Jones M., Fleming S.A. Organic Chemistry

Подождите немного. Документ загружается.

19.15 The Aldol Condensation in the Real World, an Introduction to Modern Synthesis 1009

Molecules found in Nature are sometimes quite spectacularly complicated. Yet we

are now able to modify the simple reactions we have been describing so as to be able

to make breathtakingly complicated molecules, such as the example that follows.

PALYTOXIN

Professor Yoshito Kishi (b. 1937) of Harvard University and

his co-workers set out to make a molecule called palytoxin, a

compound of the formula C

129

223

, found in a coral

resident in a small tidal pool on the island of Maui in Hawaii.

A derivative of this extraordinarily toxic molecule, palytoxin

carboxylic acid, is shown here. Palytoxin is difficult to make,

not so much because of its size, but because of its stereochem-

ical complexity and delicacy. It contains no fewer than 61

stereogenic atoms, each of which must be generated specifical-

ly in order to produce the real palytoxin.

Several aldol-related reactions were necessary in Kishi’s

spectacular synthesis. For example, one of the last critical

reactions in making palytoxin was a variation of the aldol

NCH

OH OH

(CH

)

HOOC

(CH

)

condensation, a process called the Horner–Emmons

reaction, which sewed the molecule together at the red

position with an α,β-unsaturated carbonyl group that was

later reduced (stereospecifically) to give palytoxin.

1010 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

19.16 Summary

New Concepts

Protonated carbonyl

Enol

acid

base

Enolate

–

FIGURE 19.129 Enolate formation in base and enol formation in acid

are typical reactions of carbonyl compounds bearing α hydrogens.

Y = H (aldehyde)

R (ketone)

OR (ester)

if Y = H

or R

if Y = OR

....

repeat

CHR

CHR CHR

FIGURE 19.130 Reactions of enolates and enols with various electrophiles.

This chapter deals almost exclusively with the consequences of

the acidity of a hydrogen α to a carbonyl group. This concept

is really not new, however. You have encountered the idea of

resonance stabilization of an enolate before (for example,

Problem 9.5), and you could surely have dealt with the ques-

tion of why an α hydrogen is removable in base whereas other

carbon–hydrogen bonds are not acidic.

In base, most carbonyl compounds containing α hydrogens

equilibrate with an enolate anion. In acid, it is the enol that

is formed in equilibrium with the carbonyl compound

(Fig 19.129).

Enol or enolate formation leads to exchange, halogenation,

and alkylation at the α position, as well as the more complicated

enolate additions to ketones, aldehydes, or esters. Many

of the condensation reactions are name reactions. Despite

the apparent complexity of these reactions, they all involve

fundamentally simple nucleophile plus electrophile chemistry

(Fig. 19.130).

This chapter also introduces the notion of forming an eno-

late indirectly, through Michael addition to an α,β-unsaturated

carbonyl group (Fig. 19.82).

The idea of transferring a hydride ion (H



) is elaborated in

Section 19.14. Remember: Hydride is not a good leaving group;

it cannot be displaced by a nucleophile, but it can sometimes

be transferred, providing only that a suitable acceptor Lewis

acid is available.

Y = H (aldehyde)

R (ketone)

OR (ester)

–

repeat

–

CHR

–

FIGURE 19.130 (continued)

19.16 Summary 1011

Key Terms

aldol condensation (p. 966)

Cannizzaro reaction (p. 1004)

Claisen condensation (p. 987)

Claisen–Schmidt condensation (p. 984)

crossed (mixed) aldol condensation

(p. 982)

crossed (mixed) Claisen condensation

(p. 993)

Dieckmann condensation (p. 992)

dithiane (p. 1001)

enolate (p. 934)

enone (p. 976)

haloform (p. 949)

haloform reaction (p. 948)

Hell–Volhard–Zelinsky (HVZ) reaction

(p. 950)

keto–enol tautomerization (p. 939)

β-keto ester or acetoacetate synthesis

(p. 960)

kinetic enolate (p. 985)

Knoevenagel condensation (p. 974)

lithium diisopropylamide (LDA) (p. 944)

Magid’s second rule (p. 999)

Magid’s third rule (p. 1007)

malonic ester synthesis (p. 961)

Mannich reaction (p. 1003)

Meerwein–Ponndorf–Verley–Oppenauer

(MPVO) equilibration (p. 1005)

Michael reaction (p. 976)

 position (p. 933)

Robinson annulation (p. 998)

thermodynamic enolate (p. 1008)

Reactions, Mechanisms, and Tools

The beginning point for almost all of the reactions in this chap-

ter, from which almost everything else is derived, is enolate for-

mation in base or enol formation in acid.

The enols and enolates are capable of undergoing many reac-

tions at the α position, among them exchange, racemization,

halogenation, alkylation, addition to ketones or aldehydes, and

addition to esters. The aldol condensation involves reaction of the

enolate, a strong nucleophile, with the electrophilic carbonyl

compound, or of the less strongly nucleophilic enol with the

powerful electrophile, the protonated carbonyl.

Intramolecular aldol, crossed aldol, and the related

Knoevenagel condensations involve similar mechanisms.

Another way of forming an enolate anion is the

Michael reaction, in which a nucleophile adds to the β position

of a carbon–carbon double bond of an α,β-unsaturated carbonyl

group (Fig. 19.82).

Enolates also add to esters. The biologically important

Claisen condensation is the standard reaction of this kind.

Variations of the Claisen condensation include the Dieckmann

condensation and the reverse Claisen condensation.

1012 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

Syntheses

The new synthetic procedures of this chapter are summarized

below.

1. Acids

The Cannizzaro reaction; R may not have

α hydrogen

The haloform reaction; the haloform (CHX

) is

also formed; works for methyl compounds,

X = Cl, Br, and I

RCH

KOH

–

heat

1. 2 equiv.

LDA

2. RX

3. H

RCH

HCX

KOH/H

–

2. Alcohols

The MPVO reaction; the mechanism involves

complex formation followed by hydride shift

3 Acetone

Al[O CH(CH

)

]

–

See also the Cannizzaro reaction under “Acids,”

and “

β-Hydroxy Aldehydes and Ketones”

3. Alkylated Acids, Aldehydes, Esters, and Ketones

The enamine is an intermediate

RCH

1. R

2. RX

3. H

RO CH

1. LDA

2. RX

RCH

1. LDA

2. RX

HO CH

1. 2 equiv.

LDA

2. RX

3. H

–

2. RX

R cannot be tertiary

C C C C

C H

CCH

A variety of reactions involving hydride shifts is described.The

Cannizzaro reaction is the most famous of these and involves, as

do all hydride shift reactions, a simultaneous oxidation of the

hydride donor and reduction of the hydride acceptor (Fig. 19.122).

Enamines, formed through reaction of carbonyl groups with

secondary amines, can be used to alkylate α positions. The

carbonyl group can be regenerated through hydrolysis of the

iminium ion product (Fig. 19.64).

19.16 Summary 1013

4. ␤-Aminoketones (and aldehydes)

6. ␣-Halo Acids, Aldehydes, Ketones, and Esters

In acid, the reaction stops after one halogenation;

X = Cl, Br, and I

In base, up to three

α hydrogens can be

replaced by X; the trihalo carbonyl compounds

react further in the haloform reaction

R R

RCH

Hell–Volhardt–Zelinsky (HVZ) reaction

R R

HO CH

Br CH

PBr

HO CH

R R

RO CH

–

RO C

RCH

RCX

base

5. Deuterated Aldehydes and Ketones

Mannich reaction; there is an intermediate iminium

ion; of course this is also an amine synthesis

CCH

1. HCl/EtOH/

(CH

)

2. H

NaOH

N(CH

)

All α hydrogens will be exchanged

in either acid or base

R R

RCH

RCD

KOD/D

7. Haloforms

8. ␤-Hydroxy Aldehydes and Ketones

9. ␤-Keto Esters

Starting carbonyl compound must have

a methyl group; X = Cl, Br, or I

RCH

ROH

HCX

1. base, X

2. H

The aldol condensation; dehydration often occurs

in acid, and on occasion in base

RCH

acid or base

Claisen condensation

R R

RO CH

1. full equiv. RO

–

2. H

3. H

Crossed Claisen condensation

R R

RO CH

1. LDA

1014 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

11. ␣,␤-Unsaturated Acids, Aldehydes, Esters, and

Ketones

Common Errors

10. Ketones

The MPVO reaction; the first step is formation of

a new aluminum alkoxide; the mechanism involves

complex formation and a hydride shift

1. AlCl

Decarboxylation of acetoacetic acid

S S

1. NaOH

2. H

3. heat

1. LDA

2. RX

3. H

O, Hg

The dehydration of the products of

aldol condensations is usually acid-catalyzed

RCH

Knoevenagel condensation

RO CH

O O

RO C

R¿R¿

1. RO

–

Condensation reaction problems can be daunting. At the same

time, many chemists agree that these mental exercises are fun,

and almost everyone has his or her favorites. A common error is

to set out without a plan. Don’t start on a complicated problem

without an analysis of what needs to be accomplished. Make a

map and set some goals. Ask yourself if the reaction is done in

acid or base. What connections (bonds) must be made? Are

rings opened or closed in the reaction? These are the kinds of

questions that should be asked before starting on a problem.

Two conventions, used widely in this chapter, have the poten-

tial for creating misunderstanding. In the less dangerous of the two,

charges or dots in parentheses are used to indicate the atoms shar-

ing the charge, electron, or electrons in a molecule best described

by more than one electronic description (resonance form).

The second involves drawings in which arrows of an arrow

formalism emanate from only one of several resonance forms.

Although extraordinarily convenient, this practice is dangerous,

as it carries the inevitable implication that the resonance form

used has some individual reality. It does not. What can be done

with one resonance form can always be done from all resonance

forms. For simplicity, and bookkeeping purposes, we often draw

arrow formalisms using only one of several resonance forms.

This practice can be dangerous unless we are very clear about

the shortcuts we are taking.

With the appearance of the addition–elimination process,

essentially all the major reaction types are in place.

Problems and errors become more general as complexity

increases. The most common mistake in solving problems

is a failure to analyze the problem before starting to “push

arrows.”The following Problem Solving section makes this

point again and gives an example of the kind of analysis we

are talking about.

19.16 Summary 1015

–

ROH

PROBLEM SOLVING

Provide a mechanism for the following transformation. Note the position of the

label (dot).

Use that methyl group to help create a map of what atoms in the starting

material become what atoms in the product. Methyl groups don’t have much

chemistry, and are usually unchanged in a reaction (unless they are adjacent to a

carbonyl group). If we label that methyl as 1, the adjacent atoms can be called 2

and 3. Note that the carbonyl group “A” on the left remains adjacent to what we

have called carbon 2.

–

ROH

If we count four atoms counterclockwise from A, we come to carbon “E”

which is attached to an oxygen. In the product, carbon 4 is still attached to

carbon 3 and is adjacent to the label (dot), but it is no longer attached to carbon

E as it is in the starting material. We immediately have a goal—we must break

the bond!

What bond must we make? The map tells you—we must make the

bond. How do we know that? That bond is not present in the starting material,

but it is present in the product. So now we have a second goal—make ! We

also have a third goal—oxidize carbon E from an alcohol to a carbonyl.

–

ROH

–

ROH

(continued)

1016 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

Now we are more than halfway there. We only have to make , and a

Michael reaction easily does that.

(–)

–

HOR

protonate

and redraw

Michael

deprotonate

–

So now this problem has evolved from an amorphous “How do we get from

starting material to product?” to “How do we break , make , and do

the required oxidation?” That’s a much more specific set of questions. This kind

of analysis can make very difficult problems doable, and moderate problems

almost trivial. As you start to try out reactions, those that accomplish goals feel

good and can be followed up, whereas those that do not can be discarded. Here is

a set of reactions that solves this problem:

–

Accomplishes two goals at

once! Breaks E 4 and forms

the new carbonyl. Note resonance

stabilization of the new anion

Goals: Break E 4, oxidize carbon E

(–)

–

(continued)

19.17 Additional Problems 1017

A final protonation completes the problem.

19.17 Additional Problems

PROBLEM 19.46 The “normal” bond length for a carbon–

oyygen single bond is 1.43 Å. In hydroxyethene, the enol form

of acetaldehyde, it is only 1.38 Å. Why is this carbon–oxygen

bond shorter than usual?

PROBLEM 19.47 Write mechanisms for the following acid-

and base-catalyzed equilibrations. There is repetition in this

drill problem, but being able to do these prototypal reac-

tions quickly and easily is an essential skill. Be certain you

can solve this problem easily before going on to more chal-

lenging ones.

(–)

–

PROBLEM 19.48 The following compound contains two

different types of α hydrogens. Removal of which α hydro-

gen will yield the more stable enolate? Which α hydrogen is

likely to be removed faster? Explain why these questions

need not have the same answer. That is, why might the less

stable enolate be formed faster than the more stable enolate

and vice versa?

(c)

(b)

(a)

PROBLEM 19.49 Which positions in the following molecules

will exchange H for D in D

O/DO



(a)

(b)

(c)

(d)

(e)

CO OCH

(a)

(c)

(b)

NHPh

PROBLEM 19.50 As we saw in Problem 19.49c, methyl vinyl

ketone exchanges the three methyl hydrogens for deuterium in

O/DO



. Why doesn’t the other formally “α”hydrogen

exchange as well?

–

This H does not

exchange

PROBLEM 19.51 The proton-decoupled

C NMR spectrum of

2,4-pentanedione consists of six lines (δ 24.3, 30.2, 58.2, 100.3,

191.4, and 201.9 ppm), not the “expected” three lines. Explain.

PROBLEM 19.52 Provide simple synthetic routes from cyclo-

hexanone to the following compounds. Hint: These questions

are all review.

1018 CHAPTER 19 Carbonyl Chemistry 2: Reactions at the Position␣

PROBLEM 19.58 As we have seen, alkylation of enolates gen-

erally occurs at carbon (see Problem 19.57 for an example).

However, this is not always the case. First, use the following

estimated bond strengths to explain why treatment of an eno-

late with trimethylsilyl chloride leads to substitution at oxygen

( 69 kcal/mol; 109 kcal/mol).

(a) (b)

(c)

(d)

PROBLEM 19.55 Perform retrosynthetic analyses on the

following molecules, each of which, in principle, can be synthe-

sized by an aldol condensation–dehydration sequence. Which

syntheses will be practical? Explain why some of your suggested

routes may not work in practice. What are some of the potential

problems in each part?

PROBLEM 19.56 Treatment of compound 1 with an aqueous

solution of bromine and sodium hydroxide affords, after acidifi-

cation, pivalic acid (2) and bromoform. Deduce the structure of

1 and write an arrow formalism mechanism for its conversion

into 2 and bromoform. Use your mechanism to predict the

number of equivalents of bromine and sodium hydroxide neces-

sary for this reaction.

1. NaOH/Br

2. H

O/H

CHBr

(CH

)

C COOH

PROBLEM 19.57 Treatment of ketone 1 with LDA in

dimethylformamide (DMF) solvent, followed by addition of

methyl iodide, leads to two methylated ketones. Write arrow

formalisms for their formations and explain why one product is

greatly favored over the other.

2. CH

–78 ⬚C

1. LDA/DMF

(66%)

(3%)

(CH

)

SiCl

(CH

)

SiCl

(CH

)

(78%)

OSi(CH

)

OSi(CH

)

(22%)

(1%) (99%)

LDA

–78 ⬚C

Second, explain the different regiochemical results under

the two reaction conditions shown. Hint: Remember that eno-

late formation with LDA is irreversible.

O/HO

–

(a)

(b)

O/H

PROBLEM 19.54 Write mechanisms for the following

isomerizations:

(a)

(two ways)

(b)

(c)

(d)

PROBLEM 19.53 Provide simple synthetic routes from cyclo-

hexanone to the following compounds: