SkillBuilder Review

REPLACE THE LEAVING GROUP W ITH THE NUCLEOPHILE,

AND DRAW INVERSION OF CONFIGURATION (IF RELEVANT)

DRAW THE TRANSITION STATE OF THE FOLLOW ING REACTION

TRANSITION STATE

DRAW THE ELIMINATION PRODUCTS OBTAINED W HEN THE COMPOUND BELOW IS TREATED W ITH A STRONG BASE.

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Review of Reactions
 This compound is a primary alkyl halide, but it has three methyl groups attached to the β position.
These methyl groups provide steric interactions that raise the energy of the SN2 transition state
(Figure 7.7), and as a result, the rate of SN2 is too slow to be useful. This is an interesting example,
because the substrate is a primary alkyl halide that essentially does not undergo an SN2 reaction. This
example illustrates why it is best to understand concepts in organic chemistry rather than memorize
rules without knowing what they mean.
Review of Reactions

ER
NG THE TRANSITION STATE OF AN SN2 PROCESS

skill Draw the transition state of the following reaction:

NaSH
Cl SH + NaCl

SOLUTION
First identify the nucleophile and the leaving group. These are the two groups that will be on
P1 either side of the transition state:
he
⊝
nd SH Cl
up.
Nucleophile Leaving group

P2 The transition state will need to show a bond forming with the nucleophile and a bond
on breaking with the leaving group. Dotted lines are used to show the bonds that are breaking
uc or forming:
her
δ– δ–
de.
lkyl Halides: Nucleophilic Substitution and Elimination Reactions
HS C Cl

Bond Bond

ER
Forming Breaking

Notice that a δ− symbol is placed on both the incoming nucleophile and the outgoing leav-
CTING THE ing group to indicate that the negative charge is spread out over both locations. Now we
REGIOCHEMICAL OUTCOME OF AN E2 REACTION
must draw all of the alkyl groups connected to the α position. In our example, the α position
has one CH3 group and two H’s:
skill Predict the major and minor products of the following E2 reaction:
H H

P3
ee
Cl =
Cl
NaOMe α
H 3C ? Cl

to
m, 7.3 Draw the product for each of the following S N2 reactions:
So we draw these groups in the transition state connected to the α position. One group is
SOLUTION β
ets (a) (S)-2-Chloropentane and NaSH (b) (R)-3-Iodohexane and NaCl β
placed on a straight line, and the other two groups are placed on a wedge and on a dash.
Phe 1 First identify all of the β positions that bear protons.
l β It does not matter whether the CH3 group is placed on the line,
Cl www.MyEbookNiche.eCrater.com
CH3
aw β δ– δ–
ng wedge, or dash. But don’t forget to indicate that the drawing is
ger (c) (R)-2-Bromohexane and NaCN (d) 1-Bromoheptane and NaOH HS C Cl
ns.
g a a transition state by surrounding it with brackets and using the
These are the positions that must be explored. The two positions inside the ring are identi-
te. double-dagger symbol that indicates a transition state. H H
cal, because removing a proton from either of these positions will result in formation of the
7.5 Draw the transition state for each of the following S N2 reactions:
same product:
Pthe
2 skill 7.5 Draw the transition state for each of the following SN2 reactions:
ble
cal Br NaOH OH
+ NaBr
es.
(a) 7.3 SN2 Reactions 283
Removing a proton from the other β position (outside the ring) will produce a different alkene:

O
So there are two possible regiochemical outcomes. The π bond can be formed inside the
⊝
O O
ring or outside the ring. +
⊝
P3
(b) The first outcome gives a trisubstituted alkene, while the second outcome gives a disub-
O
sev
stituted alkene. The more substituted alkene (trisubstituted) is the Zaitsev product, and the
nn NaOH
(c) Cl OH + NaCl
disubstituted alkene is the Hofmann product.
cts.
P4 This example does not employ a sterically hindered base, so we expect that the Zaitsev
Br SH
ase product will be the major product:
NaSH
ne + NaBr
uct (d) NaOMe
+
es. Cl
skill 7.6 A total synthesis of the marine natural product aldingenin C in the laboratory
Major Minor
2
resulted
7.18 Predict the major and minor products for each of the following E2 reactions:
in a significant revision of its proposed structure. The synthesis involved the conversion of
the skill 7.18 Predict the major and minor products for each of the following E2 reactions:
compound 1 to compound 2, which is an intramolecular SN2-type process. This substitu-
Cl
tion reaction involves a very poor leaving group, but the reaction is nevertheless favorable,
Cl

?
because it involves opening of the strained

?
t-BuOK
three-membered ring (called an epoxide).
NaOEt
O ⊝
O O
The relief of ring strain can be a powerful
(a) (b) ⊝
O
driving force for reactions, as seen in this
example. Draw the NaOH
?
transition state for this
reaction, and identify the leaving group.
(c) (d) 1
t-BuOK
2 ?
Br Br

? ?
RACTICE? Try Problem 7.51NaOH t-BuOK

(e) (f )
aking Pharmacology and Drug Design
7.19 For each of the following reactions, identify whether you would use hydroxide or tert-
y is the study of how drugs interact
butoxide to accomplish the desired transformation:
⊕
Cl Nuc
l systems, including the mechanisms
rug action. Pharmacology is a very Nuc ⊝
 NaOH
the page (rather than on a wedge):
? t-BuOK
?
(e) H CH3 CH3 (fRotate
) about
H central C C bond H H
H
7.19 For each of the following reactions, identify whether you would use hydroxide or tert-
Cl Cl
Cl
butoxide to accomplish the desired transformation:
Then, we rotate the central C−C bond again, in a manner that places the β proton in the
plane of the page:
(a) Cl CH3 Rotate(b)
about Br H
H H central C C bond H
CH
8skillRegiochemical
7.20 Adamantane, a tricyclic alkane consisting of fused cyclohexane rings, has an intrigu-
297
3
and Stereochemical Outcomes
Cl for E2 Reactions Cl
7.20 Adamantane,
ing structure a first
that was tricyclic alkane
proposed consisting
as a theoretical of fused cyclohexane
structure rings,
in 1924. Chemists has
set out an intrigu- ing structure that was first proposed as a
3 3
theoretical structure in 1924. Chemists set out to synthesize the molecule and succeeded
to synthesize the molecule and succeeded in 1941. Because its structure resembles the
In this conformation, the proton and the leaving group are anti-periplanar. in 1941. Because its structure resembles the
Alkyl Halides: Nucleophilic Substitution and Elimination Reactions
rbon
P carbon framework found in diamond, it was named adamantane after the Greek adamas (meaning unconquerable or invincible). An alkene
3 framework To draw the product, use the wedges and dashes as guides. In this case, the tert-butyl
found in diamond, it was named adamantane after the Greek adamas
ges 4
with the molecular formula C
group and the ethyl group are 11 H15Br was prepared from the adamantane-derived dibromide
both on wedges, so they will be
eaning unconquerable or invincible). An alkene with the molecular formula C 11cis to each other in the
H15Br was shown below. Draw the major product of
s to product: 4
epared from the adamantane-derived dibromide
anti-periplanar to the leaving shown below. Draw the major product
this reaction and explain why only a single product is formed:
is group. In SkillBuilder 7.4, this rotation was done in two
raw
this reaction and explain why only a single product is formed:
uct. stages. In some cases, it will be much easier to do both stages at the same time, as shown
H ⊝ H CH3
below. Br H Base H CH3
CH3

?
Cl Br
t-BuOK
Br H Rotate about Br
Br Adamantane
central C C bond CH
In this case, the product is the Z isomer. CH
The
3
E isomer is not obtained,
H because
3 that would

H3C H H3C H
y Problems require elimination from a syn-periplanar conformation, which is eclipsed and too high in energy.
7.59, 7.60a,d, 7.63, 7.64b, 7.67
7.21 Identify the major and minor products for the E2 reaction that occurs when each of the following substrates is treated with a strong
the skill base:
7.21 Identify the major and minor products for the E2 reaction that occurs when each of
The reaction occurs via this anti-periplanar conformation, so the wedges and dashes serve
the following substrates is treated with a strong base:
as guides to draw the correct stereoisomeric alkene, as shown:
eoselectivity of E2 Reactions
amples in the previous sections
Br focused on regiochemistry. WeBr will now focus our attentionBr

eochemistry. ForBrexample, consider ⊝performing an HE2 reaction with H

3-bromopentaneCH3as the
CH3 Base CH 3
te, as shown(a)
below.
H This substrate has two identical
(b) H3C β positions so regiochemistry
(c) is not an
H H C
n this case. Deprotonation
H 3C of either β position produces the same result. 3But in this case,
Cl Cl Cl
hemistry is relevant, because two possible stereoisomeric alkenes can be obtained:
To summarize, we expect the following products:
NaOEt
+
(d) (e) (f)
Br
Major Minor
Br NaOEt
+

tereoisomers (cis and trans) are produced, but the trans product predominates. Consider an
diagram showing formation of the cis and trans products (Figure
Major
7.14). Using the Hammond
Minor
te (Section 6.6), we can show that the transition state for formation of the trans alkene must
e stable than the transition state for formation of the cis alkene. This reaction is said to be
the skill
elective 7.25the Predict the major and minor products for each of the following E2 reactions:
because substrate produces two stereoisomers in unequal amounts.

Br

(a) Cl
NaOEt
? (b)
NaOEt
?
Potential
energy
Br cis

(c)
NaOEt
?
Reaction coordinate
trans

(d)
NaOEt
?
Br Br
eospecificity of E2 Reactions
? ?
H H
t-BuOK t-BuOK
previous example, the β position had two different protons.
(e) (f)
Br

a case, both7.27 Draw the carbocation intermediate that is expected when each of the following alkyl chlorides undergoes ionization. In each case, if
skill the cis Compound 2 was prepared as part of an effort
7.26 and the trans isomers were produced, with the trans
6 isomer being favored.
to determine the absolute stereochem-
t’s consider the carbocation is resonance-stabilized, make sure to draw the resonance structures.
aistry of compound 3, which was isolated from the liverwort plant. The synthesis of compound
case where the β position contains only one proton. For example, consider per-
g an elimination reaction with the following substrate:
2 involved the formation of four C=C double bonds. The first double bond was formed via
an E2 reaction, when compound 1 was treated with potassium tert-butoxide. Draw the prod-
Ph Br
Me α
uct of this E2 reaction, and draw curved arrows to show a mechanism for its formation:
β Ph =
β
H H
Br
example, there are two β positions. One of these positions
7.9 Unimolecular Reactions (S 1 and E1)
has no protons Nat all, and the otherH
309

?
many
O
n has only one proton. In such a case, a mixture
t-BuOK of stereoisomers
steps is not obtained. In this case,
ill only be one stereoisomeric
O Br product:
Ph HBr Ph H Br Cl
Me1 OCH3 NaOEt 2 3
(e) (f) (g) (h)
H H Me

RACTICE? Try Problems 7.58, 7.59, 7.60, 7.63, 7.64

skill 7.28 Later in this chapter (Section 7.12), we will see that a carbocation can be formed from
an alcohol substrate in the presence of an acid, and an example of such a reaction is given
below. This reaction was employed in the development of new synthetic methods that can
be applied to the preparation of medicinally relevant compounds.7 Draw the carbocation
intermediate that is expected in the SN1 reaction shown. If the carbocation is resonance-
stabilized, be sure to draw all significant resonance structures.

CH3 CH3
OH Nuc
H+
Nuc
N O N O
Ph Ph
 so we expect inversion of configuration:
Cl OEt
CONCEPTUAL CHECKPOINT
NaOEt

(S)
7.33 Draw all of the expected products for each of the following solvolysis reactions:
(R)

? ?
In summary, we expect the following products:
Br
H 2O
EtOH
heat heat
Cl Cl OEt
(a) (b)
NaOEt + + +
Br EtOH Cl
Major Minor Minor Minor

(c)
MeOH
heat ? (d)
MeOH
heat ?
SN2 product
E2 products
7.34 The following tertiary alkyl halide was heated in ethanol for several days, and the resulting mixture of products contained five differ-
the skill ent elimination products and two substitution products:
7.37 Identify the major and minor product(s) that are expected for each of the following
reactions. Br

? ?
Br Br
NaCl NaOH
(a)
(a) Draw the substitution products and identify the relationship between them.
DMSO
(b)
(b) Identify which substitution product is expected to be favored, and explain your choice.
Br
(c) Draw all of the elimination products, and identify which products are stereoisomers.

(c)
t-BuOK
? (d)
DBN
?
(d) For each pair of stereoisomeric alkenes, identify which stereoisomer is expected to be favored.

(e)
t-BuOK
? (f)
NaSH
?
Br

(g)
NaOH
? (h)
Br NaOEt
?
Br

(i)
EtOH
Heat ? (j)
NaOH
?
Br Br

(k)
NaOMe
? (l)
NaOMe
?
?
Br Br

(m)
NaOH
? (n)
NaOEt

skill 7.38 Compound A and compound B are constitutional isomers with the molecular formula
C3H7Cl. When compound A is treated with sodium methoxide, a substitution reaction pre-
dominates. When compound B is treated with sodium methoxide, an elimination reaction
predominates. Propose structures for compounds A and B.

7.39 Compound A and compound B are constitutional isomers with the molecular for-
mula C4H9Cl. Treatment of compound A with sodium methoxide gives trans-2-butene as