Derivatives of hydrocarbons I Medical Chemistry Lecture 6 200 7 (J.S.) Alcohols, phenols, ethers, thio l s, carbonyl compounds, and carboxylic acids Nomenclature Hydrocarbons
Nomenclature of organic compounds Common (trivial) names are still used; judicious use of them provides a convenient group of parent compounds for ascribing names of their derivatives. 2-Amino-3-(4-hydroxy-phenyl) propanoic acid p- Hydroxyphenylalanine Tyrosin 2-Aminopentanedioic acid α-Aminoglutaric acid Glut am ic acid 1,2,3-Propanetriol Glycer ol (Glycerine) Propanone Acet one - Octadecanoic acid - Stearic acid 2,4,6-Trinitrophenol - Picric acid Ethanoic acid - Acetic acid Systematic names Semisystematic (rational) names Common (trivial) names
The six different principles in IUPAC nomenclature <ul><li>Functional (group-functional) names </li></ul><ul><li>– are the names of hydrocarbons that express their degree of </li></ul><ul><li>unsaturation by means of suffixes </li></ul><ul><li> (e.g., pentane, penta-1,3-diene, pent-1-yne, cyclopentane) ; </li></ul><ul><li>– also the names of carboxylic acid derivatives (amides, nitriles, </li></ul><ul><li>anhydrides, halides), ethers , sulfides , simple amines </li></ul><ul><li> (e.g., acetonitrile, butyryl chloride, diethyl ether, dimethylamine), </li></ul><ul><li>and alternatively the names of alcohols, aldehydes, ketones, </li></ul><ul><li>and alkyl halides </li></ul><ul><li> (e.g., methyl alcohol, acetaldehyde, dimethyl ketone, methyl chloride). </li></ul><ul><li>Substitutive names </li></ul><ul><li>are assigned to the majority of organic compounds: </li></ul><ul><li>Compounds are viewed as simple parent structures </li></ul><ul><li>(molecules of hydrocarbons, heterocycles), which are </li></ul><ul><li>substituted by various functional groups . </li></ul>
<ul><li>Conjunctive names </li></ul><ul><li>are formed by formal joining the component names without expressing </li></ul><ul><li>a loss of atoms from any component </li></ul><ul><li>(e.g., indole-3-acetic acid, butane-1,4-diamine, 2,2 ‚- bipyridine ). </li></ul><ul><li>Additive names </li></ul><ul><li>To the name of a parent compound a additive prefix or a group name </li></ul><ul><li>is added </li></ul><ul><li> (e.g., tetrahydronaphthalene, homocysteine, styrene oxide). </li></ul><ul><li>Subtractive names </li></ul><ul><li>Subtractive prefixes express taking some atoms or groups away from </li></ul><ul><li>the parent compound </li></ul><ul><li> ( e.g., dehydroascorbate, 2-deoxyribose, demethylmorphine, noradrenalin). </li></ul><ul><li>Replacement names </li></ul><ul><li>express an exchange of a group of atoms for a different atom or group; </li></ul><ul><li>these names are nor very frequent </li></ul><ul><li> (e.g., 6-azauracil, 3-oxapentan = diethyl ether ). </li></ul>
Substitutive names - selected functional groups The decreasing order of preference in assigning a substitutive name:
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 (i n 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.
Example: <ul><li>The principal characteristic group is carbonyl (of a ketone); there are </li></ul><ul><li>no cycles in the molecule, a substitutive name will fit. </li></ul><ul><li>2 The parent "straight" chain has 6 carbons. </li></ul><ul><li>3 The hydrocarbon is hexane with one double bond in position 3, then hex-3-ene . </li></ul><ul><li>The characteristic group is carbonyl (of a ketone) in position 2 -> hex-3-en-2-one . </li></ul><ul><li>The other substituents (in alphabetical order) are 3-chloro, 6-hydroxy, and </li></ul><ul><li>5-methyl. The configuration on the double bond is cis- (= Z ) . </li></ul>The substitutive name is 3- chloro -6- hydroxy -5- methyl - cis- hex -3- en -2- one or ( Z )-3-chloro-6-hydroxy-5-methyl-hex-3-en-2-one. CH 3 Cl C CH 3 O CH C HO CH 2 CH
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 .
Alkanes All alkanes fit the general molecular formula C n H 2n + 2 . Alkanes with carbon chains that are unbranched form a homologous series (each member of this series differs from the next higher and the next lower member by a methylene group – CH 2 –. . The first eight unbranched alkanes: Name Number of carbons Molecular formula Number of branched structural isomers Methane Ethane Propane Butane Pentane Hexane Heptane Octane 1 2 3 4 5 6 7 8 CH 4 C 2 H 6 C 3 H 8 C 4 H 10 C 5 H 12 C 6 H 14 C 7 H 16 C 8 H 18 0 0 0 1 2 4 8 17
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: CH 3 CH 3 –CH 2 –CH 2 –CH–CH–CH 2 –CH 2 –CH 3 CH 3 –CH 2 –CH 2 CH–CH 3 4-propyl-5-(2-propyl)octane 3-methylhexane CH 3 –CH–CH 2 –CH 2 –CH 3 CH 2 –CH 3
The names of substituting groups Alkylidenes are also divalent groups but both hydrogens removed from the same carbon atom: Methene (or methenyl ) – CH= occurs as a bridge in tetrapyrrols (e.g. haem) and tetrahydrofolate Alkyls are derived from alkanes by removing one of the hydrogens: CH 3 – CH 3 -CH 2 – CH 3 -CH 2 -CH 2 – methyl ethyl 1- propyl 2- propyl (isopropyl) CH 3 CH 3 CH Alkyl ene s are divalent groups: – CH 2 – –CH 2 -CH 2 – CH 3 -CH 2 -CH 2 – – CH 2 -CH 2 -CH 2 – methylene ethylene propylene propan -1,3- diyl (ethan-1,2-diyl) (propan-1,2-diyl) CH 3 -CH= CH 3 -CH ethylidene ethan -1,1- diyl
Reactions of alkanes All the bonds in alkanes are single, covalent, and nonpolar; hence alkanes are relatively inert . Alkanes ordinarily do not react with most common acids, bases, or oxidizing and reducing agents. 1 Oxidation and combustion Alkanes are resistant to most common oxidants (at high temperature, the primary carbon atoms give acetic acid). With excess oxygen, alkanes burn to form CO 2 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 in sunlight) give alkyl halides (e.g. solvents, alkylating agents, chlorofluoroalkanes).
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 attached to the ring structure. CH 2 CH 2 CH 2 CH 2 H 2 C H 2 C cyclohexane C 6 H 12 cyclopropane C 3 H 6 cyclobutane C 4 H 8 cyclopentane C 5 H 10 CH 3 CH 2 CH 3 1-ethyl-2-methyl cyclopentane trans- (a,a) cis- (e,e) cis- (a,a) Monocyclic cycloalkanes
Polycyclic cycloalkanes bicyclopropane Isolated rings Spirans (one carbon atom common to two rings) spiro [4,5]decane adamantane C 10 H 16 H H H H decalin bicyclo [4,4,0]decane (decahydronaphthalene) trans- decalin cis- decalin Two or more carbon atoms common to two or more rings Fused ring systems
menthane CH 3 CH 3 CH 3 CH CH 2 CH 3 CH 3 CH 3 CH 3 ≡ 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 C 17 H 28 (cyclopentanoperhydrophenanthrene) Terpenes of plants are very oft derivatives of cycloalkanes, e.g. CH 3 CH 3
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 ; alkanes can be obtained from alkenes or alkynes by adding one or two molecules of hydrogen. C H 3 C H 3 C C H H H H + H 2 The carbon-carbon double bond consists of one σ bond and one π bond. C C H H H H The rotation round double bonds is restricted. Double bonds are very polarizable structures: C C C C C C
When two or more multiple bonds are present in a molecule, the relative 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 with nonbonding (unshared) electron pairs in the molecule, the π electrons of the multiple bond(s) as well as conjugated unshared electron pairs are spread over such a system in a delocalized molecular π orbital. Such structures are called resonance hybrids .
Alkenes - the names of substituting groups Alk en yls are derived from alkenes by removing one of the hydrogens: CH 2 =CH– CH 3 -CH=CH– CH 2 =CH–CH 2 – vinyl 1- propenyl 2- propenyl ( not ethenyl! ) allyl Alkenyl ene s are divalent groups: – CH=CH– CH 2 =CH vinylene vinylidene ethen-1,2-diyl ethen-1,1-diyl
Reactions of alkenes and of other compounds that contain a carbon-carbon double bond: 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. 1 Addition is a most common reaction addition of H 2 (hydrogenation) -> alkanes addition of halogens (e.g. Br 2 ) -> dibromoalkanes addition of hydrogen halides (e.g. Cl 2 ) -> chloroalkanes addition of water -> alcohols polymerization
Aromatic hydrocarbons - arenes Aromatic benzene ring
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 be oxidized easily, as well as side chains on the rings, if they are present. The most common reactions are electrophilic substitutions : nitration , sulfonation , halogenation , alkylation , and acylation . + X + X + X H + X + H + -complex -complex
Benzene ring has an electronegative influence on substituents attached to the ring. Polarization of the ring occurs due to directing influence of the substituents present on the ring.
Polycyclic aromatic hydrocarbons Linear fusion of aromatic rings: C H 3 toluene C H 3 C H 3 o- xylene C H C H 2 styrene CH 2 -CH 3 ethylbenzene Monocyclic arenes biphenyl difenylmethan CH 2 C H C H stilbene (1,2-diphenylethene) 1 2 naphthalene anthracene naphthacene
is one of the most potent carcinogens ; the metabolic oxidation to a diol-epoxide and other products seems to be a real culprit in causing cancer. phenanthrene pyrene benzo [a] pyrene Polynuclear aromatic hydrocarbons (PAH) e.g. Angular fusion of aromatic rings:
Names of substituting groups Aryls C H 2 Phenylalkyls , phenylalkyl ene s, phenylalkyl id ene s, etc. benzyl C H benzylidene phenyl C H 3 4-tolyl ( p -tolyl) 1,2-phenylene ( o -phenylene) Arylenes , e.g. 1 2 1-naphtyl ( α-naphtyl)
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 aromatic system , the properties of phenoli c hydroxyls differ from the hydroxyls of alcohols. Their functional group is the hydroxyl group –OH .
Alcohols Nomenclature The ending –ol (-diol, -triol, etc.) is added to the name of the hydrocarbon in the IUPAC substitutive names. In alternative functional names, the separate word alcohol is placed after the name of the alkyl group. ethan -1,2- diol propan -1,2,3- triol (ethylene glycol) (glycerol) H OH methanol propan -2- ol prop -2- en -1- ol cyclohexanol (methyl alcohol) (isopropyl alcohol) (allyl alcohol) (cyclohexyl alcohol) CH 3 –OH CH 3 -CH-CH 3 CH 2 =CH-CH 2 –OH OH CH 2 –OH CH 2 –OH CH 2 –OH CH–OH CH 2 –OH cyclohexan -1,2,3,4,5,6- hexaol ( myo -inositol) O H O H O H H O H O OH
Alcohols are classified as primary, secondary, or tertiary, depending on whether the hydroxyl-bearing carbon is the primary, secondary, or tertiary carbon atom: R–CH 2 -OH –CH 2 -OH primary alcohol primary alcoholic group secondary alcohol secondary alcoholic group tertiary alcohol tertiary alcoholic group CH-OH R R CH-OH C–OH R R C-OH R
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
O H H O R H O R H O R H O H H O H H O R H hydrogen bridges 1 Polarity of alcohols The lowest three alcohols (C 1 - C 3 ) are miscible with water entirely; the hydrophilic character of alcohols decreases with the increasing length of 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 metals and react with them to give unstable alkoxides ( alcoholates ), e.g. CH 3 -OH + Na CH 3 -O – Na + + ½H 2 sodium methoxide R-O – Na + + H 2 O R–OH + Na + + OH – When even traces of water are present, alkoxides are readily hydrolyzed to al c ohols and an alkali hydroxide:
Nomenclature : Simple ethers are named by giving the name of each alkyl or aryl group followed by the word ether . Sometimes it may be necessary to name the –O-R group as an alkoxy group . E.g., CH 3 CH 2 –O–CH 3 ethyl methyl ether, alternatively methoxyethane. Ethers are colourless compounds with lower boiling temperatures than alcohols with an equal number of carbon atoms. Ethers are relatively inert compounds , excellent hydrophobic solvents. diethyl ether ethanol + H 2 O C H 3 O C H 2 C H 2 C H 3 C H 3 C H 2 O H C H 3 C H 2 O H H 2 SO 4 (140 °C) 2 / 1 Alkylation of alcohols produces ethers To make symmetric ethers, primary alcohols are heated with H 2 SO 4 : One of the usual methods is the alkylation of sodium alkoxides by an alkyl halide: R–O – Na + + R´–Cl R–O–R´ + Na + Cl –
Diethyl ether is used as an solvent. The use of ether as an anaesthetic administered by inhalation is rather limited at present because of its high flammability a n d some undesirable side effects.. diethyl peroxide (explosive) diethyl ether hydroperoxide CH 3 CH 2 CH 2 CH 3 O O 2 , light OOH CH 3 CH CH 2 CH 3 O CH 3 CH 2 O O CH 2 CH 3 heating O O 1,4-dioxan O tetrahydropyran O oxiran (ethylene oxide) tetrahydrofuran (oxolan) C H 3 C H 2 O C H 2 C H 3 diethyl ether OH O–CH 3 guaiacol guaiaphenesine (analgesic myorelaxant) O–CH 2 –CH–CH 2 OH OH O–CH 3 O C H 3 methyl ph enyl ether (anisol)0 O di ph enyl ether
2 / 2 Acylation of alcohols gives rise to esters R–C O OH + R ' O H H + + H 2 O ester alcohol carboxylic acid – R´ R–C O O Esters of inorganic acids Alcohols can form esters by using acylating agents such as acid anhydrides or acyl halides. In the presence of small amounts of a strong acid, esterification of alcohols by carboxylic acids is possible: Alcoholic and phenolic hydroxyls may also take part in formation of ester bonds with different inorganic acids. From biological point of view, the most important inorganic esters are esters of phosphoric , sulfuric , nitric , and nitrous acids .
H 3 PO 4 O OH HO–P–OH Phosphate esters Phosphorylated sugars (intermediate metabolites) Phospholipids Nucleotides , 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 CH 2 –O– PO 3 2– Examples: glyceraldehyde 3-phosphate D -glucose 1-phosphate ATP (adenosine triphosphate
anionic tenside sodium dodecyl sulfate (SDS, sodium lauryl sulfate) O O–S–O O Na O O HO–S–OH H 2 SO 4 Esters of sulfuric acid ( sulfate esters ) alcohol + sulfuric acid (alkyl hydrogen sulfate) alkyl sulfate dialkyl sulfate + ROH – H 2 O + R O H H O S O H O O S O H O O O R – H 2 O S O O O O R R Sulfate esters of sugars in glycosaminoglycans Sulfate esters of phenols in detoxification or in inactivation of phenolic hormones
R–OH + HO–NO 2 R–O–NO 2 + H 2 O Esters of nitric and nitrous acid ( organic nitrates ) HNO 3 HNO 2 HO–N=O alkyl nitrate glycerol trinitrate ( "nitroglycerin", glyceroli trinitras), a vasodilator and a known explosive CH 2 –O–NO 2 CH–O–NO 2 CH 2 –O–NO 2 isosorbide dinitrate (isosorbidi dinitras) O O O 2 N–O O–NO 2 O HO–N (+) O (–) C O C H 2 C H 2 O C H 2 O O C H 2 N O 2 O 2 N O 2 N N O 2 pentaerythritol tetranitrate CH 3 CH 3 CH–CH 2 –CH 2 –O–N=O isopentyl nitrite (amyl nitrite)
Don't confuse or alkyl sulfate (an ester , sulfated alcohol) O O R – O –S–O O O R– S–O alkanesulfonate (a sulfonated alkane ) with with R –NO 2 R–O– N=O and R–O –NO 2 alkyl nitrite and alkyl nitrate ( esters of al c ohols) nitroalkane (a nitrated alkane )
2 / 3 Hemiacetals or hemiketals are products of addition of alcohols to carbonyl compounds This addition is of particular importance in chemistry of monosaccharides, which form intramolecular hemiacetals – cyclic forms of monosaccharides . The reaction is also included among the reactions of carbonyl. a hemiacetal (1-alkoxyalkan-1-ol) H R- OH + R´–C O R´–C– O- R H O H
3 Elimination of water from alcohols gives alkenes Don't confuse dehydration (elimination of water) with dehydrogenation (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 temperature that is required for preparation of diethyl ether): ethene ethanol + H 2 O C H 2 C H 2 C H 2 C H 2 O H H H + (180 °C)
4 Oxidation (dehydrogenation) of alcohols CH 3 -CH 2 –OH + NAD + + N A D H + H + C H 3 C H alcohol dehydrogenase O R C O O H R C O H R C H 2 O H carboxylic acid aldehyde primary alcohol ½ O 2 – 2H + 2H – 2H + 2H C H O H R R´ secondary alcohol R´ O R ketone C Tertiary alcohols do not undergo this type of oxidation. In the reaction catalyzed by alcohol dehydrogenase, NAD + is the acceptor of hydrogen atoms:
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 CH 2 -OH CH 2 -OH . oxid. . oxid. glycolaldehyde CH 2 -OH CH=O CH=O CH=O glyoxal glycolic acid CH 2 -OH COOH oxid. oxid. oxid. oxid. glyoxylic acid CH=O COOH oxalic acid COOH COOH . oxid. glycerol CH 2 -OH CH-OH CH 2 -OH oxid. oxid. dihydroxyacetone CH 2 -OH C=O CH 2 -OH glyceraldehyde CH=O CH 2 -OH CH-OH glyceric acid CH 2 -OH COOH CH-OH
Enols represent a particular type of hydroxy derivatives. In spite of their ability to form esters like alcohols and their slight acidity (like phenols), they are tautomeric forms of carbonyl compounds : the e nol form the oxo form (keto form) of a carbonyl compound OH C C C O C H
Phenols Phenolic 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 hydroxyls differ 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.
Nomenclature of simple phenols: Monohydric phenols Diphenols Triphenols OH phenol OH CH 3 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) OH OH pyrocatechol (benzene-1,2-diol) HO OH hydroquinone (benzene-1,4-diol) HO OH OH hydroxyhydroquinone (benzene-1,2,4-triol)
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 CH 3 O CH 3 R (isoprenoid chain) ubiquinone (coenzyme Q) CH 3 O ortho- and para- quinoid systems
O H C H 3 C ( C H 3 ) 3 ( C H 3 ) 3 C BHT ( t -butylated hydroxytoluene) antioxidant, food additive thymol C H 3 C H 3 O H C H 3 O H C H 3 C H 3 C H 3 C H 3 propophol (2,6-diisopropylphenol) ultra-short intravenous hypnotic O H O isoprenoid chain α- tocopherol (vitamin E) CH 3 CH 3 CH 3 CH 3 O R O CH 3 1,4-naphtoquinone (active part of vitamin K) (isoprenoid chain) Examples of phenolic compounds:
C 6 H 5 –SH thiophenol CH 3 –S–CH 2 -CH 2 -CH 2 –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–CH 2 -CH 2 -CH 2 –SH propane-1,3-dithiol CH 3 –S–CH 2 -CH 2 -CH 3 methyl propyl sulfide CH 3 -CH 2 -CH 2 –SH propane-1-thiol CH 3 –S–CH 3 dimethyl sulfide
Properties of thiols Perharps 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., p K A 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 a c ylation, and hemithioacetals by addition to carbonyl compounds. 3 Thiols are very easily oxidized (dehydrogenized) by mild oxidation agents to disulfides .
(Formation of disulfide bridges in proteins) – 2H + 2H NH 2 2 HS –CH 2 –CH–COOH cysteine HOOC–CH–CH 2 – S – S –CH 2 –CH–COOH NH 2 NH 2 cystine Oxidation of thiols and sulfides Mild oxidizing agents dehydrogenize 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– SO 2 H R– SO 3 – H + – II IV VI alkanethiol alkanesulfinic acid alkanesulfonic acid dialkyl sulfide dialkyl sulfoxide dialkyl sulfone R– S –R´ R– SO –R´ R– SO 2 –R´ – II IV VI
Thiols with their oxidable sulfanyl groups act in living systems as important 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 decarboxylation of α-ketoacids: dihydrolipoic acid S H S H C O O H lipoic acid (an oxidant) S S C O O H + 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– S H + HOOC–R Coenzyme A– S –CO-R + H 2 O Taurine , aminoethane sulfonic acid H 2 N–CH 2 -CH 2 – SO 3 H forms amides with bile acids secreted from the liver cells. Methionine, an essential amino acid, is a sulfide in its side chain that serves as a donor of the methyl group : HOOC–CH-CH 2 -CH 2 – S – CH 3 NH 2
Aldehydes and ketones Carbonyl compounds Aldehydes have at least one hydrogen atom attached to the carbonyl group. In ketones , the carbonyl carbon atom is connected to two other carbon atoms: Their functional group is the carbonyl group C=O – C H O aldehyde group formaldehyde aliphatic aldehyde aromatic aldehyde H–C H O R–C H O Ar–C H O or –CH=O aliphatic ketone alkyl aryl ketone aromatic ketone alicyclic ketone R–C R ´ O R–C Ar O Ar–C Ar O =O
Nomenclature The characteristic ending for aldehydes is –al ; for cyclic aldehydes, the suffix – carbaldehyde is used: CH=O ethanal 3- butenal benzenecarbaldehyde acetaldehyde benzaldehyde – C H O CH 3 – C H O CH 2 =CH–CH 2 The ending for ketones is –one ; if there is another preferred group in the molecule, the presence of carbonyl is expressed by using a prefix oxo- (or keto- in common names). =O CH 3 –C–CH 2 -CH 3 O O – C–CH 3 O CH 3 –C–CH 2 –COOH 2- butanone cyclohexanone methyl phenyl ketone 3- oxopropanoic acid ethyl methyl ketone acetophenone ( β-ketobutyric acid) acetoacetic acid
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, aldehydes polymerize. 1 2 3 C=O
1 /1 Tautomerism of carbonyl compounds If a carbonyl compound has a hydrogen atom attached to the carbon atom adjacent to the carbonyl group ( α-carbon atom), it may exist in an 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 and exist as their hydrates . The hydrates of most aldehydes and ketones cannot be isolated because they readily lose water to reform the carbonyl compound. the keto form of acetone the enol form of acetone (0.0003 %) C=O CH 3 CH 3 CH 2 CH 3 C–OH R–C H O + H 2 O aldehyde aldehyde hydrate H R–C O H OH
In acetals, the original hemiacetal hydroxyl is replaced by an alkoxy 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–C H O + HO–R´ aldehyde hemiacetal acetal (1-alkoxyalkan-1-ol) (1,1-dialkoxyalkane) H R–C O H O–R´ + HO–R´ – H 2 O H R–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 called hemiketals and ketals .
Monosaccharides are aldehydes and ketones that have in their molecules appropriately located hydroxyl groups, and therefore they may form intramolecular cyclic hemiacetals , cyclic forms of monosaccharides (pyranoses or furanoses).. In aqueous solution, both acyclic and cyclic forms of monosaccharides exist in equilibrium; in most hexoses and pentoses the cyclic hemiacetal form prevails. the hemiacetal hydroxyl group a hexose (acyclic aldehyde) a hexopyranose (cyclic hemiacetal form) The hemiacetal hydroxyl group of cyclic forms can react with various hydroxy derivatives to give acetals. Those acetals are called glycosides and the acetal linkage is called glycosidic bond .
1 /4 Addition of primary amines or ammonia results in formation of aldimines ( Schiff bases ) R–C H O + H 2 N–R´ aldehyde H R–C O H NH–R´ – H 2 O labile adduct is stabilized by elimination of water aldimine (Schiff base) H R–C NH addition Ketones react in the same way, their Schiff bases are ketimines . Other ammonia derivatives containing an –NH 2 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 with monosaccharides (glycation of proteins).
2 Oxidation of aldehydes to carboxylic acids C=O CH 3 CH 3 CH 3 -COOH + H-COOH KMnO 4 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 same number of carbon atoms occurs very easily. Therefore, in contrast to ketones, aldehydes are reducing agents . R–C OH O R–C H O oxidation Both aldehydes and ketones are readily reduced to primary and secondary alcohols.
3 Aldol condensation + OH – acidic H on 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 phosphate undergo aldol condensation to fructose 1,6-bisphosphate. In glycolysis , fructose 1,6-bisphosphate is split into glyceraldehyde phosphate and dihydroxyacetone. The enzyme aldolase catalyzes the reaction in both directions. Aldehydes and ketones that have a hydrogen atom on the α-carbon can add to the carbonyl group of another aldehyde or ketone molecule. This aldol "condensation" forms new C–C bonds.
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 CH 2 -OH C=O CH 2 -OH glyceraldehyde CH=O CH 2 -OH CH-OH CH 3 -CH=O acetaldehyde O=CH–CH 2 –CH=O malondialdehyde Monosaccharides are polyhydroxyaldehydes or polyhydroxyketones; the most simple of them are α-Ketoacids (e.g. pyruvate, oxaloacetate, and 2-oxoglutarate) are intermediate metabolites of saccharides and amino acids. CH 3 –CO–CH 3 acetone