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Organic Stereochemistry - Basic Concepts and Applications
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Bogdan - Cătălin Şerban Marius Bumbac
Iosif Schiketanz Mihai - Viorel Popescu
Cristina Mihaela Nicolescu Octavian Buiu
ORGANIC STEREOCHEMISTRY
BASIC CONCEPTS & APPLICATIONS
O HO
O
OH O
HO HO
HO
O HO O
OH
OH HO
O
O
OH
OH HO
O
OH O
HO
OH OH
O HO
O
OH O
2018
PREFACE
Drugs, rubber, vitamins, cloth and paper, dyes and flavorings, plastic products,
preservatives, perfumes and toiletries – all these and many others are related to the
progress of organic chemistry. Organic chemistry is a fundamental science which
connects and supports many other scientific disciplines, while being strongly connected
to everyday life; it would be almost impossible to imagine our existence without the
contribution of organic chemistry.
“Better Things for Better Living...Through Chemistry”, an old DuPont advertising

slogan, can be reconfigured, with your permission, in “Better Things for Better
Living...Through Organic Chemistry”.
Why would we need to learn more about the stereochemistry of organic

compounds?
The plain answer is very simple: stereochemistry is a key, prominent issue for a
broad number of organic synthesis reactions. Furthermore, to better understand and
acknowledge the importance of stereochemistry, we will highlight here three important
issues:
1) Physical, chemical and biological properties of the molecules are strongly

dependent of their stereochemistry.
2) Enzymes and receptors exhibit stereoselective recognition of ligands and
substrates, thus the whole biochemistry cannot be understood beyond the borders
of stereochemistry.
3) Most of the drugs which are in use today are chiral molecules being marketed
either as racemic mixture or as single- form enantiomer.
The present book consists of two parts. The first part contains a very brief
overview of stereochemistry; it refers to fundamental theoretical aspects, concepts and
terms such as conformational and configurational isomers, Cahn-Ingold-Prelog
conventions for E/Z isomerism, R/S isomerism of chiral centres such as biaryls and
cumulated polyenes, etc.
The second part contains 164 problems and exercises. These have various levels
of difficulty and are presented in different formats such as multiple-choice questions,
standard stereochemistry exercises or simple questions. The content of this second part
has been developed to support your endeavor for understanding the basic, as well as
more subtle concepts and tools of stereochemistry.
Solutions are provided for all the problems and exercises; in many cases these are
accompanied by detailed explanations.
Beyond the traditional aspects of stereochemistry (chiral recognition elements,
establishing the number of stereoisomers, racemic mixture separation, identification of
the pairs of enantiotopic ligands or diastereotopic ligands, heterotopic faces, epimers
III
and epimerization, etc.), this includes also problems based on terms and concepts less
encountered in the stereochemistry workbooks such as ambo, molecular recognition,
quasi-enantiomers, solvation diastereoisomers, supramolecular chirality, criptochirality,
quasiracemate, mutarotation, Pfeiffer effect, protein folding, eudysmic ratio, serine
octamer cluster, etc.
The chiral molecules - based reaction schemes, aspects concerning the importance
of molecule’s geometry in establishing reactivity and reaction mechanisms, as well as
problems of chemical kinetics and thermodynamics are also included.
A great deal of attention has been paid in highlighting the importance of
stereochemistry in drugs design and pharmaceutical industry (see Thalidomide case,
detailed in the book).
The second part ends with a special section named “Did you know…?”. Here the
reader can find out about great scientists who have decisively influenced the
stereochemistry field, about chiral ligands which are widely used in asymmetric
synthesis or about pharmaceuticals that are currently marketed in racemic or single -
enantiomer form, etc.
The book will not provide you with a shortcut for learning stereochemistry, as it
was not written as a substitute for a textbook. Therefore, the reader is warmly advised
to read the literature cited at the end of the book, in order to achieve a deeper
understanding of stereochemistry.
This book is recommended for chemists, chemical engineers, molecular
pharmacologists and physicians. We also consider that this book can be very useful also
for Secondary School level students, in particular for those who are considering
participation at National and International Chemistry Olympiads.
If you spot any errors or if you have any suggestions or corrections, please let us know
by email: bogdanserbanchimist@gmail.com.
We hope this book will be useful in your studies.
Authors,
Bucharest, Romania
September, 2018
IV
CONTENT
Preface
List of abbreviations and symbols............................................................................ 1
Part 1
A very brief overview of stereochemistry ............................................................... 3
Part 2
Practice problems with detailed solutions & answers............................................. 11
Did you know..?....................................................................................................... 195
References ............................................................................................................... 201

Abbreviations and Symbols

Abbreviations
BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
CIP Cahn–Ingold–Prelog (CIP) sequence rules
Chiraphos (2S,3S)-(–)-Bis(diphenylphosphino)butane
(2R,3R)-(+)-Bis(diphenylphosphino)butane
DIOP O-Isopropylidene-2,3-dihydroxy-1,4-
bis(diphenylphosphino)butane
DIPAMP Ethane-1,2-diylbis[(2-methoxyphenyl)phenylphosphane]
DuPhOS 1,2-Bis((2R,5R)-2,5-alkylphospholano)benzene
(DHQ)2PHAL phthalazine adduct with dihydroquinine
(DHQD)2PHAL phthalazine adduct with dihydroquinidine
FDA Food and Drug Administration
FTIR Fourier - transform infrared spectroscopy
HDL high - density lipoprotein
HMG-CoA reductase hydroxymethylglutaryl-coenzyme A reductase
1
H-NMR proton nuclear magnetic resonance
HPLC high performance liquid chromatography
IHD index of hydrogen deficiency
IUPAC International Union of Pure and Applied Chemistry
LDL low - density lipoprotein
MCPBA meta-chloroperoxybenzoic acid
O.P. optical purity
ORD optical rotatory dispersion
SN1 unimolecular nucleophilic substitution
SN2 bimolecular nucleophilic substitution
THF tetrahydrofurane
TsCl p - toluenesulfonyl chloride
UV-VIS Ultraviolet - visibile
-1-
Symbols
C1 symmetry point group

DG the change in Gibbs free energy
E entgegen
K equilibrium constant
Ka acidity constant
k reaction rate constant
pH -lg[a(H+)]
R rectus
r descriptor for pseudo-asymmetric carbon
Re rectus face
S sinister
s descriptor for pseudo-asymmetric carbon
Si sinister face
Z zusammen
[]D20 specific rotation
equilibrium
Δ heating
movement of one pair of electrons
He@C60 helium - C60 complex
Ne@C60 neon - C60 complex
La@C60 lanthanum - C60 complex
La@C82 lanthanum - C82 complex
Sc@C80 scandium - C80 complex
-2-
A very brief overview of stereochemistry
Historically, the birth of the field of stereochemistry is related to development of

the tetrahedral model of the carbon atom by Jacobus Henricus van’t Hoff and Joesph
Achille LeBel. Their model successfully predicted that a tetrahedral atom surrounded by
four distinct substituents leads to two possible non-superimposable arrangements.
These two possibilities were then linked to previous observations reported by French
scientists such as Louis Pasteur that some chemical compounds, with identical chemical
formulae, rotate the plane of polarization of polarized light in opposite directions, but by
the same amount.
The term stereochemistry refers to the spatial distribution of atoms within a
molecule. Compounds that are stereoisomers have identical chemical connectivity, but
different spatial arrangements. Due to the multiple ways in which compounds can have
different spatial distributions of atoms, two main classifications have subsequently
emerged:
Conformational isomers: compounds that differ in structures due to rotations
around σ-bonds.
Sigma bonds such as C-C single bonds lead to “free” rotation along their axes, and
thus multiple conformers can be generated. Although it is called free rotation, in reality
the structures are energetically different due to electronic repulsions and steric clashes
within a given molecule. However, due to the small activation barriers in most cases, the
structures quickly interconvert to one another at room temperature. For example, ethane
(C2H6) has an activation barrier of approximately 12 kJ mol-1.
12
10
Energy / kJ mol-1
8
6
4
2
0
0 60 120 180 240 300 360
θ/o
Figure 1: Potential energy diagram of an ethane molecule with respect to the

dihedral angle
Configurational isomers: compounds that have the same chemical formula but
cannot be interconverted from one to another through rotation across σ-bonds.
-3-
Such compounds can therefore be separated from a mixture, as in general they

require high thermal energies to break the chemical bonds. Further classification of
configurational isomers includes:
- Geometric Isomers: compounds that cannot interconvert due to restricted rotation
as a consequence of the presence of a double bond or a ring system
Cahn-Ingold-Prelog convention for E/Z isomerism:

In order for science to be properly communicated, the International Union of
Pure and Applied Chemistry has decided that a standardised system of naming
compounds should be employed. In the case of geometric isomerism of organic
molecules, they have opted for the use of the E/Z model proposed by Chan, Ingold
and Prelog (CIP). Below we describe the rules for assigning E or Z isomerism, using
an alkene as a model:
1. We begin by assigning priorities to the substituents at each end of the double
bond.
2. Directly attached atoms receive higher priorities if they have higher values of the
atomic number Z.
3. If they are isotopes, the one with the higher mass number receives priority.
4. Lone pairs on heteroatoms receive the lowest possible priority.
5. If the two elements have the same value of Z, then we proceed to analyse their
substituents and keep going forward on the chain until a difference is found, and then
the priority is assigned.
6. If an atom of interest is attached with multiple bonds, such as double or triple
bonds to another atom, they are treated as if they are bonded twice or three times to
that element.
7. Once all the priorities have been assigned, the relative positions of the
substituents with the highest priorities are compared:
- If they are on the same side of the double bond, the geometry is said to be Z.
higher priority D O CH3 higher priority
The subsituent with the highest
priorities are on the same sides,
therefore it is the Z isomer.
H CH3
- If they are on opposite sides of the double bond, the geometry is said to be E.
H O CH3 higher priority
The subsituent with the highest
priorities are on different sides,
therefore it is the E isomer.
higher priority D CH3
COMMON MISCONCEPTION: An older nomenclature system, known as the cis

/ trans isomerism, is not applicable to molecules that have more than two types of
substituents attached to a double bond.
-4-
- Optical Isomers: compounds that have different rotations of the plane-polarized

light.
o Enantiomers: compounds that are non-superimposable mirror images of

each other. Typically, they rotate the plane-polarized light in opposite
directions, but by the same amount.
o Diastereoisomers: compounds that have the same chemical connectivity

but are not enantiomers. They give rise to different changes in the plane of
polarization but are not opposite in sign and do not have the same
magnitude (i.e., they are not enantiomers).
OH OH
COOH HOOC
HOOC COOH
OH OH
(2R,3S)-tartaric acid (2R,3R)-tartaric acid
The two compounds have different stereochemistry but are not mirror images of
each other.
Structural features leading to asymmetry:

As noted originally by van’t Hoff, a tetrahedral centre gives rise to two non-
superimposable arrangement of four different substituents that are mirror images of each
other. Such tetrahedral centres are called asymmetric centres.
Cahn-Ingold-Prelog convention for R/S isomerism of chiral centres

As with E/Z isomerism, the IUPAC organization has decided to use a
standardized systematic way of naming chiral centres, which was also proposed by
CIP, and is called R/S isomerism. Below we present the general procedure for
assigning R/S isomerism:
1. We assign priority to the four substituents, according to the same procedure as
in the E/Z isomerism.
2. We arrange the centre in such a way that the substituent with the lowest priority
is pointing away from the direction of view.
3. If the remaining three substituents are ordered in a “clockwise” fashion
according to their priority, the centre is said to be the R isomer. If they are ordered
“counter clockwise”, the centre is said to be the S isomer.
-5-
1 1 4 4 1
4
H NH 2 H 2N H H NH 2
COOH COOH redrawing
3 3 2
HOOC 3
2 2
clockwise rotation counter-clockwise rotation

R-isomer S -isomer
However, other structural elements, such as perpendicular planes in cumulated

polyenes of even numbers, restricted rotation in biaryls (atropisomerism), spiranes,
helical structural features, etc., may lead to generation of asymmetry. Of the multiple
asymmetric compounds, the most commonly encountered are cumulated polyenes and
biaryl.
A) Cumulated polyenes:
The simplest example of a cumulated polyene, with even number of double bonds,
is allene. Substituted allenes that have different substituents at each individual end do
possess inherent asymmetry. A mirror image of such a compound is not superimposable
with the parent structure and, as such they are enantiomers.
Me Me
H
. H H . H
Me Me
the two mirror images are non-superimposable
B) Biaryls:
Substituted biaryls, that are sterically conglomerated around the C-C bond
connecting the two aromatic rings, have high activation barriers to rotation. This may
give rise to two isolable conformers that are non-superimposable mirror images of each
other (i.e., enantiomers).
-6-
Cahn-Ingold-Prelog convention for R/S isomerism of biaryls and cumulated

polyenes
In the case of molecules possessing axes of chirality, the CIP convention for
assigning R/S labels will proceed as follows:
1. A Newman projection is constructed by visualising the molecule along the axis of
chirality.
2. Priorities are assigned for the substituents on the closest ring / double bond end.
3. Priorities are assigned for the substituents on the furthest ring / double bond end.
4. If the relative position of substituents 2 and 3 is clockwise by rotating from 2 to
3, then the axis of chirality is R. If on the other hand, the rotation is counter-clockwise,
then the axis of chirality is S.
Examples:
1
Br Br
O2N 4 3
O2N Br
Br
NO2 NO2 S
2
1
Me
Me 3 4
Me
Me H
H H
H
R 2
Meso compounds:
Although some chemical compounds with multiple structural features, such as two
or more chiral centres lead to asymmetry, they may be inherently symmetric due to the
presence of symmetry elements such as planes of symmetry or, occasionally, centres of
inversion. These types of compounds do no possess a non-superimposable mirror image
of themselves and are collectively called meso compounds.
Figure 2: Diagram showing the lack of asymmetry in meso-tartaric acid
-7-
Topicity:
In the study of organic molecules, it is sometimes useful to define the relationships

between different atoms of groups of atoms with respect to each other. The study of such
relationships is called topicity and it has many important implications in Nuclear
Magnetic Resonance (NMR) and asymmetric reactions such as biochemical processes.
The three types of relationships between atoms and groups are homotopicity,
enantiotopicity and diastereotopicity:
- Homotopicity: if one of two atoms or groups is replaced (i.e., changing a hydrogen

to a bromine atom) and the two possible resulting molecules are equivalent, it is said that
the atoms or groups are homotopic.
- Enantiotopicity: if one of two atoms or groups is replaced and the two possible
resulting molecules are enantiomers, it is said that the atoms or groups are enantiotopic.
replacing Ha D Hb
COOH
HOOC The two resulting
Ha Hb R- enantiomer
COOH compounds are
HOOC mirror images of
replacing Hb Ha D
each other
COOH
HOOC
S- enantiomer
- Diastereotopicity: if one of two atoms or groups is replaced and the two possible
resulting molecules are diastereoisomers, it is said that the atoms or groups are
diastereotopic.
-8-
Prochirality:
In terms of stereochemistry, prochirality refers to generation of chiral centres

through a single operation. The precursor centres can be either sp2 or sp3 hybridised
carbon atoms and are called prochiral centres:
- Prochirality of sp3 carbon atoms: tetrahedral centres that contain enantiotopic

atoms/groups are prochiral centres. The attached enantiotopic groups are also called
prochiral atoms/groups.
- Prochirality of sp2 carbon atoms: the two faces of trigonal planar carbon atoms,
such as alkenes or carbonyls are inherently different if three distinct groups are attached
to them. If a forth distinct groups is attached, a tetrahedral centre is formed, and a different
enantiomer can be obtained.
Pictorial representations of molecules:
Written depictions of molecules are essential in communicating chemical

knowledge. A properly written structural diagram can provide essential information on
reactivity and selectivity.
Today, the modern graphical representations using wedged and hashed bonds to
provide depth to the molecules (also known as skeletal formulas) are far superior to any
other representations. However, due to historical reasons, some older representations are
still employed today, especially in the field of sugar chemistry.
- Fischer Projections: The Fischer Projections are two-dimensional representations

developed by Hermann Emil Fischer in 1891 in order to describe with ease molecules
with many stereocentres such as carbohydrates.
Fischer Projections are generated by arranging the carbon sidechain vertically with
the most oxidised group pointing up. The stereogenic centre of interest is then viewed
from the direction from where the remaining two side groups are pointing, and the two-
dimensional projection is thus generated.
-9-
Another historical nomenclature system, derived from the Fischer projections, are
the D and L descriptors. By looking at the Fischer projection of monosacharides and
amino acids, if the stereocentre lowest down on the carbon backbone has its highest
priority group on the right side, then the molecule is D. Oppositely, if it is on the left,
then it is L.
- Haworth Projections: Sir Norman Haworth proposed a three-dimensional

representation of ring-closed sugars by depicting the furanose and pyranose rings
as being flat, with the substituents pointing above and below the plane of the rings.
H OH HO H
OH
HO H OH
HO O
H OH HH O HO H
HO
HO H H OH
OH OH OH
H O
CH2OH
modern 3D diagram Haworth projection Fischer projection
- 10 -
Practice problems with detailed solutions & answers
„Once a molecule is asymmetric, its extension proceeds also in an

asymmetrical sense. This concept completely eliminates the difference
between natural and artificial synthesis. The advance of science has
removed the last chemical hiding place for the once so highly esteemed
vis vitalis.”
H. E. Fischer
(Synthesen in der Zuckergruppe, Berichte der deutschen Chemischen
Gesellschaft, 1894, 27, 3189)
PROBLEM 1
Which of the compounds from the following reaction schemes are optically active?
Which of them are meso compounds?
1.Ba(OH)2/H2O HNO3
A B C
CHO 2. H3O+
H C OH + HCN
CH2OH
1.Ba(OH)2/H2O HNO3
A' B' C'
2. H3O+
CHO CHO
H C OH H C OH
HO C H H2 H C OH H2
D E
HO C H Ni - Raney H C OH Ni - Raney
H C OH H C OH
CH2OH CH2OH
CHO CHO
H C OH H C OH
HNO3
HO C H F HO C H HNO3
G
H C OH HO C H
CH2OH H C OH
CH2OH
- 11 -
Answer:
CN COOH COOH
HO C H HO C H HO C H
H C OH H C OH H C OH
CH2OH CH2OH COOH
optically active optically active optically active
A B C
CN COOH COOH
CH2OH CH2OH COOH
optically active optically active optically inactive
(meso compound)
A’ B’ C’
CH2OH COOH
CH2OH
H C OH COOH H C OH
H C OH
HO C H H C OH H C OH HO C H
HO C H H C OH HO C H HO C H
H C OH H C OH H C OH H C OH
CH2OH CH2OH COOH COOH

optically inactive optically inactive optically inactive optically inactive
(meso compound) (meso compound) (meso compound) (meso compound)
D E F G
PROBLEM 2
Prove that the following Fischer projection formulas represent the same optically
active carboxylic acid:
CH2 H3C COOH

CH CH3 H3C
C C CH2
CH3 H3C
CH2 C C CH
CH3
COOH CH2
A B
- 12 -
COOH CH3
H2C CH C C
CH 3
CH2 CH3
Answer:
The substituent priority, in decreasing order, is:
CH3
HOOC > C CH3

>HC 2 CH > CH 2
CH3
Therefore:
(3) (3)
CH2 CH2
CH CH3 CH CH3
CH3 change CH3
(4) CH2 C C (2) (1) HOOC C C (2)
of configuration
CH3 CH3
COOH CH2
(1)
(4)
(R) (S)
(1) (3)
CH2
H3C COOH CH CH3
H3C CH3
(2) C C CH2 (4) (4) CH2 C C (2)
H3C CH3
CH COOH
CH2
(3) (1)
(R) (R)
- 13 -
Changing the place of all substituents, two by two (or, in general, an even number
of changes), does not change the configuration of the molecule.
(1)
(1)
COOH CH3
COOH
(3) H2C CH C C CH (2)
3
CH2 CH3 C Benzyl (4)
H2C CH t-Bu
(3) (2)
(4)
(R)
(R)
PROBLEM 3
2-Phenyl-1,2,3-propanetriol is esterified with butyric acid.

a) What is the number of ester isomers that can be formed in this reaction?
b) How many distinct fractions can be separated from the reaction mixture using
common physical methods?
c) How many distinct fractions can be separated from the reaction mixture if we use
(+)-2-methylbutanoic acid instead of butyric acid?
Answer:
H2C OH
a) H5 C 6 C OH + H3C (CH2)2 COOH
H2C OH
O
OH
H2C O C (CH2)2 CH3 H2C O
H5C6 C OH H5C 6 C O C (CH2)2 CH3
H2C OH H2C
OH
(±)
3 monoesters
- 14 -
O O
H2C O C (CH2)2 CH3 H2 C O C (CH2)2 CH3
H5C6 C O C (CH2)2 CH3 H 5C 6 C OH
H2C O H2 C O C (CH2)2 CH3
OH
O
(±)
3 diesters
O
O C (CH2)2 CH3
H2C O
H5C 6 C O C (CH2)2 CH3
H2C
O C (CH2)2 CH3
O
There are 7 esters formed in total: 3 monoesters, 3 diesters and one triester.
b) Racemic mixtures cannot be separated using usual physical methods. Because of
this, only five distinct fractions can be separated (two of which are racemic).
c) If during the esterification (+)-2-methylbutanoic acid is used, seven distinct
fractions can be separated (diastereoisomers are formed, with different physical and
chemical properties).
PROBLEM 4
Determine the number of stereoisomers for the following compounds:
O
O
(Show the spatial formulas for the
a) diastereoisomers)
HC CH HC CH COOH
b) HC C C C HC C CH CCl CCl CBr CBr CH2OH
Cl
Cl Cl
c)
Cl
- 15 -
Cl
d) Cl
Cl
Answer:
O O
O O
a) H H
H H
H H
HOOC H HOOC H
 - cis,  - trans  - trans,  - cis
O O
O O
H H
H H
H H
H COOH H COOH
 - cis,  - cis  - trans,  - trans
b) Eight stereoisomers:
(+)-Z-Z (+)-E-Z (-)-Z-Z (-)-E-Z
(+)-Z-E (+)-E-E (-)-Z-E (-)-E-E
c) There are two asymmetric and two pseudo-asymmetric carbon atoms. There are
eight diastereoisomers in total, four meso compounds and two pairs of enantiomers.
d) There are two asymmetric carbon atoms. The number of enantiomers is halved
because of the bridge. As such, there are only two enantiomers.
PROBLEM 5
Which of the following compounds are optically active?
- 16 -
Cl Cl
Cl Cl
CH3 Cl Cl
H
Cl N Cl
Cl Cl
Cl Cl
Cl Cl
twistane
Cl
A B C
COOH
Fe
I
CH3
D E F
CH2OH
CH3 O
H C Cl
Cl C H
H 3C H C Cl
CH3
CH2OH
G H I
I
I
I I
I
I
K
Answer:
A - asymmetric molecule;
C - perchlorotriphenylamine is chiral due to hindered rotation;
E - non-coplanar ring system;
F - achiral. For this type of compound to be chiral it must have at least two different
substituents on one ring;
The following compounds are optically active: A, C, E, G and H.
- 17 -
PROBLEM 6
C2H5OOC H NO2
N I H HOOC
C2H5OOC N
OCH3 O2N
COOH
A B C
CH3
I I
H I H COOCH3
H H
H H H3C COOCH3
N H H
I H O OCH3
CH3 CH3
CH3
D E F
12 13
CH2 S CH2 Sb COOH
O
G H
Cl Br
H5C2 C2H5 H C2H5

H H
H H H5C2 H
I K
Answer:
A – chiral nitrogen atom;

C – atropisomerism;
E – chiral nitrogen and carbon atoms.
The following compounds are optically active: A, C, E, G, H, K.
- 18 -
PROBLEM 7
Determine the number of stereoisomers for each of the following compounds:
F OH
Cl I Cl
H OH H
Cl Cl OH
A B C
O
H2 C O C (CH2)n CH CH (CH2)p CH3
O
HC O C (CH2)18 CH3
H2 C O C (CH2)n CH CH (CH2)p CH3

O
D
Answer:
Compound A - four stereoisomers (two meso compounds and a pair of enantiomers).
Compound B - eight stereoisomers:
Z-(+)-Z Z-(+)-E Z-(-)-Z Z-(-)-E
E-(+)-E E-(+)-Z E-(-)-E E-(-)-Z
Compound C - four stereoisomers (two meso compounds and a pair of enantiomers).

Compound D - four stereoisomers: cis-cis, trans-trans, (+)-cis-trans, (-)-cis-trans.
PROBLEM 8
Write down the stereoisomers for the following compounds:

a) HOOC (CHBr)3 COOCH3
b) H2N C (CHCl)4 C NH2

O O
Answer:
COOH COOH COOH COOH
H C Br Br C H Br C H H C Br
a) H C Br Br C H H C Br Br C H
H C Br Br C H H C Br Br C H
COOCH3 COOCH3 COOCH3 COOCH3
(±) (±)
- 19 -
COOH COOH COOH COOH

H C Br Br C H H C Br Br C H
Br C H H C Br H C Br Br C H
H C Br Br C H Br C H H C Br
(±) (±)
- eight stereoisomers, four racemic mixtures.
CONH2 CONH2
CONH2 CONH2
H C Cl Cl C H Cl C H H C Cl
H C Cl H C Cl H C Cl Cl C H
b)
H C Cl Cl C H H C Cl Cl C H
CONH2 CONH2
CONH2 CONH2
meso compound (±)
meso compound
CONH2 CONH2 CONH2 CONH2

Cl C H H C Cl H C Cl Cl C H
CONH2 CONH2 CONH2 CONH2
(±) (±)
CONH2 CONH2
Cl C H H C Cl
Cl C H H C Cl
H C Cl Cl C H
H C Cl Cl C H
CONH2 CONH2
(±)
- two meso compounds and four racemic mixtures.
PROBLEM 9
Photochemical cycloaddition of cinnamic acid leads to the formation of two acids:
- 20 -
COOH
CH CH COOH
h
HOOC CH CH HOOC
truxillic acid
CH CH COOH COOH
h
CH CH COOH COOH
truxinic acid
a) How many stereoisomers truxillic acid has?

b) How many stereoisomers truxinic acid has?
Answer:
Ph COOH
Ph COOH
Ph
HOOC Ph
a) HOOC
meso compound meso compound
has planes of symmetry has plane of symmetry
Ph COOH Ph
Ph
COOH
HOOC Ph HOOC
meso compound
has a centre of symmetry meso compound
has planes of symmetry
- 21 -
Ph COOH
HOOC
Ph
meso compound
has plane of symmetry
- there are five meso compounds.
b) Ph
Ph COOH
Ph
Ph COOH COOH
COOH
Ph COOH HOOC Ph
Ph Ph
COOH HOOC
(±)
COOH HOOC
Ph Ph
Ph Ph
COOH HOOC
(±)
Ph COOH HOOC Ph
Ph COOH HOOC Ph
(±)
Ph COOH HOOC Ph
COOH HOOC
Ph Ph
(±)
- there are two meso compounds and four racemic mixtures.
- 22 -
PROBLEM 10
Write down the stereoisomers for the following compound:
H3COOC (CHCl)5 COOCH3
Answer:
H C Cl H C Cl Cl C H H C Cl
H C Cl Cl C H Cl C H Cl C H
H C Cl H C Cl Cl C H H C Cl

meso compound
mezoformã meso compound
mezoformã meso
mezoformã
compound meso compound
mezoformã

(±) (±)

Cl C H H C Cl Cl C H H C Cl
(±) (±)
- 23 -

Cl C H H C Cl Cl C H H C Cl
(±) (±)
- four meso compounds and six racemic mixtures.
PROBLEM 11

Br
OH
a)
F
OH
F
b)
F
O
H2 C O C (CH2)18 COOH
O
c) HC O C (CH2)7 CH CH CH2 CH3
H2 C O C (CH2)4 CH CH (CH2)10 CH3

O
d) H3C CH2 CH CH CH Br
Cl
Answer:
a) three asymmetric carbon atoms: eight stereoisomers;

b) three asymmetric carbon atoms: eight stereoisomers;
c) eight stereoisomers
(+)-trans-trans (+)-trans-cis (-)-trans-trans (-)-trans-cis
(+)-cis-cis (+)-cis-trans (-)-cis-cis (-)-cis-trans
d) four stereoisomers:
(+)-E (+)-Z
(-)-E (-)-Z
- 24 -
PROBLEM 12
Which of the following compounds are chiral? Indicate the number of stereoisomers
for the chiral compounds.
Cl
a) Br
H3C CH2 N CH2 CH3

b)
H OH
CH3
c)
H
d) H3C CH2 CH CH CH CH CH3

Cl Br
Answer:
a) chiral: eight stereoisomers (4 racemates: exo-exo, endo-endo, exo-endoand endo-exo);

b) two stereoisomers (a pair of enantiomers);
c) chiral: four stereoisomers;
d) chiral: eight stereoisomers:
(+)-Z-(+) (-)-Z-(+) (+)-E-(+) (-)-E-(+)
(+)-Z-(-) (-)-Z-(-) (+)-E-(-) (-)-E-(-)
PROBLEM 13
a)
- 25 -
CH3
NH
b)
CH3
OH
CH3
CH2
OH CH OH
CH3 CH2 CH C CH CH2 CH3
c) HO CH OH
CH2
CH3
OH
d)
CH3
Answer:
a) achiral;
b) chiral: four stereoisomers;
c) four enantiomers and a meso compound (five stereoisomers);
d) achiral.
PROBLEM 14

O OH
Cl Br
CH3 H3C
O
CH3
HO OH
CH3 Br
C Cl
O
OCH3
A B
- 26 -
OCH3 OCH3
OH H3CO OCH3
OCH3 OCH3
OH
C D
H3 C O CH3
I I
CH3 I
N I I
O NH
H3C I
S
N O
E F
OH OH
OH OH
NH OH
HO
OH
HO
OH
G H
CH CH2
H2C
+ Cl Cl
N CH I
3
CH2
Cl Cl
Cl Cl
I K
Answer:
Compounds that are optically active: A, C, E, G, I.

Compound B is achiral; it has a symmetry centre.
Compounds D, F, H, K are achiral (plane of symmetry).
- 27 -
PROBLEM 15
CH3 CH3
Cl
CH3
CH CH
H3C
CH3 CH3
A B
CH2OH
H C Cl
OH Cl C H
N O
H C Cl
N O
Cl CH2OH
C D
O
(R) Cl C2H5 Br (S)
COOH
Br CH HC Cl
C2H5
O
E F
(R) CH3 Cl CH3 (S)

HO CH HC OH
Br
Cl
Br
G H
- 28 -
CH3 (R) Cl C2H5

O O Br CH
NH
HC Cl
C2H5 Br (S)
I K
Answer:
Compound K is achiral, it has a centre of symmetry.

Compounds B, D, E, G are achiral (plane of symmetry).
Compound F has ansa type of isomerism (ansa = handle).
Compounds that are optically active: A, C, F, H, I.
PROBLEM 16
CH3
HC Cl
a) H3C CH C H
Cl HC Cl
CH3
CH3
Br CH Br
b) H3C CH C CH CH3
Br HC Br
CH3
H3C
Br
c) H3C C
Cl
Cl Cl
d) HOOC C CH2 C COOH
H H
- 29 -
Answer:
a) four stereoisomers:
H H H H
(R) C (R) (S) C (S) (R) C (R) (S) C (S)
(R) (S) (S) (R)
(±) (±)
b) five stereoisomers:
(R) (S) (R) (S)
(R) C (R) (S) C (S) (R) C (S) (R) C (S)
(R) (S) (R) (S)
(±) (±)
(R)
(R) C (S)
(S)
meso compound
c) a pair of enantiomers;
d) three stereoisomers: a pair of enantiomers and a meso compound.
PROBLEM 17
Using optically pure (+)-tartaric acid, separate the following racemic mixtures:
a) ()-2-pentanol b) ()-amphetamine
Answer:
OH
CH3 C CH2 CH2 CH3
a)
H
COOH
(R)-2-pentanol
H C OH H+
+
OH HO C H
CH3 CH2 CH2 C CH3 COOH
H (R,R)-(+)-tartaric acid
(S)-2-pentanol
- 30 -
O CH3 O n-Pr
C O C H C O C H
H C OH n-Pr + H C OH CH3
HO C H HO C H
COOH COOH
(R)-2-pentyl-(R,R)-tartrate (S)-2-pentyl-(R,R)-tartrate
The tartrate mixture is separated chromatographically and then each diastereoisomer is

hydrolyzed in an acidic medium:
H+
(R)-2-pentyl-(R,R)-tartrate + H2O (R)-2-pentanol + (R,R)-(+)-tartaric acid
(excess)
H+
(S)-2-pentyl-(R,R)-tartrate + H2O (S)-2-pentanol + (R,R)-(+)-tartaric acid
(excess)
C6H5
CH2
b) CH3 C NH2
H COOH
(S)-amphetamine H C OH H+
+
C 6 H5 HO C H
CH2 COOH
H2N C CH3 (R,R)-(+)-tartaric acid
H
(R)-amphetamine
C6H5 C6H5
CH2 CH2
+ +
H3C C NH3 COO -
COO -
H3N C CH3
H H C OH + H C OH H
HO C H HO C H
COOH COOH
Two diastereoisomeric salts are obtained which are separated based on their
solubility difference. After the separation, salts are hydrolyzed in a basic medium to
obtain (R)-amphetamine and (S)-amphetamine.
PROBLEM 18
- 31 -
CH3
I
O
Cl
CH3
I
CH3 H
A B C
CH2 CH2
H2C CH2 CH3
H
HOOC CH2 H COOH
CH2 Fe
I
H2C CH2 I
CH2 CH2 CH3
D E F
Cl+ H3C
H
H3C H
H3C
Br+
H3 C
H H
G H
HOOC H
C As
C2H5
Fe(CO)4 H5C6
C CH3
H COOH
I K
Answer:
Compound D has ansa type of isomerism.

Compounds A, D, F, I and K are optically active.
- 32 -
PROBLEM 19
CH3
N
CH3
N
H3C
H
A B
CH3
Cl H
N
CH3
H3C CH3
C D E
D D
Ph CH3
N
Ph
H H
F G
Cl NO2 COOH
CH3
NO2 COOH
H I
H3C
P
H3C CH2 CH2
H5C 6
K
Answer:
Compounds A, D, F, H and K are optically active.
- 33 -
PROBLEM 20

Cl F F COOH
Br
Br
HOOC F F Cl
A B
C6H5 COOH
H H C C C
H H
COOH C6H5
C D
TsO-
HOOC O O CH3 CH3 CH3
C C C N
COOH CH3
H3C O O CH3
E F
H H5C2 H
N C C C
H H H
N
nicotine
G H
16
O H5C2 H
CH2 S CH3 C C C
18 H5C2 H
O
I K
Answer:
Compounds A, D, E, G and I are optically active.
- 34 -
PROBLEM 21

H3CO OCH3 COOH
H
H3C CH2 CH2 C OH
D
HOOC H CO OCH3
3
A B
CH3 H3CO F COOH
COOH
HOOC F OCH3
Br
C D
Br
H
C C C
H
Br Br
Br
E F
COOH
HOOC
H2C CH2
H2C CH2
COOH
H
G
COOH
H C OH
H C OH
COOH
COOH
I K
- 35 -
Answer:
Compounds A, C, E, G, H and K are optically active.
PROBLEM 22
H H
H H
H 3C H
C H H
H I C
H 3C CH3
H COOH
I H
A B C
H H
H F
H H C C
H H Si
H CH3
Cl
CH3
I I
D E F
CH2I
HO3S CH2
H C I
Si CH3
H C I
CH2I CH3
G H I
H H
I I
K
Answer:
Compounds A, C, E, G and I are optically active.
PROBLEM 23
for the chiral compounds:
- 36 -
F
H
N OH
HOOC F F
Cl
F
A B C
Cl
O
Cl
P O O
F H3 C CH3
NH2
D E F
CH3
H C Cl COOH CH3
CH2 O
I
H C Cl
D C CH3
CH2
H
H C Cl
H3C CH2
CH3
G H I K
Answer:
The optically active compounds are:

- A (two stereoisomers);
- D (seven stereoisomers);
- E (two enantiomers);
- I (two stereoisomers);
- K (two stereoisomers).
PROBLEM 24
- 37 -
O
H3C Br Cl
NH O
HN
C
H H2C NH
O NH Cl
CH3 Br
O
A B C
OCH3
O OH
Cl
D E F
O
NH2
H2C
H
H C OH
H C OH
H H H2C
HO NH2
O
G H
OH
O
I K
Answer:
- B (two stereoisomers);
- D (two stereoisomers). Although there are two asymmetric carbon atoms, there is
only one levorotatory form and one dextrorotatory form (racemic mixture);
- E (four stereoisomers: two racemic mixtures);
- G (eight asymmetric carbon atoms: 256 stereoisomers);
- I (three asymmetric carbon atoms: eight enantiomers, four racemic mixtures).
PROBLEM 25
- 38 -
(CH3)3C C(CH3)3
C C C C C
C C C C
Cl CH2 H2 C
Cl H3C CH3
A B
CH3 CH2 CH2 H

COOH
C C C
CH3 CH2 CH2 CH2 CH2 CH3 COOH
C D
C 2H 5 O
O H2C Cl
H C Cl C CH3
C CH3 H C OH H3C N
H3C N SO3H CH2
HO C H SO3H
CH2
H C OH
H C Cl
H2C Cl
C 2H 5 CH3
E F G H
H I
H NH2
H H
H H NH2
H
I H
I K
Answer:
The optically active compounds are: A, D, E, H and K.
PROBLEM 26
of the chiral compounds:
- 39 -
OH O
OH
HN NH
OH
HO O
OH S COOH
A B
CH3
COOH
O2N C H H C NH2
H C OH
CH3
CH3
C D
Answer:
- A: chiral – four stereoisomers ((±)-catechin, (±)-epicatechin);
- B: chiral – eight stereoisomers;
- C: achiral;
- D: chiral – four stereoisomers.
PROBLEM 27
Write down the stereoisomeric structures of the following compounds:

a) H5C2-(CHI)3-C2H5;
b) 1,2,3-triiodocyclohexane.
Answer:
C2H5 C2H5 C 2H5 C 2H5
H C I H C I H C I I C H
a) H C I I C H I C H H C I
H C I H C I I C H H C I
C2H5 C2H5 C 2H5 C 2H5
meso compound meso compound _
(+)
- two meso compounds and one racemic mixture.
- 40 -
I I
I H
I I
b) H H
H I
H H
I I
I I
I I
(±)
- two meso compounds and one racemic mixture.
PROBLEM 28
How do you determine the optical purity of a non-racemic mixture of 1-
phenylethylamine using the following optically pure compound?
O
CH C Cl
OCH3
Answer:
CH3 O CH3 O
C NH2 + Cl C CH C NH C CH
H OCH3 H OCH3
(R) A
O O
H3C C NH2 + Cl C CH H3C C NH C CH
H OCH3 H OCH3
(S) B
If we examine the 1H-NMR spectrum of the two enantiomers, we will see a doublet
for the methyl protons (enantiomers have identical 1H-NMR spectra).
The obtained diastereoisomeric amides are different and each methyl group will
have its own doublet.
- 41 -
From the intensity ratio of the two peaks we can determine the molar ratio of the
two diastereoisomers, and thus the molar ratio of enantiomers existing in the non-racemic
mixture.
[ A] [ R]
Let the following be the molar ratio: x  x  [ R]  x  [ S ] , x > 1
[ B] [S ]
[ R] x
The molar fraction of R is: R  
[ R]  [ S ] x  1
[S ] 1
The molar fraction for S is: S  
[ R]  [ S ] x  1
The optical purity is:

R-S x-1
O. P. %= ·100= ·100
R+S x+1
PROBLEM 29
a) Propose a separation scheme of a racemic mixture of mandelic acid using optically

pure (-)-menthyl amine.
b) Is it possible to separate the racemic mixture using a chromatographic column
packed with starch?
Answer:
a)
COOH
H C OH
COO-
H C OH
+ NH2 +
H3N
(R)
mandelic (-)-menthyl amine
acid
diastereomeric
COOH salts
- fractional crystallization -
HO C H COO-
HO C H
+ NH2 +
H3N
(S)
mandelic (-)-menthyl amine
acid
- 42 -
COO- COOH
H C OH H C OH
+
H3N + H+Cl- + NH3+ Cl-
(R) (-)-menthyl amonium

mandelic chloride
acid
COO- COOH
HO C H HO C H
+
H3 N
+ H+Cl- + NH3+
(S) (-)-menthyl amonium

mandelic chloride
acid
b) The racemic mixture can be separated (to some extent) given the different
interactions between the enantiomers with a chiral absorbing medium (such as starch).
Other optically active absorbing materials are: (-)-quartz, cellulose, lactose, alumina
covered in chiral compounds, etc.
PROBLEM 30
a) Write down all the stereoisomers of difluorocyclopentane.
b) Which of the following reaction products, respectively the final mixture, present
optical activity:
+ Cl2
H5C2 C2H5
+ Cl2
C 2 H5
+ Cl2
CH2
- 43 -
C 2 H5
Ni
+ H2
C2H5
C2H5
+ Br2
H C2H5
All transformations are considered quantitative.
Answers:
F H H H F F H
a)
F F F F H H F
achiral achiral (+
)
H F F
H H H
F H H
F F F
achiral
(+
)
Cl Cl Cl Cl
b) + Cl2 +
H5C2 C2H5 H5C2 C2H5 H5C2 C2H5

optically active optically active
The reaction mixture is racemic;
it does not have optical activity
- 44 -
+ Cl2 Cl + Cl
C2H5 H5 C 2 Cl H 5C 2 Cl

+ Cl2
CH2 Cl CH2 Cl
achiral
C 2 H5 C2H5 C2H5
C 2 H5 + H2 C2H5 + C2H5
C2H5 H5 C 2 H H5 C 2 H
Br Br
+ Br2 +
Br Br
H5C2 H
H5 C 2 H H5C2 H
The two compounds are diastereoisomers;
the final mixure is optically active
PROBLEM 31
The mixture of alkenes obtained through dehydrohalogenation of the following
compound:
CH3
CH2 CH C CH3
CH3 Cl
was catalytically hydrogenated.
- 45 -
The obtained hydrocarbon has an optical purity of 20 %.

Determine the molar ratio of the obtained alkanes.
Note: The halogenated compound is optically pure.
Answer:
CH3
CH2 C C CH3 A
CH3 CH3
achiral
CH2 CH C CH3
CH3 Cl CH3
optically pure CH2 CH C CH2 B
CH3
chiral
optically pure
CH3 CH3
H2
CH2 C C CH3 CH2 CH CH CH3 80 %
Ni
CH3 CH3
(±)- chiral
racemic mixture
CH3 CH3
H2
CH2 CH C CH2 CH2 CH CH CH3 20 %
Ni
CH3 CH3
chiral
optically pure
In the first hydrogenation reaction a racemic mixture is obtained, while in the second
reaction an optically pure chiral compound is obtained.
The optical purity is 20 %, which means that the proportion of the optically active
compound is 20 % and the racemic mixture has a weight of 80 %.
[ A] 80
Because of this, the ration of the two alkanes is   4.
[ B] 20
PROBLEM 32
Write down all the stereoisomers of the following compounds:
a) C3H4F2 (cyclic compound);
b) C3H4FCl (cyclic compound);
c) C4H6F2 (four membered cyclic compound);
d) C4H6FCl (four membered cyclic compound).
- 46 -
Answer:
F H H H F F H
a)
F F F F H H F
achiral achiral enantiomers
F H H H H H Cl Cl H
b)
Cl F Cl Cl F F H H F
achiral enantiomers enantiomers
F H H
H F F H
c)
F F F
F H H F
achiral achiral (+
_)
H F
H H
F H
F F
achiral achiral
H Cl
F
d) H H
Cl H
Cl
achiral F F
achiral achiral
F Cl Cl F F H H F
H H H H H Cl Cl H
(+
_) (+
_)
PROBLEM 33

Determine the number of stereoisomers of the chiral compounds.
- 47 -
HO
a) N
R
N
CH2
b) N
HO OH
c)
d) COOH
N
H
Answer:
a) 5 asymmetric atoms (4 carbon atoms and one nitrogen atom).
There should be 25 = 32 isomers, however, the nitrogen and one carbon atom are held
tightly in a bicyclic system, reducing the number of isomers to 16 (a similar situation
exists in camphor);
b) The cis-cis, trans-trans, cis-trans diastereoisomers can be separated in enantiomers.
In total there are 3 racemic mixtures, corresponding to the three diastereoisomers;
c) 4 stereoisomers (2 enantiomers, 2 meso compounds);
d) 2 stereoisomers.
PROBLEM 34
Determine the configuration of the chiral atoms (according to Cahn-Ingold-Prelog
convention) for the following compounds:
Ph CHO
C C CH2OH
A
O COOH
CH3
CH3
O C
B C
C CH
- 48 -
H2C CH3
CH
C CH3 C
Answer:
a) The order of priorities is as follows:
COOH > C6H5 C O > CHO > CH2OH
(3)
Ph CHO
(2) C C CH2OH (4)
O COOH
(1)
By interconverting two substituents, the configuration of the chiral atom is
inversed.
Ph CHO CHO
Ph
C C COOH C C CH2OH
O CH2OH O COOH
(R) (S)
Therefore, the asymmetric carbon atom of compound A has S configuration.
b) The order of priorities is as follows:

CH3
O C > H3C C6H4 >C CH > C6H11
o - tolil
(1)
O CH3
C
(4) C (2)
C
CH3
C
H
(3)
- 49 -
By interconverting two substituents the configuration of the chiral atom is inversed.
O CH3 O CH3
C C
HC C C C
C
CH3 CH3
C
H
(R) (S)
Therefore, the asymmetric carbon atom has S configuration in compound B.
c) The order of priorities is the following:
H3C C6H4 > H3C C6H4 > C6H5 > HC CH2

m - tolil p - tolil
(4)
CH2
CH3
CH
(2) H3C C (1)
(3)
By doing an even number of interconversions, the configuration of the chiral atom

remains the same.
CH2
CH3 H3C
CH
H3C C C CH3
CH
CH2
(S) (S)
Therefore, the asymmetric carbon atom of C compound has S configuration.
- 50 -
PROBLEM 35
A racemic mixture of 2-hexanol reacts with (S)-methylbutyric acid to form the

respective esters.
The obtained reaction mixture is subjected to fractional distillation. Assuming that
the racemic mixture is in excess, compared to the optically active acid, estimate:
a) How many fractions are collected during distillation? How many of them are
optically active?
b) How many compounds are collected during distillation?
Answer:
a) The enantiomers in the 2-hexanol racemic mixture react differently with the optically
pure reagent.
Therefore, two diastereoisomeric esters will be formed in the reaction mixture at
equilibrium, and the two enantiomers will be present (with one of them being in excess).
Consequently, three fractions will be collected (two diastereoisomeric esters and a
mixture of the two enantiomers). All three fractions are optically active.
b) Four compounds are collected: two diastereoisomeric esters and (R)- and (S)-2-
hexanol.
O
(S)
O
Me
(S)
O
(S)
OH O
HOOC Me
+ (R)
Me
(R) + (S) (S)
excess OH
(S)
OH
(R)
PROBLEM 36
Determine the number of stereoisomers of the following compound:
- 51 -
1 1
CH3
CH C CH2 CH3
CH C Cl
CH3
2 2
Answer:
The compound has two asymmetric carbon atoms and two double bonds that can
have E / Z configurations.
There are 16 diastereoisomers in total:
R1-R2-E1-E2 R1-R2-Z1-Z2 R1-R2-E1-Z2 R1-R2-Z1-E2
R1-S2-E1-E2 R1-S2-Z1-Z2 R1-S2-E1-Z2 R1-S2-Z1-E2
S1-R2-E1-E2 S1-R2-Z1-Z2 S1-R2-E1-Z2 S1-R2-Z1-E2
S1-S2-E1-E2 S1-S2-Z1-Z2 S1-S2-E1-Z2 S1-S2-Z1-E2
PROBLEM 37
Which of the following compounds are chiral? Determine the number of
stereoisomers.
a) Br
O
Cl
NH2
CH2OH
b)
N
CH3
c)
N
OH
d)
OH
- 52 -
Answer:
a) Two achiral stereoisomers;

b) The compound has two asymmetric atoms (four stereoisomers, two pairs of
enantiomers);
c) Four stereoisomers (two pairs of enantiomers);
d) Four stereoisomers (two enantiomers and two meso compounds).
PROBLEM 38

stereoisomers for the chiral compounds.
COOH
H
a)
N
H
H COOH
b)
N
H
H COOH
c) H COOH
N
H
d)
HOOC N COOH
H
Answer:
a) Two stereoisomers;
b) Achiral (meso compound);
c) Chiral (four stereoisomers);
d) Three stereoisomers (trans - (), cis: meso compound).
PROBLEM 39

stereoisomers for the chiral compounds.
- 53 -
CH3
HO
a)
HO
CH3
Br
CH Cl
b)
Br
Br Br
c)
O O
COOH
HOOC COOH
d)
HOOC
Br
Cl
e)
Cl
Br
CH3O OCH3
OCH3
f)
OCH3
HO
COOC2H5
g)
HO
h) H3C CH Cl
OCH3
Answer:
a) Achiral (meso compound);

b) Chiral (four stereoisomers: two pairs of enantiomers);
- 54 -
c) Six stereoisomers (three pairs of enantiomers);

d) Achiral;
e) Achiral (meso compound);
f) Chiral (two stereoisomers);
g) Four stereoisomers (two enantiomers and two meso compounds);
h) Chiral (two stereoisomers).
PROBLEM 40
Which of the following compounds display cis-trans (Z/E) isomerism?
H C2H5
a) C C C
H C2H5
Cl C2H5
b) C C
Cl H
CH3
H2C
c)
H3 C C N
S CH3
CH3
d) CH COOH
N
H
CH3 H3C
H3C CH3
C C C
e)
O2N NO2
f) N N
- 55 -
g)
C CH
3
H5C2
h)
Cl Br
i) C C
Cl Br
Answer:
The following compounds display cis-trans (Z/E) isomerism: c, d, f, g and h.

In the case of compound c, the resonance gives a double bond character to the single
bond, which prevents the rotation around its axis.
PROBLEM 41
Optically pure (-)-2-bromooctane has []D20 = -39.6. Knowing that (+)-2-octanol
has []D20 = +10.3, calculate the optical purity and the retention percentage of a solution
of 2-bromooctane with []D20 = -15.84 treated with a solution of sodium hydroxide,
obtaining 2-octanol with []D20 = +2.0.
Note: The reaction is carried out under conditions in which both types of substitutions
(SN1 and SN2) are possible.
Answer:
We note: a – molar fraction of (-)-2-bromooctane
b – molar fraction of (+)-2-bromooctane
p – retention percentage
n – inversion percentage
We can write the following scheme:
p (-)-2-octanol p (+)-2-octanol
ap bp
(-)-2-bromooctane (+)-2-bromooctane
a n (+)-2-octanol b n (-)-2-octanol
an bn
- 56 -
We can write:
a+b=1
p+n=1
-15.84 = a(-39.6) + b(+39.6)
2.00 = (+10.3)(an+bp)+ (-10.3)(ap+bn)
By solving the system, we obtain the following results:
a = 0.70; b = 0.30; p = 0.2575; n = 0.7425
The optical purity of the reactant is:
a-b 0.7 - 0.3

O. P. = ∙100 = ∙100 = 40 %
a+b 0.7 + 0.3
The optical purity of the alcohol is:

2.00
O. P. = ∙100 = 19.41 %
10.30
The retention percentage is: p = 25.75 %

The inversion percentage is: n = 74.25 %
PROBLEM 42
Calculate the equilibrium composition for the following reactions taking place at 25 oC:
HgCl (axial) HgCl (equatorial)

a)

G = + 0.25 kcal/mol
NO2 (axial) NO2 (equatorial)

b)

G = -1.10 kcal/mol
NH2 (axial) NH2 (equatorial)

c)

G = -1.40 kcal/mol
- 57 -
CH3 CH3
d) O O
S S
O O O O
(axial) (equatorial)

G = -0.52 kcal/mol
Answer:
a) G = + 0.25 kcal/mol
axial ecuatorial
G   RT ln K  250 cal  mol 1  1.987 cal  mol 1  K 1  298 K  ln K 

[equatorial] x
K  0.656    0.656  x  0.396
[axial ] 1 x
% equatorial = 39.6 %
% axial = 60.4 %
b) G = -1.10 kcal/mol
G   RT ln K  1100 cal  mol 1  1.987 cal  mol 1  K 1  298 K  ln K 

[equatorial] x
 K  6.409    6.409  x  0.865
[axial] 1 x
% axial = 13.5 %
c) G = -1.40 kcal/mol

[equatorial] x
 K  10.637    10.637  x  0.914
[axial] 1 x
% axial = 8.6 %
d) G = -0.52 kcal/mol
[ecuatorial ] x
 K  2.406    2.406  x  0.707
[axial ] 1 x
% axial = 29.3 %
- 58 -
PROBLEM 43
Determine the conformations for the following compounds:

a) cis-1-tert-butyl-2-ethylcyclohexane;
b) trans-1-tert-butyl-2-ethylcyclohexane;
c) trans-1-tert-butyl-4-ethylcyclohexane;
d) cis-1-isopropyl-3-methylcyclohexane;
e) cis-1-isopropyl-4-methylcyclohexane;
Answer:
a
a
e
a) H
e
H
H H
a
H e
H
b) H
e
H
a
a
H
e e
H
c) H
a H
a
a e
d) H
e
H
H H
a a
e
e) e H H
H H
- 59 -
PROBLEM 44
Determine the number of diastereotopic pairs of ligands for each of the following
compounds:
CH3 CH3
H H H3C CH3
H C OH H C OH C C
H C H H C H C C
H CH2 CH2 CH3 H Br
H C H CH3
CH3
A B C D
O
Br Br Br Br
C C
C C
H Cl Cl Cl Cl H
H H
E F G
Answer:
CH3
CH3
H C OH H H H3C CH3
H C OH C C
HS C HR
HS C HR C C
HS C HR H CH2 CH2 CH3 H Br
CH3
CH3
A B D
C
two pairs of one pair of one pair of
one pair of
diastereotopic diastereotopic diastereotopic
diastereotopic ligands
ligands ligands ligands
O
Br Br Br Br
C C
C C
H Cl Cl Cl Cl H
H H
E F G
one pair of diastereotopic no pairs of one pair of

ligands diastereotopic ligands diastereotopic ligands
- 60 -
PROBLEM 45
Identify the pairs of enantiotopic ligands for each of the following compounds.
Specify for each ligand if it is pro-R or pro-S.
I
I NO2 H
CH2
I C I O 2N C NO2 H 3C C CH3
CH2
H NO2 I
CH3
A B C D
CH3 CH3
H C I OH I CH2
CH2 H C I
H C I CH2
CH3 CH3
E F G H
Answer:
I
I NO2 H
HS HR
I C I O 2N C NO2 H3C C CH3
HS HR S I
H NO2 R
CH3
A B C D
no pairs of no pairs of
enantiotopic enantiotopic
ligands ligands
S
CH3 CH3 CH3 CH3
HS C I H C IS H C I H C I
H C H H C H H C H HR C HS
HR C I H C IR H C I H C I
CH3 CH3 CH3 CH3
R
E
OH I
HS HR HS HR
F G
- 61 -
R
CH3 CH3 CH3
HR H H C HS H C H
H C I H C I H C I
HS H H C HR H C H
CH3 CH3 CH3
S
H
PROBLEM 46
Identify the heterotopic faces for each of the following compounds:
a) butyraldehyde;
b) di-n-propylketone;
c) 2-chloropropane;
d) 1,1-dichloroethane;
e) cis-3-hexene;
f) ethylpropylketone.
What happens if you add the cyanide anion on the Re and Si faces of butyraldehyde?
What happens if you add sodium bisulfite?
Answer:
H7C 3 H H C3H7
a) C C
O O
Re Si
H7C3 C3H7
b) C It doesn’t have heterotopic faces.
O
H 3C Cl Cl CH3
C C
c) C C
H H H H
Re Si
H H
C
d) C It doesn’t have heterotopic faces.
Cl Cl
- 62 -
H5C2 H H C2H5
Re C Si C
e) Si C Re C
H5C2 H H C2H5
H 7C 3 C 2H5 H5C 2 C 3H 7
f) C C
O O
Re Si
H H7C3 H C3H7
H7C3
C C C R
H
O NC OH
CN  NC OH
Si
H H7C3 H C3H7
H7C3
C C C S
H
O HO CN HO CN

CN
Re
C3H7
H7C3 H H7C3 H
C C C S
H
NaO3S OH NaO3S
-
O O OH
Si
S
O O H
C3H7
H7C3 H H7C3 H
C C C R
H
O HO SO3Na HO
O SO3Na
Re S
H O O
- 63 -
PROBLEM 47
The following compounds are radically monochlorinated at 300 ℃:
- (2R, 3S)-dichloropentane (optically pure)
- (2R, 3S)-dibromopentane (optically pure)
The obtained compounds are separated by fractional distillation.
How many fractions are obtained in each case? Which of the fractions are optically
active? Assign R/S labels for each asymmetric carbon atom.
Answer:
Cl Cl Cl Cl
R S S
Cl CH2 C C CH2 CH3 CH3 C C CH2 CH3
H H Cl H
optically active optically active Cl Cl Cl
R s S
CH3 C C C CH3
Cl Cl H H H
R S meso compound
CH3 C C CH2 CH3 + Cl2
Cl Cl
H H 300 oC R
CH3 C C CH2 CH3
H Cl
optically active
Cl Cl H Cl Cl
R R R S
CH3 C C C CH3 CH3 C C CH2 CH2 Cl
H H Cl H H
There are six fractions in total: five optically active and one meso compound.
Br Br Br Br
R S R S
Cl CH2 C C CH2 CH3 CH3 C C CH2 CH3
H H Cl H
optically active optically active Br Br
R S
CH3 C C CH2 CH3
Br Br H Cl
R S
CH3 C C CH2 CH3 + Cl2 optically active
H H 300 oC Br Br Cl
R S S
CH3 C C C CH3
H H H
optically active
Br Br Br Br H
R S R S R
CH3 C C CH2 CH2 Cl CH3 C C C CH3
H H H H Cl
- 64 -
There are six fractions in total. All of them are optically active.
PROBLEM 48
The following compounds are radically monochlorinated at 300 oC:
- (S)-2-bromobutane
- (±)-2-bromobutane
How many fractions are obtained in each case? Which of the separated fractions are
optically active? Assign R/S labels for each asymmetric carbon atom.
Answer:
H Br H Br
CH3 C C CH2 Cl CH3 C C CH3
R S
H H H Cl
H Br Cl Br
CH3 C C CH3 + Cl2 CH3 C C CH3
R S
S H H 300 oC H H
optically active
H Br H Br
Cl CH2 C C CH3 CH3 C C CH3
S S S
H H Cl H
There are 5 fractions in total. All of them are optically active.
If we use the racemic mixture of sec-butylbromide, there will be 5 fractions, but
none of them will be optically active.
PROBLEM 49
Can the separation of enantiomers be achieved using urea?
Answer:
Yes. Although it is an achiral molecule, urea can generate chiral inclusion products
due to helical packing around the enantiomer. Crystallizations by inoculation or on
asymmetric surfaces are two ways of separating enantiomers using urea.
- 65 -
PROBLEM 50
- (S)-2-chlorohexane
- (S)-2-bromohexane
The obtained compounds are separated by using fractional distillation.
active? Assign R/S labels for each asymmetric carbon atom.
Answer:
Cl Cl Cl
+ Cl2 300oC
+ +
Cl
Cl
1,2-dichlorohexane 2,2-dichlorohexane
Cl Cl Cl Cl
+ + + +
Cl Cl
2,3-dichlorohexane 2,4-dichlorohexane 2,5-dichlorohexane
Cl
+ Cl
1,5-dichlorohexane
Cl Cl
Cl2
C CH3 C CH2Cl
300oC
H H
1,2-dichlorohexane
(S) optically active
(R)
Cl Cl
Cl2
C CH3 C CH3
300oC
H Cl
2,2-dichlorohexane
(S) optically inactive
- 66 -
Cl
Cl2
C CH3
300oC
H
(S)
Cl Cl H Cl
R S S S
H3C CH2 CH2 C C CH3 + H3C CH2 CH2 C C CH3
H H Cl H
2,3-dichlorohexane- two diastereoisomeric fractions
Cl
Cl2
C CH3
300oC
H
(S)
Cl Cl H Cl
R S S S
H3C CH2 C CH2 C CH3 + H3C CH2 C CH2 C CH3
H H Cl H
2,4-dichlorohexane - two diastereoisomeric fractions

Cl
Cl2
C CH3
300oC
H
(S)
Cl Cl H Cl
R S S S
H3C C CH2 CH2 C CH3 + H3C C CH2 CH2 C CH3
H H Cl H
2,5-dichlorohexane - an optically active fraction (S,S) and a meso compound (R,S)
Cl Cl
Cl2
C CH3 ClH2C CH2 CH2 CH2 C CH3 (S)
300oC
H H
1,5-dichlorohexane
(S) optically active
There will be nine fractions in total, seven of which are optically active.
- 67 -
Br Br Br
o
+ Cl2 300 C
+ +
Cl
Cl
2-bromo-1-chlorohexane 2-bromo-2-chlorohexane
Br Cl Br Br
+ + + +
Cl Cl
2-bromo-3-chlorohexane 2-bromo-4-chlorohexane 2-bromo-5-chlorohexane
Br
+
Cl
5-bromo-1-chlorohexane
Br Br
Cl2
C CH3 C CH2Cl
300oC
H H
optically active
(S) (R)
Br Br
Cl2
C CH3 C CH3
300oC
H Cl
optically active
(S) (S)
Br
Cl2
C CH3
300oC
H
(S)
Cl Br H Br
R S S S
H3C CH2 CH2 C C CH3 + H3C CH2 CH2 C C CH3
H H Cl H
- 68 -
Br
Cl2
C CH3
300oC
H
(S)
Cl Br H Br
R S S S
H3C CH2 C CH2 C CH3 + H3C CH2 C CH2 C CH3
H H Cl H
Br
Cl2
C CH3
300oC
H
(S)
Cl Br H Br
R S S S
H3C C CH2 CH2 C CH3 + H3C C CH2 CH2 C CH3
H H Cl H
Br
Cl2 Br
C CH3 o
300 C ClH2C CH2 CH2 CH2 C CH3 (S)
H
H
(S)
There will be ten fractions in total, all of them being optically active.
PROBLEM 51
- n-hexane
- 1-chlorohexane
active?
Answer:
Cl
o
300 C Cl
+ Cl2 + +
achiral (±)
+
Cl
(±)
- 69 -
There will be 3 fractions. None of the fractions will be optically active.

Cl
o
Cl 300 C Cl
+ Cl2 + Cl +
Cl (±)
Cl
+ Cl + Cl + Cl +
Cl Cl
(±) (±) (±)
+ Cl
Cl
There will be 6 fractions. None of these will be optically active: 4 racemic mixtures
and 2 achiral fractions.
PROBLEM 52
Determine the number of stereoisomers for each of the compounds marked by letters
in the following reaction scheme:
CHO
H C OH
HO C H 1. Br2 H 2O2 1. Br2 H2O2
A B C
H C OH H2O Fe2(SO4)3 H2O Fe2(SO4)3
H C OH 2.CaCO3 2.CaCO3
CH2OH
HNO3
D E
Answer:
COO-)2Ca2+
CHO COO-)2Ca2+
H C OH
HO C H HO C H
HO C H
H C OH H C OH
H C OH
H C OH H C OH
H C OH
CH2OH CH2OH
CH2OH
A B C
4 3 3
2 = 16 stereoisomers 2 = 8 stereoisomers 2 = 8 stereoisomers
- 70 -
CHO COOH
H C OH H C OH
H C OH H C OH
CH2OH COOH
E F
2
2 = 4 stereoisomers meso compound
PROBLEM 53
Which of the compounds from the following reaction scheme are optically active?
Which of them are meso compounds?
CHO
HO C H
CH3NO2
H C OH A + B
NaOH
H C OH
CH2OH
1. NaOH
A A'
2. H2SO4
1. NaOH
B B'
2. H2SO4
CHO
HO C H
Ruff degradation HNO3
H C OH C D
H C OH C4H8O4
CH2OH
Answer:
CH2 NO2 CH2 NO2
CHO
H C OH HO C H
HO C H
CH3NO2 HO C H HO C H
H C OH +
NaOH H C OH H C OH
H C OH
H C OH H C OH
CH2OH
CH2OH CH2OH
A optically active B optically active
- 71 -
CH2 NO2 CHO

H C OH H C OH
HO C H 1. NaOH HO C H
H C OH 2. H2SO4 H C OH
H C OH H C OH
CH2OH CH2OH
A optically active A' optically active
CH2 NO2 CHO

HO C H HO C H
HO C H 1. NaOH HO C H
H C OH 2. H2SO4 H C OH
H C OH H C OH
CH2OH CH2OH
B optically active B' optically active
CHO COOH COO-)2Ca2+

HO C H HO C H HO C H
Br2, H2O CaCO3 H2O2, Fe3+
CH2OH CH2OH CH2OH
CHO COOH
H C OH HNO3 H C OH
H C OH H C OH
CH2OH COOH
C optically active D optically inactive
PROBLEM 54
Which of the following synthesis are asymmetric?
a) H3C CH2 CH2 COOH + Br2 H3C CH2 CH COOH

Br
(+)-quinidine
b) CH O + HCN CH OH
CN
- 72 -
c) CH O + HCN CH OH
CN
H COOH COOH
d) C fumarase H C H
+ H2O
C HO C H
HOOC H
COOH
CN
CHO
CHOH
HO C H
e) + HCN HO C H
H C OH
H C OH
CH2OH
CH2OH
Answer:
Syntheses b, d and e are asymmetric.
PROBLEM 55
During the decarboxylation of methylethylmalonic acid in the presence of brucine,

the optically active 2-methylbutyric acid is formed. The dextrorotatory enantiomer is
10% less than the levorotatory enantiomer.
What is the molar ratio of the two enantiomers in the final mixture?
What is the optical purity of the mixture?
Answer:
C2H5 COOH Brucine C 2 H5 H
C C
H3C COOH H3 C COOH
d + l = 100
We consider the following system: l - d = 10
By solving the system we obtain l = 55 % and d = 45 %

1−d
O. P. = ∙ 100 = 10 %
1+d
PROBLEM 56
During the heating of a (S)-secondary alkyl iodide (optically pure), the ratio of the
reactions speeds of the unimolecular nucleophilic substitution and the bimolecular
nucleophilic substitution respectively is n, please calculate:
- 73 -
a) the optical purity of the reaction product;

b) the specific rotation of the reaction product;
c) the value of n for which the reaction product does not rotate the plane-polarized
light.
Note: The specific rotation of the (R)-secondary alcohol is:
[]D20 = + ao
Answer:
a) H3C (CH2)p CH (CH2)q CH3
I
(S)
H3C (CH2)p CH (CH2)q CH3

SN1
v1 OH
H3C (CH2)p CH (CH2)q CH3 H2O (R) + (S)
v2 racemic mixture
I SN2
(S) H3C (CH2)p CH (CH2)q CH3
OH
(R)
inversion of configuration
v1
n
v2
We note:
- m - number of moles of (S)-secondary alkyliodide.
- nR - number of moles of (R)-secondary alcohol generated in the racemic mixture.
- nS - number of moles of (S)-secondary alcohol generated in the racemic mixture.
- nR’- number of moles of (R)-secondary alcohol generated in the inversion reaction.
Using these notations, we can consider the following system of equations, taking
into account the ratio of the substitution reaction speeds, n:
nR + n S = n . m
n+1
nR = nS
m
nR' =
n+1
m( 2  n)
Thus, the total number of moles of (R)-secondary alcohol is R  n R  n R ' 
2(n  1)
mn
and the total number of (S)-secondary alcohol is S  n S  .
2(n  1)
R-S 1 100
O. P. (%) = ∙100 = ∙100 =
R+S n+1 n+1
1 a0
b)  [a 0 ] 
n 1 n 1
- 74 -
c) n   . Only under these conditions will the racemization occur and the plane-
polarized light will not be rotated.
PROBLEM 57
Write down the stereoisomers of the following compounds:
a) difluorocyclohexane;
b) fluorochlorocyclohexane;
Answer:
F H H H F F H
a)
F F F F H H F
achiral achiral (±)
H F F
H H
H H H
F H H
F F
F F F
(±) achiral
achiral
H F
F H
achiral
b) F H H H H
Cl F Cl Cl F
achiral (±)
H H
H Cl Cl H H H
Cl Cl
F H H F F F
(±) (±)
- 75 -
Cl Cl
H H H H H
H
H H
F F F Cl Cl F
(±) achiral
H Cl Cl H
F H H F
achiral
PROBLEM 58
Propose a reaction scheme for the resolution of 2-phenylpentane.

Answer:
H H C CH CH H H C CH CH H H C CH CH
H3C 2 2 3 H3C 2 2 3 H3C 2 2 3
C C C
CH3COCl 1. NaOCl
AlCl3 2. H3O+
C C
O CH3 O OH
(±) (±) (±)
N
H3C O H
H
H3C O N H O
H
Brucine
H H C CH CH3 H H C CH CH3
H3C 2 2 H3C 2 2
C C
+ (-) Brucine (-) BrucineH+ A
C C
O OH O O-
(+) (+)
- 76 -
H H C CH CH3 H H C CH CH3
H3C 2 2 H3C 2 2
C C
+ (-) Brucine (-) BrucineH+ B
C C
O OH O O-
() ()
H H C CH CH3
H3C 2 2
C
A H+ +
+ (-) BrucineH
C
O OH
(+)
H H C CH CH3
H 3C 2 2
C
H+ +
B + (-) BrucineH
C
O OH
()
H H C CH CH3 H H C CH CH3 H H C CH CH3
H 3C 2 2 H3C 2 2 H3C 2 2
C C C
1. SOCl2 NaOBr 1. NaNO2, HCl

2. NH3 2. H3PO2
C C NH2
O OH O NH2
(+) (+) (+)
H H C CH CH3
H3C 2 2
C
(+)
- 77 -
H H C CH CH
H3C 2 2 3
C
Obviously, a similar set of reactions is applied for:
(-)
PROBLEM 59
Determine the number of diastereoisomers for each of the following compounds:
a) Cl CH2 CH CH CH CH CH CH CH2 Cl
b) Br CH2 CH CH CH CH CH CH CH2 Cl
c) Cl CH CH CH CH Cl
d) Cl CH CH CH CH Br
Answer:
a) 6 diastereoisomers:
Z Z Z Z Z E E E Z Z E Z E Z E E E E
b) 8 diastereoisomers:
Z Z Z E E E E Z Z Z Z E
E Z E Z E E E E Z Z E Z
c) 3 diastereoisomers:
Z E E E Z Z
d) 4 diastereoisomers:
Z E E E E Z Z Z
PROBLEM 60
Determine the configuration of the following chiral compounds (using the Cahn-
Ingold-Prelog convention):
CH(CH3)2 H3C CH3

H2C C CH3
C
H CH CH2
C
D CH2 CH2 CH2 CH2 CH2 CH3
H2C CH CH2
A B
- 78 -
C(CH3)3
C
C CHCl2
HC CHO
C
Answer:
For compound A, the substituent priority in decreasing order is:

CH CH2 > CH(CH3)2 > D > H
CH(CH3)2
By interchanging the position of two substituents, the configuration
H C D of the asymmetric atom changes. In order to determine the
configuration of the asymmetric atom, the substituent with the
CH CH2 lowest priority (H) must change place with the CH=CH2 group:
(III)
CH(CH3)2 CH(CH3)2
H C D (IV) CH2 CH C D (II)
CH CH2 H
(S) (R)
For compound B, the substituent priority, in decreasing order, is:
CH3
CH2 > H3C C CH2 > H2C CH CH2 > H3C CH2 CH2 CH2 CH2
CH3
The configuration is:
(III)
H3C CH3
CH3
C
H2 C
(IV) CH2 C H2 C CH CH2 (II)

H2C
CH2 CH2 CH2 CH3
(R)
- 79 -
For compound C, the substituent priority, in decreasing order, is:
CHCl2 > CHO > C CH > C(CH3)3

C(CH3)3 CHCl2
HC C C CHO OHC C C CH
CHCl2 C(CH3)3
(S) (S)
To conclude, the configuration of the chiral atom in compound C is S.
PROBLEM 61
What is the molar ratio of  and anomers in a D-galactose solution, if we know that
its specific rotation is identical to that of a solution containing a mixture  and anomers of
D-glucose with a molar ratio of 1?
We know:
- for D-glucose: [α]α = +112.2°
[α]β = +18.7°
- for D-galactose: [α]α = +150.7°
[α]β = +52.8°
Answer:
For the D-glucose solution we note:

a – the molar fraction of anomer
b – the molar fraction of anomer
a+b=1
a => a = 0.5 and b = 0.5
=1
b
The specific rotation of the D-glucose solution will be:
[α]D-glucose = 0.5 ∙ 112.2 + 0.5 ∙ 18.7 = 65.45°
For the D-galactose solution we note:

x – the molar fraction of anomer
y – the molar fraction of anomer

x+y=1
Solving the system:
x . 150.7 + y . 52.8 = 65.45

we find that the composition of the solution is: 12.93 %  anomer and 87.07 % anomer.
- 80 -
PROBLEM 62
Compare the dextrorotatory and levorotatory lactic acid and determine which of the
following characteristics are different for these two enantiomers:
a) UV-VIS spectrum;
b) melting point;
c) specific rotation;
d) retention time in gas chromatography using a chiral stationary phase;
e) adsorption on alumina;
f) solubility in water;
g) 1H-NMR spectrum using a chiral solvent;
h) 1H-NMR spectrum in an achiral solvent, but using a chiral chemical shift reagent;
i) 1H-NMR spectrum;
j) acidity constant;
k) behavior in liquid chromatography using starch as a stationary phase.
Answer:
The characteristics that are different between these two enantiomers: c, d, g, h and k.
PROBLEM 63
a) Synthesize ethyl diacetylsuccinate using ethyl acetate as a unique source of organic

matter.
b) Write a reaction mechanism for the proposed synthesis.
c) What is the number of steric isomers of ethyl diacetylsuccinate if the compound is found
in the:
- ketonic form;
- monoenolic form;
- dienolic form.
Answer:
O O
H3 C CH2 O-Na+
a) H3 C C O CH2 CH3 + H3C C O CH2 CH3
O O

H3C C CH C O CH2 CH3
Na+
O Na+ O O O

H3C C CH C O CH2 CH3 H3C C CH C O CH2 CH3
+ I2
  2 NaI H3C C CH C O CH2 CH3
O Na+ O O O
- 81 -
O O
-
b) H3 C C O CH2 CH3 + H3C CH2 O H2 C C O CH2 CH3
+ H3 C CH2 OH

O
O
H3 C C O CH2 CH3
H3C C O CH2 CH3

H2C C O CH2 CH3 H2C C O CH2 CH3
O O
O O
H3C C CH2 C O CH2 CH3 + H3C CH2 O-
O O

H 3C C CH C O CH2 CH3 + H3C CH2 OH
O O O O
H3C C CH C O CH2 CH3 + I2 H3C C CH C O CH2 CH3
- I-
I
O O
O O
+ I-
O O
O I O
c) 3 isomers for the ketonic form: () and one meso compound.
O O O
H3C C O H3C C C CH3
H C C O C2H5 H5C2OOC C H H C COOC2H5
H C C O C2H5 H C COOC2H5 H5C2OOC C H
H3C C O H3C C C CH3

O O O
(+)

meso compound
4 isomers for the monoenolic form: (+)-E; (+)-Z; (-)-E; (-)-Z
- 82 -
H3C CH3
C OH HO C
H5C2COO COOC2H5
C C
H C COOC2H5 H5C2OOC C H
H3 C C C CH3
O O
E (+)

HO OH
H3C C COOC2H5 H5C2COO C CH3

C C
H5C2OOC C H H C COOC2H5
C CH3 H3C C
O O
Z (+)

3 isomers for dienolic form: Z-Z; Z-E; E-Z
H3C OH H3C OH
C C O
O
C C C O C2H5
C O C2H5 C2H5 O C
C2H5 O C C
C
O
O C
C
HO CH3 H3C OH
E-E E-Z
HO CH3
C O
C C O C2H5
C2H5 O C C
O
C
H3C OH
Z-Z
- 83 -
PROBLEM 64
The chloride of a halogenated hydrocarbon reacts with a hydroxide anion (ethanol

70 %, at 40 °C) according the following rate law:
v  a1  [ RCl ]  [ HO  ]  a2  [ RCl ]
If we consider the concentration of [HO-]=5.10-3 mol/L, what is the percentage of

halogenated hydrocarbon that reacts via a SN2 mechanism?
Note: We consider a1 = 5a2
Answer:
SN 2 a1 ∙[RCl]∙[HO- ] a1 ∙[HO- ]
SN 2 (%) = ∙100 = ∙100 = ∙100
SN 2+SN 1 a1 ∙[RCl]∙[HO- ]+a2 ∙[RCl] a1 ∙[HO- ]+a2
5a2 ∙[HO- ] 5∙[HO- ] 5∙5∙10

⇒ SN 2 (%) = - ∙100 = - ∙100 = ∙100 = 2,439 %
5a2 ∙[HO ]+a2 5∙[HO ]+1 5∙5∙10 +1
PROBLEM 65
How many stereoisomers has 3,9-dimethylundeca-4,7-diene?
H5C2 CH CH CH CH2 CH CH CH C2H5
CH3 CH3
Answer:
The compound has two asymmetric carbon atoms and two double bonds with E-Z
isomerism.
(+)-Z-Z-(+) (-)-Z-Z-(-) (+)-Z-Z-(-) (+)-E-E-(+) (-)-E-E-(-)
(+)-E-E-(-) (+)-E-Z-(-) (-)-E-Z-(+) (+)-E-Z-(+) (-)-E-Z-(-)
There are 10 stereoisomers in total.
PROBLEM 66
Discuss the stereochemistry of the following reactions:
a) Synthesis of halohydrine starting from cis-2-hexene;
b) Synthesis of halohydrine starting from trans-2-hexene;
- 84 -
Answer:
a)
H
Cl Cl
H H C2H5
H C2H5 C2H5
C2H5 Cl Cl
+
Cl
H H C2H5
C2H5
H C2H5
C2H5 H
+
Cl
+
Cl HO- b
H H C2H5
C2H5
a
H b C2H5
C2H5 H
+
Cl
a HO-
a b
Cl
H C2H5
H C2H5 Cl
H C2H5 OH
H
C2H5
OH
C2H5 C2H5 C2H5

H Cl HO H Cl H
HO H H Cl H OH
C2H5 C2H5 C2H5
- 85 -
b)
Cl Cl H
H
H5C2 C2H5
H5C2 C2H5
H
H
Cl Cl
+
Cl
H H C2H5
C2H5
H5C2 H
H C2H5
+
Cl
+ b
Cl HO-
H H C2H5
C2 H 5
a
H5C2 b H
H C 2H5
+
- Cl
a HO
a b a b
Cl
H C2H5 H C2H5 OH
H C2 H 5 Cl H
OH Cl H5 C 2 C2H5
H5C2 H OH H
H5C2 H H5 C 2 H Cl
OH
C2 H 5 C2H5
H Cl Cl H
H OH HO H
C2 H 5 C2H5
- 86 -
PROBLEM 67
Which is the stereochemistry for the compounds resulting from the following
reactions?
a) cis-2-hexene Baeyer reagent b) trans-2-hexene Baeyer reagent
1. performic acid 1. performic acid

c) cis-2-hexene d) trans-2-hexene
2. H2O 2. H2O
Answer:
CH3
OH CH2
HO H H OH
CH2 CH3
H OH
H
CH3 CH2 CH3 CH2
a) H
CH2 CH3
Baeyer
H meso compound
reagent
CH2
CH3 CH3
H CH2 CH3 CH2
HO H
H OH
CH2 CH3 HO H
CH2
HO
CH3
meso compound
CH3
OH CH2
CH3 H OH
HO H
CH2 HO H
H 3C
CH2 H CH2
b) H CH3
CH2 Baeyer CH3
CH2 reagent
CH3 H
CH3
CH3 CH2
H CH2 HO H
CH2 H OH
H3C H OH
CH2
HO
CH3
- 87 -
CH3
OH CH2
CH3 H OH
H CH2
H CH2
H CH3 HO H
c) HO
CH3
CH2
H CH2
1.HCO2OH CH3
CH2 2.H2O CH3
H3C
CH2
H CH2 CH3 HO H
HO
OH H OH
H CH2
CH2 CH3
CH3
racemic
CH3
OH CH2
CH3 H OH
H
CH2
CH3 H3C CH2 H OH
H
H CH2
CH2
HO
CH3
d) 1.HCO2OH
CH2
2.H2O
H3C H CH3
CH2
H CH2 CH3
HO HO H
OH HO H
H3C CH2 H CH2
CH3
meso compounds
PROBLEM 68
How can you determine the specific rotation of a pure enantiomer A, having at your
disposal a racemic mixture ()-A, an optically active compound (+)-B that can react with
each enantiomer, a gas chromatograph and a polarimeter?
Note: It is assumed that the resulting diastereoisomers can be volatilized and

chromatographically analyzed.
- 88 -
Answer:
The racemic mixture ()-A is treated with the optically pure compound (+)-B but
using only 50 % of the stoichiometric amount required. Obviously, the result will be a
diastereomeric mixture together with approximately 50 % of the initial quantity of
compound A. The two enantiomers, (+)-A and (-)-A, will react differently (different
reaction rates). Therefore, the mixture of ()-A isomers will not be equimolecular and
the following relation will be obvious:
(+) – is the number of moles of unreacted (+)A enantiomer

(-) – is the number of moles of unreacted (-)A enantiomer
  () A  ()B (+)A.(+)B – is the number of moles of formed (+)A.(+)B
where:
() () A  ()B diastereoisomer
(-)A.(+)B – is the number of moles of formed (-)A.(+)B
diastereoisomer
With the help of a gas chromatograph (after volatilization and separation), the ratio
of the diastereoisomers can be determined and thus the ratio of the unreacted enantiomers.
Once the optical purity (O.P.) has been determined, we can calculate the specific rotation
of enantiomer A using the following equation:
 probe
O.P. 
 pure enantiomer
where αprobe is the value determined using the polarimeter.
PROBLEM 69
A chemical engineer was asked to label two flasks containing 1-chloro-1-
phenylethane and ethyl chloride.
A kinetic study of alkaline hydrolysis of the chlorinated organic compound in the
flask I was carried out as follows:
- a given volume of solution from flask I was treated with an equal volume of sodium
hydroxide solution, both solutions having an initial concentration of 0.3 mol/dm3.
(Assume that the addition of the catalyst did not essentially change the sample volume).
He determined the concentration of NaOH in the reaction mixture at 25oC and at various
time intervals by treatment with HCl and obtained the following results:
t (min) 10 20 30 40
CNaOH 0.125 0.107 0.094 0.0834
(mol/L)
a) Explain how the engineer reasoned in order to identify the two halogenated
derivatives. Is there an analytical test to identify the two halogenated compounds?
b) How long does it take for the concentration to drop at half of the initial value?
c) Write down the equations for the reaction rates and the reaction mechanisms for the
two cases.
- 89 -
d) If we start with a sample of 1-chloro-1-phenylethane optically active with S

configuration, we will obtain a mixture that will contain approximately 98 % racemic
mixture and a 2 % excess of the (+) enantiomer. Explain this observation.
Answer:
Because we have one halogenated derivative that can generate a stable
carbocation(1-chloro-1-phenylethane) and one primary derivative (ethyl chloride) which
reacts differently with NaOH, we can draw some conclusions about the contents of the flasks.
The tertiary halogenated derivative will react via an unimolecular mechanism (1st order
reaction kinetics), while ethyl chloride will react via a bimolecular mechanism (2nd order
reaction kinetics).
The performed analysis allows us to determine the reaction order.
 We presume that the reaction is of 1st order.
The rate constant can be calculated using the following equation:
1 C
k  ln 0
t C
1 0.15
k ln  1.82 10 2 min 1
10 0.125
1 0.15
k  ln  1.68 10 2 min 1
20 0.107
1 0.15
k  ln  1.35 10 2 min 1
30 0.094
1 0.15
k  ln  1.47 10 2 min 1
40 0.083
The value of k is not identical in the four cases, which indicates that this is not a 1st
order reaction.
 To check whether the species being transformed is the primary halogenated
derivative, we calculate k assuming the reaction is 2nd order:
1 1
  k t
C CO
1 1
  k 10  k  0.132 L  mol-1  min-1
0.125 0.15
1 1
  k  20  k  0.133 L  mol-1  min-1
0.107 0.15
1 1
  k  30  k  0.132 L  mol-1  min-1
0.094 0.15
1 1
  k  40  k  0.133 L  mol-1  min-1
0.0834 0.15
- 90 -
The analytical test consists of reacting the halogenated derivative with AgNO3. The
formation of a white precipitate indicates the presence of an ionizable halogenated
derivative:
CH3 CH3
-
H5C6 C Cl + AgNO3 H5C6 C NO3 + AgCl
H H white precipitate
1 1
b) t1 / 2    50,31 min
k  C O 0,1325  0,15
c) If the reaction mechanism is SN2, the reaction rate can be calculated using the
equation:

v  k  R  X   HO  
A specific feature of the SN2 mechanism is that while the C-X bond is broken, the
new Y-C bond is formed simultaneously:
CH3
-
 
HO + H3C CH2 Cl HO C Cl
H H
HO CH2 CH3 + Cl-
If the reaction mechanism is SN1, the reaction rate can be calculated using the
following equation:
v  k  R  Cl 
The SN1 mechanism involves two steps: heterolysis of the halogenated compound
with formation of a carbocation and the reaction of the carbocation with a nucleophile:
CH3 CH3
(I) H5C6 C Cl H5C6 C + Cl-
H H
(slow step - rate determining step)
CH3 CH3
(II) H5C6 C + HO- H5C6 C OH

H H
d) During the hydrolysis of the optically pure (S)-1-chloro-1-phenylethanol (specific

rotation [D = -50.6), a weak optically active phenylethanol ([D = +0.8) is obtained.
- 91 -
This observation indicates that there is a small amount of the (+) enantiomer in the
reaction mixture, the rest being an equimolecular mixture of the two enantiomers.
HO-
C6H5 a b
C6H5
H H
C Cl
C
H3C
H3C
C 6 H5 C6H5
H H
HO C + C OH
CH3 H3C
a) R b) S
Formation of the racemic mixture is explained through the formation of the planar
carbocation intermediate (SN1) which competes against the SN2 mechanism.
PROBLEM 70
Write down at least four possible structures for compound X having the molecular
formula C10H18, knowing that:
a) One mole of compound X reacts with two moles of H2/Ni at 140 °C and pressure.
b) Oxidation with KMnO4 leads to two organic compounds, only one of them being a
carboxylic acid (optically active).
Answer:
2  10  2  18
IHD = 2
2
The fact that the degree of unsaturation is two and that compound X reacts with two
moles of H2/Ni leads to the conclusion that compound X has two double bonds.
During oxidation with KMnO4 only one carboxylic acid is formed. It can be
anticipated that the other compound is a ketone. The simplest optically active carboxylic
acid is:
H3 C CH2 CH COOH
CH3
A structure having two double bonds such as:
R
R
- 92 -
indicates the existence of hydrocarbon residues at both ends leading to the optically active
acid. Between the two double bonds there is also a hydrocarbon residue that leads to a
bifunctional compound (at least two carbon atoms).
These conclusions do not correspond with the data provided, as compound X has
only 10 carbon atoms.
Under these conditions, the IHD implies that there has to be a cycle in the structure
of compound X, which can be labile to the hydrogenation conditions => three-carbon
atom cycle:
CH3
C CH CH CH2 CH3
CH3
 4 stereoisomers correspond to this structure:
1) Z-(+) 3) E-(+)
2) Z-(-) 4) E-(-)
Other possible structures (with their corresponding stereoisomers):
CH3 CH3
CH3
C CH CH CH2 CH3 C CH CH CH2 CH3
CH3 CH3 CH3
CH3 CH2
C CH CH CH2 CH3
CH3
PROBLEM 71
Determine the structure of the organic compound X with the molecular formula
C6H12O3, knowing that:
- It dissolves in KHCO3 solution;
- It reacts instantaneously with the Lucas reagent;
- It has two stereoisomers;
- By heating with dilute sulfuric acid, an organic compound displaying E/Z isomerism
is formed. This compound oxidized using K2Cr2O7 and H2SO4 forms acetic acid and
acetone as unique organic compounds.
Write down the chemical reactions involved in the determination of the structure of
compound X.
Write down the reaction mechanism between compound X and the Lucas reagent.
- 93 -
Answer:
2  6  2  12
IHD = 1
2
The dissolution in the potassium hydrogen carbonate indicates the presence of a
carboxylic group in the structure of compound X.
The instantaneous reaction with the Lucas reagent means that there is a tertiary
alcohol group present (capable of forming a stable tertiary carbocation). If this compound
has two stereoisomers (the presence of the Z-E type of isomerism is excluded) it means
that there is an asymmetric carbon atom.
Possible structures:
CH3 CH2 CH3 H3C CH3
H2C H2C CH
HO C CH2 COOH HO C COOH HO C COOH

CH3 CH3 CH3
I II III
While heating with concentrated sulfuric acid, only compound I forms an alkene that
has Z-E isomerism and is capable to form acetic acid and acetone during oxidation.
CH3 CH3
H 2C H2C
HO C CH2 COOH + NaHCO3 HO C CH2 COO-Na+ + CO2 + H2O
CH3 CH3
H3C H3C
CH2 CH2
HCl/H2O
HOOC CH2 C OH HOOC CH2 C Cl + H2O
Lucas reagent
CH3 ZnCl2 CH3
H3C
CH2 CH3
H2SO4, toC
HOOC CH2 C OH HOOC CH2 C CH CH3
CH3
K2Cr2O7, H2SO4
HOOC CH2 C CH3

+ CH3 COOH
O
acetylacetic acid
- 94 -
HOOC CH2 C CH3 H 3C C CH3

- CO2
O O
acetylacetic acid
H3 C H3C
CH2 CH2
ZnCl2
HOOC CH2 C OH + ZnCl2 HOOC CH2 C O
CH3 CH3 H
H3C
CH2
ZnCl2
HOOC CH2 C + O
CH3 H
H 3C H3C
CH2 CH2
Cl-
HOOC CH2 C HOOC CH2 C Cl
CH3 CH3
PROBLEM 72
A mixture of terephthalic acid, propionic acid and succinic acid was formed when a
carboxylic acid with a molecular formula of C15H18O2 was oxidised with KMnO4 and
H2SO4. Identify all the structural and configuration isomers that meet these conditions.
Answer:
H3C CH2 CH CH CH CH CH2 CH2 COOH
8 [O]
CH3 CH2 COOH + HOOC COOH +
KMnO4 H2SO4
+ HOOC CH2 CH2 COOH
Each of the double bonds in this compound presents geometrical isomerism.

Therefore, there are four stereoisomers: Z-Z, Z-E, E-Z and E-E.
- 95 -
H3C CH2 CH CH CH2 CH2 CH CH COOH
8 [O]
CH3 CH2 COOH + HOOC CH2 CH2 COOH +
KMnO4 H2SO4
+ HOOC COOH
Each of the double bonds in this compound presents geometrical isomerism.

Therefore, there are four stereoisomers: Z-Z, Z-E, E-Z and E-E.
So, in total, there are eight stereoisomers that fit the data provided by the problem.
PROBLEM 73
Determine the structural and configuration formula of the organic compound

C5H12O2, knowing that it does not rotate the plane-polarized light and that it forms
iodoform if treated with iodine in NaOH solution.
Answer:
2  5  2  12
IHD = 0
2
This IHD value indicates a saturated alcohol or ether.

The positive iodoform test indicates a structure of the following type:
H
R C CH3
R C CH3
O
OH
R = H, alkyl or aryl R = H, alkyl or aryl

Based on above reactions and IHD values of “0” results a structure that corresponds
to the alcohol.
The data provided by the problem states that the compound C5H12O2 does not rotate
the plane-polarized light. This indicates that the compound has two asymmetrical carbon
atoms (meso compound).
CH3
H C OH
CH2
H C OH
positive test with NaI
CH3
- 96 -
PROBLEM 74
A monoglyceride forms glycerol and cis-6-ocadecenoic acid (also known as

petroselinic acid) during hydrolysis.
a) Write down the monogliceride stereoisomers that fulfil the conditions above;
b) Using petroselinic acid as the unique source of carbon, prepare the following
compounds:
I - stearic acid;
II - 1-octadecanol;
III - dodecanol;
IV - dodecyl stearate;
V - adipic acid;
VI - 2,6,7-tribromostearic acid.
Answer:
H2 C OH O
HC O C (CH2)4 (CH2)10 CH3
a)
H2 C OH
H H
O
H2C O C (CH2)4 (CH2)10 CH3
HC OH
H2C OH H H
(±)
There are three stereoisomers in total.
b) I. H3C (CH2)10 CH CH (CH2)4 C OH H2

H3C (CH2)16 COOH
Ni
O stearic acid
H2
II. H3C (CH2)10 CH CH (CH2)4 C OH H3 C (CH2)16 COOH
Ni
O stearic acid
LiAlH4
H3O+
H 3C (CH2)16 CH2 OH
- 97 -
III. H3 C (CH2)10 CH CH (CH2)4 C OH

O
1. O3
H 3C (CH2)10 CHO +
2. (CH3)2S
+ OHC (CH2)4 C OH
O
H2
H3C (CH2)10 CHO H3C (CH2)10 CH2OH
Ni
IV. H3C (CH2)16 COOH + HOCH2 (CH2)10 CH3
O
, H+
H3C (CH2)16 C O (CH2)10 CH3
V. H3C (CH2)10 CH CH (CH2)4 C OH

O
KMnO4
H3C (CH2)10 COOH +
H2O, 
+ HOOC (CH2)4 C OH
O
VI. H3C (CH2)10 CH CH (CH2)4 C OH
O
+ Br2
H3 C (CH2)10 CH CH (CH2)3 CH COOH
PBr3
Br Br Br
PROBLEM 75
A 2.5 mg sample of an unknown organic compound with the molecular mass of 236
g/mole was combusted. The resulting gas mixture was passed through a tube with
Mg(ClO4)2, increasing the mass of the tube by 1.906 mg. The passage through a soda lime
solution tube increases the mass of the tube by 8.389 mg.
a) Determine the empirical and molecular formula.
b) Determine the structural formula and the stereoisomers of the analyzed compound
knowing that:
– It decolorizes a solution Br2/CCl4, as well as a cold aqueous solution of KMnO4;
– It reacts with hydrogen gas in a 1:1 molar ratio at room temperature and low pressure;
- 98 -
– Oxidation with hot KMnO4 generates a dicarboxylic acid as the unique organic
compound (the isomers with zero dipole moment).
Answer:
a) The tube with Mg(ClO4)2 (magnesium perchlorate) retains water. The quantity of
water retained by the magnesium perchlorate is 1.906 mg.
18 g H2O.................................................................2 g H
1.906 mg H2O................................................................x mg H
x = 0.2117 mg H
The tube with soda lime solution retains carbon dioxide:
44 g CO2..............................................................12 g C
8.389 mg CO2................................................................y mg C
y = 2.288 mg C
As we can see, the organic compound is a hydrocarbon (mC + mH = mtotal).
Calculus of empirical formula:
0.21
P% H   100  8.4%
2.5
2.29
P% C   100  91 .6%
2.5
91.6 8.4
C:H  :  7.633 : 8.4  1 : 1.1
12 1
M(CH  12n  1.1n  236  n  18
1.1)n
The molecular formula is: C18H20
2  18  2  20
b) IHD = 9
2
We can deduce the following:
- The organic compound contains double bonds (it decolorizes the solutions of
Br2/CCl4 and KMnO4);
- There is only one double bond (1:1 ratio between H2:hydrocarbon) susceptible to
hydrogenation at room temperature and low pressure;
- From here it results that all the other 8 unsaturation degrees are probably part of two
aromatic rings.
The dicarboxylic acid can only be one of the three position isomers of the following
acid:
COOH
COOH
From the three isomers only the terephthalic acid has a zero-dipole moment.
- 99 -
COOH
COOH
terephthalic acid
The structure of the compound is:
H3C CH2 CH CH CH2 CH3
The two stereoisomers are:

C 2H 5
H H
C C
H
C C
H
H 5C2 C2H 5
H 5C2 trans cis
PROBLEM 76
A monofunctional optically active organic compound A, which does not give a
positive Fehling test, reacts with NH2OH to form an oxime. It also reacts with iodine in
a basic medium to form iodoform.
Treating the compound with ethylmagnesium iodide followed by hydrolysis forms
compound B.
By dehydrating compound B, compound C is obtained as the main product which,
if oxidized with KMnO4 in H2SO4, forms butanone as the only oxidation product.
a) Determine the molecular and structural formula of compound A using the
provided data.
b) Find a way to separate a racemic mixture of compound A.
Answer:
a) From the provided data we can deduce that the compound is a ketone:
- It reacts with NH2OH, proving that it’s a carbonylic compound;
- It doesn’t give a positive Fehling test, so it is a ketone;
- It is a ketone with a marginal methyl group (iodoform test).
- 100 -
R1
C C CH3 - It is an optically active ketone;
R2
- The hypothetical formula of the
O
H ketone is as shown on the left.
R1 R1 C2H5
C C CH3 + C2H5MgI H2O
R2 C C
R2 CH3
O
H H OMgI
R1 C2H5
R1 C2H5
H+
C C C C
R2 CH3
R2 CH3
H OH
R1 CH3
[O] H 3C C2H 5
C C C
R2 C2H 5 O
unique product
R1
CH3, C2H5
R2
H3C
C C CH3
So, the ketone is: H5C2
H O
b) The carbonyl compounds are transformed into substituted semicarbazones with

carboxylic acid groups that can form diastereoisomeric salts with optically active
bases:
R1
C C R + H2N NH C NH COOH
R2
O O
H
R1
C C R
R2
NH NH C NH COOH
H
O
- 101 -
PROBLEM 77
Define the following terms:
a) ambo;
b) molecular recognition;
c) denaturation of proteins in the presence of acids and bases;
d) quasi-enantiomers.
Answer:
a) Ambo is a prefix indicating that a molecule with multiple chiral centres is present
as a diastereoisomeric mixture in unspecified proportions. As an example, the dipeptide
formed from L-alanine and D/L-valine is L-alanyl-ambo-valine.
b) The term of molecular recognition refers to a specific interaction between two or
more molecular species through non-covalent forces such as: hydrogen bonding, van der
Waals forces, electrostatic forces,  interactions, hydrophobic interactions, etc..
Depending on how these interactions are manifested, the molecular recognition can be
either static or dynamic.
c) Protein denaturation is a process which usually consists of modifying the spatial
arrangement of the protein through the destruction of some bonds (hydrogen bonds, salt
bridges, etc.). The salt bridges are formed through the neutralization reaction between the
carboxyl and amino groups of the amino acids side chains. Acids and bases destroy these
bridges, leading of the denaturation of the protein.
d) Quasi-enantiomers are chemically similar species of the type MA and MB, in
which the common structural unit M has opposite chirality. As an example, (R)-2-
bromobutane is the quasi-enantiomer of (S)-2-iodobutane.
PROBLEM 78
How do you define solvation diastereoisomers?
Answer:
Solvation diastereoisomers are complexes that are formed between a chiral solvent and
two optically active antipodes with identical physical and chemical properties.
This type of interaction is extremely useful in 1H-NMR spectroscopy because it
enables the differentiation between the magnetically equivalent protons from the chiral
centre (both enantiomers give a single singlet during the recording of the spectrum).
Let us presume that we have a chiral solvent S of 100 % optical purity and a racemic
mixture of enantiomers E1 and E2 of the form R1R2CHR3 (the marked protons are
magnetically equivalent). By interacting with the chiral solvent, solvation
diastereoisomers are formed with different proton signals:
(+)E1 + (-)E2 + (+)S (+)E1(+)S + (-)E2(+)S
enantiomers chiral solvent solvation diastereoisomers
(+)E1 + (-)E2 + (-)S (+)E1 (-)S + (-)E2 (-)S
enantiomer chiral solvent solvation diastereoisomers
- 102 -
PROBLEM 79
What are epimers? What is epimerization? Give examples.
Answer:
Epimers are diastereoisomers that differ in the configuration of a single asymmetric

center. The term of epimer was introduced by the Czech chemist (as well as composer
and music theorist) E. Votocek and it has its origin in carbohydrate chemistry. D-glucose
and D-galactose are classic examples of epimers.
Epimerization represents the change in configuration of a single asymmetric

carbon atom in a molecule with at least two chiral centers. The conversion of gluconic
acid to manonic acid in the presence of quinoline (discovered by Emil Fischer) is a classic
case of epimerization.
CHO CHO
H OH H OH
HO H HO H
H OH HO H
H OH H OH
CH2OH CH2OH
D-glucose D-galactose
PROBLEM 80
Make a comparison between meso tartaric acid and (+)-tartaric acid and indicate
which of the following characteristics are different for those two acids:
a) density;
b) melting point;
c) specific rotation;
d) retention time in gas chromatography using a chiral stationary phase;
e) solubility in ether;
f) 1H-NMR spectrum in an achiral solvent;
g) 1H-NMR spectrum in an achiral solvent, but using a chiral shift reagent;
h) refractive index;
i) first acidity constant;
j) second acidity constant;
k) behaviour in liquid chromatography if cyclodextrin is used as a stationary phase.
Answer:
All the characteristics are different for the two acids.
- 103 -
PROBLEM 81
Carvone is a terpenoid which is found in dill, cumin, lovage, anise and thyme.
Carvone has curative and antiseptic properties and it is used in the food industry,
aromatherapy and alternative medicine.
O O
H H
(R) (S)
carvone
Make a comparison between R-(-)-carvone and S-(+)-carvone and indicate which
of the following characteristics are different for these two isomers:
a) the absolute value of the specific rotation;
b) melting point;
c) odour;
d) solubility in ether;
e) 1H-NMR spectrum in an achiral solvent;
f) 1H-NMR spectrum in an achiral solvent, but using a chiral shift reagent;
g) refractive index;
h) circular dichroism spectra;
i) association constant with -cyclodextrin at room temperature;
j) behaviour in liquid chromatography if cellulose triacetate is used as stationary
phase;
k) behaviour in the reaction with N2H4 and KOH (Kishner-Wolff reduction);
l) behaviour in the reaction with NaBH4 and CeCl3 (Luche reduction).
Answer:
Characteristics c, f, h, i and j are different for the two isomers.
PROBLEM 82
Make a comparison between trihydroxyglutaric acid and trimethoxyglutaric acid
with the following formulas:
COOH COOH
H C OH H C OCH3
H C OH H C OCH3
H C OH H C OCH3
COOH COOH
Which of the following characteristics are identical?
- 104 -
a) pH of a 0.1 M solution;
b) specific rotation in water at 20oC;
c) melting point;
d) refractive index;
e) specific rotation in diethyl ether at 20oC.
Answer:
The identical characteristics are presented in the items b and e.
PROBLEM 83
How do you explain that even though they are enantiomers, R-(-)-carvone has a
smell similar to that of a specie of mint (Mentha spicata) while the S-(+)-carvone has a
smell similar to that of caraway?
Answer:
The different smells of the two enantiomers can be explained because the olfactory
receptors contain chiral groups capable of discriminating between the two enantiomers.
PROBLEM 84
Regarding chiral drugs, which of the statements listed below are true:
a) two enantiomers of the same chiral drug can be absorbed, activated and degraded
by the organism at different rates;
b) there are no chiral drugs that can be administrated as a racemic mixture;
c) every time we administrate a chiral drug as a racemic mixture, 50 % of the quantity
administrated is wasted (assuming that only one of the enantiomers has the desired curative
effect);
d) two enantiomers of a chiral drug can have different pharmacological activities;
e) one of the enantiomers of a chiral drug can have the desired curative effect, while
the other one can be toxic;
f) one of the enantiomers of a chiral drug can have the desired curative effect, while
the other one can be biologically inactive;
g) antibiotics produced by fermentation are racemic;
h) there are no enantiomeric drugs that are administrated in their enantiomerically pure
forms;
i) liquid chromatography is used on a large scale in the resolution of chiral drugs in
comparison with gas chromatography due to the fact that high temperatures may increase
the risk of racemization;
j) (R)-penicillamine is used as an antiarrhythmic, while (S)-penicillamine is a
teratogen;
k) the synthesis of enantiomerically pure drugs utilize only enzymes.
Answer:
The following statements are true: a, d, e, f and i.
- 105 -
PROBLEM 85
The conversion of an alkene to an epoxide can be achieved by oxidation with

peracids (Prilezhaev reaction). The reaction is stereospecific and can be done in mild
conditions with high yield.
a) Explain usefulness of adding a base in the reaction medium.
b) How can you achieve the following transformation:
R R'
R CH CH R'
O
c) Explain how you can achieve the following transformations:
OH
C2H5
C2H5
C2H5 OH
trans-1,2-diethyl cyclohexane-1,2-diol
C2H5 H
C2H5
C2H5
OH
trans-1,2-diethyl cyclohexanol
C2H5
H
H
C2H5 O
C2H5
O
H
H
OH
H
OH
H
cis-1,2-cyclohexanol
- 106 -
Answer:
a) The peracid is reduced to a carboxylic acid during the reaction. Since carboxylic
acids can open the epoxide cycle by nucleophilic substitution, the addition of a weak
insoluble base will neutralize the formed carboxylic acid.
b) Epoxides can be converted to alkenes by reacting them with R3P: (trisubstituted

phosphine):
R R'
(C6H5) 3P
R CH CH R' + (C6H5)3P O
O
O
F3 C C C 2 H5
C 2 H5
O OH
c) C2H5
CHCl3
C 2 H5 O
1,2-diethyl cyclohexane oxide
OH
H2O C2H5
C2H5 H2SO4 C2H5
C2H5 OH
trans-1,2-diethyl cyclohexane-1,2-diol
O H
1. LiAlH4 C2H5
2. NH4Cl C2H5
OH
trans-1,2-diethyl cyclohexanol
In asymmetric cyclic systems, the epoxide is formed on the least sterically hindered
side. The epoxide can be formed on the other side (more sterically hindered) in two steps:
a halohydrin (or its acetate) is formed, which can then be transformed in the epoxide after
the reaction with alkali.
C 2H 5 O C 2 H5
C6H5 C H
O OH
CHCl3 H
O
- 107 -
CH3
C 2H 5 C 2H 5 C 2H 5
C
O O
I2, CH3COOAg
O
0o C H - CH3COI
H H
I H
Hydroxylation of a double bond can be done either cis or trans. A cis-diol can be
synthesized by oxidation with Baeyer reagent (KMnO4 in alkaline solution). An
alternative method to prepare a cis-diol is the reaction with silver acetate (CH3COOAg)
and bromine in a hot aqueous solution of acetic acid:
CH3
C
O O
Br2 
CH3COOAg
H
H
CH3COOH
Br
CH3 CH3
H
C O O C O
+ + H2O
 O O
H - HBr H
H H
Br-
O
C
O CH3 OH
+ H2O/HO-
H H
OH - CH3COOH OH
H H
PROBLEM 86
a) quasiracemate;
b) mutarotation;
c) Pfeiffer effect;
d) serine octamer cluster.
- 108 -
Answer:
a) A quasiracemate is a crystalline product between two quasienantiomers in a 1:1
molar ratio.
b) Mutarotation is the change of optical rotation accompanied by epimerization.
Mutarotation was discovered by Dubrunfaut in 1846 and is a commonly encountered
phenomenon in the chemistry of carbohydrates.
c) The Pfeiffer effect is the influence that an optically active compound has on a racemic
mixture of another compound. Due to the interactions with the chiral species, the equilibrium
concentration of the two enantiomers is shifted. Paul Pfeiffer, Alfred Werner’s student, was
the first to observe this effect.
d) The serine octamer cluster represents a cluster of eight serine molecules with an
unusual stability, which is apparently involved in the origin of homochirality. The cluster
has been revealed for the first time in mass spectrometry experiments.
PROBLEM 87
An organic chemist analyses an optically active compound using a polarimeter. The
instrument’s indication is 35 degrees. Which are the conclusions of this test?
Answer:
One polarimeter reading may be equivocal in establishing a definitive conclusion.
The value of 35 degrees can also mean a rotation of 215 degrees, 395 degrees, or any
other value of the form 35 ± 180n, where n is an integer. To determine the actual value,
the experiment must be repeated, but at a different concentration of the optically active
compound. For instance, if the concentration is halved and a rotation of 17.5 degrees is
read, the original reading of 35 degrees was correct.
PROBLEM 88
Acids and bases catalyze the mutarotation. How do you explain the mutarotation of
glucose in the absence of acids and bases?
Answer:
Mutarotation of glucose in the absence of acids and bases can be explained by the
fact that the reaction is catalyzed by glucose itself, which is a weak acid (Ka = 6.6.10-13).
PROBLEM 89
The following reaction scheme is given:
HO
OH 1. CH3MgI excess
A B C+ D + E + F
(racemic) H+ 2. hydrolysis
- HOCH2CH2OH
- 109 -
Knowing that A is the simplest monocarboxylic aliphatic acid with IHD = 2 and
the conversion A→B implies a double bond rearrangement, determine the following:
a) The structure of compounds: A-F, knowing that B has 3 achiral diastereoisomers;
b) The number of stereoisomers of compounds: C, D, E and F;
c) Synthesize compound A with butadiene as the only organic source.
Answer:
Under acidic conditions acid A isomerizes in a mixture of 2-methyl-2-butenoic acid

diastereoisomers:
H+ H CH3 H COOH
*
H2C CH CH COOH C C + C C
CH3 CH3 COOH CH3 CH3
Z E
A (racemic) angelic acid tiglic acid
Three stereoisomers are formed by esterification:
O O
CH3 CH C C O CH2 CH2 O C C CH CH3
CH3 CH3
Z Z
E E
Z E
Treatment of diester B with excess of methylmagnesium iodide, followed by

hydrolysis yields four compounds:
O OH OH
* *
OH
HO
C D E F
b) C: 2 enantiomers (as the result of Michael addition reaction), D: 2 enantiomers, E

and F are two diastereoisomers formed by 1,2- addition.
HBr 1. Mg
c)
kinetic 2. CO2
control Br 3. H2O / NH4Cl COOH
A
- 110 -
PROBLEM 90
Write down the Fischer projections for all the isomeric compounds with the
molecular formula C7H15ClO2, which contain pseudo-asymmetric carbon atoms,
knowing that:
a) they do not react with Lucas reagent, but react with CrO3/H2SO4;
b) they react with both the Lucas reagent and CrO3/H2SO4; the iodoform test is
negative;
c) they do not react either with Lucas reagent or CrO3/H2SO4.
Answer:
IHD = 0 (saturated compound).
a) In this case the isomers contain primary hydroxyl groups:
H Cl H H H H
S r R S s R
HO CH 2 C C C CH2 OH HO CH2 C C C CH2 OH
CH3 H CH3 CH3 Cl CH3
(2S, 3r, 4R)-3-chloro-2,4-dimethyl pentan-1,5-diol (2S, 3s, 4R)-3-chloro-2,4-dimethyl pentan-1,5-diol
b) In this case the isomers contain secondary hydroxyl groups:
H Cl H H H H
S r R S s R
CH3 CH2 C C C CH2 CH3 CH3 CH2 C C C CH2 CH3
OH H OH OH Cl OH
(3S, 4r, 5R)-4-chloro heptan-3,5-diol (3S, 4s, 5R)-4-chloro heptan-3,5-diol
c) In this case there are two compounds (ethers) satisfying these conditions:
H Cl H H H H
S r R S s R
CH3 C C C CH3 CH3 C C C CH3
H3CO H OCH3 H3CO Cl OCH3
(2S, 3r, 4R)-3-chloro-2,4-dimethoxypentane (2S, 3s, 4R)-3-chloro-2,4-dimethoxypentane
PROBLEM 91
Identify the pseudo-asymmetric carbon atoms in the following molecules:
- 111 -

H Br H Br H Br H Br
H Br H H H H Br H
H Br H Br H Br H Br
COOCH3 COOCH3 COOH COOCH3
CH3
Br N
H Br
H Br
H Br H
H Br CH2OH
O C
C
Br C6H5
O
Answer:
CH3
N
COOCH3 COOCH3
S S
H Br H Br
H *s Br Br *r H
r H
R R *
H Br H Br CH2OH
O C
COOCH3 COOCH3 C
C 6H5
O
PROBLEM 92
Which of the following molecules are chiral?

HOH2C
O
O O
HOH2C OH HO OH O CH2OH
O O
N OH HO
OH
HO
O O
HOH2C OH CH2OH
N HO
H3C O O CH3 O O
OH HO
OH HO O
O
O O O HO HO
HOH2C OH CH2OH
O O O
O
CH2OH
A B (-cyclodextrin)
- 112 -
SO3H
O
CH2
N N
CH2 H H
OH 8 N N
CH2
O 6
C (p-sulfonato-calix[8]arene) D (CB[6])
E (fullerene – C76)
Answer:
The following molecules are chiral: A, B and E.
PROBLEM 93
SO3H
O O
N
H3 C O O CH3
CH2
O O
OH 6
O
A B(p-sulfonato-calix[6]arene)
HOH2C
O O O
HOH2C
OH
O OH O
HO
O
CH2
N N OH HO CH2OH
O
H H O
OH HO
HOH2C
N N O
HO
CH2 O HO
OH
5
O O
HO CH2OH
O
CH2OH O
C (CB[5]) D (-cyclodextrin)
- 113 -
O CH3
O N O
H H H
H N N N H
O
N
H
N
O H
Si O
O CH3
E
Answer:
The following molecules are chiral: A, D and E.
PROBLEM 94

2+
SO3H
N
O
N N O O
Ru 2 Cl- CH2
N N
O O O
N
O 6
A B C
D (fullerene – C78)
- 114 -
O
O O
O O
O
E
Answer:
The following molecules are chiral: A, C, D and E.
PROBLEM 95
O CH3
H
O CH3
H
O N O
H H H
O N O H N N N H
H
A N
N
N
B
H H Br
H N N N H
H
N
N
N
O N O
H
C D
- 115 -
Br
O N O
H
H H
H N N N H
N
N
N
E
Answer:
Species B and E are chiral (chiral supermolecules generated by hydrogen bonds

between the two achiral components).
PROBLEM 96
Which of the following molecules are achiral?
O O
N N
O O
O
O
O O
O
N N
O O
B (fullerene – C60)
- 116 -
O
O O
CH2 5
N N
O O
H H
N N
CH2 N N
7
O
C (CB[7]) D
E (fullerene - C80)
Answer:
The achiral species are B, C and D.
PROBLEM 97
O
CH2 CH2 O O
O OH
SO2 O O
O
O
n
A B
- 117 -
NO2
COOC2H5
CH2 CH2
OH OH
4
4
C D
NO2
NO2
O2N
O2N
N
N N
N
H H
H H
H H
H H
H H
O O H5C6 C6H5
OH O O
OH
O O
O O
H5C6 O C6H5
H O H
E F
Answer:
The following molecules are chiral: A, B and D.
PROBLEM 98
Which of the following species are chiral?
SO3H
CH2
OH 4
A (fullerene C20) B (p-sulfonato-calix[4]arene)
- 118 -
O CH3
O N O
H H H
H N N N H
C D (fullerene C84)
HOH2C O
HOH2C
OH O O
O
O HO
HOH2C
OH OH
O
HO
O HO CH2OH
OH
O
O HO
OH HO O
HOH2C
O HO OH HO CH2OH
O
O
O
CH2OH
E (-cyclodextrin)
Answer:
The chiral molecules are C, D and E.
PROBLEM 99
Which of the following molecules are cryptochiral?
A B
- 119 -
H3C H H3C H H3C H H3C H H

H3C CH2 CH2 C OH
H H H H H H H H D
C D
H
F3C CF2 CH2 C Cl
D
E F
Answer:
Cryptochirality is a special case of chirality when a molecule is chiral, but its specific
rotation is non-measurable. The following molecules are cryptochiral: A, C and F.
PROBLEM 100
Limonene, C10H16, is one of the most spread terpenoids and an important

intermediate in chemical synthesis, being a precursor of carvone.
CH3 CH3
CH3 CH2 CH3 CH2

(+)-limonene (-)-limonene
Determine which of the following statements regarding (+) and (-) limonene are
true:
a) like most naturally occurring chiral compounds, only one of the enantiomers occurs
in nature, the other being available only by chemical synthesis;
b) being enantiomers, they have different smells;
c) dipentene, the racemic mixture of the two compounds, can be obtained by heating
either (+) or (-) limonene to 250oC;
d) the 1H-NMR spectra in an achiral solvent are identical;
e) the 1H-NMR spectra in an achiral solvent, but using a chiral chemical shift reagent,
are also identical;
f) a non-racemic mixture of the two enantiomers has the same optical purity value both
before and after gamma radiolysis;
g) the refractive index has the same value for both enantiomers;
h) the circular dichroism spectra are identical;
- 120 -
i) the two enantiomers of limonene can be separated by gas chromatography using -

cyclodextrin as a chiral stationary phase;
j) by heating with sulphur, both isomers form p-cymene.
Answer:
The following statements are true: c, d, g, i and j.
PROBLEM 101
Determine which of the following statements are true:
a) two enantiomeric compounds may be associated to form meso supermolecule;
b) two achiral compounds may be associated to form a chiral molecule;
c) a supermolecule can be chiral if one of its constituents is asymmetric;
d) hydrogenation catalysts often produce trans-cis isomerization;
e) it is not possible for a cis-trans isomerization to be catalyzed by trace amounts of
bromine or iodine;
f) the syn-staggered conformation of n-butane is 0.8 kcal/mol, more stable that the
anti-staggered conformation;
g) (+)-3-methylhexane does not lose its optical activity, even when heated to 600oC,
though it partially decomposes;
h) molds and bacteria grown in media containing racemic mixtures metabolize only
one of the enantiomers, usually the natural one;
i) it is not possible to resolve a racemic mixture using optically active quartz;
j) a racemic mixture of alkenes can be separated through a reaction with
diisopinocamphenylborane;
k) circular polarized light cannot be used in order to distinguish an enantiomer in the
presence of the other;
l) racemic mixtures have significantly different physical properties compared to its
component enantiomers;
m) the crystalline system of (+)-tartaric acid is similar to that of (±)-tartaric acid;
n) fullerene C32 is a chiral molecule;
o) consumption of trans fats increase the risk of cardiovascular disease by increasing the
LDL (low-density lipoprotein) level and decreasing the HDL (high density lipoprotein) level;
p) trans-1,2-cyclopentanediol increases the conductivity of boric acid by forming a
cyclic complex;
q) camphor has two asymmetric carbon atoms and thus forms two racemic mixtures;
r) borneol has one more asymmetric carbon then camphor; it also forms two racemic
mixtures;
s) at room temperature, cyclohexane molecules are almost exclusively in the boat
form;
t) the coupling constants of cis protons in olefins are higher than those of trans
protons.
Answer:
The following statements are true: a, b, c, d, g, h, j, l, n, o and r.
- 121 -
PROBLEM 102
Discuss the following statement:
“By rapidly heating fumaric acid to 300 °C, it converts itself to maleic anhydride”.
Answer:
By rapidly heating, the rotation along the double bond becomes possible and
fumaric acid (trans) converts itself to maleic acid (cis):
H COOH H COOH
C 300oC C
C C
HOOC H H COOH
The formed maleic acid is dehydrated:
O
H COOH
C H
300oC
O
C - H2O
H COOH H
O
PROBLEM 103
How many stereoisomers present the following compounds:
HO
a) CH Cl
HO
H5 C 2
b) C CH Cl
H5 C 2
c) Muconic acid
Draw the structure of the compounds from point a.
Answer:
a) Four stereoisomers, two racemic mixtures:
- 122 -
OH OH OH OH
OH H H OH
H H H H
H HO OH H
C C C C
C C C C
H Cl Cl H Cl H H Cl
+ +_
b) Four stereoisomers, two meso compounds and a racemic mixture;
c) HOOC CH CH COOH
2
Three diastereoisomers: cis-cis, cis-trans and trans-trans.
PROBLEM 104
A B B A
O O
H H HOOC H
N C
N N Fe(CO)4
H H C
N N HOOC H
A B
(CH3)2N
H OH
N H
Fe O OH H
H OH
H5C6 C6H5 OH
H5 C 6 C6 H 5 OH H
C6H5
C D
A B A B
H OH
O O
H H HO H
N OH H
N N H OH
H H H OH
N N
OH H
E F
- 123 -
Answer:
The chiral molecules are C and E.
PROBLEM 105
Which of the following statements are true?
a) the melting point of maleic acid is higher than that of fumaric acid;
b) at 25 °C, the water solubility (g/L) of fumaric acid is lower than that of maleic acid;
c) cis-stilbene can be isomerized to trans-stilbene by contact with metallic sodium;
d) trans-1,2-difluoroethene is thermodynamically more stable than cis-1,2-
difluoroethene;
e) cis-trans-isomerization of olefins cannot be achieved under acid catalysis;
f) cis-2-butene has a higher boiling point than trans-2-butene;
g) the amount of heat released during the hydrogenation of cis-2-butene is identical to
that of trans-2-butene;
h) fumaric acid is partially converted to maleic acid under UV radiation.
Answer:
The following statements are true: b, c, f and h.
PROBLEM 106

a) cis-1,3-dimethylcyclohexane is more stable than trans-1,3-dimethylcyclohexane;
b) cis-decalin is irreversibly converted to trans-decalin under the catalytic action of
AlCl3;
c) tioaldehyde trimers exist as two isomers, cis-trans;
d) Z-Benzylmonoxime, subjected to Beckmann rearrangement, forms the anilide of
benzoic acid;
e) the dipole moment of cis- and trans-azobenzene are identical;
f) most of the essential fatty acids are trans;
g) two of the following compounds are achiral:
C 2H5 C2H5
H5C2 OH H5C2 OH
H5C2 OH HO OH
HO C2H5 HO C2H5
OH C2H5
- 124 -
C2H5
C 2H5
H5C2 C2H5
HO OH
H5C2 OH
H5C2 OH
HO OH
H5 C 2 C2H5
OH
OH
h) cis- and trans-2-Butene have different heats of combustion;

i) Both in solution and as solid, indigo dye molecules have trans conformation;
j) The trans form of the indigo dye is stabilized by intramolecular hydrogen bonds.
Answer:
The following statements are true: a, b, c, h, i and j.
PROBLEM 107
a) all pheromones are chiral;
b) enantiopure version of an optically active pesticide is much more efficient than the
racemic version;
c) the pesticide enantiomer which is not active against plant pests can be frequently
harmful to mammals, fish or humans;
d) mechanical separation of enantiomers crystals is the best way of splitting the
racemates;
e) (-) - chlorosuccinic acid reacts with potassium hydroxide to form (-)-malic acid;
f) SN2 reactions cause inversion of configuration;
g) (-) - chlorosuccinic acid reacts with wet silver oxide to produce (+)-malic acid;
h) diastereoisomers can be defined as configurational stereoisomers that are not
enantiomers;
i) cis-,-unsaturated acids are stronger than their trans isomers due to a secondary
steric affect;
j) isoascorbic acid (erythorbic acid) has an antiscorbutic activity similar to that of
ascorbic acid;
k) the cyclic compound C3H3Br3 has four stereoisomers;
l) 1-ethylcyclobutene forms cis-2-ethylcyclobutanol by reacting with B2H6, followed
by hydrogen peroxide in an alkaline medium;
m) 2-bromopiperidine can be resolved into enantiomers, while 4-bromopiperidine is
achiral;
n) diastereoisomers have all their physical and chemical properties different;
o) in Diels-Alder reactions, butadiene reacts in the s-cis form;
p) maleic ester reacts with cyclopentadiene forming an adduct with trans ester groups;
q) the (S, S) stereoisomer of Ethambutol is responsible for the tuberculostatic action,
while the (R, R) causes optic neuritis;
r) the optical activity values of a DNA, in conditions different from the biological
ones, allow us to estimate of the degree of retention of the unaltered double helix
structure;
- 125 -
s) the chiral double helix structure of DNA induces a superior optical activity to that
induced by the contribution of the chiral centers of deoxyribose fragment;
t) sulfonates and sulfoxides can be separated using -cyclodextrin;
u) the drug used in the treatment of Parkinson disease, Levodopa, is used in its pure
enantiomeric form because one of the enantiomers can cause serious side effects such as
granulocytopenia.
Answer:
The following statements are true: b, c, f, h, i, k, m, n, o, q, r, s, t and u.
PROBLEM 108
H H S
H3C NH2
N N
S
(CH2)n
(CH2)m
Fe
C C H2N CH3
O O
A B C
O S O
CH2OH
I
S
Fe
Fe
Fe
D E F
H H H
HO OH
O
H
G H I
- 126 -
HO
Si(CH3)3
Fe
Answer:
Compounds A, B, D, E, F, H, I and K are chiral.
PROBLEM 109
CH2OH
N
O H C OH
C2H5
C
P(C6H5)2 C
C HOOC C2H5
S S
Fe C3H7
H C OH
CH2OH
A B C
H O N
OH N
H
CH3
H3C H
Fe
HO N
O H
D E F
H H Ph+ Ph+
H H
CH3 CH3
H H3C
CH3 H
G H I
- 127 -
H3C CH3
O
K
Answer:
Molecules A, C, F, I and K are chiral.
PROBLEM 110
Which of the following molecules are achiral:
H5C6 COOC2H5 CH3 Cl

CH3
CH3
Co+ PF6-
COOC2H5 COOH
H3C
H5C6 CH3 Br
A B
HOOC COOH
N N Fe
HOOC COOH
C D
H5C6
H5C6 COOC2H5 OH
C
C6H5
CH3 C2H5
Co+ PF6- Fe
H5C2OOC C2H5
C6H5
H3C C6H5 C
OH
C6H5
E F
- 128 -
C2H5
H5C2
Fe
H5C6
CH3
C2H5
G
Answer:
Molecules A and D are chiral; molecule B is chiral due to atropisomerism.
PROBLEM 111
Determine and draw the structures of all the stereoisomers of 1,2,3,4,5,6-

hexamethylcyclohexane and 1,2,3,4,5-pentamethylcyclohexane.
Answer:
CH3 CH3 CH3 CH3 CH3

CH3 CH3 CH3 CH3
a) CH3 CH3 CH3 H3C CH3
H 3C H 3C
CH3 CH3
meso meso meso
CH3 CH3 CH3 CH3 CH3 CH 3
CH3 CH 3
CH3 CH3 CH3 CH 3
H 3C H 3C CH3 H 3C
CH3 CH3
meso (±) meso
CH3 CH 3 CH3 CH3
CH3
CH3 CH 3
H 3C CH 3 H 3C
CH3 CH3
meso meso
- 129 -
There are eight cis-trans isomers of 1,2,3,4,5,6-hexamethylcyclohexane, seven of

these being meso compounds, while one of them can be resolved into enantiomers.
CH3 CH3 CH3 CH 3 CH3

CH3
b) CH3 CH3 CH3 CH 3 CH3 H3C
CH 3 CH3
CH3
meso meso meso
CH3 CH 3 CH3 CH3 CH3 CH3
CH3 CH3
CH3 CH 3 CH3 CH3
CH 3
CH3 CH3
meso (±) (±)
CH3 CH3 CH3 CH3 CH3
CH3 CH3
CH3 CH3
H 3C
CH3
CH3 CH3 CH3 CH3
(±) (±) (±)
CH3 CH3
CH3 (±)
CH3
CH3
There are four meso compounds and six racemic mixtures.
PROBLEM 112

OH
H3C C2H5 H
P Si
O C6H5 H3C
OC2H5
A B C
- 130 -
H3C COOH
HOOC
COOH H H
N
HOOC
HO OC2H5
CH3
D E F
OH
H3 C N OH HOOC COOH
H3C N
OH HO OH
OH
COOH HO HO OH OH
COOH
G H I
H3C CH3
HOOC
N N
COOH
H3C CH3
K
Answer:
Molecules A, B, D, E, H, I and K are chiral.
PROBLEM 113
Determine the number of stereoisomers of the following molecules:
O O
H2C O C CH CH COOR1 H2C O C CH CH COOR1
n n
HC O C CH CH COOCH3 HC O C CH CH COOCH3
O O
n m
O O
A B
- 131 -
O
H2C O C CH CH COOC2H5
n
HC O C CH CH COOCH3
O
H2C O C CH CH COOC3H7
n
O
C
assuming that all the double bonds from the acids esterified with the primary alcohol
groups have the same configuration.
Answer:
O O
all-cis
n all-trans
n
A: HC O C CH CH COOCH3 HC O C CH CH COOCH3
O O
n n
all-cis all-trans
O O
all cis Z all cis all trans Z all trans

1 2 1 2
all cis E all cis all trans E all trans

1 2 1 2
There are four stereoisomers in total.
O O
n n
all-cis all-trans
B: HC O C CH CH COOCH3 HC O C CH CH COOCH3
O O
m m
all-cis all-trans
O O
all cis Z all cis + all trans Z all trans +

1 2 1 2
all cis E all cis + all trans E all trans +

1 2 1 2
There are eight stereoisomers in total.
- 132 -
O O
H2C O C CH CH COOC2H5 H2C O C CH CH COOC2H5
n all-trans
n
all-cis
C: HC O C CH CH COOCH3 HC O C CH CH COOCH3
O O
all-cis n all-trans n
O O

1 2 1 2

1 2 1 2
PROBLEM 114
Determine the number of stereoisomers of the compound
O
H2C O C CH CH COOCH3
2
HC O C CH2 CH2 COOCH3

O
H2C O C CH CH COOCH3
2
O
assuming that 50 % of the double bonds have E configuration and 50 % have Z configuration.
Answer:
O O
H2C O C CH CH COOCH3 H2C O C CH CH COOCH3
2 2
cis-cis cis-trans
HC O C CH2 CH2 COOCH3 HC O C CH2 CH2 COOCH3
O O
trans-trans 2 cis-trans 2
O O
(±)
- 133 -
O O
2 2
cis-trans trans-cis
HC O C CH2 CH2 COOCH3 HC O C CH2 CH2 COOCH3
O O
trans-cis 2 trans-cis 2
O O
(±)
There are six stereoisomers in total.
PROBLEM 115
COOH H5 C 2 OH
Br
Br H5C2 S C2H 5
O C2H 5
A B C
O
H2C CH2 H3C
H OH HOOC N NH
H5C2
C2H5 O O
HO H H2C CH2
HOOC
D E F
HOOC OCH3
Cl H Cl
H C2H5
H 5C 2 Cl H
HOOC OCH3
G H I
- 134 -
H Cl HO C3 H 7 HN NH
H5C2
H H H O O
Cl C2H5 H7C3 OH
J K L (phenobarbital)
CHO O
N HO
H3CO
N OCH3
Fe
CH3
H3CO
M N(megaphone – found in the roots of Aniba megaphylla)

Cl
O2N
Br O O
HO (CH2)m (CH2)n OH
NO2
P
O
(diabolic acid)
O
H
HO
O
OH
H
S
R
(constipatic acid – constituent of some Australian lichens)
Answer:
The chiral molecules are A, B, C, F, I, J, K, M, N and S.
Molecule O has one plane of symmetry.
In the case of diabolic acid, its stereochemistry depends on the values of m and n
and on the carbon atom carrying the methyl group. If m is equal to n, the diabolic acid
has three stereoisomers (a racemic mixture and a meso compound), but if m is different
from n, the molecules has two racemates.
PROBLEM 116
Which of the following molecules are meso compounds?
- 135 -
CH2OH
H C OH H H
H F
H C OH F H
H C OH
H3CO OCH3 H5C2 C2H5
H C OH
CH2OH
A B C
CH3
F F H3CO H H C Br
H H
Br C H
H5C2 C2H5 H OCH3 H C Br
CH3
D E F
Answer:
Molecules A, D and F are meso compounds. Compounds B and E, even though they
are achiral, they are not meso compounds, because they do not have chiral centers.
PROBLEM 117
How many stereoisomers do the following compounds have?
Cl COOH
N CH3 OH
CH3
A B
Cl
C2H5
N
Br Br
C D
Answer:
A – four meso compounds (endo-exo, exo-endo, endo-endo, exo-exo);

B – although there are four asymmetric carbon atoms and, theoretically, sixteen
isomers are expected, the number of isomers is reduced by half because of the bicyclic
bridge system. Consequently, there are four racemates;
- 136 -
C – two asymmetric carbon atoms, therefore there are four enantiomers;

D – four stereoisomers (a racemic mixture and two meso compounds).
PROBLEM 118
Explain the following observations:
a) (R) – 1,1,2 – trimethylcyclopropane racemizes by heating the sample;
b) ortho-methylbenzoic acid is a stronger acid than the benzoic acid one;
c) toluene and tert-butylbenzene are nitrated. The ortho/para ratio for the first
compound is 1.6, while for the other it is 0.14.
d) (R) –2- butylphenylketone racemizes in basic medium;
e) if trans-2-chlorocyclohexanol is treated with very strong bases, it forms
cyclohexene oxide, while cis-2-chlorocyclohexanol forms cyclohexanone;
f) 2,6-dihydroxybenzoic acid is a stronger acid than the benzoic acid one;
g) 1-chloro-1-phenylethane racemizes if dissolved in a non-polar solvent in the presence
of SbCl5.
Answer:
H3C CH3 H3C CH3 H3C H
a) H3C H H3C H H3C CH3

(R)-1,1,2-trimethylcyclopropane (S)-1,1,2-trimethylcyclopropane
(breaking and restoring the chemical bonds around the center of chirality)
b) Deviation from coplanarity - suppresses conjugation with the benzene ring thereby
increasing acidity.
c) Steric hindrance due to the high volume of the tert-butyl group.
d) Formation of carbanion:
CH3 CH3 O-
- H3C + H2O
HO
H
H5C2 COC6H5 -H2O H5C2 COC6H5 -HO-
H5C2 C6H5
CH3
COC6H5
H 5C 2 H
OH HO- O-
e) O
H2O
Cl Cl
H OH
OH O
-
HO
OH
Cl
- 137 -
f) The formation of chelate hydrogen bonds:

H
O O
H C H
O O
g) Racemization by forming carbocation:

+
H5C6 CHCl CH3 + SbCl5 H5C6 CH CH3
(-) SbCl6-
H5C6 CHCl CH3 + SbCl5
(+)
PROBLEM 119
Comment the following statement:
“Food and Drug Administration has established that each enantiomer of a chiral
drug must be strictly tested again separately.”
Answer:
This request of Food and Drug Administration (FDA) is justified considering that
two enantiomers of a chiral drug, despite having identical physical and chemical
properties, can have very different effects.
Probably the most cited case was that of Thalidomide, whose S-enantiomer is
teratogenic. For a long time, the drug was administrated as a racemic mixture, thus
increasing the incidence of children born with limb malformations (phocomelia).
O O
N O O N
NH HN
O O O O
teratogen sedative
PROBLEM 120
a) in-out isomerism;
b) folded olefins;
c) carcerand;
d) hemicarcerand;
e) Bredt’s rule;
f) protein folding.
- 138 -
Answer:
a) in-out isomerism is a special type of isomerism, common to certain bridged
bicyclic ring systems (a, b, c have values ranging from 6-10) as a consequence of the fact
that the bridgehead hydrogen atoms (including pairs of unshared electrons) can be
situated outside the bicyclic system (out-out-isomer), in a combined arrangement interior
and exterior (in-out-isomer) or in the bicyclic ring system (in-in isomer). In-out
isomerism can also occur in bicyclic systems exclusively consisting of carbon atoms:
(CH2) (CH2)
a a
+ + - H+, + H+ + + - H+, + H+
H N N H N H N H
(CH2) (CH2)
b b
(CH2) (CH2)
c c
out, out in, out
(CH2)
a
+ +
N H H N
(CH2)
b
(CH2)
c
in-in
N N N N N N
out-out in-out in-in
b) Folded olefins are a special type of alkenes which, due to steric hindrance of the
substituents, cannot adopt a planar structure typical to double bonds and thus fold.
syn-sesquinorbornene
c) A carcerand is a molecule similar to a container or a capsule (host molecule)
capable of encapsulating a guest molecule, forming a supramolecular complex
(carceplex) stable even at high temperatures. It should be noted that the guest molecule
remains permanently within the internal volume of the carcerand. This particular type of
compound was first described in the scientific literature by D. J. Cram in 1985.
- 139 -
d) Hemicarcerand is a container or capsule molecule (host molecule) capable of

encapsulating a guest molecule that can enter and leave the internal volume of
hemicarcerand at defined temperature conditions. The complex formed from a
hemicarcerand and a guest molecule is called a hemicarceplex. Cryptophane
hemicarcerands are typical examples. They can trap small molecules such as methane,
haloalkanes, etc.
e) Bredt’s rule is an old rule of thumb pointing out that there can be no double bonds
containing carbon atoms that are bridged heads in strained bicyclic systems. Below is an
exemplified confirmation of Bredt's rule in a dehydrobromination reaction:
Br
Bredt’s rule has many exceptions.

f) Protein folding is a physical process whereby a protein is folded in its
characteristic three-dimensional structure. This process has a crucial importance for the
stability and function of the protein. There are theories according to which a number of
diseases (such as neurodegenerative diseases and some allergies) have their genesis in
the accumulation of incorrectly folded proteins. Folding of the protein occurs
spontaneously during or after biosynthesis and is dependent on factors such as type of
solvent, salt concentration, temperature, presence of chaperones, etc.
PROBLEM 121
a) anti-Bredt olefins;
b) proprochiral compound;
c) protein secondary structure;
d) protein tertiary structure;
e) protein quaternary structure;
f) DNA intercalation.
Answer:
a) anti-Bredt olefins are alkenes showing structural peculiarity of having the double
bond on the bridgehead carbon of a polycyclic system. This is possible only if the
polycyclic system bridges are long enough to allow a flat conformation (or almost flat)
of the double bond. Bicyclo[2.2.0]hex-1(4)-ene, adamantene and bicyclo[2.2.2]oct-1-ene
are examples of anti-Bredt olefins.
- 140 -
bicyclo[2.2.0]hexa-1,4-ene adamantene bicyclo[2.2.2]oct-1-ene
b) A proprochiral compound is a type of achiral compound that becomes chiral

following two operations of desymmetrization. As an example, CH3COOH becomes
prochiral as ClCH2-COOH and chiral as BrClCH-COOH
c) Secondary structure of proteins is the spatial arrangement of the polypeptide chain
and the links established between polypeptide chains. Intramolecular hydrogen bonds
that are formed between nearby peptide groups in a protein chain will generate repeated
spatial patterns such as α-helices, β-sheets, β-turns and Ω-loops.
d) The tertiary structure of a protein represents a superior level of organization of a protein.
Depending on the primary structure (which determines both the secondary and the tertiary
structure) and thus on the nature of the amino acid residues, four types of intramolecular
interaction can occur that help to stabilise the protein in a compact 3D structure:
- van der Waals interactions between alkyl residues (isoleucine, leucine, valine, etc.);
- Electrostatic interactions (between the COO- and NH3+ groups);
- Hydrogen bonds between donating groups (e.g.: the phenolic group of a tyrosine
residue) and accepting groups (e.g.: carboxylic group of an amino acid residue);
- Disulfide bonds between two –SH groups of two cysteine residues.
e) The quaternary structure of a protein represents the intermolecular association of more
polypeptide chains. The attraction forces are similar to those of the tertiary structure.
f) DNA intercalation occurs when certain ligands (both chemically and sterically
compatible) insert themselves between the base pairs of the DNA. Some ligands which
can be inserted are: polycyclic aromatic hydrocarbons, berberine, thalidomide, etc. An
interesting medical application of these ligands is the chemotherapeutic treatment of
certain forms of cancer.
PROBLEM 122
Comment on the following statement:
“Protein denaturation takes place with high variations of the enthalpy, while the
variation of entropy is very small”.
Answer:
In general, protein denaturation is a modification of the molecules’ conformation.
Enthalpies variations are small, while entropy changes are relatively large.
PROBLEM 123

“Protein denaturation is similar to digestion and involves changes in their structures”.
- 141 -
Answer:
Indeed, the digestion of proteins involves the hydrolysis of the peptide bonds,
therefore affecting their primary structure. Denaturation involves changes the secondary,
tertiary and quaternary structure of the protein, while their primary structure (amino acid
sequence) remains intact.
PROBLEM 124
Compare the heat generated by each of the following hydrocarbons through
combustion of one mole of:
a) cis-1,4-dimethylcyclohexane (1) and trans-1,4-dimethylcyclohexane (2);
b) cis-1,3-dimethylcyclohexane (1) and trans-1,3-dimethylcyclohexane (2);
c) cis-1,2-dimethylcyclohexane (1) and trans-1,2-dimethylcyclohexane (2);
d) cis-1,3,5-trimethylcyclohexane (1) and trans-1,3,5-trimethylcyclohexane (2);
Answer:
a) Q1 > Q 2 ;
b) Q1 < Q 2 ;
c) Q1 > Q 2 ;
d) Q1 < Q 2 .
PROBLEM 125
Write down all the possible stereoisomers of a triglyceride which, during alkaline
hydrolysis (NaOH), forms two moles of H3C (CH2)7 CH CH (CH2)7 COO-Na+ and
sodium lactate.
Answer:
For simplicity, we will denote fatty acid residue with N and the lactic acid with L.
Therefore:
Possible stereoisomers:
Z (+) Z
E (+) E
(Z or E) Z (-) Z
H 2C O N
(+ or -)
E (-) E
HC O L
(Z or E)
H 2C O N Z (+) E (+)
- The carbon atom
Z (+) E (-) becomes optically active.
Z (-) E (+)
Z (-) E (-)
- 142 -
(+) (+) Z Z (-) (-) Z Z

(+) (+) Z E (-) (-) Z E
(+) (+) E Z (-) (-) E Z
(+ or -)
H2C O L (+) (+) E E (-) (-) E E
(Z or E)
HC O N
H2C O N (Z or E) (+) (-) Z Z (-) (+) Z Z
(+) (-) Z E (-) (+) Z E
(+) (-) E Z (-) (+) E Z
(+) (-) E E (-) (+) E E
There are 24 stereoisomers.
PROBLEM 126
Write down the maximum number of possible stereoisomers for a triglyceride
which, during alkaline hydrolysis followed by acidification, will form:
a) one mole of lactic acid, one mole of palmitic acid and one mole of stearic acid;
b) two moles of palmitic acid and a mole of lactic acid;
c) two moles of lactic acid and a mole of palmitic acid.
Note: We consider all the alcohol groups on glycerol to be esterified and that lactic
acid is found as both of its enantiomers.
Answer:
We will note:
Palmitic acid with P: H3C (CH2)14 COOH
Stearic acid with S: H3C (CH2)16 COOH
Lactic acid with L: H3C CH COOH
OH
Therefore:
a) Possible stereoisomers:
(+) (+) (+) (+)
H2C O P (+) (-) H2C O S (+) (-)
(+
_) (+
_)
HC O S (-) (+) HC O P (-) (+)
(+
_) (+
_)
H2C O L (-) (-) H2C O L (-) (-)
(+) (+)
H2C O P
(+
_) +
_ (+) (-)
HC O L( )
(-) (+)
H2C O S
(-) (-)
There are twelve potential stereoisomers.
- 143 -
+
_ (+) (+)
H2C O P H 2C O L( )
+
_ (+) (-)
b) HC O L( ) (+) and (-) (+
_)
HC O P
(-) (+)
H2C O P H 2C O P (-) (-)
There are six stereoisomers.
(+
_) (+) (+) (+) (+) (+) (-)
H2C O L
+
_ (+) (-) (+) (+) (-) (-)
c) (+
_)
HC O L( )
(-) (+) (+) (-) (+) (-)
H2C O P (-) (-) (+) (-) (-) (-)
(+
_) (+) (+)
H 2C O L
(-) (-)
HC O P (-) r (+)
(+
_)
H 2C O L (-) s (+)
When two marginal lactic acid residues have the same configuration, the central
carbon atom becomes pseudoasymmetric.
PROBLEM 127
“All strained polycyclic compounds are extremely unstable”.
Answer:
Not all strained polycyclic compounds are extremely unstable. This is because the
reactions that lead to stabilization, by opening the cycle and releasing the strain, are
forbidden by the conservation of orbital symmetry principle.
PROBLEM 128
Draw the structural formulas for the following compounds:

a) C7H16O3, does not react with periodic acid and has a pseudoassymetric carbon atom.
It also gives a negative iodoform test;
b) C6H12O2, which reacts with periodic acid and phenylhydrazine; gives positive
iodoform test and it’s optically active;
c) C4H8O2, which reacts with boric acid, is optically inactive and does not decolorize
bromine water;
d) C4H8O2, which reacts with boric acid, is optically active and does not decolorize
bromine water.
- 144 -
Answer:
CH3 CH3
H C OCH3 H C OCH3
a)
H C OH HO C H
H C OCH3 H C OCH3
CH3 CH3
CH3 CH3
CH3 CH3
H C OH HO C H
b) H C OH HO C H
C O C O
C O C O
CH2 CH2
CH CH
CH2 CH2
H3C CH3 H3C CH3
CH3 CH3
CH3 CH3
CH3 CH3
C O C O
C O C O
H C OH HO C H
H C OH HO C H
CH2 CH2
CH CH
CH2 CH2
H3 C CH3 H3 C CH3
CH3 CH3
CH3
CH3
c)
HO OH HO OH
HO OH
d) HO OH HO OH
CH3 CH3
PROBLEM 129
For each of the following series of compounds, the chemical reaction in which they
are involved is given. State in which of the following cases the reaction products will be
exclusively optically active.
a) Reaction with chromic acid:
- 145 -
OH
OH
OH
OH
A B C D
OH
OH
E F
b) Catalytic hydrogenation:
CHO CHO CHO CHO
H C OH H C OH H C OH H C OH
H C OH HO C H H C OH HO C H
CH2OH CH2OH H C OH H C OH
CH2OH CH2OH
A B C D
CHO H3CO OCH3 H3CO OCH3

H C OH
CHO H H H H
H C OH
H C CH3
H C OH
CH2OH C C
HO C H
H C2H5 H5C2 H
CH2OH
E F G H
H OCH3 OCH3 H
OCH3 H H H3CO
C C
H C2H5 H5C2 H
I J
c) Reaction with periodic acid:

CH3
H3C CH CH CH2 CH3
H3C C C CH
OH OH
O O CH2 CH3
A B
- 146 -
H3C CH CH2 CH CH2 CH2 CH3 H 3C CH CH CH CH2 CH3

OH OH OH OH OH
C D
CHO
H C OH
HO CH2 CH2 CH CH2OH H C OH
OC2H5 H C OH
H C OH
COOH
E F
Answer:
Na2Cr2O7/H2SO4/H2O it does not react

a) B
Na2Cr2O7/H2SO4/H2O (tertiary alcohol)
A
O
optically inactive
Na2Cr2O7/H2SO4/H2O O
Na2Cr2O7/H2SO4/H2O D
C
O
optically inactive
optically active
O
Na 2Cr2O 7 /H 2SO 4 /H 2O Na2Cr2O7/H2SO4/H2O
E it does not react
F
optically active
Correct answers are A and D.
- 147 -
CH2OH CH2OH
H2/Ni H C OH H2/Ni H C OH
b) A B
H C OH HO C H
CH2OH CH2OH
optically inactive optically active
CH2OH CH2OH
H C OH H C OH
H2/Ni H2/Ni
C H C OH D HO C H
H C OH H C OH
CH2OH CH2OH
optically inactive optically inactive
CH2OH
H C OH CH2OH
H2/Ni
H C OH F H C CH3
H2/Ni
E CH2OH
H C OH
optically inactive
HO C H
CH2OH
optically active
H3CO OCH3
H3CO OCH3
H2/Ni H H
H2/Ni H H
G H
CH2
CH2
C2H5
C2H5 meso
meso optically inactive
optically inactive
OCH3 H
H OCH3
H2/Ni H H3CO
H2/Ni OCH3 H J
I
CH2
CH2
C2H5
C2H5
optically active
optically active
Correct answers: A, C, D, F, G and H.
- 148 -
HIO4
c) A H3C CHO + H3C CH2 CHO
optically inactive
H
HIO4
B H3C COOH + H3C C COOH
C2H5
optically active
HIO4
C it does not react
HIO4
D H3 C CHO + HCOOH + H3C CH2 CHO
optically inactive
HIO4
E it does not react
HIO4
F 4 HCOOH + OHC COOH
optically inactive
Correct answers: A, D and F.
PROBLEM 130
Determine the structure (including stereochemistry where necessary) of the
following compounds marked by letters:
C2 H 5
a) CH3 1. B2H6
A + A'
C2H5 2. H2O2, HO-
O
( )
H5C2 CHO C2H5
b) 1.
B + B' + C + C'
2. H2O
1. 1 mole OsO4
D
c) 2. H2O2
- 149 -
1. 2 moles OsO4
D' + D''
d) 2. H2O2
(CH3COO)2Hg C2H5OH NaBH4

e) E F G
- H+
C2H5
H C2H5
f) CHCl3
C C H
NaOH, H2O
H5C2 H
H5C2 C2H5
g) CHBr3
C C I
NaOH, H2O
H H
1. BH3 . THF
J
h) 2. H2O2, HO-
+ O K
i)
O
Answer:
C2H5 C 2 H5
CH3 CH3
a) HO HO
C2H5 C2H5
A A’
OH O OH O
H5 C 2 H5 C 2
b) C2H5 C 2 H5
B B’
OH O OH O
H5 C 2 H5 C 2
C2H5 C 2 H5
C C’
- 150 -
c) D
HO OH
meso
HO OH HO OH
d)
HO OH HO OH
meso meso
D’ D’’
H H
H Hg OOC CH3 H
+
e) Hg OOC CH3
C2H5 C2H5
C2H5 OC2H5 OC2H5
E F G
H C2H5
Cl
f) H
C2H5 H
Cl
C2H5 C2H5
Br
g) I
H H
Br
CH3
H
h) J
OH
H
O
K
O
i)
O
endo
- 151 -
PROBLEM 131
Determine the structure (including stereochemistry where necessary) of the

following compounds marked by letters:
O
C O C2H5
a) + A
C O C2H5
O
C6H5
b) H5C6  B
COOH
COOH
O
C O C2H5
c) + C
H5C2 O C
O
C 6H5 COOH
d) H 5C6  D
COOH
CH3 O
H
e) + E
CH3
H O
CH3 MCPBA
f) F + F'
H
g) + O G
- 152 -
H COOC2H5
C
h) + H
C
H COOC2H5
H5C2OOC H
C
i) + I
C
H COOC2H5
OH
k) PBr3
K
C2H5
OH
SOCl2
l) L
C2H5
OH
TsCl, pyridine NaCN

m) M N
C2H5
O
H C O O H
O
n) H3O+
Answer:
O
H
C OC2H5
a)
A
C OC2H5
H
O
- 153 -
C 6 H5
C6H5
b) O
O B
O
H
C OC2H5
C
c)
H
C
O OC2H5
d) It does not react. It cannot be dehydrated due to the trans orientation of the
carboxylic groups.
CH3
H O
e) O E
H O
CH3
f) O CH3 + O CH3
F F’
(main product, (minor product, more sterically
less sterically hindered)
hindered)
g) It does not react. 1,2,3,5,6,7-hexahydronaphthalene is a trans diene.
h) H H
COOC2H5
COOC2H5
COOC2H5
i) H I
H
COOC2H5
- 154 -
Br
K
k)
C2H5
Cl
L
l)
C2H5
OTs CN
m) M N
C2H5 C2H5
H OH
n)
O
HO H
PROBLEM 132
Explain the following reactions, taking in account their stereochemistry:
H
CHO
OH HNO2
a)
NH2
H H
H5C6 C6 H 5 O O
H2SO4 C C
b) C C
N N NH HN
H5C6 C6H5
OH HO
Z,Z- benzyl dioxime
- 155 -
OH
CHO
H HNO2
c) NH2
H H
H5C6 C6 H 5 H5C6 NH NH C6H5

H2SO4 C C
C C
d) O O
N N OH
OH
Z,E- benzyl dioxime
H O
e) OH HNO2
H
H NH2
H5C6 C6H5 H5C6 O

H2SO4 C N
f) C C
N C
HO N N OH
C6H5
E,E- benzyl dioxime
C2H5
H HO-
g) one product
Br
H
H3 C H
OH
HNO2
h) H
H O
H NH2
Answer:
H H
OH HNO2
OH
a) NH2 N2
H H H H
- 156 -
O H O
H H
+
-H
H5C6 C6H5 O O
H2SO4 C C
C C
b) Beckmann
N N rearrangement NH HN
H5C6 C6H5
OH HO
Z,Z- benzyl dioxime
H
OH
OH HNO2
H
c) NH2
N2
H H
H H
O H O
H H
+
-H
H5C6 C6H5 O C6H5

H2SO4 H2SO4
d) C C C C
Beckmann Beckmann
N N OH rearrangement H5C6 NH N OH rearrangement
OH
H5C6 NH NH C6H5
C C
O O
H H
OH HNO2 OH
e) H H
H NH2 H N2
- 157 -
O H O
H5C6 C6 H 5 H5C6 C6H5

f) H2SO4
C C C C
Beckmann +
HO N N OH rearrangement H2O N N OH
E,E- benzyl dioxime
C6H5 H5C6 O
H5C6 N - H2O
C C C N
N OH the intermediate N C
is stabilized
OH C6H5
by cyclization
C2H5 C 2 H5
H E2 anti
g) Br
H
H3C H H3C H
OH OH
HNO2
h) H H
H H
H NH2 H N2
O H - H+ O
PROBLEM 133
Explain the following experimental facts:
- 158 -
COOH
H COOH
C D2 H C D
a)
C Wilkinson's H C D
H COOH catalyst
COOH
meso-(2,3-D2)-butane-1,4-dioic acid
COOH COOH
H COOH
C D2 H C D D C H
b) +
C Wilkinson's D C H H C D
HOOC H catalyst
COOH COOH
(2R, 3R) (2S, 3S)
racemic-(2,3-D2)-butane-1,4-dioic acid
C2H5 C2H5 C2H5

H C OH HO C H HBr H C Br
c) +
H C Br Br C H H C Br
C2H5 C2H5 C2H5
erythro (racemic) meso
C2H5 C2H5 C2H5 C2H5

H C OH HO C H HBr H C Br Br C H
d) + +
Br C H H C Br Br C H H C Br
C2H5 C2H5 C2H5 C2H5
treo (racemic) treo (racemic)
e) Acetolysis of 4-methoxy-1-pentilbrosylate and 5-methoxy-1-pentilbrosylate

respectively, lead to a mixture of two reaction products.
f) Methyl mesityl ketone does not undergo addition with organic compounds.
CH3
Lindlar catalyst
g) H3C CH2 C C CH3 + H2 C C
H H
cis-alkene
H
H3C CH2 C C CH3 Na/NH3 C C
h)
H CH3
trans-alkene
- 159 -
Answer:
Syn addition:
H COOH COOH
a D C H
H D
H COOH D C H
a) C COOH
COOH
D2 D
H C D
COOH
COOH
b H COOH H C D
D
H C D
H COOH COOH
meso-(2,3-D2)-butane-1,4-dioic acid
Syn addition:
D
H COOH COOH
a D H C D
H D C H
b) HOOC H
C COOH COOH
D2
(2R, 3R)
HOOC C
H H COOH COOH
b
D D C H
HOOC H H C D
COOH
D
(2S, 3S)
Enantiomers
c) Anchimeric assistance from the halogen atoms:
C2H5 H5C2 H H5C2 H

H C OH +
Br H
OH Br +
H C Br OH2
C2H5 H C2H5 H C2H5
- 160 -
H5C2 C2H5
H
a Br H C Br
+ Br H C Br
Br H C2 H 5
C2H5
H5C2
meso
H
Br
a C2H5
H C2H5 H5C2 H Br C H
b
b H C2H5 Br C H
Br-
C2H5
Br
meso
C2H5 H5C2 H H5 C 2 H
H C OH Br H +
d) OH Br +
Br C H OH2
C2H5 H5C2 H H5 C 2 H
C2 H 5
H5 C 2 H
+ a Br H C Br
Br Br Br C H
H5C2 H5 C 2 H
C2 H 5
H
Br
a C2H5
H5C2 H H5C2 H Br C H
b
b H5C2 H H C Br
Br-
C2H5
Br
e) Identical intermediate (anchimeric assistance from the oxygen atom):
H
H O+ H
H OCH3 -
- BsO
H3C
CH3 H OBs CH3 H
I
H 3C H
H O+ H
-
O - BsO
BsO H3C
CH3 CH3 H
H
I
- 161 -
The common intermediate I undergoes similar transformations:

a H H
O
H O+ H
AcO H3C
H3C CH3 H
CH3 H
a b
H
b H OCH3
-
AcO
CH3 H OAc
f) Steric hindrance due to the high volume of the mesytil group.

g) Syn addition, heterogenic catalysis:
H2
H3C CH2 C C CH3 H3C CH2 C C CH3
poisoned Pd
H H
catalyst
CH3
C C
H H
cis-alkene
h) Addition of metallic Na to liquid NH3 leads to a partial dissolution of the metal.

Each metal atom loses an electron and becomes a cation. Both the Na+ ion and the
free electron are solvated by NH3 molecules.
Na(s) + (m+p)NH3(l) Na+(NH3)m + e- (NH3)p
H5C2
H3C CH2 C C CH3 + -e C C
CH3
H5 C 2 H H5C2
C C + H N C C + NH2
CH3 H H CH3
H5 C 2 H5 C 2
C C + -e C C
H CH3 H CH3
- 162 -
H5C2 H H5C2 H
C C + H N C C + NH2
H CH3 H H CH3
PROBLEM 134
Compare maleic acid to fumaric acid and state which of the following characteristics
are different:
a) melting point;
b) first acidity constant value;
c) second acidity constant value;
d) FTIR spectrum;
e) 1H-NMR spectrum;
f) refractive index;
g) solubility in water;
h) solubility in ethanol;
i) product of hydrogenation;
j) product of deuteration with D2 in the presence of Wilkinson catalyst;
k) the value read on the polarimeter for the previous reaction mixture;
l) UV-VIS spectrum;
m) Raman spectrum;
n) X-ray spectrum;
o) dipole moment;
p) hydrogenation enthalpies;
q) the products of reacting with HBr.
Answer:
H COOH H COOH
C C
C C
H COOH HOOC H
maleic fumaric
acid acid
The following characteristics are different: a, b, c, d, e, f, g, h, j, l, m, n, o and p.

The products of hydrogenation and addition on HBr are identical.
Even though the deuteration with D2 in the presence of Wilkinson’s catalyst are
different (maleic acid forms meso-(2,3-D)-butanedioic acid while fumaric acid forms the
racemic mixture of the threo compounds), the values read on the polarimeter are identical
(they do not rotate the plane-polarized light).
PROBLEM 135
Synthesize the following compound from accessible starting materials:
- 163 -
OH HO
HO
a) b) OH
cis-1,4-diol cis-1,5-diol
c) COOCH3
Answer:
sigmatropic
a) cycloaddition migration
[2+2] [3+3]
1,2-cis-divinyl 1,5-cyclooctadiene
cyclobutane
H2B HB
B2H6 H2O2/HO-
HO
OH
cis-1,4-diol
HB
H2B
B2H6 H2O2/HO-
b)
HO
OH
cis-1,5-diol
c) The stabilized ylide will produce the trans-alkene while the non-stabilized ylide
will produce the cis-alkene.
- 164 -
+
(I) CHO + (C6H5)3P _ COOCH3
_
+ COOCH3
(II) P(C6H5)3 + OHC
Therefore, in case (I) the ylide will produce a trans-alkene while in case (II) the
ylide will produce a cis-alkene. Thus, the correct synthesis is the following:
1. (C6H5)3P _ COOCH3
+ OHC
Cl 2. BuLi P(C6H5)3
COOCH3
PROBLEM 136
Write down the structural formulas for the compounds marked by letters in the following
reaction schemes:
COOC2H5 C2H5O-Na+ LiAlH4
A B + C
COOC2H5
diastereoisomers
TsCl, Py C2H5O-Na+
B D E
C
TsCl, Py C2H5O-Na+
F G
Answer:
O COOC2H5 HO OH HO OH HO OTs
A B C D
O HO OTs
O OTs
E F
- 165 -
OTs OTs
HO -
O
OHC
G
Grob fragmentation
PROBLEM 137
“Whenever cis-dihydroxylation of alkenes is required, potassium permanganate

(Baeyer reaction) is preferred over osmium tetroxide because it is cheaper and less toxic.”
Answer:
The choice of the chemical reagent depends largely on the material undergoing oxidation.
As an example, for cis-dihydroxilation of 3 kg of a cheap alkene, potassium
permanganate is preferred because it is cheaper and safer to handle, even though the yield
will be smaller.
However, if we start from 3 mg of a highly expensive alkene, the use of osmium
tetroxide is preferred due to its higher yield and because, when small amount is required,
it becomes safe to handle.
PROBLEM 138
The isomerization rate constant of a cis-azoderivative to its trans diastereoisomer is

0.3 h-1 at 40 °C. What is the cis:trans ratio after one hour, if we start from a pure cis
derivative sample?
Note: Consider that the reaction is ireversible.
Answer:
R
N N N N
R R R
1 c
k  ln 0 c0 – initial concentration of cis-azoderivative
t c
, c – concentration after 1 h of cis-azoderivative
V – volume of the reaction vessel.
1 c c
0.3  ln 0  0  e0.3  1.35
1 c c
After 1 h: no. moles of cis compound = cV
no. moles of trans compound = (c0 - c)V
- 166 -
cV c 1
cis:trans ratio     2.86
(c0  c)V c0  c 1.35 1
PROBLEM 139
Sucrose hydrolysis follows a 1st order kinetics (pseudo unimolecular reaction). The
rate constant can be measured by monitoring the optical activity of the solution.
During the hydrolysis of a sample of sucrose in a 1 N HBr solution the following
data was obtained:
time (s) 0.00 7.80 18.80 51.00 ∞

rotation + 27.50 + 24.10 + 19.80 + 10.00 - 11.20
a) Calculate the rate constant.

b) How can you explain that the optical rotation of the solution decreases?
c) Can sucrose be hydrolyzed under the influence of CO2 + H2O?
d) What is the mechanism of the reaction used to obtain inverted sugar syrup?
Answer:
a) We note the following:

- 0 –rotation angle at t0;
- t – rotation angle at t;
- ∞ - rotation angle at equilibrium.
 0     c0 concentration of sucrose
 t     c concentration of unreacted sucrose
Integrated kinetics equation for a 1st order reaction:
1 c 1  
k  ln 0  ln 0
t c t  
t 
1 27.0  (11.20) 1 38.70
- at t = 7.85 s  k  ln k  ln  11.78 10 3 s 1
7.85 24.10  (11.20) 7.85 35.30
1 38.70
- at t = 18.80 s  k  ln  11.80 10  3 s 1
18.80 31
1 38.70
- at t = 51 s  k  ln  11.80 10 3 s 1
51 21.20
 
k  k1 k 2 k 3  11.79 10 3 s 1
3
- 167 -
b) Fructose is highly levorotatory, while glucose and sucrose are weakly dextrorotatory.
c) Sucrose inversion can occur under weak acids.
O O O O
H+ +
d) O O
fast
glucose fructose H
moiety moiety
O O
+ fructose
+ HO
O
+ H2O
OH glucose
O+ - H+
PROBLEM 140

a) isophtalic acid cannot form an anhydride due to its plane and rigid molecular
structure, even though the carboxylic acids are placed in the 1 and 5 positions;
b) trans-1,2-cyclohexanedicarboxylic acid can form a normal trans anhydride due to
its non-planar conformation of the two rings;
c) the monoanilide of cis-1,2-cyclohexanedicarboxylic acid cannot be resolved;
d) if the chiral substance absorbs in UV and visible, ORD measurements have maxima
and minima;
e) 5-amino-2,4,6-triiodo-N,N,N’,N’-tetramethylisophtalamide has cis-trans
isomerism due to the large atomic volume of the iodine atoms which prevent the free
O
rotation of the C N(CH3)2 groups;
f) the energy content of the conformers varies in the following way:
CH3 CH3 H
CH3 H CH3
> >
H H H CH3 H CH3
g) 5-amino-2,4,6-triiodo-N,N,N’,N’-tetramethylisophtalamide cannot be resolved;

h) the allylic strain is higher for the cyclic compound compared to non-cyclic olefines,
growing with the rigidity of the system;
i) the brominated derivative with the following structure has 10 stereoisomers:
- 168 -
Br CH2 CH C CH2 CH2 CH CH2 CH2 CH CH2 CH3

C2H5 C 2 H5 C 2 H5
H 5C6 H5C6
j) HC CH CH CH3 NaOH 5M HC CH CH CH3

O HO
C2H5
O
optically pure retention of optical activity
H5C6
NaOH
HC CH CH CH3 H5C6 CH CH CH CH3
diluted solution
O OH
C2H5
O
optically pure optically inactive
k) inclusion compounds of -ciclodextrin with some drugs, food flavourings or other

food ingredients, is a way to protect these compounds;
l) He@C60, Ne@C60, La@C60, La@C82, Sc@C80 are formulas of some inclusion
compounds of fullerenes.
Answers:
f) The allylic tension increases in the following order:
CH3 CH3 H
CH3 H CH3
< <
H H H CH3 H CH3
H 2N I
O
g) I C trans diastereoisomer can be
divided in enantiomers
N(CH3)2
(CH3)2N C I
O
i) Z (-) (+) Z (+) (-)

E (+) (+) E (+) (-)
Z (-) (-) Z (-) (+)
E (-) (-) E (-) (+)
- 169 -
j) High base concentration leads to bimolecular nucleophilic substitution. The bonds

from the chiral atom are not broken and thus the configuration is preserved.
At a low base concentration, the hydrolysis takes place via a SN1 mechanism:
H5C6
HO- +
HC CH CH CH3 - H5C6 CH CH CH CH3
- C2H5COO
O
C2H5
O
+
H5C6 CH CH CH CH3
HO-
H5C6 CH CH CH CH3
+
H5C6 CH CH CH CH3 OH
The formed alcohol is optically inactive with the double bond conjugated with the
aromatic ring.
The following statements are true: a, b, d, e, h, j, k and l.
PROBLEM 141
Which of the following compounds are achiral?
2-
A B C
(CH2)n
CH3
CH3 Br H
C N CH3
O N H2 N
C2H5 n
O O O COOH
C6H5
polyalanine
Br
D E F
- 170 -
Cr
bis(benzene)chromium
myoglobin
G H
uranocene
tetra–tert-butyl-tetrahedrane
DNA
I J K
HO OCH3
H3CO OH
OH H3CO
kekulen
M N
- 171 -
Answer:
Compounds that are achiral: A, B, E, G, I, K, N.
PROBLEM 142
Hydrolysis of a sample containing synthetic triacylglycerols leads to a mixture of
oleic acid and elaidic acid.
a) What is the maximum number of triacylglycerols (including stereoisomers) that
may exist in initial sample?
b) What is the minimum number of triacylglycerols that may exist in initial sample?
Answer:
We’ll make and use the following notations:

O CH3 (CH 2)7 H
CH3 (CH2)7 (CH2)7 C O C C
C C H (CH2)7 C O
H H O
Ol (oleic acid residue) El (elaidic acid residue)
a) Maximum number of distinct triacylglycerols is eight (including stereoisomers),
as follows:
H 2C Ol H 2C El H 2C Ol
HC Ol HC El HC El
H 2C Ol H 2C El H 2C Ol
A B C
H2C Ol
H 2C El
HC Ol
HC Ol is
H2C El
H 2C El
(+
_)
D E F
b) Minimum number of triacylglycerols in the sample is one (any of the compounds

C, D(±), E, F(±)).
PROBLEM 143
Statins are a class of lipid-lowering drugs capable of reducing the mevalonic acid
biosynthesis by competitive inhibition of hydroxymethylglutaryl-coenzyme A-reductase
(HMG-CoA reductase) activity.
- 172 -
Considering that mevalonic acid is a precursor in cholesterol biosynthesis, statins

administration has the effect of decreasing cholesterol level (especially circulating LDL)
with the consequence of slowing down the atherogenesis process.
a) Propose a synthesis method for mevalonic acid (3,5-dihydroxy-3-methylvaleric
acid) using accessible raw materials;
b) Mark with an asterisk chiral centers of the following statins:
O OH
HO O
HO
O HO
O O
O O
H H
HO
Lovastatine Pravastatine
isolated from Aspergillus terreus (marketed as Lipostat)
HO
COOH
CH3 CH3
OH OH O OH
N OH F
CH3
N N
N
O S
CH3 F
O
Rosuvastatine Fluvastatin
(marketed as Crestor) (marketed as Lescol)
c) Statins administration may generate side-effects as myalgia, increased

transaminases, myopathies, etc. Also, a decrease in Q10 coenzyme levels may be
registered. What is this enzyme? Mention several potential medical applications of
Q10 coenzyme.
Answer:
O O C2H5
CH2O CH3I
a) CH3 C CH3 CH3 C CH2 CH2 N
(C2H5)2NH C2H5
Mannich reaction
- 173 -
O C2 H 5 O
+ C2H5O- CH3COOH
CH3 C CH2 CH2 N C2H5 CH3 C CH CH2
CH3 (methyl vinyl ketone)
Hofmann degradation
O O
1. BrZnCH2 COOCH3
CH3 C CH2 CH2 O C CH3
2. H2O
CH3 OH CH3 OH
CH2 CH2 1. KOH, H2O CH2 CH2
O
CH2 COOCH3 2. H+ CH2 COOH
C O HO
CH3
mevalonic acid
O OH
HO * O
HO
O *
O *
b) HO
*
* O
O
H
* O
* * * H
*
* * * * *
*
HO
eight chiral centers eight chiral centers
HO
* COOH
CH3 CH3
OH OH O OH
*
N * * OH F
CH3
N N
N
O S
CH3 F
O
two chiral centers two chiral centers
- 174 -
c) Q10 coenzyme (CoQ10) is a quinone (substituted 1,4-benzoquinone) produced by

human body, having a fundamental role in cell functioning and energy generation. An
implicit antioxidant role is associated with CoQ10.
Scientific studies indicate that serum levels of Q10 coenzyme decreases with age
and for persons associated with chronic diseases (diabetes, cardiovascular disease,
cancer, HIV infections, etc).
Administration of statins influences the CoQ10 concentration in human body; this
is a scientific fact which has a simple explanation: CoQ10 biosynthesis occurs also via
mevalonic acid.
Co-enzyme Q10 supplements may be a beneficial support for cardiovascular
diseases (cardiomyopathies, arterial hypertension), migraines, cancer, Parkinson.
However, according to Mayo clinic report “CoQ10 has been used, recommended or
intensively studied, but CoQ10 supplements’ administration remains controversial”.
PROBLEM 144
Write all individual synthetic triacylglycerols that in alkaline hydrolysis form two
moles of CH3 (CH2)5 CH CH (CH2)7 COO-Na+ and sodium mandelate.
Answer:
We note unsaturated triacylglycerol acid residue with N, and the remaining mandelic acid
with M.
CH3 (CH2)5 (CH2)7 COO-Na+ CH3 (CH2)5 H

C C C C
H H H (CH2)7 COO-Na+
Z E
Considering that stereochemistry of the unsaturated acid is not stated, we can

assume that both stereoisomers may form.
OH H
- +
C 6 H5 C COO Na C 6 H5 C COO-Na+
H OH
Considering that stereochemistry of the sodium mandelate is not stated, we can

assume that both stereoisomers may form.
- 175 -
possible stereoisomers:
H2C O N (Z sau E) Z (+) Z Z (+) E (+)
Carbon atom
E (+) E Z (+) E (-) becomes
HC O M ((+) sau (-))
Z (-) Z Z (-) E (+) optically
H2C O N (Z sau E)
(-) (-) (-) active
E E Z E
H2C O M ((+) sau (-)) (+) (+) Z Z (-) (-) Z Z

(+) (+) Z E (-) (-) Z E
HC O N (Z sau E)
(+) (+) E Z (-) (-) E Z
H2C O N (Z sau E) (+) (+) (-) (-)
E E E E
(+) (-) Z Z (-) (+) Z Z

(+) (-) Z E (-) (+) Z E
(+) (-) E Z (-) (+) E Z
(+) (-) E E (-) (+) E E
PROBLEM 145
Ricinoleic acid is an unsaturated fatty acid -9 that can be found in castor oil (in
triacylglycerol form). Ricinoleic acid has excellent analgesic and anti-inflammatory
properties. Its zinc salt is used in manufacturing of deodorants.
A racemic mixture of ricinoleic acid reacts with (R)-2-buthanol. The raw reaction
mixture is processed with high performance liquid chromatography (HPLC).
Assuming that racemic mixture is in excess relative to optically active alcohol,
please estimate:
a) How many fractions are collected by separation? Out of these, how many are
optically active?
b) How many compounds are collected by separation?
c) By oxidative pyrolysis of sodium ricinoleate in the presence of NaOH, sebacic
acid and 2-octanole are obtained. Propose a plausible reaction mechanism for
this transformation.
Answer:
Enantiomers of racemic mixture of ricinoleic acid react differentiated with 2-

butanol. Thus, two diastereoisomeric esters will form, and the reaction mixture that
reached the equilibrium will contain two enantiomers (one of them in excess).
Consequently, three fractions will be collected by separation (two diastereoisomeric
esters and the mixture of the two enantiomers). All these three fractions are optically
active.
- 176 -
a) Four compounds will be collected: two diastereoisomeric esters, (R) and (S)-
ricinoleic acid.
OH
HO-
CH3 (CH2)5 CH CH2 CH CH (CH2)7 COOH +
OH
(R) + (S) (R)
excess
O
CH3 (CH2)5 CH CH2 CH CH (CH2)7 C O (R)
OH
(R)
O
CH3 (CH2)5 CH CH2 CH CH (CH2)7 C O (R)
OH
(S) O
CH3 (CH2)5 CH CH2 CH CH (CH2)7 C OH
OH
(R) O
CH3 (CH2)5 CH CH2 CH CH (CH2)7 C OH
OH
(S)
CH3 (CH2)5 CH CH2 CH CH (CH2)7 COO-

c) -2 [H]
OH
- H+
CH3 (CH2)5 C CH2 CH CH (CH2)7 COO-
O
-
CH3 (CH2)5 C CH CH CH (CH2)7 COO-
O
- H+
CH3 (CH2)5 C CH CH CH (CH2)7 COO-
O
H2O
CH3 (CH2)5 C CH CH (CH2)8 COO-
O
- 177 -
retro - aldol
CH3 (CH2)5 C CH2 CH (CH2)8 COO-
condensation
O OH
CH3 (CH2)5 C CH3 + OCH (CH2)8 COO-

O
-
+H
CH3 (CH2)5 C CH3 CH3 (CH2)5 CH CH3
+ H+
O OH
H -
- HO- - -H
OCH (CH2)8 COO HO C (CH2)8 COO
O-
- H+
HO C (CH2)8 COO- -
OOC (CH2)8 COO-
O
PROBLEM 146
The esterification of 2-methylglycerol with hexanoic acid is performed.

a) What is the number of acylglycerols that can be formed in this reaction?
b) How many different fractions may be separated from the reaction mixture if this
is processed by thin film chromatography?
c) How many different fractions may be separated from the reaction mixture if (R)-
ricinoleic acid is used instead of hexanoic acid?
Answer:
H2C OH
a) CH3 C OH + CH3 (CH2)4 COOH
H2C OH
O
H2C O C (CH2)4 CH3 H2C OH
O
CH3 C OH CH3 C O C (CH2)4 CH3
H2C OH H2C OH
( +_ )
three 2-methylmonoacylglycerols
- 178 -
O O
H2C O C (CH2)4 CH3 H2C O C (CH2)4 CH3
CH3 C O C (CH2)4 CH3 CH3 C OH

O
H 2C OH H2C O C (CH2)4 CH3
( +_ ) O
three 2-methyldiacylglycerols
O
H2C O C (CH2)4 CH3
O
CH3 C O C (CH2)4 CH3
H2C O C (CH2)4 CH3

O
2-methyltriacylglycerols
In total, seven 2-methylacylglycerols may be formed.

b) If reaction is performed in strictly achiral conditions, five different fractions may be
separated (two of them being racemic mixtures). In chiral conditions of the reaction,
seven different fractions may be separated.
c) Regardless to reaction conditions, seven different fractions can be formed (2-
methylacylglycerol diastereoisomers with different physical and chemical properties will
be obtained).
PROBLEM 147
a) Write the number of stereoisomers for the synthetic triacylglycerols inserted below:
O O
H2C O C CH CH n COOC2H5 H2C O C CH CH n COOC2H5
O O
HC O C CH CH COOC3H7 HC O C CH CH COOC3H7
O O
H2C O C CH CH n COOC2H5 H2C O C CH CH p COOC2H5
A B
n≠p
- 179 -
O
H2C O C CH CH n COOCH3
O
HC O C CH CH COOC2H5
O
H2C O C CH CH n COOC4H9
C
assuming that all double bonds coming from the acids that are esterifying primary
alcoholic groups have the same configuration.
b) Arrange the triacylglycerols above in descending order of iodine index (assuming a
quantitative iodine addition).
Answer:
O O
a)
all-cis n all-trans
n
1 1
A: HC O C CH CH COOC3H7 HC O C CH CH COOC3H7
O O
n n
all-cis 2 all-trans 2
O O
all cis Z all cis all trans Z all trans

1 2 1 2
A:
all cis E all cis all trans E all trans
1 2 1 2
There are four stereoisomers in total.
O O
n n
B: HC O C CH CH COOC3H7 HC O C CH CH COOC3H7
O O
p p
O O

1 2 1 2

1 2 1 2
- 180 -
O O
n all-trans
n
all-cis 1 1
C: HC O C CH CH COOC2H5 HC O C CH CH COOC2H5
O O
all-cis
n all-trans n
2 2
O O

1 2 1 2

1 2 1 2

b) Iodine index is proportional with unsaturation degree of triacylglycerols.
A 2n+1 double bonds
B n+p+1 double bonds
C 2n+1 double bonds
If n > p, the requested order is: A = C>B

If n < p, the requested order is: B>A = C
PROBLEM 148
Write the maximum number of possible stereoisomers for an individual synthetic

triacylglycerol that, by hydrolysis and gentle acidification, forms:
a) one mole of mandelic acid, one mole of butyric acid and one mole of palmitic acid;
b) two moles of stearic acid and one mole of mandelic acid;
c) two moles of mandelic acid and one mole of stearic acid.
Remark:
One considers that all the three alcoholic groups from glycerol are esterified and
mandelic acid exists in both enantiomeric forms.
Answer:
We’ll make and use the following notations:

O
CH C
M - for mandelic acid residue:
OH
- 181 -
O
B - for butyric acid residue: CH3 (CH2)2 C
O
S - for stearic acid residue: CH3 (CH2)16 C
O
P - for palmitic acid residue: CH3 (CH2)14 C
Possible stereoisomers:
H 2C O B (+) (+) H2C O P (+) (+)
a) (+
_ ) HC (+) (-) (+
_ ) HC (+) (-)
O P O B
( +_ )
(-) (+) ( +_ )
(-) (+)
H 2C O M (-) (-) H2C O M (-) (-)
H2C O P (+) (+)

(+
_ ) HC ( _) (+) (-)
O M +
(-) (+)
H2C O B (-) (-)
There are twelve potential stereoisomers, which through hydrolysis, may form one
mole of palmitic acid, one mole of butyric acid and one mole of mandelic acid.
H2C O S H 2C O S (+) (+)

( _) (+
_ ) HC (+) (-)
b) HC O M + O S
(+) şi (-) (-) (+)
( +_ )
H2C O S H 2C O M (-) (-)

(+
_) (+) (+) (+) (+) (+) (-)
H2 C O M
(+ (+) (-) (+) (+) (-) (-)
c) (+
_ ) HC _)
O M
(-) (+) (+) (-) (+) (-)
H2 C O S (-) (-) (+) (-) (-) (-)
(+
_) (+) (+)
H2C O M
(+) (-)
HC O S
(-) (+)
(+
_)
H2C O M (-) (-)
- 182 -
When the two marginal mandelic acids have different configurations, the central
carbon atom is pseudo-asymmetric. There are twelve stereoisomers in total.
PROBLEM 149
Mention the number of stereoisomers for the compound inserted below:
O
H2C O C CH CH 2 CH3
O
HC O C (CH2)14 CH3
O
H2C O C CH CH 2 CH3
assuming that 50 % of the existing double bonds have E configuration and the other 50 %
have Z configuration.
Answer:
O O
H2C O C CH CH CH3 H2C O C CH CH CH3
2 2
cis-cis 1 cis-trans 1
HC O C (CH2)14 CH3 HC O C (CH2)14 CH3
O O
2 2
trans-trans 2 cis-trans
O O 2
(±)
O O
2 2
cis-trans 1 trans-cis 1
HC O C (CH2)14 CH3 HC O C (CH2)14 CH3
O O
2 2
trans-cis trans-cis
O 2 O 2
(±)
- 183 -
PROBLEM 150
Hydrolysis of a sample containing triacylglycerol(s) generated a mixture of myristic
acid, arachidic acid and linoleic acid.
a) What is the maximum number of triacylglycerols (including stereoisomers) that
may exist in the initial mixture?
b) What is the maximum number of triacylglycerols from the initial mixture if the
existing stereoisomers are in L form?
c) What is the minimum number of triacylglycerols that can exist in the initial
mixture?
Answer:
The following notations will be used:

O
M for myristic acid residue: CH3 (CH2)12 C
O
A for arachidic acid residue: CH3 (CH2)18 C
O
L for linoleic acid residue: CH3 (CH2)4 CH CH CH2 CH CH (CH2)7 C
Possible triacylglycerols:
H2C O M H2C O A H2C O L H2C O A H2C O A

HC O M HC O A HC O L HC O A HC O M
H2C O M H2C O A H2C O L H2C O M H2C O A

(±)
H2C O A H2C O A H2C O M H2C O M H2C O M

HC O A HC O L HC O M HC O A HC O M
H2C O L H2C O A H2C O A H2C O M H2C O L

(±) (±) (±)
H2C O M H2C O L H2C O L H2C O L H2C O L

HC O L HC O A HC O L HC O M HC O L
H2C O M H2C O L H2C O A H2C O L H2C O M

(±) (±)
- 184 -
H2C O M H2C O A H2C O A

HC O A HC O M HC O L
H2C O L H2C O L H2C O M

(±) (±) (±)
a) There are 27 triacylglycerols (maximum number) that, by hydrolysis, may generate

a mixture of acids myristic, arahidic and linoleic.
b) Half of the existing optical stereoisomers are in the L form. Subsequently, the
maximum number of triacylglycerols in this case will be 18.
c) One is the minimum number of triacylglycerols that may exist in the initial mixture,
any of the compounds:
H2C O M H2C O A H2C O A

HC O A HC O M HC O L
H2C O L H2C O L H2C O M

(±) (±) (±)
PROBLEM 151
Which of the following molecules belong to the C1 symmetry point group?

a) methane;
b) benzene;
c) nicotine;
d) methylene chloride;
e) acetylene.
Answer:
The right answer is c.
A molecule belongs to C1 symmetry point group only if it does not have a

symmetry element, the only possible symmetry operation being identity operation.
The only structure that respects this criterion is nicotine.
H
N
CH3
N
nicotine structure
- 185 -
PROBLEM 152
For each element of chirality, mention the prefixes R / S according to IUPAC

rules:
a) a-S, b-R, c-S

b) a-R, b-R, c-R
c) a-R, b-S, c-S
d) a-S, b-S, c-S
e) molecule is achiral
Answer:
The right answer is a.
Chirality centers (a) and (c) can be easily deduced as being „S”, according to the
CIP Convention. Also, the molecule contains one more chirality axis (b).
For the molecules containing chirality axes, R/S prefixes are assigned as follows:
 A Newmann projection is constructed, visualizing the molecule along the chirality
axis (not important if the axis is viewed from the left or right, the result is the same).
 Priority is assigned to substituents on the closest ring to the observer.
 Priority is assigned to substituents on the farthest ring to the observer.
 Similar to the CIP convention, if ordering direction of the 1, 2, 3 substituents is
similar to clockwise rotation, the molecule is R; otherwise, the molecule is S.
R 3
CH 3 O 2N NO2
2 1
(a) (b) (c)
H3C NO2
HO OH
NO 2 H 3C CH3
4
PROBLEM 153
Though the anomer β of D-glucose is thermodynamically stable, the acetylation of

D-glucose under thermodynamic control, will lead to the formation of α-penta-acetyl-D-
glucose due to:
a) steric hindrance generated by bulky acetyl groups;

b) anomeric effect;
c) the fact that α isomer has a higher symmetry, leading to a better α-penta-acetyl-
D-glucose crystal packing;
d) no answer, the question is wrong, α-D-glucose is more stable;
e) no answer, the question is wrong, α-penta-acetyl-D-glucose is more stable.
- 186 -
Answer:
The right answer is b.
Though for the glucose case, α isomer is less stable because of 1,3 – biaxial
interactions, for substituted glyosidic groups, the resulted product under thermodynamic
control is the α isomer.
..
O ..
O CH3
The orientation of the glycosylic C-O bond is anti-periplanar and it is close to a non-
participating electron pair of the oxygen atom from the six atoms cycle. In this
arrangement, the oxygen atom can donate electrons in the anti-bonding orbital σ* of C-
O bond, thus determining the stabilization of α isomer. This phenomenon is known as
anomeric effect.
PROBLEM 154
On the potential surface of cyclohexane, the boat structure is classified as:

a) a minimum point;
b) a global minimum point;
c) a maximum point;
d) a global maximum point;
e) a „saddle” point.
Answer:
The right answer is e.
In computational chemistry, a potential hypersurface represents the energies of all

tridimensional arrangements of a certain set of atoms.
On this surface, the so-called stationary points (points of zero slope for all the
functions depending of internal coordinates) may have structures of interest as reaction
products, reaction intermediates and transitions states, etc.
The minimum points correspond to compounds that theoretically can be
isolated/separated, such as products, reactants, conformers or reaction intermediates,
while points having a topology of a “saddle” correspond to transition states. Maximum
points do not have a chemical meaning.
For the cyclohexane, the boat type structure is a transition state, so it may be characterized
as a “saddle” point.
- 187 -
PROBLEM 155
Which is the major product formed by the reaction:
O H+
?
HO OH
O
O
a)
b) O
c) O
O OH
d)
e) compounds mentioned in answers a - c form in similar quantities; the expression

“major product” is inappropriate.
Answer:

The potential products of this reaction are the three spiroketals having the structures
mentioned in items a – c. Out of these, the isomers b and c are stabilized due to anomeric
effect.
Compound c is the most thermodynamically stable product, due to a double
anomeric effect that appears as both C-O bonds of the acetal functional group are axial.
Considering that the process of acetals’ formation in acidic medium has a reversible
character, the isomer c may form, almost exclusively.
- 188 -
O O
O O
O O
a) e,e b) e,a c) a,a
PROBLEM 156
Considering the reaction:
CH3 CH2 CH CH3 + (CH3CO)2O CH3 CH2 CH CH3

OH O C CH3
(S) - (-) O
Assuming that no information regarding the reaction mechanism is available,

which of the following phrases may be considered an unequivocal statement?
a) the reaction product rotates the plane-polarized light to the right;
b) based on the available information, it is impossible to predict the configuration of
the final product;
c) reaction product has S configuration;
d) reaction product is not optically active;
e) some molecules have R configuration, others have S configuration, the ones with
R configuration being major reaction products.
Answer:
Bond breakage of one asymmetric carbon does not occur. If this would happen,
reaction product should have S configuration.
PROBLEM 157
Given the reaction:
CH3 CH2 CH CH3 + (CH3CO)2O CH3 CH2 CH CH3

OH O C CH3
(S) - (-) O
and assuming that no information regarding reaction mechanism is available,
which of the following is an unequivocal statement?
- 189 -
a) reaction product rotates the plane-polarized light to the right;

b) reaction product is a racemic;
c) reaction product is optically inactive;
d) reaction product is optically active, but prediction of rotation sense of the plane-
polarized light (clockwise or counterclockwise) can be done if only further
evaluations are available;
e) reaction product rotates the plane-polarized light to the left.
Answer:
The right answer is d.
PROBLEM 158
For the reaction:
H2O/H+
CH3 CH2 CH MgBr + S CH3 CH2 CH S MgBr
CH3 CH3
(R)-(+)
CH3 CH2 CH SH
CH3
No information regarding reaction mechanism is available. Which of the

following is an unequivocal statement?
a) reaction product rotates the plane-polarized light to the left;

b) based on the available information, it is impossible to predict the configuration of
the final product;
c) reaction product will have R configuration;
d) reaction product is not optically active;
e) some molecules have R configuration, others have S configuration, the ones with
S configuration being major reaction products.
Answer:
One bond of the asymmetric carbon breaks. Without further information, it is

practically impossible to predict the configuration of reaction product.
- 190 -
PROBLEM 159
For the reaction:

H2O/H+
CH3 CH2 CH MgBr + S CH3 CH2 CH S MgBr
CH3 CH3
(R)-(+)
CH3 CH2 CH SH
CH3
a) reaction product rotates the plane-polarized light to the right

b) reaction product has S configuration
c) reaction product is optically active, but prediction of rotation sense of the plane-
evaluations are available.
d) reaction product is a racemic mixture
e) based on the available information, it is impossible to predict whether the
reaction product will rotate or not the plane-polarized light.
Answer:
One bond of the asymmetric carbon breaks. If no further information may be

available, it would be practically impossible to predict the configuration of the reaction
product.
PROBLEM 160
For the reaction:
5 4 3 2 1 PCl5 5 4 3 2 1
CH3 CH2 CH CH2 COOH + Br2 CH3 CH2 CH CH COOH
CH3 CH3 Br
(R)-(-)
and assuming that no information regarding reaction mechanism is available, which
of the following is an unequivocal statement?
a) reaction product rotates the plane-polarized light to the right.

b) reaction product is optically inactive.
- 191 -
c) reaction product is optically active, but prediction of rotation sense of the plane-
evaluations are available.
d) reaction product rotates the plane-polarized light to the left.
e) the atom C3 loses its optical activity.
Answer:
PROBLEM 161
Given the reaction:
5 4 3 2 1 PCl5 5 4 3 2 1
CH3 CH2 CH CH2 COOH + Br2 CH3 CH2 CH CH COOH
CH3 CH3 Br
(R)-(-)

a) the atom C2 has S configuration in 50 % of the reaction product molecules, and R

configuration in the remained 50 %;
b) reaction product is optically inactive;
c) for the C2 carbon atom, R configuration is predominant in the reaction product;
d) the C3 carbon atom has R configuration;
e) the C3 carbon atom has S configuration.
Answer:
The right answer is d.
PROBLEM 162
For the following reactions:
(+)-quinidine H2O/H+
C6H5 CHO + HCN C6H5 CH CN C6H5 CH COOH
OH OH
- 192 -
(-)-quinine H2O/H+
C6H5 CHO + HCN C6H5 CH CN C6H5 CH COOH
OH OH
Which of the following statements is correct?
a) in both cases, reaction products do not rotate the plane-polarized light

b) in both cases, reaction products rotate the plane-polarized light, the rotation angles
having the same value and the same sign
c) for the first case, a racemic mixture is obtained, for the second reaction the
synthesis is asymmetric, a certain stereoisomer is obtained
d) (+) quinidine and (-) quinine do not influence the reaction stereochemistry
e) being two optically active catalyzers, one may predict that different composition
of optically active reaction product mixtures will be obtained. However, value and
sense of the rotation angle cannot be evaluated without further experimental
information.
Answer:
PROBLEM 163
Which of the following chemical processes may lead to cis-compounds formation?
CH3
H 
A
H
CH3
CH3
h
B
CH3
C6H5
COOCH3
C
C +
C
COOCH3
C6H5
H CH3 
D H CH3
- 193 -
H
COOCH3
CH3 C
E +
H C
COOCH3
CH3
a) A, B
b) A, C
c) B, C, D
d) B, D, E
e) C, E
Answer:
CH3
CH3
H 
A disrotatory process
H
CH3
CH3 cis
CH3 CH3
h
B
conrotatory process
CH3 CH3
trans
C6H5
COOCH3 H C6H5
COOCH3
C
C +
C
COOCH3
COOCH3 H C6H5
C6H5
cis
 CH3
H CH3
D H CH3 conrotatory process
CH3
trans
H
COOCH3 CH3 H
COOCH3
CH3 C
E +
H C
COOCH3
COOCH3 H CH3
CH3
- 194 -
Did you know…?
Did you know…?
 Jacobus Henricus van't Hoff, Jr. (30 August 1852 – 1 March 1911) was a Dutch
physical chemist. One of the most famous scientist of his time, van't Hoff was the
first winner of the Nobel Prize in Chemistry (1901) "for his discovery of the laws
of chemical dynamics and osmotic pressure in solutions”. In 1874 he predicted the
phenomenon of optical activity by assuming that the chemical bonds between
carbon atoms and their neighbors were directed towards the corners of a regular
tetrahedron. Van't Hoff published this idea and today this contribution is
recognized as the foundation of stereochemistry. Initially, his theory has been
severely criticized by the influential chemist Herman Kolbe. Kolbe's ironic
comment (alluding to the fact that Van 't Hoff was working at the Veterinary
School at Utrecht) is presented below:
"A Dr. J. H.van’t Hoff of the Veterinary School at Utrecht has no liking,
apparently, for exact chemical investigation. He has considered it more convenient
to mount Pegasus (apparently borrowed from the Veterinary School) and to
proclaim in his ‘La chimie dans l’espace’ how, in his bold flight to the top of the
chemical Parnassus, the atoms appeared to him to be arranged in cosmic space."
 Joseph Achille Le Bel (21 January 1847 – 6 August 1930) was a French chemist,
known for his hypothesis regarding the relationship between molecular structure
and optical activity. This theory was launched in the same year by the Dutch
physical chemist Jacobus Henricus van't Hoff. In spite of similarities and related
terms, van't Hoff’s and Le Bel's theory are quite different. While the first theory
emphasizes stereogenicity and isomer- counting, the second is centered on the
notions of symmetry and optical activity.
 The Le Bel–Van't Hoff rule states that the number of stereoisomers of an organic
molecule containing no internal planes of symmetry is 2n, where n represents the
number of asymmetric carbon.
 Johannes Martin Bijvoet (23 January 1892, – 4 March 1980) was a Dutch
chemist and crystallographer who worked at the van't Hoff Laboratory at Utrecht
University. He is well -known for developing a method to establish the absolute
configuration of molecules.
 Jean-Baptiste Biot (21 April 1774 – 3 February 1862) was a French physicist,
astronomer and mathematician with significant contributions in various fields
such as optics, magnetism and astronomy.
In 1835, while investigated polarized light, Biot found that sugar solutions rotate
the plane of polarization when a polarized light beam passes through and
demonstrated that many liquid organic solutions exhibited this optical activity.
- 195 -
Did you know…?
 Hermann Emil Louis Fischer (9 October 1852 – 15 July 1919) was a German
chemist and 1902 recipient of the Nobel Prize in Chemistry. Among the notable
contributions in organic synthesis (Fischer oxazole synthesis, Fischer indole
synthesis, Fischer phenylhydrazine synthesis, Fischer – Speier esterification,
Fischer glycosidation, first synthesis of caffeine), the German chemist developed
Fischer projection, a two-dimensional representation of a three-dimensional
organic molecule by projection.
 Robert Sidney Cahn (9 June 1899 – 15 June 1981) was a British chemist, known
for his valuable work to chemical nomenclature and stereochemistry particularly
by the Cahn–Ingold–Prelog sequence rules (CIP priority rules)which he
introduced in 1966 with Christopher Kelk Ingold and Vladimir Prelog.
 Sir Christopher Kelk Ingold (28 October 1893 – 8 December 1970) was a British
chemist, a co-author of the Cahn–Ingold–Prelog priority rules, also. His work was
focused on the electronic structure of organic compounds and reaction
mechanisms, an important contribution being the introduction of the key notions
such as electrophile, nucleophile, resonance, inductive effects and descriptors such
as E1, E2, SN1, SN2.
 Macromolecules with regular substituents on the polymer chain possess a property

known as tacticity. Isotactic polymers are composed of isotactic macromolecules
(all the substituents are oriented on the same side of the macromolecular
backbone). Polypropylene synthesized by Ziegler-Natta catalysis is an example of
isotactic polymer. In comparison with atactic polypropylene, isotactic
arrangement ensures a higher degree of crystallinity and a stiffer material.
R R R R R
The structure of isotactic polymer
In syndiotactic polymers the substituents have alternate positions along the

macromolecular backbone.
R R R R R R
The structure of syndiotactic polymer
Atactic macromolecules are characterized by randomly orientation of the substituents

along the chain.
- 196 -
Did you know…?
R R R R R
The structure of atactic polymer
Macromolecules that are synthesized by free-radical mechanisms are usually atactic.
 Louis Pasteur (December 27, 1822 – September 28, 1895) was a French biologist,
microbiologist and chemist best known for his discoveries of the principles of
vaccination, pasteurization and microbial fermentation. Louis Pasteur discovered
the existence of enantiomerism in tartaric acid. Working extremely meticulously,
he separated by handpicking the oppositely shaped crystals of tartaric acid. After
crystal's separation, Pasteur prepared two solutions (one with each type of crystal)
and tested their interaction with polarized light. He observed that each solution
rotates the plane-polarized light, but in opposite directions. Pasteur' conclusion
was that this optical behaviour is a consequence of the existence of two oppositely
shaped tartaric acid molecules.
 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (abbreviated as BINAP) is an

organophosphorus chiral ligand which is widely used in asymmetric synthesis.
BINAP has axial chirality due to restricted rotation (atropisomerism).
PPh2 PPh2
(R) (S)
PPh2 PPh2
The structures of (R) and (S)- BINAP
 O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (abbreviated
as DIOP) is a chiral ligand used in asymmetric catalysis.
H
O
H 3C PPh 2
H 3C PPh 2
O
H
The structure of DIOP
- 197 -
Did you know…?
 DIPAMP (Ethane-1,2-diylbis[(2-methoxyphenyl)phenylphosphane)]) is an
organophosphorus ligand that is used in asymmetric hydrogenation. Due to the
presence of the two chiral phosphorus center with three identical substituents,
DIPAMP exists as the (R,R) and (S,S) pair of enantiomers and the achiral meso
compound.
O O
P P
The structure of DIPAMP
 Chiraphos is a chiral diphosphine used in asymmetric catalysis.
H3C CH3
Ph2P PPh2
The structure of ChiraPhos
 DuPhos is a class of organophosphorus compound that are used in asymmetric

synthesis. Applications of DuPhos ligand include the hydrogenation of
dehydrowarfarin to warfarin and synthesis of tryptophane derivatives.
R
P
R
R
P
R = Me, Et, iPr

The structure of DuPhos
 Vladimir Prelog (23 July 1906 – 7 January 1998) was a Croatian-Swiss organic
chemist and recipient of the Nobel Prize in chemistry (1975) for his contribution into
the stereochemistry of organic molecules and reactions. He was responsible for the
introduction into mainstream chemistry of concepts and notions such Cahn-Ingold-
Prelog priority rules, Prelog strain, Klyne – Prelog system, Prelog's rule.
- 198 -
Did you know…?
 The most used experimental techniques for studying protein folding are X-ray
crystallography, fluorescence spectroscopy, circular dichroism, protein nuclear
magnetic resonance spectroscopy, dual polarization interferometry
 According to IUPAC, optical yield is defined as the ratio of the optical purity of the
product to that of the precursor, reactant or catalyst (in a chemical reaction involving
chiral reactants and products). Optical yield and enantiomeric excess are not identical
notions. The optical yield is in not related to the chemical yield of the reaction.
 Pharmaceuticals that are currently marketed in racemic form include, among others:
Ibuprofen (Advil/ Motrin), Bupivacaine (Marcain), Ketoprofen (Actron), Modafinil
(Provigil), Omeprazole (Prilosec), Formoterol (Foradil), Cetirizine (Zyrtec), etc.
 Pharmaceuticals that are currently marketed in single- enantiomer form include:

Levocetirizine (Xyzal), Dexibrupofen (Seractil), Esomeprazole (Nexium), etc.
 According to IUPAC, racemic conglomerate is an equimolar mechanical mixture

of crystals each one of which contains only one of the two enantiomers
present in a racemate. The process of its formation on crystallization of a racemate is
called spontaneous resolution, since pure or nearly pure enantiomers can often be
obtained from the conglomerate by sorting.
 The eudysmic ratio refers to the difference in pharmacological activity between

the two enantiomers of a drug. Usually, where a chiral drug is biologically active,
one enantiomer is more active than the other. The eudysmic ratio is the ratio of
activity between the two enantiomers.
The eutomer is the enantiomeric form having the desired pharmacological activity,
while the distomer is the enantiomer which may have undesired bioactivity or may
be bio-inert.
 According to IUPAC definition, asymmetric synthesis (enantioselective

synthesis) is a chemical reaction (or reaction sequence) in which one or more new
elements of chirality are formed in a substrate molecule and which produces the
stereoisomeric (enantiomeric or diastereoisomeric) products in unequal amounts.
Decarboxylation of 2-ethyl-2-methylmalonic acid catalyzed by brucine was the first
enantioselective synthesis:
HOOC COOH HOOC H

brucine
heat
optically active
Sharpless dihydroxylation is one of the most versatile enantioselective synthesis:
- 199 -
Did you know…?
HO OH
(DHQD)2-PHAL
RS RM RS RM
K2OsO2(OH)4 RL H
K2CO3, K3[Fe(CN)6] RS RM
RL H (DHQ)2-PHAL RL H
HO OH
RS = Smallest substituent, RM = Medium-sized substituent RL = Largest substituent;

The chirality of the product can be modulated by the "AD-mix" used.
 AD-mix (in two forms, AD-mix α and AD-mix β) is a mixture of reagents which
is used as asymmetric catalyst for different chemical reactions, such as Sharpless
asymmetric dihydroxylation of alkenes.
Both mixtures contain potassium osmate, potassium ferricyanide, potassium
carbonate and a chiral ligand. AD-mix α contains (DHQ)2PHAL (the phthalazine
adduct with dihydroquinine), while AD-mix β contains (DHQD)2PHAL (the phthalazine
adduct with dihydroquinidine)
N N N N
O O
H H
H H
H3CO OCH3
N N
The structure of (DHQ)2PHAL
N N N
N
O O
H
H H H
H3CO OCH3
N N
The structure of (DHQD)2PHAL

Topological isomers are molecules with the same chemical formula and
stereochemical bond connectivities but different topologies. Examples of molecules for
which there exist topoisomers include DNA which can form knots and catenanes.
- 200 -
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Organic Stereochemistry - Basic Concepts and Applications

Book · November 2018

Marius Bumbac Cristina Nicolescu

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Iosif Schiketanz Mihai - Viorel Popescu

Cristina Mihaela Nicolescu Octavian Buiu

BASIC CONCEPTS & APPLICATIONS

“Better Things for Better Living...Through Chemistry”, an old DuPont advertising

Why would we need to learn more about the stereochemistry of organic

1) Physical, chemical and biological properties of the molecules are strongly

List of abbreviations and symbols............................................................................ 1

Did you know..?....................................................................................................... 195

References ............................................................................................................... 201

Abbreviations and Symbols

C1 symmetry point group

A very brief overview of stereochemistry

Historically, the birth of the field of stereochemistry is related to development of

Figure 1: Potential energy diagram of an ethane molecule with respect to the

Such compounds can therefore be separated from a mixture, as in general they

Cahn-Ingold-Prelog convention for E/Z isomerism:

COMMON MISCONCEPTION: An older nomenclature system, known as the cis

- Optical Isomers: compounds that have different rotations of the plane-polarized

o Enantiomers: compounds that are non-superimposable mirror images of

o Diastereoisomers: compounds that have the same chemical connectivity

Structural features leading to asymmetry:

Cahn-Ingold-Prelog convention for R/S isomerism of chiral centres

clockwise rotation counter-clockwise rotation

However, other structural elements, such as perpendicular planes in cumulated

the two mirror images are non-superimposable

Cahn-Ingold-Prelog convention for R/S isomerism of biaryls and cumulated

Figure 2: Diagram showing the lack of asymmetry in meso-tartaric acid

In the study of organic molecules, it is sometimes useful to define the relationships

- Homotopicity: if one of two atoms or groups is replaced (i.e., changing a hydrogen

In terms of stereochemistry, prochirality refers to generation of chiral centres

- Prochirality of sp3 carbon atoms: tetrahedral centres that contain enantiotopic

Pictorial representations of molecules:

Written depictions of molecules are essential in communicating chemical

- Fischer Projections: The Fischer Projections are two-dimensional representations

- Haworth Projections: Sir Norman Haworth proposed a three-dimensional

Practice problems with detailed solutions & answers

„Once a molecule is asymmetric, its extension proceeds also in an

CH2OH CH2OH COOH COOH

CH2 H3C COOH

The substituent priority, in decreasing order, is:

HOOC > C CH3

2-Phenyl-1,2,3-propanetriol is esterified with butyric acid.

Determine the number of stereoisomers for the following compounds:

b) HC C C C HC C CH CCl CCl CBr CBr CH2OH

The following compounds are optically active: A, C, E, G and H.

H5C2 C2H5 H C2H5

A – chiral nitrogen atom;

The following compounds are optically active: A, C, E, G, H, K.

H2 C O C (CH2)n CH CH (CH2)p CH3

Compound C - four stereoisomers (two meso compounds and a pair of enantiomers).

Write down the stereoisomers for the following compounds:

b) H2N C (CHCl)4 C NH2

COOH COOH COOH COOH

CONH2 CONH2 CONH2 CONH2