Copper-free cycloaddition of azide and alkyne in crystalline state facilitated by arene–perfluoroarene interactions

Abstract

Facilitated by arene–perfluoroarene interactions, a 1,3-dipolar cycloaddition between azide and alkyne proceeded in the crystals at room temperature in the absence of a copper(I) catalyst, and the reaction was confirmed to be a highly regioselective process giving the 1,4-triazole product.

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1,3-Dipolar cycloaddition of azide and alkyne was first discovered by Arthur Michael and further developed by Rolf Huisgen.¹ Due to the high activation energy,² these reactions used to require elevated temperature to achieve acceptable rates and yields, and typically show poor regioselectivity.³ Ever since the discovery that certain copper(I) complexes could facilitate the reactions with enhanced regioselectivity and conversion, copper-catalyzed azide–alkyne cycloaddition (CuAAC) has become one of the most versatile reactions in the “click” chemistry toolbox proposed by Sharpless.⁴ Nonetheless, the toxicity of copper ion has prohibited the application of this reaction in biological systems. Developing a highly efficient, copper-free version of AAC has attracted great efforts. So far 1,2,3-triazoles from strained cyclooctynes and tandem [3 + 2] cycloaddition-retro-Diels–Alder reactions without the copper catalyst have been reported.⁵ However, few systems have achieved regioselectivity with terminal alkynes under mild conditions in the absence of transition metal catalysts. Among the limited reports, regioselectivity facilitated by cucurbuturil or an enzyme owing to their oriented supramolecular binding of specifically designed alkynes and azides, are the intriguing examples.⁶ Here we report an example of a copper-free 1,3-dipolar cycloaddition of azide to terminal alkyne with high regioselectivity for 1,4-triazole at room temperature, which was realized by harnessing the arene–perfluoroarene interaction in the crystalline state.

It is well known that benzene and hexafluorobenzene can form 1 : 1 co-crystals with a melting point of 23.7 °C, considerably higher than either of the two individual components.⁷ The binding energy of benzene with hexafluorobenzene was estimated to be 3.7–4.7 kcal mol⁻¹ in the crystal.⁸ A similar alternating face-to-face stacking motif of phenyl and perfluorophenyl units has also been found in crystal structures of other arene–perfluoroarene-containing complexes.^7,9 The alternating arrangement was attributed to the dispersion and quadrupolar interactions between arenes and perfluoroarenes. More recently, arene–perfluoroarene interactions have also been widely utilized in supramolecular chemistry, e.g., crystal engineering,⁹ rotaxane synthesis,¹⁰ liquid crystallinity induction,¹¹ and solid-state reactions.¹²

The strategy used in our system design is shown in Fig. 1. A Schiff-base molecule was designed with azide and alkyne functional groups positioned at opposite ends, in which one of the phenyl rings was perfluorinated. It was envisioned that if the arene–perfluoroarene interactions were to take effect in the crystalline state of the molecule, the alkyne and azide functional groups may be arranged in an optimal relative position favorable for the cycloaddition to take place. The imine group was purposefully incorporated to take advantage of its facile cleavage through hydrolysis. Thereby, the polymer product resulting from the cycloaddition reaction can be conveniently degraded into small molecules, facilitating the identification and characterization of the triazole functionality projected to be formed.

Fig. 1 Schematic representation of strategy used for copper-free 1,3-dipolar cycloaddition of azide and alkyne facilitated by arene–perfluoroarene interaction.

Imine 1 (Fig. 1) was synthesized as yellow crystals soluble in most organic solvents (see the ESI).† However, after standing under ambient conditions for 14 days, imine 1 became an insoluble solid (polymer 2).¹³ Only a trace amount of imine 1 could be extracted from the resultant insoluble solid with acetone, which was a good solvent for imine 1. A characteristic band at 963 cm⁻¹ in the Raman spectrum (in-plane ring bending band of triazole)¹⁴ of 2 reveals that a triazole ring was formed in polymer 2. Hydrolysis of 2 affords compound 3 (in 40% yield) in addition to some insoluble residues that cannot be totally hydrolyzed in 3 days, likely some high molecular weight polymers. It is reported that the chemical shifts of 1,4-disubstituted triazole and 1,5-disubstituted triazole have a significant distinction.¹⁵ As a control experiment, a copper(I) catalyzed 1,3-dipolar cycloaddition was carried out for imine 1 in THF and yielded polymer 2′. Upon hydrolysis, polymer 2′ afforded a major product which was proved to be the same (compound 3) as the hydrolysis product of 2 by ¹H NMR (Fig. 2).

Fig. 2 Cycloaddition of azide and alkyne by standing under ambient condition for 14 days or catalyzed by copper(I) in THF, and facile cleavage of resulting products to generate triazole 3. The ¹H NMR spectra after hydrolytic workup reveals that triazole 3 from polymer 2 and polymer 2′ are the same.

In order to verify that the arene–perfluoroarene interaction had facilitated the cycloaddition by offering an optimal spatial arrangement of alkyne and azide groups, efforts were made at elucidating the solid-state structure of 1. Careful evaporation of a solution of imine 1 in dichloromethane–methanol at 5 °C afforded bright yellow crystals suitable for single crystal X-ray diffraction.‡ X-ray analysis (Fig. 3a and b) reveals a columnar packing of imine 1 in the crystal lattice with azide and alkyne groups aligned between columns. The phenylene and tetrafluorophenylene were stacked alternately in a face-to-face fashion, and weak C–H⋯F interactions between two neighboring molecules likely help stabilize the columnar stacking.¹⁶

Fig. 3 ORTEP drawing of the crystal structure of imine 1 with 30% probability thermal ellipsoids along [100] (a) and [010] (b). The distances between alkyne carbon atoms and azide nitrogen atoms are shown with double-head arrows.

The crystal structure of imine 1 gives certain insight into the origin of the high regioselectivity in the formation of triazoles in 2. Imine 1 was packed into columns in the crystals with alkyne and azide groups stacked alternatively. The shortest distances between the alkyne carbon atoms and 1- and 3-nitrogen atoms of the azide group within a column were 3.58 Å and 4.17 Å (Fig. 3a); the shortest corresponding distances between these two kinds of atoms from neighboring columns were 3.43 Å and 3.97 Å (Fig. 3b). Considering the similarity, the distances between azide and alkyne cannot solely provide a decisive explanation for the regioselectivity of the reaction in the crystal. The outcome of the reaction, namely the high selectivity for the 1,4-triazole product, suggests the inability for the molecules to migrate along the b-axis within the infinite stacks to give the 1,5-product. Whereas the alkyne and azide groups from neighboring columns approaching each other by migrating in the (100) plane perpendicular to the b-axis appears more feasible.¹⁷

In summary, we have demonstrated a copper-free 1,3-dipolar cycloaddition of azide and alkyne at room temperature in the solid state. Crystal packing facilitated by arene–perfluoroarene interactions offered a desirable spatial arrangement of the azide and alkyne functional groups, and therefore promoted a relatively well-controlled regioselective “click” polymerization. Hydrolysis of the imine bond in the resulting polymers yielded a soluble triazole degradation product, which provided direct evidence for the high 1,4-regioselectivity. This design opens up new opportunities for utilizing supramolecular interactions to promote and control chemical reactions.

Acknowledgement is made to the National Basic Research Program (2007CB808000 and 2002CB613402) from the Ministry of Science and Technology and National Natural Science Foundation of China.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental details, ¹H NMR, ¹³C NMR and ¹⁹F NMR spectra. CCDC 731680. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/b912337g

‡ Single Crystals of imine 1 were prepared by solvent evaporation method. Imine 1 (5 mg) was dissolved in a mixture of CH₂Cl₂ (1 mL) and methanol (1 mL). The solution was kept in a fridge at 5 °C until yellow crystals suitable for single-crystal diffraction were obtained. Crystal data for1: C₁₅H₆F₄N₄, M = 295.21, monoclinic, space group P2₁/c, a = 6.1856(12) Å, b = 7.2446(14) Å, c = 29.281(6) Å, β = 92.57(3)°, V = 1310.8(4) ų, T = 113 K, Z = 4, μ = 0.141 mm⁻¹, D_c = 1.613 g cm⁻³, F(000) = 640, λ = 0.71073 Å, total of 9472 reflections collected, 2317 independent reflections (R_int = 0.043), R1 [I > 2σ(I)] = 0.0450, wR2 [I > 2σ(I)] = 0.1170, R1 [all data] = 0.0545, wR2 [all data] = 0.1244, CCDC-731680. Structures were solved by direct methods with SHELXS-97 and refined against F² with SHELXS-97.

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