Acyl migrations sensitive to supramolecular encapsulation

Abstract

Four isomeric resorcin[4]arene tetrabenzoates interconvert via reversible, base-catalysed acyl migrations. Extraction of solid Me₄N⁺I⁻ into a chloroform solution of the isomers gradually shifts the equilibria towards the C_2V-symmetric component due to the formation of highly stable hydrogen-bonded molecular capsules.

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Dynamic covalent chemistry efficiently uses chemical equilibria and non-covalent interactions of multiple molecular modules for the synthesis of functional supramolecular and covalent aggregates.¹ The present research has been undertaken to create tuneable dynamic systems via a combination of reversible chemical reactions with supramolecular encapsulation² of a suitable thermodynamic template.

Readily available C_2V-symmetric resorcin[4]arene³ tetraesters 1–3⁴ (Scheme 1) seemed likely to undergo acyl migrations⁵ leading to three regioisomers 4, 5, and 6. Since tetrabenzoate 1a and tetraphosphate 2b form highly stable hydrogen-bonded dimeric capsules,⁶ their reversible acyl relocations were considered as unique dynamic covalent reactions sensitive to supramolecular encapsulations.

Scheme 1 Compounds 1–7 and capsular ion pair Me₄N⁺@1₂I⁻. (i) DIDEA, DMSO-d₆ or CDCl₃; (ii) DIPEA, CDCl₃ (liquid)/Me₄N⁺I⁻ (solid); (iii) DIPEA, CDCl₃ (liquid)/water (liquid); (iv) MeI, K₂CO₃, rt. The positions of characteristic protons are indicated with letters.

Herein, we report on previously unknown reversible, base-catalysed acyl migrations in resorcin[4]arene tetrabenzoates 1, which establish an equilibrium of all possible regioisomers 1, 4, 5, and 6 in chloroform and DMSO solutions. The equilibrium in chloroform can be gradually shifted towards C_2V-symmetric components 1 by the addition of solid Me₄N⁺I⁻, which serves as a thermodynamic template for controllable self-assembly of supramolecular capsules Me₄N⁺@1₂I⁻.

We have discovered that the reaction of C_2V-symmetric compounds 1a,b with MeI in the presence of K₂CO₃ (DMF, rt) affords C₄-symmetric⁷ tetramethyl ethers 7a and 7b (Scheme 1) in 30 and 17% unoptimized yields. These transformations provided a convincing piece of evidence for the acyl migrations in 1a,b leading to at least C₄-symmetric isomers 5a,b.

Slow crystallization of compound 7b from CH₂Cl₂/MeOH afforded diffraction quality crystals of 7b•CH₂Cl₂.⁸ Single crystal X-ray analysis unambiguously confirmed the chiral C₄-symmetric structure and strongly pinched boat⁹ conformation of molecule 7b (Fig. 1). Accordingly, chiral HPLC analysis of compounds 7 revealed pairs of enantiomers (Fig. S1 of ESI†).

Fig. 1 Single crystal X-ray structure of 7b• CH₂Cl₂. Hydrogen atoms are not shown.

The ¹H NMR spectra of compounds 7 (298 K, CDCl₃) contain singlets at 6.4 and 6.8 ppm for the protons in positions 2 and 5 of the resorcinol fragments, and one set of signals for all other protons (Fig. S7 and S10 of ESI†). This C₄-symmetric pattern seems likely to reflect rather fast pseudo rotation⁹ of two equivalent C₂-symmetric boat conformers similar to those found in the crystalline state (Fig. 1).

The addition of DIPEA to a solution of tetrabenzoate 1a in DMSO-d₆ unleashes the benzoyl migrations to produce isomers 4a, 5a, and 6a (Scheme 1). The ¹H NMR spectra (Fig. S12 of ESI†) and HPLC-MS chromatograms (Fig. S3 of ESI†) of the reaction mixtures change in time until the equilibrium is reached for 15% of 1a, 50% of 4a, 25% of 5a, and 10% of 6a (Fig. 2a and b). The ¹H NMR spectra of the isomeric mixtures contain theoretically anticipated seven signals for the protons of the unacylated and monoacylated resorcinol fragments (Fig. 2a) which are NOESY assigned to 1a (H(a)), 4a (H(b), H(c), H(d)), 5a (H(e)) and 6a (H(f), H(g)). Accordingly, eight theoretically anticipated hydroxyl signals are attributed to H(h) (1a), H(i)–H(l) (4a), H(m) (5a), H(n), and H(o) (6a) (Fig. 2b). The equilibria in DMSO-d₆ are characterized by apparent constants K₁ = 3.3 (Δμ⁰₁ = −RT ln K₁ = −0.7 kcal mol⁻¹), K₂ = 0.5 (Δμ⁰₂ = 0.4 kcal mol⁻¹), and K₃ = 0.2 (Δμ⁰₃ = 0.9 kcal mol⁻¹) which indicate a slight thermodynamic favourability of isomer 4a. Both HPLC-MS and ¹H NMR analysis reveal the initial formation of compound 4a, which converts then into isomers 5a and 6a (Fig. S3a and S12b of ESI†).

Fig. 2 Well-resolved parts of the ¹H NMR spectrum for the equilibrium mixture of 1a, 4a, 5a, and 6a (400 MHz, [1a]₀ = 15 mM, [DIPEA] = 60 mM, DMSO-d₆) after 148 hours of the acyl migrations at 298 K (a, b) and the putative mechanism for the base-catalysed transesterification (c). The positions of the protons are indicated in the formulas of Scheme 1. All the signals are correlated with the resonance of residual water due to chemical exchange. Proximity NOESY correlations (ca. −14%): H(a)–H(h), H(b)–H(k), H(b)–H(l), H(e)5–H(m), H(f)–H(n), H(g)–H(o), H(c)–H(i), H(d)–H(j). Relative intensities of the signals correspond to the symmetries of the structures: H(a) : H(h) = 1 : 2 (1a), H(b) : H(c) : H(d) : H(i) : H(j) : H(k) : H(l) = 1 : 1 : 1 : 1 : 1 : 1 : 1 (4a), H(e) : H(m) = 1 : 1 (5a) and H(f) : H(g) : H(n) : H(o) = 1 : 2 : 2 : 2 (6a).

Expectedly, the acyl migrations described above occur also in tetrabenzoates 1b and 1c; however, tetraphosphate 2a and tetratosylate 3a do not isomerise under the same conditions for as yet unknown reasons. The HPLC-MS analysis detected no cross-acylation products in the mixed experiment 1a/1c/DMSO-d₆ + DIPEA most probably due to the intramolecular mechanism of the acyl migrations between base-activated complexes I and III (Fig. 2c) via bridged, tetrahedral intermediate II.

The absence of the exchange NOESY cross-peaks between the signals of isomers 1a, 4a, 5a, and 6a at equilibrium indicates critically slow interconversion with k < 10⁻² s⁻¹ (Δμ^‡ > 20 kcal mol⁻¹) at 298 K.¹⁰ Accordingly, kinetic HPLC-MS studies reveal that the disappearance of 1a is characterized by the initial pseudo-first-order rate constant k = 2.0 × 10⁻⁵ s⁻¹ (Δμ^‡ = 24.3 kcal mol⁻¹)¹¹ at 303 K. The variable temperature HPLC-MS kinetic studies (Fig. S4 of ESI†) revealed Δh^‡ = 15.1 kcal mol⁻¹ and Δs^‡ = −30.5 eu between 303 and 318 K, which most probably reflect the association of 1a with DIPEA and conformational rigidification in the transition state.

The benzoyl groups of 1a migrate also in CDCl₃ + DIPEA to produce 4a, 5a, and 6a as evident from time-dependent ¹H NMR and HPLC-MS analysis of the reaction mixtures. The time-independent composition of the equilibrium mixture (Fig. 3a) at 298 K comprises 36% of 1a, 36% of 4a, 17% of 5a, and 11% of 6a, which correspond to K₁ = 1.0 (Δμ⁰₁ = 0 kcal mol⁻¹), K₂ = 0.5 (Δμ⁰₁ = 0.4 kcal mol⁻¹) and K₃ = 0.3 (Δμ⁰₁ = 0.7 kcal mol⁻¹).

Fig. 3 The section of the ¹H NMR spectrum of the equilibrium mixture of isomers 1a, 4a–6a (400 MHz, [1a]₀ = 15 mM, [DIPEA] = 60 mM, CDCl₃) at 298 K (a) and its change after the solid–liquid extraction of Me₄N⁺I⁻ for 2 (b) and 8 (c) hours. The signals of Me₄N⁺@1a₂ I⁻ are marked with an asterisk.

Slow extraction of solid Me₄N⁺I⁻ into the chloroform solution of 1a, 4a–6a gradually shifts the isomeric equilibrium towards the C_2V-symmetric component 1a due to highly exergonic self-assembly of hydrogen-bonded molecular capsule Me₄N⁺@1a₂I⁻ (Scheme 1 and Fig. 3b, c). The composition of the equilibrium mixture can be varied simply by the decantation of solid Me₄N⁺I⁻, which instantaneously ceases the formation of the capsule and the shift of the equilibrium. The capsule is stable in the presence of DIPEA; however, it can easily be disassembled by CDCl₃/water extraction removing the base and Me₄N⁺ I⁻ to recover pure 1a and complete the cycle of the dynamic covalent reactions shown in Scheme 1. The equilibria of 1a, 4a, 5a, and 6a in DMSO-d₆ + DIPEA are not affected by the addition of Me₄N⁺I⁻ since hydrogen-bonded capsule Me₄N⁺@1a₂I⁻ is not assembled in such a highly polar and H-bond competitive medium.

Although compound 1a forms stable tropylium capsule C₇H₇⁺@1a₂BF₄⁻ in CDCl₃, the addition of solid C₇H₇⁺ BF₄⁻ to the solution of 1a, 4a, 5a and 6a leads to multiple unidentified compounds (Fig. S15 of ESI†) most probably due to the reactions of the tropylium cation with DIPEA and isomeric resorcin[4]arene tetrabenzoates.¹²

New isomers 4a, 5a, and 6a were separated by preparative HPLC and characterized by NMR methods (Fig. S14, of ESI†). The addition of DIPEA to CDCl₃ or DMSO-d₆ solutions of individual isomers 4a, 5a, and 6a initiated the acyl migrations resulting in the formation of 1a and eventually the identical equilibrium mixtures (see Fig. 2a, b and 3a).

To gain more insight into the driving forces of the described above acyl migrations we have carried out theoretical studies of compounds 1a, 4a, 5a, and 6a. The perfectly C_2V-symmetric MMX¹³ energy minimized structure of 1a (Fig. 4) is deprived of intramolecular C=O–H–O hydrogen bonds and exhibits four O=C–O–H interactions (d = 3.49 Å) favourable for the acyl migrations. The energy-minimized structures of hydrogen-bonded solvates (1a, 4a–6a)•3DMSO•DIPEA, which are likely to be involved in the acyl migrations (Fig. 2c), have rather close calculated energies (ΔE = 0.1–0.7 kcal mol⁻¹) lying within the range of experimentally assessed Δμ⁰ values (−0.7–0.9 kcal mol⁻¹) in DMSO/DIPEA solution. Thus, simple modelling taking into account hydrogen-bonding solvation of the OH-groups reproduces the simultaneous NMR observability of 1a, 4a, 5a, and 6a.

Fig. 4 MMX energy minimized conformation of 1a. Close O=C–OH contacts are indicated by arrows.

In conclusion, C_2V-symmetric resorcin[4]arene tetrabenzoates undergo reversible, base-catalysed acyl migrations to establish equilibrium with their C₁-, C₄, and C_s-symmetric isomers in chloroform and DMSO solutions. All four regioisomers interconvert slowly on the NMR time scale and are simultaneously detectable by NMR spectroscopy at ambient temperature. In the CDCl₃ solution, the equilibria can gradually be shifted towards the C_2V-symmetric component owing to the formation of the highly stable hydrogen-bonded dimeric capsular complex with Me₄N⁺ I⁻. This feature demonstrates the possibility for smooth regulation of covalent equilibria via their thermodynamic coupling¹⁴ with highly exergonic supramolecular encapsulation.

This work was supported by I. F. Labs Ltd (Internal grant 00050-z01737). We thank Dr Alexey Ryabitsky for measuring 2D NOESY spectra and Dr Kit Begemit for helpful discussions.

Data availability

The data supporting this article were included as a part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Synthetic and analytical experimental details, and crystallographic information for compound 7b. CCDC 2386016. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5cc01417d

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