07 derivatives ii

Derivatives of hydrocarbons II Medical Chemistry Lecture 7 200 7 (J.S.) Carboxylic acids, e sters, amides, anhydrides, halides Substituted carboxylic acids Important biochemical reactions of acids Amines and halogen compounds.

Carboxylic acids Their functional group is the carboxyl group –C O OH Nomenclature The systematic IUPAC names consist of the of a corresponding hydrocarbon, in which the final – e is replaced with the suffix – oic (– dioic for dicarboxylic) and the word acid . When the carboxyl group is attached to a ring, the ending – carboxylic acid is added to the name of the parent structure. Many carboxylic acids have common names. Examples: CH 2 =CH–COOH propenoic acid (acrylic acid) benzene-1,2-dicarboxylic acid (phthalic acid) HOOC–CH 2 -CH 2 –COOH butandioic acid (succinic acid)

General properties and types of carboxylic acids Acidity and forming salts Carboxylic acid derivatives that are no more acids , because the hydroxyl group of the carboxyl is replaced or changed (sometimes called " functional " derivatives ): – acyl halides – acid anhydrides – esters – amides – nitriles (derived from amides) Carboxylic acids may undergo elimination of CO 2 from the carboxyl group – decarboxylation Carboxylic acids may have other functional groups attached in the carbon chain ( substituted acids) – hydroxy acids – keto acids and aldehydoacids – amino acids – halo carboxylic acids , etc. 1 2 3 4

Nearly all carboxylic acids are weak acids (p K A 3.5 – 6.0) R C O The remainder of the carboxylic acid after taking off the hydroxyl from the carboxylic group is called an acyl R C O O H + H 2 O + H 3 O carboxylate anion R C O O Carboxylic acids, when treated with a strong base, form salts. CH 3 -COO – Na + sodium acetate (sodium ethanoate) – COO – K + potassium benzoate

Long-chain monocarboxylic acids (long-chain fatty acids) will be mentioned when speaking of lipids. Unfortunately, the trivial names of important acids have to be memorized . Selected acyclic carboxylic acids Monocarboxylic acids Dicarboxylic acids saturated unsaturated saturated unsaturated C 1 formic (none) (none) (none) C 2 acetic (none) oxalic (none) C 3 propionic acrylic malonic (none) C 4 butyric crotonic succinic C 5 valeric .. glutaric .. C 6 capr o ic .. adipic .. C 8 capr y lic .. .. .. C 10 capr i c .. .. .. fumaric and maleic

Some aromatic carboxylic acids Arenecarboxylic acids Arylalkanoic and arylalkenoic acids C O O H benzoic acid C O O H C O O H phthalic acid C O O H 1-naphthoic acid (naphthalene-1.carboxylic) Aroyl groups benzoyl C 6 H 5 –CO– phthaloyl 1-naphthoyl ibuprophene 2-(4-isobutylphenyl)propionic acid a common analgesic-antipyretic -C O O H C H 2 - phenylacetic acid trans - cinnamic acid (3-phenylacrylic) C O O H

Carboxylic acid derivatives Carboxylic acid derivatives are compounds in which the hydroxyl part of the carboxyl group is replaced by other groups. All acid derivatives – comprise acyl (or aroyl) group, – are no more acidic, – can be hydrolyzed to the corresponding acid. C R O X C R O O–R´ C R O S–R´ C R O NH–R´ acyl halides acid anhydrides esters thioesters amides C R O O R–C O

Acid anhydrides Acyl halides are the most reactive of carboxylic acid derivatives. They are used as acylating agents . Example of acetylation: are reactive compounds derived from acids by removing water from two carboxyl groups and connecting the fragments: CH 3 –C O C l + CH 3 –C O O–R H O–R – HCl acetyl chloride alcohol ester (alkyl acetate) + R C OH O R C– O H O – H 2 O R C O– O C R O

Water hydrolyzes an anhydride to the corresponding acid; Alcohols give esters, and ammonia gives amides. O O O phthalic anhydride acetic anhydride (ethanoic anhydride) O CH 3 –C O O CH 3 –C succinic anhydride O O Dicarboxylic acid lose water on heating to form cyclic anhydrides , if carboxyl groups are appropriately spaced: Mixed anhydrides are anhydrides derived from two different carboxylic acids. Acyl phosphates are mixed anhydrides of carboxylic acid and phosphoric acid and important high-energy intermediate metabolites : e.g., carbamoyl phosphate in biosynthesis of urea and pyrimidine bases, 3-phosphoglyceroyl phosphate (1,3-bisphosphoglycerate) in glycolytic pathway. C–O–P–OH O H 2 N O O H carbamoyl phosphate

Esters Esters are derived from acids by replacing the hydroxyl group of carboxyl by an alkoxy group –O-R (or a phenoxy group –O-Ar). Catalytic amount of a strong acid is required. However, esterifications catalyzed by enzymes utilize other mechanisms. Esters of carboxylic acids can be formed by condensation of an acid and an alcohol or phenol. The reaction is called esterification : R – C O O–R´ + H 2 O ( H + ) R–C O OH + HO–R´ Nomenclature: Simple esters are named in a manner analogous to that for carboxylic acid salts . E.g., butyl acetate methyl benzoate phenyl propionate CH 3 -C O O–CH 2 -CH 2 -CH 2 -CH 3 O–CH 3 – C O CH 3 -CH 2 -C O O–

Hydroxy acids contain both functional groups required for ester formation. If the hydroxyl is attached to γ or δ carbon atom, it may react with carboxyl to form an cyclic intramolecular ester called lactone : Ester bonds are hydrolysable ; hydrolysis of esters with bases is called saponification : Esters can be converted to amides in the reaction with ammonia (ammonolysis). O O O C O H OH δ – H 2 O δ -hydroxyvaleric acid (5-hydroxypentanoic acid) δ-valerolactone pentano-5-lactone R–C O O–R´ R–C O O – Na + + HO–R´ + Na + OH – heat (H 2 O) ester base salt of an acid alcohol

Esters occur widely in nature. Examples: Triacylglycerols (fats and edible oils) are esters of glycerol and long-chain fatty acids. When hydrolyzed with bases, they give glycerol and soaps (alkali salts of fatty acids). Glycerophospholipids are derivatives of phosphatidic acid (a diacylglycerol esterified with phosphoric acid). Waxes (e.g. beeswax, spermaceti) are esters of higher aliphatic alcohols and long-chain fatty acids. Coumarin is the lactone of o -hydroxycinnamic acid, a pleasant smelling compound of some plants, which inhibits blood clotting in animals. C H 2 C H O C H 2 O O C C C O O O triacylglycerol C H 2 C H O C H 2 O O–P–OH C C O O O phosphatidic acid OH O

H 3 C– C O S C o A acetyl coenzyme A acetyl dihydrolipoic acid COOH S–C–CH 3 HS O Thioesters R – C O S –R´ play important roles in acyl-transfer reactions in the cells. Acyls bound to the sulfanyl group in the form of thioester are activated (those thioesters are high-energy compounds). Acetyl coenzyme A is the key intermediate in catabolism of nutrients, the acetyl of which is broken down to CO 2 in the citrate cycle. Coenzyme A is a complex nucleotide with the sulfanyl group able to bind acyls of fatty acids in the course of β-oxidation, too. Lipoic acid is a disulfide that oxidizes acetaldehyde and transfers the resulting acetyl (as acetyl dihydrolipoic acid ) to coenzyme A in the course of oxidative decarboxylation of pyruvate.

Amides Amides are the least reactive from the common carboxylic acid derivatives. They are derived from acids by replacing the hydroxyl group of carboxyl by an amino group –NH 2 (or alkylated –NH-R and aromatic –NH-Ar). Acids with ammonia or amines form (at room temperature) ammonium or alkylammonium salts. By heating these salts, water is eliminated and amides can be prepared: ammonium salt of an acid (alkylammonium carboxylate) amide ( N -alkylamide) R–C O O H 3 N–R + NH 2 –R R–C OH O + H 2 O R – C NH-R O heat Nomenclature: In the names of amides, the –ic or –oic ending of the acid name with the ending – amide. E.g., – C NH–CH 3 O – C NH 2 O CH 3 -CH 2 -CH 2 butyramide (butanamide) N- methylbenzamide ( N- methylbenzenecarboxamide) CH 3 –C N–CH 3 O CH 3 N , N- dimethylacetamide

The basicity of amines is lost by formation of amide bonds, because the unshared electron pair of the nitrogen atom is conjugated with the π bonding electron pair (existence of resonance hybrids). The free rotation round the C-N bond of amides is restricted, amide bonds have a planar geometry. Amides are non-electrolytes , not basic compounds . Amino acids contain both functional groups required for amide formation. If the amino group is attached to γ or δ carbon atom, it may react with carboxyl to form an cyclic intramolecular amide called lactam : pentano-5-lactam (piperidin-2-one) δ -aminovaleric acid (5-aminopentanoic acid) N O H N H C O O H H – H 2 O δ C N O H C N O H

Amides occur widely in nature. The most common amides are peptides and proteins . A peptide bond is an amide bond between the carboxyl group of one amino acid and the α-amino group of another amino acid. Amides of biological importance are also standard amino acids asparagine and glutamine , sphingolipids ( N -acylated aminoalcohols sphingosines) , nicotinamide (a vitamin, PPF), amino sugars (all of them are N -acylated), urea , etc. O O H NH–CO -CH 3 O H O CH 2 -OH H N -acetylglucosamine acetaminophen ( N- (4-hydroxyphenyl)acetamide) HO NH–CO -CH 3 lidocaine O NH–C -CH 2 -N C H 3 C H 3 CH 2 -CH 3 CH 2 -CH 3 As examples of synthetic amides important in medicine may serve acetaminophen (paracetamol), a common analgetic and antipyretic, and local anaesthetics lidocaine and trimecaine .

Carbonic acid derivatives O H C H O O Carbonic acid H 2 CO 3 may also be viewed as a carboxylic acid : It is a very labile compound that exists only in aqueous solution and decomposes rapidly into CO 2 and water. Derivatives, in which one of the hydroxyl group is replaced , retain the lability of carbonic acid. Carbamic acid , a monoamide, is not stabile. Its mixed anhydride with H 3 PO 4 , carbamoyl phosphate , is the high-energy intermediate of the biosynthesis of urea and pyrimidine bases. O H C H 2 N O carbamic acid C H 2 N O O P O O O carbamoyl phosphate Replacements of both hydroxyls of carbonic acid result in stabilization of the derivatives.

O -R C R´-NH O N,O- dialkyl carbamate urethane Don ′ t confuse urea (neutral in water, high solubility, carbamide) with uric acid (2,6,8-trihydroxypurine) ! N N N N O H H O O H H uric acid Esters of carbamic acid are alkyl carbamates called urethanes . NH 2 C O NH 2 urea Urea (carbamide) is the diamide of carbonic acid , the normal end product of protein metabolism in mammals. A colourless, water-soluble, crystalline solid. It is present in all human biological fluids and excreted into the urine (approximately 20 – 30 g per day). Like other amides, urea is a neutral compound ; when heated with solutions of strong acids or hydroxides, urea is hydrolyzed to carbon dioxide and ammonia (or an ammonium salt): CO(NH 2 ) 2 + H 2 O CO 2 + 2 NH 3 Some alkyl carbamates are effective insecticides, others are extremely toxic. They inhibit the enzyme acetylcholine esterase and, therefore, certain carbamates of low toxicity are utilized in medicine (e.g. neostigmine). Polyurethanes are very useful as either polyurethane foam, stretchable fibres, or very tough materials.

O H H H H H barbituric acid (malonylurea) C O N H 2 N H 2 C H 2 C C O O-R O O-R + urea dialkyl malonate – 2 R-OH barbital (diethylbarbituric acid) S thiopental sodium (pentothal) N - Acyl derivatives of urea are called ureides . Through condensation of urea with esters of dicarboxylic malonic acid, barbituric acid (malonylurea) can be synthetized : For a weak acidity of barbituric acid, the hydroxyl group of the tautomeric lactim form is responsible. Derivatives of barbituric acid obtained by substitution in position 5, commonly called barbiturates , have the pronounced sedative and hypnotic effect. Nowadays, barbiturates administered orally are used rather exceptionally; pentothal injected intravenously as general anaesthetics is still in use.

Guanidine is the imine of urea . Unlike neutral urea, guanidine is nearly a strong base ; guanidinium cation, binding a proton, is stabilized by resonance energy (existence of resonance hybrids. Creatine slowly eliminates water to give creatinine – a waste product that is excreted into the urine. Arginine (2-amino-5-guanidinopentanoic acid) is a basic amino acid. It may be hydrolyzed to urea and ornithine, it also supplies the carbimidoyl group for the synthesis of creatine , and the imino group gives nitroxide •NO by oxidation, Creatine , when phosphorylated, serves as a stock of high-energy phosphate group in skeletal muscles. N N H O HN H 3 C creatinine N COOH NH 2 HN H 3 C creatine – H 2 O N H 2 C H 2 N N H guanidine phosphocreatine P – OH O OH HN = C NH – N–CH 2 -COOH CH 3 + ADP HN = C NH 2 N–CH 2 -COOH CH 3 + ATP creatine

Substituted carboxylic acids In the molecules of substituted carboxylic acids, there is at least one functional group another in addition to carboxyl. From a biochemical point of view, the most interesting substituted acids are hydroxycarboxylic acids (including the phenolic acids) , aldehydo and keto acids , and amino acids .

Hydroxycarboxylic acids In addition to one or more carboxylic groups, hydroxy acids comprise alcoholic or phenolic groups in their molecules. Hydroxy acids present – the properties of acids (i.e. acidity, formation of salts, esters, amides, etc.), – the properties of alcohols or phenols (i.e. formation of ethers, esters, hemiacetals, they can be oxidized to carbonyl compounds), – and a capability for being dehydrated easily by heating . The position of substituents is expressed either in numerical locants (mostly in systematic names of acids), or in Greek letters (only when the trivial names of acid are used). CH 3 -CH-CH 2 -COOH OH 4 3 2 1 CH 3 -CH-CH 2 -COOH OH γ β α 3-hydroxybutanoic acid (3-hydroxybutyric acid) β-hydroxybutyric acid

When dehydrated by heating, – two molecules of α-hydroxy acids lose two molecules of water and and form cyclic lactides (2,5-dioxo-1,4-dioxanes); – β - hydroxy acids readily give α,β-unsaturated acid : R – CH=CH – COOH – H 2 O R – CH – CH – COOH OH H – γ- and δ-hydroxy acids form stable five- and six-membered rings, intramolecular cyclic esters called γ- and δ-lactones : δ -hydroxyalkanoic acid (5-hydroxyalkanoic acid) δ-lactone (alkano-5-lactone) – H 2 O OH C O OH δ R CH O O R OH R CH C O HO γ O R O – H 2 O γ-lactone (alkano-4-lactone) γ-hydroxyalkanoic acid 2,3-alkenoic acid

Important aliphatic hydroxy acids (and the products of their dehydrogenation) lactic acid lactate 2-hydroxypropanoic acid malic acid malate hydroxybutandioic acid β-hydroxybutyric acid β-hydroxybutyrate 3-hydroxybutanoic acid CH 3 CH–OH COOH (is dehydrogenized to pyruvate) glyceric acid glycerate 2,3-dihydroxypropanoic acid CH–OH COOH CH 2 -OH (gives hydroxypyruvate, when dehydrogenized at carbon 2) COOH CH 3 CH–OH CH 2 COOH CH 2 CH–OH COOH (gives acetoacetic acid by dehydrogenation) (dehydrogenized to oxaloacetate)

( R,R )- tartaric acid L -(+)-tartaric acid 2,3-butandioic acid COOH COOH H-C–OH HO–C-H citric acid citrate 2-hydroxypropan-1,2,3-tricarboxylic acid isocitric acid isocitrate 1-hydroxypropan-1,2,3-tricarboxylic acid CH 2 -COOH CH 2 -COOH HO–C–COOH CH 2 -COOH HO–CH–COOH CH–COOH Occurs as potassium hydrogen tartrate in grape juice and is the major component of tartar (lees of wine) deposited from fermented wine.

Aromatic hydroxy acids homogentisic acid 2,5-dihydroxyphenylacetic acid 1 Phenolic acids having a phenolic hydroxyl: salicylic acid 2-hydroxybenzoic acid acetylsalicylic acid aspirin methyl p -hydroxybenzoate (methylparaben), antifungal food additive Amino acid tyrosine and its metabolites: p -hydroxyphenylacetic acid tyrosine

2 Aromatic hydroxy acids with an alcoholic hydroxyl phenylalanine The most simple acid of this type is mandelic acid , the metabolite of toxic unsaturated hydrocarbon styrene: mandelic acid (phenylglycolic acid) A homolog ue of mandelic acid is, e.g., β-phenyllactic acid, the minor metabolite of phenylalanine: β-phenyllactic acid

Aldehydocarboxylic acids The most simple aldehydo acid is glyoxylic acid , which may be generated by transamination of glycine. CH=O COOH have the properties of both aldehydes and carboxylic acids. In the cells, aldoses (monosaccharides with the aldehyde group) can undergo oxidation of the primary alcoholic group to give glycuronic acids ; in this way, glucose is transformed to glucuronic acid, idose to iduronic acid, etc. CH=O H-C H-C–OH H-C–OH HO–C-H C O O D- glucurono- δ-lactone HO–C-H CH=O H-C–OH H-C–OH H-C–OH CH 2 -OH D - glucose CH=O H-C–OH H-C–OH H-C–OH HO–C-H COOH D- glucuronic acid – H 2 O

Keto carboxylic acids have the properties of both ketones and carboxylic acids. The most simple keto acid and an extremely important intermediate metabolite is pyruvic acid : CH 3 C = O COOH CH 2 C–OH COOH pyruvic acid pyruvate 2-oxopropanoic ( α-ketopropionic) acid enol form Pyruvate is the product of glycolysis, and also of transformation of some amino acid. It gives lactate by hydrogenation, or acetyl CoA by oxidative decarboxylation. Carboxylation of pyruvate generates oxaloacetic acid , the starting substrate of the citric acid cycle that condenses with acetyl Co A. Oxaloacetate is the product of oxidation of malate , and also of transamination of aspartate . COOH COOH C=O CH 2 oxaloacetic acid oxaloacetate oxopropandioic (ketosuccinic acid)

Ketone bodies The ketone bodies are formed from acetyl-Co A in the liver. They can be regarded as a water-soluble, transportable form of acetyl units, important as sources of energy for extrahepatic tissues. The term ketone bodies is used in biochemistry and medicine as a group name for three compounds: acetoacetic acid , β-hydroxybutyric acid , and acetone . CH 3 C=O CH 2 COOH acetoacetic acid acetoacetate 3-oxobutanoic acid β-ketobutyric acid CH 3 C=O CH 3 acetone CH 3 CH – OH CH 2 COOH β-hydroxybutyric acid 3-hydroxybutanoic acid – CO 2 – 2 H + 2 H

Amino acids The common name amino acids can be assigned to all carboxylic acids that comprise also an amino group . In biochemistry, the term amino acid is usually understood as the group name of only twenty standard (i.e. coded, proteinogenic) α-amino acids. The following passage will deal with quite general properties of the broad group of amino acids. Amino acids present – the properties of acids (i.e. acidity, formation of carboxylate salts with bases, esters, amides, etc.), – the properties of amines (i.e. basicity, formation of ammonium salts with acids, alkylation till the formation of tetraalkylammonium cations, acylation to amides, formation of Schiff bases with carbonyl compounds), – independent ionization of their basic and acidic groups , and – a capability for elimination of water or ammonia by heating .

When dehydrated by heating, they behave similarly to hydroxy acids: – two molecules of α-amino acids lose two molecules of water and and form cyclic 2,5- dioxo -1,4- piperazines ; – β - amino acids readily eliminate ammonia giving an α,β-unsaturated acid : R – CH=CH – COOH R – CH – CH – COOH NH 2 H – NH 3 – γ- and δ-amino acids form stable five- and six-membered rings, intramolecular cyclic amides called γ- and δ-lactams : γ-lactam (4-alkylpyrrolidin-2-one) R N R O γ H lactim form δ -aminoalkanoic acid (5-aminoalkanoic acid) δ-lactam (5-alkylpiperidin-2-one) – H 2 O

p -Aminobenzoic acid and its derivatives p -aminobenzoic acid PABA sulfanilamide (p -aminobenzenesulfonamide) p -Aminobenzoic acid (PABA) is an essential growth factor of bacteria required for the biosynthesis of folic acid . Folic acid acts as the cofactor in the transfer of one-carbon units in all living organisms. In mammals, it has to be supplied in the food. . Approximately seventy years ago, it was discovered by accident that sulfanilamide was an effective antibacterial agent. A huge amount of its various analogs called sulfa drugs were prepared. Even today some of them are still useful, although in many instances they have been replaced by more effective an safer antibiotics. Sulfa drugs act by competitive inhibiting of the enzyme, which incorporates PABA into folate in the course of the folate biosynthesis, because they have similar structure and shape, in part. .

benzocaine p -aminomethylbenzoic acid (PAMBA) Some derivatives of PABA used in medicine (examples): The homologue of PABA , p - aminomethylbenzoic acid (abbr. PAMBA) inhibits the proteolysis of fibrin and so support to stop bleeding. Esters of PABA are useful local anaesthetics. Benzocaine is nonpolar, insoluble in water, can be applied only in ointments. Procaine is soluble in acids, is usually injected to infiltrate the tissue. A widely used drug in stomatology and surgery.

The survey of important substituted aliphatic acids .. .. .. .. adipic norleucine .. .. .. capronic C 6 glutamic 2-oxoglutaric .. .. glutaric norvaline .. .. .. valeric C 5 aspartic oxaloacetic malic fumaric maleic succinic - acetoacetic β-hydroxybutyric crotonic butyric C 4 - mesoxalic .. - malonic alanine pyruvic lactic acrylic propionic C 3 - - - - oxalic glycine glyoxalic glycolic - acetic C 2 - - - - - carbamic - H 2 CO 3 - formic C 1 Amino Keto Hydroxy Unsatur. Satur. Amino Keto Hydroxy Unsatur. Satur. DICARBOXYLIC MONOCARBOXYLIC

a Only in alkaline solution . b A protolytic reaction. c Condensation by heating, water is eliminated. Reactions between the most important functional groups - - aldimine (Schiff base) salt b / amide c Amine salt b / amide c acid anhydride - ester (thioester) Acid aldimine (Schiff base) - aldol a hemiacetal (hemithioacetal) Aldehyde - ester (thioester) hemiacetal (hemithioacetal) ether (sulfide) Alcohol (Thiol) Amine Acid Aldehyde Alcohol (Thiol)

Conversions in side chains of acids catalysed by enzymes: Important biochemical reactions of acids – 2H + H 2 O CH 2 CH 2 CO– R CH CH CO– R CH 2 O=C R CO– CH 2 HO–CH R CO– – 2H + 2H – H 2 O + 2H saturated acyl (alkanoyl) α,β- unsaturated acyl (2-alkenoyl) 3-hydroxyacyl ( β-hydroxyacyl) 3-oxoacyl ( β-ketoacyl) Examples: β-Oxidation of fatty acids - butyryl -> crotonoyl -> β-hydroxybutyryl -> acetoacetyl ( -> 2 acetyl ) Biosynthesis (or elongation) of fatty acids - acetoacetyl -> β-hydroxybutyryl -> crotonoyl -> butyryl ( -> β-ketocapronoyl) Sequence in the citrate cycle – succinate -> fumarate -> malate -> oxaloacetate

The citric acid cycle is a terminal catabolic pathway, in which acetyl (in the form of coenzyme A) is oxidized to two molecules of carbon dioxide . The overall result may be written in the simplified form as CH 3 -COOH + 2 H 2 O 2 CO 2 + 8 H * + energy The eight atoms of hydrogen are released as four molecules of reduced coenzymes (3 NADH+H + and 1 FADH 2 ), the energetic yield is utilized for synthesis of one molecule of guanosine triphosphate (GTP) from GDP. C CH 2 –COOH C O O H O + CH 3 –C O S C o A + H 2 O – CoA-SH oxaloacetate acetyl coenzyme A citrate C C H 2 C O O H C O O H H O CH 2 –COOH The initial reaction of the citrate cycle is condensation of acetyl coenzyme A with oxaloacetate:

dehydrogenation dehydrogenation dehydrogenation dehydrogenation C CH 2 –COOH COOH CH 2 –COOH H O CH–COOH CH 2 –COOH C H– HO C O O H C H 2 CH 2 –COOH O=C–COOH C H 2 C H 2 C O O H O=C–S–CoA CH 2 –COOH CH 2 –COOH C C COOH H HOOC H CH 2 –COOH HO–CH–COOH CH 2 –COOH O=C–COOH CH 3 -CO–S–CoA

Transamination of amino acids The α-amino group is transferred from an amino acid to 2-oxoglutarate: Examples: alanine -> pyruvate aspartate -> oxaloacetate R–C–COOH O HOOC–CH-CH 2 -CH 2 -COOH NH 2 + α-keto acid glutamate + α- amino acid 2-oxoglutarate NH 2 R–CH–COOH HOOC–C–CH 2 -CH 2 -COOH O

Amines Amines are organic compounds derived from ammonia by replacing hydrogen atoms of ammonia with organic groups . Amines are the most important type of organic base that occurs in nature. Amines are classified as primary, secondary, or tertiary, depending on the number of organic groups (alkyls or aryls) attached to the nitrogen atom. primary amine R–NH 2 primary amino group –NH 2 secondary amino group NH R R NH secondary amine nitrogen atom in tertiary amines N R R N R tertiary amine

Nomenclature Substitutive names are not for amines. For simple amines, group-functional names or conjunctive names are used. isopropylamine propan-2-amine CH 3 -CH-CH 3 OH CH 2 –NH 2 CH 2 –NH 2 ethandiamine (ethylene diamine) H NH 2 cyclohexylamine methylamine CH 3 –NH 2 N H 2 aniline (benzenamine) CH 3 CH 3 N–CH 2 -CH 2 -CH 3 dimethylpropylamine N,N- dimethylpropan -1- amine

General properties of amines Basic character of amines due to the unshared electron pair of the nitrogen atom. Nucleophilic atom of nitrogen enables – alkylation of amines to secondary, tertiary amines and to quaternary tetraalkylammonium cations , – acylation of amines to amides (reaction with acids) – reaction with carbonyl compounds , primary amines give imines (Schiff bases). Primary and secondary amines react with nitrous acid. Some amines are sensitive to oxidizing agents, the products can be various. 1 2 3 4

The basicity of amines - weak bases Salts Hydrolysis of alkylammonium cation alkylammonium chloride R N H 2 + R N H 3 + C l - H C l + O H – H 2 O + R N H 2 R + R N H R dialkylammonium ion + H 2 O + R N H 3 + R N H 2 H 3 O + R N H 2 + H 2 O O H – - R N H 3 + + alkylammonium ion

Reaction of primary and secondary amines with HNO 2 H 2 O – N H R R ' + H + N R R ' N=O secondary amine nitrosamine HO-N=O + H N O 2 N H 2 + H C l N N C l aniline benzenediazonium chloride - 2 H 2 O Primary aromatic amines in reaction with nitrous acid give arenediazonium salts (diazot iza tion reaction): Secondary amines in reaction with nitrous acid give nitrosamines. N N C l + O H - HCl N N O H 4-hydroxydifenyldiazen (azo compound , azo dye ) Coupling of reactive diazonium salts with other aromatic amines of phenols:

Examples of biogenic amines: H O C H 2 C H 2 N H 2 H O H O C H C H 2 N H 2 H O O H H O C H C H 2 N H H O O H C H 3 dopamine adrenaline noradrenaline N N C H 2 C H 2 N H 2 H H O C H 2 C H 2 N H 2 N C H 2 C H 2 N H 2 H histamine tryptamine tyramine

N C H 3 C H 3 C H 2 C H 2 O H C H 3 choline N C H 3 C H 3 C H 2 C H 2 C H 3 O C C H 3 O acetylcholine Quaternary ammonium compounds N C H 3 C H 3 C H 3 H 3 C I tetramethylammonium iodide Examples of important compounds: B r N C H 3 C H 3 C H 3 C O C H 2 C H 3 O carbethoxypentadecinium bromide Cationic tensides (invert soaps) used as antiseptics/disinfectants succinylcholine iodide I ( H 3 C ) 3 N O O N ( C H 3 ) 3 I O O N C H 3 C H 3 C H 3 C H 2 C H H O C H 2 C O O carnitine

Solvents for degreasing or dry-cleaning chloroform CHCl 3 , trilene ClHC=CCl 2 , tetrachloromethane CCl 4 (very toxic!) Refrigerants – chlorofluorocarbons (CFC´s, Freons) – harmful for the ozone layer in the stratosphere; restrictions exist, especially for "hard" ones (abandoned as propellants in aerosol dispensers) Polymers – PVC, Teflon, chloroprene, neoprene Plasticizers – polychlorinated biphenyls (PCB´s, Arochlor) Halogen compounds Halogen compounds (organic halides) are mostly nonpolar molecules, in spite of the bond C–Hal is polar. Simple halides are used as alkylating agents for syntheses of alcohols, ethers, amines, and nitriles. Organic halides enjoy extensive use as 2,2',4,4'-tetrachlorobiphenyl (PCB) C l C l C l C l Freon 12 CF 2 Cl

CF 3 -CHBrCl CF 3 -CHCl–O–CHF 2 halothan isoflurane Biological activity of organic halides Anaesthetics Antiseptics tetraiodothyronine (thyroxine) O NH 2 HO I I I I CH 2 –CH–COOH N H 2 B r B r N C H 3 bromohexine N N F O O H H 5-fluorouracil N H C l C N H C N H ( C H 2 ) 6 N H N H N H N H N H C N H C N H C l chlorhexidine

Toxic pollutants Pesticides – insecticides, mothicides, herbicides, fungicides Lachrymators and chemical warfare agents O O C l C l C l C l dioxine C l C H C C l 3 C l DDT H O C H 2 C O O C l C l 2,4-dichlorophenoxyacetic acid 2,4-D C l C l C l C l C l C l lindane C C H 2 C l O chloroacetophenone (tear gas)

07 derivatives ii

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07 derivatives ii