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ORGANIC CHEMISTRY
For General Medicine
Ďuračková Zdeňka
2018
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 principle of the structure of organic
compounds- carbon forms four covalent bonds C
- all 4 bonds are equivalant (hybridization s-, and p-orbitals
– equilisation of all 4 bonds)
- between carbons can be simple, double, or triple bond
(σ and π bound)
– C – C – – C = C – – C = C –
- atoms of carbon form chains – simple straight, branched and
cyclic forms
- between of carbon atoms, atoms of oxygen, nitrogen or
sulphur 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 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
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
Configuration isomerism (stereoisomerism) different arrangement of atoms in space, the same connectivity (order of atoms and
double bonds are identical)
geometrical isomerism, cis – trans (maleinic and fumaric acids)
conditioned by the presence of double bond
Maleinic acid (cis) Fumaric acid (trans)
H – C – COOH HOOC – C – H
|
H – C – COOH H – C – COOH
optical - conditioned by chiral carbon C* (asymetric carbon)
- optical isomers - enantiomers
- rotation of the plane of polarized light by 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(-) - glyceraldehyde11
13
What does it mean + or - ?????
An optically active substance (optical 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 Boat14
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- ...
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
INDUCTIVE EFFECT, I ( for - bond) – related to saturated hydrocargons
effect of polar bond on polarisation in neighbouring bonds
direction of polarisation is identical as 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
Possitive inductive effeckt + I
-atom, resp. group of atoms, which push back electrons:
–CH3 (alkyls)
16
transformation of polar group effect to 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
17
Characteristic for electrons
10
electrons6
electrons
Possitive mesomeric effect, +M
groups repulsive (press out) electrons
thicken of electrons on neighborn carbons with double bonds
groups: -NH2 , -OH , -OR, -SH, -SR, -X (halogens)
O – H
-M +M
18
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 hydroxyderivatives
(alcohols)
- oxidation – cleavage of bond
• aromatic hydrocarbons X
- substitution: halogenation - Cl
(electrophilic sulphonation - SO3H
substitution) nitration - NO2
acylation - CO-R
alkylation - CH2-CH3
X
19
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 20
Prefix de - ..... Elimination of something - double bound is formed
21
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, sum formula CnH2n+2
Non-polar compounds, soluble in non-polar solvents, non-soluble
in H2O
Small reactivity, characteristic reaction - substitution (temperature,
UV radiation)
- example: methane, ethane, propane, butane, pentane,
hexane…, isobutane
HYDROCARBONS
22
Alkenes
non-saturated hydrocarbons, double bond (), binding angle 120°
homological chain, sum formula CnH2n
high reactivity, characteristic reaction – addition
(Markovnik rul)
CH2 = CH2 + HOH CH2 – CH2
OH H
ethene (ethylene) ethanol
catalyst
CH2 = CH2 + 2H CH3 – CH3
ethene ethane23
Dienes (2 double bonds)
cummulated, 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)
24
Alkynes
non-saturated hydrocarbons, triple bond (), binding angle 180°
homological chain, sum formula CnH2n-2
high reactivity, characteristic reaction – adition
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- 25
26
Markovnik 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 Boat27
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)
= =
28
PHENANTHRENE BENZPYRENE
Toxicity of arens (benzene, benzpyrene)
Stability towards oxidation
Characteristic substitution reaction
(nitration, halogenation, sulphonation)
NAPHTHALEN E ANTHRACENE
Polycyclic arens
29
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 30
N
N
N
pyridine pyrimidine pyran
(2H-pyran)
N
N NH
N
O
purine indole
pyrimidine + imidazole benzpyrole
NH
31
O
S
Biologically important derivatives of heterocyclic compounds
Furan
Ribose Deoxyribose
Tiophene
S CH3
Methyltiophene
- in grill meat
32
Biologically important derivatives of heterocyclic compounds - 2
N
S
tiasol
Thiamin – vitamin B1
• Component of carboxylases – oxidative decarboxylation
alfa-oxokyselín
• Metabolism of saccharides in brain
P P
NH
pyrol
Porphin – porphyrin - haeme33
Biologically important derivatives of heterocyclic compounds - 3
N
NH
imidasol
PurinHistidin
Biotin
34
Biologically important derivatives of heterocyclic compounds - 4
O
Pyran
Vitamin EGlucose chroman ring 35
O
saturated
Biologically important derivatives of heterocyclic compounds - 5
N
pyridin
NAD+Amid of nicotinic acid
Niacin
Vitamin PP 36
Biologically important derivatives of heterocyclic compounds - 6
N
N
pyrimidinPurin
Pyrimidin nitrogene bases37
Biologically important derivatives of heterocyclic compounds - 7
caffeine theophilline
Uric acid
38
Biologically important derivatives of heterocyclic compounds - 8
Indol
benzene + pyrol
NH
Tryptophan
Lysergic acid 39
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
Halogenhydrocarbons F
Cl
Br
I
Fluoro-
Chloro-
Bromo-
Iodo-
Nitroderivatives NO2 Nitro-
Nitrosoderivatives NO Nitróso-
Aldehydes HC=O Oxo- - e
Ketons C=O
Oxo- -on
Carboxylic acid COOH Carboxy- -ic acid
40
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- - nitril41
HALOGENDERIVATIVES
Tyroxine – Tetraiodothyronine T4
– Triiodothyronine T3
nucleophilic substitution
׀
C X δ- + OH-
↔ H-C-OH + X-
43
δ+
High TOXICITY
HALOGENEDERIVATIVES of HYDROCARBONS
- insoluble in water, soluble in alcohols and ethers
- polar covalent bond between – C halogene
• characteristic reaction
- substitution (heterolytical termination of bound), as alkylation reagents
• practical use
solvents for non-polar compounds (CCl4)
monomers for preparation of macromolekular compounds (PVC, artificial rubber,
tephlon),
in refrigerator industry (freons – dichloro-difluoromethane)
iodoform CHI3 – disinfection effects
insecticides
dioxins
narcotiks (halotan, CF3-CHBrCl) 44
• toxicity
influence on central nerves system (CNS)
tetrachlorodibenzodioxin – carcinogenic, teratogenic, mutagenic effects
(c 1mg.l-1) (dioxins)
cancerogens or suspect carcinogens (CHCl3 , CCl 4)
Toxicity of halogenederivatives
DDT – insecticide DichloroDiphenylTrichlorethane
(1948 Paul Hermann Müller won Nobel Price for DDT discovering)
45
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. 46
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
47
1. ALCOHOLS
Polarity of bond R O H - reactivity of hydroxyderivatives
Dividing:
1. according place of -OH group bounding 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)
48
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 49
Acidic character of alcohols
CH3- CH2-O-H + NaOH CH3- CH2-O- + Na+ + H2O
Sodium alcoholate
50
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
51
3. Tertiary alcohols:
stable against moderate oxidative reagens
cleavage of - C – C - bound with strong oxidative reagent (K2Cr2O7)
CH3 CH3
oxidation
CH3 –C – OH CH3 –C = O + HCOOH
CH3 acetone formic acid
52
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
53
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
54
Esterifikacion with organic acids
R – OH + HOOC – R
ester
+ H2OR – O – CO – R
55
Reaction with inorganic acidsEsterification of alcohols with sulphuric acid
R – O –H + HO – SO2 – OH - H2O
Alcohol H2SO4
56
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
57
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 of heart diseases)
58
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
59
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
60
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
61
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)
62
- 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
63
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
64
phosphoanhydric arrangement
O O
R – O - P – O ~ P – OH
protone-donoric
OH OH groups
phosphoester bound
65
ATP + H2O ADP + Pi G0 - 32 kJ.mol-1 66
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 67
- Acidic character of phenols
(higher than of alcohols)
- Toxicity of alcohols and phenols
OH + NaOH O - + Na+ + H2O
Sodium phenolate
68
Oxidation of dihydroxyarenes – diphenols
- formation of quinones, cyclical conjugated diketons
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)69
Cyclic,
nonsaturated
di-keton
- 2H
+ 2H
1,2-hydroquinone
(pyrocatechol)
1,2-benzoquinone
resorcinol
oxidátion
Gallic acid
- CO2
Pyrogalol
use in photograph,
hair daying
Tanins, antioxidantbounded to saccharid
unit 70
Koenzyme Q
Oxidation
- 2H
Reduction
+ 2H
Involved in respiratory chain in mitochondria 71
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 leaf.
72
OXO-compounds (aldehydes and ketons)(polarisation of bound to oxygen)
R – Cδ+ Cδ+ = Oδ-
Oδ-
H
R
R
Aldehydes Ketons
73
+
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 Ketons C = O
H R
- polarisation of group – reactivity of aldehydes and ketons
OXO-compounds
74
Chemical reactions of oxo-compounds
Oxidation and reduction
aldehyde
reductionR – CH2 –OH
primary alcohol
O
R – C – H
oxidationO
R – C –OH
carboxylic acid
+2H (Ni)
or donor H atom
- 2H
75
O
R – C – R
Ketone
Reduction
catalyst Ni
or donor H atoms
relatively stable against oxidation
OH
R – CH – R
secondary alcohol
Oxidation
- 2H
76
oxidation and reduction in living systems
(coenzymes of dehydrogenases as acceptors and donors of H atoms)
- NAD+ - akceptor H (hydride ion) at the oxidation of alcohol
- NADH – reduced form of coenzymes – donor of H (hydride ions)
CH3 CH – OH + NAD+ CH3 C = O + NADH + H+
H H
ethylalcohol acetaldehyde
77
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
78
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
79
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
80
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
81
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
82
Use of 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
83
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 intermediators of biochemical reactions
- binding of carbonyl compounds to free aminogroups of proteins
- H2O
84
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
85
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
86
CARBOXYLIC ACIDS
C
O
OH
120°
120°
120°
- Shift of - elektrons in group C = O
- Polarisation of – O H bound
O H
R – C = OR – C
O
O
+ H+
- Mostly weak acids, K(ionis.const.) = neer to 10-5
- According to number of – COOH groups:
mono-, di- and tricarboxylic acids
- Saturated and unsaturated 87
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
88
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 Maleinic (cis-
form) Maleinate
Lactic CH3–CH–COOH Lactate
OH
Important dicarboxylic and hydroxy-acids
89
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 90
Chemical reactions
1. Neutralisation - salt formation
CH3 – COOH + NaOH CH3 – COO- Na+ + H2O
Acetic acid sodium acetate
Sodium and potassium salts – good soluble in water
(COOH)2 + Ca(OH)2 (COO)2 Ca + H2O
Oxalic acid calcium oxalate - insoluble (urine stons)
- 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 92
2. Dekarboxylation
- 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
Oxaljantaric acid
93
dehydrogenation
HOOC–CH=CH–COOH
Fumaric acid
DERIVATIVES of CARBOXYLIC ACIDS
1. Functional derivatives
- substitution of – H or - OH group of carboxyl by another atom
or atom group
- esters, thioesters, halogenides, amides, anhydrides
2. Substitutional derivatives
- substitution of hydrogen atom/s in side chain of carboxylic acid
by another atom or atom group
- hydroxyacids, oxoacids, aminoacids, halogeneacids
94
DERIVATIVES of CARBOXYLIC ACIDS
O
R – C – O – H
- M (salt) –––––––––––––––––
– X (halogenides)
– NH2 (amides)
– O – R (esters)
– O – CO – R (anhydrides)
≡ N (nitrils)
Function derivatives
95
Acyl-
+
3. Nucleophilic substitutional reactions
- formation of functional derivatives (esters, amides,
anhydrides, halogenides)
- substitution of –OH group in carboxyl by nucleophil
(esterifikation)
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)
98
-Transport of acyl in biochemical reactions
coenzyme A, (CoA SH)
- activation of carboxylic acid in v metabolic pathways:
R – COOH + HS – CoA R – CO ~ SCoA + H2O
thioester
- thioesters – activ form of carbocylic 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) 99
Acyl-
2. Hydrolyses of esters
R – CO – O – R1 + HOH R – COOH + R1 – OH
R – rest of fatty acid Salt of fatty acid
Alcaline hydrolyse of esters, so called as saponification:
R – CO – OR1 + NaOH R – COO Na+ + R1 – OH
Ester Acid Alcohol
Soap – sodium or potassium salt of fatty acids
101
NAD+
Amides of carboxylic acid
O
R – C – O – H
O
R – C – NH2+ NH3 + H2O
Amide of carboxylic acid
Amid of nicotic acid
Niacine
Vitamin PP 103
- Substitutional derivatives
γ(4) β(3) α(2) 1 O
R – CH2 – CH2 – CH – C
OH
- X (halogene of carboxylic acid)
- OH (hydroxyacids)
- NH2 (aminoacids)
= O (aldehyde- and oxo-acids)
H
!
104
- Hydroxyacids
CH3 – CH CO O
O CO CH –CH3
lactid
CH3 – CH – COOH HO
OH HOOC+
CH – CH3
- 2 H2O
α –hydroxyacids eliminate water to lactids at higher temperature
105
Cyclic diester
106
Polylactides formation
- immunoadjuvant based on micro-
and nano-particles for oral and
parenteral administration
- material for drug delivery with the
controlled release (system for
targeted and controlled delivery of
folic acid in the body)
ß- a - Hydroxyacids
–hydroxyacids eliminate water (dehydrated) to unsaturated acids at
higher temperaturae:
-H2O
CH3 3CH – CH2 – 1COOH CH3 CH = CH COOH
T
OH
3–Hydroxybutanoic acid 2- Butenoic acid
λ –hydroxyacids dehydrated to lactons at higher temperaturae:
R – CH – CH2 – CH2 – C
O H OH
γ β α
R–CH–CH2–CH2–C=O
O
γ – hydroxyacid γ – lacton
-H2OO
107
Carnitin
ßß
Salicylic acid
ß
Important
ß-hydroxyacids
- It links FA from fatts and transports
them into mitochondria
- ATP formation
- It is present in sheep and lamd
meet
Synthesis of ascorbic acid– lactone derivative
O = C
HO – CH
HO – CH
HO – CH2
HC
O
HO – CH
L-gulono-
lacton
L-gulonolacton dehydrogenase
O
=O
OH OH
CH2 – OH
HO – CH
Kys. L-ascorbic
acid (vitamín C)
- 2H
109
L-gulonoic
acid
D – glukuronic
acid
COOH
HO – CH
HO – CH
HO – CH2
HC – OH
HO – CH
+ 2H
1
6
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 – hydroxybutiric acid Acetoacetic acid
Oxidation of hydroxyacids
110
Reaction of ß-oxoacidsimportant in the metabolism of fatt
CH3CCH2COOH
║
O
Acetoacetic acid
NADH + H+
hydrogenation
CO2 ketone
forming
cleavage
(OH- ) acid
forming cleavage
CH3CHCH2COOH
OH
-Hydroxybutyric acid
CH3COCH3
Acetone
2 CH3COOH
Acetic acid
111
CH3 – CH – CH2 COOH
OH
β – hydroxybutyric acid
CH3 – CO – CH2 – COOH acetoacetic acid
CH3 – CO –CH3 aceton
Ketone bodies in the organism
In trace amount in blood, urine
At higher concentration in urine – ketonuria (ketoacidosis) (starvation, diabetes)
112
Transamination
transaminases
Glutamic acid Phenylpyruvic acid 2-oxo-glutaric acid Phenylalanine
113
Citrate cycle
C4C6
C2
C5
C4
114
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 of medicine he studied in Berlín also
chemistry one year.
His most important discovery was Citric cycle (Krebs cycle).
Krebs Hans Adolf (1900 - 1981)
115
116
Citrate formation from Oxylacetate and
Acetyl-CoA
- CoA-SH
H
117
Citrate/Isocitrate isomerisation
118
Oxalosuccinate and α-oxoglutarate formation
CO2
119
CO2
Succinyl-CoA formation
CO2
120
Succinate formation
HOH
Fumarate formation
122
Malate formation through water addition
H2O
123
Malate dehydrogenation
124
Derivatives of H2CO3 NaHCO3 Na2CO3 inorganic salts
O
CCl ClPhosgene
Formic acidH
O
C OH
Urea
diamid od urea
O
CH2N NH2
Thiourea
S
CH2N NH2
Iminourea - quanidine
NH
CH2N NH2
oxidation
HOOC – OH =
Hydroxyformic acid
O
CHO OH Carbonic acid
DERIVATIVES OF H2CO3
H – O H2N
C = O C=O
H – O H2N
- derivative of urea H2N
C = NH
H2N
NH2
O = C
NH – CO – CH3
NH - CO
O = C CH2
NH - CO
urea
diamide of carbonic acid
iminourea
guanidine
acetylurea
barbituric acid126
NH2 NH C = O
HN = C HN = C
N – CH2 – COOH N CH2
CH3 - H2O CH3
NH2
HN = C
N – CH2 – COOH
NH ~ PO(OH)2 NH CO
HN = C HN =C
N – CH2 – COOH N CH2
creatine creatinine
׀
CH3
ATP
ADP
CH3
H3PO4
creatinphosphate creatinine
CH3
ATP
127
O=C
NH2
O ~ P
carbamylphosfate
–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
Makroergic compounds
~
128
Free energy of hydrolyses of phosphates
of some makroergic compounds
Compound ∆G0´ kJ.mol-1)
Phosphoenolpyruvate -61,86
Carbamylphosfate -51,41
Acetylphosfate -43,05
Creatínphosfate -43,05
ATP (na ADP) -30,51
Glucosa-1-phosphate -30,51
Glucosa-6-phosphate -13,79
Glucosa-3-phosphate -9,19
129
Organic compounds of nitrogene
Amines - primare R-NH2
- secondary R-NH-R
- tertiare R-N-R
R – NH2 + H+ R – NH3+
Basic properties
Formation of amonium salts
130
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
131
Biological important amines formation
– CH2 – CH – COOH
NH2 – CO2
– CH2 –CH2 –NH2
histaminehistidineN
H
N
N
H
N
132
CH2 – CH2 – CH2 – CH2 – CH – COOH
׀ ׀
NH2 NH2
CH2 – CH2 – CH2 – CH2 – CH2
׀ ׀
Lysine
CO2
NH2 NH2NH3
Cadaverine
NPyrolidine
Putrid process
In dunghill
133
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
135
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
136
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
functions137
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
138
Tiols and sulfides
Aminoacid methionine
139
Redox reaction of thiols
R – SH + HS – R R – S – S – R + 2H
oxid
red
disulfid
140
Disulfides formation
- 2H+ 2H
141
Redox reactions of thiols – structure of proteins is
changed
Oxidation – 2H
Reduction + 2H
S
S
142
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
143
Derivatives of sulfanilic acid
sulfonamides
Folic acid
Sulfanilic acid sulfonamid
Sulfanic acid
144
Thank you for your
attention........
145