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