Vollhardt  Capítulo 6 (Haloalcanos)
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Vollhardt Capítulo 6 (Haloalcanos)

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marked effect on anti-infl ammatory potency. Fluticasone is
one of a growing number of synthetic pharmaceuticals in
which replacement of hydrogen by fl uorine either generates
novel therapeutic behavior or enhances properties already
present. As the smallest element in the second row of the

periodic table, fl uorine is closest in size to hydrogen. There-
fore, fl uorine-containing molecules are sterically similar to
their natural unsubstituted counterparts and can often interact
with the same biomolecules in living systems. In addition,
the highly polarized C–F bonds can induce dipole attractions
that strengthen these interactions. In the case of fl uti casone,
the steroid binds to a protein residing in cell nuclei called
the glucocorticoid receptor, thereby interrupting the body’s
infl ammatory response.

An international study published in early 2004 found
that fl uticasone was effective in reducing asthma-inducing
infl ammation in babies from one to three years of age, while
having no signifi cant effect on their growth. Nevertheless,
the biochemistry of the glucocorticoid receptor is complex —
it does much more than just mediate infl ammation — and the
search continues for new synthetics whose interaction with
the receptor will be more specifi c and will not interfere with
the receptor’s other, essential biological functions. Further-
more, synthetic corticosteroids are medically useful for a
number of other conditions, including infl ammatory bowel
disease and transplant rejection, for which oral administra-
tion is preferable. Thus, the design of variants that will
prove to be safe for use in this way is an active area of
current research as well.

SCH2F
O CCH2CH3O

B

Cortisol

% ∞ ∞

~
%

%HO

O

H3C

H3C

Fluticasone propionate

%

%

%HO

F

O

OH3C

H3C

CH3≥

F
≥

OH
O O

OH

Applications and Hazards of Haloalkanes: “Greener” Alternatives
The properties of haloalkanes have made this class of compounds a rich source of com-
mercially useful substances. For example, fully halogenated liquid bromomethanes, such as
CBrF3 and CBrClF2 (“Halons”), are extremely effective fi re retardants. Heat-induced cleav-
age of the weak C–Br bond releases bromine atoms, which suppress combustion by inhibit-
ing the free-radical chain reactions occurring in fl ames (see Chapter 3, Problem 40). Like
Freon refrigerants, however, bromoalkanes are ozone depleting (Section 3-9) and have been
banned for all uses except fi re-suppression systems in aircraft engines. Phosphorus tribro-
mide, PBr3, a non-ozone-depleting liquid with a high weight percent of bromine, is a promis-
ing replacement. In 2006, a PBr3-based fi re-suppression cartridge system (under the trade
name PhostrEx™) was approved by both the U.S. Environmental Protection Agency (EPA)
and the U.S. Federal Aviation Administration (FAA). It is now in commercial use in the
Eclipse 500 jet aircraft.

The polarity of the carbon – halogen bond makes haloalkanes useful for applications such as
dry cleaning of clothing and degreasing of mechanical and electronic components. Alternatives

The Eclipse 500 jet over San
Francisco.

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218 C h a p t e r 6 P r o p e r t i e s a n d R e a c t i o n s o f H a l o a l k a n e s

for these purposes include fl uorinated solvents such as 1,1,1,2,2,3,4,5,5,5-decafluoropentane
(CF3CF2CHFCHFCF3), a DuPont™ product that does not decompose to release ozone-
destroying halogen atoms because the C–F bond is strong. This solvent is safe, stable, usable
for a wide variety of industrial functions, and may be readily recovered and recycled. Prob-
lem 50 introduces yet another class of “green” solvents — ionic liquids — that are revolutioniz ing
industrial chemistry.

In Summary The halogen orbitals become increasingly diffuse along the series F, Cl, Br, I.
Hence, (1) the C–X bond strength decreases; (2) the C – X bond becomes longer; (3) for
the same R, the boiling points increase; (4) the polarizability of X becomes greater; and
(5) London interactions increase. We shall see next that these interrelated effects also play
an important role in the reactions of haloalkanes.

6-2 Nucleophilic Substitution
Haloalkanes contain an electrophilic carbon atom, which may react with nucleophiles —
substances that contain an unshared electron pair. The nucleophile can be an anion, such
as hydroxide (2:O

..
. . H), or a neutral species, such as ammonia (:NH3). In this process, which

we call nucleophilic substitution, the reagent attacks the haloalkane and replaces the
halide. A great many species are transformed in this way, particularly in solution. The reac-
tion occurs widely in nature and can be controlled effectively even on an industrial scale.
Let us see how it works in detail.

Nucleophiles attack electrophilic centers
The nucleophilic substitution of a haloalkane is described by either of two general equations.
Recall (Section 2-2) that the curved arrows denote electron-pair movement.

Nucleophilic Substitutions
����

š�ðð�
�� �R X š�ððXNu

Nucleophile

Electrophile

O R NuO

R NuO

Leaving group

š�ðð
�� �R X š�ððXNu

Nucleophile

Electrophile

O [

]�
Leaving group

����

Negative nucleophile
gives neutral product

Neutral nucleophile
gives positively
charged product
(as a salt)

In the fi rst example, a negatively charged nucleophile reacts with a haloalkane to yield
a neutral substitution product. In the second example, an uncharged Nu produces a posi-
tively charged product, which, together with the counterion, constitutes a salt. In both cases,
the group displaced is the halide ion, :X

..
. . :

2, which is called the leaving group. We shall
see later that there are leaving groups other than :X

..
. . :

2. Specifi c examples of these two types
of nucleophilic substitution are shown in Table 6-3. As will be the case in many equations
and mechanisms that follow, nucleophiles, electrophiles, and leaving groups are shown here
in red, blue, and green, respectively. The general term substrate (substratus, Latin, to have
been subjected) is applied to the organic starting material — in this case, the haloalkane — that
is the target of attack by a nucleophile.

Nucleophilic substitution exhibits considerable diversity
Nucleophilic substitution changes the functional group in a molecule. A great many nucleo-
philes are available to participate in this process; therefore, a wide variety of new molecules
are accessible through substitution. Note that Table 6-3 depicts only primary and secondary
halides. In Chapter 7 we shall see that tertiary substrates behave differently toward these

REACTION

Color code
Nucleophiles: red
Electrophiles: blue
Leaving groups: green

Inhalation anesthetics such as
 halothane, CF3CHBrCl, derive their
biological activity from the polar
nature of their C–X bonds.

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 C h a p t e r 6 219

nucleophiles and that secondary halides may sometimes give other products as well. Methyl
and primary haloalkanes give the “cleanest” substitutions, relatively free of side products.

Let us inspect these transformations in greater detail. In reaction 1, a hydroxide ion,
typically derived from sodium or potassium hydroxide, displaces chloride from chloromethane
to give methanol.
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