The Algebra of Organic Synthesis : Green Metrics, Design Strategy, Route Selection, and Optimization book cover
1st Edition

The Algebra of Organic Synthesis
Green Metrics, Design Strategy, Route Selection, and Optimization

ISBN 9780367149642
Published April 15, 2019 by CRC Press
1124 Pages 2455 B/W Illustrations

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Book Description

The Algebra of Organic Synthesis combines the aims, philosophies, and efforts involved in organic synthesis, reaction optimization, and green chemistry with techniques for determining quantitatively just how "green" synthesis plans are. It provides the first complete quantitative description of synthesis strategy analysis in the context of green chemistry and reaction optimization.

Providing what is perhaps the first complete description of synthesis strategy analysis, this book:

  • Explores quantitative material efficiency for synthesizing molecules, including 1,000+ worked out synthesis plans to important target molecules
  • Explains, in simple language, the most useful ideas in graph theory that have direct application in organic synthesis
  • Reinforces the value of simple mathematical analysis in organic synthesis to help any synthetics or process chemist understand presented ideas and apply them to their own work
  • Illustrates concepts with example target plans to classical targets that are considered milestones in synthetic chemistry, from pharmaceuticals, industrial commodity chemicals, dyestuffs, agrichemicals, flavorings, natural products, and molecules of theoretical interest

The accompanying download includes a reproduction of the tables in the book, with direct electronic links to files for all plans. Files contain a list of references for each plan, including secondary references for the synthesis of starting materials if applicable. Ancillary materials also include a complete synthesis scheme with fully balanced chemical equations, a synthesis tree, a summary of green metrics parameters, a target bond map and list of reagents that end up in the target molecule, and a series of graphs that offer a visual depiction of the plan performance.

Table of Contents

Aims and Scope
What Does This Book Offer?
Chapter Descriptions
Synthesis Plan Database
How to Use Synthesis Database Compilation

General Comments on Organic Chemistry and Green Chemistry
Getting Our House in Order
Research Trends in Organic Synthesis
Research Trends in Green Chemistry Trends
Green Chemistry Trends in Industry

Problems with Literature Reporting of Synthesis Plans
Missing Information in Plans
Mistakes in Reported Yields and Amounts of Materials Used
Mismatches in Reported Reaction Yields
Tactics to Artificially Amplify Reaction Performance
Reporting of Classical Resolutions
Exaggerated Claims of Efficiency
Good "Greening" Progression But Little Detail to Substantiate Claim
"Readily Available Starting Materials"
Biotransformations Not Revealing Reaction Yields in Usual Way
Papers Describing Reactions Using Microwave Irradiation
Reviewing of Scientific Papers

Problems and Challenges in Synthesis and Green Chemistry
Philosophy and Practice of Chemistry
Chemistry Literature
Reaction Performance Improvements
Synthesis Performance
Reaction Mechanism

Overview of Green Metrics
Advantages of Using Green Metrics
Material Efficiency Metrics and Visuals
Strategy Efficiency Metrics and Visuals
Hypsicity (Oxidation Level) Analysis
Instructions on Using PENTAGON, LINEAR, and CONVERGENT Spreadsheets
Mathematical Derivations and Analysis
Complete Worked Out Examples

Worked-Out Radial Pentagon Examples
Radial Hexagon Analysis
Connectivity Analysis
Probability Analysis
An Eight-Component Coupling

Named Organic Reaction Database
Categorization of Named C–C Coupling/Addition/Cyclization Reactions
Categorization of Named Condensation Reactions
Categorization of Named Elimination/Fragmentation Reactions
Categorization of Multicomponent Reactions
Categorization of Named Non-C–C Coupling/Addition/Cyclization Reactions
Categorization of Named Oxidation Reactions (with Respect to Substrate of Interest)
Categorization of Named Rearrangement Reactions
Categorization of Named Reduction Reactions (with Respect to Substrate of Interest)
Categorization of Named Sequences
Categorization of Named Substitution Reactions
Summary of Trends in Named Organic Reaction Database

Example Transformations Illustrating Sacrificial Reagents
Single-Step Reactions
Two-Step Reactions
Sacrificial Reactions from Synthesis Database

Synthesis Strategies
Brainstorming Exercises
Direct Syntheses
Indirect Syntheses

Choice of Starting Materials for Synthesis
Comparison of Total Synthesis versus Semisynthesis
Bio-Inspired Strategies
Chemoselectivity versus Classical Resolution Comparison
Mismatch between Strategy and Waste Production
Route Selection and Reaction Networks
What Can Go Wrong with Computer-Assisted Synthesis Software

Ring Construction Strategies
Ring Construction Strategies in Synthesis Database.
Ring Contractions in Named Organic Reaction Database.
Ring Expansions in Named Organic Reaction Database
Bicyclic Formation Reactions in Named Organic Reaction Database
Sacrificial Rings
Use of the Furan Ring
Wender [x + y + z] Ring Construction Strategies
Spectacular Ring Construction Strategies
Proposal for a Computer-Searchable Ring Construction Database

Example Highlights from Database
Which Plan to Choose for Scale-Up?.
Sparse Target Bond Making Profiles
Recycling Options
Improvement in Waste Reduction
Spectacular Examples of Synergy between Strategy and Material Efficiency Metrics
Microchannel and Flow Technique Strategies
Ring Construction Novelty
Wrong Starting Materials Used
Plan with No Target Bonds Made
Old Reactions Using One of 12 Principles of Green Chemistry
Telescoping Steps
Extreme Convergence in Plans
Use of a Hub Common Intermediate
Compromise between Strategy and Material Efficiencies
Inclusion of Syntheses of Catalysts and Ligands for Complete Analysis
Synthesis Plans Tracing Back to Common Starting Materials for Fairest Comparisons
Most Challenging Molecule to Synthesize: Colchicine
Target Compound Where Fundamental Named Organic Reactions Were Discovered
Contrast between Classical and Modern Chemical Routes
Resolution with Lipase

Summary of Overall Trends in Synthesis Database
Overall Atom Economy Trends
Overall Yield Trends
Kernel Overall Reaction Mass Efficiency Trends
Degrees of Convergence and Asymmetry Trends
Target Bond Forming Profile Parameters
Sacrificial Reagents and Sacrificial Reaction Trends
Hypsicity Trends

Compounds with Multiple Plans

Appendix A
Appendix B


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John Andraos earned a Ph.D. in 1992 from the University of Toronto in physical organic chemistry. Since his appointment as Lecturer and Course Director at York University, he launched the first industrial and "green" chemistry course in the history of the Department of Chemistry. He has done consulting assignments with the pharmaceutical industry on various aspects of synthesis optimization and green chemistry education. His research spans several disciplines in organic chemistry which utilize mathematical analysis including reaction kinetics, retrosynthesis and synthesis planning, and the creation of reaction and ring construction databases. He is the author of 50 scientific papers in refereed journals and 6 book chapters on the subject of green chemistry metrics and education. In 2000 he launched the CareerChem website ( which is an in-depth resource for tracking and cataloguing all named things in chemistry and physics, chronicling the development of chemistry through scientific genealogies, and supplying career information to young researchers and students for placement in academic and industrial positions worldwide.