changes upon titration of 1 (3.05 ꢀ 10ꢁ5 M) with: (a) TBAF (b) TBAOH, and (c) the absorbance changes as a function of fluoride
concentration, in DMSO.

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E. Wagner-Wysiecka, N. Łukasik / Tetrahedron Letters 53 (2012) 6029–6034
Figure 4. 1H NMR spectra of: (a) succinic acid diamide 1 (1.27 ꢀ 10ꢁ2 M); (b) upon addition of 0.1 equiv, and (c) 1 equiv of TBAF in DMSO-d6 (for proton annotations see
Fig. 5).
Changes in the chemical shifts of the aromatic protons showed also
their different participation in anion binding. Dihydrogen phos-
phate is bound the strongest by adipic acid diamide. In anion com-
plexation, the NH and aromatic CH protons are involved. In the
case of succinic acid diamide, a slightly smaller contribution of
these protons, especially NH, was observed. Pimelic acid diamide
binds the investigated anion via both the NH and aromatic CH pro-
tons, however, to a lesser extent than that for succinic and adipic
acid diamides. The results obtained from 1H NMR experiments cor-
relate with the stability constant values obtained from UV–vis
titrations in DMSO.
Besides dihydrogen phosphates, changes in the absorption
spectra (DMSO) of the investigated diamides 1–5 were also ob-
served in the presence of tetra-n-butylammonium fluoride (TBAF).
In the presence of a large excess of salt, the color of the ligand solu-
tion 2–5 changed to bright yellow, a feature connected with the
appearance of a new band (ꢂ450 nm) in the UV–vis spectrum. This
can be exemplified from the trace derived from the titration of li-
gand 3 (see Fig. S2 in Supplementary data). Changes in the absorp-
tion spectra (no clear isosbestic point, large bathochromic shift),
upon titration with TBAF and the molar ratio plots suggest ligand
deprotonation rather than fluoride complex formation. This was
supported by the 1H NMR spectra recorded in DMSO-d6. The N-H
signal was not observed in the presence of 1 equiv of TBAF (see
Supplementary data, Fig. S3) and the aromatic protons were shifted
upfield. Opposite to the above, completely different spectral
changes were observed in the case of the spectrophotometric titra-
tion of succinic acid diamide (1) with TBAF in DMSO. The plot for
the titration of 1 with TBAF is shown in Figure 3a. An analogous
experiment in which TBAOH was used instead of TBAF (Fig. 3b)
possibly indicates that the presence of fluoride does not cause only
deprotonation of the ligand. Figure 3c shows the dependence,
being almost linear, of absorbance changes as a function of fluoride
concentration.
Thus the 1H NMR spectra of succinic acid diamide 1 in the pres-
ence of tetra-n-butylammonium fluoride were recorded (Fig. 4) in
DMSO-d6 (for proton assignments, see Fig. 5). Upon addition of a
small amount (0.1 equiv) of the fluoride salt, unexpected changes
in the 1H NMR spectrum were observed (Fig. 4b). There was no evi-
dence for both ligand deprotonation and fluoride complexation via
hydrogen bond formation under the measurement conditions. The
N–H protons were not observed and four doublets and one broad
singlet were apparent in the aromatic region. The aliphatic CH2
protons were shifted downfield slightly. These spectral changes
suggest that fluoride promotes amide bond cleavage, as a result
the 1H NMR spectra exhibit signals which can be attributed to 1-
(4-nitrophenyl)-pyrrolidine-2,5-dione (1a) and 4-nitroaniline (1b)
(Fig. 5).
These observations were supported by UV–vis absorption spec-
tra. Upon titration with TBAF the increase in the absorption band at
about 400 nm might be connected with increasing p-nitroaniline
concentration (see Fig. 3a), whereas the band in the region below
300 nm can be attributed to 1-(4-nitrophenyl)-pyrrolidine-2,5-
dione (1a). For comparison, UV–vis and 1H NMR spectra (DMSO)
of (1a) and p-nitroaniline (1b) are shown in Figures S4 and S5,
respectively (see Supplementary data). Upon addition, for example

E. Wagner-Wysiecka, N. Łukasik / Tetrahedron Letters 53 (2012) 6029–6034
6033
F,F'
C
C
O
O
N
F-
I,I'
H2N
C,C'
H'
E
E'
D'
O
O
G'
NO2
C
C
D
A
A
+
H
NH HN
B
B
G
NO2
1b
1a
A'
A'
NO2
O2N
L,L'
B'
B'
O
O
1
C
N
C
N
excess F-
K
K
J
J
K'
K'
NO2
O2N
J'
J'
1c
Figure 5. Proposed mechanism for the succinic acid diamide-fluoride interaction in DMSO.
1 equiv of TBAF (Fig. 4c) a signal at 16.2 ppm (t, J = 119 Hz) ap-
peared, which pointed to HFꢁ2 anion formation. Moreover, the aro-
matic and aliphatic CH2 signals were shifted upfield compared to
the free ligand. Such spectral changes imply the presence of succi-
1-fluoride interaction is proposed as shown in Figure 5. For com-
parison, TBAF-mediated imide formation (e.g., aspartimide) as a
side product was found to occur during solid-phase peptide
synthesis.14
To establish the influence of the solvent on the anion binding
strength, studies were conducted in acetonitrile. Due to the low
solubilities of 1–3 in this solvent, measurements were carried out
on pimelic acid diamide 4. Changes in the absorption spectra were
observed both for fluorides and for dihydrogen phosphates. These
changes upon titration of 4 with TBAF and the molar ratio plot
nic acid diamide in its deprotonated form (1c, Fig. 5) under the 1
H
NMR measurement conditions. In the presence of excess TBAOH
the 1H NMR spectrum signals only indicate the presence of the
deprotonated form. Smaller amounts of base promoted proposed
reaction in yields not exceeding 10%. On the basis of UV–vis and
1H NMR measurements the most probable mechanism for the
(a)
(b)
1.0
1.0
0.8
0.6
0.4
0.2
0.0
0.8
0.6
0.4
0.2
0.0
300
350
400
300
350
400
wavelength [nm]
wavelength [nm]
0.40
(c)
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.0
0.2
0.4
0.6
0.8
1.0
cF/cL
Figure 6. Changes in absorption spectra upon titration of 4 (4.43 ꢀ 10ꢁ5 M) with: (a) TBAF (0–3.91 ꢀ 10ꢁ5 M); (b) TBADHP (0–1.01 ꢀ 10ꢁ4 M); (c) molar ratio plot for the 4-Fꢁ
system in acetonitrile.

6034
E. Wagner-Wysiecka, N. Łukasik / Tetrahedron Letters 53 (2012) 6029–6034
are shown in Figures 6a and 6c. Figure 6b shows titration traces for
dihydrogen phosphates in acetonitrile.
Supplementary data
From the titration experiments the stoichiometries of the
formed complexes and values of the respective stability constants
were estimated using the OPIUM13 program. For small spherical
fluorides the best fit, in agreement with the molar ratio plot, was
obtained for a 2:1 (L:F) complex. For larger, tetrahedral dihydrogen
phosphates, 1:1 complex stoichiometry was found. The obtained
values of the stability constants (logK) for pimelic acid diamide
complexes are: 9.96 0.67 and 2.85 0.10 for fluorides and dihy-
drogen phosphates, respectively. The change of dipolar aprotic
non-HBD (non-Hydrogen Bond Donor) DMSO for less polar aceto-
nitrile, had a beneficial influence on anion complexation. Fluorides
in acetonitrile are not as basic as in DMSO, thus ligand deprotona-
tion does not occur under the titration conditions. Additionally, the
stability constant with dihydrogen phosphates in acetonitrile was
0.15 (logK) larger than in DMSO.
In conclusion, microwave stimulated reactions, though not
spectacularly yielding, may be used as an alternative, simple, and
more environmentally friendly method for aliphatic acid aromatic
diamide preparation. The short reaction times and less toxic sub-
strates are advantages of the proposed method. The unique behav-
ior of succinic acid diamide in the presence fluorides, after more
exhaustive studies (also in a water-containing system), might be
the basis of a simple, non-expensive fluoride detection and quanti-
tation method.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.103.
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Acknowledgments
E.W.-W. kindly acknowledges support from sources for science
in years 2010-2011, Grant No. N N204 137438. The authors also
thank Professors Jan F. Biernat and Elzbieta Luboch for valuable
_
discussions.