Experimental and Theoretical Studies on the Mechanism of DDQ-Mediated Oxidative Cyclization of N-Aroylhydrazones

Article abstract of DOI:10.1021/acs.joc.0c00937

The controversial single-electron-transfer process, frequently proposed in many 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated reactions, was investigated experimentally and theoretically using the oxidative cyclization of aroylhydrazone with DDQ. DDQ-mediated oxadiazole formation involves several processes, including cyclization to form an oxadiazole ring and N-H bond cleavage, either by proton, hydride, or hydrogen atom transfer. The detailed mechanistic study using the M06-2X density functional theory, and the 6-31+G(d,p) basis set, suggests that the pathways involving radical ion pair (RIP) intermediates, which resulted from single-electron transfer (SET), were found to be energetically nearly identical to the pathway without the SET. The substituent-dependent reactivity of oxadiazole formation was consistent with the free energy profiles of both pathways, with or without the SET. This result indicates that in addition to the electron-transfer pathway, the nucleophilic addition/elimination pathway for DDQ should be considered as a possible mechanism of the oxidative transformation reaction using DDQ.

Full text of DOI:10.1021/acs.joc.0c00937

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Article
Experimental and theoretical studies for the mechanism of
DDQ mediated oxidative cyclization of N-aroylhydrazones
Jihye Baek, Eun-kyung Je, Jina Kim, Ai Qi, Kwang-Hyun Ahn, and Yongho Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00937 • Publication Date (Web): 02 Jul 2020
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Experimental and theoretical studies for the mechanism of DDQ mediated oxidative
cyclization of N-aroylhydrazones
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Jihye Baek,,† Eun-kyung Je,,† Jina Kim, Ai Qi, Kwang-Hyun Ahn* and Yongho Kim*
Department of Applied Chemistry and Institute of Natural Sciences, Kyung Hee University,
Yongin-si, 446-701, Korea,
*Corresponding author. Tel.: +82 31 201 2456; fax: +82 31 202 7337
† These authors contributed equally to this work.
E-mail address: khahn@khu.ac.kr, yhkim@khu.ac.kr
Graphical Abstract
O H
N N
B
A
C
N N
SET
R1
R2
DDQ
R1
R2
HN N
O
O
Cyclization
OH
Termination
Cl
Cl
CN
CN
Cl
Cl
CN
CN
B
A
C
N N
Addition
DDQ
OH
O
ABSTRACT
The controversial single electron transfer process, frequently proposed in many DDQ mediated
reactions, was investigated experimentally and theoretically using the oxidative cyclization of
aroylhydrazone with DDQ. DDQ-mediated oxadiazole formation involves several processes,
including cyclization to form an oxadiazole ring and N-H bond cleavage, either by proton,
hydride, or hydrogen atom transfer. The detailed mechanistic study using the M06-2X density
functional theory, and the 6-31+G(d,p) basis set, suggests that the pathways involving radical
ion pair (RIP) intermediates, which resulted from the single electron transfer (SET), was found
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to be energetically nearly identical to the pathway without the SET. The substituent dependent
reactivity of oxadiazole formation was consistent with the free energy profiles of both pathways,
with or without the SET. This result indicates that in addition to the electron transfer pathway,
the nucleophilic addition / elimination pathway for DDQ should be considered as a possible
mechanism of oxidative transformation reaction using DDQ.
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Keywords
DDQ, 1,3,4-oxadiazole, oxidative cyclization, fluorescent oxadiazole
INTRODUCTION
The heterocyclic 1,3,4-oxadiazoles are important structural units that have been widely used
as core structures in pharmaceutical1-7 and electronic material applications.8-15 In particular, the
2,5-diaryl-1,3,4-oxadiazoles are well recognized as an electron-deficient functional group
suitable as an electron-transporting (ETM) and hole blocking material in organic multilayer
electroluminescent (EL) diodes.16-21 Because of their potential for use in various applications,
the 2,5-disubstituted 1,3,4-oxadiazoles have been a focus of study in synthetic organic
chemistry, resulting in the development of numerous synthetic methods.22-39 We have been
interested in making aromatic 1,3,4-oxadiazole compounds for electronic applications that
maintain the highest standards for the amount of impurities in the materials used. Among the
various synthetic methods, oxidative cyclization of N-aroylhydrazones in the presence of
oxidizing reagents is considered to be a versatile method for preparing compounds that help to
reduce the possibility of product contamination by by-products due to high atomic economics.
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In addition, since N-aroylhydrazones can be prepared in high yield from the reaction between
acylhydrazine and aromatic aldehydes, oxadiazoles of numerous different structures can be
readily realized.
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As for the oxidants in the oxidative cyclization method, we were interested in organic
oxidants instead of oxidizing system that uses metal as a catalyst or oxidant in order to prevent
the possibility of metal impurity contamination in the materials that could reduce the
performance of materials for electronic applications. In our search for a suitable organic
oxidant for the reaction, we found that DDQ effectively oxidized aryl aldehyde N-
aroylhydrazones to produce 1,3,4-oxadiazole compounds (Scheme 1).40,41 After the completion
of the reaction, the reduced form of DDQ can be easily removed by using an acid-base wash
to provide high purity oxadiazole in good yield. Similar result was also reported recently.42,43
Since the overall yield of the reaction varied dependent upon the substituents on R1 and R2, it
was thought that the theoretical study using computation method might be useful to understand
the reaction and to provide further details related to various DDQ-promoted oxidation reactions.
Scheme 1. One-pot preparation of 1,3,4-oxadiazoles
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), a powerful oxidant, was first synthesized
in 1906 by Thiele and Günther.44 Despite the development of numerous oxidizing agents over
the last 100 years, DDQ is still regularly utilized and demonstrates effective reactivity in
various organic reactions45,46 such as dehydrogenation, oxidation of alcohol and deprotection
of benzyl groups, making it suitable for use in the synthesis of complex molecules.47,48 Recently,
the potential of DDQ has expanded to the selective functionalization of the C-H bond49-57
,
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including cross-dehydrogenative-coupling (CDC) reactions, which is one of the key research
fields in organic chemistry. In contrast to the active search for new applications of DDQ,
mechanistic details for reactions employing DDQ are still discussed controversially.
Theoretical studies on the hydrogen abstraction processes by DDQ in various C-H bond
activation reactions have recently been reported,58,59 suggesting that hydrogen can form a bond
to either C or O of DDQ depending on the reaction condition.60,61 These reports indicate that
DDQ plays a larger role in the oxidation reaction than the initial single electron oxidant.62
Inspired by these reports, we thought that a detailed theoretical mechanistic study for the
oxidative cyclization of N-aroylhydrazones by DDQ might be useful for understanding of the
traditional DDQ-promoted oxidation as well as recent C-H activation reactions.
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The mechanistic process for the oxadiazole formation reaction can be divided into three
steps such as initiation, cyclization and termination as illustrated in Scheme 2. The initiation
step will provide activated hydrazone intermediates that will be proceeded to oxadiazole ring
through cyclization and termination. Those conceivable initiation pathways might be (a) single
electron transfer (SET), (b) Hydride transfer (HT) to either O or C of DDQ, (c) 1,2-addition of
hydrazone nitrogen to DDQ and (d) 1,4-addtion of hydrazone nitrogen to DDQ. The pathways
(a) and (b) have been generally proposed as an initial step in various quinone promoted
oxidation reactions.63 We thought that the pathways (c) and (d) might be also possible in our
reaction system and considered as potential initiation steps along with other pathways. Those
four initiation steps will be followed by cyclization and termination steps. The whole reaction
pathways were calculated and the results compared with experiments. In this study, we report
the efficient synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from aldehyde N-aroylhydrazone
3 in the reaction with DDQ (Scheme 1) and its plausible mechanism obtained from systematic
quantum mechanical calculations using the M06-2X density functional theory.64,65
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Scheme 2. Possible mechanism of oxadiazole formation reaction.
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RESULTS AND DISCUSSION
DDQ Promoted Oxidative Cyclization of N-aroylhydrazones. To understand the
mechanism of this reaction, the benzohydrazide was set up to react with various aromatic
aldehydes (Table 1, entries a – e). First, we studied the reaction between benzohydrazide and
benzaldehyde in toluene. The intermediate aroylhydrazone, 3c, was readily formed from the
reaction mixture in refluxing toluene. After 2 hr, DDQ was added to the reaction mixture
without isolation of the aroylhydrazone. Product 4c was obtained in 87% yield after heating
for 20 hr. Thus, DDQ was found to be a suitable oxidant for oxadiazole ring formation. The
isolation of the product from the reaction mixture was performed after washing with a base to
remove the hydroquinone, 4,5-dichloro-3,6-dihydroxyphthalonitrile (DDP), the reduced form
of DDQ. To optimize the reaction conditions, various solvents were tested, and toluene was
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found to be the optimal solvent for the synthesis of 2,5-diphenyl-1,3,4-oxadiazole, 4c. The
polar solvent resulted in an unfavorable outcome. As shown in Table 1, the aldehydes with an
electron-donating substituent gave an excellent yield of up to 99%. In the case of the p-
methoxybenzaldehyde, the reaction was completed within 4 hr. However, the electron-
withdrawing substituents, such as nitro groups, resulted in a relatively poor yield (31%). The
substituents in the benzohydrazides also affected the yield of the reaction. The benzohydrazides
with electron donating groups, such as methoxy and t-butyl groups, resulted in favorable yields
too (entries f – h).
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Table 1. Syntheses of 2-aryl-5-aryl-1,3,4-oxadiazoles 4a-4ga
Entry
R1
R2
Product Time (hour) Yield (%)b
a
b
c
d
e
f
Phenyl
4-Methoxyphenyl
4-Methylphenyl
Phenyl
4a
4b
4c
4d
4e
4a
4f
4
99
92
87
74
31
99
99
94
66
Phenyl
12
20
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20
4
Phenyl
Phenyl
4-Bromophenyl
4-Nitrophenyl
Phenyl
Phenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-t-Butylphenyl
4-Bromophenyl
g
h
i
4-Methoxyphenyl
Phenyl
4
4g
4d
20
20
Phenyl
a) The products were characterized by comparison of their spectral and physical data with those
of known samples reported in the literature.
b) Yield of the isolated product based on the aldehyde.
Kinetic studies for the effect of methoxy substituent position. As seen in Table 1, the
methoxy substituent greatly enhances the reaction rate. It was thought that there might be a rate
difference dependent upon the position of substituents such as 3a and 3f, and that this factor
would be helpful for the mechanistic studies of the reaction. Thus, aroylhydrazone compounds
3a and 3f were isolated, and set up to react with DDQ for the given reaction time, independently.
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The yields calculated from the fluorescence of the products of the reaction mixture were plotted
against the reaction time (Figure 1). As shown in Figure 1, the methoxy substituent at R2 (3a)
activated the substrate efficiently for oxidative cyclization and led to the completion of the
reaction earlier than did the methoxy substituent at R1 (3f). Kinetic studies using the
fluorescence of products revealed that the reaction rate with 3a was 3.93 times faster than the
rate with 3f.
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Figure 1. The yield of product after the given reaction time in the reaction with either (a) 3f or
(b) 3a. The reaction was repeated 3 times.
Theoretical mechanistic study. In the oxadiazole formation reaction, DDQ is expected to
interact with 3, initially, to form a stable charge transfer (CT) complex as has been observed in
the reaction of DDQ and polyaromatic compounds66-68 such as 10-methyl-9,10-
dihydroacridine.69 The π-π interaction between DDQ and 3 can generate two stable CT
complexes, RX and RY, depending on the position of DDQ, which are depicted in Figure 2. In
RX and RY, DDQ is closer to either the benzoyl or the benzyl moieties of 3, respectively. The
DFT calculated potential and free energies listed in Table 2 showed that RY conformers are
more stable in energy than RX conformers. This suggests that the π-π interaction of DDQ with
benzyl moiety is preferred for the formation of CT complex. Interestingly, the π-π interaction
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stabilized the complexes when the electron donating substituents are introduced at the benzyl
and benzoyl groups for RY and RX, respectively. The most stable conformers among the CT
complexes are considered as reactant complexes, RC, and RY conformers were usually more
stable than RX conformers. The positive free energies at 393 K imply that the CT complexes
would not be present abundantly in solution due to entropy, however, they could act as a key
species generated en route to the TS under the reaction temperature.
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Figure 2. Optimized structures of CT complexes with 3c and DDQ in solution
Table 2. Potential and free energies (kcal/mol) of formation for CT complexes in solution a
Aroylhydrazones
RX
RY
3c
3a
3f
−9.8 (7.6)
−9.7 (6.1)
−11.8 (4.4)
-9.8 (6.2)
−14.8 (3.7)
−16.5 (2.2)
−15.0 (3.6)
-12.5(5.5)
3e
a) Numbers in parenthesis are free energies at 393 K.
In many DDQ-mediated oxidation reactions, the initial SET from substrate to DDQ has been
suggested as a key step.52,53,57,70,71 In some instances, the electron-transfer complex was
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observed with EPR.72 The processes not initiated by SET have also been proposed as a
plausible mechanism for many DDQ-mediated oxidation reactions.73-75 In order to test the
possibility of an electron transfer step in the mechanism of our reaction, the energies of
intermediates and transition states for the processes with or without the SET were calculated
and compared.
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The mechanism without SET. The DDQ-mediated oxadiazole formation without SET
involves several processes, such as (b) HT, (c) 1,2-addition and (d) 1,4-addition to activate
hydrazone intermediates, and cyclization without an initiation step. Based on the detailed
analyses of the reaction mechanism, nine species were considered as the potential intermediates
for the reaction pathways from RC, which is depicted in Scheme 3. There are five possible
pathways to yield product starting from RC. The relative potential and free energies of
intermediates and transition states (TSs) for each step were calculated and listed in Table 3.
Scheme 3. Possible pathways of DDQ-mediated oxadiazole formation without SET. Numbers
in brackets and parenthesis are free energies of activation and relative free energies,
respectively, with respect to the free energy of reactant at 393 K for the reaction with 3c.
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We failed to obtain the TS of direct HT to form an activated intermediate IB; the HT process
continued to increase in energy without generating a stable intermediate, and every attempt to
find the TS structure led to the CT complex, RC. Therefore, the direct HT to DDQ can be
excluded from consideration as the reaction mechanism. Interestingly, activated intermediates,
ID and IC, generated by 1,2-addition + PT and 1,4-addition, respectively, were much more
stable in energy than IB, suggesting that nucleophilic addition might play an important role on
the DDQ-mediated oxidation reactions. Based on the relative free energies of all intermediates
in Scheme 3, the most probable pathway seems to be the concurrent 1,2-addition and PT
followed by cyclization, which proceeds through the intermediates ID and IH. However, in
order to determine the energetically favorable reaction mechanism, the free energy of activation
in the rate-limiting step should be considered for all possible pathways.
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Table 3. Relative potential (E) and free energies(G) of intermediates and TSs for each step
depicted in Scheme 3 for the reaction with 3c in toluene a
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E
G (393 K)
Intermediates
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IA
IB
IC
ID
IE
IF
IG
IH
II
11.7
19.2
2.2
3.7
1.2
31.7
35.9
21.8
22.2
22.0
26.6
33.8
10.4
11.8
4.4
12.9
−11.5
−6.6
Transition States
TS1 (RC → IA)
TS2 (RC → ID)
TS3 (RC → IC)
TS4 (IA → IE)
TS5 (IA → IG)
TS6 (IC → IF)
19.8
5.1
3.4
30.6
14.4
13.3
26.4
13.0
13.8
11.9
36.8
21.7
21.8
48.5
35.4
33.3
47.5
33.2
32.8
34.3
TS7 (IF → II)
TS8 (ID → IH)
TS9 (IG → IH)
TS10 (IA → IF)
a) Energies in kcal/mol.
In the reaction from RC to ID, 1,2-addition and PT occur concurrently. The intrinsic reaction
coordinate (IRC) of this step was calculated starting from the TS (TS2) to both RC and ID in
order to check that these two processes really occur simultaneously, and the results are depicted
in Figure 3. The potential energy curve changed smoothly along the proton transfer coordinate
(q1 = [r(N-H) − r(O-H)]/2) of the IRC without any intermediate, where q1 is the displacement
of H from the center of proton donor and acceptor. The C-N bond distance also changed
smoothly but reduced very rapidly in the early stage of proton transfer, showing that this
reaction proceeds concertedly but very asynchronously; C-N bond formation precedes proton
transfer.
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Figure 3. Potential energies and C-N bond distances of 3c along the IRC of concurrent 1.2-
addition + proton transfer.
Among the three reactions starting from RC, the direct cyclization forming IA without any
initiation has the highest free energy of activation (36.8 kcal/mol), whereas the other two
initiation reactions, i.e., 1,4-addition forming IC and 1,2-addition + PT forming ID, have nearly
identical free energies of activation. Thus, three reaction pathways through IA would be less
likely than the other two pathways through IC or ID. The proton transfer reaction to generate II
from IF has a very large activation free energy (47.5 kcal/mol), suggesting that the pathways
through IF are less likely. Since the intermediate IF was generated by 1,4-addition in the first
or second step from RC, any pathway involving 1,4-addition can be excluded from
consideration as a meaningful mechanistic step.
The activation free energy of hydride transfer from N-H to DDQ to produce IE from IA is
also very large (48.5 kcal/mol), so the pathway through IE can also be excluded from
consideration. Of the remaining two pathways, cyclization reaction to generate IH from ID is
the rate-limiting step with the smallest activation free energy (33.2 kcal/mol), suggesting that
1,2-addition + PT followed by cyclization is the most probable mechanism of oxadiazole
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formation of 3c. The TS of the rate-limiting step for the most probable mechanism was also
calculated for 3a, 3f and 3e, and the activation free energies were 31.4, 32.4 and 35.6 kcal/mol
for the former and the latter, respectively. The experimental reaction rate of 3a was four times
faster than that of 3f, indicating that the reaction of 3a has 1.1 kcal/mol lower activation free
energy than that of 3f. The calculated free energy difference between 3a and 3f agrees very
well with the experimental value from kinetic studies. The largest activation free energy of 3e
is also consistent with the experimental observation that gives the lowest product yield (Table
1).
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The mechanism with the SET. The SET of CT complex produces radical ion pairs (RIPs) in
triplet or open-shell singlet states. As for the mechanism involving the SET, we postulated
pathways as shown in Scheme 4. The SET from 3 to DDQ generates a RIP, RC*, which
proceeds to oxadiazole formation by two possible pathways. These include: 1) initial
cyclization of radical cation 3 to make IA*, followed by either PT or HAT to DDQ radical anion
to make IE* or IE, respectively, and 2) initial PT to DDQ radical anion to make IB* followed
by cyclization to form IE*. The most significant geometrical change of CT complex upon the
initial SET is the formation of strong hydrogen bond (H-bond) between N-H of 3 and oxygen
of DDQ. The H-bond lengths of RC* are 1.534, 1.719, and 1.602 Å for 3c, 3f, and 3a,
respectively, whereas those without SET are 2.288, 2.421, and 2.280 Å, respectively. The
relative potential and free energies for RC*, intermediates, and TSs with respect to the reactants
are listed in Table 4. Since the energy differences between open-shell singlet and triplet RIPs
were negligible, we used triplet states for our discussion unless mentioned otherwise.
Scheme 4. DDQ mediated pathways of oxadiazole formation initiated by SET. Numbers in
brackets and parenthesis are free energies of activation and relative free energies, respectively,
with respect to the free energy of reactant at 393 K for the reaction with 3c.
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The energies of TS1 and TS1* suggest that the SET catalyzed the cyclization of 3c and
reduced its activation free energy by 3.5 kcal/mol. The N-H bond cleavage, which was
impossible without SET, proceeded by isoenergetic proton transfer with nearly no energy
barrier, suggesting that a fast pre-equilibrium exists between RC* and IB*. Cyclization to
generate IA* from RC* followed by nearly barrierless proton transfer to generate IE* from IA*
would be the preferred mechanism for oxadiazole formation with 3c, because the activation
free energy of TS1* is slightly lower than that of TS11* (Table 4). In the reaction with 3a or
3f, cyclization of IB* induced back proton transfer from the hydroxyl group of DDQ-H radical
to form an N-H bond again and generated IA* through the same transition state like TS1*.
Therefore, the pathways through TS1* are the rate-limiting step of the preferred mechanism
for all cases. The activation free energy of 3a is 1.2 kcal/mol lower than that of 3f, which agree
very well with the experimental value.
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Table 4. Relative potential and free energies (kcal/mol) of intermediates and TSs for
oxadiazole formation in toluene initiated by SET a
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3a
3f
3e
RC*
10.6(24.9)
10.6(25.8)
5.6(22.0)
5.5(22.9)
10.2(24.3)
10.3(25.2)
4.6(20.7)
4.5(21.7)
17.2(33.3)
17.1(34.1)
5.9(20.6)
5.8(21.5)
11.3(24.1)
11.4(25.0)
19.0(33.8)
19.0(34.8)
6.7(21.1)
6.7(23.0)
5.11(21.8)
5.0(22.7)
8.7(22.4)
8.8(23.5)
4.5(20.6)
4.4(21.7)
14.4(30.3)
14.3(31.1)
5.6(20.5)
5.5(21.3)
9.0(22.0)
9.1(22.9)
NA
7.7(22.8)
8.6(24.8)
1.8(21.0)
1.6(21.2)
8.0(22.8)
8.0(23.7)
2.3(19.6)
2.1(20.8)
13.9(31.5)
13.7(32.2)
3.1(19.2)
3.0(20.1)
8.9(22.1)
9.0(23.1)
NA
15.6(28.3)
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IA*
8.7(26.7)
13.0(29.3)
6.6(25.1)
22.4(39.9)
8.7(27.2)
15.6(31.9)
22.5(40.0)
IB*
IE*
TS1* (RC*→IA*)
TS4* (IA*→IE*)
TS10* (RC*→IB*)
TS11* (IB*→IE*)
a) Numbers in parenthesis are free energies at 393 K, and italic numbers are for the open-shell
singlet.
For 3c, the overall activation energy of the most probable mechanism initiated by the SET
is nearly identical to that not initiated by the SET. Interestingly, the rate-limiting step of
preferred pathway is the cyclization reaction to form oxadiazole ring for both cases. The overall
activation energies of 3a and 3f with SET are about 1 kcal/mol lower than those without SET,
however, this energy difference is within the limit of chemical accuracy that can be predicted
by any computational method. Interestingly, the activation energy of 3e with SET is higher
than without SET. For a better estimate of free energy, higher level energy calculations were
performed at the B3LYP/6-311++G(2d, p) level using the B3LYP6-31+G(d,p) optimized
structures, and the quasi-harmonic-oscillator approximation76
was used for low frequencies less than 100 cm−1. The activation free energies for the rate-
limiting TSs are listed in Table 5. In the case of 3c, the activation free energy of the SET (TS1*)
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is lower than that of the best non-SET pathway (TS8) by only 0.5 kcal/mol, and this difference
becomes larger by 2.5 kcal/mol for 3a and 3f, meaning that the SET is 25 times faster for 3a
and 3f at 393 K, but only 1.9 times faster for 3c. This result imply that electron donating
substituents at aroylhydrazone make the SET pathway more preferable. However, for 3e, the
activation free energy is higher by 1.9 kcal/mol for the SET than the non-SET pathway. Unlike
the others, the SET pathway is slower by 11 times for 3e, which is attributed to the electron
withdrawing nitro group in aroylhydrazone inhibiting electron transfer to DDQ. This result
suggests that the mechanism of DDQ-mediated oxadiazole formation depends on the electron-
donating and electron withdrawing property of substituent in aroylhydrazone.
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Table 5. Free energies (kcal/mol) of activation for the rate-limiting TSs with and without the
SET calculated at the B3LYP/6-311++G(2d, p)//B3LYP6-31+G(d,p) level a
3c
3a
3f
3e
36.5
35.0
36.1
39.2
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36.0
33.5
33.6
41.1
TS1* (RC*→IA*)
a) The B3LYP/6-31+G(d,p) level vibrational frequencies scaled by 0.95 were used for the free
energies. All low frequencies less than 100 cm−1 were replaced by 100 cm−1 to reduce errors in
the estimation of free energies.
The free energy profiles for the preferred pathway with SET (for the formation of IE*
through IA* from RC*) and the corresponding pathway without SET (for the formation of IE
through IA from RC) were depicted in Figure 4 for comparison. Although RC* has a higher
energy than RC, the RIP state has a lower activation energy than the corresponding CT state.
Thus, as shown in Figure 4, two free energy curves will cross each other along the reaction
coordinates. The first step, cyclization, is endoergic and exoergic for the CT and RIP states,
respectively, which is supposed to generate product-like and reactant-like transition states,
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respectively. The C-O bond lengths are 1.988 Å and 1.700 Å at TS1* and TS1, respectively,
indicating that the former is earlier than the latter satisfying the Hammond postulate. As shown
in Figure 4, if the CT state potential curve crosses the RIP curve somewhere after the RIP state
passes TS1*, then the activation energy of ring formation would be lowered. Two state model,
in which the curve crossing or spin-crossover greatly reduced the activation barrier, has been
proposed as an important mechanism for C-H bond activation by high-spin iron(IV)-oxo
complexes.77-79
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Figure 4. Free energy profile of 3c along the preferred pathway with SET (red) and the
corresponding pathway without SET (black). Numbers in parenthesis are free energies in
kcal/mol. Bond lengths are in Å.
Since electrons move much faster than the nucleus, the electron transfer can only occur
between two energetically degenerate states under the Born-Oppenheimer approximation.
Therefore, the SET must occur at some point where the two potential energy curves of the CT
complex and the RIP cross each other along the reaction coordinates. In order to find the
crossing points, potential energies were calculated along the IRCs of cyclization. The
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calculated potential energy curves are plotted in Figure 5. The potential energy curves of 3a,
3c, and 3f in the CT state increased rapidly as the rC-O distance decreased to the normal bond
length of the oxadiazole ring. It is very interesting that the two potential energy curves for 3a
and 3c could nearly be superimposed, which suggests that there is no substituent-effect at R2,
whereas the potential energy curve for 3f showed a parallel down-shift compared with the other
two potential curves. These results suggest that cyclization in the CT state could only be
stabilized by the - interaction between DDQ and R1. The potential curves in the RIP state
are very flat and depend very much on substituents; methoxy substitution at R1 andR2 lowered
the potential energy curves. However, all crossing points appeared before the TS1* and the
energies of those points were nearly the same as the TS1* energies. This result means that even
though the curve crossing occurs during the reaction, it does not promote oxadiazole formation.
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Figure 5. Potential energy curves along the IRC of cyclization.
The dehydrogenation of IA* can proceed through two possible pathways (Schemes 4), HAT
and PT producing IE and IE*, respectively. The HAT has been frequently proposed as a key
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process after the initial SET in many DDQ-mediated oxidative dehydrogenation
reactions.53,57,70 However, the sequential process, such as proton transfer followed by the
second electron transfer, can also produce the same HAT result. Barciocchi et al.80 studied the
C-H bond cleavage of the photoinduced alkylaromatic radical cation, and reported that both
HAT and PT were possible depending on the solvent. Therefore, detailed studies were needed
to conclude the mechanism of the dehydrogenation of IA*. The HAT and PT from IA* will give
IE (ion-pair) and IE* (radical pair), respectively. We obtained the TS structure for the N-H bond
cleavage of IA*, and calculated the CM5 partial charges81 and Hirshfeld spin densities82 to
reveal the TS properties, which are depicted in Figure 6. We enforced the total spin of the TS
to be an open-shell singlet, otherwise the singlet IE cannot be generated by the HAT from IA*,
although that is the preferred process. The oxygen abstracting hydrogen has a negative charge
(−0.34), and the transferring hydrogen has a partial positive charge at the TS. The spin density
of the DDQ moiety is −0.97, while that of the oxadiazole moiety is 0.97, which indicates that
the TS is an open-shell singlet radical resulting from proton transfer.
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Figure 6. The CM5 partial charges and Hirshfeld spin densities in the TS of N-H cleavage in
IA*
These results, therefore, suggest that the dehydrogenation of the N-H bond takes place by
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proton transfer mechanism. The mechanism of DDQ-mediated C-H bond activation reactions,
such as cross-dehydrogenative coupling reactions,53,57,70 are expected to have some analogy
with this N-H bond activation reaction. A proton transfer after SET, similar to the N-H bond
cleavage reaction, might be an alternative process for the generally accepted HAT mechanism
in the DDQ-mediated coupling reaction. In summary, we proposed five possible pathways for
the DDQ mediated oxadiazole ring formation without SET and three with SET, and calculated
structures and energies of reactants, products, intermediates, and TSs for the pathways. As the
most likely mechanism, two pathways, one with and the other without SET, have been
proposed. The predicted rate constants depending on the substituents would be in the order of
3a > 3f > 3c for both pathways, which is consistent with experiments. The mechanism of DDQ-
mediated oxadiazole formation depends on the electron-donating and electron-withdrawing
property of substituent in aroylhydrazone. Electron-donating and electron-withdrawing group
preferred the SET and non-SET mechanisms, respectively.
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CONCLUSIONS
The 1,3,4-oxadiazoles were prepared from acyl hydrazides and aromatic aldehyde using
DDQ as the oxidant. The oxidative cyclization method was successfully performed without
isolation of the aroylhydrazone intermediate. Systematic quantum mechanical studies for this
reaction revealed that there are two equally possible mechanisms for the oxadiazole formation;
1) the SET from the substrate to DDQ, which is important as described in many other oxidative
reactions employing DDQ, reduces the activation energy of the intramolecular cyclization step
to form oxadiazole ring, and 2) the concurrent 1,2-addition + PT followed by cyclization to
form the oxadiazole ring without the SET. Our study demonstrates that in addition to the well-
accepted electron transfer pathway, the nucleophilic addition / elimination pathway for DDQ
should also be considered as a possible mechanism of oxidative transformation reaction using
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EXPERIMENTAL SECTION
General
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All reagents were purchased from Sigma-Aldrich, TCI and Merck. All hydrazides (1) and
aldehydes (2) were commercially available and were used as received. The 1H NMR spectra
were obtained using Jeol JNM-AL300 spectometer at 300 MHz with tetramethylsilane as the
internal reference. Melting points were measured with Mel-Temp 3.0 (Laboratory Devices
Inc., USA). Flash column chromatography was performed with Merck silica gel 60 (70-230
mesh). Products were identified from the 1H NMR and melting point after comparison with
literature data.
General Experimental Procedure
A mixture of aroylhydrazide (1.20 mmol) and aromatic aldehyde (1.01 mmol) in toluene (5 ml)
under reflux using oil bath was stirred for 2 hr. Then, DDQ (340 mg, 1.50 mmol) was added to
the reaction mixture. The reaction mixture was stirred for 20 hr and then poured into 1 N NaOH
aqueous solution. The crude mixture was extracted with ethyl acetate. The organic solution was
washed with water and dried by MgSO4. The resulting crude mixture was purified by flash
chromatography (hexanes/ethyl acetate) to provide 4.
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (4a).
Amorphous solid, (hexanes/ethyl acetate = 3:1, rf = 0.31); 249 mg, yield (99%); mp = 150-
153oC (150-151oC)83; ¹H NMR (CDCl3, 300 MHz): δ 8.12~8.15 (m, 2H), 8.09 (d, J = 8.6Hz,
2H), 7.50~7.55 (m, 3H), 7.04 (d, J = 8.6Hz, 2H), 3.90 (s, 3H).
2-Phenyl-5-p-tolyl-1,3,4-oxadiazole (4b).
Amorphous solid, (hexanes/ethyl acetate = 3:1, rf = 0.51); 217 mg, yield (92%); mp = 152-
154oC (146-148oC)38 ; ¹H NMR (CDCl3, 300MHz): δ 8.14 (dd, J = 7.7, 3.3 Hz, 2H), 8.04 (d,
J = 8.1 Hz, 2H), 7.52~7.55 (m, 3H), 7.34 (d, J = 8.1Hz, 2H), 2.45 (s, 3H).
2,5-Diphenyl-1,3,4-oxadiazole (4c)
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Amorphous solid, (hexanes/ethyl acetate = 3:1, rf = 0.50); 193 mg, yield (87%); mp = 138-
140oC (139-140oC)83; ¹H NMR (CDCl3, 300 MHz): δ 8.14~8.17 (m, 4H), 7.51~7.59 (m, 6H).
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2-(4-Bromophenyl)-5-phenyl-1,3,4-oxadiazole (4d).
Amorphous solid, (hexanes/ethyl acetate = 3:1, rf = 0.56); 223 mg, yield (74%); mp = 172-
174oC (173-174oC)83; ¹H NMR (CDCl3, 300 MHz): δ 8.14 (dd, J = 8.0, 2.4 Hz, 2H), 8.02 (d,
J = 8.6 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.51~7.60 (m, 3H).
2-(4-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole (4e).
Amorphous solid, (hexanes/ethyl acetate = 3:1, rf = 0.36); 82.8 mg, yield (31%); mp = 210-
213oC (206oC)38; ¹H NMR (CDCl3, 300 MHz): δ 8.42 (d, J = 8.8 Hz, 2H), 8.34 (d, J = 9.0
Hz, 2H), 8.17 (d, J = 7.9 Hz, 2H), 7.57~7.64 (m, 3H).
2,5-Bis(4-methoxyphenyl)-1,3,4-oxadiazole (4f).
Amorphous solid, (hexanes/ethyl acetate = 3:1, rf = 0.50); 279 mg, yield (99%); mp = 165-
167oC (159-161oC)84; ¹H NMR (CDCl3, 300 MHz): δ 8.05 (d, J = 8.4 Hz, 4H), 7.02 (d, J =
8.6 Hz, 4H), 3.89 (s, 6H).
2-(4-tert-Butylphenyl)-5-phenyl-1,3,4-oxadiazole (4g).
Amorphous solid, (hexanes/ethyl acetate = 4:1, rf = 0.48); 262 mg, yield (94%); mp = 99-
100oC (98-99oC)85; ¹H NMR (CDCl3, 300 MHz): δ 8.13 (dd, J = 7.5, 4.2 Hz, 2H), 8.06 (d, J =
8.4 Hz, 2H), 7.51~7.55 (m, 5H), 1.38 (s, 9H).
COMPUTATIONAL METHODS
The reactants, products, intermediates, and TS structures were fully optimized at the
M06-2X/6-31+G(d,p) level using the Gaussian 09 program.86 All optimized and transition state
structures were confirmed to have zero and one imaginary frequency, respectively. The SMD
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model87 was used to calculate the free energy in solution and a standard state correction was
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ACKNOWLEDGMENTS
This research was supported by a grant from the National Research Foundation of Korea
(NRF Grant No. 2015R1D1A1A09061386) and (NRF-2017R1A2B4006856).
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