Jones M., Fleming S.A. Organic Chemistry

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19.17 Additional Problems 1029

PROBLEM 19.94

Write a mechanism for the following

transformation:

1. NaOH/H

100 ⬚C

2. H

(>90%)

PROBLEM 19.95 A synthesis of pyridines involves the conden-

sation of an α,β-unsaturated ketone (1) with a methyl ketone

(2). This reaction gives a pyrilium salt (3), which then reacts

with ammonia to produce a 2,4,6-trisubstituted pyridine.

HClO

–

ClO

Propose mechanisms for the formation of pyrilium salt 3 from the

condensation of 1 and 2, and for the formation of the pyridine 4

from 3 and ammonia. Hints: The formation of 3 occurs best when

1.5–2.0 equivalents of 1 are used.The ketone 5 is a by-product of

the condensation; how can it be formed? Think “redox.”

Use Organic Reaction Animations (ORA) to answer the

following questions:

PROBLEM 19.96 Select the reaction “Aldol condensation”

and observe the reaction that is shown. The reaction stops at

the β-hydroxy aldehyde (the aldol). What conditions are

necessary to obtain the ultimate condensation product, the

α,β-unsaturated aldehyde? Stop the reaction at the first

intermediate (the enolate) and select the HOMO track.

The enolate has an anion shared between the oxygen and the

α carbon. How does the HOMO representation of the enolate

help us understand that an electrophile adds at the carbon

rather than at the oxygen?

PROBLEM 19.97 Observe the “Mixed aldol condensation”

animation. At the first transition state, the lithium coordinates

with the enolate and with the new carbonyl species (formalde-

hyde in this case). What is the size of the ring that is formed in

this transition state? What do you suppose is the shape of the

ring? How will the shape influence the orientation of more

highly substituted enolates and carbonyl electrophiles?

PROBLEM 19.98 The reaction titled “Michael addition” is also

known as 1,4-addition or conjugate addition. Select the LUMO

track of this reaction and notice the LUMO density of the

starting α,β-unsaturated ketone (enone). Is there a large differ-

ence between the LUMO density at the β carbon and the car-

bonyl carbon? Do you think that the nucleophile does 1,2- or

1,4-addition based on the orbital shown? What controls the

regioselectivity? Which do you think would be a faster process,

1,2- or 1,4-addition? Why?

PROBLEM 19.99 Observe the “Claisen condensation” and

watch the first step closely. This step is the deprotonation of

the α hydrogen. What is the orientation of the hydrogen that

is deprotonated with respect to the carbonyl? Why? Go back

and check the deprotonation step in the “Aldol condensation”

and see if the orientation of the α hydrogen matches your

prediction.

Special Topic

Reactions Controlled

by Orbital Symmetry

1030

20.1 Preview

20.2 Concerted Reactions

20.3 Electrocyclic Reactions

20.4 Cycloaddition Reactions

20.5 Sigmatropic Shift Reactions

20.6 The Cope Rearrangement

20.7 A Molecule with a Fluxional

Structure

20.8 How to Work Orbital

Symmetry Problems

20.9 Summary

20.10 Additional Problems

CONCERTED ACTIONS In the concerted reaction called a sigmatropic shift, one part of the

molecule flies about, eventually being caught at one speficic position within the same

molecule.

20.1 Preview 1031

The fascination of what’s difficult

Has dried the sap of my veins, and rent

Spontaneous joy and natural content

Out of my heart.

—WILLIAM BUTLER YEATS,

“THE FASCINATION OF WHAT’S DIFFICULT”

20.1 Preview

In Chapters 12–14, we explored the consequences of conjugation—the sideways

overlap of 2p orbitals. That study led us to the aromatic compounds, the great sta-

bility of which can be traced to an especially favorable arrangement of electrons in

low-lying bonding molecular orbitals. It can surely be no surprise to find that tran-

sition states can also benefit energetically through delocalization, and that most of

the effects, including aromaticity, that influence the energies of ground states are

important to transition states as well.

In this chapter, we will encounter reactions that were frustratingly difficult for

chemists to understand for many, many years. By now, you are used to seeing acid-

and base-catalyzed reactions,in which an intermediate is first formed and then pro-

duces product with the regeneration of the catalytic agent. Acid-catalyzed additions

to alkenes are classic examples and there are already many other such reactions in

your notes. There is one class of reactions, however, that is extraordinarily insensi-

tive to catalysis. In these reactions, bases and acids are largely without effect. Even

the presence of solvent seems of little relevance,because the reactions proceed as well

in the gas phase as in solution. What is one to make of such reactions? How does

one describe such a mechanism? We are used to speculating on the structure of an

intermediate and then using the postulated intermediate to predict the structures of

the transition states surrounding it. In these uncatalyzed reactions the starting ma-

terial and product are separated by a single transition state (a concerted reaction),

and there is very little with which to work in developing a mechanism. Indeed, one

may legitimately ask what “mechanism” means in this context. Such processes have

been called “no-mechanism” reactions. Some, in which starting material simply

rearranges into itself (a degenerate reaction), can even be called “no-mechanism,

no-reaction, reactions.” Figure 20.1 shows an arrow formalism for a typical no-

mechanism, no-reaction, reaction.

In 1965,R.B.Woodward (1917–1979) and Roald Hoffmann (b. 1937),both then

at Harvard, began to publish a series of papers that ventured a mechanistic descrip-

tion of no-mechanism reactions, and gathered a number of these seemingly differ-

ent processes under the heading of pericyclic reactions,concerted reactions that have

a cyclic transition state. Their crucial insight that bonding overlap must be main-

tained between orbitals during the course of a concerted, pericyclic reaction now

seems so simple that you may find it difficult to see why it eluded chemists for so

many years. All we can tell you is that simple things are sometimes very hard to see,

even for very smart people.Woodward–Hoffmann theory had been approached very

closely before without the crucial “aha!”, without the lightbulb over the head turn-

ing on. Perhaps what was lacking was the ability to combine a knowledge of theory

with an awareness of the chemical problem, which is precisely what the brilliant

experimentalist Woodward and the young theorist Hoffmann brought to the

William Butler Yeats (1865–1939) was an Irish poet who received the Nobel prize for literature in 1923.

1,5-Hexadiene

Still

1,5-Hexadiene

WEB 3D

FIGURE 20.1 A single-barrier,

one-transition-state,“no-mechanism,

no-reaction” reaction.The starting

material and the product are

indistinguishable.

1032 CHAPTER 20 Reactions Controlled by Orbital Symmetry

problem.Ultimately, these papers and their progeny resulted in the chemistry Nobel

prize in 1981 for Hoffmann [together with Kenichi Fukui (1918–1998) of Kyoto],

and would probably have given Woodward his second Nobel prize, had he lived long

enough.

The reaction of the chemical community to these papers ranged from enthu-

siastic admiration to “We knew all this trivial stuff already.”We would submit that

admiration was by far the more appropriate reaction, and suspect that behind much

of the carping was a secret smiting of many foreheads.Woodward–Hoffmann the-

ory is brilliant. It not only answered long-standing and difficult questions, but it

had remarkable “legs.” Its implications run far into organic and the rest of chem-

istry, and it makes what are called risky predictions. It is important to separate

theory that merely rationalizes—that which explains known phenomena—from

theory that demands new experiments.The success of Woodward–Hoffmann the-

ory can be partly judged from the flood of experiments it generated. Of course,

not all the experiments were incisive, and not all the interpretations were appro-

priate; the area entered a rococo phase quite early on. Still, some of the

work generated by the early Woodward–Hoffmann papers stands today as an

example of the combination of theory and experiment that characterizes the best

of our science.

In this chapter, we will see electrocyclic reactions in which rings open and

close, cycloaddition reactions in which two partners come together to make a new

cyclic compound, and sigmatropic shifts in which one part of a molecule flies

about coming to rest at one specific position and no other. Specificity is the hall-

mark of all these reactions; atoms move as if in lock step in one direction or anoth-

er, or move from one place to one specific new place, but no other. The chemical

world struggled mightily to understand these mysteriously stereospecific reactions,

and, thanks to the work by Woodward, Hoffmann, and several others, finally fig-

ured it out in a marvelously simple way. This chapter will show you some won-

derful chemistry.

ESSENTIAL SKILLS AND DETAILS

1. To be able to understand the course of “no-mechanism” reactions, you need only

remember that in any concerted (one barrier, one transition state) reaction, a bonding

overlap must be maintained between orbitals.The rest is all detail.

2. The opening and closing reactions of rings—electrocyclic reactions in the jargon of this

chapter—are best understood through an analysis of the HOMO (p. 133) of the open-

chain partner. Ring closing involves only bonding interactions for allowed reactions.

3. Cycloaddition reactions require an analysis of the interactions of the HOMO and

LUMO (p. 133) of the two reacting species. Allowed reactions have two bonding

interactions between the reacting partners; “forbidden” reactions do not.

4. In sigmatropic shift reactions, one portion of a molecule detaches from one atom

and reattaches at another position of the same molecule.The transition state is best

described by an atom (or group of atoms) moving across a polyenyl radical. Once

again, an analysis of the symmetry of the HOMO of the polyenyl radical is the key

to understanding. A bonding interaction must be achieved at the arrival point for

the reaction to be allowed.

20.2 Concerted Reactions

Woodward and Hoffmann provided insights into concerted reactions.As noted on page

389, a reaction is concerted if starting material goes directly to product over a single

20.2 Concerted Reactions 1033

transition state.Such reactions are “single-barrier”processes.The S

2 and Diels–Alder

reactions are nice examples of concerted reactions you know well (Fig. 20.2).

Examples

RXNu

–

RX+Nu

Diels–Alder

–

Energy

Reaction progress

Transition

state

Products

Starting

material

FIGURE 20.2 The S

2 and

Diels–Alder reactions are concerted

processes.

Addition of HBr

–

HBr

Intermediate

Energy

Reaction progress

Transition

state 2

Transition

state 1

Intermediate

Starting

material

Products

I Br

FIGURE 20.3 The S

1 reaction and

HBr addition to an alkene are

nonconcerted reactions.

Energy

Reaction progress

Transition

state

Transition

state

FIGURE 20.4 Any nonconcerted

reaction can be separated into a

series of concerted processes.

Of course,many reactions involve intermediates, and in these reactions more than

one transition state is traversed on the way from starting material to product. As

noted previously, these are called nonconcerted or stepwise reactions.Typical exam-

ples are the S

1 reaction or the polar addition of HBr to an alkene, two reactions

that go through the same intermediate, the tert-butyl cation (Fig. 20.3).

It is important to recognize that nonconcerted reactions are made up of series

of single-barrier, concerted reactions, each of which could be analyzed indepen-

dently of whatever other reactions followed or preceded (Fig. 20.4).

1034 CHAPTER 20 Reactions Controlled by Orbital Symmetry

COOCH

OOC

A cis 3,4-disubstituted

cyclobutene

COOCH

OOC

A cis,trans 1,3-butadiene

cistrans

FIGURE 20.5 The thermal opening

of a cyclobutene to a 1,3-butadiene.

The cis disubstituted cyclobutene

rearranges to the cis,trans butadiene.

Woodward and Hoffmann offered explanations of why some reactions are con-

certed and others not. They found a way to analyze reactions by determining the

pathways required to maintain bonding interactions between orbital lobes as the reac-

tion progressed. They used orbital symmetry and the aromaticity of the transition

state in their analysis. The following sections take up some examples in which

Woodward–Hoffmann theory is particularly useful.

20.3 Electrocyclic Reactions

In 1957, a young German chemist named Emanuel Vogel (b. 1927) was finding

his way through the labyrinth of the German academic system, working on the

experiments necessary for an entrance ticket for a position at a German univer-

sity: a super Ph.D. degree called the “Habilitation.” His topic included the ther-

mal rearrangements of cyclobutenes. Although cyclobutene had been studied by

R. Willstätter (1872–1942, Nobel prize in 1915) as early as 1905, and although

the rearrangement to 1,3-butadiene was noted by the American chemist John D.

Roberts (b. 1918) in 1949, only Vogel was alert enough to notice the startling

stereospecificity of the thermal reaction. For example, the cis 3,4-disubstituted

cyclobutene shown in Figure 20.5 rearranges only to the cis,trans 1,3-butadiene

and no other stereoisomer.

The arrow formalism of Figure 20.5 is easy to write, but the stereochemical

outcome of the reaction is anything but obviously predictable. It’s worthwhile to

see exactly why. There are three possible stereoisomers of the product (Fig. 20.6),

and a naive observer would certainly be forgiven for assuming that thermodynamic

considerations would dictate the formation of the most energetically favorable

isomer, the trans,trans diene, in which the large ester groups are as far apart as

possible. Notice that the opening of the cyclobutenes must initially give the

dienes in their s-cis conformations rather than in the lower energy s-trans arrange-

ments. Of course,the s-cis molecules will rapidly rotate to the lower energy s-trans

conformations.

E = COOCH

E = entgegen

cis,cis or (Z,Z)

cis,trans or (Z,E)

Thermodynamic stability

trans,trans or (E,E)

s-cis

Forms

s-trans

Forms

rotate rotate rotate

FIGURE 20.6 The three possible

stereoisomers of the diene product

for the reaction shown in Figure 20.5.

Only one, the cis,trans diene of

intermediate thermodynamic

stability, is formed in the reaction.

WEB 3D

20.3 Electrocyclic Reactions 1035

As Vogel first found, and as others showed later for many other systems, forma-

tion of the trans,trans diene is not the actual result at all; nor is the reaction stereo-

random, as only a single stereoisomer is formed. Vogel well understood that this

reaction was rather desperately trying to tell us something. In the intervening years,

many similar reactions were found and many a seminar hour was spent in a fruit-

less search for the explanation. What the reaction had to say to us waited for the

papers of Woodward and Hoffmann.

Remarkably, it was discovered that the stereochemical outcome of the reac-

tion was dependent on the energy source. Heat gave one stereochemical result

and light another. Figure 20.7 sums up the results of the thermal and photochem-

ical interconversions of cyclobutenes and butadienes. In the thermal reaction, a cis

3,4-disubstituted cyclobutene yields the cis,trans diene. By contrast, in the photo-

chemical process the same cis cyclobutene yields a pair of molecules,the cis,cis diene

and the trans,trans diene.

THE GENERAL CASE

SPECIFIC EXAMPLES

R +

trans,cis

trans,trans cis,cis

cis

cis cis,cis

trans

hν

cis,trans trans,trans

(0.005%)

(99.995%)

hν

WEB 3DWEB 3D

FIGURE 20.7 The stereochemical outcomes of the thermal and photochemical reactions of

cyclobutenes and butadienes are different.

Notice that the cis disubstituted cyclobutene can be converted into the trans

disubstituted cyclobutene through a thermal reaction and a photochemical reaction

(Fig. 20.7). Regardless of the starting material, the thermal reaction favors the more

stable 1,3-butadiene. The photochemical process, depending on the wavelength of

light used, favors the less stable cyclobutene.

1036 CHAPTER 20 Reactions Controlled by Orbital Symmetry

Energy

π*

σ*

HOMO

butadiene

FIGURE 20.8 The molecular orbitals involved in the

interconversion of cyclobutene and butadiene.

Let’s start our analysis by thinking about the thermal opening of cyclobutene

to 1,3-butadiene. Here is a general practical hint. It is usually easier to analyze

these thermal or photochemical processes, called electrocyclic reactions,by exam-

ining the open-chain polyene partner, regardless of which way the reaction actual-

ly runs. Figure 20.8 shows the molecular orbitals involved in the cyclobutene to

butadiene interconversion. The four π molecular orbitals of 1,3-butadiene are

converted into the σ, σ*, π, and π* orbitals of cyclobutene. Now comes a most

important point. The HOMO of the system controls the course of electrocyclic reac-

tions. This assumption is not ultimately necessary, but it makes predicting the

products of these reactions very easy—and it works! It derives from the aro-

maticity of the transition state, and it can be defended in the following way. It

is the electrons of highest energy, the valence electrons located in the highest

energy orbital, that control the course of atomic reactions, and it should be no

surprise that the same is true for molecular reactions. To do a complete analy-

sis of any reaction, atomic or molecular, we really should follow the changes in

energy of all electrons. That process is difficult or impossible in all but a very

few simple reactions. Accordingly, theorists have sought out simplifying

assumptions, one of which says that the highest energy electrons, those most

loosely held, are most important in the reaction. These are the electrons in the

HOMO. The HOMO of butadiene is

, and we assume that it is the con-

trolling molecular orbital. Now ask how

must move as 1,3-butadiene

becomes cyclobutene. Don’t worry that we are analyzing the reaction in the

counterthermodynamic sense. If we know about the path in one direction, we

know about the path in the other direction as well. In order to create the ring-

forming bond between the butadiene end carbons, the p orbitals on the end car-

bons must rotate 90°, and this rotation must be in a fashion that creates a bond (σ)

20.3 Electrocyclic Reactions 1037

between the atoms, not an antibond (σ*) (Fig. 20.9).There are four possible rota-

tions we can consider: both p orbitals clockwise, both counterclockwise, left one

clockwise and right counterclockwise, and left one counterclockwise and right

one clockwise.

Now look at the symmetry of the end orbitals of

, the controlling HOMO

of butadiene. There are two ways to make a bond: in one the blue lobes overlap, in

the other it is the green lobes that overlap (Fig. 20.10). In each case we have creat-

ed a bonding interaction. In this example, the blue/blue overlap requires that the

two ends of the molecule rotate in a clockwise fashion. The green/green overlap

requires that the two ends rotate counterclockwise.

Antibonding

not ok

rotate

Antibonding

not ok

rotate

Bonding

End lobes of

the HOMO, Φ

rotate

FIGURE 20.9 In the interconversion

of cyclobutene and butadiene, the

orbitals at the end of the diene must

rotate so as to form a bond, not an

antibond.

conrotation

(both lobes

clockwise)

conrotation

(both lobes

counter-

clockwise)

Bonding

counter-

clockwise

counter-

clockwise

clockwiseclockwise

FIGURE 20.10 Formation of a

bonding interaction requires what is

called conrotation of the ends of the

diene.There are two, equivalent

conrotatory modes.

disrotation

Antibonding!

counter-

clockwise

counter-

clockwise

FIGURE 20.11 Disrotation creates an

antibonding interaction between the

lobes at the ends of the diene.

Neither of the two possible

disrotatory modes can be a favorable

process for butadiene.

These two modes of rotation,in which the two ends rotate in the same direction,

are called conrotatory motions, and the whole process is known as conrotation.

There is another rotatory mode possible, called disrotation, in which the two

ends of the molecule rotate in different directions. Figure 20.11 shows the two pos-

sible disrotatory motions. In both, an antibond, not a bond, is created between the

two end carbons. Disrotation cannot be a favorable process in this case.

An electrocyclic reaction is as easy to analyze as that. Identify the HOMO, and

then see whether conrotatory or disrotatory motion is demanded of the end carbons

by the lobes of that molecular orbital. All electrocyclic reactions can be understood

in this same simple way. The theory tells us that the thermal interconversion of

cyclobutene and 1,3-butadiene must take place in a conrotatory way. For the

cyclobutene studied by Vogel, conrotation requires the stereochemical relationship

that he observed. The cis 3,4-disubstituted cyclobutene can only open in conrota-

tory fashion, and conrotation forces the formation of the cis,trans diene. Note that

there are always two possible conrotatory modes (Fig. 20.12), either one giving the

same product in this case.

1038 CHAPTER 20 Reactions Controlled by Orbital Symmetry

Same molecule!

COOCH

OOC

COOCH

trans,cis

OOC

conrotation

OOC

COOCH

cis,trans

OOC

conrotation

COOCH

FIGURE 20.12 For the cis

disubstituted cyclobutene studied

by Vogel, both conrotatory modes

demand the formation of the diene

with one cis and one trans double

bond.

WORKED PROBLEM 20.1 Show through an equivalent analysis that a mixture of

the cis,cis and trans,trans dienes should be formed in the thermal opening of trans

3,4-disubstituted cyclobutenes.

ANSWER Because the opening takes place thermally, it must be conrotatory.

There are two conrotatory modes for the trans compound. One leads to the cis,cis

(Z,Z) isomer and the other to the trans,trans (E,E) isomer.

cis,cis (Z,Z)

conrotation

trans,trans (E,E)

conrotation

trans Substituted

cyclobutene

Now what about the photochemical reaction? Look again at the molecular

orbitals of 1,3-butadiene (Fig. 20.8). Recall that absorption of a photon pro-

motes an electron from the HOMO to the LUMO (p. 528), in this case from