ORGANIC CHEMISTRY For General Medicine Ďuračková Zdeňka Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry Medical Faculty of Comenius University 1
ORGANIC CHEMISTRY
For General Medicine
Ďuračková Zdeňka
Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry
Medical Faculty of Comenius University
1
Structure of organic compounds(relation between structure and properties and functions of biologically important
organic compounds)
Organic chemistry – chemistry of hydrocarbons and their derivatives
6C 1s2 2s2 2px12py
1 C = O
Carbon in basic state
2
Structure of organic compounds(relation between structure and properties and functions of biologically important
organic compounds)
Organic chemistry – chemistry of hydrocarbons and their derivatives
6C 1s2 2s2 2px12py
1 2pz C = O
Carbon in basic state
6C 1s2 2s1 2px1 2py
1 2pz1 O = C = O
Carbon in excited stateC
3
1s 2s 2px 2py 2pz
Electron configuration of carbon
➢ basic state
➢ excited state
➢ 4 unpaired electrons – four covalent bonds
C
4
Basic principles of the structure of organic
compounds- carbon forms four covalent bonds C
- all 4 bonds are equivalant (hybridization s-, and p-orbitals
– equalization of all 4 bonds)
- between carbons can be simple, double, or triple bond
(σ and π bond)
– C – C – – C = C – – C = C –
- atoms of carbon form chains – simple straight, branched and
cyclic forms
- between carbon atoms, atoms of oxygen, nitrogen or
sulfur can be bound5
Types of hydrocarbon structures
HYDROCARBONS
Heterocyclic compounds (O, S, N,)
Acyclic
(non-cyclic)
Cyclic
Saturated
Non-saturated
Alkenes
Alkynes
Alicyclic
Aromatic
Cycloalkanes
Cycloalkenes
6
STRUCTURE of ORGANIC COMPOUNDS
1. Acyclic (non-cyclic)
➢ Unbranched (straight chain)
CH3-CH2-CH3
➢ Branched chain
CH3-CH-CH3
CH3
2. Cyclic
➢ alicyclic (cyclic)
➢ aromatic (arenes)
➢ heterocyclic
Organic compounds – according to hydrocarbone chain arrangement
N 7
Isomerism of organic compounds
(two or more compounds with identical molecular formula,
but different structure)
Types of isomerism
• Constitutional (n-propanol, 2-propanol)
• Configuration (stereoisomerism)
- geometrical (cis-, trans-) (fumaric, maleinic acids)
- optical (chirality, D/L - isomers) (D-AA, L-AA)
• Conformation of molecules (chair, boat)
8
Relation between structure and biological properties
• Isomerism- identical sum (molecular) formula
- different arrangement of atoms and atom groups (different structure)
1. Constitutional isomerism- different constitution placement of atoms or kind of bonds
➢ carbon skeleton n-butane CH3 isobutane
CH3 – CH2 – CH2 – CH3 CH3 – CH –CH3
➢ placement 1-propanol OH 2-propanol
CH3 – CH2 – CH2 – OH CH3 – CH – CH3
➢ placement of double bounds 1-butene 2-butene
1CH2 = CH – CH2 – CH3 CH3 –2CH = CH – CH3
➢ Tautomerism (oxo-enol, or lactam-lactim tautomerism)
CH2 = CH – OH CH3 – C = O
vinylalcohol
H acetaldehyde
9
C4H10
C3H8O
C4H8
C2H4O
Tautomerism - positional isomerism –
reverse position of H and the double bond
CH2 = CH – OH → CH3 – C = OH
vinylalcohol ethanal
(acetaldehyde)
N
N
NH
HN
O
H2N N
N
NH
N
OH
H2N
Lactam – form Lactim – form
guanine
11
Amino - / Imino-tautomerison
In DNA – They cause mutagenic mispairings during DNA replication
In RNA -Tautomeric nucleoside analogs have therapeutic applications as antiviral
drugs because of their ability to induce lethal mutagenesis
12
Amino - / Imino-tautomerison
Change pairing from A-T to G-C
Use in antivirals
Configuration isomerism (stereoisomerism)➢ different arrangement of atoms in space, the same connectivity (order of atoms and
double bonds are identical)
➢ geometrical isomerism, cis – trans (maleic and fumaric acids)
conditioned by the presence of double bond
Maleic acid (cis) Fumaric acid (trans)
H – C – COOH HOOC – C – H
|
H – C – COOH H – C – COOH
➢ optical - conditioned by chiral carbon C* (asymmetric carbon)
- optical isomers - enantiomers
- rotation of the plane of polarized light to the same degree but to opposite
direction (+ / - )
configuration D- a L-H – C = O H – C = O
|
H – C* – OH HO – C* – H
|
CH2OH CH2OH
D(+)- glyceraldehyde L(-) - glyceraldehyde13
15
What does it mean + or - ?????
An optically active substance (optically active carbon is
present – C*) in solution is able to rotate the plane of
polarised monochromatic light (light of only a single
frequency) passing through a solution to the right or to
the left
Not linear
polarised lightLinear polarised light
Conformation of molecules
➢ Arrangement in space
➢ Rotation of atom groups around axis passing two carbon atoms linked by simple
bond
Example: two conformations of cyclohexane:
Chair Boat16
REAGENTS in ORGANIC CHEMISTRY
➢ low-molecular weight compounds (molecules, ions, radicals) react with
substrate
Nucleophilic – donor of electrons to substare for new bond formation is
reagent: OH- , X- (halogenid), H2O, NH3
Nu + -C+ Cl
Electrophilic – acceptor of electrons from substrate for new bond
formation is reagent : +SO3H, +NO2 , Cl+, H+
E+ + CH2=CH- ...
Nu + -C+ Cl
INDUCTIVE EFFECT, I ( for - bond) – related to saturated hydrocarbons
➢ effect of polar bond on polarisation of neighbouring bonds
➢ direction of polarisation is identical with polarity of original bond
➢ effect is dependent on distance
Negative inductive effect – I
-atom, resp. group of atoms linked to carbon, which attracts electrons :
–F, –Cl , –Br , –I, =O, –OR, –SR, –NH2 , –NO2
Positive inductive effect + I
-atom, resp. group of atoms, which push electrons back:
–CH3 (alkyls)
18
➢ transformation of polar group effects the conjugation system of double bonds
Negative mesomeric effect -M
➢ groups attracting electrons
➢ dilution of electron density on neighbouring double bonds
➢ groups: -NO2 , -COH, =C=O, -COOH, -C=N
R – CH = CH – C = O
H
MESOMERIC EFFECT, M
+M -M
NO2
+M -M
19
Characteristic for electrons
10
electrons6
electrons
Possitive mesomeric effect, +M
➢ groups that repel (press out) electrons
➢ thickening of electrons on adjacent carbons with double bonds
➢ groups: -NH2 , -OH , -OR, -SH, -SR, -X (halogens)
O – H
-M +M
20
4
electrons6
electrons
Reactivity of hydrocarbons• Saturated hydrocarbons (alkanes)
- substitution (radical reaction, catalyst, UV)
- elimination (dehydrogenation) (catalyst) (Pt, enzyme)
• Non-saturated hydrocarbons (alkenes, alkynes)
- addition: hydrogene (hydrogenation) alkanes
halogene (halogenation) dihalogenalkanes
halogene derivatives monohalogenalkanes
water hydroxy derivatives
(alcohols)
- oxidation – cleavage of bond
• aromatic hydrocarbons X
- substitution: halogenation - Cl
(electrophilic sulphonation - SO3H
substitution) nitration - NO2
acylation - CO-R
alkylation - CH2-CH3
X
21
REACTIONS of ORGANIC COMPOUNDS
1. Addition
2. Substitution (displacement of atom/atom group)
3. Elimination
2H
CH2 = CH2 --------> CH3 – CH3
CH3 – CH2 – Cl + OH- --------> CH3 – CH2 – OH + Cl-
- H2O
CH3 – CH – CH – CH2 ---------> CH3 – CH = CH – CH3
| |
OH H
2 – butanol 2 – butene 22
Prefix de - ..... Elimination of something - double bond is formed
23
Dehydration - H2OCH3 – CH – CH – CH2 ---------> CH3 – CH = CH – CH3
| |
OH H
2 – butanol 2 – butene
- 2HCH3 – CH – CH – CH2 ---------> CH3 – CH = CH – CH3
| |
H H
butan 2 – butene
Dehydrogenation
Deamination
- NH3
CH3 – CH – CH – CH2 ---------> CH3 – CH = CH – CH3
| |
NH2 H
2 – aminobutan 2 – butene
Acyclic (aliphatic) hydrocarbons
Alkanes:
➢ Saturated hydrocarbons, simple () bonds, binding angle 109°
➢ homologic chain, -CH2- homologic increase, molecular formula
CnH2n+2
➢ Non-polar compounds, soluble in non-polar solvents, insoluble in
H2O
➢ Small reactivity, characteristic reaction - substitution (temperature,
UV radiation)
- example: methane, ethane, propane, butane, pentane,
hexane…, isobutane
HYDROCARBONS
24
Alkenes
➢ non-saturated hydrocarbons, double bond (), binding angle 120°
➢ homological chain, sum formula CnH2n
➢ high reactivity, characteristic reaction – addition
(Markovnik rule)
CH2 = CH2 + HOH CH2 – CH2
OH H
ethene (ethylene) ethanol
catalyst
CH2 = CH2 + 2H CH3 – CH3
ethene ethane25
Dienes (2 double bonds)
➢ cumulated, conjugated or isolated double bonds
➢ high reactivity, important reaction – addition polymerisation
n CH2 = C – CH = CH2 -----→ --CH2 - C = CH – CH2-n-
CH3 CH3
2-metyl-1,3-butadiene natural rubber
isoprene polymer of isoprene
- Isoprenoids (for example: terpenes, steroids)
26
Alkynes
➢ non-saturated hydrocarbons, triple bond (), binding angle 180°
➢ homological chain, sum formula CnH2n-2
➢ high reactivity, characteristic reaction – addition
CH CH + HCl → CH2 = CH – Cl
Ethyne (acethylene) chloroethene (vinylchloride)
CH CH + HOH → CH2 = CH – OH → CH3 – C = OH
Ethyne (acetylene) vinylalcohol ethanal(acetaldehyde)
Tautomerism :enol- oxo- 27
28
Markovnik´s rule
1-propene 2-propanol
non-symetric non-symetric
hydrocarbon molecule
Addition of
CH2 = CH – CH3 + H - OH CH2 – CH – CH3
H OH
CH2 = CH – CH3 + H - OH CH2 – CH – CH3
H OH
Cyclic hydrocarbons
ALICYCLIC
For ex.: cyclopentane, cyclohexane, cyclohexene, cyclohexadiene,
cyclopentanoperhydrophenantrene
Stereochemistry cyclohexane
➢ chair and boat form (bound angle 109°)
Chair - more stable Boat29
AROMATIC hydrocarbons (ARENS)
➢ basic hydrocarbon – benzene (benzol)
➢ aromatic character –
- plane structure (120°bound angle)
π – electrons are delocalized arround whole circle
1858, F. A. Kekule
(Heidelberg)
= =
30
PHENANTHRENE BENZPYRENE
➢ Toxicity of arens (benzene, benzpyrene)
➢ Stability towards oxidation
➢ Characteristic substitution reaction
(nitration, halogenation, sulphonation)
NAPHTHALEN E ANTHRACENE
Polycyclic arens
31
➢ five- or six-membered rings with one or more heteroatoms
➢ condensed heterocyclic compounds with two or more heteroatoms
HETEROCYCLIC COMPOUNDS
O NH S
N
NH
N
S
furane pyrrole thiophene
imidazole thiazole 32
N
N
N
pyridine pyrimidine pyran
(2H-pyran)
N
N NH
N
O
purine indole
pyrimidine + imidazole benzpyrole
NH
33
O
S
Biologically important derivatives of heterocyclic compounds
Furan
Ribose Deoxyribose
Tiophene
S CH3
Methyltiophene
- in grill meat
34
Biologically important derivatives of heterocyclic compounds - 2
N
S
thiazol
Thiamin – vitamin B1
• Component of carboxylases – oxidative decarboxylation
alpha-oxoacids
• Metabolism of saccharides in brain
P P
NH
pyrol
Porphin – porphyrin - haeme35
Biologically important derivatives of heterocyclic compounds - 3
N
NH
imidasol
PurinHistidin
Biotin
36
Biologically important derivatives of heterocyclic compounds - 4
O
Pyran
Vitamin EGlucose chroman ring 37
O
saturated
Biologically important derivatives of heterocyclic compounds - 5
N
pyridin
NAD+Amid of nicotinic acid
Niacin
Vitamin PP 38
Biologically important derivatives of heterocyclic compounds - 6
N
N
pyrimidinPurin
Pyrimidin nitrogene bases39
Biologically important derivatives of heterocyclic compounds - 7
caffeine theophilline
Uric acid
40
Biologically important derivatives of heterocyclic compounds - 8
Indol
benzene + pyrol
NH
Tryptophan
Lysergic acid 41
DERIVATIVES of HYDROCARBONS
➢ replacing hydrogen atom/atoms in hydrocarbons with another atom
or a group of atoms, so called functional group
CHARACTERISTIC GROUPS and their marking
Compound Characteristic
group
Prefix Affix
Halogen hydrocarbons ⎯ F
⎯ Cl
⎯ Br
⎯ I
Fluoro-
Chloro-
Bromo-
Iodo-
Nitroderivatives ⎯ NO2 Nitro-
Nitrosoderivatives ⎯ NO Nitróso-
Aldehydes ⎯ HC=O Oxo- - e
Ketones ⎯ C=O
Oxo- -on
Carboxylic acid ⎯ COOH Carboxy- -ic acid
42
Alcohols ⎯ OH Hydroxy- -ol
Thiols ⎯ SH Merkapto-
Thio-
-tiol
Ethers ⎯ O-R R-oxy
Sulphides ⎯ S-R R-thio
Disulphides ⎯ S-S ⎯
Sulphonic acids ⎯ SO3 H Sulpho- Sulphonic acid
Amines ⎯ NH2 Amino- - amine
Imines =NH Imino- - imine
Oxims =N-OH Hydroxylimino- - oxime
Nitrils ⎯ CN Cyano- - nitril43
HALOGEN DERIVATIVES
Tyroxine – Tetraiodothyronine T4
– Triiodothyronine T3
nucleophilic substitution
׀
C X δ- + OH-
↔ H-C-OH + X-
45
δ+
High TOXICITY
HALOGENE DERIVATIVES of HYDROCARBONS
- insoluble in water, soluble in alcohols and ethers
- polar covalent bond between – C halogene
• characteristic reaction
- substitution (heterolytical cleavage of bonds), as alkylation reagents
• practical use
➢ solvents for non-polar compounds (CCl4)
➢ monomers for preparation of macromolecular compounds (PVC, artificial rubber,
tephlon),
➢ in refrigerator industry (freons – dichloro-difluoromethane)
➢ iodoform CHI3 – disinfection effects
➢ insecticides
➢ dioxins
➢ narcotics (halotan, CF3-CHBrCl) 46
• toxicity
➢ influence on central nervous system (CNS)
➢ tetrachlorodibenzodioxin – carcinogenic, teratogenic, mutagenic effects
(c 1mg.l-1) (dioxins)
➢ cancerogens or suspected carcinogens (CHCl3 , CCl 4)
Toxicity of halogene derivatives
DDT – insecticide DichloroDiphenylTrichlorethane
(1948 Paul Hermann Müller won Nobel Price for DDT discovery)
47
Key facts related to dioxins
➢ Dioxins are a group of chemically-related compounds that are persistent
environmental pollutants.
➢ Dioxins are found throughout the world in the environment and they accumulate in
the food chain, mainly in the fatty tissue of animals, mainly meat and dairy
products, fish and shellfish.
➢ Dioxins are highly toxic and can cause reproductive and developmental
problems, damage the immune system, interfere with hormones and also cause
cancer.
➢ Due to the omnipresence of dioxins, all people have background exposure, which
is not affecting human health. However, due to the highly toxic potential of
this class of compounds, efforts need to be undertaken to reduce current
background exposure.
➢ Prevention or reduction of human exposure is best done via source-directed
measures, i.e. strict control of industrial processes to reduce formation of dioxins
as much as possible. 48
Sources of dioxin contamination
➢ products of industrial processes or also result from
natural processes (volcanic eruptions and forest fires)
➢ products of a wide range of manufacturing processes
(smelting, chlorine bleaching of paper pulp, the
manufacturing of some herbicides and pesticides)
➢ uncontrolled waste incinerators (solid waste and hospital
waste) are often the worst culprits, due to incomplete
burning
49
1. ALCOHOLS
Polarity of bond R O H - reactivity of hydroxyderivatives
Dividing:
1. according to the place of -OH group bound in the chain
- primary (1- butanol) CH3 – CH2 – CH2 – CH2 – OH
CH3 – CH2 – CH – CH3
OH
CH3
CH3 – C – CH3
OH
- secondary (2-butanol)
- tertiary (tert. butanol)
HYDROXYDERIVATIVES of HYDROCARBONS
(alcohols a phenols)
50
2. According to a number of –OH groups
- monohydroxyderivatives (monohydric)
- dihydroxyderivatives (diols) (dihydric), ethanediol (ethyleneglycol)
- trihydroxyderivatives (triols) (trihydric), propanetriol (glycerol)
- polyhydroxyderivatives (polyols) (saccharides)
CH2 – OH
CH2 – OH
CH2 – OH
CH – OH
CH2 – OH
O
CH2OH
OH
OH
OH
OH
ethyleneglycol glycerol glucose 51
Acidic character of alcohols
CH3- CH2-O-H + NaOH CH3- CH2-O- + Na+ + H2O
Sodium alcoholate
52
Alkaline character of alcohols and ethers
Alcoxonic salt
H
CH3 – O – CH3 + H+Cl- CH3 – O – CH3 Cl-
+
Alcoxonic salt
CH3- CH2-O-H + H+Cl- CH3- CH2- O-H Cl-
H +
R-CH2-OH R-CH=O R-COOH
R R
CH-OH C=O
R R
R - alcohol R – OH
Ar – phenol Ar – OH
H H- O -
Ether R – O – R
HYDROXYDERIVATIVES
ox
-2H
ox
-2H
ox
H2O
bond cleavage
between carbon atoms
ox
Oxidation of alcohols
53
3. Tertiary alcohols:
➢ stable against moderate oxidative reagents
➢ cleavage of - C – C - bond with strong oxidative reagent (K2Cr2O7)
CH3 CH3
oxidation
CH3 –C – OH CH3 –C = O + HCOOH
CH3 acetone formic acid
54
Oxidation of diols
CH2 – OH COOH COOH COOH
→ → →
CH2 – OH CH2 – OH HC=O COOH
Ethylene glycol
Ethane diole glycolic acid glyoxalic acid oxalic acid
Oxidation of triols
CH2 – OH CH2 – OH HC = O COOH
ox. ox ox
C = O CH – OH CH – OH CH – OH
CH2 – OH CH2 – OH CH2 – OH CH2 – OH
dihydroxyacetone glycerol glyceraldehyde glyceric acid
55
Hydrogene bond formation
R – O Hδ- δ+
δ-δ+
H O – R
R – O – R
R – O – R
Higher boiling
point
cca 80°C
cca 40°C
56
H3C – O – CH3
Esterification with organic acids
R – OH + HOOC – R
ester
+ H2OR – O – CO – R
57
Reaction with inorganic acidsEsterification of alcohols with sulphuric acid
R – O –H + HO – SO2 – OH - H2O
Alcohol H2SO4
58
Esterification of alcohols with suphuric acid
R – O –H + HO – SO2 – OH R – O – SO2 – OH
- heteropolysaccharides
chondroitinsulphate
dermatansulphate
- glycolipids
sulphatides
- H2O
Alkylsulphate, ester of sulphuric acid
59
Esterification with nitric acid
HNO3
CH2 – OH + H – O – NO2 CH2 – O – NO2
CH – OH + H – O – NO2 → CH – O – NO2 + 3 H2O
CH2 – OH + H – O – NO2 CH2 – O – NO2
glyceroltrinitrate
(drug for heart diseases)
60
Alfred Nobel (1833-1896) explosive compound
dynamit discovering (1867)
– Nobel foundation - 9 millions for Nobel prices
Reactions with inorganic phosphoric acid
OH OH
R – OH + HO – P = O R – O – P = O
OH OH
- H2O
monoester
61
Reaction with inorganic acids
OH OH
R – OH + HO – P = O R – O – P = O
OH OH
OH + HO – R
R – O – P = O
OH
- H2O
monoester
- H2O
62
Reaction with inorganic acids
OH OH
R – OH + HO – P = O R – O – P = O
OH OH
OH + HO – R O – R
R – O – P = O R – O – P = O
OH OH
- H2O
diester
monoester
- H2O
63
Esterification of glycerol with phosphoric acid
H3PO4
CH2 – OH 1CH2 – OH
CH – OH OH CH – OH OH + H2O
CH2 – OH + H – O – P = O 3CH2 – O – P = O
OH OH
glycerol-3-phosphoric acid
( unit of complex lipids)
64
- in the form of ions at different pH values of body fluids:
O O
- H+ - H+
R-O – P – OH R-O – P – O- R-O – P – O-
+ H+ + H+
OH OH O-
pH << 7 pH 7 pH 7
= = =
o
65
➢ esters of phosphoric acid, diphosphoric and triphosphoric acids in living systems
HO –P– OH HO –P– O – P– OH HO – P– O –P– O – P – OH
OH OH OH OH OH OH
phosphoric diphosphoric triphosphoric
acid acid acid
O O O O O O
R-O–P– OH R-O –P– O – P– OH R-O – P– O – P– O – P – OH
OH OH OH OH OH OH
alkyl phosphate alkyl diphosphate alkyl triphosphate
= ===
=
= O O O O O O
66
67
phosphoanhydric arrangement
O O
R – O - P – O ~ P – OH
protone-donor
OH OH groups
phosphoester bond
ATP + H2O ADP + Pi G0 - 32 kJ.mol-1 68
PHENOLS
- one or more - OH groups are linked directly to aromatic ring
- higher acidity of phenols in comparison to alcohols
- chemical reactions
COOH
OH
Salicylic acid
OH
OH
Hydroquinone
OH
Phenol 69
- Acidic character of phenols
(higher than of alcohols)
- Toxicity of alcohols and phenols
OH + NaOH O - + Na+ + H2O
Sodium phenolate
70
Oxidation of dihydroxyarenes – diphenols
- formation of quinones, cyclic conjugated diketones
OH
OH
O
O
-2H
+2H
p-dihydroxybenzene p-benzoquinone
( hydroquinone) (1,4-benzoquinone)
- antioxidant function of phenols is related to reversible oxidation of
diphenols to quinones (CoQ – ubiquinone in mitochondria)
-Desinfective properties of phenols (carbolic acid)71
Cyclic,
nonsaturated
di-ketone
- 2H
+ 2H
1,2-hydroquinone
(pyrocatechol)
1,2-benzoquinone
resorcinol
oxidátion
Gallic acid
- CO2
Pyrogalol
use in photograph,
hair coloring
Tannins, antioxidantbound to saccharide
unit 72
Coenzyme Q
Oxidation
- 2H
Reduction
+ 2H
Involved in respiratory chain in mitochondria 73
Vitamin Kphylochinone
O
O
CH3
CH2CH C (CH2CH2CH2CH)3
CH3
CH3
CH3
Important for blood coagulation (prothrombin formation).
It is important for photosynthesis in plants.
Deficiency – malfunction of blood coagulation – risk of bleeding
Source – vegetable leafs
74
OXO-compounds (aldehydes and ketones)(polarisation of bond to oxygen)
R – Cδ+ Cδ+ = Oδ-
Oδ-
H
R
R
Aldehydes Ketones
75
+ −
Carbonyl group (oxo-group) - C = O
- all three atoms linked to carbonyl carbon form angle 120°
- they lie in one plane
R R
Aldehydes C = O Ketones C = O
H R
- polarisation of group – reactivity of aldehydes and ketones
OXO-compounds
76
Chemical reactions of oxo-compounds
Oxidation and reduction
- 2H
77
aldehyde
reductionR – CH2 –OH
primary alcohol
O
R – C – H
oxidationO
R – C –OH
carboxylic acid
+2H (Ni)
or donor H atom
O
R – C – R
Ketone
Reduction
catalyst Ni
or donor of H atoms
relatively stable against oxidation
OH
R – CH – R
secondary alcohol
Oxidation
- 2H
78
oxidation and reduction in living systems
(coenzymes of dehydrogenases as acceptors and donors of H atoms)
- NAD+ - acceptor of H− (hydride ion) during the oxidation of alcohol
- NADH – reduced form of coenzyme – donor of H− (hydride ions)
CH3 CH – OH + NAD+ CH3 C = O + NADH + H+
H H
ethylalcohol acetaldehyde
79
Redox propertiesO O
R – CH2 – OH R – C R – C
H OH
R R
CH – OH C = O
R R
-2H
+ 2H
H2O
-2H
-2H Ox
+2H
Aldehyde
Ketone
Reducing properties
80
Addition and condensation reactions
- formation of hemiacetals and acetals
Aldehyde Alcohol Hemiacetal Acetal
- hemiacetal in cyclic form (cyclic monosaccharides - relatively stable
intermediates at the formation of acetals - glycosides)
R – C – H + CH3 – OH R– C – H + CH3OH R – C –H + H2O
O – CH3 O – CH3
O – CH3
hemiacetal
hydroxyl
OHO
- hemiacetals are unstable
81
Addition and condensation reactions
- formation of hemiacetals and acetals
Aldehyde Alcohol Hemiacetal Acetal
- hemiacetal in cyclic form (cyclic monosaccharides - relatively stable
intermediates at the formation of acetals - glycosides)
R – C – H + CH3 – OH R– C – H + CH3OH R – C –H + H2O
O – CH3 O – CH3
O – CH3
hemiacetal
hydroxyl
OHO
- hemiacetals are unstable
82
O OH
OH −
CH3 – C – H + CH3 – CH2– C – H CH3 – CH – CH – C – H
O OCH3
Aldol condensation (aldehydes with -hydrogene)
3- hydroxyaldehyde = aldol
O OH
OH −
CH3 – C – H + CH3 – C – CH3 CH3 – CH – CH2 – C – CH3
4-hydroxy-2-pentanone
O O
1
3
83
O OH
OH −
CH3 – C – H + CH3 – CH2– C – H CH3 – CH – CH – C – H
O OCH3
Aldol condensation (aldehydes with -hydrogene)
3- hydroxyaldehyde = aldol
O OH
OH −
CH3 – C – H + CH3 – C – CH3 CH3 – CH – CH2 – C – CH3
4-hydroxy-2-pentanone
O O
1
3
84
Aldol condensation in metabolism
HO
dihydroxyaceton-
-phosfate
H2C O
C O
CH2
P Cδ+
C
H2C O P
OHH
glyceraldehyd-
-phosfate
H Oδ¯
H2C O
C O
P
(CHOH)3
H2C O P
fructose -1,6-bifosphate
aldolase
P = PO3H2
85
Condensation with primary amines -
Formation of imines (Schiff bases)
R – CH = O + H2N – CH3 R – CH = N – CH3
• aldimine
R – C = O + H2N – CH3 R – C = N – CH3
| |
R ketone R ketimine
Schiff bases
- important intermediates of biochemical reactions
- binding of carbonyl compounds to free amino groups of proteins
- H2O
86
retinal (vitamin A)
Rhodopsin – red color pigment in the retina of the eye sensitive to light
CH=N opsin
+ H2N opsin
rhodopsin
- H2O
Biological importance of Schiff bases formation
87
Nonezymaticglycation of proteins
- H2OHO
HO
HO
C
CH2
OHOH
OHOH
OH
H O
D- glukóza
H2N proteín+
CH2
OHOH
OHOH
OH
CH N proteín
aldimín
(Schiffova zásada)
CH2
OOH
OHOH
OH
CH2 NH proteín
ketoamín
(fruktózamín)
aldimine
D-glucose
protein
protein
protein
Ketoamine
(fructosamine)
Schiff base
88
CARBOXYLIC ACIDS
C
O
OH
120°
120°
120°
- Shift of - electrons in group C = O
- Polarisation of – O H bond
O H
R – C = OR – C
O
O
+ H+
- Mostly weak acids, K(ionis.const.) = near to 10-5
- According to the number of – COOH groups:
mono-, di- and tricarboxylic acids
- Saturated and unsaturated 89
Monocarboxylic acids Dicarboxylic acids
formula
Name
formula
Name
substitutio
nal
common substitutional common
HCOOH Metanoic Formic
CH3 COOH Ethanoic Acetic HOOC–COOH Ethanedionic Oxalic
CH3 CH2 COOH Propanoic Propionic HOOC– CH2 –COOH Propanedioic Malonic
CH3(CH2)2 COOH Butanoic Butyric HOOC–(CH2)2 COOH Butanedioic Succinic
CH3(CH2)3 COOH Pentanoic Valeric HOOC–(CH2)3COOH Pentanedioic Glutaric
CH3(CH2)4 COOH Hexanoic Caproic HOOC–(CH2)4COOH Hexanedioic Adipic
Examples of saturated mono- and dicarboxylic acids
90
Acid name formula R-COOH salt name R-COO−
Oxalic HOOC–COOH Oxalate
Malonic HOOC–CH2–COOH Malonate
Succinic HOOC– (CH2)2–COOH Succinate
Glutaric HOOC– (CH2)3–COOH Glutarate
Fumaric (trans- form) HOOC–CH=CH-COOH Fumarate Maleic (cis-form)
Maleate
Lactic CH3–CH–COOH Lactate
OH
Important dicarboxylic and hydroxy-acids
91
Important dicarboxylic, hydroxy- and oxo- acids II
Tartaric HOOC–CH–CH–COOH Tartarate
Acid name formula R-COOH salt name R-COO−
3-Hydroxybutyric CH3–CH–CH2–COOH 3-Hydroxybutyrate
OH
Malic HOOC–CH–CH2–COOH Malate
OH
OH OH
Citric CH2–COOH Citrate
HO–C–COOH
CH2–COOH
Pyruvic CH3–CO–COOH Pyruvate
Acetoacetate CH3–CO-CH2-COOH Acetoacetate
Oxalacetic HOOC-CO–CH2-COOH Oxalacetate
2-Oxoglutaric HOOC–(CH2)2–CO–COOH 2-Oxoglutarate
(α-ketoglutaric) (α-ketoglutarate)
Oxalosuccinic HOOC–CO–CH(COOH)CH2(COOH) Oxalosuccinate 92
Chemical reactions
1. Neutralisation - salt formation
CH3 – COOH + NaOH CH3 – COO- Na+ + H2O
Acetic acid sodium acetate
Sodium and potassium salts – well soluble in water
(COOH)2 + Ca(OH)2 (COO)2 Ca + H2O
Oxalic acid calcium oxalate - insoluble (urine stones)
- organic acids at pH near to 7.4 form in cells salts
- dissociated in the form of anions R – COO-
- soaps – sodium and potassium salts of fatty acids
- palmitic acid CH3–(CH2)14 - COONa
- stearic acid CH3–(CH2)16 - COOK 94
2. Decarboxylation
- CO2CH3 – CH2 – COOH CH3 - CH3
propanoic acid ethane
HOOC–CH2–CH2–CO–COOH (O)
– CO2
HOOC–CH2–CH2–COOH
Succinic acidOxoglutaric acid
– CO2
O=C–COOH
CH – COOH
CH2– COOH
Oxalsuccinic acid
95
dehydrogenation
HOOC–CH=CH–COOH
Fumaric acid
DERIVATIVES of CARBOXYLIC ACIDS
1. Functional derivatives
- substitution of – H or - OH group of carboxyl with another atom
or atom group
- esters, thioesters, halogenides, amides, anhydrides
2. Substitution derivatives
- substitution of hydrogen atom/s in side chain of carboxylic acids
with another atom or atom group
- hydroxyacids, oxoacids, amino acids, halogene acids
96
DERIVATIVES of CARBOXYLIC ACIDS
O
R – C – O – H
- M (salt) –––––––––––––––––
– X (halogenides)
– NH2 (amides)
– O – R (esters)
– O – CO – R (anhydrides)
≡ N (nitrils)
Functional derivatives
97
Acyl-
+
3. Nucleophilic substitution reactions
- formation of functional derivatives (esters, amides,
anhydrides, halogenides)
- substitution of –OH group in carboxyl by nucleophile
(esterification)
H+
H – COOH + HO – CH3 H – CO – O –CH3 + H2O
Formic acid Methyl formiate
Methylester of formic acid
(+) (-)
Synthesis of aspirin
1899 The First Bottle
of Aspirin
aspirin
COOH
OH
+ CH3COOH- H2O
COOH
O CO CH3
2-Hydroxybenzoic acid (salicylic acid)
Acetic acid Acetylsalicylic acid
esterification
Charles Frederic
Gerhardt (1853)
100
-Transport of acyl in biochemical reactions
coenzyme A, (CoA SH)
- activation of carboxylic acid in metabolic pathways:
R – COOH + HS – CoA → R – CO ~ SCoA + H2O
thioester
- thioesters – active form of carboxylic acids (acyls) in cells
CH3– CO ~ S-CoA acetyl – CoA
CH3 – CO ~ CoA the key intermediate of metabolism
of lipids, saccharides and proteins
- substrate for Krebs cycle (citric acid cycle) 101
Acyl-
2. Hydrolysis of esters
R – CO – O – R1 + HOH → R – COOH + R1 – OH
R – rest of fatty acid Salt of fatty acid
Alkaline hydrolysis of esters, so called saponification:
R – CO – OR1 + NaOH → R – COO− Na+ + R1 – OH
Ester Acid Alcohol
Soap – sodium or potassium salt of fatty acids
103
NAD+
Amides of carboxylic acid
O
R – C – O – H
O
R – C – NH2+ NH3 + H2O
Amide of carboxylic acid
Amide of nicotic acid
Niacine
Vitamin PP 105
- Substitution derivatives
γ(4) β(3) α(2) 1 O
R – CH2 – CH2 – CH – C
OH
- X (halogene of carboxylic acid)
- OH (hydroxy acids)
- NH2 (amino acids)
= O (aldehyde- and oxo-acids)
H
!
106
- Hydroxy acids
CH3 – CH CO O
O CO CH –CH3
lactide
CH3 – CH – COOH HO
OH HOOC+
CH – CH3
- 2 H2O
α –hydroxy acids eliminate water to lactides at higher temperature
107
Cyclic diester
ß- a - Hydroxy acids
–hydroxy acids eliminate water (dehydrated) to unsaturated acids at
higher temperature:
-H2O
CH3 − 3CH – CH2 – 1COOH CH3 − CH = CH − COOH
Temp.
OH
3–Hydroxybutanoic acid 2- Butenoic acid
γ –hydroxy acids dehydrated to lactons at higher temperature:
R – CH – CH2 – CH2 – C
O H OH
γ β α
R–CH–CH2–CH2–C=O
O
γ– hydroxy acid γ – lactone
-H2OO
109
CH3 – CH – COOH
OH
+2H
-2H
CH3 – C – COOH
O
Lactic acid Pyruvic acid
CH3 – CH – CH2 –COOH
+2H
-2H
CH3 – CO –CH2 –COOH
OH
αβ
β – hydroxybutyric acid Acetoacetic acid
Oxidation of hydroxy acids
112
Reaction of ß-oxoacidsimportant in the metabolism of fat
CH3−C−CH2−COOH
║
O
Acetoacetic acid
NADH + H+
hydrogenation
− CO2 ketone
forming
cleavage
(OH- ) acid
forming cleavage
CH3−CH−CH2−COOH
OH
-Hydroxybutyric acid
CH3−CO−CH3
Acetone
2 CH3−COOH
Acetic acid
113
CH3 – CH – CH2 COOH
OH
β – hydroxybutyric acid
CH3 – CO – CH2 – COOH acetoacetic acid
CH3 – CO –CH3 acetone
Ketone bodies in the organism
In trace amount in blood, urine
At higher concentration in urine – ketonuria (ketoacidosis) (starvation, diabetes)
114
Transamination
transaminases
Glutamic acid Phenylpyruvic acid 2-oxo-glutaric acid Phenylalanine
115
Citrate cycle
C4C6
C2
C5
C4
116
Nobel price for physiology and
medicine, 1953
Discovery of citric acid cycleHe was born in Hildesheimu (Germany) in the family of Judaic
physician. After studying medicine he studied also chemistry
in Berlin for one year.
His most important discovery was Citric cycle (Krebs cycle).
Krebs Hans Adolf (1900 - 1981)
117
118
Citrate formation from Oxaloacetate and
Acetyl-CoA
- CoA-SH
H
119
Citrate/Isocitrate isomerisation
120
Oxalosuccinate and α-oxoglutarate formation
CO2
121
CO2
Succinyl-CoA formation
CO2
122
Succinate formation
HOH
Fumarate formation
124
Malate formation through water addition
H2O
125
Fumarate
Malate dehydrogenation
126
Derivatives of H2CO3 NaHCO3 Na2CO3 inorganic salts
O
CCl ClPhosgene
Formic acidH
O
C OH
Urea
diamide of carbonic acid
O
CH2N NH2
Thiourea
S
CH2N NH2
Iminourea - guanidine
NH
CH2N NH2
oxidation
HOOC – OH =
Hydroxyformic acid
O
CHO OH Carbonic acid
O=C
NH2
O ~ P
Carbamoyl phosphate
–O P O–~
O
O
C CH2C
O–
O
phosphoenolpyruvate
CH2 O P O–
O
HC OH O–
O C O~ P
O–
O–
O
1,3–bisphosphoglycerate
Macroergic compounds
~
130
Free energy releases through hydrolyses of
phosphates of some macroergic compounds
Compound ∆G0´ kJ.mol-1)
Phosphoenolpyruvate -61,86
Carbamoyl phosphate -51,41
Acetyl phosphate -43,05
Creatine phosphate -43,05
ATP (na ADP) -30,51
Glucose-1-phosphate -30,51
Glucose-6-phosphate -13,79
Glucose-3-phosphate -9,19
131
Organic compounds of nitrogen
Amines - primary R-NH2
- secondary R-NH-R
- tertiary R-N-R
R – NH2 + H+ R – NH3+
Basic properties
Formation of amonium salts
132
AMINOFENOS - Catecholamines
HO CH – CH2 – NH2 HO CH – CH2 – NH – CH3
HOnoradrenaline
HO
OHOH
adrenaline
BIOGENIG AMINES
- decarboxylation of aminoacids
CH2 – CH - COOH
OH NH2 - CO2
CH2 – CH2
OH NH2ethanolamine
serine
AMINODERIVATIVES OF HYDROCARBONS
133
Biological important amines formation
– CH2 – CH – COOH
NH2 – CO2
– CH2 –CH2 –NH2
histaminehistidineN
H
N
N
H
N
134
CH2 – CH2 – CH2 – CH2 – CH – COOH
׀ ׀
NH2 NH2
CH2 – CH2 – CH2 – CH2 – CH2
׀ ׀
Lysine
CO2
NH2 NH2NH3
Cadaverine
NPyrolidine
Putrid process
In dunghill
135
Reaction of amines with nitric acid/nitrates
NH
R
R
+ HO N O N
R
RON + H2O
sekundárny
amín
kyselina
dusitá
nitrózamínSecondary
amine
Nitrous
acid
Nitrosamine
Carcinogen !!
R – CH2 – NH2 + HNO2 R – CH2 – OH + N2 + H2O
Primary amine
Secondary amine
nitrosoamine
137
strong effect on organisms,
high doses are toxic
natural compounds with nitrogene – basic
properties
occurence: products of aminoacid metabolism in
plants
nitrogen - as heterocycle
in water insoluble
botter taste
ALCALOIDs
138
➢Alcaloids derived from pyridine
nicotine – isolated from tabacco leaf
- lethal dose for man - 50 mg
➢Alcaloids derived from thropane
atropine - has very specific effect on the body – is used in treating colitis,
renal and biliary colic, peptic ulcer and irritable bowel syndrome
cocaine - local analgetic
➢Alcaloids derived from chinoline and isochinoline
morphine - a potent opiate analgesic medication
codeine – make softer caugh
heroine (diacetylmorphine) - a semi-synthetic opioid drug synthesized from
morphine, a derivative of the opium poppy - is used as an analgesic.
Frequent and regular administration is associated with
tolerance and physical dependence, which may develop into addiction
➢Alcaloids derived from indole (produced by the ergot fungus and some plants)
lysergid (LSD) – hallucinogens
➢Alcaloids derived from purine
copheine
theobromine
theophyline
Analeptics stimulate CNS, but didnot influence significantly psychic
functions139
ORGANIC COMPOUNDS OF SUPHUR
• Thiols R-SH (disulphides, thioesters)
• Sulphides R-S-R (sulphoxides, sulphons)
• Sulphonic acids, sulphonamides R – SO3H
• Heterocyclic compounds with suphur
(thiophene, thiazol)
S
N
S
thiophene thiazol
140
Tiols and sulfides
Aminoacid methionine
141
Redox reaction of thiols
R – SH + HS – R R – S – S – R + 2H
oxid
red
disulfid
142
Disulfides formation
- 2H+ 2H
143
Redox reactions of thiols – structure of proteins is
changed
Oxidation – 2H
Reduction + 2H
S
S
144
OOC-CH-CH2-CH2-CO-NH-CH-CO-NH-CH2-COO-
NH3+ CH2
SH
SH
NH3+ CH2
OOC-CH-CH2-CH2-CO-NH-CH-CO-NH-CH2-COO
dehydrogenation
- 2H
2 GSH GSSG + 2H
Oxidation of glutathione
145
Thank you for your
attention........
147