Workbook For Organic Chemistry - Supplemental Problems and Solutions

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WORKBOOK FOR
ORGANIC CHEMISTRY
SUPPLEMENTAL PROBLEMS AND SOLUTIONS
Jerry A. Jenkins
Otterbein College
W.H. Freeman and Company

New York
© 2010 by W.H. Freeman and Company
All rights reserved.
Printed in the United States of America
ISBN-13: 978-1-4292-4758-0
ISBN-10: 1-4292-4758-4
First printing
W.H. Freeman and Company

41 Madison Avenue
New York, NY 10010
Houndmills, Basingstoke
RG21 6XS England
www.whfreeman.com/chemistry
TABLE OF CONTENTS
PREFACE v
About the author vi | Acknowledgments vi | Selected concepts/reactions locator vii
TIPS viii | Common abbreviations ix
CHAPTER 1 THE BASICS 1

1.1 Hybridization, formulas, physical properties 1 | 1.2 Acids and bases 4 | 1.3 Resonance 7
CHAPTER 2 ALKANES 11
2.1 General 11 | 2.2 Nomenclature 12 | 2.3 Conformational analysis, acyclic 13
CHAPTER 3 CYCLOALKANES 15
3.1 General 15 | 3.2 Nomenclature 16 | 3.3 Conformational analysis, cyclic 18
CHAPTER 4 REACTION BASICS 21
CHAPTER 5 ALKENES AND CARBOCATIONS 27

5.1 General 27 | 5.2 Reactions 30 | 5.3 Syntheses 36 | 5.4 Mechanisms 39
CHAPTER 6 ALKYNES 49
6.1 Reactions 49 | 6.2 Syntheses 50 | 6.3 Mechanisms 53
CHAPTER 7 STEREOCHEMISTRY 55
7.1 General 55 | 7.2 Reactions and stereochemistry 61
CHAPTER 8 ALKYL HALIDES AND RADICALS 65

CHAPTER 9 SN1, SN2, E1, AND E2 REACTIONS 69

9.1 General 69 | 9.2 Reactions 71 | 9.3 Syntheses 76 | 9.4 Mechanisms 78
CHAPTER 10 NMR 87
CHAPTER 11 CONJUGATED SYSTEMS 93

CHAPTER 12 AROMATICS 103

12.1 General 103 | 12. Reactions 105 | 12.3 Syntheses 109 | 12.4 Mechanisms 111
CHAPTER 13 ALCOHOLS 117

CHAPTER 14 ETHERS 129

CHAPTER 15 ALDEHYDES AND KETONES 139

CHAPTER 16 CARBOXYLIC ACIDS 167

CHAPTER 17 CARBOXYLIC ACID DERIVATIVES 177

iv • Table of Contents Workbook for Organic Chemistry
CHAPTER 18 CARBONYL Į-SUBSTITUTION REACTIONS AND ENOLATES 201

CHAPTER 19 CARBONYL CONDENSATION REACTIONS 209

CHAPTER 20 AMINES 229

SOLUTIONS TO PROBLEMS 241
CHAPTER 1 THE BASICS 243
CHAPTER 2 ALKANES 251
CHAPTER 3 CYCLOALKANES 255
CHAPTER 4 REACTION BASICS 261
CHAPTER 5 ALKENES AND CARBOCATIONS 263
CHAPTER 6 ALKYNES 281
CHAPTER 7 STEREOCHEMISTRY 287
CHAPTER 8 ALKYL HALIDES AND RADICALS 295
CHAPTER 9 SN1, SN2, E1, AND E2 REACTIONS 299
CHAPTER 10 NMR 315
CHAPTER 11 CONJUGATED SYSTEMS 319
CHAPTER 12 AROMATICS 327
CHAPTER 13 ALCOHOLS 341
CHAPTER 14 ETHERS 351
CHAPTER 15 ALDEHYDES AND KETONES 357
CHAPTER 16 CARBOXYLIC ACIDS 379
CHAPTER 17 CARBOXYLIC ACID DERIVATIVES 387
CHAPTER 18 CARBONYL Į-SUBSTITUTION REACTIONS AND ENOLATES 405
CHAPTER 19 CARBONYL CONDENSATION REACTIONS 413
CHAPTER 20 AMINES 427

PREFACE
WORKBOOK FOR ORGANIC CHEMISTRY
SUPPLEMENTAL PROBLEMS AND SOLUTIONS
Organic Chemistry is mastered by reading (textbook), by listening (lecture), by writing (outlining,
notetaking), and by experimenting (laboratory). But perhaps most importantly, it is learned by doing, i.e.,
solving problems. It is not uncommon for students who have performed below expectations on exams to
explain that they honestly thought they understood the text and lectures. The difficulty, however, lies in
applying, generalizing, and extending the specific reactions and mechanisms they have “memorized” to the
solution of a very broad array of related problems. In so doing, students will begin to “internalize”
Organic, to develop an intuitive feel for, and appreciation of, the underlying logic of the subject. Acquiring
that level of skill requires but goes far beyond rote memorization. It is the ultimate process by which one
learns to manipulate the myriad of reactions and, in time, gains a predictive power that will facilitate
solving new problems.
Mastering Organic is challenging. It demands memorization (an organolithium reagent will undergo
addition to a ketone), but then requires application of those facts to solve real problems (methyllithium and
androstenedione dimethyl ketal will yield the anabolic steroid methyltestosterone). It features a highly
logical structural hierarchy (like mathematics) and builds upon a cumulative learning process (like a
foreign language). The requisite investment in time and effort, however, can lead to the development of a
sense of self-confidence in Organic, an intellectually satisfying experience indeed.
Many excellent first-year textbooks are available to explain the theory of Organic; all provide extensive
exercises. Better performing students, however, consistently ask for additional exercises. It is the purpose
of this manual, then, to provide Supplemental Problems and Solutions that reinforce and extend those
textbook exercises.
Workbook organization and coverage. Arrangement is according to classical functional group

organization, with each group typically divided into Reactions, Syntheses, and Mechanisms. To emphasize
the vertical integration of Organic, problems in later chapters heavily draw upon and integrate reactions
learned in earlier chapters.
It is desirable, but impossible, to write a workbook that is completely text-independent. Most textbooks
will follow a similar developmental sequence, progressing from alkane/alkene/alkyne to aromatic to
aldehyde/ketone to carboxylic acid to enol/enolate to amine chemistry. But within the earlier domains
placement of stereochemistry, spectroscopy, SN/E, and other functional groups (e.g., alkyl halides, alcohols,
ethers) varies considerably. The sequence is important because it establishes the concepts and reactions
that can be utilized in subsequent problems. It is the intent of this workbook to follow a consensus
sequence that complements a broad array of Organic textbooks. Consequently, instructors utilizing a
specific textbook may on occasion need to offer their students guidance on workbook chapter and problem
selection.
Most Organic textbooks contain later chapters on biochemical topics (proteins, lipids, carbohydrates,
nucleic acids, etc.). This workbook does not include separate chapters on such subjects. However,
consistent with the current trend to incorporate biochemical relevance into Organic textbooks, numerous
problems with a bioorganic, metabolic, or medicinal flavor are presented throughout all chapters.
To produce an error-free manual is certainly a noble, but unrealistic, goal. For those errors that remain, I
am solely responsible. I encourage the reader to please inform me of any inaccuracies so that they may be
corrected in future versions.
Jerry A. Jenkins
Otterbein College
Westerville, OH 43081
[email protected]
Grindstones sharpen knives; problem-solving sharpens minds!

vi • Preface Workbook for Organic Chemistry
ABOUT THE AUTHOR

Jerry A. Jenkins received his BA degree summa cum laude from Anderson University and PhD in Organic
from the University of Pittsburgh (T Cohen). After an NSF Postdoctoral Fellowship at Yale University (JA
Berson), he joined the faculty of Otterbein College where he has taught Organic, Advanced Organic, and
Biochemistry, and chaired the Department of Chemistry & Biochemistry. Prof. Jenkins has spent
sabbaticals at Oxford University (JM Brown), The Ohio State University (LA Paquette), and Battelle
Memorial Institute, represented liberal arts colleges on the Advisory Board of Chemical Abstracts Service,
and served as Councilor to the American Chemical Society. He has published in the areas of oxidative
decarboxylations, orbital symmetry controlled reactions, immobilized micelles, chiral resolving reagents,
nonlinear optical effects, and chemical education. Prof. Jenkins has devoted a career to challenging
students to appreciate the logic, structure, and aesthetics of Organic chemistry through a problem-solving
approach.
ACKNOWLEDGMENTS
I wish to express gratitude to my students, whose continued requests for additional problems inspired the
need for this book; to Mark Santee, Director of Marketing, WebAssign, for encouraging and facilitating its
publication; to Dave Quinn, Media and Supplements Editor, W. H. Freeman, for invaluable assistance in
bringing this project to completion; to the production team at W.H. Freeman, specifically Jodi Isman,
Project Editor, for all their assistance with the printing process; to Diana Blume, Art Director, and Eleanor
Jaekel for their assistance in the cover design; and to my wife Carol, for her endless patience and support.
Supplemental Problems and Solutions • vii
SELECTED CONCEPTS/REACTIONS LOCATOR

The location of problems relating to the majority of concepts and reactions in most Organic textbooks will
be generally predictable: pinacol rearrangements will be found under ALCOHOLS, benzynes under
AROMATICS, acetals under ALDEHYDES AND KETONES, etc. Placement of others, however, may vary
from one text to another: diazonium ions may be under AROMATICS or AMINES, thiols may be under
ALCOHOLS or ETHERS, the Claisen rearrangement may be under ETHERS or AROMATICS, etc. The
following indicates where problems on several of these often variably placed concepts or reactions are
initially encountered in Workbook for Organic Chemistry.
Selected concept/reaction Chapter
Active methylene chemistry (e.g., malonic/acetoacetic 18

ester syntheses)
Brønsted-Lowry/Lewis equations 1
Carbocation rearrangements 5
cis-, trans- (geometric) isomers 3
Claisen, Cope, oxy-Cope rearrangements 14
Conformational analysis 2, 3
Curved arrow notation vi, 1
Degrees of unsaturation (units of hydrogen deficiency) 5
Diazonium ions 20
Diels-Alder reaction 11
Enamines, synthesis of 15
Enamines, reactions of 19
Epoxides, synthesis of 5
Epoxides, reactions of 14
Free radical additions 5
Free radical substitutions 8
Hydrogens, distinguishing different 2
Isocyanates, ketenes 17
Kinetic isotope effects 9
Kinetics, thermodynamics 4
Neighboring group participation 9
Nitriles 16
Organometallics (Grignard, organolithium, Gilman), 8
synthesis of
Phenols 12
Polymers 5
Reaction coordinate diagrams 4
Reaction types/mechanisms 4
Resonance 1
Thiols, (di)sulfides 14
UV/VIS spectroscopy 11
viii • Preface Workbook for Organic Chemistry
TIPS (TO IMPROVE PROBLEM SOLVING)

Mechanism arrows. All reactions (except nuclear) involve the flow of electrons. Arrows are used to
account for that movement. They originate at a site of higher electron density (e.g., lone pairs, S bond)
and point to an area of lower electron density (e.g., positively or partially positively charged atoms).
H
O O H O H O H
right: wrong:
Equilibrium vs. resonance arrows. Equilibrium arrows interrelate real species (as above).
Resonance arrows interrelate imaginary valence bond structures. Do not interchange them.
O H O H O H O H
right: wrong:
(resonance arrow) (equilibrium arrows)
Hydrogen nomenclature. The word “hydrogen” is commonly misused. Be more specific.
(H
O :H O + H2
A proton (H ) is removed by hydride (H: ) to form hydrogen (H2).
H
X H
+ H X
H
A hydrogen atom (H ) is removed by a free radical species.
State of association/dissociation. Correct identification of the appropriate charge state on a species in

a particular environment is important. Generally speaking, alkoxides (hydroxide), carboxylates,
carbanions, enolates, amines, etc., exist under alkaline conditions. Protons, carboxylic acids,
carbocations, enols, etc., exist under acidic conditions. For example, hydroxide does not exist in an
acidic solvent
OH
H3O OH
wrong
H2O -H
right OH2
and a proton is not directly available in base.

O H O O OH O
OR +H
H H H
ROH wrong
H) OR
+ROH, -RO
right
Supplemental Problems and Solutions • ix
COMMON ABBREVIATIONS
The following abbreviations and symbols are used throughout this workbook:
Ac acetyl (CH3CO-)
AcOH acetic acid
* chiral center or isotopic label
B: base
Bn benzyl (PhCH2-)
Bu butyl (C4H9-)
CA conjugate acid
CB conjugate base
' heat energy
D-A or (4+2) Diels-Alder
DB double bond(s)
DCC dicyclohexylcarbodiimide
DIBAH diisobutylaluminum hydride
DMF dimethylformamide
DMSO dimethyl sulfoxide
EAS electrophilic aromatic substitution
ee enantiomeric excess
equiv equivalent(s)
Et ethyl (CH3CH2-)
F-C Friedel-Crafts
[H] reduction
~H+ proton shift
HMPA hexamethylphosphoramide
HSCoA coenzyme A
hQ light energy
H-V-Z Hell-Volhard-Zelinsky reaction
inv inversion of configuration
L leaving group
LDA lithium diisopropylamide
mCPBA m-chloroperbenzoic acid
Me methyl (CH3-)
NAS nucleophilic acyl (or aryl) substitution
NBS N-bromosuccinimide
NGP neighboring group participation
NR no reaction
Nu: nucleophile
[O] oxidation
PCC pyridinium chlorochromate
Ph phenyl (C6H5-)
Pr propyl (C3H7-)
py pyridine
Ra-Ni Raney nickel
ret retention of configuration
rds rate determining step
taut tautomerization
THF tetrahydrofuran
TMS tetramethylsilane or trimethylsilyl
Ts tosyl (p-toluenesulfonyl)
TsOH tosyl acid (p-toluenesulfonic acid)
TS transition state
W-K Wolff-Kishner reduction
X halogen
(XS) excess
PROBLEMS
CHAPTER 1
THE BASICS
1.1 Hybridization, formulas, physical properties

1. SeldaneTM is a major drug for seasonal allergies; RelenzaTM is a common antiviral.
c
a HO OH OH O
O
HO OH
N OH
b N
H d
NH
O NH
H2N
2 SeldaneTM
RelenzaTM
a. Complete the molecular formula for each. SeldaneTM: C___H___NO2 RelenzaTM: C___H___N4O7
b. Draw all the lone electron pairs in both structures.
c. Which orbitals overlap to form the covalent bonds indicated by arrows a, b, and c?
a ____________ b ____________ c ____________
d. What is the hybridization state of both oxygens in SeldaneTM and of nitrogen d in RelenzaTM?
2. Place formal charge over any atom that possesses it in the following structures:
a. :C C: b. H C O: c. :O N O: d. the conjugate base of NH2CH3
Cl
e. N
O f. O O
H
H
BenadrylTM (antihistamine) zingerone (a constituent of the spice ginger)
3. a. One type of carbene, [:CH2], a very reactive species, has the two unshared electrons in the same
orbital and is called “singlet” carbene. Identify the orbital and predict the HCH bond angle.
b. Another type of carbene is called “triplet” carbene and has a linear HCH bond angle. Identify the
orbitals housing the two lone electrons.
HO OH
4. a. Which has the higher bp? N H or N b. lower mp? or HO OH
catechol hydroquinone

2 • Chapter 1 The Basics
5. Must the indicated carbon atoms in each of the following structures lie in the same plane?
H H H
a. b. c. d.
H H
H3C CH3 H3C H

e. (CH3)3C f. C C C g. h. C C C C
all four carbons H H H CH3
6. Which species in each pair has the higher molecular dipole moment (P)?
a. CHCl3 or CFCl3 b. CH3NH2 or CH3NO2 c. CO2 or SO2
7. Penicillin V and the antiulcerative cimetidine (TagametTM – the first billion dollar ethical drug) have the
structures below:
a
O H b N
N C
S N
d c
N HN N N
O S
H H
CO2H N
penicillin V cimetidine
a. Complete the molecular formulas for each.
penicillin V: C_____H_____N_____O_____S cimetidine: C_____H_____N_____S
b. Identify the type of orbital (s, p, sp, sp2, sp3) that houses the lone electron pairs on the atoms indicated
by arrows a, b, and c in the above structures.
a ________ b ________ c ________
c. The bond between the carbonyl carbon and nitrogen (indicated by arrow d) is somewhat stronger than a
single but weaker than a double bond. Given that fact, what type of orbital houses the lone pair of electrons
on that nitrogen? (Suggestion: do this problem after studying resonance.)
d. How many lone pairs of electrons are in each structure?
penicillin V: ________ cimetidine: ________

Problems • 3
8. Sumatriptan is often prescribed for the treatment of migraines. Prostacyclin is a platelet aggregation
inhibitor.
HO2C
H
O
O N
MeHN S
O NMe2
HO OH
sumatriptan prostacyclin
a. Complete the molecular formulas for each.
sumatriptan: C____H____N____O____S prostacyclin: C____H____O____
b. Sumatriptan contains _____ sp2 and _____ sp3 carbons; prostacyclin contains _____ sp2 and _____
sp3 carbons.
c. Sumatriptan and prostacyclin possess _____ and _____ lone pairs of electrons, respectively.
9. RozeremTM is prescribed for the treatment of insomnia, ChantixTM for smoking cessation, and RitalinTM
for ADHD.
N N H H
O
NH N O
H
N O
RoseremTM ChantixTM Ritalin TM
a. What is the molecular formula for each?
RozeremTM ___________ ChantixTM ___________ RitalinTM ___________
b. How many lone pairs of electrons are there in each?
RozeremTM ___________ ChantixTM ____________ RitalinTM ___________
10. Theobromine (Greek theobroma – “food of the gods”) is a constituent of cocoa. How many lone pairs
of electrons are in its structure? How many lone pairs of electrons are in the plasticizer melamine?
O CH3 NH2
HN N N N
O N N H2N N NH2
CH3
theobromine melamine

11. Which functional groups are present in each of the following medicines?
O OH
O
HO2C F C CH
O
a. O O b. c.
N N N
H NH HO
NH2
TamifluTM (antiviral) CiproTM (antibiotic) YasminTM component (OCP)
1.2 Acids and bases

1. What is the strongest base that can exist in ammonia?
Sodium hydride (NaH) is, in fact, a stronger base than the above answer. Write a reaction to describe what
happens when NaH is added to NH3. Use arrows to show the flow of electrons.
2. Which is the stronger base: (CH3)2NH or CH3-O-CH3?
3. Using curved arrow notation, write Lewis acid/base equations for each of the following. Remember to
place formal charge on the appropriate atoms.
a. O + AlCl3
b. Ph3P: + BF3
c. N O + BH3
4. Place formal charge on all appropriate atoms. Label the reactants on the left of the arrow as Lewis acids
(LA) or Lewis bases (LB) and draw curved arrows to show the movement of electron pairs in each reaction.
a. H3C O + CH3CH2 Cl: CH3 O CH2CH3 + Cl
b. H2C CH2 + BF3 CH2 CH2 BF3
1.2 Acids and bases

Problems • 5
c. H3C O H + :CH2 CH3 H3C O + H3C CH3
d. :Cl Cl: + AlCl3 Cl + AlCl4
S
e. CH3 N C S : + :NH3 CH3 N C
NH3
5. Lynestrenol, a component of certain oral contraceptives, has the structure
Ha
O Hb
C C
a. Calculate the molecular formula: C___H___O.
b. The pKas of hydrogens a and b are about 16 and 25, respectively, and the pKa of ammonia is about 35.
Write a Brønsted-Lowry equation for the reaction of the conjugate base of lynestrenol with ammonia.
c. Is the Keq for the above reaction about equal to, greater than, or less than 1?
6. The structure of ibuprofen (A) and acetaminophen (B) are drawn below.
HO NH
CO2H
O
A B
a. Write a reaction for the conjugate base of A with B.
1.2 Acids and bases

b. Identify the weak and strong acids and bases.
c. Is Keq about equal to, less than, or greater than 1?
7. Which compound has the lowest pKa?
a. EtOH b. HOAc c. H2O d. PhOH e. H2 f. NH3
8. Which species has the ability to quantitatively (completely) remove the proton Ha (pKa 22) from
R C C Ha ?
a. hydroxide b. CB of NH3 c. CA of hydride d. CB of EtOH
9. Stress levels in horses may be monitored by measuring urine estradiol. Comment on the Keq for the
reaction of the conjugate base of nitromethane (pKa 10.3) with estradiol.
OH
CH3NO2
HO
estradiol nitromethane
10. Pyridinium chloride is drawn below.

a. Place the appropriate formal charge on the atoms that bear it.
Cl
N
H
b. The pKas for pyridinium chloride and sodium bicarbonate (NaHCO3) are 5.2 and 10.2, respectively.
Write a Brønsted-Lowry equation for the reaction of pyridinium chloride with the conjugate base of
bicarbonate. Use curved arrow notation to show the flow of electrons.
c. Is Keq greater than, less than, or about one?
1.2 Acids and bases

Problems • 7
1.3 Resonance
1. Identify the type of orbital housing the electrons specified by the arrows.
CH2 O
H3C C O
N
H
2. Which species has the lower pKa, H C N or H O C N ?
3. How many nuclei can reasonably bear the charge in each of these ions?
a. HO CH NH2
b.
O
c. O
d. H2C O CH3
4. The compound below can be protonated at any of the three nitrogen atoms to give a guanidinium ion
derivative (creatine phosphate and the amino acid arginine possess this moiety). One of these nitrogens is
much more basic than the others, however. Draw the conjugate acids resulting from such protonation, then
identify the conjugate acid which is most stable. Why?
H3C NH C NH2
NH
1.3 Resonance
5. Draw a resonance structure that is more stable than the one given. Use curved arrows to derive.
H
N
a. O O O b.
ozone
OH
H
c. C C N: d.
H
6. How many nuclei can reasonably bear the charge in each of the following ions?
O
a. b.
N
H
CH2
c. d.
7. Recalling that resonance is a stabilizing force, explain why the pKa of Ha in A is (only!) about 10.
H Ha
O O
A
8. Either oxygen in acetic acid (HOAc) could, in theory, be protonated to produce two different conjugate
acid forms. Draw each and explain which is more favored.
1.3 Resonance
Problems • 9
9. How many nuclei can reasonably bear the charge or odd electron in each of the following?
a. b. c.
N N
H
O
d. e. f.
O N CH2
.
g.
. CH3O
i.
h. H
Cl
10. B’s molecular dipole moment (P) is larger than A’s. Explain.
O O
A B
11. Bioluminescence in fireflies is a result of the conversion of chemical energy (in ATP) to light energy.
Specifically, ATP, O2, and the enzyme luciferase cause luciferin (~ 9 mg can be collected from about
15,000 fireflies!) to be oxidatively decarboxylated to an electronically excited oxyluciferin. Relaxation of
the latter to its ground state is accompanied by the emission of light (fluorescence). Subsequent
regeneration reactions then recycle oxyluciferin back to luciferin. Draw the two resonance structures of the
CB of oxyluciferin in which either oxygen bears the negative charge.
CO2H O
N N N N
ATP, O2
+ hv
HO S S luciferase S S
HO
-CO2
luciferin oxyluciferin
1.3 Resonance
CHAPTER 2
ALKANES
2.1 General
1. Which compound has the highest mp?
1. n-octane 2. 2,5-dimethylhexane 3. 2,3,4-trimethylpentane
4. bicyclo[2.2.2]octane 5. all have the same number of carbons and would melt at the same T
2. Which compound has the highest bp?
1. n-pentane 2. neopentane (dimethylpropane) 3. isopentane
3. Dodecahedrane, one of the three Platonic solids (tetrahedron, hexahedron, and dodecahedron), is a
regular polyhedron consisting of twelve cyclopentane rings (think soccer ball). Eicosane is a straight-chain
compound. Although both are C20 hydrocarbon alkanes, one melts at 4200 and the other at 370. Explain.
4. How many constitutional (structural) isomers exist for
a. C6H14? b. C7H16?
5. How many different kinds (constitutional) of hydrogens are in
a. 2,3-dimethylpentane? b. 2,4-dimethylpentane?
c. 3-ethylpentane? d. 2,2,4-trimethylpentane?
e. 2,5,5-trimethylheptane? f. 4-ethyl-3,3,5-trimethylheptane?
2.1 General
12 • Chapter 2 Alkanes
2.2 Nomenclature
Give the IUPAC name for each of the following. Be certain to specify stereochemistry when relevant.
I
Et
1. CH CHNO2 2.
s-Bu t-Bu
Br
3. 4.
Et n-Pr
5. 6.
7. 8.
i-Pr
9. 10. isohexyl iodide
n-pentyl
i-Bu
11. 12. t-Bu n-Pr

neopentyl
Cl
Give the correct IUPAC names for problems 13 – 16.
13. 2-isopropyl-4-methylheptane 14. 3-(1-methylbutyl)octane
2.2 Nomenclature
Problems • 13
15. 3-s-butyl-7-t-butylnonane 16. tetraethylmethane
17. Draw structural formulas, using bond line notation, for the following:
a. neopentyl alcohol (R-OH) b. isobutyl n-pentyl ether (R-O-R’) c. allyl bromide (R-X)
2.3 Conformational analysis, acyclic

1. The rotational energy barrier about the C-C bond in EtBr is 3.7 kcal/mole. What is the energy cost of
eclipsing a C-H and C-Br bond?
2. Draw Newman projections of the

a. most stable conformer , looking down the C2-C3 bond, of 2-cyclopentyl-6-methylheptane
b. gauche conformer of 1-phenylbutane, looking down the C1-C2 bond (use two-letter
abbreviations for R groups).
3. Give the common name for (a) and the IUPAC name for (b).
OH s-Bu
Me H H Et
a. b.
H H H t-Bu
Me
(R-OH = alkyl alcohol)

4. Draw the conformer of isopentane that corresponds to the highest minimum in a plot of the potential
energy vs. rotation about the C2-C3 bond (use a Newman projection).
PE
rot'n about C2 - C3 bond
5. The molecular dipole moment (P) for FCH2CH2OH is much larger than that for FCH2CH2F. Use
conformational analysis to explain.

CHAPTER 3
CYCLOALKANES
3.1 General
1. Which compound has the highest molecular dipole moment (u)?
a. Cl
b. anti conformer of 2,3-dichlorobutane c. C2Cl2 d. cis-1,3-dichlorocyclobutane
Cl
2. How many constitutional (structural) isomers exist for
a. dichlorocyclopentane?
b. C6H12 that have a cyclopropyl ring in their structure?
3. How many cis/trans stereoisomers exixt for
a. dichlorocyclopentane?
b. diphenylcyclohexane?
c. 2-chloro-4-ethyl-1-methylcyclohexane?
4. How many different kinds [constitutional and geometric (cis/trans)] of hydrogens are there in
a. 1-ethyl-1-methylcyclopropane?
b. allylcyclobutane?
c. methylcyclobutane?
3.1 General
16 • Chapter 3 Cycloalkanes
d. chlorocyclopentane?
e. vinylcyclopentane?
5. Which bicyclic compound is least strained?
. . .
a. b.
. c. d.
.
6. Three structural isomers are possible for methylbicyclo[2.2.1]heptane. One of them has two
stereoisomeric forms. Draw structures for all four isomers.
7. In view of the previous problem, how many structural and geometric isomers exist for
methylbicyclo[2.2.2]octane?
3.2 Nomenclature
Give the IUPAC name for each of the following. Be certain to specify stereochemistry when relevant.
1. isoamyl 2.
3. (three names!) 4.
3.2 Nomenclature
Problems • 17
5. 6.
Br
F
7. 8.
Cl
t-butyl I
9. 10.
neopentyl
F
11. Ph 12.
13. 14.
roof-methylhausane (!)
15. 16.
3.2 Nomenclature
3.3 Conformational analysis, cyclic

1. Draw the most stable conformer of
Me Me
= =
OH OH
i-Pr i-Pr
menthol neomenthol
2. In each of the following predict whether Keq is about equal to, greater than, or less than one:
a. trans-1,3-diphenylcyclohexane "flipped" conformer
b. i-Pr n-Pr "flipped" conformer
(if i-Pr is equatorial)
c. H Me "flipped" conformer
Et
3. Which has the most negative heat of combustion ('Hcomb) in each of (a), (b), or (c)?
a.
t-Bu t-Bu t-Bu

Problems • 19
b.
Me Me Me
c.
Et s-Bu Et s-Bu Et s-Bu
4. a. Which has the least negative heat of combustion ('Hcomb)?
Et Et Et Et
Me Me Me Me
Et Et Et Et
b. Which two structures in (a) are the same compound?
5. Many alkyl halides undergo loss of HX in the presence of base. For example, chlorocyclohexane gives
cyclohexene when treated with sodium hydroxide. The reaction mechanism generally requires both the
leaving proton and halide to occupy axial positions, a process known as a trans-diaxial elimination.
Therefore, which do you think would react faster, cis-1-chloro-2-t-butylcyclohexane or trans-1-chloro-2-t-
butylcyclohexane?
6. Trans-4-fluorocyclohexanol exists largely in a chair conformation, whereas the cis-isomer favors a

twist-boat conformation. Explain.

7. Glucose, like cyclohexane, exists in a chair conformation. Two configurations of glucose are possible;
they are drawn below:
O OH O OH
HO HO
and
HO OH HO OH
OH OH
1 2
a. Complete the chair conformations below to show the most stable conformer of 1 and 2.
O O
1 2
b. Which configuration would you predict would be less stable, i.e., burn with a more negative heat of
combustion?
8. One of the chair conformations of cis-1,3-dimethylcyclohexane is 5.4 kcal/mol more stable than the
other. If the steric strain of 1,3-diaxial interactions between hydrogen and methyl is 0.9 kcal/mol, what is
the strain cost of a 1,3-diaxial interaction between the two methyl groups?
9. a. How many cis/trans stereoisomers exist for 1,2,3,4,5,6-hexamethylcyclohexane?
b. For three of those stereoisomers, Keq = 1 for conformational chair-chair flipping. Draw them.
c. Of those three, which is the least stable?
d. Which stereoisomer would be least likely to undergo conformational flipping?

CHAPTER 4
REACTION BASICS
1. Which type of reaction – addition, elimination, rearrangement, substitution, reduction [H], or oxidation [O]
– best describes each of the following?
OLi
a. MeLi + O
Me
OH O
b. H
H
OH
O
c. RCO2R + NH2R RCONHR + HOR
d. O + H2NMe NMe + H2O
H
e. + Me2NOH
O
N
O O
f.
OH OH OH
g. RHC CHR RC CR
h. + H2O OH
i. PhCO2H PhCHO
j.
k. BnOH PhCHO
4. Reaction Basics
22 • Chapter 4 Reaction Basics
l. Ac2O + H2O 2 AcOH
m. CHCl3 + KO-t-Bu :CCl2 + t-BuOH + KCl
n. + HC CH
o. Br2 2 Br
Ph Ph
p. Ph Ph
q. OH O
r. vinyl chloride C2H2
O
CO2H
s. O + H2O
CO2H
O
t. isohexyl alcohol isohexane
2. Imagine a 2-step (A to B and B to C) endothermic reaction for which 'Go values for each step are,
respectively, +3 and +7 kcal/mole. The 'G± value for the rate determining step is 11 kcal/mole. (a) Draw a
potential energy diagram for this reaction. (b) What is the 'G± value for the conversion of C to B?
'Go
rx
4. Reaction Basics
Problems • 23
3. A simplified mechanism for the exothermic substitution reaction below involves two steps:
O OH O
slow fast
+ HOR' R Cl + HCl
R Cl R OR'
OR'
a. Draw an overall energy diagram and label the transition state(s), intermediate, 'G± for the rate determining
step, and 'Go.
'Go
rx
b. The overall Keq for the conversion of RCOCl to RCO2R’ could be calculated from 'Go according to the
equation:
Keq = ________________________________
c. If 'G± is known, the rate of the reaction could be calculated according to the equation:
rate = ________________________________
4. Bromoform (A) in the presence of base (:B-) can form a very reactive intermediate, dibromocarbene (B),
which can rapidly add to olefins to produce gem-dibromocyclopropane derivatives. The following summarizes
the two-step mechanism:
:B
(1) Br3C H Br3C: + H-B
A
-Br
(2) Br3C: Br2C:
B
Br Br
(3) Br2C: +
a. Assuming that 'Go for the overall reaction is +2.5 kcal/mol and that step (2) is rate-determining,
draw a reaction energy diagram that depicts all three steps.
'Go
rx
b. Calculate Keq for this reaction (R = 2 cal/mol.K, T = 300).
4. Reaction Basics
5. Consider the following reaction mechanism for A in equilibrium with B:
H H
O O O O O O
+ H OH2 + H OH2
A + H2O B
75%
a. The overall reaction is an example of a(n) ___________________ (type) reaction that occurs by a(n)
____________________ mechanism.
b. Draw curved arrows to show the electron flow that has occurred in each step.
c. Calculate Keq, assuming only A and B are present (note: B is formed in 75% yield).
Keq = ____________________________________
If Keq is known, then 'Go = __________________________.
d. Which species is (are) nucleophilic in this reaction?
e. Draw a qualitative energy diagram for the reaction (assume the first step is slower than the second). Label
the transition state(s) and intermediate.
'Go
rx
6. Consider the following reaction:
I + MeOH OMe + HI
The rate law for the reaction may be expressed as: rate = k[A]. Given that methyl alcohol is not in the rate law,
propose a reaction for the rate determining step.
4. Reaction Basics
Problems • 25
7. Below are reactions we shall examine in more detail later. Classify the mechanisms as polar/ionic, free
radical, or pericyclic (concerted).
a.
b.
hausene
D
D2 / Pt
c.
D
+H +Cl
d.
H Cl
e. =
Br Br +Br Br
Br
f.
-Br Br
Cl2
g. + HCl
hv Cl
H Et
S H
h. -Cl S -H S
Et Et
Cl
4. Reaction Basics
Ph Ph
Ph
i.
H BH2 H BH2
H BH2
:B
H)
O O
j.
Cl -BH, -Cl
4. Reaction Basics
CHAPTER 5
ALKENES AND CARBOCATIONS
5.1 General
1. Nomenclature. Give the complete IUPAC name for the following:
H
H
a. b. H
H
Cl
c. 4-vinyldecane (an incorrect name!) d.
2. Identify each of the olefins below as (E)- or (Z)-:
CO2H NC vinyl
a. b.
CH2OH H2NH2C t-Bu
O O
Ph NH O
c. d.
NH2 O O
O O
O
NH2 Ph SH
e. f. H
CH2F
O
3. a. How many alkenes, C7H12, could you treat with H2 / Pt to prepare methylcyclohexane?
b. Which would have the least negative heat of hydrogenation?
4. How many geometric isomers exist for 2,4-heptadiene?
5.1 General
28 • Chapter 5 Alkenes and Carbocations
5. Which carbocation is the most stable?

O
OMe
6. Degrees of unsaturation (units of hydrogen deficiency).

a. The antidepressant fluoxetine (ProzacTM), C17H18F3NO, when treated with H2 / Ni gives a structure with
molecular formula C17H30F3NO. It contains no triple bonds. How many rings are in fluoxetine?
b. CiproTM is an antibacterial that is used to treat anthrax. Its molecular formula is C17H18FN3O3. The drug has
four rings and no triple bonds. How many double bonds does it contain?
c. RU 486 is an abortion medication. Its molecular formula is C28H35NO2. Its structure contains five double
bonds and one triple bond. How many rings are in RU 486?
d. The COX-2 inhibitor rofecoxib (VioxxTM), an anti-inflammatory agent, has been taken off the market
because of potential increased cardiovascular risk. Its molecular formula is C17H14O4S. There are three rings
and no triple bonds in rofecoxib. How many double bonds are there? (Note: for each sulfur atom, subtract four
hydrogen atoms to arrive at the equivalent hydrocarbon formula.)
e. The antibiotic floxacillin, C19H17ClFN3O5S, contains eight double bonds. How many rings are present?
(In this case, treat sulfur as you would oxygen.)
f. The antidepressant PaxilTM has the molecular formula C19H20FNO3. Upon exhaustive hydrogenation
(H2/Pt) a compound C19H32FNO3 is formed. How many double bonds and how many rings are in PaxilTM?
5.1 General
Problems • 29
7. How many stereoisomers exist for 2,4-hexadiene? for 2-chloro-2,4-hexadiene?
8. Draw structural formulas for each of the following:
a. (Z)-3-methyl-2-phenyl-2-hexene b. propylene dichloride
c. styrene bromohydrin d. trans-cyclohexene glycol e. isobutylene epoxide
9. Draw an energy vs. progress of reaction diagram for the exothermic reaction of vinylcyclobutane with
HCl to yield 1-chloro-1-methylcyclopentane. Be certain the number of intermediates is clearly indicated.
'Go
rx
10. Draw the most
a. important contributing resonance structure of the conjugate acid of 6-methyl-1,3,5-heptatriene
b. stable intermediate in the following reaction:
MeOH, H
11. The following 1,2-hydride shift does not occur. Why?
H H
H
~ H:
H
adamantyl carbocation
5.1 General
12. Which reaction demonstrates NEITHER regiospecificity nor stereospecificity?
HF Cl2
a. trans-2-pentene b. 1-pentene
(XS) NaBr
Cl2 D2 / Pt
c. cyclobutene d. 1-ethylcyclopropene
H2O
13. Why, and how, does E-pinene readily isomerize to D -pinene in the presence of an acid catalyst?
E-pinene D-pinene
5.2 Reactions
Draw the structural formula of the major organic product(s). Show stereochemistry where appropriate.
HCl
1. Ph
NO2
HI
2.
H3O
3.
1. Cl2 / '
4. cyclopentane
2. KOMe, MeOH
3. Br2, CHCl3
5.2 Reactions
Problems • 31
NMe3
5. HI
Et
HF
6. F
DCl
7. vinylcyclohexane
HBr
8.
9. OH H
O
(complete)
HBr
10. CCl3
Et
DBr
11.
1. H2 / Pd
12. cyclopentene
2. Br2 / hv
5.2 Reactions
H, EtOH
13.
14. HF
MeO D
Cl HI
15.
Cl2 / H2O
16.
1. B2D6
17.
2. H2O2, OH
Cl2
18. propylene
(XS) NaI
Et 1. Hg(OAc)2, PhOH
19.
2. NaBH4
(XS) CH2I2
20. H2C C CH2
Zn(Cu)
allene
5.2 Reactions
Problems • 33
1. KMnO4, OH
21. AcO 2. HIO4
1. O3
22.
2. H3O, Zn
HBr, di-t-butyl peroxide

23. Ph
diazomethane
24. (E)-3-hexene
hQ
1. base
2. OsO4
25. cyclopentyl bromide
3. NaHSO3
IN3
26. 3-methyl-1-butene
1. BD3, THF
27.
2. H2O2, OH
HO
cholesterol
O
H, MeOH
28.
5.2 Reactions
29. H
(complete)
HIO4
30. styrene glycol
OH
1. H2SO4
31.
2. KMnO4, OH
H HCl
32. C C O
H
OR 1. BH3, THF O O
33. O
2. H2O2, OH
O
O
artemisinin (antimalarial)
1. Br2, H2O
34. estrone
2. base
HO
H
35.
O
(complete)
5.2 Reactions
Problems • 35
1. OR
36. chlorocyclopentane
2. mCPBA
3. EtOH, H
Br2, s-BuOH
37.
OH
OH
HIO4
38.
HO
pregnenolone
39. Draw the structure of the largest carbon-containing product in the following reaction:
OH KMnO4, H
vitamin A
1. OsO4
40. O 2. NaHSO3
O 3. HIO4
O
incensole acetate
(found in frankincense)
HCl
41.
two 1,2-shifts
(complete)
5.2 Reactions
1,1-elimination cyclohexene
42. PhCH2Cl + n-BuLi
-HCl
(a very strong base)
(CH3)2CI2 (1 equiv)
43. Cl O
O Zn(Cu)
Cl O
permethrin (insect repellent)
5.3 Syntheses
Supply a reagent or sequence of reagents that will effect the following conversions.
Br
1.
2. cyclohexyl alcohol cyclohexyl chloride
3. t-BuCl t-BuF
Cl
4.
5.3 Syntheses
Problems • 37
5. D
O O
6. cycloheptane HO OH
Cl
7.
Br
H
8. allylbenzene
O
9. ethylene bromocyclopropane
10. cyclopentyl alcohol
OH
11.
OH
5.3 Syntheses
Br
O
12.
O
D
13. cyclohexane
Br
Br
14. Br
15. isobutane isobutyl alcohol
Cl
CO2H
16.
CO2H
Cl
17. t-butyl chloride isobutylene chlorohydrin
18.
O O
5.3 Syntheses
Problems • 39
OEt
19.
20. Br
21. ethylene HO OH
O O
22. t-butyl bromide (only source of carbon) di-t-butyl ether
23. cyclobutyl alcohol hausane (bicyclo[2.1.0]pentane)
5.4 Mechanisms
Outline a detailed mechanism for each of the following. No other reagents than those given are necessary. Use
arrows to explain the flow of electrons and show all intermediates. NO WORDS!
H
1.
5.4 Mechanisms
H
2.
H OMe
3.
MeOH
isoprene
H
4.
I
I2
5.
CO2H O
O
6. Isobutylene in the presence of excess propylene and a trace of acid yields C7H14. Deduce this product.
5.4 Mechanisms
Problems • 41
H
7.
1. Hg(OAc)2
8. O
OH 2. NaBH4
9.
H
(a C11 olefin)
H
N I2 N
10.
-HI
I
N N
11. + H2C N N
diazomethane
5.4 Mechanisms
12. The reaction of 3-bromocyclohexene with HBr yields only trans-cyclohexene dibromide, i.e., no cis-
product is formed. In contrast, 3-methylcyclohexene reacts with HBr to yield a mixture of cis- and trans-
stereoisomers, as well as a tertiary alkyl halide. Explain with appropriate structures and arrows.
13. The natural products caryophyllene and isocaryophyllene (odor somewhere between cloves and turpentine)
are stereoisomers that differ in the configuration of a double bond. They have the molecular formula C15H24.
Catalytic hydrogenation of either yields the same compound, C15H28. Ozonolysis, followed by zinc and
aqueous acid, yields A and an other aldehyde. Suggest structures for the caryophyllenes.
O
O
O
H
A
14. Treatment of an unknown alkene with Hg(OAc)2 in H2O/THF, followed by a NaBH4 workup, produces an
alcohol isomeric to one obtained by hydroboration-oxidation of the same alkene. Reduction of the alkene
affords the compound C5H12, while ozonolysis yields an aldehyde, CH3CHO, as one of the products. Deduce
the structure of the alkene.
15. Partial catalytic hydrogenation of C5H8 (A) yields a mixture of B, C, and D. Ozonolysis, followed by a
reductive work-up (Zn, H3O+), of B gives no new products. When treated in the same way, C gives
formaldehyde and 2-butanone and D gives formaldehyde and isobutyraldehyde. Provide structures for
compounds A through D. What is the common name of A?
O O O
H H H
formaldehyde 2-butanone isobutyraldehyde
5.4 Mechanisms
Problems • 43
16. E-Myrcene, C10H16, found in bayleaves and hops, is an intermediate in the manufacture of perfumes. When
treated with H2/Pt, 2,6-dimethyloctane is formed (E-myrcene has no triple bonds). Treatment of E-myrcene
with ozone, followed by an acidic zinc work-up, yields A (C5H6O3), acetone (Me2CO), and two equivalents of
formaldehyde. What are the structures of E-myrcene and A?
17. Reaction of A, C10H16, with H2/Pd yields B. When treated with KMnO4, a brown precipitate forms. When
A is treated with ozone followed by zinc in acid, compound C and another product are produced. What are the
structures of A and the other ozonolysis product?
O
O
H
O
B C
18. Draw
a. the structure of the monomer that would give the following polymer by an addition mechanism:
CO2Me CO2Me
CO2Me CO2Me
b. a segment (three or four repeating units) of poly(styrene).
19. t-Butyl vinyl ether is polymerized commercially by a cationic process for use in adhesives. Show the
mechanism for linking three monomeric units.
'
20. 2 CH2N2 ethylene + 2 N2
5.4 Mechanisms
CH2N2, hQ
21.
H
22.
H
23.
isocomene (from goldenrod)
24. Hydride shifts and alkyl migrations occur in many enzyme-catalyzed reactions in all living species –
including you as you are working these problems! Below is one such biochemical reaction (see 14.3, 6 for
perhaps the very best example). Account for the formation of all intermediates leading to the product.
(Hint: positive sulfur, like positive oxygen, is a good leaving group, i.e., it easily leaves a carbon to which it
is attached, taking with it both bonding electrons.)
R R'
S SAM (S-adenosylmethionine, a common methylating agent in all of us)
CH3
D D D
D CO2H CO2H
C8H17 C8H17
oleic acid (a fatty acid)
5.4 Mechanisms
Problems • 45
1. Hg(OAc)2, H2O
25. O
2. NaBH4
H
26.
27. Elaidic acid (C18H34O2), a fatty acid, is present in processed foods such as margarine and may
contribute to elevated levels of cholesterol. Reaction of elaidic acid with Simmons-Smith reagent produces
compound I, whereas reaction with acidic permanganate yields II and III. What is the structure of elaidic
acid? Indicate stereochemistry.
R O O
O
R' HO OH
OH
I II III
28. Compound A (C10H18O) reacts with H2SO4 to give B (C10H16) and an isomer C. Ozonolysis of B
yields a diketone; ozonolysis of C yields D. (a) Draw structures for A, B, and C. (b) Describe a simple
chemical color test that would differentiate A from B or C.
CHO
_______________ _______________ _______________
A B C D
5.4 Mechanisms
OH H
29.
limonene (volatile in lemons and oranges)
Hint: some alcohols can be protonated to form oxonium ions which may then “leave” as water to
give a carbocation.
30. Aziridines (B) are nitrogen analogs of epoxides and can be made from azides (A) by the following
reaction:
R
R N3 '
+ Me N Me + N2
A
B
Recalling the mechanism of generating carbene from diazomethane, and the fact that nitrogen is an
excellent “leaving group,” (a) draw the resonance structure of A that best illustrates how it can decompose
to extrude N2 and (b) supply electron flow arrows to show the structure of the reactive intermediate derived
from A that reacts with cis-2-butene to give B.
N2 + B
A
(c) Given the observed stereochemistry, what type of mechanism does this addition reaction illustrate?
31. H
(an olefin - complete)
1. Cl2, H2O
32. styrene (vinylbenzene)
2. base
3. dry HCl
5.4 Mechanisms
Problems • 47
In CCl3
33. + BrCCl3
(a free radical initiator)
Br
34. Compound A, C16H30O, is a sex attractant (pheremone) for the male silkworm moth. Given the data
from the following three experiments, deduce the structure of A, clearly showing its stereochemistry.
a. Catalytic hydrogenation of A yields C16H34O.
b. Ozonolysis of A, followed by treatment with zinc and acid, yields compounds B, C, and D.
O O O
H HO
H H H
O
B C D
c. Incomplete reaction of A with diazomethane (CH2N2) gives a mixture of E and F (the C11 and C9
substituents contain one oxygen atom). Note: this experiment establishes the stereochemistry of A.
C3 C11 C9
C5
E F A = _______________________________
35. 1,4-Cyclohexadiene undergoes isomerization to 1,3-cyclohexadiene in the presence of acid. Two

mechanisms are possible: protonation followed by deprotonation (path a) vs. protonation followed by a 1,2-
hydride shift and subsequent deprotonation (path b):
H H
H H
-H
H
path a
H
path b 1,2-H: H -H
shift
H
If 3,3,6,6-tetradeuterio-1,4-cyclohexadiene is treated with acid, 1,2,5,5-tetradeuterio-1,3-cyclohexadiene is

formed. Which path is favored? (Note: C-H bonds are slightly weaker than C-D bonds.)
5.4 Mechanisms
36. Carbonyl groups greatly affect the acidity of nearby (D-) protons. For example, the pKa of
cyclohexane is about 60, but the pKa of Ha in cyclohexanone is about 20. This dramatic increase in acidity
is largely a consequence of resonance stabilization of the conjugate base of the latter (for an example of the
additive effect on pKas of 1,3-dicarbonyls, see problem 1.3, 7), and allows an easy exchange of D-
hydrogen for deuterium atoms by the following mechanism:
O :B O O D OD O
Ha D
+B: +D2O
-BH - OD
cyclohexanone
Under the same conditions, however, species A does not undergo hydrogen-deuterium exchange. Explain.
Hint: consider the geometric constraints of olefinic moieties.
:B, D2O
H D
O O
A
5.4 Mechanisms
CHAPTER 6
ALKYNES
6.1 Reactions
1. NaH
1. 3-penten-1-yne
2. D2O
H, HgSO4, PhOH
2. 1-octyne
1. B2H6
3. phenylacetylene
2. H2O2, OH
1. OMe, HOMe
4. n-BuCl 2. Cl2
3. (XS) NaNH2
4. BH3.THF
5. H2O2, OH
5. RC C :
Cl
1. Li / NH3
6.
2. HBr, di-t-butyl peroxide
1. H2 / Pd(Pb)
2. BH3
7. isopropylacetylene
3. H2O2, OH
1. NaH
2. CH3(CH2)12Cl
8. 1-decyne
3. Lindlar catalyst
muscalure (pheremone for house fly)
1. (XS) NaNH2
9. 1,1-dichlorobutane
2. H3O, HgSO4
6.1 Reactions
50 • Chapter 6 Alkynes
Cl2, H2O
10. C CH
1. (XS) HI
11. PhC CH
2. Zn(Cu), cyclopentene
O
Cl Cl
PCl5 1. (XS) NaNH2
12.
2. D2O
OMe OMe
1. LiNH2 (2 equiv)
13. H C C CH2OH
2. n-C5H11Br (1 equiv)
3. H
1. NaNH2 (1 equiv)
2. n-Pr-I
14. acetylene
3. NaNH2
4. t-Bu-Cl
6.2 Syntheses
Br
1. OH
Br O
2. acetylene n-pentyl bromide
6.2 Syntheses
Problems • 51
3. vinyl chloride methyl vinyl ether
4. acetylene (E)-3-octene
5. t-butylacetylene 2-chloro-2,3-dimethylbutane
6.
7. propyne
8. propyne n-propyl bromide
O
9. C CH
6.2 Syntheses
10. styrene (E)-1-phenyl-1-butene
11. diphenylacetylene cis-1,2-diphenylcyclopropane
PhCHO
Et Cl
12. 3-hexyne
Cl
Et
n-Bu Et
13. Cl
Cl Cl
14. acetylene
(odor of cheddar cheese)
15. acetylene
O
disparlure (pheremone for female gypsy moth)
6.2 Syntheses
Problems • 53
O
16. 1-pentyne 2 OH
6.3 Mechanisms
Br
C
HO
C
1. O [I ] O
O
O
O
OH OH O
O Br
I
CH3 O
OH C
C H3O
2.
1. NaH
2. ethylene epoxide
3. C CH
3. H OH
6.3 Mechanisms
Me2N Me2N
O OH CH3
1. H3CC C:
4. H H
H 2. H H
O O
mifepristone (RU-486)
5. In the presence of very strong base an internal triple bond in any position of a straight chain alkyne will
shift to the terminus of the chain, a process known as the acetylene zipper reaction:
strong base
R CH3 R CH2 C C:
6.3 Mechanisms
CHAPTER 7
STEREOCHEMISTRY
7.1 General
1. Which of the following molecules are chiral?
Me H Me S
a.
b. c.
H CO2H Et
O
Cl
Ph Me O
d. e. f. CO2H
Me Ph
Cl
g. h. HC C C C CH C CH CH CHCH2CO2H
(an antibiotic)
Me
H Me
Ph
i. j. k.
H
OH adamantane (an anti-

viral agent)
Br HH Br HO O
l. m. the C2-epimer of n. Cl N NMe2
Ph
Ph
loperamide (ImodiumTM - antidiarrheal)
2. How many chiral carbons are there in each of the following molecules?
H
Bn
N N
S
a. O b.
N N
O
CO2H
O O
penicillin G strychnine
7.1 General
56 • Chapter 7 Stereochemistry
O O
N
CO2Me O
c. d.
O
O Ph
O OCH3
O
cocaine aflatoxin B1
3. Identify each chiral center as (R)- or (S)-.
H
HO H Ph
OH CH2CH2NH2
NH2 Me Br
a. HO b. c. N
Br H
H
Me
(-)-norepinephrine
Ph
O O CO2H
d. H2N H
e. f.
H Ph HS N
H Me
NH2
H
captopril (antihypertensive)
O
O OMe
g. Me OH misoprostol (CytotecTM - promotes cervical ripening)
HO
4. Identify each of the following pairs of structures as identical, enantiomers, or diastereomers.
Me H CH2OH CHO
a. Cl H Et Cl b. H CHO HO CH2OH
Et Me HO H
Et H
H F Me F
c. d.
H Me H Et
Me Me
7.1 General
Problems • 57
CHO H
e. H OH HO CHO f. AcO
CH3 CH3
OAc
vinyl
H Cl Cl
g. h. H
O O Cl H Cl H
vinyl
D-pinene (from pine resin)
Et
O O O Et
i. j. Et Me
Me
O Et
5. How many “kinds” of hydrogens (enantiomeric and diastereomeric hydrogens are different!) are there in
a. isohexane? b. (R)-2-chloropentane? c. (S)-4-chloro-1-pentene?
6. Nomenclature. Give the complete IUPAC name for the following:

Cl Me
H Bn allyl Br
a. b. H OH c. s-Bu
vinyl CH2Cl n-Pr
vinyl Et
Me H i-Pr
H Me
d. I e. s-Bu H f. Et H
H OMe
allyl Me
7.1 General
7. How many
a. pairs of enantiomers exist for bromochlorocyclopentane?
b. geometric diastereomers exist for 1,3-dichloro-2,4-dimethylcyclobutane?
c. pairs of enantiomers are possible for chlorofluorocyclobutane?
OH OH
d. meso stereoisomers and how many enantiomeric pairs exist for ?
Cl
e. meso stereoisomers exist for 2,3,4,5-tetrachlorohexane?
8. a. D-Xylose is a common sugar found in maple trees. Because it is much less likely to cause tooth decay
than sucrose, D-xylose is often used in the manufacture of candy and gum. D-Xylose is the C4-epimer of the
enantiomer of A. Draw its structure.
CHO
HO H H
H OH MeHN Me
H OH H OH
CH2OH Ph
A (-)-ephedrine
b. Ephedrine, a very potent dilator of the air passages in the lungs, has been used to treat asthma. The naturally
occurring stereoisomer, isolable from the plant Ephedra sinica, is levorotatory ([D] = -400) and has the
configuration above.
(i) Assign (R)- or (S)- configuration to each chiral center.
(ii) If a solution of (+) and (-) ephedrine has a specific rotation of +100, what percentage of the
mixture is dextrorotatory enantiomer?
7.1 General
Problems • 59
9. Optically pure quinine has a specific rotation of -1700. What percent of levorotatory form is present in an
optically impure sample whose [D] is +680? How many chiral carbons are there in quinine?
N
N
OH
quinine
10. (S)-Naproxen is an active non-steroidal anti-inflammatory drug (NSAID), but the (R)-enantiomer is a
harmful liver toxin. Assign the configuration for the (S)-enantiomer.
Me
CO2H
MeO
naproxin
11. For each of the molecules below, indicate whether it is capable of enantiomerism only (E), diastereomerism
only (D), or both enantiomerism and diastereomerism (ED).
Ph
H Me
a. b. c. d. e.
O CO2H
Ph
O
Cl
O
f. Me g. h.
S
12. Thalidomide was used as a sedative and anti-nausea drug for pregnant women in Europe (1959-62).
Unfortunately, it was sold as a racemate and each enantiomer has a different biochemical activity. One
enantiomer, the (S)-form, is a teratogen that was responsible for thousands of serious birth defects. Which
of the following is (R)-thalidomide?
O O H O O H
N N
O O
N vs. N
H H
O O
7.1 General
13. Another example of different enantiomers having remarkably different biochemical activities is
penicillamine. The (S)-form has anti-arthritic properties, whereas the (R)-form is toxic. Which form is the
following configuration?
Me
HS Me
H CO2H
NH2
penicillamine
14. Taxol is an anticancer agent active against ovarian and breast tumors. (a) How many chiral carbons are
in taxol? (b) If the specific rotation of optically pure taxol is -120o, and a synthetic preparation of taxol
containing only its two enantiomers shows a specific rotation of +24o, what is the percentage of
dextrorotatory enantiomer in the mixture?
AcO O OH
HO
O
Ph N
H O HO O O
Ph AcO
O
O Ph
taxol
15. Compound A below has _____ chiral carbons, _____ meso stereoisomers, and _____ pair(s) of
enantiomers.
CO2H
Cl O
O
HO OH
A B PGE2 (a prostaglandin)
The number of stereoisomers possible for B is _____ (do not change cis/trans configurations of the
olefins).
7.1 General
Problems • 61
16. The antibiotic cephalosporin C has a specific rotation of +103o in water.
O
N S
H
H2N N O
O
HO2C CO2H O
cephalosporin C
a. What is the maximum number of stereoisomers for the above structure?
b. If a synthetic sample of cephalosporin C has an optical rotation of +82o, what percent of the enantiomers
is levorotatory?
7.2 Reactions and stereochemistry

1. Draw the stereochemical formula for the major organic product(s) in the following reactions by
completing the Fisher projections.
Me OH
H
1. OsO4
Ph 2. NaHSO3
Me
Ph
Me
Br2 / H2O
Ph
2. Have the following reactions proceeded with syn- or anti- stereochemistry?
A
A B Me H
a. cis-2-butene
B H
Me
Me
D Me
b. C C C D
D
Me D
Me
C

c. Fumarase catalyzes the following reaction in mitochondria:
CO2H
HO2C H D2O DO H
H CO2H D H
fumarase
CO2H
malic acid
3. For each of the following reactions, (a) how many fractions could be collected by fractional distillation
or recrystallization, and (b) for each fraction describe whether it is one enantiomer (E), a racemate (R), or a
meso compound (M).
Ph
Ph Cl
HCl
a.
HBr
Br2
b. (Z)-3-hexene
KMnO4, H
c.
HI
d. (S)-3-phenyl-1-butene
H HF
e.
Cl
Me
D2 / Ni
f.

Problems • 63
Me
H, MeOH
g. H
H
1. BH3
h.
2. H2O2, OH
Et OH
H3O
i. H
H2 / Pt
1. Hg(OAc)2, H2O
2. NaBH4
1. OsO4
j.
2. NaHSO3
1. mCPBA
2. H3O
O MeOH, H
k.
4. Outline syntheses for the following conversions that ensure the indicated stereochemical outcomes.
Br
a. Ph Ph racemic Ph
Ph
Br

b. 2-butyne meso-2,3-dibromobutane
OH
c. racemic
OH
d. trans-2-butene meso-glycol only
OH
5. Consider the structure NHMe , and answer the following:
Ph
a. How many stereoisomers are possible?
b. Two of the structures are the decongestants ephedrine and pseudoephedrine:
OH H OH H
N N
Ph Me Ph Me
Me Me
ephedrine pseudoephedrine
Which stereochemical term best describes their structural relationship?
c. The HCl salt of ephedrine has a specific rotation of -34o. What would you predict for the specific
rotation of the HCl salt of pseudoephedrine?
d. Both ephedrine and pseudoephedrine can be dehydrated to an olefin, which upon hydrogenation
produces methamphetamine (“speed,” “meth”).
i. How many stereoisomers exist for the olefin?
ii. How many stereoisomers are possible for “meth”?

CHAPTER 8
ALKYL HALIDES AND RADICALS
8.1 Reactions
1. How many different dichlorides could be isolated by ordinary physical methods (e.g., fractional
distillation) from the following reaction? Would each, as collected, be optically active or inactive?
H Cl2, hv
Cl
2. Calculate the maximum % of (R)-2-bromopentane that could be formed from the reaction of bromine with
n-pentane.
1. Br2, '
2. Mg
3. 2,3-dimethylbutane
3. D2O
1. conc HCl
2. Li
3. CuI
4. OH
4. allyl iodide
1. Cl2, hQ 2. Li
5. cyclobutane 3. CuI
4. vinyl iodide 5. HI
1. Br2, '
6. propane 2. Mg
3. phenylacetylene
1. Li 2. CuI
3. n-PrBr 4. NBS, peroxides
7. bromobenzene
5. KOH 6. Br2 / H2O
8.1 Reactions
66 • Chapter 8 Alkyl Halides and Radicals
8.2 Syntheses
1. Br
O
2.
O
Br
3. isopentane
4. iodobenzene
Me
5. cyclopentane
Bn
CHO
6. chlorobenzene
3 ways!
7. cyclohexene deuteriocyclohexane
8.
8.2 Syntheses
Problems • 67
8.3 Mechanisms
arrows to explain the flow of electrons and show all intermediates.
O2, ROOR
1.
O OH
Cl
Cl
1. CH2N2, hv 2. Cl2, hv
2. H2C C CH2 + + Cl
Cl
allene spiropentane Cl
(propose a mechanism for step 2)
3. Bergman reaction:
D
' D
D
D
4. Alkyl nitrite esters (RO-NO) readily undergo photolytic homolysis. The Barton reaction utilizes this
fact to functionalize the remote G-position of steroids. Use conformational analysis to explain.
R R
G O N CH2
hv
H H
D
AcO AcO
H H
O OH
N O
8.3 Mechanisms
5. a. The vinylcyclopropane – cyclopentene rearrangement proceeds by a free radical mechanism.

Explain. Hint: the cyclopropyl C-C bond is easily homolyzed.
'
b. Predict the product:
'
6. Aspirin, as well as other non-steroidal anti-inflammatory drugs (NSAIDS), blocks the synthesis of
certain inflammation-mediating prostaglandins by inhibiting the enzyme cyclooxygenase (COX – see 5.1,
6d). COX converts arachidonic acid to the prostaglandin PGG2, which subsequently undergoes reduction
to give PGH2. Other prostaglandins derive from the latter. Outline a mechanism for the synthesis of PGG2.
Hint: begin by a free radical removal of one of the doubly allylic hydrogen atoms.
CO2H
COX enzyme O CO2H
O
H H 2 O2
R O
PGG2 OH
arachidonic acid
[H]
O CO2H
other prostaglandins
O
OH
PGH2
8.3 Mechanisms
CHAPTER 9
SN1, SN2, E1, AND E2 REACTIONS
9.1 General
For problems 1 – 9, circle the
1. reaction that will go faster:

ethanol
a. AcO + allyl chloride
HMPA
b. AcO + allyl chloride
2. structure with the poorest leaving group:
a. R-SH b. R-NH2 c. R-OAc d. R-OH
3. stronger nucleophile:
a. N b. Et3N
4. alkyl halide most reactive by an SN2 pathway:
Br
a. Br b. c.
Br
5. solvent that will maximize the rate of the reaction of Et3N with n-BuBr:
a. DMSO b. MeOH c. PhH d. chloroform
6. halide that will react more rapidly by an E2 pathway:
a. Me b. Me
Me Br Me Br
7. approximate value of kH / kD when PhCHBrCH3, vs. PhCDBrCD3, is allowed to react with potassium t-
butoxide:
a. 1 b. <1 c. >1
9.1 General
70 • Chapter 9 SN1, SN2, E1, and E2 Reactions
8. reaction that will yield the more stereochemically pure product(s):
Et Br
methanolysis (SN)
a. (or diastereomer)
Et
MeO , MeOH (SN)

b. (R)-2-bromopentane (or enantiomer)
9. change in rate of reaction if the concentration of Ph2CHBr is tripled and the concentration of ethanol is
doubled:
a. rate is unaffected b. rate triples c. rate doubles

d. rate increases 5-fold e. rate increases 6-fold
_____________________________________________________________
10. Which would be the reaction of choice (higher yielding) for each of these syntheses?
OMe O-t-Bu
a. Br
Br
b. OH OH
Br
Br
c. + OR vs. SR (which?) to maximize SN

Br
11. Which reaction would be expected to show a primary hydrogen kinetic isotope effect?
KO-t-Bu
a. H(D)
Cl t-BuOH
KOH
b. H(D)
Cl H(D) MeOH
KOMe
c. Cl
MeOH
(D)H H(D)
9.1 General
Problems • 71
12. The following reaction might be envisioned as occurring by an intramolecular SN2 process. However,
kinetic evidence indicates a bimolecular mechanism. Explain.
SO2 SO2
O O
CH3
C: C CH3
TsO H TsO H
9.2 Reactions
Identify (if not already stated) each reaction as largely SN1, SN2, E1, or E2 – then draw the structural formula
of the major organic product(s). Show stereochemistry where appropriate.
MeOH
1. n-octyl bromide + KOCH3
2. 3-iodo-3-methylpentane + sodium ethoxide / EtOH
3. potassium t-butoxide + sec-BuCl
4. 2-bromo-3-methylbutane + lithium diisopropylamide
KCN / DMF
5. n-hexyl iodide
methanolysis (RT)
6.
Cl
refluxing EtOH
7.
Br
O acetolysis (SN)
8.
Cl
9.2 Reactions
9. n-propyl bromide + Me2NH
10. isopropyl bromide + sodium t-butoxide
sodium acetate / DMF

11. 3-iodopentane
Cl
NaSH (1 equiv)
12.
Cl
ethanolysis (SN)
13.
Cl
Br
OAc / Ag
14.
Ph
Et
15. Me H OEt (E)
Cl H
Me
OMe / MeOH
16.
Cl
17. E2
D D
Cl
9.2 Reactions
Problems • 73
CH3
18. H D E2
Br H
Ph
19. acetone
OH
Br
triphenylphosphine
20. 4-iodo-1-pentane
t-butyl alcohol (SN)
S Cl methanolysis
21.
NMe2
'
22. I
Cl
23. conjugate base of H2Se +
OH
NHMe PhCH2Cl (1 equiv)
24. Ph
ephedrine
HO Me3O BF4
25. NMe3
choline
9.2 Reactions
OH 1. TsCl
26.
2. OH (SN)
H
PhNH2
27. S
HO
NHMe
Br
28. +
OH (1 equiv)
F
OH
epinephrine
29. refluxing MeOH

Cl
I F
(XS) NaSePh
30.
O
EtBr (1 equiv)
31. H2N NEt2
O
NovocaineTM
1. NaNH2
32. Ph C CH
2. cyclohexyl bromide
MeOH (E1)
33.
9.2 Reactions
Problems • 75
KSCN
34. Ph OTs
Br
acetolysis
35.
RT
1. MeI
36. S
2. refluxing EtOH
KO-t-Bu / t-BuOH
37.
O
Br
AromasinTM (an aromatase inhibitor
used in breast cancer therapy)
38. N N (XS) MeI
paraquat (an herbicide)
39.
H Br Me
EtO
a. O
O EtOH
H
H Me Br
EtO
b. O
O EtOH
H
9.2 Reactions
9.3 Syntheses
Ph Ph
1. Ph Ph
OH
Br
Ph
Ph
OCH3
Ph
Ph
t-Bu
Br
2. t-Bu
3.
Br
H D
H
Ph Me
Ph
4. Me H
H I Me
Me H
Et
I
5.
OPh
6. Br +
9.3 Syntheses
Problems • 77
7. Cl O Ph
Br
8. Br
9.
EtO
10.
O
Br
CO2H
CO2H
Ph Ph
11.
Ph Ph
OTs
12. Ph
OTs Ph
13.
OH
9.3 Syntheses
14. OH Cl
S
15. ethylene
S
via an alkyne H
16.
O
17.
I
Br
D
D
18.
Br
D H
9.4 Mechanisms
arrows to explain the flow of electrons and show all intermediates.
Br S
1. NaSH / HCO3
Br
9.4 Mechanisms
Problems • 79
acetolysis
2.
Cl OAc
Me Me
N Me N C
Br C N N
3.
Cl NEt2
4. OH
Ph Ph
NEt2 OH
O
H dil OH O
5. H
O
O
Cl
OH
(Note: retention of configuration!)
S vinyl
I DMF
6.
SH
7. n-butyl bromide + O
N
H
O
pyridine N-oxide
9.4 Mechanisms
8. When treated with hydroxide, trans-A yields B. However, when cis-A is treated with hydroxide, no B is
observed. Explain.
O
HO Cl
A B
_______________________________________________________
Problems 4 and 5 above illustrate the concept of “neighboring group participation” (NGP), wherein an
internal nucleophilic atom (e.g., N and O, respectively, in those examples) facilitates the ejection of the
leaving group by an intramolecular SN2 attack to form an unstable intermediate. This type of mechanism is
often evidenced by (1) rearrangement (problem 4), (2) stereochemistry (problem 5), or (3) kinetic data
(problem 9 below). Problems 9 – 16 are additional examples. Account for the observations
mechanistically.
9. Unlike most primary alkyl halides the molecules below, types of sulfur and nitrogen mustard gases, do
NOT undergo second order hydrolysis, but rather first order: -d[RX]/dt = k[RX]. Yet their rates of
hydrolysis are enormously faster than those of most primary alkyl halides.
Cl Cl HO OH
S S
H2O
Cl Cl HO OH
N N
10. Compound II undergoes acetolysis at 75o about 103 times more rapidly than I and yields a racemate.
Explain. What stereochemical outcome would you predict for the product from I?
OTs OTs
HOAc
OAc OAc
a racemate
I II
9.4 Mechanisms
Problems • 81
O OAc O
HOAc OAc
11. OTs O +
60% 40%
12. Paquette (OSU) observed that II undergoes solvolysis, e.g., acetolysis about 104 times more rapidly
than I.
X X
I II
13. Cl OH undergoes ethanolysis 5,700 times more rapidly than Cl OH .
14. Sometimes a carbon-carbon double bond can act as a neighboring group nucleophile. For example, II
undergoes acetolysis ~ 1011 times faster than I and does so with retention of configuration. Explain.
OTs OTs
I II
15. In view of the previous problem, account for the following:
HOAc
OTs AcO
NaOAc
9.4 Mechanisms
16. DNA is stable in dilute aqueous hydroxide solution, but RNA rapidly hydrolyzes. A mechanistic clue
is provided in the observation that hydrolysis of the latter yields not only 3’-phosphates but also 2’-
phosphates. Explain.
O O O O
RO P O CH2 NR"2 RO P O CH2 NR"2 RO P O CH2 NR"2 RO P O CH2 NR"2
O O O O
O O dil OH, H2O O O
3' 2' +
O O O O O O OH
OH OH O
R'O P R'O P O P
O P O
O O O O
DNA RNA a 3'-phosphate a 2'-phosphate
_______________________________________________________
'
17. racemic camphene + HCl
Cl
camphene hydrochloride
O
O P O adenine adenine
O O O
18. O P O O
+ PPi
O OH OH O P O OH
O P OH O
O ATP cAMP
9.4 Mechanisms
Problems • 83
Some terpene chemistry…
19. The biosynthesis of terpenes (natural products constructed from the essence of n units of isoprene)
begins with a “head-to-tail” coupling of two derivatives of isoprene, dimethylallyl pyrophosphate (DMA-
PP) and isopentenyl pyrophosphate (I-PP) to form geranyl pyrophosphate (G-PP):
O-PP O-PP
base H2O
a. +
O-PP OH
DMA-PP I-PP G-PP geraniol
O O (a monoterpene)
PP = P O P OH (-OPP is a good leaving group)
O O
H
b. geraniol OH
terpineol
c. A similar coupling of G-PP with I-PP yields the C15-sesquiterpene farnesyl pyrophosphate (F-PP) to
produce a C20-diterpene:
O-PP
I-PP
O-PP
O-PP
F-PP
[O] (a C20-diterpene)
H3O
x2
x2
OH
triterpenes (C30) A
(e.g., squalene => cholesterol) tetraterpenes (C40)
H (e.g., lycopene, E-carotene)
OH
vitamin A (retinol)
Outline a mechanism for the coupling and for the conversion of the diterpene A to vitamin A.
9.4 Mechanisms
d. F-PP can isomerizes to nerolidol pyrophosphate (N-PP). F-PP and N-PP undergo a “head-to-head”
reductive coupling by an E1 reaction to form the C30-triterpene squalene. Outline the mechanisms for each
of these events. Hint: reductive coupling is initiated by hydride attack on N-PP as shown below.
O-PP :H
O-PP
F-PP
N-PP
reductive coupling
squalene
20. The most common methylating agent in biochemistry is SAM (S-adenosylmethionine), formed by an
SN reaction between the amino acid methionine and ATP. An example of a metabolic methylation is the
conversion of norepinephrine (the prefix “nor” means one-less-carbon-than) to epinephrine. Formulate a
mechanism for producing SAM and draw the structure of epinephrine.
O
S O P O adenine S
O adenine
O
O
+ O P O H2N
H2N O OH OH
CO2H CO2H OH OH
O P OH
O
methionine ATP SAM
OH
HO NH2
HO
norepinephrine
epinephrine
9.4 Mechanisms
Problems • 85
TsOH EtOH
21. Ph2C N N Ph2CHOEt
-N2
O
22. PhCH2Cl + :P(OMe)3 PhCH2 P(OMe)2 + MeCl
KOH, H2O
23. HCCl3 + KI HCCl2I (Note: reaction does NOT occur in the absence of KOH!)
9.4 Mechanisms
CHAPTER 10
NMR
Deduce the structures in problems 1 - 17 from the 1H NMR and IR information.
1. C6H12: G0.9 (t, 3H), 1.6 (s, 3H), 1.7 (s, 3H), 2.0 (p, 2H), 5.1 (t, 1H); no long-range coupling evident.
2. C6H12Cl2O2: G1.3 (t, 6H), 3.6 (q, 4H), 4.4 (d, 1H), 5.4 (d, 1H).
3. C8H18O2: IR (3405 cm-1). 1H NMR į 1.3 (s, 12H), 1.5 (s, 4H), 1.9 (s, 2H).
4. C10H14O: IR (3200 cm-1). 1H NMR į 1.2 (s, 6H), 1.6 (s, 1H), 2.7 (s, 2H), 7.2 (s, 5H).
5. C5H10O4: į 3.2 ( (s, 6H), 3.8 (s, 3H), 4.8 (s, 1H).
6. C8H9BrO: į 1.4 (t, 3H), 3.9 (q, 2H), 6.7 (d, 2H), 7.4 (d, 2H).
7. C3H5ClF2: į 1.75 (t, 3H), 3.63 (t, 2H).
8. C9H10: į 2.04 (m, 2H), 2.91 (t, 4H), 7.17 (s, 4H).
10. NMR
88 • Chapter 10 NMR
9. C8H9Br: į 2.0 (d, 3H), 5.3 (q, 1H), 7.6 (m, 5H).
10. C4H6Cl2: į 2.18 (s, 3H), 4.16 (d, 2H), 5.71 (t, 1H).
11. C9H11Br: į 2.15 (m, 2H), 2.75 (t, 2H), 3.38 (t, 2H), 7.22 (s, 5H).
12. C9H10O3: į 2.3 (t, 2H), 4.1 (t, 2H), 7.3 (m, 5H), 11.0 (br s, 1H).
13. C6H11Br: į 1.0 (s, 9H), 5.5 (d, 1H, J = 17 Hz), 6.6 (d, 1H, J = 17 Hz).
14. C8H14: į 1.7 (s, 6H), 1.8 (s, 6H), 6.0 (s, 2H).
15. C6H11FO2: IR (3412 cm-1). 1H NMR į 1.2 (s, 6H), 2.2 (s, 3H), 3.8 (d, 1H), 4.1 (s, 1H).
16. C7H14O2: IR (1610 cm-1). 1H NMR į 1.0 (s, 9H), 2.1 (m, 2H), 3.8 (br s, 1H), 4.0 (t, 1H), 8.6 (t, 1H).
10. NMR
Problems • 89
17. C11H12O2: IR (1705 cm-1). 1H NMR į 2.2 (s, 3H), 2.5 (s, 3H), 5.8 (m, 1H), 7.1 (d, 2H), 7.9 (d, 2H),
9.8 (s, 1H).
____________________________
18. What is the maximum multiplicity for either of the methylene protons in the proton NMR for
F
H
Cl ?
H CH3
F
19. The structure below represents two diastereomeric compounds, A and B. Compound A gives a singlet
proton NMR for the methylene group, but B gives a multiplet for the same group. What are the structures
of A and B?
Br
Me, Br
Me
20. Trans-3-bromo-1-phenyl-1-propene shows a spectrum in which the vinylic proton at C2 is coupled with
the C1 proton (J = 16 Hz) and the C3 protons (J = 8 Hz). What is the expected multiplicity for that proton?
Use a spin tree diagram to explain.
21. a. What is the multiplicity of the chemical shift at highest field in the proton NMR of (R)-1,2-dichloro-
2-fluoropropane?
b. Use a spin tree diagram to explain why the lowest field chemical shift appears as a triplet.
10. NMR
22. What is the maximum multiplicity for Ha in the amino acid phenylalanine?
Ha
CO2H
Ph
NH2
phenylalanine
23. A compound has only two singlets in its 1H NMR spectrum: į 1.4 and 2.0 with relative intensities of
3:1. Its 13C NMR spectrum has chemical shifts at į 22, 28, 80, and 170. A strong absorption in its IR
occurs at 1740 cm-1. Draw a possible structure for the compound.
24. The following questions relate to deuterated cholesterol, drawn below:
DO
a. Predict the theoretical multiplicity of the lowest field proton.
b. What is the maximum number of 13C chemical shifts that would be expected for the C8H17 alkyl side
chain?
25. Treatment of 2,3-dibromo-2,3-dimethylbutane with SbF5 (a very strong Lewis acid) in SO2 at -600
yields SbF6- and a substance whose 1H NMR shows only a singlet at į 2.9. Draw the structure of that
substance.
26. What is the multiplicity of the methylene group in the following compound?
O O
P P
(i-Pr-O)2 (O-i-Pr)2
10. NMR
Problems • 91
27. Below is the structure and partial 1H NMR for an organoplatinum compound. Platinum has three
isotopes: 195Pt (I = ½, 34% natural abundance), 194Pt (I = 0), and 196Pt (I = 0) – the latter two account for the
remaining 66% natural abundance. (Note: aromatic proton resonances are not shown.)
PPh3
Cl Pt H
PPh3
G -13.6 -16.1 -19.6 ppm
a. Explain the relative amplitude and multiplicity of the signal at G -16.6. Clearly explain JH, ? by using a
spin tree diagram.
b. Explain the amplitude and multiplicity of the two signals at G -13.6 and -19.6. Again, clearly explain
JH,? by using a spin tree diagram.
c. What do the very negative chemical shift values of the signals suggest about the magnetic environment
of the resonating proton?
10. NMR
28. Pettit (UT) observed that the protonation of cyclooctatetraene (COT) yields a carbocation
(homotropylium ion) that possesses homoaromatic stabilization. (Homoaromatics refers to S systems that
are interrupted by a saturated center but in which the geometry still permits significant overlap of the p
orbitals across a gap.)
Ha Hb
H
H2SO4
H =
COT homotropylium ion
The 1H NMR of the homotropylium ion shows a remarkable chemical shift difference of 5.5 ppm for
geminal protons Ha (G 0.5) and Hb (G 5.0). Each appears as a pseudoquartet. Explain both the location of
the chemical shifts and multiplicities of these protons.
29. The 1H NMR spectrum of NaBH4 is shown below. Boron has two isotopes: 10B (I = 3) and 11B (I =
3/2) whose natural abundances are 20% and 80%, respectively. Interpret the spectrum.
H
Na H B H
H
G 0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 ppm
10. NMR
CHAPTER 11
CONJUGATED SYSTEMS
11.1 Reactions
HBr (1 equiv)
1.
(1,4-addition)
DCl (1 equiv)
2.
(1,4-addition)
D-farnesene (in waxy coatings of apple skins)
3. isoprene + MeO2C CO2Me
4. retro D-A
'
O
HBr (1 equiv)
5.
(product of thermodynamic control)
'
6.
2-butyne +
DBr (1 equiv)
7. 3-methyl-1,3,5-hexatriene
ROOR (1,4-addition)
8. N
O + N Ph
N
O
Cookson's dienophile
11.1 Reactions
94 • Chapter 11 Conjugated Systems
9. + (Z)-1,2-diphenylethene
N
H
1. NBS, ROOR
2. KOMe (E2)
10. cyclohexene
3. phenylacetylene
1. ' (retro D-A)

11. 4-vinylcyclohexene
2. trans-2-butene
C CH intra D-A
12.
1. vinyl chloride
13. O
2. KO-t-Bu
1. CO2Me
14. 1,3-cyclohexadiene
2. O3 3. Zn, H
15. ' (retro 4+2)
11.1 Reactions
Problems • 95
1. ' (retro D-A)

16.
2. cis-1,2-diphenylethylene
CO2H
17. + '
HO2C
fumaric acid
18. + estrone
MeO
O
19.
.. HO2C CO2H
OAc ' '
+
OAc
CO2Me
20.
CO2Me
O
N '
21. SO2 +
O2S
11.1 Reactions
22. base 4+2

C19H24O2
MeO
NMe3 I
MeO Br
R
Si CHO
23.
Me2
OMe
R'
N 4+2
24. +
Me3SiO R R
Danishefsky's diene
11.2 Syntheses
1. cyclohexane via a conjugated diene
Br
2. cyclohexane bicyclo[2.2.2]octane
Me
3. cyclohexene
Me
11.2 Syntheses
Problems • 97
4. vinylcyclohexane
5. A Diels-Alder dimerization of A gives the indicated product. Draw the structure of A.
O H
(4 + 2)
A
O
6. Draw the structures of the starting materials that may be used to synthesize the following product:
Me
N
(4 + 2)
? O
O
O
7. The Alder-ene reaction, like the Diels-Alder, is a concerted (pericyclic) reaction:
R
C ' R
C
Z Z = C, O Z
R H R H
How could the following compound be prepared by an ene reaction?
' CO2Et
+
OH
11.2 Syntheses
11.3 Mechanisms
Outline a detailed mechanism for each of the following. No other reagents than those given are necessary.
Use arrows to explain the flow of electrons and show all intermediates.
1. Phenolphthalein in solutions below pH 8.5 is colorless, but in solutions above pH 8.5 is a deep red-
purple color. Explain.
O H
HO
phenolphthalein
2. '
3. Similar to the Diels-Alder the following electrocyclic reaction is generally concerted (pericyclic) and
readily reversible.
'
Explain the observed conversions:
O O
a. '
+ O O
O O
O
O
b. '
11.3 Mechanisms
Problems • 99
4. The structure of pyridine is shown below:
..N
pyridine
a. Describe the longest wavelength Omax electronic transition in terms of VV SS or n.
b. Comment on the probability of that transition. What term in the Beer-Lambert equation reflects this
probability?
c. Draw the conjugate acid of pyridine. How would that transition in (a) be affected?
5. Compound A, upon standing in acid, yields a new isomeric compound B whose 1H NMR is G 1.7 (s,
3H), 1.8 (s, 3H), 2.3 (br s, 1H), 4.1 (d, J = 8 Hz, 2H), 5.5 (t, J = 8 Hz, 1H). Draw the structure of
compound B and give its mechanism of formation.
OH
A
6. One approach to synthesizing the sesquiterpene occidentalol, found in New England white cedar trees,
begins with a forward Diels-Alder reaction, followed by a retro-Diels-Alder, to form A. Explain.
Me Me
O
+ '
O O
O
CO2Me H H OH
CO2Me
A occidentalol
11.3 Mechanisms
7. An early stage reaction in Paquette’s (OSU) total synthesis of dodecahedrane employed the following
“domino” Diels-Alder:
R R
R
R
O O
'
8.
O O
tautomerize
9. ' (ene reaction)
(see 11.2, 7)
Ts
NC CN N
N hQ
Ts N
N -N2
CN
CN
11.3 Mechanisms
Problems • 101
11. The degradation of heme proceeds by way of the bile pigments biliverdin and bilirubin, green and red,
respectively. Elevated levels of the latter produce jaundice. Bilirubin, a principal antioxidant in blood
plasma, is formed by reducing biliverdin. Label the structures below as biliverdin or bilirubin and identify
the site of reduction in the former. Explain the difference in color of the two pigments.
OH OH
N OH N OH
NH H N N H N
N N
CO2H CO2H
CO2H CO2H
12. Depending upon the number of S electrons in a pericyclic process, reversible cycloaddition reactions
may be classified as thermally “allowed” or “forbidden” (a theoretical prediction of the probability that
such a reaction will occur). The Diels-Alder reaction is the most common example of a thermally allowed
(4+2) cycloaddition. Examples of thermally forbidden reactions include (2+2) and (4+4) cycloadditions
(they do occur, however, under photochemical conditions). Formation of the dibenzenes below could be
envisioned by a cycloaddition mechanism. Identify each as (2+2), (4+2), or (4+4). Which would be
expected to undergo a thermal retro-cycloaddition to benzene most rapidly?
a. b. c.
11.3 Mechanisms
CHAPTER 12
AROMATICS
12.1 General
1. Circle the compounds that would be expected to have aromatic character.
O
N
a. B b. c. N
d. N N
O
H
N O N g. h.
e. O f. N
H O
H B H
i. j. N N HN
k.
B B
H N H O N
H
H
l. carbocation in the reaction of SbF5

Cl
2 Li
m. product in the reaction of 2 Li +
2 MeLi
n. product in the reaction of 2 MeH +
Br
o. product in the reaction of Zn

-ZnBr2
Br
calicene
2. Which would have the largest molecular dipole moment (P)?
a. b. c.
12.1 General
104 • Chapter 12 Aromatics
3. Which nitrogen atom is least basic in purine and most basic in ZofranTM?
O
N N
N N
CH3
N N N
H
CH3
purine ZofranTM (antiemetic)
4. One of the following ketones is unstable and undergoes a Diels-Alder reaction rapidly. Which?
a. O b. O c. O
5. Which of the following compounds would most easily form its conjugate base?
a. b. c. d.
6. Which would undergo an SN1 reaction most readily?
O O
O
a. b. c.
Cl
Cl Cl
7. Circle the more(most) basic electron pair in each of the following:

O
H N
a. N b. c.
N N
O
8. Use a Frost mnemonic to explain why 7-chloro-1,3,5-cycloheptatriene gives a singlet 1H NMR spectrum
when dissolved in a solvent containing a Lewis acid.
anti-
bonding
0
bonding
12.1 General
Problems • 105
9. Which ketone has the largest molecular dipole moment (ȝ )?
O
O
a. b. c. O d. O
10. A in the presence of HBF4 forms a salt. Explain.
O
HBF4
Ph Ph
A
11. Explain the regioselectivity of the following addition:
HCl
Cl
12. The 1H NMR spectrum for the following [14]annulene compound shows two major chemical shifts.
Simulate their approximate location and predict the integration of each.
a [14]annulene
12.2 Reactions
NHCOPh
1. fuming H2SO4
HONO2 / H2SO4
2. o-methylphenol
12.2 Reactions
..
PH2
H2SO4, SO3
3.
4. Cl2 / Fe
N
H
1. PhCH2CH2Br, AlCl3
2. NBS, R2O2
5. benzene
3. KOMe, MeOH
Br2 / CCl4
6.
Br2, Fe
NBS, R2O2
Se
Me ICl, Fe
7.
Br2, FeBr3
8. Ph N O
Cl2, FeCl3
9. SH
Cl2, BF3
10.
N
12.2 Reactions
Problems • 107
OH
H2SO4
11. 2 Cl Cl + formaldehyde
Cl
(C13H6Cl6 - hexachlorophene, a disinfectant)
O 1. ' (-CO2, -N2)

12.
N N 2. 1,3-cyclohexadiene
13. picric acid
F
CN
NH3
14.
Cl
NMe2
1. MeLi
15.
2. H
Br
Cl
1. HNO3, H2SO4
16.
2. NaOMe, MeOH
CF3
H
17. toluene + O
-H2O
(a bicyclic C13 compound)
12.2 Reactions
OH
18.
H
BHT (C15H22O - a food preservative)
Br2 / Fe
19.
O O
D-pyrone
1. fuming HNO3 (x2!)

20. F3C Br
2. i-Pr2NH
Trifluralin BTM (a pre-emergent herbicide)
1. MeI, AlCl3
2. NBS, ROOR
21. anisole
3. KOH
(flavor in licorice)
partial 1 H NMR: G7.2 (d, 2H), 7.9 (d, 2H)
22. Although iodination of aromatic rings does not occur as readily as bromination, it can be observed
when activating substituents are present, e.g., in the biosynthesis of the hormone thyroxine:
I I
I2
HO HO O CO2H
CO2H
catalyst
NH2 I I NH2
tyrosine
thyroxine
12.2 Reactions
Problems • 109
1. [O] 2. Cl2, BF3 3. [H]

23.
N N N
O
(complete-
pyridine N-oxide
contrast to 12.2, 10)
12.3 Syntheses
1. benzene
Cl
D D
2. benzene
3. benzene D D
4. benzene 1,2-diphenylethane
5.
Cl
12.3 Syntheses
6. PhH
7.
8. benzene o-nitrobenzoic acid
9. benzene
10.
NHMe
N
11. benzene
CO2H
ibuprofen
12. acetone, phenol HO OH HO
12.3 Syntheses
Problems • 111
13. 2,4-D and 2,4,5-T are the active agents in the defoliant Agent OrangeTM. How could they be prepared
from the indicated starting materials?
Cl Cl OCH2CO2 Cl
Cl Cl Cl Cl
,
Cl , Cl
Cl Cl Cl OCH2CO2
2,4-D 2,4,5-T
Br
O NH OH
14.
NO2
TylenolTM
O
H2N CO2H H2N
15. p-hydroxybenzoic acid O
O NEt2
O
proparacaine (a local anesthetic)
12.4 Mechanisms
H
1. styrene
Ph
2. Epoxides, because of ring strain, are much more reactive than most ethers. Account for the following:
O
, H
anisole O
OH
12.4 Mechanisms
O
AlCl3
3. (XS) N,N-dimethylaniline + COCl2
phosgene Me2N NMe2
Michler's ketone
4. The Kolbe reaction is used industrially to convert phenol to salicylic acid, an immediate precursor to
aspirin.
OH OH OAc
1. OH CO2H
2. Dry Ice CO2H
3. H
salicylic acid aspirin
Br
Br2 / AlCl3
5. + isobutylene
O
1. R C X , AlCl3
6.
2. HBr
12.4 Mechanisms
Problems • 113
O O AlCl3 OH
7.
R R
Cl Cl Cl O Cl
NaOH
8.
Cl Cl Cl O Cl
dioxin
BF3
9.
Br
MeO MeO
10. Formyl chloride, A, does NOT exist; therefore, one cannot do a Friedel-Crafts type acylation to
produce benzaldehyde. However, the latter can by synthesized by the reaction of benzene with carbon
monoxide and HCl (a process known as the Gatterman-Koch reaction). Outline a mechanism.
O CHO
CO / HCl
H Cl
A
H2O2
11. toluene OH (a convenient way to substitute an hydroxyl group
CF3SO3H onto an aromatic ring)
12.4 Mechanisms
12. Dyes such as indigo blue (see 19.1, 34) do not bond well to cotton and tend to wash off after repeated
laundering; they are known as surface dyes. On the other hand, reactive dyes bind covalently to cotton,
resulting in greater color retention (‘fastness’). The following process illustrates the latter. An amino-
containing dye is initially bound to cyanuryl chloride to give a product that subsequently is allowed to react
with the hydroxyl groups of cotton. Show a mechanism for this process that illustrates how cyanuryl
chloride serves to crosslink the dye with cotton. What type of reaction describes each step?
Cl
N N 1. dye-NH2
Cl N Cl 2. cotton-OH
cyanuryl chloride
13. Malaria, which claims over one million lives per year, mostly children and largely in Africa, could be
eradicated with the judicious use of DDT. Banned in the US in 1972, in large part because of Rachael
Carson’s 1962 book The Silent Spring, exhaustive scientific review has since shown DDT, in moderation,
not only to be safe for humans and the environment, but also the single most effective anti-malarial agent
ever formulated. Although the World Health Organization and the US have now reversed their anti-DDT
stance, emotional opposition to the pesticide remains so fierce that its use continues to be resisted – at the
cost of millions of unnecessary deaths.
DDT is easily prepared as follows:
O
H2SO4 H
Cl3C H + 2 chlorobenzene Cl Cl
CCl3
DDT
1. BF3
14. +
Cl 2. H
12.4 Mechanisms
Problems • 115
H
15.
CHO
OH OH
16. When poly(styrene) is treated with chloromethyl methyl ether and SnCl4 (a strong Lewis acid),
Merrifield resin (named after Nobel laureate Bruce Merrifield who pioneered in vitro peptide syntheses) is
formed.
ClCH2 O CH3
SnCl4
CH2Cl
poly(stryene) Merrifield resin
1. Br2 2. :B 3. H2O
17. C7H8Br2 C7H7Br
O
ditropyl ether
Me
H OTs HOAc
18.
Ph H
SN (acetolysis)
Me
(a racemate)
Hint: recall the concept of neighboring group participation (9.4, 9-16) in some nucleophilic
substitution reactions; even aromatic rings are sometimes capable of acting as a “neighboring
group.”
12.4 Mechanisms
CHCl3 Cl
19.
N OR
H N
H
20.
OMe OMe
H3PO4 / H2SO4
21.
PO3H2
12.4 Mechanisms
CHAPTER 13
ALCOHOLS
13.1 Reactions
1. NaBH4
2. NH4Cl (a weak acid)
1. benzyl methyl ketone
3. PCl3
4. KO-t-Bu
1. H2 / Pd
2. H2SO4
1. i-PrMgBr
2. 3-ethyl-3-pentanol
Br
2.
OH
3. 1. H2SO4
2. H3O
HCl
1. TsCl
4. 5-hydroxy-2-heptanone
2. NaOAc
1. NaH
5. 1-hexen-3-ol
2. O
MeO S OMe
O
O
1. PhMgCl
6. Ph O 2. H
1. LiAlH4
2. H
13.1 Reactions
118 • Chapter 13 Alcohols
1. Li
2. diisopropyl ketone
7. iodomethane
3. H
1. HBr
2. LDA
8. 2-butanol
3. BH3.THF
4. H2O2, HO
O
O
1. NaBH4
OMe
9. 2. H
O Ph 1. LiAlH4
O 2. H
H2 / Pt
Me
H OH POCl3
10.
Me D pyridine
H
HO
1. NaOH
11. O
NMe 2. CH3I (1 equiv)
HO
morphine codeine
OH OH
Jones reagent
12.
HO HO
13.1 Reactions
Problems • 119
1. Br2, H2O
2. Me3SiCl
13.
3. Li
4. acetone
5. H3O
O
1. (XS) MeLi
14. BnO OBn
2. H
1. LiAlH4
15. p-hydroxybenzoic acid
2. (XS) HBr
O
O
OAc 1. NaBH4
16.
2. H
O
cortisone acetate
1. LiAlH4
2. H
OH
H
17.
HO (pinacol rx)
18. H
Ph
OH OH
O O
aromatase 1. NaBH4
19.
2. H
O HO
andostenedione estrone estradiol
13.1 Reactions
O OH
1. SOCl2, Et2O
20. 2. Mg
3. H
patchouli alcohol (used as a fragrance)
O
Ph OEt
1. n-PrMgCl
21.
N 2. H
Me
DemerolTM (narcotic analgesic)
OCH3 O
1. toluene, '
22. +
2. H
TMSO
Danishefsky's diene
13.2 Syntheses
O D
1.
O
O
CHO
2. cyclohexanol
13.2 Syntheses
Problems • 121
OH
3. 1-butene
Ph
OH H
4.
H OH
racemic s-BuCl
*OH
H
(* = 18O)
5. n-butane
HO
OH
6. cyclohexane O
7. vinyl chloride 1,3,5-hexatriene
8. n-hexyl alcohol C N
13.2 Syntheses
D
CO2H
9.
10. p-chlorophenol p-hydroxybenzaldehyde (via a Grignard)
OH O
11.
HO HO
estradiol
OH
12.
O
13. n-butane OH
Cl OH
14.
OH
OH
15.
13.2 Syntheses
Problems • 123
OH O
O
16.
Cl
OH OH
17.
OH
HO CH
C
18.
HO HO
OH OH
C CH
19.
HO Me
O
estradiol
O
OH
C CH
HO
O
EnovidTM constituents (OCPs)
20.
Br
13.2 Syntheses
21. Berson (Yale) discovered that the bicyclic carbocation A undergoes a clever rearrangement in which
the cyclopropyl ring circumambulates around the cyclopentenium ring. Beginning with B, synthesize a
deuterium-labeled species that would support this observation.
etc.
O
A B
13.3 Mechanisms
1. dil H2SO4
OH
OH
(a cyclic ether)
1. NaBH4
2.
2. H2SO4
O H
retinal
H
3. cycloheptene glycol
C7H12O
IR: 1729 cm-1
1H NMR: G (d, 1H),
plus other chemicals shifts
13.3 Mechanisms
Problems • 125
Ph
H Ph
4. OH
OH O
H
5. +
OH
H H
6. glycerol
O
H
7.
OH OH
(an aldehyde)
2. MgCl
8. 1. H3PO4
CO2H 3. H3O
O 4. HBr
5. Me2NH
NMe2
amitriptyline
(an antidepressant)
13.3 Mechanisms
9. Aflatoxin B1 is one of the most potent carcinogens known. In the presence of water and acid, compound
A is formed.
O O O O
O H O
H3O
O
O H
O OCH3 O OCH3
O
H
aflatoxin B1 A
CH3 CH3 CH3

10. H Br HBr H Br Br H
+ racemate
HO H Br H H Br
CH3 CH3 CH3
Note: retention at C2,3 inversion at BOTH C2,3!
This observation by Winstein (UCLA) provided stereochemical support for the concept of neighboring
group participation (see 9.4, 9-16).
Similarly,
Br Br
11. or HBr
only trans-product is formed!
OH OH
12. A step in the biosynthesis of the amino acid valine:
O
OH OH 1. [H] CO2H
H
CO2H
CO2H 2. (-H2O) NH2
O
valine
13.3 Mechanisms
Problems • 127
13. H2SO4
OH
14. The conversion of ethylene glycol to acetaldehyde under acidic conditions could occur by one of two
pathways: (1) dehydration to an enol followed by tautomerization, or (2) a pinacol-like rearrangement. In
view of the following experiment, which pathway is suggested?
O O
H2C CD2 H
OH OH DH2C D NOT H3C D
15. Cyclohexene glycol in the presence of acid forms cyclohexanone. Similar to problem 14, two
pathways are possible: dehydration/tautomerization vs. a pinacol-like rearrangement:
H H
OH +H
taut - H2O ~ H: H
- H2O OH -H
O OH OH O
H
cyclohexene glycol
Synthesis of deuterium-labeled glycol A, when treated with acid, yields B:
OH D
D H D
D
O
OH
A B
a. Which pathway is consistent with this observation?
b. Suggest a preparation of A from cyclohexene.
13.3 Mechanisms
O OH
H
16.
( = 13C)
OH O
Cl 1. Li
2. acetone
17. C4H8 +
3. H
(1H NMR shows only a singlet at G 8.2)
OH Cl
D
:PPh3 D
18. D
CCl4 D
19. OH H
D-pinene (a constituent in oil of turpentine - interestingly,

the dextrorotatory form is found in North American
oils and the levorotatory form in European oils)
13.3 Mechanisms
CHAPTER 14
ETHERS
14.1 Reactions
1. HBr (1 equiv)
1. 2. TsCl
O
3. KOAc, 18-crown-6
(XS) HI
2. benzyl phenyl ether
3. phenyl mercaptan + Me3S I
OH
4. KOH
Br
O 1. HF
5.
2. PCC
NaCN
6. 2-isopropyloxirane
MeOH
1. styrene epoxide
7. PhLi
2. H2SO4
OMe 1. HI (1 equiv)
2. CrO3, H
8.
3. NaBD4
4. H
14.1 Reactions
130 • Chapter 14 Ethers
1. PhCO3H
9.
2. PhOH, H
H, MeOH
10.
11. The fungicide flutriazole can be synthesized by the following scheme:
F MgI
2.
1. ClCH2COCl F
AlCl3 3. H
F N N 4. base
5.
N
F OH 6. H
N N
N
flutriazole
1. mCPBA
12.
Ph 2. MeNH2
ephedrine (bronchodilator)
13. The Claisen rearrangement of allyl phenyl ethers:
1. NaOH
OH
2.
Br
3. ' (Claisen)
14.1 Reactions
Problems • 131
14. The Claisen rearrangement can be generalized to include allyl vinyl ethers:
'
O O
Draw the expected Claisen rearrangement product for each of the following:
O
CO2H
a. '
OBn
b. A stage in the biosynthesis of aromatic amino acids (draw the structure of prephenic acid and give a
mechanism for its conversion to phenylpyruvic acid):
HO CO2H
' H
CO2H
O Claisen
O
HO2C
chorismic acid prephenic acid phenylpyruvic acid
15. Mechanistically similar to the Claisen rearrangement is the Cope rearrangement:
'
This specific example became known as the “degenerate Cope,” a moniker that did not particularly please
its discoverer, Prof. A. Cope! Of course, the degeneracy can be removed:
'
Cope
14.1 Reactions
16. Going back to problem 14.1, 13, if the ortho positions are blocked the initial Claisen rearrangement
product may be followed by a Cope rearrangement. Fill in the brackets.
Claisen Cope
' '
OH
~H
17. A slight variation of problem 14.1, 15 is the oxy-Cope rearrangement:
HO HO O
' tautomerize
H
Predict the oxy-Cope product for the reaction below:
OH
'
SH
18. 2 [O]
H2N CO2H
cysteine cystine [crystallization in kidneys can lead

to one type of calculi (stone)]
OH
SH [O]
19. HS
OH
dithiothreitol C4H8O2S2
14.1 Reactions
Problems • 133
14.2 Syntheses
1. 3-methylpentane 3-methoxy-3-methylpentane
2. cyclohexene trans-cyclohexene glycol
OTs
3.
S
4. propylene
2
diallyldisulfide (found in garlic)
O
5. cyclohexane via an epoxide
H
6. cyclohexene oxide cyclohexane
14.2 Syntheses
O O
7. N HS N
CO2H CO2H
captopril (antihypertensive)
S S
8.
CO2H
CO2H
asparagusic acid (isolable from asparagus)
14.3 Mechanisms
BF3, Et2O
1. styrene epoxide CHO
1. LDA
2. methyloxirane allyl alcohol
2. H
3. H
O OH
14.3 Mechanisms
Problems • 135
O O O OH O OH
OH, MeOH O
4.
5. Complex ladder polyether natural products, so named for their rung-like structure, are the active toxins
found in harmful algal blooms known as red tides, which cause devastating ecological damage. Brevetoxin
B is an example.
HO H
O
H O O
H H
HO
H H H O O H
O O
H
O O
H H H
O O O
H H H
brevetoxin B
Twenty years ago Nakanishi (Columbia) proposed such products arise biosynthetically from an elaborate
cascade of epoxide ring-opening reactions that zip up the polyether structure. The following reaction,
discovered by Jamison (MIT) in 2007, supports this hypothesis.
H
HO H H H H
O O
O O H2O
O
O H HO O O
H H H H
6. The biosynthesis of steroids involves an absolutely gorgeous (!) polycyclization reaction of squalene
epoxide, followed by two sequential 1,2-hydride shifts and two 1,2-methide shifts to form lanosterol
(lanosterol is then converted to cholesterol, the precursor to most other steroid hormones):
HO
O
squalene epoxide lanosterol
14.3 Mechanisms
7. Biochemical hydroxylation of aromatic compounds proceeds via arene oxides, which subsequently
undergo ring opening to form phenols:
H
O H OH OH
O
cytochrome P450 +H (a) - H
benzene oxide A
(b) 1,2-H: shift tautomerization
H
O O
H H
-H
H H
Phenol could be formed from intermediate A simply by an E1-like loss of a proton (path a) or,
alternatively, by a pinacol-like rearrangement followed by tautomerization (path b). Support for path b was
provided by chemists at the NIH who observed the following conversion:
D OH
O
H D
H3O
Explain. Account for the role of the methyl substituent. (This rearrangement of an arene oxide has now
become known as the NIH shift!)
CO3H
R OH R OH O
R' 1. Cl 2. BF3, Et2O R
8. R'
O R'
OH
Step 2 illustrates a semi-pinacol type rearrangement. Propose a mechanism for that step.
14.3 Mechanisms
Problems • 137
PhO N S DBN PhO N S

9. H H
O N O N
O O O
O CH2Cl
Note: DBN (1,5-diazabicyclo[4.3.0]non-5-ene) is a sterically hindered nitrogen base that favors

elimination over substitution:
H
N N H A N
N A
DBN
14.3 Mechanisms
CHAPTER 15
ALDEHYDES AND KETONES
15.1 Reactions
1. CrO3, H
1. OH
2. hydrazine, H
1. Ph3P
2. MeLi
2. PhOCH2Br
3. methyl ethyl ketone
a vinyl ether (see 15.1, 12, 13 and 15.3, 3, 33 for
examples of their reactivity)
O H3O
3.
O Ph
4. + opsin-NH2
H O
11-cis-retinal (a protein) rhodopsin
O OH
H3O
5.
Ph
OH
1. PCC
6. 2. H3O
3. HOEt, H
O
1. KO-t-Bu / t-BuOH
Cl
7.
2. HCl
15.1 Reactions
140 • Chapter 15 Aldehydes and Ketones
1. NaBD4
8. methyl n-propyl ketone 2. H
3. H2SO4 (E1)
1. KMnO4
2. semicarbazide
9.
3. H2 / Pt (XS)
HO
vitamin D
O
1. ethylene glycol, H
CH 2. DIBAH, -78o
10.
OMe 3. Ph3P=CMe2
O 4. H3O
citronellal
O
1. Ph3P
O
11. p-nitrobenzaldehyde
2. H3O
a fluorescent "spy dust" ingredient
1. Ph3P-CHOCH3
12. O
2. H3O
an aldehyde
13. Using the above reaction (12) as a model, how could you prepare pentanal from butanal?
15.1 Reactions
Problems • 141
OMe
1. CH2I2 / Zn (Cu)
14. 2. H3O
O
3. Ph3P=CHC=CH2
OMe
1. H3O
15. cyclopropanecarbaldehyde hydrazone 2. EtMgI
3. H
1. H3O
16. acetophenone diphenyl ketal
2. H2NOH
O
CHO H3O
17.
a heterocycle
1. Ph3P
18. O 2. n-BuLi
O
Br
3. butanal
4. H3O
O
H3O
19.
O O
1. H3O, Hg2+
20. t-butylacetylene
2. hydrazine, OH
15.1 Reactions
1. Br2, H2O
2. O ,H
21.
3. Li
4. ethylene oxide
5. H3O
1. HONO2 / H2SO4
22.
2. H2NOH, H
CHO
O
nitrofuroxime (used in treating urinary tract infections)
H3O
23. Et O
O
multistriatin
(European elm bark beetle pheremone)
OH / ROH
24. 2-oxopropanal
(intra-Cannizzaro)
CHO
1. N2D4, OD, D2O

25.
OMe 2. HI
OH
vanillin
CO2H CN CO2H
O O Ph O OH
26. H3O
OH H OH
+ HCN + ??
OH OH
OH OH
This reaction, with the release of the very toxic HCN, provides a defense mechanism for millipedes.
15.1 Reactions
Problems • 143
O
H3O
27.
O
frontalin (insect pheremone)
MeOH, H
28. 3-oxobutanal
C6H12O3 IR: 1715 cm-1

1H NMR: G 2.2 (s, 3H), 2.8 (d, 2H), 3.4 (s, 6H), 4.9 (t, 1H)
O O OMe
H3O
29.
O
30. H3O
O
safrole (odor of sassafras)
NH2
H 1. H
31.
CO2H
2. H2 / Pt
O
proline (an amino acid)
AcO O
OH
32. 1. LiAlH4
MeO 2. H3O
MeO
cortisone acetate dimethyl ketal
15.1 Reactions
O O
OH
33.
H H
OAc
1. LiAlH4
34. OAc
2. H3O
HO
O
HO O
35. H3O
O
O
F
flunisolide (anti-inflammatory
in allergy medication)
(XS) hydroxylamine
36. 1,2-cycloheptanedione
heptoxime (used in quantitative determination of Ni)
H3O
37. O O O O
paraformaldehyde
38. Chain degradation of a hexose:
OH OH O
1. NH2OH, H
H
2. Ac2O (dehydrates
OH OH OH an oxime)
15.1 Reactions
Problems • 145
O
Me
N
N N mild acid
39. H
O
O
O
tadalafil (CialisTM)
H H
O N N
40. Me2N S mild acid
MeNH2 +
NO2
ranitidine (ZantacTM - antiulcerative)
N
N
H3O
41.
N
H S
olanzapine (ZyprexaTM - antipsychotic)
1. PCC 2. Me2CuLi
42. OH
3. H3O
citral
H
N
H3O
43. O O
F
paroxetine (PaxilTM - antidepressant)
15.1 Reactions
44. Ammonia is produced in the mitochondria primarily by the oxidation of glutamate to produce an
imine, which is subsequently hydrolyzed:
NH2
[O]
H3O
O2C CO2 + NH4
glutamate
D-ketoglutarate
O
O
45.
H3O 4 steps
HO
O
diosgenin (from Mexican yams)
progesterone
OH
1. PCC
46. 2. MeLi
EtO 3. H3O
EtO
testosterone diethyl ketal 17-methyltestosterone (an anabolic steroid)
47. A step in Woodward's (Harvard) synthesis of strychnine:
N O
1. HC CNa / THF
N 2. H2 / Lindlar catalyst
H O
O
dehydrostrychninone
15.1 Reactions
Problems • 147
48. Aldehyde protons are non-acidic. However, if the aldehyde is converted to a 1,3-dithiane (the sulfur
analog of an acetal), the proton can then be quantitatively removed by NaNH2 or organolithiuim bases. The
resultant anion (Corey-Seebach reagent) readily undergoes SN2 or carbonyl addition reactions. Subsequent
hydrolysis of the product unmasks the starting carbonyl.
O S S
R n-BuLi
R 1. R'X O
+
R H SH SH H S S 2. H3O R R'
Li
a dithiane Corey-Seebach reagent
Predict the products of the following reactions:
1. HS(CH2)3SH, H
2. MeLi
a. benzaldehyde
3. EtI
4. H3O
1. n-BuLi
S 2. n-decyl bromide
b.
S 3. H3O
1. HS SH , H
c. acetaldehyde
2. NaNH2
3. cyclohexanone
4. H3O
49. The amino acid serine can undergo a retro-aldol-like reaction (see CARBONYL CONDENSATION
REACTIONS) to form glycine and formaldehyde; in cells this reaction is catalyzed by a derivative of
pyridoxine (vitamin B6):
OH
O
retro-aldol
H2N CO2H H2N CO2H + H H
serine glycine
(cont. on next page)
15.1 Reactions
Catabolic reactions that produce formaldehyde, as above, generally occur in the presence of another
vitamin derivative, tetrahydrofolic acid (FH4). The later detoxifies formaldehyde by reacting with it to
produce A. On the other hand, many anabolic reactions require formaldehyde as a building block (e.g.,
biosyntheses of the nucleoside bases). In those instances A undergoes hydrolysis to yield FH4 and
formaldehyde in situ. Draw the structure of FH4.
H
H2N N N
N H3O
FH4 + CH2O H N FH4 + CH2O
O N
catabolism anabolism
A
O
HN CO2H
CO2H
[Note: Unlike us, bacteria can synthesize FH4 de novo from precursors such as p-aminobenzoic acid
(PABA). Sulfa drugs are effective competitive inhibitors to enzymes that utilize PABA, thus destroying
the ability of the bacteria to synthesize FH4.]
N
N
N
50. H
NH2
O -H2O
Cl
XanaxTM (anxiolytic)
15.1 Reactions
Problems • 149
15.2 Syntheses
HO CO2H
1. cis-2-butene
NH2
OCH3
OH
2.
H
D
3. cyclopentanone CO2H
O Cl
4.
D
5. benzaldehyde Ph CO2H
15.2 Syntheses
O O
O
6. Ph C CH2Cl C Ph
O
OH
OH
OH O
OMe
O O OH O
7. OMe OMe
OH
OH
OH
8. via a Wittig
O
9. MVK (methyl vinyl ketone)
OMe
15.2 Syntheses
Problems • 151
via a Wittig
10. OH
O O
O H
11. +
Br O
HO
CHO
12. Hydrazones can be deprotonated by strong bases to give carbanions that act as nucleophiles, e.g.,
NR2 NR2
N N
n-BuLi
(H
-H
O OH
How could this observation be used to form Ph from acetone and benzaldehyde?
CHO CHO
13.
O
O
14. H
15.2 Syntheses
OH OH
C CH
15.
O O
major component in OCPs
O Ph Et
16. Ph , benzaldehyde Ph
R R
(R = -OCH2CH2NMe2) tamoxifen (NolvadexTM - antiestrogen)
O
17. 1-butene
18.
CO2Me
CO2Me
H O
19.
H
OH O
chrysomelidial (secreted by larvae of some
beetles in self-defense)
15.2 Syntheses
Problems • 153
20. The hotness of chili peppers can be quantified by determining their Scoville heat units (SHUs). An
SHU is the amount of dilution needed before the chili is undetectable. The hottest, according to the
Guinness Book of World Records, is the bhut jolokia from India, firing up at around 1,041,427 SHU, i.e., a
drop of extract needs about a million drops of water! (Jalapeño and Tabasco range a mild 5,000 – 25,000
and 100,000 – 200,000, respectively, on the SHU scale.) The active ingredient is capsaicin. Formulate a
synthesis of the carboxylic acid moiety from 6-bromo-1-hexanol.
OH
HO HO
Br O OMe
O N
H
capsaicin
21. Similar to benzyl carbon-oxygen single bonds, carbon-sulfur single bonds readily undergo
hydrogenolysis. This observation provides a more gentle reduction of aldehyde or ketone carbonyls than
the highly alkaline Wolff-Kishner or acidic Clemmensen reductions. Complete the following illustration of
this approach:
O
H2 / Ra-Ni
Ph Ph PhCH2Ph
(hydrogenolysis)
a dithiane (see 15.1, 48)

(or thioketal)
O
22. O via an enamine H
N
O
15.2 Syntheses
15.3 Mechanisms
H, H218O
1. O 18O
H3O
2. H2N
CHO
N
3. Vinyl ethers, unlike ordinary ethers, hydrolyze rapidly in water with just a trace of added acid.
Draw the products and mechanism for
TsOH / H2O
??
O
O H
4. + hydrazine N
N
H
H
Cl OH
OMe / HOMe
5.
O OMe
H MeO
15.3 Mechanisms
Problems • 155
O O R
H2NOH, H
6. R R R
N O
HO
O O O
O H
7. OH
8. Fugu, a fish, is a Japanese delicacy. Unfortunately it produces a very toxic substance, tetrodotoxin (an
adult fugu contains enough to kill 30 people), in organs that must be removed by a licensed chef. To
become a fugu chef requires training for years with a master and culminates in a battery of state-
administered exams, including eating a fugu prepared by oneself ! Though the risk of fugu poisoning is
practically nil, if prepared by a master, a handful of diners succumb to fugu each year; perhaps that is why
Japan’s Imperial Family is forbidden from tasting one of their country’s choicest dishes. Deduce the
structure and outline the mechanism of the carboxylic acid produced when tetrodotoxin is treated with
aqueous acid.
O
HO O
H O
H2N
N OH H3O
N
HO
H OH
OH
tetrodotoxin
9. E. J. Corey (Harvard) found that sulfur ylids, similar to the Wittig reagent, can be prepared as follows:
O 1. SN2 O
S + CH3I Me2 S CH2
2. n-BuLi
When treated with cycloheptanone a 70% yield of A is obtained. Explain, showing clearly how the
intermediate betaine’s behavior to form an epoxide differs from that of a typical Wittig intermediate.
15.3 Mechanisms
O
OH
HCl
10.
Cl
O
OH
O H3O
11. acetaldehyde
O
OH
H3O
12.
O O
diazomethane
13. cyclohexanone cycloheptanone
Ph
N H NHPh
14. + acetaldehyde
N H NHPh
Ph
15.3 Mechanisms
Problems • 157
15. The Vedejs olefin inversion reaction readily converts cis-to-trans or trans-to-cis stereoisomers:
1. mCPBA
(Hint: think Wittig-like)
2. Ph3P
:P(OMe)3
16. propylene epoxide propylene
HO
HO
OH
O NHR
17. H O
+ NH2R
OH OH
OH OH
H
18. 2 phenol + acetone C15H16O2
bisphenol A (a starting material in the synthesis of LexanTM)
O
n-PrNH2 Et
19. H
N
15.3 Mechanisms
20. Another protecting group for alcohols (in addition to TMS or vinyl ether derivatives) is MOM
(methoxymethyl). MOM is stable to base, but can be cleaved upon treatment with mild acid. The
following sequence illustrates its use:
Cl Cl
1. Li
1. NaH 2. CH2O
OH 2. ClCH2OCH3 O HO OH
3. H3O
MOM
a. Draw the structure of the MOM derivative and explain its mechanism of formation.
b. Outline the mechanism of the last step. What other two organic products are formed from the MOM
group?
Br O
H3O
21.
O OH
SCH3
22. MeSH
0o
O OH
O
CN H2O, OH
23.
NC H
OH
15.3 Mechanisms
Problems • 159
O OEt O
1. MeLi
24.
2. H3O
E-vetivone
Et
H H
O O EtNH2 N
25.
26. Outline the mechanism for steps 2 and 3.

TMS O
2. OMe Ph
Ph
1. (Danishefsky's diene) N
PhCHO + PhNH2
N O Ph
Ph 3. H
27. Aromatic aldehydes cannot be prepared by direct Friedel-Crafts acylation (formyl chloride is unstable).
One alternative is the Gatterman-Koch reaction (12.4, 10). Other options include the following two
reactions:
a. the Reimer-Tiemann reaction
OH OH
1. CHCl3, OH CHO
2. H
15.3 Mechanisms
b. the Vilsmeier reaction (outline a mechanism for both steps)
Me OH
Me O2PCl2
N H POCl3 1. phenol CHO
Me N Cl
Me C
O H 2. H3O
salicaldehyde
Vilsmeir reagent
28. Another approach to enhancing the acidity of an aldehyde proton (see 15.1, 48 – Corey-Seebach
reaction) is illustrated by the benzoin condensation reaction:
O OH
CN
2 PhCHO
Ph Ph
benzoin
29. NH formaldehyde, H N
OH OH
HO HO
OH
O H O
30.
OH
OH OH OH OH
E-D-ribose D-D-ribose
(Carbohydrate chemists call this process "mutarotation" and refer to
the two epimeric diastereomers as "anomers.")
15.3 Mechanisms
Problems • 161
31. The final step in the urea cycle:
NH2 H O
H3O NH2
N NH
HO2C H2N NH2 + NH2
HO2C
NH2
arginine urea ornithine
32. Fluorescamine reacts with amines to give a highly fluorescent derivative. As little as a nanogram of an
amino acid, for example, can be detected by this method. (Warning: do not attempt this one alone!)
Ph R Ph
O N
O RNH2
O OH O
H CO2H
O
fluorescamine highly fluorescent derivative
33. Unlike other types of phospholipids, plasmalogens undergo hydrolysis to produce not only fatty acids
but also fatty aldehydes. Explain the formation of the latter.
(CH2)nCH3
O O
R C O H3O
O
P OR'
O O
a plasmalogen (platelet activating factor)
34. Although ketones are generally not reactive with most oxidizing agents, they are readily oxidized to
esters when treated with peracids (Baeyer-Villager reaction).
O O
+ RCO3H
Ph Ph Ph O Ph
15.3 Mechanisms
35. Many historians of chemistry credit the discovery of molecular rearrangements to the benzilic acid
rearrangement:
O O OH
KOH, EtOH
Ph CO2
Ph Ph
Ph
benzil CB of benzilic acid
Discovered by Liebig in 1838, it is a rare example of a rearrangement under alkaline conditions (most
require acidic environments). Because of (1) disagreements over atomic weights at the time (the
“conventional” weights for carbon and oxygen were thought to be 6 and 8!), and (2) the (erroneous as we
now know) dogma propagated by Kekulé that carbon skeletal rearrangements could not occur in the course
of chemical reactions, many wrong structures for benzilic acid were proposed -- until Baeyer finally got it
right nearly forty(!) years later in 1877.
a. Propose a mechanism for the benzilic acid rearrangement.
b. Baeyer observed a benzilic acid-type rearrangement when phenanthrenequinone is treated with base.
Draw the expected product.
O 1. NaOH
O 2. H
phenanthrenequinone
c. Another more modern benzilic acid-type rearrangement:
O O 1. MgX O
OH
Ph Ph
2. H Ph Ph
15.3 Mechanisms
Problems • 163
Problems 36 – 40 illustrate the dienone – phenol-type rearrangements.
O
OH
36. H
R R R
R
OH
HO
37. base acid
OTs
30% HClO4
38.
O
HO
However (!),
H2SO4
39.
O
OH
15.3 Mechanisms
And, lastly, a steroid dienone – phenol rearrangement:
HO HO
O O
O OH O OH
OH
H
40.
prednisone (anti-inflammatory)
Problems 41 and 42 illustrate the Favorskii-type rearrangement.
O
CO2R CO2R
Cl OR
41.
+ ( = 13C tag)
HOR
50% 50%
Br
O CO2R
OR
42.
Br HOR
OMe
H3O
43. +
NMe2 OH
O NMe2
O
15.3 Mechanisms
Problems • 165
R
N
44. Br2 / H2O N R
CHO
45. Sheehan’s (MIT) classic total synthesis of penicillin V involved a condensation step between the
following reactants. Formulate a mechanism. (Note: the product is simply a nitrogen – sulfur analog of an
acetal.)
O O
HS
C H O
N H
+
CO2R H2N CO2H N
O S
O
penicillamine HN
RO2C
CO2H
46. Woodward (Harvard) envisioned the biosynthesis of strychnine as beginning with a condensation of
derivatives of the amino acids tryptophan (trp) and phenylalanine (phe). Sketch a likely sequence of
events.
trp
NH2
N NH
H
O
H N strychnine
H
phe
HO
OH
HO
OH
15.3 Mechanisms
47. Thioketones, in the presence of aqueous acid, form hydrates via an intermediate ketone:
S
HO OH
Br Br H3O Br Br
Br Br Br Br
48. Many aldehydes autooxidize in air. For example, a white powder (benzoic acid) may often be seen
around the cap of a bottle of previously opened benzaldehyde (liquid). Such autooxidation is thought to
proceed by the addition of O2 to a molecule of benzaldehyde via a free radical process to form perbenzoic
acid. The perbenzoic acid then reacts with a second molecule of benzaldehyde to form two molecules of
benzoic acid. Outline a mechanism for the second step. Hint: recall the Baeyer-Villager oxidation of
ketones to esters (15.3, 34).
O
O O H O
O2 OH
H O OH
2
49. An impressive biomimetic conversion in Johnson’s (Stanford) total synthesis of progesterone (see
19.3, 16 for the final stage):
O O
O
O
1. O H O H
O 2. aq K2CO3
H H H H
CF3CO2H
OH
progesterone
15.3 Mechanisms
CHAPTER 16
CARBOXYLIC ACIDS
16.1 Reactions
1. KMnO4, H
N
N
nicotine niacin
1. NaOH
2. phenylacetic acid
2. Me3O BF4
1. NaBH4
3. 3-oxobutanoic acid
2. H
Ph O Ph
1. H3O
4.
O O 2. CrO3, H
Ph
1. NaOH (1 equiv)
5. J-bromobutyric acid
2. '
3. LiAlH4
4. H3O
1. KOH
OH 2. acrylic acid (propenoic acid)
6.
3. BH3
4. H3O
1. NaCN
2. PhMgCl
7. benzyl chloride
3. H3O
O
1. SOCl2
8. NH2
2. DIBAH, -78o
3. H3O
16.1 Reactions
168 • Chapter 16 Carboxylic Acids
9. N 1. (XS) PhLi
Ph CO2H
OH
2. H
Ph OH
fexofenadine (AllegraTM - antihistaminic)
OAc 1. LiAlH4
10.
CO2H 2. H
aspirin
OH
1. KCN, H
2. H3O
11.
O 3. BH3
4. H3O
testosterone
CO2H 1. EtLi
12. Ph NMe2
2. H
Ph
methadone
1. H3O
13. CO2H CO2 +
2. PCC
14. A reaction in the biosynthesis of the amino acid leucine:
CO2H
1. [O]
CO2H
HO 2. (-CO2) CO2H
H2N
leucine
16.1 Reactions
Problems • 169
15. The alkaloid cocaine, isolable from coca leaves, can be converted to tropinone, a precursor to the
antispasmodic atropine (see 20.3, 12). Deduce the structure of tropinone.
N O
N
OMe 1. OH CO2H 3. Jones reagent
2. H 4. '
O
O Ph OH
cocaine ecgonine tropinone
OH
CO2H 1. NaOH (2 equiv)
16.
2. MeI (1 equiv)
3. H
17. Chemical structures for medicinals that contain acid-base components are routinely drawn incorrectly
in prescription information supplied by drug companies. For example, sumatriptan succinate, an active
ingredient of TreximetTM (prescribed for migraines) is drawn as shown below. Draw its correct structure.
CH2CH2N(CH3)2
CH3NHSO2CH2 COOH
N
. CH2
CH2
=
H COOH
16.2 Syntheses
1. benzoic acid PhCH2CO2H
2. propylene pentanedioic acid
16.2 Syntheses
O
3. OH acetone + CO2
4. o-chloroacetophenone
CO2H
CO2H
5.
styrene
ibuprofen (MotrinTM - antipyretic)
CO2Na
6. 1-butanol
sodium valproate (used in the treatment of epilepsy)
CO2H O
7. OH
CO2H O O
HO
via a nitrile CHO

8. benzyl bromide
16.2 Syntheses
Problems • 171
NC N N
9. O
NC
O
10. pentanedioic acid
11. RCO2H RCH2 R'
O OH
12. 3-oxobutanoic acid
Ph
13. ethanol butanedioic acid (succinic acid)
CO2H
14.
CO2H
16.2 Syntheses
15. acetylene hexanoic acid
OH OH
OH O
16.
16.3 Mechanisms
H
1. CO2H O
OH OH
2. CO2H '
-CO2
O O
tetrahydrocannabinolic acid THC
O
Cl
Cl
OH
3.
Cl
CO2
16.3 Mechanisms
Problems • 173
4. Isobutylene and carbon monoxide, in the presence of acid, give dimethylpropionic acid. Explain.
5. The carboxyl group may be protected by allowing it to react with 2-amino-2-methylpropanol to form an
oxazoline derivative. Outline the mechanism. (Acid hydrolysis of the oxazoline regenerates the carboxylic
acid.)
O
N
R OH + HO R
H2N O
(an oxazoline)
O
OMe
MeOH, H
6. O
CO2H
O
7. The aldehyde flavorings formed in the roasting of cocoa beans is caused by the Strecker degradation of
amino acids:
NH2 O
O O H3O, '
+ + CO2 + N N
R CO2H R H
8. Strecker also developed a synthesis of amino acids:
O R' O
H3O N
R H + R'NH2 + CN H OH
R
16.3 Mechanisms
9. The biosynthesis of the amino acid phenylalanine involves an acid-catalyzed decarboxylation of pre-
phenic acid:
CO2H
HO H
CO2H
CO2H CO2H
-CO2
O O H2N
prephenic acid
phenylalanine
10. Ninhydrin reacts with amino acids to give a blue dye which can be colorimetrically assayed. Sketch
the intermediates.
O O O O
OH -H2O
O + NH2CHRCO2H N
OH
O O O O
+ CO2 + RCHO
ninhydrin
a blue dye
11. The vitamin niacin is used to form nicotinamide adenosine dinucleotide, which readily shuttles
between its oxidized (NAD+) and reduced (NADH) forms. The latter serves as a cellular equivalent to
NaBH4. The essential portions of the structures are shown below. Outline a mechanism for the cellular
conversion of pyruvate to lactate. (Note: like NaBH4, NADH cannot reduce carboxylic acid carbonyls.)
O H H O
NH2 [H] NH2 O OH
NADH
N N CO2 CO2
[O]
R R
NAD+ NADH pyruvate lactate
12. The cellular biosynthesis of glucose (gluconeogenesis) begins with the conversion of oxaloacetate
(OAA) to phosphoenolpyruvate (PEP!) via a decarboxylation-phosphorylation pathway. Provide arrows.
O O CO2
O O O
O CO2 + O P O P O P O guanosine CO2 + O + GDP
OH O O O P OH
O
OAA GTP PEP
16.3 Mechanisms
Problems • 175
13. Unlike ȕ-ketocarboxylic acids, Į-ketocarboxylic acids do NOT undergo mild thermal decarboxylation.
However, the enzyme pyruvate decarboxylase (PDC) gently converts pyruvate to acetaldehyde at 37o. The
key is provided by an essential cofactor, a derivative of vitamin B1 (thiamine). The activity of thiamine
resides in the thiazolium ring, shown below. A mechanistic clue was offered by Breslow’s (Columbia)
discovery that Ha rapidly undergoes exchange with deuterium when thiamine is dissolved in D2O,
suggesting that Ha is relatively acidic. Propose a mechanism for thiamine-assisted decarboxylation of D-
ketocarboxylic acids. (Hint: begin with the conjugate base of thiamine, then consider how the thiazolium
nitrogen can serve as an ‘electron sink’ to accept the electrons from decarboxylation.)
R'
O O
PDC
R N S + CO2
CO2 thiamine H
Ha
pyruvate
thiazolium ring
14. Another biochemical approach to decarboxylation:

Vitamin B6 (pyridoxine) is a precursor to the coenzyme PLP (pyridoxal phosphate), a catalyst for many
reactions, such as decarboxylations, that involve amino acids. Outline a mechanism. (Hint: form an imine
from PLP and the amino acid, then consider the role of the pyridinium nitrogen as an ‘electron sink.’)
H O
CO2H
NH2
R OH PLP
NH2
NH -CO2 NH
N N
N
H
histidine histamine
PLP
15. Determination of the molecular mass of acetic acid in a nonpolar solvent, e.g., hexane, yields a value of
120. Explain.
16.3 Mechanisms
CHAPTER 17
CARBOXYLIC ACID DERIVATIVES
17.1 Reactions
O
OEt Et2NH (1 equiv) / pyridine
1.
Cl
O
2. butyric anhydride + methylamine
EtOH (XS), H
3. cyclopropyl cyclohexanecarboxylate
4. propane -1,3-diol phosgene
1. PCl3
5. oxalic acid
2. LiAlH(O-t-Bu)3
3. H
H3O
6. N,N-diisopropylpropionamide
1. isopropyl magnesium bromide

7. phenyl hexanoate
2. H3O
O MeOH, H
8.
O
1. LiAlH4
2. H
9.
3. Ac2O
CO2H
17.1 Reactions
178 • Chapter 17 Carboxylic Acid Derivatives
saponification
10. H-caprolactone
O
NH
Bn S H2O, OH
11.
N
O
CO2H
penicillin G
O
Et OR
12. + urea
Et OR
O
VeronalTM (a barbiturate, sedative)
O
N
1. OH
O 2. H
13.
3. Jones reagent
4. '
Ph
O
cocaine O
O
OH
..
SCoA
14.
NH2CH2CO2H (glycine)
HO OH
cholyl coenzyme A (a rare example of

cis-fused A-B rings in steroids) glycocholate (a major bile salt)
N 1. H3O
15. 2. CH2N2
N
O O
strychnine
17.1 Reactions
Problems • 179
OH
1. H3O (a lactone)
16. OEt 2. PhMgCl
3. H
O
O
O 1. LiAlH4
17.
2. H
O O
Spanish fly
H
1. phosgene
18. N
N 2. LiAlH4
H 3. H
protein
O
OH
19. O P F
Me
SarinTM (a cholinesterase inhibitor)
H CO2H
N 1. SOCl2
20.
2. diethylamine
N
LSD
H lysergic acid
O
O
21. S Cl + H2N N
O H
OrinaseTM (for diabetes)

O
H2O, OH
22. NH
S
O O
saccharin
17.1 Reactions
acetic anhydride
23. p-hydroxyaniline
(1 equiv)
acetaminophen (TylenolTM - antipyretic)
Al2O3, ' aniline

24. acetic acid H2C C O
(-H2O)
ketene
O O
H
25. + [ethylene glycol]n
MeO OMe
dimethyl phthalate n
DacronTM
26. LexanTM, a high-molecular weight “polycarbonate,” is manufactured by mixing bisphenol A (see 15.3,
18) with phosgene (COCl2) in the presence of pyridine. Draw a partial structure for LexanTM.
HO OH
bisphenol A
OH
27. Me N C O +
methyl isocyanate
(active ingredient in the insecticide SevinTM)
O 1. Li
2. CuI
28. O
3. benzoyl chloride
4. H3O
Cl
O NHMe 1. propionic anhydride

29.
2. LiAlH4
F3C 3. H
fluoxetine (ProzacTM - antidepressant)
17.1 Reactions
Problems • 181
HO O
O O
O
NH3
30.
simvastatin (ZocorTM - antilipemic)
O
C CH
31. 1. saponification
2. H3O
N
OH
Ortho TriCyclinTM (OCPs)
O
MeO 1. LiAlH4
32. N
H
HO 2. H3O
capsaicin (active agent in cayenne pepper)
O
H2N
S
O 1. H2O, OH
33. N
N 2. SOCl2
CF3 3. urea
celecoxib (CelebrexTM - anti-inflammatory)
F
S O
HO
O
O
H3O
34.
F
O
F
fluticasone propionate (FlonaseTM - anti-inflammatory)
17.1 Reactions
CO2Na 1. PhLi
35.
2. H3O
MeO
naproxen sodium (AleveTM - anti-inflammatory)
O HN N
N
S H3O
36. NO N
N OEt
sildenafil (ViagraTM - treatment of ED)
1. base, '
37. Br CO2H
2. NH2
NH OH
38. n
H-caprolactam Nylon 6 (a polyamide)
NH 1. ethyl chlorocarbonate
39.
N
2. Et2NH
diethylcarbamazine (anthelmintic)
O OEt
N H3O
40.
CO2
Cl
loratadine (ClaritinTM - antihistaminic)
17.1 Reactions
Problems • 183
NH
1. ethyl benzoate
41. 2. LiAlH4
3. H
Cl
Cl
sertraline (ZoloftTM - antidepressant)
OMe
CO2H 1. SOCl2
42.
H2N
OMe S
2.
N
O
CO2H methicillin [an estimated 90,000 people in the US
fall ill each year from MRSA (methicillin resistant
Staphylococcus aureus)]
CF3
O N
H
43. H3O
CF3
O N
H
dutasteride (AvodartTM - treatment of BPH)
CO2H
O
H3O
N
44. H2N H OMe
O
Ph
aspartame
O Cl
N N
N exhaustive hydrolysis
45.
N O
O
N
zopiclone (LunestaTM - sedative, hypnotic)
17.1 Reactions
O
1. NaBH4
46. CO2H 2 H2O + C6H8O4
2. H
pyruvic acid
47. Chain elongation of a tetrose sugar:
1. HCN, CN
OH O 2. H3O
3. SOCl2
H
OH OH 4. LiAlH(t-BuO)3
5. H
(see chain degradation of a sugar, 15.1, 38)
48. Consider the reaction of amino acid A with amino acid B. Four possible products are possible: A-A,
B-B, A-B, and B-A, if simply A and B are heated together. A more rational synthesis of, for example, A-B
is to first treat A with t-butyl chlorocarbonate (C), which has the effect of eliminating (blocking) the
nucleophilicity of the nitrogen in A. The blocked species is termed a t-BOC amino acid (t-butoxy-
carbonyl).
R O O
R R'
N
+ H2N H OH
H2N CO2H H2N CO2H O Cl
O R'
A B A-B C
a. Draw the product of the reaction of A with C.
b. The t-BOC-A is then condensed with B to yield a derivative of A-B. A-B is formed by treating that
derivative with mild acid. Show the mechanism of removing the blocking group to form A-B. (Hint: CO2
and isobutylene are by-products.)
17.1 Reactions
O
H
53. O glucose + glucose
OH
tuliposide tulipaline (a J-lactone)
(found in tulip bulbs) (produced when bulbs are damaged - a fungicide)
N O 1. SOCl2
N N 2. ammonia
54.
3. SOCl2
F CO2H
O
LevaquinTM (antibacterial)
OH O N
N H3O N
55. H S
N ' CO2 + MeNH3 + H3N + ??
S S
O O (gives a positive Tollens' test)
meloxicam (MetacamTM - anti-inflammatory)
17.2 Syntheses
1. sec-butyl acetate
O O
O O
2. R NH2 R H
R CH3
17.2 Syntheses
Problems • 187
O O
NH N
3.
4.
O
5. 1,3-cyclopentadiene, acetylenedicarboxylic acid
O
O
OH
6. CO2H
H
O
O
7. benzamide Ph
O
8. butanal 2-pentanone
17.2 Syntheses
9. Following is an outline for the synthesis of diazepam (ValiumTM). Supply the appropriate reagents for
each step.
O O
NHCH3
NCH3 NCH 3
Cl O
Cl Cl
CH3
O H
N
NCH3
Cl
O
Cl O
Cl
CH3 H3C
O O
N N
NH2
O
Cl Cl N
ValiumTM
10. 3-oxohexanedioic acid O
11. methyl benzoate methyl phenylacetate
17.2 Syntheses
Problems • 189
12. Following is an outline for the synthesis of fluoxetine (ProzacTM). Supply reagents for each step.
O O
NaO N O N O NH2
O F3C O
F3C
O N O N OEt
H CH3 H
O
F3C F3C
ProzacTM (antidepressant)
Ph
13. Ph N N
EtO
O
DemerolTM (analgesic)
14. Following is an alternative synthesis of ProzacTM (see 17.2, 12). The reagent for step 5 is indicated;
supply reagents for all the other steps. Outline a mechanism for step 5.
O O NMe2 HO NMe2
O
O NMe2 Cl NMe2
5. Cl OEt
F3C
mechanism?
Me Me
O N OEt O N
H
O
F3C F3C
ProzacTM
mechanism:
17.2 Syntheses
Et HO2C
15.
ibuprofen
O O O
16.
OH
CO2H
O
OH
17. O
Cl
CONEt2
18.
DEET (N,N-diethyl-m-toluamide - insect repellent)
19. Melatonin mediates circadian rhythm, the 24-hour sleep-wake cycle. Because its biosynthesis is
inhibited by light, it is produced in the brain when the eye is not receiving light. Outline a synthesis from
the neurotransmitter serotonin.
H
NH2 O H
HO N O
MeO O N
N N H
H H
serotonin (5-HT) melatonin RoseremTM
Insomnia affects one in every eight people. RoseremTM, a selective melatonin receptor agonist, is an
example of several drugs approved to treat short- and long-term insomnia.
17.2 Syntheses
Problems • 191
20. The two monomers (B and C) for the synthesis of Nylon 66 can be prepared from a sugar derivative A.
Supply the necessary reagents.
Br
O catalyst O O
CHO
(- CO)
Br
A
O
Cl
Cl CN
O B
Nylon 66
CN
H2N
NH2
C
21. Name the following polymer and devise a synthesis for it. Remember, OH is not an
appropriate starting monomer. Why?
OH OH OH OH
22. Some members of the morphine family of opium alkaloids…
RO CH3O CH3O
O O O OH
N N N
R'O O O
R, R' = H (morphine) hydrocodone (a component oxycodone (HCl salt = OxyContinTM,
of VicodinTM) a component of PercosetTM)
R = Me, R' = H (codeine)
R, R' = Ac (heroin)
How can the following conversions be accomplished?
a. morphine codeine
17.2 Syntheses
b. morphine heroin
c. codeine hydrocodone
d. In aqueous solution codeinone exists in dynamic equilibrium with its EJ-unsaturated isomer, neopinone,
hydration of which yields oxycodone. Write a mechanism for the equilibration.
CH3O CH3O
H
H3O
O O oxycodone
N N
O O
codeinone neopinone
OH
H
N N O2C
CO2H
23.
N N OH
CO2H NMe2
O AmbienTM (sedative)
17.2 Syntheses
Problems • 193
17.3 Mechanisms
H2*O, H
1. J-butyrolactone (show location of the labeled oxygen)
1. (XS) RMgX
2. O t-BuOH + ??
O
2. H
Cl
3. Lactic acid (D-hydroxypropanoic acid) forms a cyclic compound, C6H8O4. Formulate a structure for this
compound. Why does lactic acid not form a simple D-lactone?
*O
TsOH
4. O an alkene + ?? (show location of the labeled oxygen)
Et
O
PhMgCl (1 equiv) O
5. ethyl 5-oxohexanoate
Ph
17.3 Mechanisms
6. Phenylisothiocyanate (A, PITC, Edman reagent) can be used to sequence proteins, i.e., to determine the
order of amino acids (primary structure). For example, treatment of dipeptide B with A in the presence of
acid yields C (a phenylthiohydantoin, or PTH, derivative of the amino acid). Characterization of C
identifies the first (from the N-terminal end) amino acid, in this case alanine.
valine residue
S
O Ph
H N
Ph N C S + H2N OH NH +
N
PITC H H2N CO2H
O O
A B C valine
alanine residue PTH-alanine
O 1. Me3O BF4 O
7.
NH2 2. H3O OMe
8. The Swern oxidation:
a. "activation" of DMSO step: b. oxidation step:

H OH
O O O + O
- CO2 R R
S +
Me Me R R
Cl Cl - CO NR3
DMSO oxalyl chloride
a chlorosulfonium salt
17.3 Mechanisms
Problems • 195
9. Similar to the Swern is the Corey-Kim oxidation:
O H OH
+ O
S + Cl N R R
NR3 R R
O
N-chlorosuccinimide
a chlorosulfonium salt
10. The biosynthesis of pyrimidine bases, e.g., uracil, begins with the formation of dihydoorotic acid.
Formulate a mechanism.
O O
O O CO2H H H
N N
P + H2N
H2N O O
OH CO2H O N CO2H O N
H H
carbamoyl phosphate aspartic acid dihydroorotic acid uracil
11. The antimalarial mefloquine can be synthesized from substituted 4-quinolones by the following
sequence of reactions. Outline a mechanism for step 1 and draw the structures in brackets.
O
Br
2. Li
1. POBr3 3. CO2
N CF3 4. H
H N CF3
CF3 5. (- 600)
CF3
N Li
6. H3O
HO
N
H
7. [H]
N CF3
CF3
mefloquine
17.3 Mechanisms
12. Acid halides react with diazomethane to give diazomethyl ketones, which, like diazomethane,
decompose to give carbenes.
O
CH2N2 O O
hQ
R Cl .. H + N2
R C N N R
..C
H
a diazomethyl ketone
a. Formulate a mechanism.
b. This reaction was used in the synthesis of twistane. Draw the structures in brackets.
1. SOCl2
hQ
2. CH2N2 - N2
CO2H
[D]D +480
1. H2 / Pd
2. Wolff-Kishner
=
twistane
[D]D +4340
13. Cyanogen bromide (CNBr) specifically cleaves certain peptide (amide) bonds to yield a lactone:
H O R'
R H
N 1. N C Br
N O N
+ H2N
O R H
2. H3O O R'
S O
17.3 Mechanisms
Problems • 197
14. Draw the structure in brackets and give a mechanism for the conversion of A to strychnone.
OH
N H (Baeyer-Villager oxid)
N H2O2, H
O O
pseudostrychnine
O
O N N H
O
H3O
N N
O O O O
strychnone A
15. A step in Woodward’s (Harvard) classic total synthesis of strychnine:
Ac
N Ac
N
Ac2O, pyridine
N CO2H Me
N
O OAc
O
17.3 Mechanisms
16. The final step in Sheehan’s (MIT) total synthesis of penicillin V involved the formation of a strained E-
lactam. To accomplish this he employed a new reagent, dicyclohexylcarbodiimide (DCC), first reported
from his lab two years earlier to smoothly form amides from an aqueous mixture of a carboxylic acid and
an amine at room temperature. [That important advance in the state of the art for forming amide bonds was
subsequently utilized by Merrifield (Rockefeller) in his solid-phase approach to synthesizing proteins by
linking amino acids together through amide (peptide) bonds.] Propose a mechanism for the lactamization
reaction.
OPh
OPh
N S N C N
H N S
DCC H
O CO2 N
O N
H CO2 O
CO2
salt of penicillin V
OH ONa
O 1. PCl3 (2 equiv),
H3PO3 (1 equiv) O P OH pH 4.3 O P OH
17. H2N
OH OH OH
2. H2O
J-aminobutyric acid H2N O P OH H2N O P OH
(GABA) OH OH
(a bisphosphonic acid) TM
Fosamax (alendronate sodium,
bone resorption inhibitor)
Hint: phosphorous acid exists in two tautomeric forms; use the nucleophilic form to attack the product
of the reaction of GABA with PCl3. This one is rather challenging.
17.3 Mechanisms
Problems • 199
18. Tertiary alcohols are weakly nucleophilic because of steric hindrance near the hydroxyl group and,
therefore, do not readily undergo Fischer esterification. One approach to form acetate esters of such
alcohols is to allow them to react with isopropenyl acetate in the presence of an acid catalyst. Hint: the
actual acetylation step involves an SN1-like reaction of the alcohol with an acylium ion.
OMe
OMe
O
O ,H
O
OH O
O
O
19. In contrast to phenyl acetate, the conjugate base of aspirin (acetylsalicylic acid) readily undergoes
hydrolysis in water, suggesting kinetic enhancement by the latter’s carboxylate moiety. Consider two
possible pathways and outline a mechanism for each.
a. The carboxylate anion acts as a nucleophile, attacking the acetate ester to form a mixed anhydride, which
is subsequently hydrolyzed by water:
b. The carboxylate anion acts as a base, removing a proton from water to form hydroxide, which
subsequently attacks the ester:
c. Experimental evidence indicates that when the reaction is conducted in the presence of 18O-labeled
water, no label is found in the salicylic acid product. Which pathway is supported by this experiment?
H O
1. H
NH2 2. NaBH4
20. + CO2Me N
3. H H N O
N
H
17.3 Mechanisms
CHAPTER 18
CARBONYL Į-SUBSTITUTION REACTION AND ENOLATES
18.1 Reactions
1. LDA
1. O
2. n-PrBr
1. OMe, MeOH
2. benzoyl bromide
2. methyl 3-oxopentanoate
3. H3O, '
1. EtOCO2Et, LDA
2. OEt
3. cyclohexanone
3. EtI
4. H3O, '
1. base
2. benzoic anhydride
4. diethyl malonate
3. H3O, '
Cl
CN 1. OEt
5. + NC-CH2-CO2Et
2. H3O, '
NO2
6. + NaCH(CO2R)2
OTs
1. H3O
2. CrO3, H
7. (E)-3-pentene-2-one
3. NaH (2 equiv)
4. benzyl chloride (1 equiv)
5. H
18.1 Reactions
202 • Chapter 18 Carbonyl Į-Substitution Reactions and Enolates
1. OEt
2. isobutylene epoxide
8. diethyl malonate
3. H3O, '
1. (XS) NaOEt
2. Br(CH2)4Br
9. ethyl acetoacetate
3. H3O, '
(C7H12O)
O
1. LDA
2. PhSeBr
10.
3. H2O2
4. MeOH, H
O 1. Br2, H
O 2. KO-t-Bu / t-BuOH
11.
O 3. LiMe2Cu
4. H3O
1. Br2, H
2. (CN)2CH:
12. t-butyl methyl ketone
3. H3O, '
1. OEt, HOEt
2. butanoyl chloride
13. diethyl malonate 2 CO2 +
3. H3O, '
O
1. a. Br2, OH b. H
2. PCl3, Br2
14.
3. MeOH
O
15. + NaOEt
H H (pKa 15) HOEt

(C8H10)
18.1 Reactions
Problems • 203
O
1. LDA
16.
2. Cl2, H
Br
1. HCl (1,4-addition)
2.
O O
17.
isoprene 3. H3O, '
O
1. Cl2, H
18.
2. OH (SN2)
3. KMnO4
1. Cl2, H
2. KO-t-Bu
3. H3O
4. KMnO4
Cl
CH2(CO2Me)2 1. KOH, EtOH

19.
LiH (XS) 2. '
Cl
95% 91%
1. SOCl2
2. Me2NH
3. m-chloroperbenzoic acid
O O O O
1. base tautomerize
20.
O 2. OH O
O
coumadin (WarfarinTM - an
anticoagulant)
18.1 Reactions
18.2 Syntheses
1. butyric acid ethylpropanedioic acid
2. dimethyl malonate G-valerolactone

(valeric acid is a common name for pentanoic acid)
3. dimethyl malonate butanedial
4. dimethyl malonate NH
O N O
H
seconal (a sedative)
5. dimethyl malonate 2-benzylbutanoic acid
6. dimethyl malonate + styrene Ph

OH
7. dimethyl malonate + methyl acrylate Br Br

(acrylic acid is propenoic acid)
8. ethyl acetoacetate s-Bu-CONH2
18.2 Syntheses
Problems • 205
O O
9. ethyl acetoacetate OH
O O
10. ethyl acetoacetate O
O O Cl Cl
12. ethyl acetoacetate s-butyl methyl ketone 2-methylbutanoate
13. cyclopentanone
OAc
14. cyclopentanol CO2H
O O
15. 2,4-pentanedione
18.2 Syntheses
16. methyl acetoacetate 2,4-pentanedione
via an organoselenium cmpd

17. 3-pentanone ethyl vinyl ketone
O O
Cl O
18. chlorobenzene
N
H
WellbutrinTM (an antidepressant)
OH O N
H
O OH
19.
,
OH
propranolol (a E-adrenergic blocker, developed by Sir

James Black, recipient of '88 Nobel Prize in medicine;
greatest breakthrough in pharmaceuticals for heart illness
since discovery of digitalis approximately 200 years ago)
S
H
N N Na
20. dimethyl malonate
O O
sodium pentothal
(used to induce pre-surgical anesthesia
in combination with sedatives)
CN Ph Ph
21. N N
O
NC
O
Et
meperidine (an analgesic)
18.2 Syntheses
Problems • 207
18.3 Mechanisms
O OH
1. H O
OH OH OH H
(a central reaction in glycolysis catalyzed by the enzyme TIM, triose isomerase)
O O
1. EtO, HOEt
O
2. propylene oxide
3. 1,3-Diphenyl-1,3-propanedione gives a positive iodoform test even though it is not a methyl ketone. In
addition to CHI3, two equivalents of benzoate are formed. Explain.
O O
H
4. H
racemization
O O
OMe
5.
MeOH
O
O O
18.3 Mechanisms
O
H
6.
O O
7. The vitamin biotin is necessary for many metabolic carboxylation reactions. It reacts initially with CO2
to form unstable A, which then “donates” CO2 to a substrate. Outline the mechanism for carboxylation of
pyruvic acid to oxaloacetic acid (OAA).
O
O O
HN NH CO2, ATP O
HN N OH O
CO2H
CO2H
HO2C S CO2H
HO2C S
biotin A pyruvic acid OAA
OH
H O
8. O
O O
O P O H
OH
O Me3N O TMS
9. + Me3Si Cl
18.3 Mechanisms
CHAPTER 19
CARBONYL CONDENSATION REACTIONS
19.1 Reactions
1. OH, (-H2O)
1. benzaldehyde + acetophenone 2. NaCH(CO2R)2
3. H3O
H
2. isobutryaldehyde
O
3. OEt, EtOH
+ CHO
4. OMe, MeOH
OMe
1. OMe
5. dimethyl heptanedioate CO2 +
2. H3O, '
OH, ROH
6.
(conj. add'n + retro-aldol)
O
OH
7.
O
cis-jasmone (a perfume)
1. BrCH2CO2Me, t-BuO
8. propionaldehyde
2. H3O, ' (Darzen's cond.)
19.1 Reactions
210 • Chapter 19 Carbonyl Condensation Reactions
1. base
9. MeO CHO + propionic anhydride
2. acid (Perkin cond.)
OCH3 OCH3
base
10. + ethyl vinyl ketone
O
(complete)
OH
11. benzaldehyde + CH3NO2
OMe, MeOH (retro-Claisen)

12.
CO2Me
O
1. NaOEt / EtOH (-H2O)

13. cyclopentanone
2. NH2NHPh
O 1. OMe, MeOH
O
2. Cl
14. CO2 + C5H6O
MeO O 3. H3O
OH 1. CH2(CO2Me)2, OMe
15. acetone
(aldol) 2. H3O, '
C6H10O C8H12O2
19.1 Reactions
Problems • 211
CHO
OH (-H2O)
16. + 3-pentanone
CHO
OH OH
O retro-aldol
17.
OH OH H
1. methyl vinyl ketone

18. N
2. H3O
3. NaOH (aldol)
OH
19. acetaldehyde + (XS) formaldehyde
C(CH2OH)4 -- pentaerythritol
O
PhCHO, H
20.
CHO
21. 1. base
+ CH2(CO2Et)2
OH 2. H
C12H10O4
O
CHO
22. KOH
+
CHO
O
(a pentacyclic dione)
19.1 Reactions
23. A reaction in the biosynthesis of the amino acid leucine:

O
O 1. SCoA (aldol)
CO2H 2. hydrolysis
24. Trans-resveratrol, isolable from red wine, has been implicated as a cardioprotective and can be
synthesized as follows:
MeO CHO
MeO 1. OEt
+ + CO2
CN 2. H3O
OMe
HO OH
3. BBr3, RT
(hydrolysis)
trans-resveratrol (82%) OH
O 1. H3O
25. 2. KO-t-Bu (retro-aldol)
26. Forward and retro-aldol-like reactions that occur in plants:
CO2 O
O
retro-aldol SCoA
CO2 hydrolysis
O2C H
HO malate
CO2 - O2C CO2 glyoxylate
succinate
19.1 Reactions
Problems • 213
O
O
+ OEt / EtOH
27.
O (Robinson annulation)
28. The biosynthesis of glucose involves aldolase, an enzyme that catalyzes both forward and retro-aldol
reactions. The forward process illustrates a mixed aldol wherein the enzyme initially binds with A,
promoting its tautomerization and subsequent reaction with B to form a ketohexose:
O O
aldolase
+ H OH
OH OH OH
A B
29. The Krebs Cycle begins with an aldol-like condensation of a thioester (acetyl coenzyme A) with
oxaloacetate, followed by hydrolysis:
O O
H3O
+ CO2
SCoA O2C
oxaloacetate
citric acid
30. The following sequence illustrates how fatty acids are catabolized to acetyl coenzyme A, a process
known as E-oxidation. Fill in the brackets.
O
H3O [O]
SCoA
(conj. add'n)
HSCoA
O (retro-Claisen)
+
SCoA
19.1 Reactions
31. Excessive accumulation of acetyl CoA can lead to metabolic ketosis by the following pathway:
H3O
Claisen
A
O
[H] - CO2
2 SCoA
C
B
[A, B, and C (unfortunately!) are referred to as “ketone bodies;” accumulation of acids A and C lowers
blood pH (acidosis).]
___________________________________________________
32. A cortisone story…
Cortisone is one of 43 steroids found in adrenal cortical glands. It was first isolated by Kendall (Mayo
Clinic) in 1934 (extraction of ~ 1,000 lbs of beef adrenal glands yielded only 85 – 200 mg of cortisone).
One of the earliest total syntheses of cortisone was published by Sarett (Merck) in 1952. The following
reactions illustrate his strategy.
a. The initial sequence of reactions formed the A-B-C rings. Draw the missing structures.
O
HO
O Diels-Alder 1. H2 / Ni (1 equiv) H C
OH
B H
2. a. LiAlH4
EtO b. H EtO
C
1. H3O (=> a ketone)
A B 2. methyl vinyl ketone, base
(Robinson annulation)
(complete)
19.1 Reactions
Problems • 215
b. Construction of the D ring began as follows. Fill in the bracketed structure and outline the mechanism
for step 3.
R
1. X , t-BuO R
C 3. mild acid
C
O 2. a. EtO C C MgX H
b. H CO2Et
c. Subsequent selective reduction followed by tosylation produced the indicated structure, which was then
treated with the sequence of reagents shown. Draw the product of step 2 and give the mechanism for step
3.
O O
O
C
C D
H
OTs
1. a. OsO4 b. NaHSO3
2. KIO4 3. OMe / MeOH
d. The above product was then subjected to the following steps. Draw structures for the critical
intermediates in steps 2 -4.
OAc
O O O O
O
1. O 2. I2, OH
O O O
C D RO OR 3. OH, '
C D
O C D
H OR RO 4. KOAc
H
H
19.1 Reactions
e. The final four steps yielded cortisone. Deduce the structure of cortisone acetate.
OAc
O 1. HCN
O
2. (-H2O)
C D
H 3. KMnO4, OH
(- HCN)
OH
O
O
OH
4. H3O
cortisone cortisone acetate
___________________________________________________
CO2Me 1. OMe, MeOH

33.
CO2Me 2. H3O, '
O
O H
H CH3NO2 N
34.
NO2 NaOMe / MeOH N
H O
C8H7N2O5 Na
indigo blue (probably oldest known
coloring agent - used to dye bluejeans)
35. A step involving an intra-Michael reaction in Corey’s (Harvard) synthesis of longifolene, a component
of Indian turpentine oil:
Et3N
O
longifolene
19.1 Reactions
Problems • 217
19.2 Syntheses
via an aldol
1. ? + ? 1,3-diphenyl-1-propanol
O O
via an enamine
2. cyclohexanone
via an aldol CHO

3. ?
OH
via an aldol O
4. ?
5. diethyl ketone
6. acetone
O
CO2R
7.
CO2R
CO2R
O
19.2 Syntheses
8. cyclohexanone 4-benzyl-1,3-cyclohexadione
9. 1-pentene
CHO
10. phenylacetaldehyde PhCH(CH2OH)2
O
via a Robinson annulation
11. ? + ?
O
12.
via a Wittig*
13. cyclohexanone, acetone
O *Why not via an aldol?
O O
via a Robinson annulation
14.
O
O
19.2 Syntheses
Problems • 219
O
15.
H
16. acetone
19.3 Mechanisms
O O
H
1.
OH
O O
2. + CH2N2 + N2
O
O O
NaOEt / EtOH
3. OEt
O
19.3 Mechanisms
O O
1. CH3NH2
OCH3
4. 2 methyl acrylate
2. OMe N
OH
OH
5. p-chlorobenzaldehyde + CHBr3 Cl
CO2
CO2Et 1. NaOEt, EtOH, MVK

2. H2O, OH
6.
O 3. ' O
O O
H 1. acetone, OEt
7.
2. H
geranial
(a step in the commercial synthesis of vitamin A)
O O O O
OEt
+ PhCO2Et + ethyl acetate
8. OEt Ph OEt
19.3 Mechanisms
Problems • 221
O OH
O
OH
9. + methyl vinyl ketone
CHO
H O
O
HCO2 +
10. The anaerobic breakdown of glucose (glycolysis) involves the following isomerization and retro-aldol:
HO
O HO OH OH O OH
H O aldolase
OH H
OH OH +
OH
OH OH OH OH OH O
D-D-glucose D-D-fructose
R2N CO2R R1

R2N CO2R CO2R
11. [Br ] '
%r 1
(from NBS)
NH NH
12. The following illustrates the Stobbe reaction. Hint: a key intermediate is a J-lactone.
CO2R O
base Ph CO2R
+
Ph Ph
CO2R Ph CO2
19.3 Mechanisms
O
O
13. 1. OMe / MeOH 2. H O
O O O
O OR
14. O
CO2R CO2R
O EtO O
EtO OEt, EtOH

15.
O O
O O
16. The final stage of Johnson’s (Stanford) historic total synthesis of progesterone (give a mechanism for
step 2):
O O
1. ozonolysis
2. aq KOH
O
progesterone
19.3 Mechanisms
Problems • 223
1. NH, H
17. +
2. EtI O
O O
3. H2O
Et Et
O O
CO2Me base
18.
CO2Me
1. NaH O
19.
CO2Me 2. H2O
CO2Me
20. Humulones are found in hops. When boiled, the insoluble humulones isomerize to the soluble
isohumulones, which give beer its distinctive bitterness. (Caution: difficult!)
OH O O O
R H, H2O R
HO O ' HO
HO OH
O
humulone: R = i-Bu
cis- and trans-isohumulones
cohumulone: R = i-Pr
adhumulone: R = s-Bu
19.3 Mechanisms
21. Woodward’s (Harvard) total synthesis of the alkaloid strychnine included the following steps:
NMe2
OMe 1. CH2O, Me2NH
OMe
N H
H OMe N
H OMe
92%
2. MeI
3. NaCN, DMF
CO2Et
N
CN
OMe 4. LiAlH4, THF OMe
N N
5. ?? H OMe
H OMe
97%
a. Step 1 is an example of the (name) _______________ reaction.
b. Outline the mechanism for steps 2 and 3.
c. Supply the missing reagent in step 5.
22. Enzyme-catalyzed mixed aldol reactions are very common in metabolism. The beginning sequence in
the de novo synthesis of aromatic amino acids, for example involves the following steps. Fill in the
structures and write a mechanism for step 4.
OH O
O
HO
P OH H
O 1. hydrolysis 2.
O OH
CO2
phosphoenolpyruvate (PEP)
an enol
3. - H2O
O
OH
HO CO2H 4. H HO2C
phenylalanine, tyrosine
HO O OH O
19.3 Mechanisms
Problems • 225
23. The biosynthesis of porphyrin rings (e.g., heme) begins with an annulation reaction that involves an
aldol reaction and imine formation in the dimerization of G-aminolevulinic acid (ALA) to form
porphobilinogen.
CO2H
O
NH2 H CO2H
2 HO2C
ALA N
H3N H
porphobilinogen
24. Several steps in Sheehan’s (MIT) total synthesis of penicillin V are shown below.
CO2H O
CO2H
1. ClCH2COCl 2. Ac2O
NH O
NH2
N
valine O
Cl
O
O SH isomerization
3. SH, OMe
O
Me N CO2Me MeOH
H N
a. Propose a mechanism for step 2.
b. Propose a mechanism for step 3.
25. The biosynthesis of fatty acids begins with a Claisen-like reaction:

O O
O O
SR + SR CO2 + SR
O O
19.3 Mechanisms
26. The CD – CE bond in E-hydroxyketones is easily cleaved via a retro-aldol reaction; the carbonyl – CD
bond is unreactive. In D-hydroxyketones, however, the CD – CE bond is unreactive; but, in the presence of
thiamine, the carbonyl – CD bond can be cleaved (2).
OH O O O
retro-aldol
(1) E D +
H R'
R N S
O O
1. thiamine H R
(2) + (CB of thiamine)
O
OH 2. O OH
R H
Recalling the mechanism for thiamine-assisted decarboxylation of D-ketocarboxylic acids (problem 16.3,
13), formulate a mechanism for reaction (2).
27. The biosynthesis of cholesterol begins with the formation of HMG-CoA (3-hydroxy-3-methylglutaryl
coenzyme A):
OH O
O
3 SCoA
SCoA
CO2
HMG-CoA
a. Formulate a mechanism.
19.3 Mechanisms
Problems • 227
b. HMG-CoA is subsequently reduced to mevalonate by an enzyme, HMG-CoA reductase. Because this

reaction is the major control (rate-limiting) step, considerable research has been devoted toward developing
a class of medicines that inhibits the action of this enzyme, notably the statins [e.g., atorvastatin
(LipitorTM)].
OH OH P O O PP
a reductase ATP
HMG-CoA
CO2 CO2
mevalonate O
P = P O
OH
O O
PP = P O P O
O OH
Mevalonate then undergoes phosphorylation and decarboxylation to form I-PP (isopentenyl

pyrophosphate) and DMA-PP (dimethylallyl pyrophosphate) – recall problem 9.4, 19a. Outline the
mechanisms for decarboxylation to form I-PP and isomerization of the latter to form DMA-PP.
P O O PP
- CO2 O PP O PP
CO2
I-PP DMA-PP
O OH OH O
N N OH
H
F
LipitorTM
19.3 Mechanisms
CHAPTER 20
AMINES
20.1 Reactions
1. base
2. ClCH(CO2Et)2
3. base
1. phthalimide
4. isopropyl chloride
5. H3O
alanine
1. (XS) CH3I
2. Ag2O, H2O, '
3. OsO4
2. 2-methyl-2-hexylamine
4. NaHSO3
5. (XS) COCl2
6. NH3
C9H18N2O4 - MiltownTM
1. (XS) MeI
2. Ag2O, H2O
3. N-ethylcyclohexylamine
3. '
4. 1. (XS) MeI
2. Ag2O, H2O
N
3. '
H
coniine (toxin in hemlock, killed Socrates)
HO
1. (XS) CH3I
5.
O 2. Ag2O, H2O, '
N
HO
morphine
Me
1. H2O2
6. Ph2N H
H Me 2. '
Et
20.1 Reactions
230 • Chapter 20 Amines
1. SOCl2
2. NaN3
7. cyclopropanecarboxylic acid
3. ', H2O
OH
OH 1. (XS) MeI
8.
2. Ag2O, H2O, '
NHMe
HO
epinephrine
D Hofmann elimination
H
9. NMe2
H
Cope elimination
H
10. 3-pentanone + dimethylamine + formaldehyde
(Mannich rx)
NH2
11. N HONO
O N H2O
H
cytosine uracil
12. Ph 1. Li 2. CO2 3. H
Cl 4. SOCl2 5. NH3
6. Br2, OH, H2O
phentermine (a diet drug)
20.1 Reactions
Problems • 231
OH
NH2 Br2, OH
13. Me NH3 +
O H2O
1. NaNH2
2. ethylene oxide
3. PBr3
14. Ph2CHOH
4. Me2NH
diphenhydramine (BenadrylTM - antihistamine)
1. HBr, ROOR
2. potassium phthalimide
15.
3. hydrazine
amphetamine (CNS stimulant)
Me2N
OH
1. MeI
16.
MeO 2. Ag2O, H2O, '
3. H
EffexorTM (antidepressant) (gives a positive DNP test)
Ph 1. SOCl2
2. NH3
OH
17. 3. Br2, OH, H2O
O
OH 4. I (2 equiv)
DetrolTM (treatment of urinary incontinence)
1. a. Br2, PBr3 b. H2O

2. KO-t-Bu
18. CO2H
3. HCN, CN
4. H2 / Pt
pregabalin (LyricaTM - first treatment
approved for fibromyalgia)
20.1 Reactions
1. Br2
2. NaNO2, HCl
19. p-toluidine (p-aminotoluene)
3. KI
1. Cl2, FeCl3
2. NaNH2 / NH3
20. benzonitrile
3. KNO2, H
4. CuCN
5. H3O
1. KMnO4, H
2. fuming nitric acid
3. Fe, HCl
21.
4. NaNO2, HCl
5. HBF4
1. Br2, Fe
H 2. Cl2, Fe
N 3. H2O, OH
22.
O 4. I-Cl, Fe
5. HONO
6. H3PO2
1. NaH
CO2Me 2. H3O
23. O 3. NaBH4
+
N N
4. HBr (SN1)
5. ' (-HBr) nicotine
HO O
1. H
24. O OH
NH NaBH3CN, EtOH
2. HCl
HO
NubainTM (narcotic)
20.1 Reactions
Problems • 233
20.2 Syntheses
1. methylcyclohexane 1-methyl-1-cyclohexylamine
2. cyclohexane NH2
3. isopentane 3-methyl-1-butene (via a Hofmann elimination)
4. 3-methyl-1-butene isopropylamine
OMe OMe OMe
MeO OMe MeO OMe MeO OMe

5.
NH2 O H NHPh
mescaline (from peyote cactus)
6. p-nitrotoluene p-nitrobenzylamine
7. p-nitrotoluene p-nitroaniline
20.2 Syntheses
O
8.
NH2 O
9. HO3S NO2 HO3S N N NEt2
methyl orange
N O
N
CO2Me
10.
OCOPh O
cocaine tropinone
11. toluene 2,6-dichlorotoluene
12. p-nitroaniline HO N
H
acetaminophen (TylenolTM)
O
NEt2
13. 1-nitro-2,6-dimethylbenzene, ethylene oxide, diethylamine N
H
lidocaine
14. benzene anisole
20.2 Syntheses
Problems • 235
15. NO2 N N NH2
butter yellow
H
16. benzyl methyl ketone N
Ph
methamphetamine
H Me Me
N N Br
O
17.
S S
O S O S
OH OH
O O
tiotropium bromide (SpirevaTM - bronchodilator)
N NO2
OH N
18. , benzene OH
para-red dye
19. benzene
OH OH
20.
NHAc propofol (intravenous anesthetic)
20.2 Syntheses
20.3 Mechanisms
H
OH N OPh
1. butanamide + phenol + Br2
O
O
1. Cl2, H2O, OH CO2H
2. NH
2. H NH2
O
anthranilic acid
CO2H 1. HONO
2. adjust to pH 8
3.
NH2 3. 1,3-butadiene
O O
1. HCN, CN
2. H2 / Pt
4.
3. NaNO2, HCl
O
1. NH2OH
5. cyclohexanone
2. H NH
H-caprolactam
(This is an example of the Beckmann rearrangement, similar to the Hofmann and Curtius rearrangements.)
20.3 Mechanisms
Problems • 237
6. Sir Robert Robinson (Oxford) observed that thebaine (a dimethylated derivative of the alkaloid
morphine) forms phenyldihydrothebaine when treated with phenylmagnesium halide. Formulate a
mechanism and draw the Hofmann elimination product.
CH3O
CH3O
Ph
1. PhMgX 1. (XS) MeI
O HO
N
N 2. H 2. Ag2O, H2O, '
CH3O CH3O
thebaine phenyldihydrothebaine
7. The Curtius rearrangement not only occurs with acyl halides but also alkyl azides. Draw the bracketed
structure and deduce a mechanism for its formation.
Cl N3 O
NaN3 ' H3O
NH3
SN2 - N2 H
an alkyl azide
8. Hydrazoic acid (HN3) undergoes addition to ketones to form a product that readily rearranges to an
amide (Schmidt reaction):
O HO O
N3
HN3 ' NH
20.3 Mechanisms
9. The Fischer indole synthesis involves an isomerization known as a [3,3] sigmatropic rearrangement,
shown by the arrows below:
O
H2SO4
PhNH-NH2 +
Ph
N Ph
N H
H N Ph 2-phenylindole
H
tautomerization
[3,3]
N N
H N Ph Ph
H N
H
H
Outline a mechanism for conversion of the intermediate in brackets to the indole product.
10. CH2O
NH2 NH
H
O
H
11. acetophenone + CH2O + NH3
Ph N
3
20.3 Mechanisms
Problems • 239
12. Atropine, an antidote to cholinesterase inhibitors (e.g., nerve gases), can be easily synthesized from
tropinone. The first total synthesis of tropinone required 17 steps. Years later Robinson (Oxford)
accomplished its synthesis in a one-step, one-pot reaction (Robinson-Schopf condensation)! Sketch the
critical intermediates in this synthesis.
N N
O
CHO 1. [H]
+ H2NMe + 2. esterification
CO2 CO2
CHO Ph
O O
tropinone atropine
O OH
13. The Ritter reaction offers a way to prepare amides (or, by subsequent hydrolysis, amines) from good
precursors to carbocations:
O
H2SO4
a. + acetonitrile N
H
O
O
CN O t-Bu
b. N
H
MeO H2SO4 MeO
14. A convenient method of synthesizing pure secondary amines involves (1) treating the sulfonamide of a
primary amine with hydroxide, followed by (2) an alkyl halide, then (3) hydrolysis. Outline such an
approach to preparing N-methylaniline.
20.3 Mechanisms
15. The Corey-Link reaction (step 2) may be used to prepare D-amino acids:
O OH N3
1. LiCCl3 2. base NH2
4. H2 / Pd
R H R CCl3 R CO2Me
H 3. NaN3, MeOH R CO2H
H 5. hydrolysis H
a. Outline a mechanism for steps 2 and 3.
b. Account for the product in a mechanistically similar reaction:
HO O O
1. :CCl3 2. NH2
O
N
H
16. Parkinson’s disease is associated with low levels of dopamine, a neurotransmitter. The enzyme
monoamine oxidase (MAO) deaminates dopamine, thereby decreasing its concentration. One approach to
treating Parkinson’s utilizes (-)-DeprenylTM, a “suicide inhibitor” to MAO. The mechanism first involves
oxidation of the drug by a flavin cofactor of MAO, followed by a conjugate addition reaction between the
reduced flavin and oxidized drug to irreversibly “kill” any future normal activity by the MAO enzyme.
Outline the mechanism for formation of the adduct.
H
R R H R H
N N O N N O N N O
[H]
NH NH NH
N N N
flavin cofactor O reduced flavin H O O
H C
C H
H C
H N N
N [O] H C C
H C C Ph Ph
Ph H
H
DeprenylTM oxidized drug
20.3 Mechanisms
SOLUTIONS TO PROBLEMS
CHAPTER 1
THE BASICS

1. a. SeldaneTM: C32H42NO2 RelenzaTM: C12H20N4O7
c
HO
OH OH O
a
HO O
OH
b. N b OH
N
H NH d
2 O NH
H2N
c. a: sp3 – sp3; b: sp3 – sp2; c: sp2 – sp2 d. SeldaneTM oxygens: sp3; nitrogen d: sp2
2. a. :C C: b. H C O: c. O N O d. the conjugate base of :NH2CH3
-H
H
Cl H3C N
N O
e. O f. O
H
H
H
3. a. :C sp2 => bond angle ~ 1200 b. H H = CH2
H
a linear HCH bond angle implies sp hybridization;
therefore, each lone electron lies in an un-
hybridized p orbital with spins aligned (Hund's rule)
H
G+
4. a. higher bp: N H N b. lower mp: catechol
G-
O G+ catechol, unlike hydroquinone, can under-
this isomer is capable of intermolecular
H
H-bonding, thereby increasing intermolecular go intramolecular H-bonding, which decreases
attractive forces and raising its bp O G- intermolecular attractions and results in lower-
relative to the other amine H ing its mp relative to hydroquinone
5. a. no b. no c. yes d. yes e. yes f. no g. yes h. yes
6. a. CHCl3 b. CH3NO2 c. SO2

P F
H P P
CH3 S
C vs. C N vs. O N O C O vs. O O
Cl Cl Cl Cl H H O
H3C P linear, P = 0 bent, P > 0
Cl Cl
permanent charge
separation (> H)
7. a. penicillin V: C16H18N2O4S cimetidine: C10H16N6S
b. arrow a: sp2 b: sp3 c: sp

O O
c. N N
H H
Ph Ph
this resonance structure suggests some double bond character;
electrons must be in a p orbital in order to resonate
d. lone pairs: penicillin V: 12; cimetidine: 8.

O N:
N S C
H HN N
N S
O N N N
O H H
HO
8. a. sumatriptan: C14H21N3O2S prostacyclin: C20H32O5
b. Sumatriptan contains 8 sp2 and 6 sp3 carbons; prostacyclin contains 5 sp2 and 15 sp3 carbons.
HO
c. lone pairs: sumatriptan: 7; prostacyclin: 10.
H O
O N O
S
MeHN
O
NMe2 HO OH
9. a. RozeremTM: C16H21NO2 ChantixTM: C13H13N3 RitalinTM: C14H20NO2
b. lone pairs: RozeremTM: 5; ChantixTM: 3; RitalinTM: 4.

O
N H H
N
H O NH N O
N
O
10. lone pairs: theobromine: 8; melamine: 6.

O NH2
CH3
HN N N N
O N N H2N N NH2
CH3
11. a. alkene, amide, amine, ester, ether b. alkene, amine, arene, carboxylic acid, halide, ketone
c. alcohol, alkyne, arene.

Solutions • 245
1.2 Acids and bases
1. strongest base in ammonia: H2N amide anion - the CB of ammonia
H2N (H :H H2N + H2
2. stronger base: (CH3)2NH nitrogen is more electron-releasing than oxygen
AlCl3
3. a. O AlCl3 O
b. Ph3P: BF3 Ph3P BF3
c. O N BH3 O N
BH3
4. a. CH3 O CH3CH2 Cl CH3 O CH2CH3 + Cl
LB LA
b. H2C CH2 BF3 CH2 CH2 BF3
LB LA
c. H3C O (H :CH2 CH3 H3C O + H3C CH3
LA LB
(also Bronsted-Lowry acid-base, respectively)
d. Cl Cl AlCl3 Cl + AlCl4
LB LA
S
e. CH3 N C S :NH3 CH3 N C
NH3
LA LB
pKa ~ 35 pKa ~ 16
O O H
5. a. C20H28O b. H) NH2 + NH2 c. Keq << 1
C C (' pKas > 4)
C C
H H
WB WA SA SB
1.2 Acids and bases

O O
H pKa ~ 5
O O NHAc O
H)
6. a. + O NHAc
pKa ~ 10
i-Bu i-Bu
b. WB WA SA SB
c. Keq << 1 ('pKas > 4)
7. lowest pKa: b. a. ~ 16 b. ~ 5 c. ~ 16 d. ~ 10 e. ~ 38 f. ~ 35
NH2 Keq >> 1

8. quantitative rx: b. R C C (H R C C + :NH3
pKa 22 SB WB pKa ~ 35
a. hydroxide (Keq << 1) c. H2 (NR) d. EtO (Keq << 1)
OH pKa ~ 16 OH
9. + CH3NO2
O O pKa ~ 10
Keq ~ 1 (' pKas ~ 0)
H
:CH2NO2
pKa ~ 10
10. a. b. + HCO3
O
N Cl N N pKa ~ 10
H O O
H
pKa ~ 5
SA WA
c. Keq >> 1 (' pKas > 4)
1.3 Resonance
CH2 O
1. CH3 C O
p* N
sp2 H
p* sp2
* not sp3 per
VSEPR; electrons may resonate
if housed in a p orbital
1.3 Resonance
Solutions • 247
-H O C N:
2. lower pKa: H-O-CN H) O C N: O C N:
negative charge delocalization => more stable CB
H) C N: -H :C N: negative charge localized on C
3. a. 3. HO C NH2 HO C NH2 HO C NH2

H H H
b. 1. localized charge
saturated, no p orbital
O O O O O
c. 5.
O O O O O
OCH3 OCH3 OCH3 OCH3 OCH3
d. 5.
CH2 CH2 CH2 CH2 CH2
most basic H
NH NH NH NH
+H H
4. Me Me vs. Me vs. Me
N NH2 N NH2 N NH2 N NH2
H H H H
H
no important resonance contributions
H H H
4 resonance structures NH NH NH
=> a more stable CA Me Me Me
N NH2 N NH2 N NH2
H H H
H H
N N
5. a. O O O O O O b.
oxygen 'octetted,'
closer charge separation carbon 'octetted,'
additional S bond
1.3 Resonance
OH OH
H H
c. C C N: C C N: d.
H H
negative charge is carbon 'octetted,'
borne by more additional S bond
electronegative atom
O O O
6. a. 2. b. 3.
N N
H H
CH2
c. 1. d. 3.
O O O
H (Ha
-Ha
7.
O O O O O O O O
A CB of A is stabilized by charge delocalization over three nuclei and,

therefore, more easily formed => pKa of Ha is lowered
O
H charge localized
O O
+H H
8. vs. H H
OH O O
charge delocalized, => > stability
OH OH therefore, more favored CA species
9. a. 5.
NMe2 NMe2 NMe2 NMe2 NMe2
b. 5.
H H H H H
c. 4.
not
N N N N N
nitrogen 'sextetted'
1.3 Resonance
Solutions • 249
O O O
d. 2. e. 3.
O O
f. 4.
N CH2 N CH2 N CH2 N CH2
g. 4.
OCH3 OCH3 OCH3 OCH3
h. 4.
H Cl H Cl H Cl H Cl
i. 2.
O O O O O O
10. vs.
A B
these additional resonance structures increase
both H and d (P = H x d); therefore, PB > PA
N N O N N O
11.
O S S O S S
CB of oxyluciferin
1.3 Resonance
CHAPTER 2
ALKANES
2.1 General
1. highest mp: 4. bicyclo[2.2.2]octane (most spherical)
2. highest bp: 1. n-pentane (least branched)
3.
eicosane, mp 370 dodecahedrane, mp 4200

spherical molecules (dodecahedrane) pack more closely in the solid state than linear (eicosane) ones,
therefore requiring more energy to separate (melt) them
4. constitutional isomers for
a. C6H14: 5.
b. C7H16: 9.
5. different kinds (constitutional) of hydrogens in
Ha Ha
H
Hc e H
f
a. 2,3-dimethylpentane: 6. b. 2,4-dimethylpentane: 3.
Hb Hb
Hc
Hd
Hb
Hc
c. 3-ethylpentane: 3. d. 2,2,4-trimethylpentane: 4. Ha Hd
Ha Hc
Hb
He
Ha Hd
Hd Hf Hb Hi
Hg
e. 2,5,5-trimethylheptane: 7. f. 4-ethyl-3,3,5-trimethylheptane: 10.
Hb Hf
Hc Hg Ha Hj
He Hc Hh
2.1 General
2.2 Nomenclature
I
NO2
1. 2. 1
5
7 1 9
Br
3-nitro-4-ethyl-2,2,5-trimethylheptane 7-bromo-2-iodo-3-ethyl-5,6-dimethylnonane
7
4
3. 4.
3 1 8
1
4-ethyl-3,3,5-trimethylheptane 5-ethyl-3,5-dimethyloctane
5
5. 4 6. 1
7
1 F
4-fluoro-2-methyl-2-phenylheptane 5-ethyl-3,4-dimethyloctane
5 4
7. 9 8. 8
3
(1) (3)
1
1
5-(1,2-dimethylpropyl)nonane 2,3,7-trimethyl-4-n-propyloctane
(choose path with more branching)
I
9. 10.
9
2,3-dimethyl-4-n-propylnonane 1-iodo-4-methylpentane
1 7
4
11. 10 4
12.
(1) (3) 1
Cl
5-(2-chloro-2-methylpropyl)-4-methyldecane 4-t-butyl-2,2,6-trimethyl-4-n-propylheptane
not 4-t-butyl-4 -isobutyl-2,2-dimethylheptane
(less branching)
2.2 Nomenclature
Solutions • 253
1
10
13. 14.
8
1
2,3,5-trimethyloctane 5-ethyl-4-methyldecane
7 3
15. 10
16.
3,7-diethyl-2,2,8-trimethyldecane diethylpentane
(3,3- not necessary!)
17. a. OH Br
b. O c.
Br H 3.7 kcal/mol
3.7 kcal/mol
1. -2.0 (2 x 1.0 kcal/mol)
H PE
1.7 kcal/mol H HH
1.0 kcal/mol
rot'n
H
H
2
2. a. = largest R-groups are anti
Me
3 H
1 H
H Et
b. 2 = gauche: dihedral angle ~ 60 0
H Ph
H
Me H H
OH s-Bu
7
Me H OH H Et Ph
3. a. = Me b. = 1
H H H t-Bu
Me H Ph H
H
isobutyl alcohol 4-t-butyl-3-methyl-5-phenylheptane

H
PE H H dihedral angle
4. only 600 between
Me Me both methyls
Me
rot'n about C2-3 bond
H
5. intramolecular hydrogen-bond FO F
stabilizes a nearly eclipsed conformer H H
vs.
for FCH2CH2OH H H H
H HH F
P >> 0 P~0

CHAPTER 3
CYCLOALKANES
3.1 General
Cl
P! Cl H H
1. highest molecular dipole moment: d. a. b. c. Cl C C Cl
Cl H H
Cl
Cl Cl
P=0
Cl
Cl
2. constitutional isomers for Cl
Cl Cl
a. dichlorocyclopentane: 3.
Cl
1,1- 1,2- 1,3-
b. C6H12 that contain a cyclopropyl ring: 6.
Cl
3. cis/trans stereoisomers for Cl
a. dichlorocyclopentane: 2 pairs. Cl + trans- Cl + cis-
1,2- 1,3-
Ph
Ph Ph
b. diphenylcyclohexane: 3 pairs. + cis- + trans- + cis-
Ph Ph Ph
1,2- 1,3- 1,4-
Cl Cl Cl Cl
c. 2-chloro-4-ethyl-1-methylcyclohexane: 4.
Hg
4. different kinds (constitutional and geometric) of hydrogens in
Hf Hh
Ha Hc Ha Hc
a. 1-ethyl-1-methylcyclopropane: 5. b. allylcyclobutane: 9. Hi
Hb He
Hd He
Hb Hd
Ha and Hb are cis- and trans- to methyl,
and so are 'different'
c. methylcyclobutane: 6. d. chlorocyclopentane: 5. e. vinylcyclopentane: 8.

He
Hf
Ha Hc Ha Hc Cl He
Ha Hc
Hg
Hf
Hb Hd Hb He
Hd Hb Hh
Hd
3.1 General
H
H
H
5. least strained: a. b. H H
H
H H
cis- H
trans-
diaxial strain
no strain H
c. d.
ring strain prevents angle strain
alkene from being planar -
violates Bredt's rule
H Me
Me H
6. H Me
Me exo- endo-
stereoisomers
H Me
Me H
7. only 2. + = =
H Me
Me
identical structures (for now!)
3.2 Nomenclature
1 4
2
1. 1 2.
4
1-cylclopropyl-3-methylbutane
4-s-butyl-1-ethyl-2-n-propylcyclohexane
1
(2)
4
3. 4. (1) 7
t-pentylcyclopentane 4-(2-cyclohexylethyl)-3-methylheptane
(1,1-dimethylpropyl)cyclopentane
2-cyclopentyl-2-methylbutane
3.2 Nomenclature
Solutions • 257
5. 6.
Br
trans-1-bromo-2-s-butylcyclopentane
cis-1-isopentyl-5-n-propylcyclodecane
Cl F
(4) 1 6
7. (1) 8.
(2)
3
(2-chloro-1-methylbutyl)cycloheptane
1-fluoro-6-t-butyl-3-vinylcyclooctane
1
I
(2)
(1) 6
9. 10. 3
9
cis-1-allyl-2-isobutylcyclohexane 5-iodo-3-(1-cyclobutylethyl)-6-ethyl-
2,2,8,8-tetramethylnonane
6
1
F 2
11. Ph 12.
7
5
trans-1-fluoro-3-phenylcyclohexane
2,6,6-trimethylbicyclo[3.1.1]heptane
6 5
7
1 4
13. 10 14.
2
2 1
9
5-methylbicyclo[2.1.0]pentane
7-allylbicyclo[4.3.1]decane
9
2 1
(1) 8
15. 16.
7
(4) 2,9,9-trimethylbicyclo[5.2.0]nonane
trans-1-(2,3-dimethylbutyl)-2-n-propylcycloheptane
3.2 Nomenclature
H H
H OH
1. most stable conformer: Me Me
O H
H H H
menthol neomenthol
Ph
2. a. Ph degenerate structures (same energy)

Ph therefore, Keq = 1
Ph
H H
H H
b. H H
H H
> 1,3-diaxial interactions => less stable conformer
therefore, Keq < 1
H
H
c. Me H
H
Et
Et Me
larger ethyl group in more stable equatorial position
therefore, Keq > 1
3. most negative 'Hcomb (=> least stable):
a. t-Bu t-Bu t-Bu
least stable (most stable, therefore,

least negative 'Hcomb)
Me Me Me
Me
b. Me
Me
> dimethyl repulsion
therefore, least stable
c.
least stable (most stable)

Solutions • 259
4. least negative 'Hcomb (=> most stable):
a. =
all alkyl groups are equatorial

therefore, most stable b. same compound!
H H
:B t-Bu
5. most stable conformer for: t-Bu vs. t-Bu
Cl H
(-HCl)
H Cl
trans- cis-
t-butyl group prevents 'flipping,' so chlorine cannot assume the axial position in the trans-isomer
therefore, the cis-isomer would react more rapidly
OH
OH F
6. F OH vs. F
trans- cis-
twist-boat stabilized by
intramolecular hydrogen-
bonding; not possible in chair
conformer (or in trans-isomer)
OH
HO HO
O OH O
7. a. HO OH HO OH
HO HO
1 2
b. configuration 2 is less stable (one substituent must be axial) and would burn with a more negative 'Hcomb
H Me
Me 5.4 kcal/mol
-0.9
8. Me Me (2 Me-H 1,3-diaxial strain interactions)
-0.9
3.6 kcal/mol (Me-Me 1,3-diaxial strain interaction)
5.4 kcal/mol less stable than
9. a. number of cis/trans stereoisomers: 8.
1 2 3 4 5 6 7 8

b. for conformational chair-chair flipping, Keq = 1 for configurations 1, 3, and 5: 3e/3a 3a/3e
1 2 3 4
3e/3a 4e/2a 3e/3a 5e/1a
5 6 7 8
3e/3a 4e/2a 4e/2a 6e/0a
three 1,3-diaxial steric interactions exist between two methyl groups

c. least stable: 1. 1 (only one such interaction exists in configurations 3 and 5)
d. least likely to flip: 8. 8
all methyls are equatorial all axial!

CHAPTER 4
REACTION BASICS
1. a. addition b. oxidation [O] c. substitution d. substitution
e. elimination f. reduction [H] g. oxidation [O] h. addition
i. reduction [H] j. rearrangement k. oxidation [O] l. substitution
m. elimination n. addition o. reduction [H] p. reduction [H]
q. rearrangement r. elimination s. substitution t. reduction [H]
b. 'G = 11 - 7 = +4 kcal/mol
+11 kcal/mol
C
+7 kcal/mol
2. a. 'Go
B +3 kcal/mol A B +3 kcal/mol
A B C +7
rx A C +10 kcal/mol
TS
'G for rds

intermediate
-'Go / RT
3. a. 'Go b. Keq = e
'Go = -'G / RT
c. rate = k[conc. term(s)] = koe
rx
'G for rds

B
4. a. 'Go b. 'Go = -RT ln Keq

-'G / RT
Br3C: Keq = e = e -2,500 / (2)(300)
A Keq = 1.6 x 10-2
rx 'Go = +2.5 kcal/mol
4. Reaction Basics
5. a. type of reaction: rearrangement; mechanism: polar / ionic.
H H
O O O O O O
H) OH2
b. + H OH2
A H) B
H2O
c. Keq = [B] / [A] = 75% / 25% = 3.0; 'Go = -RT ln Keq.
d. nucleophiles: A, H2O, and B.
e.
TS
intermediate
'Go
'G0 =
rx
rds fast
6. I OMe
-I +MeOH, -H
7. a. pericyclic b. free radical c. pericyclic d. polar / ionic
e. pericyclic f. polar / ionic g. free radical h. polar / ionic
i. pericyclic j. polar / ionic
4. Reaction Basics
CHAPTER 5
ALKENES AND CARBOCATIONS
5.1 General
H H
1 3 H H 1
1. a. b. = 2
H
Cl Ph H Ph 5 H
8 H
(E)-3-chloromethyl-4-s-butyl-2- trans-5-phenyl-2-pentene
methyl-3-octene
1
3 1 9
c. 3 9 d.
7
6
3-n-propyl-1-nonene 6-methylbicyclo[5.2.0]-3,8-nonadiene
2. a. (Z)- b. (E)- c. (Z)- d. (Z)- e. (Z)- f. (Z)-
3. a. number of alkenes: 4.
H2
Pt
b. least negative 'Hhydrogenation: most stable (trisubstituted)
4. number of geometric isomers: 4.
trans, trans- cis, cis- trans, cis- cis, trans-
OMe OMe
5. most stable carbocation:
H
6. a. no. deg. unsat: C17H36 - C17H20(18+3-1) = H16 => H16/2 = 8 deg. O N
hydrogenation: C17H30F3NO - C17H18F3NO = H12 => H12/2 = 6 DB

F3C
no. rings = 8 - 6 DB = 2.
fluoxetine
HN
b. no. deg. unsat: C17H36 - C17H16(18+1-3) = H20 => H20/2 = 10 deg. N N
no. DB = 10 - 4 rings = 6. OH
F
O O
CiproTM
5.1 General
N
OH
c. no. deg. unsat: C28H58 - C28H34(35-1) = H24 => H24/2 = 12 deg. C C
no. rings = 12 - 5 DB -1 TB(= 2 DB!) = 5.
O
RU 486
O
d. no. deg. unsat: C17H36 - C17H10(14-0-4) = H26 => H26/2 = 13 deg. O

no. DB = 13 - 3 rings = 10.
O
S
O rofecoxib
F
O
e. no. deg. unsat: C19H40 - C19H16(17+2-3) = H24 => H24/2 = 12 deg. N S

H
no. rings = 12 - 8 DB = 4. Cl N N
O O
O
HO
floxacillin
H
N
f. no. deg. unsat: C19H40 - C19H20(20+1-1) = H20 => H20/2 = 10 deg. O O

hydrogenation: C19H32FNO3 - C19H20FNO3 = H12 => H12/2 = 6 DB
O
no. rings = 10 - 6 DB = 4.
F PaxilTM
7. number of stereoisomers for 2,4-hexadiene: 3; for 2-chloro-2,4-hexadiene: 4.

Cl Cl
Cl
Cl
Cl
8. a. b. => Cl
(Z)-3-methyl-2-phenyl-2-hexene propylene dichloride

(note: no double bond)
OH Br
OH
O
c. , NOT d. e.
Br OH
OH
styrene bromohydrin trans-cyclohexene glycol isobutylene epoxide
5.1 General
Solutions • 265
+H 1,2-R: 1
9. 2 3
shift H
1 2 'G0
+Cl 1,2-H: 'G0 =
Cl shift
3
rx
10. a. +H
H CA most important contributing

H resonance structure
H H H
+H 1,2-H:
b.
shift
most stable intermediate:
benzylic carbocation
H H
~H: H
11.
H
rigidity of the carbon skeleton

prevents carbocation from being planar
F
HF
12. neither regiospecificity nor stereospecificity: a. +
Br F
Cl2 Cl
b. regiospecific
(XS) NaBr
Cl
Cl2 / H2O D2 / Pt
c. d.
anti-add'n syn-add'n
OH D D
stereospecific stereospecific
5.1 General
H
+H -H
13.
H
E-pinene D-pinene
more highly substituted double
bond => more stable olefin
therefore, Keq >> 1
5.2 Reactions
HCl 1,2-H: shift +Cl

1. Ph Ph Ph
Ph Cl
+H
O
NO2 N NO2
HI O
2.
I
+H 1,2-R: shift +H2O

3. OH
-H
Br
1. Cl2, ' 2. KOMe 3. Br2
4. Cl Br
MeOH CHCl3
NMe3 NMe3 NMe3 NMe3

HI 1,2-H:
5.
shift
Et Et Et Et I
HF F
6. F F F
F
Cl
D D D
DCl 1,2-H:
7.
shift
5.2 Reactions
Solutions • 267
HBr 1,2-R: again!

8.
shift Br
+H -H
9.
O O
O O (H
H H
HBr
10. CCl3 CCl3 CCl3
Br
Et Et Br Et
Et
DBr Br Et Br
11. + =
D D D D
H H H H
anti-add'n syn-add'n
1. H2 / Pd 2. Br2 / hv
12. Br
OEt
+H +EtOH
13.
-H
H F H OMe H
HF
14. +
MeO D MeO
D OMe D F D
syn- anti-
Cl HI Cl Cl Cl
15.
I
Cl
Cl2 / H2O
16.
OH
1. B2D6 2. H2O2, OH
17.
D BD2 D OH
5.2 Reactions
I
Cl2 Cl
18. G+ G+
Cl
I
Et Et
Et 1. Hg(OAc)2, PhOH 2. NaBH4
19. OPh OPh
HgOAc
(XS) CH2I2
20. H2C C CH2
Zn(Cu)
spiropentane
CHO
1. KMnO4, OH 2. HIO4
21. AcO AcO
OH AcO
OH CHO
1. O3
22. O
2. H3O, Zn
H O
HBr +HBr
23. Ph Ph Br -Br Ph Br
O O H
note: opposite regioselectivity than HBr without peroxide -
and no rearrangement
Et
H2C N2
24. + N2
hv Et
trans-
OH
1. base 2. OsO4
25. Br OH
-HBr
3. NaHSO3
I
I N3 I
26. N
N3 N
N
5.2 Reactions
Solutions • 269
.
1. BD3 THF
27.
2. H2O2, OH
HO HO
D
OH
O O O O OMe
+H +MeOH
28.
-H
H H
H
29. +H -H
H)
OH O
O
HIO4 H
30. + H H
OH
OH OH
1. H2SO4 2. KMnO4, OH
31.
-H2O
OH
O
H HCl
32. C C O H3C C O H3C C O H3C Cl
H
Cl
OR OR
1. BH3 THF.
33.
2. H2O2, OH
HO
5.2 Reactions
OH Br
Br OH
34. 1. Br2, H2O

+
HO HO HO
O
a halohydrin
2. base
HO -HBr
H)
+H -H
35.
O H O HO HO
O OH
Cl 1. OR 2. mCPBA 3. EtOH, H
36.
-HCl
OEt
trans-
Br Br
Br2 +s-BuOH
37. O
-H
HO
OH
O
OH
HIO4 +
38.
O
HO HO
H
O O
OH KMnO4, H
39. OH
O
largest C-containing product
5.2 Reactions
Solutions • 271
O
H
OH
OH
1. OsO4 3. HIO4 O
40. O O
2. NaHSO3 OH O
O O O
OH
O O O +
O
H
O
HCl 1,2-R: 1,2-H:
41. +
+H shift H shift Cl
Li
:CH2
(H
-Cl Ph
42. Ph CH Ph CH PhCH
Cl -H Cl
a 1,1- (or D-) elimination to produce a carbene
H3C CH3
Cl (CH3)2CI2 Cl
43. O O
OPh (1 equiv) OPh
Cl Cl O
O Zn(Cu)
more electron-rich (nucleophilic)
double bond
5.3 Syntheses
Br
HBr 1,2-H: shift +Br

1.
OH Cl
1. H2SO4 2. HCl
2.
-H2O
1. KOH, EtOH 2. HF
3. Cl F
-HCl
5.3 Syntheses
Cl
1. OMe, MeOH 2. H2 / Pt
4.
-HCl
D
1. Cl2, hv 2. NaOEt / EtOH 3. D2 / Pd
5. Cl D
-HCl
Cl
CO2H
1. Cl2, ' 2. KO-t-Bu 3. KMnO4, H
6. CO2H
t-BuOH
Cl2 Cl
7. Cl
(XS) NaBr Br
Br
H
1. O3
8.
O
2. Zn, H
1. CH2N2, hv 2. Br2, hv Br
9. H2C CH2
1. H2SO4 2. CH2I2, Zn(Cu)

10. OH
-H2O
1. Hg(OAc)2, H2O OH
11. no rearrangement
2. NaBH4
OH
H3O 1,2-H: +H2O

shift -H
O
Br
1. KOMe 2. O3
12.
MeOH
3. Zn, H
O
Br D
1. Br2, hv 2. NaOH 3. DBr
13.
Br
5.3 Syntheses
Solutions • 273
1. KO-t-Bu 2. HBr
14. Br
t-BuOH peroxide
Br
1. Br2, ' 2. KOH .

3. BH3 THF
15. Br
4. H2O2, OH OH
Cl
O
1. 2. KMnO4, H CO2H
16.
CO2H
OH
Cl
1. OEt, EtOH 2. Cl2, H2O Cl +H2O Cl

17. Cl
-H
OH
OH2
1. H 1,2-R: -H
18.
shift
2. O3
O O 3. Zn, H
1. Hg(OAc)2, EtOH
19. (not EtOH, H => rearrangement)
2. NaBH4 OEt
OH
1. H3O 2. H2SO4 3. HBr, ROOR
20. Br
Cl
1. CH2N2, hv CO2H
21. H2C CH2 2. Cl2, ' 3. NaOH 4. KMnO4, H
MeOH CO2H
5.3 Syntheses
1. KOMe 2. H3O
22. Br OH
MeOH
3. Hg(OAc)2,
3. H t-BuOH
+ OH O or O
2 4. NaBH4 2
OH
1. H2SO4 2. CH2I2, Zn(Cu)
23.
5.4 Mechanisms
+H 1,2-R: -H
1.
shift
(H
H
H)
+H -H
2.
H
H
H) Me
O OMe
+H -H
3.
H
O
Me H
H
+H 1,2-R: -H
4. (H
shift
I I
+I2 I
-H
5.
-I
O O
CO2H O C H) O
O O
H
5.4 Mechanisms
Solutions • 275
H
+H -H
6.
H)
+H -H
7.
H)
HgOAc OAc HgOAc

Hg
1. Hg(OAc)2 O (H
8.
OH OH :H
HgOAc -H
O 2. NaBH4 O
+H 1,2-H: -H
9.
shift (H
H H H
N +I2 N N -H N
10.
-I
I
I I I I
H2C N N
11.
N N N
H2C N N N
5.4 Mechanisms
Br Br Br
+H anti-attack
12.
Br
100% trans-
H Br
+Br cis- and trans-

syn- + anti-
+H attack
+ Br
1,2-H: +Br Br
shift
13. A is C14 => other aldehyde is CH2O; no. deg. unsat: C15H32 - C15H24 = H8 => H8/2 = 4 deg.
hydrogenation: C15H28 - C15H24 = H4 => H4/2 = 2 DB; therefore, 2 rings are present
caryophyllene isocaryophyllene incorrect: cannot exist in

cis/trans forms
OH .
1. BH3 THF 1. Hg(OAc)2, H2O
14.
2. H2O2, OH 2. NaBH4
OH
O O
ozonolysis [H]
+
H
C5H12
H2 / Pd
15. + +
(partial)
A B C D
isoprene
16. no. deg. unsat: C10H22 - C10H16 = H6 => H6/2 = 3 deg.
C10H16 H2 / Pt hydrogenation: C10H22 - C10H16 = H6 => H6/2 = 3 DB

C10H22
O O O
1. O3 H H
+ 2 +
H H
2. Zn, H O O
myrcene acetone formaldehyde A
5.4 Mechanisms
Solutions • 277
O
17. hydrogenation: C10H20 - C10H16 = H4 => H4/2 = 2 DB A = H H
B A other ozonolysis product
18. a. n CO2Me poly(methyl methacrylate)
Ph Ph Ph Ph Ph Ph Ph Ph Ph
b. +H
etc.
t-Bu
O
+H
19. O O O O
H
t-Bu t-Bu O
O O
etc.
O
20. H2C N N H2C N N CH2 + N2
CH2
N N H2C CH2 + N N
hv
21. CH2N2 H2C: +
-N2
+H 1,2-R: 1,2-R: -H
22. H)
shift shift
+H 1,2-R: -H
23. (H
shift
5.4 Mechanisms
R R'
S
H3C D D
24. CH3
D CO2H
-RSR' D
C8H17 1,2-D:
C8H17 shift
D D
CO2H -H D D
H2C
H)
C8H17
C8H17
OAc
Hg HO HgOAc
1. Hg(OAc)2 +H2O
25.
H2O -H
+HgOAc
O H) O HgOAc
HgOAc
2. NaBH4 -H
O
HgOAc
AcO Hg
(H
+H -H
26.
R
27. CO2H
=> trans- DB
R' elaidic acid
OH
28. a.
A B C
b.
Br2 Br2
A NR (deep red color of bromine persists); B or C color discharged
or Baeyer test:
KMnO4 KMnO4
A NR (purple color of MnO4 persists); B or C brown ppt (MnO2) forms
5.4 Mechanisms
Solutions • 279
OH +H OH2 -H2O
29.
rot'n
-H
(H
30. a., b. R N N N R N + N2
A a nitrene
c. retention of configuration suggests a concerted (or pericyclic) mechanism
+H 1,2-H: 1,2-R:
31.
H shift shift
H)
-H 1,2-R:
shift
:B
(H
O O
1. Cl2, H2O 2. base
32.
Cl -HCl
Cl H
O
+Cl 3. dry HCl
OH +H
Cl
33. In Br CCl3 InBr + Cl3C

Cl3C
Br
Br CCl3
etc. CCl3 +
Cl3C
(this mechanism is similar to the addition of HBr in the presence of peroxides)
5.4 Mechanisms
34. a. no. deg. unsat: C16H34 - C16H30 = H4 => H4/2 = 2 deg.

hydrogenation: C16H34O - C16H30O = H4 => H4/2 = 2 DB
c. E => a cis- DB at C12; F => a trans- DB at C10
1. O3
OH B + C + D
12 10
A 2. Zn, H
D D D D D
H H
+H path a
35. H not observed
-D
H
D D D D D D
D D
vs. (H D
path b -H
D observed
1,2-D: shift
D D D D
therefore, path b is favored
36. The rigidity of the bicyclic structure in the conjugate base of A prevents delocalization of the negative
charge onto oxygen: such a contributing resonance structure would violate Bredt’s rule (the olefinic region
cannot be planar). Loss of this stabilization prevents the carbanion from forming (pKa of A is raised
relative to cyclohexanone), as required by the proposed mechanism, and therefore prevents hydrogen-
deuterium exchange.
-H
H
O O O
A
5.4 Mechanisms
CHAPTER 6
ALKYNES
6.1 Reactions
1. 1. NaH 2. D2O
H D
H, HgSO4, PhOH OPh

2.
1. B2H6 Ph taut H
3. Ph C CH Ph
2. H2O2, HO H OH
O
3. (XS) NaNH2
Cl
4. Cl 1. OMe (E2) 4. BH3.THF taut
Cl OH H
2. Cl2 5. H2O2, OH
O
RC C
5.
Cl + RC CH 3o R-X => elimination, not substitution!
1. Li / NH3 2. HBr, ROOR

6.
(peroxide effect) Br
1. H2 / Pd(Pb) 2. BH3
7. C CH
3. H2O2, OH OH
1. NaH
8.
2. CH3(CH2)12Cl
3. Lindlar catalyst (cis-[H])
Cl 1. (XS) NaNH2 OH O
9. Et C C 2. H3O, HgSO4 taut
Cl
10. C CH Cl2 / H2O Cl taut

Cl
HO
O
6.1 Reactions
Me Ph
I
1. (XS) HI 2. Zn(Cu) ..
11. Ph [PhCCH3]
Ph
I
Cl Cl D
C C
C C
12. 1. (XS) NaNH2 2. D2O
OMe OMe OMe
1. LiNH2 O 2. n-C5H11Br
13. HC C CH2OH O
C C C C
(2 equiv) (1 equiv)
less stable anion 3. H
therefore, more reactive
OH
C C
1. NaNH2
(1 equiv) 3. NaNH2
14. HC CH HC C n-Pr C C
2. n-Pr-I
4. Cl
elimination,
+ C C H
not alkylation 3o RX!
6.2 Syntheses
Br
O
1. 1. (XS) NaNH2 2. KMnO4, H
Et C C Et
OH
Br
1. NaH (1 equiv)
2. HC CH 3. H2 / Pd(Pb) 4. HBr, R2O2
2. n-PrBr Br
Cl 1. (XS) NaNH2 2. H, HgSO4, MeOH

3. C C O
1. NaH (1 equiv)
2. Et-I 4. n-Bu-I 5. Li / NH3
4. HC CH Et C C Et C C n-Bu
3. NaH trans-[H]
6.2 Syntheses
Solutions • 283
1. H2 / Pd(Pb) 2. HCl 1,2-R: Cl

5. C CH
shift
1. Br2
3. H2 / Lindlar
6.
2. (XS) NaNH2 cis-[H]
1. NaNH2 3. H2 / Pd(Pb)
7. 4. CH2I2
2. Me-Br Zn(Cu)
1. Li / NH3 2. HBr, (t-Bu)2O2

8. Br
or H2 / Lindlar
H, HgSO4, H2O OH O
taut
9.
1. BH3.THF
taut
2. H2O2, OH OH O
H
1. Li / NH3 2. O3
O
3. Zn, H
H
C Et
1. Cl2 C C
3. Et-I C 4. Li / NH3
10. Ph
2. (XS) NaNH2 trans-[H]
1. H2 / Pd(Pb) Ph Ph 2. CH2N2, hv Ph
11. Ph C C Ph
Ph
O
1. Na / NH3 Ph 2. O3
H
Ph
3. Zn, H
1. Na / NH3 Et Et Cl
12. 2. CHCl3, KO-t-Bu
Et
=> [:CCl2] Cl
Et
6.2 Syntheses
1. KOH n-Bu Et
13. 2. Cl2 4. EtCl n-Bu
CHCl3
Cl 3. (XS) NaNH2 5. Li / NH3 Et base
Cl Cl
1. NaH (1 equiv) 3. H3O, HgSO4 taut

14. HC CH HC C n-pentyl
2. n-pentyl chloride
OH O
1. NaNH2 (1 equiv) 4. 1-bromo-5-methyl-

2. n-decyl bromide hexane
15. HC CH n-decyl C C O
3. NaNH2 5. H2 / Lindlar
6. mCPBA
1. NaNH2 O
C CH 3. O3
16.
2 OH
2. n-Pr-I 4. Zn, H
(or 3. KMnO4, H )
6.3 Mechanisms
Br Br Br
C
I H C H C I
HO O C O
C I C
O
O +I O O O
1. -H O
O O O OH O
OH O OH O OH O Br
I
H
OH C C
2. C +H C
-H2O ..
+H2O:
O H OH
(H
-H
~H
taut
6.3 Mechanisms
Solutions • 285
1. -H2 2.
3. H 3. +H
H: O O H OH
O H Me
O HO Me
C C C C
4.
1. C C Me 2. +H
-H R C C CH
5. R C C CH2 R C C CH2
H H
~H
B:
H H H
~H
R C C C R C C CH R C C CH
H
6.3 Mechanisms
CHAPTER 7
STEREOCHEMISTRY
7.1 General
1. chiral molecules: a, b, f, h, and l.
H
Bn N N
S
2. a. 3. b. 6.
O N N
O
CO2H O O
O O
N
CO2Me O
c. 4. d. 2.
O
O Ph
O OCH3
O
HO H
H (R)- Ph
OH NH2 CH2CH2NH2
3. a. HO b. Me Br c. (R)-
Br H N
H (R)-
(S)- Me
meso-
O
(R)- O CO2H OMe
Ph O
O
H2N H g.
d. e. f. HS N Me OH
H Ph H Me
(S)- (S)-
NH2 H
(S)- HO
meso- (R)- (S)-
4. a. enantiomers b. enantiomers c. diastereomers d. enantiomers
e. identical f. diastereomers g. enantiomers h. diastereomers
i. enantiomers j. enantiomers
7.1 General
Ha
Hd Cl HbHe Hf Hc Hd Hf
Hc
5. a. 8. He c. 7. Ha
b. 7. Hg
Hb Hd' Cl Hb He
Ha' Hc' Ha Hc Hd Hg
a, a'; c, c'; d, d' c, d; e, f are c, d; f, g are
are enantiomeric diastereomeric diastereomeric
Cl CH3 Br
6. a. H b. H OH c.
Ph
Cl
(R)-3-chloro-4-phenyl-1-butene (S)-1-chloro-2-propanol (R)-4-bromo-5-methyl-4-n-
propyl-1-heptene
(R)-
H
H Me
CH3 (S)-
Et
d. I e. f. Et H
OCH3 H
H
Me
(R)-1-iodoethyl methyl ether (3S, 4R)-3-s-butyl-4-isopropyl- meso-3,4-dimethylhexane
1,6-heptadiene
Br Br Br Br
Cl Cl
7. a. 4 pairs.
_)
(+ _) Cl
(+ _)
(+ Cl (+
_)
Cl Cl Cl Cl
Cl Cl
b. 5.
Cl
Cl Cl Cl
Cl F Cl
c. 2 pairs.
F
_)
(+ _)
(+
7.1 General
Solutions • 289
Et Et Et
H OH H OH H OH
d. 2 meso-isomers, 1 pair of enantiomers. H Cl Cl H H Cl
H OH H OH HO H
Et Et Et
meso- meso'- _)
(+
Me Me
H Cl H Cl
e. 2 meso-isomers. H Cl Cl H
H Cl Cl H
H Cl H Cl
Me Me
CHO CHO
H OH H OH
epimerize at C4
8. a. HO H HO H
HO 4 H H OH
CH2OH CH2OH
enantiomer of A D-xylose
(S)-
H MeHN Me
b. i. MeHN Me H ii. ee = +10o / +40o = 25% (+), 75% (+_)

= OH
H OH H
therefore, % (+) = 25% + (75% / 2) = 63%
Ph
Ph (R)-
N
_)
9. ee = +68o / +170o = 40% (+), 60% (+ no. chiral carbons: 4. N
therefore, % (-) = 60% / 2 = 30%
OH
H Me
CO2H
10.
MeO (S)-
7.1 General
11. a. ED b. D c. ED d. ED e. D f. D
g. E h. ED
O Me
O
HS Me
NH
12. N 13. H
O CO2H
H
O NH2 (S)-
(R)-thalidomide
AcO O
OH
14. a. 11. HO O b. ee = +24o / +120o = 20% (+), 80% (+_)

HO O O O therefore, % (+) = 20% + (80% / 2) = 60%
Ph N O
H Ph Ac
O
O Ph
Cl
O Cl meso- O CO2H
Cl
15. (!)
O O
A Cl HO OH
B
O (+
_)
3 chiral carbons, 2 meso stereoisomers, 1 pair no. stereoisomers: 2n = 24 = 16.
of enantiomers
N S
H
16. a. no. stereoisomers: 23 = 8. H2N O N O
O
CO2H CO2H O
_); therefore, % (-) = 20% / 2 = 10%

b. ee = +82o / +103o = 80% (+), 20% (+
7.1 General
Solutions • 291
OH
Me OH
H 1. OsO4 Me H
1. HO H Me
= + enantiomer
Ph 2. NaHSO3 HO Me
Me Ph Me Ph
Br syn-add'n
Me
Br2, H2O Me H Br H
= + enantiomer
Ph Me OH
Me
Ph
OH
anti-add'n
A Me
Me H Me H
2. a. anti-add'n. Me H rot'n B - A-B H
= B
B H H A A
Me Me
Me Me H H
cis-
C
Me Me
C D
C D rot'n Me D - C-C D
b. syn-add'n. =
Me D Me D Me C
D
C C D Me Me
trans-
OD
CO2H HO2C
DO H rot'n HO2C H - D2O H
c. anti-add'n. DO H =
D H D H CO2H H CO2H H
CO2H CO2H
CO2H D
(E)-
Ph Cl Ph Ph Cl Ph Ph Cl Ph
+H 1,2-H:
3. a.
Et Et shift Et
Ph Cl Ph Br Ph Cl Ph Cl
Et Et Et Et meso-
+ +Br +Cl +
Ph ClBr Ph Ph Cl Cl Ph
Et Et Et Et chiral
diastereomers => diastereomers =>

2 fractions: each E 2 fractions: 1 M + 1 E

H Br
Et H Et
b. Br2 H Et
H + Br Br
anti-add'n H enantiomers => 1 fraction: R
Et Et
H Et
Br
CO2H
KMnO4, H
c. => 1 fraction: M
CO2H
I
+H 1,2-H: +I Ph
d. +
shift enantiomers =>
Ph Ph Ph Ph 1 fraction: R
I
H
Cl
F H Me
H HF
e. Cl + diastereomers => 2 fractions: each E
H
Me Cl
H F Me
D D
D2 / Ni
f. + diastereomers => 2 fractions: each M
syn-add'n
D D
Me OMe
Me Me Me H Et
g. +H 1,2-H: Et +MeOH
H H H H +
H shift -H
Me Et
H OMe
diastereomers =>
2 fractions: each E
1. BH3.THF
h. + H OH enantiomers => 1 fraction: R
2. H2O2, OH
syn-add'n H OH

Solutions • 293
Et OH Et OH Et OH Et OH
H3O Et Et OH
+H2O
i. OH + Et
H +H, 1,2-H: -H
shift meso- chiral
Et OH
Et diastereomers => 2 fractions: 1 M + 1 E
H2 / Pt
syn-add'n H
1 fraction: E Et OH Et OH
1. Hg(OAc)2, H2O OH H
H + OH
H H
2. NaBH4
diastereomers => 2 fractions: each E
OH
1. OsO4
j. + diastereomers =>
OH OH
2. NaHSO3 2 fractions: each M
OH
OH
1. mCPBA
+ enantiomers => 1 fraction: R
OH
2. H3O
OH
OH
O O O H O
+H +MeOH OMe
k. + enantiomers =>
-H OMe H 1 fraction: R
H Br
1. H2 / Lindlar catalyst Ph 2. Br2 H Ph
4. a. Ph Ph H Ph +
syn-add'n anti-add'n Br Br
H H Ph
Ph H Ph
Br
cis-
racemate
note: reduction of the alkyne to a trans-olefin, followed by Br2 addition, would yield the meso-dibromide (see next problem)

Br
H
1. Li / NH3 Me 2. Br2, CCl4 H Me
b. Me Me
anti-add'n Me anti-add'n Me H
H
Br
meso-
OH
1. Na / NH3 2. OsO4 H t-Bu

c. HO + enantiomer _)
(+
3. NaHSO3
t-Bu H
H OH
O O
Me 1. mCPBA H 2. H3O
d. Me Me H Me H Me
Me Me Me H
H H
OH
OH2 meso-glycol
5. a. 22 = 4. b. diastereomers c. cannot predict (actual [D]D = +62o)
CH2Ph CH2Ph
Ph Me Ph NHMe H2 / Pd
d. i. 2. + ii. 2. H NHMe + MeHN H
H NHMe H Me Me Me
_)
(+

CHAPTER 8
ALKYL HALIDES AND RADICALS
8.1 Reactions
1
2
H 1 + 1 meso
1. Cl2, hv 7 are optically active
9 fractions
1 2 are optically inactive
Cl
1 2
Br
Br2, hv
2. + +
Br (+
-) Br
(no. H) x (reactivity) = 6 x 1.0 = 6.0 4 x 82 = 328 2 x 82 = 164
% racemic 2-bromopentane = 328/(6 + 328 + 164)*100 = 66%; therefore, % (R)- = 33%
1. Br2, ' 2. Mg 3. D2O

3.
Br MgBr D
1. conc HCl 2. Li 4.
4. OH Cl CuLi
3. CuI 2
Gilman reagent I
1. Cl2, hv
2. Li CuLi 4. 5. HI
5.
3. CuI 2 I I
1,2-R: 1,2-H:
shift shift
1. Br2, ' 2. Mg 3. Ph H
6. Br MgBr Ph C C +
Br 1. Li 3. n-PrBr Br
7. 4. NBS, R2O2
Ph2CuLi Ph
2. CuI Ph
OH
6. Br2 5. KOH
Ph Ph
H2O
Br
8.1 Reactions
8.2 Syntheses
1. Cl2, ' 2. OMe / MeOH 3. NBS

1. Cl
(-HCl) t-Bu
O O
Br
t-Bu
Br O
1. Br2, hv 2. OH 3. O3
2.
(-HBr) 4. Zn, H O
3. 1. Br2, ' 2. OEt, HOEt (-HBr) 3. HBr, ROOR Br
Br
I
1. Li 3. Ph-I
4. Ph2CuLi
2. CuI
1. Br2, hv 6. Li
2. Li 5. Br2, hv 7. CuI
5.
3. CuI Br Ph
8. PhCH2I
4. MeI
O
Cl 1. Li
2. CuI 4. O3
6. H
3. I 5. Zn, H
1. H2 / Pt 1. DCl 1. NBS, R2O2

2. Cl2, hv 2. Mg D
2. H2 / Pd
7. or or
3. Li 3. H2O 3. Li
4. D2O 4. D2O
Br
2. KO-t-Bu / t-BuOH
1. NBS, ROOR 3. NBS, ROOR
8.
4. KO-t-Bu / t-BuOH
8.2 Syntheses
Solutions • 297
8.3 Mechanisms
H
O R R O O R etc.
+
1.
O2H
-H H
O O
O O
Cl
Cl
2. Cl Cl2 Cl
+ + Cl
H
-H Cl
Cl Cl Cl
Cl
Cl Cl
Cl Cl
Cl Cl
D
D D D
3.
D D D
D
CH3 N O H
H2 C
O O
hv
4. AcO AcO
6-membered ring TS
O
H2C N H2 C N O
OH OH
AcO AcO
8.3 Mechanisms
5. a.
b.
-HR +O2
6.
H
H O
R O
O2
H R
+O2 O
O
O
O O
OOH OH
8.3 Mechanisms
CHAPTER 9
SN1, SN2, E1, AND E2 REACTIONS
9.1 General
Cl SN2 OAc
1. faster reaction: b. AcO +
solvent effect: acetate in HMPA (polar aprotic) is more nucleophilic than in ethanol (polar
protic); the later H-bonds to acetate, thereby dampening its nucleophilicity
2. poorest leaving group: b. 'leavability' parallels the acidity of the CA of the leaving group;
:NH3 is the weakest CA (of the choices, c has the best leaving group)
Et Et
3. stronger nucleophile: a. Et N: :N Et rapid pyramidal inversion lowers nucleophilicity;
Et Et such "flipping" is impossible with a
b
4. most reactive by an SN2 pathway: c. least sterically crowded target carbon; note that even though a is primary,
it is neopentyl-like, which generally never undergoes an S N2 reaction
SN2 Br
5. solvent that will maximize the rate of reaction: a. Et3N: + Br NEt3
polar solvents (a or b) stabilize the developing charge in the TS; the amine is more nucleophilic in DMSO
(polar aprotic) than methanol (polar protic):
Et3N: H H-bonding stabilizes the amine, thereby increasing 'G

O Me
b
Me Me
Me H
6. more reactive by an E2 pathway: b. H vs. H
H Me
Br
a Br b
no trans-diaxial anti-periplanar TS possible
hydrogen available
Br
H(D) O-t-Bu
7. approximate kH / kD: c. Ph Ph
E2
a carbon-hydrogen (deuterium) bond is broken in the rate-determining-step; therefore,
a primary hydrogen kinetic isotope effect (~7) is observed
9.1 General
8. reaction to yield the more stereochemically pure product: b.

Et Br Et Br Et Et OMe
MeOH +MeOH
a. or
SN1 -H
Et Et Et Et
either diastereomer would give the same ratio of diastereomeric ethers because of a common intermediate
H OMe Br H
b. OMe OMe
or
SN2 SN2
Br H H OMe
(R)- (S)- (S)- (R)-
stereospecific: either enantiomer gives an optically pure, but different, ether
Ph EtOH Ph +EtOH Ph
9. change in rate of reaction: b. Br H OEt
Ph SN1 Ph -H Ph
rds
rate = k[RX] ; changing the concentration of EtOH has no effect on the rate
O-t-Bu OMe
10. a. vs. Br SN2 > E2
Br ~100% E2!
OH OH
b. vs. Br
Br
30 RX => ~100% E2 20 RX => SN2 + E2
OR SR
c. + vs. >>
Br OR Br SR
RS is a better nucleophile, and weaker base, than RO ; therefore, SN2 / E2 ratio is larger for RS
9.1 General
Solutions • 301
11. expected primary hydrogen kinetic isotope effect: b.

H) KO-t-Bu
a. H(D) no carbon-hydrogen (deuterium) bond is
Cl E2 - Hofmann broken in rds; therefore, kH / kD ~ 1
KOH a carbon-hydrogen (deuterium) bond is

b. H(D)
E2 - Zaitsev H(D) broken in rds; therefore, kH / kD ~ 7
Cl (H(D)
(H
KOMe
c. Cl + SN2 + E2
OMe
(D)H H(D)
no carbon-hydrogen (deuterium) bond is
broken in rds
O2 O2
S S
O if intramolecular O G-
12.
CH3 G- CH3
C: C
TsO H TsO H
G- G-
unfavorable TS: Nu R L bond angle not linear
O2 O2
however, S CH3
S CH3 O
if bimolecular O
G-
CHOTs C CHOTs
C: O2 TsO O2
TsO H H3C S H C S
O H3 O
G-
a linear TS is possible => < 'G ;

therefore, an intermolecular reaction
is kinetically favored
9.2 Reactions
Br KOMe, MeOH
1. O
Me
SN2 > E2
I OEt
2.
E2 - Zaitsev
Cl
E2
3. + O
Hofmann
Br
E2
4. + N
2 Hofmann
9.2 Reactions
KCN / DMF N:
5. I C
SN2
MeOH, RT +MeOH
6.
Cl SN1 > E1 -H OMe
refluxing EtOH -H
7.
E1 > SN1 Zaitsev
Br
O -Cl O O +HOAc O
8.
SN1 -H
Cl OAc
racemate
Me Me
Br Me2NH N Me -H N Me
9. +
SN2 > E2 (H
10. Br + O-t-Bu
E2
I O OAc
11. + O
SN2 > E2
Cl Cl
SH (1 equiv)
12.
SN2
Cl SH
reactivity: 10 > 20
OEt
EtOH +EtOH
13. +
SN1 -H
Cl OEt
Br
-AgBr 1,2-H: OAc
14.
SN1 shift Ph OAc
Ph Ph Ph
9.2 Reactions
Solutions • 303
Et H
Me H Me
Me H rot'n Me OEt, -HCl Et
15. = Cl Et
Cl H H Et H Me E2 H
Me Me Cl Me
anti-periplanar TS
t-Bu
H
Me
OMe, -HCl
16. =
H E2
Cl Cl
trans-diaxial TS Hofmann olefin
t-Bu
H
D
-HCl
17. = HD
E2
D D H D D
Cl
Cl
(C-H bond slightly weaker than C-D bond)
CH3 H
H D Me
H D rot'n -HBr D
18. = Br Me D
Br H H CH3 H Ph E2 H
Ph
Ph Br Ph
-Br -H
19.
SN1
OH O O O
Br H H
I PPh3 I
:PPh3
+
20.
SN2 O -t-Bu O -t-Bu
OH
1,2-H:
SN1 shift
MeOH +MeOH
21. S Cl S S S OMe
SN1 -H
N I
-I
22. I N
intra- SN2
9.2 Reactions
Cl
23. HSe +
SN2 >> E2
SeH
OH H OH Me
Ph Cl (1 equiv)
24. Ph N N Ph
Me SN2 Ph
Me
O Me -Me2O, -H Me BF4
Me3N Me3N
25. OH Me O
SN2
OH OTs H
1. TsCl 2. OH
26.
ret SN2, inv
H H OH
Me
S :NH2
27. Me S + :N
SN2 H
Me
HO HO F
NHMe better leaving group N
+ F
28. Br
SN2
OH (1 equiv) OH
OH OH
refluxing MeOH rigidity of bicyclic structure prevents formation of a planar carbocation

29. NR! backside attack impossible
Bredt's rule precludes double bond at bridgehead
Cl
Ph
I F I Se
SePh (XS)
(vinyl halides unreactive under SN2 conditions)
30. SN2
O O
EtBr (1 equiv) Br
31. H2N NEt2 H2N NEt3
O SN2 O
more nucleophilic nitrogen
9.2 Reactions
Solutions • 305
Br
1. NaNH2 2.
32. Ph C CH Ph C C: Ph C CH +
E2 > SN2
MeOH 1,2-R: -H
33.
E1 shift
I (H
OTs
34. + S C N: NR! (aryl tosylates unreactive under SN conditions)
Br OAc
HOAc, RT 1,2-R: +HOAc
35.
SN1 shift -H
1. MeI 2. refluxing EtOH -H

36. S S
SN2 -Me2S, E1
O O
O-t-Bu
37.
E2
O O
Br Hofmann olefin
(XS) MeI
38. :N N: Me N N Me 2I
SN2
anti-
H Br
Me
OEt
39. a. O O
O E2 - Zaitsev O
H H
syn-
H Br H
Me
OEt
b. O O
O E2 - Hofmann O
H H
9.2 Reactions
9.3 Syntheses
Ph Ph Ph Ph
H2O, Ag 1,2-H: +H2O
1. Ph
SN1 Ph shift Ph -H Ph
Br OH
Ph
NaOMe, MeOH
SN2 Ph
Ph OMe
LDA or KO-t-Bu
E2 - Hofmann Ph
Br
MeOH, ' -H
2.
E1
(not OMe! => E2 - Hofmann olefin)
D
3. H OEt
=
Br H -DBr, E2
H D Br
H Hofmann olefin
(not HOEt, '! => E1 - Zaitsev olefin)
Ph H
Me H Me
Me H rot'n KOEt, EtOH Ph
4. = Me
H I
H I Ph Me
Ph
H E2 Me
Me Me H
I
Et
I EtOH, ' 1,2-R: -H
5.
E1 shift
OPh
Br PhOH, AgNO3 1,2-R: +PhOH, -H
6. +
SN1 + E1 shift or, -H
O
O
Ph OH +PhCO2H
7. Cl O Ph
SN1 -H
9.3 Syntheses
Solutions • 307
Br 1. KO-t-Bu, t-BuOH 2. HBr, ROOR

8.
E2 - Hofmann Br
1. Br2, hv 2. EtOH, RT
9.
Br SN1 EtO
(not OEt! => 100% E2)
O
1. MeOH, ' 2. O3
10.
E1
3. Zn, HCl
Br O
CO2H
1. KO-t-Bu, t-BuOH 2. KMnO4, H
E2 - Hofmann
CO2H
Ph 1. NBS, peroxide Ph 3. HBr, peroxide Ph

11.
Ph 2. NaOMe (E2) Ph 4. KO-t-Bu (E2 - Hofmann) Ph
OH OTs
1. KOH, EtOH 2. H3O 3. TsCl
12. Ph Ph Ph Ph
E2
OTs
1. Br2, ' 2. KOMe .

3. BH3 THF
13.
Br E2
4. H2O2, OH
OH
SOCl2
14. OH O
S O Cl
-HCl -SO2
Cl
[SN2 reactivity slow (neopentyl-like); avoid SN1 (rearrangement)]
HS S S
1. Br2, CCl4 2. SH -Br
15. H2C CH2 Br
Br SN2
base, SN2 Br S S
9.3 Syntheses
C:
1. HCl CuLi 4. vinyl chloride 5. Cl2 C
16. 2. Li
2 6. (XS) NaNH2
3. CuI
H
taut OH 7. BH3 THF.
O
8. H2O2, OH
1. Li 2. H2O 3. Br2, hv
17.
I Li H Br
(SN or E not possible)
H D
MeOH, ' -H
D
-Br, E1 H
D H D D
18.
Br D
D H
D = OMe / MeOH
H
H -DBr, E2
Br
trans-diaxial elim D
9.4 Mechanisms
Br SH
-HBr S -Br S
Br
1. SN2
SN2
Br
HOAc 1,2-R: +HOAc

2. =
SN1 shift -H
Cl OAc
HOAc
CH3 CH3 CH3

N CH3 N CH3 N C N:
SN2 -CH3Br
3. C Br SN2
:N C Br N:
9.4 Mechanisms
Solutions • 309
Cl HO Ph NEt2
-Cl
4. Ph N Ph
SN2 SN2
Et Et OH
Et2N:
O O
H O inter-SN2 H
intra-SN2 O
5. O double inv = net ret
inv inv O
Cl H OH
OH
O
HO
(in conc OH, product is O , formed by initial inter-SN2)
H
H (H
S S S
I DMF -H
6.
-I
SH SN1
- N H
-Br O
7.
N SN2 N
H
O O
Br H (H
H H
H OH
O H O O
H Cl -Cl -H
HO Cl
8.
intra-SN2
H trans-A with inv possible B
H
Cl
O Cl
H H
HO H B intra-Walden inv not possible
H cis-A OH H
HO OH
therefore, inter-SN2
with inv H
rds Cl +H2O repeat

9. Cl S
S S S
-Cl -H Cl OH OH OH
Cl OH2
9.4 Mechanisms
9. (cont.) similarly,
Cl rds Cl +H2O repeat

N: N N N
-Cl -H OH OH
Cl OH
Cl
OH2
H AcOH H
OAc
10. OTs intra-SN2 (NGP) therefore, OTs +HOAc
not possible inter-SN2:
O -TsOH OAc
I O OAc
trans-enantiomer only
vs. AcOH
OTs
OAc OAc
NGP +HOAc
H O +
-TsO -H OAc OAc
O
II O O
racemate
H Ac O (H O
O -H
O OAc
OTs Ac
O NGP O 40%
11.
- OTs H) Ac
O OAc
-H
O O
O
H Ac
60%
X X OAc
NGP O +HOAc
12. vs.
O rds -H O
I II
O
NGP not possible - H Ac
therefore, no kinetic
enhancement
H H
O NGP, rds O +EtOH
EtO
13. OH
k -H
Cl
less strained intermediate => < 'G
vs.
therefore, k >> k'
H
O NGP, rds H +EtOH
O EtO OH
Cl k' -H
9.4 Mechanisms
Solutions • 311
H Ac
O
OTs OTs H
OAc
14. - OTs +HOAc

vs.
II -H
I
ret
NGP not carbocation
possible stabilized by S electrons
TsO
NGP + OAc
15. = H = AcO
- OTs
OTs OAc H
OAc
CH2 NR"2 CH2 NR"2 CH2 NR"2

O dil OH O -R'O O
16. RNA:
-H, NGP
O OH O O O O
R'O P
O R'O P O P
+ OH O O
O O OH
CH2 NR"2 CH2 NR"2 CH2 NR"2
O O O
2' 3'
OH O HO (H O O H) OH O OH
P P P
O O or O O (H O O
O O O
2'-phosphate 3'-phosphate
CH2 NR"2
O
DNA:
O NGP not possible; therefore, more stable in dil base

R'O P
O
O
' -H
17. Cl + racemate
-Cl
(H
(H
1,2 -R: -H
shift
9.4 Mechanisms
O adenine
2- O adenine
HO6P2 O P O
O O
18. O
O P O OH
2-
OH OH HO6P2 O
O (H
adenine
O -H
O
O O
O P O OH - HO P O P O = PPi
O O O
OPP OPP
19. a. . . -BH
-OPP
.. OPP
(H :B
OH +H rot'n
b.
-H2O
+H2O
-H
OH2
OH
c. coupling mechanism:
bond formed
OPP
. +I-PP
-H, -OPP
..
OPP
. OPP
(H
conversion of A to vitamin A:
OH +H OH
A
H
H
(H
-H OH
vitamin A
9.4 Mechanisms
Solutions • 313
OPP
- OPP + OPP
d.
F-PP PPO
N-PP
:H
OPP H)
. . [H]
.. -H-OPP
squalene
- OPP
OPP OPP
F-PP N-PP
CO2H
H3C
S NH2 CH3
O
O adenine S adenine
20. PP O P
O O
O SN2 H2N
OH OH CO2H OH OH
SAM
OH
OH
HO NH2 CH3
HO N CH3
S adenine H
HO O SN2
H2N HO
epinephrine
CO2H OH OH
+H -N2 +HOEt Ph
21. Ph2 C N N: Ph2CH N2 Ph2C OEt
-H Ph
H) OTs
Cl
-Cl O Cl OMe
22. Ph CH2 Ph P CH3 Ph P OMe + CH3Cl
SN2 SN2
:P(OMe)3 (OMe)2 O
OH Cl
-Cl +I Cl2C I
23. Cl3C (H Cl2C: Cl2C: Cl2C I
-H H
H OH
I
note: HCCl3 + I HCCl2I via SN2
9.4 Mechanisms
CHAPTER 10
NMR
Cl O OH
1. 2. 3. 4.
Cl O OH OH
O F
5. O 6. Br O Cl 8.
O 7.
O F
Br
Cl O
9. 10. Br 12.
11.
Cl OH
O
13. Br 14. 15. 16. H
HO
J => trans- F OH O
O
17. O
H
Fa
Ha Cl
18. Ha and Hb are diastereomeric protons; 19F (I = 1/2)
Hb CH3
Fb therefore, max multiplicity for Ha or b = doublet x doublet x doublet = 8 lines
Ha Ha
Br Me Br Br
19. vs.
Me Br Me Me
Ha Hb
A B
methylene protons are identical Ha => doublet; Hb => doublet

=> singlet (appears as a multiplet)
10. NMR
Ha
Ja,b = 16 Hz
Ja,c = 8 Hz
Hb Hc Hc
1 2
3 Br multiplicity: 5 lines (pentuplet)
20.
Ha
Cl F
Hc Ha
21. a. highest field proton is Ha
Hb
Cl Ja,F => doublet
Hb (Hc)
Jb,c
Jb,F
b. Hb and Hc are diastereomeric: Jb,c ~

~ Jb,F => triplet
Hb Hc H
a
22. CO2H Hb and Hc are diastereomeric and independently couple with Ha; if Ja,b Ja,c,
Ph
Ha would appear as a doublet x doublet = 4 lines (assuming no coupling through nitrogen)
NH2
O
23.
O
1
2 3
5
6
4
24. a. Ha (lowest field proton): doublet x doublet => 4 lines 8
7
b. C7 and C8 are diastereomeric carbons; therefore, 8 chemical shifts Hb
DO Hc
Ha
Br Br Br
25. -SbF5Br Me Me
Me Me
Br
SbF5
all methyls are equivalent
therefore, appear as a singlet
26. 31P (I = 1/2), nP = 2; therefore, 2nI + 1 = 3 (triplet)

Ha Ha
(i-Pr-O)2 (O-i-Pr)2
P P
O O
10. NMR
Solutions • 317
Ha
27. a. amplitude: signal at G -16.1 is highest amplitude because most molecules PPh3 JH,P
(66%) contain Pt with I = 0 (no further spin-spin coupling with Ha Cl Pt Ha
is observed, i.e., JH,Pt = 0) PPh3
multiplicity: 31P (I = 1/2), so JH,? = JH,P > 0, nP = 2

therefore, 2nI + 1 = triplet
-16.1
Ha
JH,Pt
b. amplitude: signals at G -13.6 and -19.6 arise from fewer (34%) JH,P
molecules containing 195Pt (I = 1/2) per above
multiplicity: Ha now undergoes spin-spin coupling with both

P and Pt to give a doublet of triplets (JH,Pt >> JH,P)
-13.6 -19.6
c. Ha is very highly shielded, essentially a hydride, because of the polarization of the G+ G-

Pt Ha
Pt-H bond (much higher electron density around Ha than typically encountered in
C-H bonds)
Ha
Ha
Hb Ja,c
Bo Because of magnetic anisotropy of
the aromatic ring current, Ha experiences
diamagnetic (and Hb paramagnetic) lines Ja,b
28. Hc
of force relative to applied field Bo.
Hc Therefore, Ha is more shielded (and Hb
deshielded) than normally observed in
hydrocarbon protons on sp3 carbons.
pseudo-quartet
(same for Hb)
5.5 ppm!
5.0 (Hb) 0 0.5 (Ha)
H H
29. multiplicities: H 11B H vs. 10B H
H
H H
11B (I = 3/2) 10B (I = 3)
therefore, 2nI + 1 = quartet therefore, 2nI + 1 = septet
(higher amplitude) (lower amplitude)
relative amplitudes of quartet/septet reflect the natural abundance of 11B/10B = 80%/20%
10. NMR
CHAPTER 11
CONJUGATED SYSTEMS
11.1 Reactions
H
+H +Br
1. Br
(1,4-addition)
D D
2. DCl (1 equiv)
1,4-add'n
most stable carbocation
D D
Cl +Cl
CO2Me
CO2Me CO2Me
D-A
3. = =
CO2Me
MeO2C CO2Me
retro-D-A
4. =
O
O O
HBr
5. H
+H H
Cl Cl
+Cl +Cl
H H
1,2-add'n 1,4-add'n
product of thermodynamic control -
more conjugated system than 1,4-adduct,
therefore, more stable
11.1 Reactions
'
6. +
retro-D-A
DBr (1 equiv),
ROOR +DBr
7.
1,4-add'n -Br
Br D
Br Br Br
O O
O
N D-A N O
8.
N N (4 + 2) N
Ph N Ph
O
O
H H
N N
Ph D-A
9.
Ph
Ph Ph
1. NBS, R2O2 Ph Ph
3.
10. =
2. KOMe (E2)
Me
1. retro-D-A 2.
11. 2 Me
' Me
Me
(E)-
intra-D-A
12. =
11.1 Reactions
Solutions • 321
O O O
1. D-A 2. KO-t-Bu
13.
E2, -HCl
Cl Cl
H O
1. D-A 2. O3
14.
3. Zn, H CO2Me
CO2Me CO2Me
O H
O
15. '
+
retro-D-A
1. retro-D-A 2.
16. 2 Ph
' Ph
Ph Ph
cis-
CO2H
HO2C CO2H
17. =
'
s-cis-diene CO2H
O O
(4 + 2)
18.
O O
MeO MeO
11.1 Reactions
AcO
AcO
CO2H CO2H
19. = ' CO2H '
+
OAc
CO2H OAc
HO2C CO2H
CO2Me (4 + 2) CO2Me
20.
CO2Me CO2Me
O O
O
N ' N (4 + 2) N
21.
- :SO2
O2S
O O O
H)
B:
base, E2 (4 + 2)
22.
-NMe3
MeO MeO MeO
NMe3 I C19H24O2
MeO MeO
R R
Si D-A Si
23. Br Me2 Br Me2
H CHO
OMe OMe
R' R'
N (4 + 2) N
24. +
R
Me3SiO R R Me3SiO
R
11.1 Reactions
Solutions • 323
11.2 Syntheses
D
1. Cl2, hv 3. NBS 4. KOMe (E2) 5. DBr
1.
2. KOMe (E2) ROOR Br 1,4-add'n
Br
1. Cl2, hv
2. KOMe 5. ethylene 6. H2 / Pt
2. CH2
3. NBS, R2O2 H2C D-A
4. KOMe
1. NBS, peroxides 3. Me
3.
2. KO-t-Bu, t-BuOH 4. H2 / Ni
Me
1. NBS, R2O2 3. 2-butyne

4.
2. KO-t-Bu (E2) CH3 D-A
H3C
O
O
(4 +2)
5. A
O
Me Me
N
O N
(4 + 2)
6. NMe + O = O
O O
O O
O
O
O H CO2Et CO2Et
'
7. + = O
H CO2Et OH
H
11.2 Syntheses
11.3 Mechanisms
O O
O
O
> pH 8.5
1. O
-H
(H
O OH
HO HO
- sp3 carbon prevents conjugation - > conjugation results in a 'red shift;'
from one ring to the other two; absorption occurs at a longer wavelength,
therefore, absorption occurs at shorter moving into the VIS, and the molecule,
wavelengths (UV in this case) therefore, is "colored"
' '
2. +
retro-D-A D-A
O O
' (4 + 2)
3. a. O O
O O
O O O
' '
3. b.
4. a. longest Omax: n S*
N
b. low probability A = H c d H (molar absorptivity) only ~ 10 - 100 for n S* transitions

(vs. > 10,000 for S S* transitions)
c. no non-bonding electrons in the CA of pyridine; therefore, no n S* transition

N
H
11.3 Mechanisms
Solutions • 325
+H -H2O
5.
OH OH2 OH2
G 1.70 H
H G 4.10
-H +H2O
OH = OH G 2.25 OH2
H G 1.79 H G 5.45
B
O O O
O Me
O ' retro-D-A
6. =
O D-A -CO2
O
CO2Me R R H
O O CO2Me
R = -CO2Me
A B
R inter-D-A intra-D-A
7. =
R R
R R R
O O
O
D-A
8. =
(H C H2 H CH2
O O O
taut '
9.
ene-reaction
Ts Ts
N N
N hv CN
10. Ts N Ts N =
N - :N N: CN
CN CN
11.3 Mechanisms
OH OH
N OH N OH
[O]
NH H N N H N
11.
N [H] N
CO2H CO2H b
c
site of
redox CO2H CO2H
bilirubin (red) biliverdin (green)
Increased conjugation promotes a ‘red shift’ in Omax, causing the color of pigments to move
toward the green-blue end of the VIS spectrum:
x biliverdin is conjugated from Ca to Cb, whereas bilirubin’s conjugation is disrupted (as a
consequence of reduction) at Cc
x biliverdin, therefore, absorbs at longer wavelengths (red) than bilirubin; alternatively,
biliverdin is transparent to shorter wavelengths (green).
12. a. b. c.
(4 + 4) (2 + 2) (4 + 2)
thermally forbidden thermally allowed
therefore, most likely to occur
11.3 Mechanisms
CHAPTER 12
AROMATICS
12.1 General
1. The following compounds obey the Hückel (4n +2) rule and would be expected to have aromatic
character:
= lone pairs of electrons are in a p orbital (other lone pairs are in sp2 orbitals)
H
N N H B H
b. d. N f. O i. j. N N
N N B B
O H N H
H
O OH
HN taut N
k. (6 S electrons)
O N HO N
H
2 Li 2-
m. product: 2 Li (6 S electrons)
H H
n. product: 2 MeLi
2 Li (10 S electrons)
H) -2 CH4
(H H
H3C: H
:CH3
Br ZnBr
Zn -ZnBr2
o. product:
Br Br both rings are aromatic

P >> 0!
SbF5
Note: l. carbocation from the reaction of (8 S electrons = 4n+ 2)
Cl -SbF5Cl
12.1 General
2. largest P: a.
etc. G+ G-
P
both rings are aromatic
note: flow of electrons in either direction in b or c would result in one ring being aromatic and
the other anti-aromatic, thereby lessening the benefit of charge separation and lowering P.
O N
N N
N
3. H3C
N N most basic (localized)
H
least basic (delocalized, part N
of aromatic ring current) CH3
4. least stable: b. O O
anti-aromatic
a and c have corresponding aromatic, and therefore stabilizing, contributing resonance structures
-H
5. most acidic: d. etc.
(H
aromatic CB
loss of a proton from a, b, or c would produce a resonance-stabilized, but not aromatic, CB
O O O
-Cl aromatic (4n + 2)
6. most likely to undergo an SN1 reaction: a. contributing structure
Cl stabilizes carbocation
most basic
more basic (localized)
O OH OH
H N
N +H
7. a. b. c.
N N
O O O
aromatic
more basic (localized)
12.1 General
Solutions • 329
_
-Cl
8. = 0
Cl +
aromatic - all protons are equivalent all bonding MOs are filled
O O
O O
9. largest molecular dipole moment: b. vs. d.
aromatic contributor aromatic contributor

with longer charge with shorter charge
separation (>d) separation
P=H d
-aromaticity promotes charge separation in b and d (but not a or c), thereby increasing H
-charge separation distance (d) is greater in b than d
O OH OH OH OH BF4
H
HBF4
10.
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph
aromatic cyclopropenium moiety
H
+H H
11. +Cl
Cl
aromatic note: does not undergo
a 1,2-H: shift!
(10)
Hb ~ G7 (4)
Ha ~ G-1
12. Ha Hb
1H NMR:
G10 G0
magnetic anisotropy causes the four Ha protons to be highly shielded (above TMS) and
the ten Hb protons to be deshielded (into the aromatic region)
12.1 General
12.2 Reactions
N N
H fuming sulfuric acid H
1. + o-isomer
O O
HO3S
OH OH
no! (avoid 1,2,3-subst'n)
Me Me
HONO2 / H2SO4
2.
NO2
o-, p-director H m-director

PH2 PH2 PH3
H2SO4, SO3
3.
+H
SO3H
(H (H (H -H
N Cl
N Cl Cl N Cl N
H H H H
Cl2 / Fe
4. vs. H H
N more important set of
H Cl Cl
contributing resonance structures
N N
H H
1. AlCl3 1,2-H:- PhH Ph

5. Ph Ph Ph
Br shift F-C alkylation
CH2
2. NBS, R2O2
Ph 3. KOMe Ph
Br
E2
Br
Br2 / CCl4
Br Br
Br
Br2, Fe
6.
Br Br
Br
NBS, R2O2
+
12.2 Reactions
Solutions • 331
G+ G- Se Se
-FeX3Cl Me Me
7. I Cl [I ] + + p-isomer
EAS
FeX3 I
N N N
O Br2, FeBr3 O O
8. +
Br Br
SH SH
Cl2, FeCl3
9. + p-isomer
Cl
H Cl H Cl H Cl
N N N
Cl2, BF3 least important
10.
N (H (H (H Cl
-H
Cl Cl Cl
N N N N
more important set of contributing resonance structures
OH OH
O OH OH Cl Cl
+H EAS OH
11. H H H H +
H H
Cl Cl +H
HO Cl Cl Cl
OH OH OH
Cl Cl Cl
EAS -H2O OH2
Cl Cl
Cl Cl Cl
Cl Cl Cl
O 1. -CO2, -N2 2. D-A

12. +
N N:
benzyne
12.2 Reactions
Me OH Me
O2N NO2 NO2
Me
13. +
Me Me O2N OH
Me
NO2 NO2
a S-complex
F NH2
F NH3
CN CN CN
:NH3 -HF
14.
nucleophilic add'n - elim
aromatic subst'n mechanism
Cl Cl Cl
NMe2 NMe2 NMe2 NMe2

1. MeLi (-HBr) + MeLi 2. H
15.
NAS,
Br Me Me
benzyne mechanism
Cl Cl OMe
NO2 NO2
1. HNO3, H2SO4 2. NaOMe, MeOH
16.
EAS NAS,
add'n - elim mechanism
CF3 CF3 CF3
+H
17. O O H OH
EAS
OH
EAS +H
-H2O
OH OH OH
18. +H EAS
+
again
12.2 Reactions
Solutions • 333
Br Br
Br
Br2, Fe -H
19. H) H)
O O EAS O O O O O O
most stable intermediate
Br Br N
O2N NO2 2. i-Pr2NH O2N NO 2
1. fuming HNO3
20.
EAS NAS, -HBr
CF3 CF3 CF3
OMe OMe OMe OMe

Ha
1. MeI, AlCl3 2. NBS, ROOR 3. KOH
21.
SN2
Hb
Br OH
1H NMR: aromatic a-b quartet suggests p-subst'n
I
I2
22. HO HO
catalyst thyroxine
CO2H CO2H
H2N I H2N
H H H
Cl Cl Cl
3-subst'n N N N
2. Cl2, BF3 O O O
23.
N Cl
H) Cl H) Cl H) Cl
O
-H
+
4-subst'n 3. [H]
N N N N N Cl
(or 2-subst'n)
O O O
best resonance
structure
12.2 Reactions
12.3 Syntheses
1. CH3I, AlCl3 2. Cl2, Fe 3. H2 /Pt

1.
F-C Cl high T, P
Cl
Br Li H
D D D D D D
1. Br2, Fe 3. Li 4. H2O
2.
2. dil D2SO4 (EAS)
D D D
Cl MgCl D
1. Cl2, AlCl3 2. Mg 3. D2O

3.
(x2) Et2O
Cl MgCl D
O OH H H
1. PhCH2COCl 2. H2 / Ra-Ni followed by
4.
AlCl3 Ph hydrogenation Ph hydrogenolysis Ph
Br
1. Cl2, BF3 3. KOMe, MeOH
5.
2. NBS, ROOR Cl E2 Cl
1. cyclohexyl chloride 2. NBS 3. NaOH

6.
AlCl3 ROOR E2
Br
1. O3
2. Zn, HCl 4. SOCl2
7.
3. O2 [O] CO2H 5. AlCl3 (F-C)
O
12.3 Syntheses
Solutions • 335
Cl CO2H
1. 2. HONO2, H2SO4 3. KMnO4, H
8.
AlCl3
NO2 NO2
1. Cl2, Fe Cl
2. PhLi PhLi 3. H
9.
-HCl Ph 4. MeI, AlCl3 Ph
1. Br2, FeBr3 2. NaNH2

10. NHMe
NHMe NHMe :NH3
Br
~H
N N (H
Me Me
O
O
Cl
1. EtCl, BF3 2. 3. H2, Ra-Ni
11.
Et AlCl3 Et Et
O OH OH
1. H2SO4 OH 2. PhH, H
12. HO OH
EAS +H, -H2O
t-Bu
3. ,H EAS
HO Ph HO Ph HO
EAS
t-Bu (see 12.2, 18)
Cl O O CO2
Cl Cl Cl
13. 1. NaOH 2. Cl CO2
(Cl)H NAS SN2
(Cl)H (Cl)H
Cl Cl Cl
12.3 Syntheses
Br O OH O O OH
1. OH (NAS) 2. a. SnCl2, HCl 3. O

14.
b. neutralize (1 equiv)
NO2 NH2 -HOAc NH
NO2
O
CO2H CO2H CO2 CO2H
1. HONO2 2. KOH 4. SnCl2, HCl

15.
H2SO4 Cl
NO2 3. NO2 5. neutralize NH2
OH OH (1 equiv) O O
12.4 Mechanisms
H
EAS -H
1. Ph
Ph
(H Ph Ph
O O
OH O
H)
O +H O EAS -H
2.
H) OH
OH
NMe2
O AlCl3 O AlCl3 O AlCl3 NMe2
3. Cl Cl Cl Cl Cl Cl
EAS
Cl AlCl3
O
O NMe2 NMe2 Cl
EAS -Cl -AlCl4

Me2N NMe2
Me2N
C
Cl O
O
O C O
OH O O O OH
(H CO2H
1. OH 2. CO2 -H CO2 3. H
O
4. C
-H O
12.4 Mechanisms
Solutions • 337
[Br ]
Br Br
Br2, AlCl3 -H
5. +
(H
O
1. AlCl3
6. R X R C O:
-AlCl3X
Ph EAS Ph 2. HBr
-H Ph
R R +H
R C O: H) HO R
O H) O H
-H3O ~H EAS
R H2O R HO R (H
AlCl3 AlCl3 AlCl3 H

O O O O O O OH
~H
7.
R R (H R
R
:O C R O O
HO
Cl Cl Cl O Cl O Cl
-HCl -Cl
8. Cl Cl
Cl Cl NAS NAS Cl
Cl Cl Cl Cl
Cl Cl Cl
HO
Cl O Cl Cl O Cl
-Cl -HCl
Cl O Cl NAS Cl O Cl NAS
Cl
-BF3Br
9. Br
MeO BF3 MeO MeO
(H
-H EAS
MeO MeO
12.4 Mechanisms
O O
EAS H
-H
10. :C O: H C O: H) H
H
+H
11. H O O H H
O
O
H
H O
EAS -H
-H2O H)
H HO
OH
Cl Cl Cl O Cotton
N N 1. NAS N N -HCl N N 2. Cotton-OH N N
12. Cl
Cl N Cl N Cl HN N Cl -2 HCl Cotton
H2N HN N O
Dye NAS x2
Dye Dye
H2N Dye
O OH OH Cl OH
+H
13. Cl3C H Cl
Cl3C H Cl3C H EAS CCl3
+H
H Cl -H2O
Cl Cl Cl
CCl3 EAS CCl3
1. BF3 H
14.
Cl -BF3Cl EAS
BF3
2. H
(H
-H 1,2-R: H
shift
12.4 Mechanisms
Solutions • 339
H EAS +H (H
15. -H
H
O OH -H -H2O E1
OH
H
OH H
OH OH OH OH
O Cl -SnCl5 O -H, EAS

16. O
SnCl4
+SnCl4
O
+Cl -MeOSnCl4
SN1-like
SnCl4
Cl O
Br Br
17. 1. +Br2 +Br 2. :B
Br
-Br Br -HBr
Br Br
Br H) C7H7Br
C7H8Br2
3. H2O, -Br
O OH
+H2O
-H -H SN1
aromatic
Me Me H
H OTS
H OTs rot'n -OTs
18. = Ph OTs
Ph H H Me
NGP Me H
Me Me Me HOAc
H
Me H
Ph +HOAc
Me H
+HOAc -H
Me H Ph
Me H OAc
-H Me H
Me H
Me H OAc
HOAc
enantiomers
12.4 Mechanisms
Cl
OR
-Cl
19. Cl3C (H Cl2C: Cl2C: + Cl
Cl N N
H
H
Cl Cl -Cl
-H
N N
H
+H 1,2-R: shift
20. H
H
-H 1,2-R: shift
(H
O O O
+H -H2O
21. HO P OH HO P OH2 HO P OMe
OH OH OH
O EAS
-H H)
(HO)2 P OMe OMe
H2O3P
12.4 Mechanisms
CHAPTER 13
ALCOHOLS
13.1 Reactions
O OH Cl
1. NaBH4 3. PCl3
1. 4. KO-t-Bu
Ph 2. NH4Cl Ph Hofmann, E2
Ph Ph
OH
1. H2 / Pd 2. H2SO4
Ph
Ph E1
OH O
1. i-PrMgBr 2. Br
2. + Et3COH
Hofmann
OH
3. 1. H2SO4 2. H3O
E1 OH
HCl, SN1 1,2-H: +Cl

+H, -H2O shift Cl
O O O
1. TsCl 2. NaOAc
4.
-HCl SN2
OH OTs O
OH Me
O O
5. 1. NaH 2. Me OSO3Me
-OSO3Me, SN2
O O O
1. PhMgCl PhMgCl 2. H
6. Ph O Ph Ph Ph Ph Ph3COH
-n-BuO Ph
not isolable
O O
1. LiAlH4 LiAlH4 2. H
PhCH2OH
-n-BuO Ph H Ph H
H
not isolable
O
O OH
1. Li 2. 3. H
7. CH3I CH3Li
-LiI
13.1 Reactions
1. HBr 2. LDA, E2 3. BH3.THF

8.
HO
Hofmann
OH Br 4. H2O2, HO
O OH
1. NaBH4 CO2Me
CO2Me
9. 2. H OH
O2CPh
O Ph 1. LiAlH4 OH
+ PhCH2OH
O
2. H OH
CO2Me OH
H2 / Pt
O2CPh
Me O OPOCl2 H
H OH POCl3 H O PCl2 Me
10. rot'n H E2
Me D py Me Me
D Me Me D -HOPOCl2
-HCl Me
H D
H H
:py
HO O O
Me
1. OH 2. Me-I
11. O O O
NMe SN2 NMe
NMe
HO HO HO
OH OH OH O
12. CrO3, H O
HO HO HO HO
O
1. Br2, H2O 2. Me3SiCl 4.
13. OH OSiMe3 OH
Br 3. Li Li 5. H3O
OH
O
O O O
1. MeLi -OBn MeLi O
14. O O -OBn
BnO OBn BnO BnO
Ph Ph
O
2. H MeLi
OH
13.1 Reactions
Solutions • 343
CO2H O
15. 1. LiAlH4 2. (XS) HBr Br
O SN1
HO HO
O OH
O OAc HO OAc
16. 1. NaBH4
OH
2. H
HO OH
O HO
1. LiAlH4
+ EtOH
2. H HO
OH OH O
+H 1,2-R: -H
17.
OH -H2O O shift
H
18. +H 1,2-R:
Ph -H
-H2O shift Ph
OH OH O Ph Ph
H O (H O
O OH
1. NaBH4
19.
2. H
HO HO
OH MgCl
O O O HO
1. SOCl2, Et2O 3. H
20.
2. Mg
O O
O HO
Ph Ph Ph
OEt Ph
21. 1. n-PrMgCl n-PrMgCl 2. H
N -OEt
N N N
Me Me H Me
Me
13.1 Reactions
OCH3 O
OMe O OMe O
22. 1. ' 2. H
D-A taut
TMSO Si O O
13.2 Syntheses
O D
5. NaBD4
1. H2 / Pt 3. H3O 6. H
1.
O
2. H2SO4 4. CrO3, H 7. POCl3 / py
O O
3. CH2O 6. i-PrLi
OH 1. HBr Li
4. H H 7. H
2.
2. Li 5. PCC [O] 8. Na2Cr2O7 [O]
1. H3O O
3. PhMgCl OH
3.
2. CrO3, H 4. H
Ph
OH OTs H
4. 1. TsCl (ret) 2. OH (SN2 - inv)
H H OH
Me
HCl Et +Cl
racemic
SN1 H Cl
*OH
H *OH
1. PCl3 (inv) 2. (SN2 - inv)
(* = 18O)
Cl double inv => net ret H
1. Br2, hv 3. CH2O 5. H2SO4

5. 6. H3O
2. Mg MgBr 4. H E2 HO
OH
1. Cl2, ' Br O O Me
2. KOMe (E2) 4. KOH (SN2) 6. MeLi 7. H2SO4
6.
3. NBS, R2O2 5. Jones reagent E1
13.2 Syntheses
Solutions • 345
O
1. Mg 3. H2SO4
7. Cl
2. H E1
1. TsCl N
8. OH OTs 2. KCN / DMF C
SN2
1. LiAlH4 3. SOCl2 or PCl3 4. Mg

CO2H
9. OH Cl D
2. H 5. D2O
OH O TMS O TMS OH OH
1. TMS-Cl 2. Mg
10. 4. H3O 5. PCC
(protect) 3. CH2O (deprotect) [O]
Cl Cl CH2O CH2OH
H O
OH Li O
1. PCl3 (not HCl) 4. CH3CHO

11.
2. Me3SiCl 5. H3O
HO 3. Li TMSO 6. PCC HO
1. BH3.THF
4. Li
2. H2O2, OH 5. CH2O
12.
3. PBr3 Br OH
6. H
1. Br2, hv 3. BH3.THF
13. 5. K2Cr2O7 O
2. KO-t-Bu / t-BuOH 4. H2O2, OH [O]
OH OH
(Zaitsev E2)
1. AlCl3 2. H2 / Pd
14.
Cl O F-C hydrogenation, then
O hydrogenolysis
OH 5. LiAlH4 CO2H 3. KMnO4, H

OH
6. H CO2H
13.2 Syntheses
O O
3. B2H6 6. MeLi
OH 1. HCl (SN1) 4. H2O2, OH H
15. 7. H Me
2. LDA (E2) 5. PCC 8. PCC
H
OH OTMS 3. OH O
1. Me3SiCl O 5. KMnO4, H
16.
Cl MgCl
2. Mg 4. H3O
HO O
OH O OH
1. H2SO4 (E1) 2. O3 4. MeMgI
17.
3. Zn, H 5. NH4Cl
O (weak acid to OH
avoid dehydration)
1. TMS-Cl OH OH
4. CrO3, H C CH
2. BH3.THF
18. 5. LiC CH
HO 3. H2O2, OH TMSO HO
6. H3O
OH O OH CH
C
1. NaOH
2. MeI (SN2) 4. HC CLi
19.
5. H
3. CrO3, H MeO MeO
HO
O O OH
C CH C CH
1. TMS-Cl 3. H3O
2. LiC CH 4. CrO3, H
HO O O
TMS
1. Mg 3. H
20. -H2O
2. CH2O
Br
O OH2
-H 1,2-R: shift
H)
13.2 Syntheses
Solutions • 347
1. NaBD4 OH
SbF5
21. etc.
2. H (- OH)
O D D D
B
deuterium is 'equilibrated' among all
five cyclopentenium carbons
13.3 Mechanisms
+H
1. -H
OH -H2O O O
OH O H)
H H
1. NaBH4 2. +H
2.
2. H2SO4 -H2O
1. H:
O H HO
2. H
-H
H)
O (H 1729 cm-1 O
OH OH
3. +H 1,2-R: H -H H
-H2O H shift
OH
G 9.5 (d)
Ph Ph
Ph Ph
OH +H 1,2-H: -H
4. H
-H2O shift
OH OH O (H O
H
(H
+H 1,2-R: -H
5.
OH -H2O shift
1,2-R: -H
shift
(H
13.3 Mechanisms
OH
H H H (H
+H H H H
6. 1,2-H: ~H E2 H
-H2O H
OH OH OH OH shift -H3O
OH O H OH2 O
O
H
7. +H H
1,2-H: 1,2-H: H
-H2O shift H
OH OH shift,
OH O (H -H O
Ph 1. H3PO4 Ph -H2O EAS

8.
+H -H
CO2H OH2 C
O O O
2. MgCl
-HBr 4. HBr (SN1)
3. H3O
Br
5. Me2NH OH
NMe2
+H +H2O
9. O O O O
O O
HO OH2 O
O H H2O H
O
H O ~H
O taut HO
H H
-H H O
O O OCH3 O
O O O
H) H H
H H
Br Br Me
H Br H Me
10. Me +H Me -H2O +Br
H H Me Br Br H
HO H H Br
Me = H Br
Me H Me Br H Me
OH2 Me
Br (+)
-
Br
Me
+Br H Me H Br
H =
Me Br H
Br Me
13.3 Mechanisms
Solutions • 349
Br Br Br
+H NGP
11.
OH -H2O
+Br
trans- anti- OH2
Br
Br Br
+H Br
SN2
OH2
OH +Br, -H2O
Br
cis- gauche- Br NGP not possible
trans-dibromide
O H H
O O H
OH +H O
12. OH O (H 1,2-R: shift
CO2H O
CO2H CO2H -H
CO2H
CO2H OH
taut CO2H
2. -H2O OH 1. [H]
O OH E1
CO2H
H
+H -H H
13. +H
OH -H2O +H -H
H
H 1,2-H: shift
no energy benefit to -H
1,2-H: shift
pathway (1) - E2 HO D H D O O
14. H2C CD2 + H, taut
-HOH or DOH +
OH OH H D H OH H CD2H H3C D
NOT formed
pathway (2) - H) O D H D O O
+ D 1,2-H: or D: +
pinacol H D H H CD2H DH2C D
H O (H shift, -H
+H, -H2O formed
-- therefore, pathway (2) is favored
D H
-DOH H, taut
15. a. dehydration-tautomerization: A D NOT B
OH O
vs.
D D
pinacol-like: A +H 1,2-D: shift -H
D D B
-H2O
OH O (H
-- therefore, the pinacol-like pathway is favored
13.3 Mechanisms
OH O OH
1. OsO4 3. CrO3, H 4. NaBD4
15. b. D
2. NaHSO3 OH O 5. H D
OH
A
O OH OH H
1,2-H: OH
+H -H
16. OH
shift
OH OH OH O (H O
H
alternatively,
H H
O OH OH
taut taut
OH ~H
(H O (H ~H O
O
Cl Cl
1. Li
17. 3. +2H
+ +
2. O -H2O
aromatic C4H8
carbocation
Cl O PPh
3 Cl
SN2 SN2 - Ph3P O
18. Ph3P: CCl3 Ph3P CCl3 D D
Cl -Cl -HCCl3
O D D
(H
D
D
OH +H OH2 -H2O
19.
H
-H
13.3 Mechanisms
CHAPTER 14
ETHERS
14.1 Reactions
1. HBr 2. TsCl 3. KOAc

1. Br
O Br SN2 Br
SN1 OH OTs OAc
H
Ph HI OH
O I HI
2. +
H SN1-like NR!
Ph -Me2S Ph Me
3. -H S
S S S Ph Me
SN2
H
H
(H
O
O
KOH
4.
-HBr
Br
O H 1. HF F 2. PCC F
5.
SN1 [O] O
OH
H
NaCN / MeOH
6. :N C: N
SN2 C
O
OH
O
O 1. PhLi 2. H Ph
7. Ph
Ph
Ph :Ph E1 Ph
H
O CH OH O OH
3 1. HI 2. [O] 3. - 4. [H]
8. SN2 D
I
1. PhCO3H 2. H +PhOH, -H
9.
SN1
O O OPh
H OH
14.1 Reactions
H Me
O
OMe
H, MeOH
10. H
H
O OH
H
trans-diaxial ring opening determines regioselectivity
F F 2. MgI
F
1. ClCH2COCl
11. F
AlCl3
3. H
Cl F OH
O
Cl
F F
5. 4. base
OH 6. H
F F O
N N N N
N N
Me NH2
Ph Me
1. mCPBA 2.
12. Ph
Ph O Me NHMe
OH
OH O O OH
1. NaOH H
3. ' taut
13.
2. RX
O H
CO2H ' O
14. a.
CO2H
OBn
OBn
O (H
HO CO2H CO2H O
' HO +H -H
14. b.
O -H2O -CO2 CO2H
O CO2H HO2C O
HO2C O
14.1 Reactions
Solutions • 353
'
15.
O O OH
O
' ' taut
16.
OH OH O
' taut
17.
H2N CO2H
[O]
18. H2N S
SH S NH2
HO2C
CO2H
OH
[O] HO
19. HS S
SH
S
OH HO
14.2 Syntheses
1. Br2, hv Br OMe
2. HOMe
1.
SN1
not OMe ( => 100% E2!)
OH
1. mCPBA 2. H3O
2. O
OH
MgBr O OTs
O
1. NBS, ROOR 3. 4. H
3.
2. Mg 5. TsCl
14.2 Syntheses
1. NBS, ROOR 2. H2N NH2

5. I2
4. S
3. OH, H2O [O] S
Br SH
4. H
1. Cl2, ' Li O O
3. 5. PCC
5.
OH [O] H
2. Li 4. H
O 3. H2 / Pd
1. NaBH4 2. H2SO4
6. O
H
-H2O
H
:H
O O 2. thiourea O
7. 1. HCl 3. OH
N Cl N HS N
conjugate addition 4. H
HO2C HO2C HO2C
Br Br SH SH S S
1. NBS, R2O2 2. HBr 3. thiourea 6. Br2
8. Br
CO2H CO2H 4. OH [O]
CO2H 5. H CO2H CO2H
14.3 Mechanisms
O BF3 O BF3 O ~H: H -BF3

1. Ph BF3 Ph PhCH2CHO
Ph Ph H H
O BF
3
CH2 1. LDA
2. (H N 2. H OH
O 2
O
H
H)
3. -H
OH OH OH
O H
-- see 14.3, 6 for an even more impressive polycyclization!
14.3 Mechanisms
Solutions • 355
O O O HO O O O
4. OH
HO
H) OMe
HO O O OH HO O O O
H
HO O O H H
O O O
5. SN2, ~H
O
O H
O O
H H
H
H H H
HO O ~H
~H O
product
O O
H H H
H
H
6.
Me
Me
HO
H O
H
Me Me
H H
-H
Me H Me two 1,2-H: shifts followed by
HO HO two 1,2-R: shifts
H
D D OH H
O D OH O OH
H H D D
7. 1,2-D: shift -H
(H
path (b)
D OH
OH observed
H
H -D
methyl
group determines path (a)
direction of ring not observed
opening
14.3 Mechanisms
R R R O (H O
OH OH OH
2. 1,2-R: R -BF R
8. R' R' R' 3
BF3 shift R' ~H R'
O O BF3
O BF3 O BF3 OH
H
N S N S Cl
9. PhO H -DBN-H PhO H
(H
O N CH2 O N
O O O
O DBN:
Cl
N S N S -Cl
PhO H PhO H
~H
O N O N
O O O
O H
DBN:
DBN H
14.3 Mechanisms
CHAPTER 15
ALDEHYDES AND KETONES
15.1 Reactions
1. CrO3, H
1. OH N
NH2
2. H2NNH2, H
O O
O Br 1. Ph3P O PPh3 3.
2.
2. MeLi
a Wittig ylid a vinyl ether
O
H
O acetal H3O O H3O
3. + H
Ph
O Ph O OH OH
OH
-H2O
4. + opsin-NH2
H O H N opsin
OH O
O
H3O
5. HO Ph
Ph
hemiketal
O
OH
CHO OH OEt
6. 1. PCC 2. H3O H 3. H 3. HOEt, H
OH O O
O O O
Cl 1. KO-t-Bu / t-BuOH 2. HCl
7.
E2 conj. add'n
Cl
O D
1. NaBD4 D OH
3. H2SO4
8.
2. H E1
15.1 Reactions
1. KMnO4 [O] 3. H2 / Pt
9.
O [H]
HO 2. N
H2NNH NH2 HN
NH
NH2 NH
(-H2O) NH2
O
O
O O O
CH 1. HO OH , H 3. Ph3P=CMe2
10. O H
OMe 2. DIBAH, -78o H 4. H3O
O O
O O
CHO 1. Ph3P
11. O H
O2N 2. H3O
O2N
OH O
1. Ph3P=CHOCH3 O CH3 2. H3O O H3O H
12. O
(+H2O) CH3 (-MeOH)
O
1. Ph3P: 3. H OR O
4. H3O
13. RO-CH2-X Ph3P-CHOR
2. MeLi (-HOR) H
OMe OMe O
H H H
1. CH2I2 2. H3O H 3. Ph3P=CHC=CH2
14. O O
Zn (Cu) H
H H H
OMe OMe O
H O OH
1. H3O 2. EtMgI
15. N NH2 H
3. H3O
PhO OPh O
1. H3O 2. H2NOH Ph
16. N
Ph Me Ph Me OH
(-2 PhOH) (-H2O) Me
15.1 Reactions
Solutions • 359
OH
O O O OH
CHO H3O OH H
17.
OH
O
O 1. Ph3P O 3. H O O
O O O 4. H3O
18. Br PPh3
2. n-BuLi
acetal H hemiacetal H
O O OH O O O
H3O H3O H3O
19. + 2
O O O O H H O O etc. H H
H
1. H3O, Hg2- 2. H2NNH2 W-K

20. C CH
+H2O, taut OH N NH
O 2
OH O
Br 2. ,H
1. Br2, H2O O O
21.
3. Li
Li
OH O O
5. H3O 4. O
HO O
22. 1. HONO2, H2SO4 2. H2NOH, H

N OH
CHO CHO
O O2N O O2N O
note position of EAS!
H3O Et O H3O
23. Et O Et HO
O OH O
HO HO
O O O OH
H OH O 1,2-H: shift ~H O
O
24.
OH H
O H OH O
15.1 Reactions
D
CHO H
C D CHD2
1. D2NND2, OD, D2O 2. HI
25. + MeI
OMe W-K SN2-like
OMe OH
OH OH OH
CO2H CN CO2H
O O Ph O OH O
26. H3O HO CN
OH H OH + HCN +
OH Ph H Ph H
OH
OH OH
OH
O O
H3O H3O
27.
O HO HO
OH O
O O 1715 cm-1 O O
MeOH, H
28. H O H
H
H H 4.9 3.4
G2.2 2.8
O O OMe HO HO O OMe HO OMe HO O O

HO OH
H3O OH -H2O
29.
-HOMe
O OH O
H3O
30. +
O H H
OH
NH2
H 1. H 2. H2 / Pt
31. CO2H
-H2O N CO2H N CO2H
O
H
O O HO OH
O
OH OH
1. LiAlH4
32. + EtOH + MeOH
MeO 2. H3O
O
MeO
15.1 Reactions
Solutions • 361
O O O O O O HO
1,2-H: shift ~H O
33.
OH H H
H H OH H H intra-Cannizzaro H OH H O
O
O OH O
1. LiAlH4 -H2O
34. O EtOH + OH
2. H3O
O
HO O HO O
HO O HO OH
O
O H3O OH
35. +
O O
F F
OH
O N
H2NOH
36.
O N
OH
O
37. H3O
O O O O n H H
acetal
OH
OH OH O OH OH N OH OH
N
1. NH2OH, H 2. Ac2O C
38. H H
OH OH OH -H2O
OH OH OH OH OH OH
a hexose OH OH
an unstable cyanohydrin
H
OH OH O -HCN
a pentose
15.1 Reactions
O O
Me Me O
N N
mild acid
39. N N + H H
N N
H H
O O
O acetal OH
O OH
H H H H H
O OH2 O
N N mild acid N ~H N
40. Me2N S NHMe NH2Me
OH2
H NO2 H NO2 H NO2
-H
H H
O -MeNH2
N O -H N O (H
Me2N S
NO2 NO2
N N
N NH2 O N
NH2
CO2H N
H3O H3O
41.
N +
N N N
S H H H
H S S
O O
1. PCC 2. LiMe2Cu
42. OH
[O] H H
3. H3O
H H
N N
O O OH O
O H3O
43. +
H H
O
acetal OH
F F
H
NH2 N O
[O] H3O
44. O2C CO2 O2C CO2 HO2C CO2H + NH4
15.1 Reactions
Solutions • 363
O
O
O ketal H3O
45. OH
OH
HO HO
OH O OH
Me
1. PCC 2. MeLi
46.
EtO EtO 3. H3O
EtO EtO O
O N O
N
1. HC CNa / THF
47. OH
O 2. H2 / Lindlar catalyst
N N
H H
O O
note: addition to ketone, not amide carbonyls
O O
1. HS(CH2)3SH, H S Ph 3. EtI S Ph 4. H3O
48. a. Ph H
SN2 Et Ph
2. MeLi S S
S O
S 1. n-BuLi
3. H3O
b.
2. CH3(CH2)9Br S H
S
SN2
S
O O
1. HS SH, H S 3. O
c. S
H
2. NaNH2 S
O
O
or 4. H3O
-H2O HO
15.1 Reactions
H H
H2N N N H2N N N
+H2O
N N
49. H N H N
-H2O H
O N O HN
+
nitrogen analog of H O
an acetal
H
O formaldehyde O
HN CO2H HN CO2H
CO2H CO2H
tetrahydrofolic acid
N N
N N
N N
NH2 H
50.
Cl O -H2O N
Cl
XanaxTM - (anxiolytic)
15.2 Syntheses
1. H3O O HO CN HO CO2H
3. CN, HCN 4. H3O
1.
2. CrO3, H
OH O NH NH2
1. Hg(OAc)2, H2O 3. KMnO4 4. NH3 5. H2 / Pt
2. NaBH4 -H2O
OCH3 OH OH
O 3. NaBD4
1. HI 2. Cr2O72-
2.
H H D
-CH3I 4. H
3. H2NNH2, OH
W-K
15.2 Syntheses
Solutions • 365
1. HCN, CN OH 2. H3O
3. O 4. H2 / Pd
CO2H CO2H
CN 3. H2SO4 (-H2O)
O 1. NaBD4 OH Cl
3. SOCl2
4.
D SNi - ret D
2. H
O OH O
1. HCN, CN CO2H 3. CrO3, H
H CO2H
5.
2. H3O
O O O O
1. OH 2. PCC 3. ethylene glycol, H
6. Ph Cl OH O O
SN2 Ph Ph Ph
[O] (1 equiv)
H O
(aldehyde more reactive than ketone)
OH
1. LiAlH4
OH
2. H
O O OH O
1. NaBH4
7. OMe OMe
2. H
OH O
H2 / Pd
OMe
O O 1. LiAlH4 OH
2. H
7. (cont.) OMe OH
3. H2 / Pd
O
1. ethylene glycol, H (protect ketone)
OH
2. LiAlH4
3. H3O
O
.
1. BH3 THF OH 3. PCC H 4. Ph3P
8.
2. H2O2, OH
O O OH
1. H3O 2. H O MeOH, H O
9.
conj. add'n OH OMe
15.2 Syntheses
O
1. MeOH, H 2. PCC
10. OH OH H
MeO OMe MeO OMe
O
Ph3P
4. H3O 3.
MeO OMe
O
O
H 1. HO OH, H
H MgBr 3.
11. O O HO
Br O 2. Mg 4. H3O
CHO
NR2
1. H2NNR2 NR2 2. n-BuLi NR2 3. PhCHO N
12. O N N
H
O
O OH Ph
4. H3O
Ph
CHO O O CHO
1. HO OH 2. KMnO4, OH 3. CrO3, H
13. O O
H or 2. a. OsO4
HO 4. H3O O
b. NaHSO3
OH O
O O
H 1. LiMe2Cu H 2. H2NNH2, OH
14.
W-K
OH O HO
C CH
1. ethylene glycol, H 3. HC CLi

15.
O
2. K2Cr2O7 4. H3O
O O
O
15.2 Syntheses
Solutions • 367
O OH Et
1. EtMgBr 3. HBr
H Et Li
16.
2. H 4. Li O
5. R
Ph Et Ph Et Ph
-H2O 6. H3O
Ph OH Ph
R R
OH O O
1. NBS, R2O2 3. PCC [O] 4. Me2CuLi
17.
2. OH (SN2) 5. H
1. DIBAH, -780 3. Ph3P=CH2

18. CO2Me CHO
CO2Me 2. H
CHO
O
1. PCC 2. O3
19. H O
3. Zn, H H
OH O O
H
OH O O
1. Me3SiCl TMS 2. Ph3P TMS
20.
Br Br 3. MeLi PPh3
O
O
CO2H 5. H (deprotect) TMS 4.
H
6. CrO3, H
O
SH SH H2 / Ra-Ni
21. Ph Ph S S PhCH2Ph
H
Ph Ph
O
1. HNMe2 2. O3
22. O NMe2 H
-H2O N
3. Zn, H O
15.2 Syntheses
15.3 Mechanisms
H OH2 (H
O O HO OH2 O O
H2O O H
+H +H2O ~H -H2O -H
1.
= 18O
O
+H ~H -H H
2.
N N OH2 N OH2 N O (H NH2
H H H
H H
H H H
3. ~H
O O O OH2 O OH2 CA of a O OH
hemicetal
H
O -H
OH H HO O (H
H
O H OH -H O H OH
4.
H conj. add'n NH2 H taut HN H N N
NH2 NH2 H H H
H2N NH2
-H -H2O ~H
OH2
N N N N
N N
H H (H
H H
Cl Cl
OMe -Cl OMe
5.
O OMe OMe
O
H O
Me Me
O O
Me Me
O O
OH O H) OMe
H
O O OH O OH2 O
~H -H2O R R
6. R R R R R R
H2N HN
H2N OH N O
OH OH H O
H
H) R R R R
R R R ~H
-H3O R ~H
N O OH N O
N O N O OH2 H O H
H
15.3 Mechanisms
Solutions • 369
H
H
O O
7. O OH
O O
OH OH OH
OH OH
O O
-H
O O (H
O H O H O (H
O H O H O H
8. O O O
OH OH OH
OH OH O OH
O
HO
OH O H
OH
O -H
OH OH H3O
HO hydrolysis OH
OH
OH
OH
O O
O O O
H S O
9. C S + S
H
H
O O H O H O H OH
10. -H
(H
Cl Cl
Cl Cl
O O O O OH
H H
O O O O
11. ~H
H O H O O O
H2O H O
H2O H
O O H)
O
-H
O H
H + O + H)
taut O
15.3 Mechanisms
OH OH OH OH
H H H
12. OH2
O O O
O
~H
OH2
OH2 OH OH
(H
-H3O ~H -MeOH
OH
O
O OH O H
O O O
N N 1,2-R: shift
13. + N2
CH2 N N
Ph Ph Ph Ph
N N N N
14. OH2
N N OH2
NHPh NHPh
Ph H Ph
H ~H
Ph
(H NHPh H
O O N
-H
+ OH
H H NHPh NHPh
H H Me
Me 1. mCPBA O Me
2. O rotate
15. PPh3
Me Me PPh3
H Me H
PPh3
Me PPh3
H Me H
-OPPh3 O O
Me Me H
H
Me H Me H
O O
O P(OMe)3 -OP(OMe)3
16. P(OMe)3
:P(OMe)3
15.3 Mechanisms
Solutions • 371
HO
OH HO HO
O OH2 :NH2R
17. +H O -H2O O
OH OH
OH OH OH OH
HO HO H)
NHR NHR
O -H O
OH OH OH OH
O OH OH
+H HO
EAS
18. OH OH
H)
-H
HO
+H
HO OH OH HO OH
-H, EAS -H2O
O
Et O Et
19. ~H
H
N H taut N
O
H2N H2 H
H
Et Et (H Et Et
-H - OH ~H
N N N H N
OH O
1. -H2 2. SN2 O O
20. a. O
O O Williamson
Cl (H :H Cl Cl Cl MOM
ether synthesis
b. 3.
O O O O HO OH
H
OH H +
OH H2O
O O
H3O +H2O
+ MeOH H2C O Me
H H OH -H
15.3 Mechanisms
Br Br Br OH2
H3O OH2
21. Br
H
O O (H
-HBr -H
Br
O H
HS Me O Me O OH
S (H SMe
(H ~H ~H
22. SMe
conj. add'n taut
O O OH OH
HO H O
C N -HCN H H
23.
NC H
O + CN
OH O CN O
(H :C N
:Me
O OEt
O OEt H2O OEt
1. MeLi 2. H -H2O
24.
1,2-add'n
O O (H OH2
-H OEt OEt OEt
~H +H2O
-HOEt H
OH2
H Et Et Et H
H
CHO O
EtNH2 CHO N ~H H N H HO N
25. H O
-H2O (H
Et Et Et
N N H2O N ~H
-H -H2O
H)
OMe OMe H
OMe
Ph Ph Ph Ph
N 2. D-A N 3. H N -H N
26.
O -MeOH
Ph O Ph O Ph O Ph
TMS TMS (H
15.3 Mechanisms
Solutions • 373
O O Cl O
Cl2C
OH ~H Cl C
27. a. Cl2C (H Cl2C: H
D-elim H
Cl
HO
O OH O O Cl O
C C H) C SN2 -Cl
H 2. H H -HCl O
H
Me O O
N H -Cl Me O P Cl +Cl Me O P Cl Me H
b. Me N C Cl N C N C
O Me H Me H Cl Me Cl
O2PCl2
Cl Cl
Cl
O P Cl
Cl
OH OH OH Cl
H Me (H
1. -H NMe2
C N NMe2
Cl Me
Cl
OH OH -Cl
CHO
2. H3O NMe2
hydrolysis
O
O OH H OH O
28. Ph H ~H O
Ph H Ph Ph H
CN CN Ph Ph
:C N CN
O OH O OH ~H
- CN
Ph H
Ph Ph
CN Ph
O H
NH H H N OH ~H N OH2
29. H
OH OH OH
-H2O
N N N
-H (H EAS
OH OH OH
15.3 Mechanisms
HO HO H HO H
OH OH H
O +H O E- O
30. OH
bottom-side
OH OH hemiacetal OH OH attack OH OH
HO HO H
O -H top-side
O
D- attack
OH OH
OH OH OH OH
NH2 H NH2 H OH2 NH2 H

H OH2
N NH2 +H2O N
N NH HO2C NH2
31. HO2C HO2C
NH2 NH2 NH2
NH2 H
NH2 O O (H
-H N ~H
NH2 + HO2C NH2
HO2C H2N NH2 H
NH2
Ph Ph R R
H) O O
O O H N HN
O O Ph -H Ph
32. O
:NH2R O O H
H CO2H CO2H CO2H
O
HO NHR H H
N
R H
+H +H2O H2O:
O
O
-H Ph H -H
O Ph
CO2H O
OH CO2H
OH2
R N Ph (H Ph
R N R N
+H Ph -H3O
OH O
OH O OH O
CO2H
CO2H CO2H
OH2 OH2
O O O
+H H ~H
33. RO2C H H
H H
O
PO3R'
O (H
H
OH O
RO2C O
(CH2)nCH3 -H H
O + H H
PO3R'
15.3 Mechanisms
Solutions • 375
O H
OH OH
O 1,2-R: shift
34. Ph Ph Ph Ph O Ph O RCO2H
O O
O O Ph R
R H +
O
R O (H H (H
O O
-H
Ph Ph
Ph O Ph O
O O O O O O O OH
1,2-R: ~H
35. a. Ph Ph HO Ph shift HO Ph O Ph
Ph Ph Ph
OH
OH
OH O O
O
1. 1,2-R: 2. H
b. O O OH
O O shift, ~H OH OH
O O O
1. O O 2. H O
1,2-R:
c. O OH
Ph Ph shift
Ph Ph
Ph Ph Ph Ph
O OH OH OH OH
+H 1,2-R: -H
36. R
shift
(H R
R R R R R R R R
O (H :B O OH OH OH OH
+H 1,2-R: -H
37.
-HOTs shift (H
OTs
H)
+H 1,2-R: -H
38.
shift
O HO HO HO HO
15.3 Mechanisms
+H 1,2-R:
39.
shift
O HO HO HO
-H 1,2-R:
HO shift
H) HO
OH
.
O
. .
O O
40.
O . +H
HO . HO . 1,2-R:
.
shift
..
O
HO
O . -H
HO
O
H)
1,2-R:
shift
HO
. .
HO OH
O
O
O O OR H
O RO
H) Cl OR
-HCl
41. RO H) OR
O
H
H) OR OR
Br RO O
O O
-HBr OR -Br
42. Br CO2R
Br Br
(H
OR
OMe
H
+H 1,2-R: -H
43.
-MeOH shift (H
O NMe2 O NMe2 O O
NMe2 NMe2
A
15.3 Mechanisms
Solutions • 377
OH2 OH2
43. (cont.)
NMe2 O O
O
NMe2 NMe2 ~H
A
O
NMe2 -H
+ H
NMe2
OH O
H O (H
R R H
N R R
N N N
-Br ~H
44. OH2 O (H
Br Br Br OH2 Br Br
H
R
(H N
-H
N R -H N R -Br CHO
CHO CHO Br
O O O
CO2R CO2R CO2R
+H ~H
45. N H N OH NH N OH2
O 2 NH2
O H NH2 O S O S
CO2H CO2H
HS H
CO2H -H2O
O O
CO2R O
CO2R CO2R
H -H H
N N
N N (H N
NH2
CO2H CO2H
O S O S
O S CO2H
46. H +H ~H
N H2N: NH2 NH
O N N
H H OH H OH2
H HO HO
HO HO -H2O
HO
OH
NH NH
-H
N NH
N N
H H
HO
HO HO
OH OH HO
15.3 Mechanisms
H
S SH SH2 O H
Br Br +H3O Br Br ~H Br Br -H Br Br
47.
Br Br Br OH2 Br Br O Br -H2S Br Br
OH2 (H
H) OH2
HO OH HO OH +H3O
Br Br -H Br Br
Br Br Br Br
O H OH H) O H
H OH ~H O
48.
O O O O
O H
O
O H
-H
1,2-H:
O shift
OH
2
O
O
1. +H !! O
49.
-H2O
OH (H
OO :B
O O O O
O O
2. +H2O
H) OH2
OH -H
15.3 Mechanisms
CHAPTER 16
CARBOXYLIC ACIDS
16.1 Reactions
CO2H
N KMnO4, H
1.
N N
1. OH O 2. -Me2O O
2. Ph CO2H Ph O Ph Me
O BF4 SN2
O
O O OH O
1. NaBH4
3. OH OH
2. H
O O
Ph O Ph
4. 1. H3O H 2. CrO3, H OH
O O 3
Ph acetal
O
E O O
1. OH 2. ' 3. LiAlH4
5. J D
OH O O
Br SN2 OH
Br 4. H3O OH
OH O O
1. OH 3. BH3
6.
O OH
2. CO2H 4. H3O
(conj. add'n)
OH
1. NaCN 2. PhMgX 3. H3O

7. PhCH2Cl Ph C N Ph C N Ph
Ph
SN2
Ph O
O
1. SOCl2 N O
8. C 2. DIBAH, -780 N 3. H3O
NH2 C
-H2O H H
16.1 Reactions
1. (XS) PhLi 2. H -H2O

9.
CO2H O OH O
O HO Ph
Ph Ph
O O 1. LiAlH4 OH
10. + OH
OH
CO2H 2. H
11. 1. HCN, CN 2. H3O 3. BH3

O conj. add'n O O O
CN CO2H 4. H3O
OH
O
O Et
CO2H O Et
1. EtLi Ph NMe2 2. H
12. Ph NMe2 Ph NMe2
Ph -H2O
Ph Ph
1. H3O O O
CO2H 2. PCC
13. CO2H
conj. add'n HO [O] H OH
H)
O OH O O
taut
+ CO2
H H H O
labile carboxyl
CO2H 1. [O] CO2H
14. D 2. -CO2
CO2H E
CO2H CO2H
HO O O
N N N
CO2H CO2H
3. CrO3, H 4. '
15.
[O] -CO2
H
OH O O
16.1 Reactions
Solutions • 381
OH O OMe OMe
CO2H CO2 CO2 CO2H
1. OH (2 equiv) 2. MeI (1 equiv) 3. H
16.
SN2
more stable anion,
therefore, less reactive
CH2CH2N(CH3)2 COO
CH3NHSO2CH2 H CH2
17. a salt!
CH2
N COOH
H
16.2 Syntheses
CO2H
1. LiAlH4 OH 3. TsCl
1. CN 5. H O CO2H
3
2. H 4. KCN (SN2)
1. NBS, ROOR O O
3. NaCN 4. H3O
2.
2. HBr, ROOR Br Br SN2 CN CN HO OH
O OH O O O O
1. H3O 2. CrO3, H '
3. OH OH OH
conj. add'n Jones reagent -CO2
O O
O O
1. HO OH , H 3. CO2
4.
Cl 2. Mg 4. H3O
MgCl CO2H
O
1.
5. Cl O 2. H2NNH2, OH
AlCl3 W-K
CO2H CN
3. HBr
5. H3O 4. KCN
16.2 Syntheses
1. PCC n-Pr 3. HCl

6. OH n-Pr
2. n-PrLi O Cl
n-Pr 5. NaOH, H2O n-Pr 4. NaCN
CO2Na CN
CO2H O
1. H3O O O 3. ' (-CO2) O 4. BH3 O
7. OH
2. CrO3, H HO2C OH CO2H 5. H
HO
8. Ph Br 1. KCN (SN2) 2. DIBAH, -78o N 3. H3O O

Ph CN Ph Ph
H hydrolysis H
N NH2 N N
H
CN 1. DIBAH, -78o CHO CHO
9. O 3. NH2NH2, H
O
CN 2. H3O CHO -H2O -H2O
O O
1. KMnO4, H HO2C CO2H 2. ' HO OH

10.
CO2H CO2H -2 CO2
O O
1. LiAlH4 3. SOCl2 or HCl 5. R'MgX

11. RCO2H RCH2OH RCH2-CN RCH2COR'
2. H3O 4. NaCN 6. H3O
5. H3O
or 6. R'Li
7. H3O
O O 1. BH3 O O OH
3. HO 5. PhMgBr
12.
OH , H
O O O
OH OH Ph
2. H3O 4. PCC H 6. H3O
1. H2SO4 (E2) O
Br NC 4. H3O
13. 3. (XS) KCN HO
OH
Br OH
2. Br2, CCl4 CN
O
16.2 Syntheses
Solutions • 383
O O O OH
1. Cl 2. CH3Cl 3. H2 / Ni
14.
AlCl3 AlCl3 hydrogenation
CO2H a benzylic alcohol

4. KMnO4, H
hydrogenolysis
CO2H
1. NaNH2 (1 equiv) 3. KMnO4, H

15. HC CH HC C HO
2. n-pentyl chloride
O
OH O O OH
1. NaH (2 equiv) 2. Et-I 3. H

16.
OH O (1 equiv) O O
Et Et
more reactive anion
16.3 Mechanisms
O O O
H
+H O
1. CO2H -H
O (H O
H
H)
OH O O
CO2H OH
taut C
2. O '
n-pentyl -CO2
n-pentyl
O n-pentyl
tautomerization to E-ketocarboxylic acid facilitates decarboxylation
O
H)O O
HO Cl Cl O2C Cl CO2
+OH -H -Cl
3.
Cl Cl Cl Cl
16.3 Mechanisms
+H +CO +H2O O -H
4. C O CO2H
O (H
C O OH2 H
O OH H)
HO OH O
HO ~H HO
5. R OH R N
H2N N
H R H
O O
-H2O HO -H
R N R N
(H
O O H
OH OH2
+H ~H
6. O H O
O
CO2H H
O (H O H O
O O O
Me Me -H2O
-H +MeOH Me
O O O
O O O
O O
NH2
N O -CO2 taut
7. N OH N O
R CO2H (H
-H2O R O
R H R H
O
N O H2N H3O
dimerize hydrolysis
+
N -2 H2O NH2 O -RCHO
O H
+H OH ~H OH2 R' H
8. R'HN -H2O
R H R'N N
H R R H R
H
R'NH2
R' O N C
R' H
N H3O N
H OH C N
hydrolysis H R
R
16.3 Mechanisms
Solutions • 385
O
CO2H (H
+H O -H
9. HO CO2H H2O CO2H
-CO2 CO2H
O O O
O O (H
O CO2H O O H
H2N CHR 1. -CO2
10. O N R N R
-H2O 2. taut
O O O -RCHO H2O
O
O O O
-H N -H2O
blue dye O + H2N
(H
O O O
O
H O2C O2C
11. R N O H) OH OH R N H
+
H H
NH2 NH2
O O
NADH NAD+
O O O O CO2
-CO2 O -GDP
12. O CO2 O P O P
CO2 O
OH O PO3H
GTP
R' R' R'

R'
-H S -CO2 S
13. R N
S S R N R N
R N
O (H
(H CO2 O
OH O
O H OH H)
R' OH
R'
O
-H S
H
+ S R N
R N
(H
O
H
16.3 Mechanisms
O
R'
H
O H N
H N R'
-H2O -CO2 H
14. PLP + histidine R OH
R OH
N
R' = N H
NH H H
N H
H N
R' +H
R OH
H3O
PLP + histamine
imine hydrolysis N
H
O O H
O intermolecular hydrogen bonding forms a
15. 2 OH O tight dimeric complex in nonpolar solvents
H O
MW = 60 MW = 120
16.3 Mechanisms
CHAPTER 17
CARBOXYLIC ACID DERIVATIVES
17.1 Reactions
O O
OEt Et2NH (1 equiv)
1. OEt
Cl Et2N
-HCl
more O O
reactive than ester
O O O O
2. O + MeNH2 Me +
N OH
H
O O
O (XS) EtOH, H OEt

3. + OH
transesterification
O
O O
-HCl -HCl O O
4. +
OH OH Cl Cl HO O Cl
O O 1. PCl3 O O 2. LiAlH(O-t-Bu)3 O O
5.
HO OH (or SOCl2) Cl Cl 3. H H H
O
H3O
6. CO2H +
N NH2
hydrolysis
O O
Ph MgBr MgBr
1. 1. or
7. O
OH
- OPh 2. H3O -H2O
not isolable
O O
MeOH, H Me MeOH, H MeO OMe
O O
8.
NAS CO2H O O
O
O O
1. LiAlH4 3. O
9.
2. H NAS
CO2H OH O O
17.1 Reactions
O
O
O OH, H2O
10. HO
saponification O
H D
H NH2
Bn N S S
OH, H2O CO2 O2C
11. +
O N N
O H
CO2H CO2
O O
Et
Et OR H2N - 2 HOR NH
12. + O Et
Et OR H2N
O N O
O H
O O
N N N
O 1. OH 3. CrO3, H
13. PhCO2H + OH
2. H + 4. '(-CO2)
MeOH
O Ph OH O
O O
OH OH
SCoA NH
NH2CH2CO2H CO2
14. A B
HO OH -HSCoA
H HO OH
H
N N N
1. H3O 2. CH2N2
15.
N N (diazomethane) N
H H
O O O O
O OH O OCH3
OH O OH OH
1. H3O O 2. PhMgCl or
OEt O Ph Ph
16.
-HOEt 3. H HO Ph -H2O
a J-lactone Ph
17.1 Reactions
Solutions • 389
O O
O 1. LiAlH4 OH O
17. =
2. H OH HO OH
O O
O O
H O
N 1. Cl Cl N
18. Cl 2. LiAlH4
N N N N N
N -HCl
H -HCl H 3. H
protein protein
O
OH O O
19. O P F P
-HF O Me
Me
O O
H CO2H H H
Cl NEt2
N 1. SOCl2 N 2. HNEt2 N
20.
-HCl
N N N
H H H
lysergic acid diethylamide
O O
O O
-HCl
21. S Cl + H2N NH S N N
O H H
n-Bu O
tosyl chloride more nucleophilic nitrogen
O O
OH, H2O O
22. NH + NH3
S SO3
O O
O O
O
O
23. HO NH2 HO N + HOAc
1 equiv H
O OH O
~H taut
24. H2C C O H2C C H2C
NH2Ph NHPh NHPh
:NH2Ph
17.1 Reactions
H
25. dimethyl phthalate + HO OH O
transesterification
O
O O
O
O O
O O
O
a polyester
O O
O
26. HO OH + Cl Cl
- n HCl
O O O O
O O
O
O O
O OH O
O
H O N Me O N Me
OH C O N Me
H
N taut
~H
27. Me
O
O
O O
1. Li LiCu 3. Ph Cl O
Ph
28. O O
2. CuI 2 4. H3O
Cl Gilman reagent
O
O NHMe Me
1. 2O N
29. 2. LiAlH4
F3C OH O
- 3. H
O Me
O N
F3C
17.1 Reactions
Solutions • 391
HO O
O H2N OH
O O
:NH3 O OH
30. NH2 + OH
O
O OH
C CH C CH
1. OH, H2O
31.
2. H3O
+ HOAc + NH3OH
N O
OH
O
MeO 1. LiAlH4 MeO
N N
32. H H
HO 2. H3O HO
O
H2N O O
H2N N
S 1. H2O, OH H S
O 2. SOCl2 O
33. N N 3. O N N
CF3 CF3
H2N NH2
F HO
S O
O
HO OH
HO O
O
H3O
34.
O
F
F
O + HSCH2F +
O OH
F
F
O O
CO2Na 1. PhLi 2. H3O
35. O
MeO Ph -H2O Ph
MeO
17.1 Reactions
O O
O HN N O HN N
N H N
S H3O N H HO S
36. N N N
O Me N + O
N
Me OEt H OEt
O
O O
1. base O NH2
-Br 2.
37. O N
Br CO2H SN2 H
OH
Br
O O
OH O
NH NH NH2
38. O2C NH2 ~H
O2C N
~H H
O
O O
H NH
N etc.
O2C N N
H H
O
O O O
NH 1. Cl OEt N OEt 2. Et2NH N NEt2
39.
N N N
-HCl -HOEt
O OEt O OH H
N N N
H3O -CO2 N
40. N N
Cl Cl Cl
O H H
NH N Ph N Ph
O
1. Ph OEt 2. LiAlH4
41.
-HOEt 3. H
Cl Cl Cl
Cl Cl Cl
17.1 Reactions
Solutions • 393
H2N S
OMe OMe O N OMe O H
CO2H O N
1. SOCl2 Cl 2. CO2H S
42.
OMe OMe -HCl OMe N
O
CO2H
O CF3 O
N OH CF3
H
H3O H3N
43. +
CF3
CO2H
O N CF3
H H3N
O
CO2H
O CO2H H3N
H3O OH
44. N
H2N H OMe + + MeOH
H3N CO2H Ph
O
Ph aspartic acid phenylalanine
O Cl CO2H
N N CO2H N
N N
exhaustive Cl
45. N + N
N hydrolysis H
N N
O O O
H
a carbinolamine
N
-CO2 H
N N CO2H Cl
N N
+ +
H H2N
N N
O
O
1. NaBH4 OH HO O O O
H
46. CO2H +
2. H - 2 H2O O O
O OH HO
OH O OH OH OH OH OH
1. HCN 2. H3O Cl 4. LiAlH(t-BuO)3 HO
47. H CN OH
CN 3. SOCl2 OH 5. H HO
OH OH OH OH OH O
a tetrose a cyanohydrin O
H
a pentose
17.1 Reactions
O R
O R
48. a. -HCl
O Cl :NH2 CO2H
O N CO2H
H
O R O (H
O R O
+H -H
b. N N
O N H OH O N OH
H H
O R' H
H H O R' +
R O O R O
N -CO2
H) N
H2N H OH O N H OH
O R' H
O R'
H
O OH
49. SCoA +
-HSCoA
CO2 NMe3 transesterification
O
CO2
O
NMe3
CH3(CH2)14CO2H, H
50. O
-H2O
HO CH3(CH2)14 O
O O
HN H3O HO
51. NH4 + CO2 +
O N H3N
H
O O O OH O
1. ATP 2. H2N
52. P OH
OH O OR' N
O -HPO4R' (AMP) H
NAS O
2. HSCoA
-HPO4R' S CoA
17.1 Reactions
Solutions • 395
+H -H
53. O O HO-glucose
transesterification O +
O O O O glucose O
H glucose H) H
N O 1. SOCl2 N O N O
3. SOCl2 N N
54. N N N N
2. NH3
O
F CO2H F F C
N
O O NH2 O
OH O N OH O O O
N N
S H3O OH taut OH
55. H H3N +
N S NHMe
S NHMe
SO3H
O O SO3H
OH
H OH O
NHMe NHMe NHMe -CO2
H taut
SO3H SO3H SO3H
OH
H3O O
MeNH3 + (aldehyde gives a positive Tollens' test)
H
SO3H
17.2 Syntheses
O 1. H3O
-HOAc 3. Li 5. MeOH, H
1. O
2. PCl3 Cl 4. CO2 CO2 MeO O
O O
1. H2O, OH O
3. LiAlH(O-t-Bu)3
2. R NH2 R Cl R H
2. SOCl2 4. H
1. H3O O 2. SOCl2 O or 2. MeLi (2 equiv) O

R OH R Me R OH
3. LiMe2Cu 3. H, -H2O
O O
NH 1. LiAlH4 NH 3. Ac2O N
3.
2. H -HOAc
17.2 Syntheses
4.
.
1. BH3 THF
3. CrO3, H
[O] 5. AlCl3, -HCl
2. H2O2, OH O Cl O F-C acylation

H 4. PCl3
O
CO2H 1. D-A 2. Ac2O, or

5. CO2H O
C
C '
H2SO4, -H2O
HO2C O
CO2H
O
HO H 1. BH3 HO H H OH
6.
O O 2. H O O
HO O
or 1. OH 2. a. LiAlH4
H CO2H O b. H3O
O O
1. H3O 3. LiAlH(O-t-Bu)3 O O
5. HO OH
7. Ph NH2 Ph
Ph Cl Ph H O
2. SOCl2 4. H H
O O O
1. AgNO3, EtOH 2. MeLi O O 3. H
8. H OH
(Tollens' reagent) Me
(2 equiv) -H2O
O O
O
NHCH3 Ac2O NCH3 NCH3
9. Ph Cl , AlCl3
F-C acylation O
Cl Cl Cl
CH3 H
O
N O NCH3
Cl Cl
O Cl O H2O, OH
Cl Cl
-HCl, NAS
CH3 H3C
O O
N N
NH2
NH3 (SN2) O H
Cl Cl N
-HCl -H2O
17.2 Syntheses
Solutions • 397
O O HO
CO2H 1. ' (-CO2) 2. NaBH4 H
10. O
CO2H CO2H CO2H -H2O
3. H
O
O 1. LiAlH4
2. H 4. KCN (SN2) 6. CH2N2
O O
11. Ph OMe Ph OTs Ph Ph
3. TsCl 5. H3O -N2
OH OCH3
O O
NaO N F3C F
O N
12.
O nucleophilic aromatic subst'n O
F3C
OH, H2O
O
O N OEt Cl OEt O NH2
H
O
F3C F3C
1. LiAlH4
H H :H H
H H
N -EtO N H +H: H +AlH3 N
N
OEt H
O O O OAlH3
H
O N H :H
CH3 +H: N - OAlH3 2-
CH2
F3C 2. H3O
O
1. NBS Br 2. Li O2C 4. EtOH, H EtO
13. Ph N N N N
peroxide Ph Ph Ph
3. CO2
O O NMe2 HO NMe2 Cl NMe2

2. a. NaBH4
1. Me2NH b. H 3. PCl3
14.
conj. add'n
Me O
O N O NMe2
H F3C O
5. Cl OEt 4.
F3C F3C
6. OH, H2O SN2
-CO2
(continued on next page)
17.2 Syntheses
14. (cont.) Mechanism for step 5:

Me
O NMe2 CH3 Cl
-Cl +Cl O N OEt
CH3
N
F3C Cl OEt NAS -CH3Cl O
F3C
EtO O
O
O
Et O Br
1. Cl 2. NBS, R2O2
15. Et
AlCl3 3. H2 / Ni (or W-K)
HO2C 5. CO2 BrMg 4. Mg
6. H
O O O O
1. KCN, HCN 2. H3O 3. BH3

16. OH
CN CO2H 4. H
O 5. HO
O O O OH ,
7. MeLi 6. PCC O
H
OH 8. H3O O OH
H
O
O O
1. KMnO4, H HO 2. '
17. OH OH
O O -CO2
O
O 3. OH OH, H
OH
H O 4. LiAlH4 OH
O O
O
OH
5. H3O
O O
1. Li
Cl 2. CO2 CO2H
4. SOCl2 Cl 5. Et2NH NEt2
18.
3. H -HCl
O H
HO NH2 O NH2 O N Ac
1. KOH Me Me
19. 3. 2O
more
2. MeI nucleophilic -HOAc
N N N
H H than NAS H
17.2 Syntheses
Solutions • 399
Br CN
O H2 / Pt O (XS) HBr (XS) NaCN / DMF
20.
high pressure/temp SN2
Br O CN
1. H3O 2 . SOCl2 Cl
CN Cl
O B
H2 / Ni
CN H2N
NH2
or 1. LiAlH4
C
2. H
21. Poly(vinyl alcohol). Vinyl alcohol is unstable and rapidly tautomerizes to acetaldehyde:
O
taut
OH H
1. H
OAc
OAc OAc OAc OAc OAc OAc etc.
HOAc,
H, Hg2+
2. H3O
HC CH
OH OH OH or saponification
OAc OAc OAc
poly(vinyl alcohol) poly(vinyl acetate)
HO O CH3O
1. NaOH 2. CH3-I c.
22. a. O O O
N N SN2 N
HO HO HO
codeine 1. H2 / Pd
morphine
2. PCC
O CH3O
O O
b. O
(XS) O
O O
NAS O N N
O O
heroin hydrocodone
CH3O CH3O CH3O CH3O
~H ~H +H2O
d. O O O O
taut taut -H
N N N N
H (H OH
H)
O O O O
H H
codeinone neopinone oxycodone
17.2 Syntheses
17.3 Mechanisms
H
O O HO OH2 HO O (H H) O OH
OH2
+H O O ~H O H O H
1. O =
-H -H
O O
-label appears in both carboxyl
oxygens - but NOT in alcohol oxygen OH + OH
HO HO
O O
O O
1. (XS) RMgX
2. O Cl O R O + R
R R R
:R R
:R
:R
2. H 2. H
t-BuOH R3COH
OH
O -H2O O
3. D-lactone does NOT form because of ring strain
O
OH
O O
O
-H2O O -H2O O
= O
intermolecular OH intramolecular O O
condensation HO2C condensation O
O much less ring strain
H
O +H O O Et -H
4. H +
O O
Et Et O (H
30 carbon
O OEt O OEt OEt O O

O
O PhMgCl - OEt
5. Ph O Ph O Ph
(1 equiv)
Ph:
ketone more reactive
than ester
S H S S
O PhN H
NH2 PhN Ph
~H NH +H
6. Ph N C S H2N N
R N NH
H HO
R N R N
H O O H HN
H R
S S
R= CO2H
Ph Ph
N NH -H N NH ~H
+
H2N CO2H O
O H)
HN
H R
17.3 Mechanisms
Solutions • 401
Me Me
O O O OMe OMe
7. 1. Me3O BF4 2. H3O
Me NH2
NH2 NH2 -Me2O NH2
H2O OH2
OMe
OMe ~H
-NH4
NH3
O O
(H
O O O
Me O Cl
8. a. -Cl +Cl
S O Cl Cl S Cl S Cl :C O:
+ CO2 +
Me O
Cl
R H :NR3
:NR3 O
b. -NHR3 R (H -NHR3
R O (H R R
-Cl R O S -Me2S
S Cl
O O
O
R2CHOH, NR3
9. S Cl N S Cl N R R
[O]
O O (mechanism per 17.3, 8)
O OH
O
-HPO42- ~H HO
10. H2N PO3H HO
O H2N
NAS H2N
CO2H N CO2H N CO2H
H H
H2N O H O
O CO2H
HO OH
H) O OH2
HN -H3O ~H H2N
HN
O N CO2H O N CO2H
H O N CO2H
H H
O Br O POBr2 Br
Br2P Br Br OPOBr2
O 1. POBr3 +Br -HO2PBr2
11.
N CF3 -Br N CF3 N CF3 N CF3
H H
CF3 CF3 CF3 (H CF3
N
O 2. Li
CO2H
3. CO2
7. [H] 5. C5H4NLi, -600 4. H
mefloquine
N CF3 6. H3O N CF3
CF3 CF3
17.3 Mechanisms
O O
O
-Cl -H N N:
12. a. R Cl N N:
R R
H
H (H H
:C N N:
H :CH2N2
1. SOCl2 hQ
b.
2. CH2N2 -N2
CO2H C C
O H N N: O H O
2. W-K 1. H2 / Pd
hydrogenolysis of
cyclopropyl bond
O
cleavage here R
H O R' H O R' H H
N N N
N 1. BrCN -MeSCN
13. N N
O R H
-Br O R H O O R'
S Br S
CN
C O
N R
H 2. H3O
O + H3N N
iminium hydrolysis
O (see 17.3, 7 for mechanism)
R'
a carbinolamine
OH O N H
O
N N H O
H H2O2, H
14.
N N (see 15.3, 34) N
O O O O O O
A
+H
O N O N H O N
H
HO O
-H2O -H H
N N N
H
O O O O O O
17.3 Mechanisms
Solutions • 403
Ac
N O O
O O O
O -pyH
15.
-HOAc O O
N CO2H O
H) O
O O O
Ac :py O O
N
O -CO2
- OAc O
=
Me
N
OAc O
O O
S S O
O N +H O N +H
16. H H N N
O O H H
CO2 CO2
R dicyclohexylurea
RN C NR R = cyclohexyl N NHR
H H +
N
PhO H S S
-H
O N N
O O H)
CO2 CO2
O OH
~H
17. H P OH :P OH R = -CH2CH2NH2
OH taut OH
nucleophilic form
O H H)
O O O
OH
(H 1. :PCl3 +Cl :P(OH)3
R O PCl2 P OH
-HCl R O -POCl2 R Cl R
PCl2 Cl O (H
Cl
Cl -HCl
OH OH (H OH -H
O H
O P OH O
-H R P(OH)2 2. +3H2O R PCl3 :PCl3 :PCl3
OH
P(OH)2 P(OH)2 R P(OH)2
H2N O P OH -3 HCl
O O O
OH
O O O
+H
18. + Me C O:
O O
an acylium ion
OMe OMe OMe
H
-H
O O O
OH O O
H) O O
Me C O:
Me Me
17.3 Mechanisms
19. a. Carboxylate as a nucleophile:

O O O O
O O ~H O
+ HOAc
O O OH
O
O H H 18O-label appears in salicylate
b. Carboxylate as a base:
O O O
O
H H
O OH ~H O + HOAc
O O OH
O O no label!
HO
c. Therefore, pathway b is preferred.
H H :H
H O
NH2 1. -H2O N C
20.
CO2Me H CO2Me
N N
H H
OR
2. NaBH4, HOR
O OMe 3. H
N H) N O
-HOMe
N N
H H
17.3 Mechanisms
CHAPTER 18
CARBONYL Į-SUBSTITUTION REACTION AND ENOLATES
18.1 Reactions
1. LDA 2. n-PrBr
1. O O O
H
O
OMe 1. OMe O
OMe 2. Ph Br
2. CO2Me
O O MeOH O O
O Ph O
O O
CO2H 3. H3O
'
Ph
-CO2
Ph O
O
O O O
O O 2. OEt
EtO OEt
3.
1. LDA
OEt Et 4. H3O
3. EtI ' Et
NAS CO2Et
O
O O O
CO2Et 1. base O
CO2Et 3. H3O, ' -CO2
4. Ph
CO2Et -CO2 Ph OH Ph
2. (PhCO)2O CO2Et
NC CO2Et HO2C
Cl NO2
H CN CO2H
1. OEt NC 2. H3O, '
5. NC-CH2-CO2Et
C CO2Et
N -Cl -CO2
nucleophilic aromatic subst'n NO2 NO2
H H
NaCH(CO2R)2
6. H Me HC Me
SN2 (RO2C)2
OTs H
cis- trans-
O O O O O
O
1. H3O 3. NaH 4. PhCH2Cl 5. H
7. 2 equiv 1 equiv
2. CrO3, H O Ph
O O
more reactive enolate Ph
18.1 Reactions
CO2Et 1. OEt EtO2C H CO2Et

2. 3. H3O, ' O
8.
CO2Et EtO2C EtO2C -CO2 OH
O OH
O
O O O
O
1. (XS) OEt -Br 3. H3O, ' O
9. OEt
2. Br(CH2)4Br CO2Et -CO2
EtO O
Br
O O Ph O O
1. LDA
Se
2. PhSeBr -PhSeOH 4. MeOH
10. O
3. H2O2 H H
OMe
O O O O
O O O
1. Br2, H 3. LiMe2Cu 4. H3O O
11.
O O O
2. KO-t-Bu
O O O O
1. Br2, H 2. (CN)2CH: 3. H3O, ' OH
12.
SN2 -CO2
Br CH(CN)2 O
O
O
EtO2C 1. OEt EtO2C H EtO2C H
2. n-Pr Cl 3. H3O, '
13.
EtO2C EtO2C EtO2C
NAS -2 CO2
O
O O O O
1. a. Br2, OH
(-CHBr3) OH 2. PCl3, Br2 Cl 3. MeOH OMe
14. Br Br
haloform rx H-V-Z rx
b. H
H OEt H +EtOH H -H2O

15.
H O -EtO OH
18.1 Reactions
Solutions • 407
O O
1. LDA O 2. Cl2, H Cl
16. O
-H -Br
Br
Br
OEt
1. HCl 2.
17. O O 3. H3O, '
conj. add'n Cl EtO2C
-Cl -CO2
O O
O O O O O
O 3. KMnO4 OH
1. Cl2, H 1. Cl2, H 3. H3O
18.
2. OH 2. E2 4. [O]
O
Cl -Cl C(CO2Me)2 -Cl CO2Me 1. KOH

19. CO2
Cl LiH CO2Me EtOH
:CH(CO2Me)2 Cl 2. '
1. SOCl2
O O 2. Me2NH
CH2(CO2Me)2 LiH 3. mCPBA
O
NMe2 NMe2
O O O O O O
base Ph O taut
20.
conj. add'n
O O O Ph O
18.2 Syntheses
O O O O
1. PCl3, Cl2
3. KCN 4. H3O
1. OH OH OH OH
2. H2O Cl SN2 CN CO2H
H-V-Z rx
18.2 Syntheses
CO2Me 1. OMe, MeOH (CO2Me)2 CO2H

3. H3O -H2O
2.
CO2Me 2. Br OH -CO2
OH OH O O
O O
CO2Me 1. OMe MeO2C CO2Me
3. H3O Cl 5. LiAlH(O-t-Bu)3 H
3.
CO2Me 2. Br CO2Me CO2Me -CO2 Cl H
4. PCl5 6. H
O O
O
1. OMe O
CO2Me 2. 2-chloropentane
4.
CO2Me 5. H2N NH2
CO2Me NH
3. OMe CO2Me (urea)
4. allyl chloride -2 MeOH O N O
H
O
CO2Me 1. OMe Et CO2Me 3. OMe Et CO2Me
5. 5. H3O, ' OH
CO2Me H CO2Me -CO2
2. EtI 4. PhCH2Br Bn CO2Me
Ph
1. BH3.THF 3. CrO3, H O
5. (MeO2C)2CHNa
6.
OH Cl
2. H2O2, OH 4. SOCl2
NAS
OH OH O
7. NaBH4 6. H3O, '
O O O CH(CO2Me)2
8. H (-H2O) -CO2
3. H3O (-CO2)
CO2Me 1. OMe OH Br
CO2Me 4. LiAlH4 6. HBr
7.
CO2Me O OH Br
(CO2Me)2 5. H SN2
2.
OMe
O O
1. NaOEt, HOEt 3. H2NNH2 4. NH3
8.
Et 2. MeI Et OH, ROH Et
O O O O O O H2N O
W-K
18.2 Syntheses
Solutions • 409
O
O O O O
1. OEt O 3. H3O, '
9. OH
Et O O -CO2
O O Et OEt O
2. O O
EtO OEt
O O O O
1. KOEt / EtOH 3. H
10. O
Et -HOEt
O O 2. Cl OH Et
O O OH transesterification
O
O
1. OEt 3. H3O, ' O 4. NaBH4
11. Cl
Et -CO2
O O 2. EtO2C O O 5. H
O 6. PCl3 Cl
O 1. OEt O O
O
2. EtI Me 5. H3O, '
12. 6. I2, OH
O
Et Et -CO2 haloform rx
O O 3. OEt Et
4. MeI O O
+ HCI3
O O O O
1. Cl2, H 3. H3O 4. Ac2O
13.
2. KO-t-Bu (E2)
OH OAc
[or 3. HCl, 4. NaOAc (SN2)]
OH O O
1. Jones reagent 3. KCN
Br CO2H
14.
2. Br2, H 4. H3O
[or 3. ethylene glycol, H, 4. Mg, 5. CO2, 6. H ]
O O O O (H O
taut O
15.
-H
+H
18.2 Syntheses
O
O O O O
1. OMe 3. H3O
16.
Me O O '
O O 2. Me
O O -CO2
O
O 1. LDA O O
3. H2O2 O
17. -PhSeOH
2. PhSeBr
Se Se
Ph Ph O
OH OH O OH 4. H3O
6. CH2O, H 5. H2 / Pt
O O
Cl O Cl O Cl O Cl O
1. NH2
Cl 2. Cl2, H 3.
18.
AlCl3 Cl -HCl N -t-Bu
H
OH CO2H CO2H
O O
1. KOH 3. Br2, PCl3 Br
19.
2. 4. H2O
CO2H
H-V-Z rx
O
5. SOCl2
O N O N 6. H2N-i-Pr
H 7. LiAlH4 H
OH 8. H Br
9. OH ((SN2)
S S S Na
1. NaOMe / MeOH O O
CO2Me 2. EtI 5. H2N NH2 HN NH 6. NaO-t-Bu HN N
20. MeO OMe
CO2Me 3. NaOMe / MeOH
thiourea O O (1 equiv) O O
4. 2-iodopentane
-2 MeOH
NC
CN 1. NaNH2 NC H MeN(CH2CH2Cl)2 NMe intra-S N2 NC
21. Ph NMe
Ph SN2 (-Cl , ) -H -Cl Ph
Cl
O O
3. EtOH, H 2. OH, ROH
EtO O
NMe NMe
Ph Ph
18.2 Syntheses
Solutions • 411
18.3 Mechanisms
O O H O H HO OH
H H
+H (H -H +H H -H O
1.
OH OH OH OH OH O H OH O (H OH H
O O O O O O
O O
2. OEt
2. 1. OEt O -OEt
OEt O
Et -H O
Et O
O O O O
I H I I
O O I2 O O I2 O O -H I O
3. PhCO2 +
Ph Ph OH Ph Ph OH Ph Ph I Ph
OH
O I I
I3CH + PhCO2 I3C: H) O Ph
I3C Ph
O OH
(H
O OH OH O O
+H -H +H -H
4.
H (H
-H +H -H +H
H H H
achiral
O O O
O H) OMe
5. +MeO
+
MeO -MeO
O
O O O
MeO
H H H
O
taut O O O O
~H -H3O
6. O
+H OH OH2 ~H
O H
H) H)
18.3 Mechanisms
O O
H)
O O H O
taut HO N NH -H OAA
7. HO C CO2H +
2 HO2C HO2C
H biotin
S CO2H
OH
H OH OH OH O
H H
8. taut -HPO42- H -H H taut H
O O O O H
O (H O O
PO3H PO3H
H Me3N:
O O H) Si
taut SN2 O -H O TMS
9. Si Cl
-Cl
18.3 Mechanisms
CHAPTER 19
CARBONYL CONDENSATION REACTIONS
19.1 Reactions
O RO2C CO2R
1. OH 2. :CH(CO2R)2 O
1. PhCHO + PhCOCH3 Ph Ph
-H2O Michael Ph Ph
aldol HO2C
O 3. H3O
-CO2
Ph Ph
O
OH
O H H
2. H
H
H taut aldol
O OH
O O O
OEt O
3. t-Bu-CHO
t-Bu or
Knoevenagel t-Bu
O O O OH O
O O
O
OMe OMe OMe - OMe
4.
-H
O
O O
CO2Me CO2Me CO2Me

1. OMe - OMe 2. H3O
5.
OMe OMe Dieckmann -CO2
O O
O O
O O
O
OH, ROH
6.
conj. add'n OH retro-aldol
O
O O
HO
OH -H2O
7.
-H
O Et O Et O Et O Et
19.1 Reactions
O
H 1. BrCHCO2Me -Br O
8. CO2Me CO2Me
O O Br O H 2. H3O, '
taut -CO2
H OH
H) O O
O
O
O O
1. base O NAS
9. MeO CHO MeO MeO
CO2
O
O (H
CO2H 2. acid CO2
O O MeO MeO
-CH3CH2CO2H
OCH3 OCH3 OCH3
base -H2O
10.
Michael aldol
O O
(Robinson annulation)
O
O
O
OH
OH PhCHO NO2
11. O2N CH3 O2N CH2 NO2 or Ph
Ph
O
OMe, MeOH
12. MeO
CO2Me OMe
retro-Claisen CO2Me
O MeO O
O
O O O O
1. NaOEt -H2O 2. NH2NHPh

13.
aldol OH conj. add'n
NHNHPh
O O CO2Me O
O O O
1.
OMe -Cl 3. H3O, ' aldol
14.
2. Cl Cl
O O -CO2 -H2O
O O O H O H O
O O O
O O
OH 1. :CH(CO2Me)2 -MeO
15. O 2. H3O
Michael O -CO2 O
OMe
mesityl oxide CO2Me CO2Me dimedone
19.1 Reactions
Solutions • 415
HO
CHO
CHO
OH -2 H2O
16. O O O O
CHO
HO HO
OH OH OH
H
O retro-aldol H OH taut
17. + HO O
HO
OH O H OH O H
(H H
O
O
1. 2. H3O 3. NaOH
18. N N
O O O
O O O O O
again HOCH2 HO
+ mixed again
19. H H H H H H
aldol CH2OH CH2OH
OH OH
O
O
HO
H
H H OH
HCO2 + C(CH2OH)4
mixed Cannizzaro
OH O
O OH O
~H Ph H -H
20.
taut H -H2O
mixed aldol
HO Ph Ph
OH
CHO CO2Et CO2Et CO2Et
21. 1. :CH(CO2Et)2 2. H
CO2Et -H2O O -HOEt
OH OH O O O
H OEt
transesterification
O O O
CHO OHC
KOH again
22. + +
CHO -2 H2O
OHC
aldol
O O O
OH O OH O
O
O 1.
23. + 2. H3O
SCoA OH
CO2H SCoA CO2H
CO2H
19.1 Reactions
OMe
MeO CHO CN OMe
24. 1. OEt 2. H3O
+ MeO
OMe HO
CN OMe
O (H
OMe O OMe
-CO2
MeO MeO
-H2O
HO
OMe OMe
H
O
H OH
O O
1. H3O 2. KO-t-Bu
25. taut
conj. add'n retro-aldol H H
O (H O O
CO2
CO2 O taut O2C
O retro-aldol CO2
26. O CO2 CO2
H O
O H HO HO
H) H aldol hydro-
CO2 O
O CO2 O lysis
CO2 O O2C
SCoA SCoA
O O
O
O O
OEt C
C taut
27. Michael EtO (H
O O O
O O O
-H2O aldol
O O
OH
O H
H)
O O O OH
H OH
taut ~H
28. OH OH
OH OH OH OH aldolase OH OH OH
19.1 Reactions
Solutions • 417
OH CO2H
O O CO2
CO2 H3O
29. O C + O2C SCoA HO CO2H
2 SCoA
O CO2H
O OH O O O H
H3O [O]
30. SCoA SCoA SCoA
S
O O OH H) CoA
+ taut
SCoA SCoA SCoA
retro-Claisen
O O OH O
[H]
O
Claisen H3O OH
31. O C
SCoA -CO2
CoAS O HO O
A B
O O HO
H 1. H2 / Ni (1 equiv) H
32. a. D-A
+ O OH
EtO H H
2. a. LiAlH4
EtO b. H EtO
O
a vinyl ether
1. H3O
HO HO HO
H H H
aldol 2. MVK, base
OH OH OH
H -H2O H H
O Michael
O O O
R R R
1. X , t-BuO
b. 3. +H
O C C C C
2. a. EtO C C MgX OEt -H2O
OEt
OH
b. H
R R R
taut +H2O
C H C C OEt -H C C
CO2Et OEt
OH
19.1 Reactions
O O
1. a. OsO4 O O
c. 2. KIO4
OH OH
b. NaHSO3
OTs OTs OTs
O
O O O 3. OMe
-OTs
-H
H OTs
O O I
O I
O 1. RO2CCO2R O 2. I2, OH O
O O
d.
OR CO2R CO2R
3. OH
O I O O
I I
I
O O O
C OH OH ' O
C
O O -CO2, -I
O
O
~H taut O O
O I I OAc
-CO2 O O
O taut
C O
O 4. KOAc
SN2
OAc OAc
OH NC
O
O O OAc
1. HCN O CN 2. -H2O
e.
3. KMnO4, OH
O
OAc
O NC OAc
OH
O O (H
4. H3O -HCN
cortisone OH
O
cortisone acetate
O O
CO2Me O 2. H3O, '
33. 1. - OMe
Dieckmann OMe -CO2
CO2Me
19.1 Reactions
Solutions • 419
O H OMe OH O OH O Na
N N
OMe H O -H O
34. O2N CH2 O2N CH2 H)
(H O2N NO2 NO2
O O O O
O Et3N O O +H O
35.
-H Michael taut
19.2 Syntheses
O O O OH
1. H3O 2. H2 / Pt
1. Ph H + Ph Ph Ph
Ph Ph
-H2O
O
O N
1. H 2. N
2. +
N -H2O
H O O
O
3. H3O
O O O
H OH, ROH H H
3.
H H
O OH
O
OH
H3O O O
4. O -H2O
O HO
O
1. OH (aldol) 2. H2 / Pd 3. H2SO4 (E1)
5.
-H2O
4. H2 / Pd
19.2 Syntheses
1. LDA O
O HO O O
2. MeI 4. OH O 5. Ph3P: O
6.
3. Cl2, H Cl H (protect) 6. MeLi
Cl PPh3
O O
8. H3O 7. acetone
- via a Wittig, not a mixed
aldol! O Wittig
O O O
CO2R
1. NaCH2CO2R OR 2. OR, HOR
7. CO2R
CO2R Claisen OR Dieckmann
O O
O O O O
1. Cl2, H 3. H3O
8. 5. NaH (2 equiv)
2. KO-t-Bu (E2) 4. CrO3, H O O
O O
7. H 6. PhCH2Br
Ph Ph
(1 equiv)
O O
O
.
1. BH3 THF
4. N ,H
N O
2. H2O2, OH H H 5. Cl
9. H H
-H2O 6. H3O
3. PCC
OH OH
O 1. CH2O, OH O 2. NaBH4 OH
10.
H mixed aldol H 3. H
O O O
OR, ROH OR, ROH
11. +
O Michael O -H2O, aldol
O O O
O O
O
1. O3
3. KOH, EtOH -H2O
12.
2. Zn, H aldol
O OH
19.2 Syntheses
Solutions • 421
O 1. Br2, H 5. O
2. ethylene glycol, H O O
13. PPh3
3. Ph3P: (SN2) O
6. H3O
4. n-BuLi
- the reaction of cyclohexanone with acetone via an aldol would yield four possible products!
O
O O O O
1. OR, HOR 3. , OR OR, -H2O
14.
2. MeI Michael aldol
O O O
O O
O OH
1. O3 O O
H 3. H -H2O
15. H
2. Zn, H aldol H H
O
O O O
O O
OH, HOR aldol
16. 3
aldol, -H2O conj. add'n -H2O
O
19.3 Mechanisms
O OH O
OH OH
1. +H -H taut taut
retro-aldol
HO
H) O
O O O O O
OH
(H
-H ~H +H
-H2O aldol
OH2 OH
O
O 1,2-R: shift O
2. + N2
:CH2 N N: N N:
19.3 Mechanisms
O O O
H) OEt
O
retro-
3. O OEt CO2Et
Claisen
O OEt O
OEt
H)
OMe OMe
4. OMe 1. conj. add'n 1. again
NH O N O
O Me
Me OMe
:NH2Me
CO2Me
O O O
O OMe
2. OMe
MeO - OMe OMe
-H
Dieckmann O
N N
Me Me
O O
5. -Br O
Cl Cl Cl
H CBr2
OH Br Br Br
CHBr3 Br3C: OH HO
OH
Cl Cl
O -HBr O -Br
O HO Br
CO2Et CO2Et CO2Et CO2Et

1. OEt, aldol -H2O
6.
O O O O
Michael O
HO (H
O
H) OH O O 2. H2O, OH
3. '
O O -CO2 O
O O OH O O O
H
H 1. -H2O 2. H
7.
aldol
O O
(H
-H
O O O O O O
retro- + Claisen
8. OEt EtO
Claisen OEt EtO O EtO Ph
OEt - OEt
Ph
19.3 Mechanisms
Solutions • 423
O O OH OH
O O
9. OH, Michael O aldol
CHO
CHO HO
H O HO O
O (H H
O O
~H - OH
-HCO2
RO (H
HO HO HO HO
H (H
O OH OH O
10. OH H taut H
OH OH taut OH
OH O O OH
(H OH OH OH OH
OH OH O H A O
(H
H
D-D-fructose
OH OH OH
HO -H H
HO
O
OH retro- (H
H OH O
HO +
O aldol O
HO H
H ~H
O (H
OH taut
OH OH
A OH
R2N CO2R R2N CO2R R2N CO2R O O

R2N OR R2N
(H Br OR
11. -H Br (H -Br
Br Br N
NH -H N
NH NH
RO2C OR Ph O
Ph Ph O O Ph CO2R
12. base - OR Ph -H
O
RO2C Ph Ph O RO2C Ph CO2
(H
CO2R :B
O O O
1. OMe
13. O
O O O H) OMe O
19.3 Mechanisms
OH OH
13. 2. H -H taut O
OH
(cont.)
O O (H O O
O O
OR OR CO2R
14. O retro- H ~H Dieck-
OR OR
O Claisen mann O
OR
CO2R OR
O O OR O
O O O
EtO OEt EtO EtO

15.
-H
O O O
EtO O EtO O
H)
O
O O
EtO (H
O O
O O
1. a. O3 2. OH
16.
b. Zn, H O O
O O
HO (H aldol
-H2O
O O
H) OH
NH, H
1. +H
17. -H
N -H2O
O N N
OH (H
H A - a dienamine
2. EtI (SN2) 2. EtI (SN2)
N 3. H3O O O 3. H3O
A N
A
Et I Et Et
I Et
O O O H B O
:B taut
18.
Michael Michael
OMe CO2Me CO2Me

MeO O
O
19.3 Mechanisms
Solutions • 425
O O O O
19. 1. NaH 2. H2O
MeO (H O
MeO HO MeO MeO O
O O
OH O OH O OH O
R' R' R'
R taut, +H2O R retro-aldol- R
20. OH O
R' = like H
HO O H O HO
HO R' O (H OH
HO R' H) O R'
O O (H
O O OH O aldol- like
R' R R' R' R
HO taut R -H2O
OH HO HO O
O (H
O O H O OH
R'
R' R' H
NMe2 :N C: N CN
Me I 2. -I 3. -NMe3
21. a. Mannich b. R R R
N SN2 N SN2 N
H H H
CN O O H
4. LiAlH4 NH2 N
c. R 5. H OEt , H
CO2Et
R R
N [H] N -H2O N
H H H
H O OH
OH
(H H OH (H
1. H3O O OH HO2C
22. PEP
H
-H2PO4 HO2C 2. aldol O OH OH OH 3. -H2O, taut
O O H) H) O
OH
-H2O CO2H CO2H 4. H
HO CO2H HO HO HO2C
OH aldol O taut
O OH O
HO HO H HO H
CO2H CO2H CO2H

CO2H CO2H CO2H CO2H CO2H
23. H) H, -H2O
+H -H
O O aldol -H2O (H
H O N N
H3N NH2 H H
H3N H3N H3N H3N
H
19.3 Mechanisms
O O O
O AcO H)
O O
O(H -HOAc -HOAc O
24. a. O N O N
NH O H)
Cl Cl
O O
O O Cl
~H -H
-Cl O
O H) O
N N
N H Cl
O O O O
+MeOH OMe
b. HS O HS O HS O OMe
- OMe HS
N N N N
taut H
MeO (H
O
O O O O O O
-CO2 - SR
25. O SR RS SR SR
R' R' R'

R' O H
R'
R N S R N S - R N S
1. H R
26. R N S 2.
R N S
OH OH O (H
+ -H
H OH
HO H) O R O
O O
O (H -H
H R
H H
OH
O OH O OH O
O
Claisen aldol- partial
27. a. SCoA SCoA SCoA
SCoA like
-HSCoA O (H SCoA hydrolysis
O CO2
H SCoA O
PO3H
O
P2O6H 2- -CO2 P2O6H 2- ~H
b. O P2O6H 2-
O 2- O
-HPO4
(H
O H
O
19.3 Mechanisms
CHAPTER 20
AMINES
20.1 Reactions
O O O
1. base CO2Et (CO2Et)2
1. NH 3. base
N H N
2. ClCH(CO2Et)2 CO2Et 4.
O Cl
SN2 O O
O
CO2H CO2H 5. H3O
phthalic acid + 5.
N CO2H
NH3 -CO2
O
Cl O
NH2 OH
1. (XS) CH3I OH O
3. OsO4 O Cl
2. 5. (XS) COCl2
2. Ag2O, H2O, ' 4. NaHSO3 -2 HCl O
O NH2
O O 6. NH3
O
NH2 -2 HCl
Me Me Me
N 1. (XS) MeI N N Me
H OH 3. '
3. + H2C CH2
2. Ag2O, H2O -H2O
1. (XS) MeI OH 3. '

4.
N 2. Ag2O, H2O -H2O
H N N
HO HO HO
1. (XS) CH3I OH
5. '
O O O
N 2. Ag2O, H2O N -H2O N
HO HO HO
Ph2N H NPh2
O Me
Me 1. H2O2 2. '
6. Me H H
H Me H) + Ph2NO
Cope Et
Et Et (cis-elimination) Me
Me
20.1 Reactions
O O
1. SOCl2 3. ', -N2
7. CO2H N N N N C O
2. NaN3 N N N
Curtius
O H2O
-CO2
NH2
N OH
H
OH OH OH
OH 1. (XS) MeI OH OH
taut
8.
2. Ag2O, H2O, '
NHMe
HO HO O
D
H
D Hofmann elimination anti-periplanar
H
H
9.
NMe2 NMe3
H
D
Cope elimination D
syn-
(H
N O
O
+H H -H
N N N
10. Me2NH + H H
-H2O H
OH O
O taut OH
NH2 N N OH O
N HONO N H2O N taut

11. HN
O N O N -N2 O N O N
H H H H
1. Li
12. Ph 2. CO2 4. SOCl2 6. Br2, OH
Cl Ph Ph NH2
CO2H Ph
3. H 5. NH3 H2O NH2
O
OH OH O
Br2, OH
13. NH2 NH3
Me Me NH2 +
H2O Me H
O
a carbinolamine
20.1 Reactions
Solutions • 429
1. NaNH2
Ph2CH O 3. PBr3 Ph2CH Br 4. Me2NH
14. Ph2CHOH O Ph2CH NMe2
2. O O
O
O
N O
1. HBr 2. O NH
15. +
ROOR Br NH2 NH
3. H2NNH2
O
Me2N H
(H O
OH O
1. MeI 3. H
16.
2. Ag2O, H2O, ' pinacol-like
MeO MeO rearrangement
MeO
Ph Ph
OH 1. SOCl2 NH2 3. Br2, OH
17.
O 2. NH3 O H2O
OH OH
Ph Ph
2 I
4.
N NH2
OH OH
CO2 CO2H CO2H

N
1. a. Br2, PBr3 C H2N
CO2H b. H2O (H-V-Z) 3. HCN, CN 4. H2 / Pt
18.
2. KO-t-Bu (E2) conj. add'n
Br Br Br
NH2 NH2 N2 I
1. Br2 2. NaNO2 3. KI
19.
HCl -N2
Br Br Br
CN CN CN CN CO2H
1. Cl2 2. NaNH2 3. KNO2, H
20. 5. H3O
FeCl3 (NAS via 4. CuCN
benzyne)
Cl NH2 CN CO2H
CO2H CO2H CO2H

1. KMnO4, H 3. Fe, HCl 5. HBF4
21.
2. fuming nitric 4. NaNO2, HCl
NO2 N2 F
acid
20.1 Reactions
1. Br2, Fe Cl Cl Cl
NHAc 2. Cl2, Fe NH2 4. ICl, Fe N2
22. 5. H3PO2
3. H2O, OH Br 5. HONO Br
Br I I
CO2Me
O
23. 1. NaH N 2. H3O

O N -H2 N
O -OMe N
Me N O -CO2
Me
Br Me O
NHMe
N 5. ' 3. NaBH4
Me
N -HBr N 4. HBr N
H)N
Me
HO O HO
H
1. H
24. O OH N C reductive
O OH
NH NaBH3CN amination N
HO HO HO
O OH 2. HCl
N
H
Cl
HO
20.2 Syntheses
1. Br2, hv
2. Mg 5. SOCl2 NH2
1. 7. Br2, OH
CO2H NH2
3. CO2 6. NH3
O H2O
4. H
1. Cl2, ' Cl CN 3. LiAlH

2. KCN 4 NH2
2.
SN2 4. H
4. potassium
1. Br2, hv 3. HBr phthalimide
3. 6. (XS) MeI
2. KOH (E2) R2O2 Br 5. H2O, OH NH2 7. Ag2O,
H2O, '
20.2 Syntheses
Solutions • 431
1. KMnO4 2. SOCl2
4. OH 4. Br2, OH
NH2
H 3. NH3 NH2
O H2O
O
OMe OMe OMe OMe

1. (XS) MeI
MeO OMe 2. Ag O, H O, ' MeO OMe MeO OMe MeO OMe
2 2 5. H2NPh
5.
3. O3 NaBH3CN
NH2 4. Zn, H
H O H NPh NHPh
N K
1. NBS, ROOR 2.
6. Br O NH2
O2N
O2N 3. H2O, OH O2N
O
CO2H
7. 1. KMnO4, H 2. PCl3 NH2 4. Br2, OH NH2
O2N 3. NH3 O N
O2N 2 H2O
O2N
1. (XS) CH3I 3. O3 5. HO OH O
8. O
NH2 2. Ag2O, H2O 4. Zn, H H O
1. SnCl2, H 3. PhNEt2
9. HO3S NO2 HO3S N2 HO3S N N NEt2
2. NaNO2, HCl
N O O
CO2Me N N 4. MeI
1. H3O 3. ' 5. Ag2O, H2O, '
10. OH
2. CrO3, H -CO2 6. repeat 4. and 5.
O Ph
O O (double Hofmann)
O
1. HONO2,
Cl Cl Cl Cl Cl Cl
H2SO4 3. SnCl2, HCl 5. H3PO2
11.
2. Cl2, Fe 4. NaNO2, HCl
NO2 N N
20.2 Syntheses
NH2
1. Ac2O NHAc 3. KNO2, H NHAc
12.
O2N 2. SnCl2, HCl 4. H2O
H2N HO
NHEt2 OH 1. CrO3, H
13. Cl NEt2
O Et2N Et2N
2. SOCl2 O O
-HCl NH
Fe, H
NO2 NH2
1. HONO2, NH2 OH OMe

H2SO4 3. NaNO2, H 5. KOH
14.
2. Fe, HCl 4. H2O 6. MeI
NO2 N2
1. SnCl2, HCl 3. PhNH2
15. N N NH2
2. KNO2, HCl -H EAS
H2NMe (-H2O)
16. [H]
O NaBH3CN, H N NHMe
Me
(alternatively, 1. H2NMe, 2. H2 / Pd)
H H
N N N Br
O O
1. mCPBA 2. (XS) MeBr
17.
S S SN2 S
O S O S O S
OH OH OH
O O O
1. HONO2, H2SO4
2. SnCl2, HCl NHAc 4. HONO , H SO NH2
2 2 4
18.
3. Ac2O 5. OH, H2O O2N
OH
N NO2
N 7. N2 6. NaNO2, HCl
OH
O2N
20.2 Syntheses
Solutions • 433
NO2 NO2 3. Fe, HCl

1. HONO2, 4. KNO2, HCl
19. 2. DCl
H2SO4 EAS 5. H3PO2
D D D D
OH OH OH OH
1. propylene, H 2. H3O 3. KNO2, HCl
20.
F-C alkylation -HOAc 4. H3PO2
NHAc NHAc NH3
20.3 Mechanisms
O O O
H OH Br Br
1. -HBr Br
N N N
H (H -Br
O ~H
N C O
H OPh N C N C O
taut O
H) Ph
HO Ph
O O
OH CO2
1. Cl2
2. NH -H
NCl
OH, H2O N
O Cl -Cl
O O
CO2H CO2
-CO2 OH CO2
NH2 2. H N CO2 taut

H N C O
O
CO2H CO2H
3. 1. HONO 2. pH 8 O
NH2 N N -H -CO2
N N
-N2
3.
D-A
20.3 Mechanisms
O HO HO
CN NH2
1. HCN 2. H2 3. NaNO2
4.
CN Pt HCl
H)
O O HO HO N2
-H -N2
OH OH2
OH2
O N N
1. NH2OH 2. H -H2O
5. N
-H2O
O OH OH2
taut -H +H2O
NH N N
MeO MeO MeO

XMg
1. PhMgX
6. O XMg O XMg O
NMe NMe NMe
MeO MeO MeO
MeO MeO MeO

Ph Ph
HO 1.
NMe XMg O NMe XMg O
2. H NMe
MeO MeO MeO
MeO MeO
Ph Ph
Hofmann : HO 1. (XS) MeI HO NMe2

NMe
2. Ag2O, H2O, '
MeO MeO
Cl SN2, -Cl ' N

7. N N N N N N
N N N -N2
20.3 Mechanisms
Solutions • 435
H) N3
O HO H O OH O
N N N N N N
N N N -N2 N ~H NH
8.
'
Ph
+H (H ~H
9.
N NH2
N N Ph NH2 Ph H H
H N Ph H
H N N
H ~H
H H H H)
-NH4 Ph
Ph
N N NH3
H H
10. +H ~H EAS -H
NH2 NH2 -H2O NH NH NH
H H H2C H
H OH
O
O (H
O O
H O
11. -H CH2O, H
Ph CH3 CH2
taut Ph Mannich Ph NH2 Ph N
CH2O + NH3 H2C NH2 H
H)O H)O
O O O -H
O O
Ph , -H CH2O, H Ph
Ph N Ph N Ph
3 Ph N Ph
(again) (again) H
CH2
taut
acetone dicarboxylate H)O
OH OH
CHO CO2
~H N ~H - OH CO2 -H
12. (H N N
H
CHO H2NMe
O OH OH O
N N O2C CO2
CO2 N
-2 CO2 CO2
-H - OH
N
O(H taut
O2C
OH
O O CO2
20.3 Mechanisms
OH2
+H OH2 -H
13. a. N CMe N NHAc
N CMe Me taut
O O
+H -HOAc
b. N C OMe
O O
H
O
+H2O, -H
OMe N C OMe
t-Bu N taut
H
OH2
O O H O
Ph NH2 1. OH 2. CH3I
14. Ph S Cl Ph S N Ph S N Ph
O -HCl O Ph SN2
O
CH3 O
3. H2O, OH CH3
PhSO3 + N Ph S N
H Ph
O
(H :B
O O
O R O
2. -HCl Cl 3. -Cl 3. -HCl R
15. a. R CCl2 N3 Cl NAS
Cl R Cl N3 OMe
N N N O
H) Me
H H
Cl O N N
1. :CCl3 2. -HCl
b. O -HCl
-Cl O
Cl
O Cl O O
OH H
NH
H)
R H R H R H
N N O N N O N N O
-H
16. NH
NH NH +H
N N N
H)
H O C O H C O
H C C H
N
Ph C N H C
H C C Ph
H H N
H
Ph
20.3 Mechanisms

Workbook For Organic Chemistry - Supplemental Problems and Solutions

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W.H. Freeman and Company

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Printed in the United States of America

W.H. Freeman and Company

CHAPTER 1 THE BASICS 1

CHAPTER 4 REACTION BASICS 21

CHAPTER 5 ALKENES AND CARBOCATIONS 27

CHAPTER 8 ALKYL HALIDES AND RADICALS 65

CHAPTER 9 SN1, SN2, E1, AND E2 REACTIONS 69

CHAPTER 11 CONJUGATED SYSTEMS 93

CHAPTER 12 AROMATICS 103

CHAPTER 13 ALCOHOLS 117

CHAPTER 14 ETHERS 129

CHAPTER 15 ALDEHYDES AND KETONES 139

CHAPTER 16 CARBOXYLIC ACIDS 167

CHAPTER 17 CARBOXYLIC ACID DERIVATIVES 177

CHAPTER 18 CARBONYL Į-SUBSTITUTION REACTIONS AND ENOLATES 201

CHAPTER 19 CARBONYL CONDENSATION REACTIONS 209

CHAPTER 20 AMINES 229

SOLUTIONS TO PROBLEMS 241

CHAPTER 1 THE BASICS 243

CHAPTER 2 ALKANES 251

CHAPTER 3 CYCLOALKANES 255

CHAPTER 4 REACTION BASICS 261

CHAPTER 5 ALKENES AND CARBOCATIONS 263

CHAPTER 6 ALKYNES 281

CHAPTER 7 STEREOCHEMISTRY 287

CHAPTER 8 ALKYL HALIDES AND RADICALS 295

CHAPTER 9 SN1, SN2, E1, AND E2 REACTIONS 299

CHAPTER 10 NMR 315

CHAPTER 11 CONJUGATED SYSTEMS 319

CHAPTER 12 AROMATICS 327

CHAPTER 13 ALCOHOLS 341

CHAPTER 14 ETHERS 351

CHAPTER 15 ALDEHYDES AND KETONES 357

CHAPTER 16 CARBOXYLIC ACIDS 379

CHAPTER 17 CARBOXYLIC ACID DERIVATIVES 387

CHAPTER 18 CARBONYL Į-SUBSTITUTION REACTIONS AND ENOLATES 405

CHAPTER 19 CARBONYL CONDENSATION REACTIONS 413

CHAPTER 20 AMINES 427

Workbook organization and coverage. Arrangement is according to classical functional group

Grindstones sharpen knives; problem-solving sharpens minds!

ABOUT THE AUTHOR

SELECTED CONCEPTS/REACTIONS LOCATOR

Selected concept/reaction Chapter

Active methylene chemistry (e.g., malonic/acetoacetic 18

TIPS (TO IMPROVE PROBLEM SOLVING)

Hydrogen nomenclature. The word “hydrogen” is commonly misused. Be more specific.

A proton (H ) is removed by hydride (H: ) to form hydrogen (H2).

A hydrogen atom (H ) is removed by a free radical species.

State of association/dissociation. Correct identification of the appropriate charge state on a species in

and a proton is not directly available in base.

1.1 Hybridization, formulas, physical properties

b. Draw all the lone electron pairs in both structures.

a ____________ b ____________ c ____________

a. :C C: b. H C O: c. :O N O: d. the conjugate base of NH2CH3

BenadrylTM (antihistamine) zingerone (a constituent of the spice ginger)

a b c

penicillin V: C___H_N_O_S cimetidine: C_H_N___S

a b c

penicillin V: cimetidine:

sumatriptan: CHNOS prostacyclin: CHO

RozeremTM _____ ChantixTM _ RitalinTM _______

RozeremTM _ ChantixTM RitalinTM _

a. Calculate the molecular formula: C_H_O.