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Vollhardt Capítulo 7 (Haloalcanos 2)

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Substitution of a Secondary Haloalkane Under SN2 Conditions

G

C Br
Acetone

CH3S
H3C

H3C
CH3S C� Br ��

H

C

( CH3

CH3

H

G
C
(

O Oš
š
š Bršš

š
šš

š
š

š
š�

A visual demonstration of relative
SN1 reactivity. The three test
tubes contain, from left to right,
solutions of 1-bromobutane,
2-bromopropane, and 2-bromo-
2-methylpropane in ethanol,
 respectively. Addition of a few
drops of AgNO3 solution to each
causes immediate formation of a
heavy AgBr precipitate from the
tert-bromoalkane (right), less AgBr
precipitation from the secondary
substrate (center), and no AgBr
formation from the primary halide
(left).

Exercise 7-8

Working with the Concepts: Secondary Haloalkanes

Explain the following results.

(a) �
H

CN� Acetone

Cl H
R S

CN
/∑ /∑

(b) �

�

H
CH3OH

OCH3I
R R S

/∑ A

Strategy
Both reactions have secondary substrates with good leaving groups, giving the options of substitu-
tion by either an SN1 or an SN2 pathway. As we did in Exercise 7-4, let’s look at the nucleophiles
and solvents in each case.
Solution
• In reaction (a), cyanide ion, CN2, is a good nucleophile (Table 6-7), and acetone is a polar
aprotic solvent, a combination that favors the SN2 mechanism. Backside attack occurs, leading to
inversion at the site of displacement (see Figure 6-4).
• In reaction (b), methanol, CH3OH, is both the solvent and the nucleophile. As in Exercise 7-4,
we have the conditions for solvolysis via the SN1 mechanism, leading to both enantiomeric ether
products.

Exercise 7-9

Try It Yourself

Would treatment of R-2-chlorobutane with aqueous ammonia be a good synthetic method for the
preparation of R-2-butanamine, R-CH3CH2CH(NH2)CH3? Why or why not? Can you think of a
better route?

MODEL BUILDING

The fi rst fi ve sections of this chapter have given us the background for understanding
how the SN1 mechanism takes place and what factors favor its occurrence. It is useful
to keep in mind that two conditions must be satisfi ed before dissociation of a carbon –
halogen bond into ions can occur: The carbon atom must be secondary or tertiary so that
the carbocation has suffi cient thermodynamic stability to form, and the reaction must
take place in a polar solvent capable of interacting with and stabilizing both positive and

tarik
Rectangle

 C h a p t e r 7 263

negative ions. Nevertheless, carbocations are common intermediates that will appear
in the reactions of many of the compound classes that we will study in the chapters
to come.

Which is “greener”: SN1 or SN2?
The contrast between the stereochemical outcomes of the SN1 and SN2 mechanisms directly
affects the comparative utility of the two processes in synthesis. The SN2 process is stereo-
specifi c: Reaction of a single stereoisomeric substrate gives a single stereoisomeric product
(Section 6-6). In contrast, virtually all reactions that proceed via the SN1 mechanism at a
stereocenter give mixtures of stereoisomers. And it gets worse: The chemistry of carboca-
tions, the intermediates in all SN1 reactions, is complex. As we shall see in Chapter 9, these
species are prone to rearrangements, frequently resulting in complicated collections of prod-
ucts. In addition, carbocations undergo another important transformation to be described
next: loss of a proton to furnish a double bond.

In the fi nal analysis, SN1 reactions, unlike SN2 processes, are of limited use in synthe-
sis because they fail the fi rst two criteria of “green” reactions (see Chemical Highlight 3-1):
They are poor in atom effi ciency and wasteful overall, because they tend to lead to mixtures
of stereoisomeric substitution products as well as other organic compounds. SN2 is
“greener.”

7 - 5 E f f e c t o f t h e A l k y l G r o u p o n t h e S N 1 R e a c t i o n

CHEMICAL HIGHLIGHT 7-1

Unusually Stereoselective SN1 Displacement in Anticancer Drug Synthesis
SN1 displacements normally give mixtures of stereoisomeric
products. The high-energy carbocation intermediate reacts
with the fi rst nucleophilic species it encounters, regardless of
which lobe of the carbocation p orbital the nucleophile
approaches. The example shown below is a very unusual

exception: A secondary haloalkane, a good leaving group
(bromide), a highly polar, protic solvent but a poor nucleo-
phile (water) — ideal circumstances for an SN1 reaction — and
displacement of bromide by water occurs with over 90%
retention of confi guration!

The structure of the relevant carbocation is shown at
the right. Approach of a nucleophile toward the top lobe of
its p orbital is partly blocked by the ethyl group two car-
bon atoms over and to a lesser extent by the ester function
one carbon farther away (green). In addition, the hydroxy
group on the bottom face of the ring “directs” nucleophilic
addition of a water molecule from below by hydrogen
bonding, as shown.

This stereochemical result is of critical importance
because the product, named aklavinone, is a component in a
powerful anticancer drug called aclacinomycin A. This com-
pound belongs to a class of chemotherapeutic agents called
anthracyclines, whose clinical utility is compromised by

their toxicity; aclacinomycin is less cardiotoxic than other
anthracyclines and thus has been under careful study by
medical researchers for over two decades.

OH O

S S

O

OH

OH
CO2CH3

CH2CH3

Br

!

≥ ≥

∑ ∑
%

OH O

O

OH

OH
CO2CH3

CH2CH3

OH

!
%

H2O
�HBr

O

HO H

H

O

OH

H3CO2C
CH2CH3

ð�

ð
�HO O A

A

�

%
$

264 C h a p t e r 7 F u r t h e r R e a c t i o n s o f H a l o a l k a n e s

In Summary Tertiary haloalkanes are reactive in the presence of nucleophiles even though
they are too sterically hindered to undergo SN2 reactions: The tertiary carbocation is read-
ily formed because it is stabilized by hyperconjugation. Subsequent trapping by a nucleo-
phile, such as a solvent (solvolysis), results in the product of nucleophilic substitution.
Primary haloalkanes do not react in this manner: The primary cation is too highly energetic
(unstable) to be formed in solution. The primary substrate follows the SN2 route. Secondary
systems are converted into substitution products through either pathway, depending on the
nature of the leaving group, the solvent, and the nucleophile.

7-6 Unimolecular Elimination: E1
We know that carbocations are readily attacked by nucleophiles at the positively charged
carbon. However, this is not their only mode of reaction. A competing alternative is depro-
tonation by the nucleophile acting as a base, furnishing a new class of compounds, the
alkenes. This process is possible because the proton neighboring the positive charge is
unusually acidic.

Competition Between Nucleophilic and Basic Attack on a Carbocation

Nucleophilic
substitution product

Carbocation Alkene

Nuð
~i

i[
&

C C

Nu
�

R
R

H

R
R

Δ
O ~i

i

&
C C
�

R H

RR
R

i
O

i

i

i
C C

R R

RR

iðB
�HB�

Starting from a haloalkane, the overall transformation constitutes the removal of HX
with the simultaneous generation of a double bond. The general term for such a process is
elimination, abbreviated E.

Elimination

Base: ð
H B X�� �O OC CP

G

G
H

C
G

X

G

D

D

B�
C

Eliminations can take place by several mechanisms. Let us fi rst establish the mechanism
that is followed in solvolysis.

When 2-bromo-2-methylpropane is dissolved in methanol, it disappears rapidly. As
expected, the major product, 2-methoxy-2-methylpropane, arises by solvolysis. However,
there is also a signifi cant amount of another compound, 2-methylpropene, the product of
elimination of HBr from the original substrate. Thus, in competition with the SN1 process,
which leads to displacement of the leaving group, another mechanism transforms the ter-
tiary halide, giving rise to the alkene. What is this mechanism? Is it related to the SN1
reaction?

Once again we turn to a kinetic analysis and fi nd that the rate of alkene formation
depends on the concentration of only the starting