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

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

Background Information Crosslinking – strengthens Crosslinking – strengthens

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. 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 Also known as Mannich condensation ***Unfortunately, it’s not really this simple*** Here’s a more accurate depiction of the reaction

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

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)

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

Reaction with Ammonia Ammonia + Ethyl acrylate Primary Amine

Applications to crosslinking Remember - In Vivo 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 With a primary amine Possible Possible

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

Applications to crosslinking Remember - In Vivo 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 With a secondary amine Also possible Also possible

Reaction of a secondary amine Tertiary Amine Secondary 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.

Final thoughts Review of possible reactions For applications In Vivo 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 secondary amine To form a secondary amine React with a primary amine Possible To for a tertiary amine To for a tertiary amine React with a secondary amine React with a secondary amine Also possible Also possible Definitely some potential for biomedical applications as a crosslinking agent Definitely some potential for biomedical applications as a crosslinking agentQuestions?