Derivatives of hydrocarbons I

Medical ChemistryLecture 6 2007 (J.S.)

Alcohols, phenols, ethers, thiols, carbonyl compounds, and carboxylic acids

NomenclatureHydrocarbons

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Nomenclature of organic compounds

Common (trivial) names

Semisystematic (rational) names

Systematic names

Acetic acid - Ethanoic acid

Picric acid - 2,4,6-Trinitrophenol

Stearic acid - Octadecanoic acid

- Acetone Propanone

(Glycerine) Glycerol 1,2,3-Propanetriol

Glutamic acid α-Aminoglutaric acid 2-Aminopentanedioic acid

Tyrosin p-Hydroxyphenylalanine 2-Amino-3-(4-hydroxy-phenyl) propanoic acid

Common (trivial) names are still used; judicious use of them providesa convenient group of parent compounds for ascribing names of their derivatives.

3

The six different principles in IUPAC nomenclature

1 Functional (group-functional) names – are the names of hydrocarbons that express their degree of unsaturation by means of suffixes (e.g., pentane, penta-1,3-diene, pent-1-yne, cyclopentane); – also the names of carboxylic acid derivatives (amides, nitriles, anhydrides, halides), ethers, sulfides, simple amines

(e.g., acetonitrile, butyryl chloride, diethyl ether, dimethylamine),

and alternatively the names of alcohols, aldehydes, ketones, and alkyl halides

(e.g., methyl alcohol, acetaldehyde, dimethyl ketone, methyl chloride).

2 Substitutive names are assigned to the majority of organic compounds:

Compounds are viewed as simple parent structures (molecules of hydrocarbons, heterocycles), which are substituted by various functional groups.

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3 Conjunctive names are formed by formal joining the component names without expressing a loss of atoms from any component

(e.g., indole-3-acetic acid, butane-1,4-diamine, 2,2‚-bipyridine).

4 Additive names

To the name of a parent compound a additive prefix or a group name is added

(e.g., tetrahydronaphthalene, homocysteine, styrene oxide).

5 Subtractive names

Subtractive prefixes express taking some atoms or groups away from the parent compound

(e.g., dehydroascorbate, 2-deoxyribose, demethylmorphine, noradrenalin).

6 Replacement names express an exchange of a group of atoms for a different atom or group; these names are nor very frequent

(e.g., 6-azauracil, 3-oxapentan = diethyl ether).

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Functional class

Suffix

(only one is used) Prefix (when other groups

as substituents)

ACIDS carboxylic sulfonic

–oic acid (carboxylic, sulfonic)

carboxy- sulfo-

Acid anhydrides, esters, halides, amides, nitriles

ALDEHYDES

KETONES

–al, –carbaldehyde

–one

oxo-, formyl-

oxo-

ALCOHOLS, PHENOLS –ol hydroxy-

THIOLS –thiol sulfanyl-

AMINES 0 amino-

ETHERS 0 (R)oxy- (e.g. alkyloxy-)

SULFIDES 0 (R)sulfanyl-

NITRO compound 0 nitro-

HALOGEN compound 0 fluoro-, chloro- ….

Substitutive names - selected functional groups

The decreasing order of preference in assigning a substitutive name:

6

Assigning a systematic IUPAC name to the compound(Generalities)

1 Assessing the functional class of the compound preliminarily and choosing the kind of name (substitutive, functional,...).

2 If a substitutive name seems to fit, deciding about the parent structure or chain

(in acyclic compounds, the parent chain contains – the majority of principal functions, – as many as possible multiple bonds, – alkyl substituents or groups not having their own suffixes, – the longest sequence of carbon atoms),

3 and assigning the name of hydrocarbon, adding the endings for the multiple bonds, numbering their positions,

4 adding the ending for the characteristic principal group(s),

5 assigning other substituents as prefixes and numerical locants, and listing them in the alphabetical order.

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Example:

CH3

Cl

C CH3

O

CH C

HO CH2 CH

1 The principal characteristic group is carbonyl (of a ketone); there are no cycles in the molecule, a substitutive name will fit.2 The parent "straight" chain has 6 carbons.3 The hydrocarbon is hexane with one double bond in position 3, then hex-3-ene.4 The characteristic group is carbonyl (of a ketone) in position 2 → hex-3-en-2-one.5 The other substituents (in alphabetical order) are 3-chloro, 6-hydroxy, and 5-methyl. The configuration on the double bond is cis- (= Z).

The substitutive name is

3-chloro-6-hydroxy-5-methyl-cis-hex-3-en-2-oneor (Z)-3-chloro-6-hydroxy-5-methyl-hex-3-en-2-one.

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Hydrocarbons are classified as

– acyclic (aliphatic) saturated alkanes (only single bonds), and

unsaturated alkenes and alkynes (with multiple bonds, including also polyenes);

both types may exist as unbranched ("straight" chain)and branched molecules;

– cyclic hydrocarbons are either saturated and unsaturated cycloalkanes or

with the "aromatic" system of conjugated double bonds – arenes.

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AlkanesAll alkanes fit the general molecular formula CnH2n + 2 .

Alkanes with carbon chains that are unbranched forma homologous series (each member of this series differs fromthe next higher and the next lower memberby a methylene group –CH2–..

The first eight unbranched alkanes:

Name Number of carbons Molecular formulaNumber of branchedstructural isomers

MethaneEthanePropaneButanePentaneHexaneHeptaneOctane

12345678

CH4

C2H6

C3H8

C4H10

C5H12

C6H14

C7H16

C8H18

0 0 0 1 2 4 817

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The names for branched alkanes

1 The root name is that of the longest continuous chain of carbon atoms.

2 The groups (alkyls) attached as branches to the main chain are taken as

substituents.

3 The main chain is numbered in such a way that the first substituent encountered along the chain receives the lowest possible number. The names of the substituent groups (with the numerical locants) are placed before the name of the parental structure in the alphabetical order.

4 The names of substituted substituents are enclosed in parenthesis.

Examples:

CH3

CH3–CH2–CH2–CH–CH–CH2–CH2–CH3

CH3–CH2–CH2 CH–CH3

4-propyl-5-(2-propyl)octane3-methylhexane

CH3–CH–CH2–CH2–CH3

CH2–CH3

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The names of substituting groups

Alkyls are derived from alkanes by removing one of the hydrogens:

CH3– CH3-CH2– CH3-CH2-CH2–

methyl ethyl 1-propyl 2-propyl (isopropyl)

CH3 CH3

CH

Alkylenes are divalent groups:

–CH2– –CH2-CH2– CH3-CH2-CH2–

– CH2-CH2-CH2–

methylene ethylene propylene propan-1,3-diyl (ethan-1,2-diyl) (propan-1,2-diyl)

Alkylidenes are also divalent groups but bothhydrogens removed from the same carbon atom:

CH3-CH= CH3-CH

ethylidene ethan-1,1-diyl

Methene (or methenyl)–CH= occurs as a bridgein tetrapyrrols (e.g. haem)and tetrahydrofolate

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Reactions of alkanes

All the bonds in alkanes are single, covalent, and nonpolar; hencealkanes are relatively inert.Alkanes ordinarily do not react with most common acids, bases, oroxidizing and reducing agents.

1 Oxidation and combustionAlkanes are resistant to most common oxidants (at high temperature,the primary carbon atoms give acetic acid).

With excess oxygen, alkanes burn to form CO2 and water → fuels.If insufficient oxygen is available for complete combustion,partial oxidation may occur → carbon monoxide CO, carbon (soot).

2 Substitution reactions Chlorination and other halogenations (at high temperature or insunlight) give alkyl halides (e.g. solvents, alkylating agents,chlorofluoroalkanes).

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Cycloalkanes

are saturated hydrocarbons that have at least one ring of carbon atoms.Cycloalkanes react in the similar way as alkanes.

Cis-trans isomerism occurs when at least two substituents are attachedto the ring structure.

CH2

CH2

CH2

CH2

H2C

H2C

cyclohexaneC6H12

cyclopropaneC3H6

cyclobutaneC4H8

cyclopentaneC5H10

CH3

CH2CH3

1-ethyl-2-methylcyclopentane

X

X

X

X

X

X

trans- (a,a) cis- (e,e) cis- (a,a)

Monocyclic cycloalkanes

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Polycyclic cycloalkanes

bicyclopropane

Isolated rings Spirans(one carbon atom common to two rings)

spiro[4,5]decane

adamantaneC10H16

H

H

H

Hdecalin bicyclo[4,4,0]decane

(decahydronaphthalene) trans-decalin cis-decalin

Two or more carbon atoms common to two or more ringsFused ring systems

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menthane

CH3 CH3

CH3

CH

CH2

CH3

CH3

CH3 CH3

≡

bicyclo[2,2,1]heptane bornane bicyclo[3,2,1]octane

Numerous naturally occurring compounds contain fused ring systems

Carbon skeleton of steroid compounds

Sterane C17H28

(cyclopentanoperhydrophenanthrene)

Terpenes of plants are very oft derivatives of cycloalkanes, e.g.

CH3CH3

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Alkenes and alkynes

Alkenes contain a carbon-carbon double bond (alkadienes two,alkatrienes three, polyenes many double ponds).Alkynes are hydrocarbons with a carbon-carbon triple bond.

Both of these classes of hydrocarbons are unsaturated; alkanescan be obtained from alkenes or alkynes by adding one or two moleculesof hydrogen.

CH3 CH3C CH

H

H

H+ H2

The carbon-carbon double bond consists of one σ bond and one π bond.

C CHH

H H

The rotation round double bonds is restricted.

Double bonds are very polarizable structures:

C C C C C C

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When two or more multiple bonds are present in a molecule, therelative positions of the multiple bonds are important:

–C=C–C–C=C– isolated (nonconjugated) double bonds,

–C=C–C=C– conjugated double bonds,

–C=C=C– cumulated double bonds.

If there are conjugated multiple bonds or multiple bonds conjugated withnonbonding (unshared) electron pairs in the molecule, the π electronsof the multiple bond(s) as well as conjugated unshared electron pairsare spread over such a system in a delocalized molecular π orbital.Such structures are called resonance hybrids.

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Alkenes - the names of substituting groups

Alkenyls are derived from alkenes by removing one of the hydrogens:

CH2=CH– CH3-CH=CH– CH2=CH–CH2–

vinyl 1-propenyl 2-propenyl ( not ethenyl! ) allyl

Alkenylenes are divalent groups:

–CH=CH– CH2=CH

vinylene vinylidene ethen-1,2-diyl ethen-1,1-diyl

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Reactions of alkenes and of other compounds that containa carbon-carbon double bond:

1 Addition is a most common reaction

addition of H2 (hydrogenation) → alkanes

addition of halogens (e.g. Br2) → dibromoalkanes

addition of hydrogen halides (e.g. Cl2) → chloroalkanes

addition of water → alcohols

polymerization

2 Oxidation → alkandiols (glycols) → oxidative cleavage at the site of double bond

(to a carbonyl compound and an acid) → ozonides that also undergo the cleavage

3 Substitution is possible but not for hydrogens attached directly to the unsaturated carbons.

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Aromatic hydrocarbons - arenes

Aromatic benzene ring

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Due to the molecular π orbital (resonance hybrid),benzene ring does not behave as unsaturated compounds:

– additions don't occur readily,

– benzene ring resists to oxidation,only fused rings (naphthalene, anthracene, etc.) can beoxidized easily, as well as side chains on the rings, ifthey are present.

The most common reactions are electrophilic substitutions:

nitration,sulfonation,

halogenation,alkylation, andacylation.

+ X+ X+

X

H+

X

+ H+

-complex -complex

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Benzene ring has an electronegative influence on substituentsattached to the ring.

Polarization of the ring occurs due to directing influence of thesubstituents present on the ring.

IOI H

- -

-

X+

X+X+C

H OI

- -

X+ X+

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CH3

toluene

CH3

CH3

o-xylene

CH CH2

styrene

CH2-CH3

ethylbenzene

Monocyclic arenes

Polycyclic aromatic hydrocarbons

biphenyl difenylmethan

CH2 CH CH

stilbene(1,2-diphenylethene)

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naphthalene anthracene naphthacene

Linear fusion of aromatic rings:

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is one of the most potent carcinogens; the metabolic oxidation to a diol-epoxide andother products seems to be a real culprit incausing cancer.

phenanthrene

pyrene benzo[a]pyrene

Polynuclear aromatic hydrocarbons (PAH)

e.g.

Angular fusion of aromatic rings:

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Names of substituting groups

Aryls

CH2

Phenylalkyls, phenylalkylenes, phenylalkylidenes, etc.

benzyl

CH benzylidene

phenyl

CH34-tolyl(p-tolyl)

1,2-phenylene(o-phenylene)

Arylenes, e.g.

1

2

1-naphtyl(α-naphtyl)

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Alcohols and phenols

Hydroxy derivatives of hydrocarbons

Alcohols R–OH – a hydroxyl is attached to an alkyl group(alcoholic hydroxyl)

Phenols Ar–OH – a hydroxyl is attached directly to an aromatic ring (phenolic hydroxyl);because of the electronegative influence of an aromaticsystem, the properties of phenolic hydroxyls differ from thehydroxyls of alcohols.

Their functional group is the hydroxyl group –OH .

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AlcoholsNomenclature

The ending –ol (-diol, -triol, etc.) is added to the name of thehydrocarbon in the IUPAC substitutive names.

In alternative functional names, the separate word alcohol is placedafter the name of the alkyl group.

HOH

methanol propan-2-ol prop-2-en-1-ol cyclohexanol (methyl alcohol) (isopropyl alcohol) (allyl alcohol) (cyclohexyl alcohol)

CH3–OH CH3-CH-CH3 CH2=CH-CH2–OH

OH

CH2–OH

CH2–OHCH2–OH

CH–OH

CH2–OH

ethan-1,2-diol propan-1,2,3-triol(ethylene glycol) (glycerol)

OH OH

OH

OH

OH

HO

cyclohexan-1,2,3,4,5,6-hexaol(myo-inositol)

OHOH

OHHOHO

OH

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Alcohols are classified as primary, secondary, or tertiary,depending on whether the hydroxyl-bearing carbon is the primary, secondary, or tertiary carbon atom:

R–CH2-OH –CH2-OHprimary alcohol primary alcoholic group

secondary alcohol secondary alcoholic group

tertiary alcohol tertiary alcoholic group

CH-OHR

RCH-OH

C–OHR

R

C-OHR

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General properties of alcohols

Polarity of the hydroxyl group –O H

Nucleophilic atom of oxygen –O–H that enables – alkylation of alcohols to ethers, – acylation of alcohols to esters, – addition of alcohols to carbonyl compounds

results in hemiacetals

Elimination of water (dehydration) to alkenes

Oxidation (dehydrogenation) aldehydes or ketones

1

2

3

4

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O

H

HO

R

HO

R

HO

R

H

O

H

HO

H

H

O

R

H

hydrogen bridges

1 Polarity of alcohols

The lowest three alcohols (C1 - C3) are miscible with water entirely;the hydrophilic character of alcohols decreases with the increasing lengthof their aliphatic chain (and increases with the number of hydroxyl groups.Water-soluble alcohols form clusters connected through hydrogen bonds.

In the presence of water, alcohols are neutral compounds.However, anhydrous alcohols exhibit very weak acidity to alkali metalsand react with them to give unstable alkoxides (alcoholates), e.g.

CH3-OH + Na CH3-O– Na+ + ½H2

sodium methoxide

R-O– Na+ + H2O R–OH + Na+ + OH–

When even traces of water are present, alkoxides are readily hydrolyzedto alcohols and an alkali hydroxide:

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diethyl etherethanol

+ H2OCH3

OCH2

CH2CH3CH3 CH2 OH

CH3 CH2 OH

H2SO4

(140 °C)

Nomenclature: Simple ethers are named by giving the name of eachalkyl or aryl group followed by the word ether. Sometimes it may benecessary to name the –O-R group as an alkoxy group.E.g., CH3CH2–O–CH3 ethyl methyl ether, alternatively methoxyethane.

Ethers are colourless compounds with lower boiling temperatures thanalcohols with an equal number of carbon atoms.Ethers are relatively inert compounds, excellent hydrophobic solvents.

2 /1 Alkylation of alcohols produces ethers

To make symmetric ethers, primary alcohols are heated with H2SO4:

One of the usual methods is the alkylation of sodium alkoxides byan alkyl halide:

R–O– Na+ + R´–Cl R–O–R´ + Na+Cl–

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diethyl peroxide(explosive) diethyl ether hydroperoxide

CH3CH2 CH2CH3

O O2, light

OOH

CH3CH CH2CH3

OCH3CH2 O

O CH2CH3heating

O

O

1,4-dioxan

O

tetrahydropyran

O

oxiran(ethylene oxide)

tetrahydrofuran

O

(oxolan)

CH3CH2O

CH2CH3

diethyl ether

OH

O–CH3

guaiacol guaiaphenesine(analgesic myorelaxant)

O–CH2–CH–CH2

OH OH

O–CH3

OCH3

methyl phenyl ether (anisol)0

O

diphenyl ether

Diethyl ether is used as an solvent. The use ofether as an anaesthetic administered by inhalationis rather limited at present because of its highflammability and some undesirable side effects..

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2 /2 Acylation of alcohols gives rise to esters

R–C

O

OH+ R' OH

H+

+ H2O

esteralcoholcarboxylicacid

–R´R–C

O

O

Esters of inorganic acids

Alcohols can form esters by using acylating agents such as acidanhydrides or acyl halides. In the presence of small amounts of a strong acid, esterificationof alcohols by carboxylic acids is possible:

Alcoholic and phenolic hydroxyls may also take part in formation ofester bonds with different inorganic acids.From biological point of view, the most important inorganic estersare esters of phosphoric, sulfuric, nitric, and nitrous acids.

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H3PO4O

OH

HO–P–OH

Phosphate esters

Phosphorylated sugars (intermediate metabolites)PhospholipidsNucleotides, nucleoside triphosphates, and nucleic acids

(with phosphodiester bonds)Phosphorylated proteins (side chains of Ser, Thr, and Tyr,

phosphorylation as an important regulatory principle)Organophosphate insecticides and nerve gases

CH–OH

CH=O

CH2–O– PO 32–

Examples:

glyceraldehyde 3-phosphate

D-glucose 1-phosphate ATP (adenosine triphosphate

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anionic tenside sodium dodecyl sulfate (SDS, sodium lauryl sulfate)

O

O–S–O

O

Na

O

O

HO–S–OHH2SO4Esters of sulfuric acid (sulfate esters)

alcohol + sulfuric acid(alkyl hydrogen sulfate)

alkyl sulfate dialkyl sulfate

+ ROH – H2O+R OH HO S OH

O

O

S OH

O

O

OR– H2O

S O

O

O

OR R

Sulfate esters of sugarsin glycosaminoglycans

Sulfate esters of phenols indetoxification or in inactivationof phenolic hormones

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R–OH + HO–NO2 R–O–NO2 + H2O

Esters of nitric and nitrous acid (organic nitrates)

glycerol trinitrate ("nitroglycerin",glyceroli trinitras), a vasodilator and

a known explosive

CH2–O–NO2

CH–O–NO2

CH2–O–NO2

isosorbide dinitrate (isosorbidi dinitras)

O

OO2N–O

O–NO2

HNO3O

HO–N(+)

O(–)

C

OCH2

CH2O

CH2O

OCH2

NO2

O2N

O2N

NO2

pentaerythritol tetranitrate

HNO2HO–N=O

alkyl nitrate

CH3

CH3

CH–CH2–CH2–O–N=O

isopentyl nitrite (amyl nitrite)

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Don't confuse

alkyl sulfate (an ester, sulfated alcohol)

O

O

R–O–S–O

O

O

R–S–O

alkanesulfonate(a sulfonated alkane)

with

or

with R–NO2R–O–N=O and R–O–NO2

alkyl nitrite and alkyl nitrate (esters of alcohols)

nitroalkane(a nitrated alkane)

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2 /3 Hemiacetals or hemiketals are products of addition of alcohols to carbonyl compounds

a hemiacetal (1-alkoxyalkan-1-ol)

H

R-OH + R´–CO

R´–C–O-R

H

OH

This addition is of particular importance in chemistry ofmonosaccharides, which form intramolecular hemiacetals –

cyclic forms of monosaccharides.The reaction is also included among the reactions of carbonyl.

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3 Elimination of water from alcohols gives alkenes

Don't confuse dehydration (elimination of water) withdehydrogenation (oxidation by taking off two atoms of hydrogen!

Alcohols can be dehydrated by heating them with a strong acid.E.g., when ethanol is heated at 180 °C (i.e. at higher temperaturethat is required for preparation of diethyl ether):

etheneethanol

+ H2OCH2CH2CH2 CH2

OHH

H+

(180 °C)

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4 Oxidation (dehydrogenation) of alcohols

CH3-CH2–OH + NAD+ + NADH + H+ CH3 C

H

alcohol dehydrogenaseO

R C

O

OH

R C

O

H

R CH2 OH

carboxylic acidaldehydeprimary alcohol

½ O2 – 2H

+ 2H

– 2H

+ 2HCH OH

R

R´

secondary alcohol

R´O

Rketone

C

Tertiary alcohols do not undergo this type of oxidation.

In the reaction catalyzed by alcohol dehydrogenase, NAD+ is the acceptorof hydrogen atoms:

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Alcohols with more than one hydroxyl group are oxidized similarly.

For example, the stepwise oxidation of dihydric alcohol ethylene glycol:

Oxidation of glycerol:

ethylene glycol

CH2-OH

CH2-OH.oxid. .oxid.

glycolaldehyde

CH2-OH

CH=O

CH=O

CH=Oglyoxal

glycolic acid

CH2-OH

COOH

oxid.

oxid.

oxid.

oxid.

glyoxylic acid

CH=O

COOH

oxalic acid

COOH

COOH

.oxid.

glycerol

CH2-OH

CH-OH

CH2-OH oxid.

oxid.

dihydroxyacetone

CH2-OH

C=O

CH2-OH

glyceraldehyde

CH=O

CH2-OH

CH-OH

glyceric acid

CH2-OH

COOH

CH-OH

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Enols represent a particular type of hydroxy derivatives.In spite of their ability to form esters like alcohols and their slightacidity (like phenols), they are tautomeric formsof carbonyl compounds:

the enol form the oxo form (keto form) of a carbonyl compound

OHC C C

OC

H

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PhenolsPhenolic hydroxyl is the hydroxyl group that is attached directly to an aromatic ring (a benzene ring or a pseudo aromatic ring of maximally unsaturated heterocycles).

Alcohols and phenols have many similar properties. However, because of the electronegative influence of an aromatic system, the properties of phenolic hydroxylsdiffer in some features from those of alcoholic hydroxyls:

– Phenols are weak acids mainly because the corresponding phenoxide (phenolate) anions are stabilized by resonance.

– Phenols with a sole hydroxyl cannot be oxidized easily, but o- and p-diphenols are dehydrogenized readily to quinones..– Phenols undergo aromatic ring substitution under very mild conditions.

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Nomenclature of simple phenols:

Monohydric phenols

Diphenols

Triphenols

OH

phenol

OH

CH3

o-cresol

OH

OH

OH

pyrogallol(benzene-1,2,3-triol)

HO

OH

OH

phloroglucinol(benzene-1,3,5-triol)

OH

OH

resorcinol(benzene1,3-diol)

OHOH

pyrocatechol(benzene-1,2-diol)

HO

OH

hydroquinone(benzene-1,4-diol)

HO

OH

OH

hydroxyhydroquinone(benzene-1,2,4-triol)

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Dehydrogenation of o- and p-diphenols

benzene-1,2-diol 1,2-benzoquinone benzene-1,4-diol 1,4-benzoquinone (pyrocatechol) (hydroquinone)

OH

OH

– 2H

O

O

+ 2H

– 2H

+ 2H

OH

OH

O

O

O

O

CH3O CH3

R(isoprenoid chain)

ubiquinone (coenzyme Q)

CH3O

ortho- and para-quinoid systems

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OH

CH3

C(CH3)3(CH3)3C

BHT(t-butylated hydroxytoluene)

antioxidant, food additive

thymol

CH3

CH3

OH

CH3

OH CH3CH3

CH3 CH3

propophol(2,6-diisopropylphenol)

ultra-short intravenous hypnotic

O

HO

isoprenoid chain

α-tocopherol(vitamin E)

CH3

CH3

CH3

CH3

O

R

O

CH3

1,4-naphtoquinone(active part of vitamin K)

(isoprenoid chain)

Examples of phenolic compounds:

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C6H5–SH thiophenol CH3–S–CH2-CH2-CH2–OH 3-methylthiopropan-1-ol

Thiols (thioalcohols and thiophenols)

a thiol R–SH a thiophenol a dialkyl sulfide R–S–R´SH

an alcohol R–OH a phenol an ether R–O–R´OH

are the sulfur analogs of alcohols and phenols:

The –SH group is called the sulfanyl group (formerly also the sulfhydryl or mercapto group).

Nomenclature:

HS–CH2-CH2-CH2–SH propane-1,3-dithiol CH3–S–CH2-CH2-CH3 methyl propyl sulfide

CH3-CH2-CH2–SH propane-1-thiol CH3–S–CH3 dimethyl sulfide

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Properties of thiolsPerharps the most distinctive feature of thiols is their intense and disagreeable stench (e.g., butenethiol responsible for the odour of skunk or fitchew, diallyl disulfide responsible for the odour of fresh garlic).

Some properties of thiols resemble those of alcohols because of the small difference in the electronegativity of sulfur and oxygen; nevertheless, thiols differ from alcohols in being slightly acidic and easily oxidable.

1 Thiols are very weak acids (e.g., pKA of ethanethiol is 10.6) that form thiolates in alkaline solutions. Because of their ability to bind readily some toxic cations, particular thiols serve as antidotes in, e.g., mercury or lead poisoning (the former name for thiols were mercaptans from "mercury captans").

2 Similarly to alcohols, thiols give dialkyl sulfides by alkylation, thioesters by acylation, and hemithioacetals by addition to carbonyl compounds.

3 Thiols are very easily oxidized (dehydrogenized) by mild oxidation agents to disulfides.

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(Formation of disulfide bridges in proteins)

– 2H

+ 2HNH2

2 HS–CH2–CH–COOH

cysteine

HOOC–CH–CH2–S–S–CH2–CH–COOH

NH2NH2

cystine

Oxidation of thiols and sulfides

Mild oxidizing agentsdehydrogenize two molecules of thiols to dialkyl disulfides:

thiol dialkyl disulfide

2 R–SH– 2H

R–S–S–R+ 2H

Example:

Oxidation of thiols and sulfides by strong oxidation agents:

R–SH R–SO2H R–SO3–H+

–II IV VI

alkanethiol alkanesulfinic acid alkanesulfonic acid

dialkyl sulfide dialkyl sulfoxide dialkyl sulfone

R–S–R´ R–SO–R´ R–SO2–R´–II IV VI

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Thiols with their oxidable sulfanyl groups act in living systems asimportant reducing agents (e.g. tripeptide glutathione, G–SH).

On the other hand, lipoic acid (a disulfide) acts as an oxidant;it accepts hydrogen atoms in the course of oxidative decarboxylationof α-ketoacids:

dihydrolipoic acidSHSH

COOH

lipoic acid (an oxidant)

SS

COOH + 2H

- 2H

Examples of other important sulfur containing compounds in living systems:

Coenzyme A is a thiol that transfers acyls in the form of thioesters

Coenzyme A–SH + HOOC–R Coenzyme A–S–CO-R + H2O

Taurine, aminoethanesulfonic acid H2N–CH2-CH2–SO3H forms amides with bile acids secreted from the liver cells.

Methionine, an essential amino acid, is a sulfide in its side chain that servesas a donor of the methyl group: HOOC–CH-CH2-CH2–S–CH3

NH2

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Aldehydes and ketones

Carbonyl compounds

Their functional group is the carbonyl group C=O

Aldehydes have at least one hydrogen atom attached to the carbonyl group.

–CH

O

aldehyde group formaldehyde aliphatic aldehyde aromatic aldehyde

H–CH

OR–C

H

OAr–C

H

Oor –CH=O

In ketones, the carbonyl carbon atom is connected to two othercarbon atoms:

aliphatic ketone alkyl aryl ketone aromatic ketone alicyclic ketone

R–CR´

OR–C

Ar

OAr–C

Ar

OC=O

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Nomenclature

The characteristic ending for aldehydes is –al ; for cyclic aldehydes, the suffix –carbaldehyde is used:

CH=O

ethanal 3-butenal benzenecarbaldehydeacetaldehyde benzaldehyde

–CH

OCH3 –C

H

OCH2=CH–CH2

The ending for ketones is –one ; if there is another preferred groupin the molecule, the presence of carbonyl is expressed by usinga prefix oxo- (or keto- in common names).

=OCH3–C–CH2-CH3

O O

–C–CH3

O

CH3–C–CH2–COOH

2-butanone cyclohexanone methyl phenyl ketone 3-oxopropanoic acidethyl methyl ketone acetophenone (β-ketobutyric acid)

acetoacetic acid

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Some reactions of carbonyl compounds

Polarity of the unsaturated carbonyl group – tautomerization (oxo-forms and enol-forms exist); – additions to a carbonyl group: addition of water → labile hydrates, addition of an alcohol → hemiacetals or hemiketals, addition of ammonia or an amine → unstable adducts

that eliminate water to give aldimines or ketimines.

Oxidation of aldehydes to carboxylic acids.

Aldol "condensation" of two molecules (in slightly alkaline solutions) gives aldols; in acidic solutions, aldehydespolymerize.

1

2

3

C=O

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the keto form of acetone the enol form of acetone (0.0003 %)

C=OCH3

CH3

CH2

CH3

C–OH

R–CH

O+ H2O

aldehyde aldehyde hydrate

HR–C

OHOH

1 /1 Tautomerism of carbonyl compounds

If a carbonyl compound has a hydrogen atom attached to the carbonatom adjacent to the carbonyl group (α-carbon atom), it may exist inan enol form:

Most simple aldehydes and ketones exist mainly in the keto form.

1 /2 Addition of water – hydration of aldehydes and ketones

In water, carbonyl compounds can add reversibly water molecules andexist as their hydrates. The hydrates of most aldehydes and ketones cannot be isolated because they readily lose water to reform the carbonylcompound.

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In acetals, the original hemiacetal hydroxyl is replaced by analkoxy group (–O-R) of an alcohol.

An acetal can be hydrolyzed to its aldehyde or ketone and alcohol components in the presence of an acid; in alkaline solutions, the acetal bond resist hydrolysis.

condensation

addition

R–CH

O+ HO–R´

aldehyde hemiacetal acetal (1-alkoxyalkan-1-ol) (1,1-dialkoxyalkane)

HR–C

OHO–R´ + HO–R´

– H2O HR–C

O–R´O–R´

1 /3 Addition of alcohols gives hemiacetals,

that can react further to form acetals

Ketones react in the same way; the products are sometimes calledhemiketals and ketals.

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Monosaccharides are aldehydes and ketones that have in their molecules appropriately located hydroxyl groups, and thereforethey may form intramolecular cyclic hemiacetals,cyclic forms of monosaccharides (pyranoses or furanoses)..In aqueous solution, both acyclic and cyclic forms of monosaccharidesexist in equilibrium; in most hexoses and pentoses the cyclic hemiacetal form prevails.

the hemiacetalhydroxyl group

a hexose(acyclic aldehyde)

a hexopyranose(cyclic hemiacetal form)

The hemiacetal hydroxyl group of cyclic forms can react with varioushydroxy derivatives to give acetals. Those acetals are called glycosidesand the acetal linkage is called glycosidic bond.

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1 /4 Addition of primary amines or ammonia results in

formation of aldimines (Schiff bases)

R–CH

O+ H2N–R´

aldehyde

HR–C

OHNH–R´ – H2O

labile adduct is stabilized by elimination of water aldimine (Schiff base)

HR–C

NH

addition

Ketones react in the same way, their Schiff bases are ketimines.

Other ammonia derivatives containing an –NH2 group (e.g. hydroxylamine or hydrazine) react with carbonyl similarly to primary amines.

Imines are important intermediates in some biochemical reactions,e.g. in enzyme-catalyzed transamination of amino acids and α-ketoacids, or in undesired non-catalyzed reaction of proteins withmonosaccharides (glycation of proteins).

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2 Oxidation of aldehydes to carboxylic acids

C=OCH3

CH3

CH3-COOH + H-COOHKMnO4

Ketones can be oxidized only by strong oxidants and this oxidation result in splitting the carbon chain:

Oxidation of aldehydes to carboxylic acids with the samenumber of carbon atoms occurs very easily.Therefore, in contrast to ketones, aldehydes arereducing agents.

R–COH

OR–C

H

O oxidation

Both aldehydes and ketones are readily reduced toprimary and secondary alcohols.

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3 Aldol condensation

+OH–

acidic Hon α-carbon

carbanion β-aldol(3-hydroxyaldehyde)

An example of the reversible aldol condensation:In the synthesis of glucose from pyruvate (gluconeogenesis),glyceraldehyde 3-phosphate and dihydroxyacetone phosphateundergo aldol condensation to fructose 1,6-bisphosphate.In glycolysis, fructose 1,6-bisphosphate is split into glyceraldehydephosphate and dihydroxyacetone.The enzyme aldolase catalyzes the reaction in both directions.

Aldehydes and ketones that have a hydrogen atom on theα-carbon can add to the carbonyl group of another aldehyde orketone molecule. This aldol "condensation" forms new C–C bonds.

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Various examples of carbonyl compounds – important in biochemistry

vanillin

OH

CH=O CH=O

OH

salicylaldehyde

O

O

1,4-benzoquinone

CH=O

benzaldehyde

dihydroxyacetone

CH2-OH

C=O

CH2-OH

glyceraldehyde

CH=O

CH2-OH

CH-OH

CH3-CH=O

acetaldehyde

O=CH–CH2–CH=O

malondialdehyde

Monosaccharides are polyhydroxyaldehydes or polyhydroxyketones;the most simple of them are

α-Ketoacids (e.g. pyruvate, oxaloacetate, and 2-oxoglutarate) are intermediatemetabolites of saccharides and amino acids.

CH3–CO–CH3

acetone