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Organic Chemistry
Medical Chemistry
and Biochemistry
Winter term
© Institute of Medical Biochemistry and Laboratory Diagnostics of the General University Hospital and of The First
Faculty of Medicine of Charles University in Prague - 2005-2015
Synthesis of urea
(Wöhler 1828) (Thermic rearrangement)
Teplo
Heat
N
O
O NH 4
C
NH 2
C
NH 2
Friedrich Wöhler (1800-1882): Organic compound formed from inorganic compounds
Jan Horbaczewski (1854-1942): He graduated on the Faculty of Medicine in Wienna by
prof. Ludwig; Founder of the Department of Medical Chemistry
Synthesis of uric acid (Horbaczewski 1882 – age of 28)
O
O
NH2
O
+
C
NH2
H2C
NH2
C
heat
Teplo
H
N
HN
OH
O
O
NH
NH
Urea + Glycine + (heat) = Uric acid
(very low efficiency)
(discovered by Schulz 1776)
Organic chemistry 2014/2015
3
Synthesis of uric acid (Horbaczewski 1882)
OH
O
O
C
H
N
HN
HC
O
O
NH
NH
CH2
Acrylic acid
Uric acid
During further experiments he proved that uric acid is formed by
decomposition of nucleus-containing cells only, this process was not
observed in cells without nucleus (e.g., erythrocytes)
He successfully separated uric acid from xanthine and other purine
bases and correctly supposed that uric acid is formed from these
substances.
Organic chemistry 2014/2015
4
Bonds in organic compounds
The bond polarity depends on the difference of electronegativities. Presence of
polar and non-polar bonds significantly affects the resulting character of the
organic compound:
Bind distance and binding energy - examples
Bond
Energy [kJ.mol-1] Distance [pm]
C-C
347
154
C=C
611
133
CC
837
120
C-H
414
106
C-N
293
147
CN
891
116
C-O
352
143
C=O
732
122
N-H
389
101
O-H
464
100
Organic chemistry 2014/2015
Values of energy are
approximate
(„average“). In
molecules are influenced
by surrounding
structures, i.e., by other
parts of the molecule.
There are s. c. hybrid
(partial) bonds (e.g.,
benzene – 1.5).
5
Stereochemistry (Three-dimensional structure of organic
compounds) – Formulas of organic compounds
Constitution: Inner structure of the molecule of organic compounds
Molecular formulas are in organic chemistry practically
inapplicable, because they do not yield the most important
information about the inner structure of the molecule.
e.g., C2H6O can be :
1) Ethanol (CH3-CH2-OH)
2) Dimethylether (CH3-O-CH3)
Therefore, the structural formulas are used, because they show all bonds among atoms.
Disadvantage of such formulas consists in their complicity in case of more complicated
compounds. Most frequently the rational formulas are used, in which are marked out
only such bonds, which are necessary for unambiguous determination of the constitution
– three dimensional configuration. For absolutely exact definition of 3D organization of
the organic molecule, it is necessary to use perspective formulas (the bonds aiming
upwards and downwards, forwards, backwards are differentiated). The use of models,
which can help by solving of e.g. DNA structure (Watson and Crick - Nobel prize for
chemistry), seems to be optimal. The computers can simplify significantly the work with
Organic chemistry 2014/2015
6
such models.
Isomers
Isomers: Isomers are molecules, which have the same molecular
formula, but they have a different arrangement of the atoms in space.
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Isomers I.
Basic types of isomerism:
Constitutional (Structural) isomerism: Isomers have different constitution,
i.e., they have a different arrangement of the atoms in space or in molecule.
Chain: Butane, isobutene (arrangement of chain)
Position: chains have variable amounts of branching
(groups: 1-propanol, 2-propanol)
(bonds: 1-buten, 2-buten)
Tautomerism - Isomers differs in the position of the hydrogen and double bond,
e.g., acetamide (Amide of acetic acid)
O
H
O
C
H3C
C
H3C
H
N
NH2
The dynamic equilibrium is established between both tautomers.
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8
Isomers II.
Keto-enol-tautomerism is best known
CH3
C
CH2
COOH
CH3
CH
COOH
OH
O
Keto (oxo) form
C
Acetoacetic acid
enol form
Conformation of the molecule is given by the free rotation
of molecules along single bonds. There are (theoretically)
possible (by more complicated molecules) large amounts of
conformations; they are limited by energy of the positions
and by weak bonds (hydrogen bridges, ionic and non-polar
interactions).
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Isomers III.
Stereoisomerism (spatial): the bond structure is the same, but the
geometrical positioning of atoms and functional groups in space
differs.
Various configurations are given by double bond (cis-trans isomers)
or by presence of a chiral center (an asymmetric carbon C*).
cis-trans (geometric) isomerism is a result of the impossibility of
the rotation along the double bond (it is caused by binding
-orbitals).
H
CH3
CH3
CH3
C
H
C
C
H
cis-2-butene
C
H
CH3
trans-2-butene
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10
Isomers VI.
Asymmetric carbon has each bond occupied by completely different
single-bonded atom or group of atoms, therefore the structure has not
any symmetry plane. There exit two possible space arrangements:
subject and its mirror image. By their differentiation we go out from
structure of glyceraldehyde:
O
O
H
C
C
H
H
C
OH
CH2OH
D-
HO
C
H
CH2OH
D- and L- isomers are characterized
by equal chemical reactivity, but
biochemically can differ mutually
substantially (reactions with enzymes
or antibodies)
L-
Compounds containing asymmetric carbon show optical rotation and they form
optical antipodes - enantiomeres.
Rotation is labeled: (+) – to the right and (-) – to the left.
The aim of light rotation is not connected with the D- and L- labeling!!!!!
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11
Classification of organic compounds
Organic compounds
Aliphatic
Saturated
(single
bonds)
Cyclic
Unsaturated
(multiple
bonds)
Isocyclic
(carbocyclic,
C only)
Alicyclic
Saturated
Aromatic
(conjugated double
Unsaturated bonds in ring)
Saturated
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Heterocyclic (in
ring are other
atoms then C)
Unsaturated
Aromatic
12
Most important arenes I
Benzene
Naphtalene
Anthracene
Tetracene
(partly hydrogenated „tetracycline“)
Phenanthrene
Cyclopentano perhydrophenanthrene base of steroids
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Most important arenes II
Pyrene
Benzopyrene (carcinogenic)
Benzo[a]pyrene
Biphenyl (Polychlorated biphenyls
- toxic for CNS of children)
H
Diphenylmethane
C
H
Base of DDT –
p,p’-dichloro diphenyl trichloroethane
1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane
Organic chemistry 2014/2015
14
Halogen derivatives of hydrocarbons
One or more hydrogens are substituted by a halogen (X = F, Cl, Br, I)
Bond is weak polar – insoluble in water, good soluble in non-polar solvents. Most of
these compounds are volatile liquids, which are very good non-polar („organic“ or
„fat“) solvents. Chemically are very reactive, especially with nucleophilic substances.
Application:








Solvents - Tetrachloromethane, CCl4 (toxic, carcinogenic). It forms phosgene
(COCl2) with water
Freons (Fluorochloroalkanes) - CCl3F, CCl2F2 and other in refrigerators –
they damage ozonosphere
Plastics - PVC, synthetic rubber, Teflon
Chlorophorm CCl3H - toxic, Bromophorm CBr3H – against cough, Iodoform
CI3H - disinfection, antiseptic agent, proof of acetone (iodoform reaction)
Anesthetic - local - earlier ethyl chloride CH3CH2Cl („kelene“ - freezing)
Anesthetic – general - Trichloroethylene CHCl=CCl2 (narcotic)
Halothane CF3-CHBrCl
Biologically active substances – thyroid gland hormones (triiodo-Lthyronine, Tetraiodo-L-thyronine=thyroxine)
Older insecticide - DDT, HCH (hexachlorocyclohexane - Lindane) – its use is
prohibited at present
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15
Hydroxy derivatives (alcohols, phenols)
Hydroxyl group -OH gives to hydrocarbons, especially to aromatic,
weak acidic character (Attention – they are not hydroxides!!!)
O
R
H
O
R
H
O
H
R
Bond C-OH is covalent, nevertheless strong polar, therefore the
hydrogen bridges can be formed. Consequently, the simpler alcohols
are good miscible with water, only by higher alcohols the non-polar
character of side chain prevails (pentanol – amyl alcohol)
Terminology:
By aliphatic - hydrocarbon + -ol (methanol, ethanol)
By aromatic compound used frequently more trivial
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Hydroxy derivatives (alcohols, phenols)
Hydroxyl group of alcohols is strongly reactive.
With alkali metals produces alkoxides
C2H5OH + Na = C2H5ONa + 1/2H2
The hydroxyl group with acids produces esters
with mineral acids are formed:
R-OH + H-X = R-X + H2O
with organic acids are formed:
O
R
H
+ HO
C
R'
R
O
C
R'
+
H2O
O
O
Esterification is typical reversible reaction – (hydrolytic)
dissociation of esters can be realized, producing alcohol and
acid – common reaction in life organisms.
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Alcohols and phenols I
Methanol: CH3OH toxic, blinding, danger of death
Ethanol: CH3 CH2OH - euphoric, narcotic effect. Habitudinal
drug – most often toximania (drug addiction).
Higher alcohols - propanol, butanol, pentanol have some isomers.
Higher alcohols can be a part of lipids.
More functional alcohols:
1,2-ethandiol (ethylene glycol) HO-CH2-CH2-OH
toxic, heavy poisons, harmful for kidneys.
Glycols are parts of antifreeze mixtures for cooling systems
automobile radiator („Fridex“) - sweet –soluble in water.
1,2,3-propanetriol (glycerol)
CH
CH2
Part of most of lipids.
OH
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OH
CH2
OH
18
Alcohols and phenols II
Cyclohexanol (inositol): Biologically important
compound, similar type as vitamins
OH
HO
OH
HO
OH
OH
Phenol: (weak acid)
Toxic, corrosive !!!
Hydroquinone
(1,4-benzenediol)
O
O
H
O + H+
O
OH
Para-benzoquinone
-2H
+2H
OH
O
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(Redox =
Oxidation –
reduction systems)
19
Biologically important alcohols I
Sphingosine (sphingenine)
(trans-D-erythro-)2-amino-4-octadecene-1,3-diol-18-carbon
alcohol contained in complex lipids, especially in encephalic lipids
Ethanolamine: HO-CH2-CH2-NH2
Part of lipids
Choline
CH3
HO
Part of lipids.
CH2
CH2
N+
CH3
OH-
CH3
Its ester with acetic acid is very important for transport of neural
excitements.
Strong basic, Quaternary ammonium base.
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Biologically important alcohols II
We can classify also vitamins soluble in fats (exclusive vitamin K)
as alcohols
Vitamin A - retinol
Vitamin E - tocopherol
Vitamin D - cholecalcipherol and ergocalcipherol
Fat-soluble vitamins are described in detail in chapter
„Steroids and isoprenoids“
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21
Aldehydes and ketones (oxo-derivatives) I
R
Carbonyl group
Common group for
R'
C
O
ketones - carbonyl on secondary carbon
aldehydes - carbonyl on primary carbon
Aldehydes can be aliphatic or aromatic, ketones are mixed.
Carbonyl group is polar, therefore the compounds have good
miscibility with polar solvents. Character of the group does not
enable formation of large clusters by means of hydrogen bridges.
Therefore, the boiling point is lower than by alcohols, but higher
than by corresponding hydrocarbons. Most of aldehydes and
ketones are at normal temperature (laboratory temperature, in our
country 25 oC- 298 K) (exclusive formaldehyde H2CO) liquid.
Organic chemistry 2014/2015
22
Aldehydes and ketones (oxo-derivatives) II
They exhibit very high reactivity. The addition on carbonyl is very easy
realizable.
The formation of hemiacetal is very important (see carbohydrates).
Difference: Aldehydes have reducing character (reductants)– they are
easy oxidized to carboxylic acids vs. ketones do not have reducing
character.
Aromatic aldehydes form with primary amines Schiff base
H
C
O
+
H
N
CH3 -H2O
C
N
CH3
H
H
Benzaldehyde
Methylamine Benzylidenemethylamine
(Schiff Base)
Important by transamination – Schiff base forms
pyridoxal-phosphate with ammonium group of amino acids
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23
ETHERS
General formula:
R1-O-R2
Esters do not form hydrogen bridges. Therefore the boiling point
is lower than by corresponding alcohols:
CH3OH
CH3-O-CH3
Mol. mass [g.mol-1]
32
46
Boiling point [oC]
65
-24
They are practically non-polar. Higher, e.g., diethylether, are used for
extraction of non-polar compounds from aqueous solutions.
Diethylether is the most frequently used ether: CH3-CH2-O-CH2-CH3
Attention – the vapors are explosive. Explosive peroxides are formed
on light and in the presence of air. It is necessary to store it in dark
bottles and to stabilize (e.g., diphenylamine).
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24
ETHERS II
Important aromatic ethers, e.g.:
OH
(1-hydroxy-methoxybezene)
Guaiacol
O
CH3
Part of cough-syrups.
OH
Gujacuran
O
CH2
O
CH
CH2
OH
CH3
1-(2-methoxyphenoxy)-2,3-propanediol
Medicine calming and lowering hypermyotonia (muscular stress)
Organic chemistry 2014/2015
25
Carboxylic acids I
Characteristic group:
R
Carboxyl group
OH
C
O
According to the number of these groups we call these compounds
mono-, di-, tri- and polycarboxyl(s). They are relatively weak
acids (pKA = 4-5).
Carboxyls form mutually hydrogen bridges, and therefore the
carboxylic acids exist mostly in form of dimers or of polymers.
R
OH
C
O
O
C
OH
Organic chemistry 2014/2015
R
26
Carboxylic acids II
Hydroxyl group of carboxyl dissociates proton (in consequence
of the transfer of the electrons), therefore the carboxylic acids
have character of acids.
O
R
R
C
O
+
O
C
H
O
-
+ H+
The strength of carboxylic acid is influenced also by the rest of
molecule (e.g., number of carbons, number of carboxyls or of
other substituents).
Organic chemistry 2014/2015
27
Carboxylic acids III
Labeling of carbons in the molecule: 5
4
3
2
1
R-CH2-CH2-CH2-CH2-COOH
Properties:




1. Formation of salts
2. Possible decarboxylation, i.e., elimination of CO2 under production of the
one carbon shorter hydrocarbon (common reaction in biochemistry, in
industrial organic chemistry very complicated process).
3. Reaction of carboxyl under formation of functional derivatives of
carboxylic acids
4. Substitution on hydrocarbon part  substitution derivatives of carboxylic
acids
The radical formed by removing of -OH group from carboxyl is
(generally) called ACYL. The names of radicals are derived from the
name of the acid + ending -YL.
H
C
O Formyl
Organic chemistry 2014/2015
CH3
C
O
Acetyl
28
Monocarboxylic acids I
Formula
Trivial
English
name
- acid
Systematic
English name
- acid
Latin
name
acidum
Salt name
HCOOH*
Formic
Methanic
Formicum Formiate
CH3COOH
Acetic
Ethanic
Aceticum
CH3CH2COOH
Propionic
Propionic
Propionate
CH3(CH2)2COOH
Butyric
Butanic
Butyrate
(CH3)2CHCOOH
Isobutyric
Isobutanic
Isobutyrate
CH3(CH2)3COOH
Valeric
Pentanic
Valerate
CH3(CH2)14COOH
Palmitic
Hexadecanoic
Palmitate
Acetate
*Character of an aldehyde, i.e. reducing agent
Organic chemistry 2014/2015
29
Monocarboxylic acids II
Formula
Trivial
Systematic
English name English name
- acid
- acid
CH3(CH2)16COOH
Stearic
Octadecanoic
Stearate
CH3(CH2)7CH=CH(CH2)7COOH
Oleic
cis-9Octadecenoic
acid
Oleate
CH2=CHCOOH
Acrylic
2-en 1-propanic
Acrylate
Benzoic
Latin name Salt name
acidum
benzoicum
Benzoate
COOH
Organic chemistry 2014/2015
30
Attention: malate – maleate - malonate
Dicarboxylic acids
Formula
Trivial
English
name
- acid
Systematic English Latin name
name
acidum
- acid
Salt name
HOOC-COOH
Oxalic
1,2-Ethandiic
Oxalicum
Oxalate
HOOC-CH2-COOH
Malonic*
Propan-1,3-diic
Malonicum*
Malonate*
HOOC-(CH2)2COOH
Succinic
Butan-1,5-diic
Succinicum
Succinate
HOOC-(CH2)3COOH
Glutaric
Pentan-1,5-diic
Glutamicum
Glutarate
Maleic*
cis-but-2-en-1,5dioic
Maleate*
Fumaric
trans-but-2-en-1,5dioic
Fumarate
Phthalic
o-Benzenedicarboxylic
acid
Phthalate
COOH
HOOC
C
C
H
H
HOOC
H
C
C
H
COOH
COOH
COOH
Organic chemistry 2014/2015
31
Tricarboxylic acids
HOOC
CH2
C
CH
HOOC
COOH
cis-aconitic acid, important metabolite of Krebs cycle; salt:
cis-aconitate
OH
HOOC
CH2
C
HOOC
CH
COOH
citric acid, important metabolite of Krebs cycle; salt: citrate
In detail: see substitution derivatives of carboxylic acids
Organic chemistry 2014/2015
32
Substitution derivatives of carboxylic acids I
1) Halogen acids - trichloroacetic, monofluoroacetic – poison
2) Hydroxy acids – biochemically and medically important!
CH3
CH
COOH
-2H
+2H
CH3
COOH
C
O
OH
lactic acid (lactate)
pyruvic acid
-hydroxy propionic
(pyruvate)
Hydroxy propionic
Ketoacid
Organic chemistry 2014/2015
33
Substitution derivatives of carboxylic acids II
- and -hydroxy acids are esterified within their molecules
→ a cyclic ester is formed - lactone




O
R
CH
CH2
CH2
OH
C
-H2O


O
R
CH
CH2
CH2
C
O
OH
- lactone
E.g., Vitamin C
= L-ascorbic acid = dehydrolactone of gulonic acid
Carbonic acid
Hydroxyl
OH
HO
The simplest hydroxy acid
Organic chemistry 2014/2015
Carboxyl
C
O
34
Most important hydroxy acids I
1) Lactic acid, acidum lacticum, lactate ( L and D forms)
COOH
2) Glyceric acid, salt: glycerate
CH2
CH
2,3-dihydroxypropionic acid
OH
OH
Glycolysis (1 i 2)
3) Malic acid, acidum malicum, malate
OH
CH
(2-hydroxybutandiic acid)
(Krebs cycle)
4) Tartaric acid, acidum tartaricum, tartarate
COOH
H
C
HO
C
OH
H
COOH
(+) Tartaric acid
“right-handed“ tartaric
COOH
HO
C
H
C
H
OH
COOH
(-) Tartaric acid
“Left-handed“ tartaric
Organic chemistry 2014/2015
CH2
COOH
COOH
COOH
H
C
OH
H
C
OH
COOH

HO
C
H
HO
C
H
COOH
COOH
Mesotartaric
35
Most important hydroxy acids II
5) Citric acid, acidum citricum, citrate
CH2
COOH
Isocitric acid, isocitrate
HO
C
CH2
COOH
CH
COOH
CH
COOH
COOH
CH2
COOH
HO
6) Salicylic acid
COOH
Acetylsalicylic acid
p-aminosalicylic acid
COOH
OH
COOH
O
C
CH3
OH
O
Wide application in medicine - Acylpyrin (in Czech) (Aspirin)
Organic chemistry 2014/2015
NH2
36
Remedy against tuberculosis
Most important hydroxy acids III
Sulfosalicylic acid
COOH
OH
Very sensitive reaction for
the proof of peptides
(principle denaturalization)
SO3H
7) Gentisic acid
COOH
OH
Anti-rheumatic
effect
HO
Organic chemistry 2014/2015
37
Most important keto acids I
1) Pyruvic acid, acidum pyruvicum, Pyruvate
CH2
COOH
C
CH3
C
COOH
Keto-form
Enol-form
O
OH
(In biochemistry one of the most important acids!!!)
2) Acetoacetic acid, acidum acetaceticum, acetoacetate
C
CH3
CH2
COOH
CO2
O
CH3
C
CH3
O
(keto-, enol- tautomery)
Acetone
Acetoacetate is formed by degradation of lipids (FA)
3) Oxalacetic acid, -, oxalacetate
O
CH2
COOH
C
COOH
Important part of Krebs cycle
Organic chemistry 2014/2015
38
Most important keto acids II
4) -ketoglutaric acid, -, -ketoglutarate
O
C
COOH
Very important metabolite of Krebs cycle,
amino acids (glutamic acid) can be formed
from this acid, as well as the compounds
necessary for porphyrins synthesis (hem)
CH2
CH2
COOH
connection between metabolism of peptides and of saccharides
5) Oxalsuccinic acid, ac. oxalsuccinicum, oxalsuccinate
O
C
COOH
CH
COOH
CH2
COOH
-CO2
Metabolite of Krebs cycle, formed from
iso-citrate and it is transformed by
decarboxylation to -ketoglutarate
Organic chemistry 2014/2015
39
Nitrogen containing derivatives of hydrocarbons I.
Nitro compounds
R-NO2
They are often toxic, important mainly in the industrial
chemistry. Possibilities of poisons.
Examples:
NO2
Nitroethane: CH3-CH2-NO2
Nitrobenzene:
CH3
Trinitrotoluene:
NO2
In nature are very rare.
Exception: Chloramphenicol
NO2
NO2
O2N
(Antibiotic from streptomyces venezuelae)
CH
CH
CH2
OH
NH
CO
OH
CHCl2
Nitroglycerin: incorrect name, correctly it is glycerol nitrate ester of glycerol with nitric acid, it is not nitro compound!
Organic chemistry 2014/2015
40
Nitrogen containing derivatives of hydrocarbons II.
Ammines
Primary
R
NH2
Secondary
Tertiary
R
R
R''
N
NH
R'
R'
Quaternary ammonium bases
R
R'
+
N
R''
R'''
They are actually organic derivatives of ammonia, therefore they
have mostly basic character. Amino group is strong polar.
Ammines belong often to biologically important substances – amino
acids, biogenic ammines (emphatic physiologic effect), alkaloids (toxic
and pharmaceutical compounds of vegetative origin), synthetic
pharmaceutical compounds.
Organic chemistry 2014/2015
41
Reactions of secondary amines with nitrous acid
(nitrites) in the presence of HClNitrosamines
R
H + HO
N
N
O +HCl
R'
R
N
N
O + H2O + HCl
R'
Nitroso-amine
Nitroso-amines exhibit carcinogenic effects!!!
Some important amines International Agency for Research on Cancer (IARC)
NH2
Aniline – toxic – industrial poisons
HOOC
Ethylene Diamino Tetra
HOOC
Acetic acid
CH2
N
CH2
CH2
CH2
CH2
COOH
CH2
COOH
N
EDTA - calcium salt of this acid is often administrated as antidote by heavy metals
poisons
Chelaton II and III – important in analytical
CH3
chemistry
H 3C
N
+
CH3
CH2
CH2
OH
Choline – Amino alcohol
Organic chemistry 2014/2015
42
Biologically important amines
HO
OH
HO
HO
NH2
Dopamine
HO
HO
NH
NH2
Noradrenaline
CH3
Adrenaline
… and similar alkaloids and drugs
OH
HO
OH
HO
OH
H 3C
H 3C
HO
O
O
NH2
NH
NH2 CH3
CH3
CH3
NH CH3
O
CH3
CH3
Isoprenaline Amphetamine (Psychoton) Ephedrine Mescaline
Synthetic drugs
Alkaloids
Similarity in structure and in effects!!!
Organic chemistry 2014/2015
43
Functional derivatives of carboxylic acids
X-halogen R
X
C
R
NH2
C
O
O
Acyl halide
R
C
O
O
C
O
R
C
Nitril
Amide
R R
C
O
R
O
N
R
C
S
R
O
Anhydrides
Esters
Thioesters
 Acyl halides – use in organic synthesis
 Anhydrides - use in organic synthesis
 Esters – low polarity, hydrogen bridges are not formed. Solvents
of lipids!
 Thioesters – acetyl coenzyme A
 Amides - urea, nicotinamide, amides of amino acids
 Nitril – hydrocyanic acid - nitril of formic acid - toxic!
Organic chemistry 2014/2015
44
Functional derivatives of carboxylic acids –
derivatives carbonic acid (H2CO3) I
1) Halogen derivatives- phosgene - toxic!!!
O
Dichloride of carbonic acid:
2) Amides
Diamide of carbonic acid = urea:
Cl
C
Cl
NH2
O
C
NH2
Monoamide of carbonic acid = carbamic acid
(Unstable, it exists only as phosphate)
NH2
O
P
C
O
P
O
OH
P
OH
NH2
C
OH
O
Important for biosynthesis
of urea
Phosphate group
Organic chemistry 2014/2015
45
Functional derivatives of carboxylic acids –
derivatives carbonic acid (H2CO3) II
3) Esters carbamic acid = Urethanes
they have sedative and sleeping (narcotic) effects, relatively toxic,
and therefore they are not used at present (with one exception):
O
H3C
CH2
O
C
NH2
CH2
O
C
NH2
C
CH2
CH2
O
H3C
2-methyl-2-propyl-1,3-propanediolcarbamate
MEPROBAMATE
Organic chemistry 2014/2015
46
Derivatives of urea I
1) Biuret – is formed by heating up of the urea, ammonia is released
H2N
CO
NH2 + H
N
CO
NH2 -NH3 H2N
CO
N
CO
NH2
H
H
biuret
2) Guanidine (iminourea)-oxygen is substituted by an imine group =NH
NH2
NH
C
Is formed by oxidative cleavage of guanine
NH2
Its derivative – amino acid Arginine (see amino acids)
OH
Creatine - N–methyl-guanidine-acetic acid
N
NH2
NH
C
N
P
OH
O
CH2
COOH
CH3
Very important for transport of energy in muscles
Organic chemistry 2014/2015
47
Derivatives of urea II
Creatinine is formed from creatine as its anhydride
H
H
N
NH
OH
H
C
N
CH2
C
O
-H2O
CH3
NH
N
C
N
CH2
O
C
CH3
Creatinine is not utilizable for a muscle. It is excreted by urine
(kidneys - diuresis) and therefore it is used in clinical
biochemistry for monitoring of their functions („clearance“ of
creatinine)
Organic chemistry 2014/2015
48
Ureides I
Ureides are derived from carboxylic acids by substitutions of the
hydroxy group by the urea (analogy to amides):
CH3
C
OH
+ H
N
CO
NH2
-H2O
CH3
Acetic acid
N
CO
NH2
H
H
O
CO
Urea
Ureide of acetic acid
(acetyl urea)
Many of ureides belong to important remedies, e.g.:
Br
CH3
Bromisoval (sedative)
CH
CH3
CH
CO
N
H
CO
NH2
Ureide of -bromoisovaleric
acid
Organic chemistry 2014/2015
49
Ureides II
The cyclic ureides can be formed with dibasic acids. Such
compound can be classified as heterocyclic compounds:
H
O
C
OH
CH2
O
C
H
+
OH
C
H
O
N
N
C
NH
CH2 C
O
O
C
O
NH
H
Malonic acid
Urea
Barbituric acid
Many drugs with sedative, hypnotic and in higher doses with
narcotic effects are derived from barbituric acid - Barbiturates
Organic chemistry 2014/2015
50
Thio derivatives I
1) Thioalcohols (and thiophenols): R
„yperite“
Mustard gas
3) Disulfides:
Cl
R
R
S
CH2
S
CH
CH2
OH
SH
SH
SH
Amino acid
Cysteine
2) Thioethers (sulfides):
CH2
Dimercaptol (BAL)
Bond with heavy metals
R
S
CH2
CH2
CH2
Cl
R
S
Amino acid
Cystine
Disulphidic bridges (peptides)
-lipoic acid = (6,8-dithiooctanic acid)=1,2-Dithiolane-3-pentanoic acid
Reduced form
Oxidized form
2H+
CH2
SH
CH2
CH2
SH
(CH2)4
COOH
CH2
S
Organic chemistry 2014/2015
CH2
CH2
(CH2)4
COOH
S
51
Thiolic derivatives II
O
4) Sulfonic acids:
sulfosalicylic acid
R
S
OH
(see hydroxy acids)
O
O
Sulfonamides
5) Sulfones:
R
S
R (antimicrobial, chemotherapy)
O
6) Sulfur containing heterocycles:
Thiophene (5member ring with 1-heteroatom S), thiazole,
phenothiazine
Organic chemistry 2014/2015
52
Sulfonamides (chemotherapeutics)
Sulfones – derivatives of sulfanilic acid
H2N
SO2 OH
which is antagonist of para-aminobenzoic acid (PABA)
4-aminobenzoic acid
„vitamin H“
COOH
H2N
PABA is essential bacterial growth factor
sulfanilamide
H2N
SO2 NH2
sulfoguanidine
H2N
SO2 NH
C
NH2
NH
N
sulfothiazole
H2N
SO2 NH
Organic chemistry 2014/2015
S
53
Heterocycles – Basic structures I
(usually 3rd class of secondary (grammar, high) school)
N
N
H
N
H
N
H
N
1H-Pyrrole 1H-Imidazole 1H-Pyrazole
NH
N
H
Imidazolidine
N
H
N
H
Pyrrolidine
Pyrroline
(2-shown)
N
N
H
N
H
Imidazoline
(2-shown)
NH
N
H
Pyrazolidine
N
NH
Pyrazoline
(3-shown)
N
N
N
N
N
N
Pyridine
Pyrazine
Pyrimidine
Pyridazine
H
N
N
H
Piperidine
N
N
N
H
Piperazine
Organic chemistry 2014/2015
Quinuclidine
54
Heterocycles – Basic structures II
(usually 3rd class of secondary (grammar, high) school)
H
N
N
NH
N
Indolizine
H
N
N
1H-Indole
H
N
N
3H-Indole
H
N
NH
N
N
1H-Indazole
2H-Isoindole
7H-Purine
Indoline
N
N
N
Isoindoline
N
N
N
N
4H-Quinolizine
N
Quinoline
N
Isoquinoline
N
N
N
Phthalizine
Pteridine
N
N
N
Naphthyridine
(1,8-shown)
Quinazoline
Organic chemistry 2014/2015
Cinnoline
55
Heterocycles – Basic structures III
(usually 3rd class of secondary (grammar, high) school)
O
O
Furan
Tetrahydrofuran
O
S
2H-Pyran
Thiophene
O
O
Benzofuran
Isobenzofuran
O
Chroman
O
O
Isochroman
2H-Chromene
S
O
O
S
S
Xanthene
Thianthrene
Phenoxathiin
Organic chemistry 2014/2015
56
Heterocycles - Basic structures IV
5member ring
O
Furan
(furanoses)
hydroxy
derivatives Sugars
Tryptamine
N
S
H
Thiophene
hydrogenated Pyrrole – base of cyclic and
base of biotin - linear tetrapyrroles porphyrines - hem, bilirubine
vitamin H
(bile pigment) (In Czech žlučové barvivo)
In combination with benzene:
Benzopyrrole (indole)
Amino acid Tryptophan
5-hydroxytryptamine
„biogenic amines“ – physiologically very effective compounds
N
H
Ergotic alkaloids (affect the tonus of smooth muscles (uterus-obstetrics) +
LSD - diethylamide of lysergic acid (hallucinogenic compound (chemically prepared
Organic chemistry 2014/2015
57
psychosis))
Aflatoxin B1
Toxic and carcinogenic compound from fungus Aspergillus flavus,
which is growing on foods (especially groundnut – monkey nuts
O
O
etc.).
O
Biotin (vitamin H)
Essential for carboxylation reactions
(incorporation of CO2 into organic
acids) - prosthetic group of enzymes
O
O
O
CH3
L-ascorbic acid - vitamin C
O
HN
HO
O
OH
O
-2H
NH
H
O
OH
S
O
O
HO
HO
H
H
H
O
O
HO
H
HO
H
Dehydro-L-ascorbic acid
Non-enzymatic transfer of hydrogen
Organic chemistry 2014/2015
58
Indole (1H-Benzo[b]pyrrole)
N
H
Lysergic acid
O
Ergometrine
(ergot alkaloid)
CH3 OH
OH
O
NH
N
H
H
N
CH3
N
CH3
N
H
Its diethylamide = LSD
(hallucinogenic)
N
H
Organic chemistry 2014/2015
59
Five member heterocycles with two heteroatoms
1H-pyrazole
N
H
N
 antipyretic (antipyrine, amidopyrine)
N
imidazole
Amino acid histidine  histamine („biogenic
amine“)
N
H
CH2
N
N
S
CH2
NH2
N
H
Thiazole tetra hydrogenated base of
penicillin structure
Vitamin B1 thiamine and amiphenazole are derived from thiazole
– drug increasing irritability of CNS (hyperirritability)
Organic chemistry 2014/2015
60
Five member heterocycles with two heteroatoms
– derived drugs I
From pyrazole:
CH3
O
N
N
CH3
CH3
N
O
phenazon (antipyrine)
CH3
H3C
N
N
CH3
aminophenazone (amidopyrine)
and more complicated phenylbutazone and ketophenylbutazone
(ketazone)
Organic chemistry 2014/2015
61
Five member heterocycles with two heteroatoms
– derived drugs II
From thiazole:
Penicillins:
HOOC
N
H3C
H3C
O
G-penicillin
NH
S
R
-R=benzyl
O
-lactam ring – can be split by enzyme -lactamase, which have some
bacteria (gold staphylococcus). Thereby the effect of penicillin is
destroyed, and therefore, in case of these bacteria, it has no any sense to
administer it.
Thiamine (vitamin B )
1
(pyrimidine + thiazole)
+
N
H3C
N
N
CH3
S
Organic chemistry 2014/2015
CH 2 CH 2
OH
62
6-member heterocycles with one heteroatom
-pyran
Tetrahydropyran
(4H-pyran)
O
O
Sugars „pyranoses“
stable hyroxy
derivatives
Benzo derivatives of -pyran
O
Chroman
Vitamin E is derived of chroman
-pyron
Oxo derivative of -pyran (2H pyran)
O
O
Benzo derivative -pyron - coumarin
O
O
Derived compound with (blood)
anticoagulation effect (Warfarin)
Organic chemistry 2014/2015
63
6-member heterocycles with one heteroatom – derived compounds
Coumarin:
O
O
Some derived compounds have
anticoagulation effects –
decelerate blood coagulation. This
effect is medically used.
Warfarin - antagonist to K vitamins:
O
CH3
CH 2
CH
C
K1 Vitamin
CH3
CH3
CH 2
CH 2
CH 2 HC
O
CH 2
H
3
CH3
Vitamin K is necessary for synthesis of
prothrombin in livers.
Vitamin K2
CH3
CH2
CH
C
CH2
6
O
Organic chemistry 2014/2015
H
64
6-member heterocycles with one heteroatom (nitrogen)
Toxic. Alkaline, with acids produces salts.
Pyridine:
+HCl
N
+
N
Important derivatives
Nicotinic acid
Cl-
N
H
COOH
Medicament for bloodvessel extension
N
Nicotine amide
C
O
N
NH2
„vitamin PP“ part of NAD
and NADP
very important compound
Organic chemistry 2014/2015
65
6-member heterocycles with one heteroatom (nitrogen)
Isonicotinic
acid
HOOC
NH
O
and its hydrazide
NH2
C
INH – medicament against
T.B. (tuberculosis)
N
N
Piperidine
Formed from
pyridine by
hydrogenation
Derived synthetic
analog of morphine pethidine (Dolsin)
+ 6H
N
H
N
Benzo derivatives: Cinnoline is a part of alkaloid quinine and
of other synthetic antimalaria drugs.
N
N
N
Cinnoline
Isocinnoline
Organic chemistry 2014/2015
Acridine
66
Alkaloids and drugs with 6-member heterocycles with one heteroatoms
Derived from
pyridine
N
N
nicotine
O
diethylamide of
nicotinic acid
(central analeptics)
C2H5
C
C2H5
N
CH3
Quinoline
Isoquinoline
H3C
N
N
H3C
O
O
Quinine (and other antimalarial drug )
CH 2
H3C
CH 2
N
CH 2
CH3
CH 2
HO
CH
N
O
CH3
N
O
O
CH3
N
Papaverine (spasmolytics,
release spasms of smooth muscles)
Organic chemistry 2014/2015
uvolňuje křeče
67
6-member heterocycles with two heteroatoms I
N
N
N
N
N
Pyridazine
N
Pyrimidine
Pyrazine
The most important: Some bases of nucleic acids are derived from pyrimidine
O
NH2
O
NH
H3C
NH
N
Cytosine
NH
O
NH
O
O
OH
NH
NH
O
Thymine
Uracil
Tautomerism of the
uracil basis
NH
OH
N
O
NH
Lactam
Organic chemistry 2014/2015
N
O
N
Lactim
OH
68
6-member heterocycles with two heteroatoms II
H
N
N
H
full hydrogenated derivative of pyrazine is used as
medicament by goat (in Czech „dna“) (arthritis uratica) and
furthermore as antihelminticum (medicament against
pinworms and roundworms (in Czech „roupům a škrkavkám“)
Piperazine
Thiazines
S
(the most important
derivative
N
Phenothiazine)
H
Other derivatives: Methylene blue and
neuroleptics – medicaments used in psychiatry
Organic chemistry 2014/2015
69
Compounds with two condensed heterocycles
N
Purine
Some bases of nucleic acids are derived from
purine
N
N
N
H
O
NH2
N
N
Adenine
(ATP!!!)
NH
N
H2N
Both compounds are degraded via
xanthine
hypoxanthine
OH
N
N
NH
HO
OH
N
HN
NH
NH
Guanine
to uric acid
OH
N
HN
N
HN
NH
N
HN
HO
OH
NH
NH
Uric acid can crystallize in urine – gravel (urolithiasis) (in Czech „močové kameny“)
Alkaloids derived from xanthine: caffeine, theophyline, theobromine
Surplus – accumulation in tissues = gout (in Czech „dna“)
Organic chemistry 2014/2015
70
Phenothiazine
S
N
H
S
CH3
CH 2
N
N
CH 2
CH 2
N
Cl
CH3
R1
R2
S
Chlorpromazine
2-chlor-10-(3-dimethylaminopropyl)
phenothiazine
Basic structure of phenothiazine neuroleptics
O
Caffeine
1,3,7-trimethylxanthine
H3C
N
N
O
CH3
N
N
CH3
Organic chemistry 2014/2015
71
Heterocyclic vitamins
Pteridine is formed by two aromatic azines: pyrimidine and pyrazine
N
HO
HO
N
H
N
N
N
N
N
H2N
Pteridine
N
CH2
CH2
OH
OH
HN
CH3
H2N
N
Biopterine
Reduced form
N
H
CH2
CH2
OH
OH
N
H
Tetrahydrobiopterine
Donor of hydrogen
Folic acid (ptero-glutamic) is derived from pteridine
HO
H
N
HN
CH2
NH
C
NH
O
H2N
N
H
Pterine
CH3
CH
CH2
CH2
COOH
COOH
N
H
PABAGlutamic acid
para-aminobenzoic
acid (PABA)
Organic chemistry 2014/2015
72
Heterocyclic vitamins II
N
N
N
H
N
O
NH
N
N
N
O
Benzopterine
Alloxazine
Riboflavin, B2
H2C
Pyridoxine, B6
(derivative of pyridine)
N
HO
R
N
H3C
N
OH
OH
OH
CH
CH
CH
CH2
N
O
NH
CH3
OH
CH2
H3C
OH
O
R= -CH2OH pyridoxol
R= -CHO pyridoxal
R= -CH2NH2 pyridoxamine
Organic chemistry 2014/2015
73
Organo-metallic compounds
1.
2.
3.
4.
5.
6.
Arsenic benzenes - salversan, neosalversan – formerly used
as antiparasitics and antimicrobial drugs – not at present
(toxic, carcinogenic)
War agent - Lewsit ClCH=CHAsCl2 – used relatively
recently (antidote BAL-dimercaptol)
Tetraethylplumban („tetraethyl lead“) anti-detonation
O
additive into petrol – highly toxic (C2H5)4Pb H N
CH
O C
C
Anti-tumoric compounds - carboplatin
Pt
CH
H N
O
C
Dimethylmercury
O
(CH3)2Hg – used in organic synthesis – highly toxic, possible
industrial poisons (occupational medicine)
Organic compound of gold - antirheumatic agent
gold sodium thiomalate
2
3
2
2
Organic chemistry 2014/2015
74
CH3
Organophophates
Organophophates R
1
O
Soman:
CH3
O
P
P
R2
F
C3H7O
R3
Blocker of acetylcholinesterase o-isopropyl methylfluorophosphate
Insecticide - commonly
used in agriculture
C 2 H 5O
S
(farming) – for man less
Parathione
P
toxic, but accidentally can
occur the heavy
O
C2H 5O
NO2
professional poisons.
Malathione
CH3O
antidote – antagonistic
ACh - atropine aj.
S
P
CH3O
S
CH
COOC2H5
CH2
N
COOC2H5
Organic chemistry 2014/2015
H2C
HC
C6 H5
CH2
CH2HC
CH3 HC
CH2
O
C
O
HC
CH2OH
75