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Organic Chemistry

Medical Chemistry and Biochemistry

Winter term

© Institute of Medical Biochemistry and Laboratory Diagnostics of the General University Hospital and of The First Faculty of Medicine of Charles University in Prague - 2005-2015

Synthesis of urea

(Wöhler 1828) (Thermic rearrangement)

NH 2 N C O NH 4 O C NH 2

Friedrich Wöhler (1800-1882): Organic compound formed from inorganic compounds Jan Horbaczewski (1854-1942): He graduated on the Faculty of Medicine in Wienna by prof. Ludwig; Founder of the Department of Medical Chemistry

Synthesis of uric acid

( Horbaczewski 1882 – age of 28) O NH2 O O C NH2 + H2C C OH H N H N O NH2 O NH NH Urea + Glycine + (heat) = Uric acid (very low efficiency)

(discovered by Schulz 1776)

Organic chemistry 2014/2015 3

Synthesis of uric acid

(Horbaczewski 1882)

O OH O C H N H N HC O O NH NH CH2 Acrylic acid Uric acid

During further experiments he proved that uric acid is formed by decomposition of nucleus-containing cells only, this process was not observed in cells without nucleus (e.g., erythrocytes) He successfully separated uric acid from xanthine and other purine bases and correctly supposed that uric acid is formed from these substances.

Organic chemistry 2014/2015 4

Bonds in organic compounds

The bond polarity depends on the difference of electronegativities. Presence of polar and non-polar bonds significantly affects the resulting character of the organic compound: Bind distance and binding energy - examples Bond Energy [kJ.mol

-1 ] Distance [pm] C-C C=C C  C C-H 347 611 837 414 154 133 120 106 C-N C  N C-O C=O N-H O-H 293 891 352 732 389 464 147 116 143 122 101 100 Organic chemistry 2014/2015

Values of energy are approximate („average“). In molecules are influenced by surrounding structures, i.e., by other parts of the molecule. There are s. c. hybrid (partial) bonds (e.g., benzene – 1.5).

5

Stereochemistry (Three-dimensional structure of organic compounds) – Formulas of organic compounds

Constitution:

Inner structure of the molecule of organic compounds

Molecular formulas

are in organic chemistry practically inapplicable, because they do not yield the most important information about the inner structure of the molecule.

e.g., C 2 H 6 O can be : 1) Ethanol (CH 3 -CH 2 -OH) 2) Dimethylether (CH 3 -O-CH 3 ) Therefore, the

structural

formulas are used, because they show all bonds among atoms. Disadvantage of such formulas consists in their complicity in case of more complicated compounds.

Most frequently

the

rational

formulas are used, in which are marked out only such bonds, which are necessary for unambiguous determination of the constitution – three dimensional configuration. For absolutely exact definition of

3D

organization of the organic molecule, it is necessary to use

perspective

formulas (the bonds aiming upwards and downwards, forwards, backwards are differentiated). The use of

models

, which can help by solving of e.g.

DNA

structure (Watson and Crick - Nobel prize for chemistry), seems to be optimal. The computers can simplify significantly the work with such models.

Organic chemistry 2014/2015 6

Isomers

Isomers:

Isomers are molecules, which have the same molecular formula, but they have a different arrangement of the atoms in space.

Organic chemistry 2014/2015 7

Basic types of isomerism:

Isomers I.

Constitutional (Structural) isomerism:

Isomers have different constitution, i.e., they have a different arrangement of the atoms in space or in molecule.

Chain:

Butane, isobutene (arrangement of chain)

Position:

chains have variable amounts of branching (groups: 1-propanol, 2-propanol) (bonds: 1-buten, 2-buten)

Tautomerism

- Isomers differs in the position of the hydrogen and double bond, e.g., acetamide (Amide of acetic acid) O H O H3C C NH2 H3C C N H The dynamic equilibrium is established between both tautomers. Organic chemistry 2014/2015 8

Isomers II.

Keto-enol-tautomerism

is best known CH3 C CH2 COOH CH3 O Keto (oxo) form

Acetoacetic acid

C OH CH enol form COOH

Conformation

of the molecule is given by the free rotation of molecules along single bonds. There are (theoretically) possible (by more complicated molecules) large amounts of conformations; they are limited by energy of the positions and by weak bonds (hydrogen bridges, ionic and non-polar interactions). Organic chemistry 2014/2015 9

Isomers III.

Stereoisomerism (spatial):

the bond structure is the same, but the geometrical positioning of atoms and functional groups in space differs.

Various configurations are given by double bond (cis-trans isomers) or by presence of a chiral center (an asymmetric carbon C*).

cis-trans (geometric) isomerism

is a result of the impossibility of the rotation along the double bond (it is caused by binding  -orbitals). CH3 CH3 CH3 H C C C C H H H CH3

cis

-2-butene

trans

-2-butene Organic chemistry 2014/2015 10

Isomers VI.

Asymmetric carbon

has each bond occupied by completely different single-bonded atom or group of atoms, therefore

the structure has not any symmetry plane

. There exit two possible space arrangements:

subject and its mirror image

. By their differentiation we go out from structure of glyceraldehyde: O H O H H C C OH CH2OH HO C C H CH2OH D- and L- isomers are characterized by equal chemical reactivity, but biochemically can differ mutually substantially (reactions with enzymes or antibodies) D L Compounds containing asymmetric carbon show optical rotation and they form

optical antipodes - enantiomeres.

Rotation is labeled: (+) – to the right and (-) – to the left.

The aim of light rotation is not connected with the D- and L- labeling!!!!!

Organic chemistry 2014/2015 11

Classification of organic compounds

Organic compounds

Aliphatic Cyclic Saturated (single bonds) Unsaturated (multiple bonds) Isocyclic (carbocyclic, C only) Heterocyclic (in ring are other atoms then C) Alicyclic Saturated Aromatic (conjugated double Unsaturated bonds in ring) Saturated Unsaturated Aromatic Organic chemistry 2014/2015 12

Most important arenes I

Benzene Naphtalene Anthracene Tetracene (partly hydrogenated „tetracycline“) Phenanthrene Cyclopentano perhydrophenanthrene base of steroids Organic chemistry 2014/2015 13

Most important arenes II

Pyrene Benzopyrene (carcinogenic) Benzo[

a

]pyrene Biphenyl (Polychlorated biphenyls - toxic for CNS of children) Diphenylmethane H C H Base of DDT – p,p’-dichloro diphenyl trichloroethane Organic chemistry 2014/2015 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane 14

Halogen derivatives of hydrocarbons

One or more hydrogens are substituted by a halogen (X = F, Cl, Br, I) Bond is

weak polar

– insoluble in water, good soluble in non-polar solvents. Most of these compounds are volatile liquids, which are very good non-polar („organic“ or „fat“) solvents. Chemically are very reactive, especially with nucleophilic substances.

Application:

        Solvents -

Tetrachloromethane,

CCl 4 (COCl 2 ) with water

Freons (Fluorochloroalkanes)

(toxic, carcinogenic). It forms phosgene - CCl 3 F, CCl 2 F 2 and other in refrigerators – they damage ozonosphere

Plastics

- PVC, synthetic rubber, Teflon Chlorophorm CCl 3 H - toxic, Bromophorm CBr 3 H – against cough, Iodoform CI 3 H - disinfection, antiseptic agent, proof of acetone (iodoform reaction) Anesthetic - local - earlier ethyl chloride CH 3 CH 2 Cl („kelene“ - freezing) Anesthetic – general - Trichloroethylene CHCl=CCl 2 Halothane CF 3 -CHBrCl

Biologically active substances

(narcotic) – thyroid gland hormones (triiodo-L thyronine, Tetraiodo-L-thyronine=thyroxine) Older insecticide - DDT, HCH (hexachlorocyclohexane - Lindane) – its use is prohibited at present Organic chemistry 2014/2015 15

Hydroxy derivatives (alcohols, phenols)

Hydroxyl group

-OH

gives to hydrocarbons, especially to aromatic, weak acidic character (

Attention – they are not hydroxides!!!

) O H O H O H R R R Bond

C-OH

is covalent, nevertheless

strong polar

, therefore the hydrogen bridges can be formed. Consequently, the simpler alcohols are good miscible with water, only by higher alcohols the non-polar character of side chain prevails (pentanol – amyl alcohol)

Terminology:

By aliphatic - hydrocarbon +

-ol

(methanol, ethanol) By aromatic compound used frequently more

trivial

Organic chemistry 2014/2015 16

Hydroxy derivatives (alcohols, phenols)

Hydroxyl group

of alcohols is strongly reactive.

With

alkali metals

produces

alkoxides

C 2 H 5 OH + Na = C 2 H 5 ONa + 1/2H 2 The hydroxyl group with

acids

produces esters with

mineral

acids are formed: R-OH + H-X = R-X + H 2 O with

organic

acids are formed: O H + HO C R' R O C R' + H2O R O O

Esterification

is typical

reversible

reaction – (hydrolytic) dissociation of esters can be realized, producing alcohol and acid – common reaction in life organisms.

Organic chemistry 2014/2015 17

Alcohols and phenols I

Methanol:

CH 3 OH toxic, blinding, danger of death

Ethanol:

CH 3 CH 2 OH - euphoric, narcotic effect. Habitudinal drug – most often toximania (drug addiction).

Higher alcohols

- propanol, butanol, pentanol have some isomers.

Higher alcohols can be a part of lipids.

More functional alcohols: 1,2-ethandiol (ethylene glycol) HO-CH 2 -CH 2 -OH

toxic, heavy poisons, harmful for kidneys.

Glycols are parts of antifreeze mixtures for cooling systems automobile radiator („Fridex“) - sweet –soluble in water.

1,2,3-propanetriol (glycerol)

Part of most of lipids. CH2 CH OH OH CH2 OH Organic chemistry 2014/2015 18

Alcohols and phenols II

Cyclohexanol (inositol):

Biologically important compound, similar type as vitamins H O H O OH OH OH OH

Phenol:

(weak acid)

Toxic, corrosive !!!

O H O O + H+

Hydroquinone (1,4-benzenediol)

OH OH -2H +2H O O Organic chemistry 2014/2015

Para-benzoquinone

(Redox = Oxidation – reduction systems) 19

Biologically important alcohols I

Sphingosine (sphingenine)

(trans-D-erythro-)2-amino-4-octadecene-1,3-diol-18-carbon alcohol contained in complex lipids, especially in encephalic lipids

Ethanolamine: HO-CH 2 -CH 2 -NH 2

Part of lipids CH3

Choline

HO CH2 CH2 N+ CH3 OH Part of lipids. CH3 Its ester with acetic acid is very important for transport of neural excitements.

Strong basic, Quaternary ammonium base.

Organic chemistry 2014/2015 20

Biologically important alcohols II

We can classify also vitamins soluble in fats (exclusive vitamin K) as alcohols

Vitamin A - retin ol Vitamin E - tocopher ol Vitamin D - cholecalcipher ol and ergocalcipher ol

Fat-soluble vitamins are described in detail in chapter „Steroids and isoprenoids“ Organic chemistry 2014/2015 21

Aldehydes and ketones (oxo-derivatives) I

R

Carbonyl group

Common group for R' C O

ketones

carbonyl on secondary carbon

aldehydes

carbonyl on primary carbon Aldehydes can be aliphatic or aromatic, ketones are mixed.

Carbonyl group is polar, therefore the compounds have good miscibility with polar solvents. Character of the group does not enable formation of large clusters by means of hydrogen bridges.

Therefore, the boiling point is lower than by alcohols, but higher than by corresponding hydrocarbons. Most of aldehydes and ketones are at normal temperature

country 25 o C- 298 K) (laboratory temperature, in our

(exclusive formaldehyde H 2 CO) liquid.

Organic chemistry 2014/2015 22

Aldehydes and ketones (oxo-derivatives) II

They exhibit very high reactivity. The addition on carbonyl is very easy realizable.

The formation of

hemiacetal

is very important (

see carbohydrates

).

Difference

: Aldehydes have reducing character (reductants)– they are easy oxidized to carboxylic acids vs. ketones do not have reducing character. Aromatic aldehydes form with primary amines

Schiff base

H C O + H N CH3 -H2O C N CH3 H H Benzaldehyde Methylamine Benzylidenemethylamine (Schiff Base) Important by transamination – Schiff base forms pyridox

al-

phosphate with ammonium group of amino acids Organic chemistry 2014/2015 23

ETHERS

General formula:

R 1 -O-R 2 Esters do not form hydrogen bridges. Therefore the boiling point is lower than by corresponding alcohols: Mol. mass [g.mol

-1 ] CH 3 OH 32 CH 3 -O-CH 3 46 Boiling point [ o C] 65 -24 They are practically non-polar. Higher, e.g., diethylether, are used for extraction of non-polar compounds from aqueous solutions.

Diethylether

is the most frequently used ether: CH 3 -CH 2 -O-CH 2 -CH 3

Attention – the vapors are explosive.

Explosive peroxides are formed on light and in the presence of air. It is necessary to store it in dark bottles and to stabilize (e.g., diphenylamine).

Organic chemistry 2014/2015 24

ETHERS II

Important aromatic ethers, e.g.:

OH

Guaiacol

O CH3 (1-hydroxy-methoxybezene) Part of cough-syrups.

Gujacuran

O CH2 OH CH CH2 OH O CH3 1-(2-methoxyphenoxy)-2,3-propanediol Medicine calming and lowering hypermyotonia (muscular stress) Organic chemistry 2014/2015 25

Characteristic group:

Carboxylic acids I

OH R C

Carboxyl group

O According to the number of these groups we call these compounds

mono-

,

di-

,

tri-

and

polycarboxyl(s)

. They are relatively weak acids (pK A = 4-5).

Carboxyls form mutually hydrogen bridges, and therefore the carboxylic acids exist mostly in form of dimers or of polymers . R C OH O C R O OH Organic chemistry 2014/2015 26

Carboxylic acids II

Hydroxyl group of carboxyl dissociates proton (in consequence of the transfer of the electrons), therefore the carboxylic acids have character of acids.

R C O O H R + C O O + H+ The strength of carboxylic acid is influenced also by the rest of molecule (e.g., number of carbons, number of carboxyls or of other substituents). Organic chemistry 2014/2015 27

Carboxylic acids III

Labeling of carbons in the molecule: 5 4 3 2 1

Properties:

1. Formation of salts

R-CH

2

-CH

2

-CH

2

-CH

2

-COOH

   2. Possible decarboxylation, i.e., elimination of CO 2 under production of the one carbon shorter hydrocarbon (common reaction in biochemistry, in industrial organic chemistry very complicated process).

 3. Reaction of carboxyl under formation of functional derivatives of carboxylic acids 4. Substitution on hydrocarbon part  substitution derivatives of carboxylic acids The radical formed by removing of

-OH

group from carboxyl is (generally) called

ACYL

. The names of radicals are derived from the name of the acid + ending

-YL

.

H CH3 C O Formyl C O Acetyl Organic chemistry 2014/2015 28

Formula

Monocarboxylic acids I

Trivial English name - acid Formic Systematic English name - acid Latin name acidum Methanic Formicum Salt name Formiate HCOOH* CH 3 COOH CH 3 CH 2 COOH CH 3 (CH 2 ) 2 COOH (CH 3 ) 2 CHCOOH CH 3 (CH 2 ) 3 COOH CH 3 (CH 2 ) 14 COOH Acetic Propionic Butyric Isobutyric Valeric Palmitic Ethanic Propionic Butanic Isobutanic Pentanic Hexadecanoic

*Character of an aldehyde, i.e. reducing agent

Organic chemistry 2014/2015 Aceticum Acetate Propionate Butyrate Isobutyrate Valerate Palmitate 29

Monocarboxylic acids II

Formula Trivial English name - acid Stearic Systematic English name - acid Octadecanoic CH 3 (CH 2 ) 16 COOH CH 3 (CH 2 ) 7 CH=CH (CH 2 ) 7 COOH Oleic CH 2 =CHCOOH Acrylic cis-9 Octadecenoic acid 2-en 1-propanic Latin name acidum Salt name Stearate Oleate Acrylate Benzoic benzoicum Benzoate COOH Organic chemistry 2014/2015 30

Dicarboxylic acids

Formula Trivial English name - acid

Attention: malate – maleate - malonate

Systematic English name - acid Latin name acidum Salt name HOOC-COOH Oxalic 1,2-Ethandiic Oxalicum Oxalate HOOC-CH 2 -COOH Malonic* Propan-1,3-diic Malonicum* Malonate* Succinic Butan-1,5-diic Succinicum Succinate HOOC-(CH 2 ) 2 COOH HOOC-(CH 2 ) 3 COOH HOOC COOH C C H H HOOC H C C H COOH COOH COOH Glutaric Maleic* Fumaric Phthalic Pentan-1,5-diic cis-but-2-en-1,5 dioic trans-but-2-en-1,5 dioic o-Benzenedicarboxylic acid Glutamicum Glutarate Maleate* Fumarate Phthalate Organic chemistry 2014/2015 31

Tricarboxylic acids

HOOC CH2 C CH HOOC COOH cis-aconitic acid, important metabolite of Krebs cycle; salt: cis-aconitate OH HOOC CH2 C CH HOOC COOH citric acid, important metabolite of Krebs cycle; salt: citrate

In detail: see substitution derivatives of carboxylic acids

Organic chemistry 2014/2015 32

Substitution derivatives of carboxylic acids I

1) Halogen acids

trichloroacetic, monofluoroacetic – poison

2) Hydroxy acids

– biochemically and medically important!

CH3 CH COOH -2H +2H CH3 OH lactic acid (lactate)  -hydroxy propionic

Hydroxy propionic

C COOH O pyruvic acid (pyruvate)

Ketoacid

Organic chemistry 2014/2015 33

R

Substitution derivatives of carboxylic acids II

 - and  -hydroxy acids are esterified within their molecules → a cyclic ester is formed -

lactone

      CH CH2 CH2 C O -H2O R CH CH2 CH2 C O OH OH O  - lactone

E.g., Vitamin C

=

L-ascorbic acid = dehydrolactone of gulonic acid Carbonic acid

Hydroxyl The simplest hydroxy acid HO Organic chemistry 2014/2015 C OH Carboxyl O 34

Most important hydroxy acids I

1)

Lactic acid

, acidum lacticum, lactate ( L and D forms) 2)

Glyceric acid

, salt:

glycerate

CH2 CH COOH 2,3-dihydroxypropionic acid Glycolysis (1 i 2) OH OH 3)

Malic acid,

acidum malicum, malate OH CH (2-hydroxybutandiic acid) 4) (Krebs cycle)

Tartaric acid

, acidum tartaricum,

tartarate

COOH COOH COOH CH2 COOH COOH COOH H HO C C OH H HO H C C H OH H H C C OH OH  HO HO C C H H COOH (+) Tartaric acid “right-handed“ tartaric COOH (-) Tartaric acid “ Left-handed“ tartaric Organic chemistry 2014/2015 COOH Mesotartaric 35 COOH

Most important hydroxy acids II

5) Citric acid, acidum citricum, citrate CH2 COOH Isocitric acid, isocitrate CH2 COOH HO C COOH CH COOH CH2 COOH HO CH COOH 6)

Salicylic acid

COOH OH

Acetylsalicylic acid

COOH O C CH3

p-aminosalicylic acid

COOH OH O Wide application in medicine - Acylpyrin (in Czech) (Aspirin) Organic chemistry 2014/2015 NH2 36 Remedy against tuberculosis

Most important hydroxy acids III

Sulfosalicylic acid

COOH OH Very sensitive reaction for the proof of peptides (principle denaturalization) SO3H 7)

Gentisic acid

COOH Anti-rheumatic effect OH HO Organic chemistry 2014/2015 37

Most important keto acids I

1)

Pyruvic acid,

acidum pyruvicum

, Pyruvate

Enol-form CH2 C COOH CH3 C COOH OH O 2) (In biochemistry one of the most important acids!!!)

Acetoacetic acid

, acidum acetaceticum,

acetoacetate

CH3 C CH2 COOH CO2 CH3 C Keto-form CH3 O O (keto-, enol- tautomery)

Acetone Acetoacetate is formed by degradation of lipids (FA)

3)

Oxalacetic acid, -, oxalacetate

CH2 COOH O C COOH Important part of Krebs cycle Organic chemistry 2014/2015 38

Most important keto acids II

4) 

-ketoglutaric acid, -,



-ketoglutarate

O C COOH CH2 Very important metabolite of Krebs cycle, amino acids (glutamic acid) can be formed from this acid, as well as the compounds necessary for porphyrins synthesis (hem) CH2 COOH connection between metabolism of peptides and of saccharides 5)

Oxalsuccinic acid, ac. oxalsuccinicum, oxalsuccinate

O C COOH

-CO

2

CH COOH Metabolite of Krebs cycle, formed from iso-citrate and it is transformed by decarboxylation to  -ketoglutarate CH2 COOH Organic chemistry 2014/2015 39

Nitrogen containing derivatives of hydrocarbons I.

Nitro compounds

R-NO

2 They are often toxic, important mainly in the industrial chemistry. Possibilities of poisons.

Examples:

NO2 CH3 Nitroethane: CH 3 -CH 2 -NO 2 Trinitrotoluene: NO2 Nitrobenzene: NO2 NO2 In nature are very rare.

Exception:

Chloramphenicol

(Antibiotic from streptomyces venezuelae) O2N CH CH OH NH CH2 CO OH CHCl2

Nitroglycerin

: incorrect name, correctly it is

glycerol nitrate

ester of glycerol with nitric acid, it is not nitro compound!

Organic chemistry 2014/2015 40 -

Nitrogen containing derivatives of hydrocarbons II.

Ammines

Primary R NH2 Secondary R R Tertiary NH N R'' R' R' Quaternary ammonium bases R R'' N + R' R''' They are actually organic derivatives of

ammonia

, therefore they have mostly

basic character

. Amino group is

strong polar

.

Ammines belong often to biologically important substances –

amino acids, biogenic ammines

(emphatic physiologic effect), and pharmaceutical compounds of vegetative

pharmaceutical compounds

.

Organic chemistry 2014/2015

alkaloids

origin), (toxic

synthetic

41

Reactions of secondary amines with nitrous acid (nitrites) in the presence of HCl



Nitrosamines

R N H + HO N O +HCl R N N O + H2O + HCl R' R' Nitroso-amine

Nitroso-amines exhibit carcinogenic effects!!!

Some important amines International Agency for Research on Cancer (IARC)

NH2 Aniline – toxic – industrial poisons HOOC CH2 CH2 COOH Ethylene Diamino Tetra HOOC Acetic acid CH2 N CH2 N CH2 COOH

EDTA

poisons - calcium salt of this acid is often administrated as antidote by heavy metals Chelaton

II

and

III

– important in analytical CH3 chemistry H3C N + CH2 OH CH3

Choline

– Amino alcohol Organic chemistry 2014/2015 42

HO

Biologically important amines

OH HO HO HO NH2 Dopamine HO NH2 Noradrenaline

… and similar alkaloids and drugs

OH HO OH OH HO NH CH3 Adrenaline H3C O HO H3C O NH NH2 NH CH3 O NH2 CH3 CH3 CH3 CH3 CH3

Isoprenaline Amphetamine (Psychoton) Ephedrine Mescaline Synthetic drugs Alkaloids

Similarity in structure and in effects!!!

Organic chemistry 2014/2015 43

Functional derivatives of carboxylic acids

X-halogen R C

Acyl halide

X O R C O C R R C R O NH2 C

Amide

O R R R C S C N

Nitril

R O O O O   

Anhydrides Acyl halides Anhydrides Esters Esters

– use in organic synthesis - use in organic synthesis

Thioesters

– low polarity, hydrogen bridges are not formed. Solvents    of lipids

!

Thioesters

– acetyl coenzyme A

Amides Nitril

- urea, nicotinamide, amides of amino acids – hydrocyanic acid - nitril of formic acid - toxic!

Organic chemistry 2014/2015 44

Functional derivatives of carboxylic acids – derivatives carbonic acid (H

2

CO

3

) I

1)

Halogen derivatives - phosgene

- toxic!!!

Dichloride of carbonic acid: 2)

Amides Diamide of carbonic acid = urea:

O O C C Cl Cl NH2 NH2

Monoamide of carbonic acid = carbamic acid

(Unstable, it exists only as phosphate) NH2 OH O O C P O P P OH C NH2 OH O

Important for biosynthesis of urea Phosphate group

Organic chemistry 2014/2015 45

Functional derivatives of carboxylic acids – derivatives carbonic acid (H

2

CO

3

) II

3) Esters carbamic acid = Urethanes they have sedative and sleeping (narcotic) effects, relatively toxic, and therefore they are not used at present (with one exception): O H3C CH2 C CH2 H3C CH2 CH2 O O C C O NH2 NH2 2-methyl-2-propyl-1,3-propanediolcarbamate

MEPROBAMATE

Organic chemistry 2014/2015 46

Derivatives of urea I

1) Biuret – is formed by heating up of the urea, ammonia is released H2N CO NH2 + H N CO NH2 -NH3 H2N CO N CO NH2 2) H

Guanidine (iminourea)

oxygen is substituted by an H biuret

imine group =NH

NH2 NH C Is formed by oxidative cleavage of

guanine

NH2 Its derivative – amino acid

Creatine Arginine

(see amino acids) - N–methyl-guanidine-acetic acid OH NH2 N P OH NH C O N CH2 COOH CH3 Very important for transport of energy in muscles Organic chemistry 2014/2015 47

Derivatives of urea II

Creatinine

is formed from

creatine

as its anhydride H H N H OH NH C N N CH2 C O -H2O NH C N CH3 CH3 C CH2 O Creatinine is not utilizable for a muscle. It is excreted by urine (kidneys - diuresis) and therefore it is used in clinical biochemistry for monitoring of their functions („clearance“ of creatinine) Organic chemistry 2014/2015 48

Ureides I

Ureides are derived from carboxylic acids by substitutions of the hydroxy group by the urea (analogy to amides): CH3 C OH + H N CO NH2 -H2O CH3 CO N CO NH2 O Acetic acid H Urea H Ureide of acetic acid (acetyl urea) Many of ureides belong to important remedies, e.g.: Br CH3

Bromisoval (sedative)

CH3 CH CH CO N H CO NH2 Ureide of acid  -bromoisovaleric Organic chemistry 2014/2015 49

Ureides II

The cyclic ureides can be formed with dibasic acids. Such compound can be classified as heterocyclic compounds: H O C O C OH H N NH CH2 + C O CH2 C O NH O C OH H N O C Malonic acid H Urea Barbituric acid Many drugs with sedative, hypnotic and in higher doses with narcotic effects are derived from barbituric acid -

Barbiturates

Organic chemistry 2014/2015 50

Thio derivatives I

1)

Thioalcohols (and thiophenols)

: R 2)

Thioethers (sulfides)

: R Amino acid Cysteine S CH2 CH CH2 SH OH SH SH Dimercaptol (

BAL

) Bond with heavy metals R „yperite“ Mustard gas Cl CH2 CH2 S CH2 CH2 Cl 3)

Disulfides:

R S S R Disulphidic bridges (peptides) Amino acid  Cystine

-lipoic acid = (6,8-dithiooctanic acid)=1,2-Dithiolane-3-pentanoic acid

Reduced form Oxidized form CH2 CH2 CH2 (CH2)4 COOH 2H+ CH2 CH2 CH2 (CH2)4 COOH SH SH S Organic chemistry 2014/2015 S 51

4)

Sulfonic acids:

Thiolic derivatives II

O sulfosalicylic acid R S OH (see hydroxy acids) O 5)

Sulfones:

R O S Sulfonamides R (antimicrobial, chemotherapy) O 6)

Sulfur containing heterocycles:

Thiophene (5member ring with 1-heteroatom S), thiazole, phenothiazine Organic chemistry 2014/2015 52

Sulfonamides (chemotherapeutics)

Sulfones –

derivatives of sulfanilic acid H 2 N SO 2 OH which is antagonist of

para-aminobenzoic acid (PABA) 4-aminobenzoic acid „vitamin H“

H 2 N COOH

PABA

is essential bacterial growth factor

sulfanilamide

H 2 N SO 2 NH 2

sulfoguanidine sulfothiazole

H 2 N H 2 N SO 2 NH C NH N NH 2 SO 2 NH S Organic chemistry 2014/2015 53

Heterocycles – Basic structures I

(usually 3 rd class of secondary (grammar, high) school)

N N H N N H N H 1H-Pyrrole 1H-Imidazole 1H-Pyrazole N H Pyrrolidine N H Pyrroline (2-shown) NH N N H Imidazolidine N H Imidazoline (2-shown) N NH N H Pyrazolidine NH N H Pyrazoline (3-shown) N N Pyridine N Pyrazine N Pyrimidine N N Pyridazine H N N N N H Piperidine N H Piperazine Organic chemistry 2014/2015 Quinuclidine 54

Heterocycles – Basic structures II

(usually 3 rd class of secondary (grammar, high) school)

H N NH N N Indolizine 1H-Indole 2H-Isoindole 3H-Indole H N N 1H-Indazole H N N N N 7H-Purine H N Indoline NH Isoindoline N 4H-Quinolizine N Quinoline N Isoquinoline N N N Pteridine N N N Phthalizine N N N Naphthyridine (1,8-shown) Organic chemistry 2014/2015 N Quinazoline N N Cinnoline 55

Heterocycles – Basic structures III

(usually 3 rd class of secondary (grammar, high) school)

O Furan O Tetrahydrofuran O 2H-Pyran S Thiophene O Chroman O Xanthene O Benzofuran O Isobenzofuran O Isochroman S S Thianthrene Organic chemistry 2014/2015 O 2H-Chromene O S Phenoxathiin 56

5member ring

Heterocycles - Basic structures IV

O

Furan (furanoses)

hydroxy derivatives Sugars S

Thiophene

hydrogenated base of biotin vitamin H N H

Pyrrole

– base of cyclic and linear tetrapyrroles porphyrines - hem, bilirubine (bile pigment) (In Czech žlučové barvivo) Tryptamine 5-hydroxytryptamine Amino acid In combination with benzene: Tryptophan Benzopyrrole (indole)

„biogenic amines“

– physiologically very effective compounds N H Ergotic alkaloids (affect the tonus of smooth muscles (uterus-obstetrics) + LSD - diethylamide of lysergic acid (hallucinogenic compound (chemically prepared psychosis)) Organic chemistry 2014/2015 57

Aflatoxin B

1

Toxic and carcinogenic compound from fungus

Aspergillus flavus

, which is growing on foods (especially groundnut – monkey nuts etc.). O O O

Biotin (vitamin H)

Essential for carboxylation reactions (incorporation of CO 2 into organic acids) - prosthetic group of enzymes O O O O H O

L-ascorbic acid - vitamin C

O OH -2H CH 3 O H N NH S OH O O H O O H O H O H H O H H O H O H Dehydro-L-ascorbic acid H Non-enzymatic transfer of hydrogen Organic chemistry 2014/2015 58

Indole (1H-Benzo[b]pyrrole)

Lysergic acid

O OH N CH 3 N H

Ergometrine (ergot alkaloid)

CH 3 OH NH N O H H N CH 3 N H Its diethylamide = LSD (hallucinogenic) Organic chemistry 2014/2015 N H 59

Five member heterocycles with two heteroatoms

N H N

1H-pyrazole

 antipyretic (antipyrine, amidopyrine) N H S N N

imidazole

Amino acid histidine amine“)  histamine („biogenic CH2 CH2 NH2 N N H

Thiazole

tetra hydrogenated base of penicillin structure Vitamin B 1 thiamine and amiphenazole are derived from thiazole – drug increasing irritability of CNS (hyperirritability) Organic chemistry 2014/2015 60

Five member heterocycles with two heteroatoms – derived drugs I

From pyrazole:

O N N CH 3 CH 3 H 3 C CH 3 N O N N CH 3 CH 3

phenazon (antipyrine) aminophenazone (amidopyrine)

and more complicated phenylbutazone and ketophenylbutazone (ketazone) Organic chemistry 2014/2015 61

Five member heterocycles with two heteroatoms – derived drugs II

From thiazole: Penicillins:

HOOC H 3 C N O G-penicillin NH R H 3 C S -R=benzyl O  -lactam ring – can be split by enzyme  -lactamase, which have some bacteria (gold staphylococcus). Thereby the effect of penicillin is destroyed, and therefore, in case of these bacteria, it has no any sense to administer it.

Thiamine (vitamin B 1

(pyrimidine + thiazole)

)

N N + CH 3 H 3 C S N Organic chemistry 2014/2015 CH 2 CH 2 OH 62

6-member heterocycles with one heteroatom



-pyran

O

Tetrahydropyran (4H-pyran)

O Sugars „pyranoses“ stable hyroxy derivatives

Benzo derivatives of



-pyran

O

Chroman

Vitamin E is derived of chroman 

-pyron

Oxo derivative of O O

Benzo derivative



-pyron - coumarin

 -pyran (2H pyran) O O Derived compound with (blood) anticoagulation effect (Warfarin) Organic chemistry 2014/2015 63

6-member heterocycles with one heteroatom – derived compounds Coumarin:

O Some derived compounds have anticoagulation effects – decelerate blood coagulation. This effect is medically used. O Warfarin

-

antagonist to

K

vitamins: O CH 3 O CH 2 CH CH 3 C CH 2 CH 2 CH 3 CH 2 HC CH 2 H 3 Vitamin K is necessary for synthesis of

prothrombin

in livers.

K 1

Organic chemistry 2014/2015

Vitamin

O CH 3

Vitamin K 2

CH 2 CH CH 3 C CH 2 H 6 64

6-member heterocycles with one heteroatom (nitrogen)

Pyridine:

Toxic. Alkaline, with acids produces salts. N

Important derivatives Nicotinic acid

COOH + H Cl Cl N N + H Medicament for blood vessel extension N

Nicotine amide

C O NH 2 „vitamin PP“ part of NAD and NADP

very important compound

N Organic chemistry 2014/2015 65

6-member heterocycles with one heteroatom (nitrogen)

HOOC O NH

Isonicotinic acid

and its hydrazide C NH 2

INH –

medicament against T.B. (tuberculosis) N N

Piperidine

Formed from pyridine by hydrogenation N + 6H N H Derived synthetic analog of morphine -

pethidine

(Dolsin)

Benzo derivatives: Cinnoline

is a part of alkaloid quinine and of other synthetic antimalaria drugs.

N N

Cinnoline Isocinnoline

Organic chemistry 2014/2015 N

Acridine

66

Alkaloids and drugs with 6-member heterocycles with one heteroatoms Derived from pyridine

O

nicotine

N N CH 3

diethylamide of nicotinic acid

(central analeptics) N C N C 2 H 5 C 2 H 5

Quinoline Isoquinoline

H 3 C H 3 C N H 3 C O O N

Quinine

(and other antimalarial drug ) O H O CH N CH 2 N N CH 2 CH 2 CH 2 CH 3 O CH 3 O

Papaverine

CH 3 (spasmolytics, release spasms of smooth muscles) Organic chemistry 2014/2015 uvolňuje křeče 67

6-member heterocycles with two heteroatoms I

N N N N

Pyridazin

e N

Pyrimidine

N

Pyrazine

The most important: Some bases of nucleic acids are derived from

pyrimidine

NH 2 O O H 3 C N NH NH NH O

Cytosine

NH

Uracil

O O OH NH

Thymine

O OH

Tautomerism of the uracil basis

NH NH O NH Lactam Organic chemistry 2014/2015 N O N N Lactim OH 68

6-member heterocycles with two heteroatoms II

H N full hydrogenated derivative of

pyrazine

is used as medicament by

goat

(in Czech „dna“) (arthritis uratica) and N H

Piperazine

furthermore as

antihelminticum

(medicament against pinworms and roundworms (in Czech „roupům a škrkavkám“)

Thiazines

( the most important derivative

Phenothiazine)

S N H Other derivatives: Methylene blue and neuroleptics – medicaments used in psychiatry Organic chemistry 2014/2015 69

Purine

Compounds with two condensed heterocycles

N N N Some bases of nucleic acids are derived from

purine

N H NH 2 O

Adenine (ATP!!!)

N N N NH H 2 N H N N N NH

Guanine

Both compounds are degraded via

hypoxanthine

OH

xanthine

OH

to uric acid

OH H N N H N N N H N OH N NH H O NH NH H O NH NH Uric acid can crystallize in urine – gravel (urolithiasis) (in Czech „močové kameny“) Alkaloids derived from xanthine: caffeine, theophyline, theobromine Surplus – accumulation in tissues = gout (in Czech „dna“) Organic chemistry 2014/2015 70

Phenothiazine

S N H S CH 2 N CH 2 CH 3 CH 2 Cl N CH 3 N R 1 R 2 S Basic structure of phenothiazine neuroleptics

Chlorpromazine

2-chlor-10-(3-dimethylaminopropyl) phenothiazine O

Caffeine

1,3,7-trimethylxanthine H 3 C N O N CH 3 Organic chemistry 2014/2015 N CH 3 N 71

Heterocyclic vitamins

Pteridine is formed by two aromatic azines:

pyrimidine and pyrazine

N H O H O N H N N H N N CH 2 OH CH 2 OH CH 3 N N H 2 N N N H 2 N N H N H

Pteridine Biopterine

Reduced form CH 2 OH CH 2 OH CH 3

Tetrahydrobiopterine

Donor of hydrogen

Folic acid (ptero-glutamic)

is derived from pteridine H O H N H N CH 2 NH C O NH CH CH 2 CH 2 COOH COOH H 2 N N H

Pterine

N H

PABA-

acid (PABA) Organic chemistry 2014/2015

Glutamic acid

para-aminobenzoic 72

N N

Heterocyclic vitamins II

H N N O N

Benzopterine

N N O

Alloxazine

NH

Riboflavin, B

2

H 2 C

Pyridoxine, B 6 (derivative of pyridine)

N CH 3 H O CH 2 R H 3 C H 3 C OH

R= -CH 2 OH pyridox R= -CHO pyridox al ol R= -CH 2 NH 2 pyridox

Organic chemistry 2014/2015

amine

73 CH 2

Organo-metallic compounds

1.

2.

3.

4.

5. 6. Arsenic benzenes -

salversan, neosalversan – formerly used as antiparasitics and antimicrobial drugs – not at present (toxic, carcinogenic)

War agent -

Lewsit ClCH=CHAsCl 2 – used relatively recently (antidote BAL-dimercaptol)

Tetraethylplumban

(„tetraethyl lead“) anti-detonation additive into petrol – highly toxic (C 2 H 5 ) 4 Pb

Anti-tumoric compounds -

carboplatin H 2 N Pt O O C C CH 3 CH 2 H 2 N O C

Dimethylmercury

O (CH 3 ) 2 Hg – used in organic synthesis – highly toxic, possible industrial poisons (occupational medicine) CH 3

Organic compound of gold - antirheumatic agent

gold sodium thiomalate Organic chemistry 2014/2015 74

Organophophates

Organophophates

Blocker of acetylcholinesterase

Parathione Malathione

C2H5O C2H5O CH3O CH3O P R1 R2 P S S O S P O R3

Soman:

CH3 P O C3H7O F o-isopropyl methylfluorophosphate NO2

Insecticide

- commonly used in agriculture (farming) – for man less toxic, but accidentally can occur the heavy professional poisons.

antidote

– antagonistic

ACh

- atropine aj.

CH COOC2H5 CH 2 HC CH2 COOC2H5 Organic chemistry 2014/2015 H 2 C HC N CH 2 CH 3 HC CH 2 O C HC O C 6 H 5 CH 2 OH 75