Klein Ch12

1212.1 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

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

Vitamins 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 land-mark 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 chal-lenging multistep problems. The goal of this chapter is

to develop the fundamental skills required for proposing a

synthesis.

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12.1 One-Step Syntheses 537

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.

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 one-step 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

O

O

HBr

Br

OH

Br

OH

En±

Br

Br

En±

OH

Br

En±

OH

OH

En±

OH

OH

En±

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538 CHAPTER 12 Synthesis

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 perform-ing an elimination reaction followed by an addition reaction. For example:

Br BrAdditionElimination

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

HBrROOR

HBr

Br

t-BuOK HBrROOR

BrNaOEt HBr

12.2

Br

Br

BrBr Br

O

H

Br

BrBr Br

Br

BrOH

O

C

O

O

±

CH3

O


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12.2 Functional Group Transformations 539

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 bet-ter leaving group), and only then can the technique be employed (elimination followed by addition):

OH OTs

HOAdditionEliminationConvert OH into a better leaving group

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

HO

HO2) t-BuOK1) TsCl, pyridine 1) BH3 THF

2) H2O2, NaOH

OH

2) NaOEt1) TsCl, pyridine H3O±

1) Hg(OAc)2, H2O2) NaBH4

1) BH3 THF2) H2O2, NaOH

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:

NaOEt

NaOEt

BrHBr t-BuOK

Br

ROORHBr t-BuOK

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In Chapter 11, we developed one other important technique: installing functionality in a com-pound with no functional groups:

Br

Radicalbromination

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 Catalystor

Na, NH3

1) Br2/CCl42) xs NaNH2

3) H2O

H2 , Pt

1) Br2, hn

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.

BY THE WAY

Br

SOLUTION-

C-2 and C-3are functionalized

12

34

5

C-1is functionalized

Br 12

34

5

-

-

π

SKILLBUILDER12.1 CHANGING THE IDENTITY OR POSITION OF A FUNCTIONAL GROUP

LEARN the skill

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12.2 Functional Group Transformations 541

πanti

X

Anti-Markovnikovaddition

Hofmannelimination

anti

Br (Racemic)

OH (Racemic)

1) BH3 THF

2) H2O2, NaOH

HBrROOR

anti

Br

OH OTs

HBrROOR

1) BH3 THF

2) H2O2, NaOH TsCl

Pyridinet-BuOK

t-BuOK

anti

Br

HBrROOR

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Br

1) HBr, ROOR

2) t-BuOK3) HBr, ROOR

1) BH3 THF2) H2O2, NaOH

3) TsCl, pyridine4) t-BuOK5) HBr, ROOR

-

12.3

(a)

Br

Br

(b)

(c) (d)

OH

OH

(e)

Br

OH(f)

OH

Br

(g)

OH

OH

(h)

12.4

12.5

12.6

Try Problems 12.17, 12.21, 12.22

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12.3 Reactions That Change the Carbon Skeleton 543

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:

Three carbon atoms

C

H

H

C C

H

H

X

H

H

H NaX

Four carbon atoms

C

H

H

C C

H

H

H C Na+–

±

Seven carbon atoms

C

H

H

C C

H

H

H C C

H

H

C C

H

H

H

H

H ±

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:

C

H

H

C C

H

H

CCH

H

H H

H

H

Five carbon atoms

C

H

H

C C

H

H

COH

H

H H

Four carbon atoms

C

H

HO

One carbon atoms

1) O3

2) DMS±

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.

Br

SOLUTION

NaX

Alkynide

±R X

Alkyl halide

C C RRC CR Na±–

SKILLBUILDER12.2 CHANGING THE CARBON SKELETON

LEARN the skill

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from the perspective of the alkyne

Starting material

C CH H RC CH1) NaNH2

R X2)

R X

Startingmaterial

C C HRC C HNa

± –

Br CC

H

Na±

C C H–

12.7

(a)

Br

(b)

O

(c)

12.8

Br(a)

Br

O

H(b)

Br

Br Br

(c)

12.9

Try Problems 12.18, 12.19, 12.20, 12.23, 12.26

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MEDICALLYSPEAKINGVitamins

-

-

-

-

-

--

Thiamine (vitamin B1)

Amino group

N

N

N

S OH

NH2

±

vital amine

-

12.3 Reactions That Change the Carbon Skeleton 545

Retinol (vitamin A)

OH

Sources:Deficiency disease:

Thiamine (vitamin B1)N

N

N

S OH

NH2

±


Vitamin C

O

HO OH

O OH

OHH


Ergocalciferol (vitamin D2)HO

H

H

Sources:

Deficiency disease:

O

O

Phylloquinone (vitamin K1)


-

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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.

SOLUTION

1. Is there a change in the carbon skeleton?

12

34

56

712

34

5

2. Is there a change in the identity or location of the functional group?

12

34

56

712

34

5

SKILLBUILDER12.3 APPROACHING A SYNTHESIS PROBLEM

LEARN the skill

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12.4 How to Approach a Synthesis Problem 547

need more PRACTICE?

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 loca-tion. 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.

12.10 Identify reagents that can be used to achieve each of the following transformations:

(b)(a)

OH

OBr

Br

(c) (d)

(e)

OH

H

O

(f)

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

HO

OH

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

H

O

Try Problems 12.19–12.26

PRACTICE the skill

APPLY the skill

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MEDICALLYSPEAKINGThe Total Synthesis of Vitamin B12

-

-

-

-

-

-

-

-

→ -→

Macrocyclizationoccurs betweenring A and ring D

A D ApproachMacrocyclizationoccurs betweenring A and ring B

A B Approach

A B

CD

M

NN

NN

A

D

M

NN

NN

B

C

A

D

M

N

NN

B

C

Chlorophyll a

NN

NN

OMeO2C

O

Mg Porphyrinring system

Vitamin B12

NN

NN

Co

H2N

O

H

H2N

O

H2N

O

NH

O

OO

O

O

HON

N

OH

NH2

O

NH2

O

NH2

O

CN

±

–

Corrinring system

O

O

P

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12.5 Retrosynthetic Analysis 549

--

-

-

intrainter

-

-

-

-

-

-

-

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

N NB C

R

RR S

Temporary tether

NB

R

R

NC R

N NB C

R

RR

±

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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:

An alcohol

OH

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:

Focuson this step

OH

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 retrosyntheticanalysis. 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 mate-rial 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 transfor-mation cannot be accomplished even in two steps. So we approach this problem backwardand 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:

Geminaldibromide

BrBr

Vicinaldibromide

Br

Br

Geminaldibromide

Br

Br

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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

BrBr

?

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

OH ?

Br

Br

1) xs NaNH22) H2O

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

can be made from...

this dibromide

Br

Br

This alkyne

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

Br

alkene

Can be made from:

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:

Product

Br

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 catalystor

Na, NH3

1) Br2 /CCl42) xs NaNH2

3) H2O

H2 , Pt

1) Br2, hn

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

Br

Br

Br2

CCl4

1) xs NaNH22)H2O?

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

OTs

Br

Br

NaH Br2

CCl4

TsClpy

1) xs NaNH22) H2O

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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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:

OH1) TsCl, py2) NaH3) Br2/CCl44) xs NaNH25) H2O

(b)H

O

(a)

SOLUTION(a) -

12

34 6

12

34

5 H

O

-

-

H

O

61

23

45 61

23

4 5

Can be made from:

612

34 5 X1

23

4 ± C C HNa+ –

Can be made from:

SKILLBUILDER12.4 RETROSYNTHETIC ANALYSIS

LEARN the skill

klein_c12_536-563hr.indd 553 7/15/10 12:47 PM


-

H

O

X

1) R2BH2) H2O2 , NaOH

C C HNa+ –

?

anti -

H

O

3) R2BH4) H2O2 , NaOH

1) HBr, ROORCNaCH2)

(b)

12

1

2

3

-

-

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Na, NH3 (l )

1) NaNH2

2) MeI

?

Never draw a carbon atom with five bonds

-

Br

Addition Elimination

anti

Br

t-BuOKHBr, ROOR

Br

Na, NH3 (l )

2) MeI1) NaNH2t-BuOK

HBrROOR

?

WATCH OUT

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-

2) xs NaNH2

3) H2O

1) Br2/CCl4

1) HBr, ROOR2) t-BuOK3) Br2/CCl44) xs NaNH25) H2O

6) NaNH27) MeI8) Na, NH3 (l )

12.13

Br

OH(a)Br

O(b)

Br Br O

(c)

O

(d)

OH

(e)

Br Br

OH

O

(f)

Br

OH

En

(g)

±

(h)

12.14 trans

12.15 cis

12.16 -

H

O

Try Problems 12.19–12.26

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12.6 Practical Tips for Increasing Proficiency 557

-

-

-

Longifolene

OMe

H

O

Me

-

-

-

PRACTICALLYSPEAKINGRetrosynthetic Analysis

12.6 Practical Tips for Increasing Proficiency

Organizing a Synthetic “Toolbox” of ReactionsAll 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 thefunctional 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 ProblemsA 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

2) MeI1) NaNH2

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

2) MeI1) NaNH2

2) MeIH2

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 cre-ating 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 AnswersRemember 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:

OH

1) BH3 THF

2) H2O2, NaOH

1) HBr, ROOR2) 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 path-ways 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 VOCABULARYSECTION 12.1

SECTION 12.2-

π -

SECTION 12.3

bond cleavage

SECTION 12.4

-

SECTION 12.5retrosynthetic analysis

-

KEY TERMINOLOGYbond cleavage retrosynthetic analysis

SKILLBUILDER REVIEW12.1 CHANGING THE IDENTITY OR POSITION OF A FUNCTIONAL GROUP

Change the position of a halogen.

Br

Change the position of a π bond.

Install a functional group.

Interconvert between single, double, and triple bonds.

Br BrElimination

Elimination

Elimination

Addition

Br

Addition

Radicalbromination

H2, Lindlar’s Catalystor

Na, NH3

1) Br2/CCl42) xs NaNH2

3) H2O

H2, Pt

1) Br2, hn

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.

C!C bond cleavage.

Three carbon atoms

C

H

H

C C

H

H

X

H

H

H

Four carbon atoms

C

H

H

C C

H

H

H C–

±

Seven carbon atoms

C

H

H

C C

H

H

H C C

H

H

C C

H

H

H

H

H

C

H

H

C C

H

H

CCH

H

H H

H

H

Five carbon atoms

C

H

H

C C

H

H

COH

H

H H

Four carbon atoms

C

H

HO

One carbon atoms

1) O3

2) DMS±

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

Try Problems 12.10–12.12, 12.19–12.26

12.4 RETROSYNTHETIC ANALYSIS

Br

BrCan be made

fromCan be made

fromCan be made

from

Product Startingmaterial

Try Problems 12.13–12.16, 12.19–12.26

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Practice Problems 561

PRACTICE PROBLEMS Note:WileyPLUS

12.17

Br

Br

OH

OH

OH

Br

Br

Br

OH

OH

12.18

Br

Br

BrBr

Br

CH3

O O

H

Br

Br

Br Br

Br

Br

C

O

O

OH

O

±

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12.19

12.20

12.21

OH

OH

(a)

O(b)

12.22

12.23

OH

O(a)

BrOH

O

(b)

BrH

O

(c)

(d)

12.24R R

S S

12.25R S

S R

12.26

O

(a)

O(b)

OH

O

(c)

H

O

(d)

O

H

O

(e)

INTEGRATED PROBLEMS12.27

N -

C

C

H

–O

C

C

H

OH

HO

H

H+

OC CH–

O+

OH

klein_c12_536-563hr.indd 562 7/15/10 12:47 PM

Challenge Problems 563

12.28

R-

C

C

H

R R

OHH

OH

H±

C

C

H

R R

O–

R R

O–

C CH

O+

OH

12.29

HO O

Br

En±

12.30

12.31

O

O

1,4-Dioxane

CHALLENGE PROBLEMS

klein_c12_536-563hr.indd 563 7/15/10 12:47 PM

Klein Ch12

Documents

onestep synthesis problems

multistep synthesis

organic synthesis

synthesis problem12

laboratory synthesis

synthesis strategies

complex problems

pm538 chapter