Mechanisms of the cascade synthesis of substituted 4-amino-1,2,4-triazol-3- one from huisgen zwitterion and aldehyde hydrazone: A DFT study

Article abstract of DOI:10.1002/jcc.22906

The detailed reaction mechanisms of the title reaction are shed light on by using the density functional theory (DFT). The calculated results have demonstrated that the whole reaction takes place via four processes (processes (I-IV)), among which, three possible reaction mechanisms are proposed for process (II) (channels 1-3) and two for process (IV) (channels 4-5). According to our calculated results, channel 3 and channel 5 are verified to be most energetically favorable. As interpreted in the text, in process (II), the proton transfer should be performed prior to the nucleophilic attack, and the AA-Type transfer strategy is more likely to occur. The global reactivity index (GRI) and frontier molecular orbital (FMO) analyses of the aldehyde hydrazone have further supported the AA-Type mechanism. In process (IV), however, the titled product has been demonstrated to be formed by the synergetic elimination of two protons via a six-membered ring transition state. Taking an integrated view, the highest energy barrier for the whole reaction along the most favorable pathway is 32.19 kcal/mol, which is consistent with the mild thermal experimental conditions. More interestingly, the qualified mechanisms in this work have given a perfect explanation to the optimal reactants molar ratio of highest yields (R1/R2/R3 = 2/1/1) employed in the experiment.

Full text of DOI:10.1002/jcc.22906

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Mechanisms of the Cascade Synthesis of Substituted
4-Amino-1,2,4-triazol-3-one from Huisgen Zwitterion
and Aldehyde Hydrazone: A DFT Study
Wenjing Zhang,[a] Yanyan Zhu,*[a] Donghui Wei,[a] and Mingsheng Tang*[a]
The detailed reaction mechanisms of the title reaction are shed
light on by using the density functional theory (DFT). The
calculated results have demonstrated that the whole reaction
takes place via four processes (processes (I–IV)), among which,
three possible reaction mechanisms are proposed for process
(II) (channels 1–3) and two for process (IV) (channels 4–5).
According to our calculated results, channel 3 and channel 5
are verified to be most energetically favorable. As interpreted in
the text, in process (II), the proton transfer should be
performed prior to the nucleophilic attack, and the AA-Type
transfer strategy is more likely to occur. The global reactivity
index (GRI) and frontier molecular orbital (FMO) analyses of the
aldehyde hydrazone have further supported the AA-Type
mechanism. In process (IV), however, the titled product has
been demonstrated to be formed by the synergetic elimination
of two protons via a six-membered ring transition state. Taking
an integrated view, the highest energy barrier for the whole
reaction along the most favorable pathway is 32.19 kcal/mol,
which is consistent with the mild thermal experimental
conditions. More interestingly, the qualified mechanisms in this
work have given a perfect explanation to the optimal reactants
molar ratio of highest yields (R1/R2/R3 ¼ 2/1/1) employed in
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the experiment. 2012 Wiley Periodicals, Inc.
DOI: 10.1002/jcc.22906
Inspired by all these works, more recently, Wang and coworkers
developed another effective cascade synthesis of a series of sub-
stituted 4-amino-1,2,4-triazol-3-ones 3 from Huisgen zwitterions,
which is produced via the reaction of dialkyl azodicarboxylates 1
with PPh3 and the aldehyde hydrazones 2 (as shown in Scheme
1).[27] The procedure was validated to be most efficient when
compounds 1, 2 and PPh3 were mixed at a molar ratio of 2/1/1 in
toluene at 80ꢀC for 1 h. The reaction was performed in a single
step and the process was general and efficient.
Introduction
Triazolinones are an important class of azaheterocyclic organic
compounds with low molecular weights. As pharmacophores,
triazolinones work well with very wide biological activities in
resisting a variety of diseases,[1–7] especially as the potent non-
nucleoside inhibitors of HIV reverse transcriptase.[8] In agricul-
ture, phenyl triazolinone derivatives with herbicidal activities,
known as inhibitors of an enzyme in the chlorophyll biosyn-
thetic pathway,[9,10] have attracted considerable attention from
the field of pesticide chemistry.[11–15] Consequently, great
efforts have been made in developing more efficient synthetic
methods for construction of triazolinones, the majority of
which involves cyclization of semicarbazide,[16] intramolecular
cyclocondensation of hydrazidehydrazones,[17] formyl semicar-
bazides,[18] amidrazone with phosgene or a phosgene surro-
gate,[19] and the Mitsunobu reaction of isocyanates and diiso-
propyl azodicarboxylate.[20]
A possible reaction mechanism was proposed as well. Accord-
ing to the prediction by Wang and coworkers, four processes
should be included (as shown in Scheme 2): (I) formation of the
Huisgen zwitterion M1; (II) involvement of R3; (III) domino proc-
esses of cycloisomerizations; and (IV) generation of the product P.
However, it is still difficult to understand the reaction mechanisms
thoroughly unless we can obtain more details at the molecular
level. For instance: (1) how is the Huisgen zwitterion M1 gener-
ated? (2) Does the nucleophilic attack of M1 to R3 go on first or
the isomerization of R3 induced by proton H11 transfer first? (3)
How many steps are there in the domino process? (4) Does the
elimination of protons H11 and H12 happen step-by-step as pre-
dicted by Wang and coworkers? If not, what’s the pathway? (5)
How about the energy barriers? (6) Why does the most
Particularly, Wang and coworkers have recently reported a
facile access to the diazaheterocyclic compounds pyrazolines
of the Huisgen zwitterions with aziridines via the cascade reac-
tion,[21] which is a very novel and efficient approach to the
azaheterocyclic compounds. The Huisgen zwitterions used can
be generated from the redox couple of triphenylphosphine
(PPh3) and dialkyl azodicarboxylates.[22] Utilizing the Huisgen
zwitterions, Nair et al. have successfully synthesized a variety
of important compounds.[23] Moreover, due to the unarguable
advantages of cascade reactions of being fast, clean, and atom
economy,[24] the cascade reactions can be considered to fall
under the banner of ‘‘green chemistry,’’[25] and has been one
of the subjects of intense researches in recent years.[26]
[a] W. Zhang, Y. Zhu, D. Wei, M. Tang
Department of Chemistry, Zhengzhou University, Zhengzhou, Henan
Province 450001, People’s Republic of China
E-mail: zhuyan@zzu.edu.cn or mstang@zzu.edu.cn
Contract/grant sponsor: National Natural Science Foundation of China;
Contract/grant number: 21001095; Contract/grant sponsor: China
Postdoctoral Science Foundation; Contract/grant number: 20100480858.
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vibrational frequencies of
the stationary points.[38,39]
The corresponding vibra-
tional frequency calcula-
tions were then performed
based on the optimized
geometries at the same
level, so as to confirm that
all the reactants, intermedi-
ates, and product have no
imaginary frequencies, and
each transition state has
one and only one imagi-
nary frequency. To corrob-
orate which are the corre-
spondent minima linked by
the considered transition
state, normal coordinate
analyses are performed on
these transition state struc-
tures by intrinsic reaction
coordinate (IRC) routes[40]
in both reactant and prod-
uct directions. Further-
more, as for more accurate
energy profiles, all the
Scheme 1.
Scheme 2. The four processes for the title reaction. [Color figure can be viewed in the online issue, which is available
at wileyonlinelibrary.com.]
vibrational
frequencies
were recalculated based on
the optimized geometries
appropriate equivalent ratio among the reactants R1/R2/R3 equal
by level A, with all atoms involved in the reaction sites at a
higher level of B3LYP/6-311þþG(3d,p),[41] while others invaria-
ble (B3LYP/6-31G(d,p)) (level B). All energies reported in this ar-
ticle include the zero-point vibrational energy (ZPVE) correc-
tion. The electronic properties of the complexes were
discussed using the natural bond orbital (NBO) analysis at level
A by the NBO 3.1 program.[42]
2/1/1? How do the reactants participate in the reaction? Chal-
lenges to response all these questions motivate the present work.
The computational model studied in this project was
selected based on the experimental results.[27] As it was stated,
the two highest yields of the titled product occur when the
substituent groups R1 ¼ Bn/Et, R2 ¼ 4-NO2C6H4, R3 ¼ Ph and
the yields come up to 98%/97%, respectively. Taking the com-
putational cost into account, we set R1 ¼ Et, R2 ¼ 4-NO2C6H4,
and R3 ¼ Ph. That is, as shown in Scheme 2, the compounds
of diethyl diazene-1,2-dicarboxylate (assigned as R1), PPh3
(assigned as R2), and 4-nitrobenzylidene-2-phenylhydrazine
(assigned as R3) were chosen as the objects of investigation.
Results and Discussion
Discussion in this article has been launched in terms of the four
processes presented in Scheme 2. Possible reaction mechanisms
for each process are given in Schemes 3–6, respectively. The
corresponding potential energy profiles along the optimized
S3-S6
Computational Details
All theoretical calculations were performed using the Gaussian
03[28] program, with the density functional theory (DFT) which
has been widely utilized in the study of reaction mecha-
nism.[29] Noteworthy, the solvent effects of toluene (chosen
from the available experiment[27]) were included and simulated
by the polarized continuum model (PCM)[30–34] in all the fol-
lowing stated geometry optimizations and vibrational fre-
quency calculations. All structures of the reactants, product,
transition states, and intermediates were optimized at the
B3LYP/6-31G(d,p)[35–37] level (level A). Compared with other
levels of theory, the B3LYP method has been recognized to be
sufficiently accurate for predicting reliable geometries and
Scheme 3. Proposed mechanism for process (I). [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
geometrical parameters of the stationary points for each pro-
cess are displayed in the relevant figures. Unless otherwise
specified, the energies (E þ ZPVE) of 2 ꢁ R1 þ R2 þ R3 þ R30
are set as 0.00 kcal/mol as reference in the potential energy
profiles. The detailed calculated results are illustrated as follows.
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Scheme 4. Proposed mechanisms for process (II) (channels 1–3). [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
˚
˚
Process (I): Formation of the Huisgen zwitterion M1
double bond (1.246 A) in R1 to a single bond (1.435 A) in M1.
Consequently, the Huisgen zwitterion M1 is formed, with the
positive NBO charge (NC) concentrated on the P7 atom
(NC(P7) ¼ 1.926e) and the negative one on the N2 atom
(NC(N2) ¼ –0.590e) (Table 1). The energy barrier of this pro-
cess is 7.91 kcal/mol (Fig. 1), which successfully corresponds to
the fact that the Huisgen zwitterions can be produced at
room temperature.[22] Moreover, according to our calculated
results, the energy of M1 is 11.29 kcal/mol lower than that of
the reactants, indicating an exothermic process, which further
demonstrates the stability of the Huisgen zwitterions.
There is only one step, demonstrated by our calculated results,
in the reaction of R1 with R2 via the transition state TS1 to
form M1 (Scheme 3). With the approaching of R1 to R2, one
of the nitrogen atoms (numbered as N1) in the azodicarboxy-
late attacks the phosphor atom (numbered as P7) of the tri-
phenylphosphine, and the transition state TS1 presents. As
can be seen from Figure 1, the distance of N1–P7 reaches
˚
2.385 A in TS1, which is further shortened to 1.675 A in M1.
˚
Meanwhile, the bond length of N1–N2 is elongated from a
Scheme 5. Proposed mechanism for process (III). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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prior to the nucleophilic attack and
is performed via the intermolecular
pathway with the help of M1 (desig-
nated as AB-Type). We have not
focused our discussion on these two
competitive channels because they
are both energetically unfavorable.
In channel 1, a three-membered ring
transition state TS22(1) occurs in
the second procedure, and the
energy barrier of 46.64 kcal/mol
(Supporting Information Fig. S1) is
too high for the reaction to occur
under the experimental conditions.
Channel 2, which is mainly associ-
ated with the base (M1) catalyzed
proton transfer, demanded for the
electrophilic activation of R3, is too
energetic as well (42.79 kcal/mol,
Supporting Information Fig. S2).
Therefore, it is difficult for the reac-
tion of process (II) to proceed via
Scheme 6. Proposed mechanisms for process (IV) (channels 4–5). [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
Process (II): Involvement of R3
either channe1 or channel 2. If interested, one can find
the more detailed discussion (Part S1-S2) in Supporting
Information.
The Huisgen zwitterion M1 generated in process (I) by the
reaction of R1 with R2 is then intercepted by R3. For the
involvement of R3, two sub-procedures are necessary: the
nucleophilic attack of M1 to R3 forming a bond between N2
and C8, and the H11 proton transfer from N10 to N9. Now the
questions are: which sub-procedure happens first? How is the
proton transfer accomplished? Three possible reaction chan-
nels (channels 1–3, Scheme 4) have been hypothesized and
illustrated in the following sections.
Channel 3
Reaction Mechanism. Channel 3, as well as channel 2, also sug-
gests that the intermolecular proton transfer of H11 occurs
prior to the nucleophilic attack. The difference is the transfer
strategy. As shown in Scheme 4, in channel 3, the H11 (H110)
atom is proposed to migrate with the bimolecular-transfer
mechanism between two R3 molecules (designated as AA-
Type).
Channel 1 and channel 2. As shown in Scheme 4, channel 1
assumes the nucleophilic attack of M1 to R3 occurs first, while
channel 2 proposes that the proton transfer of H11 occurs
According to our calculated results, the two protons H11
and H110 are transferred synergistically via the six-membered
ring transition state TS21(3), from the intermediate M20(3)
that is generated as two R3 molecules approach each other.
As shown in Figure 2, the obvious elongation of bond length
0
0
˚
of N10(N10 )–H11(H11 ) (1.018 A (1.018 A), 1.273 A (1.635 A),
˚
˚
˚
˚
˚
and 1.893 A (1.893 A) in M20(3), TS21(3), and M21(3), respec-
tively), along with the distinct shortening of N9(N90)–
0
˚
˚
˚
˚
˚
H11 (H11), (2.115 A (2.115 A), 1.087 A (1.314 A) and 1.041 A
˚
(1.041 A) in M20(3), TS21(3), and M21(3), respectively), has
unequivocally demonstrated the breaking and formation of
the corresponding bonds. What needs to be specially illus-
trated is that, the reaction accounted in process (I) (R1 with
R2) and the one occurring between two molecules of R3 are
two procedures conducted independently. As displayed in
Table 1. NBO charges (NC, e) distributed on some atoms of M1, M3,
and M4 calculated at level A.
Figure 1. Optimized geometries of R1, R2, TS1, M1 calculated at level A
and the potential energy profile (E þ ZPVE) at level B for process (I) (hydro-
gen atoms not involved in reaction sites are omitted; the superscript a rep-
N2
C3
O4
P7
N10
M1
M3
M4
–0.590
–
0.956
–
–
1.926
1.909
1.916
–
–0.504
–
˚
resents adding the energies of R1 þ R3 þ R3’; distances in A; energies in
–0.672
–0.828
—
kcal/mol). [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
–
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Global Reactivity Indexes (GRI) Analysis
of R3. To further explain the proton
transfer mechanism in channel 3,
the GRI of R3 is discussed. The
molecule global electrophilicity
character is measured by electro-
philicity index x,[43a] which is given
by the following expression, x ¼
(l2/2g)[43a–e], in terms of the elec-
tronic chemical potential l and the
chemical hardness g. Both quanti-
ties may be approached in terms
of energies of the frontier molecu-
lar orbital HOMO and LUMO, eH
and eL, as l ꢂ (eH þ eL)/2 and g ꢂ
(eL ꢃ eH). Moreover, according the
HOMO energies obtained within
the Kohn-Sham scheme,[43d] Domi-
ngo et al. gave the nucleophilicity
index N to handle a nucleophilicity
scale.[43e–h] The nucleophilicity
Figure 2. Optimized geometries of M20(3), TS21(3), M21(3), TS22(3), M22(3) calculated at level A and the
potential energy profile (E þ ZPVE) at level B for process (II) via channel 3 (hydrogen atoms not involved in
reaction sites are omitted; for the stationary points with superscript c, the energies of 2 ꢁ R1 þ R2 þ 2 ꢁ
R3 are set as 0.00 kcal/mol as reference; the superscripts c and d represent adding the energies of 2 ꢁ R1 þ
index is defined as N ¼ eH(Nu)
ꢃ
e
H(TCE), in which, the HOMO energy
of tetracyanoethylene (TCE) is
taken as the reference and eH(Nu)
represents the HOMO energy of
the nucleophile (Nu). In our previ-
˚
R2 and R1, respectively; distances in A; energies in kcal/mol).
Figure 2, the energy of M21(3) is much higher than that of
ous studies, these indices have been successfully used to set
forth the [2 þ 2][29a] and [4 þ 2][29b] cycloaddition reaction
mechanisms. Following these definitions, the electrophilic and
nucleophilic indices of the reactant R3 are calculated (Table 2).
As displayed, both the values of x (2.593 eV) and N (3.211 eV)
of R3 are substantial enough to classify R3 as not only a fine
electrophile but also an elegant nucleophile. That is, it is reason-
able for the bimolecular-transfer of the proton H11 (H110)
between two molecules of R3 to take place.
M20(3), which means that M21(3) is able to exist for only a
short period of time in the whole reaction process. Never-
theless, this thermodynamically unfavorable reaction can be
driven by the effective interaction of M1 with M21(3).
Herein, as shown in Scheme 4, we assume that the formation
of M3 is accomplished by the nucleophilic attack of the N2
atom in M1 to the C8 atom in M21(3), accompanied with
providing a R3’ molecule. As shown in Figure 2, the elonga-
0
0
˚
tion of the bond length of N10 –H11 (1.893 A, 2.024 A, and
˚
˚
2.131 A in M21(3), TS22(3), and M22(3), respectively) and
˚
the shortening of the length of N2–C8 (1.858 A in TS22(3)
Frontier Molecular Orbital Analysis of R3. The bimolecular-transfer
mechanism (AA-Type) of the proton H11 (H110) can be verified
to be rational on the basis of frontier molecular orbital (FMO)
considerations as well. As shown in Figure 3, in R3, all of the
N9 (N90), N10 (N100), and H11 (H110) atoms are involved in the
˚
to 1.540 A in M22(3)) indicate that the hydrogen bond N9–
…
H110 N100 is broken simultaneously with the nucleophilic
attack of the N2 atom to the C8 atom. M22(3) is then disso-
ciated to one M3 molecule and one R3’ molecule. This R3’
can again react with M1 and form another M3 via TS23(2),
with an energy barrier of 17.21 kcal/mol (see the last step in
channel 2). The highest energy barrier of channel 3 is 29.41
kcal/mol, a reasonable obstacle for the experimental
conditions.[27]
Table 2. Energies of HOMO (eH), LUMO (eL), electronic chemical
potential (l), chemical hardness (g), gobal electrophilicity (x), and global
nucleophilicity (N) of R3 calculated at level A.
eH (a.u.)
eL (a.u.)
l (a.u.)
g(a.u.)
x (eV)
N (eV)[a]
R3
–0.209
–0.091
–0.150
0.118
2.593
3.211
[a] eH (TCE) ¼ –0.327 a.u.
Figure 3. The FMO analysis of R3.
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Figure 4. Optimized geometries of M3, TS3, M4, TS4, M5, TS5, M6, Ph3PO, TS6, M7 calculated at level A and the potential energy profile (E þ ZPVE) at
level B for process (III) (hydrogen atoms not involved in reaction sites are omitted; the superscripts b, e represent adding the energies of R1 þ R3’ and R1
˚
þ R3’ þ Ph3PO; distances in A; energies in kcal/mol).
area where HOMO or LUMO is localized, which indicates the
reactivity of these activated atoms. Moreover, as displayed, the
population shapes of FMO accord perfectly with the require-
ments of maximum overlap and symmetry match principles
defined in FMO theory. All of these have supplied the prereq-
uisite for the interactions between HOMO and LUMO of R3.
With the approach of the two molecules, the HOMO and
LUMO overlaps, and the six-membered ring transition state
TS21(3) forms.
charge distributed on it has increased significantly from –
0.672e in M3 to –0.828e in M4, which, together with the
increased positive charge on the P7 atom from 1.909 e in M3
to 1.916 e in M4 (Table 1), facilitates the construction of
another five-membered ring (P7N1N2C3O4) transition state
˚
TS4. The distance of P7–O4 is shortened from 3.761 A in M4
˚
˚
to 2.370 A in TS4 and then further to 1.656 A in M5 (Fig. 4).
Concomitantly, the two bonds of N1–P7 and C3–O4 are elon-
˚
gated with the bond lengths increasing from 1.720 A and
˚
˚
˚
Among all the three channels proposed above, the mecha-
nism stated in channel 3 has the lowest energy barrier for the
formation of M3 (29.41 kcal/mol) than those of the other two
channels (63.45 kcal/mol for channel 1 and 42.79 kcal/mol for
channel 2), indicating that channel 3 is the main pathway for
forming M3. Therefore, the H11 atom should be transferred
via bimolecular-transfer (AA-Type) mechanism and prior to the
nucleophilic attack of M1 to R3.
1.269 A in M4 to 1.760 A and 1.304 A in TS4, respectively.
Following, the newly formed five-membered ring is broken
with the continuous elongation of bonds N1–P7 and C3–O4,
˚
˚
˚
˚
from 2.028 A and 1.460 A in M5 to 2.447 A and 1.706 A in
TS5, respectively, resulting in the releasing of a Ph3PO mole-
cule. M6, the product of this step, however, is not a stable
molecule because it contains both the bond-unsaturated N1
atom and the bond-oversaturated O5 atom. Therefore, a rear-
rangement takes place with the ethyl group linked to O5
migrating to the N1 atom through the transition state TS6.
Process (III): Domino process of cycloisomerizations
˚
The bond length of O5–C6 is elongated from 1.478 A in M6
Because of process (III), M3 has been thrown into an ordered
domino reaction process of the intramolecular cycloisomeriza-
tions for the formation of M7. Four steps (two ring-closures,
one molecule-releasing, and one ethyl rearrangement) are
underway (as shown in Scheme 5).
˚
to 3.671 A in M7, while the N1–C6 bond is shortened from
˚
˚
3.011 A in M6 to 1.475 A in M7. The rate-determining step of
this process appears in the last step via TS6, and the energy
barrier is 23.70 kcal/mol (Fig. 4).
Based on results and discussions above, the general skeleton
of the substituted 4-amino-1,2,4-triazolidin-3-one has been
constructed so far. The remaining work is to modify the com-
pound M7 to the title product P.
First, as shown for the NBO population of M3 in Table 1, the
positive charge distributed on the C3 atom (NC(C3) ¼ 0.956e)
and the negative charge on the N10 atom (NC(N10) ¼ –0.504e)
enable the formation of the five-membered ring configuration
(C3N2C8N9N10) transition state TS3. The bond length
Process (IV): Generation of the title product P
˚
of C3–N10 is shortened from 2.862 A in M3 to 2.275 A in
˚
˚
TS3, and further to 1.531 A in M4 (Fig. 4). As a result, the
Two possible strategies (channels 4–5) for the formation of P
from M7 are proposed and illustrated in Scheme 6. As shown,
nucleophilicity of the O4 atom is increased as the negative
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Interestingly, according to our calculated results, the whole
process of the title reaction can be formulized as 2 ꢁ R1 þ R2
þ R3 ¼ P þ Ph3PO þ H2–R1. This means that the mixed
molar ratio of the three reactants should be R1/R2/R3 ¼ 2/1/
1, which is perfectly consistent with the ratio of the best yield
selected in the experiment.[27]
Conclusions
The detailed reaction mechanism for the cascade synthesis of
substituted 4-amino-1,2,4-triazole-3-one from the Huisgen
zwitterion and the aldehyde hydrazone has been investigated
by using the DFT. The solvent effects of toluene were simu-
lated by the PCM. The calculated results demonstrate that
this cascade reaction takes place via four processes: (I) the
Huisgen zwitterion M1 is formed from the reaction of R1
with R2; (II) R3 is involved via two steps, and the isomeriza-
tion induced by the H11 proton transfer proceeds prior to
the nucleophilic attack of M1 to R3. The AA-Type proton
transfer mechanism (channel 3) is demonstrated to be the
most energetically favorable among the three proposed
channels. The GRI and FMO analyses have further supported
the AA-Type proton transfer strategy; (III) the domino process
of cycloisomerization from M3 to M7 involves four steps: two
intramolecular ring-closures, one molecule-releasing, and one
ethyl rearrangement; (IV) the eliminations of the H11 and
H12 atoms are accomplished with the participation of a R1
molecule. The calculated results showed that the pathway
(channel 5) via a six-membered ring transition state has a
much lower energy barrier and therefore is energetically
favored.
Figure 5. Optimized geometries of M7, TS7(5), P, H2-R1 calculated at level
A and the potential energy profile (E þ ZPVE) at level B for process (IV) via
channel 5. (hydrogen atoms not involved in reaction sites are omitted; the
superscript f represents adding the energies of R3’ þ Ph3PO; distances in
˚
A; energies in kcal/mol). [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
the formation of P is to be accomplished by eliminating the
H11 and H12 atoms and forming a double bond between C8
and N9. According to our calculated results, a molecule of R1
must be involved to help the removal of the two protons.
Channel 4. Channel 4 assumes that the protons H11 and H12
are eliminated step-by-step as predicted by Wang and co-
workers. Similar to channel 1, we are reluctant to make
detailed discussion on channel 4 because along the reaction
path, there are two four-membered ring transition states with
very high potential energies (TS71(4) and TS72(4), Scheme 6),
especially the energetic fused configuration of the four-mem-
bered ring (C8H12N1’N9) and the five-membered ring
(N9N10C3N2C8) in TS72(4), which contribute a lot to the
extremely high barrier (100.45 kcal/mol, Supporting Informa-
tion Fig. S3) of the second procedure. Therefore, the reaction
is unlikely to take place under the experimental conditions
along channel 4. Likewise, the more detailed discussion (Sup-
porting Information Part S3) of channel 4 has been provided
in Supporting Information.
In conclusion, the most probable route for the whole reac-
tion to occur is ‘‘process (I) ! process (II) by channel 3 !
process (III) ! process (IV) by channel 5.’’ As it can be seen
from the potential energy profiles for the whole reaction
(see Supporting Information Fig. S4), the highest energy bar-
rier appears in the procedure from M1 þ M21(3) to TS3,
and the obstacle of 32.19 kcal/mol is consistent with the
mild thermal experimental conditions. More interestingly, the
mechanism suggested in this article has also perfectly
responded the experimental fact that the title product can
be afforded in best yield with mixed molar ratio of R1/R2/R3
¼ 2/1/1. All calculated results are in good agreement with
the experiments.
Keywords: reaction mechanisms cascade reaction Huisgen
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Channel 5. Channel 5 supposes that protons H11 and H12 are
transferred synergistically via the six-membered transition state
TS7(5) (Scheme 6). As can be seen from Figure 5, lengths of
the four bonds, N9–H11, H11–N20, N10–H12, and H12–C8, are
Zwitterion proton transfer Domino process DFT
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How to cite this article: W. Zhang, Y. Zhu, D. Wei, M. Tang,
˚
˚
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J. Comput. Chem. 2012, 33, 715–722. DOI: 10.1002/jcc.22906
1.329 A, 1.226 A, 1.918 A, and 1.138 A, respectively, in TS7(5),
after which the bond type of C8–N9 is changed from a single
bond to a double bond, indicating the formation of the title
product P. Due to the much more stable six-membered ring
configuration in TS7(5), the activation barrier is greatly low-
ered (14.23 kcal/mol vs. 100.45 kcal/mol). Therefore, for the
last process of the title reaction, channel 5 is much more ener-
getically favorable.
Additional Supporting Information may be found in the
online version of this article.
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