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TCI Practical Example: The Condensation Reaction Using a Capsule Reagent

We are proud to present the condensation reaction of 4-bromobenzoic acid and morpholine using the capsule reagent. This reagent can omit weighing the condensing agents. 0.25 mmol of EDCI·HCl and 0.04 mmol of HOBt·H₂O are encapsulated in each capsule.

Used Chemicals

• 4-Bromobenzoic Acid [B0553]
• Morpholine [M0465]
• Reagents for Condensation Reactions (HPMC encapsulated) (EDCI·HCl, HOBt·H₂O) [R0274]
• Water

Procedure

Reagents for condensation reactions (HPMC encapsulated) (one capsule) was added to a solution of 4-bromobenzoic acid (40 mg, 0.20 mmol, 1.0 eq.), morpholine (17 μL, 0.20 mmol, 1.0 eq.) in water (1 mL) at room temperature and the mixture was stirred at 30 °C for 24 hours. The reaction solution was diluted with sat. Na₂SO₄ aq. (15 mL) and extracted with ethyl acetate (15 mL x 2), and the organic layer was washed with 2 mol/L HCl aq. (15 mL), sat. NaHCO₃ aq. (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (hexane:ethyl acetate = 2:1 - 1:1) to afford (4-bromophenyl)(morpholino)methanone (48 mg, 89% yield) as a white solid.

Experimenter’s Comments

The reaction mixture was monitored by UPLC.
The shape of the capsule is like below image and each capsule includes EDCI·HCl (ca. 0.25 mmol) and HOBt·H₂O (ca. 0.04 mmol).
The material of the capsule is water-soluble HPMC (hydroxypropyl methylcellulose).

Analytical Data

(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).

Lead Reference

• 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.

Other References

• 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.