Vollhardt  Capítulo 7 (Haloalcanos 2)
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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\ufffd Br \ufffd\ufffd
H
C
( CH3
CH3
H
G
C
(
O O\u161
\u161
\u161 Br\u161\u161
\u161
\u161\u161
\u161
\u161
\u161
\u161\ufffd
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) \ufffd
H
CN\ufffd Acetone
Cl H
R S
CN
/\u2211 /\u2211
(b) \ufffd
\ufffd
H
CH3OH
OCH3I
R R S
/\u2211 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\u2019s look at the nucleophiles 
and solvents in each case.
Solution
\u2022 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).
\u2022 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 \u2013 
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 \u201cgreener\u201d: 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 \u201cgreen\u201d 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 
\u201cgreener.\u201d
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) \u2014 ideal circumstances for an SN1 reaction \u2014 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 \u201cdirects\u201d 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
!
\u2265 \u2265
\u2211 \u2211
%
OH O
O
OH
OH
CO2CH3
CH2CH3
OH
!
%
H2O
\ufffdHBr
O
HO H
H
O
OH
H3CO2C
CH2CH3
ð\ufffd
ð
\ufffdHO O A
A
\ufffd
%
$
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
\ufffd
R
R
H
R
R
\u394
O ~i
i
&
C C
\ufffd
R H
RR
R
i
O
i
i
i
C C
R R
RR
iðB
\ufffdHB\ufffd
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\ufffd\ufffd \ufffdO OC CP
G
G
H
C
G
X
G
D
D
B\ufffd
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