Goldilocks Effect of Base Strength on Site Selectivity in Acylation of Amphiphilic Diols

Dedicated to Prof. Christian Bruneau for his outstanding contribution to catalysis

Abstract

Two series of competitive acylation experiments with a polar and an apolar alcohol substrate, imitating two parts of amphiphilic diols, examined the influence of bases of varying strength on the substrate selectivity. While weakly basic 2,4,6-collidine only mildly accelerates the acylation of the polar substrate without affecting that of the apolar one, the acylation of both substrates is drastically hastened by strongly basic DBU. In both cases there is a notable, though not overwhelming, shift of the substrate selectivity towards the polar substrate, compared to the base-free acylation, which favors that of the apolar one. The extraordinarily strong change in the substrate selectivity in favor of the polar substrate was induced, however, by aliphatic tertiary amine bases, DIPEA and Et₃N, of ‘Goldilocks’ moderate base strength, which strongly accelerate the acylation of the polar substrate, while almost not affecting that of the apolar one. These effects of the bases on the substrate selectivity are reflected in the site-selectivity trends observed in the acylation of a model diol amphiphile.

Key words

acylation - site selectivity - substrate selectivity - basicity - amphiphiles

Publication History

Received: 12 July 2021

Accepted after revision: 02 September 2021

Accepted Manuscript online:
02 September 2021

Article published online:
21 September 2021

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For this frequently invoked mechanistic trajectory, see:
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• 18 At 50% consumption that ensures less than 10% contamination by the diacylated product.
• 19 It was verified that interconversion between 2 and 3 does not occur in the presence of the base or the catalysts.
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• 21 DFT calculations at the BP86(D3)/def2-SVP level of theory, reported in ref. 15, demonstrated that, in the gas phase, the acidity constant of the alcohol of the apolar arm is ca. 24-fold larger than that of the alcohol of the polar arm.
• 22 Since in the preceding paper (see the Supporting Information of ref. 15) we demonstrated that other anhydrides follow the general trend of the site selectivity observed with butyric anhydride, particularly with the DIPEA base, we decided to focus the current study specifically on the latter, which provided the greatest span of the selectivity ratios.
• 23 The synthesis and the full characterization of the substrates 9 and 10, the full characterization of their butyrylation products 11 and 12, as well as the typical chromatograms of the reaction mixtures were reported in an earlier communication (ref. 15).
• 24 Typical Procedure for the Acylation (Butyrylation) Reaction of the Monosite Substrates 9 and 10 – Separate Experiments To the solution of the monosite substrate (9 or 10, 0.2 mmol, 2.0 hydroxyl equiv) in dry benzene (1 mL) the base (0.005–0.3 mmol, 0.05–3.0 equiv, in the experiments including base) and butyric anhydride (65 μL, 0.4 mmol, 4.0 equiv) were added. The solution was stirred at room temperature. During the reaction aliquots were taken at constant intervals (30 μL each sample) and quenched with methanol (0.5 mL). Each sample was analyzed using HPLC to determine the degree of the conversion. These data from the parallel experiments were used to determine the ratio of the products.
• 25 Typical Procedure for the Acylation (Butyrylation) Reaction of the Monosite Substrates 9 and 10 – Mixed Experiments To the solution of the monosite substrates 9 (0.1 mmol) and 10 (0.1 mmol) in dry benzene (1 mL), the base (0.005–0.3 mmol, 0.05–3.0 equiv, in the experiments including base), and butyric anhydride (65 μL, 0.4 mmol, 4.0 equiv) were added. The solution was stirred at room temperature. During the reaction aliquots were taken at constant intervals (30 μL each sample) and quenched with methanol (0.5 mL). Each sample was analyzed using HPLC to determine the ratio of the products and the degree of the conversion.
• 26 In order to include the ratios with the average consumptions comparable to those with DIPEA and collidine.
• 27 Nelson H, Richard W, Brown H, Medlin A, Light C, Heller ST. Angew. Chem. Int. Ed. 2021; 60: in press DOI: 10.1002/anie.202107438.
• 28 For all the experiments summarized in the charts, except for those with DBU, the 12/11 ratios at 8 h were used. In order to compare the data at alike consumptions, for the experiments with DBU the ratios at 1 h were applied.
• 29 The synthesis and the full characterization of the substrate 1, the full characterization of its butyrylation products 2–4, as well as the typical chromatogram of the reaction mixture were reported in an earlier communication (ref. 15).
• 30 Typical Procedure for the Acylation (Butyrylation) Reaction of the Bisite Substrate 1 To the solution of the bisite substrate (1, 0.1 mmol, 1.0 equiv, 2.0 hydroxyl equiv) in dry benzene (1 mL) the base (0.005–0.3 mmol, 0.05–3.0 equiv, in the experiments including base) and butyric anhydride (0.4 mmol, 4.0 equiv) were added. The solution was stirred at room temperature. During the reaction aliquots were taken at constant intervals (30 μL each sample) and quenched with methanol (0.5 mL). Each sample was analyzed using HPLC to determine the ratio of the products and the degree of the conversion.