Klein Ch12

12 12.1 One-Step Syntheses 12.2 Functional Group Transformations 12.3 Reactions That Change the Carbon Skeleton 12.4 How to Approach a Synthesis Problem 12.5 Retrosynthetic Analysis 12.6 Practical Tips for Increasing Proficiency

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Synthesis DID YOU EVER WONDER… what vitamins are and why we need them?

V

itamins are essential nutrients that our bodies require in order to function properly, and a deficiency of particular vitamins can lead to diseases, many of which can be fatal. Later in this chapter, we will learn more about the discovery of vitamins, and we will see that the laboratory synthesis of one particular vitamin represented a landmark event in the history of synthetic organic chemistry. This chapter serves as a brief introduction to organic synthesis. Until this point in the text, we have only seen a limited number of reactions (a few dozen, at most). In this chapter, our modest repertoire of reactions will allow us to develop a methodical, step-by-step process for proposing syntheses. We will begin with one-step synthesis problems and then progress toward more challenging multistep problems. The goal of this chapter is to develop the fundamental skills required for proposing a synthesis.

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12.1

537

One-Step Syntheses

DO YOU REMEMBER? Before you go on, be sure you understand the following topics. If necessary, review the suggested sections to prepare for this chapter. UÊ -iiV̈˜}Ê,i>}i˜ÌÃÊ̜Ê
VVœ“«ˆÃ…Ê՘V̈œ˜>ÊÊ ÀœÕ«Ê/À>˜ÃvœÀ“>̈œ˜Ê­-iV̈œ˜ÊÇ°™®

UÊ -ÕLÃ̈ÌṎœ˜ÊÛÃ°Ê ˆ“ˆ˜>̈œ˜Ê­-iV̈œ˜Ên°£Î®Ê

UÊ -ޘ̅iÈÃÊ-ÌÀ>Ìi}ˆiÃÊvœÀÊ
Ži˜iÃÊ>˜`Ê
ŽÞ˜iÃÊÊ ­-iV̈œ˜Ãʙ°£Î]ʣ䰣£® 6ˆÃˆÌÊÜÜܰ܈iÞ«ÕðVœ“Ê̜ÊV…iVŽÊޜÕÀÊ՘`iÀÃÌ>˜`ˆ˜}Ê>˜`ÊvœÀÊÛ>Õ>LiÊ«À>V̈Vi°

12.1 One-Step Syntheses The most straightforward synthesis problems are the ones that can be solved in just one step. For example, consider the following: Br Br

This transformation can be accomplished by treating the alkene with Br2 in an inert solvent, such as CCl4. Other synthesis problems might require more than a single step, and those problems will be more challenging. Before approaching multistep synthesis problems, it is absolutely essential to become comfortable with one-step syntheses. In other words, it is critical to achieve mastery over all reagents described in the previous chapters. If you can’t identify the reagents necessary for a onestep synthesis problem, then certainly you will be unable to solve more complex problems. The following exercises represent a broad review of the reactions in previous chapters. These exercises are designed to help you identify which reagents are still not at the forefront of your consciousness:

CONCEPTUAL CHECKPOINT 12.1 `i˜ÌˆvÞÊ Ì…iÊ Ài>}i˜ÌÃÊ ˜iViÃÃ>ÀÞÊ ÌœÊ >VVœ“«ˆÃ…Ê i>V…Ê œvÊ Ì…iÊ ÌÀ>˜ÃvœÀ“>̈œ˜ÃÊ Ã…œÜ˜Ê LiœÜ°Ê vÊ ÞœÕÊ >ÀiÊ …>ۈ˜}Ê ÌÀœÕLi]Ê Ì…iÊ Ài>}i˜ÌÃÊvœÀÊ̅iÃiÊÌÀ>˜ÃvœÀ“>̈œ˜ÃÊ>««i>Àʜ˜Ê«>}iÊ{{{]ÊLÕÌÊޜÕÊŜՏ`ÊwÀÃÌÊÌÀÞÊ̜ʈ`i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃÊޜÕÀÃivÊ܈̅œÕÌʅi«\ O Br

H OH

O

± En

Br

OH OH ± En

Br

OH

OH ± En Br OH Br ± En

± En Br

OH

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CHAPTER 12

Synthesis

12.2 `i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃʘiViÃÃ>ÀÞÊ̜Ê>VVœ“«ˆÃ…Êi>V…ÊœvÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜Ã°ÊvÊޜÕÊ>Àiʅ>ۈ˜}ÊÌÀœÕLi]Ê̅iÊÀi>}i˜ÌÃÊ vœÀÊ̅iÃiÊÌÀ>˜ÃvœÀ“>̈œ˜ÃÊ>««i>Àʜ˜Ê«>}iÊ{nÓ]ÊLÕÌÊޜÕÊŜՏ`ÊwÀÃÌÊÌÀÞÊ̜ʈ`i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃÊޜÕÀÃivÊ܈̅œÕÌʅi«\ Br

Br

Br

O O

CH3

H

Br

Br Br Br

Br

O

O OH

±

Br

Br

C

Br

O

12.2 Functional Group Transformations In the previous few chapters, we developed several synthesis strategies that enable us to move the location of a functional group or change its identity. Let’s briefly review these techniques, as they will be extremely helpful when solving multistep synthesis problems. In Chapter 9, we developed a technique for changing the position of a halogen by performing an elimination reaction followed by an addition reaction. For example: Br

Br Addition

Elimination

In this two-step process, the halogen is removed and then reinstalled at a different location. The regiochemical outcome of each step must be carefully controlled. The choice of base in the elimination step determines whether the more substituted or the less substituted alkene is formed. In the addition step, the decision whether or not to use peroxides will determine whether a Markovnikov addition or an anti-Markovnikov addition occurs. Br HBr

NaOEt

HBr ROOR

Br

HBr

t-BuOK

HBr ROOR

Br

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12.2

539

Functional Group Transformations

As we saw in Chapter 9, this technique must be slightly modified when the functional group is a hydroxyl group (OH). In such a case, the hydroxyl group must first be converted into a tosylate (a better leaving group), and only then can the technique be employed (elimination followed by addition): OTs

OH Convert OH into a better leaving group

Addition

Elimination

HO

After converting the hydroxyl group into a tosylate, the regiochemical outcome for elimination and addition can be carefully controlled, as summarized below: OH H3O±

1) TsCl, pyridine 2) NaOEt

1) BH3 THF 2) H2O2, NaOH

HO

1) Hg(OAc)2, H2O

2) NaBH4

1) BH3 THF

1) TsCl, pyridine 2) t-BuOK

2) H2O2, NaOH

HO

In Chapter 9, we also developed a two-step technique for moving the position of a double bond. For example: Br Addition

Elimination

Once again, the regiochemical outcome of each step can be controlled by choice of reagents, as summarized below: Br

HBr

t-BuOK

NaOEt

NaOEt

HBr ROOR

t-BuOK

Br

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CHAPTER 12

Synthesis

BY THE WAY vÊޜÕÀÊÃÌ>À̈˜}ʓ>ÌiÀˆ>ÊˆÃÊ >˜Ê>Ž>˜i]Ê̅iʜ˜ÞÊÕÃivÕÊ Ài>V̈œ˜ÊޜÕÊŜՏ`ÊVœ˜Ãˆ`iÀÊ ˆÃÊ>ÊÀ>`ˆV>Ê…>œ}i˜>̈œ˜°

In Chapter 11, we developed one other important technique: installing functionality in a compound with no functional groups: Br Radical bromination

Elimination

This procedure, together with the other reactions covered in the previous chapters, enables the interconversion between single, double, and triple bonds: H2 , Lindlar’s Catalyst or Na, NH3

H2 , Pt

1) Br2/CCl4 2) xs NaNH2 3) H2O

1) Br2, h n 2) NaOEt

We will soon learn a new way of approaching synthesis problems (rather than relying on a few, precanned techniques). For now, let’s ensure mastery over the reactions and techniques that allow us to change the identity or position of a functional group.

SKILLBUILDER 12.1

CHANGING THE IDENTITY OR POSITION OF A FUNCTIONAL GROUP

LEARN the skill

*Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜\

Br

SOLUTION 7iÊLi}ˆ˜ÊLÞÊ>˜>Þ∘}Ê̅iʈ`i˜ÌˆÌÞÊ>˜`ʏœV>̈œ˜ÊœvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«Ãʈ˜ÊLœÌ…Ê̅iÊÃÌ>À̈˜}ʓ>ÌiÀˆ>Ê>˜`Ê̅iÊ«Àœ`ÕVÌ°Ê/…iʈ`i˜ÌˆÌÞʜvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«Ê…>ÃÊViÀÌ>ˆ˜ÞÊV…>˜}i`Ê­>˜Ê >Ži˜iʅ>ÃÊLii˜ÊVœ˜ÛiÀÌi`ʈ˜ÌœÊ>˜Ê>ŽÞÊ…>ˆ`i®]Ê>˜`Ê̅iÊ«œÃˆÌˆœ˜ÊœvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«Ê…>ÃÊ >ÃœÊV…>˜}i`°Ê/…ˆÃÊV>˜ÊLiÊÃii˜Ê“œÀiÊi>ȏÞÊLÞʘՓLiÀˆ˜}Ê̅iÊ«>Ài˜ÌÊV…>ˆ˜\

1

3 2

5 4

C-2 and C-3 are functionalized

Br

1

3 2

5 4

C-1 is functionalized

/…iÊ ‡ÓÊ>˜`Ê ‡ÎÊ«œÃˆÌˆœ˜ÃÊ>ÀiÊv՘V̈œ˜>ˆâi`Ê­…>ÛiÊ>Êv՘V̈œ˜>Ê}ÀœÕ«®Êˆ˜Ê̅iÊÃÌ>À̈˜}ʓ>ÌiÀˆ>]ÊLÕÌÊ̅iÊ ‡£Ê«œÃˆÌˆœ˜ÊˆÃÊv՘V̈œ˜>ˆâi`ʈ˜Ê̅iÊ«Àœ`ÕVÌ°Ê/…iÀivœÀi]ÊLœÌ…Ê̅iʏœV>̈œ˜Ê>˜`Ê Ì…iʈ`i˜ÌˆÌÞʜvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«Ê“ÕÃÌÊLiÊV…>˜}i`°Ê/…>ÌʈÃ]ÊÜiʓÕÃÌÊw˜`Ê>ÊÜ>ÞÊ̜Êv՘V̈œ˜>ˆâiÊ̅iÊ ‡£Ê«œÃˆÌˆœ˜ÊLÞʓœÛˆ˜}Ê̅iÊi݈Ã̈˜}Êv՘V̈œ˜>Ê}ÀœÕ«°Ê7iʅ>ÛiÊ>Ài>`ÞÊÃii˜Ê>Ê Ìܜ‡ÃÌi«Ê“i̅œ`ÊvœÀÊV…>˜}ˆ˜}Ê̅iʏœV>̈œ˜ÊœvÊ>ÊπÊLœ˜`\

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12.2

541

Functional Group Transformations

/…ˆÃÊ ÃÌÀ>Ìi}ÞÊ ÜœÕ`Ê >V…ˆiÛiÊ Ì…iÊ `iÈÀi`Ê }œ>Ê œvÊ v՘V̈œ˜>ˆâˆ˜}Ê Ì…iÊ ‡£Ê «œÃˆÌˆœ˜]Ê >˜`Ê Ì…ˆÃÊ ÌÞ«iʜvÊÌÀ>˜ÃvœÀ“>̈œ˜ÊV>˜ÊLiÊ>VVœ“«ˆÃ…i`Êۈ>Ê>``ˆÌˆœ˜ÊvœœÜi`ÊLÞÊiˆ“ˆ˜>̈œ˜°Ê˜ÊœÀ`iÀÊ ÌœÊ“œÛiÊ̅iÊ«œÃˆÌˆœ˜ÊœvÊ̅iÊπÊLœ˜`]Ê̅iÊÀi>}i˜ÌÃʓÕÃÌÊLiÊV…œÃi˜ÊV>ÀivՏÞÊvœÀÊi>V…ÊÃÌi«Ê œvÊ̅iÊ«ÀœViÃðÊ-«iVˆwV>Þ]Ê>˜Êanti‡>ÀŽœÛ˜ˆŽœÛÊ>``ˆÌˆœ˜Ê“ÕÃÌÊLiÊvœœÜi`ÊLÞÊ>Êœv“>˜˜Ê iˆ“ˆ˜>̈œ˜\ Anti-Markovnikov addition

Hofmann elimination

X

œÀÊ Ì…iÊ wÀÃÌÊ ÃÌi«Ê œvÊ Ì…ˆÃÊ «ÀœViÃÃ]Ê ÜiÊ …>ÛiÊ i>À˜i`Ê œ˜ÞÊ ÌÜœÊ Ài>V̈œ˜ÃÊ Ì…>ÌÊ «ÀœVii`Ê Ûˆ>Ê anti‡>ÀŽœÛ˜ˆŽœÛÊ>``ˆÌˆœ˜\Ê­>®ÊiˆÌ…iÀÊ>``ˆÌˆœ˜ÊœvÊ ÀÊ܈̅ʫiÀœÝˆ`iÃʜÀÊ­L®Ê…Þ`ÀœLœÀ>̈œ˜‡ œÝˆ`>̈œ˜\

HBr ROOR

Br (Racemic)

1) BH3 THF 2) H2O2, NaOH

OH

(Racemic)

œÌ…Ê Ài>V̈œ˜ÃÊ ÜˆÊ «Àœ`ÕViÊ >˜Ê anti‡>ÀŽœÛ˜ˆŽœÛÊ >``ˆÌˆœ˜°Ê œÜiÛiÀ]Ê Ü…i˜Ê …Þ`ÀœLœÀ>̈œ˜Ê œÝˆ`>̈œ˜ÊˆÃÊÕÃi`]Ê̅iÊÀiÃՏ̈˜}ʅÞ`ÀœÝޏÊ}ÀœÕ«Ê“ÕÃÌÊ̅i˜ÊLiÊVœ˜ÛiÀÌi`Ê̜Ê>Ê̜Ãޏ>ÌiÊ«ÀˆœÀÊÌœÊ Ì…iÊœv“>˜˜Êiˆ“ˆ˜>̈œ˜Ê«ÀœViÃÃ\

HBr ROOR

t-BuOK

Br

1) BH3 THF 2) H2O2, NaOH

t-BuOK

TsCl Pyridine

OH

OTs

œÌ…ÊÀœÕÌiÃÊ܈ÊܜÀŽ]Ê>Ì…œÕ}…Ê̅iÊwÀÃÌÊÀœÕÌiʓˆ}…ÌÊLiʓœÀiÊivwVˆi˜Ì]ÊLiV>ÕÃiʈÌÊÀiµÕˆÀiÃÊ viÜiÀÊÃÌi«Ã° œÜÊ̅>ÌÊ̅iÊ ‡£Ê«œÃˆÌˆœ˜Ê…>ÃÊLii˜Êv՘V̈œ˜>ˆâi`]Ê̅iʏ>ÃÌÊÃÌi«ÊˆÃÊ̜ʈ˜ÃÌ>Ê>ÊLÀœ“ˆ˜iÊ >̜“Ê >ÌÊ Ì…iÊ ‡£Ê «œÃˆÌˆœ˜°Ê /…ˆÃÊ V>˜Ê LiÊ >VVœ“«ˆÃ…i`Ê ÜˆÌ…Ê >˜Ê anti‡>ÀŽœÛ˜ˆŽœÛÊ >``ˆÌˆœ˜Ê œvÊ À\

HBr ROOR

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Br

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CHAPTER 12

Synthesis

˜ÊÃՓ“>ÀÞ]Ê̅iÀiÊ>ÀiÊÌܜʫ>ÕÈLiÊÀœÕÌiÃÊ̜Ê>V…ˆiÛiÊ̅iÊ`iÈÀi`ÊÃޘ̅ïVÊÌÀ>˜ÃvœÀ“>̈œ˜\ 1) HBr, ROOR 2) t-BuOK 3) HBr, ROOR

Br 1) BH3 THF 2) H2O2, NaOH 3) TsCl, pyridine 4) t-BuOK 5) HBr, ROOR

ÌʈÃÊÛiÀÞÊVœ““œ˜Ê̜Êw˜`Ê̅>ÌʓՏ̈«iÊÀœÕÌiÃÊV>˜ÊLiÊÕÃi`Ê̜Ê>V…ˆiÛiÊ>Ê`iÈÀi`ÊÌÀ>˜ÃvœÀ“>̈œ˜°Ê œ˜½ÌÊv>Êˆ˜ÌœÊ̅iÊÌÀ>«ÊœvÊ̅ˆ˜Žˆ˜}Ê̅>ÌÊ̅iÀiʈÃʜ˜Þʜ˜iÊVœÀÀiVÌÊ܏Ṏœ˜Ê̜Ê>ÊÃޘ̅iÈÃÊ «ÀœLi“°Ê/…iÀiÊ>ÀiÊ>“œÃÌÊ>Ü>ÞÃʓՏ̈«iÊ«>̅Ü>ÞÃÊ̅>ÌÊ>ÀiÊvi>ÈLi°

PRACTICE the skill 12.3 *Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜Ã\ Br Br (a)

(b)

(c)

(d)

Br OH (f)

OH

(e)

OH

OH

OH Br (h)

(g)

APPLY the skill

OH

12.4 `i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃÊޜÕÊܜՏ`ÊÕÃiÊ̜ÊVœ˜ÛiÀÌÊӇLÀœ“œ‡Ó‡“i̅ޏLÕÌ>˜iʈ˜ÌœÊ ·“i̅ޏ‡£‡LÕÌޘi° 12.5 `i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃÊޜÕÊܜՏ`ÊÕÃiÊ̜ÊVœ˜ÛiÀÌÊ£‡«i˜Ìi˜iʈ˜ÌœÊ>Ê}i“ˆ˜>Ê`ˆLÀœ“ˆ`iÊ ­º}i“ˆ˜>»Êˆ˜`ˆV>ÌiÃÊ̅>ÌÊLœÌ…ÊLÀœ“ˆ˜iÊ>̜“ÃÊ>ÀiÊVœ˜˜iVÌi`Ê̜Ê̅iÊÃ>“iÊV>ÀLœ˜Ê>̜“®° 12.6 `i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃÊޜÕÊܜՏ`ÊÕÃiÊ̜ÊVœ˜ÛiÀÌʓi̅ޏVÞVœ…iÝ>˜iʈ˜ÌœÊi>V…ÊœvÊ̅iÊ vœœÜˆ˜}\ ­>® >ÊÎcÊ>ŽÞÊ…>ˆ`i

­L®Ê >ÊÌÀˆÃÕLÃ̈ÌÕÌi`Ê>Ži˜i

­V® >ÊÓcÊ>Vœ…œ

­`®Ê ·i̅ޏVÞVœ…iÝi˜i

need more PRACTICE? Try Problems 12.17, 12.21, 12.22

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12.3

543

Reactions That Change the Carbon Skeleton

12.3 Reactions That Change the Carbon Skeleton In all of the problems in the previous section, the functional group changed its identity or location, but the carbon skeleton always remained the same. In this section, we will focus on examples in which the carbon skeleton changes. In some cases, the number of carbon atoms in the skeleton increases, and in other cases, the number of carbon atoms decreases. If the size of the carbon skeleton increases, then a C—C bond-forming reaction is required. Thus far, we have only learned one reaction that can be used to introduce an alkyl group onto an existing carbon skeleton. Alkylation of a terminal alkyne (Section 10.10) will increase the size of a carbon skeleton: H

H

H

C

C

H

H

–

C

C

+

±

Na

Four carbon atoms

X

H

H

H

C

C

C

H

H

H

H

H

H

H

C

C

H

H

Three carbon atoms

C

C

H

H

H

C

C

C

H

H

H

H

±

NaX

Seven carbon atoms

Over time, we will see many other C—C bond-forming reactions, but for now, the knowledge that we have only seen one such reaction should greatly simplify the problems in this section, enabling a smooth transition into the world of synthetic organic chemistry. If the size of the carbon skeleton decreases, then a C—C bond-breaking reaction, called bond cleavage, is required. Once again, we have only seen one such reaction. Ozonolysis of an alkene (or alkyne) achieves bond cleavage at the location of the π bond: H H H

C H

H

H C

C

C

H

H

C

1) O3

H

2) DMS

H

H

H

H

H

C

C

C

H

Five carbon atoms

H

H

O ±

C

H

C O

H

H

One carbon atoms

Four carbon atoms

Over time, we will see other reactions that involve C—C bond cleavage. For now, the knowledge that we have only seen one such reaction should greatly simplify the problems in this section.

SKILLBUILDER 12.2

CHANGING THE CARBON SKELETON

LEARN the skill

`i˜ÌˆvÞÊÀi>}i˜ÌÃÊ̅>ÌÊV>˜ÊLiÊÕÃi`Ê̜Ê>V…ˆiÛiÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜\ Br

SOLUTION

œÕ˜ÌÊ̅iÊV>ÀLœ˜Ê>̜“Ãʈ˜Ê̅iÊÃÌ>À̈˜}ʓ>ÌiÀˆ>Ê>˜`ʈ˜Ê̅iÊ`iÈÀi`Ê«Àœ`ÕVÌ°Ê/…iÀiÊ>ÀiÊÃiÛi˜Ê V>ÀLœ˜Ê >̜“ÃÊ ˆ˜Ê ̅iÊ ÃÌ>À̈˜}Ê “>ÌiÀˆ>]Ê >˜`Ê Ì…iÀiÊ >ÀiÊ ˜ˆ˜iÊ V>ÀLœ˜Ê >̜“ÃÊ ˆ˜Ê ̅iÊ «Àœ`ÕVÌ°Ê /…iÀivœÀiÊÌܜÊV>ÀLœ˜Ê>̜“ÃʓÕÃÌÊLiʈ˜ÃÌ>i`°Ê7iʅ>Ûiʜ˜Þʏi>À˜i`ʜ˜iÊÀi>V̈œ˜ÊV>«>LiÊ œvʈ˜ÃÌ>ˆ˜}ÊÌܜÊV>ÀLœ˜Ê>̜“Ãʜ˜Ê>˜Êi݈Ã̈˜}ÊV>ÀLœ˜ÊÎii̜˜°Ê/…ˆÃÊ«ÀœViÃÃÊÀiµÕˆÀiÃÊ̅iÊÕÃiÊ œvÊ>˜Ê>ŽÞ˜ˆ`iʈœ˜Ê>˜`Ê>˜Ê>ŽÞÊ…>ˆ`i\ R

C

–

C

Alkynide

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±

Na

R

X

R

C

C

R

±

NaX

Alkyl halide

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CHAPTER 12

Synthesis

1˜ÌˆÊ˜œÜ]Ê̅ˆÃÊÀi>V̈œ˜Ê…>ÃÊ>Ü>ÞÃÊLii˜ÊۈiÜi`Êfrom the perspective of the alkyne°Ê/…>ÌʈÃ]Ê Ì…iÊ>ŽÞ˜iʈÃÊ̅iÊÃÌ>À̈˜}ʓ>ÌiÀˆ>]Ê>˜`Ê̅iÊ>ŽÞÊ…>ˆ`iʈÃÊÕÃi`Ê>ÃÊ>ÊÀi>}i˜Ìʈ˜Ê̅iÊÃiVœ˜`ÊÃÌi«Ê œvÊ̅iÊ«ÀœViÃÃ]Ê̅iÀiLÞÊ>V…ˆiۈ˜}Ê̅iʈ˜ÃÌ>>̈œ˜ÊœvÊ>˜Ê>ŽÞÊ}ÀœÕ«Ê­,®\ H

C

C

1) NaNH2

H

2) R

H

C

C

R

X

Starting material


ÌiÀ˜>̈ÛiÞ]Ê̅ˆÃÊÀi>V̈œ˜ÊV>˜ÊLiÊۈiÜi`ÊvÀœ“Ê̅iÊ«iÀëiV̈ÛiʜvÊ̅iÊ>ŽÞÊ…>ˆ`i°Ê/…>ÌʈÃ]Ê̅iÊ >ŽÞÊ…>ˆ`iʈÃÊ̅iÊÃÌ>À̈˜}ʓ>ÌiÀˆ>]Ê>˜`Ê>˜Ê>ŽÞ˜ˆ`iʈœ˜ÊˆÃÊÕÃi`Ê̜Ê>V…ˆiÛiÊ̅iʈ˜ÃÌ>>̈œ˜ÊœvÊ >ÊÌÀˆ«iÊLœ˜`ʜ˜ÌœÊ>˜Êi݈Ã̈˜}ÊV>ÀLœ˜ÊÎii̜˜\ ±

Na

R

–

C

C

H

R

X

C

C

H

Starting material

7…i˜ÊۈiÜi`ʈ˜Ê̅ˆÃÊÜ>Þ]Ê̅iÊ>ŽÞ>̈œ˜Ê«ÀœViÃÃÊÀi«ÀiÃi˜ÌÃÊ>ÊÌiV…˜ˆµÕiÊvœÀʈ˜ÌÀœ`ÕVˆ˜}Ê>˜Ê >ViÌޏi˜ˆVÊ}ÀœÕ«°Ê/…ˆÃʈÃÊiÝ>V̏ÞÊ܅>ÌʈÃʘii`i`Ê̜Ê܏ÛiÊ̅ˆÃÊ«ÀœLi“\ ±

Br

Na

–

C

C

H

C C H

˜Êv>VÌ]Ê̅ˆÃʜ˜iÊÃÌi«Ê«ÀœÛˆ`iÃÊ̅iÊ>˜ÃÜiÀ°Ê/…ˆÃʈÃʍÕÃÌÊ>ʜ˜i‡ÃÌi«ÊÃޘ̅iÈÃÊ«ÀœLi“°

PRACTICE the skill 12.7 `i˜ÌˆvÞÊÀi>}i˜ÌÃÊ̅>ÌÊV>˜ÊLiÊÕÃi`Ê̜Ê>V…ˆiÛiÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜Ã\

(a)

Br (b) O (c)

APPLY the skill

12.8

*Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜Ã\

(a)

Br O

(b)

Br

H Br

(c)

Br

Br

12.9 7…i˜Ê·LÀœ“œ‡Î‡i̅ޏ«i˜Ì>˜iʈÃÊÌÀi>Ìi`Ê܈̅ÊÜ`ˆÕ“Ê>ViÌޏˆ`i]Ê̅iʓ>œÀÊ«Àœ`ÕVÌÃÊ >ÀiÊ·i̅ޏ‡Ó‡«i˜Ìi˜iÊ>˜`Ê>ViÌޏi˜i°Ê Ý«>ˆ˜Ê܅ÞÊ̅iÊV>ÀLœ˜ÊÎii̜˜Ê`œiÃʘœÌÊV…>˜}iʈ˜Ê ̅ˆÃÊV>Ãi]Ê>˜`ʍÕÃ̈vÞÊ̅iÊvœÀ“>̈œ˜ÊœvÊ̅iʜLÃiÀÛi`Ê«Àœ`ÕVÌð need more PRACTICE? Try Problems 12.18, 12.19, 12.20, 12.23, 12.26

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12.3

545

Reactions That Change the Carbon Skeleton

MEDICALLYSPEAKING Vitamins 6ˆÌ>“ˆ˜ÃÊ>ÀiÊVœ“«œÕ˜`ÃÊ̅>ÌʜÕÀÊLœ`ˆiÃÊÀiµÕˆÀiÊvœÀʘœÀ“>Êv՘V̈œ˜ˆ˜}Ê>˜`ʓÕÃÌÊLiʜLÌ>ˆ˜i`ÊvÀœ“Êvœœ`°Ê
˜Êˆ˜>`iµÕ>Ìiʈ˜Ì>ŽiʜvÊ ViÀÌ>ˆ˜ÊۈÌ>“ˆ˜ÃÊV>ÕÃiÃÊëiVˆwVÊ`ˆÃi>ÃiðÊ/…ˆÃÊ«…i˜œ“i˜œ˜Ê…>`Ê Lii˜ÊœLÃiÀÛi`ʏœ˜}ÊLivœÀiÊ̅iÊiÝ>VÌÊÀœiʜvÊۈÌ>“ˆ˜ÃÊÜ>ÃÊ՘`iÀÃ̜œ`°Ê œÀÊ iÝ>“«i]Ê Ã>ˆœÀÃÊ Ü…œÊ Ài“>ˆ˜i`Ê >ÌÊ Ãi>Ê vœÀÊ iÝÌi˜`i`Ê «iÀˆœ`ÃÊܜՏ`ÊÃÕvviÀÊvÀœ“Ê>Ê`ˆÃi>ÃiÊV>i`ÊÃVÕÀÛÞ]ÊV…>À>VÌiÀˆâi`Ê LÞÊ̅iʏœÃÃʜvÊÌii̅]ÊÃܜi˜Êˆ“LÃ]Ê>˜`ÊLÀՈȘ}°ÊvʏivÌÊ՘ÌÀi>Ìi`]Ê Ì…iÊ `ˆÃi>ÃiÊ ÜœÕ`Ê LiÊ v>Ì>°Ê ˜Ê £Ç{Ç]Ê >Ê ÀˆÌˆÃ…Ê ˜>Û>Ê «…ÞÈVˆ>˜Ê ˜>“i`Ê>“iÃʈ˜`Ê`i“œ˜ÃÌÀ>Ìi`Ê̅>ÌÊ̅iÊivviVÌÃʜvÊÃVÕÀÛÞÊVœÕ`Ê LiÊÀiÛiÀÃi`ÊLÞÊi>̈˜}ʜÀ>˜}iÃÊ>˜`ʏi“œ˜Ã°ÊÌÊÜ>ÃÊÀiVœ}˜ˆâi`Ê̅>ÌÊ œÀ>˜}iÃÊ>˜`ʏi“œ˜ÃʓÕÃÌÊVœ˜Ì>ˆ˜Êܓiʺv>V̜À»Ê̅>ÌʜÕÀÊLœ`ˆiÃÊ ÀiµÕˆÀi]Ê>˜`ʏˆ“iʍՈViÊLiV>“iÊ>ʘœÀ“>Ê«>ÀÌʜvÊ>ÊÃ>ˆœÀ½ÃÊ`ˆiÌ°ÊœÀÊ Ì…ˆÃÊÀi>ܘ]Ê ÀˆÌˆÃ…ÊÃ>ˆœÀÃÊÜiÀiÊV>i`ʺˆ“iÞð» "̅iÀÊÃÌÕ`ˆiÃÊÀiÛi>i`Ê̅>ÌÊ>ÊÛ>ÀˆiÌÞʜvÊvœœ`ÃÊVœ˜Ì>ˆ˜i`ʓÞÃÌiÀˆœÕÃʺ}ÀœÜ̅Êv>V̜Àð»ÊœÀÊiÝ>“«i]ʜ܏>˜`Êœ«Žˆ˜ÃÊ­1˜ˆÛiÀÈÌÞÊ œvÊ >“LÀˆ`}i®ÊVœ˜`ÕVÌi`Ê>ÊÃiÀˆiÃʜvÊiÝ«iÀˆ“i˜ÌÃʈ˜Ê܅ˆV…Ê…iÊVœ˜ÌÀœi`Ê̅iÊ`ˆiÌ>ÀÞʈ˜Ì>ŽiʜvÊÀ>ÌðÊiÊvi`Ê̅i“ÊV>ÀLœ…Þ`À>ÌiÃ]Ê«ÀœÌiˆ˜ÃÊ >˜`Êv>ÌÃÊ­ÃiiÊ …>«ÌiÀÃÊÓx]ÊÓÈÊ>˜`ÊÓÇ®°Ê/…ˆÃʓˆÝÌÕÀiÊÜ>Ãʈ˜ÃÕvwVˆi˜ÌÊ ÌœÊÃÕÃÌ>ˆ˜Ê̅iÊÀ>ÌÃ]Ê>˜`ʈÌÊÜ>ÃʘiViÃÃ>ÀÞÊ̜Ê>``Ê>ÊviÜÊ`Àœ«ÃʜvʓˆŽÊ ̜Ê̅iˆÀÊ`ˆiÌ>ÀÞʈ˜Ì>ŽiÊ̜Ê>V…ˆiÛiÊÃÕÃÌ>ˆ˜>LiÊ}ÀœÜ̅°Ê/…iÃiÊiÝ«iÀˆ“i˜ÌÃÊ`i“œ˜ÃÌÀ>Ìi`Ê̅>ÌʓˆŽÊVœ˜Ì>ˆ˜i`ÊܓiÊ՘Ž˜œÜ˜Êˆ˜}Ài`ˆi˜Ì]Ê œÀÊv>V̜À]ʘiViÃÃ>ÀÞÊvœÀÊ«Àœ“œÌˆ˜}Ê«Àœ«iÀÊ}ÀœÜ̅°Ê -ˆ“ˆ>ÀÊ œLÃiÀÛ>̈œ˜ÃÊ ÜiÀiÊ “>`iÊ LÞÊ >Ê ÕÌV…Ê «…ÞÈVˆ>˜]Ê

…ÀˆÃ̈>>˜Ê ˆŽ“>˜]Ê ˆ˜Ê ̅iÊ ÕÌV…Ê Vœœ˜ˆiÃÊ ˆ˜Ê ˜`œ˜iÈ>°Ê 7…ˆiÊ ˆ˜ÛiÃ̈}>̈˜}Ê̅iÊV>ÕÃiÊvœÀÊ>ʓ>ÃÈÛiʜÕÌLÀi>ŽÊœvÊLiÀˆLiÀˆ]Ê>Ê`ˆÃi>ÃiÊV…>À>VÌiÀˆâi`ÊLÞÊ«>À>ÞÈÃ]ʅiʘœÌi`Ê̅>ÌÊ̅iʅi˜Ãʈ˜Ê̅iʏ>LœÀ>̜ÀÞÊLi}>˜Ê̜Êi݅ˆLˆÌÊ>ÊvœÀ“ÊœvÊ«>À>ÞÈÃÊ>ÃÊÜi°ÊiÊ`ˆÃVœÛiÀi`Ê Ì…>ÌÊ Ì…iÞÊ ÜiÀiÊ Liˆ˜}Ê vi`Ê ÀˆViÊ vÀœ“Ê ܅ˆV…Ê ̅iÊ wLÀœÕÃÊ …ÕÃŽÊ …>`Ê Lii˜ÊÀi“œÛi`Ê­V>i`Ê«œˆÃ…i`ÊÀˆVi®°Ê7…i˜Ê…iÊvi`Ê̅iʅi˜ÃÊÀ>ÜÊ Ü…œiÊÀˆVi]Ê̅iˆÀÊVœ˜`ˆÌˆœ˜Êˆ“«ÀœÛi`Ê`À>Ã̈V>Þ°ÊÌÊÜ>ÃÊ̅iÀivœÀiÊ Ài>ˆâi`Ê̅>ÌÊ̅iÊwLÀœÕÃʅÕÎʜvÊÀˆViÊVœ˜Ì>ˆ˜i`ÊܓiÊۈÌ>Ê}ÀœÜÌ…Ê v>V̜À°Ê˜Ê£™£Ó]Ê>Ê*œˆÃ…ÊLˆœV…i“ˆÃÌʘ>“i`Ê >ȓˆÀÊ՘ŽÊˆÃœ>Ìi`Ê Ì…iÊ >V̈ÛiÊ Vœ“«œÕ˜`Ê vÀœ“Ê ÀˆViÊ …ÕÃŽÃ°Ê >ÀivÕÊ ÃÌÕ`ˆiÃÊ ÀiÛi>i`Ê Ì…>ÌÊ Ì…iÊ ÃÌÀÕVÌÕÀiÊ Vœ˜Ì>ˆ˜i`Ê >˜Ê >“ˆ˜œÊ }ÀœÕ«]Ê >˜`Ê Ì…iÀivœÀiÊ Liœ˜}ÃÊ̜Ê>ÊV>ÃÃʜvÊVœ“«œÕ˜`ÃÊV>i`Ê>“ˆ˜iÃÊ­ÃiiÊ …>«ÌiÀÊÓή\Ê

OH Retinol (vitamin A)

Sources:ʈŽ]Êi}}Ã]ÊvÀՈÌ]ÊÛi}iÌ>LiÃ]Ê>˜`ÊwÅ Deficiency disease:Ê ˆ}…̇Lˆ˜`˜iÃÃÊ­ÃiiÊ-iV̈œ˜Ê£Ç°£Î® NH2 N

Thiamine (vitamin B1)

S

N

OH

Sources:ʈÛiÀ]Ê«œÌ>̜iÃ]Ê܅œiÊ}À>ˆ˜Ã]Ê>˜`ʏi}Փià Deficiency disease:Ê iÀˆLiÀˆ OH O

O

H OH Vitamin C

HO

OH

Sources:Ê ˆÌÀÕÃÊvÀՈÌÃ]ÊLiÊ«i««iÀÃ]Ê̜“>̜iÃ]Ê>˜`ÊLÀœVVœˆ Deficiency disease:Ê-VÕÀÛÞ H

H HO

Ergocalciferol (vitamin D2)

Sources:ʈÅ]Ê«Àœ`ÕVi`ÊLÞÊ̅iÊLœ`ÞÊ܅i˜ÊiÝ«œÃi`ÊÌœÊ Ã՘ˆ}…Ì Deficiency disease:Ê,ˆVŽiÌÃÊ­ÃiiÊ-iV̈œ˜Ê£Ç°£ä® O

NH2

Amino group

±

N

Phylloquinone (vitamin K1) ±

N

N N

S

OH

Thiamine (vitamin B1)

ÌÊÜ>ÃʜÀˆ}ˆ˜>ÞÊLiˆiÛi`Ê̅>ÌÊ>ÊۈÌ>Ê}ÀœÜ̅Êv>V̜ÀÃÊÜiÀiÊ>“ˆ˜iÃ]Ê ÃœÊ̅iÞÊÜiÀiÊV>i`ÊۈÌ>“ˆ˜ÃÊ­>ÊVœ“Lˆ˜>̈œ˜ÊœvÊvitalÊ>˜`Êamine®°Ê ÕÀ̅iÀÊÀiÃi>ÀV…Ê`i“œ˜ÃÌÀ>Ìi`Ê̅>ÌʓœÃÌÊۈÌ>“ˆ˜Ãʏ>VŽÊ>˜Ê>“ˆ˜œÊ }ÀœÕ«]Ê ÞiÌÊ Ì…iÊ ÌiÀ“Ê ºÛˆÌ>“ˆ˜Ã»Ê «iÀÈÃÌi`°Ê œÀÊ Ì…iˆÀÊ `ˆÃVœÛiÀÞÊ œvÊ Ì…iÊ ÀœiÊ ÛˆÌ>“ˆ˜ÃÊ «>ÞÊ ˆ˜Ê ˜ÕÌÀˆÌˆœ˜]Ê ˆŽ“>˜Ê >˜`Ê œ«Žˆ˜ÃÊ ÜiÀiÊ >Ü>À`i`Ê̅iÊ£™Ó™Ê œLiÊ*Àˆâiʈ˜Ê*…ÞȜœ}ÞʜÀÊi`ˆVˆ˜i°Ê 6ˆÌ>“ˆ˜ÃÊ>ÀiÊ}ÀœÕ«i`ʈ˜ÌœÊv>“ˆˆiÃÊL>Ãi`ʜ˜Ê̅iˆÀÊLi…>ۈœÀÊ ­À>̅iÀÊ̅>˜Ê̅iˆÀÊÃÌÀÕVÌÕÀi®ÆÊi>V…Êv>“ˆÞʈÃÊ`iÈ}˜>Ìi`Ê܈̅Ê>ʏiÌÌiÀ°ÊœÀÊiÝ>“«i]ÊۈÌ>“ˆ˜Ê ʈÃÊ>Êv>“ˆÞʜvʓ>˜ÞÊVœ“«œÕ˜`Ã]Êi>V…Ê `iÈ}˜>Ìi`Ê܈̅Ê>ʏiÌÌiÀÊ>˜`Ê>ʘՓLiÀÊ­ £]Ê Ó]Ê Î]ÊiÌV°®°Ê/…iÊÌ>LiÊ Ã…œÜÃÊÀi«ÀiÃi˜Ì>̈ÛiÊۈÌ>“ˆ˜ÃÊvÀœ“ÊÃiÛiÀ>Êv>“ˆˆiÃ\Ê

klein_c12_536-563hr.indd 545

O

Sources:Ê-œÞLi>˜Êœˆ]Ê}Àii˜ÊÛi}iÌ>LiÃ]Ê>˜`ʏiÌÌÕVi Deficiency disease:Êi“œÀÀ…>}ˆ˜}Ê­ˆ˜ÌiÀ˜>ÊLii`ˆ˜}®

>ÀÞÊÃÌÕ`ˆiÃÊÀiÛi>i`Ê̅iÊÃÌÀÕVÌÕÀiʜvÊۈÌ>“ˆ˜Ê ]Ê܅ˆV…Êi˜>Li`Ê V…i“ˆÃÌÃÊ ÌœÊ `iۈÃiÊ >Ê Ãޘ̅ïVÊ ÃÌÀ>Ìi}ÞÊ vœÀÊ «Ài«>Àˆ˜}Ê ÛˆÌ>“ˆ˜Ê

Ê ˆ˜Ê ̅iÊ >LœÀ>̜ÀÞ°Ê -ÕVViÃÃÊ i`Ê ÌœÊ Ì…iÊ «Ài«>À>̈œ˜Ê œvÊ ÛˆÌ>“ˆ˜Ê ʜ˜Ê>˜Êˆ˜`ÕÃÌÀˆ>ÊÃV>i°Ê-ÕV…Êi>ÀÞÊÃÕVViÃÃiÃÊi˜VœÕÀ>}i`Ê Ì…iÊ ˜œÌˆœ˜Ê ̅>ÌÊ V…i“ˆÃÌÃÊ ÜœÕ`Ê Ãœœ˜Ê iÕVˆ`>ÌiÊ Ì…iÊ ÃÌÀÕVÌÕÀiÃÊ œvÊ >Ê ۈÌ>“ˆ˜ÃÊ >˜`Ê `iۈÃiÊ “i̅œ`ÃÊ vœÀÊ Ì…iˆÀÊ «Ài«>À>̈œ˜Ê ˆ˜Ê ̅iÊ >LœÀ>̜ÀÞ°Ê /…iÊ Ãޘ̅iÈÃÊ œvÊ ÛˆÌ>“ˆ˜Ê £Ó]Ê …œÜiÛiÀ]Ê ÜœÕ`Ê «ÀœÛiÊ̜ÊLiʓœÀiÊVœ“«iÝ]Ê>ÃÊÜiÊ܈ÊÃiiʈ˜Ê̅iʘiÝÌÊi`ˆV>ÞÊ -«i>Žˆ˜}ÊLœÝ°

7/15/10 12:47 PM

546

CHAPTER 12

Synthesis

12.4 How to Approach a Synthesis Problem In the previous two sections, we covered two critical skills: (1) functional group transformations and (2) changing the carbon skeleton. In this section, we will explore synthesis problems that require both skills. From this point forward, every synthesis problem should be approached by asking the following two questions: 1.

Is there a change in the carbon skeleton? Compare the starting material with the product to determine if the carbon skeleton is gaining or losing carbon atoms.

2.

Is there a change in the identity or location of the functional group? Is one functional group converted into another, and does the position of functionality change?

The following example demonstrates how these two questions should be applied.

SKILLBUILDER 12.3

APPROACHING A SYNTHESIS PROBLEM

LEARN the skill

*Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜\

SOLUTION

ÛiÀÞÊÃޘ̅iÈÃÊ«ÀœLi“ÊŜՏ`Ê>Ü>ÞÃÊLiÊ>˜>Þâi`Ê̅ÀœÕ}…Ê̅iʏi˜ÃʜvÊ̅iÊvœœÜˆ˜}ÊÌÜœÊ µÕiÃ̈œ˜Ã\ 1. Is there a change in the carbon skeleton?Ê /…iÊÃÌ>À̈˜}ÊVœ“«œÕ˜`ʅ>ÃÊwÛiÊV>ÀLœ˜Ê >̜“Ã]Ê>˜`Ê̅iÊ«Àœ`ÕVÌʅ>ÃÊÃiÛi˜ÊV>ÀLœ˜Ê>̜“ðÊ/…ˆÃÊÌÀ>˜ÃvœÀ“>̈œ˜Ê̅iÀivœÀiÊÀiµÕˆÀiÃÊ̅iÊ ˆ˜ÃÌ>>̈œ˜ÊœvÊÌܜÊV>ÀLœ˜Ê>̜“Ã\ 5 2 1

4

2 1

3

4 3

6 5

7

7…i˜Ê˜Õ“LiÀˆ˜}Ê̅iÊV>ÀLœ˜Ê>̜“Ã]Ê>ÃÊŜܘÊ>LœÛi]ʈÌʈÃʘœÌʘiViÃÃ>ÀÞÊ̜ÊvœœÜÊ1*
Ê ÀՏiÃÊvœÀÊ>ÃÈ}˜ˆ˜}ʏœV>˜ÌðÊvÊÜiÊÜiÀiʘ>“ˆ˜}Ê̅ˆÃÊVœ“«œÕ˜`]ÊÜiÊܜՏ`ÊLiÊVœ“«ii`ÊÌœÊ ÕÃiÊ«Àœ«iÀʏœV>˜ÌÃʭ̅iÊÌÀˆ«iÊLœ˜`ÊܜՏ`ÊLiÊLiÌÜii˜Ê ‡£Ê>˜`Ê ‡Ó]ÊÀ>̅iÀÊ̅>˜ÊLiÌÜii˜Ê

‡{Ê>˜`Ê ‡x®°Ê ÕÌÊ̅iʘՓLiÀÃʅiÀiÊ>Àiʜ˜ÞÊ̜œÃÊ>˜`ÊV>˜ÊLiÊÕÃi`ʈ˜Ê܅>ÌiÛiÀÊÜ>ÞʈÃÊ i>ÈiÃÌÊvœÀÊޜÕÊ̜ÊVœÕ˜Ì° 2. Is there a change in the identity or location of the functional group?Ê iÀÌ>ˆ˜Þ]Ê̅iÊ ˆ`i˜ÌˆÌÞʜvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«Ê…>ÃÊV…>˜}i`Ê­>ÊÌÀˆ«iÊLœ˜`ʅ>ÃÊLii˜ÊVœ˜ÛiÀÌi`ʈ˜ÌœÊ>Ê `œÕLiÊLœ˜`®]ÊLÕÌÊVœ˜Ãˆ`iÀÊ̅iʏœV>̈œ˜ÊœvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«\ 5 2 1

4 3

2 1

4 3

6 5

7

"˜ViÊ>}>ˆ˜]Ê̅iÃiʘՓLiÀÃÊ>ÀiʘœÌÊ1*
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ʘՓLiÀˆ˜}ÊÃÞÃÌi“Ê ܜՏ`ʅ>ÛiÊLii˜ÊVœ˜vÕȘ}Ê>˜`ʓˆÃi>`ˆ˜}°

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12.4

547

How to Approach a Synthesis Problem

By asking both questions, the following two tasks have been identified: (1) two carbon atoms must be installed and (2) the triple bond must be converted into a double bond in its current location. For each of these tasks, we must determine what reagents to use:

1. What reagents will add two carbon atoms to a skeleton? 2. What reagents will convert a triple bond into a trans double bond? Two new carbon atoms can be introduced via alkylation of the starting alkyne: 1) NaNH2 2) EtI

Now that the correct carbon skeleton has been established, reduction of the triple bond can be accomplished via a dissolving metal reduction to afford the trans alkene: Na , NH3 (l )

The solution to this problem requires two steps: (1) alkylation of the alkyne followed by (2) conversion of the triple bond into a double bond. Notice the order of events. If the triple bond had first been converted into a double bond, the alkylation process would not work. Only a terminal triple bond can be alkylated, not a terminal double bond.

PRACTICE the skill 12.10 Identify reagents that can be used to achieve each of the following transformations: (a)

(b) Br

O Br OH

(c)

(d) OH

O H

(e)

APPLY the skill

(f)

12.11 Propose a plausible synthesis for the following transformation (many steps are required): OH HO

12.12 Propose a plausible synthesis for the following transformation, in which the carbon skeleton is increased by only one carbon atom: O H

need more PRACTICE? Try Problems 12.19–12.26

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548

CHAPTER 12

Synthesis

MEDICALLYSPEAKING The Total Synthesis of Vitamin B12 /…iÊ Ã̜ÀÞÊ œvÊ ÛˆÌ>“ˆ˜Ê £ÓÊ Chlorophyll a Vitamin B12 Li}>˜Ê ܅i˜Ê «…ÞÈVˆ>˜ÃÊ ÀiVO NH2 œ}˜ˆâi`Ê Ì…>ÌÊ >˜i“ˆ>]Ê >Ê v>Ì>Ê H2N `ˆÃi>ÃiÊV>ÕÃi`ÊLÞÊ>ʏœÜÊVœ˜O Vi˜ÌÀ>̈œ˜ÊœvÊÀi`ÊLœœ`ÊViÃ]Ê O H2N VœÕ`Ê LiÊ ÌÀi>Ìi`Ê ivviV̈ÛiÞÊ N N N CN N LÞÊ vii`ˆ˜}Ê Ì…iÊ «>̈i˜ÌÊ ˆÛiÀ°Ê NH2 Mg O Co Porphyrin /…ˆÃÊ w˜`ˆ˜}Ê Ã«>ÀŽi`Ê >Ê À>ViÊ Corrin H ring system H2N ring system N N N ̜ÊiÝÌÀ>VÌÊ̅iÊVœ“«œÕ˜`Ãʈ˜Ê N ˆÛiÀÊ >˜`Ê ˆÃœ>ÌiÊ Ì…iÊ ÛˆÌ>“ˆ˜Ê O O V>«>LiÊ œvÊ ÌÀi>̈˜}Ê >˜i“ˆ>°Ê NH2 O ˜Ê£™{Ç]ÊۈÌ>“ˆ˜Ê £ÓÊÜ>ÃÊwÀÃÌÊ O ± O MeO2C N ˆÃœ>Ìi`Ê>˜`Ê«ÕÀˆwi`Ê>ÃÊ`ii«Ê O NH Ài`Ê VÀÞÃÌ>ÃÊ LÞÊ `Ê ,ˆVŽiÃÊ N HO ­>Ê ÃVˆi˜ÌˆÃÌÊ ÜœÀŽˆ˜}Ê >ÌÊ Ì…iÊ O iÀVŽÊ V…i“ˆV>Ê Vœ“«>˜Þ®°Ê O – P

vvœÀÌÃÊ Ì…i˜Ê vœVÕÃi`Ê œ˜Ê O O O `iÌiÀ“ˆ˜ˆ˜}Ê Ì…iÊ ÃÌÀÕVÌÕÀi°Ê OH -œ“iÊ ÃÌÀÕVÌÕÀ>Ê vi>ÌÕÀiÃÊ ÜiÀiʈ˜ˆÌˆ>ÞÊiÕVˆ`>Ìi`]ÊLÕÌÊ Ì…iÊ Vœ“«iÌiÊ ÃÌÀÕVÌÕÀiÊ Ü>ÃÊ ÃÕVViÃÃvՏÞÊ`iÌiÀ“ˆ˜i`ÊLÞÊ œÀœÌ…ÞÊ ÀœÜvœœÌÊœ`}Žˆ˜Ê­"ÝvœÀ`Ê “i̅œ`ÃÊ vœÀÊ Vœ˜ÃÌÀÕV̈˜}Ê Ì…iÊ VœÀÀˆ˜Ê Àˆ˜}Ê ÃÞÃÌi“Ê >ÃÊ ÜiÊ >ÃÊ Ì…iÊ 1˜ˆÛiÀÈÌÞ®ÊÕȘ}Ê8‡À>ÞÊVÀÞÃÌ>œ}À>«…Þ°Ê-…iÊvœÕ˜`Ê̅>ÌÊ̅iÊÃÌÀÕVÃÌiÀiœV…i“ˆV>ÞÊ `i“>˜`ˆ˜}Ê Ãˆ`iÊ V…>ˆ˜°Ê i>˜Ü…ˆi]Ê
LiÀÌÊ ÌÕÀiÊ œvÊ ÛˆÌ>“ˆ˜Ê £ÓÊ ˆÃÊ LՈÌÊ Õ«œ˜Ê >Ê VœÀÀˆ˜Ê Àˆ˜}Ê ÃÞÃÌi“]Ê Ü…ˆV…Ê ˆÃÊ

ÃV…i˜“œÃiÀÊ­>ÌÊ̅iÊ /ʈ˜Ê˜`®ÊÜ>ÃÊ>ÃœÊܜÀŽÃˆ“ˆ>ÀÊ̜Ê̅iÊ«œÀ«…ÞÀˆ˜ÊÀˆ˜}ÊÃÞÃÌi“Ê«ÀiÃi˜Ìʈ˜ÊV…œÀœ«…ޏ]Ê̅iÊ ˆ˜}Ê œ˜Ê >Ê Ãޘ̅iÈÃÊ œvÊ Ì…iÊ ÛˆÌ>“ˆ˜°Ê œÜiÛiÀ]Ê Ì…iÊ ÌÜœÊ “i˜Ê ÜiÀiÊ }Àii˜Ê«ˆ}“i˜ÌÊ̅>ÌÊ«>˜ÌÃÊÕÃiÊvœÀÊ«…œÌœÃޘ̅iÈÃÊ­ÃiiÊ>LœÛi®° `iÛiœ«ˆ˜}Ê `ˆvviÀi˜ÌÊ ÃÌÀ>Ìi}ˆiÃÊ vœÀÊ Vœ˜ÃÌÀÕV̈˜}Ê Ì…iÊ VœÀÀˆ˜Ê Àˆ˜}Ê /…iÊ VœÀÀˆ˜Ê Àˆ˜}Ê ÃÞÃÌi“Ê œvÊ ÛˆÌ>“ˆ˜Ê £ÓÊ ˆÃÊ >ÃœÊ Vœ“«ÀˆÃi`Ê œvÊ ÃÞÃÌi“°Ê 7œœ`Ü>À`½ÃÊ
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Ê >˜`Ê ]Ê Ü…ˆiÊ ÃV…i“œÃiÀ½ÃÊ
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12.5

ÕÀˆ˜}Ê Ì…iÊ `iÛiœ«“i˜ÌÊ œvÊ i>V…Ê «>̅Ü>Þ]Ê R ՘iÝ«iVÌi`ʜLÃÌ>ViÃÊi“iÀ}i`Ê̅>ÌÊÀiµÕˆÀi`Ê R ̅iÊ`iÛiœ«“i˜ÌʜvʘiÜÊÃÌÀ>Ìi}ˆiÃÊ>˜`ÊÌiV…B ˜ˆµÕiÃ°Ê œÀÊ iÝ>“«i]Ê ÃV…i˜“œÃiÀÊ …>`Ê ÃÕVN ViÃÃvՏÞÊ`i“œ˜ÃÌÀ>Ìi`Ê>ʓi̅œ`ÊvœÀÊVœÕ«ˆ˜}Ê Ì…iÊ …iÌiÀœVÞViÃ]Ê i˜>Lˆ˜}Ê Vœ˜ÃÌÀÕV̈œ˜Ê œvÊ >Ê Ãˆ“«iÊVœÀÀˆ˜ÊÃÞÃÌi“ʭ܈̅œÕÌÊ̅iʏ>À}i]ÊLՏŽÞÊ Ãˆ`iÊ }ÀœÕ«ÃÊ vœÕ˜`Ê ˆ˜Ê ۈÌ>“ˆ˜Ê £Ó®ÆÊ …œÜiÛiÀ]Ê Ì…ˆÃÊ >««Àœ>V…Ê v>ˆi`Ê ÌœÊ VœÕ«iÊ Ì…iÊ …iÌiÀœVÞViÃÊ̅>Ìʘii`i`Ê̜ÊLiʍœˆ˜i`Ê̜ÊvœÀ“Ê̅iÊ R VœÀÀˆ˜ÊÀˆ˜}ÊÃÞÃÌi“ÊœvÊۈÌ>“ˆ˜Ê £Ó°Ê/…ˆÃÊv>ˆÕÀiÊ Ü>ÃÊ >ÌÌÀˆLÕÌi`Ê ÌœÊ Ì…iÊ ÃÌiÀˆVÊ LՏŽÊ œvÊ Ì…iÊ ÃÕLR Ã̈ÌÕi˜ÌÃʜ˜Êi>V…Ê…iÌiÀœVÞVi°Ê/œÊVˆÀVՓÛi˜ÌÊ B ̅iÊ «ÀœLi“]Ê ÃV…i˜“œÃiÀÊ `iÛiœ«i`Ê >˜Ê N ˆ˜}i˜ˆœÕÃʓi̅œ`ÊLÞÊ܅ˆV…Ê…iÊÌi̅iÀi`ÊÌÜœÊ Àˆ˜}ÃÊ̜}i̅iÀÊ܈̅Ê>ÊÌi“«œÀ>ÀÞÊÃՏvÕÀÊLÀˆ`}i°Ê ÞÊ `œˆ˜}Ê Ãœ]Ê Ì…iÊ VœÕ«ˆ˜}Ê «ÀœViÃÃÊ LiV>“iÊ >˜Ê intra“œiVՏ>ÀÊ «ÀœViÃÃÊÀ>̅iÀÊ̅>˜Ê>˜Êinter“œiVՏ>ÀÊ«ÀœViÃÃÊ­ÃiiÊ>LœÛi®° /…iÊ ÃՏvÕÀÊ LÀˆ`}iÊ Ü>ÃÊ Ài>`ˆÞÊ iÝ«ii`Ê `ÕÀˆ˜}Ê Ì…iÊ VœÕ«ˆ˜}Ê «ÀœViÃÃ]Ê >˜`Ê Ì…iÊ œÛiÀ>Ê «ÀœViÃÃÊ LiV>“iÊ Ž˜œÜ˜Ê >ÃÊ ºÃՏvˆ`iÊ Vœ˜ÌÀ>V̈œ˜°»Ê /…ˆÃÊ ˆÃÊ ÕÃÌÊ œ˜iÊ iÝ>“«iÊ œvÊ Ì…iÊ VÀi>̈ÛiÊ ÃœṎœ˜ÃÊ Ì…>ÌÊ Ãޘ̅ïVÊ V…i“ˆÃÌÃÊ “ÕÃÌÊ `iÛiœ«Ê ܅i˜Ê >Ê «>˜˜i`Ê Ãޘ̅ïVÊ ÀœÕÌiÊ v>ˆÃ°Ê
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±

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Retrosynthetic Analysis

R

C N

Temporary tether

R S

R

C

B N C

R

N

R

N

ÕÀˆ˜}Ê …ˆÃÊ œÕÀ˜iÞÊ ÌœÜ>À`Ê Ì…iÊ ÌœÌ>Ê Ãޘ̅iÈÃÊ œvÊ ÛˆÌ>“ˆ˜Ê £Ó]Ê 7œœ`Ü>À`Ê i˜VœÕ˜ÌiÀi`Ê >Ê V>ÃÃÊ œvÊ Ài>V̈œ˜ÃÊ Ì…>ÌÊ ÜiÀiÊ Ž˜œÜ˜Ê̜ʫÀœVii`Ê܈̅Ê՘iÝ«>ˆ˜i`ÊÃÌiÀiœV…i“ˆV>ÊœÕÌVœ“iÃ°Ê /œ}i̅iÀÊ܈̅ʅˆÃÊVœi>}ÕiÊ,œ>`Êœvv“>˜˜]ʅiÊ`iÛiœ«i`Ê>Ê Ì…iœÀÞÊ >˜`Ê >Ê ÃiÌÊ œvÊ ÀՏiÃÊ Ì…>ÌÊ ÜœÕ`Ê ÃÕVViÃÃvՏÞÊ iÝ«>ˆ˜Ê ̅iÊ ÃÌiÀiœV…i“ˆV>Ê œÕÌVœ“iÃÊ œvÊ >˜Ê i˜ÌˆÀiÊ >Ài>Ê œvÊ œÀ}>˜ˆVÊ V…i“ˆÃÌÀÞÊV>i`Ê«iÀˆVÞVˆVÊÀi>V̈œ˜Ã°Ê/…ˆÃÊV>ÃÃʜvÊÀi>V̈œ˜ÃÊ܈ÊLiÊ VœÛiÀi`ʈ˜Ê …>«ÌiÀÊ£ÇÊ̜}i̅iÀÊ܈̅Ê̅iÊ܇V>i`Ê7œœ`Ü>À`q œvv“>˜˜ÊÀՏiÃÊÕÃi`Ê̜Ê`iÃVÀˆLiÊ>˜`Ê«Ài`ˆVÌÊ̅iÊÃÌiÀiœV…i“ˆV>Ê œÕÌVœ“iÃÊ vœÀÊ Ì…iÃiÊ Ài>V̈œ˜Ã°Ê /…iÊ `iÛiœ«“i˜ÌÊ œvÊ Ì…iÃiÊ ÀՏiÃʏi`Ê̜Ê>˜œÌ…iÀÊ œLiÊ*Àˆâiʈ˜Ê£™n£]ÊvœÀÊ܅ˆV…Ê7œœ`Ü>À`Ê ÜœÕ`Ê …>ÛiÊ Lii˜Ê >Ê Vœ‡ÀiVˆ«ˆi˜ÌÊ …>`Ê …iÊ ˜œÌÊ `ˆi`Ê ÌÜœÊ Þi>ÀÃÊ i>ÀˆiÀ° /…iÊ Ã̜ÀÞÊ œvÊ ÛˆÌ>“ˆ˜Ê £ÓÊ ˆÃÊ >Ê Üœ˜`iÀvÕÊ iÝ>“«iÊ œvÊ …œÜÊ œÀ}>˜ˆVÊ V…i“ˆÃÌÀÞÊ «Àœ}ÀiÃÃiÃ°Ê ÕÀˆ˜}Ê Ì…iÊ ÌœÌ>Ê Ãޘ̅iÈÃÊ œvÊ >Ê ÃÌÀÕVÌÕÀ>ÞÊ Vœ“«iÝÊ Vœ“«œÕ˜`]Ê Ì…iÀiÊ ˆÃÊ ˆ˜iۈÌ>LÞÊ >Ê «œˆ˜ÌÊ >ÌÊ܅ˆV…Ê̅iÊ«>˜˜i`ÊÀœÕÌiÊv>ˆÃ]ÊÀiµÕˆÀˆ˜}Ê>ÊVÀi>̈Ûiʓi̅œ`Ê vœÀÊ VˆÀVՓÛi˜Ìˆ˜}Ê Ì…iÊ œLÃÌ>Vi°Ê ˜Ê ̅ˆÃÊ Ü>Þ]Ê ˜iÜÊ ˆ`i>ÃÊ >˜`Ê ÌiV…˜ˆµÕiÃÊ >ÀiÊ Vœ˜ÃÌ>˜ÌÞÊ `iÛiœ«i`°Ê ˜Ê ̅iÊ `iV>`iÃÊ Ãˆ˜ViÊ Ì…iÊ ÌœÌ>Ê Ãޘ̅iÈÃÊ œvÊ ÛˆÌ>“ˆ˜Ê £Ó]Ê Ì…œÕÃ>˜`ÃÊ œvÊ Ãޘ̅ïVÊ Ì>À}iÌÃ]Ê “œÃÌÊ œvÊ Ì…i“Ê «…>À“>ViṎV>Ã]Ê …>ÛiÊ Lii˜Ê Vœ˜ÃÌÀÕVÌi`°Ê iÜÊ ÌiV…˜ˆµÕiÃ]Ê Ài>}i˜ÌÃ]Ê >˜`Ê «Àˆ˜Vˆ«iÃÊ Vœ˜ÃÌ>˜ÌÞÊ i“iÀ}iÊ vœÀ“Ê ̅iÃiÊ i˜`i>ۜÀÃ°Ê 7ˆÌ…Ê ̈“i]Ê Ãޘ̅ïVÊ Ì>À}iÌÃÊ >ÀiÊ }iÌ̈˜}Ê “œÀiÊ >˜`Ê “œÀiÊ Vœ“«iÝ]Ê >˜`Ê Ì…iÊ i>`iÀÃÊ ˆ˜Ê ̅iÊ vˆi`Ê œvÊ œÀ}>˜ˆVÊ V…i“ˆÃÌÀÞÊ >ÀiÊ Vœ˜ÃÌ>˜ÌÞÊ «Õň˜}Ê Ì…iÊ LœÕ˜`>ÀˆiÃÊ œvÊ Ãޘ̅ïVÊ œÀ}>˜ˆVÊ V…i“ˆÃÌÀÞ]Ê Ü…ˆV…Ê Vœ˜Ìˆ˜ÕiÃÊ ÌœÊ iۜÛiÊ œ˜Ê >Ê `>ˆÞÊL>ÈðÊ

12.5 Retrosynthetic Analysis As we progress through the course and increase our repertoire of reactions, synthesis problems will become increasingly more challenging. To meet this challenge, a modified approach will be necessary. The same two fundamental questions (as described in the previous section) will continue to serve as a starting point for analyzing all synthesis problems, but instead of trying

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to identify the first step of the synthesis, we will begin by trying to identify the last step of the synthesis. Analysis of the following synthesis problem will illustrate this process:

?

OH

An alcohol

An alkyne

Rather than focusing on what can be done with an alcohol that will ultimately lead to an alkyne, we instead focus on reactions that can generate an alkyne:

OH

Focus on this step

In this way, we work backward until arriving at the starting material. Chemists have intuitively used this approach for many years, but E. J. Corey (Harvard University) was the first to develop a systematic set of principles for application of this approach, which he called retrosynthetic analysis. Let’s use a retrosynthetic analysis to solve the problem above. We must always begin by determining whether there is a change in the carbon skeleton or in the identity or location of the functional group. In this case, both the starting material and the product contain five carbon atoms, and the carbon skeleton is not changing in this instance. However, there is a change in the functional group. Specifically, an alcohol is converted into an alkyne but remains in the same location in the skeleton. We have not learned a way to do this in just one step. In fact, using reactions covered so far, this transformation cannot be accomplished even in two steps. So we approach this problem backward and ask: “How are triple bonds made?” We have only covered one way to make a triple bond. Specifically, a dihalide undergoes two successive E2 eliminations in the presence of excess NaNH2 (Section 10.4). Any one of the following three dihalides could be used to form the desired alkyne: Geminal dibromide

Br Br Br

Vicinal dibromide

Br Br Br Geminal dibromide

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Retrosynthetic Analysis

The geminal dibromides can be ruled out, because we only saw one way to make a geminal dihalide—and that was starting from an alkyne. We certainly do not want to start with an alkyne in order to produce the very same alkyne: OH

?

Br Br

Therefore, the last step of our synthesis must be formation of the alkyne from a vicinal dihalide: OH

? 1) xs NaNH2 2) H2O

Br

Br

A special retrosynthetic arrow is used by chemists to indicate this type of “backward” thinking: this dibromide

This alkyne can be made from...

Br

Br

Don’t be confused by this retrosynthetic arrow. It indicates a hypothetical synthetic pathway thinking backward from the product (alkyne). In other words, the previous figure should be read as: “In the last step of our synthesis, the alkyne can be made from a vicinal dibromide.” Now let’s try to go backward one more step. We have learned only one way to make a vicinal dihalide, starting with an alkene: Br

Can be made from:

Br alkene

Notice again the retrosynthetic arrow. The figure indicates that the vicinal dibromide can be made from an alkene. In other words, the alkene can be used as a precursor to prepare the desired dibromide.

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Therefore, our retrosynthetic analysis, so far, looks like this: Br

Product

Br Alkene

This scheme indicates that the product (alkyne) can be prepared from the alkene. This sequence of events represents one of the strategies discussed earlier in this chapter—converting a double bond into a triple bond: H2 , Lindlar’s catalyst or Na, NH3

H2 , Pt

1) Br2 /CCl4 2) xs NaNH2 3) H2O

1) Br2, h n 2) NaOMe

In order to complete the synthesis, the starting material must be converted into the alkene. At this point, we can think forward, in an attempt to converge with the pathway revealed by the retrosynthetic analysis: OH

?

1) xs NaNH2 2)H2O

Br Br2 CCl4

Br

This step can be accomplished with an E2 elimination. Just remember that the hydroxyl group must first be converted into a tosylate (a better leaving group). Then, an E2 elimination will create an alkene, which bridges the gap between the starting material and the product: OH

TsCl py

1) xs NaNH2 2) H2O

Br OTs NaH

Br2 CCl4

Br

The synthesis seems complete. However, before recording the answer, it is always helpful to review all of the proposed steps and make sure that the regiochemistry and stereochemistry of each step will lead to the desired product as a major product. It would be inefficient to involve

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Retrosynthetic Analysis

any steps that would rely on the formation of a minor product. We should only use steps that produce the desired product as the major product. After reviewing every step of the proposed synthesis, the answer is recorded like this: 1) TsCl, py 2) NaH 3) Br2 /CCl4 4) xs NaNH2 5) H2O

OH

SKILLBUILDER 12.4

RETROSYNTHETIC ANALYSIS

LEARN the skill

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2 3

1

2

6

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1

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O 2 1

6

4 3

5

2

H

1

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5

3

6

œ˜Ìˆ˜Õˆ˜}Ê܈̅Ê>ÊÀiÌÀœÃޘ̅ïVÊ>˜>ÞÈÃ]ÊÜiʓÕÃÌÊVœ˜Ãˆ`iÀÊ̅iÊÃÌi«Ê̅>Ìʓˆ}…ÌÊLiÊÕÃi`ÊÌœÊ «Àœ`ÕViÊ̅iÊ>ŽÞ˜i°Ê,iV>Ê̅>ÌʜÕÀÊÃޘ̅iÈÃʓÕÃÌÊVœ˜Ì>ˆ˜Ê>ÊÃÌi«Êˆ˜ÛœÛˆ˜}Ê̅iÊ>ŽÞ>̈œ˜ÊœvÊ >˜Ê>ŽÞ˜i°Ê7iÊ̅iÀivœÀiÊ«Àœ«œÃiÊ̅iÊvœœÜˆ˜}ÊÀiÌÀœÃޘ̅ïVÊÃÌi«\ Can be made from: 2 1

klein_c12_536-563hr.indd 553

4 3

5

2 6

1

4 3

X

±

+ –

Na

C

C

H

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CHAPTER 12

Synthesis

/…ˆÃÊÃÌi«Ê>VVœ“«ˆÃ…iÃÊ̅iʘiViÃÃ>ÀÞʈ˜ÃÌ>>̈œ˜ÊœvÊÌܜÊV>ÀLœ˜Ê>̜“ð /œÊVœ“«iÌiÊ̅iÊÃޘ̅iÈÃ]ÊÜiʍÕÃÌʘii`Ê̜ÊLÀˆ`}iÊ̅iÊ}>«ÊLiÌÜii˜Ê̅iÊÃÌ>À̈˜}ʓ>ÌiÀˆ>Ê>˜`Ê̅iÊ>ŽÞÊ…>ˆ`i\ O H

?

1) R2BH 2) H2O2 , NaOH + –

Na

X

C

C

H

7œÀŽˆ˜}ÊvœÀÜ>À`ʘœÜ]ʈÌʈÃÊ>««>Ài˜ÌÊ̅>ÌÊ̅iʘiViÃÃ>ÀÞÊÌÀ>˜ÃvœÀ“>̈œ˜ÊV>˜ÊLiÊ>V…ˆiÛi`ÊÜˆÌ…Ê >˜Êanti‡>ÀŽœÛ˜ˆŽœÛÊ>``ˆÌˆœ˜]Ê܅ˆV…ÊV>˜ÊLiÊ>VVœ“«ˆÃ…i`Ê܈̅Ê Àʈ˜Ê̅iÊ«ÀiÃi˜ViʜvÊ«iÀœÝˆ`iðʘÊÃՓ“>ÀÞ]ÊÜiÊ«Àœ«œÃiÊ̅iÊvœœÜˆ˜}ÊÃޘ̅iÈð O

1) HBr, ROOR 2) H C CNa 3) R2BH 4) H2O2 , NaOH

H

(b)
Ü>ÞÃÊLi}ˆ˜ÊLÞÊ`iÌiÀ“ˆ˜ˆ˜}Ê܅i̅iÀÊ̅iÀiʈÃÊ>ÊV…>˜}iʈ˜Ê̅iÊV>ÀLœ˜ÊÎii̜˜°Ê/…iÊ ÃÌ>À̈˜}ÊVœ“«œÕ˜`ʅ>ÃÊ>ÊÌܜÊV>ÀLœ˜ÊV…>ˆ˜ÊVœ˜˜iVÌi`Ê̜Ê̅iÊÀˆ˜}]Ê܅ˆiÊ̅iÊ«Àœ`ÕVÌʅ>ÃÊ>Ê Ì…Àii‡V>ÀLœ˜ÊV…>ˆ˜ÊVœ˜˜iVÌi`Ê̜Ê̅iÊÀˆ˜}\ 1

3

1 2 2

/…ˆÃÊÌÀ>˜ÃvœÀ“>̈œ˜Ê̅iÀivœÀiÊÀiµÕˆÀiÃÊ̅iʈ˜ÃÌ>>̈œ˜Êœvʜ˜iÊV>ÀLœ˜Ê>̜“° iÝÌÊ`iÌiÀ“ˆ˜iÊ܅i̅iÀÊ̅iÀiʈÃÊ>ÊV…>˜}iʈ˜Ê̅iʈ`i˜ÌˆÌÞʜÀʏœV>̈œ˜ÊœvÊ̅iÊv՘V̈œ˜>Ê }ÀœÕ«°Ê˜Ê̅ˆÃÊV>ÃiÊ̅iʈ`i˜ÌˆÌÞʜvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«Ê`œiÃʘœÌÊV…>˜}i]ÊLÕÌʈÌÃʏœV>̈œ˜Ê`œiÃÊ V…>˜}i° ˜Ê œÀ`iÀÊ ÌœÊ >V…ˆiÛiÊ Ì…iÊ ˜iViÃÃ>ÀÞÊ V…>˜}iÊ ˆ˜Ê ̅iÊ V>ÀLœ˜Ê Îii̜˜]Ê œÕÀÊ Ãޘ̅iÈÃÊ “ÕÃÌÊ ˆ˜ÛœÛiÊ>˜Ê>ŽÞ˜iÊ̅>ÌÊ܈ÊLiÊ>ŽÞ>Ìi`Ê>˜`Ê̅i˜ÊVœ˜ÛiÀÌi`ʈ˜ÌœÊ̅iÊ«Àœ`ÕVÌ°Ê7œÀŽˆ˜}ÊL>VŽÜ>À`]ÊÜiÊvœVÕÃʜ˜Ê̅iÊ>ŽÞ˜i\

/…iÊ«Àœ`ÕVÌÊV>˜ÊLiʓ>`iÊvÀœ“Ê̅ˆÃÊ>ŽÞ˜iÊۈ>Ê>Ê`ˆÃ܏ۈ˜}ʓiÌ>ÊÀi`ÕV̈œ˜°Ê,iV>Ê̅iÊÀi>Ü˜Ê vœÀÊ}œˆ˜}Ê̅ÀœÕ}…Ê̅iÊ>ŽÞ˜iʈ˜Ê̅iÊwÀÃÌÊ«>Vi\Ê̜ʈ˜ÌÀœ`ÕViÊ>ÊV>ÀLœ˜Ê>̜“Êۈ>Ê>ŽÞ>̈œ˜°Ê/…iÊ >ÃÌÊÌܜÊÃÌi«ÃʜvʜÕÀÊÃޘ̅iÈÃÊV>˜Ê̅iÀivœÀiÊLiÊÜÀˆÌÌi˜Êˆ˜Ê̅iÊvœœÜˆ˜}ÊÜ>Þ]ÊÕȘ}ÊÀiÌÀœÃޘ̅ïVÊ>ÀÀœÜÃ\

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12.5

555

Retrosynthetic Analysis

œÜÊÜiʓÕÃÌÊLÀˆ`}iÊ̅iÊ}>«\

?

Na, NH3 (l )

1) NaNH2 2) MeI

/œÊLÀˆ`}iÊ̅iÊ}>«]Ê>Ê`œÕLiÊLœ˜`ʓÕÃÌÊLiÊVœ˜ÛiÀÌi`ʈ˜ÌœÊ>ÊÌÀˆ«iÊLœ˜`Ê>˜`ʈÌÃÊ«œÃˆÌˆœ˜Ê“ÕÃÌÊ LiʓœÛi`°Ê7iÊV>˜˜œÌÊVœ˜ÛiÀÌʈÌʈ˜ÌœÊ>ÊÌÀˆ«iÊLœ˜`ʈ˜ÊˆÌÃÊVÕÀÀi˜ÌʏœV>̈œ˜p̅>ÌÊܜՏ`Ê}ˆÛiÊ>Ê «i˜Ì>Û>i˜ÌÊV>ÀLœ˜]Ê܅ˆV…ʈÃʈ“«œÃÈLi\

WATCH OUT iÛiÀÊ`À>ÜÊ>Ê «i˜Ì>Û>i˜ÌÊV>ÀLœ˜Ê LiV>ÕÃiÊ̅>ÌÊܜՏ`Ê Ûˆœ>ÌiÊ̅iʜVÌiÌÊÀՏi°Ê ,iV>Ê̅>ÌÊV>ÀLœ˜Êœ˜ÞÊ …>ÃÊvœÕÀʜÀLˆÌ>ÃÊÜˆÌ…Ê Ü…ˆV…Ê̜ÊvœÀ“ÊLœ˜`Ã]Ê >˜`Ê>ÃÊ>ÊÀiÃՏÌ]ʈÌÊ V>˜Ê˜iÛiÀÊvœÀ“Ê“œÀiÊ Ì…>˜ÊvœÕÀÊLœ˜`ð

Never draw a carbon atom with five bonds

7iʓÕÃÌÊwÀÃÌʓœÛiÊ̅iÊ«œÃˆÌˆœ˜ÊœvÊ̅iÊ`œÕLiÊLœ˜`Ê>˜`ʜ˜ÞÊ̅i˜ÊVœ˜ÛiÀÌÊ̅iÊ`œÕLiÊLœ˜`Ê ˆ˜ÌœÊ>ÊÌÀˆ«iÊLœ˜`°Ê/…iʏœV>̈œ˜ÊœvÊ̅iÊ`œÕLiÊLœ˜`ÊV>˜ÊLiʓœÛi`ÊÕȘ}Ê̅iÊÌiV…˜ˆµÕiÊ`ˆÃVÕÃÃi`Êi>ÀˆiÀʈ˜Ê̅iÊV…>«ÌiÀp>``ˆÌˆœ˜ÊvœœÜi`ÊLÞÊiˆ“ˆ˜>̈œ˜\ Br Addition

Elimination

/>ŽiÊëiVˆ>Ê˜œÌiʜvÊ̅iÊÀi}ˆœV…i“ˆÃÌÀÞʈ˜Êi>V…ÊV>Ãi°Ê˜Ê̅iÊwÀÃÌÊÃÌi«]Ê>˜Êanti‡>ÀŽœÛ˜ˆŽœÛÊ >``ˆÌˆœ˜ÊœvÊ ÀʈÃʘii`i`]ÊÜʫiÀœÝˆ`iÃÊ>ÀiÊÀiµÕˆÀi`°Ê/…i˜]ʈ˜Ê̅iÊÃiVœ˜`ÊÃÌi«]Ê̅iÊœv“>˜˜Ê «Àœ`ÕVÌʭ̅iʏiÃÃÊÃÕLÃ̈ÌÕÌi`Ê>Ži˜i®ÊˆÃʘii`i`]ÊÜÊ>ÊÃÌiÀˆV>Þʅˆ˜`iÀi`ÊL>ÃiʈÃÊÀiµÕˆÀi`\ Br HBr, ROOR

t-BuOK

i̽ÃÊÃՓ“>ÀˆâiÊ܅>ÌÊÜiʅ>ÛiÊÜÊv>À]ÊܜÀŽˆ˜}ÊvœÀÜ>À`°

HBr ROOR

Na, NH3 (l )

Br t-BuOK

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1) NaNH2 2) MeI

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/œÊLÀˆ`}iÊ̅iÊ}>«]Ê>Ê`œÕLiÊLœ˜`ʓÕÃÌÊLiÊVœ˜ÛiÀÌi`ʈ˜ÌœÊ>ÊÌÀˆ«iÊLœ˜`°Ê"˜ViÊ>}>ˆ˜]Ê̅ˆÃʈÃÊ œ˜iʜvÊ̅iÊÌiV…˜ˆµÕiÃÊÀiۈiÜi`Êi>ÀˆiÀʈ˜Ê̅ˆÃÊV…>«ÌiÀ°ÊÌʈÃÊ>VVœ“«ˆÃ…i`Ê̅ÀœÕ}…ÊLÀœ“ˆ˜>̈œ˜ÊœvÊ̅iÊ>Ži˜iÊvœœÜi`ÊLÞÊÌܜÊÃÕVViÃÈÛiÊiˆ“ˆ˜>̈œ˜ÊÀi>V̈œ˜ÃÊ̜ʫÀœ`ÕViÊ>˜Ê>ŽÞ˜i°

1) Br2/CCl4 2) xs NaNH2 3) H2O

˜ÊÃՓ“>ÀÞ]Ê̅iÊ`iÈÀi`ÊÌÀ>˜ÃvœÀ“>̈œ˜ÊV>˜ÊLiÊ>V…ˆiÛi`Ê܈̅Ê̅iÊvœœÜˆ˜}ÊÀi>}i˜ÌÃ\ 1) HBr, ROOR 2) t-BuOK 3) Br2 /CCl4 4) xs NaNH2 5) H2O 6) NaNH2 7) MeI 8) Na, NH3 (l )

PRACTICE the skill 12.13 *Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜Ã\ Br

Br OH

(a) Br

(b)

O

O

Br

O (d)

(c) OH

Br

Br

(f)

(e)

O OH

Br ± (g)

APPLY the skill

OH

En (h)

12.14 1Ș}Ê>ViÌޏi˜iÊ>ÃÊޜÕÀʜ˜ÞÊÜÕÀViʜvÊV>ÀLœ˜Ê>̜“Ã]Ê`iÈ}˜Ê>ÊÃޘ̅iÈÃʜvÊtrans‡x‡ `iVi˜i\

12.15 1Ș}Ê>ViÌޏi˜iÊ>ÃÊޜÕÀʜ˜ÞÊÜÕÀViʜvÊV>ÀLœ˜Ê>̜“Ã]Ê`iÈ}˜Ê>ÊÃޘ̅iÈÃʜvÊcis‡Î‡ `iVi˜i\

12.16 1Ș}Ê>ViÌޏi˜iÊ>ÃÊޜÕÀʜ˜ÞÊÜÕÀViʜvÊV>ÀLœ˜Ê>̜“Ã]Ê`iÈ}˜Ê>ÊÃޘ̅iÈÃʜvÊ«i˜Ì>˜>Ê­˜œÌi\Ê«i˜Ì>˜>Ê…>ÃÊ>˜Êœ``ʘՓLiÀʜvÊV>ÀLœ˜Ê>̜“Ã]Ê܅ˆiÊ>ViÌޏi˜iʅ>ÃÊ>˜ÊiÛi˜Ê ˜Õ“LiÀʜvÊV>ÀLœ˜Ê>̜“î\ O H

need more PRACTICE? Try Problems 12.19–12.26

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12.6

Practical Tips for Increasing Proficiency

557

PRACTICALLYSPEAKING Retrosynthetic Analysis /…ÕÃÊ v>À]Ê ÜiÊ …>ÛiÊ œ˜ÞÊ iÝ«œÀi`Ê >Ê ˆ“ˆÌi`Ê ˜Õ“LiÀÊ œvÊ Ài>V̈œ˜Ã]Ê >˜`Ê̅iÊVœ“«i݈ÌÞʜvÊÃޘ̅iÈÃÊ«ÀœLi“ÃʈÃÊ̅iÀivœÀiʏˆ“ˆÌi`°Ê
ÌÊ Ì…ˆÃÊÃÌ>}i]ʈÌʓˆ}…ÌÊLiÊ`ˆvwVՏÌÊ̜ÊÃiiÊ܅ÞÊÀiÌÀœÃޘ̅ïVÊ>˜>ÞÈÃÊ ˆÃÊÜÊVÀˆÌˆV>°ÊœÜiÛiÀ]Ê>ÃÊÜiÊiÝ«>˜`ʜÕÀÊÀi«iÀ̜ˆÀiʜvÊÀi>V̈œ˜Ã]Ê ÜiÊ܈ÊLi}ˆ˜Ê̜ÊiÝ«œÀiÊ̅iÊÃޘ̅iÈÃʜvʓœÀiÊÜ«…ˆÃ̈V>Ìi`ÊÃÌÀÕVÌÕÀiÃ]Ê>˜`Ê̅iʘii`ÊvœÀÊÀiÌÀœÃޘ̅ïVÊ>˜>ÞÈÃÊ܈ÊLiVœ“iʓœÀiÊ >««>Ài˜Ì°

°Ê °Ê œÀiÞÊ wÀÃÌÊ `iÛiœ«i`Ê …ˆÃÊ ÀiÌÀœÃޘ̅ïVÊ “i̅œ`œœ}ÞÊ >ÃÊ>Êv>VՏÌÞʓi“LiÀÊ>ÌÊ̅iÊ1˜ˆÛiÀÈÌÞʜvʏˆ˜œˆÃ°Ê ÕÀˆ˜}ʅˆÃÊÃ>LL>̈V>ÊÞi>À]Ê܅ˆV…Ê…iÊëi˜ÌÊ>ÌÊ>ÀÛ>À`Ê1˜ˆÛiÀÈÌÞ]ʅiÊÅ>Ài`ʅˆÃÊ ˆ`i>ÃÊ ÜˆÌ…Ê ,œLiÀÌÊ 7œœ`Ü>À`Ê ­Ì…iÊ ÛiÀÞÊ Ã>“iÊ 7œœ`Ü>À`Ê Ü…œÊ `iÛiœ«i`Ê>Ê̜Ì>ÊÃޘ̅iÈÃʜvÊۈÌ>“ˆ˜Ê £Ó]Ê`iÃVÀˆLi`ʈ˜Ê̅iÊ«ÀiۈœÕÃÊ i`ˆV>ÞÊ -«i>Žˆ˜}Ê LœÝ®°Ê œÀiÞÊ `i“œ˜ÃÌÀ>Ìi`Ê …ˆÃÊ ˆ`i>ÃÊ LÞÊ «ÀiÃi˜Ìˆ˜}Ê >Ê ÀiÌÀœÃޘ̅ïVÊ >˜>ÞÈÃÊ œvÊ œ˜}ˆvœi˜i]Ê >Ê ˜>ÌÕÀ>Ê Vœ“«œÕ˜`Ê̅>ÌÊÀi«ÀiÃi˜Ìi`Ê>ÊV…>i˜}ˆ˜}ÊÌ>À}iÌÊLiV>ÕÃiʜvʈÌÃÊ Õ˜ˆµÕiÊÌÀˆVÞVˆVÊÃÌÀÕVÌÕÀi°Ê œÀiÞʈ`i˜Ìˆwi`Ê̅iÊvœœÜˆ˜}ÊÃÌÀ>Ìi}ˆVÊ Lœ˜`ʜvʏœ˜}ˆvœi˜iÊvœÀÊ`ˆÃVœ˜˜iV̈œ˜\ O Me O H

Me

Longifolene

/…iÊv՘V̈œ˜>Ê}ÀœÕ«Ãʈ˜Ê̅iÊ«ÀiVÕÀÜÀÊÃiÀÛiÊ>Ãʅ>˜`iÃÊi˜>Lˆ˜}Ê vœÀ“>̈œ˜Ê œvÊ Ì…iÊ ÃÌÀ>Ìi}ˆVÊ Lœ˜`Ê ­Ṏˆâˆ˜}Ê >Ê Ài>V̈œ˜Ê ̅>ÌÊ ÜiÊ ÜˆÊ

iÝ«œÀiÊ ˆ˜Ê …>«ÌiÀÊ ÓÓ®°Ê œ˜}ˆvœi˜iÊ Ài«ÀiÃi˜Ìi`Ê >˜Ê iÝVii˜ÌÊ iÝ>“«iÊ œvÊ Ì…iÊ «œÜiÀÊ œvÊ œÀiÞ½ÃÊ ÀiÌÀœÃޘ̅ïVÊ `ˆÃVœ˜˜iV̈œ˜Ê >««Àœ>V…°Ê œÀÊ “œÃÌÊ œvÊ Ì…iÊ Lœ˜`ÃÊ ˆ˜Ê œ˜}ˆvœi˜i]Ê `ˆÃVœ˜˜iV̈œ˜Ê ܜՏ`Ê «Àœ`ÕViÊ >Ê Vœ“«iÝÊ ÌÀˆVÞVˆVÊ «ÀiVÕÀÜÀ°Ê /…>ÌÊ ˆÃ]Ê Ì…iÀiÊ >ÀiÊ ˜œÌʓ>˜ÞÊÃÌÀ>Ìi}ˆVÊLœ˜`ÃÊ̅>ÌÊV>˜ÊLiÊ`ˆÃVœ˜˜iVÌi`Ê̜ʫÀœÛˆ`iÊ>Ê Ãˆ“«iÀÊ«ÀiVÕÀÜÀ°Ê7œœ`Ü>À`ÊÜ>Ãʈ“«ÀiÃÃi`ÊLÞÊ œÀiÞ½Ãʈ˜Ãˆ}…ÌÃÊ >˜`ʈ““i`ˆ>ÌiÞÊÀiVœ}˜ˆâi`Ê̅>ÌÊ œÀiÞÊܜՏ`Êܜ˜ÊLiÊ>˜œÌ…iÀÊ i>`iÀʈ˜Ê̅iÊwi`°Ê/…ˆÃʏˆŽiÞÊ«>Þi`Ê>ʏ>À}iÊÀœiʈ˜Ê̅iʜvviÀÊ̅>ÌÊ

œÀiÞÊÃÕLÃiµÕi˜ÌÞÊÀiViˆÛi`Ê̜ʍœˆ˜Ê̅iÊV…i“ˆÃÌÀÞÊ`i«>À̓i˜ÌÊ>ÌÊ >ÀÛ>À`Ê>ÃÊ>Ê«ÀœviÃÜÀ°

œÀiÞÊ `iÛiœ«i`Ê …ˆÃÊ ˆ`i>ÃÊ vÕÀ̅iÀÊ >˜`Ê iÃÌ>LˆÃ…i`Ê >Ê ÃiÌÊ œvÊ ÀՏiÃÊ >˜`Ê «Àˆ˜Vˆ«iÃÊ vœÀÊ «Àœ«œÃˆ˜}Ê ÀiÌÀœÃޘ̅ïVÊ >˜>ÞÃˆÃ°Ê iÊ>ÃœÊëi˜ÌʓÕV…Ê̈“iÊVÀi>̈˜}ÊVœ“«ÕÌiÀÊ«Àœ}À>“ÃÊ̜Ê>ÃÈÃÌÊ V…i“ˆÃÌÃÊ ˆ˜Ê «iÀvœÀ“ˆ˜}Ê ÀiÌÀœÃޘ̅ïVÊ >˜>ÞÃˆÃ°Ê ÌÊ ˆÃÊ Vi>ÀÊ Ì…>ÌÊ Vœ“«ÕÌiÀÃÊV>˜˜œÌÊÀi«>ViÊ̅iÊV…i“ˆÃÌÊ>Ìœ}i̅iÀ]Ê>ÃÊ̅iÊV…i“ˆÃÌʓÕÃÌÊ«ÀœÛˆ`iÊ̅iʈ˜Ãˆ}…ÌÊ>˜`ÊVÀi>̈ۈÌÞʈ˜Ê`iÌiÀ“ˆ˜ˆ˜}Ê܅ˆV…Ê ÃÌÀ>Ìi}ˆVÊ Lœ˜`ÃÊ ÌœÊ `ˆÃVœ˜˜iVÌ°Ê ˜Ê >``ˆÌˆœ˜]Ê Ì…iÊ V…i“ˆÃÌÊ “ÕÃÌÊ i݅ˆLˆÌÊVÀi>̈ۈÌÞÊ܅i˜Ê>Ê«>˜˜i`ÊÀœÕÌiÊv>ˆÃ°Ê
ÃÊ`ˆÃVÕÃÃi`ʈ˜Ê̅iÊ «ÀiۈœÕÃÊLœÝ]Ê̅ˆÃʈÃʅœÜʘiÜʈ`i>Ã]ÊÀi>}i˜ÌÃ]Ê>˜`ÊÌiV…˜ˆµÕiÃÊ >ÀiÊ`iÛiœ«i`°Ê œÀiÞÊÕÃi`ʅˆÃÊ>««Àœ>V…ÊvœÀÊ̅iÊ̜Ì>ÊÃޘ̅iÈÃÊ œvÊ `œâi˜ÃÊ œvÊ Vœ“«œÕ˜`Ã°Ê ˜Ê ̅iÊ «ÀœViÃÃ]Ê …iÊ `iÛiœ«i`Ê “>˜ÞÊ ˜iÜÊÀi>}i˜ÌÃ]ÊÃÌÀ>Ìi}ˆiÃ]Ê>˜`ÊÀi>V̈œ˜ÃÊ̅>ÌʘœÜÊLi>ÀʅˆÃʘ>“i°Ê

œÀiÞÊÜ>ÃÊ>˜Êˆ˜ÃÌÀՓi˜Ì>Ê«>ÞiÀʈ˜Ê`iÛiœ«ˆ˜}Ê̅iÊwi`ʜvÊÃޘ̅ïVÊ œÀ}>˜ˆVÊ V…i“ˆÃÌÀÞ°Ê ,iÌÀœÃޘ̅ïVÊ >˜>ÞÈÃÊ ˆÃÊ ˜œÜÊ Ì>Õ}…ÌÊ ÌœÊ>ÊÃÌÕ`i˜ÌÃʜvʜÀ}>˜ˆVÊV…i“ˆÃÌÀÞ°Ê-ˆ“ˆ>ÀÞ]ʘi>ÀÞÊ>ÊÀi«œÀÌÃÊ œvÊ ÌœÌ>Ê Ãޘ̅iÈÃÊ ˆ˜Ê ̅iÊ V…i“ˆV>Ê ˆÌiÀ>ÌÕÀiÊ Li}ˆ˜Ê ÜˆÌ…Ê >Ê ÀiÌÀœÃޘ̅ïVÊ>˜>ÞÈðÊœÀʅˆÃÊVœ˜ÌÀˆLṎœ˜ÃÊ̜Ê̅iÊ`iÛiœ«“i˜ÌʜvÊ Ãޘ̅ïVʜÀ}>˜ˆVÊV…i“ˆÃÌÀÞ]Ê œÀiÞÊÜ>ÃÊ>Ü>À`i`Ê̅iÊ œLiÊ*ÀˆâiÊ ˆ˜Ê …i“ˆÃÌÀÞʈ˜Ê£™™ä°

12.6 Practical Tips for Increasing Proficiency Organizing a Synthetic “Toolbox” of Reactions All of the reactions in this course will collectively represent your “toolbox” for proposing syntheses. It will be very helpful to prepare two lists that parallel the two questions that must be considered in every synthesis problem (change in the carbon skeleton and change in the functional group). The first list should contain C—C bond-forming reactions and C—C bond-breaking reactions. At this point, this list is very small. We have only seen one of each: alkylation of alkynes for C—C bond forming and ozonolysis for C—C bond breaking. As the course progresses, more reactions will be added to the list, which will remain relatively small but very powerful. The second list should contain functional group transformations, and it will be longer. As we move through the course, both lists will grow. For solving synthesis problems, it will be helpful to have the reactions categorized in this way in your mind.

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Creating Your Own Synthesis Problems A helpful method for practicing synthesis strategies is to construct your own problems. The process of designing problems often uncovers patterns and new ways of thinking about the reactions. Begin by choosing a starting compound. To illustrate this, let’s begin by choosing a simple starting compound, such as acetylene. Then choose a reaction expected for a triple bond, perhaps an alkylation: 1) NaNH2 2) MeI

Next, choose another reaction, perhaps another alkylation: 1) NaNH2

1) NaNH2

2) MeI

2) MeI

Then, treat the alkyne with another reagent. Look at the list of reactions of alkynes and choose one; perhaps hydrogenation with a poisoned catalyst: 1) NaNH2

1) NaNH2

2) MeI

2) MeI

H2 Lindlar’s catalyst

Finally, simply erase everything except for the starting compound and the final product. The result is a synthesis problem:

Once you have created your own synthesis problem, it might be a really good problem, but it won’t be helpful for you to solve it. You already know the answer! Nevertheless, the process of creating your own synthesis problems will be very helpful to you in sharpening your synthesis skills. Once you have created several of your own problems, try to find a study partner who is also willing to create several problems. Each of you can swap problems, try to solve each other’s problems, and then get back together to discuss the answers. You are likely to find that exercise to be very rewarding.

Multiple Correct Answers Remember that most synthesis problems will have numerous correct answers. As an example, anti-Markovnikov hydration of an alkene can be achieved through either of the two possible routes: 1) BH3 THF 2) H2O2, NaOH

OH 1) HBr, ROOR 2) NaOH

The first pathway represents hydroboration-oxidation of the alkene to achieve anti-Markovnikov addition of water. The second pathway represents a radical (anti-Markovnikov) addition of HBr followed by an SN2 reaction to replace the halogen with a hydroxyl group. Each of these pathways represents a valid synthesis. As we learn more reactions, it will become more common to encounter synthesis problems with several perfectly correct answers. The goal should always be efficiency. A 3-step synthesis will generally be more efficient than a 10-step synthesis.

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SkillBuilder Review

559

REVIEW OF CONCEPTS AND VOCABULARY SECTION 12.1 UÊ ÌʈÃÊiÃÃi˜Ìˆ>Ê̜Ê>V…ˆiÛiʓ>ÃÌiÀÞʜÛiÀÊ>ÊÀi>}i˜ÌÃÊ`iÃVÀˆLi`Ê ˆ˜Ê̅iÊ«ÀiۈœÕÃÊV…>«ÌiÀð

SECTION 12.2 UÊ /…iÊ«œÃˆÌˆœ˜ÊœvÊ>ʅ>œ}i˜ÊV>˜ÊLiʓœÛi`ÊLÞÊ«iÀvœÀ“ˆ˜}Êiˆ“ˆ˜>̈œ˜ÊvœœÜi`ÊLÞÊ>``ˆÌˆœ˜° UÊ /…iÊ«œÃˆÌˆœ˜ÊœvÊ>ÊπÊLœ˜`ÊV>˜ÊLiʓœÛi`ÊLÞÊ«iÀvœÀ“ˆ˜}Ê>``ˆÌˆœ˜ÊvœœÜi`ÊLÞÊiˆ“ˆ˜>̈œ˜° UÊ
˜Ê>Ž>˜iÊV>˜ÊLiÊv՘V̈œ˜>ˆâi`Êۈ>ÊÀ>`ˆV>ÊLÀœ“ˆ˜>̈œ˜°

SECTION 12.3 UÊ vÊ Ì…iÊ ÃˆâiÊ œvÊ Ì…iÊ V>ÀLœ˜Ê Îii̜˜Ê ˆ˜VÀi>ÃiÃ]Ê Ì…i˜Ê >Ê p Ê Lœ˜`‡vœÀ“ˆ˜}ÊÀi>V̈œ˜ÊˆÃÊÀiµÕˆÀi`°

UÊ vÊ Ì…iÊ ÃˆâiÊ œvÊ Ì…iÊ V>ÀLœ˜Ê Îii̜˜Ê `iVÀi>ÃiÃ]Ê Ì…i˜Ê >Ê p Ê Lœ˜`‡LÀi>Žˆ˜}ÊÀi>V̈œ˜]ÊV>i`Êbond cleavage]ʈÃÊÀiµÕˆÀi`°

SECTION 12.4 UÊ ÛiÀÞÊÃޘ̅iÈÃÊ«ÀœLi“ÊŜՏ`ÊLiÊ>««Àœ>V…i`ÊLÞÊ>Έ˜}Ê̅iÊ vœœÜˆ˜}ÊÌܜʵÕiÃ̈œ˜Ã\ UÊ ÃÊ̅iÀiÊ>˜ÞÊV…>˜}iʈ˜Ê̅iÊV>ÀLœ˜ÊÎii̜˜¶ UÊ ÃÊ̅iÀiÊ>˜ÞÊV…>˜}iʈ˜Ê̅iʈ`i˜ÌˆÌÞʜÀʏœV>̈œ˜ÊœvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«¶

SECTION 12.5 UÊ ˜Ê >Ê retrosynthetic analysis]Ê Ì…iÊ >ÃÌÊ ÃÌi«Ê œvÊ Ì…iÊ Ãޘ̅ïVÊ ÀœÕÌiʈÃÊwÀÃÌÊiÃÌ>LˆÃ…i`]Ê>˜`Ê̅iÊÀi“>ˆ˜ˆ˜}ÊÃÌi«ÃÊ>ÀiÊ`iÌiÀ“ˆ˜i`]ÊܜÀŽˆ˜}ÊL>VŽÜ>À`ÊvÀœ“Ê̅iÊ«Àœ`ÕVÌ°

KEY TERMINOLOGY bond cleavage

retrosynthetic analysis

x{Î

xxä

SKILLBUILDER REVIEW 12.1 CHANGING THE IDENTITY OR POSITION OF A FUNCTIONAL GROUP Change the position of a halogen.

Br

Br Elimination

Addition

Change the position of a π bond.

Br Elimination

Addition

Install a functional group.

Br Radical bromination

Elimination

Interconvert between single, double, and triple bonds. H2, Lindlar’s Catalyst or Na, NH3 1) Br2/CCl4 2) xs NaNH2 3) H2O

H2, Pt

1) Br2, h n 2) NaOEt

Try Problems 12.3–12.6, 12.17, 12.21, 12.22

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12.2 CHANGING THE CARBON SKELETON C!C bond formation.

H

H

H

C

C

H

H

–

C

±

C

Four carbon atoms

X

H

H

H

C

C

C

H

H

H

H

H

H

H

C

C

H

H

Three carbon atoms

C

C

H

H

H

C

C

C

H

H

H

H

Seven carbon atoms

C!C bond cleavage.

H H H

H

H

C

C

C

H

H

H

C C

H

1) O3 2) DMS

H

Five carbon atoms

H

H

H

H

C

C

C

H

H

H

H

O ±

C

Four carbon atoms

C O

H

H

One carbon atoms

Try Problems 12.7–12.9, 12.18, 12.19, 12.20, 12.23, 12.26

12.3 APPROACHING A SYNTHESIS PROBLEM BY ASKING TWO QUESTIONS £°Ê ÃÊ̅iÀiÊ>˜ÞÊV…>˜}iʈ˜Ê̅iÊV>ÀLœ˜ÊÎii̜˜¶

œ“«>ÀiÊ̅iÊÃÌ>À̈˜}ʓ>ÌiÀˆ>Ê܈̅Ê̅iÊ«Àœ`ÕVÌÊ̜Ê`iÌi“ˆ˜iʈvÊ̅iÊV>ÀLœ˜Ê Îii̜˜ÊˆÃÊ}>ˆ˜ˆ˜}ʜÀʏœÃˆ˜}Ê>˜ÞÊV>ÀLœ˜Ê>̜“ð Ó°Ê ÃÊ̅iÀiÊ>˜ÞÊV…>˜}iʈ˜Ê̅iʈ`i˜ÌˆÌÞʜÀʏœV>̈œ˜ÊœvÊ̅iÊv՘V̈œ˜>Ê}ÀœÕ«¶ ˜ÊœÌ…iÀÊܜÀ`Ã]ʈÃʜ˜iÊv՘V̈œ˜>Ê}ÀœÕ«ÊVœ˜ÛiÀÌi`ʈ˜ÌœÊ>˜œÌ…iÀ]Ê>˜`Ê`œiÃÊ Ì…iÊ«œÃˆÌˆœ˜ÊœvÊv՘V̈œ˜>ˆÌÞÊV…>˜}i¶

Try Problems 12.10–12.12, 12.19–12.26

12.4 RETROSYNTHETIC ANALYSIS Can be made from

Product

Can be made from

Can be made from

Br

Br

Starting material

Try Problems 12.13–12.16, 12.19–12.26

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Practice Problems

Note:ÊœÃÌʜvÊ̅iÊ*ÀœLi“ÃÊ>ÀiÊ>Û>ˆ>LiÊ܈̅ˆ˜ WileyPLUS]Ê>˜Êœ˜ˆ˜iÊÌi>V…ˆ˜}Ê>˜`ʏi>À˜ˆ˜}Ê܏Ṏœ˜°

PRACTICE PROBLEMS 12.17

561

`i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃʘiViÃÃ>ÀÞÊ̜Ê>V…ˆiÛiÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜Ã\

Br

OH

Br

OH OH

OH

12.18

OH

Br

Br

Br

`i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃʘiViÃÃ>ÀÞÊ̜Ê>V…ˆiÛiÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜Ã\ O

O

Br

CH3 H

Br Br

Br

Br

Br

Br Br Br

Br Br

O

O OH

±

C O

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12.19 1Ș}Ê>ViÌޏi˜iÊ>ÃÊޜÕÀʜ˜ÞÊÜÕÀViʜvÊV>ÀLœ˜Ê>̜“Ã]Ê ˆ`i˜ÌˆvÞÊ>ÊÃޘ̅ïVÊÀœÕÌiÊvœÀÊ̅iÊ«Àœ`ÕV̈œ˜ÊœvÊӇLÀœ“œLÕÌ>˜i°

O (c)

Br H

12.20

1Ș}Ê>ViÌޏi˜iÊ>ÃÊޜÕÀʜ˜ÞÊÜÕÀViʜvÊV>ÀLœ˜Ê>̜“Ã]Ê ˆ`i˜ÌˆvÞÊ>ÊÃޘ̅ïVÊÀœÕÌiÊvœÀÊ̅iÊ«Àœ`ÕV̈œ˜ÊœvÊ£‡LÀœ“œLÕÌ>˜i° (d)

12.21

*Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}Ê ÌÀ>˜ÃvœÀ“>̈œ˜Ã\ OH

(a)

12.24 1Ș}Ê>˜ÞÊVœ“«œÕ˜`ÃÊ̅>ÌÊVœ˜Ì>ˆ˜ÊÌܜÊV>ÀLœ˜Ê>̜“ÃÊ œÀÊviÜiÀ]ÊŜÜÊ>ÊÜ>ÞÊ̜ʫÀi«>ÀiÊ>ÊÀ>Vi“ˆVʓˆÝÌÕÀiʜvÊ­ÓR]ÎR®‡ Ó]·`ˆ…Þ`ÀœÝÞ«i˜Ì>˜iÊ>˜`Ê­ÓS]ÎS®‡Ó]·`ˆ…Þ`ÀœÝÞ«i˜Ì>˜i° 12.25 1Ș}Ê>˜ÞÊVœ“«œÕ˜`ÃÊ̅>ÌÊVœ˜Ì>ˆ˜ÊÌܜÊV>ÀLœ˜Ê>̜“ÃÊ œÀÊviÜiÀ]ÊŜÜÊ>ÊÜ>ÞÊ̜ʫÀi«>ÀiÊ>ÊÀ>Vi“ˆVʓˆÝÌÕÀiʜvÊ­ÓR]ÎS®‡Ê >˜`Ê­ÓS]ÎR®‡Ó]·`ˆ…Þ`ÀœÝÞ«i˜Ì>˜i°

OH

12.26

*Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}Ê ÌÀ>˜ÃvœÀ“>̈œ˜Ã\

(b)

O

O (a)

12.22

1Ș}Ê >˜ÞÊ Ài>}i˜ÌÃÊ ÞœÕÊ ˆŽi]Ê Ã…œÜÊ >Ê Ü>ÞÊ ÌœÊ Vœ˜ÛiÀÌÊ £‡“i̅ޏVÞVœ«i˜Ìi˜iʈ˜ÌœÊ·“i̅ޏVÞVœ«i˜Ìi˜i°

O

(b) O

12.23

*Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊi>V…ÊœvÊ̅iÊvœœÜˆ˜}Ê ÌÀ>˜ÃvœÀ“>̈œ˜Ã\

(c)

OH O

OH (a)

(d)

O

O

O Br

(b)

H

(e)

OH

O H

INTEGRATED PROBLEMS 12.27

˜Ê̅ˆÃÊV…>«ÌiÀ]ÊÜiʅ>ÛiÊÃii˜Ê̅>ÌÊ>˜Ê>ViÌޏˆ`iʈœ˜ÊV>˜Ê v՘V̈œ˜Ê>ÃÊ>ʘÕViœ«…ˆiÊ>˜`Ê>ÌÌ>VŽÊ>˜Ê>ŽÞÊ…>ˆ`iʈ˜Ê>˜Ê-NÓÊ«ÀœViÃðÊœÀiÊ}i˜iÀ>ÞÊëi>Žˆ˜}]Ê̅iÊ>ViÌޏˆ`iʈœ˜ÊV>˜Ê>ÌÌ>VŽÊœÌ…iÀÊ iiVÌÀœ«…ˆiÃÊ >ÃÊ Üi°Ê œÀÊ iÝ>“«i]Ê ÜiÊ ÜˆÊ ÃiiÊ ˆ˜Ê …>«ÌiÀÊ £{Ê Ì…>ÌÊi«œÝˆ`iÃÊv՘V̈œ˜Ê>ÃÊiiVÌÀœ«…ˆiÃÊ>˜`Ê>ÀiÊÃÕLiVÌÊ̜Ê>ÌÌ>VŽÊ LÞÊ >Ê ˜ÕViœ«…ˆi°Ê œ˜Ãˆ`iÀÊ Ì…iÊ vœœÜˆ˜}Ê Ài>V̈œ˜Ê LiÌÜii˜Ê >˜Ê >ViÌޏˆ`iʈœ˜Ê­Ì…iʘÕViœ«…ˆi®Ê>˜`Ê>˜Êi«œÝˆ`iʭ̅iÊiiVÌÀœ«…ˆi®\ H

C

C

–

/…iÊ>ViÌޏˆ`iʈœ˜Ê>ÌÌ>VŽÃÊ̅iÊi«œÝˆ`i]ʜ«i˜ˆ˜}ÊÕ«Ê̅iÊÃÌÀ>ˆ˜i`]Ê Ì…Àii‡“i“LiÀi`Ê Àˆ˜}Ê >˜`Ê VÀi>̈˜}Ê >˜Ê >ŽœÝˆ`iÊ ˆœ˜°Ê
vÌiÀÊ Ì…iÊ Ài>V̈œ˜ÊˆÃÊVœ“«iÌi]Ê>Ê«ÀœÌœ˜ÊÜÕÀViʈÃÊÕÃi`Ê̜ʫÀœÌœ˜>ÌiÊ̅iÊ >ŽœÝˆ`iÊ ˆœ˜°Ê ˜Ê >Ê Ãޘ̅iÈÃ]Ê Ì…iÃiÊ ÌÜœÊ ÃÌi«ÃÊ “ÕÃÌÊ LiÊ Ã…œÜ˜Ê Ãi«>À>ÌiÞ]Ê LiV>ÕÃiÊ Ì…iÊ >ViÌޏˆ`iÊ ˆœ˜Ê ܈Ê ˜œÌÊ ÃÕÀۈÛiÊ ˆ˜Ê ̅iÊ «ÀiÃi˜ViʜvÊÎO+°Ê1Ș}Ê̅ˆÃʈ˜vœÀ“>̈œ˜]Ê«Àœ«œÃiÊ>Ê«>ÕÈLiÊ Ãޘ̅iÈÃÊvœÀÊ̅iÊvœœÜˆ˜}ÊVœ“«œÕ˜`ÊÕȘ}Ê>ViÌޏi˜iÊ>ÃÊޜÕÀÊ œ˜ÞÊÜÕÀViʜvÊV>ÀLœ˜Ê>̜“Ã\

O

OH

O

–

OH

H +

O

C

H

H

C C

C H

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Challenge Problems

12.28 ˜Ê̅iÊ«ÀiۈœÕÃÊ«ÀœLi“]ÊÜiÊÃ>ÜÊ̅>ÌÊ>˜Ê>ViÌޏˆ`iʈœ˜Ê V>˜Ê>ÌÌ>VŽÊ>ÊÛ>ÀˆiÌÞʜvÊiiVÌÀœ«…ˆiðÊ˜Ê …>«ÌiÀÊÓä]ÊÜiÊ܈ÊÃiiÊ Ì…>ÌÊ>Ê R"ÊLœ˜`ÊV>˜Ê>ÃœÊv՘V̈œ˜Ê>ÃÊ>˜ÊiiVÌÀœ«…ˆi°Ê œ˜Ãˆ`iÀÊ Ì…iÊ vœœÜˆ˜}Ê Ài>V̈œ˜Ê LiÌÜii˜Ê >˜Ê >ViÌޏˆ`iÊ ˆœ˜Ê ­Ì…iÊ ˜ÕViœ«…ˆi®Ê>˜`Ê>ʎi̜˜iʭ̅iÊiiVÌÀœ«…ˆi®\ O H

C

O

C

–

R

R

OH

H

–

O H

R

/…iÊ >ViÌޏˆ`iÊ ˆœ˜Ê >ÌÌ>VŽÃÊ Ì…iÊ Ži̜˜i]Ê }i˜iÀ>̈˜}Ê >˜Ê >ŽœÝˆ`iÊ ˆœ˜°Ê
vÌiÀÊ̅iÊÀi>V̈œ˜ÊˆÃÊVœ“«iÌi]Ê>Ê«ÀœÌœ˜ÊÜÕÀViʈÃÊÕÃi`ÊÌœÊ «ÀœÌœ˜>ÌiÊ̅iÊ>ŽœÝˆ`iʈœ˜°Ê˜Ê>ÊÃޘ̅iÈÃ]Ê̅iÃiÊÌܜÊÃÌi«ÃʓÕÃÌÊ LiÊŜܘÊÃi«>À>ÌiÞ]ÊLiV>ÕÃiÊ̅iÊ>ViÌޏˆ`iʈœ˜Ê܈Ê˜œÌÊÃÕÀۈÛiÊ ˆ˜Ê ̅iÊ «ÀiÃi˜ViÊ œvÊ ÎO+°Ê 1Ș}Ê Ì…ˆÃÊ ˆ˜vœÀ“>̈œ˜]Ê «Àœ«œÃiÊ >Ê «>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊ>ÞÊ>Vœ…œ]ÊÕȘ}Ê>ViÌޏi˜iÊ>ÃÊޜÕÀʜ˜ÞÊ ÃœÕÀViʜvÊV>ÀLœ˜Ê>̜“Ã\

±

OH H

R

R

R

C

C

C

C

H

H

CHALLENGE PROBLEMS 12.29 `i˜ÌˆvÞÊ̅iÊÀi>}i˜ÌÃÊޜÕʓˆ}…ÌÊÕÃiÊ̜Ê>V…ˆiÛiÊi>V…ÊœvÊ Ì…iÊvœœÜˆ˜}ÊÌÀ>˜ÃvœÀ“>̈œ˜Ã\ Br

HO

± O

12.30 -Ì>À̈˜}Ê܈̅Ê>ViÌޏi˜iÊ>ÃÊޜÕÀʜ˜ÞÊÜÕÀViʜvÊV>ÀLœ˜Ê >̜“Ã]Ê ˆ`i˜ÌˆvÞÊ …œÜÊ ÞœÕÊ ÜœÕ`Ê «Ài«>ÀiÊ i>V…Ê “i“LiÀÊ œvÊ Ì…iÊ vœœÜˆ˜}ʅœ“œœ}œÕÃÊÃiÀˆiÃʜvÊ>`i…Þ`iÃ\ ­>® ̅>˜>Ê ­V® ÕÌ>˜>Ê

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En

12.31 -Ì>À̈˜}Ê܈̅Ê>ViÌޏi˜iÊ>ÃÊޜÕÀʜ˜ÞÊÜÕÀViʜvÊV>ÀLœ˜Ê >̜“Ã]Ê«Àœ«œÃiÊ>Ê«>ÕÈLiÊÃޘ̅iÈÃÊvœÀÊ£]{‡`ˆœÝ>˜i\ O

O 1,4-Dioxane

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7/15/10 12:47 PM