Amines and Reductive Amination in Pharmaceutical Synthesis
Module Overview
This module explores the synthesis of amines with a focus on the reductive amination reaction. Numerous examples from the discovery and commercial manufacturing of pharmaceuticals are included. After an introduction to traditional reductive amination methods, students evaluate the traditional methods using green chemistry principles and systems thinking approaches. Students also compare traditional methods to newer technologies, including greener chemical methods and bioenzymatic reduction processes. Students are introduced to key concepts in systems thinking and explore connections between multistep synthesis of amine-containing pharmaceuticals and UN SDGs 3 (Good Health and Well-Being) and 12 (Responsible Production and Consumption). To scaffold student learning on systems thinking topics, Unit 1 focuses primarily on laboratory scale synthesis and systems within the laboratory, with attention to laboratory worker safety. Unit 2 broadens systems thinking topics to include larger scale syntheses, including manufacturing processes, and systems beyond the laboratory, such as environmental systems.
Module Goal
Students will be able to explain the mechanism for the reductive amination process and apply this reaction toward proposed syntheses of amines in pharmaceuticals. Using green chemistry principles and systems thinking analysis, students will identify benefits and limitations of reductive amination methods by comparing traditional methods, alternative green reagents and enzymatic processes. Finally, students will critique the multistep discovery and manufacturing processes for amine-containing pharmaceuticals using green chemistry principles, systems thinking analysis and connection to the UN Sustainability Goals 3 (Good Health and Well-Being) and 12 (Responsible Consumption and Production).
Audience
Second-semester organic chemistry undergraduates
Class Time Requirement
Approximately one 90-minute class period and one 100-minute class period
Module Authors
Amy Dounay, Colorado College; Jessica Tischler, University of Michigan-Flint
Module Summary
Assumed Prior Knowledge
Students should be able to demonstrate the following skills and concepts to successfully begin this module:
- Familiarity with nucleophilic addition reactions to ketones and aldehydes, particularly imine formation and reduction reactions
- Ability to draw reaction mechanisms using curved arrow formalism
- Familiarity with using retrosynthetic analysis and proposing multistep syntheses
Learning Objectives
Students will be able to:
- Categorize amines as 1°, 2°, 3°.
- Draw detailed mechanisms for reductive amination reactions.
- Predict products for traditional reductive aminations.
- Apply the reductive amination reaction in synthesis of amines by proposing appropriate starting materials and reagents to complete a targeted synthesis.
- Use Safety Data Sheets (SDSs) to identify key hazards of reagents and to consider how reaction scale (e.g., g vs. kg) impacts laboratory worker safety, risk assessment and management planning.
- Provide examples of ways in which green chemistry and systems thinking can be used to improve processes for synthesis of pharmaceuticals.
- Using systems thinking terminology, evaluate a chemical reaction in a reaction flask as a system and define its inputs and outputs.
- Describe connections between green chemistry, systems thinking, and students’ individual/personal learning and future career goals.
- Articulate specific ways in which chemists can directly impact UN SDGs through key decisions in the design, synthesis and production of pharmaceuticals.
- Use principles of green chemistry and systems thinking to identify strengths and weaknesses of classical, updated and biocatalytic reductive amination protocols.
- Use green chemistry and systems-thinking approaches to recommend the best method for a chemical synthesis.
- Explain how the purpose and scale of drug synthesis affects choices and impacts (e.g., discovery research scale vs. manufacturing scale).
- Use systems thinking and SOCMEs to illustrate how a pharmaceutical product participates in multiple interacting systems.
Unit Overview
Unit 1: Introduction to Amine Synthesis and Reductive Amination
1.1 | Pre-class homework: Unit 1 Worksheet Review Questions (20–30 minutes outside class) |
1.2 | Lecture (30–40 minutes in class). Slides with an introduction to the module goals, outline of the day and introduction to reductive amination |
1.3 | Collaborative activity (45–60 minutes in class) Worksheet activity on amine synthesis |
1.4 | Homework (20–30 minutes) Application of reductive amination, synthesis problems |
Unit 2: Alternate reductive amination methods: Reaction analysis through green chemistry and systems thinking
2.1 | Pre-class homework (PowerPoint slides, Word Art or reflection assignment: 60 minutes outside class) |
2.2 | Lecture (30–40 minutes in class). Slides with review of key concepts from Unit 1 and Unit 2 pre-work (homework assignment) and introduction to greener reductive amination methods |
2.3 | Collaborative activity (30–60 minutes in class). Worksheet activity on analysis of reactions using green chemistry and systems thinking criteria |
2.4 | Homework: (30–60 minutes) Complete worksheet questions |
Download Module
Amines Includes:
- Module Overview Document
- Units 1-2
- Summative Assessments
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About the Green Chemistry Module Project
The ACS Green Chemistry Instiute has partnered with chemistry instructors from over 45 institutions to develop green chemistry education resources for undergraduate students studying general and organic chemistry.
