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 \ufffdCN
Ethanol
(Solvent)
Excess
Cl
CH3
CH3
CH3
CH3
NC
H
NC
H
H
H
\ufffd
2S,3R
Reactive stereocenters
(both possess good
leaving groups)
I\ufffd
Acetone
(Solvent)
CH3
H
CH2CH3
CH3
\ufffd
Br\ufffd Cl\ufffd\ufffd \ufffd
1
2
3
I
2R,3R
H
CH2CH3
CH3
H
Br\ufffd\ufffd
CH31
2
3
H Br
Reactive stereocenter
Inert stereocenter
(no leaving group)
Exercise 6-16
Solution
\u2022 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.
\u2022 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
\ufffdNH3
CH3CHCOO\ufffd
ANH3, H2O,25\ufffdC, 4 days
\ufffdHBr
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 
 \u201cdiastereomers produce diastereomers.\u201d 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 \u201crule\u201d?
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\ufffd
I
H
trans-1-Iodo-
3-methylcyclohexane
CH3
¥*
/\u2211 /\u2211
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\u2013X bond. Are there struc-
tural features that might allow us to predict, at least qualitatively, whether a leaving group 
is \u201cgood\u201d or \u201cbad\u201d? 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 \u201cgood\u201d leaving group; fl uoride, however, is so \u201cpoor\u201d 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.
\u161\ufffd
ð ð
OO
B
O
ðO
ð ðO
Methyl sulfate ion
Sulfate and Sulfonate Leaving Groups
CH3O S
B
\ufffd \u161\ufffd
ð ð
OO
B
O
ðO
ð ðO
Methanesulfonate ion
(Mesylate ion)
CH3 CH3S
B
\ufffd \u161\ufffd
ð ð
OO
B
O
ðO
ð ðO
Trifluoromethanesulfonate ion
(Triflate ion)
CF3 S
B
\ufffd \u161\ufffd
ð ð
O
B
O
ðO
ð ðO
4-Methylbenzenesulfonate ion
( p-Toluenesulfonate
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