Abstract
In this study, we performed density functional theory calculations using
the B3LYP, M052X, M062X, and APFD functionals to investigate substituent
effects on the mechanism of 1,3-dipolar cycloaddition, a classical and
effective method for the synthesis of heterocyclic compounds. The
results showed that changing the substituents on the chloroxime
compounds affects the energy level of the highest occupied molecular
orbital and consequently, the progress of the reaction. Finally, it
provided an effective idea for this kind of reaction in the design of
organic synthesis and the necessary theoretical basis for revealing the
course of this reaction.
Keywords: 1,3-dipolar cycloaddition reaction; Density
functional theory; Reaction mechanism;
Introduction
1,3-Dipolar cycloaddition is a reaction that not only plays an important
role in the synthesis of five-membered heterocyclic compounds, but also
has great significance in theoretical organic chemistry.1-4 Diversity-oriented synthesis refers to a kind of
forward synthesis that usually uses branching diffusion to focus on the
diversity and complexity of compounds with the aim of expanding the
compound library from point to face.5-7 Because this
synthetic method can use combinatorial chemistry to synthesize similar
compounds, the properties and structure-activity relationship of the
synthesized compounds can be easily studied.8Moreover, it hastens the building of a library of natural products with
diverse molecular skeletons, complex structures, and rich chemical
properties and facilitates the discovery of more lead
compounds.9
To discover anti-tumor compounds with novel, molecularly diverse
skeletons, several research groups have joined the field of antitumor
treatment. At present, in the context of drug resistance, the use of the
1,2,4-oxadiazole skeleton has become a new direction in drug
design.10-13 Among the compounds with this skeleton,
3-aryl-5-(3-chlorothiophene-2-yl)-1,2,4-oxadiazole compounds have
exhibited good activity for a few breast and colon cancer cell lines and
retained activity in experiments with mice.14 A series
of novel triaryl-1,2,4-oxadiazole derivatives synthesized by Miralinaghi
et al. also showed good cytotoxic activity against the MCF-7 tumor cell
line (IC50 = 6.50 μM).15 Gakh et al. developed a
series of diaryl-5-amino-1,2,4-oxadiazole derivatives as powerful
tubulin inhibitors. The 4-position PhNH fragment on the aryl group of
the compound is the decisive pharmacophore of compound activity.
Compounds DCP 10500071 and DCP 10500078 showed particularly good
activity against tubulin with IC50 values of 2.6 and 1.9 μM,
respectively.16 Muraglia et al. developed a series of
4-(3-(quinoline-2-yl)-1,2,4-oxadiazole-5-yl) piperazine urea compounds
for the treatment of tumors with abnormal Hedgehog signaling pathway.
Moreover, a structure-activity relationship study confirmed that these
compounds are particularly effective antagonists and show a certain
antitumor activity in mice.17 In addition, the
1,2,4-oxadiazole derivatives, BDM31343, BDM31381, and BDM41906, which
were designed by structure-activity relationship analysis, were found to
be useful reagents for the treatment of pulmonary tuberculosis. They
have shown improved activity, through indirect in vivo experiments, and
have effectively overcome the resistance of pulmonary tuberculosis to
ethylthioisoamide.18-19 In addition, a few
1,2,4-oxadiazole derivatives showed great potential in the treatment of
Alzheimer’s disease. Specifically, these drugs can prevent amyloid
protein polymerization and related oxidative stress, resulting in
neuroprotective effects.20 Phidianidine has been
synthesized and used to evaluate the neuroprotective effects of
compounds on SH-SY5Y cells by introducing it simultaneously with
neurotoxic substances, such as Aβ 25-35, hydrogen peroxide, and oxidized
glucose. The results showed that phidianidine exhibited a good
neuroprotective effect in vitro and counteracted the effects of these
neurotoxic substances.21-22 Indolone, as the main
skeleton of alkaloids, has always been considered by pharmaceutical
chemists, especially in the development of new therapeutic
drugs.23-25 Indolone derivatives have a good
biological potential because of its various biological
activities,26 such as antibacterial,
anti-tuberculosis, antioxidant, antihistamine, anti-HIV,
anti-inflammatory, anti-Parkinson, anti-diabetic, and antitumor
activities.27 At present, several of these biological
activities have also been well studied. Through these studies, indolone
can be modified more scientifically and reasonably, and this will play a
vital role in the development of effective drug therapy in the
future.28 In addition, the synthesis and properties of
oxime compounds remains an important direction in pesticide
research.29 Therefore, by using the 1,3-dipolar
compound, o -chlorobenzoxime, and compounds with both
electrophilic and affinity sites, heterocyclic compounds with novel
structures and natural products can be synthesized by a simple and rapid
method. However, details of the 1,3-dipolar cycloaddition mechanism of
substituted chloroxime compounds remains unclear because theoretical
analysis of such reactions is rarely reported. In view of the current
research on the 1,3-dipolar cycloaddition mechanism, the purpose of this
study was to analyze the effect of substitution of chloroxime compounds
by quantum chemical calculations combined with thermodynamic and kinetic
studies. The effects of different substituents on the liquid- and
gas-phase reaction mechanisms were explained.
In this study, the 1,3-dipolar cycloaddition product synthesized by
multiple guiding methods was used as the system. Using four different
density functionals, B3LYP, M052X, M062X, and APFD, the 1,3-dipolar
cycloaddition mechanism was determined theoretically. In summary, we
revealed the effects of different chloroxime substituents on the
1,3-dipolar cycloaddition mechanism, which are consistent with the law
of organic reaction. Thus, our findings provide a theoretical
explanation of experimental phenomena and guidance for the development
of new processes.
Computational Details
In this study, geometry optimization and vibrational analysis of a
series of reactants, products, intermediates, and transition states were
carried out using the 6-31G(d) basis set and B3LYP, M052X, M062X, and
APFD functionals. The calculated results were analyzed, and the
similarities and differences between these functionals were determined.
Studies of the reaction mechanism in the solution and gas phases and the
search for the transition states were performed using the Gaussian 09W
D.01 9.0 program.30 Configuration optimization of the
reactants, products, intermediates, and transition states was carried
out at the B3LYP/6-31G(d) level. The reaction mechanism in solution was
calculated at the B3LYP/6-31G(d) level using the intrinsic reaction
coordinate (IRC) and polarizable continuum model (PCM) methods. The
curves of the bond angle, bond length and energy of the transition state
with the reaction coordinates are obtained. The vibrational states of
the optimized transition states, TS1–TS3, were analyzed to determine
whether the force constant matrix only has one negative eigenvalue and
confirm the authenticity of the transition state. The vibration mode
corresponding to the eigenvector pointed to the corresponding reactants
and products in the reaction. And we used GaussView 5.0 to view the
frontier orbitals of the molecules at the B3LYP/6-31G(d) level. The
transition state is searched and the vibration frequency is analyzed at
the M062X/6-31G(d) level, and the reaction intermediate and transition
state can be determined by vibration analysis. We also carried out the
(IRC) analysis of the intrinsic reaction coordinates to determine
whether the transition state can truly reflect the relationship between
the reactants and the products. Finally, the single-point energies of
the stationary points were calculated at the MP2/cc-pVTZ level, and the
relevant thermodynamic data (zero-point energy and Gibbs free energy)
were obtained. The reactions of different substituted compounds and
trends in the activation energies (ΔE a) during
the reaction were compared and analyzed.
Results and Discussion
In this study, we initially used substituted chloroxime
(1a –o ) and isatin (2a –e ) compounds
as the raw materials. As indicated in the synthetic route shown in
Scheme 1, novel polyheterocyclic 1,2,4-oxadiazolindolone compounds were
obtained in high yield in a one-step reaction under relatively mild
reaction conditions without using any metal catalyst. A total of 36
target compounds were synthesized with yields of 46–96%. The proposed
reaction mechanism is shown in Scheme 2. In addition, our research group
has published our main synthetic methods and related results (for
specific synthetic methods and characterization, see Supporting
Information 1).31 To deeply and systematically study
the details of the 1,3-dipolar cycloaddition mechanism and effect of
different substituents, we performed density functional theory
calculations using various functionals.
Scheme 1. Synthesis of heterocyclic 1,2,4-oxadiazolindolone
compounds.