12.1 One-Step Syntheses

12.1 One‐Step Syntheses 12.1 One‐Step Syntheses

• When building a HOME, you must have the right tools, • You may be able to solve one‐step syntheses by but you also need to know HOW to use the tools. matching the reaction pattern with an example in the • When building a MOLECULE (designing a synthesis), a textbook. lot of tools are available. Where are they? – To add Br–Br across a C=C double bond, an alkene is generally treated with Br / CCl in the dark. • To optimize your synthesis, you must understand HOW 2 4 the tools work. WHY? • How do you solve such syntheses without the textbook and without having to memorize each set of reagents? • What tools (reagents and conditions) are needed for – Learning to use any tool requires PRACTICE. the synthesis below? – Its also helpful to know mechanisms. WHY?

12.2 Functional Group 12.1 One‐Step Syntheses Transformations • Solving one‐step syntheses: • Let’s review some synthetic tools we have learned so 1. Analyze the structures of the reactant and product. far. 2. Assess HOW the functional groups have changed. • In Chapter 9, we learned how to shift the position of a 3. Use the reactions and mechanisms you have learned to halide. determine appropriate reagents and conditions. 4. Check your answer by working out the mechanism. • Solve the synthesis.

• The regiochemical considerations in this process are • Practice with CONCEPTUAL CHECKPOINTs vital to making the correct product. 12.1 and 12.2. Copyright 2012 John Wiley & Sons, Inc. 12 -3 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 12 -4 Klein, Organic Chemistry 1e

12.2 Functional Group 12.2 Functional Group Transformations Transformations

• The techniques are slightly modified for an –OH group. • Explain the • Explain the regiochemistry for each regiochemistry for reaction. each reaction.

Copyright 2012 John Wiley & Sons, Inc. 12 -5 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 12 -6 Klein, Organic Chemistry 1e 12.2 Functional Group 12.2 Functional Group Transformations Transformations • In Chapter 11, we learned how to introduce a halide.

• In Chapter 9, we learned how to shift the position of a C=C double bond. • With the introduction of a halide and its subsequent • Explain the elimination, we can control the degree of saturation. regiochemistry for each reaction.

12.2 Functional Group 12.3 Carbon Skeleton Transformations Transformations • Practice with SKILLBUILDER 12.1. • There are many important molecules that have complex carbon skeletons. • Give necessary reagents for the function group • The ability to design syntheses that produce a desired transformation below. Multiple steps are necessary. carbon skeleton is highly prized. • Some reactions will INCREASE the number of carbons in the molecule. • Some reactions will DECREASE the number of carbons in the molecule.

12.3 Carbon Skeleton 12.3 Carbon Skeleton Transformations Transformations • So far, we have learned only one transformation that • We have also learned a way to decrease the number of increases the number of carbons in a molecule. carbons in a molecule.

• In the future, we will discuss many more reactions that alter the carbon skeleton. • Practice with SKILLBUILDER 12.2. Copyright 2012 John Wiley & Sons, Inc. 12 -11 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 12 -12 Klein, Organic Chemistry 1e 12.3 Carbon Skeleton 12.4 Approach for Complex Transformations Syntheses • Give necessary reagents for the transformation below. • Some syntheses require a change in both the carbon Multiple steps are necessary. skeleton and in the functional groups. • To solve such syntheses, you must: 1. Analyze the structures of the reactant and product. 2. Assess HOW the carbon skeleton has changed. 3. Assess HOW the functional groups have changed. 4. Review the proposed steps to make sure that the regioselectivity and stereoselectivity in each step lead to the desired product. • Practice with SKILLBUILDER 12.3.

12.4 Approach for Complex 12.5 Retrosynthetic Analysis Syntheses • For the synthesis below: • For more challenging, complex multi‐step syntheses, it 1. Analyze the structures of the reactant and product. is often helpful to work backwards (retro) in our 2. Assess HOW the carbon skeleton has changed. analysis, although the same basic analysis is performed. 3. Assess HOW the functional groups have changed. • Perform a retrosynthetic analysis for the reaction 4. Review the proposed steps to make sure that the below. regioselectivity and stereoselectivity in each step lead to the desired product.

1. Analyze the structure of the reactant and product. What functional groups are we dealing with?

12.5 Retrosynthetic Analysis 12.5 Retrosynthetic Analysis

• Perform a retrosynthetic analysis for the reaction • Perform a retrosynthetic analysis for the reaction below. below. Work backwards; focus on the last step in the synthesis. 3. Assess HOW the functional groups have changed. We want to make an alkyne, so what reactions do we know that can be used to make an alkyne? 2. Assess HOW the carbon skeleton has changed. In this specific case, the carbon skeleton is not changing.

Copyright 2012 John Wiley & Sons, Inc. 12 -17 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 12 -18 Klein, Organic Chemistry 1e 12.5 Retrosynthetic Analysis 12.5 Retrosynthetic Analysis

• We only learned • The last step in the synthesis must involve a geminal one method to dihalide. synthesize an – WHY not a vicinal dihalide? How would a vicinal dihalide be alkyne. made? – Review the regioselectivity and stereoselectivity in each step.

12.5 Retrosynthetic Analysis 12.5 Retrosynthetic Analysis

• A retrosynthetic arrow is used by chemists to show the • Analyze the structure of the reactant and product. sequence of reactions in the reverse direction. Do we know of a method to synthesize a geminal dihalide? – Yes, we can use an addition reaction.

• Now, let’s continue the analysis by working another – What reagents do we need? step backwards.

12.5 Retrosynthetic Analysis 12.5 Retrosynthetic Analysis

• In the full retrosynthetic analysis, so far we have the • Recall that we used this method previously for last two steps worked out. converting alkenes to alkynes.

Copyright 2012 John Wiley & Sons, Inc. 12 -23 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 12 -24 Klein, Organic Chemistry 1e 12.5 Retrosynthetic Analysis 12.5 Retrosynthetic Analysis

• One step remains in the analysis, so we can work in • Review the proposed steps to make sure that the the forward direction. regioselectivity and stereoselectivity in each step lead Why is the Ts to the desired product. group necessary?

• Practice with SKILLBUILDER 12.4.

12.6 Practical Tips – 12.5 Retrosynthetic Analysis Create a List of Tools • Perform a retrosynthetic analysis for the conversion • To build a molecule, you must be able to choose the below. right tools for the job. • It will be helpful if you create a list of tools and categorize them into two sets of reactions: 1. Reactions that alter the carbon skeleton—see Section 12.3. 2. Reactions that alter the functional groups —see Section 12.2.

• As we learn more reactions, expand your list.

12.6 Practical Tips – 12.6 Practical Tips – Create Your Own Problems Create Your Own Problems • A great way to practice syntheses is to design your • Let’s work through an example: own problems: 1. Start with a relatively simple reactant compound. 1. Start with a relatively simple reactant compound. Let’s start with acetylene. 2. Choose a set of reagents to change the compound’s carbon 2. Choose a set of reagents to change the compound’s carbon skeleton or functional groups, and predict the structure of the skeleton or functional groups, and predict the structure of product. the product. 3. Repeat step 2 a few more times. 4. Take out all of the intermediates and reagents so you don’t give the answer away. 5. Swap problems with a classmate to practice more. • This process will help you to think about syntheses in new ways. Copyright 2012 John Wiley & Sons, Inc. 12 -29 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 12 -30 Klein, Organic Chemistry 1e 12.6 Practical Tips – 12.6 Practical Tips – Create Your Own Problems Create Your Own Problems 3. Repeat step 2 a few more times. • There will often be more than one way to solve a synthesis problem.

4. Take out all of the intermediates and reagents so you don’t give the answer away. • In general, a chemist’s goal is to find the most facile synthesis generally having the fewest steps. 5. Swap problems with a classmate.