Ďuračková zdeňka - zona.fmed.uniba.sk · carbon in basic state 2. ... carbon skeleton n-butane...

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