Jones M., Fleming S.A. Organic Chemistry

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5.6 Disubstituted Ring Compounds 209

and chemical properties. In principle, each could be isolated and resolved. So there

is a total of four possible cis isomers, the two shown in Figure 5.42 and their mir-

ror images (Fig. 5.43).

Mirror

CH(CH

)

CH(CH

)

(CH

)

flip

CH(CH

)

FIGURE 5.43 The four stereoisomers

of cis-1-isopropyl-2-methyl-

cyclohexane. Two pairs of

enantiomers exist.

The rigid molecule cis-1-isopropyl-2-methylcyclopropane cannot undergo any

ring flip, and there is only a single pair of enantiomers. The lack of a possible ring

flip reduces the total number of possible stereoisomers (Fig. 5.44).

Mirror

CH(CH

)

(CH

)

FIGURE 5.44 The two enantiomers of

cis-1-isopropyl-2-methylcyclopropane.

The rigid ring prevents any ring flip.

Mirror

CH(CH

)

(CH

)

FIGURE 5.45 The single pair of enantiomers

of trans-1-isopropyl-2-methylcyclopropane.

Again, the rigid cyclopropane ring prevents

any ring flip.

PROBLEM 5.18 Label the stereogenic carbons of Figures 5.43 and 5.44 as (R) or (S).

The situation is similar in the case of the trans form.

Although the inflexible cyclopropane ring has but a sin-

gle pair of enantiomers (Fig. 5.45), there are two pairs of

enantiomers in the flexible cyclohexane (Fig. 5.46).

Mirror

CH(CH

)

CH(CH

)

(CH

)

flip

CH(CH

)

FIGURE 5.46 The four stereoisomers of trans-1-isopropyl-2-

methylcyclohexane. Two pairs of enantiomers exist.

210 CHAPTER 5 Rings

PROBLEM 5.19 Point out the pairs of enantiomers and diastereomers in Figure

5.46. Assign all the stereogenic carbons as (R) or (S).

WORKED PROBLEM 5.20 Use the data of Table 5.3 (p. 202) to estimate the energy

difference between (a) the two chair forms of cis-1-isopropyl-2-methylcyclohexane

and (b) the two chair forms of trans-1-isopropyl-2-methylcyclopropane.

ANSWER (a) For the cis compound, ring flipping converts A with an axial iso-

propyl group and an equatorial methyl group into B in which the isopropyl group

is equatorial and the methyl is axial. Table 5.3 tells you that an isopropyl group is

more stable in the equatorial position by 2.61 kcal/mol. A methyl group is more

stable in the equatorial position by only 1.74 kcal/mol. The more stable confor-

mation will be B by (2.61  1.74) kcal/mol  0.87 kcal/mol.

(b) The trans compound has both groups axial (C) or both groups equatorial (D).

Conformation D will be preferred by (2.61  1.74) kcal/mol  4.35 kcal/mol.

However, D suffers a methyl–isopropyl gauche interaction that will be destabiliz-

ing by somewhat more than 0.6 kcal/mol. So, our final answer would be approx-

imately (4.35  0.6) kcal/mol  3.75 kcal/mol.

Equatorial group Equatorial group

cis

ring flip

CH(CH

)

Axial groupAxial group

CH(CH

)

Axial group

Equatorial groups

trans

CH(CH

)

CH(CH

)

ring flip

PROBLEM 5.21 Estimate the energy difference between the two conformational

isomers of cis-1,3-dimethylcyclohexane.

PROBLEM 5.22 Does ring flip racemize trans-1,3-dimethylcyclohexane, as it does

cis-1,2-dimethylcyclohexane (Fig. 5.39, p. 207)?

Summary

The “take-home lesson” here is that it takes a careful analysis of the stereoiso-

mers formed by ring flipping of substituted cyclohexanes to see all the possibil-

ities.First,be sure you have made a good drawing (follow the procedure on p. 190).

Next, determine whether or not the isomer is chiral by drawing the mirror image

and seeing if it is superimposable on the original. Now do a ring flip of the orig-

inal isomer. Is the ring-flipped isomer the same as the original? Is it the mirror

image? Is it completely different? Differently substituted cyclohexanes give all

three possibilities.

5.7 Bicyclic Compounds 211

5.7 Bicyclic Compounds

Now that we have dealt with both simple and complicated cycloalkanes (molecules con-

taining a single ring), it is time to look briefly at molecules containing more than one

ring. We have met such structures before, in both Chapter 2 (p. 85) and Chapter 3

(p. 121).

Of course,one can imagine all sorts of molecules containing two separated rings.

There is nothing special about such molecules. However, there are other molecules

in which two rings share a carbon or carbons, and these compounds are more inter-

esting. There are three general ways in which two rings can be connected by shar-

ing carbons.They can share a single carbon,two carbons, or more than two carbons.

These modes of attachment are called spiro (one carbon shared), fused bicyclic

(two carbons shared), and bridged bicyclic (more than two carbons shared). Fused

is really a special case of bridged, with n  0 (Fig. 5.47).

Fused substitution

(two carbons are

shared)

Fused bicyclic

Bridged substitution

(more than two carbons

are shared; if n = 0,

the molecule is fused)

(CH

)

Bridged bicyclic

Spiro substitution

(one carbon is shared)

Spiro

FIGURE 5.47 Rings can share a single

carbon (spiro), two carbons (fused

bicyclic), or more than two carbons

(bridged bicyclic).

C C

The two-dimensional

picture of spiropentane

is highly misleading…

…because the central

carbon must look like

this…nearly tetrahedral

…the two rings

must lie in different,

perpendicular planes

FIGURE 5.48 A two-dimensional

picture of spiropentane is misleading.

The two rings lie in perpendicular

planes.

WEB 3D

A [5]triangulane Tricyclo[4.1.0.0

4,6

]heptane

Bakkenolide-A

Agarospirol

FIGURE 5.49 Some spiro compounds. Don’t worry about the exotic names.

Spiro substitution is common in both natural products and in molecules so

far encountered only in the laboratory. Note in Figure 5.48 how poorly a two-

dimensional picture represents the real shape of such molecules. Even the sim-

plest spirocyclic compound, spiropentane, is badly served by the flat page. The

central carbon is approximately tetrahedral,and we really must use wedges to give

a three-dimensional feel to this kind of molecule.

Figure 5.49 shows some “natural” (the first two compounds) and “unnatural”

(the second two compounds) spiro compounds. Of course, the distinction is purely

formal—the chemical laboratory is part of Nature.

212 CHAPTER 5 Rings

Bicyclic molecules in which two rings share two or more carbons are even

more important than the spirocyclic compounds. The simplest way in which two

rings can share more than one carbon is for two adjacent carbons to be shared

in a fused structure. The “fusion” positions, or “bridgeheads” (p. 121), are shown

in red (Fig. 5.50).

FIGURE 5.50 Some schematic, two-

dimensional structures for fused

bicyclic compounds in which two

rings share a pair of adjacent carbon

atoms.

WEB 3D

Aflatoxin B

(very toxic)

trans Ring fusion

Cortisone (anti-inflammatory agent)

trans Ring fusion

cis Ring fusion

OCH

FIGURE 5.51 Two fused polycyclic

molecules. Note the cis and trans ring

fusions.

The hydrogens attached at the ring junction,or fusion positions, can be either

on the same side (cis) or on opposite sides (trans). In practice, both stereo-

chemistries are possible for larger rings, but for the small rings only the cis form

is stable (see Problem 5.23). Figure 5.51 shows two compounds that contain

fused rings.

PROBLEM 5.23 Use your models to convince yourself that trans stereochemistry

is not possible for the three molecules on the left of Figure 5.50.

Particularly important are cis- and trans-decalin, the compounds formed by

the fusion of two cyclohexanes. Although Figure 5.52 shows these compounds

in schematic form, by now we can certainly guess that the real shape will be

much more intricate. It’s easy enough to draw them though, if one goes about

it carefully.

Decalin

Schematic picture of

cis-decalin

Schematic picture of

trans-decalin

FIGURE 5.52 In decalin, the two

hydrogens at the bridgeheads can be

either on the same side of the rings

(cis), or on opposite sides (trans).

5.7 Bicyclic Compounds 213

For trans-decalin first draw a single, perfect chair cyclohexane, and put in the

axial and equatorial bonds at two adjacent carbons (Fig 5.53a). As for any trans di-

substituted cyclohexane (p.207), the two rings of trans-decalin will be attached either

through two equatorial bonds or through two axial bonds.As shown in Figure 5.53b,

attachment through two axial bonds is impossible—the distance to be bridged is too

great (try it with models).So we are left with only the two equatorial bonds for trans

(b)

(a)

FIGURE 5.53 A futile attempt to construct

trans-decalin by connecting two axial carbons

with a pair of methylene groups. It is not

possible to span the two axial positions with

only four methylene groups; two methylene

groups occupy axial positions leaving only two

others (blue) to complete the ring.

attachment of a second ring, and this time the new chair fits in easily. trans-Decalin

can be made by connecting two adjacent equatorial positions through a chain of four

methylene groups (Fig. 5.54).

It is ea

sy to

conne

ct tw

equa

toria

positions w

ith a ch

ain of four

ethy

lenes;

the hydrog

ens a

t the

fusion

positi

ons (b

ridgeh

eads)

must be axial

trans-D

eca

lin:

o fu

sed c

hair

cyclo

hexan

WEB 3D

FIGURE 5.54 trans-Decalin.

To m

ake a

cis junc

tion w

ust connect one

axial

and

one equato

rial po

sitio

n w

ith a

four-c

arbon

chain

cis-Decalin

The two bridgehead

hydrogens occupy

one axial and one

equatorial position

WEB 3D

FIGURE 5.55 cis-Decalin.

cis-Decalin is quite different because cis substitution must involve one axial and

one equatorial bond in the attachments to the second ring (Fig.5.55). If we pay atten-

tion to the rules for drawing perfect chairs, it’s easy to produce a good drawing for

this molecule. Remember that every ring bond in a cyclohexane is parallel to the

bond directly across the ring (p. 191).

PROBLEM 5.24 Use models to convince yourself that cis-decalin is a mobile mol-

ecule, undergoing easy double chair–double chair interconversions, whereas trans-

decalin is rigidly locked.

214 CHAPTER 5 Rings

Now imagine two rings sharing three carbons in a bridged bicyclic molecule.

Two cyclopentanes, for example, can share two or three carbons. We have seen

the first case before (Fig. 5.50) and the second is drawn in Figure 5.56. In each

case, the carbons at the fusion points are called the bridgehead positions (p. 121).

Bridgehead position

FIGURE 5.56 Two five-membered

rings sharing three carbons.The

shared carbons are shown in red.

WEB 3D

Lycopodine

Calicheamicin

Several

sugars

NHCOOCH

β-Pinene

FIGURE 5.57 Three naturally occurring bicyclic molecules.The

shared carbons are highlighted in red.

The shared carbons are shown in red in Figure 5.56; the carbon–carbon bonds in

blue complete one cyclopentane. A more complete structure for this bicyclic hydro-

carbon is also shown. Such bridged molecules are extremely common. Three com-

pounds found in Nature are shown in Figure 5.57.

WORKED PROBLEM 5.25 Design a molecule in which two rings share four carbons.

ANSWER One sure-fire way to do a problem such as this is to start by drawing the car-

bons to be shared (four, in this example).Then add the remainders of the other rings.

Here they are incorporated

into another ring

Here are those four

carbons incorporated

into one ring

The four

carbons to

be shared

FIGURE 5.58 Part of the naming protocol for a

typical bicyclic compound.

CONVENTION ALERT

Bicyclic compounds are named in the following way: One first counts the number

of carbons in the ring system. The molecule in Figure 5.58 has eight ring carbons.

5.7 Bicyclic Compounds 215

Thus the base name is “octane.” The molecule is numbered by counting from the

bridgehead carbon [carbon number 1, C(1)] around the longest bridge first,proceed-

ing to the other bridgehead. One then continues counting around the second-longest

bridge,and finally numbers the shortest bridge. Any substituents can now be assigned

a number. So the compound in Figure 5.58 is a 3,3-dimethylbicyclooctane.

The bridges are counted from the bridgeheads and assigned numbers equal to the

number of atoms in the bridges, not counting the bridgehead atoms. These numbers are

enclosed in brackets,largest number first,between the designation “bicyclo”and the rest

of the name (Fig. 5.59). So this compound is called 3,3-dimethylbicyclo[3.2.1]octane.

(a) (b) (c) (d) (e)

1-Atom

bridge

3-Atom

bridge

3,3-Dimethylbicyclo[3.2.1]octane

2-Atom

bridge

FIGURE 5.59 More of the naming

protocol for bridged bicyclic

compounds.This molecule is 3,3-

dimethylbicyclo[3.2.1]octane. The

red dots show the bridgehead atoms.

These are not counted in sizing the

bridges, but are counted in

numbering the compound.

PROBLEM 5.26 Make drawings of (a) cis-bicyclo[3.3.0]octane, (b) 1-fluorobicy-

clo[2.2.2]octane, (c) trans-9,9-dimethylbicyclo[6.1.0]nonane.

PROBLEM 5.27 Name the following compounds:

PROBLEM 5.28 How many signals would appear in the

C NMR spectrum for

each of the molecules in Problem 5.27?

As with 1,2-fused systems, we must worry about the stereochemistry at the

bridgehead positions in bridged molecules. At first,this task may seem trivial—where

could these hydrogens be but where they are shown in the figures? The answer is,

“inside the cage!” In the compounds we have already examined, it is not easy for

hydrogens to occupy the inside position. As shown in Figure 5.60, all four bonds of

one or both of the bridgehead carbons of bicyclo[3.2.1]octane would be pointing

in the same direction if one or both bridgehead hydrogens were inside the cage.

“Out, out” bicyclo[3.2.1]octane

“In, out” bicyclo[3.2.1]octane

Side view of “in, out”

bicyclo[3.2.1]octane

as seen by the eye

“In, in” bicyclo[3.2.1]octane

FIGURE 5.60 Three stereoisomers of bicyclo[3.2.1]octane.

Only the “out, out” isomer is known.

216 CHAPTER 5 Rings

But now imagine increasing the size of the bridges. In principle, it should be pos-

sible to make the bridge chains long enough so that a normal, nearly tetrahedral,

arrangement can be achieved with one or both bridgehead hydrogens inside the cage

(Fig. 5.61). And so it is.The molecules shown in Figure 5.62 are both known, as are

several other examples.

FIGURE 5.61 If the bridges are long

enough, there is no angle strain in an

“in, out” isomer.

WEB 3D

(CH

)

(CH

)

(CH

)

FIGURE 5.62 Two known “in” or “in, out” compounds.

5.8 Special Topic: Polycyclic Systems

We needn’t stop here. More rings can be attached in fused or bridged fashion to pro-

duce wondrously complex structures.The naming protocols are complicated,if ultimate-

ly logical, and won’t be covered here.Many of the compounds have common names that

are meant to be evocative of their shapes.Prismane and cubane are examples.The molec-

ular versions of the Platonic solids, tetrahedrane, cubane, and dodecahedrane are all

known,although the parent,unsubstituted tetrahedrane still evades synthesis (Fig.5.63).

Tetra-tert-butyltetrahedrane

Cholesterol

a polycyclic compound

a steroid

Cubane

Dodecahedrane

Prismane

C(CH

)

C(CH

)

C(CH

)

(CH

)

FIGURE 5.63 Polycyclic natural

(cholesterol) and “unnatural” (the

rest) products.

WEB 3D

Tricyclo[1.1.1.0

1,3

]pentane

([1.1.1]propellane)

WEB 3D

Bicyclo[1.1.1]pentane

FIGURE 5.64 Two polycyclic small

ring compounds.

Spectacular new molecules containing rings are always appearing. In 1984,

Professor Kenneth B.Wiberg (b. 1927) of Yale University reported the construction

of the polycyclic molecule, tricyclo[1.1.1.0

1,3

]pentane (also known as [1.1.1]propel-

lane, Fig. 5.64), a marvelously exciting molecule.You are now only five chapters into

your study of organic chemistry, yet it is possible for you to appreciate why the chem-

ical world was knocked out by this compound.

5.9 Special Topic: Adamantanes in Materials and Biology 217

PROBLEM 5.29 Why is tricyclo[1.1.1.0

1,3

]pentane unusual (Fig. 5.64)? Would

you expect it to be especially stable or unstable with respect to its cousin bicy-

clo[1.1.1]pentane? Why?

Wiberg’s molecule was synthesized in a chemistry laboratory, and probably (?)

does not occur in Nature. Nature is by no means played out as a source of fasci-

nating polycyclic molecules, however. For example, in 2003 Sanae Furuya and

Shiro Terashima reported the synthesis of optically active tricycloillinone, a mol-

ecule isolated from the wood of Illicium tashiori (Fig. 5.65). This molecule

enhances the activity of choline acetyltransferase, an agent that catalyzes the syn-

thesis of acetylcholine. Why should we care about tricycloillinone? A form of

senile dementia (Alzheimer’s disease) is associated with reduced levels of acetyl-

choline, and a molecule that might be useful in increasing levels of acetylcholine

is of obvious importance to all of us.

FIGURE 5.65 Tricycloillinone.

o-Carborane

The dots are carbons; every

other vertex is a boron. There is a

hydrogen atom at every vertex

CARBORANES: WEIRD BONDING

or six bonds, the dreaded red “X” is sure to follow. How does

Nature get away with it? If you did Problems 1.62 and 1.63,

you encountered triangular H

, and H



, molecules related

to the carboranes in that they, too, contain “too many”

bonds, in this case, two bonds to hydrogen. The answer to

this seeming impossibility is that those bonds are not the

simple two-electron bonds we are becoming used to, but

partial bonds containing fewer than two electrons.

Far from being “weird” and thus presumably exotic in

properties, the carboranes are almost unbelievably stable

compounds, sitting in bottles seemingly forever, and show-

ing a rich history and chemistry. Professor William

Lipscomb (b. 1919) won the Nobel Prize for chemistry in

1976 for explaining the bonding in carboranes. They are

now being used in both medicinal chemistry and materials

science. In Japan, for example, carboranes are used in

treating certain brain tumors in “Boron-neutron capture

therapy.” However, it must be admitted that the practical

development of these compounds was slow to happen.

Why? Perhaps we chemists were wary of all those

potential red X’s, sure to arrive if we drew too many bonds

to carbon!

As you’ve seen in this chapter, ring compounds can be

straightforward (cyclopentane, p. 190, is a nice example),

moderately complex (the mobile cyclohexanes, p. 197), or

exotic ([1.1.1]propellane, p. 216). Here is a compound that

surely qualifies as exotic, if not downright weird. It is com-

posed of two carbons (the dots) and ten borons (the other

10 vertices), and contains no fewer than 20 three-membered

rings of carbons and borons. Why “weird?” Count the bonds

to carbon. There are six bonds emanating from the carbon!

Six bonds? How can that be? If you draw a carbon with five

5.9 Special Topic: Adamantanes in

Materials and Biology

Consider constructing a polycyclic molecule by expanding a chair cyclohexane.

First, connect three of the axial bonds to a cap consisting of three methylene

(CH

) groups all connected to a single methine (CH) group. This process

218 CHAPTER 5 Rings

produces the beautiful molecule tricyclo[3.3.1.1

3,7

]decane, better known as

“adamantane,” C

(Fig. 5.66).

Chair

cyclohexane

Add three methylene

groups

Cap with a CH Adamantane

)

FIGURE 5.66 A schematic

construction of the polycyclic

molecule adamantane.

(a)

(b)

(c)

(d)

FIGURE 5.67 Adamantane is

composed entirely of chair

cyclohexanes. Those in (a) and (b) are

easy to see as chairs, but those in (c)

and (d) may require the use of

models.

As Figure 5.67 shows,adamantane is composed entirely of perfect chair six-mem-

bered rings. As you would expect, this molecule is nearly strain-free and constitutes

the thermodynamic minimum for all the C

isomers.

WEB 3D

DiamantaneAdamantane

Triamantane

One isomer of tetramantane

cap

FIGURE 5.68 The continuation

of the capping process leads to

polyadamantanes and, ultimately,

to diamond.

Adamantane was first found in the 1930s in trace amounts in petroleum residues

by the Czech chemist Stanislav Landa (1898–1981), but it can now be made easi-

ly in quantity by a simple process discovered by the American chemist Paul von R.

Schleyer (b. 1930).

Consider what happens when we continue the capping process begun in our

transformation of chair cyclohexane into adamantane in Figure 5.66. Adamantane

itself is composed of only chair cyclohexanes, so we have a number of possible

places to start the process (Fig. 5.68). Addition of one more four-carbon cap