Jones M., Fleming S.A. Organic Chemistry

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18.14 Special Topic: A Family of Concerted Rearrangements of Acyl Compounds 919

PROBLEM 18.30 Can you guess what nitrene chemistry will be like? What prod-

ucts do you anticipate from the reaction of a nitrene with the carbon–carbon dou-

ble bond? What product would you get from reaction with a carbon–hydrogen

bond? Remember that a nitrene is the nitrogen analogue of a carbene (p. 431).

Isocyanates, like ketenes, are very sensitive to nucleophiles. For example,

alcohols add to isocyanates to give carbamate esters (Fig. 18.71).

18.14c Hofmann Rearrangement of Amides Amides are able to take part

in a reaction similar to the Wolff and Curtius rearrangements.The reaction is called

the Hofmann rearrangement

and it allows you to convert an amide into an amine

with the loss of the carbonyl carbon.This process occurs in two steps.The amide is

first brominated to give the N-bromoamide (Fig. 18.72). Base then removes the

very acidic α hydrogen and rearrangement to the isocyanate ensues. The question

of whether a nitrene is involved in this rearrangement is not completely settled, but

we would bet on the direct rearrangement shown in Figure 18.72.

A carbamate este

An isocyanate

ROH

FIGURE 18.71 Isocyanates react with

alcohols to give carbamate esters.

PROBLEM 18.31 Write a mechanism for the addition of an alcohol to an isocyanate

to give a carbamate ester (Fig. 18.71).

PROBLEM 18.32 Write a mechanism for the formation of the amine in the

following reaction:

OHNa

–

migration of R

An isocyanate

(but not isolable under these conditions)

FIGURE 18.72 The first stages in the Hofmann

rearrangement. An isocyanate is an intermediate, but

cannot be isolated.

In earlier, more colorful times, this reaction was known as the “Hofmann degradation.”

920 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

The isocyanate is not isolable, as it is in the Curtius rearrangement. Instead,

in this reaction, it is born in the presence of base and is hydrolyzed to the carbam-

ic acid, which is unstable and decarboxylates (Fig. 18.73, recall Problem 18.32).

–

addition

decarboxylation

protonation

OCO

–

A carbamic

acid

An amine—

the end product

of the Hofmann

rearrangement

WEB 3D

FIGURE 18.73 The isocyanate reacts

with hydroxide or water to make an

intermediate carbamic acid, which

decarboxylates to give the amine.

The end product is the amine. There is an essential difference between the Curtius

rearrangment and the Hofmann rearrangement. Both involve the formation of iso-

cyanates, but only in the Curtius rearrangement is this intermediate isolable. In the

Hofmann rearrangement,base is present and the isocyanate cannot survive (Fig.18.74).

This synthesis of amines is not easy to remember because it involves many steps, thus

making it a great favorite of problem writers (open-book, of course).

–

NNN

–

Isolable! No

nucleophiles

present

Curtius

But Hofmann

NNH

–

Not isolable—

born in the

presence of

–

FIGURE 18.74 The Curtius and Hofmann rearrangements contrasted.

Do you remember the Hofmann elimination (p. 308)? It’s the same Hofmann.

Summary

In this section we have explored a number of rearrangement reactions that

involve ketenes or ketene-like intermediates.Notice that each of these rearrange-

ments is a name reaction (Wolff, Arndt-Eistert, Hofmann,

and Curtius).

Don’t panic about keeping the specifics of the reactions connected to the names.

Most instructors will not ask you to reproduce the reactions by name. However,

if your future includes organic chemistry, you will see them again and become

familiar with them. Of course if your future does not include organic chemistry,

at least you can appreciate the predictability and trends these reactions illustrate.

18.15 Summary 921

EAT YOUR BROCCOLI!

The last section showed a set of reactions unified by

formation of an intermediate containing two cumulated

(adjacent) double bonds. Their common ancestor is

allene, . Are these molecules mere

curiosities, chemical oddities of no real importance

outside a textbook or exam? Not at all. In 1992, broccoli

was shown to contain a sulfur-containing isocyanate, an

isothiocyanate, that induces formation of something called

a “phase II detoxication enzyme,” which is involved in the

metabolism of carcinogens. Eat your broccoli and study

your orgo.

CCH

Allene Ketene

Isocyanate Isothiocyanate

OCH

CNOR

CNRS

1-Isothiocyanato-(4R)-

(methylsulfinyl)butane

(an anticancer agent found in broccoli)

18.15 Summary

New Concepts

This chapter is filled with detail, but there are no new funda-

mental concepts. Most important, although not really new, is

the continuation of the exploration of the addition–elimination

reaction of carbonyl compounds begun in Chapter 17. When

nucleophiles add to carbonyl compounds that do not bear a

–

CCR

reversal

protonation

–

CCL

protonation

elimination

FIGURE 18.75 Carbonyl groups bearing good leaving groups can undergo the

addition–elimination reaction; others cannot.

leaving group (for example, aldehydes or ketones) reversal of the

addition or protonation are the only two possible reactions.

When there is a leaving group attached to the carbonyl, as there

is with most acid derivatives, another option is loss of the leav-

ing group (Fig. 18.75).

922 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

Key Terms

acid derivative (p. 877)

acid halide (p. 880)

acyl compound (p. 877)

Arndt–Eistert reaction (p. 917)

Baeyer–Villiger reaction (p. 907)

Beckmann rearrangement (p. 909)

Curtius rearrangement (p. 918)

diazo ketone (p. 915)

ester hydrolysis (p. 895)

Hofmann rearrangement (p. 919)

imide (p. 882)

isocyanate (p. 918)

nitrene (p. 918)

nitrile (p. 883)

Rosenmund reduction (p. 892)

transesterification (p. 896)

Wolff rearrangement (p. 916)

xanthate ester (p. 914)

Reactions, Mechanisms, and Tools

The addition–elimination reaction, introduced in Chapter 17,

dominates the reaction mechanisms discussed in this

chapter.

The chemistry of nitriles is similar to that of carbonyl com-

pounds. The carbon–nitrogen triple bond can act as an acceptor

of nucleophiles in addition reactions.

There is a class of intramolecular thermal elimination reac-

tions that provides a new route to alkenes. Esters, xanthates, and

amine oxides are commonly used in this reaction.The reactions

are concerted (one-step), and steric requirements dictate that a

syn elimination must occur in the reaction, as the carbonyl group

cannot reach a hydrogen in an anti position (Fig. 18.61).

Syntheses

Here are the many important synthetic reactions found in this

chapter. A few have been touched upon already in Chapter 17,

but most are new to you, at least in a formal sense. Many of the

following reactions share a common (addition–elimination)

mechanism.

cid- or base-induced hydrolysis of acid

halides, anhydrides, esters, and amides;

X = Cl, Br, I, O CO R, OR, NH

O/H

or H

O/HO

–

Acid- or base-induced hydrolysis of

nitriles; the amide is an intermediate

CN R

O/H

or H

O/HO

–

Hydration of ketenes

2. Acyl Azides

Addition–elimination reaction

–

3. Alcohols

1. 2 equiv. RLi

2. H

1. 2 equiv. RLi

2. H

The ketone is an intermediate but cannot be isolated;

all three R groups may be the same, but all three

R’s cannot be different, RMgX also works

RRC

Other metal hydride donors also work; the

aldehyde is an intermediate, but cannot be

isolated

1. LiAlH

2. H

Other metal hydride donors also work; the aldehyde

is an intermediate, but cannot be isolated

1. LiAlH

2. H

The ester and ketone are intermediates,

but cannot be isolated; all three R groups

must be the same, RMgX also works

1. RLi

2. H

1. Acids

18.15 Summary 923

4. Aldehydes

Other encumbered metal hydrides also work

1. LiAlH[OC(CH

)

]

2. H

Diisobutylaluminum hydride (DIBAL-H) will not

reduce the aldehyde if the reaction is carefully run

1. DIBAL-H

2. H

Rosenmund reduction

poisoned catalyst

5. Alkenes

–

Note that only a cis hydrogen can be removed

⌬

C RCOOH+C

Xanthate ester pyrolysis requires lower

temperature than ester pyrolysis

⌬

A Cope elimination

⌬

6. Amides

Substituted amines give substituted amides

Acid catalysis also works

–

Substituted amines give substituted amides

C CO

The Beckmann rearrangement

7. Amines

Catalytic hydrogenation

/catalyst

Loss of a metal oxide from the initially

formed intermediate is the key to this reaction

NHR

CN R CH

NHRR

1. LiAlH

2. H

1. LiAlH

2. H

Loss of a metal oxide from the initially

formed intermediate is the key to this reaction, too

The Hofmann rearrangement;

an isocyanate is an intermediate

1. Br

2. H

O/KOH

8. Anhydrides

–

OCOR

–

OCOR

924 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

9. Carbamates

C ORN

ROH

RNH

10. Carbonates

The mixed carbonate cannot be made this way

ROH

12. Esters

11. Diazo Ketones

Addition–elimination mechanism followed

by removal of an acidic hydrogen

CHN

ROH

Fischer esterification

ROH

Acid-catalyzed transesterification;

this transformation also works with base catalysis

ROH

COOOH

The Baeyer–Villiger reaction

15. Ketones

The cuprate will react with the acid

chloride but not with the product ketone

–

CuR

Friedel–Crafts acylation; this reaction

works with the anhydride as well

AlCl

The imine is an intermediate

1. RLi

2. H

CN R

13. Isocyanates

or hν

Curtius rearrangement

14. Ketenes

RCH

Elimination using a tertiary amine as base

CHN

Wolff rearrangement

RCH

or hν

16. Lactams

Amide-forming reactions applied in an

intramolecular way will work

Lactams are formed by the cyclic version

of the Beckmann rearrangement

polyphosphoric

acid

18.16 Additional Problems 925

17. Lactones

Ester-forming reactions applied in an

intramolecular way will work

Lactones are formed by the cyclic version

of the Baeyer–Villiger reaction

O H

18. Nitriles

2 displacement

–

Dehydration of amides

⌬

X R R NC

19. Xanthate Esters

–

+ CS

SCH

—I

PROBLEM 18.33 Write mechanisms for the following conversions:

(a)

(b)

(CH

)

NCH

(CH

)

CH NHCH

(CH

)

NaN

(CH

)

PROBLEM 18.34 Write mechanisms for the following conver-

sions in acid:

(a)

(b)

(CH

)

OCH

(CH

)

HOCH

(CH

)

OCH

(CH

)

OCD

HOCH

Analyze problems before starting. Do not be too proud to do the

obvious. Use the molecular formula to see what molecules must

be combined. In acid (H



, HCl, etc.), carbocations are the

likely intermediates. In base (



OH,



OR, etc.), carbanions are

probably involved. Try to identify what must be accomplished in

a problem. Although sometimes it will be hard to plan, and you

may have to try all possible intermediates, usually a problem will

tell you much of what you must do.

Ask yourself questions and set goals. What rings must be

opened? What rings must be closed? What atoms become

incorporated in the product? Pay attention to “stop signs.”

Primary carbocations are stop signs. Unstabilized carbanions are

stop signs. If you are forced to invoke such a species in an

answer, it is almost certainly wrong, and you must backtrack.

Hard problems become easier if you keep such questions in

mind. All of this advice sounds obvious, but it’s not. Thinking a

bit about what must be done in a problem saves much time in

the long run and avoids the generally hopeless random arrow

pushing that can trap you into a wrong answer.

Common Errors

Let’s warm up with some simple problems, just to be certain

that the basic (and acidic) mechanisms of this chapter are under

control. Then we can go on to other things. Please be sure you

can do the “easy” problems before you try the more difficult

ones at the end of this section.

18.16 Additional Problems

926 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

PROBLEM 18.35 Now write the mechanism for a slightly more

complicated acid-catalyzed hydrolysis.

HCl

PROBLEM 18.36 Write a mechanism for the acid-catalyzed

formation of ethyl hexanoate from ethanol and hexanoic acid.

PROBLEM 18.37 Show a synthetic route to methyl benzoate

starting with methanol and toluene. Assume you have access

to any other needed reagents.

PROBLEM 18.38 Write Lewis structures for the following

compounds:

(a) propanoic acid

(b) propanoyl chloride

(d) methylketene

(e) propyl cyclopropanecarboxylate

(f) phenyl benzoate

PROBLEM 18.39 Give the IUPAC name for each of the

following molecules:

COOCH

OCH

(a) (b)

OCH

(e) (f)

(g) (h)

PROBLEM 18.43 Analysis of the IR stretching frequencies of

carbonyl compounds involves an assessment of resonance and

inductive effects. This assessment is a somewhat risky business,

and it must be admitted that near-circular reasoning is some-

times encountered. Nonetheless, see if you can make sense of

the following observations taken from Table 18.2. In each case,

it will be profitable to think of all the important resonance

forms of the acyl compound.

(a) Acetone absorbs at 1719 cm

1

, whereas acetaldehyde

absorbs at 1733 cm

1

(b) Explain why methyl acetate absorbs at higher frequency

(1750 cm

1

) than acetone (1719 cm

1

(1688 cm

1

) than methyl acetate (1750 cm

1

PROBLEM 18.44 Is your explanation in Problem 18.43 (b)

consistent with the observation that the carbonyl carbon of

methyl acetate appears at δ 169 ppm in the

C NMR spec-

trum, whereas the carbonyl carbon of acetone is far downfield

at δ 205 ppm? Explain.

PROBLEM 18.45 Give the major organic products expected in

each of the following reactions or reaction sequences.

PROBLEM 18.40 Show how you would synthesize N-phenyl-

1-pentanamine from 1-pentanol, aniline, tosylchloride, and any

necessary inorganic reagents.

PROBLEM 18.41 Amine oxides can be formed by the reaction

of a tertiary amine with a peroxy acid. Show the synthetic steps

you would use to make cyclohexene from cyclohexanamine

using any necessary reagents.

PROBLEM 18.42 Provide structures for compounds A–F in

this series of reactions.

Br)

)

CCl

HBr

500 °C

1. Mg

2. CO

3. H

O/H

1. LiAlH

2. H

COOH

(a)

1. SOCl

2. HN(CH

)

3. LiAlH

4. H

18.16 Additional Problems 927

(b)

(c)

(d)

(e)

2. CS

3. CH

1. NaH

4. 210–235 C

O, Δ

OH, Δ

ONa

HCl

HOOC

PROBLEM 18.46 We learned in Chapter 17 that most β-keto

acids decarboxylate very easily (p. 858). The compound below is

an exception, as it survives heating to very high temperature

without losing carbon dioxide. Explain.

PROBLEM 18.47 In Section 18.12c, we saw that primary amides

could be dehydrated to nitriles (cyanides) with P

. Nitriles

can also be prepared by treating aldoximes (1) with dehydrating

agents such as acetic anhydride. Propose a mechanism for the

formation of benzonitrile from the reaction of 1 with acetic

anhydride. How are oximes prepared?

Ph C N

PROBLEM 18.48 Reaction of benzonitrile (1) and tert-butyl

alcohol in the presence of concentrated sulfuric acid, followed

by treatment with water, gives N-tert-butylbenzamide (2).

Provide an arrow formalism mechanism for this reaction.

NHC(CH

)

Ph C N

(CH

)

COH

1. conc. H

2. H

PROBLEM 18.49 Devise syntheses for the following molecules.

You may start with benzene, methyl alcohol, sodium methoxide,

ethyl alcohol, sodium ethoxide, butyl alcohol (BuOH), phos-

gene, and propanoic acid as your sources of carbon. You may

also use any inorganic reagent and solvents as needed.

(a)

(e)

(b) (c)

(d)

PROBLEM 18.50 Propose syntheses for the following target mol-

ecules starting from the indicated material. You may use any other

reagents that you need. Use a retrosynthetic analysis in each case.

(a) from

(b) from

C(CH

)

C(CH

)

(d) from

N OH

HBr

Br Ph

R NH

928 CHAPTER 18 Derivatives of Carboxylic Acids: Acyl Compounds

PROBLEM 18.51 Propose syntheses of the following molecules

starting from cyclopentanone:

(a) (b)

PROBLEM 18.52 Provide an arrow formalism mechanism for

the following reaction:

O Ph

PROBLEM 18.53 Here is the problem concerning the forma-

tion of the Vilsmeier reagent we promised you in Chapter 17.

As we saw in Section 17.7d, acid chlorides can be prepared

from carboxylic acids and reagents such as thionyl chloride,

phosphorus pentachloride, phosgene, and oxalyl chloride. The

conditions for these reactions are sometimes quite severe. It is

possible to prepare acid chlorides under appreciably milder

conditions by using the Vilsmeier reagent (Problem 17.42).

The Vilsmeier reagent is prepared from DMF and oxalyl

chloride. Write an arrow formalism mechanism for its forma-

tion. Hint: DMF acts as a nucleophile, but not via the nitro-

gen atom.

(CH

)

NCl

DMF Oxalyl chloride

(CH

)

Vilsmeier reagent

–

[CH

OAlR

]CH

(major)

1. DIBAL-H

–70 ⬚C

2. H

1. DIBAL-H

–70 ⬚C

2. warm to

0 ⬚C

3. H

(90%)

(minor)

OCH

(major)

OCH

PROBLEM 18.55 γ-Aminobutyrate transaminase (GABA-T)

is the key enzyme controlling the metabolism of γ-aminobu-

tyric acid (GABA), a mammalian inhibitory neurotransmitter.

In the following synthesis of the hydrochloride salt of the

putative GABA-T inhibitor, 3-amino-1,4-cyclohexadiene-1-

PROBLEM 18.54 In Section 18.8, we saw that aldehydes

are available from the reduction of esters at low temperature

(70 °C) by diisobutylaluminum hydride (DIBAL-H; see

Fig. 18.38). If the reaction mixture is allowed to warm before

hydrolysis, the yield of aldehyde drops appreciably. For example,

reduction of ethyl butyrate with DIBAL-H at 70 °C followed

by hydrolysis at 70 °C, affords a 90% yield of butyraldehyde.

However, if the reaction mixture is allowed to warm to 0 °C

before hydrolysis, the yield of aldehyde is less than 20%.

Among the products under these conditions are ethyl

butyrate (recovered starting material) and butyl alcohol

(CH

OH), formed from hydrolysis of

(R  isobutyl). Rationalize these

observations with arrow formalism mechanisms.

AlR