Evaluation of Substituent Effect in Z -Isomer Stability of Arylazo-1 H -3,5-dimethylpyrazoles: Interplay of Steric, Electronic Effects and Hydrogen Bonding

Article abstract of DOI:10.1021/acs.joc.7b02604

The electronic and steric effects of aryl substituents and the influence of hydrogen bonding in Z-isomer stability of phenylazopyrazole derivatives have been investigated. In this regard, 38 substituted phenylazopyrazole derivatives and 6 N-methyl phenyla

Full text of DOI:10.1021/acs.joc.7b02604

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Evaluation of Substituent Effect in Z-Isomer Stability
of Arylazo-1H-3,5-dimethylpyrazoles – Interplay of
Steric, Electronic Effects and Hydrogen Bonding
Sudha Devi, Mayank Saraswat, Surbhi Grewal, and Sugumar Venkataramani
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02604 • Publication Date (Web): 22 Mar 2018
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Evaluation of Substituent Effect in Z-Isomer Stability
of Arylazo-1H-3,5-dimethylpyrazoles – Interplay of
Steric, Electronic Effects and Hydrogen Bonding
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†
†
†
Sudha Devi , Mayank Saraswat , Surbhi Grewal , and Sugumar Venkataramani*
Department of Chemical Sciences, Indian Institute of Science Education and
Research Mohali,
Sector 81, Knowledge City, S.A.S. Nagar, Manauli - 140306, Punjab, India
E-mail: sugumarv@iisermohali.ac.in
Abstract: The electronic and steric effects of aryl substituents, and the influence of
hydrogen bonding in Z-isomer stability of phenylazopyrazole derivatives have been
investigated. In this regard, 38 substituted phenylazopyrazole derivatives and six N-
methyl phenylazopyrazole (with meta-substitutions) have been synthesized. Their
photoswitching behavior, photostationary states (PSS) and kinetics of thermal reverse
isomerization were evaluated experimentally using UV-Vis and NMR spectroscopic
techniques. Furthermore, density functional theory (DFT) computations have been
performed for more detailed insights. Despite the presence of substantial substituent
effects inferred through Taft and Hammett relationships, concentration dependency in
controlling the isomerization rates has also been observed. Kinetics studies at
different concentration, solvent effects and computations have confirmed the decisive
role of hydrogen bonding and solvent assisted tautomerism in this regard. Through
this study, a complex interplay of steric, electronic effects and hydrogen bonding as
factors in dictating the stability of Z-isomers in arylazo-1H-3,5-dimethylpyrazoles has
been
demonstrated.
Keywords: Phenylazopyrazole, Photoswitching, Isomerization, Substituent effects
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Introduction
Light driven processes are very attractive in the development of variety of
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applications such as molecular machines, data storage, molecular recognition,
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artificial ion channels, sensors and catalysis etc. Azobenzenes are one of the very
important classes of photoswitchable molecules that show light induced reversible
7
switching between E- (thermodynamically stable state) and Z-isomers. Despite the
8
fact that azobenzenes are well known for more than hundred years, the interest in it is
not subsided at all. The main reason is the potential applications of them in key areas
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such as material chemistry, biochemical applications and medicinal chemistry etc.
All such applications completely rely on the photoswitching behavior (forward E-Z,
and the reverse Z-E isomerization processes) and the thermal stability of Z-isomer.
Various mechanisms such as rotation, inversion, concerted-inversion, or inversion-
assisted rotation with inversion have been proposed for the photochemical
isomerization.12 On the other hand, under thermal conditions, the reverse
isomerization happens either through the inversion mechanism, or through rotation
mechanism.13
The salient features of azobenzene as photoswitchable molecules are
robustness in switching, rate of E-Z forward switching, extent of photostationary state
(PSS) and thermal half-life of Z-isomer. Based on the gap between * and n*
transitions of azo group, azoarenes have been classified as azobenzenes (well-
separated), aminoazobenzenes (overlapping), and pseudo-stilbenes (nearly
14
degenerate). Such classifications are mainly due to the type of substitutions that can
dictate the switching ability as well as the stability of Z-isomer. Furthermore, the
choice and the introduction of specific substituents such as fluoro and alkoxy at all the
four ortho positions with respect to azo group can lead to visible light induced
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isomerization in azoarenes.15 Hence, position of the substituent in the aryl ring is
equally important in controlling the photoswitching characteristics. For variety of
applications, all these properties need to be altered. Replacing arenes with
heterocycles is an alternative strategy, which is an emerging area in this regard.
Pyridine containing heteroazoarenes are one of the well-known photoswitches that
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have found many interesting applications. Despite the presence of many literature
on the analogous five-membered heteroazoarenes, the studies on them have been
17
limited to synthesis and evaluation of medicinal properties in the past. However,
such systems found a considerable attention only after their photoswitching properties
have been evaluated. Herges and coworkers have synthesized an imidazole-connected
18
azoarene, which had a long half-life in its Z-form. Fuchter and coworkers enhanced
the stability of Z-isomer upto 1000 days, when they introduced N-methyl pyrazole
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moiety. After these findings, many groups started utilizing them for various light-
driven processes and as photoswitches.20
Fuchter’s group has explored the effects of N-methylated five-membered
21
heterocycles towards tuning the photoswitching behavior. Using experimental rate
constants and computational data, they investigated the influence of heterocycles on
the stability of Z-isomer. Recently, Kꢀnig and coworkers have tuned the lifetimes of
Z-isomer of phenylazoindoles from nanoseconds to days by controlling the hydrazone
tautomerization.13f Despite the presence of enormous literature on azoarenes and their
derivatives, including their mechanistic studies, the general role of substituents in the
photoswitching is not explored in a systematic way. Few issues like the choice of
substituents in enhancing the Z-isomer stability and the role of electronic effects in
photoswitching behavior and reverse isomerization can be vital in design and
development of azoarene based molecular switches. In order to address these issues,
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we have chosen phenylazopyrazole 1d as our target, which structurally lacks the N-
methyl group (1e) that was previously reported by Fuchter and co-workers.19 The
advantages of this choice are the ease of synthetic access to variety of substituted
derivatives, and also the possibility of post-functionalization at pyrazole N-H. Apart
from that, the kinetic studies on such NH phenylazopyrazole 1d showed almost three
order of magnitude higher rate constant than that of 1e, which provide a better
opportunity to study the enormous insights into the role of substituents. In this regard,
the modus operandi of substituents, particularly with respect to the photoswitching
behavior, stability of Z-isomer, and their influence in the thermal reverse switching of
the Z-isomer, which are the primary focus of this investigation.
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We utilized a common strategy to synthesize various substituted pyrazole
based azoarenes in good to excellent yields. The influence of position (ortho-, meta-
and para-) and nature (electron donating vs electron withdrawing) of the substituents
have been investigated. Also, the role of substituents in photoswitching behavior,
thermal reverse isomerization kinetics, and half-lives of the Z-isomers has been
studied using UV-Vis and NMR spectroscopic techniques. Additionally,
computational studies have been carried out in order to get deeper insights and
rationalization of these results. Herein, we report the synthesis of wide range of
pyrazole based substituted azoarenes, their photoswitching properties and
computational studies in understanding the effects of electronic, steric and hydrogen
bonding.
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Results and Discussion
A. Synthesis:
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Scheme 1. Synthesis of substituted phenylazopyrazoles 1-38d and selected N-methyl
phenylazopyrazoles [R = H(1e); 3-F(3e); 3-Cl(6e); 3-Br(9e); 3-OCH (15e); 3-
CF (18e)]
3
3
A two-step strategy has been adopted to prepare the desired 1H-3,5-
dimethylpyrazole connected azoarene derivatives. The first and foremost step is to
22
synthesize the arylazoacetylacetone derivatives (1c-38c). These derivatives can be
accessible through the diazotization of readily available aryl amines, followed by the
treatment with acetylacetone (Scheme 1 and Table S1 in SI). The yields are
particularly high when aqueous sodium acetate has been used along with
acetylacetone. On reacting the isolated 1c-38c with hydrazine led to the target
pyrazole based substituted heteroazoarene derivatives (1d-38d). Additionally, N-
methylation has been performed at the pyrazole NH using KOH as a base and CH I
3
on a set of pyrazole derivatives 1d, 3d, 6d, 9d, 15d and 18d. This led to synthesis of
the corresponding N-methylated pyrazole connected azoarenes with different meta-
substitutions 1e, 3e, 6e, 9e, 15e and 18e.
B. Analysis of photoswitching through UV-Vis and NMR spectroscopic
techniques:
Traditionally UV-Vis spectroscopic studies play a very important role in
understanding the E-Z isomerization of azobenzenes. This is because of the
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distinguishable spectral features for E- and Z-isomers, arising due to drastic changes
in the electronic structure. In order to understand the effects of substituents on their
electronic spectra, the spectral data of the E- and Z-isomers of phenylazopyrazole
derivatives 1-38d have been compared. For comparison, all the photoswitching and
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kinetics experiments have been carried out in acetonitrile, and at a temperature of 25
o
±
1 C in order to minimize the errors due to external parameters. Electronic
spectroscopic parameters such as max and molar extinction coefficient () have been
obtained for all the E- and Z- isomers in this regard (Figure 1, 2, Table 1 and Table
S2 in SI). Upon irradiation at a wavelength of 365 nm, almost all of the derivatives
exhibited E to Z isomerization. The data on the shifts in the max corresponding to

* and n* absorptions of Z-isomers have been included in the table S2 in SI. The
values of * and n* transitions of Z-isomers have been estimated based on the

PSS composition and its corresponding absorption values.23 The plots on the
absorption maxima vs  of the individual * transitions of E- and Z-isomers show
that only the former is sensitive to the electronic effects (Figure 1a and 1b). Due to
the breaking of conjugation, the azo group in Z-isomers is less sensitive to the
electronic influence, and so majority of the substituted Z-arylazopyrazoles exhibit
similar * absorption properties. However, there is a reasonable steric influence,
which can be understood from the deviation for those derivatives having ortho
substituents in the phenyl ring with respect to the parent 1d. On the other hand, both
E- and Z-isomers show more deviation in the n* absorption properties (Figure 1c
and 1d) that can be attributed to the electronic effects of substituents on the azo
nitrogen.
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Figure 1. Effect of substituents in the absorption properties of E- and Z-isomers of the
substituted phenylazopyrazoles: (a) and (b) corresponding to * absorptions for E-
and Z-isomers, respectively; (c) and (d) corresponding to n* absorptions for E- and
Z-isomers, respectively. (The absorption variation and max shifts are separated into
four quadrants with respect to the absorbance and max of parent 1d as origin.)
Few derivatives such as 2-hydroxy 11d and 4-hydroxy phenylazopyrazole 13d
derivatives exhibit minimal spectral changes albeit a small to substantial decrease in
their intensities. Interestingly, the spectral features of 11d with two split-up bands in
the * region resemble that of 2-hydroxyazobenzene. The intramolecular hydrogen
bonding and/or solvent assisted tautomerization leading to the hydrazone form may be
the plausible reason for this behavior.14 Simillarly 2-nitro 20d and 4-nitro
phenylazopyrazole 22d also showed a little change in the spectra after irradiation.
Presumably, both of them behave like a push-pull type azobenzene, for which the
switching rates are expected to be fast. Furthermore, the 3-nitro phenylazopyrazole
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1d also showed a very high reverse isomerization (Z-E) rate. The reasons for this
non-switching nature of 20d and 22d can be attributed to resonance, whereas
inductive effects of the nitro group influence a fast reverse switching in 21d that
renders a push-pull type mechanism. The plausible tautomers and resonance
structures governing this behavior of 11d, 13d, 20d and 22d are indicated. (for details
see SI Scheme S2)
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Figure 2. Representative figure on photoswitching in phenylazopyrazole derivative
1
d: (a) Analysis of photoswitching of 1d in DMSO using UV-Vis spectroscopy
(Spectral trace in blue – (E)-1d; red – after 365 nm irradiation to attain PSS); (b)
Reversible photoisomerization of 1d; (c) First order kinetics trace corresponding to
the thermal reverse Z-E isomerization of 1d (using NMR spectroscopy); NMR
spectrum of (E)-1d in DMSO-d (d) before irradiation, and (e) after irradiation at 365
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Table 1. UV-Vis spectroscopic data of E- and Z-isomers of arylazopyrazole
derivatives (1d-38d)
E-isomera
Z-isomera
[
M]
kd, min-1
R=
mol.
-
1
L
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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3
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7
8
9
1d
2d
3d
4d
5d
6d
7d
8d
9d
10d
H
330 (19369 ± 278)
334 (23807 ± 862)
334 (25338 ± 2314)
330 (19853 ± 278)
339 (34674 ± 681)
336 (32797 ± 278)
336 (29398 ± 1823)
340 (23530 ± 1509)
335 (20818 ± 1147)
337 (21721 ± 1530)
421 (1199 ± 57)
85
90
87
85
84
80
90
88
86
92
293
287
292
293
292
290
295
289
296
293
436
442
437
436
432
418
439
431
437
440
77
75
74
96
86
77
94
72
73
72
1.31 x 10-3 ± 5.99 x 10-6
37
29
29
27
21
19
23
22
24
31
2.73 x 10-3 ± 9.48 x 10-6
2-F
418 (910 ± 108)
417 (1129 ± 116)
426 (1532 ± 26)
426 (1641 ± 125)
418 (3694 ± 185)
430 (2397 ± 106)
424 (1383 ± 83)
416 (1293 ± 34)
416 (1355 ± 52)
3-F
1.85 x 10-3 ± 2.35 x 10-5
1.62 x 10-3 ± 1.24 x 10-5
4.03 x 10-3 ± 1.58 x 10-5
4-F
2-Cl
3-Cl
4-Cl
2-Br
3-Br
4-Br
1.14 x 10-2 ± 7.89 x 10-5
1.67 x 10-3 ± 3.04 x 10-5
4.29 x 10-3 ± 1.13 x 10-5
5.87 x 10-2 ± 4.82 x 10-4
1.79 x 10-3 ± 5.39 x 10-6
1
0
1
2
1
1
11d
2-OH**
332 (17638)
366 (16042)
-
-
-
-
-
39
12d
13d
14d
15d
16d
17d
18d
19d
20d
21d
22d
23d
24d
25d
3-OH
330 (16678 ± 1556)
412 (1179 ± 52)
400 (1433)
86
-
292
-
437
-
69
2.88 x 10-3 ± 1.96 x 10-5
38
39
31
24
13
4-OH***
342 (16786)
-
3.28 x 10-1 ± 7.12 x 10-3
1
1
1
1
4
5
6
7
2-CF
3
335 (19703 ± 1221)
332 (22045 ± 392)
334 (22010 ± 858)
350 (13044 ± 338)
330 (21893 ± 364)
342 (33110 ± 1817)
339 (32724)
428 (1122 ± 26)
419 (1320 ± 84)
392 (1578 ± 53)
421 (1483 ± 42)
419 (1605 ± 3)
403 (2293 ± 68)
-
41
83
79
92
85
92
327
294
297
294
292
301
-
437
436
436
430
437
441
-
87
86
80
56
65
68
-
3-CF
3
2.65 x 10-3 ± 9.46 x 10-6
2.96 x 10-2 ± 1.15 x 10-4
1.04 x 10-3 ± 1.72 x 10-5
4-CF
3
29
45
24
16
41
37
33
18
30
31
2-OMe
3-OMe
4-OMe
18
2.97 x 10-3 ± 2.00 x 10-5
1.20 x 10-3 ± 1.22 x 10-5
1
2
2
2
9
0
1
2
2-NO
3-NO
4-NO
2
***
**, e
***
-
1.04 x 10-3 ± 1.72 x 10-5
-
2
332 (17420 ± 630)
360 (29247)
421 (897)
24
-
426
-
91
-
2
-
-
23
2-CH
3-CH
4-CH
3
336 (34578 ± 3434)
331 (18375 ± 1608)
335 (16747 ± 2099)
423 (2914 ± 197)
419 (1046 ± 35)
416 (1262 ± 18)
92
88
90
292
292
295
435
441
437
80
61
73
6.92 x 10-3 ± 1.16 x 10-5
1.99 x 10-3 ± 1.15 x 10-5
2
2
2
4
5
6
3
1.45 x 10-3 ± 3.24 x 10-6
3.04 x 10-2 ± 6.50 x 10-5
4.41 x 10-2 ± 1.22 x 10-4
3
26d
27d
28d
29d
30d
31d
3-CO
4-CO
2
2
H
H
332 (19329 ± 235)
342 (15675 ± 967)
329 (16296 ± 858)
350 (19166 ± 886)
337 (20424 ± 1608)
324 (18479 ± 881)
419 (1045 ± 15)
410 (1002 ± 66)
423 (1024 ± 72)
410 (2382 ± 46)
425 (1096 ± 57)
431 (950 ± 125)
81
83
86
91
92
79
295
300
285
303
293
288
435
441
438
445
436
429
65
81
78
68
74
77
27
38
34
36
29
26
27
28
3-NHAc
4-NHAc
2-Et
5.44 x 10-2 ± 1.43 x 10-4
1.44 x 10-3 ± 4.99 x 10-6
2
3
3
3
9
0
1
2
1.30 x 10-2 ± 1.08 x 10-5
3.62 x 10-3 ± 5.46 x 10-6
4.35 x 10-3 ± 3.69 x 10-6
2,4,6-triMe
32d
33d
34d
35d
36d
Ar = α-Np
2,5-diCl
2,6-diCl
2,4-diF
366 (18852 ± 882)
346 (19153 ± 419)
307 (12943 ± 732)
336 (14567 ± 635)
343 (21844 ± 1048)
-
89
92
33
85
66
307
294
298
292
300
446
432
421
427
429
72
68
92
69
77
32
30
44
36
26
33
425 (1140 ± 43)
423 (609 ± 38)
418 (1442 ± 34)
428 (1653 ± 35)
4.45 x 10-2 ± 3.23 x 10-5
1.89 x 10-3 ± 2.52 x 10-5
3
3
3
4
5
6
3.26 x 10-3 ± 9.69 x 10-6
2.83 x 10-1 ± 2.31 x 10-3
2,5-diF
37
37d
38d
2,6-diF
3,5-diF
321 (20491 ± 559)
334 (22857 ± 1168)
418 (1482 ± 37)
426 (1069 ± 63)
62
56
299
294
421
433
81
84
6.46 x 10-3 ± 1.21 x 10-5
8.27 x 10-2 ± 3.77 x 10-4
26
23
3
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2
2
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2
2
2
2
2
2
3
3
3
3
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4
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5
5
5
5
5
5
5
6
a
-1
-1
b
The values of max are given in nm and in L.mol .cm ; PSS for E-Z
2
3 c
isomerization has been estimated at 365 nm ; PSS for Z-E isomerization has been
2
3
d
estimated at white light (CFL lamp) irradiation with 2-5% uncertainty ; Rate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
e
o
constant in CH
3
CN at 25 ± 1 C; Kinetics has been measured in DMSO at 23 ± 1 C.
(
Ar = α-Np is α-naphthyl; (**Upon 365 nm irradiation, the absorptions showed a
decrease with the appearance of isosbestic points; ***For 4-OH derivative,
photoirradiation did not lead to any spectral change)
The photoswitching studies have also been carried out using NMR
2
4
spectroscopy. Both photoswitching and reverse thermal isomerization kinetics have
o
been studied in CD
3
CN at 25 C. In order to understand the influence of the
substituents in the structural features of the E- and Z-isomers, a closer inspection at
the NMR spectral analysis was carried out. Upon switching from E- to Z-isomer, the
ortho-protons of the aryl group, the two-methyl groups of the pyrazoles and also the
N-H protons exhibited major shifts towards shielding regions. In spite of showing
shifts upon isomerization from E to Z, the meta- and para-protons of the aryl group
are not considered in this analysis due to overlapping nature of the signals. The
changes in the chemical shift values () for all the substituents that we studied are
included (Table 2). The results showed that the ortho proton showed a larger upfield
shift when electron-withdrawing substituent is present either at ortho or meta position.
Also, the same effect is observed, when electron-donating power increases for the
substituent at the para position. Upon isomerization, the two-methyl groups showed
upfield shifts in the range between 0.67 and 0.72, except for 3,5-difluoro substituted
system that showed a shift of 0.62. This clearly indicates that the methyl groups of the
pyrazoles showed less perturbation upon isomerization due to the remote distance
from the position of substituents at the aryl ring. Also, their shifts further confirm that
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the role of steric factor, which is nearly equal in all the cases irrespective of the
position of the substituents. Similarly, N-H protons also showed only a negligible
effect in the chemical shift values upon varying the substituents. The same trend was
observed in the case of N-methylated derivatives as well. For all these molecules, Z-E
reverse isomerization kinetics have been followed and the rates have been tabulated
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Table S6 in SI). However, we found that the rates are quite different from the UV-
Vis kinetics experiments, which can be attributed to electronic and steric effects apart
from the difference in the concentration and the reasons are explained in the section-D
and E.
Table 2. NMR spectroscopic data of the selected protons of E- and Z-isomers of
different substituted phenylazopyrazoles and N-methyl phenylazopyrazoles
Aromatic regionb
N – H regionb
(Z)-
CH
3
regionb
(
ortho–H)
(
E)-

(E)-
(Z)-

(E)-
(Z)-

1
2
3
4
5
6
7
8
1d
2d
5d
14d
3d
6d
9d
15d
H
2-F
2-Cl
2-CF
3-F
3-Cl
3-Br
3-CF
3
89
85
81
69
85
89
77
92
10.83
10.88
10.88
10.93
10.88
10.88
10.89
10.90
10.66
10.71
10.72
10.85
10.69
10.70
10.73
10.71
0.17
0.17
0.16
0.08
0.19
0.18
0.16
0.19
2.49
2.49
2.51
2.49
2.49
2.49
2.49
2.50
1.77
1.81
1.83
1.79
1.81
1..81
1.81
1.78
1.81
0.72
0.68
0.68
0.70
0.68
0.68
0.68
0.72
0.68
7.77
7.72
7.69
7.83
7.63
7.72
7.76
8.02
7.38
7.39
7.81
7.76
7.67
7.91
7.00
6.94
6.66
6.70
6.84
6.95
6.99
7.21
6.59
0.77
0.78
1.03
1.13
0.79
0.77
0.77
0.81
0.79
0.84
0.73
0.74
0.72
0.74
3
2
3.85
.49
9
18d 3-OCH
3
63
10.76
10.63
0.13
c
c
c
d
d
d
3.72
0.13
0.68
0.68
0.68
0.71
0.67
6.55
10
4d
7d
10d
16d
4-F
4-Cl
4-Br
85
86
86
88
10.83
10.85
10.83
10.92
10.65
10.67
10.67
10.72
0.18
0.18
0.16
0.20
2.48
2.48
2.48
2.50
1.80
1.80
1.80
1.79
1.80
7.08
7.02
6.95
7.17
1
1
1
1
2
3
4-CF
3
2
.47
1
4
19d 4-OCH
3
62
10.71
10.59
0.12
7.76
6.89
0.87
c
c
c
3
.85
3.78
0.07
0.69
0.62
15 36d
16 38d
2,5-diF
3,5-diF
89
80
10.94
10.94
10.77
10.78
0.17
0.16
2.49
2.48
1.80
1.86
7.47
7.40
6.82
6.67
0.65
0.73
Aromatic regionb
N – H regionb
regionb
3
CH
(
ortho–H)
2
2
2
2
2.40
2.55
2
2
2.42
.41
.55
.41
.55
1.47
2.15
1.50
2.10
1.49
2.11
1.49
2.11
1.46
0.94
0.40
0.91
0.40
0.91
0.44
0.91
0.44
0.96
17
1e
3e
6e
H
26
35
45
3.73
3.60
3.61
3.62
0.13
0.12
0.11
7.76
7.63
7.72
7.02
0.74
0.77
0.76
1
1
8
9
3-F
3.73
3.73
6.86
6.96
3-Cl
3-Br
.40
.55
2
2
0
1
9e
51
62
3.73
3.74
3.62
3.61
0.11
0.13
7.76
8.05
6.99
7.41
0.77
0.64
15e
3-CF
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2
2.41
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.57
2.08
1.51
2.08
0.47
0.90
0.47
2
2
18e 3-OCH
3
76
3.73
3.60
0.13
7.38
6.60
0.78
a
b
E-Z conversion during photoisomerization using 365 nm at PSS; Chemical shift
c
d
values are in ppm; Bold = OMe protons; Two distinct ortho protons have been
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
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8
9
0
1
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9
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3
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7
8
9
0
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3
4
5
6
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8
9
0
observed (All the spectra have been recorded in CD CN at 298 K in 400 MHz NMR).
3
C. Computational Studies:
In order to understand the effects of the substituents in spectral
properties, photoswitching behavior and also the structural aspects, DFT
calculations have been performed. Attention was paid to those substituents, for
which both NMR and UV-Vis photoswitching studies have been performed. In
this regard, we have optimized the structures of both E- and Z-isomers of the
phenylazopyrazole derivatives to the minima. The energy relationship between
the HOMO, LUMO and HOMO-1, have been tabulated for various substitutions
(
Table S4 in SI). The closer inspection at the MOs of the E-isomer revealed that
the HOMO, LUMO and HOMO-1 can be attributed to , * and norbitals,
respectively (Figure 3a). On the other hand, the Z-isomer showed a change in
the order, where the HOMO and LUMO can be attributed to nand *-orbital,
respectively. However, the HOMO-1 showed a mixed character of n and

orbitals. In the case of E-isomers, the energy gaps corresponding to *
(HOMO – LUMO gap) and n* (HOMO-1 – LUMO gap) are found to be nearly
unperturbed upon meta-substitution, whereas, the para-substitutions led to a
reasonable effect in the energy gap. This is in line with our experimentally
observed spread of max corresponding to * and n* transitions, for which
the meta-substitution led to a smaller changes, whereas the para-substitutions
caused larger deviations in the shifts.
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2
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3
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3
3
3
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4
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0
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9
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0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. (a) Molecular orbitals corresponding to HOMO, LUMO and HOMO-1 of
E- and Z- isomers of 1d and 1e. The orbital energies (in eV) are indicated. (All the
orbitals and their corresponding energies are obtained at B3LYP/6-311G(d,p)
level of theory) (b) Computed inversion barrier for the thermal reverse
isomerization of 1d (The relative energies with respect to Z-isomer are given;
Bold – B3LYP/6-311G(d,p); Normal – M06-2X/6-311G(d,p); Italics – B3LYP/6-
311G(d,p) in CH CN, solvent model)
3
In the case of Z-isomers, computationally estimated energy gaps (HOMO –
LUMO gap and HOMO-1 – LUMO gap) showed more deviations for para
substitutions. This is once again reflected in the observed changes in the UV-Vis
absorption maxima of both * and n* transitions in the case of para-
substituted derivatives. However, except OCH group, rest of the substituents at
3
meta- position exhibited no deviation with respect to computational and the
experimental observations in this regard. The corresponding N-methyl
phenylazopyrazoles with meta- substitutions also showed less perturbation with
respect to the energy gaps of the orbitals.
Since the thermal reverse isomerization is depending on the geometries
of the Z-isomer, we tried to understand the molecular properties of them that
can influence the stability of Z-isomer and also the kinetics.21 In this regard,
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2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
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4
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5
6
various parameters such as dihedral angles, charges at the azo nitrogen and
bond orders have been compared for meta and para substituted Z-isomers
(Table S3 in SI). Indeed, attempts have been made to relate those individual
properties with the rate constants; however, in none of the cases we observed a
good correlation.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
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4
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8
9
0
Apart from the structural insights through computations, we have
estimated the thermal barriers and rate constants for the conversion of Z- to E-
isomer through inversion mechanism at the azo nitrogen.25 Since all the
derivatives utilized in this investigation are unsymmetrical azoarenes, there are
two possible inversion barriers. Among them, the inversion happens at the azo
nitrogen connected to the aryl group is found to be the minima in majority of the
cases (Figure 3b and Table S9 in SI). The only exception was observed in the
case of 4-OCH
3
substituted system, where the inversion at pyrazole ring
connected azo nitrogen was found to be the lower energy pathway. In all the
cases, the transition state was found to acquire a twisted geometry, due to the
presence of two methyl groups in the pyrazole. We considered both the
transition states and obtained weighted average barriers for estimating the rate
constants.26
D. Effects of substituents and hydrogen bonding in the stability of Z-
isomers:
The effects of substituents on the stability of Z-isomer have been studied
through thermal reverse isomerization kinetics using UV-Vis spectroscopy in
o
CH
3
CN at 25 ± 1 C. All the substituted phenylazopyrazole derivatives have been
switched from E- to Z-isomer using a light of wavelength 365 nm, followed by the
thermal reverse isomerization kinetics have been measured. The
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photoisomerization has been performed in such a way that maximum Z-isomer
conversion is observed or the irradiation is done until the establishment of
photostationary state (PSS). Upon the thermal reverse isomerization, the
exponential rate of formation of the E-isomer has been plotted at an absorbance
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

max corresponding to the * transition of the E-isomer. Using the first order
rate constant, the half-life of the Z-isomer has also been deduced. For
comparison, the kinetics experiments have been studied for the selected
substituents using NMR spectroscopy and also computations (Table S6 in SI).
For minimizing the solvent effects, the kinetics experiments have been done in
3
CD CN (for NMR) experiments and using acetonitrile as solvent model (for
computations). In the case of NMR studies, a CD
3
CN solution of E-isomer in a
quartz NMR tube has been irradiated at 365 nm to reach a PSS, subsequently the
formation of E-isomer has been followed. Using the integral ratios of identical
protons of both the isomers (often aromatic ortho protons, which are non-
overlapping), the growth rate of E-isomer has been estimated (Figure S3 of
supporting information).
For understanding the effects and influence of the substituents in the
stability of Z-isomer, a quantitative relationship of the involvement of steric and
electronic effects comprising resonance, field and inductive effects, respectively
in the reverse isomerization kinetics is necessary. In this regard, we have
27
28
considered the Taft (for ortho substitution) and Hammett (for meta and para
substitutions) relationships. For the ortho substituted derivatives, a Taft plot has
been plotted between the log(k
R
/kMe) vs the steric substituent constant (E ),
s
where k is the isomerization rate of the ortho substituted phenylazopyrazole
R
derivatives and kMe is the rate corresponding to the 2-CH derivative 23d
3
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(
Figure 4). The resulting plot showed a good correlation with a negative slope
indicating the influence of steric factors (arising from the ortho substitutions at
the phenyl ring) in the thermal reverse isomerization processes. This indicates
that the transition state possesses less steric repulsion relative to the
corresponding Z-isomer. Indeed, these results are in consistent with the earlier
reports on azoheteroarenes possessing ortho substituents, whose rates of
thermal isomerization were high.21 Due to this reason, for the NMR and
computational kinetics studies, we have considered only the electronic effects
and so focused on the meta and para substituents.
0
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9
0
1
2
3
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6
7
8
9
0
Figure 4. Taft plot for the steric effects in the kinetics of reverse thermal
isomerization of phenylazopyrazole 1d and their ortho-substituted derivatives
o
using UV-Vis spectroscopy in CH
3
CN at 25 ± 1 C.
For meta and para substituents, we have considered the Hammett
relationship by plotting log(k /k ) vs substituent constants. When the kinetics
R
H
rate constants from UV-Vis spectroscopic data have been utilized, we observed a
non-linear correlation, however, it showed a reasonable positive trend in both
the cases (Figure S6 in SI). Based on the linear free energy relationships, it is
very clear that electronic factors strongly influence the reaction rates. Either
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change in the mechanism (rotation vs inversion) upon changing the substituents
or the combined perturbations due to solvents (solvent assisted tautomerism)
and steric factors (due to the two methyl groups) along with the electronic
1
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29
effects could be the reason for the non-linearity. To understand this behavior,
we have plotted the Hammett relationship using computed rate constants
(Figure 5d and 5e). Not only those plots showed a very good correlation with
positive slopes for both meta- and para- substituted arylazopyrazoles, but also
confirmed the presence of substantial electronic effects in the rate of
isomerization. Apparently, accumulation of negative charges has been observed
at the two azo nitrogens for both the transition states (Table S5 in SI).
Figure 5. Substituent effects in kinetics of reverse thermal isomerization of
phenylazopyrazole and N-methyl phenylazopyrazole derivatives using NMR
spectroscopy in CD CN at 298 K: Hammett plots for (a) meta substitutions; (b)
3
para substitutions; (c) N-methylated meta substitutions; using computations at
B3LYP/6-311G(d,p) level of theory: Hammett plot for (d) meta substitutions; (e)
para substitutions; (f) N-methylated meta substitutions.
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On contrast, the Hammett relationships for meta and para substituted
phenylazopyrazoles using rate constants derived from NMR revealed a trend
with a negative slope (Figure 5a and 5b). This trend is completely opposite to
the computational (in gas phase) and UV-Vis (in acetonitrile) based
relationships. The major difference between the rate of the reverse
isomerization kinetics in NMR and UV-Vis spectroscopic experiments can be the
concentration. For UV-Vis spectroscopy, the experiments have been performed
at M concentration, whereas, for NMR studies, we have utilized a concentration
range of mM. The higher concentration, in principle can influences the rates in
the following ways namely, supramolecular interactions through -stacking or
through hydrogen bonding. Due to the presence of two methyl groups, the -
stacking interactions can be unfavourable. However, the presence of a free N-H
in phenylazoprazole derivatives can potentially form hydrogen bonding at
various sites that include azo nitrogens, pyrazole nitrogen and the hydrogen
bond acceptor substituents, if any. Also, due to the steric reasons only the azo
nitrogens of Z-isomer can accept intermolecular hydrogen bonding. This
assumption is particularly fitting very well with the change in the slope for
Hammett plots, upon increasing the concentration. Under such circumstances,
the charge at the inverting azo nitrogen center is expected to gain more positive
values or less negative charge, which is in perfect corroboration with the
computed charges at azo nitrogen centers. The hydrogen bonding at one of the
azo nitrogen’s led to lowering of negative charges at the adjacent nitrogen atom,
which undergoes inversion (Table S5 in SI). Apart from the substantial
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electronic effects, the hydrogen bonding is expected to play a crucial role in the
reverse switching of phenylazopyrazole derivatives.
In order to downplay the hydrogen bonding, six meta substituted N-
methyl phenylazopyrazole derivatives (1e, 3e, 6e, 9e, 15e and 18e) have been
chosen and Hammett relationship has been studied. Since the unsubstituted N-
methyl derivative 1e, has been extensively studied by Fuchter and coworkers,
the rate constant for its thermal isomerization has been taken from their
studies.19, 21 For the rest of the derivatives, the Z-E isomerization kinetics have
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been performed in CD CN at 298 K and the Hammett relationship has been
3
plotted (Figure 5c). The results for N-methylated derivatives revealed that the
plot once again reverted back to a positive slope, which is similar to their
corresponding computational plot in figure 5f. This clearly demonstrates the role
of pyrazole NH in hydrogen bonding.
E. Concentration dependency and solvent effects in Z-isomer stability:
During our investigations on photoswitching and reverse isomerization
behavior of substituted phenylazopyrazoles, we realized the importance of effects of
concentration. Apart from the reverse isomerization rate, photoswitching efficiency
also strongly depend on the concentration. In this regard, we did the concentration
dependent kinetics for the compound 1d (Figure S7 in SI). The results suggested that
the half-life of the (Z)-1d decreases by three times (21.6 min to 8.2 min) when the
concentration increases by approximately 14 times (0.004 M to 0.055 M). The results
clearly confirm that at the higher concentration, the Z-E isomerization rate constant
increases and the half-life of Z-isomer decreases. Besides, we observed a marginal
downfield shift in the N-H proton of 1d, whereas other protons showed no significant
shifts upon increasing the concentration. These observations clearly further confirms
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the possibility of hydrogen bonding involving pyrazole N-H. To understand the mode
of hydrogen bonding in concentration dependency, we estimated the association
constant of the hydrogen bonding dimer of the (E)-1d. Using NMR spectroscopy, the
spectral shifts of the pyrazole NH protons accompanying the concentration changes
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(relative to the residual protons of the solvent) have been considered. Using the open
access web based bindfit program, a non-linear fitting process has been executed in
3
0
this regard. The resulting binding constant for the 1:1 (E)-1d dimer was found to be
-3
-4
-1
1
.47 x 10 ± 1.69 x 10 L mol . (See the details in Figure S9 and S10 in SI). In
order to differentiate the solute-solute and solute-solvent interactions, the
phenylazopyrazole 1d has been subjected to NMR kinetics in DMSO-d , which is
6
known for the breaking of intermolecular hydrogen bonding (Figure 1). As a result,
the half-life of the Z-isomer has increased and the rate of reverse isomerization has
been decreased.
To emulate such hydrogen bonding possibilities and also to understand the
effects of it in the thermal reverse isomerization, computations are highly desired. In
this regard, we explored the barriers for the thermal isomerization step using simple
pyrazole as a model compound, with and without hydrogen bonding (Figure 6). From
those calculations, we inferred that the thermal isomerization barriers indeed showed
a lowering of Gibbs free energy of activation upon hydrogen bonding. Although the
changes in the barrier energies are found to be very small, it indeed significantly
influenced the rate constants and half-lives. Similar trend has also been observed
when actual dimeric phenylazopyrazole dimers are invoked in the computations (See
Figure S4 in SI)
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Figure 6. Effects of hydrogen bonding in the Z-E thermal isomerization in
phenylazopyrazoles: Computed barriers for the thermal reverse isomerization with
the H-bonding of pyrazole at various positions in phenylazopyrazole (The TS barriers
(in kcal/mol) for various channels are indicated with respect to E-1d + pyrazole
(individual hydrogen bonded complexes); Bold – B3LYP/6-311G(d,p); Normal –
M06-2X/6-311G(d,p)
In the same context, we have also studied the effects of solvents in the thermal
reverse Z-E isomerization rate by varying the polarity of the solvents at the identical
concentration. The results are tabulated (Table 3 and Figure S11 in SI). Based on the
results, the polar protic solvents such as ethanol and methanol showed a maximum
influence such that 1d underwent fast thermal Z-E isomerization. Indeed in methanol
the rate could not be determined. On the other hand, rate constants are estimated to be
smaller in the case of non-polar solvents such as toluene, whereas the polar aprotic
solvents still influence the rate from moderate to high.
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Table 3. Solvent effects in the UV-Vis spectroscopic thermal reverse isomerization
(Z-E) rates of phenylazopyrazole 1d and N-methyl phenylazopyrazole 1e
b
S.
No.
Solvent Parameters
Solventa
a
-1
c
-1
k (min )
k (min )

N
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0


 
E
T


x ±
x  
x ±
x  
x ±
x  
x ± x ±
x  
x ±
x  
x ± x ±
1
.
Acetonitrile
0.19 0.40 0.66 0.460
-
-





2. Chloroform
0.20 0.10 0.69 0.259





3
4
.
.
Dichloromethane    0.309
-





DMF
0.00 0.69 0.88 0.386
0.00 0.45 0.45 0.228



x 



5. Ethyl acetate
-






6
7
.
.
Ethanol
0.86 0.75 0.54 0.654
0.98 0.66 0.60 0.762
0.00 0.11 0.49 0.099



x  
x 
Methanol





x ± x ±
x  
x ±
x  
x ± x ±
x  
8. Toluene
THF
0. DMSO




x 


9
.
0.00 0.55 0.55 0.207
0.00 0.76 1.00 0.444
-






1



x 
a
All the solutions of 1d have been studied in different solvents at an identical
o
b
concentration (29 M) and the rates have been measured at 25 ± 1 C; Solvent
parameters are the Kamlet–Taft parameters for hydrogen bonding ability () and
hydrogen donating ability () and the solvatochromism scales * and E
N; cAll the
T
solutions of 1e have been studied in different solvents at an identical concentration
o
(
34 M) and the rates have been measured at 60 ± 1 C.
31
To relate the effects of solvents in the reverse isomerization, various properties of
the solvents such as Kamlet–Taft parameters for hydrogen bonding ability () and
3
2-34
N35
hydrogen donating ability () and the solvatochromism scales *
and E
T
have
been considered. Previous studies on limited number of azobenzenes revealed that the
solvent polarity rather than the viscosity of the solvents is vital for the thermal
isomerization kinetics.31b,c The correlation between the individual parameters with the
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rate constants, (plots of lnk vs solvent parameters) have been clearly showed a
remarkable influence of hydrogen bonding effects (Figure 7 and Figure S12 in SI).
Particularly the solvents with higher proton donating abilities strongly influence the
reverse isomerization rates. The exceptions in the case of DMSO and THF can be
rationalized on the basis of their hydrogen bond breaking abilities. All these
1
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36
observations are in consistent with the results related to the aryazoimidazoles and
1
3f
phenylazoindoles , where the involvement of protic molecules has been proposed for
fast isomerization through tautomerization mechanism.
Figure 7. Solvent effects in the thermal Z-E isomerization rate of 1d. (a) Graphical
plots showing the relation between lnk and the Kamlet–Taft parameters for hydrogen
donating ability, ; (b) Possible mechanism for the solvent assisted thermal Z-E
isomerization through tautomerization (Relative energies in kcal/mol are computed at
B3LYP/6-311G(d,p) level of theory)
In a similar way, solvent effects have been studied for the N-methylated
derivative 1e. Due to the very slow rate of Z-E isomerization, the studies have been
o
performed at 60 C (Figure S11 in SI). Hence, the experiments have been performed
only in low volatile solvents such as DMSO, DMF, toluene and ethanol. Remarkably,
the isomerization rates in all these solvents have been estimated to be in the same
order (Table 3). All these data clearly demonstrate that the hydrogen bonding and
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proton donation are the most influential factors for the faster Z-E isomerization
kinetics. Particularly when the azo groups are forming hydrogen bonding, the rates
are very high, whereas, the non-covalent interactions involving the solvents and the
pyrazole-NH decrease the thermal isomerization rates.
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Based on all these studies, we obtained the following general trends: (1)
Hydrogen bonding either increases the rate of reverse isomerization and/or inhibits
the photoswitching efficiency; (2) Any solvent that can protonate azo nitrogen or
forming hydrogen bonding with them increases the rate of the thermal reverse
isomerization through tautomerization mechanism; (3) At higher concentration, the
hydrogen bonding interactions competitively play important roles in deciding the
photoswitching behavior. For designing new photoswitches, the intermolecular
hydrogen bonding possibilities may also need to be taken care, in particular, for
controlling the Z-isomer stability.
Conclusions:
In summary, we have synthesized 38 substituted phenylazopyrazole
derivatives and six N-methylated phenylazopyrazole derivatives using a two/three-
step synthetic method with good to excellent yields. The UV-Vis spectroscopic
investigations on those molecules revealed the importance of steric factor in attaining
highly strained Z-isomer geometries that favor a faster reverse switching. Taft plot
clearly proved the release of steric factor during reverse isomerization in ortho
substituted phenylazopyrazoles. On contrast, the meta and para substituted
azopyrazoles undergo reverse isomerization with electronic influence, however,
Hammett plot exhibited a deviation from linear correlation. Substantial influences of
electronic effects have been further confirmed by Hammett plots using computed rate
constants for the selected meta and para-substituted derivatives. The NMR
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spectroscopic studies also revealed the influence of electronic effects in thermal
reverse isomerization, however, the slopes are completely opposite to that of UV-Vis
spectroscopic and computational studies. The similar studies on the N-methylated
derivatives with meta substitution reverted back to the positive slope in the Hammett
plot. Concentration dependency in half-life of the Z-isomer, NMR shifts in the
pyrazole NH, solvent effects and also the computations clearly demonstrate the
decisive role of hydrogen bonding. The solvent or any proton donor can influence the
isomerization rate through assisting in the protonation leading to tautomerization.
Thus, the non-linear behavior in the substituent effects of isomerization rate and Z-
isomer stability can be due to a combined effect of steric, electronic effects and the
hydrogen bonding. At higher concentrations, hydrogen bonding dominates and at
lower concentrations, apart from the electronic and steric factors, solvent assisted
tautomerization also prevail in deciding the rate of thermal reverse isomerization, in
turn, the stability of Z-isomers.
1
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Computational Methods:
All the structures (reactants, products and transition states) optimization have
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39
been performed at density functional theory with B3LYP , M06-2X functional
with 6-311G(d,p)40 basis set in gas phase as well as in solvent phase41. All the
geometry optimization have been verified to minima/transition state by frequency
4
2
calculations. The transition states have also been verified by computing the intrinsic
reaction coordinates (IRC).43 Natural bond orbital (NBO)44 calculations were
45
performed at same level of theory in order to obtain the Wiberg index for selected
azopyrazole derivatives. Wiberg index values provided the information about the
bond order between the two nitrogen atoms of azo group. All these calculations were
performed using Gaussian09 suite of program.46 We have estimated the transition
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states and corresponding energy barriers for the Z-E isomerization through inversion
mechanism.14, 47 Potential energy surface scan calculations have been performed for
obtaining the barriers for rotation mechanism by varying C-N=N-C dihedral angle.21
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Using those rate constants, the Hammett relationship has been plotted for meta- and
para-substituted derivatives. For computations involving solvents, calculations have
been performed using polarization continuum model (PCM) and acetonitrile as a
solvent.41
Experimental section:
General methods:
All the reactions have been carried out with the oven dried glasswares. The
reagents (AR or LR grade) and the solvents have been purchased from commercially
available sources such as Sigma Aldrich, Merck and TCI etc. Anhydrous solvents for
the reactions and for column chromatography have been distilled before use. The
NMR spectra have been recorded in Bruker Avance-III 400 MHz NMR spectrometer.
1
13
H and C NMR were recorded at operational frequencies 400 MHz and 100 MHz,
respectively. For recording the samples, CDCl , DMSO-d6, CD CN and CD OD have
3
3
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been used as the solvents. The chemical shift () values are reported in parts per
million (ppm) and the coupling constants (J) are reported in Hz. High resolution mass
spectra (HRMS) have been recorded using Waters Synapt G2-Si Q-TOF mass
spectrometer. HRMS data were obtained from a TOF mass analyser using
electrospray ionization (ESI) in both positive and negative modes. Melting points
were recorded on SMP20 melting point apparatus, which are uncorrected. IR spectra
were recorded on a Bruker Alpha ZnSe ATR FT-IR spectrometer. Column
chromatography was performed over silica gel (100–200 mesh). Thin layer
chromatography was performed on Merck Silica gel 60 F254 TLC plates and
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visualized using UV (λ = 254 nm) chamber. The arylazoacetylacetone derivatives 1c-
2
2
2
8c, 29c-30c, and 33c-37c have been synthesized as described in the literature. UV-
Vis photoswitching and kinetics studies have been performed either using a Cary
000 or Cary 60 spectrophotometer, whereas the corresponding NMR experiments
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have been performed in Bruker Avance-III 400 MHz NMR spectrometer. For forward
photoswitching (E-Z isomerization) samples were irradiated at 365 nm using a LED
light source either from Applied Photophysics, SX/LED/360 with an bandwidth 20
nm or a commercial 9W LED light source. The reverse isomerization has been
induced by using either a 35 W CFL lamp or a 405 nm LED. The PSS has been
established by irradiating the sample for prolonged time such that no further spectral
change is observed.
General procedure for synthesis of arylazoacetylacetone derivatives (1-38c):
A mixture of aniline or substituted anilines (20.0 mmol) and deionized water
o
in a two neck round bottom flask was cooled to 0 C. To this 37% conc. HCl (6.5 mL)
was added and stirred to get a clear solution. Then a cold aqueous solution of sodium
nitrite (1.52 g, 22.0 mmol in 20 mL of water) was added dropwise into the reaction
mixture slowly. After the addition, the diazonium salt started forming. The reaction
o
mixture was allowed to stir for half an hour for completion. Afterwards, at 0 C a cold
aqueous solution of sodium acetate (5.90 g, 70.0 mmol) and acetyl acetone (2.00 g,
20.0 mmol in 100 mL of water and 10 ml of ethanol) was added. The reaction was
continued at rt and was monitored by TLC. After completion of the reaction, the
reaction mixture was filtered off to obtain a yellow-orange solid product, which was
dried under vacuum to yield the desired product.
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General procedure for synthesis of arylazopyrazole derivatives (1-38d):
A mixture of arylazoacetylacetone derivative (1.0 mmol), hydrazine
dihydrochloride (2.0 mmol) and Na
2
CO (4.0 mmol) in 10 mL absolute ethanol was
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refluxed. The reaction was followed using TLC upto the completion of the reaction.
After completion of the reaction, the product was purified by column
chromatography. (Eluent: 1:1 ethylacetate/n-hexane)
Arylazoacetylacetone Derivatives
N-(3-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl)phenyl)acetamide (28c):
o
1
Yellow-orange solid, mp = 187-189 C, 222.01 mg, 85% yield. H NMR (400 MHz,
CD OD) δ 2.15 (s, 3H), 2.44 (s, 3H), 2.51 (s, 3H), 7.01–7.11 ( d, J , Hz, 1H),
7.277.33 ( m, 2H), 7.91 ( s, 1H), ); C NMR (100 MHz, CD
3
1
3
3
OD) δ 22.6, 25.3, 30.3,
1
06.8, 111.4, 116.4, 129.6, 132.8, 140.1, 142.0, 170.4, 197.2, 197.5; HRMS (ESI-
+
1
TOF): calcd for C13
H N
15 3
O [M-H] : 260.1035; found: 260.1026; IR (ATR, cm ):
3
3292, 3078, 1666, 1624, 1596, 876.
3
-(2-mesitylhydrazono)pentane-2,4-dione (31c):
o
1
Yellow solid, mp = 110-111 C, 209.4 mg, 85% yield. H NMR (400 MHz, CDCl
3
) δ
13
2
.32 (s, 3H), 2.42 ( s, 3H), 2.43 (s, 3H), 2.64 (s, 3H), 6.94 ( s, 2H), 15.03 (s, 1H); C
NMR (100 MHz, CDCl
3
) δ 19.3, 20.9, 27.0, 31.6, 129.8, 130.3, 133.4, 135.7, 136.3,
+
197.3, 197.5; HRMS (ESI-TOF): calcd for C14
H
18
N
2
O
2
[M-H] : 245.1290, found:
1
2
45.1278; IR (ATR, cm ): 2790, 2918, 1714, 1656, 1611.
3-(2-(naphthalen-1-yl)hydrazono)pentane-2,4-dione (32c):
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Yellow solid, mp = 153-155 C, 167.89 mg, 66% yield. H NMR (400 MHz, CDCl
3
)
δ 2.59 (s, 3H), 2.72 (s, 3H), 7.56–7.66 (m, 3H), 7.757.77 (d, J  8.2 Hz, 1H),
1
3
7
.937.95 (d, J  7.9 Hz, 1H), 8.058.07 (d, J  8.1 Hz, 1H), 15.78 (s, 1H); C NMR
1
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(
100 MHz, CDCl ) δ 26.8, 31.8, 112.0, 119.6, 123.4, 126.1, 126.1, 126.6, 127.1,
3
1
28.8, 134.1, 134.3, 136.5, 197.3, 198.2; HRMS (ESI-TOF): calcd for
+
1
C
15
H
14
N
2
O [M-H] : 253.0977, found: 253.0965; IR (ATR, cm ): 3057, 2987, 2921,
2
1
661, 1621, 1494.
3-(2-(3,5-difluorophenyl)hydrazono)pentane-2,4-dione (38c):
o
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Yellow solid, mp = 151-153 C, 237.81 mg, 99% yield. H NMR (400 MHz, CDCl )
3
δ 2.51 (s, 3H), 2.63 (s, 3H), 6.626.67 (tt, J  9.1, 2.2 Hz, 1H), 6.936.96 (d, J  8.0,
13
1
9
.9 Hz, 1H), 14.49 (s, 1H); C NMR (100 MHz, CDCl
3
) δ 26.6, 31.8, 99.5 (J = 20.3,
.0 Hz), 100.6 (J = 25.7 Hz), 133.9, 144.0, 163.8 (J = 247.0, 14.2 Hz), 196.9, 198.5
+
HRMS (ESI-TOF): calcd for C11
H
10
F
2
N
2
O
2
, [M-H] : 239.0632, found: 239.0620; IR
1
(
ATR, cm ): 3059, 1675, 1602, 1524, 1471, 1407.
Arylazopyrazole Derivatives
(
E)-3,5-dimethyl-4-(phenyldiazenyl)-1H-pyrazole (1d):
o
1
Yellow solid, mp = 141-143 C, 170.2 mg, 85% yield. H NMR (400 MHz, CDCl ) δ
3
1
3
2
.64 (s, 6H), 7.41-7.43 (m, 1H), 7.78-7.52 (t, J = 7.2 Hz, 2H), 7.82-7.84 (m, 2H); C
NMR (100 MHz, CDCl
3
) δ 12.2, 121.9, 128.9, 129.5, 134.7, 141.5, 153.6; HRMS
+
(ESI-TOF): calcd for C11
H
12
N
4
[M+H] : 201.1140, found: 201.1132; IR (ATR,
1
cm ): 3114, 3042, 2968, 2887, 1411, 1322, 1118, 829.
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