Organic Chemistry Questions and Answers - Volume I: July 2020

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ORGANIC CHEMISTRY QUESTIONS AND ANSWERS - Volume I
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Bogdan - Marius Bumbac
Iosif Schiketanz Valentin-
Octavian Buiu Cristina-Mihaela Nicolescu
Mihai - Viorel Popescu
ORGANIC CHEMISTRY
QUESTIONS AND ANSWERS
Volume I
2020
In memory of my grandparents,
Bogdan
PREFACE
inspiring and reader-friendly text, from both the format and content perspective.
This volume contains, as the name suggests, a collection of questions and answers
together with mechanistic and evidence based explanatory texts, that are motivating the
reader to understand the chemical processes, and not just learn the facts.
Thus, the book targets both the traditional aspects of organic chemistry (organic
syntheses, reaction mechanisms, stereochemistry, symmetry groups, aromaticity,
reaction schemes, determining the structure of organic compounds, instrumental analysis,
acids and bases), and questions about some more unconventional aspects, most of which
you might find in day to day life: in the kitchen, at a barbeque, in a beauty salon or even
in a medical tests laboratory.
(or just refresh their memory)
of:
Macrocyclic ligands (crown ethers, cyclodextrines, calixarenes, cucurbiturils,
hemicucurbiturils, pillararenes, lariat ethers, podands, cryptands, carcerands, etc.) and
their various applications. Thus, the reader will notice that these compounds, with
sophisticated molecular structures, have very diverse applications ranging from
manufacturing cigarettes to conditioning toothpastes and deodorants.
Compounds with applications in medicine (alginic acid, hyaluronic acid, human
serum albumin, interferons, uric acid, fibrinogen, erythropoietin, botulinum toxin,
prostaglandins, oxitocin).
The allotropes of carbon with numerous uses (carbon nanotubes, colossal carbon
nanotubes, graphene, fullerenes).
Compounds which are present in many commercial products, some of them well-
dodecylsulfate/laurylsulfate).
Lesser known chemical reactions (lethargic reactions, template reactions, the quasi-
Favorski transposition, the semipinacol transposition).
The toxic compounds created when grilling meat and how we can limit their
formation.
The complex and incompletely researched chemical processes known as Maillard
reactions and their importance.
How we can tenderize meat using kiwi fruits or pineapples.
The cascade of chemical reactions that take place when we cut open an onion.
more.
All the questions in this book have highly detailed answers associated.
The pictures of molecules in this book were reproduced, according to the standard
protocol, with permission of Protein Data Bank.
conferences as well as websites that were used when elaborating this book.
As usual, we remain open to any suggestion coming from our readers.
You can reach us through the following e-mail addresses:
bogdanserbanchimist@yahoo.com, mariusbumbac@gmail.com,
i_schiketanz@yahoo.com
The authors,
May, 2020
When you hold this book, you are holding molecules. When you drink
coffee, you are ingesting molecules. As you sit in a room you are bombarded
by a continuous storm of molecules. When you appreciate the color of an
orchid and the textures of a landscape you are admiring molecules. When
you savour food and drink you are enjoying molecules. When you sense
decay, you are smelling molecules. You are clothed in molecules, you eat
molecules, and you excrete molecules. In fact, you are made of molecules
P.W Atkins,
Second Edition
Cambridge
University Press,
2003
ABBREVIATIONS AND SYMBOLS
Abbreviations
Ac acetyl
acac acetylacetonate
AGEs advanced glycation end products
AIBN azobisisobutyronitrile
AIDS acquired immunodeficiency syndrome
Asn asparagine
B[a]P benzo[a]pyrene
B[b]Flu benzo[b]fluoranthene
Boc2O di-t-butyl dicarbonate
(Bpin)2 bis(pinacolato)diboron
BTX botulinum toxin
CAs carbonic anhydrases
CB[n] cucurbituril
CDI 1,1'-carbonyldiimidazole
Cis cysteine
CNTs carbon nanotubes
CVD chemical vapor deposition
COX-1 cyclooxygenase-1
COX-2 cyclooxygenase-2
2D bidimensional
Da Dalton
DABCO 1,4-diaza-bicyclo[2.2.2]octane
dba dibenzalacetone
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DMAP 4-dimethylaminopyridine
DME 1,2-dimethoxyethane
DMF dimethylformamide
5
DMSO dimethylsulfoxide
DNA deoxyribonucleic acid
E+ electrophile
E1cB conjugate base unimolecular elimination
EPO erythropoietin
Et ethyl
FDA Food and Drug Administration
19F- RMN fluorine nuclear magnetic resonance
FLPs frustrated Lewis pairs
FLU fluoranthene
Gli glycine
Gln glutamine
HSA human serum albumin
HCAs heterocyclic aromatic amines
Hemicuc[n] hemicucurbiturils
HMF hydroxymethylfurfural
HOPG high orientation pyrolytic graphite

HPLC high performance liquid chromatography
1H-RMN proton nuclear magnetic resonance
HSAB Hard Soft Acid Bases
Ile isoleucine
i-Pr isopropyl
IQ 2-amino-3-metilimidazo[4,5-f] quinoline
IR infrared
IU international unit
Leu leucine
LNDD Le Laboratoire National de Depistage de Dopage
MAO monoaminooxidase
Me methyl
MeIQ 2-amino-3,4-dimetilimidazo[4,5-f]quinoline
MeIQx 2-amino-3,8-dimetilimidazo[4,5-f] quinoxaline
6
Mg(TMP)2 magnesium tetramethylpiperidine
MU microwaves
MWCNTs multi-walled carbon nanotubes
NBS N-bromsuccinimide
NMO N-methyl morpholin-N-oxide (4-methyl morpholin-4-oxide)
Nu- nucleophile
o- ortho
OLED organic light-emitting diode
PAHs polycyclic aromatic hydrocarbons
PAGE polyacrylamide gel for electrophoresis

PDE-5 phosphodiesterase-5
Pd(dppf)Cl2 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Ph phenyl
PhIP 2-amino-1-methyl-6-phenilimidazo[4,5-b] pyridine
Pro proline
PCy3 tricyclohexylphosphine
PEGilat functionalized with polyethylene glycol
PPA polyphosphoric acid
PPO polyphenol oxidase
PVP polyvinylpyrrolidone
Py pyridine
ROS reactive oxygen species
ScCO2 supercritical CO2
Sc(OTf)3 scandium triflate
SDS sodium dodecylsulfate
SN1’ unimolecular nucleophilic substitution accompanied by allylic
transposition
SN2’ bimolecular nucleophilic substitution accompanied by allylic
transposition
SWCNTs single-walled carbon nanotubes
TBAI tetra-n-butylammonium iodide
Tyr tyrosine
7
TosMIC 4-toluene-sulfonyl-methyl isocyanide
TPAP tetra-n-propylammonium perruthenate, [N(C3H7)4]+[RuO4]-
THF tetrahydrofuran
TMP 2,2,6,6-tetramethylpiperidine
TMSOTf trimethylsilyl trifluoromethanesulfonate
TsCl p-toluensulfonyl chloride
TsOH p-toluensulfonic acid
XO xanthin oxidase
Symbols
η yield
Δ reflux
hυ irradiation
M molecular mass
R rectus
S sinister
movement of an electron pair
synthesis
movement of lone electron
[O] oxidation
[H] reduction
chemical
structure unstable reaction intermediate
8
Questions and Answers
Question 1
How can one obtain alkylpyridines?
Answer:
Under the conditions of a classic Friedel-Crafts alkylation, pyridine is not a highly reactive
substrate. However, there are some synthesis pathways of alkyl-pyridines with rather good
efficiencies, for example:
a) heating pyridine with alkyl halides:
CH 3
CH 3I 300 oC
+
+
N N I- N CH 3 N
CH 3
Mixtures of mono and di-alkyl-pyridines are obtained.
b) alkylation of pyridine with carboxylic acids:
1. AgNO3, H2SO4, H2O

+ R COOH +
2. (NH4)2S2O8
N N N R
A radical mechanism applies, as follows:
2Ag + + S 2O 8 2- 2Ag 2+ + 2SO 42-
R COOH + Ag2+ R COO + Ag+ + H+

R COO R + CO 2
9
Organic Chemistry - Questions and Answers
c) acylation of pyridine followed by a reduction step:
2 (CH3CO)2O 
2 CH3 C N N C CH3
Zn
N O O
CH2 CH3
H COCH3
Zn/AcOH
+
N N N
CO
CH3
d) Ziegler alkylation of pyridine:
BuLi 
Bu
N N N Bu
H
Li
e) reaction with ammonia of some pyrylium salts:
CH3 CH3 R
NH3
- HCl CH3
+ CH3 C C CH3
CH3 O CH3 CH3 O NH2
Cl- O H2N
CH3
- H 2O
CH3 N CH3
Question 2
How many stereoisomers do each of the following compounds have?
10
CH2 CH3
CH CH3 CH3O N CH2 CH3
O2N COOH B
O2N COOH
OCH3
CH CH3 CH3
CH2 CH3
A C
OCH3
NO2
Cl
OCH3
Fe CH CH
CH3
D E F
Answer:
A: six stereoisomers (three racemates: RRR-SSS, RSR-SRS, RRS-SSR);
B: two stereoisomers (one racemate);
C: eight stereoisomers (four racemates: endo-endo, endo-exo, exo-exo, exo-endo);
D: four stereoisomers (meso forms: endo-endo, endo-exo, exo-exo, exo-endo);
E: two stereoisomers (one racemate);
F: eight stereoisomers (four racemates: cis-cis, cis-trans, trans-trans, trans-cis).
11
Question 3
How would you perform the transformation: Ar CHO ArH ?
Answer:
H 2SO 4
Ar CHO ArH + CO
The reaction occurs with good efficiencies for trialkyl and trialcoxy-benzaldehydes.
Question 4
How would you perform the transformation: R CH2 NO2 R C N ?
Answer:
NaBH 2S 3
R CH 2 NO 2 R C N
Question 5
What are the crown ethers? How are these compounds synthesized and what are their
practical applications?
Answer:
Crown ethers are synthetic oligoethers with molecules of the type (-CH2-CH2-O-)n,
with n ≥ 3:
O O
O O
O
O
O O
O
O
O
21-crown-7 dibenzo-12-crown-4
12
O
O O
O O
O O O O
O O O O
O O O O
O
di-cyclohexyl-24-crown-8 30-crown-10
Crown ethers were first synthesized by the American chemist, Charles Pedersen, who
published the first article on this class of compounds in 1967.
There are numerous strategies for synthesizing these ethers, some of them are
summarized herein:
HO OH O O
LiClO4
+
Cl O O Cl O O
12-crown-4
HO O OH O O
NaOH
+
Cl O O Cl O O
O
15-crown-5
O O
HO O O OH t-BuOK
+ O O
TsO O O OTs
O O
18-crown-6
BF3 (gas)
12-crown-4 + 15-crown-5 + 18-crown-6
O MBF4
The cation of the fluoroborate salt significantly influences the proportion of crown
ethers in the final reaction mixture. Along with the crown ethers, variable amounts of linear
13
compounds are also produced. The use of alkali metal cations leads to significant
improvements in reaction yields.
Crown ethers have numerous applications in organic synthesis, for example as phase-
transfer catalysts:
Cl F
NO2 NO2
18-crown-6
+ KF
CH3CN
NO2 NO2
O Cl O CN
C C
18-crown-6
+ NaCN
CH2Cl2
-NaCl
Here there are some other areas in which crown ethers are extensively used:
• analytical separations (liquid membrane separations with a macrocyclic carrier,
separation by solvent extraction, chromatographic separations, masking processes);
• electrochemistry (ion-selective electrodes, metal-complex electrodes, etc.);
• polymer stabilizers.
Question 6
What is Human Serum Albumin (HSA)? What is its role in the body, and why its
dosing is so important?
Answer:
Albumin is the most important protein component in human blood plasma, and it is
synthesized by hepatic parenchymal cells. It is a non-glycosylated, water-soluble globular
protein with a molecular weight of M = 66,437 Da.
Structure of human serum albumin complexed with palmitic acid

(Protein Data Bank ID: 1E7H)
14
Albumin has multiple roles in the body, being responsible, among other things, for:
• maintaining oncotic pressure;
• transport of various compounds (hormones, free fatty acids, medicines, etc.);
• pH buffering.
The normal serum albumin concentration levels range from 3.4 to 5.4 g / dL. Low
levels of albumin (hypoalbuminemia) may be caused by a decrease in liver function
(cirrhosis, malnutrition, chronic alcoholism) or by losses through the kidneys (nephrotic
syndrome) or skin (enlarged burns).
An elevated level of albumin (hyperalbuminemia) may be correlated with a protein-
rich diet. Moreover, hyperalbuminemia may also be an indicator of severe dehydration.
Human serum albumin is available as aqueous solutions with concentrations ranging
from 5 % to 25 %, and these are used therapeutically to restore and maintain plasma levels
in patients who have lost blood.
Question 7
What is alginic acid? What are the practical applications of this compound?
Answer:
Alginic acid is a natural polysaccharide with molecular formula (C6H8O6)n. It is

composed of -D-mannuronic acid (M) and -L-guluronic acid (G) units linked by 1-4
bonds. These monomers may be disposed in either M and G consecutive units (M-M-M-
M-M) or (G-G-G-G-G), or randomly (M-G-G-M-G-M-G):
COOH COOH COOH COOH COOH

O O O O O
OH OH OH OH O OH OH O OH OH O OH OH O
O
Structural formula of a segment -M-M-M-M-M-

(poly-M)
O O O O O
COOH COOH COOH COOH COOH O
O O O O
OH OH OH OH OH OH OH OH OH OH
Structural formula of a segment -G-G-G-G-G-

(poly-G)
COOH COOH
O O O O
COOH O COOH
O O O
OH OH OH OH OH OH OH OH
Structural formula of a mixed segment -M-G-M-G-M-
15
Alginic acid is extracted from the brown algae cell walls by maceration in an alkaline
solution. Due to its biocompatible, biodegradable, non-toxic, and non-allergenic properties,
alginic acid has many practical applications:
• food additive (E400), being used as a stabilizer, thickening agent, gelling agent;
• component of specific pharmaceutical preparations (Gaviscon, Bisodol, etc.);
• ingredient in many cosmetics;
• material to make molds in dentistry;
• chelating agent for heavy metal cations such as cadmium, mercury, lead.
Sodium Alginate (E401) is a key ingredient in molecular gastronomy, where the
spherification procedure uses this compound.
Some other substances used as food additives are alginic acid derivatives: potassium
alginate (E402), ammonium alginate (E403), calcium alginate (E404), and propylene glycol
alginate.
Question 8
What is hyaluronic acid? What are hyaluronidases? What medical applications do

these compounds have?
Answer:
Hyaluronic acid is a natural polymer with a linear structure, and composed of D-

glucuronic acid and N-acetylglucosamine units, alternatively linked by β-1,3 and -1,4
glycosidic bonds.
-
O H
H
C O CH2OH
O O HO O
H H
H H O
HO O
OH H NH
H H H
C
O CH3
n
Structure of hyaluronic acid
Molecular weight of hyaluronic acid may have different values depending on its
origin, the variation being in the range of 104 to 107 Da.
Hyaluronic acid is generally synthesized by microbial fermentation. The human body
contains hyaluronic acid in the skin, synovial fluid, umbilical cord, vitreous humor, and it
is also an essential component of extracellular fluid.
Hyaluronic acid has important properties. It is biocompatible, biodegradable, non-
toxic, non-allergenic, and has excellent moisturizing and lubricating properties. Based on
16
these properties, here there are some of the applications of hyaluronic acid in medical and
dermato-cosmetic fields:
 in treatment of knee pain caused by osteoarthritis; hyaluronic acid acts as a true joint
lubricant, cushioning the shocks;
 in ophthalmic surgery (corneal transplant, cataract), for tissue healing in the post-
operative treatment;
 as an ingredient in many creams, lotions, and shampoos due to its excellent tissue
repair and hydrating properties;
 dermato-cosmetic surgery, as a filler for cheekbones, lips, wrinkles, giving the skin
suppleness and elasticity;
 prognosis of several pathologies (breast cancer, prostate cancer).
Structure of human hyaluronidaze 1

(Protein Data Bank ID: 2PE4)
Hyaluronidazes are a family of enzymes that catalyze the hydrolysis of hyaluronic

acid, thus increasing its tissue permeability. These enzymes increase the absorption of drugs
injected either subcutaneously or intramuscularly, and are also used in ophthalmic surgery
in conjunction with local anesthetics.
Question 9
What are the persistent carbenes?
Answer:
Persistent carbenes are a special category of carbenes having stability that is atypical
for this class of compounds. Similar to carbenes, the persistent carbenes may exist in both
triplet and singlet states. Stability of persistent carbenes comes from both electronic and
steric effects.
The best-known persistent carbenes have the general formula (R2N)2C:
17
N N
N N
N N
O
N N O
N
N N
N
Question 10
Aliphatic aldehydes can participate in the Darzens reaction (the base being EtONa),
but the reaction yields to obtain the respective glycidic esters are unsatisfactory. How can
the performance of these reactions be improved?
Answer:
The experimental procedure that provides a satisfactory yield (~ 80 %) is the reaction

of the α-halogen-ester with lithium bis (trimethylsilyl) amide, LiN(SiMe3)2, in
tetrahydrofuran at -78 °C, followed by addition of the aldehyde to this solution.
Under these conditions, not only do aliphatic aldehydes react, but also aromatic
aldehydes and ketones, react with acceptable yields.
Question 11
How would you perform the transformation: R CN R H ?
Answer:
Na/NH3
R CN R H R: C6H5 CH2 , (CH3)3C
C6H5 , (C6H5)3C
Na/Fe(acac)3
R CN R H R: CH 3 , CH 3 CH 2
18
Question 12
How many stereoisomers does the following compound have?
CH3 CH2 CH C
4
Cl
Answer:
The compound has four asymmetric carbon atoms. Usually, there would be 24=16
stereoisomers. However, only five stereoisomers exist for this compound:
R S R S R
R C R S C S R C S R C S R C S
R S R S S
(+)
- (+)
- mesoform
Question 13
How can one obtain secondary amines with good yields (no contamination with
primary and tertiary amines allowed) using a halogenated derivative as the alkylating agent
of the nitrogen atom?
Answer:
2- 1. H3O+
2R X + N CN - R2N CN R2NH
-2 X 2. HO-
This reaction sequence involves alkylation of calcium cyanamide with two moles of
the halogenated derivative, followed by hydrolysis and decarboxylation. The yield may be
improved when phase-transfer catalysis is applied for this reaction.
Question 14
How many stereoisomers does each of the compounds listed below have?
OCH3
F OCH3
CH 3O OCH3
CH3 CH 3
C H Cl Br
OCH3
OCH3 Br
OCH3
A B C D
19
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: three asymmetric carbon atoms: eight stereoisomers;
C: three asymmetric carbon atoms: eight stereoisomers;
D: two asymmetric carbon atoms and two pseudo-asymmetric carbon atoms (2 and 5).
The compound has four meso forms and two pairs of enantiomers (eight
stereoisomers in total).
Question 15
How would you carry out the transformation: R CHO R H?
Answer:
The aliphatic and aromatic aldehydes can be decarbonylated using the Wilkinson
catalyst RhCl(PPh3)2:
RhCl(PPh3)2
R CHO R H
Question 16
How do you explain the formation of the compound shown below when performing the
Kolbe electrolysis of sodium propionate in the presence of butadiene?
CH3 CH2 CH2 CH CH CH2 CH2 CH CH CH2 CH2 CH3
Answer:
COO- -e - - CO2
(+) C H 3 CH2 CH3 CH2 COO CH3 CH2
CH3 CH2 + CH3 CH2 CH2 CH CH CH2
CH 3 CH 2 CH 2 CH CH CH 2 + CH 2 CH CH CH 2 CH 2 CH 3
CH3 CH2 CH2 CH CH CH2 CH2 CH CH CH2 CH2 CH3
20
Question 17
Which of the following compounds are chiral? How many stereoisomers do each of
the compounds have?
Et COOH
Et C C C
C C C C Et Et
Et Et
A B
CH 3 CH 2 CH CH CH CH CH HC C HC C CH C C C C CH2 OCH3
OMe OEt Br Br Cl Cl
C D
Br
HOOC NO2
HOOC NO2 O2N NO2
HOOC COOH
CH Ph
Et
E F
Answer:
The chiral compounds are: C, D and E.
C: eight stereoisomers:
(+)-Z-(+) (+)-E-(+) (+)-Z-(-) (+)-E-(-)
(-)-Z-(+) (-)-E-(+) (-)-Z-(-) (-)-E-(-)
D: eight stereoisomers:
(+)-Z-Z (-)-Z-Z (+)-E-Z (-)-E-Z
(+)-Z-E (-)-Z-E (+)-E-E (-)-E-E
E: four stereoisomers: two pairs (±).
Question 18
What are frustrated Lewis acid-base pairs?
21
Answer:
Lewis pairs (frustrated Lewis pairs, FLPs) are subgroups of Lewis theory, opening
surprising perspectives in the general theory of chemical reactivity, as well as in catalysis.
This concept refers to the incapacity of sterically hindered Lewis acids and bases to
form acid-base classical adducts:
THF + -
(C 6F 5)3B + P(CH 3)3 (CH 3) 3P B(C 6F 5)3
classical adduct
(C6H 5)3B THF - O

+ P (C6H 5)3B +
P
frustrated Lewis pairs adduct
As you can see, the remaining THF (resulting from the nucleophilic attack of t-Bu3P)
is interposed between the Lewis acid and the Lewis base, thus reducing steric hindrance.
Question 19
What are calixarenes? How are they synthesized, and what applications do they have?
Answer:
Calixarenes are a class of macrocyclic ligands belonging to the [1n]-

methacyclophanes family, having their origins in phenol-formaldehyde chemistry, which
has been around for over a century.
The best-known calixarenes have a structure containing p-substituted phenol units and
methylene bridges (originating in formaldehyde).
OH
OH HO
OH
OH HO
OH
OH HO
OH
HO
p-tert-butylcalix[4]arene p-tert-butylcalix[7]arene
22
As suggested by their names (in Greek, the meaning of the word calix is chalice), these
compounds have the spatial structure of a cup:
R
R R
R
Many one-step or multi-step syntheses have been performed and optimized for these
compounds, both in acidic or basic media:
a) one-step synthesis of p-tert-butylcalix[6]arene in alkaline medium:
OH
OH
HO
KOH
+ CH2O
(37 %) 0.34 base equivalents /
OH HO
phenol equivalents
OH OH
p-tert-butylcalix[6]arene
b) one-step synthesis of p-tert-butylcalix[8]arene in alkaline medium:
OH OH
OH
OH
NaOH
+ (CH2O)n
OH
OH
OH OH OH
p-tert-butylcalix[8]arene
23
c) multi-step synthesis of p-hexamethyl-p-tert-butylcalix[7]arene in acidic medium:
CH 3 CH 3 CH 3
CH 3 OH
Br2 HCHO
NaOH HCl
Br Br CH 2OH
OH OH OH
CH 3 CH 3 CH 3 CH 3
CH 3 OH
HCHO
NaOH HCl
Br Br CH 2OH
OH OH OH OH
CH 3 CH 3 CH 3 CH 3 CH 3 CH 3
HCHO
NaOH
Br Br CH 2OH
OH OH OH OH OH OH
CH 3 CH 3 CH 3
CH 3 OH
HCHO
HCl NaOH
Br
OH OH 2 OH
CH 3 CH 3 CH 3
CH 3 OH
Br CH 2OH HCl
OH OH 2 OH
CH3 CH3 CH3 CH3 CH3 CH3
HCHO
NaOH
Br Br CH2OH
OH OH 3 OH OH OH OH
3
24
CH 3 CH 3 CH 3
CH 3 OH
HCHO
HCl NaOH
Br
OH OH 4 OH
CH3 CH3 CH3
OH
Br CH2OH HCl
OH OH 4 OH
CH 3 CH 3 CH 3 CH 3
HCHO H 2, cat.
NaOH
Br Br CH 2OH
OH OH 5 OH OH OH OH
5
CH3 CH3
HCl, AcOH
CH2OH
OH OH 5 OH
OH
OH HO
OH
HO
OH
HO
p-hexamethyl-p-tert-butylcalix[7]arene
25
Due to the ability to coordinate various species, calixarenes have numerous

applications in analytical chemistry (extraction, liquid membrane transport),
microelectronics (anisotropic silicon etching), catalysis, electrochemistry (manufacture of
electrochemical sensors), gas detection, medicine.
Question 20
What are hemicucurbiturils? How can they be prepared, and what are their main uses?
Answer:
Hemicucurbiturils (abbreviated as hemicuc[n]) are macrocyclic compounds composed

of ethylene-urea units connected by methylene bridges, in an alternate conformation:
N N CH2 N N CH2
O
n
An optimized synthesis of hemicuc[6] consists of the reaction between ethylene urea

and 37 % formaldehyde solution (equimolar amounts), in the presence of 4N HCl at room
temperature:
O
N N
N N
N O N
CH2O 37% O O
HN NH O
HCl 4N, 25oC N
N
O several minutes
N N
N N
O
hemicucurbit[6]uril
alternated configuration
An optimized synthesis of hemicuc[12] consists of the reaction between ethylene urea

and 37 % formaldehyde solution (equimolar amounts), in the presence of 1N HCl, at 55 oC,
for 3 hours:
26
O
O
N N N N
N
N O N
N N
O
N O
N O
HCl 1N N
HN NH + CH2O O
55oC
O N
O N O
N N
O
N N
N N
N N N
O
O
hemicucurbit[12]uril
alternated configuration
Hemicuc[6] does not form complexes with cations, and this behavior is probably due
to its alternate conformation. This molecule can form complexes with anions (such as Cl-
or SCN-) or with neutral molecules such as propargyl alcohol.
Question 21
How would you synthesize 4-bromo-2-carboxydiphenylsulphone from accessible raw

materials?
Answer:
CH3 CH3 CH3

NO2 NH2
HNO3 Fe + HCl (CH3CO)2O
H2SO4
CH3 CH3
NHCOCH3 NHCOCH3
Br2 H2O/H+
Br
27
1. NaNO2/HCl, 0-5oC
CH3 S CH3
NH2 2. C2H5 - +
O C SK SH
Cl2
3. KOH, EtOH,  AcOH
Br Br
4. H2SO4, H2O
CH3 CH3
SO2Cl
CrO3
Br SO2
AlCl3
Br
COOH
Br SO 2
4-bromo-2-carboxydiphenylsulphone
Question 22
How would you synthesize 3-bromo-2-carboxydiphenylsulphone from available raw

materials?
Answer:
CH3 CH3 CH3 CH3

Br Br Br Br
H2SO4 Br2 H2O/
 AlBr3
SO3H SO3H
Br CH3 Br CH 3
1. Mg H 2O2/AcOH
S SO 2
2. C6H 5-SH
Br COOH
KMnO 4
SO 2
28
Question 23
What are cyclodextrins, and what are their applications?
Answer:
Cyclodextrins are a class of non-reductive, cyclic oligosaccharides consisting of 6 up

to 100 units of -glucopyranose, bonded through 1- 4 units. The best-known cyclodextrins
are those consisting of 6, 7, and 8 glucopyranose units, respectively, known in scientific
literature as ,  and .
HO
O HO O
O O O
OH O OH HO
HO HO HO HO HO
O
HO HO
O HO O O HO
OH
OH OH O
HO
O O HO
O
O OH HO
OH OH
HO OH
OH
O O
OH O
HO
HO HO O
OH OH
OH OH O
O HO O
O OH
O OHO
OH OH
O
-cyclodextrin -cyclodextrin
O
HO
OH O
O HO HO
O OH HO
O
HO HO
OH
O O
HO OH
O OH
HO O
HO OH O
O OH
OH
OH
O
OH OH HO O
OH O HO O
O OH
-cyclodextrin
These compounds have intramolecular toroidal cavities that are hydrophobic and can
form complexes with a large variety of chemical species. This phenomenon is known as
molecular encapsulation.
Cyclodextrins may be synthesized by enzymatic hydrolysis of starch, in the presence
of glycosyltransferase. The result is a mixture of  and  cyclodextrins, along with
traces of compounds with a higher number of glucopyranose units.
29
Various practical uses of cyclodextrins are based on their properties: complex forming
abilities, low toxicity, and low allergic reactions, no major health risks at moderate
consumption, etc. Some examples are shown below:
 Food industry. Cyclodextrins are used to stabilize aromas in various foods, to mask
unpleasant tastes and odors, and to improve the quality and processing technology of food.
 Tobacco industry. In the manufactory process of cigarettes, most flavor compounds
are used as inclusion complexes with β-cyclodextrins. Also, some cyclodextrins-based
polymers may be used to produce cigarettes filters.
 Cosmetic and household products industry. Cyclodextrins are successfully used for
the conditioning of toothpaste and deodorants. Due to their characteristic to form inclusion
compounds with detergents, cyclodextrins may be used as un-foaming agents. Hydroxy-
propyl--cyclodextrin is the active ingredient of some room deodorants.
 Pharmaceutical and nutraceutical industry. Cyclodextrins are widely used in
controlled drug delivery, and as food supplements.
 Agriculture. Some insecticides, herbicides, fungicides active ingredients are
cyclodextrins-based inclusion compounds. Also, cyclodextrins are successfully used as
conditioners for fruits ripening agents.
 Analytical separations applications. Cyclodextrins are used as stationary phases in
high performance liquid chromatography and in gas chromatography. Due to their chiral
character, they are used in separations of some enantiomers.
Question 24
What is the mechanism of the reaction below?
CHO COOMe COOMe

NaOMe, MeOH (68%)
+
MeO , 6 h
COOMe MeO COOH
OH
OH
Answer:
COOMe - COOMe
H 2C HC
-
+ MeO
H 2C H 2C
COOMe COOMe
30
O H
C - COOMe
H COOMe
HC CH
+ O
H2C - CH2
MeO COOMe MeO MeO C
OH OH O
H COOMe H COOMe
CH CH
MeO -
O CH 2 O CH 2
-MeO - -MeOH
MeO - MeO
MeO O O
OH OH
-
O O
H C OMe H C OMe
-
C C
O CH2 O CH2
MeO MeO
O O
OH OH
O
H C OMe
C COOMe
MeOH
- CH2
-MeO-
MeO O MeO COOH
O
OH OH
This reaction is quoted in the literature as Stobbe reaction.
Question 25
How one can perform the following transformation?
31
OH OH
O O
Answer:
OH Cl
O O CH N
SOCl2 2 2
2 eq.
CHN2 CH2Cl
O O
HCl AcOH, Zn
Br
O O
Br2
AcOH, HBr (cat.)
OH
O O
Py,  CrO3, AcOH
- CH 3COCOOH
32
Question 26
What are pillararenes? How are they synthesized, and what are their applications?
Answer:
Pillararenes are macrocyclic ligands composed of hydroquinone units connected by

methylene bridges:
OH
CH2
OH n
General structure of the pillararenes
Pillar[5]arene can be synthesized according to the following scheme:
OC2H5 OC2H5 OH
(CH2O)n CH2 CH2

BBr3
FeCl3, CHCl3 excess
OC2H5 OC2H5 OH
5 5
Pillararenes have applications in controlled release of drugs, liquid crystal

synthesis, sensors manufacturing, cervical cancer therapy, etc.
Question 27
What are lariat ethers, and what applications do these compounds have?
Answer:
Lariat ethers (as suggested by their name coming from lasso/rope) are polyetheric
macrocyclic ligands that possess donor groups attached to a base ring via flexible chains.
33
O R
O R n
O O O O N
OCH3 -Et 2,3
OCH3 -iBu 2,3
O O O O O O
O O
n
O OH
H O S
O
O O
O O
O
These flexible side chains may be covalently bonded to nitrogen atoms (lariat ethers
with pivoting nitrogen atoms) or to carbon atoms (lariat ethers with pivoting carbon atoms).
These compounds possess superior coordinating abilities for cationic species
compared to macrocyclic ligands without side chains.
Lariat ethers have applications in analytical separation techniques (selective
extractions, liquid membrane transport).
Some lariat-type ether compounds have anti-tumor and anti-AIDS activities.
Question 28
What are the podands?
Answer:
Podands are compounds with an open chain, like coronands and cryptands:
O O
O O
O O
O O
O O
OH HO
Me Me
The podands’ affinity for cations (and, in general, their complexation capacity) is
lower when compared to their cyclic analogues, and this is due to the lack of a preorganized
structure.
34
Their ability to coordinate increases significantly if rigid groups (e.g. aromatic

residues) are bonded to the ends of the chains. These groups add an extra degree of
organization (end group concept):
O
O O
HOOC COOH
O N O
O O
O
MeO O OMe
O
O
O
MeO
Question 29
What are coronands, and what applications do they have?
Answer:
Coronands are a class of macrocyclic ligands comprised of one single ring and any
number and type of heteroatoms.
S O
S S S S
S S O O
S O
thio-coronands
35
R
N H H
N N
O O
N N
N N
R R H H
O
aza-coronands
Ph
O O
Ph
P P P P
Ph Ph
P P
O O
Ph Ph O
coronands with phosphorus
Coronands are widely used in analytical separation techniques (transportation of

analytes through liquid membranes, chromatographic separations, masking processes),
electrochemistry (ion-selective electrodes, metal-complex electrodes, etc.), sensors.
Question 30
What are cryptands? What applications do these compounds have?
Answer:
Cryptands are a class of macrocyclic ligands that contain polyether chains linked by
nitrogen bridgehead atoms:
O O
N O O N
O O
Structure of the cryptand [2.2.2] (1,10 di-aza-4,7,13,16,21,24-hexa-oxa-

bicyclo[8.8.8]hexacosane)
Usually, this compound is named cryptand [2.2.2]. The numbers in brackets indicate
the number of oxygen atoms in each chain bonded by nitrogen bridgehead atoms.
36
The etymology of the word nominating this class of compounds resides in Greek,
where cryptos mean cave, and thus suggesting the special architecture of these substances.
The literature also describes cryptands with Sulphur and nitrogen bonded in bridges, as well
as cryptands with bridgehead carbon atoms.
Several cryptands synthesis strategies were described, two of them are depicted below:
O O
O O
NEt3, C6H6
NH2 H2N high dilution LiAlH4
1) + NH HN
Cl Cl
O O
O O O O O
O
O O Cl Cl O O
O O
O O
O O BH3.THF
NH HN N O O N
NEt3, C6H6
high dilution O O
O O
O O O O
- + + - 1. H+
H 3B N O O N BH3 N O O N
2. HO-
O O O O
O O O O
NH2 H 2N K2CO3
2) + N O O N
OTs OTs CH 3CN
O O O O
Cryptands are coordinating agents with higher selectivity than their crown ether
counterparts and their complexes with alkali or alkaline earth metal cations being known as
cryptates.
Cryptands are used in analytical separation, as coordinating agents in liquid-liquid
extraction and the manufacture of ion-selective electrodes.
37
Question 31
How can indanthrene (indanthrone blue) be synthesized from available raw materials?
NH O
O HN
O
Indanthrene (indanthrone blue)
Answer:
O
Cl COOH Cl
AlCl3 PPA, 
O +
O
O
O O
Cl NH2
NH3, 200oC
O O
O
O
NH O
NH2 KOH, 250oC
O O HN
O +
H2N
O
O
Note:
A temperature increase to 300 - 350 ℃ leads to formation of flavanthrene:
38
O O
NH2 KOH, 300-350oC N

O + O
N
H2N
O O
Flavanthrene
Question 32
What are carcerands? What about hemicarcerands? What applications do they have?
Answer:
Carcerands are container-like molecules (host molecules) capable of encapsulating a

guest molecule. This class of unusual compounds was first described in the literature by D.
J. Cram in 1985.
The supramolecular complex formed is called a carceplex, and it is stable even at high
temperatures. The etymology of the word is suggestive, its name deriving from the Latin
carcer which translates into prison. An important observation is that the encapsulated
molecule remains permanently inside of the carcerand.
Hemicarcerands are container-like molecules (host molecules) capable of
encapsulating a guest molecule that, compared to carcerands, can not only enter but also
exit, in certain specifically defined reaction conditions. The complex formed by
hemicarcerand with a guest molecule is called a hemicarceplex. The synthesis of such
compound occurs as follows:
Cl SH
O O O O
O O O O
Cl HS Cs2CO3, Ar
+
Cl DMF, THF
SH
O O O O
O O O O
Cl HS
39
S
carcerand
S
S
carceplex
Hemicarcerands have some interesting applications in preparative and applicative

chemistry:
• isolation of some extremely reactive molecules (i.e. cyclobutadiene) becomes
possible even at room temperature, these molecules can be stabilized in hemicarcerands’
cavities;
• controlled release of drugs, a property closely linked with their complex forming
abilities;
• catalysis of some chemical processes – when hemicarcerands’ cavities are
sufficiently wide.
Due to the property of carcerands to permanently encapsulate the guest molecule these
compounds have a narrower range of applications, the most recent ones being in molecular
electronics and molecular machines synthesis.
Question 33
Indicate the structure for each of the compounds marked with letters in the diagram
below:
Cl Cl HO O
P
N N NaH
Cl Cl + O A
P P (C8H16P3N3Cl4O5)
N
Cl Cl HO O
40
B (C10H22O5P3N5Cl2)
H2N CH2 CH2 NH2
A C (C18H38O10H8P6Cl6)
D (C20H44O10P6N10Cl4)
H
S N
HS SH
A E F
(C24H48O10P6N6S6Cl4) (C32H64O10P6N6S6)
Answer:
Cl Cl Cl Cl
P P
N N N N
Cl Cl
P P P P
O N O O O N
N N
H H
CH2 CH2
O O O O
O O
A B
Cl Cl Cl Cl
P P
N N N N
Cl NH CH2 CH2 NH Cl
P P P P
O N O O N O
O O O O
O O
C
O O NH CH2 CH2 NH O O
Cl PN P N Cl
O P N N P O
Cl N P P N Cl
O O NH CH2 CH2 NH O O
41
O O Cl Cl O O
P N S CH2 CH2 S CH2 CH2 S N P
O N P P N O
O O Cl Cl O O
O O N N O O
O N P P N O
O O N N O O
Question 34
Indicate the structures of the compounds marked with letters in the diagram below:
O
OH
EtBr, K2CO3 NaBH4 BBr3, CH2Cl2
A B
DMF i-PrOH (C18H18O2)
OH
O
O O
NaH, Br CH 2 COOEt 1. NaOH, EtOH, N 2 Cl C C Cl
C D E
2. HCl C 6H 6
4,13-diaza-18[crown]6 BH3, THF 1. CF3COOH, THF

F G H I
Et3N, benzene, high dilution 2. NEt4OH, H2O
Answer:
O
O O
O O
O
A B
42
OH O CH2 COOEt
OH O CH2 COOEt
C D
O CH2 COOH O CH2 COCl
O CH2 COOH O CH2 COCl

E F
O
-
BH3
+
N N
O O O O O O
O O O O O O
+
N N
-
BH3
O
G H
N
O O O
O O O
N
Question 35
Which are the diastereotopic ligand pairs for each of the following compounds?
Me Me Cl H
C CH3 C CH CH2 CH3
C CH2 CH3 CH2 CH C
C Cl H CH3
H Cl
A B C D
43
O
Cl Cl Br H
(S)-bromide of sec- C
(S)-bromide of n-pentyl
butyl C
H Br
H H
E F G H
CH 3
H C Cl CH3 CH3
C
H C H
C
H C Cl H Cl
CH 3
I J
Answer:
Me Me Cl H H
C C
C CH2
C Cl C
H Cl H CH2 CH3
C
A B
one pair of
one pair of no diastereotopic
diastereotopic ligands
diastereotopic ligands ligands
CH3
CH3 CH3 Cl Cl
C H C Br C
C HS C HR C
H CH2 CH3 H Br
CH3
D E F
one pair of one pair of one pair of
diastereotopic ligands diastereotopic ligands diastereotopic ligands
CH3 CH3
O
Br H H C Br H C Cl CH3 CH3
C
HS C HR HR C HS
HS C HR H C Cl C
H H H Cl
CH3 CH3
G H I J
one pair of two pairs of one pair of one pair of
diastereotopic diastereotopic diastereotopic diastereotopic
ligands ligands ligands ligands
44
Question 36
Indicate the pairs of enantiotopic ligands and their configuration for each of the
following compounds.
CH 3
Br
Br F OCH 3 H C Br
CH2
Br C Br F C F CH 3 C CH 3 CH 2
CH2
H F H H C Br
CH3
CH 3
A B C D E
CH3 CH3 CH3 OH

Cl C H H C OCH3 H C H
H H C Cl H C OCH3 CH 3 C CH 3
H H CH3 CH3 H
F G H I
Answer:
Br
Br F OCH 3
HS C HR
Br C Br F C F S
CH 3 C CH 3
HS C HR R
H F H
CH3
A B
C D
no enantiotopic no enantiotopic
ligands ligands
S
CH 3 CH3 CH3
CH3 CH3
HS C Br H C BrS H C Br
Cl C H
H C H H C H H C H H
H C Cl
HR C Br H C BrR H C Br
HS HR CH3
CH 3 CH3 CH3
R
G
E F no enantiotopic
ligands
S
CH 3 CH3 CH 3 OH OH
HS C OCH 3 H C OCH3 S H C OCH 3 HS C HR H C H
S R
HR C OCH 3 H C OCH3 R H C OCH 3 CH 3 C CH 3 CH 3 C CH 3
CH 3 CH3 CH 3 H H
R
H I
45
Question 37
What are dextrans, and what are they used for?
Answer:
Dextrans are polysaccharides with the molecular formula (C6H10O5)n, comprised of D-
glucopyranose units linked mainly by 1α-6-glycosidic bonds. Depending on the synthesis
pathway, some of these bonds may be 1α-4- and 1α-3-glycosidic bonds.
OH
O CH2 OH O CH2

O OH O
OH OH
O 

OH O CH2 HO O
OH OH
General structure of dextrans
Dextran can be obtained from sucrose by biosynthesis in the presence of Leuconostoc
mesenteroides bacteria. The obtained dextran is then hydrolyzed either enzymatically (with
endodextranase) or in acidic environment (HCl) up to molecular weights of 40 and 70 kDa,
respectively.
O
O CH2 OH O CH2
O OH O
OH OH
O
OH O CH2 HO O
OH O
CH2
CH OH
CH2
O
O CH2 OH O CH2
O OH O
OH OH
OH O
CH2 CH CH2 O O CH2 HO O
OH OH
Example of a commercial dextran fragment
(SephadexTM, sold by the Swedish “Pharmacia” company since 1959)
Dextran is a white powder, soluble in water and solutions of various salts, while being
insoluble in many organic solvents.
Dextrans have multiple applications in:
• medicine – it is administrated as an intravenous infusion to improve blood circulation and
for their antithrombotic effect. It is also used as an intravenous infusion solution in
46
parenteral nutrition. The complex formed by iron hydroxide and dextran is used as an
antianemia drug in veterinary medicine;
• analytical separation – a dextran crosslinked with epichlorohydrin (SephadexTM) is used
as a stationary phase in steric exclusion chromatography;
• sensors – because of their biocompatibility, dextrans are used in biosensors
immobilizations.
Question 38
What are resorcinarenes? Name several applications of these compounds.
Answer:
Resorcinarenes are macrocyclic ligands obtained by cyclocondensation of resorcinol
with aldehydes, in acidic environment:
HO OH
HO OH
HO OH R R
H+
+ R CH O
R R
HO OH
HO OH
New synthesis methods for resorcinarenes were recently developed. They use a
catalyst of molybdate sulfuric acid, and aromatic aldehydes with the following structures:
CHO
CHO CHO
OH CHO Cl
OCH3
Cl
Molybdate sulfuric acid can be obtained according to the procedure:
ONa OSO 3 H
O Mo O + 2 HSO 3 Cl O Mo O + 2 NaCl
ONa OSO 3 H
The use of the above-mentioned catalyst in the resorcinarenes synthesis leads to

significantly improved yields (up to 85-90 %), lower reaction times, and higher purity of
the reaction products. On top of these advantages, it is also a solvent-free synthesis.
47
Resorcinarenes’ applications are related to the production of optical chemo sensors,

selective membranes, of stationary phases for HPLC, obtaining of supramolecular tectons,
etc. Also, resorcinarenes have applications in the extraction of heavy metal cations, where
their coordination abilities are key properties.
Question 39
Which of the following compounds are not aromatic?

O
+
N N
H O
H
A B C D E
+ H
N
N
N N
N H H
H
F G H I J
SO3H
H OH H
H
B
B
+
N
H H
HO3S
K L M N O P
Answer:
Compounds noted with B, D, E, G, I, K, N, O do not have an aromatic character.
Question 40
Indicate the heterotopic faces of the following compounds:

a) pentanal;
b) di-n-butyl ketone;
c) 2-iodopropene;
d) 1,1-dibromoethylene;
e) cis-4-octene;
f) methyl-ethyl-ketone;
g) dimethyl maleate;
h) dimethyl fumarate;
48
Answer:
C 4H 9 Re H H Si C4H9
a) C C
O O
C 4H 9 C 4H 9
C
b) No heterotopic faces are present.
O
CH3 Re I I Si CH3
C C
c)
C C
H H H H
H H
C
d) No heterotopic faces are present.
C
Br Br
C3H7 Re H H Si C 3H 7
C C Two equivalent pairs of enantiotopic
e)
C C faces
C3H7 Si H C 3H 7 Re H
C 2H 5 Re CH 3 CH 3 Si C2H5
C C
f)
O O
H Re COOCH 3 CH3OOC Si H
C C
g) C C
H Si COOCH 3 CH3OOC Re H
H Re COOMe MeOOC Si H
C C
h)
C C
MeOOC Re H H Si COOMe
Question 41
What is the stereochemistry of the products resulting in the addition of cyanide anion
to the Re and Si of the pentanal? Same question for the addition of sodium bisulfite.
49
Answer:
C4H 9
C 4H 9 H C 4H 9 H R
C C C
H
NC OH NC
O OH
Si
CN -
C4H9
C4H9 H C4H9 H S
C C C
H
HO CN HO
O CN
Re CN -
C4H9
C4H9 H C4H9 H S
C C C
H
NaO3S OH NaO3S
-
O O OH
Si
S
O O H
C4H 9
C 4H 9 H C 4H 9 H R
C C C
H
O HO SO 3Na HO
O SO 3Na
Re S
H O O
Question 42
What are lethargic reactions?
Answer:
Lethargic reactions (a term introduced in 1962 by D.E. Pearson and O.D. Keaton) are
those reactions that are extremely slow, lasting for weeks or months at room temperature,
and that cannot be accelerated by raising the temperature as side reactions occur. The
synthesis of sterically hindered ketoximes may be indicated as the most relevant example.
The reaction is conducted in a strongly alkaline environment:
50
O -K +
Ar C R + NH2OH Ar C R + H 2O
O N
OH
OH
The table below shows the ketones subjected to oximation, reaction times, and
recorded yields (, in %):
Reaction time
Structure of the carbonyl compound , %
(h)
C 16 450
O
C CH3 98 32
O
C CH3 81 420
O
Attempts to perform oximation reactions at reflux lead to lower yields, most

probably because of side reactions occurring (i.e., decomposition of hydroxylamine into
ammonia, water, and maybe some other products that could form).
Question 43
What are quasi-enantiomers, and what are quasi-racemates?
Answer:
Quasi-enantiomers are optically active chemical compounds with similar structures of
the type M-A and M-B, where the common structural unit (M) has opposite chirality (e.g.,
(R)-2-bromobutane quasi-enantiomer is (S)-2-iodobutane).
51
HOOC CH2 H2C COOH

C C
HOOC HOOC
Cl Br
H H
Quasi-enantiomers
When the quasi-enantiomers are present in a molar ratio of 1:1, they are called quasi-
racemates.
Question 44
How many distinct signals will show the following compounds in their 1H-NMR or
19
F-NMR spectra?
CH3 H CH3 H H2C CH2

CH3 CH CH2
C C C C
H2C O O
CH3 H Br H
A B C D
Br Br H Br CH3 CH CH2 CH3

CH2 CH CH2 OH C C C C
H H H Br Cl
E F G H
OH Cl
(CH3)3C F
CH CH2 Cl (CH3)3C F
dissolved in SbF5
I J K K’
(CH3)2CH F
(CH3)2CH F CFCl2 CFCl2 CFCl2 CFCl2
dissolved in SbF5
(19F-RMN, at 25 ℃) (19F-RMN, at -120 ℃)
L L’ M M’
CF2Br CBr2CN CF2Br CBr2CN

( F-RMN, at 25 ℃)
19
( F-RMN, at -98 ℃)
19
N N’
Determine the multiplicity of the NMR signals for the compounds K, K’, L, L’, M, M’, N, N’.
52
Answer:
H Hb H c
- three 1H-NMR signals (the
a H
C H a two vinylic hydrogen atoms
H C H
H
C C - two signals H are diastereotopic and lead to
C C different signals in the
C H
H Br H b corresponding spectrum)
H
Hb H Four signals (the two

d c
H C C H
a H H Hb methylene protons
- two signals H C C C Ha from the epoxide
H C O H O cycle are
H diastereotopic)
Hd Hb Br Br
C C C O H a - five signals C C - one signal
e H H
H Hc H
e d b a - five 1H-NMR signals

H Br H H H H
C C (hydrogen atoms b and c
- one signal H C C C C H
H Br are diastereotopic)
H Cl H c H
a Hd Hc H a
H Hc e e
O H H C C Cl
- six H-NMR
1
H H H Cl H b - six 1H-NMR signals
bH signals
H fH Hd
Hd Hf
He
(CH3)3C F - one 1H-NMR signal (doublet, due to the coupling with the F atom)
(CH3)3C F The following reaction occurs in SbF5:

-
dissolved in SbF5 (CH 3)3C F + SbF5 (CH 3)3C +SbF6
The 1H-RMN spectrum shows one signal, a singlet this time.
(CH3)2CH F - two signals (two doublets and two multiplets, respectively, due to
the couplings H-H and H-F)
53
(CH3)2CH F The following reaction occurs in the presence of SbF5:

+ -
dissolved in SbF5 (CH 3 ) 2 CH F + SbF 5 (CH 3 ) 2 CH SbF 6
The 1H-RMN spectrum also shows two signals (as in the above-
mentioned example), but in this case, one doublet and one multiplet,
as there is no more coupling with the F atom.
CFCl2 CFCl2 - one signal (19F-NMR at 25 ℃) – fast interconversion of

conformers occurs;
- two signals (19F-NMR at -120 ℃) – slower interconversion of
conformers.
F F F
Cl Cl F Cl Cl F
Cl Cl Cl Cl Cl Cl
F Cl Cl
achiral chiral chiral
Due to the equivalence of fluorine atoms in all possible conformers, the two 19F-NMR
signals do not undergo splitting.
CF2Br CBr2CN - one signal (19F-NMR at 25 ℃) – fast interconversion of

conformers occurs;
- two signals (19F-NMR at -98 ℃) – significantly slower
interconversion of conformers.
Br Br Br
Br Br NC Br Br CN
F F F F F F
CN Br Br
achiral chiral chiral
The 19F-NMR shows two doublets (corresponding to the two chiral conformers), and
one singlet (corresponding to the achiral conformer).
This multiplicity appears due to the inequivalence of the fluorine atoms in the chiral
conformers.
Question 45
_
Which of the following compounds have IR absorption peaks at   3000 cm 1 ?
54
HOH2C
O
O O
HOH2C OH HO OH O CH2OH
O O
OH HO
OH
HO
O O
A
HOH2C OH CH2OH
HO
O O
OH HO
OH HO O
O
O HO HO
HOH2C OH CH2OH
O O
O
CH2OH
B C
-ciclodextrin
COOH
Br Br
Cl Cl
D E F G
Br CH2 C C CH2 Br CH3 CH2 C N

O
H I J
CH3 CH3
N O C O CH3
CH3 C NH2
O
K L M N
O O
O
N CH3 CH2 CH2 NH2
H O O N
O P R S T
Indicate a synthesis pathway for compounds E, F, and G, starting from readily

available raw materials.
55
Answer:
Compounds A, C, D, E, F, G, K, L, N, O, R, S, T do show absorption peaks at

_
  3000 cm 1 .
Synthesis of the compound E:
O
COOH Zn(Hg), HCl COOH PPA
O
AlCl3
acylation
O
O Br O
EtOOC CH2 OZnBr
CH2 C OEt H+
Zn
COOEt
EtOOC CH2 OH
H+ NaOH(aq)
COO-Na+ O
COOH
H+ PPA
Zn(Hg) / HCl Pd, 
E
pyrene
56
Synthesis of compound F:
Br MgBr
Mg/Et2O 1. PBr3
O
+
2. H2O/H3O OH
NaCN H 2O/H 2SO 4 SOCl 2

Br CN - NH 3 COOH
AlCl3 H2/cat. H2SO4, 

F
COCl
indene
O OH
Synthesis of compound G:
Cl
, AlCl3 H2SO4 fumans Br2, AlBr3
SO3H
Br Br Br Br
diluted H 2SO 4 1. KMnO 4, NaOH/
2. H 3O +
SO 3H
COOH COOH
Br Br Br Br
Cl2, AlCl3
Cl Cl
Question 46
Arrange the following compounds in order of increasing of the vibration frequencies

for the bonds indicated by arrows:
57
O O
O
a) O
O
O
A B C
O O
O
H
b) N H
N N
H
A B C
H
c) CH3 CH2 CH 3 C CH
CH3 CH2 C C H
H CH 3
A B C
O O
O O
d) CH3 CH CH C
H
A B C D
Answer:
a) B<C<A c) A < B < C
b) A<B<C d) A < D < C < B
Question 47
How do you explain the presence of an m/z = 74 peak in the mass spectrum recorded
for methyl hexanoate?
Answer:
The appearance of m/z = 74 may be explained by a McLafferty rearrangement:
58
CH2
H +
CH3
HC O
CH3 CH2 CH CH2 +
CH2 C CH3
CH2 O
H +
O
+
C CH3
CH2 O
m/z = 74
Question 48
What are cucurbiturils? Indicate a possible synthesis pathway and applications for
these compounds.
Answer:
Cucurbiturils (CB) are macrocyclic ligands consisting of glycoluryl units

(tetrahydro[4,5-d]imidazol-2,5-dione) connected by methylene bridges. The name of these
compounds resides in their structural similarity with pumpkin, a plant from Cucurbitaceous
family:
o
O 3,9 A
N N CH2
o
CH CH 5,8 A o
9,1 A
N N CH2
O n
Structure of CB[n], where n may be 5, 6, 7, 8, 9, 10
Cucurbiturils were firstly synthetized in 1905 (Behrend) by condensation of glycoluryl

with formaldehyde, in acidic medium. Glycoluryl is synthetized from urea and glyoxal.
O O O
H2N NH2 HN NH N N CH2

CH2O
OHC CHO CH CH CH CH
H2SO4
H2N NH2 HN NH N N CH2
O O O n
glicoluryl
59
The molecular structure of cucurbiturils was first elucidated by Freeman in 1981. The
presence of carbonyl groups in cucurbiturils’ structures ensures their hydrophilic properties,
while their internal cavity has a hydrophobic character.
Cucurbiturils may form complexes with other molecules via ion-dipole interactions
and hydrogen bonds, but also through hydrophobic interactions.
Due to their complex-forming properties and ability to act as host molecules,
cucurbiturils have various applications in pharmacology (controlled drugs delivery),
organic chemistry (asymmetric synthesis), and supramolecular catalysis. Recently,
cucurbiturils have been successfully used as stabilizers for dyes and fluorescent molecules,
enhancing their photostability.
Question 49
What do we mean by ipso attack?
Answer:
The model of electrophilic substitution of mono-substituted benzene usually considers
the electrophilic reactant (E+) attack in the ortho, meta, para positions. The ipso attack
refers to the attack in the position where a substituent “X” already exists:
X
ipso
orto
meta
para
+ E+ other
E X reactions
a
X E
e
Nu- H Nu
E +
b X
d E
- X+
c
+ H
X
E
X E
E
+
X -H + H
60
Several scenarios may be considered for stabilizing the arenium ion formed as a result
of the ipso attack:
Reaction a: the arenium ion loses E+ and returns to the initial compound;
Reaction b: the arenium ion loses X+;
Reaction c: the ipso-substituent undergoes a 1, 2 migration followed by the loss of one
proton;
Reaction d: the electrophilic reactant undergoes a 1, 2 migration followed by the loss of one
proton;
Reaction e: reaction of the arenium ion with a nucleophile (some cyclohexadiene
derivatives were isolated).
Several electrophilic aromatic substitutions occurring through ipso attack are
included below:
H
+ H+
+
C6 H 5 C 6H 5 +
O O
OH OH
HO3S O2 N
HNO3
H2SO4
Nucleophilic aromatic substitution may occur as well through ipso attack:

Cl OCH3
O2N O2N
-
+ O CH3
- Cl-
NO2 NO2
The resulting intermediates are Meisenheimer complexes:
-
Cl O Cl OCH3 O Cl OCH3
+ +
O2N - N - - N
- O O
+ O CH3
+ +
NO2 N - N -
O O O O
61
O Cl O Cl O Cl OCH3
OCH3 OCH3 +
+ + - N
- N - N -
O O O
- - Cl-
+ +
N
+
- N - N -
- O O
O O O O
OCH3
O2N
NO2
Question 50
What are interferons, and what are their applications?
Answer:
Interferons are proteins belonging to the class of cytokines, usually synthesized in

some of the body cells, in response to the presence of pathogens such as viruses, bacteria,
parasites, and tumors. Many types of interferons exist, of which the ,  and  types are
the best known and frequently used in medical therapy.
Recombinant human interferon -2a

(Protein Data Bank ID: 1ITF)
62
 Human interferon  Recombinant bovine interferon

(Protein Data Bank ID: 1AU1) (Protein Data Bank ID: 1RFB)
Interferons can be obtained through both classical (from blood cells and fibroblasts)
and genetic engineering-based techniques. These molecules’ name originates from their
ability to interfere with the process of viral replication in host cells. Based on their antiviral,
antiparasitic, antimicrobial, antiproliferative and immunomodulatory properties,
interferons are used in the treatment of various diseases, including multiple sclerosis, B, C
and D viral hepatitis, malignant melanomas, kidney and liver cancer, hairy cell leukemia,
multiple myeloma, Kaposi's sarcoma, etc. However, several side effects have been often
reported for the treatment with interferon, such as alopecia, depression, loss of appetite,
diarrhea, edema, sub febrility, muscle pain, nasal discharge, chills, muscle and bone aches,
diabetes decompensation, etc.
Standard interferon is often administered in its PEGylated formula (functionalized
with polyethylene glycols), to ensure constant concentrations and long-lasting action in the
body.
Due to genetic recombination technologies, a significant increase in interferon
stability was recorded in later years. However, interferon therapy remains an expensive
procedure.
Question 51
What is the SN1’ reaction mechanism? Same question for the SN2’ mechanism.
Answer:
The SN1’ reaction mechanism refers to the fast occurring nucleophilic substitution of
allylic substrates, accompanied by allylic transpositions:
63
+ Nu-
R CH CH CH 2 X R CH CH CH2 Nu + R CH CH CH2
- X-
Nu
We can explain the formation of the two reaction products with the fact that the allylic
(carbocation) intermediate is a resonance hybrid:
+ +
R CH CH CH2 R CH CH CH2
Reactions that occur by SN1’ mechanism often involve pairs of ions:
CH3 CH CH CH2 OH
NaOH 0,8N 60%
CH3 CH CH CH2 Cl
25oC
CH3 CH CH CH2
OH
40%
CH3 CH CH CH2
NaOH 0,8N OH
CH3 CH CH CH2 62%
25oC
Cl
CH3 CH CH CH2 OH
38%
If the reactions evolved through the formation of free mesocarbocations, the same
ratio of alcohol isomers would be obtained. This skewed distribution of reaction products
(product spread) can be explained by the formation of ion pairs and it gets closer and
closer to even when rising the polarity of the solvent. A higher solvent polarity contributes
to the rise of free carbocation stability.
Nucleophilic substitution at the allylic carbon atom can also occur through a
conventional SN2 mechanism. When the substitution process is accompanied by
transpositions, it is called nucleophilic SN2’ substitution:
R1 R3 R1 R3
R1 C C C X R1 C C C R3
- X-
- R2 R3 Nu R2
Nu
Question 52
What is cine-substitution?
64
Answer:
Cine-substitution represents a substitution reaction (usually in the aromatic series)

where the new group (entering group) will occupy a position adjacent to the leaving
group.
An example of this is the reaction of o-bromoanisole with the amide ion in liquid
ammonia:
OCH3 OCH3
-
Br
NH2
NH3
NH2
Cine-substitution may be interpreted through the following reaction mechanism:
OCH3 OCH3 OCH3

Br Br
-
NH2 - NH3 -
H - Br-
2,3-dehydroanisole
benzyne type intermediate
OCH3 OCH3 OCH3

- H
NH3
- -
NH2 - NH2 NH2
NH2
I
Formation of carbanion I is facilitated through stabilization by the electron-

withdrawing effect of the OCH3 group (inductive effect). Some other examples of cine-
substitutions are included herein:
NO 2
COOH
KCN
EtOH, H 2O
Me Me
COOH
NO2
KCN
EtOH, H2O
65
H OMe
NO2
MeONa
MeOH
NO2 NO2
CH(COMe)2
O 2N NO2 O2N
CH2(COMe)2
Et3N
N O N O
NO2 Me NO2 Me
Question 53
What do one mean by tele-substitution?
Answer:
Tele-substitution represents a substitution reaction where the new group (entering

group) enters farther than one atom away from the leaving group.
Some examples of tele-substitution are presented below:
NH 2
N NH 3 N
N N
N N
N N
Br
X
N N NH2
N KNH2 N
NH3(l)
X = Cl, Br
Question 54
What is the E1cB reaction mechanism?
66
Answer:
The E1cB reaction mechanism refers to a type of unimolecular elimination reaction

involving a conjugated base:
H
base -
STEP (I) C C L C C L
L - "leaving group"
-
STEP (II) C C L C C
Elimination reactions can occur according to the mechanisms E1 (unimolecular

elimination), E2 (bimolecular elimination) and E1cB, which differ in the elimination timing
of the proton at the α-C atom. When the E2 reaction mechanism is considered, the L and H
groups are eliminated simultaneously. In the case of the E1 reaction mechanism, the L
group leaves the molecule before the hydrogen from the α-C atom with the formation of a
carbocation intermediate.
E1cB reaction mechanism occurs in basic conditions when the hydrogen from the α-
C atom is relatively acidic. Thus, a carbanion (the conjugate base of the substrate) is formed
as a result of the removal of the hydrogen atom before the removal of the leaving group.
Considering the rate of each step described above, three types of E1cB mechanism are
possible:
(E1cB)R: Step I is reversible and the resulting carbanion can rebuild the substrate,
because formation of the final product (Step II) is slower than Step I.
(E1cB)I: Step II is irreversible because Step I is slow and once the carbanion is
formed, it is rapidly converted into the final product.
(E1)anion: Step I is fast; this reaction mechanism applies when stabilized carbanions
are formed.
Several examples of reactions occurring by the E1cB reaction mechanism are shown
below:
- -
O H O R O - X-
a) C C C O
X - ROH
X
HO-, NaOH -
b) R C CH2 CH2 X R C CH CH2 X
- H2O - X-
O O
R C CH CH2
O
Some reactions that occur through the E1cB mechanism lead to ion pairs involving
the carbanion, thus rendering it more stable:
67
Br Br Br Br
DMF +
C C + Et3N - C C Br C C H + Et3NHBr-
H H H
+
Et3NH
Question 55
What are colossal carbon tubes? How are they synthesized, and what are their uses?
Answer:
Colossal carbon tubes are a new type of carbon-based tubular material. Compared to
carbon nanotubes, colossal carbon tubes have diameters ranging from 40 to 100 μm, and
their lengths are in the order of centimeters, making them visible to human eye. The walls
of colossal carbon tubes are corrugated and have many macroscopic rectangular pores in
their columnar structure. Colossal carbon tubes are obtained through chemical vapor
deposition by heating a precursor mixture of ethylene and paraffin oil to 850 ℃.
Due to their excellent electrical and mechanical properties, colossal carbon tubes are
tested to obtain light composite materials with increased strength (for the automotive
industry and aeronautics), bulletproof vests, electronic devices, etc.
Question 56
What is fibrinogen?
Answer:
Fibrinogen is a plasma glycoprotein with a molecular weight of approximately 340

kDa, known for its essential role in blood clotting. It consists of three pairs of polypeptides
(two Aa, two Bb, and two ) bound by 29 disulfide bridges. Fibrinogen is synthesized by
hepatic parenchymal cells (1.7 - 5 g / day), and it is converted to fibrin during the blood
clotting process. According to the Mayo Clinic, its concentration is a marker for
cardiovascular disorders. The normal values for fibrinogen concentration are in the range
of 200 - 400 mg / 100 mL blood.
Hyperfibrinogenemia may indicate an increased risk of myocardial infarction or
cerebrovascular accident. Sedentarism, smoking, estrogen supplements, and fish oil do alter
the measured value of fibrinogen concentration in blood.
Human fibrinogen
(Protein Data Bank ID: 1M1J)
68
Question 57
What are carbon nanotubes? How are they obtained and how are they covalently
functionalized and what are their practical uses?
Answer:
Carbon nanotubes (CNT) are an allotrope of the element carbon, with a cylindrical
structure - a tube-shaped network of benzene rings with half a molecule of fullerene at each
end.
O
C O CH2 (CH2 O CH2)n CH2 OH
CNT
H+,  CH2 CH2 O CH2 CH2

n
OH OH
PEG
COO (CH2)17 CH3 COOC6H5
+
OH, H , 
H 3C (CH2)17 OH
H+, 
CNT
CNT
COOH
HNO3

CNT
CNT
COONa COCl
NaOH, 25oC, 1hour SOCl2, DMF
CNT CNT
COO (CH2)17 CH3
CH3 (CH2)17 Cl CH3 (CH2)17 OH

120oC, 5 days Et3N, 100oC, 8 days
CNT
Methods of covalent functionalization of carbon nanotubes
69
Carbon nanotubes are either single-walled, SWNT, or multi-walled, MWNT. MWNT

are made of two or more nested SWNT with different diameters, or out of graphene sheets
rolled up like a scroll.
The techniques used to obtain CNT include electric arc discharge, chemical vapor
deposition (CVD), and laser vaporization.
The covalent functionalization of carbon nanotubes is important both in terms of
increasing their solubility, as well as their chemical reactivity.
O
R C Cl, AlCl3 Li, MeOH, MCl3
R C C R CNT
F2 H H
O O 25-600oC
F F
CNT CNT
CNT
F F
R R RO OR
RMgX RONa
CNT
CNT CNT
R
R
RNH NHR +
N N
RNH2 R
electrochemical
reduction
CNT CNT
70
EtOOC COOEt
EtOOC COOEt
CNT
EtOOC COOEt
DBU CH
Br
Bingel
reaction
Cl Cl O3 O O
CHCl3, NaOH O O
Cl Cl O O
CNT CNT CNT

NaBH4
O
S O
O HO OH
Diels Alder HO OH
cycloaddition [4+2]
CNT
CNT
Due to their exceptional electrical, thermal, and optical properties, carbon nanotubes
are widely used in electronics (e.g., nano-diodes based on CNT), chemical and biochemical
sensors, catalysis (catalyst support), pharmacology (controlled drug delivery), separations
(nanofiltrations), nonlinear optics, etc.
Question 58
What is graphene? How is this compound synthesized? What are the practical
applications of this compound?
71
Answer:
Graphene is a single layer of carbon atoms (2D), with sp2 and ordered in a planar,
hexagonal structure:
Graphene structure
Graphenes may be synthesized by various techniques:

a) mechanical exfoliation of highly oriented pyrolytic graphite (HOPG);
b) chemical exfoliation, a process consisting of alkali metal atoms interposing
between graphite layers, followed by an ultrasonic exfoliation in various organic
or inorganic solvents (acetic acid, acetic anhydride, concentrated sulfuric acid);
c) sodium ethoxide pyrolysis;
d) chemical vapor deposition (CVD) using a mixture of precursor gases (acetylene,
methane, and hydrogen);
e) chemical synthesis of graphene, a process consisting of the oxidation of graphite
in the presence of KMnO4 and sulfuric acid. The oxidation reaction has the effect
of increasing the interplanar spacing of the graphite oxide. Exfoliating graphite
oxide by ultrasonication leads to graphene oxide which, by reduction with
hydrazine, leads to reduced graphene oxide. Reduced graphene oxide and graphene
are two substances with significant differences in structure and properties;
however, there are some literature references that incorrectly use the word
graphene for the reduced graphene oxide.
72
1. KMnO4, H2SO4
2. ultrasonication
graphite
O OH O
COOH
O OH
HOOC COOH
OH HO OH NH2 NH2
HOOC OH O O
OH
HOOC COOH
O OH
O OH
OH COOH OH
COOH
HO
HOOC COOH
OH OH
reduced graphene oxide
Due to its exceptional optical, electrical and mechanical properties, graphene is used
in electronics, photovoltaic cells, synthesis of composite materials, biochemical sensors,
gas sensors, ultrafiltration, optoelectronics (OLEDs, liquid crystals), controlled drug
delivery, cancer therapy, etc.
Question 59
What is erythropoietin? What medical applications does it have?
Answer:
Erythropoietin (EPO) is a glycoprotein hormone that stimulates the production of red

blood cells. Erythropoietin is mainly synthesized by the kidneys. Small amounts of EPO
are produced also in the liver, in the perisinusoidal cells. The molecular weight of EPO is
30-34 kDa, the polypeptide chain mass being 18 kDa.
73
Stimulation of bone marrow with synthetic erythropoietin (obtained by genetic

engineering - recombinant DNA technology) improves hemoglobin levels, thus avoiding or
decreasing the frequency of transfusions in:
• anemia related to chronic renal failure or other kidney pathologies;
• anemia related to radiotherapy or chemotherapy;
• anemia related to antiretroviral therapy;
EPO administration leads to an increase in hemoglobin blood volume, which translates
to a higher amount of oxygen transported and finally to the rise in exercise capacity (it is
worth mentioning that an increase in hemoglobin of 0.3 g / dL has resulted in an increase
in exercise capacity by 1 %). For this reason, EPO has been used for years by those who
practice endurance sports (cycling, marathon, biathlon, triathlon). Now EPO is on the list
of prohibited substances being banned since the early 1990s.
Due to their structural quasi-similarity, it has long been impossible to differentiate
endogenous erythropoietin from the synthetic one, and possible cases of doping were not
detected. It is the merit of the French National Anti-Doping Laboratory (LNDD - Le
Laboratoire National de Dépistage du Dopage) to develop a methodology for the
differentiation of the two types of EPO in 2000 (there are subtle structural differences due
to post-translational changes). Doping with EPO is very dangerous, resulting in increased
blood viscosity and eventually, cardiovascular thrombotic events (acute myocardial
infarction, stroke).
Structure of human erythropoietin determined by

nuclear magnetic resonance spectroscopy applied to proteins (protein NMR)
(Protein Data Bank ID: 1BUY)
Question 60
What is Botulinum toxin? What medical applications does it have?
Answer:
Botulinum toxin (BTX) is a protein produced by the anaerobic bacterium Clostridium

botulinum, being one of the most dangerous neurotoxins known to date. There are eight
types of botulinum toxin (A, B, C [C1, C2] D, E F, G, H). The average lethal dose (LD-50)
is 1.3-2.1 ng / kg body weight for intravenous or intramuscular administration and 10-13
ng / kg body weight for the inhaled toxin.
74
The crystalline structure of type A botulinum neurotoxin

(Protein Data Bank ID: 3BTA)
Botulism is a very serious illness and occurs due to the ingestion of botulinum toxin-
contaminated foods (usually home-made canned foods, salted or smoked home-cooked fish,
home-made sausages).
Despite its high toxicity, botulinum toxin is used for therapeutic purposes and is
indicated in the treatment of many disorders such as hemifacial spasm, cervical dystonia,
blepharospasm, headache, hypersalivation, anal fissures, bruxism, diabetic neuropathies,
etc.
In recent years, botulinum toxin is used in dermato-cosmetology to treat facial
wrinkles, correct facial asymmetries, hyperhidrosis, etc.
Question 61
What are auxins? What applications do these compounds have?
Answer:
Auxins, phytohormones with indole nucleus, are of major importance in the growth
and development of plants, having an important role in processes such as: cell division,
geotropism, transport, and storage of substances in different organs of the plant,
phototropism, hydrotropism, etc. The most common, naturally occurring, auxin is 3-
indolylacetic acid:
CH2 COOH
N
H
3-indolylacetic acid
Together with 3-indolylacetic acid, some plants may contain other related auxins:
75
CH2 CHO COOH

CH2 CH2 COOH
CH 2 C
O
N N
H N
H H
3-indolyl propionic acid 3-indolyl acetic aldehyde 3-indolyl pyruvic acid
Numerous compounds with auxin activity are currently synthesized. Three of them
are presented below:
CH 2 COOH CH 2 COOH
CH2 COOH
Cl Cl
Cl
Cl Cl
2,4-dichlorophenoxyacetic 2,4,5-trichlorophenoxyacetic 1-naphthylacetic acid
acid acid
(2, 4 – D) (2, 4, 5 – T)
Both natural and synthetic auxins are widely used in agriculture and horticulture as
growth promoters as well as herbicides.
Question 62
What is sodium dodecyl sulphate? What applications does this compound have?
Answer:
Sodium dodecyl sulfate (sodium lauryl sulphate, SDS or NaDS) is an anionic

surfactant with the molecular formula:
CH3 (CH2)11 O SO3Na
SDS can be synthesized according to the following reactions:
CH3 (CH2)11 OH + SO3(g) CH3 (CH2)11 O SO3H

lauric alcohol
CH3 (CH2)11 OSO3H + NaOH CH3 (CH2)11 O SO3Na
It is widely used in the composition of cleaning products, as well as in personal care

products (toothpaste, shampoo, shaving cream, bath foam, etc.)
Sodium dodecyl sulfate is used as a protein denaturing agent in polyacrylamide gel
electrophoresis, a technique known as sodium dodecyl sulfate - polyacrylamide gel
electrophoresis (SDS-PAGE).
76
Question 63
What is PEGylation? What applications does this process have?
Answer:
PEGylation is a process for the functionalization of some drugs (usually proteins or

peptides used in medical therapy) with polyethylene glycol (PEG).
Polyethylene glycol is a reasonable option for the drugs’ functionalization because it
is inert, has good solubility in water, higher mobility in solution, low immunogenicity, and
is non-toxic.
Administration of PEGylated drugs provides several significant benefits:
 increase the water-solubility of the hydrophobic drugs;
 PEGylation causes a decrease in the rate of drug elimination from the body, thus
reducing the administration frequency of the respective drug;
 increase drug stability;
 reduces immunogenicity.
The first stage of PEGylation is the functionalization of polyethylene glycol.
Several examples of PEGylation of some proteins or polypeptides (noted H 2 N R ) are
presented below:
NaBH3CN
PEG O H + H2N R PEG O HN R
neutral pH or
weak
O alkaline
solution
pH=8,5 - 9,5
PEG O CH CH2 + H2N R PEG O CH CH2 HN R
O OH
pH = 8
PEG O O SO2 CF3 + H2N R PEG O HN R
Question 64
What is the reaction mechanism of the esterification below:
O Cl
C
Cl 1. Et3N
HO CH2 (CH2)n CH2 CH2 COOH +
2. DMAP, 
Cl Cl
77
O O Cl
C
O HO
+
n Cl Cl
Answer:
O +
- HNEt3
HO (CH2)n O H + NEt3
Cl
O
C Cl
O Cl
- Cl
HO (CH2)n O
- Cl
O O
HO (CH2)n O C Cl
- Cl-
Cl
Cl
CH3
O N N
CH3
HO (CH2)n O Cl
C
O
Cl Cl
CH3
+
N
CH3 O
-
O N
HO (CH2)n N
HO (CH2)n O Cl
- + CH3
C O Cl + N
O CH3
C
O
Cl Cl
Cl Cl
78
CH3
+
N
O CH3
-
(CH2)n N O N
+ CH3 H +
N O
OH
CH3
n
O
CH3
- H+ O
+ N N
CH3
n
Question 65
What is the structural motif of a protein?
Answer:
The combinations of several elements of some secondary structures in a protein with

a specific geometric arrangement are called supersecondary structures or structural motifs.
Structural motifs may be common to several proteins; however, they bear no meaning when
predicting the biological function of proteins as similar structural motifs may appear in
proteins with different functions.
The term structural motif is not to be confused with the term sequence motif, the last
one referring to a specific sequence of amino acids common to proteins.
The main structural motifs are:
a) -hairpin – two polypeptide chains arranged in β-sheets, antiparallel, and linked
together (the N-terminus of a sequence is linked to the C-terminus of the other) through
a sequence of two to five amino acids.
Protein Data Bank ID: 1HAA

-hairpin
b) helix hairpin – two polypeptide chains that adopt the -helix configuration bound
together (the N terminus of a sequence is linked to the C-terminus of the other strand) by
a sequence of two to five amino acids.

79
Protein Data Bank ID: 1EI0

helix hairpin
c) Greek key – four polypeptide -strains antiparallel oriented linked by short amino
acid sequences. The name is due to the similarity with an ornamental pattern present in
Greek artworks.
Protein Data Bank ID: 1CSQ

Greek key
d) -meander - strands of polypeptide chains arranged in β-sheets, antiparallel and

linked together by short sequences of amino acids. -Meanders are equivalent to multiple
linked hairpins.
Protein Data Bank ID: 1FGN

-meander
e) parallel polypeptide sheets linked together with by an -helix by short

sequences of aminoacids.
80
Joint Center for Structural Genomics:

TM0207



f)  antiparallel polypeptide -strands linked together with an -helix by short
sequences of amino acids.
Protein Data Bank ID: 1FSD




g) helix-loop-helix – a loop in the protein structure is a structural motif with two C
atoms of two polypeptide chains, separated by a few peptide bonds (up to five) that reach
a small distance from each other (< 7 Å). 

Protein Data Bank ID: 1HP8

helix-loop-helix (helix-turn-helix)

81
h) psi-loop – between two antiparallel β-strains there is another β-chain, the structure
being stabilized by hydrogen bonds. Thus, proteins are organized in the form of the Greek
letter Ψ.
Protein Data Bank ID: 2L69

psi-loop
i) -barrel – cylindrical barrel structure.
Protein Data Bank ID: 4CU4 Protein Data Bank ID: 1DC9
-barrel
j) TIM Barrel - a structure with eight parallel -strains and eight -helix alternating
in-between. The structure appears in triosephosphate isomerase and is common to several
proteins.
Protein Data Bank ID: 2X1T

TIM Barrel (triosephosphate isomerase barrel structure)
82
k) zinc finger - is a structural motif where one or more zinc atoms are coordinated to
stabilize the folding of the molecule
Protein Data Bank ID: 4ZNF Protein Data Bank ID: 1ZAA
zinc finger
l) coiled coil - is a structural motif with -helix strands coiled together, wrapped around
each another as in a rope.
Protein Data Bank ID: 1UIX Protein Data Bank ID: 2HY6
Question 66
What is the protein domain?
Answer:
The protein domain is a sequence in the structure of a protein that can evolve, function and
exist independently of the rest of the molecule. Most proteins contain several structural domains.
A structural domain can appear in several proteins.
The length of the protein domains may range from 25 to 500 amino acids. Their common
features are their compact structure, their function, and specific folding. Specific folding is the
key in distinguishing the protein domains and also the cause for performing different functions
in macromolecule. In a protein with multiple protein domains, each protein domain performs its
own function, or it can act in a concerted manner with the neighboring domains of the
macromolecular structure.
83
The difference between structural motifs and protein domains is given by their
functionality. Structural motifs represent only structural features repeatable in several proteins,
while protein domains are functional regions of proteins. One protein domain may contain one
or more structural motifs.
pyruvate kinase – a protein with three protein

domains
(Protein Data Bank ID – 1PKN)
Protein domains are the basic units within the tertiary structures of proteins,
connecting to each other via loop regions (short amino acid sequences).
Question 67
In the initial experiment, the Kolbe-Schmitt reaction was carried out in an open vessel
(atmospheric pressure) at a temperature of 180-200 °C (Kolbe, 1860).
How do you explain that, under these reaction conditions, only half of the phenol
introduced in the reaction vessel was converted, after acidification, into salicylic acid?
Answer:
O- Na+ OH
COO-Na+
1 atm, 180-200oC
(1) + CO2
OH O- Na+ OH
- + - +
COO Na COO Na
+-
(2) + Na O +
The phenol obtained in the second reaction is carried away by the excess carbon
dioxide.
Consequently, only half of the phenol introduced into the process is converted to
salicylic acid, after acidification.
84
Question 68
What is formed when sodium and potassium salicylates are each heated above 230
°C? How does sodium p-hydroxybenzoate behave if heated at 280 ℃? How do you explain
these chemical reactions?
Answer:
OH
230oC
2 COO- K+ K+ -O COO- K+ + OH + CO2
OH O- Na+
230oC
2 COO- Na+ COO- Na+ + OH + CO2
O- Na+
280oC
2 HO COO- Na+ COO- Na+ + OH + CO2
The Kolbe reaction is reversible at high temperatures due to its being

thermodynamically controlled.
The type of the cation used (lithium, sodium, or potassium) has a strong influence on
the balance between the ortho and para isomers:
O-
-
COO- O COO-
Sodium and lithium cations have a small volume and can chelate with both anionic
groups, thus stabilizing the ortho form. On the other hand, potassium ions chelate to a lesser
extent due to their higher volume (at high temperatures chelation with potassium ions is no
longer even possible).
Question 69
What are parabens? How are they synthesized, and what are their applications?
85
Answer:
Parabens are esters of p-hydroxybenzoic acid, traditionally named by attaching the -

paraben suffix to the name of the alkyl radical, for example butylparaben, hexylparaben,
etc.
COOCH3 COOCH2CH3 COOCH2CH2CH3 COOCH 2CH 2CH 2CH3
OH OH OH OH
methylparaben ethylparaben propylparaben butylparaben
The classical way to synthesize parabens is by the esterification of p-hydroxybenzoic

acid with ethanol in acid catalysis:
COOH COOR
montmorillonite K10
+ ROH + H2O

OH OH
Some other preparation methods are outlined below:
COOH COOCH3
H2SO4
+ CH3OH
MU
OH OH
COOH COOCH2CH2CH2CH3
ZnCl2
+ CH3 CH2 CH2 CH2 OH + H2O
MU
OH OH
Parabens are widely used as preservatives, both in the cosmetics and food industry,
being generally active against yeasts and molds. Typically, to achieve satisfactory results,
a mixture of several parabens and other preservatives is used to provide products with an
antimicrobial spectrum as wide as possible.
Recently, the safety of parabens has been questioned by a study published in the
Journal of Applied Toxicology, showing that parabens have been detected in breast tumors.
86
The conclusion of this study was even more worrying, as the influence of parabens on
estrogen levels was already being questioned (considering the correlation between high
levels of estrogen and breast cancer). The study raised interest and controversy in the
scientific community. For example, it did not prove a direct causal effect between the
presence of parabens in the affected tissue and the appearance of cancer. It also did not
provide information about the possible existence of parabens in healthy tissues in proximity
of the tumor.
Furthermore, numerous studies on the estrogenic activity of parabens have been
performed, and they have shown that it is much lower than initially thought. For example,
butylparaben has an estrogenic activity 10,000 to 100,000 times smaller than that of
estradiol.
In conclusion, although there were suspicions, it can be stated that there are no
scientific studies certifying an unquestionable link between the use of parabens and the
occurrence of breast cancer.
The EMA (European Agency for the Evaluation of Medicinal Products) and FDA
(Food and Drug Administration) regard parabens as safe and effective preservatives at least
for the cosmetics industry, their use being allowed by European laws.
Question 70
What are the applications of carbon dioxide in organic chemistry?
Answer:
Carbon dioxide has multiple uses in preparative organic chemistry, being used as a
reagent, catalyst, and solvent.
 CO2 – reagent – may participate in reactions with:
- Grignard reagents
HX
R MgX + CO2 R C OMgX R C OH
O O
Usually, carbon dioxide is added to the reaction in the form of dry ice due to it being
easier to handle. The procedure is useful in the synthesis of isotopically-labeled carboxyl
compounds (marked CO2 is commercially available).
Addition of CO2 to geminal organometallic compounds leads to the formation of
malonic acid derivatives:
M COOH
1. 2CO2
R CH R CH
2. H+
M COOH
87
- metallated aldimines:
1. 2CO2
R N C R' R' C COOH
2. H+
Li O
Metallated aldimines are obtained from the reaction of an organolithium compound

with the corresponding isonitrile:
-
R N+ C + R' Li R N C R'
Li
- phosphorus ylides:
R'
1. H2O/HO-
R' R' R CH COOH
+ + 2. H+
R C PPh3 + CO2 R C PPh3 R
-  R
COO- C C C
R, R' = H R' R'
- amines:
Py
R NH2 + CO2 R NH C NH R
HPO(OPh)2
O
+
R NH2 + CO2 R NH COO- NH3 R
O CH3
R2NH + CO2 + CH2 CH O CH2 CH3 R2N C O CH O CH2 CH3
- alkoxides:
R O- + O C O R O C O-
O
- phenoxides (Kolbe-Schmitt reaction):
O-Na+ OH
COOH
1. 125oC, 6 atm.
+ CO2
2. H+
salicylic acid
88
 CO2 is also a useful catalyst. Some examples of such reactions are presented below:
OH
H2O, CO2 (20 bar)
O
50oC, 9h, 85%
OH
HO O HO OH
H2O, CO2 (20 bar) O
O HO
O 60oC, 6h, 80% OH + 2
O OH HO OH
O HO
OH
H2O, CO2 (20 bar)

50oC, 35h, 95%
All of the above examples are acid catalyzed:

CO 2 + H 2 O HCO 3 - + H +
The reaction medium is slightly acid due to the formation and dissociation of carbonic
acid.
 Supercritical CO2 is widely used as a solvent in organic chemistry, as it is

inexpensive, readily available, non-toxic, and non-flammable.
Several reactions occurring in supercritical CO2 (ScCO2) are shown below:
Cl Cl
NO2 NH2
H2, ScCO2
Pd/C
CHO
OH O2, ScCO2
Pd/Al2O3
O
6,5 %, Sc(OTf)3
+
O ScCO 2, 50 oC, 15 h
89
+
O
O O
O
endo exo
Selectivity, yield, reaction rate are sensibly improved parameters for many of the
reactions made in supercritical carbon dioxide.
 CO2 as an extracting agent
The hydrolysis of the cyclohexanone ketal is an example of a reaction where ScCO2
was successfully used as an extracting agent:
O
O O 20 bar CO2, H2O
+
65oC, 4h, 96% HO OH
The raw reaction mixture contains water, cyclohexanone and ethylene glycol;
however, only cyclohexanone has significant solubility in ScCO2, and thus may be
separated from the mixture by extraction into ScCO2.
Also, caffeine can be extracted from coffee beans using ScCO2 extraction.
 CO2 as mobile phase in chromatographic processes
ScCO2 is used as a mobile phase in supercritical fluid chromatography.
 CO2 as cooling agent
A suspension of solid CO2 (carbon ice) in an organic solvent is used in organic
chemistry as a refrigerant mixture.
Question 71
What are prostaglandins? What applications do these compounds have?
Answer:
Prostaglandins are a family of organic compounds derived from fatty acids with a
common structure based on prostanoic acid:
COOH
CH3
prostanoic acid
90
The Swedish physiologist Ulf von Euler discovered and isolated these compounds in
1930. The name prostaglandin derives from the belief that these molecules are exclusively
derived from the prostate as initially assumed, although today it is known that
prostaglandins can be synthesized in any cell of the body. The best-known prostaglandins
are F1α, F2α, E1, abbreviated as PG F1α, PG F2α, and PG E1:
HO HO
COOH
COOH
CH3 CH3
HO OH HO OH
prostaglandin F1 prostaglandin F2
O
COOH
CH3
HO OH
prostaglandin E1
Prostaglandins act as mediators in a variety of physiological and pathological

phenomena: activation of the inflammatory response, fever, pain, blood coagulation,
vasodilation, contraction of the smooth digestive muscles. Prostaglandin analogs are
effective therapeutic agents and find use in gastroenterology (because of their protective
effect on the gastric mucosa, rendering them useful in the treatment of peptic ulcer),
obstetrics-gynecology (for triggering birth or termination of pregnancy), ophthalmology
(treatment of glaucoma), treatment of pulmonary hypertension, etc. Prostaglandins are also
therapeutic targets.
Non-steroidal anti-inflammatories inhibit cyclooxygenases (COX-1, COX-2, enzymes
required in prostaglandin synthesis) and, therefore, are useful in the treatment of pain and
inflammation.
Question 72
What are ceramides? What applications do these compounds have?
Answer:
Ceramides are a family of lipids consisting of a sphingosine molecule ((2-amino-4-

trans-octadecene-1,3-diol)) and a fatty acid:
91
OH
HO
NH2
sphingosine
O
H
N
HO
OH
ceramid C6
O
H
N
HO
OH
ceramid C16
Beyond their importance as a structural element in the cell membrane, ceramides play
a significant role in cell differentiation, proliferation, and apoptosis. Ceramides are the
major constituents of the skin in stratum corneum, as well as of vernix caseosa, the fatty
layer covering the skin of newborns.
They play an essential role in water retention in the cell matrix, preventing wrinkles
and attenuating existing ones. Thus, many skincare products contain ceramides. Recently,
ceramide-based supplements and foods (biscuits and soft drinks) have been marketed.
Scientific studies and tests of corneometry (measuring the bioelectric potential of the
skin that varies with the amount of water in the tissues) show that after three months of
administering ceramide supplements, hydration improved significantly (35.1 %, compared
with 0.85 % for placebo).
Question 73
What are the applications of carbon monoxide in preparative organic chemistry?
Answer:
Carbon monoxide has various applications in organic synthesis, being used in

various reactions, for example:
 with boranes, for the synthesis of alcohols and aldehydes:
O
HO CH 2 CH 2 OH H 2O 2
a) R 3B + CO CR 3 B R 3C OH
100 - 125oC NaOH
O
92
1. LiBH4
b) R3B + CO R CH2 OH
2. H2O2/HO-
1. LiAl(OMe)3H
c) R3B + CO R CHO
2. H2O2/NaH2PO4-Na2HPO4
 with diazonium salts:

+ Pd(OAc)2
Ar N N BF4- + CO Ar COOH
NaOAc
 with amines
Et3N.H2Se
a) Ar NH2 + CO Ar NH CHO
Increased reaction time, CO pressure, and temperature rises reaction yields.

The catalyst can be generated in situ according to the following reaction:
Ar NH2 + CO + Se + Et3N Ar NH C NH Ar + Et3N.H2Se

O
+ - O2
b) 2 R NH2 + Se + CO R NH3 R NH C Se
O
R NH C NH R + H2O + Se
O
c) R NH2 + CO + PdCl2 R N C O + Pd + 2HCl

The reaction proceeds in the following sequence:
R NH2 + CO R NH CHO
R NH CHO + PdCl2 R N C O + Pd + 2HCl
d) 2R NH2 + CO + S R NH C NH R + H2S
O
 with nitriles:
Et3N
R CN + Se + CO + H2O R C NH2 + CO2
Se
1. Et3N
R CN + Se + CO + H2O R C NH R'
2. R' NH2
Se
93
 with arylthallium bis(trifluoroacetate):

PdCl2
ArTl(CF3COO)2 + ROH + CO Ar C OR
O
 with imines and trialkyl boranes:
Co2(CO)8
R3B + C N R' + CO R C N C
O R' H
 with ketones and organolithium compounds:
-110oC H3O+
C O + RLi + CO R C C R C C
O OLi O OH
 the Gattermann - Koch reaction:
AlCl3
Ar H + CO + HCl Ar CHO
CuCl
 with alkenes:
H COOH
H+
C C + CO + H 2 O C C
a) 100 - 350 o C
500 - 1000 atm.
Koch reaction
H CHO
Co 2 (CO)8
b) C C + CO + H 2 C C
pressure
H CH 2 NR 2
Rh complex
c) C C + CO + H 2O + R 2NH C C
d) PdCl2
C C + CO + ROH ROOC C C COOR
HgCl2
 the carbonylation reaction:
CO R' X
a) R X + Na2Fe(CO)4 RCOFe(CO)4- R C R'
O
94
CO Ar2I+X-
b) R X + Na2Fe(CO)4 RCOFe(CO)4- R C Ar
O
SbCl5/SO2
c) R X + CO + R' OH R C OR'
- 70oC
O
Question 74
How can the following alcohol be synthesized from ethyl alcohol and ethylene glycol
as the only sources of organic matter?
OH
Answer:
400 - 450oC
2 C2H5OH + 2H2O + H2
SiO2/Ta2O5
diglyme
TiCl4, (C 2H 5)2AlCl BH 3.Et3N
3
butadiene C 6H 6 130-200 oC
trimerization
1,5,9 - cyclododecatriene
O
B O
CO, 70 atm, 150oC

B
HO CH2 CH2 OH
H2O2, NaOH OH
95% EtOH
95
Question 75
What are carbonic anhydrases?
Answer:
Carbonic anhydrases (CAs) are a category of metalloenzymes that catalyze one of the
simplest, but fundamental chemical reactions occurring in living cells, namely the
reversible interconversion between carbon dioxide and bicarbonate anion, according to
equation:
carbonic anhydrase
H2O + CO2 HCO3- + H+
An enzyme of this type was first identified in 1933.
Structure of human carbonic anhydrase II with bicarbonate complex

(Protein Data Bank ID: 2VVB)
There are several families of carbonic anhydrases, called alpha, beta, gamma.
Although there are no significant structural similarities (no similar amino acid sequences)
between members belonging to different families of carbonic anhydrases, it is worth noting
that these enzymes perform the same functions and contain the zinc ion as active situs.
Carbonic anhydrase plays a crucial role in regulating blood acidity, breathing, etc.
The way carbon anhydrase works is a very interesting example of combining Brønsted
- Lowry and HSAB (hard soft acid bases) theories.
Water molecule, though a very weak Brønsted acid, can lose a proton to form the
hydroxide anion. This deprotonation is orchestrated by the presence of zinc cation acting
as a Lewis acid (borderline Lewis acid) that bound a water molecule, which becomes acidic
(the oxygen atom is acting as a strong Lewis base).
Thus, the water proton becomes sufficiently acidic to react with the nitrogen atoms in
the imidazole rings belonging to histidine residues (these acting as Brønsted bases). The
hydroxyl anion generated may then react with carbon dioxide to form the bicarbonate anion.
In the bicarbonate anion formation, the reaction catalyzed by carbonic anhydrase, a
proton is also formed, which is then replaced by the sodium ion, and thus the bicarbonate
is reabsorbed. By administration of carbonic anhydrase inhibitors (drugs that suppress the
activity of this enzyme), sodium and potassium ions are eliminated synchronously with the
water equivalent, causing diuresis. These drugs are used as diuretics, antiepileptics, in the
96
treatment of glaucoma, osteoporosis, neurological disorders, etc. Some examples of

carbonic anhydrase inhibitors are shown below:
O O
S S
O N
SO2 NH2 N N
Ac HN SO 2 NH 2
S
NH
Brinzolamide Acetazolamide
CH3 O S O
S
H SO2 NH2
H
NH
Dorzolamide
Recently, a type of cadmium-containing carbonic anhydrase has been isolated from

marine algae. The surprise of discovering such a molecule was doubled by the general and
widely accepted fact that this metal is toxic and has no biological functions.
Question 76
What is oxytocin and what are its medical applications?
Answer:
Oxytocin, a peptide hormone discovered by the Italian scientist Nicholas Farraye

in 1835, is synthesized by the hypothalamus and released in the bloodstream by the
posterior lobe of the pituitary gland. Regarding its chemical structure, oxytocin is a cyclic
nonapeptide with the sequence: cysteine – tyrosine – isoleucine – glutamine – asparagine –
cysteine – proline – leucine – glycine - amide (Cys-Tyr-iLeu-Gln-Asn-Cys-Pro-Leu-Gly-
NH2). Its molecular weight is 1007 Daltons, and one international unit (IU) of oxytocin
values 2 micrograms of pure polypeptide.
The synthetic product, similar to the pituitary oxytocin hormone, is used in medical
therapy to induce and maintain labor; its effect is to enhance the physiological uterine
contractions. Oxytocin also stimulates the myoepithelial cells of the mammary glands,
favoring milk ejection in breastfeeding.
Oxytocin acts as a neurotransmitter in the brain, some recent research highlights
its role in the reproductive life and social behavior of all mammals. It is often called the
97
hormone of happiness and attachment, oxytocin being responsible for good communication
in couples, and for the development of the maternal instinct.
Crystalline structure of the complex Neurophysin - Oxytocin

(Protein Data Bank: 1NPO)
Question 77
Ouzo (ούζο), a Greek traditional drink, is a colorless liquid that turns milky-white
when water is added. How do you explain this phenomenon?
ouzo ouzo + water

Answer:
This alcoholic beverage, similar to arak and absinthe, is used as an appetizer in Greece
and Cyprus. The clouding effect is due to the presence of anethole (a component of the
anise essential oil), a basic ingredient in the drink’s manufacturing process. Anethole is
highly soluble in ethanol, but insoluble in water. Thus, once the alcohol concentration drops
below 38 % (v/v) by adding water, this hydrophobic essential oil forms a stable oil-water
microemulsion. Droplets of this emulsion have the capacity to scatter light, and thus give
the milky white appearance of the diluted drink.
CH3
CH3
O
trans-anethol
98
Question 78
What are the Baldwin rules and what are their implications in organic chemistry?
Answer:
Baldwin's rules are empirical guidelines, based on experimental observations on

cyclization reactions from both a kinetic and a stereochemical viewpoint. They were first
proposed by the British chemist, Sir Jack Baldwin in 1976, and they show the importance
of interatomic distances as well as the orientation of chemical bonds (more specifically, the
molecular orbitals). These rules are useful when predicting reaction products when multiple
possible reaction paths are possible:
O
O
5-endo-trig 5-exo-trig
OEt
OEt O
N N
NH2
H H
Nomenclature:
The numeral prefix indicates the size of the ring formed in the reaction. The endo
and exo prefixes indicate how the chemical bond in question is breaking: endo, meaning
inside the newly formed ring, and exo, meaning outside of it:
-
Y
5-endo 4-exo
-
X Y X Y X Y X
Suffixes: dig, trig and tet indicate the geometry of the attacked carbon atom:
• Dig(onal) for sp hybridization
• Trig(onal) for sp2 hybridization
• Tet(ragonal) for sp3 hybridization
Examples:
4 4
5
Y 3 4
3 Y 3
5
5
6 2
2 X 2
X X Y
1 1
1
6-endo-trig 5-exo-tet 5-exo-dig
99
Baldwin Rules:
Rule no. 1:
 All exo-tet reactions are favored. This is due to the fact that there is no steric or electronic
hindrance present to inhibit the reaction. The lone pair of the donor atom, X, can easily interact
with the σ* orbital of the C-Y bond.
 All endo-tet reactions are unfavorable.
Rule no. 2:
 All exo-trig reactions are favored. This is because the lone pair of the donor atom, X,
can very easily interact with the antibonding π* orbital of the C=Y bond.
 Most 3-5-endo-trig are unfavorable. The molecule lacks the necessary geometry such that
the non-bonding electron pair can interact with the π* orbital of the C=Y bond. The 3-5-endo-
trig reactions are only possible if the ring is especially large.
H
N 6-endo-tet N
O O
Rule no. 3:
 3-4-exo-dig reactions are unfavorable
 5-7-exo-dig reactions are favored
 3-7-endo-dig reactions are favored
For the easiness of use, these rules are neatly summarized in the table below:
dig trig tet

endo exo endo exo endo exo
3     
4     
5      
6      
7     
An aspect to be considered is that, as previously mentioned, these rules are purely

empirical, based on experimental evidence and stereochemical judgment. Thus, the term
unfavorable does not mean that reactions are not possible, but only that their reaction rates
are low when compared to the favored reactions. Many exceptions from these rules may
be found and, in general, the unfavorable reactions require distortions of chemical bonds
and angles. Also, these rules do not apply to elements belonging in the 3rd period of the
periodic table (i.e., sulphur).
Baldwin's rules may also be applied to ketone enolates, as such the nomenclature
was adapted by implementing the enolendo and enolexo prefixes:
 if the reaction product contains the carbonyl group inside the newly created ring, the
enolendo prefix will be used.
100
 if the reaction product contains the carbonyl group outside the newly created ring, the
enolexo prefix is used.
Examples:
6-enolendo-exo-tet
-
O Br O
-
O 6-enolexo-exo-trig
O
O O-
Rules:
 6-7-endoenol-exo-tet reactions are favored

 3-5-enolendo-exo-tet reactions are disfavored
 3-7-enolexo-exo-tet reactions are favored
 3-7-enolexo-exo-trig reactions are favored
 6-7-enolendo-exo-trig reactions are favored
 3-5-enolendo-exo-trig reactions are disfavored
Example:
Br O
5-exo-tet 5-endoenol-exo-tet
> 70% - 0%
O O
Question 79
Telomeres are DNA units that protect chromosome endings. Telomeres shorten with
every division until a certain critical length, at that moment cell apoptosis is triggered.
Unfortunately, human cells can’t regenerate their telomeres. Even worse, cancerous cells
can regenerate their telomers by using a special enzyme named telomerase.
101
OSO3Na OSO3Na
HO HO
NH NH
MeO2C OH O OH
N N
HO OH HO OH
HO HO
dictyodendrin A dictyodendrin B
As such, dedicated research is looking for an organic chemical compound that may act as a
selective telomerase inhibitor, and that could be used in cancer treatment. Two compounds
with this property have been extracted from the marine sponge Dictyodendrilla
verongiformis. Some of their proposed synthesis pathways are shown below:
Br
I n-BuLi, PhMe 1. Fe, FeCl2, EtOH, HCl
A B
MeO 2. Boc2O, Et3N, MeCN
Br OMe
NO2
1. Mg(TMP)2 . 2LiBr, THF 1. TMSOTf, 2,6-lutidine, CH2Cl2

C D
2. CuI, Pd(PPh3)4 2. DDQ, PhMe
MeO MeO
3.
I Br
KOH, DMF
AgOTf, THF 1. (Bpin)2, [PdCl2(dppf)] CH2Cl2, AcOK, dioxane

E F
MeO 2. [PdCl2(dppf)] CH2Cl2, NaOH, dioxane
Ot-Bu
CO2Me
Br N3
Friedel-Crafts alkylation I
102
o-C6H4Cl2 1. BCl3, pentamethylbenzen, CH2Cl2 1. BCl3, TBAI, CH2Cl2

G H
reflux 2. Cl3CCH2OSO2Cl, DABCO, CH2Cl2 2. Zn, MeOH, HCO2NH4
dictyodendrin A
O NO2
OH i-PrBr, K2CO3 MeONa, MeOH, 70oC
I J
DMF, 100oC MeO
CHO
1. TosMIC, NaH, THF, -30 oC Fe, HCl CH 2Cl2, Et3N, DMAP

K L M
MeO EtOH O
2. Cl
Br OMe
OMe
reflux
TiCl3 / 2 KC8, DME hv, MeCN, Pd/C NBS, THF 1. MeLi, THF, -78oC
N O P
Py, reflux PhNO2 0oC 2. n-BuLi
1. p-MeOC6H4CHO TPAP, NMO BCl3 Cl3CCH2OSO2Cl

Q R S T V
2. H+, H2O CH2Cl2 CH2Cl2 DABCO, CH2Cl2
1. BCl3, TBAI, CH2Cl2
dictyodendrin B
2. Zn, HCO2NH4, MeOH
What are the structures of the compounds marked with letters A through V?
Answer:
MeO
OMe OMe
Br
Br Br
BocHN N OMe
O2N
Boc
Br OMe Br OMe
OMe
A B C
103
MeO MeO
Br Br
MeO2C
N OMe N OMe
OMe
MeO
OMe
MeO
MeO
D E
Ot-Bu
MeO MeO Ot-Bu
N3
NH
MeO2C OMe MeO2C OMe

N N
MeO OMe MeO OMe
MeO MeO
F G
O O NO2
MeO O
S
O CCl3 Oi-Pr
O
NH
I
MeO2C OMe
N
O NO2
Oi-Pr
MeO OMe
MeO
MeO
H J
104
OMe OMe
O NO2 O NH2
Oi-Pr Oi-Pr
N N
MeO MeO
K L
OMe
Oi-Pr
MeO
OMe
MeO NH
O HN O OMe
N
Oi-Pr
OMe
MeO
MeO
M N
Oi-Pr Oi-Pr
MeO MeO
NH NH
OMe OMe
Br
N N
OMe OMe
MeO MeO
O P
105
Oi-Pr Oi-Pr
MeO MeO
N Li NH
OMe HO OMe
Li
N N
OMe MeO OMe
MeO MeO
Q R
Oi-Pr OH
MeO MeO
NH NH
O OMe O OMe
N N
MeO OMe MeO OMe
MeO MeO
S T
O
O
MeO S
O CCl3
O
NH
O OMe
N
MeO OMe
MeO
V
106
Question 80
Sildenafil Citrate (Viagra ™) is a selective inhibitor of phosphodiesterase 5 (PDE-

5) and it is prescribed for the treatment of erectile dysfunction, and for pulmonary arterial
hypertension. The discovery and first synthesis procedure of this drug belong to researchers
from Pfizer (a well-known pharmaceutical company), and the succession of reactions below
describes the corresponding steps:
OEt
COOH HN N CH3
ClSO3H CDI
A B C
EtO2C CO2Et CH3NHNH2 HNO3 NH3 H2

D E F G H I
EtONa, 40oC EtOH, 5oC H2SO4 EtOH Pd/C
O CH3
N
OEt HN
N
+C t-BuOK
N
J
t-BuOH
Sildenafil
O2S
N
N
CH3
The compound D (C5H10O) has the following spectral characteristics:

Compound IR,  (cm-1), CCl4
1
H-RMN, ppm), CDCl3
D 2.4 2.13 1.6 0.93
1716
(C5H10O) triplet singlet multiplet triplet
Determine the intermediate compounds in the synthesis of Sildenafil Citrate.
Answer:
O
1,6
The compound D:
2,13 2,4 0,93
107
OEt OEt O
OEt COOH
N
COOH
N
O 2S O 2S
N N
SO2Cl
N N
CH3 CH3
A B C
O CH3 O CH3
O O
N N
EtO N EtO N
EtOOC
O2N
E F G
O
CH3
H 2N
N
OEt O
N
O CH3 O CH3
N
N N H
H 2N N H 2N N
O 2N H2N O2S
N
N
CH3
H I J
Question 81
What is the mechanism of the following transformation?
O HBr, CH3COOH
Br 150oC, 7h, 21% Br
108
Answer:
O O
+
+ H + H
Br Br
-H+
HO H HO
Br Br
+
+ H+ H2O 1,4 - elimination
Br Br
- H2O
- H+
Question 82
What is the pathway for the following transformation?
CH3
OH C O
OH
H H H H
H H H H
O O
Nandrolone Gestonorone
(19-nortestosteron) (progestin used
in prostate hypertrophy)
109
Answer:
OH OH
H H H H
HO CH2 CH2 OH
H H TsOH O H H
O
O
O NC
OH
H H H H
CrO3 1. NaHSO3
O 2. NaCN H H
O
O O
H3C
NC C O
OH OH
H H H H
CH3MgBr
O H H H H
O
O O
H 3C
C O
OH
H H
HCl
H H
O
Question 83
Nilutamide, a drug used in the treatment of prostate cancer in its advanced stages,
has the following structure:
F 3C O
CH 3
O 2N N CH 3
NH
Propose a synthesis pathway for this compound starting from available raw materials.
110
Answer:
CH3 CCl3 CF3 CF3
Cl2 NaF HNO3

AIBN H2SO4
NO2
CF3 CF3 CF3 CF3

O 2N
Fe/HCl AcCl HNO3
+
H2SO4
NH2 NHAc NHAc NHAc
main product NO2
CF3 CF3
O
O 2N O 2N
H2O/HO- Cl C OEt
NHAc NH2
CF 3 EtOOC F 3C O
O 2N CMe2 CH 3
H 2N
O 2N N CH 3
NH C OEt NH
O O
Ethyl 2,2-dimethylglycolate may be obtained according to the following reaction

scheme:
Br2 H2O/HO- 1. (CH2)6N4

Me2CH COOH Me2C COBr Me2C COOH
red P 2. HCl, 
Br Br
EtOH, H+
Me2C COOH Me2C COOEt
NH 2 NH2
Question 84
Propose synthesis pathways for the following compounds:
111
CN
CN NC
Cl Cl -
HC NH 3+ O 3S CH 3
CN NC
B C
A
Propose two
synthesis pathways
CH 3
CN
CH 3 C CN
CH3 CH2 C NH2
CH 3
CN
D E
Answer:
Synthesis of the compound A:

O
COOEt
O2/V2O5 2EtOH 2NH3
O
400oC-500oC H+ - EtOH
- H2O COOEt
O
O
C NH 2 CN
2SOCl2
- 2SO 2
C NH 2 CN
- 4HCl
O
Synthesis of the compound B:

NH2 NHCOCH3 NHCOCH3 NHCOCH3
Cl Cl
(CH3CO)2O HNO3 Cl2
Py H2SO4 cat.
NO2 NO2
NHCOCH3 NHCOCH3
Cl Cl Cl Cl
Sn + HCl 1. HNO2, H+ H2O/H+
2. H3PO2
NH2
112
NH2 CN
Cl Cl Cl Cl
1. HONO, H+
2. CuCN
Sandmeyer reaction
An alternative method to produce 2,6-dichlorobenzonitrile uses toluene as raw

material instead of aniline:
CH 3 CH3 CH 3 CH 3
Cl Cl Cl Cl
HNO 3 Cl2 Sn + HCl
H 2SO 4 AlCl3
NO 2 NO 2 NH 2
CH3 CN
Cl Cl Cl Cl
1. HNO2, H+ NH3, O2
2. H3PO2 Pt, 
Synthesis of the compound C:
NaHCO 3 NaCN
Cl CH 2 COOH Cl CH 2 COO -Na + NC CH 2 COO -Na +
- CO 2 - NaCl
- H 2O
HCl EtOH NH3
NC CH2 COOH +
NC CH2 COOEt
H - EtOH
PCl5 NaNO 2, AcOH
NC CH 2 CONH 2 NC CH 2 CN
-POCl3 H 2O
-2HCl
NC NC p-TsOH
Al(Hg), THF
C N OH HC NH 2 C
NC NC
Synthesis of the compound D:

NaCN HCN HCN
CH3 CH2 Cl CH3 CH2 C N CH3 CH2 C NH
CN- CN-
CN
CN
CH 3 CH 2 C NH 2
CN
113
Synthesis of the compound E:

CH3 CH3 CH3
Mg 1. CO2 1. NH3
CH3 C Cl CH3 C MgCl CH3 C COOH
2. H2O/H+ 2. 
CH3 CH3 CH3
CH3 CH3
O P2O5
CH3 C C CH3 C CN
- H2O
CH3 NH2 CH3
Question 85
Mescaline or 3,4,5-trimethoxyphenethylamine is a psychedelic alkaloid that may be

isolated from Lophophora williamsii, a species of cactus usually found in northern Mexico,
Central America and in the Rio Grande River’s basin.
The American natives have used dried mescal buttons for more than 3,000 years in
their religious rituals to achieve spectacular psychic conditions. The most common effects
of mescaline consumption are: colorful hallucinations, altered object size, depression and
euphoria, dream-like sensations, alertness, floating away sensations, etc.
Soon after its isolation and identification in 1897 by the German chemist Arthur
Heffter and its synthesis in 1919, mescaline began to be used substantially in the artistic
and intellectual circles of the time.
One of the well-known mescaline consumers was the English writer Aldous Huxley,
who described his experience of using this drug in the essay: “The doors of perception”.
Propose a pathway to synthesize mescaline starting from:
a) p-cresol
b) gallic acid
Answer:
CH3 CHBr2 CHO
Br2 H3O+ NaOCH3, Cu2Cl2

a) Cl CH3OH
Br Br Br Br
OH Cl OH OH
CHO CHO
Me2SO 4, NaOH CH 3NO 2

H 2O NaOH
MeO OMe MeO OMe
ONa OMe
114
CH CH NO2 CH2 CH2 NH2
LiAlH4
MeO OMe MeO OMe

OMe OMe
Mescaline
COOH COOH COOCH 3
1. NaOH
b) +
2. CH 3I excess
HO OH H 3CO OCH 3 H 3CO OCH 3
OH OCH 3 OCH 3
CH2OH CH2OTs
1. LiAlH4 TsCl KCN

2. H2O Py
H3CO OCH3 H3CO OCH3
OCH3 OCH3
CH2CN CH2CH2NH2
1. LiAlH4
2. H2O
H3CO OCH3 H3CO OCH3
OCH3 OCH3
Mescaline
Question 86
What are the structures of the compounds marked with letters in the following reaction
schemes?
Br S
OHC B(OH)2
[Pd(dba)3] NBS
N A
PCy3, K3PO 4 C28H19NO 2S2 THF
dioxane/H 2O 90%
100oC, 18h
Br
115
HOOC B(OH)2
NC CN, Et3N
B C D
Pd(dppf)Cl2.CH2Cl2 CH3CN
K2CO3
Br
O
S B
O
OHC N E
Pd(dppf)Cl2 . CH2Cl2
K2CO3
CH3OH/toluene
Br
70oC
Ag2O, NaOH POCl3, DMF NC CN, Et3N

F G H
EtOH
Br
OHC S B(OH)2
POCl3 Ag2O, NaOH
N I J
DMF Pd(dppf)Cl2 . CH2Cl2
K2CO3
NC CN, Et3N
K L
EtOH, 80oC
Answer:
CHO CHO
S S
N Br N
S S
CHO CHO
A B
116
CHO
HOOC N
S
CHO
C
CN
S
CN
HOOC N
CN
S
CN
D
S S
OHC N HOOC N
S S
E F
117
CHO
HOOC N
S
CHO
CN
S
NC
HOOC N
NC
S
CN
H
Br Br
OHC N HOOC N
I J
118
CHO
HOOC N
CN
S
NC
HOOC N
Question 87
What are the structures of the compounds indicated by letters in the scheme below?
O
C CH2 OAc
OH
H
TsCl, Py AcONa OsO4
A B
H AcOH
O
M e 2 CO , H + H O Cl N aO H HF SeO 2
C D E F G H
Note: In the reaction of the compound B with osmium tetroxide, only the16 bond will
be attacked.
119
Answer:
O O
C CH2 OAc C CH2 OAc
OTs
H H
H H
O O
A B
O O
C CH2 OAc C CH2 OAc
OH O Me
H OH H O Me
H H
O O
C D
O O
C CH2 OAc C CH2 OAc
HO Me O Me
O O
H O H O
Me Me
Cl H H
O O
E F
O O
C CH2 OAc C CH2 OAc
HO Me HO Me
O O
H O H O
Me Me
F H F H
O O
G H
120
Question 88
What is tyramine? Propose pathways for its synthesis, starting from:

a) anethole
b) phenol
Answer:
Tyramine or 4-hydroxyphenethylamine is a natural amine that is present in the human
body, as well as in certain foods and beverages. It is metabolized by the enzyme named
monoamine-oxidase (MAO):
OH
CH 2 CH 2 NH 2
tyramine
At lab scale, tyramine can be easily synthetized by thermal or enzymatic
decarboxylation of tyrosine:
OH
COOH
- CO2
NH2
HO
CH2 CH2 NH2
tyrosine tyramine
Here are some examples of foods and alcoholic beverages containing tyramine or bacteria
whose enzymes can convert tyrosine to tyramine: salami, sausages, aged and fermented
cheeses, soy sauces, fish brine, herring, chocolate, meat, wine, beer, eggplant, etc.
Tyramine levels in food products depend on their processing and preservation
procedures.
The administration of monoamine-oxidase inhibitors that are still successfully used in
the treatment of depressions, if associated with consumption of foods having a high content
of tyramine, may trigger hypertension crisis. This particular example highlights the
importance of diet adjustments for persons receiving a specific medication.
The pathway to synthetize tyramine starting from anethole as a readily available raw
material may occur as follows:
CH CH CH 3 CHO CH CH NO 2
1. O 3, Zn CH 3NO 2 H 2/Ni
2. AcOH HO -
OMe OMe OMe
121
CH2 CH 2 NO 2 CH2 CH 2 NH2
1. HI, 
2. HO -
OMe OH
Tyramine synthesis starting from phenol may have the following steps:
OH OH OH
CN, AlCl3 1. NaOH, H2O, reflux

2. HCl
CN COOH
OH OH
NH2 NH2.H2O NaNO2

HCl, 25oC
O O
+ -
C NH NH2 C N N N
OH OH
75-80oC 1. HCl/H2O
2. NaOH
CH2 CH2 NH2

N C O
Question 89
Suggest a synthesis pathway for 2,7-octanedione, starting from fructose as the unique
source of organic matter.
122
Answer:
HO CH2 CH2OH
O HO CH2 O CHO
H2SO4 , Amberlist-15
HO
OH -3H2O
OH HMF
O
2 H2O
+ HCOOH
H2SO4 COOH
levulic acid
O O
2KOH Kolbe synthesis
2 2
COOH COO-K+ -2CO2
Question 90
Which specific symmetry group belongs to each of the following compounds:
a) CH4 j) Cyclopentadienyl Anion

b) CH2Cl2 k) Cyclobutadiene
c) CHCl3 l) Tropylium Cation
d) C2H4 m) Cyclohexane (chair conformation)
e) C2H2 n) Cyclohexane (boat conformation)
f) C2HD o) Adamantane
g) Allene p) DABCO
h) Benzene q) Fullerene C60
i) Pyridine r) CH3+
123
Answer:
a) CH4 Td j) D5h
b) C2v k) D4h
c) C3v l) D7h
d) D2h m) D3d
e) C2H2 D∞h n) C2v
f) C2HD C∞v o) Td
g) D2d p) D3h
h) D6h q) Ih
C60
i) C2v r) D3h
Note: The diagrams in the table above show only the specific elements needed to assign the
particular symmetry group of respective chemical species.
124
Question 91
What are the template reactions? What do we understand by the template effect?
Answer:
The template reactions class comprises all the transformations occurring between two or
many coordination centers of the same metal ion. Same organic compounds involved in a
template-type reaction would lead to different reaction products in the absence of the metal ion.
The template effect is an indication of the metal cation role in the synthesis of an
organic compound, and it is related to the preorganization of the organic ligands determined
by the coordination sphere of the metal ion.
The following figure shows an example of a template reaction:
Br 2+
N S N S
Ni + Ni 2Br-
N S N S
Br
In certain situations, a notable disadvantage of template reactions is related to the
difficulty of extracting the metal ion from the newly created cavity.
Question 92
To synthetize a certain organic compound in the lab, the following recipe was used:
Into a 100 mL round-bottom flask, add the following substances: 1.0 g of nickel (II)
acetate tetrahydrate, 1.8 g of 1,2-diaminobenzene, 1.7 mL of 2,4-pentadione and 25 mL of
1-butanol. The purple reaction mixture was refluxed for 8 hours, then cooled to -5 °C, and
a precipitate was formed at the bottom of the flask. The reaction product was filtered,
washed with cold methanol, and then left to dry. A quantity of 1.2 g of very dark purple
crystals was obtained.
The IR and 1H-NMR (200 MHz, CDCl3) analysis of the resulted crystals were
performed, and the following spectra were recorded:
125
a) What is the structure of the reaction product?

b) Assign the spectroscopic signals to this structure.
c) Suggest a mechanism of the reaction leading to this product.
d) What are the possible side reaction products in this reaction?
e) Which symmetry group does this reaction product belong to?
f) Indicate a reaction route for the conversion:
O
NH2 N C NH
2
NH2 N
Pyrazinamide,
drug used in
tuberculosis treatment
g) What is the reaction mechanism for the following transformation?

NH 2 O N CH 3
H 2SO 4
+
- 2H 2O
NH 2 O N CH 3
Answer:
N N
Ni
a)
N N
Ni(TMTAA)
126
b)
IR characteristic

1
H-NMR, ppm), CDCl3
bands  (cm-1)
3053.88 – C-H aromatic 6.78-6.55 4.85 2.15 1.5 7.3
2953.39 – C-H alkene localized vinylic methyl water solvent
2916.51 – C-H aliphatic protons on protons group protons protons
1529.81 – C=C aromatic the aromatic protons (impurities
1456.83 – C=N imine ring of CDCl3)
H B
H
H2 + -
c) N
O O HN O
O HN HO
2+ 2+
O
Ni Ni Ni2+
N N N
H2 H2 H2
HN +
OH2 O N N N
O x4
Ni2+ Ni2+ Ni 2+
N N
N N
B H H
N N N N N N
Ni 2+ Ni + Ni
N N N N N N
B H H Ni(TMTAA) Ni(TMTAA)
d) A by-product of this reaction is a benzodiazepine derivative. This is obtained by

formation of a second intramolecular imine bond:
N O N N
H B
- B
NH2 -
N O N OH
H2 H
B
N N
H
+ + - BH
N OH2 N H
H
H
127
H
N N
H+
+
N N
H H
benzodiazepine
Due to the template-type characteristic of this reaction, the benzodiazepine derivative

will form in small amounts.
e) D2h
NH2 N N COOH
CHO 2NaHSO3 KMnO4
f) +
CHO Na2S2O3 HO-, 80oC
NH2 N N COOH
80oC
O
N COOH N COOMe N C NH
, xilen CH3OH, H+ NH3 2
- CO2
N N N
+
O O O O H
-
g) + H OSO3H + HSO4
H OH
+ +
NH2 H O NH C CH3 -
C CH3 OSO3H
+
O - H2SO4
NH2 O NH2
CH3 CH3
+
NH C OH NH C OH2
C CH3 H OSO3H C CH3
O - -OSO3H O
NH2 NH2
CH3 CH3
+
N C - N C
C CH3 OSO3H H OSO3H
H C CH3
O - H2SO4 O - -OSO3H
NH2 NH2
128
CH3
N C N CH3
C CH3 OSO3H
H CH3
NH2 O+ N
+ - H2SO4
H OH
H
N CH3 N CH3
H OSO3H
CH3 CH3
- -OSO3H +
N N OH2
OH
H H
N CH3 N CH3
OSO3H
+ - H2SO4
N CH3 N CH3
H
Question 93
How is the transformation
NH2 S C 6H 5
possible without using halogenated derivatives or alcohol intermediates.
Answer:
NH2, NHR, NR2 are extremely weak leaving groups, and thus, for this reagent the
direct substitution of the amino group is not possible. By conversion to ditosylate, the
leaving group the ability of the amino group increases:
TsCl/NEt3 1. NaH
NH2 DMF NHTs 2. TsCl
Ph S-Na+
Ph
NTs2 S
129
Question 94
How would you describe the Katritzky method aiming to improve the leaving group
abilities of amino group?
Answer:
The Katritzky method consists of treating the amine with a pyrilium salt (the
commonly used is the 2,4,6-triphenylpyrylium salt). Once this salt is heated, the anion
(counterion) acts as a nucleophile:
C6H5 C6H5

R NH2 +
+ +
C6 H 5 O C 6H5 C6 H 5 N C6H5
Y- -
RY
C 6H 5
+ R Y
H 5C 6 N C 6H 5
In certain cases, the tetrafluoroborate of the pyrilium salt is used (the anion is non-
nucleophilic), and the nucleophile of interest is added in a further step:
C6H5
R1COONa
BF4- R1 COOR
+ 200oC
C6 H 5 N C6H5
R
C 6H 5 C6H 5
150oC 120oC
I- R I Br- R Br
+ +
C 6H 5 N C 6H 5 C 6H 5 N C 6H 5
R R
C6H5
ONa
OR
+
N dioxane
R solution
100oC R = n-C12H25
n-C6H13
130
C6H5
S
S
EtO C S-H+
+ EtOH, 80oC EtO C S R
C6H5 N C6H5
R
C6H5
SCN-
R SCN
+ , 1,1-5 h
C6H5 N C6H5
R
C6H 5
NaN3
BF4- R N3
+ DMF, 120oC
C 6H 5 N C6H 5
R
Question 95
Though acetals, ketals, and orthoesters hydrolyze in acidic media, thioacetals

SR'
R SR1
( R CH ) and thioketals ( C ) do not react to this type of treatment. What are
SR' R SR1
the appropriate reagents for the hydrolysis of these compounds?
Answer:
The following compounds may be used for the hydrolysis of thioacetals and thioketals:
HgCl2, HgO-BF3, H2O2-HCl, tert-BuBr-Me2SO, (PhSeO)2O, PbO2-BF3-etherate, Me2SO-
HCl-dioxane.
Question 96
What is uric acid, and how can it be synthesized starting from:

a) urea and ethyl-cyanoacetate;
b) barbituric acid.
Indicate possible routes for the following transformations:
131
Adenine Purine
uric acid
Xanthine Hypoxanthine
Guanine
What is the practical importance of uric acid (serum or urinary) quantitative analysis
in the evaluation of the health state of a patient?
Answer:
The uric acid (2,6,8-trihydroxipurine) is a solid, colorless and odorless compound,

with molecular formula of C5H4N4O3, and may be represented through the formulas:
OH
O
H
N H N
N N
OH
O
HO N N N
O N
H H
H
lactim form lactam form
The uric acid is not soluble in water, alcohol, and ether, but it dissolves in sulfuric
acid.
The uric acid can be obtained from guano, a natural organic fertilizer found in
significant quantities in South America, originating from the accumulation of birds and bats
excrements (feces and urine). The fecal materials of birds and snakes are rich in uric acid.
It is also known that insects produce uric acid during protein breakdown (catabolism),
and the process have effects in butterflies’ iridescence.
Many categories of living organisms use uric acid as a raw material for the synthesis
of some pigments called pterins, having spectacular colors and nuances. These types of
molecules were first isolated from butterflies’ wings, where their name originates (pteron
is a Greek word meaning wing):
OH
OH
N OH
N OH N
N
H2N N N OH
H2N N N
xanthopterine leucopterine
(yellow) (white with blue fluorescence)
132
Synthesis of uric acid starting from urea and ethyl-cyanoacetate will go by following
steps:
O
EtOOC CH 2
H 2N CH 2 C 2H 5O -Na+
HN C N
C NH 2 CN
O NH 2
O
O O
HNO2
HN NH H N NH2
N N
O H O H
O NO O NH2 Cl C OR
4[H] O
H N NH2 H N NH2
N N
O H O H
O H
O NH C O N O
OR
- ROH N
H N NH2 H N
H
N N
O H O H
uric acid
The conversion of the uric acid to:

 adenine through the following reactions scheme:
O Cl
H
H N N
N POCl3 N POCl3
O O
O N N Cl N N
H H
H
2,6-dichloro-8-hydroxypurine
133
Cl NH2 NH2
N N N
N NH3 N HI N
Cl Cl
Cl N N Cl N N N N
H H H
2,6,8-trichloropurine adenine
 purine according to the following scheme:
O Cl
H
H N N N
N N HI N
O Cl
O N N Cl N N N N
H H H
H
2,6,8-trichloropurine purine
 hypoxanthine involves the following reaction scheme:
O H Cl
H N N
N N KOH
O Cl
O N N Cl N N
H H H
2,6,8-trichloropurine
OH OH
N N
N HI N
Cl
Cl N N N N
H H
dichloro-hypoxanthine hypoxanthine
 guanine involves the following reactions:

O H OH
H N N
N N NH 3
O Cl
O N N Cl N N
H H
H
dichloro-hypoxanthine
134
OH OH
N N
N HI N
Cl
H2N N N N
H2N N
H H
chloroguanine guanine
 xanthine through the following scheme:
O H Cl
H N N
N N EtONa
O Cl
O N N Cl N N
H H H
2,6,8-trichloropurine
OEt OH
N N
N HI N
Cl
EtO N N HO N N
H H
xanthine
Uric acid is a product of nucleic acids degradation, and thus the outcome of purine
metabolism. A high level of uric acid in the blood, over the generally accepted reference
range, it is called hyperuricemia and may have multiple causes, such as: diuretic
medication, a diet that is rich in purines (i.e., sardines, anchovies, animal internal organs,
asparagus, beans, lentils, beer, mushrooms, beef meat, shells, peas), excessive consumption
of alcoholic beverages, immunosuppressive medication, kidney failure, obesity, etc.
Hyperuricemia can trigger gout attacks. The gout is a form of arthritis caused by the
urate deposits in human body joints.
Structure of xanthyn-oxidase
(Protein Data Bank ID: 3NVW)
135
Regular quantitative analysis of uric acid is very important in gout treatment

monitoring, evaluation of renal failure, monitoring of cytostatic treatment, etc.
Administration of xanthine oxidase (XO) inhibitors is used as an anti-gout therapeutic
option. This enzyme containing iron and molybdenum, and having a molecular mass of 270
kDa, generates reactive oxygen species (ROS) and catalyzes the oxidation of hypoxanthine
to xanthine, and further to uric acid.
Consequently, a medication that blocks the activity of this enzyme (such as i.e.
Allopurinol) leads to a decrease of uric acid level in blood.
O
N
NH
N NH
Chemical structure of Allopurinol, a drug administrated in
hyperuricemia treatment by inhibition of xanthine-oxidase
Decreased levels of serum uric acid (hypouricemia) may be associated with Wilson's
disease, in a genetic disorder called xanthinuria (xanthine-oxidase deficiency), some types
of neoplasm, low zinc diets, some types of anemia, etc.
Question 97
What are lignins, and what applications do these compounds have?
Answer:
Lignin (derived from lignum, a Latin word meaning wood) is a biopolymer, with a
molecular mass in the range of 700 -100 000 Da, and that accompanies cellulose in various
plants tissues and organs. It was firstly mentioned in 1813 by the Swedish botanist A.P. de
Candolle.
Some particularities related to the spread and structure of lignin are worth
emphasizing:
a) it is the second most common biopolymer found in nature, after cellulose;
b) among all biopolymers existing in cells walls of plants, lignin is the only one that
doesn’t consist of carbohydrate monomer units;
c) among biopolymers generally existing in biomass, lignin has the characteristic of
containing aromatic groups; thus, lignin is composed of three types of monomers, all
derived from phenylpropane (monolignols):
CH3O
OH OH
HO HO
p-coumaryl alcohol coniferyl alcohol
136
CH3O
OH
HO
OCH3
sinapyl alcohol
d) different types of lignins have different structures, and may have different types and
numbers of structural units, depending on the plant of origin;
e) lignin is a dendritic polymer with a complex structure.
OCH3 H3CO
OH
HO
OH OCH3 OCH3
O
O OCH3
OH HO O
HO
OH
O HO OR OH
OCH3 H3CO
H3CO O
O
O HO OCH3
RO OH
O
OH
O OH H3CO OH OH
H3CO O
O OCH3
HO O HO
HO
HO HO
O OH OCH3
HO
O
O
H3CO HO
H3CO OH OO
OH
H3CO
H3CO
O OCH3
Structure of a fragment of lignin molecule
Lignosulfonates (generated in the process of cellulose production from wood using

bisulfite) are used as dispersants, complexation agents or emulsifying agents. Lignins that
are synthesized by the Kraft method are used as dispersants for dyes and pesticides. Also,
lignin is used as raw material in synthesis of some valuable compounds such as vanillin,
DMSO, xylitol, humic acid, carbon black.
Question 98
What is the Baker-Nathan effect?
137
Answer:
The Baker-Nathan effect refers to the kinetics of certain chemical reactions, in which
the reactivity of certain series of substrates cannot be rationally explained in terms of the
inductive electronic effects of the substituents.
The effect was described in the literature in 1935 by J. W. Baker and W. S. Nathan.
Studying the reaction of pyridine with various p-substituted benzyl bromides, the two
researchers found an inverted sequence of reaction rates relative to that predicted by the
inductive effect of the substituents at the para position:
+
R CH2 Br + N R CH2 N
Br-
R: CH3 > CH3 CH2 > CH3 CH CH3 > CH3 C CH3
CH3
Stricto sensu, if electronic effects are considered, substituted p-tert-butyl bromide
should be the most reactive.
Baker and Nathan explained these experimental findings considering the
hyperconjugation:
H H+ H+ H+ H
H H
H C H C H C H C H
(-) (-)
(-)
Hyperconjugation may thus explain that the bromide derivative with the methyl group
is the most reactive (three C-H bonds available for hyperconjugation) and the one with the
least reactive tert-butyl group (no C-H bond available for hyperconjugation).
Recent research has shown that the Baker-Nathan effect, although often encountered
in solution, does not operate in the gas phase, as the order of reactivity is completely
reversed. The conclusion of these studies was that the origin of this effect is not
hyperconjugation, but the steric effects due to differentiated solvation.
Question 99
Propose two possible mechanisms for the following transposition:

R1 R4 R4 R1
H+
R2 C C O R2 C C O
3 3
R R
How can one discriminate between these mechanisms?
138
Answer:
4
R1 R4 R1 R4 R1 R
+
a) R2 C C O + H+ R2 C C O H R2 C C OH
+
3 3 3
R R R
R4 R4 R4
+ +
R2 C C OH R2 C C OH R2 C C O
3 1 3 1 - H+
R R R R R3 R1
As observed, in the above-mentioned mechanism, the two alkyl groups migrate in

opposite directions.
R1 R4 R1 R4 R2 R4
+ +
b) R2 C C O + H+ R2 C C O H R1 C C
R3 R3 R3 OH
R3 R2 R4 R4
+
+ -H
R1 C C R4 R1 C C R2 R1 C C R2
+
O OH R3 O R3
H
This mechanism takes into consideration the presence of some epoxy type
intermediates. A notable aspect is that the two alkyl groups migrate in the same direction.
One can discriminate between the two mechanisms by using a ketone with 14C marked
at the carbonyl group. If the first mechanism is followed, the marked carbon atoms will be
found in the carbonyl group, while if the second mechanism is followed, via the epoxy
intermediates, the 14C atoms will be found in the position with respect to the carbonyl
group.
Question 100
What do you understand by the quasi-Favorskii rearrangement?
Answer:
The quasi-Favorskii rearrangement refers to -haloketones that do not contain

hydrogen atoms in the ' position, with respect to the other part of the carbonyl group:
139
R2
R1 C C R3
O Cl
It is obvious that in their case the intermediate of the type cyclo-propanone cannot
form. The accepted mechanism, also named semi-benzylic mechanism, is shown below:
R2 R1 R2 R1
- 4
OR
R1 C C R3 R4O C C R3 R4O C C R3
- Cl-
O Cl O Cl O R2
-
Question 101
What is the semipinacolic transposition?
Answer:
Semipinacolic transposition is a transposition reaction related to the classic pinacolic

transposition, wherein the substrate is a heterosubstituted alcohol such as this:
R2 R3
R1 C C R4
OH X
where X may be one of the following: Cl, Br, I, NH2, Ts etc.
The following are two examples of semipinacolic transposition:

C6H5
H O C CH2 + Ag+ AgI + C6H5 CH2 C CH3
- H+
CH3 I O
CH3 C6H5 CH3 C6H5

HNO2/H+ -N2
CH3 C CH CH3 C CH CH3 C CH C6H5
- 2H2O + - H+
OH NH2 H O N N O CH3
Question 102
How do you explain that apples and other fruits and vegetables, once peeled or sliced,
begin to brown while in contact with the air? How can this phenomenon be avoided?
140
Answer:
By peeling or cutting fruit into slices, it is released a specific enzyme, called
polyphenol oxidase (PPO):
Crystalline structure of polyphenol oxidase obtained from grapes

(Grenache grape variety) - Protein Data bank ID: 2P3X
In the presence of oxygen in the air, this enzyme catalyzes the formation of brown
pigments, called melanins. The process, otherwise very complex, is called enzymatic
browning. Reactions leading to formation of brown melanin-like polymers are presented in
the following schematic path:
OH OH
O2
enzymatic process
R R OH
OH O
O2
- H 2O
R OH enzymatic process R O
aminoacids, proteins,
O
quinones, phenols
brown melaninic polymers
R O non-enzymatic oxidative
condensation reactions
The quinones, another reaction product that result in the fruits oxidation process, are
also colorful, but they have a weak contribution to the browning process. This is mostly
caused by the melanin polymers formed in the non-enzymatic condensation process.
The enzymatic browning occurs optimally at a pH between 5 and 7, and when heated
at temperatures below the one where the PPO enzyme inactivation starts. Presence of
copper or iron accelerates the process, and this is easily observed when cutting the fruit
with a slightly oxidized knife or when in contact with a copper vessel.
Enzymatic browning can be avoided by using:
a) ascorbic acid - vitamin C acts as an antioxidant and reacts with oxygen in the air,
thus suppressing the oxidation of phenolic compounds;
b) sulphites - these compounds prevent the formation of melanin compounds;
c) citric acid - by lowering the pH (pH < 3) the activity of the enzyme is inhibited;
141
d) water - keeping the peeled fruits in a water bath limits the amount of oxygen coming
into contact with the exposed tissue.
Question 103
One of the classic syntheses of Schiff bases is the condensation of carbonyl

compounds with primary amines. Why is the pH important in controlling the kinetics of
this reaction?
Answer:
To understand the role of pH in the synthesis of Schiff bases, one must formulate the
following plausible reaction mechanism:
H
+
H N H
O O
R3
C + H A C
R1 R2 - A- R1 R2
R2 R2 R2
+
R1 C OH A- R1 C OH H A R1 C OH2
+
H N H - HA H N - A- H N
R3 R3 R3
carbinolamine
R1 R2
C A- R1
H N + C N R3
-H2O - HA R2
R3
Schiff base
A careful analysis of the proposed reaction mechanism shows that:
a) if the pH is too high (low protons concentration), the carbonyl group will not be
protonated, nor will carbinolamine protonate;
b) if the pH is low (high protons concentration), the amine will be protonated, and
thus, it will not act as a nucleophile agent.
Experiments demonstrate that the reaction rate is maximal at a pH ~ 4.5.
Question 104
What is polyvinylpyrrolidone? How can this compound be synthesized, and what

applications does this compound have?
142
Answer:
Polyvinylpyrrolidone (PVP) is a polymer soluble in water and other polar solvents,

obtained by polymerization of vinylpyrrolidone, in basic medium, and in presence of H2O2:
H2O2, NaOH
n
O O
N N
CH CH2 CH CH2
n
M = 40000 - 60000 Da
The monomer can be synthesized according to the following reaction scheme:
CH2O, Cu2C2 H2/Ni

HC CH o HO CH2 C C CH2 OH
100 C, 5 atm. o
100 C, 200 atm.
210oC, Cu-Cr
HO CH2 CH2 CH2 CH2 OH
O
O
NH 3 HC CH, N 2
o
200 C, 200 atm. O 150-180 oC, 15-20 atm. O
N N
H
CH CH 2
Alternatively, N-2-hydroxyethylpyrrolidone may be used:
H 2N CH 2 CH2 OH SOCl2
O o
180-190 C O
O N
CH 2 CH 2 OH
KOH
O O
N N
CH2 CH2 Cl CH CH2
Polyvinylpyrrolidone has multiple uses:

 in medicine, as synthetic plasma substitute. Also, the polyvinyl pyrrolidone-iodine
complex (Povidone-iodine, Betadine) is an effective antiseptic with prolonged
antimicrobial action (due to gradual release of iodine);
143
 in production of membranes for dialysis and water purification processes;

 in cosmetics, as an ingredient in some shampoo recipes, toothpaste, hair gels, etc.;
 in agriculture, as a binder and complexing agent;
 in pharmaceutical industry, as drug conditioning agent (binder);
 in food industry, acting as an emulsifier, stabilizer, thickening and icing agent
(E1201);
 in other industrial applications, as a special additive in the manufacturing of
batteries, ceramics, inks, etc.
Question 105
What are Maillard’s reactions?
Answer:
Maillard reactions, named after the French biochemist Louis Camille Maillard (1878-
1936), are reactions between amino acids and reducing sugars. Maillard reactions usually
occur at elevated temperatures and are largely responsible for the aroma and color of bread,
roasted coffee, cakes, cooked rice, beer, fries. Along with caramelization, it is another form
of non-enzymatic browning.
These reactions occur daily in every kitchen, bakery, or patisseries in the world, being
by far the most common chemical transformations. To better understand this phenomenon,
it is sufficient to mention that the yellow-brown appearance of the bread from the bakery
or the color and flavor of fried potatoes are effects of the Maillard reactions.
J. E. Hodge (1914-1996), an Afro-American chemist born in Kansas City, is the one
who elucidated the mechanism of the Maillard reactions, and it is now quoted in the
literature as the Hodge sequence. His article, entitled Chemistry of browning reactions in
model systems published in 1953, in the Journal of Agricultural and Food Chemistry has
been cited in the literature more than 1400 times and has been named Citation classic by
Science Citation Index, in 1979.
According to Hodge's theory, Maillard reactions involve three stages:
a) reaction of a reducing monosaccharide with an amino acid:
CHO CH N R
H C OH H C OH
HO C H H2N R HO C H H2N-R amino acid symbolization
H C OH - H2O H C OH
H C OH H C OH
CH2OH CH2OH
144
b) Amadori transposition, with ketosamine formation:
H H H H H
+
C N R C N R + C N R CH2 NH R
H
H C OH H C OH C O H C O
- H+ HO C H
+
HO C H 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 H C OH H C OH
CH2OH CH2OH CH2OH

CH2OH
ketosamine
c) The formed ketosamines undergo various reactions of dehydration, cleavage,

transposition, addition, polymerization with the formation of thousands of compounds
responsible for the aroma, color, and texture of the respective food.
Among them, one can mention:
CH 3 C C CH 3
HO CHO O O
O
hydroxymethylfurfural diacetyl
CH 3
N
N O
O
6-acetyl-2,3,4,5-tetrahydropyrimidine 2-acetyl pyrroline
The nature and proportions of the compounds resulting in the Maillard reactions are
influenced by several parameters, such as: pH, processing temperature, the type of amino
acid and monosaccharide, presence of oxygen, water, etc.
Some of the compounds resulting from Maillard reactions are toxic or potentially
carcinogenic. An example of this is acrylamide, a compound detected in fried potatoes at a
temperature higher than 120 °C.
Maillard reactions also occur in the human body. They represent a step in the
formation of advanced glycation end-products (AGEs), and these are (at least partially)
responsible for the complications generated by diabetes, pulmonary fibrosis, and
neurodegenerative diseases.
Question 106
What do one understand by caramelization?
145
Answer:
Caramelization is a physico-chemical process of thermal decomposition and browning
of sugar, widely used in the food industry to obtain characteristic aromas and tastes.
The product obtained, caramel, is used in a wide range of products such as cakes,
candies, soft drinks, chips, etc. As well as Maillard reactions, caramelization is a type of
non-enzymatic browning.
Considering the chemical perspective, caramelization is a complex process, generating
hundreds of new compounds that may form by condensation, anomerization, dehydration,
fragmentation, polymerization, etc.
Caramelization depends on pH, on processing temperature (each saccharide has its
own caramelization temperature), as well as on the presence of other substances.
Question 107
Certain fruits in their natural state (papaya, kiwi, pineapple), as well as their extracts,
are used in cooking to tenderize the meat, as an alternative to the classical processes
(namely cutting the meat into thin slices or using a meat hammer). How would you explain
this phenomenon?
Answer:
The above-mentioned fruits (and also some others) contain enzymes of the cysteine
protease type (papain in papaya, bromelain in pineapple), having the ability to break down
proteins into smaller peptide fractions or amino acids, thus attacking the connective tissue
and contributing to meat tenderization.
Meat slices should get in contact with the fruit juice and maintained for 20-30 minutes,
at the cold. However, prolonged contact with fruit juice can make the meat too soft and
spongy. Also, some mixtures of enzymes (fruit extracts and conditioning agents) that have
the role of meat tenderizing are marketed; in fact, proteases are widely used in the food
industry, accounting for more than half of the total enzyme market. It should be noted that
this method of tenderizing the meat requires certain precautions (allergies to pineapple or
the fact that bromelain may interfere with the use of antibiotics or anti-platelet medication).
The crystalline structure of the papain complex E64-c

(Protein Data Bank ID: 1PPP)
146
Question 108
During the preparation of the grilled meat, a series of chemical reactions occur, some
leading to the formation of compounds toxic for the human body. What are these
compounds, how do they form, and how could their generation be limited?
Answer:
Numerous thorough investigations and chemical analyzes have confirmed that during
the meat grilling process, polycyclic aromatic hydrocarbons (PAHs) and aromatic
heterocyclic amines (HCAs) are formed.
Polycyclic aromatic hydrocarbons result mainly from fats, proteins, carbohydrates or
some other compounds with steroidal structure (such as cholesterol), once the heating
process is conducted at temperatures higher than 500 °C. Structures of several PAHs
detected in grilled meat are included herein:
Fluoranthene Benzo[b]fluoranthene Benzo[a]pyrene

Flu B[b]Flu B[a]P
The type of substances acting as raw materials for the synthesis of PAHs are correlated
with the meat grilling temperature. Thus, at temperatures of about 500 oC, PAHs is
generally produced from carbohydrates, while at higher temperatures (700 oC), fatty acids
are the ones responsible for PAHs synthesis.
Many PAHs have been proved to have mutagenic, carcinogenic, and teratogenic
properties, so ingesting these substances may be dangerous.
Heterocyclic amines are another class of organic compounds that are generated during
the preparation of grilled meat. Their synthesis starts from creatinine, amino acids,
carbohydrates, when heated to temperatures of 125 oC - 300 oC.
Some structural formulas of heterocyclic amines identified as present in grilled meat
are included below:
NH2
CH 3 N
N N CH
3
NH 2
N N
N
(PhIP) (IQ)
2-amino-1-methyl-6-phenylimidazo [4,5-b] 2-amino-3-methylimidazo [4,5-f]
pyridine quinoline
147
NH2 NH2
N N
CH3 N N CH N CH
3 3
N N CH3
(MeIQx) MeIQ
2-amino-3,8-dimethyl-imidazo [4,5-f] 2-amino-3,4-dimethyl-imidazo [4,5-f]
quinoxaline quinoline
Recent studies confirm a causal link between the consumption of these heterocyclic
amines (considered to be carcinogenic) and the incidence of colon, rectum, prostate,
pancreas, and other types of cancer.
Several tricks may be applied to limit the formation of these toxic compounds when
grilling:
 avoiding the direct contact between meat and the open flame;
 maintaining a lower processing temperature (frying the meat in longer times);
 use of a stronger type of wood/hardwood to make the fire; thus, lower
concentrations of PAHs will be generated;
 use of an aluminum foil with small perforations; this will prevent fat leakage
directly into the flame, and thus avoiding formation of toxic compounds in higher amounts;
 use of low-fat meat;
 use of a microwave oven before grilling, thus limiting the meat grilling time;
 marinating the meat in advance, with various spices; recent studies show that
marinade in dark beer reduces the formation of PAHs by up to 68 %.
Question 109
The meat of young animals is more tender when compared to that of older animals.
How can you explain this from a chemical perspective?
Answer:
The explanation resides in the covalent bonding of the collagen chains (cross-linking):
the older the animal, the higher the proportion of crosslinked collagen. The process is
demonstrated below:
oxidative
deamination
+ C H
H 3N
O
148
CHO
crotonic C
+ condensation C
C H C H
O O
The higher the number of bonds between the collagen chains, the tougher the meat will be.
Question 110
How do you explain the tears we experience when cutting onions? Is there a way to
avoid this day to day nuisance?
Answer:
Believe it or not, the burning sensation is actually due to sulfuric acid forming in your
eyes. While cutting the onion, a volatile compound (propantial-S-oxide) is released, which
then reacts with water in your eyes and forms sulfuric acid.
+ -
CH3 CH2 CH S O
Structural formula of propantial-S-oxide
It is worth mentioning that onions do not normally contain propantial-S-oxide. This

compound is forms when the onions are cut, which releases enzymes that contribute to a
cascade of reactions, ultimately producing propantial-S-oxide.
COOH
+ alliinase
CH 3 CH CH S CH 2 CH CH 3 CH CH S OH
- H 2O
O NH 2
S-1-propenyl-L-cisteine-sulfoxide 1-propenylsulfenic acid
lachrymatory-factor + -
CH3 CH2 CH S O
synthase
propantial-S-oxide
There are several ways to avoid tears when cutting onions, some of which include:
- cooling the onion before cutting; by cooling, less volatile S-oxide will be released; also,
the enzymes required for the chemical reactions will be rendered inactive;
- cutting the onion under a jet of water (the lachrymatory compound that forms will react
with the water before reaching your eyes);
- wearing protective glasses, already produced and sold by specialized companies.
149
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liquid membrane with calix[4]arenes and O-alkylated calix[4]arenes as carriers“, 12th
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ORGANIC CHEMISTRY QUESTIONS AND ANSWERS - Volume I

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QUESTIONS AND ANSWERS

E1cB conjugate base unimolecular elimination

FLPs frustrated Lewis pairs

HSA human serum albumin

HCAs heterocyclic aromatic amines

HOPG high orientation pyrolytic graphite

HSAB Hard Soft Acid Bases

OLED organic light-emitting diode

PAHs polycyclic aromatic hydrocarbons

PAGE polyacrylamide gel for electrophoresis

How can one obtain alkylpyridines?

a) heating pyridine with alkyl halides:

b) alkylation of pyridine with carboxylic acids:

1. AgNO3, H2SO4, H2O

A radical mechanism applies, as follows:

2Ag + + S 2O 8 2- 2Ag 2+ + 2SO 42-

R COOH + Ag2+ R COO + Ag+ + H+

c) acylation of pyridine followed by a reduction step:

d) Ziegler alkylation of pyridine:

e) reaction with ammonia of some pyrylium salts:

How many stereoisomers do each of the following compounds have?

A: six stereoisomers (three racemates: RRR-SSS, RSR-SRS, RRS-SSR);

B: two stereoisomers (one racemate);

C: eight stereoisomers (four racemates: endo-endo, endo-exo, exo-exo, exo-endo);

D: four stereoisomers (meso forms: endo-endo, endo-exo, exo-exo, exo-endo);

E: two stereoisomers (one racemate);

F: eight stereoisomers (four racemates: cis-cis, cis-trans, trans-trans, trans-cis).

How would you perform the transformation: Ar CHO ArH ?

How would you perform the transformation: R CH2 NO2 R C N ?

Structure of human serum albumin complexed with palmitic acid

Alginic acid is a natural polysaccharide with molecular formula (C6H8O6)n. It is

COOH COOH COOH COOH COOH

Structural formula of a segment -M-M-M-M-M-

Structural formula of a segment -G-G-G-G-G-

Structural formula of a mixed segment -M-G-M-G-M-

What is hyaluronic acid? What are hyaluronidases? What medical applications do

Hyaluronic acid is a natural polymer with a linear structure, and composed of D-

Structure of human hyaluronidaze 1

Hyaluronidazes are a family of enzymes that catalyze the hydrolysis of hyaluronic

What are the persistent carbenes?

The experimental procedure that provides a satisfactory yield (~ 80 %) is the reaction

How would you perform the transformation: R CN R H ?

How many stereoisomers does the following compound have?

How would you carry out the transformation: R CHO R H?

CH3 CH2 CH2 CH CH CH2 CH2 CH CH CH2 CH2 CH3

CH3 CH2 + CH3 CH2 CH2 CH CH CH2

CH3 CH2 CH2 CH CH CH2 CH2 CH CH CH2 CH2 CH3

(C6H 5)3B THF - O

frustrated Lewis pairs adduct