Derivatives of hydrocarbons II

Medical ChemistryLecture 7 2007 (J.S.)

Carboxylic acids, esters, amides, anhydrides, halides Substituted carboxylic acids

Important biochemical reactions of acidsAmines and halogen compounds.

2

Carboxylic acids

Their functional group is the carboxyl group –CO

OH

NomenclatureThe systematic IUPAC names consist of the of a correspondinghydrocarbon, 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:

CH2=CH–COOH

propenoic acid(acrylic acid) benzene-1,2-dicarboxylic acid

(phthalic acid)

HOOC–CH2-CH2–COOH

butandioic acid(succinic acid)

3

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 replacedor changed (sometimes called "functional" derivatives):

– acyl halides – acid anhydrides – esters – amides – nitriles (derived from amides)

Carboxylic acids may undergo elimination of CO2 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

4

Nearly all carboxylic acids are weak acids (pKA 3.5 – 6.0)

R C

OThe remainder of the carboxylic acid after taking off the hydroxyl fromthe carboxylic group is called an acyl

R CO

OH+ H2O + H3O

carboxylate anion

R CO

O

Carboxylic acids, when treated with a strong base, form salts.

CH3-COO– Na+

sodium acetate(sodium ethanoate)

–COO– K+

potassium benzoate

5

Unfortunately, the trivial names of important acids have to be memorized.

Selected acyclic carboxylic acids

Long-chain monocarboxylic acids (long-chain fatty acids) will bementioned when speaking of lipids.

Monocarboxylic acids Dicarboxylic acids

saturated unsaturated saturated unsaturated

C1 formic (none) (none) (none)

C2 acetic (none) oxalic (none)

C3 propionic acrylic malonic (none)

C4 butyric crotonic succinic

C5 valeric .. glutaric ..

C6 caproic .. adipic ..

C8 caprylic .. .. ..

C10 capric .. .. ..

fumaric andmaleic

6

Some aromatic carboxylic acids

Arenecarboxylic acids

Arylalkanoic and arylalkenoic acids

COOH

benzoic acid

COOH

COOH

phthalic acid

COOH

1-naphthoic acid(naphthalene-1.carboxylic)

Aroyl groups

benzoyl C6H5–CO–phthaloyl1-naphthoyl

ibuprophene2-(4-isobutylphenyl)propionic acida common analgesic-antipyretic

-C O OHCH2-

phenylacetic acid trans-cinnamic acid(3-phenylacrylic)

COOH

7

Carboxylic acid derivatives

Carboxylic acid derivatives are compounds in which thehydroxyl 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.

CR

O

XCR

O

O–R´

CR

O

S–R´

CR

O

NH–R´

acyl halides acid anhydrides esters thioesters amides

CR

O

OR–C

O

8

Acid anhydrides

Acyl halidesare the most reactive of carboxylic acid derivatives. They are used as acylating agents.Example of acetylation:

CH3–CO

Cl

+ CH3–CO

O–R

HO–R– HCl

acetyl chloride alcohol ester (alkyl acetate)

are reactive compounds derived from acids by removing water from twocarboxyl groups and connecting the fragments:

+R C

OH

ORC–

O

HO

– H2OR C

O–

O

C

R

O

9

Water hydrolyzes an anhydride to the corresponding acid;Alcohols give esters, and ammonia gives amides.

O

O

O

phthalic anhydride

acetic anhydride(ethanoic anhydride)

OCH3–C

O

OCH3–C

succinic anhydride

O OO

Dicarboxylic acid lose water on heating toform cyclic anhydrides, if carboxyl groupsare appropriately spaced:

Mixed anhydridesare anhydrides derived from two different carboxylic acids.Acyl phosphatesare 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

H2N

O

OH

carbamoyl phosphate

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EstersEsters are derived from acids by replacing the hydroxyl group ofcarboxyl 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 andan alcohol or phenol. The reaction is called esterification:

R–CO

O–R´

+ H2O(H+)

R–CO

OH+ HO–R´

Nomenclature: Simple esters are named in a manner analogous to that forcarboxylic acid salts. E.g.,

butyl acetate methyl benzoate phenyl propionate

CH3-CO

O–CH2-CH2-CH2-CH3 O–CH3

–CO CH3-CH2-C

OO–

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Hydroxy acids contain both functional groups required for esterformation. If the hydroxyl is attached to γ or δ carbon atom, it may react with carboxyl to form an cyclic intramolecular ester calledlactone:

O OOC O

HOH

δ

– H2Oδ-hydroxyvaleric acid

(5-hydroxypentanoic acid)

δ-valerolactonepentano-5-lactone

Ester bonds are hydrolysable; hydrolysis of esters with bases iscalled saponification:

R–CO

O–R´R–C

OO–Na+

+ HO–R´+ Na+OH–heat

(H2O)

ester base salt of an acid alcohol

Esters can be converted to amides in the reaction with ammonia(ammonolysis).

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Esters occur widely in nature.Examples:

CH2

CH

O

CH2

O

O

C

C

C

O

O

Otriacylglycerol

CH2

CH

O

CH2

O

O–P–OH

C

CO

O

Ophosphatidic acid

OH

Triacylglycerols (fats and edible oils) are esters of glyceroland long-chain fatty acids. When hydrolyzed with bases, theygive 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 aliphaticalcohols and long-chain fatty acids.

Coumarin is the lactone of o-hydroxycinnamicacid, a pleasant smelling compound of someplants, which inhibits blood clotting in animals.

O O

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H3C–CO

S CoA

acetyl coenzyme A acetyl dihydrolipoic acid

COOH

S–C–CH3HS

O

Thioesters

R–CO

S–R´

play important roles in acyl-transfer reactionsin the cells. Acyls bound to the sulfanyl groupin the form of thioester are activated (thosethioesters are high-energy compounds).

Acetyl coenzyme A is the key intermediate in catabolism of nutrients, the acetyl of which is broken down to CO2 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.

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AmidesAmides are the least reactive from the common carboxylic acid derivatives.They are derived from acids by replacing the hydroxyl group of carboxylby an amino group –NH2 (or alkylated –NH-R and aromatic –NH-Ar).

Acids with ammonia or amines form (at room temperature) ammonium oralkylammonium 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

H3N–R

+ NH2–RR–C

OH

O

+ H2OR–C

NH-R

Oheat

Nomenclature: In the names of amides, the –ic or –oic ending of the acid name with the ending –amide. E.g.,

–CNH–CH3

O–C

NH2

OCH3-CH2-CH2

butyramide(butanamide)

N-methylbenzamide(N-methylbenzenecarboxamide)

CH3–CN–CH3

O

CH3

N,N-dimethylacetamide

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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 amidesis restricted, amide bonds have a planar geometry.

Amides are non-electrolytes, not basic compounds.

Amino acids contain both functional groups required for amideformation. If the amino group is attached to γ or δ carbon atom, it may react with carboxyl to form an cyclic intramolecular amide calledlactam:

pentano-5-lactam (piperidin-2-one)

δ-aminovaleric acid(5-aminopentanoic acid)

N OH

NHC O

OHH

– H2Oδ

CN

O

H

CN

O

H

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Amides occur widely in nature.

The most common amides are peptides and proteins.A peptide bond is an amide bond between the carboxyl groupof one amino acid and the α-amino group of another amino acid.

Amides of biological importance are also standardamino acids asparagine and glutamine,sphingolipids (N-acylated aminoalcoholssphingosines), nicotinamide (a vitamin, PPF),amino sugars (all of them are N-acylated),urea, etc.

O

OH

NH–CO-CH3

OH

O

CH2-OH

H

N-acetylglucosamine

acetaminophen(N-(4-hydroxyphenyl)acetamide)

HO NH–CO-CH3

lidocaine

O

NH–C-CH2-N

CH3

CH3

CH2-CH3

CH2-CH3

As examples of synthetic amides important in medicine may serve acetaminophen (paracetamol), a common analgetic and antipyretic, andlocal anaesthetics lidocaine and trimecaine.

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Carbonic acid derivatives

OH

CHO

O

Carbonic acid H2CO3 may also be viewed as a carboxylic acid:

It is a very labile compound that exists only in aqueous solution and decomposes rapidlyinto CO2 and water.

Derivatives, in which one of the hydroxyl group is replaced, retain the lability of carbonic acid.Carbamic acid, a monoamide, isnot stabile. Its mixed anhydridewith H3PO4, carbamoyl phosphate,is the high-energy intermediate of the biosynthesis of urea and pyrimidinebases.

OH

CH2N

O

carbamic acid

CH2N

O

O

P

O

O

O

carbamoyl phosphate

Replacements of both hydroxyls of carbonic acid result in stabilizationof the derivatives.

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O-R

CR´-NH

O

N,O-dialkyl carbamateurethane

Don′ t confuse urea (neutral in water, high solubility, carbamide) with uric acid (2,6,8-trihydroxypurine) !

N

N

N

NOH

HO

OH

Huric acid

Esters of carbamic acid are alkyl carbamates called urethanes.

NH2

CONH2

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 excretedinto the urine (approximately 20 – 30 g per day). Like other amides, urea is a neutral compound; whenheated with solutions of strong acids or hydroxides, urea

is hydrolyzed to carbon dioxide and ammonia (or an ammonium salt):

CO(NH2)2 + H2O CO2 + 2 NH3

Some alkyl carbamates are effective insecticides,others are extremely toxic. They inhibit the enzymeacetylcholine esterase and, therefore, certain carbamatesof low toxicity are utilized in medicine (e.g. neostigmine).Polyurethanes are very useful as either polyurethanefoam, stretchable fibres, or very tough materials.

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OH

HH

HH

barbituric acid(malonylurea)

CONH2

NH2

CH2

C

CO 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 thetautomeric lactim form is responsible.

Derivatives of barbituric acid obtained by substitution in position 5,commonly called barbiturates, have the pronounced sedative andhypnotic effect. Nowadays, barbiturates administered orally are used rather exceptionally; pentothal injected intravenously as general anaesthetics is still in use.

20N

NH

OHN

H3C creatinine

N

COOHNH2

HN

H3C creatine

– H2O

Guanidine is the imine of urea.

NH2

CH2N

NH

guanidine

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 waterto give creatinine – a waste productthat 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.

phosphocreatine

P–OH

O

OHHN=C

NH–

N–CH2-COOH

CH3

+ ADPHN=C

NH2

N–CH2-COOH

CH3

+ ATP

creatine

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Substituted carboxylic acids

In the molecules of substituted carboxylic acids, there isat least one functional group another in addition to carboxyl.

From a biochemical point of view, the most interestingsubstituted acids are

hydroxycarboxylic acids (including the phenolic acids),

aldehydo and keto acids, and

amino acids.

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Hydroxycarboxylic acidsIn addition to one or more carboxylic groups, hydroxy acidscomprise 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 thetrivial names of acid are used).

CH3-CH-CH2-COOHOH

4 3 2 1

CH3-CH-CH2-COOHOH

γ β α

3-hydroxybutanoic acid(3-hydroxybutyric acid)

β-hydroxybutyric acid

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When dehydrated by heating,

– two molecules of α-hydroxy acids lose two molecules of water andand form cyclic lactides (2,5-dioxo-1,4-dioxanes);

– β-hydroxy acids readily give α,β-unsaturated acid:

R–CH=CH–COOH– H2O

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)

– H2O

OH

C O

OH

δR CH

O OR OH

R CH

C OHO

γ

O

R

O

– H2O

γ-lactone(alkano-4-lactone)γ-hydroxyalkanoic acid

2,3-alkenoic acid

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Important aliphatic hydroxy acids(and the products of their dehydrogenation)

lactic acidlactate

2-hydroxypropanoic acid

malic acidmalate

hydroxybutandioic acid

β-hydroxybutyric acidβ-hydroxybutyrate

3-hydroxybutanoic acid

CH3

CH–OH

COOH(is dehydrogenized to pyruvate)

glyceric acidglycerate

2,3-dihydroxypropanoic acid

CH–OH

COOH

CH2-OH

(gives hydroxypyruvate, when dehydrogenized at carbon 2)

COOH

CH3

CH–OH

CH2

COOH

CH2

CH–OH

COOH

(gives acetoacetic acid bydehydrogenation)

(dehydrogenized tooxaloacetate)

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(R,R)-tartaric acidL-(+)-tartaric acid

2,3-butandioic acid

COOH

COOH

H-C–OH

HO–C-H

citric acidcitrate

2-hydroxypropan-1,2,3-tricarboxylic acid

isocitric acidisocitrate

1-hydroxypropan-1,2,3-tricarboxylic acid

CH2-COOH

CH2-COOH

HO–C–COOH

CH2-COOH

HO–CH–COOH

CH–COOH

Occurs as potassium hydrogen tartrate in grape juice and is themajor component of tartar (lees of wine) deposited from fermented wine.

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Aromatic hydroxy acids

homogentisic acid2,5-dihydroxyphenylacetic acid

1 Phenolic acids having a phenolic hydroxyl:

salicylic acid2-hydroxybenzoic acid

acetylsalicylic acidaspirin

methyl p-hydroxybenzoate(methylparaben),

antifungal food additive

Amino acid tyrosine and its metabolites:

p-hydroxyphenylacetic acidtyrosine

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2 Aromatic hydroxy acids with an alcoholic hydroxyl

phenylalanine

The most simple acid of this type is mandelic acid, the metabolite oftoxic unsaturated hydrocarbon styrene:

mandelic acid(phenylglycolic acid)

A homologue of mandelic acid is, e.g., β-phenyllactic acid, the minormetabolite of phenylalanine:

β-phenyllactic acid

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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) canundergo oxidation of the primary alcoholic group to give glycuronic acids;in this way, glucose is transformed to glucuronic acid, idose to iduronicacid, etc.

CH=O

H-C

H-C–OH

H-C–OH

HO–C-H

CO

O

D-glucurono-δ-lactone

HO–C-H

CH=O

H-C–OH

H-C–OH

H-C–OH

CH2-OH

D-glucose

CH=O

H-C–OH

H-C–OH

H-C–OH

HO–C-H

COOH

D-glucuronic acid

– H2O

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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:

CH3

C=O

COOH

CH2

C–OH

COOH

pyruvic acid pyruvate2-oxopropanoic (α-ketopropionic) acid

enol form

Pyruvate is the productof glycolysis, and also oftransformation of some aminoacid. It gives lactate by hydrogenation, or acetyl CoAby oxidative decarboxylation.

Carboxylation of pyruvate

generates oxaloacetic acid,the starting substrate of the citricacid cycle that condenses withacetyl Co A. Oxaloacetate is theproduct of oxidation of malate, andalso of transamination of aspartate.

COOH

COOH

C=O

CH2oxaloacetic acidoxaloacetateoxopropandioic(ketosuccinic acid)

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Ketone bodies

The ketone bodies are formed from acetyl-Co A in the liver. They can be regardedas a water-soluble, transportable form of acetyl units, important as sourcesof energy for extrahepatic tissues.

The term ketone bodies is used in biochemistry and medicineas a group name for three compounds:acetoacetic acid, β-hydroxybutyric acid, and acetone.

CH3

C=O

CH2

COOH

acetoacetic acidacetoacetate

3-oxobutanoic acidβ-ketobutyric acid

CH3

C=O

CH3

acetone

CH3

CH–OH

CH2

COOH

β-hydroxybutyric acid3-hydroxybutanoic acid

– CO2

– 2 H

+ 2 H

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Amino acidsThe common name amino acids can be assigned to all carboxylicacids that comprise also an amino group.In biochemistry, the term amino acid is usually understood as the group name ofonly twenty standard (i.e. coded, proteinogenic) α-amino acids.

The following passage will deal with quite general properties of thebroad 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.

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When dehydrated by heating, they behave similarly to hydroxy acids:

– two molecules of α-amino acids lose two molecules of water andand form cyclic 2,5-dioxo-1,4-piperazines;

– β-amino acids readily eliminate ammonia giving an α,β-unsaturated acid:

R–CH=CH–COOHR–CH–CH–COOH

NH2H– NH3

– 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 formδ-aminoalkanoic acid(5-aminoalkanoic acid)

δ-lactam(5-alkylpiperidin-2-one)

– H2O

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p-Aminobenzoic acid and its derivatives

p-aminobenzoic acidPABA

sulfanilamide(p-aminobenzenesulfonamide)

p-Aminobenzoic acid (PABA) is an essential growth factorof bacteria required for the biosynthesis of folic acid. Folic acid actsas the cofactor in the transfer of one-carbon units in all livingorganisms. In mammals, it has to be supplied in the food. .

Approximately seventy years ago, it was discoveredby accident that sulfanilamide was an effectiveantibacterial agent. A huge amount of its variousanalogs called sulfa drugs were prepared. Eventoday some of them are still useful, although in manyinstances they have been replaced by more effectivean safer antibiotics.Sulfa drugs act by competitive inhibiting of the enzyme,which incorporates PABA into folate in the course ofthe folate biosynthesis, because they have similarstructure and shape, in part. .

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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 sosupport 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.

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MONOCARBOXYLIC DICARBOXYLIC

Satur. Unsatur. Hydroxy Keto Amino Satur. Unsatur. Hydroxy Keto Amino

C1 formic - H2CO3 - carbamic - - - - -

C2 acetic - glycolic glyoxalic glycine oxalic - - - -

C3 propionic acrylic lactic pyruvic alanine malonic - .. mesoxalic -

C4 butyric crotonicβ-

hydroxy-butyric

acetoacetic

- succinicfumaric maleic malic oxaloacetic aspartic

C5 valeric .. .. .. norvaline glutaric .. ..2-

oxoglutaricglutamic

C6 capronic .. .. ..norleucin

eadipic .. .. .. ..

The survey of important substituted aliphatic acids

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a Only in alkaline solution. b A protolytic reaction.c Condensation by heating, water is eliminated.

- -aldimine(Schiff base)

salt b / amide cAmine

salt b / amide cacid anhydride-ester(thioester)

Acid

aldimine(Schiff base)

-aldol ahemiacetal(hemithioacetal)

Aldehyde

-ester(thioester)

hemiacetal(hemithioacetal)

ether(sulfide)

Alcohol (Thiol)

AmineAcidAldehydeAlcohol(Thiol)

Reactions between the most important functional groups

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Conversions in side chains of acidscatalysed by enzymes:

Important biochemical reactions of acids

– 2H + H2OCH2

CH2

CO–

R

CH

CH

CO–

R

CH2

O=C

R

CO–

CH2

HO–CH

R

CO–

– 2H

+ 2H – H2O + 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

38

The citric acid cycleis a terminal catabolic pathway, in which acetyl (in the form ofcoenzyme A) is oxidized to two molecules of carbon dioxide.

The overall result may be written in the simplified form as

CH3-COOH + 2 H2O 2 CO2 + 8 H* + energy

The eight atoms of hydrogen are released as four molecules of reducedcoenzymes (3 NADH+H+ and 1 FADH2), the energetic yield is utilizedfor synthesis of one molecule of guanosine triphosphate (GTP) from GDP.

C

CH2–COOH

COOHO+ CH3–C

O

S CoA

+ H2O

– CoA-SH

oxaloacetate acetyl coenzyme A citrate

C

CH2

COOH

COOH

HO

CH2–COOH

The initial reaction of the citrate cycleis condensation of acetyl coenzyme A with oxaloacetate:

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dehydrogenation

dehydrogenation

dehydrogenation

dehydrogenation

C

CH2–COOH

COOH

CH2–COOH

HO

CH–COOH

CH2–COOH

CH–HO COOH

CH2

CH2–COOH

O=C–COOH

CH2

CH2 COOH

O=C–S–CoA

CH2–COOH

CH2–COOH

C

C

COOHH

HOOC H

CH2–COOH

HO–CH–COOH

CH2–COOH

O=C–COOH

CH3-CO–S–CoA

40

R–C–COOH

O

HOOC–CH-CH2-CH2-COOH

NH2

+

α-keto acid glutamate

+

α-amino acid 2-oxoglutarate

NH2

R–CH–COOH HOOC–C–CH2-CH2-COOH

O

Transamination of amino acidsThe α-amino group is transferred from an amino acid to2-oxoglutarate:

Examples: alanine → pyruvate aspartate → oxaloacetate

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Amines

Amines are organic compounds derived from ammonia byreplacing hydrogen atoms of ammonia with organic groups.Amines are the most important type of organic base thatoccurs in nature.

Amines are classified as primary, secondary, or tertiary,depending on the number of organic groups (alkyls oraryls) attached to the nitrogen atom.

primary amine R–NH2 primary amino group –NH2

secondary amino groupNHR

RNHsecondary amine

nitrogen atom in tertiary amines NR

R

NRtertiary amine

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Nomenclature

Substitutive names are not for amines.For simple amines, group-functional names or conjunctive namesare used.

isopropylamine propan-2-amine

CH3-CH-CH3

OH

CH2–NH2

CH2–NH2

ethandiamine(ethylene diamine)

HNH2

cyclohexylamine

methylamine

CH3–NH2

NH2

aniline(benzenamine)

CH3

CH3

N–CH2-CH2-CH3

dimethylpropylamineN,N-dimethylpropan-1-amine

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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, theproducts can be various.

1

2

3

4

44

alkylammonium chloride

R NH2 + R NH3+ Cl

-HCl

+ OH–H2O+ R NH2 R+

R NH R

dialkylammonium ion

+H2O+R NH3+

R NH2 H3O+

R NH2 + H2O OH–-R NH3+

+

alkylammonium ion

The basicity of amines - weak bases

Salts

Hydrolysis of alkylammonium cation

45

Reaction of primary and secondary amines with HNO2

H2O– NHR

R'

+H

+

NR

R'

N=O

secondary amine nitrosamine

HO-N=O

+ HNO2NH2 + HCl N N Cl

aniline benzenediazonium chloride

- 2 H2O

Primary aromatic amines in reaction with nitrous acidgive arenediazonium salts (diazotization reaction):

Secondary amines in reaction with nitrous acid give nitrosamines.

N N Cl + OH- HCl

N N OH

4-hydroxydifenyldiazen(azo compound, azo dye)

Coupling of reactive diazonium salts with other aromatic amines of phenols:

46

HO CH2CH2NH2

HO

HO CHCH2NH2

HOOH

HO CHCH2NH

HOOH

CH3

dopamine adrenalinenoradrenaline

N

N

CH2CH2NH2

H

HO CH2CH2NH2

N

CH2CH2NH2

H

histamine tryptaminetyramine

Examples of biogenic amines:

47

N

CH3

CH3

CH2CH2OHCH3

choline

N

CH3

CH3

CH2CH2CH3 O C CH3

O

acetylcholine

Quaternary ammonium compoundsN

CH3

CH3

CH3H3C I

tetramethylammonium iodideExamples of important compounds:

Br N

CH3

CH3

CH3C

OCH2CH3

O

carbethoxypentadecinium bromide

Cationic tensides(invert soaps) used asantiseptics/disinfectants

succinylcholine iodide

I (H3C)3NO

ON(CH3)3 I

O

O

N

CH3

CH3

CH3

CH2CHHO

CH2

COO

carnitine

48

Solvents for degreasing or dry-cleaningchloroform CHCl3, trilene ClHC=CCl2,tetrachloromethane CCl4 (very toxic!)

Refrigerants – chlorofluorocarbons (CFC´s, Freons) – harmful for theozone layer in the stratosphere; restrictions exist, especiallyfor "hard" ones (abandoned as propellants in aerosol dispensers)

Polymers – PVC, Teflon, chloroprene, neoprene

Plasticizers – polychlorinated biphenyls(PCB´s, Arochlor)

Halogen compoundsHalogen 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 ofalcohols, ethers, amines, and nitriles.

Organic halides enjoy extensive use as

2,2',4,4'-tetrachlorobiphenyl (PCB)

Cl

Cl

Cl

Cl

Freon 12

CF2Cl

49

tetraiodothyronine(thyroxine)

O

NH2

HO

I

I

I

I

CH2–CH–COOH

NH2

Br

Br

N CH3

bromohexine

N

N

F

O

O

H

H

5-fluorouracil

NHCl C NH C NH (CH2)6 NH

NH NH NH NH

C NH C NH Cl

chlorhexidine

CF3-CHBrCl CF3-CHCl–O–CHF2

halothan isoflurane

Biological activity of organic halides

Anaesthetics

Antiseptics

50

O

O

Cl

ClCl

Cl

dioxine

Cl CH

CCl3

Cl

DDT

HO CH2COOCl

Cl

2,4-dichlorophenoxyacetic acid2,4-D

Cl Cl

ClCl

ClCl

lindane

C CH2Cl

O

chloroacetophenone(tear gas)

Toxic pollutants

Pesticides – insecticides, mothicides, herbicides, fungicides

Lachrymators andchemical warfare agents