Zirconium(IV)-catalyzed one-pot synthesis and oxidation of bis- and tris(indolyl)methanes into conjugated chromophores as new pH indicators or calorimetric chemosensors for transition metals

Article abstract of DOI:10.1016/j.tetlet.2014.05.028

Zirconium(IV) oxynitrate hydrate catalyzed efficiently the condensation reactions of indoles and aldehydes in acetonitrile, under ambient conditions. The bis- or tris(indolyl)methane products were then dehydrogenated in one pot by using a stoichiometric amount of DDQ, to give conjugated chromophores that showed feasible applications as new pH indicators with excellent sensitivity in the pH range 8-10. Hypsochromic effects were observed in the presence of transition metal cations in acetonitrile with a significant color change for cobalt(II).

Full text of DOI:10.1016/j.tetlet.2014.05.028

Accepted Manuscript
Zirconium(IV)-catalyzed one-pot synthesis and oxidation of bis- and tris(indol-
yl)methanes into conjugated chromophores as new pH indicators or calorimetric
chemosensors for transition metals
Alireza Khorshidi, Neda Mardazad, Zahra Shaabanzadeh
PII:
S0040-4039(14)00817-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.028
TETL 44619
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 January 2014
19 April 2014
7 May 2014
Please cite this article as: Khorshidi, A., Mardazad, N., Shaabanzadeh, Z., Zirconium(IV)-catalyzed one-pot
synthesis and oxidation of bis- and tris(indolyl)methanes into conjugated chromophores as new pH indicators or
calorimetric chemosensors for transition metals, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.05.028
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1
Zirconium(IV)-catalyzed one-pot synthesis and
oxidation of bis- and tris(indolyl)methanes into
conjugated chromophores as new pH indicators or
calorimetric chemosensors for transition metals
Alireza Khorshidi*, Neda Mardazad, Zahra Shaabanzadeh
1

2
3
Zirconium(IV)-catalyzed one-pot synthesis and oxidation of bis- and
tris(indolyl)methanes into conjugated chromophores as new pH indicators or
calorimetric chemosensors for transition metals
4
5
6
7
8
Alireza Khorshidi*, Neda Mardazad, Zahra Shaabanzadeh
Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box: 41335-1914, Rasht, Iran.
9
Abstract
10 Zirconium(IV) oxynitrate hydrate catalyzed efficiently the condensation reactions of indoles and
11 aldehydes in acetonitrile, under ambient conditions. The bis- or tris(indolyl)methane products were
12 then dehydrogenated in one pot by using a stoichiometric amount of DDQ, to give conjugated
13 chromophores that showed feasible applications as new pH indicators with excellent sensitivity in
14 the pH range 8-10. Hypsochromic effects were observed in the presence of transition metal cations
15 in acetonitrile with a significant color change for cobalt(II).
16 Keywords: Zirconium(IV) oxynitrate hydrate; Chromophore; Dehydrogenation; pH indicator;
17 (indolyl)methane
18
19 Numerous indole derivatives occur in many pharmacologically and biologically active compounds.1
20 In particular, bis(indolyl)methanes possess a wide range of biological activity and their synthesis
21 has received a considerable amount of interest.2,3 Generally, bis(indolyl)methanes are prepared by
* Corresponding author. Tel: +98 911 339 7159, Fax: +98 131 322 0066
2
Email-address: khorshidi@guilan.ac.ir

22 the condensation of indoles with various aldehydes or ketones in the presence of either protic or
23 Lewis acids; many other methods have also been devised for their preparation.4 Little attention
24 however, has been paid to the dehydrogenation of bis- or tris(indolyl)methanes. Contributions in this
25 context include a few examples and their application mainly as anion receptors.5-8 Our interest in the
26 study of indole-type molecules, their derivatives, and the catalytic activity of transition metal
27 species in the synthesis of these compounds,9-13 prompted us to evaluate the synthesis of bis- and
28 tris(indolyl)methanes, the oxidation of the meso hydrogen, and the study of the spectroscopic and
29 chromogenic behavior of the products at different pH values and toward various transition metal
30 cations.
31
32 During our previous work on the preparation of bis- and tris(indolyl)methanes,9 we noticed that
33 during the purification step, the products were unstable on chromatographic silica gel plates and
34 their color changed slightly. This observation was attributed to the possible oxidation of the
35 products on exposure to air. Therefore, we were decided to investigate the oxidation of the aliphatic
36 C-H bond at the meso position of bis- or tris(indolyl)methanes. With a one-pot procedure in mind,
37 2-methylindole and 3-phenoxybenzaldehyde were selected as substrates, and the reaction conditions
38 were optimized with respect to the oxidant, solvent and temperature. Since most bis- or
39 tris(indolyl)methanes are insoluble in alcohols such as methanol and ethanol, aprotic solvents were
40 considered, and the best solvent was found to be CH3CN (Table 1). The best catalyst in this solvent
41 was found to be zirconium(IV) oxynitrate hydrate with an optimum loading of 5 mol% (entry 3).
3

42 With respect to the oxidant, the best result was obtained by using 1.5 equivalents of 2,3-dichloro-
43 5,6-dicyano-1,4-benzoquinone (DDQ). Finally, it was found that employing elevated temperatures
44 had no significant effect on the yield of the target product.
45
<<Table 1>>
46 The optimized conditions for the one-pot synthesis and oxidation of bis- and tris(indolyl)methanes
47 are summarized in Scheme 1.
48
<<Scheme 1>>
49 With optimized conditions in hand, a variety of indoles and aldehydes were used in this reaction to
50 demonstrate the generality and scope of the process. Typical results are shown in Table 2.
51
<<Table 2>>
52 Indoles and aldehydes bearing different functional groups yielded the desired products. To the best
53 of our knowledge, this is the first report on the one-pot application of zirconium(IV) oxynitrate
54 hydrate in the condensation reaction of indoles with aldehydes and subsequent oxidation of the
55 products with DDQ. Oxidation of the aliphatic C-H bond at the meso position of bis- and
56 tris(indolyl)methanes is associated with deep color changes due to the formation of a highly
57 conjugated chromophore system. Thus we can propose products 4a-j as potential dye molecules.
1
58 The structures of the products were established from their spectra (FTIR, H-NMR and 13C-NMR).
59 Generally, the bis- and tris(indolyl)methanes exhibited a singlet for the aliphatic C-H proton (meso
60 position) at about 5.5-6.0 ppm,9 which disappeared upon oxidation. Since all of the products were
61 soluble in DMSO-d6, the broad singlets for the NH protons were diminished due to exchange with
4

62 residual water present in DMSO. Intermolecular hydrogen bonding may be responsible for the
63 reduced intensity of the NH stretching vibrations in the FTIR spectra. The presence of both an anion
64 receptor subunit5 (NH) and a cation receptor moiety (N) prompted us to evaluate the behavior of the
65 products as potential pH indicators. Many dyes have been used as pH indicators due to the
66 reversible action of acids and bases. It was found that our products could act as pH indicators in the
67 range 9.0-10.5 with an extremely sharp and clear color change. For example, the color transition
68 along with the conjugated acid-base structures of compound 4d, are depicted in Figure 1.
69
<<Figure 1>>
70 A dilute solution of 4d (5×10-6 M, EtOH 70%), appeared red in color and displayed strong
71 absorption bands at 400 and 550 nm, which may be attributable to the intramolecular charge transfer
72 (ICT) arising from the π-extended conjugated structure of this compound, according to Shao et al.5
73 Upon addition of dilute acid (0.1 M HCl) or alkali (0.1 M NH4OH) to this solution, however, color
74 changes were observed. Figure 2 shows the spectroscopic behavior of 4d at different pH values.
75 While decreasing the pH only increased the intensities of the above mentioned bands, increasing the
76 pH resulted in the disappearance of these bands and the appearance of a new band at 450 nm.
77
<<Figure 2>>
78 To determine the color transition range of the indicator, the absorption was measured at 450 nm
79 with addition of dilute alkali solution (NH4OH). The result is shown in Figure 3. As is apparent, a
80 sharp color transition was observed in the pH range of 8.0 to 10.0, which is comparable to thymol
81 blue and phenolphthalein.14
5

82
<<Figure 3>>
83 Encouraged by these results, we decided to study the ability of our products sense transition metal
84 cations. It was found that these conjugated chromophores interact with transition metal cations and
85 exhibit spectral changes. For example, compound 4d exhibited hypsochromic effects in the presence
86 of M2+ transition metal cations (where M=Ni, Co, Mn and Hg). The most intense color change was
87 observed for Co2+ in acetonitrile solution. The UV-Vis spectrum of 4d (5×10-6 M) and Co2+
88 (1.25×10-4 M) solutions in CH3CN, before and after mixing, are shown in Figure 4. An excess
89 amount of Co2+ (25 equivalents) was selected to ensure maximum interaction.
90
<<Figure 4>>
91 As is shown in Figure 4, Co2+ shows classic transitions of a d7 cation in an octahedral field
92 corresponding to transitions from the 4T1g(F) ground state to the 4T1g(P), 4A2g and 4T2g excited states
93 of the metal cation. After mixing 4d and Co2+ solutions, a blue shift of about 30 nm for the 414 nm
94 band of 4d was observed that might be due to N-bonding of 4d to the metal center.
95 The spectral responses of 4d to other M2+ transition metal cations (where M=Ni, Co, Mn and Hg)
96 are depicted in Figure 5.
97
<<Figure 5>>
98 In order to gain insight into the interaction mechanism between the cation and the receptors, a
99 similar experiment with Co2+ was conducted in acetonitrile at acidic pH (pH=2.0). In this case, the
100
101
blue-shifted band was not observed upon addition of the metal, revealing that no interaction took
place, due to the fact that the indol-3-ylidene moiety of 4d was N-protonated. A 4:1 stoichiometry
6

102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
of the complex as indicated by the changes in the colorimetric response of 4d, in the presence of the
varying concentrations of Co2+ (Figure 6), is also in agreement with N-coordination of the metal.
<<Figure 6>>
In conclusion, the efficient one-pot formation and dehydrogenation of bis- and tris(indolyl)methanes
catalyzed by zirconium(IV) oxynitrate hydrate as a homogeneous catalyst and DDQ as the oxidant
has been described. The products showed applications as pH indicators with excellent sensitivity.
The UV-Vis spectroscopy analyses of mixtures of these conjugated structures with various
transition metal cations revealed that these conjugated compounds can be utilized as effective
chromophores for sensing these cations. We are currently undertaking further studies on the
conjugated structures shown in this work as well as similar systems.
General procedure for the preparation of 4a-j
Indole 1 (2.00 mmol), ZrO(NO3)2.H2O (12.46 mg, 0.05 mmol), aldehyde 2 (1.05 mmol) and MeCN
(5 mL) were added to a flask and the resulting mixture stirred at room temperature until the
disappearance of the starting indole was complete (monitored by TLC). This step typically took
between 3 to 10 min. After completion of the first step, a solution of DDQ (1.5 equiv.) in MeCN
was added dropwise over 10 min. Upon addition of the oxidant, the color of the solution turned deep
red. After completion of the oxidation step (see Table 2, indicated by TLC), the mixture was
purified by short column chromatography (n-hexane/EtOAc, 10:4) to provide the desired products.
2-Methoxy-4-[(2-methyl-1H-indol-3-yl)(2-methyl-3H-indol-3-ylidene)methyl]phenol (4a):
7

122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
Dark red solid, m.p. 259-261 oC, IR (KBr): υ (cm-1); 3408, 1483, 1371, 1346, 1226, 1120, 746. 1H
NMR (400 MHz, DMSO-d6, 25 oC): δ = 2.07 (s, 6H, CH3), 3.46 (s, 3H, -OCH3), 6.30 (d, 1H, J = 9.6
Hz), 6.63 (s, 1H), 6.71-6.87 (m, 4H), 7.05 (t, 2H, J = 7.2 Hz), 7.21 (d, 1H, J = 8.8 Hz), 7.38 (d, 2H,
J= 7.8 Hz), 11.9 (bs, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6, 25 oC): δ = 13.0, 54.4, 111.4,
112.5, 118.8, 120.3, 121.6, 124.2, 124.8, 128.5, 131.0, 135.9, 137.2, 141.0, 148.8, 151.8. Anal.
Calcd. for C26H22N2O2; C, 79.16; H, 5.62; N, 7.10; found: C, 79.15; H, 5.65; N, 7.14.
Acknowledgements
Partial support of this study by the Research Council of the University of Guilan is gratefully
acknowledged.
References
1. Sundberg, R. J.; Indoles; Academic Press: London, 1996.
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Prod. 2000, 63, 596.
3. Porter, J. K.; Bacon, C. W.; Robins, J. D.; Himmelsblach, D. S.; Higman, H. C. J. Agric.
Food Chem.1977, 25, 88.
4. Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Chem. Rev. 2010, 110 , 2250.
5. He, X.; Hu, S.; Liu, K.; Guo, Y.; Xu, J.; Shao, S. Org. Lett. 2006, 8, 333.
6. Wang, L.; He, X.; Guo, Y.; Xu, J.; Shao, S. Org. Biomol. Chem. 2011, 9, 752.
7. Martinez, R.; Epinosa, A.; Tarraga, A.; Molina, P. Tetrahedron 2008, 64, 2184.
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144
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153
8. Silveira, C. C.; Mendes, S. R.; Villetti, M. A.; Back, D. F.; Kaufman, T. S. Green Chem.
2012, 14, 2912.
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10. Khorshidi, A. Chin. Chem. Lett. 2012, 23, 903.
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12. Khorshidi, A. Ultrason. Sonochem. 2012, 19,570.
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14. Hunger, K. In Industrial Dyes: Chemistry, Properties and Applications. Wiley-VCH: 2002;
526-537.
9

154
155
Table 1. The effect of experimental parameters on the one-pot condensation and oxidation reaction
between 2-methylindole and 3-phenoxybenzaldehyde a
Entry
Catalyst
Loading
Temp (oC)
Solvent
Oxidant
Yield
(%)
0
(mol%)
1
2
3
4
5
6
7
8
9
None
Cu2+
-
RT
RT
RT
RT
RT
RT
RT
RT
50
CH3CN
CH3CN
CH3CN
CH3CN
1,4-Dioxane
CH2Cl2
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
H2O2
O2
5
5
20
5
5
5
5
5
45
ZrO2+
I2
77
32
ZrO2+
ZrO2+
ZrO2+
ZrO2+
ZrO2+
38
<5
37
CH3CN
CH3CN
CH3CN
18
DDQ
73
156
157
a The reaction was carried out according to the general experimental procedure.
158
10

159
160
Table 2. ZrO(NO3)2.H2O-catalyzed formation of bis- and tris(indolyl)methanes, and their oxidation
to conjugated chromophores a
Dehydrogenated
Time (min),
Yield b (%)
160, 73
130, 65
120, 56
175, 77
210, 65
250, 47
150, 55
150, 42
150, 57
90, 43
Entry
Indole
Aldehyde
product
4a
1
2
2-methylindole
2-methylindole
2-methylindole
2-methylindole
2-methylindole
2-methylindole
2-methylindole
5-nitroindole
vanillin
3-nitrobenzaldehyde
3,4-dimethoxybenzaldehyde
3-phenoxybenzaldehyde
2-nitrobenzaldehyde
4-chlorobenzaldehyde
indole-3-carbaldehyde
indole-3-carbaldehyde
indole-3-carbaldehyde
indole-3-carbaldehyde
4b
4c
3
4
4d
4e
5
6
4f
7
4g
8
4h
4i
9
5-methoxyindole
5-bromoindole
10
4j
161
162
a All products were characterized by 1H NMR, 13C NMR and IR data. b Isolated yields.
11

163
164
Figure 1. pH indication using 4d
165
12

166
167
Figure 2. Spectral changes of 4d (5×10-6 M, EtOH 70%) at different pH values.
168
13

169
170
Figure 3. Effect of pH on the absorption intensity titration of 4d: λmax 450 nm.
171
14

172
173
Figure 4. UV-Vis spectra of 4d (5×10-6 M), Co2+ (1.25×10-4 M), and a 1:1 mixture of 4d and Co2+
174
175
solutions in acetonitrile.
15

176
177
Figure 5. The spectral responses of 4d to other M2+ transition metal cations (where M=Ni, Co, Mn
178
and Hg)
16

179
180
Figure 6. A Job plot for the complexation of 4d with Co2+ indicating the formation of a 4:1 complex
181
17

182
183
Scheme 1. One-pot synthesis and oxidation of bis- and tris(indolyl)methanes into π-conjugated
184
185
products
18