A theoretical study on the metal-free triazole formation through tandem [3+2] cycloaddition/retro-Diels-Alder reaction of benzyl azide and oxanorbornadienedicarboxylate
Introduction
One of the efficient methods for the selective modification of biomolecules, particularly proteins, is Huisgen azide-alkyne cycloaddition reaction [1]. The azides have been introduced into glycans, lipids, and proteins in living cells [[2], [3], [4]], as a bioorthogonal chemical reporter which can be detected through the Cu-catalyzed azide-alkyne cycloaddition reaction. However, this reaction is not compatible with biological systems due to the toxicity of the copper catalyst. To deal with this problem, the strain promoted cycloadditions of azides and cyclooctyne derivatives (SPAAC), which take place catalyst-free under physiological conditions with appropriate reactivity, were introduced by Bertozzi and co-workers [[5], [6], [7]]. This reaction is used for the imaging of cell surface glycoproteins by fluorescence lifetime imaging microscopy [8,9].
Due to the ring strain and electron deficiency, the oxanorbornadiene (OND) derivatives are also effective ethylenes in the cycloaddition reactions [10]. Tandem [3+2] cycloaddition/retro-Diels-Alder (32CA/R-DA) reaction of azides and oxanorbornadiene derivatives is an efficient metal-free bio-orthogonal conjugation method by creating stable triazole adducts [11]. In a sequence of cycloaddition/retro-Diels-Alder reaction, the OND derivatives behave as other forms of acetylenic compounds. However, the higher reactivity of the substituted OND in comparison with the linear precursors has been explained in terms of the ring strain [10].
In 2011, Blanco and co-workers reported a procedure for synthesis of pyrrolines through a microwave-assisted tandem 32CA/R-DA reaction of azomethine ylides to 7-oxanorbornadiene derivatives in high yields [12]. The required temperature for thiol and amine promoted R-DA reactions of 7-oxanorbornadienes were decreased from above 100 °C–37 °C [13]. A theoretical analysis on the reactivity of oxanorbornadiene thiol and amine adducts was carried out at M06-2X density functional by Fell and co-workers [14]. They utilized the distortion/interaction (D/I) model to analyze the activation energies and amine and thiol role in the fragmentation, as well as substituent effects on the fragmentation rates and reaction energetics.
32CA/R-DA reaction of diazoacetamides with OND, accelerated by the relief of strain in the transition state was reported [15]. Interestingly, due to favourable interactions with the fluoro groups, the rate of the reaction of diazoacetamides with unstrained ethyl 4,4,4-trifluoro-2-butynoate is 35-fold faster than OND. The binding and releasing of drugs from serum albumins using oxanorbornadienedicarboxylates were investigated by Kislukhin [16].
Recently, the role of the strain in the reactivity and regioselectivity of the 32CA reactions of cyclohexyne with methyl azide and methoxycarbonyl diazomethane have been studied within the Molecular Electron Density Theory (MEDT) by Domingo and co-workers [17]. According to MEDT, the reactivity in organic chemistry can be determined through quantum chemical analysis of the changes in the electron density as well as the energies of these changes along the reaction path [18]. Also, the 32CA reactions of acetonitrile oxide with two 7-oxanorborn-5-en-2-ones were studied in the context of a MEDT analysis, where noncovalent interactions (NCI) [19] topological analysis of TSs was used to explain the observed complete syn diastereofacial selectivity [20].
The importance of the relationship between structure and reactivity in the mechanism of the cycloaddition reactions prompted us to study the domino 32CA/R-DA reaction between 7-oxabicyclo [2.2.1]hepta-2,5-diene-2,3-dicarboxylate (OND) 2 and benzyl azide 1 within the MEDT framework using DFT quantum mechanical methods (Scheme 1). Van Berkel et al., experimentally found that this domino reaction is faster than the cycloaddition reaction of the corresponding linear alkyne, dimethyl acetylenedicarboxylate (DMAD) with benzyl azide with similar triazole product [10]. It is noteworthy that the formation of a 1,2,3-triazole in the course of 32CA/R-DA domino reaction has not been studied by theoretical methods. Despite the importance of the click reaction of OND as a metal-free bio-orthogonal method to prepare the stable triazole adducts but, to our knowledge, there isn’t any theoretical study on its mechanism and selectivity, especially within the MEDT framework. In this work, the energy pathways for the 32CA reaction were compared with the reaction of benzyl azide with DMAD as a strain-free reaction. Electron localization function (ELF) topological analysis of the structures involved in the IRC pathway of the reaction as well as NCI gradient isosurfaces in the possible transition states were studied. Finally, to shed more light on the mechanism of this domino reaction, the attractive interactions in the possible TSs of the 32CA reactions and the repulsive interactions in TSs of the furan loss steps have been studied for the first time within NCI topological analysis.
Section snippets
Computational methods
DFT calculations were carried out using Gaussian 09 package [21] at B3LYP/6-31G (d,p) and M06-2X/6-31G (d,p) levels of theories. Previously, we used B3LYP and M06-2X functionals successfully to study the molecular mechanisms of various 32CA reactions [[22], [23], [24], [25], [26]]. All calculations were carried out in the gas phase. The geometries of the transition states were optimized using Berny method without any symmetrical restriction [27,28]. The calculated frequencies were utilized to
DFT analysis based on the global reactivity indices
To study the mechanism of the 32CA reaction of OND 2 and benzyl azide 1, global indices named the electronic chemical potential, chemical hardness, global electrophilicity index are calculated for the reactants (Table 1). The global electrophilicity index, which is the total ability to attract electrons, defined as the ratio ω = μ2/(2η), where μ is the electronic chemical potential and η is the chemical hardness [31]. The electronic chemical potential (μ) and chemical hardness (η) are the mean
Conclusion
In summary, the mechanism and selective behaviour of the 32CA/R-DA reaction between OND 2 and benzyl azide 1 were studied within the MEDT framework at B3LYP/6-31G (d,p) and M06-2X/6-31G (d,p) levels of theory. The GEDT calculations at TSs showed that only TS2a has the polar character and the other reactions are non-polar.
Based on the thermodynamic quantities, the 32CA reaction between benzyl azide 1 and OND 2 occurs with less activation energy in comparison with the reaction of benzyl azide 1
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors acknowledge University of Mazandaran and Islamic Azad University, Jouybar Branch for financial support of this work.
References (39)
- et al.
Strain promoted click chemistry of 2- or 8-azidopurine and 5-azidopyrimidine nucleosides and 8-azidoadenosine triphosphate with cyclooctynes. Application to living cell fluorescent imaging
Bioconjugate Chem.
(2015) - et al.
A DFT study of inter- and intramolecular aryne ene reactions
Eur. J. Org Chem.
(2015) - et al.
Mechanism and origins of the regioselectivity in the [3+2] cycloaddition reaction of an azomethine ylide with benzoimidazole-2-yl-3-phenylacrilonitrile: a DFT approach
J. Mol. Graph. Model.
(2018) A density functional theory study on the reaction mechanism of hydrazones with α-oxo-ketenes: comparison between stepwise 1,3-dipolar cycloaddition and Diels–Alder pathways
Compt. Rendus Chem.
(2017)- et al.
A DFT study of inter- and intramolecular aryne ene reactions
Eur. J. Org Chem.
(2015) - et al.
Chemistry in living systems
Nat. Chem. Biol.
(2005) - et al.
Selective identification of newly synthesized proteins in mammalian cells using bioorthogonal noncanonical amino acid tagging (BONCAT)
Proc. Natl. Acad. Sci. U. S. A.
(2006) - et al.
Chemical probes for the rapid detection of fatty-acylated proteins in mammalian cells
J. Am. Chem. Soc.
(2007) - et al.
Cell surface engineering by a modified Staudinger reaction
Science
(2000) - et al.
A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems
J. Am. Chem. Soc.
(2004)
A comparative study of bioorthogonal reactions with azides
ACS Chem. Biol.
A strain-promoted [3 + 2] Azide−Alkyne cycloaddition for covalent modification of biomolecules in living systems
J. Am. Chem. Soc.
Copper-free click chemistry for dynamic in vivo imaging
Proc. Natl. Acad. Sci. U. S. A.
Metal-free triazole formation as a tool for bioconjugation
Chembiochem
Application of Metal-free Triazole Formation in the Synthesis of Cyclic RGD – DTPA Conjugates
Modular Degradable Hydrogels Based on Thiol-Reactive Oxanorbornadiene Linkers
Theoretical Analysis of the Retro-Diels − Alder Reactivity of Oxanorbornadiene Thiol and Amine Adducts
1,3-Dipolar cycloaddition with diazo groups: noncovalent interactions overwhelm strain
Org. Lett.
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