Mannich Reaction in Acrylate Crosslinking Mechanism

1. Assessment of the Mannich Reaction as a cross-linking mechanism for acrylates Presented to Dr. Lang’s Chemistry 496 class February 13, 2004

2. Introduction Why was this topic selected? • Research with biological polymers • Systems must meet several criteria: • Biocompatible • Have appropriate physical properties • Biodegradable • Be able to “cure” in vivo

3. Background Information • Crosslinking – strengthens

4. The Mannich Reaction • In the simplest form, the Mannich reaction is the reaction between an iminium-ion (generated from formaldehyde) and an enol or enolate. • Also known as Mannich condensation ***Unfortunately, it’s not really this simple*** Here’s a more accurate depiction of the reaction

5. The Mannich Reaction Why is this reaction special? • Forms C-C bonds • Includes reactions with acrylates • Used in the synthesis of many bioactive molecules and complex natural products • Can react under aqueous conditions • Mild, low temp reactions • Can be functionalized for cleavage

6. A Biological Pathway For example, Below is an example of the Mannich reaction in the synthesis of a natural product. It was even the first example of a biomimetic synthesis (in 1917)

7. Applications to crosslinking • Remember - In Vivo • Can’t use formaldehyde • Reaction with acrylates • With ammonia (BP of -33˚C) • NO! • Reaction is with liquid ammonia in SS bomb (~30 psi)

8. Reaction with Ammonia Ammonia + Ethyl acrylatePrimary Amine

9. Applications to crosslinking • Remember - In Vivo • Can’t use formaldehyde • Reaction with acrylates • With ammonia • NO! • Reaction is with liquid ammonia in SS bomb • With a primary amine • Possible

10. Reaction with primary amine Organic Syntheses, CV 3, 258 DI-β-CARBETHOXYETHYLMETHYLAMINE [Propionic acid, β,β'-(methylimino)di-, diethyl ester] Example

11. Applications to crosslinking • Remember - In Vivo • Can’t use formaldehyde • Reaction with acrylates • With ammonia • NO! • Reaction is with liquid ammonia in SS bomb • With a primary amine • Possible • With a secondary amine • Also possible

12. Reaction of a secondary amine Tertiary AmineSecondary Amine • This complete reaction proceeds to a specific % equilibrium regardless of the reactant ratio. • This can be overcome by adding an easily removable substituent (most used a carbethoxy group) to stop the reaction at the secondary amine. • The final product can be removed by distillation and the reaction re-run to the equilibrium again.

13. Final thoughts Review of possible reactions • For applications In Vivo • No formaldehyde • Possible reaction with acrylates • To form a primary amine • React with liquid ammonia • NO! • Reaction is with liquid ammonia in SS bomb • To form a secondary amine • React with a primary amine • Possible • To for a tertiary amine • React with a secondary amine • Also possible • Definitely some potential for biomedical applications as a crosslinking agent Questions?