CHAPTER 11—REACTIONS OF ALCOHOLS

11-1
(a) Both reactions are oxidations.
(b) oxidation, oxidation, reduction, oxidation
(c) One carbon is oxidized and one carbon is reduced—no net change (elimination of H and OH).
(d) reduction: C—O is replaced by C—H
(e) oxidation (addition of X2)
(f) Neither oxidation nor reduction—the C still has two bonds to O.
(g) neither oxidation nor reduction (addition of HX)
(h) first step: neither oxidation nor reduction (elimination of H2O); second step: reduction (addition of H2)
(i) oxidation: adding an O to each carbon of the double bond
(j) The first reaction is oxidation as a new C—O bond is formed to each carbon of the alkene; the second
reaction is neither oxidation nor reduction, as H2O is added to the epoxide, and each carbon still has one
bond to oxygen.
(k) oxidation: adding a Cl to one carbon and an O to the other
(l) Neither oxidation nor reduction: overall, only H and OH are added, so there is no net oxidation nor
reduction.
11-2 O OH O

(a) H2CrO4 or PCC or

NaOCl/HOAc 1 eq. NaOCl
TEMPO
OH
(b) H2CrO4 or 3° alcohols are
PCC or resistant to
no reaction no reaction
NaOCl/HOAc 1 eq. NaOCl oxidation.
TEMPO
O OH O
(c) OH H2CrO4 or PCC or H
NaOCl/HOAc 1 eq. NaOCl
O TEMPO

(d) H2CrO4 or PCC or Ketones are

no reaction no reaction resistant to
NaOCl/HOAc 1 eq. NaOCl oxidation.
TEMPO
(e) H2CrO4 or PCC or Hydrocarbons
no reaction no reaction are resistant to
NaOCl/HOAc 1 eq. NaOCl oxidation.
TEMPO
O H2CrO4 or OH PCC or O
(f)
Ph NaOCl/HOAc Ph 1 eq. NaOCl Ph
TEMPO
O H2CrO4 or OH PCC or O
(g)
HO NaOCl/HOAc 1 eq. NaOCl H
TEMPO
O H2CrO4 or O PCC no reaction Aldehydes are
(h) H3C C OH H3C C H resistant to PCC but
NaOCl/HOAc 1 eq. NaOCl O
can be oxidized with
277 TEMPO H3C C OH excess NaOCl.
Copyright © 2017 Pearson Education, Ltd.
11-3 O O Cr begins with bonds to four oxygen atoms and ends with
bonds to three oxygen atoms. Whether the bonds between
(a) HO Cr OH HO Cr OH the metals and the oxygen are single or double is not
O important—note this is NOT true of carbon! What matters
here is the number of oxygen atoms bonded to the oxidizing
atom.
(b) O Cl Cl Cl begins with one bond to oxygen and ends with no bonds to oxygen.
O
S begins bonded to one oxygen and ends with no bonds to
(c) H3C S CH3 H3C S CH3 oxygen.

AcO OAc OAc

(d) I OAc I Iodine begins with four bonds to oxygen and ends with two
O O bonds to oxygen.

O O
OH O C begins with one bond to O and (at least) one bond to H. It ends with
(e) C C two bonds to O and one fewer bond to H. This is one definition of
oxidation: replacing a C—H bond with a C—O bond.
H
11-4 Note that PCC, DMP, Swern oxidation, and 1 equiv. NaOCl/TEMPO stop at the aldehyde when
oxidizing a primary alcohol. Chromic acid and excess NaOCl take a primary alcohol to the carboxylic acid.

Na2Cr2O7 O
(a) CH3(CH2)6 OH
H2SO4 CH3(CH2)6 OH
1 equiv. O
PCC DMP NaOCl
CH3(CH2)6 OH AND AND CH3(CH2)6 H
TEMPO

(b) All four reagents give the same ketone product with a secondary alcohol.
CH3(CH2)4 [O] CH3(CH2)4 [O] is the general abbreviation for an
oxidizing agent.
OH O
O O
(c) Na2Cr2O7
H H2SO4 OH
OH O
O 1 equiv. O NaOCl oxidizes aldehydes
faster than 2° alcohols. If
NaOCl
you assumed the opposite, the
H OH correct answer would have
TEMPO
OH OH been the structure below.

O O
PCC DMP
AND
H These do not oxidize aldehydes. H
OH O
278
Copyright © 2017 Pearson Education, Ltd.
11-4 continued
OH OH
[O] All four reagents give the same ketone product
(d) with a secondary alcohol. Tertiary alcohols are
resistant to oxidation.

OH O

To the student: For consistency, this Solutions Manual will use these laboratory methods of oxidation:
—1 eq. NaOCl/TEMPO to oxidize 1° alcohols to aldehydes;
—excess NaOCl/TEMPO to oxidize 1° alcohols to carboxylic acids;
—NaOCl/HOAc to oxidize 2° alcohols to ketones.
Understand that other choices are legitimate and you should follow the guidelines given by your
instructor; for example, DMP and Swern oxidation and PCC work as well as 1 eq. NaOCl in the
preparation of aldehydes, and chromic acid will oxidize a 1° alcohol to a carboxylic acid as well as
excess NaOCl does. All of these five oxidizing agents will convert a 2° alcohol to a ketone. If you
have a question about the appropriateness of a reagent you choose, consult the table in the text before
Problem 11-3.

11-5 None of the five oxidation reagents affects the 3° alcohol. All five oxidize the 2° alcohol to a ketone.
Chromic acid and excess NaOCl oxidize the 1° alcohol to COOH, whereas PCC, DMSO/oxalyl chloride
(Swern), and DMP oxidize the 1° alcohol to an aldehyde.
OH O
2° OH O
(b) PCC OR
CH3 1° (d) DMSO/ClCOCOCl OR
(e) DMP CH3 H
3° OH O OH
(a) H2CrO4 OR O
(c) NaOCl
CH3 OH
OH
11-6 NaOCl reagents shown over the arrow; Cr reagent shown beneath the arrow. Other non-Cr reagents
added in text after the reaction.
1 eq. NaOCl O
TEMPO
(a) OH H other non-Cr: DMP or DMSO/ClCOCOCl (Swern)
PCC
excess NaOCl O
TEMPO (Z or E not specified)
(b) OH H2CrO4 OH other non-Cr: none

NaOCl
HOAc
(c) other non-Cr: DMP or DMSO/ClCOCOCl (Swern)
H2CrO4
OH or PCC O

279
Copyright © 2017 Pearson Education, Ltd.
11-6 continued
NaOCl CH2CH3
OH HOAc O EtMgBr H3O+
(d)
H2CrO4 ether OH
or PCC
other non-Cr: DMP or DMSO/ClCOCOCl (Swern)

OH 1 eq. NaOCl O OH
TEMPO EtMgBr H3 O+
(e)
H ether CH2CH3
PCC
other non-Cr: DMP or DMSO/ClCOCOCl (Swern)

OH NaOCl
OH O
H2SO4 1) BH3 • THF HOAc
(f)
∆ 2) H2O2, HO– H2CrO4
− H2O or PCC

other non-Cr: DMP or DMSO/ClCOCOCl (Swern)

11-7 A chronic alcoholic has induced more ADH enzyme to be present to handle large amounts of imbibed
ethanol, so requires more ethanol "antidote" molecules to act as a competitive inhibitor to "tie up" the extra
enzyme molecules.

11-8 OH OH O O O O
[O] [O]
CH3 CH CH2 CH3 C CH CH3 C COH
pyruvaldehyde pyruvic acid
Pyruvic acid is a normal metabolite
in the breakdown of glucose ("blood sugar").

11-9 From this problem on, "Ts" will refer to the "tosyl" or "p-toluenesulfonyl" group:
O
Ts S CH3
O
CH3 CH3 Lower temperature
(a) CH3CH2 OTs + KO C CH3 CH3CH2O C CH3 + KOTs favors substitution.
Higher temperature
CH3 CH3 favors elimination.
(E2 is possible with this hindered base; the product would be ethylene, CH2=CH2.)

(b) OTs + NaI I + NaOTs

TsO H
H CN
(c) + NaCN + NaOTs inversion—SN2
R S

280
Copyright © 2017 Pearson Education, Ltd.
11-9 continued
OTs NH3 OTs NH2
excess
NH3 NH3
(d) + NH4 OTs

(e) OTs + Na+ C CH C CH + NaOTs

11-10 All parts begin with forming the tosylate.

TsCl KCN
OH OTs CN
pyridine
(d)
NaBr excess NaOCH2CH3
Br NH3
(a) NH2
O
(b) (c)
11-11
O
(a) TsCl
CH2OH CH2OTs OR CH2O S CH3
pyridine
O
LiAlH4
(b) CH2OTs CH3

CH3 CH2 CH3

(c) HO CH3 (d)
H2SO4 H2
∆ Pt
11-12 major minor
(a) SN1 on 3° alcohol
H
O H O H Br
− H2O C Br
H Br

carbocation
(b) SN2 on 1° alcohol intermediate

OH OH2
H Br + H2O
Br Br

11-13 CH3 CH3 CH3 CH3

H Cl − H2O Cl
H3C C OH H3C C OH2 H3C C H3C C Cl
CH3 CH3 CH3 CH3
281
Copyright © 2017 Pearson Education, Ltd.
11-14 The two standard qualitative tests are:
1) chromic acid—distinguishes 3° alcohol from either 1° or 2°
R H2CrO4 R(or H) H2CrO4 R(or OH)
(orange) (orange)
R OH no reaction R OH R C O + Cr3+
(stays orange) blue-green
R H
3° 1°, 2°
2) Lucas test—distinguishes 1° from 2° from 3° alcohol by the rate of reaction
R R
ZnCl2
3° R OH + HCl R Cl + H2O insoluble—"cloudy" in < 1 minute
R R
soluble
R R
ZnCl2
2° R OH + HCl R Cl + H2O insoluble—"cloudy" in 1-5 minutes
H H
soluble
H H
ZnCl2
1° R OH + HCl R Cl + H2O insoluble—"cloudy" in > 6 minutes
(No observable reaction at room temp.)
H H
soluble

OH
(a) OH

Lucas: cloudy in 1-5 min. cloudy in < 1 min.

H2CrO4: immediate blue-green no reaction—stays orange
(b) OH O

Lucas: cloudy in 1-5 min. no reaction

H2CrO4: immediate blue-green no reaction—stays orange
(c) OH
OH

Lucas: no reaction cloudy in 1-5 min.

H2CrO4: DOES NOT DISTINGUISH—immediate blue-green for both
(d) OH OH (**Remember that allylic cations are resonance-
stabilized and are about as stable as 3° cations.
Lucas: cloudy in < 1 min. ** no reaction Thus, they will react as fast as 3° in the Lucas test,
H2CrO4: DOES NOT DISTINGUISH— even though they may be 1°. Be careful to notice
immediate blue-green for both subtle but important structural features!)
(e) O
OH

Lucas: no reaction cloudy in < 1 min.

H2CrO4: DOES NOT DISTINGUISH—stays orange for both

282
Copyright © 2017 Pearson Education, Ltd.
11-15 3°
CH3 methyl Br
H Br − H2O shift CH3 Br
OH OH2 C C
CH2 CH2

1°
Even though 1°, the neopentyl carbon is hindered to backside attack, so SN2 cannot occur easily.
Instead, an SN1 mechanism occurs, with rearrangement.

11-16 H H H This 3° carbocation is planar at the

CH3 CH3 – H2O CH3 C+ so that the Cl– can approach
C CH from the top or bottom giving both
CH3 H Cl CH3 3 the cis and trans isomers.
OH O H approach from below
approach
H from
above Cl
Cl
H H
CH3 CH3
methyls trans methyls cis
Cl CH3
CH3 Cl
11-17
ZnCl2 (from HCl)
CH3 CH3 CH3 CH3
H H H 3°
CH3 Cl
OH O H H C Cl
ZnCl2 C
H H 2°
hydride
shift
rearrangement
11-18
OH Br
3 + PBr3 3 + P(OH)3

6 CH3(CH2)14CH2OH + 2 P + 3 I2 6 CH3(CH2)14CH2I + 2 P(OH)3

OH Br
3 + PBr3 3 + P(OH)3

11-19 OH Cl
SOCl2
(a) retention

CH3 CH3

283
Copyright © 2017 Pearson Education, Ltd.
11-19 continued
OH OTs Cl
TsCl NaCl Another possible answer would
(b) be to use PCl3 or PCl5 .
pyridine
SN2—inversion
CH3 CH3 CH3
11-20 H Cl
H Cl H Cl
(a)
D O S O D O S O D O S O
Cl Cl
+ Cl

− HCl
allylic! Cl
D D
D O S O
Cl C
O S O +
CH

Cl Cl
D
SO2 + Cl D Cl
+
Cl
(b) The key is that the intermediate carbocation is allylic, very stable, and relatively long-lived. It can
therefore escape the ion pair and become a "free" carbocation. The nucleophilic chloride can attack any
carbon with positive charge, not just the one closest. Since two carbons have partial positive charge, two
products result.
11-21 (b) OH HCl Cl
(a) HCl ZnCl2
OH no reaction unless heated,
ZnCl2 then
Cl HBr Br
HBr
Br
PBr3
Br PBr3 Br
P
I2 I (poor reaction on 3°)
SOCl2 On 3° alcohols, P I
Cl these reagents
often give more I2
elimination than (poor reaction on 3°)
substitution.
SOCl2 Cl

284
Copyright © 2017 Pearson Education, Ltd. (poor reaction on 3°)
11-21 continued
Cl
(c) HCl no reaction unless heated, then
OH
ZnCl2 SN1—rearrangement
1°, neopentyl
HBr Br
Br +

SN2—minor SN1—rearrangement
(hindered)

PBr3
Br

P
I
I2

SOCl2
Cl

(d) OH HCl Cl Cl SN1—carbocation intermediate

ZnCl2 can be attacked from either
side by chloride.

HBr Br Br SN1 at 2° carbon—carbocation

intermediate can be attacked
from either side by bromide.
PBr3 Br
SN2 with inversion of configuration

P I
SN2 with inversion of configuration
I2

SOCl2 Cl
See the Problem Solving
retention of configuration Hint next to Problem 11-20
of the text.

285
Copyright © 2017 Pearson Education, Ltd.
11-22 Water is also produced in each of these dehydration reactions.
OH
(a) H2SO4 , ∆
+

major minor
OH H2SO4 , ∆
(b) + Rearrangement
is likely.
major (cis + trans) minor
OH
(c) H2SO4 , ∆
+
major (cis + trans) minor

OH
H2SO4 , ∆
(d) +

major minor

(e) OH H2SO4 , ∆
+ + Rearrangement
is likely.
major minor trace

11-23 good leaving group

O
H H O N O H
P
O Cl Cl O P Cl O P Cl N
Cl
Cl Cl
H

E2 N

H
O N
Cyclohexene was formed
without a carbocation O P Cl
intermediate.
Cl
This product can react with two
more alcohols to become leaving
groups in the E2 elimination.

286
Copyright © 2017 Pearson Education, Ltd.
11-24
Both mechanisms begin with protonation of the oxygen.
H H H H H
H A
H C C O H H C C O H
H H H H
One mechanism involves another molecule of ethanol acting as a base, giving elimination.
H H H H H
H C C O H C C + H2O
HO Et
H H H H

The other mechanism involves another molecule of ethanol acting as a nucleophile, giving substitution.
H H H H
HO Et
H C C O H CH3CH2 O CH2CH3 CH3CH2 O CH2CH3
HO Et
H H
11-25 An equimolar mixture of methanol and ethanol would produce all three possible ethers. The
difficulty in separating these compounds would preclude this method from being a practical route to any
one of them. This method is practical only for symmetric ethers, that is, where both alkyl groups are
identical.
H2SO4
CH3CH2OH + HOCH3 H2O + CH3CH2OCH3 + CH3OCH3 + CH3CH2OCH2CH3
∆
11-26 H
(a) H H H
OH H O H
H H A H C H H2O
∆
H
− H2O
H H H

H O H
(b)
OCH3 OCH3 OCH3 OCH3
C H2O
H H H
H H A
H H H
H2O

OH CH3 OH
O H O H O OCH3
C – CH3OH
H A H
H H H
H
H H H H
H2O
O

287
Copyright © 2017 Pearson Education, Ltd.
11-26 continued H
1° CH H H
(c) CH2OH CH2 O H 2 C
H H H hydride
H C H
H A ∆ shift
− H2O H
ring This 1° carbocation
would be very unstable. H2O
expansion
H H CH2 CH3
C H H
H2O
+
H

(d)
H OEt H
O H A HO C
HO HO HO OEt
C

starting material
redrawn to show H OEt
relationship to HO OEt
product

11-27
H2C H
H3C CH3 H3C CH3 H3C CH3
CH3 CH3 CH3 C CH3
∆ H3C
OH O H C
H A − H2O ring
H contraction H2O
CH2
11-28 CH3
H3C
(a) − H2O

H A
H3C CH3 H3C CH3 H3C C CH3
HO OH HO O H HO
H
Methyl shift

H3C C CH3 C CH3 CH3 CH3

HO H O CH3 H O CH3 O CH3

H2O

11-28(a) continued on next page

288
Copyright © 2017 Pearson Education, Ltd.
11-28(a) continued
Alkyl shift—ring contraction

H3C C CH3 H3C H3C H3C

C CH3 CH3 H2O CH3
HO H O H O O

(b)
OH H A OHH – H2O OH 3° and doubly
benzylic carbocation
OH O H
C
ring
Ph Ph Ph Ph Ph Ph expansion

O O H O H
H2O C
Ph Ph Ph
Ph Ph Ph

11-29
ring O H O H
OH H2SO4 OH
H C H expansion C C
C C C C H C CH3 C CH3
H H H H H H
Similar to the pinacol rearrangement, this mechanism B Another oxygen in the reaction
involves a carbocation next to an alcohol, with O mixture is the likely base,
rearrangement to a protonated carbonyl. Relief of removing this proton.
some ring strain in the cyclopropane is an added
advantage of the rearrangement. CH3
11-30 O O O
CH2 O
C O O
(a) 2 (b) (c) +H (d)
H3C H H
H
O
O O
11-31 (a) CH3CH2CH2 C Cl + HOCH2CH2CH3 (b) CH3(CH2)3OH + Cl CCH2CH3
O O
(c) H3C OH + Cl CCH(CH3)2 (d) OH + Cl C

289
Copyright © 2017 Pearson Education, Ltd.
11-32 The strength of an acid is determined by the stability of its conjugate base. The more stable the
conjugate base, the stronger the acid.
O O O O

H3C S O H H+ + H3C S O H3C S O H3C S O

O O O O

O O O
H3C C O H H+ + CH3 C O CH3 C O

The methanesulfonate anion is stabilized by resonance and by induction: It has three equivalent resonance
forms, plus the sulfur atom is more electronegative than carbon and plays a small role in stabilizing the
negative charge on oxygen. The acetate ion has two equivalent resonance forms, but no inductive effect to
stabilize the anion. Acetate is good, but the methanesulfonate ion is even better.

Question in Key Mechanism 11-6

In many, but not all, cases of the Williamson ether synthesis, there will be two possible pathways to make
new bonds to oxygen. Because this is an SN2 reaction, always choose the pathway in which an alkoxide
attacks a 1° carbon, or if that is not possible, a 2°carbon. SN2 reactions cannot take place at 3° carbons,
nor at sp2 carbons.
SN2 at 1° carbon—GOOD SN2 at 2° carbon—not as good
O O Br
+ + O
Br

11-33 Proton transfer (acid-base) reactions are much faster than almost any other reaction. Methoxide will
act as a base and remove a proton from the oxygen much faster than methoxide will act as a nucleophile
and displace water.
CH3O–
CH3CH2 OH + H+ CH3CH2 OH2 CH3CH2 O CH3

CH3O–

CH3CH2OH + CH3OH

11-34
(a) CH3CH2OH TsCl CH3CH2OTs
pyridine
OCH2CH3
Na
OH O Na+

(b) There are two problems with this attempted bimolecular dehydration. First, all three possible ether
combinations of cyclohexanol and ethanol would be produced. Second, heat and sulfuric acid are the
conditions for dehydrating secondary alcohols like cyclohexanol, so elimination would compete with
substitution.

290
Copyright © 2017 Pearson Education, Ltd.
11-35
(a) What the student did:
Na+ O H CH3CH2 O H
TsO CH2CH3
H3C CH2CH3 H3C CH2CH3
sodium (S)-but-2-oxide (S)-2-ethoxybutane
The product also has the S configuration, not the R. Why? The substitution is indeed an SN2 reaction,
but the substitution did not take place at the chiral center, so the configuration of the starting material is
retained, not inverted.
(b) There are two ways to make (R)-2-ethoxybutane. Start with (R)-butan-2-ol, make the anion, and
substitute on ethyl tosylate similar to part (a), or do an SN2 inversion at the chiral center of (S)-butan-2-ol.
SN2 works better at 1° carbons so the former method would be preferred to the latter.
(c) This is not the optimum method because it requires SN2 at a 2° carbon, as discussed in part (b).
HO H Ts O H Na+ –OCH2CH3 H OCH2CH3
TsCl
H3C CH2CH3 pyridine H3C CH2CH3 low temperature H3C CH2CH3
(high temp.
(S)-butan-2-ol (S)-2-butyl tosylate favors elimination) (R)-2-ethoxybutane
no inversion yet INVERSION!
11-36
NaOH
OH O Na+ + CH3 O SO3CH3 OCH3 + O SO3CH3

1 equiv. O OH O
11-37 NaOCl 1) CH3CH2MgBr NaOCl
(a) CH3CH2CH2OH CH3CH2 C H
TEMPO 2) H3O+ HOAc

O CH2CH3 CH2CH3
1) 2 CH3CH2MgBr H2SO4
(b) CH3CH2 C Cl CH3CH2 C CH2CH3 CH3CH C CH2CH3
2) H3O+
OH

1) BH3 • THF
CH2CH3 CH2CH3 2) H2O2, HO–
NaOCl
CH3CCHCH2CH3 CH3CHCHCH2CH3
HOAc
O OH
11-38
(a)
OH H2SO4 HCO3H OH Any peroxy acid can be used to form the
epoxide, which is cleaved to the trans-
∆ H3O+ diol in aqueous acid.
OH
(b) OH Cl
OH NaOCl O H3O+ HCl
HOAc CH3CH2MgBr
PBr3 Mg, ether
CH3CH2OH CH3CH2Br
291
Copyright © 2017 Pearson Education, Ltd.
11-38 continued
O OH
(c) OH Br MgBr
PBr3 Mg H3O+ H2SO4
ether from part (b) ∆
NaOCl HOAc O H2SO4 mCPBA
OR: ∆
OH PBr3 Br Mg H3O+ O
OH
ether

O
(d)
PBr3 MgBr
OH Br Mg O OCH3
ether from (c) CH3I

alternative P, I2
S N1 H3O+ CH3OH

CH3OH
OCH3 OH
H2SO4

(e) There are several possible combinations of Grignard reactions on aldehydes or ketones. This is one
example. Your example may be different and still be correct. Compare with others in your study group.
CH3CH2CH2OH
TEMPO
1 eq. NaOCl O

PBr3 Mg H H3O+ NaOCl

OH Br
ether OH HOAc O
NBS
H2SO4 or Br2 Mg
OH Br MgBr
∆ hν ether

H3O+

CH3CH2Br Na
OCH2CH3
OH

(f)
OCH3 In a complex synthesis, it is worth the time to analyze what pieces need to
be put together to create the carbon skeleton; this is called "retrosynthesis"
(reverse synthesis), or the "disconnection" approach. This target has a
cyclopentane ring and two four-carbon fragments, so the new C—C bonds
should be made using Grignard reactions.

11-38(f) continued on next page

292
Copyright © 2017 Pearson Education, Ltd.
11-38(f) continued
OH
PBr3
Mg
Br ether MgBr HO
combine H3O+ PBr3
HO O H
1 eq. Mg ether
NaOCl
TEMPO BrMg
O
OCH3 OH H3O+
CH3I Na
from (b)

11-39 O O
H OTs H Br
(a) (b) (c) (d) H
R R
(from inversion)
CH2OMgBr
COOH Cl
(e) (f) (g) Br (h) + CH3CH3

H O
(i) OCH3 (j) + CH3OH (k) (l) O
H
O
(m) (n) (o)
O + + EtOH
major minor H

(p)
O
H

11-40 Stereochemistry is not specified in this problem.

H2SO4 TsCl
(a) OH (b) OH OTs
∆ pyridine

OH
OH NaOCl O H2O
(c) (d)
HOAc H2SO4
or H2CrO4 or PCC or DMP or Swern from (a)

293
Copyright © 2017 Pearson Education, Ltd.
11-40 continued

CH3MgI H3O+ PBr3

(e) O (f) OH Br
ether OH
from (c)
OR

acetyl OTs KBr Br

chloride ∆
O
from (b)
OH Cl O Br OH
(g) (h) HBr HBr
O
from (a) from (d)
11-41 2°
SOCl2 (b) OH SOCl2 Cl
(a) OH Cl
1°
PBr3 PBr3 Br
Br

P P I
I2 I I2
3°
OH Cl 2°
OH SOCl2 Cl
(c) HCl (d)

Br
HBr PBr3 Br

I
HI I
P
I2

11-42
OH O Na+ OCH2CH3
Na CH3CH2Br
(a)
Williamson ether synthesis

294
Copyright © 2017 Pearson Education, Ltd.
11-42 continued
(b) Br OH O MgBr Br
1 eq.
NaOH NaOCl H Mg
+
TEMPO ether

H3O+

OH

H2SO4
∆

O OH O
(c) Br MgBr H2CrO4
Mg 1) H
ether 2) H3O+
H OH
1 eq.
(d) OH NaOCl O 1) CH3CH2MgBr
TEMPO 2) H3O+
11-43 Major product for each reaction is shown.

(a) (b) (c) (d) (e) (f)

cis + trans—rearranged cis + trans cis + trans

rearranged
Note that (d), (e), and (f) produce the same alkene.
11-44 O O
O
(a) CH3 (b) CH3CH2ONO2 (c) (d)
O O
O P OH
O O CH3
(e)
O

OH OH These two dehydrations follow the E1

11-45 H2SO4 H2SO4 mechanism with a common carbocation
∆ ∆ intermediate. The stereochemistry plays
no role in the E1 mechanism.
cis Zaitsev product trans
OTs Elimination of the tosylate with base
OTs O-t-Bu follows the E2 mechanism with the
H stereochemical requirement that the H
CH3 trans and the OTs must be anti-coplanar; see
H
cis CH2 only product text section 7-14.
H
O-t-Bu
295
Copyright © 2017 Pearson Education, Ltd.
11-46
HO H Cl H
SOCl2
(a)
S S—retention
HO H TsO H H Br Alternatively, PBr3
(b) TsCl KBr could be used.
pyridine
S S R—inversion

HO H TsO H H OH
(c) TsCl NaOH
pyridine Keep cold to
S S R—inversion
avoid elimination.

11-47
(a) OH OH2
2° H hydride H
3°
H Br − H2O C shift
C
H H H

Br
Br

(b) PBr3 converts alcohols to bromides OH Br

without rearrangement because no
carbocation intermediate is produced. PBr3
Alternatively, making the tosylate and
displacing with bromide would also work.

11-48 H
1 eq.
OH NaOCl O
(a)
TEMPO

(b) OH PBr3 Br

OH O Na+ OCH3
(c) Na CH3I

(d) H OH H Cl HO H TsO H H Cl
SOCl2 TsCl Cl–
OR
pyridine S N2
H H H H H
CH3 CH3 CH3 CH3 CH3
retention 296 inversion
Copyright © 2017 Pearson Education, Ltd.
11-48 continued
OH
H2SO4 1) O3, –78 °C HIO4
(e) O OH
∆ 2) Me2S
O OH

excess
CH2OH NaOCl COOH NaOCl
(f) (g) OH O
TEMPO HOAc

H H H H
TsCl
(h)
pyridine
CH3 OH CH3 OTs
cis cis

11-49 PBr3 OH 1) TsCl, pyridine

(a) Br Br (e)
2) NaBr
inversion
HBr inversion, SN2
HCl
SOCl2 ZnCl2
(b) Cl
Br SN1
Cl
retention SN1 cis and trans
cis and trans
(c) (d)
11-50 OH

(a) OH
Lucas: no reaction cloudy in 1−5 min.
OH OH
(b)

Lucas: cloudy in 1−5 min. cloudy in < 1 min.

H2CrO4: immediate blue-green no reaction—stays orange

(c)
OH
Lucas: cloudy in 1−5 min. no reaction
H2CrO4: immediate blue green no reaction—stays orange
(d) OH O
Lucas: cloudy in 1−5 min. no reaction
H2CrO4: immediate blue green no reaction—stays orange
(e) O
OH
Lucas: no reaction cloudy in < 1 min.
297
Copyright © 2017 Pearson Education, Ltd.
11-51
The first equivalent of NaH will remove the most acidic proton from the COOH; the second equivalent will
remove the phenolic proton; the final equivalent will remove the proton from the 1° alcohol.
COOH
HO NaH CH3I
pKa 4-5
pKa 16
∆
OH pKa 10

COOCH3 COOCH3 COOCH3

HO HO H3CO
(a) (b) (c)

OH OCH3 OCH3

PBr3 Mg D
11-52 *
ether
A OH C Br MgBr H3O+ OH
+
NaOCl/HOAc
E OMgBr
B O
11-53 HO
OH PBr3 Br Mg MgBr H3O+
ether O
W X Y
H2CrO4 O
O Alternatively, the last step O
could dehydrate the 3° CH3C
alcohol, making this alkene Z. O CH3C Cl
V Keep cold to
avoid elimination.
Z
11-54 OH OH2 H H
CH2 H
H H C
H A − H2O O O
O O O H H

alkyl shift— ring expansion from 1°

ring expansion carbocation to 2°, resonance- H2O
NOTE: Recall that 1° carbocations stabilized carbocation
probably do not exist; this could
CH2 H H be considered a transition state. H
H H
O C H
O O

The migration directly above does NOT occur

as the cation produced is not resonance-stabilized.

continued on next page 298

Copyright © 2017 Pearson Education, Ltd.
An alternative mechanism could be proposed: protonate the ring oxygen, open the ring to a 2°
carbocation followed by a hydride shift to a resonance-stabilized cation, ring closure, and dehydration.
hydride shift to resonance-
stabilized cation
H H
OH OH H OH OH OH
C HC
H A H H C H H H
O O O O O

2° carbocation
H
H H
H H O H H+ off one O, H+ HO H
H C
O H2O O O − H2O O on the other O
H O
H H

11-55 H H
C Cl Cl
(a) OH O ZnCl2
ZnCl2
H
In this presentation of the mechanism, the + H2O ZnCl2
rearrangement is shown concurrently with Cl– + H2O + ZnCl2
cleavage of the C-O bond with no 1° H Cl H+
carbocation intermediate.

(b) ∆ C
H OSO3H C
OH O H H
H + H2O
H
OH2
Once this 3° carbocation is
formed, removal of adjacent C
protons produces the
compounds shown.
H OH2

299
Copyright © 2017 Pearson Education, Ltd.
11-55 continued
(c) All three of the products go through a common carbocation intermediate.
H H H
OH O
H OSO3H
∆ C
+ H2O

OH OH OH O
H
nt
an g eme H OSO3H
rearr H
C H
– H2O
C
C H O
O H H H
H2O H2O

C H
O H2O This is the product from a pinacol rearrangement.
O
11-56
CH3 CH3
(a) OH NaOCl O
O O
HOAc CH3MgBr
MgBr Br
Mg, ether
PBr3
CH3OH CH3Br PBr3
HO
CH3 HO CH3
OR: alternative ending—
not as good as above as OH O
more side products are H2SO4
possible after hydrolysis of
Grignard product
S N1

OH
(b) OH Br MgBr
PBr3 Mg H3O+
ether O NaOCl
HOAc
H O
CH3CH2OH 1 eq.
NaOCl
TEMPO
300
Copyright © 2017 Pearson Education, Ltd.
11-56 continued
MgBr
O MgBr OCH3
OH NaOCl O CH3I
(c)
HOAc from (b)

PBr3 Mg
(d) 2 OH 2 Br ether 2 MgBr
O EtOH, H+ O
H3O+ C C
OEt OH
OH excess NaOCl
TEMPO
MgBr O OH OH
(e) 1)

2) H3O+
from (b)

(f) HO PBr3 Mg
BrMg OH
H3O+
ether from (d)
H
1 eq. NaOCl
Br
OH TEMPO O PBr3

(g) TsCl KCN

HO pyridine TsO H
H H NC

Br MgBr
(h) O 1 eq. NaOCl
OH H SO NBS TEMPO
2 4 Mg
H HO
∆ hν ether

O O BrMg O
OsO4
H2O2 CH3CH2Br
OH
OH PBr3
CH3CH2OH

301
Copyright © 2017 Pearson Education, Ltd.
11-57 For a complicated synthesis like this, begin by working backwards. Try to figure out where the
carbon framework came from; in this problem we are restricted to alcohols containing five or fewer
carbons. The dashed boxes show the fragments that must be assembled. The most practical way of
forming carbon-carbon bonds is by Grignard reactions. The epoxide must be formed from an alkene, and
the alkene must have come from dehydration of an alcohol produced in a Grignard reaction.
fragment A 1 eq. HO
NaOCl fragment A
TEMPO PBr3
fragment B fragment B Mg
BrMg Br
OH ether
O H O
fragment C
mCPBA H3O+

HO
NaOCl/HOAc
fragment C
MgBr
H3O+
major 1. TsCl, py
isomer 2. KOH, ∆ O
1. PBr3
Avoid carbocation conditions OH 2. Mg
to prevent rearrangement. ether OH

11-58
(a) Both of these pseudo-syntheses suffer from the misconception that incompatible reagents or conditions
can co-exist. In the first example, the SN1 conditions of ionization cannot exist with the SN2 conditions of
sodium methoxide. The tertiary carbocation in the first step would not wait around long enough for the
sodium methoxide to be added in the second step. (The irony is that the first step by itself, the solvolysis
of tert-butyl bromide in methanol, would give the desired product without the sodium methoxide.)
In the second reaction, the acidic conditions of the first step in which the alcohol is protonated are
incompatible with the basic conditions of the second step. If basic sodium methoxide were added to the
sulfuric acid solution, the instantaneous acid-base neutralization would give methanol, sodium sulfate, and
the starting alcohol. No reaction on the alcohol would occur.
(b)
CH3OH
Br OCH3 SN1 solvolysis conditions
warm
Several synthetic sequences are possible for the second synthesis.
Na CH3I
OH O– Na+ O

TsCl NaOCH3
OR OH OTs O
pyridine
PBr3 NaOCH3
OR OH Br O

302
Copyright © 2017 Pearson Education, Ltd.
11-59
Compound X : —must be a 1° or 2° alcohol with an alkene; no reaction with Lucas leads to a 1°
alcohol; can't be allylic as this would give a positive Lucas test.
OH

Compound Y : —must be a cyclic ether, not an alcohol and not an alkene; other isomers of cyclic
O ethers are possible.

11-60 OH OTs
TsCl NaOCH3
NO REACTION!
pyridine cannot do an SN2 reaction
this reaction
works fine,
but wait.......

The Williamson ether synthesis is an SN2 displacement of a leaving group by an alkoxide ion. In addition
to being a 3° substrate, this tosylate cannot undergo an SN2 reaction for two reasons. First, backside attack
cannot occur because the back side of the bridgehead carbon is blocked by the other bridgehead. Second,
the bridgehead carbon cannot undergo inversion because of the constraints of the bridged ring system.

This carbon cannot invert

Backside
attack is H OTs H OTs which is required in the SN2
blocked. mechanism.

side view side view

Na CH3I
alternative synthesis: R OH R O– Na+ R OCH3

11-61 Let's begin by considering the facts.

The axial alcohol is oxidized ten times as fast as the equatorial alcohol. (In the olden days, this
observation was used as evidence suggesting the stereochemistry of a ring alcohol.)

CH3 CH3 CH3

H2CrO4 H2CrO4

faster slower HO
O
OH H H H

Second, it is known that the oxidation occurs in two steps: 1) formation of the chromate ester; and
2) loss of H and chromate to form the C=O. Let's look at each mechanism.
AXIAL CH3 CH3 CH3
H2CrO4
H FASTER
Step 1 Step 2
O
OH H H H
O
Base CrO3H
(H2O)
continued on next page
303
Copyright © 2017 Pearson Education, Ltd.
11-61 continued
EQUATORIAL
CH3 CH3 CH3
H2CrO4 CrO3H
HO O SLOWER
Step 1 Step 2
O
H H H H
Base
(H2O)
So what do we know about these systems? We know that substituents are more stable in the
equatorial position than in the axial position because any group at the axial position has 1,3-diaxial
interactions. So what if Step 1 were the rate-limiting step? We would expect that the equatorial
chromate ester would form faster than the axial chromate ester; since this is contrary to what the data
show, Step 1 is not likely to be rate-limiting. How about Step 2? If the elimination is rate limiting,
we would expect the approach of the base (probably water) to the equatorial hydrogen (axial chromate
ester) would be faster than the approach of the base to the axial hydrogen (equatorial chromate ester).
Moreover, the axial ester is more motivated to leave due to steric congestion associated with such a
large group. This is consistent with the relative rates of reaction from experiment. Thus, it is
reasonable to conclude that the second step of the mechanism is rate-limiting.

H
11-62
H OH H O H Protonation of the OH makes a good leaving group.
(a)
H Br There are two reaction paths possible, SN1 and SN2.

start with R
– H2O
Br SN1 would give a racemic mixture.
Br H H Br H H Br
Br
+
C

SN2 would give 100% S. planar 50% S 50% R

The data show that the product has "racemization with excess inversion", that is, more S than R. The best
explanation is that a mixture of SN1 and SN2 is happening. This is not surprising as secondary halides are on
the fence between the two mechanisms.
There is another explanation: when the water leaves, it might not leave all the way so it blocks the incoming
bromide ion from giving the product with retention of configuration, and the SN2 type backside attack is the
dominant pathway.
bromonium ion!
(b) symmetric! racemic mixture!
Br 50:50
– H2O
Br H Br H Br Br H H Br
H Br
H OH H H O H H H H Br Br H
chiral
This mechanism is the reverse of bromohydrin formation, passing through the same bromonium ion
intermediate, leading to a racemic mixture of trans-1,2-dibromocyclopentane. The participation of the Br is
called neighboring group assistance and explains the difference in results between (a) and (b).
304
Copyright © 2017 Pearson Education, Ltd.
11-63
(a) – CH3OH
H3O+ H
C
O OCH3 O OCH3 O H O H

H2O

H H H
C H H3O+ H2O
HO O O O O
OH OH O
H H H
H

H H
HO O H2O HO O
H

It is equally likely for protonation to occur first on the ring oxygen, followed by ring opening, then
replacement of OCH3 by water.
My colleague Dr. Kantorowski suggests this alternative. He and I will arm wrestle to determine
which mechanism is correct.

H2O H H
O H O O H H2O HO O
H
H H
O
(b)
O H2O O
C O O

H3O+
H H
H2O

H
H OH OH
O O H
OH C OH O H3O+ O

H2O O
OH

305
Copyright © 2017 Pearson Education, Ltd.
11-64 One of the keys to solving these "roadmap" or "structure proof" problems is making inferences from
each piece of information given. Ask the question: "What is this fact telling me?"
Q has molecular formula C6H12O Q has one element of unsaturation Q has a ring OR
C=C or C=O
Q cannot be separated into enantiomers Q does not have an asymmetric carbon atom
Q does not react with Br2, KMnO4, H2 Q has no C=C

Q reacts with H2SO4 and loses H2O Q is an alcohol, not a C=O Q has a ring

R has C=C; ozonolysis gives one acyclic product, S R has a C=C in its ring
R has enantiomers the dehydration that produced the C=C also created an asymmetric carbon atom

S is a ketoaldehyde one C of the C=C has an H, the other has an R

Putting all this together gives a 4-membered ring: 3 is too small to fit the optical activity results, 5 is too large.
CH3
CH3 CH3
OH H SO 1) O3, –78 °C
2 4
∗ ∗ O
2) Me2S H
H3C Q H3C R H3C O S

11-65

H H OH H
O H Cl O O O
Cl Cl Cl H
N N N N

Protonation of TCICA increases the polarization of the N-Cl bond. +

Cl Cl H
O O O
H2O H2O

H H

11-66
O O
(a) (b) (c) (d) O

Ph
Ph
O

306
Copyright © 2017 Pearson Education, Ltd.