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Peptoid Coupling (Bromoacetic Acid / DIC)

Overview

Peptoid residues are incorporated on solid phase using a two-step submonomer approach:

  1. Bromoacetic acid addition -- The resin-bound amine is acylated with bromoacetic acid using DIC activation.
  2. Amine addition -- The bromide is displaced by a primary amine to install the desired side chain.

Step 1: Bromoacetic Acid Addition

  1. Prepare a solution of bromoacetic acid (1 M in DMF).
  2. Prepare a solution of DIC (0.5 M in DMF).

  3. Mix the two solutions and allow to pre-activate for 20 minutes at room temperature.

    Note

    The 20-minute pre-activation period is important. Shorter activation times can result in incomplete acylation.

  4. Add the activated solution to the resin.

  5. Agitate for 45 minutes at room temperature.
  6. Wash resin 3x DMF.

Step 2: Amine Addition

  1. Prepare a solution of the desired primary amine (1 M in DMF).
  2. Add the amine solution to the resin.

  3. Agitate overnight at room temperature.

    Tip

    For most amines, 2-4 hours is sufficient. Overnight coupling is recommended for sterically hindered amines or when maximum conversion is desired.

  4. Wash resin 3x DMF, 3x DCM.

  5. Check by LCMS for completion.

Tips and Troubleshooting

Dimer Formation

If the bromoacetylation step is left too long or the DIC is in excess, dimer formation can occur. Stick to the recommended 45-minute coupling time for the bromoacetic acid step.

Timing

The two-step peptoid coupling can be done sequentially in a single day. Start the bromoacetic acid coupling in the morning, wash, then add the amine before the end of the day and leave overnight.