Jones M., Fleming S.A. Organic Chemistry

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16.16 Oxidation of Thiols and Other Sulfur Compounds 809

(c)

(f)

(b)

(e)

(a)

(d)

OTs

PROBLEM 16.27 Starting from inorganic reagents, tosyl chloride, formaldehyde,

acetaldehyde, acetone, and butyl alcohol, devise syntheses of the following

molecules:

16.16 Oxidation of Thiols and Other Sulfur

Compounds

Like alcohols, thiols (mercaptans) can be oxidized,but oxidation usually takes place

not at carbon, as with alcohols, but on sulfur to give sulfonic acids (Fig. 16.76).

HNO

Butanethiol Butanesulfonic acid

(85%)

FIGURE 16.76 Oxidation of thiols

(mercaptans) with nitric acid gives

sulfonic acids.

KHCO

, 25 ⬚C

KHCO

(95%)

BrCH

–

SCH

.. ..

FIGURE 16.77 Mild oxidation with bromine

(or iodine) in base gives disulfides.

Milder oxidation, using halogens (I

or Br

) in base, is a general source of disulfides.

This reaction probably involves a sequence of displacement reactions (Fig. 16.77).

810 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

Unlike ethers, sulfides (thioethers) can easily be oxidized to sulfoxides, usually

with hydrogen peroxide,H

. Sulfoxides have the general formula R

SO.Further

or more vigorous oxidation gives a sulfone, a compound of the formula R

(Fig. 16.78).

(76%)

(90%)

Sulfoxide

Sulfide

Sulfone

30% H

OH, NaOH

COOH

COOOH

⬚

50 C

R R

THE GENERAL CASE

SPECIFIC EXAMPLES

FIGURE 16.78 Sulfides can be oxidized to sulfoxides with hydrogen

peroxide. Further oxidation gives sulfones.

Sulfoxides and sulfones are more complicated structurally than they appear.

First, they are not planar, but approximately tetrahedral.Second, the uncharged res-

onance forms are not the major contributors to the structures. Better representa-

tions involve charge-separated resonance forms in which the sulfur octet is not

expanded (Fig. 16.79).

Sulfoxides

–

– –

–

Sulfones

FIGURE 16.79 A resonance description of sulfoxides and sulfones.

16.17 The Wittig Reaction 811

Summary

Thiol and sulfide chemistry resembles alcohol and ether chemistry.There are dif-

ferences,but many of the differences are quantitative, not fundamental. For exam-

ple, we have learned that mercaptides (RS



) are much better nucleophiles than

alkoxides (RO



), but even an alkoxide can undergo the S

2 reaction given the

right conditions and reagents.There are areas in which substantial differences do

appear; for example, sulfur is far more prone to oxidation than oxygen.

16.17 The Wittig Reaction

As we have seen, all manner of nucleophiles add to carbon–oxygen double bonds,

often leading to useful compounds such as alcohols. Now we will learn about a syn-

thetically useful carbonyl addition reaction that produces certain kinds of alkenes.

This reaction was discovered in the laboratories of Georg Wittig (1897–1987) and

is called the Wittig reaction.Wittig shared the 1979 Nobel prize in chemistry large-

ly for his work on this reaction.The process begins with the reaction between phos-

phines, (R

P), and alkyl halides to give phosphonium halides (Fig. 16.80). Although

we have not encountered reactions of phosphorus yet, it sits right below nitrogen in

the periodic table and, like nitrogen, is a good nucleophile. Formation of the phos-

phonium halide takes place through an S

2 displacement.

A phosphonium ion

(Ph)

–

Triphenyl-

phosphine

FIGURE 16.80 Displacement

of iodide by the nucleophilic

phosphorus atom of

triphenylphosphine leads to

phosphonium ions.

The phosphonium ion contains acidic hydrogens that can be removed by

strong bases such as alkyllithium reagents. The product is an ylide (pronounced

ill-id), a compound containing opposite charges on adjacent atoms (Fig. 16.81).

–

(Ph)

–

An ylide Butane

(Ph)

BuH

FIGURE 16.81 Protons adjacent to

the positively charged phosphorus

atom can be removed in strong base

to give ylides.

–

(Ph)

–

(Ph)

An oxaphosphetane

(Ph)

Triphenylphosphine

oxide

Product

alkene

FIGURE 16.82 Ylides are nucleophiles and will add to carbonyl compounds to give intermediates that can close

to oxaphosphetanes.These four-membered ring compounds can open to give triphenylphosphine oxide and the

product alkenes.

The carbon of the ylide is a nucleophile, and like other nucleophiles, adds to

carbon–oxygen double bonds (Fig. 16.82). Intramolecular closure of the intermediate

812 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

leads to a four-membered ring,an oxaphosphetane. Oxaphosphetanes are strained

and unstable relative to their quite stable constituent parts, phosphine oxides and

alkenes. Therefore, it is easy for these intermediates to fragment.

The Wittig synthesis does contain some unfamiliar intermediates. You have

not seen either an ylide or an oxaphosphetane before,for example.Yet the key reac-

tions, the S

2 displacement to form the phosphonium halide (Fig. 16.80) and the

addition to the carbonyl group (Fig. 16.82), are simple variations on basic process-

es. In a practical sense, it is worth working through the new parts of the Wittig

reaction because it is so useful synthetically. Note that the Wittig reaction is, in a

formal sense, the reverse of ozonolysis (p. 436). Figure 16.83 shows some specific

examples.

Wittig

ozonolysis

GENERAL INTERCONVERSIONS

(43%)

10 h, 170 ⬚C

CHCOOC

(Ph)

O C

COOC

12 h, 65 ⬚C

ether

OCH

(Ph)

(67%)

H H

SPECIFIC EXAMPLES

FIGURE 16.83 Some typical synthetic uses of the Wittig reaction. It converts

an aldehyde or ketone into an alkene.

The Wittig reaction is very useful. How else could we convert cyclohexanone

into pure methylenecyclohexane? We can use the reactions of this chapter to devise

a different synthesis. Some thought might lead to a sequence in which cyclohexa-

none reacts with methyllithium to give, after hydrolysis, a tertiary alcohol. An acid-

catalyzed elimination reaction would give some of the desired product, but there is

no easy way to avoid the predominant formation of the undesired isomer, 1-methylcy-

Wittig reaction

16.18 Special Topic: Biological Oxidation 813

2. H

1. CH

MinorMajor

(a)

NaH

DMSO

(86%)

(b)

P CH

FIGURE 16.84 (a) The dehydration approach fails to give very much of the desired

product. (b) The Wittig reaction is the preferred alternative.

(a) (b)

16.18 Special Topic: Biological Oxidation

We have seen several examples of redox reactions in the last few sections. Related

processes are of vital importance in biological systems. We humans, for example,

derive much of our energy from the oxidation of ingested sugars and fats.However,

we do not use chromium reagents or nitric acid as oxidizing agents to accomplish

these reactions, for these reagents are far too unselective and harsh. They would

surely destroy most of our constituent molecules; a quite uncomfortable process one

imagines.Instead, a series of highly selective oxidizing biomolecules has evolved, each

dedicated to a particular purpose. One of these, nicotinamide adenine dinucleotide

(NAD



is the subject of this section. Recall that we first looked at this molecule

in Chapter 14 (p. 679).

A glance at the structure of this molecule, and some brief thoughts on how complicated its systematic name

must be, quickly reveal the obvious reasons why biochemists are addicted to acronyms.

PROBLEM 16.28 Explain why the acid-catalyzed dehydration reaction of Figure

16.84a will give mostly the undesired 1-methylcyclohexene.

PROBLEM 16.29 Starting with cycloheptanone, cyclopentanone, triphenylphos-

phine, propyl iodide, butyllithium, and inorganic reagents of your choice, devise

synthesis of the following molecules:

clohexene (Fig. 16.84). The Wittig reaction solves this synthetic problem and is an

important constituent of any synthetic chemist’s bag of tricks.

814 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

Nicotinamide adenine dinucleotide

is a pyridinium ion, and its full structure

is shown in Figure 16.85. The business

end of the molecule,the pyridinium ion,

is connected through a sugar (ribose)

and a pyrophosphate linkage to a second

ribose which is, in turn, attached to the

base adenine. The molecule is a coen-

zyme, a molecule needed by an enzyme

to carry out a reaction. In this case,

the enzyme is alcohol dehydrogenase.

The enzyme binds the alcohol, which is

the molecule to be oxidized, and NAD



which will be reduced.Ethanol is a com-

mon alcohol in our diet (it is in bread,

fruit, flavoring, and often in our drinks)

and it is on this alcohol that much of the

research on the mechanism of NAD



has been performed.

In this reaction, the NAD



behaves

as a Lewis acid, and accepts a hydride

ion. Ethanol is a Lewis base in this set-

ting,because it donates the H



.The enzyme serves to bring the NAD



and the ethyl

alcohol together, but this bringing together is of immense importance to the reac-

tion, as it allows the redox process to take place without the requirements that mol-

ecules in solution have for finding each other and orienting properly for reaction.

The NAD



is a strong acid by virtue of its positively charged quaternary nitro-

gen.It can be reduced by transfer of a hydrogen with its pair of electrons (a hydride reduc-

tion), from ethyl alcohol (Fig. 16.86). The reaction is completed by deprotonation to

give the product acetaldehyde and removal of the products from the enzyme. This

removal is easy because the enzyme has evolved to bind ethyl alcohol and NAD



, and

not acetaldehyde and NADH, the reduced form of NAD



. It is the acetaldehyde that

causes most of the health problems associated with significant ethanol consumption.

We will see NADH again in Chapter 23 as a biological hydride source.

This hydride reduction may seem strange, but it is not. There is a close relative

in the intramolecular hydride shifts in carbocation chemistry. These, too, are redox

Ethanol

NAD

Acetaldehyde

NADH

FIGURE 16.86 The NAD



is reduced by transfer of hydride (H



) from ethanol.

–

Sugar

The pyridinium

ion

Adenine

Sugar

Pyrophosphate

FIGURE 16.85 Nicotinamide adenine dinucleotide, NAD



16.18 Special Topic: Biological Oxidation 815

hydride

shift

Oxidized

in the

reaction

Secondary

carbocation

Tertiary

carbocation

Reduced

in the

reaction

FIGURE 16.87 Hydride shifts in

carbocations are also redox reactions.

WORKED PROBLEM 16.30 (a) Each methylene hydrogen of ethanol can be replaced

by deuterium to give a pair of chiral deuterioethanols. Show this process and indi-

cate which of the new compounds is (R) and which is (S). (b) Oxidation of (R)-

1-deuterioethanol produces deuterio-NADH (NADD) and acetaldehyde.Predict the

products of the oxidation of (S)–1–deuterioethanol with NAD



. Explain carefully.

ANSWER (a) Replacement of one methylene H with D gives the (S) enantiomer;

replacement of the other gives the (R) enantiomer.The hydrogens are enantiotopic.

This structure shows the priorities for the (

R ) compound;

the 1 ... 2 ... 3 arrow is clockwise

Replace this

hydrogen

Replace this

hydrogen

This carbon is (S)

This carbon is (R)

(b) The product will be 1-deuterioacetaldehyde. The binding site of the enzyme

is chiral and therefore the enantiotopic hydrogens are distinguishable.

reactions.The originally positive carbon is reduced and the carbon from which the

hydride moves is oxidized (Fig. 16.87).

816 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

16.19 Summary

New Concepts

The centerpiece of this chapter and its unifying theme is the

addition reaction in which nucleophiles of all kinds add to car-

bonyl groups. This process can be either acid- or base-catalyzed,

and starts with the overlap of a filled orbital on the nucleophilic

Lewis base with the empty π* orbital of the carbonyl to give an

alkoxide in which the highly electronegative oxygen atom bears

the negative charge (Fig. 16.22). The π system of the carbonyl

group is constructed through combinations of carbon and

oxygen 2p orbitals.This process leads to the π orbitals of

Figure 16.4.

Many addition reactions are equilibria, and in these cases

the position of the equilibrium depends on the relative stabili-

ties of the starting materials and products. These stabilities

depend, as always, on a variety of factors including electronic

structure, substitution pattern, and steric effects.

The close relationship between alcohols and carbonyls has

become apparent in this chapter. Oxidation of alcohols produces

the carbonyl group and reduction of the carbonyl, by hydrides

or organometallic reagents, produces the alcohol. Protecting

groups for alcohols, aldehydes, and ketones were introduced in

Section 16.10.

The concept of retrosynthetic analysis appears in this chap-

ter. Retrosynthetic analysis simply means that it is best to

approach problems of synthesis by searching not for the ulti-

mate starting material, but rather to undertake the much easier

task of finding the immediate precursor of the product. This

process can be repeated until an appropriate level of simplicity

is reached (Fig. 16.88).

Key Terms

acetal (p. 786)

benzaldehyde (p. 768)

carbinolamine (p. 790)

coenzyme (p. 814)

cyanohydrin (p. 781)

dial (p. 767)

dione (p. 768)

enamine (p. 795)

gem-diol (p. 776)

hemiacetal (p. 783)

hydrate (p. 773)

imine (p. 792)

iminium ion (p. 795)

oxaphosphetane (p. 812)

protecting group (p. 788)

retrosynthetic analysis (p. 807)

Schiff base (p. 792)

silyl ether (p. 789)

sulfone (p. 810)

sulfoxide (p. 810)

tetrahydropyranyl (THP) ether (p. 789)

Wittig reaction (p. 811)

ylide (p. 811)

Reactions, Mechanisms, and Tools

As mentioned in the New Concepts section, there is a single,

central reaction in this chapter, the addition of a nucleophile to

the Lewis acid carbonyl group.The details of the mechanism

vary, depending on whether the reaction is acid-catalyzed, base-

catalyzed, reversible, or irreversible. Here are some general

examples.

A simple case is the acid- or base-catalyzed reversible addi-

tion reaction (Fig. 16.35). Examples are hydration or cyanohy-

drin formation.

A slightly more complicated reaction involves an addition

followed by loss of water. An example is the reaction of primary

amines with carbonyl groups to give substituted imines

(Fig. 16.51).

If there is no proton that can be removed after loss of water,

a second addition reaction can occur, as in acetal formation

(Fig. 16.43).

There are also irreversible additions, as in the reactions of

organometallic reagents or metal hydrides with carbonyl com-

pounds. Protonation of the initial products, alkoxides, gives

alcohols (Fig. 16.59).

This chapter also introduces the oxidation reactions of

alcohols. These reactions involve addition reactions in their

first steps. For example, in the oxidation of primary alcohols

by CrO

, the first step is addition of the alcohol to the

chromium–oxygen double bond (Figs. 16.67 and 16.68).

The oxidation is completed by an elimination in which the

new carbon–oxygen double bond is constructed.

Target

molecule

Last

precursor

molecule

precursor

molecule

Simple

starting

material

FIGURE 16.88 Retrosynthetic analysis.

16.19 Summary 817

Syntheses

This chapter contains lots of new syntheses.

1. Acetals

2. Acids

3. Alcohols

The alkoxide is an intermediate;

LiAlH

can also be used

1. NaBH

2. H

1. RMgX or RLi

2. H

The alkoxide is an intermediate

Primary alcohols

Other oxidizing agents such as KMnO

work also.

The aldehyde and its hydrate are intermediates

CrO

Acetals can be used as protecting groups for

aldehydes and ketones; treatment with H

O/H

regenerates the aldehyde. The hemiacetal

is an intermediate

ROH

4. Aldehydes

5. Alkenes

The Wittig reaction

(Ph)

P CR

Hydrolysis of an acetal

HIO

Oxidation of a primary alcohol; water must be absent

Periodate cleavage of a vicinal diol; reaction

involves a cyclic intermediate

CrO

pyridine

OHHO

The alkoxide is an intermediate;

the R groups can be the same or different

1. NaBH

2. H

The alkoxide is an intermediate; the R groups can be

the same or different, depending on the structure of

the ketone; LiAlH

can also be used

Secondary alcohols

1. RMgX or RLi

2. H

Tertiary alcohols

1. RMgX or RLi

The product can be R

COH, R

RCOH, or

RRRCOH, depending on the structures

of the starting ketone and organometallic reagent

818 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

6. Alkylithium Reagents

7. Bisulfite Addition Products

8. Cyanohydrins

9. Disulfides

10. Enamines

11. Grignard Reagents

12. Hemiacetals

Rarely isolable; exceptions are cyclic hemiacetals,

especially sugars; the reaction usually goes

further to give the full acetal

ROH

, ROH

ROH

, ROH

ether

RRMgX

The structure of the organometallic reagent is complicated,

as RMgX is in equilibrium with other molecules; the ether

solvent is also critical to the success of the reaction

At least one

α-hydrogen must be available;

the amine must be secondary

α-Position

base

RSH RSSR

KCN

Cyanohydrin formation is more favorable

for aldehydes than for ketones

HSO

–

Also works with some ketones

–

R RLi

X = Cl, Br, or I

RLi is a simplistic picture of the reagent, which is

not monomeric

13. Hydrates

14. Hydrocarbons

15. Imines

16. Ketones

The hydrolysis of an acetal

HO OH

CrO

HIO

Many other oxidizing agents will oxidize secondary

alcohols to ketones

Periodate cleavage of a vicinal diol

involves a cyclic intermediate

RNH

This reaction works for ketones as well;

many varieties of imine are known,

depending on the structure of R in the

amine, which must be primary

RMgXRH

–

RLi RH

R X must be primary or secondary

Unstable; for ketones the starting material

is usually favored

More likely to be favored at equilibrium than

the hydrated ketones; not usually isolable