Jones M., Fleming S.A. Organic Chemistry

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16.10 Protecting Groups in Synthesis 789

into group Y through a base-catalyzed reaction. But we know that carbonyl com-

pounds are sensitive to base, and the starting material may be destroyed in the

attempted reaction. The solution is first to convert the carbonyl group into an

acetal (which is unreactive in base), then carry out the conversion of X to Y, and

finally regenerate the carbonyl group.

16.10b Protecting Groups for Alcohols It is often desirable to protect a

hydroxyl group so that further reactions in base can take place without complica-

tion. One widely used method is to convert the hydroxyl group into a tetrahy-

dropyranyl (THP) ether through reaction with dihydropyran (Fig. 16.45). The

mechanism involves protonation of dihydropyran to give the resonance-stabilized

cation, which is then captured by the alcohol. The result is an acetal, a molecule

stable to base, but not to acid (p. 783). Regeneration of the alcohol can be accom-

plished through acid-catalyzed hydrolysis.

O / H

Dihydropyran

acid catalyst

15.5 h, 25 ⬚C

ROH

Alcohol to be

protected

A THP ether—an acetal

and a protected alcohol

The

regenerated

alcohol

+ ROH

(97%)

THE GENERAL CASE

A SPECIFIC EXAMPLE

FIGURE 16.45 The use of THP ethers as protecting groups for alcohols.

Another type of protecting group for alcohols is a silyl ether. A silyl ether

has the general formula of . The reaction of an alcohol with

a trialkylsilyl halide leads to a trialkylsilyl ether in near-quantitative yield

R¿

SiR

790 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

16.11 Addition Reactions of Nitrogen Bases: Imine

and Enamine Formation

The nitrogen atom of an amine (RNH

) is a nucleophile, and like the related oxy-

gen nucleophiles, it can add to carbonyl compounds. Indeed, the acid-catalyzed reac-

tion between a carbonyl compound and an amine to give a carbinolamine is quite

analogous to the reactions of water and alcohols we have just seen (Fig. 16.47).

–

(89%)

(100%)

HCl

25 ⬚C

(CH

)

Si Cl

Si C(CH

)

Si C(CH

)

FIGURE 16.46 The use of trialkylsilyl

ethers as protecting groups for

alcohols.

COH

Protonation

steps

Deprotonation

steps

Addition

steps

Hemiacetal

ROH

....

COH

ROH

COH

Carbinolamine

COH

RNH

HOH

COH

Hydrate

(gem-diol)

HOH

....

COH

FIGURE 16.47 Analogous reactions of carbonyl compounds give hydrates (called gem-diols), hemiacetals,

and carbinolamines. The usual sequence of protonation, addition, and deprotonation steps is followed.

(Fig. 16.46). The reaction depends for its success on the enormous strength of the

silicon–oxygen bond ( 110 kcal/mol).The silyl group can be removed through reac-

tion with fluoride ion or hydrogen fluoride. The silicon–fluorine bond is even

stronger ( 140 kcal/mol) than the silicon–oxygen bond, and the formation of the

trialkylsilyl fluoride provides the thermodynamic driving force for the reaction.

So, alcohols can be protected by converting them into THP or silyl ethers, and

regenerating them when needed.

16.11 Addition Reactions of Nitrogen Bases: Imine and Enamine Formation 791

Although the amine is more basic than the carbonyl oxygen, there still must be

sufficient protonation of carbonyl and availability of the free amine under the acid-

catalyzed conditions.

PROBLEM 16.17 Write the base-catalyzed versions of the reactions in Figure 16.47.

Like the hemiacetal, the carbinolamine is not a final product in acid. Further

steps in the two reactions are all similar. An OH is protonated, and then lost as

water (note that



OH is not the leaving group) to give a resonance-stabilized cation

(Fig. 16.48).

COH

Resonance-stabilized

cations

Hemiacetal

ROH

Carbinolamine

RNH

Hydrate

HOH

CC CC

FIGURE 16.48 Continuation of the reactions from Figure 16.47. Loss of water leads

to a resonance-stabilized intermediate in all three reactions.

792 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

Imine

Carbonyl

ROH

RNH

HOH

RNH

COR

Acetal

Here there is no proton that

can be lost from oxygen

In these cases, there is a proton

that can be lost from N or O

WEB 3D

FIGURE 16.49 Continuation of

reactions from Figure 16.48. In the

reaction with water, loss of a proton

leads to the recovered carbonyl

compound. In the alcohol reaction,

there is no proton to be lost, and

a second molecule of alcohol adds

to give an acetal. In the reaction

with amine, loss of a proton leads

to an imine.

In the acid-catalyzed reaction with alcohol shown in Figures 16.47 and 16.48,

the resonance-stabilized cation reacts by adding a nucleophile, ROH, because R



cannot usually be lost. Instead, the cation goes on to acetal formation by a second

addition of alcohol. For the water and amine additions, however, there remains an

available hydrogen on the resonance-stabilized cation that can be lost as a proton,

as shown in Figure 16.49. In the hydration reaction, this loss simply completes the

re-formation of the carbonyl group of the starting material, but in the amine exam-

ple it leads to the formation of a carbon–nitrogen double bond, called either a Schiff

base or an imine (Fig. 16.49).

There is a vast variety of imines formed from primary amines (RNH

monosubstituted derivatives of ammonia, NH

), and each has its own common

name. Many of them were once useful in analytical chemistry because they are

generally solids, and therefore could be characterized by their melting points.

Imine formation

16.11 Addition Reactions of Nitrogen Bases: Imine and Enamine Formation 793

For example, formation of a 2,4-dinitrophenylhydrazone or a semicarbazone

(Fig. 16.50) from an unknown was not only diagnostic for the presence of a car-

bonyl group, but it yielded a specific derivative that could be compared to a similar

sample made from a compound of known structure. Figure 16.50 gives a few of

these substituted imines. Be sure to note that all of these reactions are the same—

the only difference is the identity of the R group.If you know one,you know them

all—but you have to know that one.

acid catalyst

Imine

Phenyl imine

.. ..

Hydrazone

NHPh

.. ..

PhHN

Phenylhydrazone

.. ..

2,4-Dinitrophenylhydrazone

....

Semicarbazone

.. ..

Oxime

THE GENERAL CASE

EXAMPLES OF R NH

WEB 3D

FIGURE 16.50 Formation of some substituted imines.

What happens if one or both of these hydrogens is missing? Tertiary amines

N) carry no hydrogens and undergo no visible reaction with carbonyl groups.But

this masks reality. In fact, addition to the carbon–oxygen double bond does take place,

but the unstable intermediate has no available reaction except reversal to starting

material (Fig. 16.52).

794 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

First loss of

a hydrogen

Second loss of

a hydrogen

HNH

COH

Carbinolamine

protonation

COH

.. ..

RNH

An imine

FIGURE 16.51 In order to form an

imine, there must be two hydrogens

(red) on the starting amine.That is,

the amine must be either primary

(RNH

) or ammonia (NH

No H on N to lose

(the reaction can

only reverse)

COH

A tertiary

amine

Protonated

carbonyl

FIGURE 16.52 Tertiary amines (R

can add to carbonyl groups, but the

only available further reaction is

reversion to starting materials.

PROBLEM 16.18 Write a mechanism for the general reaction of Figure 16.50, the

acid-catalyzed reaction of a carbonyl compound with RNH

Note also that the success of the imine-forming reaction relies on the presence

of at least two hydrogens in the starting amine. One is lost as a proton in the first

step of the reaction, the formation of the carbinolamine. The second proton is lost

in a deprotonation step as the final imine is produced (Fig. 16.51).

Secondary amines (R

NH) have one hydrogen, and so carbinolamine formation

is possible (Fig. 16.53).This reaction can be followed by protonation and water loss

to give a resonance-stabilized cation, called an iminium ion. An iminium ion has

the general structure . Deprotonation of the iminium ion on nitrogen

is not possible as there remains no second proton on nitrogen to be lost.

16.11 Addition Reactions of Nitrogen Bases: Imine and Enamine Formation 795

first (and only)

deprotonation

An iminium ion (no proton can be lost from nitrogen

to give an imine because there is no H left attached to N)

COH

C COH

Carbinolamine

protonation

of oxygen

loss of

water

Secondary

amine

FIGURE 16.53 For secondary amines

NH) carbinolamine formation is

possible, then water is lost to give a

resonance-stabilized iminium ion.There

is no hydrogen remaining on nitrogen

that can be lost to give an imine.

Think now about what you know of the possibilities for proton loss by carbo-

cations. The E1 reaction (p. 298) is a perfect example. In the E1 reaction, a leav-

ing group departs to give a carbocation, which reacts further by deprotonating at

all possible adjacent positions. If an adjacent carbon-attached hydrogen is avail-

able, the iminium ion can do this same reaction. Figure 16.54 makes the analogy.

This reaction gives a molecule called an enamine, which is the final product of

the reaction of secondary amines and simple aldehydes and ketones. Enamine is

the name used to describe a compound that has an alkene attached to an amine.

Base

Alkene

Enamine

B+

FIGURE 16.54 Deprotonation of an

iminium ion to give an enamine is

exactly like deprotonation of a

carbocation to give an alkene.

796 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

Notice that enamines are the nitrogen counterpart of enols (p. 448). Now comes an

important question: Why doesn’t the iminium ion formed from primary amines or

ammonia (Fig. 16.49) also lose a proton from carbon to give an enamine? Why is

imine formation preferred when there is a choice (Fig. 16.55)? The answer is extraor-

dinarily simple: Just as the ketone tautomer is more stable than the enol, the imine

is more stable than the enamine and so is preferred when possible. It is only in cases

where imine formation is not possible, as when secondary amines are used, that

enamines are formed. We hope you have noticed that the imine- and enamine-

forming reactions are reversible. The reactions work best under slightly acidic con-

ditions with heat applied to drive off water. If water is added to an imine or enamine,

the reverse reaction occurs to yield the carbonyl compound and an amine.

Base

Iminium ion from

a secondary amine

No choice here—base can

only remove H

from C;

there are no H atoms on N

Base

Iminium ion from

a primary amine

Here there is a choice;

base can remove H

from

either C (red) or N (green)

Enamine

(less stable)

Enamine

Imine

(more stable)

WEB 3D

FIGURE 16.55 Why don’t iminium

ions formed from primary amines

give enamines rather than imines?

PROBLEM 16.19 Many enamines and imines are in equilibrium. Write a mecha-

nism for the forward and the reverse pathways in the acid- and base-catalyzed

reactions below.

Imine

RNH

Enamine

–

16.12 Organometallic Reagents 797

Summary

All manner of oxygen and nitrogen bases will add reversibly to carbonyl com-

pounds. The ultimate fate of the reaction and the ultimate structure of the

product depend on concentration, and, for nitrogen bases, on the number of

hydrogens available on nitrogen.

16.12 Organometallic Reagents

Not all additions to carbonyl compounds are reversible. Some of the irreversible reac-

tions are of great importance in synthetic chemistry, as they involve the creation of

carbon–carbon bonds. In order to discuss these, we must first talk a bit about the

formation of organometallic reagents.

We first met organometallic reagents in Section 6.3 (p. 227). It would be a very

good idea to go back and re-read those few pages carefully. You will recall that we

can make Grignard reagents (RMgX) and organolithium reagents (RLi) from the

corresponding alkyl halides. We observed that these reagents will react with water

or D

O to produce or , respectively (p. 229). We have also noted that

organometallic compounds add to epoxides (p. 429).

PROBLEM 16.20 Given inorganic reagents of your choice (including D

O), devise

syntheses of the following molecules from the indicated starting materials:

Neither Grignard reagents nor organolithium reagents are good nucleophiles

toward organic halides (Fig. 16.56). If they were, the syntheses we use to generate

the organometallic reagents in the presence of the starting organic halide would be

quite ineffective,because hydrocarbons would be the major products.Small amounts

of coupling are sometimes observed, especially with highly reactive halides such as

allyl bromides.

RX RLiLi RX RR

LiX

FIGURE 16.56 Organometallic reagents are strong bases but not strong nucleophiles.

There are organometallic reagents that can be used to displace halides to good

effect. The most common examples are the organocuprates formed from organo-

lithium compounds and copper iodide. The organocuprates are quite versatile

reagents, and undergo a variety of synthetically useful reactions. We will meet them

again a number of times, but for now, note that they are able to displace chloride,

bromide, and iodide ions, as well as other good leaving groups, from primary alkyl

798 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

halides and often from secondary alkyl halides (Fig.16.57).This capability gives you

another quite effective synthesis of hydrocarbons.

X = I, Cl, Br, or other good leaving groups

R = Primary or secondary alkyl group

OTs = tosylate, an excellent leaving group

(77%)

(98%)

0 ⬚C, ether

CuLi X

excess

(CH

)

CuLi

–75 ⬚C, ether

(CH

)

CuLi

OTs

LiX

RCu

THE GENERAL CASE

SPECIFIC EXAMPLES

FIGURE 16.57 Lithium

organocuprates will react

with primary and

secondary alkyl halides to

give hydrocarbons.

Many metal hydrides,such as lithium aluminum hydride (LiAlH

),undergo reac-

tions that are similar to those of organometallic reagents. Many hydride reagents react

violently with moisture to liberate hydrogen gas. Lithium aluminum hydride and

some other metal hydrides are strong enough nucleophiles to displace halides from

most organic halides.Lithium triethylborohydride,LiHB(Et)

,is an especially effec-

tive H:



source that can be used as a displacing agent (Fig. 16.58).

LiH

HOAlH

Lithium aluminum hydride (LAH)

Lithium triethylborohydride

OLiAlH

–

LiAlH

ether

LiHB(Et)

THF

(100%)

(99%)

25 ⬚C

FIGURE 16.58 Metal hydrides react

with water to generate hydrogen, and

are often strong enough nucleophiles

to displace halides and generate

hydrocarbons.

PROBLEM 16.21 Why is tosylate such a good leaving group? If you can’t recall the

structure of tosylate—and you need that first—see page 283.

PROBLEM 16.22 One possible mechanism for hydrocarbon formation by

organocuprates is an S

2 displacement by one of the R groups on the alkyl halide.

Can you devise an experiment to test this possibility?