Practical Functional Group Synthesis

Robert A. Stockland

• Publisher: Wiley
• Year: 2016
• ISBN:
  9781119015772
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

A practical handbook for chemists performing bond forming reactions, this book features useful information on the synthesis of common functional groups in organic chemistry.

•Details modern functional group synthesis through carbon-heteroelement (N, O, P, S, B, halogen) bond forming reactions with a focus on operational simplicity and sustainability.
•Summarizes key and recent developments – which are otherwise scattered across journal literature – into a single source
•Contains over 100 detailed preparations of common functional groups
•Included 25 troubleshooting guides with suggestions and potential solutions to common problems.
•Complements the text in enhanced ebook editions with tutorial videos where the author provides an introduction to microwave assisted chemistry

1
INTRODUCTION TO PRACTICAL FUNCTIONAL GROUP SYNTHESIS

1.1 GENERAL APPROACHES FOR DESIGNING SYNTHESES

The construction of functionalized organic compounds remains one of the most challenging areas of synthetic chemistry, and scientists continue to redefine the limits of chemical reactions through the development of processes with increased chemoselectivity, enantioselectivity, and operational simplicity. In many cases, classic reactions are still the most effective means to generate the functional group of interest. Many of these reactions have been modernized to increase the tolerance to preexisting functional groups, decrease the required catalyst loading, increase the selectivity of the process, or minimize the waste generated from the process.

Despite years of education, many novice researchers flounder when trying to design a successful synthesis. They often get stuck on a specific step in a synthesis or are unable to purify an intermediate or product due to contamination by secondary products or solvent. While there are “chemistry” pitfalls that plague new synthetic methods, there are also a range of practical considerations that could render a clever synthesis unachievable. Other syntheses never get started because the starting materials are inaccessible. To help address these issues, a list of general questions for the design of a successful synthesis is provided below:

• What is the goal of the synthesis?
• How pure do the intermediates and products need to be?
• Are all of the reagents/catalysts/additives commercially available?
• If the starting materials are not commercially available, how long will it take to make them?
• Are there any reaction specific issues that need to be considered?
• How long will it take to complete the proposed synthesis?
• Is the shortest route really the most practical?
• Will the chemistry benefit from microwave irradiation?
• Is a glovebox required?
• Does the chemistry require the use of a vacuum/inert gas manifold?
• What are the safety concerns for this approach?
• Are the reagents/catalysts sensitive to light?
• Is a solvent needed?
• Do the solvents need to be rigorously dried?
• Will the solvents be easy to remove?
• Do the solvents need to be degassed/deoxygenated?
• Are the products stable to air?
• How will the products be purified?
• How will the products be stored?
• How will the products be characterized?

What is the goal of the synthesis?

This might seem like an obvious question, but many researchers get bogged down with parts of the synthesis that are not relevant to why the compound will be prepared. If a few milligrams of a target compound are all that is needed in order to screen for a specific activity/property, it is not an appropriate use of time and resources to spend weeks searching the literature or running dozens of screening reactions to optimize the conditions. Simply find a decent synthesis, make the amount that is needed, and submit it for screening. Alternatively, if the project is focused on method development, and the product yields are critical for establishing the scope of the reaction, time needs to be spent optimizing the conditions so an accurate comparison between the new method and established protocols can be made.

How pure do the intermediates and products need to be?

This might seem like another question with an obvious answer, but there are several aspects that need to be considered. It is rarely a good use of time and effort to prepare analytically pure samples of an intermediate in a multistep synthesis if that intermediate will simply be transformed into something else. If the next step in the synthesis will not be inhibited by the impurities in the crude reaction mixture, do not spend time purifying the intermediate. Instead, wait until the end of the synthesis and rigorously purify the final compound.

Are all of the reagents/catalysts/additives commercially available?

If all of the starting materials are commercially available, the chemist will be able to begin work on the proposed synthesis quickly. Given the vast array of reagents and catalysts that are commercially available, the likelihood that the specific materials needed for the proposed synthesis is high. Arguably, this is the most important contributing factor when adopting a new synthesis.

If the materials are not commercially available, how long will it take to make the starting materials?

If the starting materials are not available, the literature preparations must be carefully analyzed to determine how long it will take to generate usable quantities of the starting materials and catalysts.

Are there any reaction specific issues that need to be considered?

In some cases, the unintended reactivity of substrates, catalysts, and additives can complicate a reaction that looks reasonable on paper. Each component of the reaction needs to be evaluated against the remainder to anticipate unintended reaction pathways.

How long will it take to complete the proposed synthesis?

Naturally, this is a bit of a tricky question. The level of difficulty of each step in the synthesis needs to be evaluated as well as how long it will take to make/purify the starting materials and any intermediates. After analyzing the individual steps and calculating a time frame, add 30% to the total because something will not work as planned. Once the overall calculation is complete, an accurate assessment of the approach can be made.

Is the shortest route really the most practical?

In many cases, adding one or two operationally trivial steps to a synthesis is much easier than fighting with a single challenging reaction.

Will the chemistry benefit from microwave irradiation?

Fundamentally, if a reaction needs to be heated, it is likely to be more efficient, cleaner, and faster in a microwave reactor. Since time is one of the most prec...

Table of contents

• COVER
• TITLE PAGE
• TABLE OF CONTENTS
• PREFACE
• ACKNOWLEDGMENTS
• 1 INTRODUCTION TO PRACTICAL FUNCTIONAL GROUP SYNTHESIS
• 2 PREPARATION OF ALCOHOLS, ETHERS, AND RELATED COMPOUNDS
• 3 SYNTHESIS OF AMINES, AMIDES, AND RELATED COMPOUNDS
• 4 SYNTHESIS OF ORGANOPHOSPHINES, PHOSPHONATES, AND RELATED COMPOUNDS
• 5 SYNTHESIS OF THIOETHERS, SULFONES, AND RELATED COMPOUNDS
• 6 SYNTHESIS OF ORGANOBORONIC ACIDS, ORGANOBORONATES, AND RELATED COMPOUNDS
• 7 SYNTHESIS OF ORGANOHALIDES
• INDEX
• END USER LICENSE AGREEMENT