An introduction to A Level organic chemistry

The functional groups of A Level organic chemistry

Everything you met at AS Level still holds: the functional group is the part of the molecule that decides how it reacts, and it is usually the polar part, so it also decides the boiling point and the solubility. At A Level the table of classes of compound grows. You must now recognise the arene, the halogenoarene, the phenol, the acyl chloride, secondary and tertiary as well as primary amines, primary, secondary and tertiary amides, and the amino acid. Each one has a functional group that fixes its chemistry, and every question you meet in the later topics is a question about one of these groups.

The arene group is the delocalised benzene ring itself, not a pair of alternating double bonds. Benzene is C6H6, a flat hexagon in which the six ring electrons are spread over all six carbon atoms, and that is why benzene does not behave like cyclohexene: it reacts by substitution, keeping the stable ring, instead of by addition, which would destroy it. In a halogenoarene such as chlorobenzene the halogen is joined directly to a ring carbon. That bond is short and strong, because a lone pair on the chlorine is partly delocalised into the ring and gives the carbon-chlorine bond some double-bond character, so chlorobenzene does not hydrolyse with hot aqueous alkali the way 1-chlorobutane does. In a phenol, such as phenol itself, C6H5OH, the OH group is joined directly to the ring. That is what makes phenol a weak acid: the ring delocalises the negative charge of the phenoxide ion, whereas an alcohol has no such stabilisation and is neutral.

An acyl chloride has the group COCl, for example propanoyl chloride, CH3CH2COCl. The carbon is joined to oxygen by a double bond and to chlorine by a single bond, both of which are strongly polar, so the carbon is very electron-deficient (delta-positive) and is attacked easily by any nucleophile; acyl chlorides are the most reactive of the acid derivatives and fume in moist air. Amines may be primary, RNH2, secondary, R2NH, or tertiary, R3N. The nitrogen has a lone pair, which makes amines bases and nucleophiles, and the more alkyl groups surround the nitrogen the more electron density it has, so a tertiary amine is a stronger base than ammonia. The naming of secondary and tertiary amines is not required, but you must be able to recognise them and to see that an amine nitrogen has one, two or three carbon groups plus a lone pair. An amide has the group CONH2 (primary), CONHR (secondary) or CONR2 (tertiary); amides are named -amide, so propanamide comes from propanoic acid, and the C-N bond of an amide is far less reactive than that of an acyl chloride because the nitrogen lone pair is delocalised into the carbonyl group. An amino acid contains both an amine and a carboxyl group in the same molecule, for example 2-aminoethanoic acid, HOOC-CH2-NH2, so it can act as an acid or as a base and exists in water as a zwitterion, with an ammonium group and a carboxylate group in the same molecule.

Formulas and systematic names for the A Level groups

You must still read and write the general formula (the family), the molecular formula (the actual number of atoms), the empirical formula (the simplest whole-number ratio), the structural formula (the groups written along one line) and the displayed formula (every atom and every bond drawn out). The skeletal formula matters most for these new groups: the carbon skeleton is drawn as a zig-zag or as a hexagon, every vertex and every end of a line is a carbon, the hydrogens joined to carbon are left out, and every other atom is written in full. A benzene ring is drawn as a hexagon with a circle inside it to show the delocalised system, and the syllabus does not expect you to draw a displayed formula for the ring - use the skeletal hexagon and write the substituent in full.

Naming aliphatic compounds. Find the longest chain that contains the principal functional group, and that chain gives the stem: meth-, eth-, prop-, but-, pent- or hex- for one to six carbon atoms. Number from the end that gives the principal group the lowest number, then the first substituent. The group becomes the suffix -ol, -al, -one, -oic acid, -amine or -amide, and halogens and alkyl groups become prefixes. Cyclic compounds with a single ring of up to six carbons are named by adding the prefix cyclo-: cyclohexane, cyclohexene, cyclohexanol and methylcyclohexane are all fair game. Esters are named in two parts, alkyl then alkanoate, so CH3CH2COOCH2CH3 is ethyl propanoate; an ester or an amide may have six carbons of alcohol part plus six of acid part, and esters and nitriles are required as straight chains only.

Naming aromatic compounds. With one benzene ring, the ring itself is usually the parent, so methylbenzene, nitrobenzene, chlorobenzene and benzoic acid need no number. When a group such as COOH, CHO, SO3H or OH is present it is the principal group and its carbon or its attachment point is taken as position 1, and the ring is numbered so that the other substituents take the lowest possible locants. That gives 2-methylphenol rather than 6-methylphenol, and 3-nitrobenzoic acid rather than 5-nitrobenzoic acid, because benzoic acid has C1 as the carbon of the COOH group. Where two or more substituents are present, list them in alphabetical order, so 1-bromo-2-methylbenzene.

Worked example. Two molecules, and the formula that follows from each. 3-Nitrobenzoic acid is benzoic acid, C6H5COOH, with one hydrogen of the ring replaced by NO2: the molecular formula is C7H5NO4 (C 7, H 5, N 1, O 4). 2,4,6-Tribromophenol is phenol, C6H6O, with three ring hydrogens replaced by bromine, so the molecular formula is C6H3Br3O. Notice that the molecular formula alone would not tell you which phenol or which nitrobenzoic acid you had, because 2-, 3- and 4-nitrotoluene all have the same molecular formula; that is why names must carry locants.

• Longest chain containing the principal group gives the stem: meth- to hex- for one to six carbon atoms.
• Number to give the principal group the lowest locant, then the first substituent the lowest possible number.
• Cyclic compounds with one ring of up to six carbons take the prefix cyclo-.
• Esters: alkyl group first, then alkanoate, for example ethyl propanoate.
• Aromatic molecules: the principal group is at position 1 and the ring is numbered to give the substituents the lowest locants.
• Use the skeletal hexagon for a benzene ring; a displayed formula for the ring is not expected.

Characteristic reaction types and the meaning of their names

The names of organic reactions say what happens to the skeleton and who does the attacking, so they can be worked out rather than learned. Addition joins two molecules into one with nothing lost, and it is possible because a pi bond opens up; ethene with bromine gives 1,2-dibromoethane. Substitution replaces one atom or group with another and leaves the skeleton intact, so methane with chlorine gives chloromethane and hydrogen chloride. Elimination removes a small molecule and leaves a double bond behind, as when propan-2-ol is dehydrated to propene. Hydrolysis is the breaking of a bond by water, condensation is the joining of two molecules with the loss of a small molecule such as water, and oxidation and reduction are the familiar gain and loss of oxygen or hydrogen, written [O] and [H] for one atom each.

Electrophilic substitution is the reaction of an aromatic ring. The delocalised pi system is a region of high and exposed electron density, so it attracts an electron-deficient species, an electrophile, and the ring replaces one of its hydrogen atoms. The electrophile adds to the ring to give a delocalised positive intermediate, and the ring is then restored by the loss of a hydrogen ion from the carbon that gained the electrophile. Nitration of benzene with concentrated nitric and sulphuric acids and bromination with bromine and iron(III) bromide both take place this way. Notice the two-part shape of the mechanism: an addition of the electrophile, then an elimination of H+. Benzene always survives with its ring intact.

Addition-elimination is the mechanism of the acid derivatives and of some carbonyl reactions. A nucleophile adds to a carbon-oxygen double bond, giving a tetrahedral intermediate in which the carbon now carries four groups and the oxygen carries a negative charge, and that intermediate then collapses: the C=O double bond is re-formed and a group is pushed out as a leaving ion. The clearest example is an acyl chloride. Water, an alcohol or ammonia adds to the delta-positive acyl carbon, and the intermediate then expels a chloride ion to re-form the C=O, giving a carboxylic acid, an ester or an amide with hydrogen chloride as the other product. The same pattern explains the formation of a 2,4-dinitrophenylhydrazone: the hydrazine adds to the carbonyl group, and water is then eliminated. Recognise the fingerprint: something is added, something else is eliminated, and the C=O comes back.

Curly arrows and the six mechanisms you must describe

A curly arrow shows the movement of a pair of electrons, so it must begin where those electrons are: on a lone pair or in the middle of a bond. Never start an arrow on an atom, on a hydrogen atom or on a plus sign, and never draw one arrow through two bonds. Almost every step uses two arrows: one starts on a lone pair or pi bond and points to the atom that is being attacked, and one starts in the bond that is breaking and points to the atom that keeps the electrons. Get the arrows right and the charges look after themselves, because the atom that receives both electrons ends up negatively charged and the atom that loses them ends up positively charged.

Free-radical substitution. Ultraviolet light splits a chlorine molecule homolytically: Cl2 -> 2Cl (each Cl is a radical with one unpaired electron), and because only one electron moves from each atom this step is drawn with single-headed, half-curly arrows. A chlorine radical then takes a hydrogen atom from methane, leaving a methyl radical and hydrogen chloride, and the methyl radical takes a chlorine atom from another chlorine molecule, so the chain continues. Termination is any step in which two radicals join, which is why traces of ethane, CH3CH3, appear alongside chloromethane. Radical stability follows the same order as carbocation stability, tertiary > secondary > primary, because alkyl groups release electron density by induction, so bromination is more selective than chlorination and substitutes preferentially at the carbon that gives the more stable radical.

Electrophilic addition. The pi bond of a C=C is exposed electron density above and below the plane, so it polarises the molecule that approaches it, giving an induced dipole - in ethene with bromine, the near bromine atom becomes delta-negative and the far one delta-positive. A curly arrow from the pi bond of the C=C to the hydrogen of H-Br, and a second from the H-Br bond to the bromine, gives a carbocation and a bromide ion; the bromide then attacks the positive carbon. Which carbocation forms decides the product, because the more stable one is reached more easily: with propene and HBr the secondary carbocation, CH3CH+CH3, is formed in preference to the primary CH3CH2CH2+, so the major product is 2-bromopropane. This is Markovnikov's rule - the hydrogen goes to the carbon with more hydrogens - and the reason is the inductive release of electron density by the alkyl groups, which stabilises the positive charge.

Nucleophilic substitution. The carbon of a C-X bond is delta-positive because the halogen is more electronegative than carbon, so a nucleophile attacks it. In a primary halogenoalkane with a strong nucleophile such as hydroxide, the nucleophile attacks the carbon from the side opposite the halogen in a single step, and the new bond forms as the old one breaks; this SN2 mechanism inverts the arrangement around the carbon, like an umbrella turning inside out. In a tertiary halogenoalkane the surrounding alkyl groups block that approach, so the C-X bond breaks first, in a slow step, to give a planar carbocation which the nucleophile then attacks from either side; this is SN1. The two mechanisms matter to the rate and to the product: SN1 gives a mixture of the two optical isomers when the carbon was chiral, because a flat carbocation can be attacked equally from either face.

Nucleophilic addition. Aldehydes and ketones are the target here, because the carbon of a C=O is delta-positive and the oxygen is delta-negative. The cyanide ion in a mixture of potassium cyanide and dilute acid has a lone pair on the carbon, and that lone pair attacks the carbonyl carbon; a second arrow from the pi bond of the C=O to the oxygen puts the negative charge on the oxygen. In a second step a hydrogen ion from the acid joins that oxygen, giving the hydroxynitrile: ethanal and hydrogen cyanide give 2-hydroxypropanenitrile, CH3CH(OH)CN. That product contains a chiral centre, and it is formed as a racemic mixture, because the carbonyl carbon is flat and the cyanide ion attacks it from above and below with equal probability.

Electrophilic substitution. Benzene is nitrated by the nitronium ion, NO2+, formed when concentrated sulphuric acid protonates concentrated nitric acid and a molecule of water is lost. A curly arrow from the delocalised pi system of the ring to the nitrogen of NO2+ gives a delocalised carbocation intermediate in which the ring is no longer fully delocalised, and a second arrow from the C-H bond of that carbon to the ring restores the delocalised system as a hydrogen ion is lost. The product is nitrobenzene. The ring gives up a hydrogen rather than adding the electrophile and keeping it, because losing H+ restores the full delocalisation energy of the ring, and that stabilisation is worth far more than the bond that a second addition would form. The same mechanism runs with bromine and iron(III) bromide, with a chloroalkane and anhydrous aluminium chloride to give an alkylbenzene, and with an acyl chloride and anhydrous aluminium chloride to give a ketone.

The shape of benzene and why the ring is so stable

Each carbon of benzene is sp2 hybridised. It forms three sigma bonds - one to each neighbouring carbon and one to hydrogen - using three sp2 orbitals that point to the corners of a triangle, so the bond angles are 120 degrees and the six carbon atoms and six hydrogen atoms all lie in one plane. That leaves one unhybridised p orbital on each carbon, sticking out perpendicular to the plane, one lobe above and one below, and each holds one electron. The six p orbitals overlap sideways all the way round the ring, so the six electrons occupy a delocalised pi system spread over the whole molecule rather than sitting in three separate double bonds.

Two pieces of evidence confirm this picture. First, the bond lengths. X-ray diffraction shows all six carbon-carbon bonds of benzene to be identical, at about 0.139 nm, which lies between the 0.154 nm of the carbon-carbon single bond in ethane and the 0.134 nm of the double bond in ethene. If the ring really contained alternating single and double bonds, the lengths would alternate with it. Second, the enthalpy of hydrogenation. The hydrogenation of cyclohexene, which has one localised double bond, releases about 120 kJ mol-1, and hydrogenation of benzene releases only about 208 kJ mol-1, not the roughly 360 kJ mol-1 that three separate double bonds would give. The difference, about 150 kJ mol-1, is the delocalisation energy (sometimes called the resonance energy): benzene is that much more stable than the imaginary cyclohexatriene, and it is the energy the ring would have to spend to behave like three alkenes.

That extra stability explains the chemistry. Benzene does not decolourise bromine water, it does not take part in the electrophilic addition reactions of an alkene, and it reacts with bromine only in the presence of a halogen carrier such as iron(III) bromide, giving bromobenzene by substitution. The ring keeps its delocalised system in every one of these reactions, which is why an electrophile that adds to it is immediately followed by the loss of a hydrogen ion.

Other aromatic molecules have the same ring, and what is attached to it changes how reactive the ring is. An OH group releases electron density into the ring, so phenol is more reactive than benzene: it reacts with bromine water at room temperature and with no halogen carrier at all to give a white precipitate of 2,4,6-tribromophenol, and it can be nitrated with dilute nitric acid at room temperature. A nitro group does the opposite and withdraws electron density, so nitrobenzene is less reactive than benzene and needs harsher conditions for a second substitution, which then goes mainly to the 3 position. The same electronic reasoning - whether a substituent pushes electron density into the ring or pulls it out - explains the directing effect of every group you meet in the later topics.

• Each ring carbon is sp2: three sigma bonds at 120 degrees, planar, one unhybridised p orbital left over.
• The six p orbitals overlap sideways above and below the plane, giving a delocalised pi system of six electrons.
• All six C-C bonds are equal at about 0.139 nm, between the 0.154 nm single bond of ethane and the 0.134 nm double bond of ethene.
• Hydrogenation of cyclohexene releases about 120 kJ mol-1 per double bond, so three localised double bonds would release about 360 kJ mol-1, but benzene releases only about 208 kJ mol-1; the difference of about 150 kJ mol-1 is the delocalisation energy.
• An OH group on the ring activates it, so phenol brominates with bromine water alone; a nitro group deactivates it and directs further substitution to the 3 position.

Optical isomerism: chirality, enantiomers and racemic mixtures

A chiral centre is a carbon atom joined to four different atoms or groups. Butan-2-ol has one at C2, where the four groups are H, OH, CH3 and CH2CH3; 2-hydroxypropanoic acid (lactic acid), 2-aminopropanoic acid (alanine) and the 2-hydroxypropanenitrile made from ethanal and hydrogen cyanide all have one too. A molecule with one chiral centre cannot be superimposed on its own mirror image, and the two mirror-image forms are called enantiomers, or optical isomers. A carbon carrying two identical groups is never chiral, and neither is a carbon of a C=C or a C=O, because such a carbon has only three groups attached to it plus its pi bond. A molecule may contain more than one chiral centre, and you should be able to find them all; meso compounds and the names of other stereoisomer relationships are not required.

Enantiomers have identical physical properties - the same melting point, boiling point, density, solubility and infrared spectrum - because the atoms are joined in the same order and the same bonds are present. They also react identically with achiral reagents, such as sodium hydroxide or hydrogen cyanide. The one difference is that they rotate the plane of plane-polarised light in opposite directions, by exactly equal amounts. One turns it clockwise and is described as the (+) isomer, and the other turns it anticlockwise and is the (-) isomer; a substance that rotates the plane of plane-polarised light at all is optically active, and a polarimeter measures the angle. A racemic mixture (a racemate) contains equal amounts of the two enantiomers, so the two opposite rotations cancel exactly and the mixture is optically inactive.

Chirality matters in drug synthesis because the molecules of life are chiral. Enzymes and cell receptors are built from single enantiomers of amino acids and sugars, so the two enantiomers of a drug fit their binding site differently and can have completely different biological effects: one enantiomer may be an effective medicine while the other is inactive, or has different side effects, or is harmful. Thalidomide is the standard example: one enantiomer is an effective sedative, while the other causes severe birth defects. Ibuprofen is another, because the (S)-(+) enantiomer is the one that relieves pain while the (R) form is largely inactive. When a drug is chiral, this is why a single pure enantiomer is preferred to a racemic mixture: half of a racemate is not doing the job it was prescribed for, and in the worst case the other half is doing harm.

There are two practical answers. The first is separation of the racemate. The two enantiomers cannot be separated by ordinary distillation or crystallisation, because their physical properties are the same; they must be separated by a chiral method, such as passing the mixture through a chiral chromatography column, or reacting it with a single pure enantiomer of another compound so that the two products are no longer mirror images and have different physical properties, which can then be separated and the chiral auxiliary removed. The second, cheaper answer is asymmetric synthesis with a chiral catalyst: a chiral transition-metal complex, for example a rhodium complex carrying a chiral diphosphine ligand, hydrogenates a prochiral alkene so that the hydrogen atoms add to one face only, giving one enantiomer in excess. The industrial preparation of L-DOPA, the drug used for Parkinson's disease, was developed in exactly this way. The reason a plain laboratory route will not work is worth remembering: when a nucleophile attacks a flat carbonyl carbon or an alkene, it can approach from either side with equal probability, so a racemic mixture is the automatic result.

• A chiral centre is a carbon joined to four different atoms or groups; two identical groups on a carbon rule it out, and so does a double bond at that carbon.
• Enantiomers have identical physical properties and identical reactions with achiral reagents, and rotate plane-polarised light equally in opposite directions.
• A racemic mixture is an equimolar mixture of the two enantiomers, so it is optically inactive.
• Receptors and enzymes are chiral, so the two enantiomers of a drug can have different biological activity; thalidomide and ibuprofen are the standard examples.
• Separate a racemate by chiral chromatography or by forming salts with a pure chiral reagent; make a single enantiomer directly with a chiral catalyst, as in the industrial synthesis of L-DOPA.
• Attack on a planar carbon - a carbonyl carbon or a carbocation - gives a racemic mixture, because either face is attacked equally.

Functional-group interconversions you must be able to link

The A Level topics that follow this one are all about turning one functional group into another with named reagents and conditions, so it is worth having the map in one place. Two things go wrong most often: naming the reagent without the conditions, and choosing a reagent that would work on a different functional group. Learn each conversion as a triple of reagent, condition and reaction type, and read it back to yourself as a sentence - 'propanoyl chloride and water at room temperature give propanoic acid and fumes of hydrogen chloride by nucleophilic addition-elimination'.

The arenes are converted by electrophilic substitution. Nitration uses a mixture of concentrated nitric acid and concentrated sulphuric acid at 50-60 C, and the nitric acid must be concentrated because the electrophile NO2+ is made from it. Bromination uses bromine with iron(III) bromide, and chlorination uses chlorine with aluminium chloride; both need a halogen carrier, and neither takes place at a useful rate without one. Friedel-Crafts alkylation uses a chloroalkane with anhydrous aluminium chloride to give an alkylbenzene, and Friedel-Crafts acylation uses an acyl chloride with anhydrous aluminium chloride to give a ketone such as phenylethanone. Contrast the phenolic ring: phenol needs no catalyst to brominate, because the OH group has already increased the electron density of the ring.

The acyl chlorides are the most reactive derivatives, and every one of their reactions is nucleophilic addition-elimination: with water they give the carboxylic acid, with an alcohol they give an ester, with ammonia they give a primary amide, and with a primary amine they give a secondary amide. Hydrogen chloride is produced every time, which is why the reactions fume and why they are carried out in a fume cupboard. Amides are then hydrolysed back to carboxylic acids by heating under reflux with dilute acid, which also releases the ammonium salt, or with aqueous alkali, which gives the carboxylate salt and ammonia. Nitrobenzene is reduced to phenylamine by tin and concentrated hydrochloric acid followed by sodium hydroxide, and phenylamine is converted to benzenediazonium chloride by sodium nitrite and hydrochloric acid below 10 C; coupling that diazonium salt with alkaline phenol gives an azo dye, which is an electrophilic substitution on the ring. Chlorobenzene is the exception that proves the value of these ideas: it has a halogen but no halogenoalkane chemistry, and it does not hydrolyse to phenol under the conditions that hydrolyse 1-chlorobutane, because the C-Cl bond is strengthened by the interaction of the chlorine lone pair with the ring. Phenol is made industrially from benzene by the cumene process instead.