Based
on above results, the mechanism of Cu(OTf)2 catalyzed
[3+2] cycloaddition of trifluoromethylated Nacylhydrazones and
isoprene can be summarized as Figure 12. The initial reactant A can
isomerize to B firstly. After that, the B isomer forms complex C with
Cu(OTf)2. With the addition of isoprene, the initial
configuration CR1 for the [3+2] cycloaddition is formed. From CR1,
the intermediate structure M1 that combined the final product and
Cu(OTf)2 catalyst can be formed via a concerted
asynchronous mechanism after overcoming a small barrier of 3.2 kcal/mol:
the CC bond forms first and then CN bond is formed immediately. This
process is driven by the electrostatic interactions. After the departure
of the Cu(OTf)2 catalyst, we can finally get the
[3+2] product CF3substituted synpyrazolidine P1.
It is worth to notify that another enantiomer of P1, P5, can also be
formed in the similar way via the enantiomer of C, CR1, TS1 and M1 with
the same syn conformation. During the reaction process, the
Cu(OTf)2 is revealed to play an important role for the
diastereoselectivity and accelerating of the reaction process.
Figure 12. The concerted asynchronous mechanism of
Cu(OTf)2 catalyzed [3+2] cycloaddition of
trifluoromethylated Nacylhydrazones and isoprene based on our present
computational results.
Conclusions
In this work, we have systematically investigated the underlying
mechanism of Cu(OTf)2 catalyzed [3+2] cycloaddition
of trifluoromethylated Nacylhydrazones and isoprene to synthesis
CF3substituted pyrazolidine using high level density
functional theory method. About eight possible initial configurations of
the [3+2] reaction is considered and all relevant reactants,
transition states and products are optimized. The related IRC paths are
also explored in detail. Based on the transition state structures, IRC
paths and the wavefunction analysis, we concluded that the
Cu(OTf)2 catalyzed [3+2] cycloaddition follow a
concerted asynchronous mechanism. The CN bond forms immediately after
the formation of the CC bond. The lowest energy barrier for the
[3+2] reaction that lead to the CF3substituted
synpyrazolidine are about 3.2 kcal/mol, which might be the reason of
the diastereoselectivity that observed in experiment. To figure out the
exact role of the Cu(OTf)2 played in the [3+2]
reaction, we have also investigated the reaction processes that without
Cu(OTf)2 molecule. The computational results indicate
that the energy barriers that form the diastereoisomers are much closer
and also larger than the Cu(OTf)2 catalyzed one, i.e.
2.4 kcal/mol vs 3.7 kcal/mol and 8.0 kcal/mol vs 3.2 kcal/mol.
Therefore, Cu(OTf)2 catalyst play an important role for
the diastereoselectivity of the [3+2] cycloaddition reaction. Our
present work not only provides the detail mechanism of the
Cu(OTf)2 catalyzed [3+2] cycloaddition of
trifluoromethylated Nacylhydrazones and isoprene, but also can be
helpful for the future designation of Cu(OTf)2 based
cycloaddition processes.
Supporting Information
Available
Additional figures, tables and all optimized Cartesian coordinates can
be found in Supporting Information.
Acknowledgement
This paper was supported by the High Performance Computing Center of
Sichuan Normal University, China.
Keywords: Density Functional Theory [3+2] Cycloaddition
Concerted Asynchronous Mechanism CF3substituted
Pyrazolidine
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