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

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Strategy
If you write out the equation for this reaction, you will notice something unusual about it: This
SN2 reaction uses iodide as the nucleophile as well as the leaving group. Therefore, iodide displaces
iodide. This is the key insight to approaching the problem.

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230 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

In substrates bearing more than one stereocenter, inversion takes place only at the car-
bons that undergo reaction with the incoming nucleophile. Note that the reaction of (2S,4R)-
2-bromo-4-chloropentane with excess cyanide ion results in a meso product. This outcome
is particularly readily recognized using Fischer projections.

SN2 Reactions of Molecules with Two Stereocenters

H

H

H

2S,4R 2R,4S: Meso

Br

H �CN
Ethanol

(Solvent)
Excess

Cl

CH3

CH3

CH3

CH3

NC

H

NC

H

H

H

�

2S,3R

Reactive stereocenters
(both possess good

leaving groups)

I�
Acetone
(Solvent)

CH3

H

CH2CH3

CH3
�

Br� Cl�� �

1

2

3

I

2R,3R

H

CH2CH3

CH3

H
Br��

CH31
2

3

H Br
Reactive stereocenter

Inert stereocenter
(no leaving group)

Exercise 6-16

Solution
• The optical activity of (S)-2-iodooctane originates from the fact that it is chiral and a single
enantiomer. Its structure appears in the text on the previous page. The stereocenter is C2, the
carbon bearing the iodine atom. (S)-2-Iodooctane is a secondary haloalkane and, as we have seen
in several examples in this chapter, it may undergo SN2 reaction, which proceeds by backside
displacement and inversion at the site of reactivity.
• As noted earlier, I2 is both a good nucleophile and a good leaving group. Because it functions
in both roles in this reaction, the transformation occurs rapidly. Each time displacement occurs,
the stereocenter undergoes stereochemical inversion. Because the process is fast, it takes place
multiple times for every substrate molecule, inverting the stereochemistry each time. Ultimately,
this leads to an equilibrium (i.e., racemic) mixture of (R) and (S) stereoisomers of the starting (and
ending) compound.

MODEL BUILDING

Try It Yourself

Amino acids are the building blocks of peptides and proteins in nature. They may be prepared in
the laboratory by SN2 displacement of the halogen in 2-halocarboxylic acids using ammonia as
the nucleophile, as illustrated by the conversion of 2-bromopropanoic acid into alanine.

2-Bromopropanoic
acid

Alanine

Br

CH3CHCOOH
A

�NH3

CH3CHCOO�
ANH3, H2O,25�C, 4 days

�HBr

The stereocenter in alanine, like that in most naturally occuring amino acids, has the S confi gu-
ration. Draw both a clear stereochemical structure for S-alanine and one for the enantiomer of
2-bromopropanoic acid that would be required to produce S-alanine according to the equation
above.

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 C h a p t e r 6 231

In these equations, ethanol and acetone, respectively, are the solvents for the indicated
transformations. These solvents are polar (Section 1-3) and particularly good at dissolving
salts. We shall come back to the infl uence of the nature of the solvent on the SN2 reaction
in Section 6-8. In the second example, notice that the reaction taking place at C2 has no
effect on the stereocenter at C3.

Exercise 6-17

As an aid in the prediction of stereochemistry, organic chemists often use the guideline that
 “diastereomers produce diastereomers.” Replace the starting compound in each of the two preced-
ing examples with one of its diastereomers, and write the product of SN2 displacement with the
nucleophile shown. Are the resulting structures in accord with this “rule”?

Similarly, nucleophilic substitution of a substituted halocycloalkane may change the
stereochemical relation between the substituents. For example, in the disubstituted cyclo-
hexane below, the stereochemistry changes from cis to trans.

¥*

Br NaI, acetone
H

H
cis-1-Bromo-

3-methylcyclohexane

CH3

H
NaBr�

I

H
trans-1-Iodo-

3-methylcyclohexane

CH3

¥*

/∑ /∑

In Summary Inversion of confi guration in the SN2 reaction has distinct stereochemical
consequences. Optically active substrates give optically active products, unless the nucleo-
phile and the leaving group are the same or meso compounds are formed. In cyclic systems,
cis and trans stereochemical relations may be interconverted.

6-7 Structure and SN2 Reactivity: The Leaving Group
The relative facility of SN2 displacements depends on several factors, including the nature
of the leaving group, the reactivity of the nucleophile (which is affected by the choice of
reaction solvent), and the structure of the alkyl portion of the substrate. We employ kinetics
as our tool to evaluate the degree to which changes in each of these structural features
affect their function in the SN2 reaction. We begin by examining the leaving group. Subse-
quent sections will address the nucleophile and the substrate.

Leaving-group ability is a measure of the ease
of its displacement
As a general rule, nucleophilic substitution occurs only when the group being displaced, X,
is readily able to depart, taking with it the electron pair of the C–X bond. Are there struc-
tural features that might allow us to predict, at least qualitatively, whether a leaving group
is “good” or “bad”? Not surprisingly, the relative rate at which it can be displaced, its
leaving-group ability, can be correlated with its capacity to accommodate a negative
charge. Remember that a certain amount of negative charge is transferred to the leaving
group in the transition state of the reaction (Figure 6-4).

For the halogens, leaving-group ability increases along the series from fl uorine to iodine.
Thus, iodide is regarded as a “good” leaving group; fl uoride, however, is so “poor” that
SN2 reactions of fl uoroalkanes are rarely observed.

6 - 7 S t r u c t u r e a n d S N 2 R e a c t i v i t y : T h e L e a v i n g G r o u p

MODEL BUILDING

Some Variables Affecting
the SN2 Reaction

ð

ð

R XNu O

Reactivity
of
Nu

Structure
of
R

Nature
of
X

Leaving-Group Ability

I2 . Br2 . Cl2 . F2

 Best Worst

Increasing

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232 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

Exercise 6-18

Predict the product of the reaction of 1-chloro-6-iodohexane with one equivalent of sodium methyl-
selenide (Na12SeCH3).

Decreasing

Basicity

I2 , Br2 , Cl2 , F2

 Least Most

Halides are not the only groups that can be displaced by nucleophiles in SN2 reactions.
Other examples of good leaving groups are sulfur derivatives of the type ROSO3

2 and
RSO3

2, such as methyl sulfate ion, CH3OSO3
2, and various sulfonate ions. Alkyl sulfate

and sulfonate leaving groups are used so often that trivial names, such as mesylate, trifl ate,
and tosylate, have found their way into the chemical literature.

š�

ð ð

OO
B
O

ðO

ð ðO
Methyl sulfate ion

Sulfate and Sulfonate Leaving Groups

CH3O S
B

� š�

ð ð

OO
B
O

ðO

ð ðO
Methanesulfonate ion

(Mesylate ion)

CH3 CH3S
B

� š�

ð ð

OO
B
O

ðO

ð ðO
Trifluoromethanesulfonate ion

(Triflate ion)

CF3 S
B

� š�

ð ð

O
B
O

ðO

ð ðO
4-Methylbenzenesulfonate ion

( p-Toluenesulfonate
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