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. 2024 Oct 30;146(43):29496-29502.
doi: 10.1021/jacs.4c09066. Epub 2024 Oct 21.

Skeletal Editing of Mechanically Interlocked Molecules: Nitrogen Atom Deletion from Crown Ether-Dibenzylammonium Rotaxanes

Maxime Gauthier  1 , Jessica B M Whittingham  1 , Avantika Hasija  1 , Daniel J Tetlow  1 , David A Leigh  1   2
Affiliations

Skeletal Editing of Mechanically Interlocked Molecules: Nitrogen Atom Deletion from Crown Ether-Dibenzylammonium Rotaxanes

Maxime Gauthier et al. J Am Chem Soc. .

Abstract

Removing the nitrogen atom from secondary amines while simultaneously linking the remaining fragments is a powerful form of late-stage skeletal editing. Here, we report its use for the deletion of the nitrogen atom of the dibenzylammonium template used to assemble crown ether rotaxanes. The reaction uses an anomeric amide that activates secondary amines to generate a carbon-carbon bond that replaces the amine nitrogen. Despite the potential for dethreading of the intermediate diradical pair, the nitrogen atom was successfully deleted from a series of rotaxane axles as long as the macrocycle could access coconformations that did not inhibit the reaction of the amine group. The skeletally edited interlocked molecules were obtained directly from the parent crown ether-dibenzylammonium rotaxanes in modest yields (23-36%) and characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. One skeletally edited rotaxane shows a network of weak CH···O hydrogen bonds between the crown ether and benzylic methylene groups of the axle in the solid state, in place of the crown ether-ammonium binding motif used to assemble the parent, unedited, rotaxane.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Skeletal editing of crown ether-dibenzylammonium rotaxanes by nitrogen deletion. Mechanistic outline: I. Deprotonation with base. II. Reaction of the secondary amine with anomeric amide 1. III. Formation of a reactive isodiazene intermediate. IV. Extrusion of molecular nitrogen and formation of a diradical pair. V. If recombination of the diradical pair to form a C–C bond is faster than dethreading from the pseudorotaxane radical, the nitrogen-deleted rotaxane is formed. VI. If dethreading is faster than radical recombination, or one of the radical fragments leaves the solvent cage, then dethreaded products result.
Figure 2
Figure 2
(A) Skeletal editing of dibenzylammonium rotaxanes by nitrogen atom deletion from the axle template with Levin’s anomeric amide 1. Reagents and conditions: (i) for 2·HPF6, 3·HPF6, and 5·HPF6: polymer-supported 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) (2–5 equiv), CD3CN, RT, 2 h, quant. (ii) For 4·HPF6: polymer-supported 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6 equiv), CD3CN, RT, 2 h, quant. (iii) 1 (2 equiv), THF, RT, overnight, 28–36%. (B) Rotaxanes 6–9 generated by nitrogen deletion.
Figure 3
Figure 3
1H NMR spectra (CD3CN, 600 MHz, 298 K) of rotaxanes 2·HPF6 (top), 2 (middle), and 6 (bottom).
Figure 4
Figure 4
Limitations in the scope for nitrogen deletion of crown ether-amine rotaxanes. Steric hindrance of the dibenzylamine by (A) lack of room on the axle for the macrocycle to move away from the amine, or (B) having a secondary binding site close to the amine, the proximity of the macrocycle inhibiting reaction of the axle amine with anomeric amide 1. (C) In the absence of groups on both axle fragments to stabilize the radicals formed in step IV (Figure 1), hydrazone formation occurs instead of nitrogen deletion. Reagents and conditions: (i) 1 (3 equiv), THF, RT, overnight, 42%.
Figure 5
Figure 5
(A) Metal-free active template synthesis of 14·HPF6 (a rotaxane with an extended axle and no secondary binding site for the macrocycle) and its subsequent nitrogen deletion to give symmetrical [2]rotaxane 17 with an all-carbon backbone. Reagents and conditions: (i) 15 (2 equiv), 16 (1 equiv), 24C8 (2 equiv), toluene, RT, 21 h, then NH4PF6 (6 equiv), CHCl3/H2O (1:1), 57%. (ii) Polymer-supported 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) (5 equiv), CD3CN, RT, 2 h, quant. (iii) 1 (2 equiv), THF, RT, overnight, 23%. (B) 1H NMR of 14·HPF6 (top), 14 (middle), and 17 (bottom) (CD3CN, 600 MHz, 298 K). (C) X-ray crystal structure of 17. (D) Side view to show the CH···O hydrogen bonding between the macrocycle and diarylethane region of the thread. Hydrogen bond lengths: O2···HC10 2.759 Å, O4···HC10 2.617 Å, O6···HC9 2.413 Å, and O8···HC9 2.575 Å. Hydrogen bond angles: O2···HC10 165.3°, O4···HC10 170.8°, O6···HC9 147.4°, and O8···HC9 165.0°. Carbon, gray; oxygen, red; hydrogen, white; fluorine, yellow. Hydrogen bonds are shown in green. Additional hydrogen atoms and solvent molecules are omitted for clarity.
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