Reagents for Condensation Reactions (HOTU) (HPMC encapsulated)

• 4-Bromobenzoic Acid [B0553]
• Morpholine [M0465]
• Reagents for Condensation Reactions (HPMC encapsulated) (HOTU) [R0297]
• N,N-diisopropylethylamine (= DIPEA) [D1599]
• DMF

Reagents for condensation capsule (HOTU) (one capsule) was added to a solution of 4-bromobenzoic acid (50 mg, 0.25 mmol, 1.0 eq.), morpholine (27 μL, 0.31 mmol, 1.25 eq.) and N,N-diisopropylethylamine (85 μL, 0.50 mmol, 2 eq.) in DMF (1 mL) at r.t. and the mixture was stirred at 30 °C for 2 hours. After the reaction, the mixture was diluted with ethyl acetate (15 mL) and filtered through Celite to remove HPMC. The filtrate was washed with sat. Na₂SO₄ aq. (10 mL), 2 mol/L HCl aq. (10 mL), sat. NaHCO₃ aq. (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (hexane:ethyl acetate = 2:1 - 1:1) to afford (4-bromophenyl)(morpholino)methanone (54 mg, 80% yield) as a white solid.

The reaction mixture was monitored by UPLC.
The shape of the capsule is like below image and each capsule includes ca. 0.25 mmol of HOTU.
The material of the capsule is water-soluble HPMC (hydroxypropyl methylcellulose).
HPMC was removed with filtration through Celite pad and saturated sodium sulfate solution used in the participation, but separating funnel was clogged due to the precipitation of sodium sulfate. Therefore, the precipitated sodium sulfate was filtered, and ethyl acetate was added to the filtrate for extraction. Use of a more dilute sodium sulfate solution may reduce clogging problems.

(4-Bromophenyl)(morpholino)methanone

¹H NMR (400 MHz, CDCl₃); δ 7.57 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 3.74-3.44 (m, 8H).

• Hydrophobic Pockets of HPMC Enable Extremely Short Reaction Times in Water
  • D. Petkova, N. Borlinghaus, S. Sharma, J. Kaschel, T. Lindner, J. Klee, A. Jolit, V. Haller, S. Heitz, K. Britze, J. Dietrich, W. M. Braje, S. Handa, ACS Sustainable Chem. Eng. 2020, 8, 12612.

• HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water
  • S. Sharma, T. N. Ansari, S. Handa, ACS Sustainable Chem. Eng. 2021, 9, 12719.