406   CHAPTER 8    Addition Reactions of Alkenes

REVIEW OF REACTIONS
O 10
1
X H

O
2 OH
1) O3 1) OsO4
2) DMS + En
HX 2) NaHSO3
Br H2O OH
9
HBr,
ROOR KMnO4
NaOH, cold
H3O+
OH
OH 1) RCO3H
+ En
3 2) H3O +

1) Hg(OAc)2, H2O OH
2) NaBH4 Br2, H2O
8

1) BH3 ∙ THF H2 Br2

2) H2O2, NaOH Pt OH
+ En
Br
7
+ En

4 OH
Br
+ En
Br
5 6

1. Hydrohalogenation (Markovnikov) 4. Hydroboration-oxidation 8. Anti dihydroxylation

2. Hydrohalogenation (anti-Markovnikov) 5. Hydrogenation 9. Syn dihydroxylation

3. Acid-catalyzed hydration and 6. Bromination 10. Ozonolysis

oxymercuration-demercuration
7. Halohydrin formation

REVIEW OF CONCEPTS AND VOCABULARY

Section 8.1
• Addition reactions are characterized by the addition of two
groups across a double bond.
Section 8.2
• Alkenes are abundant in nature.
• Ethylene and propylene, both formed from cracking petroleum,
are used as starting materials for a wide variety of compounds.
Section 8.3
• In addition to their systematic and common names, alkenes
are also classified by their degree of substitution, which refers
to the number of alkyl groups connected to a double bond.
Section 8.4
• Addition reactions are thermodynamically favorable at low
temperature and disfavored at high temperature.
Section 8.5
• Hydrohalogenation reactions are characterized by the addi­
tion of H and X across a π bond, where X is a halogen.
• For unsymmetrical alkenes, the placement of the halogen
represents an issue of regiochemistry. Hydrohalogenation
­reactions are regioselective, because the halogen is gen­
erally installed at the more substituted position, called
Markovnikov addition.
• In the presence of peroxides, addition of HBr proceeds via an
anti-Markovnikov addition.
• The regioselectivity of an ionic addition reaction is deter­
mined by the preference for the reaction to proceed through
the more stable carbocation intermediate.
• When one new chiral center is formed, a racemic mixture of
enantiomers is obtained.
• Hydrohalogenation reactions are only efficient when carbo­
cation rearrangements are not a concern.
Section 8.6
• Addition of water (H and OH) across a double bond is called
hydration.
• Addition of water in the presence of an acid is called acid-
catalyzed hydration, which generally proceeds via a
Markovnikov addition.
• Acid-catalyzed hydration proceeds via a carbocation inter­
mediate, which is attacked by water to produce an oxonium
ion, followed by deprotonation.
 Review of Concepts and Vocabulary    445

REVIEW OF REACTIONS
1. Elimination
3 4 5
2 X O O 2. Hydrohalogenation (two
xs HX CH3 ­equivalents)
R R R H
3. Hydrohalogenation (one
HgSO4
X HX ­equivalent)
H2SO4, H2O 1) R2BH
1) xs NaNH2 (one
1 X 2) H2O2, NaOH
2) H2O
equiv.) 4. Acid-­catalyzed hydration
R
X2 (one equiv.)
X 5. Hydroboration-­oxidation
R
CCl4 6 6. Halogenation (one equivalent)
X R X
1 1) xs NaNH2 xs X2
7. Halogenation (two equivalents)
X X X
R 2) H2O 1) NaNH2 1) O3 CCl4 8. Ozonolysis
2) RX 2) H2O X
R 7 9. Alkylation
9 8
H2 O O X
12 R R 10. Dissolving metal reduction
R R Lindlar's cat. + C
R OH 11. Hydrogenation
O
12. Hydrogenation with a poisoned
H2 Na
R R 10 catalyst
11 R Pt NH3 (l) R

REVIEW OF CONCEPTS AND VOCABULARY

SECTION 9.1 • Catalytic hydrogenation in the presence of a poisoned cata-
• A triple bond is comprised of three separate bonds: one σ lyst (Lindlar’s catalyst or Ni2B) yields a cis alkene.
bond and two π bonds. • A dissolving metal reduction will convert an internal alkyne
• Alkynes exhibit linear geometry and can function as bases or into a trans alkene. The reaction involves an intermediate radi­
as nucleophiles. cal anion and employs fishhook arrows, which indicate the
movement of only one electron.
SECTION 9.2
• Alkynes are named much like alkanes, with the following SECTION 9.6
additional rules: • Alkynes react with HX via a Markovnikov addition.

The parent is the longest chain that includes the ​CC​ bond.
• The suffix “ane” is replaced with “yne.”
• alkynes involves a vinylic carbocation, while another possi-
• The triple bond should receive the lowest number possible.
• The position of the triple bond is indicated with a single
locant placed either before the parent or the suffix.
• Monosubstituted acetylenes are terminal alkynes, while
disubstituted acetylenes are internal alkynes.
SECTION 9.3
• The conjugate base of acetylene, called an acetylide ion, is rela-
tively stabilized because the lone pair occupies an sp-­hybridized
orbital.
• The conjugate base of a terminal alkyne is called an alkynide
ion, which can only be formed with a sufficiently strong base,
such as NaNH2.
SECTION 9.4
• Alkynes can be prepared from either geminal or vicinal
­dihalides via two successive E2 reactions.
SECTION 9.5
• Catalytic hydrogenation of an alkyne yields an alkane.
• One possible mechanism for the hydrohalogenation of
ble mechanism is termolecular.
• Addition of HX to alkynes probably occurs through a vari-
ety of mechanistic pathways all of which are occurring at the
same time and competing with each other.
• Treatment of a terminal alkyne with HBr and peroxides gives
an anti-­Markovnikov addition of HBr.
SECTION 9.7
• Acid-­catalyzed hydration of alkynes is catalyzed by mercuric
sulfate (HgSO4) to produce an enol that cannot be isolated
because it is rapidly converted into a ketone.
• Enols and ketones are tautomers, which are constitutional
isomers that rapidly interconvert via the migration of a proton.
• The interconversion between an enol and a ketone is called
keto-­enol tautomerization and is catalyzed by trace amounts
of acid or base.
• Hydroboration-­oxidation of a terminal alkyne proceeds via an
anti-­Markovnikov addition to produce an enol that is rapidly
converted into an aldehyde via tautomerization.
• In basic conditions, tautomerization proceeds via a resonance-­
stabilized anion called an enolate ion.
344 CHAPTER 7 Alkyl Halides: Nucleophilic Substitution and Elimination Reactions

Certainly, this elimination product is also accompanied CONCEPTUAL CHECKPOINT

by a substitution product. But let’s focus our attention on 7.45 For each pair of compounds below, identify which one is
elimination, and let’s compare the rate equation for each of expected to undergo elimination more rapidly when treated with
these elimination processes: a strong base, and explain your answer.
Cl H2O Br CD3 Br Br H Br D
heat Rate = kH [C4H9Cl]
(a) D3C CD3 (b) D3C CD3

D3C Cl CD3 D D D
H2O
Rate = kD [C4D9Cl] Cl
heat D
D3C CD3 D3C (c) D D Cl

D
7.46 Identify whether each of the following reactions is expected
In this case, the ratio of the rate constants (kH/kD) is measured to exhibit a primary isotope effect if (CD3)3CBr is used instead of

effect. Therefore, we conclude that the CH bond must be

to be 1.1. This value indicates the absence of a primary isotope (CH3)3CBr. Explain your reasoning in each case.

breaking during a step that is NOT the rate-determining step. Br

NaOEt
Br
EtOH

CH bond is broken in the second step of the mechanism, after

This finding is consistent with an E1 mechanism, in which the (a) (b)

the rate-determining step has occurred (Mechanism 7.3).

REVIEW OF REACTIONS
SN2 Reactions
H H
− SN2 −
Nuc + R C X R C Nuc + X
H H

E2 Reactions
H − −
E2
C C + Base C C + H Base + X
X

SN1 and E1 Reactions

X ROH OR
+
+
SN1 product E1 product

Synthetically Useful Transformations

Primary Substrates
NaOH Br NaCN
R
An alkyl halide

HBr CH3CO2Na CN
OH
R R
An alcohol A nitrile
DBU or DBN NaOCH3 NaSH
or
TsCl, t-BuOK
NaOH
py

OTs t-BuOK OCH3 SH O

R R R R R
An alkyl tosylate An alkene An ether A thiol An ester O
 Review of Concepts and Vocabulary 345

Tertiary Substrates

HBr
Br t-BuOK

An alkyl halide NaOH

H2O

OH conc.H2SO4

An alcohol An alkene An alkene

NaOH (Zaitsev product) (Hofmann product)

OTs
TsCl, t-BuOK
py

An alkyl tosylate

REVIEW OF CONCEPTS AND VOCABULARY

SECTION 7.1
• In an alkyl halide, the halogen can serve as a leaving group,
for substitution reactions and elimination reactions.
• Good leaving groups are the conjugate bases of strong
acids.
SECTION 7.6
• A cis alkene will generally be less stable than its stereoiso-
meric trans alkene. This can be verified by comparing heats
of combustion for isomeric alkenes.
• A trans π bond cannot be incorporated into a small ring.
When applied to bicyclic systems, this rule is called Bredt’s

bon of a bicyclic system to possess a CC double bond if it

SECTION 7.2
• The alpha (α) position is the carbon atom connected directly
to the halogen, while the beta (β) positions are the carbon
atoms connected to the α position.
• Alkyl halides are classified as primary (1°), secondary (2°), or
tertiary (3°) based on the number of alkyl groups connected
to the α position.
SECTION 7.3
• Bimolecular nucleophilic substitution reactions are called
SN2 reactions.
• SN2 reactions proceed via inversion of configuration,
because the nucleophile can only attack from the back side.
• SN2 reactions cannot be performed with tertiary alkyl halides.
• An SN2 process will generally not occur if there are three sub-
stituents at a β position.
SECTION 7.4
• There are many factors that contribute to nucleophilicity,
including polarizability and the presence of a charge.
• In the laboratory, methylation is accomplished via an
SN2 process using methyl iodide. In biological systems, a
methylating agent called SAM (S-adenosylmethionine) is
employed.
SECTION 7.5
• A weak base is a stabilized base, and a strong base is an
unstable base.
• There is an inverse relationship between the strength of
a base and the strength of its conjugate acid.
• When treated with a strong base, an alkyl halide can undergo
a type of elimination process, called beta elimination, also
known as 1,2-elimination.
• Bimolecular elimination reactions are called E2 reactions.
rule, which states that it is not possible for a bridgehead car-
involves a trans π bond being incorporated in a small ring.
SECTION 7.7
• E2 reactions are regioselective and generally favor the more
substituted alkene, called the Zaitsev product.
• When both the substrate and the base are sterically hindered,
an E2 reaction can favor the less substituted alkene, called the
Hofmann product.
• If the β position has two different protons, the resulting E2
reaction can be stereoselective, because the trans isomer will
be favored over the cis isomer (when applicable).
• If the β position has only one proton, an E2 reaction is said to
be stereospecific, because the proton and the leaving group
must be anti-periplanar to one another.
SECTION 7.8
• When a tertiary alkyl halide is dissolved in a polar solvent that
is both a weak base and a weak nucleophile (such as ethanol,
EtOH), substitution and elimination products are both observed.
• Unimolecular nucleophilic substitution reactions are called SN1
reactions. An SN1 mechanism is comprised of two core steps:
1) loss of a leaving group to give a carbocation intermediate; and
2) nucleophilic attack.
• When a solvent molecule functions as the attacking nucleo-
phile, the resulting SN1 process is called solvolysis.
• Unimolecular elimination reactions are called E1 reactions.
• SN1 processes are favored by polar protic solvents.
• SN1 and E1 processes are observed for tertiary alkyl halides,
as well as allylic and benzylic halides.
• When the α position is a chiral center, an SN1 reaction gives nearly
a racemic mixture. In practice, there is generally a slight prefer-
ence for inversion over retention of configuration, as a result of
the effect of ion pairs.
 Review of Reactions 819

many exciting applications. These compounds are also being

explored as novel drug delivery systems. Tubular fullerenes have
also been prepared:

These compounds, which are called nanotubes, can be

thought of as a rolled-up sheet of graphite capped on either
end by half of a buckyball. Nanotubes have many potential
applications. They can be spun into fibers that are stronger
and lighter than steel, and they can also be made to carry
electrical currents more efficiently than metals. The next
several decades are likely to see many exciting applications
of buckyballs and nanotubes. For their discovery of fullerenes,

maggio07/Getty Images
Kroto, Curl, and Smalley were awarded the 1996 Nobel Prize
in Chemistry.

maggio07/Getty Images

REVIEW OF REACTIONS
Reactions at the Benzylic Position

Oxidation Free-Radical Bromination

O Br

Na2Cr2O7 OH NBS
H2SO4, H2O Heat

1) KMnO4, H2O, heat Elimination Reactions

2) H3O+

Substitution Reactions OH Conc. H2SO4

+ H2O
E1

Br H2O OH
+ HBr
SN1
Br NaOEt
+ EtOH + NaBr
Br OH E2
NaOH
+ NaBr
SN2

Reduction

Catalytic Hydrogenation Birch Reduction

O O
Ni
R R
+ 3 H2 100 atm
150°C Na, CH3OH Na, CH3OH
NH3 NH3
872   CHAPTER 18   Aromatic Substitution Reactions

18.36 When 2-ethyl-5-chlorotoluene was treated with sodium hydroxide at high tempera-
ture, followed by treatment with H3O+, three constitutional isomers with the molecular for-
mula C9H12O were obtained. Draw all three products.

APPLY the skill 18.37 The welwitindolinones are a class of natural products that exhibit a host of bio-
logical activities including insecticidal, fungicidal, and anti-cancer properties. The following
reaction was performed using SnCl4, a Lewis acid, in a model study en route to the core
skeleton of the welwitindolinones.7

Cl
O H3CO H
Me H
Br O Br CH3 CH3
CH3 CH3
H3C Cl O O SCN
O CH3
SnCl4 H
N N O
N
H H N
CH3
CH3
N-methylwelwitindolinone C
isothiocyanate

(a) Each of the aromatic substitution reactions that we have encountered involves a key
intermediate (sigma complex, Meisenheimer complex, or benzyne intermediate). Determine
which type of aromatic substitution pathway is occurring in the first reaction shown above,
and draw the key intermediate for the process.
(b) Show a mechanism of the formation for the intermediate drawn in (a).
(c) Typically this type of reaction cannot be performed in the presence of secondary
amines (R2NH), which are basic and will react with the Lewis acid. Explain why the aromatic
substitution works in this case.

need more PRACTICE? Try Problems 18.49–18.51, 18.56, 18.72, 18.78

REVIEW OF REACTIONS
Electrophilic Aromatic Substitution

Br2 Cl2 HNO3 CH3Cl Cl

Dilute Fuming
H2SO4 AlCl3
AlBr3 AlCl3 H2SO4 H2SO4 AlCl3
O
Br Cl NO2 SO3H CH3

1 2 3 4 5 6
Excess 1) KMnO4,
1) Fe or Zn, HCl NBS H2O, heat Zn(Hg), HCl
2) NaOH (Section 17.6) 2) H3O+ heat
(Section 17.6)
O
NH2 CBr3
OH

7 8 9 10

1. Bromination 4. Sulfonation/desulfonation 7. Reduction 10. Clemmensen reduction

2. Chlorination 5. Friedel–Crafts alkylation 8. Benzylic bromination
3. Nitration 6. Friedel–Crafts acylation 9. Oxidation

Other Aromatic Substitution Reactions               
Nucleophilic Aromatic Substitution
Br OH
1) NaOH, 70°C
2) H3O+
NO2 NO2
REVIEW OF CONCEPTS AND VOCABULARY
SECTION 18.1
• Alkenes undergo addition when treated with bromine, while
benzene is inert under the same conditions.
• In the presence of iron, an electrophilic aromatic substitu-
tion reaction is observed between benzene and bromine.
SECTION 18.2
• Iron tribromide is a Lewis acid that interacts with Br2 and
­generates Br+, which is sufficiently electrophilic to be
attacked by benzene.
• Electrophilic aromatic substitution involves two steps:
• Formation of the sigma complex, or arenium ion. This
step is endergonic.
• Deprotonation, which restores aromaticity.
• Aluminum tribromide (AlBr3) is another common Lewis acid
that can serve as a suitable alternative to FeBr3.
• Chlorination of benzene is accomplished with a suitable
Lewis acid, such as aluminum trichloride.
SECTION 18.3
• Sulfur trioxide (SO3) is a very powerful electrophile that is
present in fuming sulfuric acid. Benzene reacts with SO3 in a
reversible process called ­sulfonation.
SECTION 18.4
• A mixture of sulfuric acid and nitric acid produces a small
amount of ­nitronium ion (NO2+). Benzene reacts with the
nitronium ion in a process called nitration.
• A nitro group can be reduced to an amino group, providing
a two-step method for installing an amino group.
SECTION 18.5
• Friedel–Crafts alkylation enables the installation of an alkyl
group on an aromatic ring.
• In the presence of a Lewis acid, an alkyl halide is converted
into a carbocation, which can be attacked by benzene in an
electrophilic aromatic substitution.
• A Friedel–Crafts alkylation is only efficient in cases where car-
bocation rearrangements cannot occur.
• When choosing an alkyl halide, the carbon atom connected
to the halogen must be sp3 hybridized.
• Polyalkylations are common and can generally be avoided by
controlling the reaction conditions.
Review of Concepts and Vocabulary    873
Elimination-Addition
Cl OH
1) NaOH, 350°C
2) H3O+
Cl NH2
NH2
1) NaNH2, NH3 (l )
+
2) H3O+
SECTION 18.6
• Friedel–Crafts acylation enables the installation of an acyl
group on an aromatic ring.
• When treated with a Lewis acid, an acyl chloride will generate an
acylium ion, which is resonance stabilized and not susceptible
to carbocation rearrangements.
• When a Friedel–Crafts acylation is followed by a Clem-
mensen reduction, the net result is the installation of an alkyl
group. This two-step process is a useful synthetic method for
installing alkyl groups that cannot be installed efficiently with
a direct alkylation process.
• Polyacylation is not observed, because introduction of an
acyl group deactivates the ring toward further acylation.
SECTION 18.7
• A methyl group is said to activate an aromatic ring and is an
ortho-para director.
• An aromatic ring is even more highly activated by a methoxy
group, which is also an ortho-para director.
• All activators are ortho-para directors.
SECTION 18.8
• A nitro group is said to deactivate an aromatic ring and is a
meta director. Most deactivators are meta directors.
SECTION 18.9
• Halogens (such as Cl, Br, or ) are an exception in that they are
deactivators but are ortho-para directors.
SECTION 18.10
• Strong activators are characterized by the presence of a
lone pair immediately adjacent to the aromatic ring.
• Moderate activators exhibit a lone pair that is already delo-
calized outside of the ring. Alkoxy groups are an exception
and are moderate activators.
• Alkyl groups are weak activators.
• Halogens (such as Cl, Br, or ) are weak deactivators.
• Moderate deactivators are groups that exhibit a π bond to
an electronegative atom, where the π bond is conjugated
with the aromatic ring.
• Strong deactivators are powerfully electron withdrawing,
either by resonance or induction.
574 CHAPTER 12 Alcohols and Phenols

REVIEW OF REACTIONS
Preparation of Alkoxides SN2 Reactions with Alcohols

NaH − + HBr
ROH or Na
RO Na
OH Br
1) TsCl, py
Preparation of Alcohols via Reduction 2) NaBr
R S
NaBH4 , MeOH
H
O PBr3
O
H2
Pt, Pd, or Ni
R H SOCl2
R H
1) LiAIH4 H py
2) H3O+ OH Cl

NaBH4 , MeOH R S
O OH HCl
H2 ZnCl2
R R Pt, Pd, or Ni R R
1) LiAIH4
E1 and E2 Reactions with Alcohols
2) H3O+

conc. H2SO4
O OH + H2O
Heat
1) Excess LiAIH4
R OH 2) H3O+ R OH

TsCl NaOEt
O OH py OTs
1) Excess LiAIH4
+ MeOH
R OMe 2) H3O+ R OH
Oxidation of Alcohols and Phenols

OH O
Preparation of Alcohols via Grignard Reagents Na2Cr2O7
H2SO4 , H2O
O OH R R R R
1) RMgX Secondary Ketone
2) H3O+ alcohol
R
OH O
O OH Na2Cr2O7
1) Excess RMgX H2SO4 , H2O
+ MeOH R R OH
2) H3O+ R R
R OMe Primary Carboxylic
R alcohol acid

OH PCC, CH2Cl2 O
Protection and Deprotection of Alcohols or DMP, CH2Cl2
TMSCl R or 1) DMSO, (COCI)2 R H
Et3N 2) Et3N
Primary Aldehyde
R OH R OTMS alcohol

TBAF
OH O

Na2Cr2O7
SN1 Reactions with Alcohols
H2SO4 , H2O
R R
HX Phenol
OH X + H2O O
R R
R R Benzoquinone
 Review of Reactions 623

PRACTICE the skill 13.24 Propose an efficient synthesis for each of the following transformations:
OH
Br OH Br

(a) (b)
O
Br OH Br

(c) (d)
Cl
Cl Cl Cl

(e) (f )
OH
Cl OH

(g) (h)
OH

(i)

APPLY the skill 13.25 Decytospolides A and B are fungal natural products that are toxic to some cancer
cells. In a synthesis of these natural products, compound 3 was prepared via the reaction
between an epoxide (compound 2) and a Grignard reagent.7 Draw the structure of 2, and
provide a complete mechanism for the conversion of 1 to 3.
OBn OBn
MgBr
NaH 1)
2
TsO 2) H3O+
OH 1 OH 3
RO
O
Bn =
O
Decytospolide A (R = H)
Decytospolide B (R = COCH3)

need more PRACTICE? Try Problems 13.49, 13.58, 13.59

REVIEW OF REACTIONS
Preparation of Ethers
Williamson Ether Synthesis Alkoxymercuration-Demercuration

1) NaH
R H RO H
1) Hg(OAc)2, ROH
R OH 2) RX
R O R
2) NaBH4 R H
R R R R

Reactions of Ethers
Acidic Cleavage Autooxidation
Excess OOH
HX O2
R O R Heat
R X + R X + H2O
O (slow) O
Excess
HX A hydroperoxide
O R OH + R X
Heat
624 CHAPTER 13 Ethers and Epoxides; Thiols and Sulfides

Preparation of Epoxides
MCPBA

H H O

H H
R R 1) Br2, H2O R R
2) NaOH
cis cis

Enantioselective Epoxidation
O
(CH3)3COOH
Ti[OCH(CH3)2]4
R OH
(+)-DET

R OH

O
(CH3)3COOH
Ti[OCH(CH3)2]4
(–)-DET
R OH

Ring-Opening Reactions of Epoxides

Strong nucleophile
O Acid-catalyzed

1) NaOR 1) NaCN 1) NaSR 1) RMgBr 1) LiAlH4 HX [H+] [H+]

2) H3O+ 2) H3O+ 2) H3O+ 2) H3O+ 2) H3O+ H2O ROH

OH OH OH OH OH HO HO HO

RO NC RS R H X OH OR

Thiols and Sulfides

Thiols Sulfides
Br SH 1) NaOH
R SH R S R
NaSH 2) RX
R1 R2 R1 R2 Me
MeX + −
S S + X
NaOH/H2O R R R R
Br2
H2O2
RSH + RSH R S S R
O O
A disulfide Na O4 H2O2
HCl, Zn S S R S R
R R R R
O

Sulfide Sulfoxide Sulfone

 Review of Reactions 927

H 5

1 2 2

FIGURE 19.10
A 1H NMR spectrum 10 9 8 7 6 5 4 3 2
of an aldehyde. Chemical Shift (ppm)

13
C NMR Signals
In a 13C NMR spectrum, a carbonyl group of a ketone or aldehyde will generally produce a weak
signal near 200 ppm. This signal can often be identified with relative ease, because very few signals
appear that far downfield in a 13C NMR spectrum (Figure 19.11).

O
209.1

FIGURE 19.11 220 200 180 160 140 120 100 80 60 40 20 0

A 13C NMR spectrum of a ketone. Chemical Shift (ppm)

CONCEPTUAL CHECKPOINT
19.42 Compound A has the molecular formula C10H10O and exhibits a strong
1) [H+], HS SH
signal at 1720 cm−1 in its IR spectrum. Treatment with 1,2-ethanedithiol followed Compound A
2) Raney Ni
by Raney nickel affords the product shown. Identify the structure of compound A.

REVIEW OF REACTIONS SYNTHETICALLY USEFUL REACTIONS

1. Hydrate Formation
O
[H+], H2O RCO3H O
2. Acetal Formation HO OH
1 15
3. Cyclic Acetal [H+] O
Formation ROH, – H2O H2C PPh3
[H+]
4. Cyclic Thioacetal RO OR OH
Formation HO 14
2 KCN, HCl
– H2O [H+]
5. Desulfurization SH
OH
1) RMgBr
HS 2) H3O+
6. Imine Formation O O
– H2O 13
1) LiAIH4 CN
7. Enamine Formation 3 2) H3O+ OH
[H+] [H+]
8. Oxime Formation RNH2 [H+] [H+] NH2NH2
S S – H2O R2NH NH2OH – H2O R 12
9. Hydrazone Formation – H2O – H2O OH
4
10. Wolff–Kishner Reduction R
N
R R NH2 11
11. Reduction of a Ketone N N
Raney OH
12. Grignard Reaction Ni N
5 6
13. Cyanohydrin Formation 7 9
14. Wittig Reaction 8
H H NaOH, H2O, heat
15. Baeyer–Villiger Oxidation
10
 Review of Reactions 985

REVIEW OF REACTIONS
Preparation of Carboxylic Acids Reactions of Carboxylic Acids

1) NaCN OH
R
R Br 2) H3O+, heat O H H
O 1) xs LiAlH4
+
O R OH 2) H3O R OH
1) Mg
R Br BH3 THF
2) CO2 R OH
3) H3O+

Preparation and Reactions Preparation and Reactions

of Acid Chlorides of Acid Anhydrides

O O O
O O O
R
R OR NH2 N
OR NH2 N
xs
H
ROH
ROH xs xs H xs RNH2
RNH2 NH3 O
Pyridine NH3
O
H2O R
H 2O R N
N xs
xs O O R2NH R
O O 1) NaOH
O R2NH R OH
SOCl2 1) xs LiAlH4
OH 2) CH3COCl O
1) xs LiAlH4 OH
Cl 2) H3O+ H
OH
2) H3O+ H Heat H
R2CuLi 1) xs RMgBr
R2CuLi 1) xs RMgBr H 2) H3O+ 1) LiAl(OR)3H
2) H3O+ 1) LiAl(OR)3H 2) H3O+
2) H3O+ O OH
O O
OH
O
R
R R H
R R
R H

Preparation of Esters Reactions of Esters

H3O+

O O O O
1) NaOH NH3 1) NaOH, heat
2) CH3
CH3 2) H3O+ + ROH
R OH R O R OR R OH

O O 1) xs 1) xs RMgBr
[H+] LiAlH4 2) H3O+
+ H2O 2) H3O+ 1) DIBAH
R OH MeOH R OMe
2) H3O+

O OH O OH
O O
ROH R
R NH2 R R H R
R Cl Pyridine R OR R

Preparation of Amides Reactions of Amides

H3O+
O O
NH3 O heat O

R Cl (two equivalents) R NH2

R NH2 R OH
1) NaOH, heat
2) H3O+

1) xs LiAlH4
2) H2O
R NH2
986   CHAPTER 20    Carboxylic Acids and Their Derivatives

Preparation of Nitriles Reactions of Nitriles

H3O+
heat
O
NaCN
R Br R C R C N
N 1) NaOH, heat R OH
2) H3O+
O
SOCl2 O
R C N
R NH2 – SO2 1) RMgBr
R C N
– 2 HCl 2) H3O+ R R

H H
1) xs LiAlH4
R C N
2) H2O R NH2

REVIEW OF CONCEPTS AND VOCABULARY

SECTION 20.1
• Carboxylic acids are abundant in nature, and they are widely
used in the pharmaceutical and other industries.
• For industrial purposes, acetic acid is converted into vinyl
acetate, which is a carboxylic acid derivative.
SECTION 20.2
• Compounds containing a carboxylic acid group are named
with the suffix “oic acid.”
• Compounds containing two carboxylic acid groups are
named with the suffix “dioic acid.”
• Many simple carboxylic acids and diacids have common
names accepted by IUPAC.
SECTION 20.3
• Carboxylic acids can form two hydrogen-bonding interactions.
• Treatment of a carboxylic acid with a strong base, such as
SECTION 20.6
• Carboxylic acid derivatives exhibit the same oxidation state
as carboxylic acids.
• Acid halides are named by replacing the suffix “ic acid” with
“yl halide.”
• Acid anhydrides are named by replacing the suffix “ic acid”
with “anhydride.”
• Esters are named by first indicating the alkyl group attached
to the oxygen atom, followed by the carboxylic acid, for
which the suffix “ic acid” is replaced with “ate.”
• Amides are named by replacing the suffix “ic acid” or “oic
acid” with “amide.”
• Nitriles are named by replacing the suffix “ic acid” with “nitrile.”
SECTION 20.7
• Carboxylic acid derivatives differ in reactivity, with acid

• The CN bond of an amide has double-bond character and

sodium hydroxide, yields a carboxylate salt.
• Carboxylate ions are named by replacing the suffix “ic acid”
with “ate.”
• The pKa of most carboxylic acids is between 4 and 5.
• The acidity of carboxylic acids is due to the stability of the
conjugate base, which is resonance stabilized.
• Using the Henderson–Hasselbalch equation, it can be
shown that carboxylic acids exist primarily as carboxylate
salts at physiological pH.
• Electron-withdrawing substituents can increase the acidity of
a carboxylic acid; the strength of this effect depends on the
distance between the electron-withdrawing substituent and
the carboxylic acid group.
SECTION 20.4
• When treated with aqueous acid, a nitrile will undergo
hydrolysis, yielding a carboxylic acid.
halides being the most reactive and amides the least reactive.
exhibits a relatively high barrier to rotation.
• When a nucleophile attacks a carboxylic acid derivative, a
nucleophilic acyl substitution can occur in which the nucle-
ophile replaces the leaving group. The process involves two
core steps and often utilizes several proton transfer steps as
well (especially in acidic conditions).
• When drawing a mechanism, avoid formation of a strong
base in acidic conditions and avoid formation of a strong acid
in basic conditions.
• When a nucleophile attacks a carbonyl group to form a tet-
rahedral intermediate, always re-form the carbonyl group if
possible but avoid expelling H− or C−.
SECTION 20.8

• Carboxylic acids can also be prepared by treating a Grignard • Acid chlorides can be formed by treating carboxylic acids
reagent with carbon dioxide. with thionyl chloride.
• When treated with water, acid chlorides are hydrolyzed to
SECTION 20.5 give carboxylic acids.
• Carboxylic acids are reduced to alcohols upon treatment with • When treated with an alcohol, acid chlorides are converted
lithium aluminum hydride or borane. into esters.
 Review of Reactions 1089

REVIEW OF REACTIONS
Preparation of Amines

From Alkyl Halides

H H
NaCN N 1) xs LiAIH4
Br C C H
SN2 2) H2O N
H

From Carboxylic Acids

O O
1) SOCl2 1) xs LiAIH4
OH 2) xs NH3 NH2 2) H2O NH2

From Benzene

H2
NO2 NH2
Pt

HNO3
H2SO4
1) Fe, Zn, Sn, or SnCl2
H3O+
2) NaOH

The Azide Synthesis

H2
Pt
NaN3

X N3 NH2
1) LiAIH4
2) H2O

The Gabriel Synthesis Via Reductive Amination

1) KOH NH2
Br NH3
O
+
2) NH2 [H ], NaBH3CN

N H
3) H2NNH2 R
HN
O R NH2
O
[H+], NaBH3CN

H R R
N N
R R
[H+], NaBH3CN

Reactions of Amines

Acylation Reactions with Nitrous Acid

O H
NaNO2 + −
H O R N R N N Cl
Cl HCl
R N R + HCl H A diazonium salt
N
H
H R R O
NaNO2
N H HCl
N N
Hofmann Elimination R R
An N-nitrosamine
NH2
1) Excess CH3
2) Ag2O, H2O, heat
1090 CHAPTER 22 Amines

Reactions of Aryldiazonium Salts

Sandmeyer Reactions
+
N N

CuBr CuCl Cu CuCN

Br Cl CN

Fluorination (Schiemann Reaction) Other Reactions of Aryldiazonium Salts

+ N + N
N F N OH
HBF4 H 2O
Heat

+ N
N H
H3PO2

Azo Coupling
Azo
group
R N
+
N N R N
(R = an activating group)

Reactions of Nitrogen Heterocycles

H H N N
Br2
N N
Br2 Br 300°C
0°C Br
Pyridine 3-Bromopyridine
Pyrrole 2-Bromopyrrole

REVIEW OF CONCEPTS AND VOCABULARY

SECTION 22.1
• Amines are derivatives of ammonia, in which one or more of
the protons are replaced with alkyl or aryl groups.
• Amines are primary, secondary, or tertiary, depending on the
number of groups attached to the nitrogen atom.
• Naturally occurring amines isolated from plants are called
alkaloids.
• The lone pair on the nitrogen atom of an amine can function
as a base or as a nucleophile.
SECTION 22.2
• Amines can be named as alkyl amines or as alkanamines,
depending on the complexity of the alkyl groups.
• When naming an amine as an alkanamine, the most complex
alkyl group is chosen as the parent, and the other alkyl groups
are listed as N substituents.
• Aromatic amines, also called aryl amines, are generally
named as derivatives of aniline.
SECTION 22.3
• The nitrogen atom of an amine is typically sp3 hybridized; the
lone pair occupies an sp3-hybridized orbital.
• Amines containing three different alkyl groups are chiral, but
they are generally not optically active at room temperature.
• Amines with fewer than five carbon atoms per functional
group will typically be water soluble, while amines with more
than five carbon atoms per functional group will be only spar-
ingly soluble.
• The boiling point of an amine increases as a function of its
capacity to form hydrogen bonds.
• Amines are effectively protonated even by weak acids.
• The basicity of an amine can be quantified by measuring
the pKa of the corresponding ammonium ion. A large pKa
indicates a strongly basic amine, while a low pKa indicates a
weakly basic amine.
• The ease with which amines are protonated can be used
to remove them from mixtures of organic compounds in a
process called solvent extraction.
 Review of Reactions    1229

Science Source
structure or activity of hemoglobin. However, some variations can be deadly. In one such variation,

Mary Martin/
called HbS, the sixth residue from the N terminus of the β chain (consisting of 146 residues) is valine
instead of glutamic acid. This variation greatly affects the structure and activity of hemoglobin, caus-
ing red blood cells to be distorted, or sickle shaped (Figure 25.20). These distorted cells are highly
(a) (b) susceptible to rupturing, and they interfere with the regular flow of blood. This condition is called
FIGURE 25.20
(a) Healthy red blood cells and
sickle-cell anemia, and it can be fatal. A person with sickle-cell anemia has inherited two copies of
(b) sickle-shaped red blood cells. the gene for abnormal hemoglobin, one from each parent. A person who carries only one copy of
the sickle-cell gene is said to have the sickle-cell trait, which is a less severe form of the disease, but it
can still cause serious problems under conditions of stress. Interestingly, the sickle-cell trait offers an
advantage in that it seems to be accompanied by a resistance to malaria. This example illustrates how
a change in a single amino acid residue can greatly affect the structure and function of a protein.

REVIEW OF REACTIONS
Analysis of Amino Acids
Reaction with Ninhydrin
⊝
O O O
H2O
R COOH OH NaOH
+ N + CO2
OH
NH2 RCHO
O O O
An amino acid Ninhydrin Purple-colored product By-products

Synthesis of Amino Acids

Via an α-Haloacid
O O O
1) Br2, PBr3 Excess NH3
R R R
OH 2) H2O OH SN2 OH
Br NH2

Via the Amidomalonate Synthesis

O O O O O
1) NaOEt H3O + R
EtO OEt EtO OEt OH
2) RX Heat
R N
N +
NH3
H H
O
O

Via the Strecker Synthesis

O
N +
O H2N H3N
NH4Cl
C H3O + C
OH
R H NaCN R H R H

Enantioselective Synthesis
O O O

OH H2 OH 1) NaOH, H2O OH
NHAc NHAc 2) H3O+
Ph + NH3
Ph
P Cl 99% ee L-Phenylalanine
Ru
P Cl
Ph
Ph

(S)-(–)-Ru(BINAP)Cl2
1230   CHAPTER 25    Amino Acids, Peptides, and Proteins

Analysis of Amino Acids

Edman Degradation

Ph S
O
1) Ph N C S N
PEPTIDE NH2 PEPTIDE H +
N 2) CF3CO2H N NH
O
H R H
R
This residue
is removed PTH derivative

Synthesis of Peptides
Peptide Bond Formation

O O
DCC
+ H2N
OH N
H

Protection and Deprotection of the N Terminus

O O

O O O O
O H
O N
H2N OH
OH
CF3COOH O R
R
Boc
protecting group

Protection and Deprotection of the C Terminus

[H+]
O ROH O
H2N H2N
OH OR
R NaOH R
H2O An ester

REVIEW OF CONCEPTS AND VOCABULARY

SECTION 25.1
• Proteins are large compounds formed from amino acids
linked together.
• Each amino acid contains one amino group and one ­carboxylic
acid group. Amino acids in which the two functional groups
are separated by exactly one carbon atom are called alpha
amino acids.
• Amino acids are coupled together by amide linkages called
peptide bonds.
• Relatively short chains of amino acids are called peptides.
SECTION 25.2
• Amino acids are said to be amphoteric, because they can
function either as acids or as bases.
• Only 20 amino acids are abundantly found in proteins, all of
which are l amino acids, except for glycine, which lacks a
chiral center.
• Amino acids have two pKa values, one for the carboxylic acid
group and one for the ammonium group.
• Amino acids with basic or acidic side chains will exhibit a third
pKa value.