Organic Reactions

Alkanes with chlorine and bromine

Homolytic fission takes place the attacking species is a free radical.

In this reaction, all curly arrows have half-heads. This denotes the transfer of a single electron. The mechanism is as follows: The initiating step is the breaking of the H-X bond by a photon of light as this bond is weaker than the C-H or C-C bonds and therefore can be broken in this way.

Alkenes
Alkenes undergo electrophillic addition across the double bond.

Halogens
Halogens are symmetrical and add via the following mechanism:

Hydrogen Halides with unsymmetrical alkenes.

An unsymmetrical alkene is e.g. propene, CH3CH=CH2. It is possible for the hydrogen to add to either the number 1 or number 2 carbon atom in the molecule. Markownikoff s Rule states that when a substance of the type HX undergoes an addition reaction with an unsymmetrical C=C double bond, the main product is the one in which the hydrogen adds on to the carbon atom which already has the most hydrogen atoms. Thus the major product (about 90%) will be 2chloropropane.

The reason for this can be seen by considering the mechanism for the reaction: The secondary carbocation is more stable, as the surrounding alkyl groups can release electrons to stabilise it. Since this carbocation is of lower energy (more stable), the activation energy to form it will be lower and it will be formed more quickly. Thus there will be more of these carbocations available to react with the anion. This reaction is said to be thermodynamically controlled.

Concentrated sulphuric acid

Alkenes react with concentrated sulphuric acid at room temperature to produce alkylhydrogensulphates. RCH=CHR + H2SO4 RCH(OSO2OH)CH2R Note that if one of the carbon atoms across the double bond is at the end of the chain (i.e. a =CH2 group) the H will add on to this group. Mechanism:

Alkylhydrogensulphates are easily hydrolysed by water to form alcohols, reforming the acid. R(OSO2OH) + H2O ROH + H2SO4 Since alkenes are formed by the cracking of oil, this is a method for manufacturing alcohols industrially. However, ethanol is made by the direct hydration of ethene using steam and phosphoric acid as a catalyst, at 300C and 60atm.

Oxidation of alkenes with alkaline manganate (VII)

Ethene is oxidised to ethane-1,2-diol by alkaline manganate (VII), the manganate being reduced to green manganate (VI), MnO42-. Overall equation:

This is Baeyers test for double bonds. Ethane-1,2-diol is used in car antifreeze and the manufacture of terylene.

Primary, secondary and tertiary alcohols

With acidified dichromate (VI)
Acidified dichromate is an orange solution, and acts as an oxidising agent. Primary alcohol aldehyde carboxylic acid Secondary alcohol ketone Tertiary alcohol no reaction (oxidation involves breaking a C-C or C-H bond).

Achieving oxidation to the carboxylic acid requires a concentrated solution of dichromate and reflux.

Dehydrating agents
In the vapour phase, alcohol vapour can be passed over ho aluminium oxide (acts as a catalyst). In the case of ethanol, ethene is formed. In the liquid state, concentrated sulphuric acid is used. This can produce an ether or an alkene, depending on the conditions used:

Concentrated H2SO4 and ethanol at 170C gives ethene. The mechanism is as follows: With ethanol in excess and at 140C the ethanol molecules can act as nucleophiles and can attack the intermediate. An ether is produced (in this case, ethoxyethane).

Excess sulphuric acid protonates the ethanol molecules, preventing them acting as nucleophiles.

Halogenation
Addition of solid PCl5 to an alcohol produces copious steamy fumes of HCl and substitutes a chloro group for the OH group.

Chlorination
The alcohol is heated with concentrated HCl in the presence of anhydrous ZnCl2 catalyst.

Bromination

The HBr required is produced in situ by the reaction of concentrated sulphuric acid with KBr. This mixture is then heated with the alcohol. This is a messy reaction as Br2 is also produced. The substitution proceeds as above.

Iodination
A mixture of red phosphorus and iodine acts like phosphorus (III) iodide. This then carries out the iodination. One other product is phosphonic acid. 3ROH + PI3 3RI + H3PO3

Primary amines with hydrogen ions

An amine can be viewed as an ammonia molecule in which an alkyl or aryl group has been substituted for a hydrogen atom. Where just one hydrogen is replaced, the amine is a "primary" amine with the functional group -NH2. Some examples of aliphatic amines:CH3NH2 methylamine C2H5NH2 ethylamine C4H9NH2 butylamine etc An aromatic amine C6H5NH2 phenylamine The amines, like ammonia, act as bases and accept H+ ions. They are actually slightly stronger bases than ammonia because the alkyl groups release electrons, which allow the nitrogen to accept a proton more easily.

Carboxylic acids
Esterification
Acids react with alcohols to give esters and water. This reaction is catalysed by H+ ions, usually in the form of concentrated sulphuric acid as this removes water, pushing the equilibrium to the right. As esters have no hydrogen bonds, they are more volatile than the other reagents and thus can be removed by distillation during the process. Esters are hydrolysed using either acid as a catalyst, in which case an equilibrium is set up, or alkali, in which case the salt of the acid is produced. This can then by converted back to the acid using a mineral acid (e.g. H2SO4).

Reduction
A powerful reducing agent is needed to reduce an acid. The once commonly used is lithium tetrahydridoaluminate(III), or litium aluminium hydride. It needs to be used in completely anhydrous conditions or hydrolysis of the agent takes place. The solvent usually used is dry ethoxyethane, or ether. The first step of the mechanism is shown below.

Phosphorus pentachloride
When solid PCl5 is added to a carboxylic acid at room temperature a vigorous reaction occurs, and HCl and an acyl chloride is produced.

Arenes
Arenes with nitrating mixture
The term "arene" is equivalent to the term "aromatic", referring to an (organic) compound containing a benzene ring. To nitrate benzene a mixture of concentrated nitric and sulphuric acids is needed. This mixture is refluxed with the benzene at 60C. The reaction between the two produces the NO2+ ion, which attacks the electrons on the benzene ring, giving an electrophillic substitution. HNO3 + 2H2SO4 NO2+ + H3O+ + 2HSO4For activated arenes (e.g. phenol, toluene), dilute nitric acid and sodium nitrate is used.

Mechanism:

Oxidation of side chains with manganate (VII)

Hot concentrated manganate (VII), alkaline, acidic or neutral, will oxidise all side chains on a benzene ring to carboxylic acid groups. This is very useful in diagnosis, although not so in synthesis.

Friedel-Crafts
The Friedel-Crafts reaction is a method of introducing a side chain onto a benzene ring. This is useful because it allows compounds to be synthesised from the benzene. It is carried out using a chloroalkane in the presence of anhydrous aluminium chloride as a catalyst. The mechanism is as follows: The chloroalkane reacts with the AlCl3 to form an electrophile:

This then substitutes into the benzene ring, reforming the catalyst. If an acid chloride is used in the place of the chloroalkane, the same reaction takes place, but leading to the first group on the chain being a carbonyl group, which may be useful for reactions.

Halogenoalkanes
Hydroxide ions
With a cold, dilute, aqueous solution of hydroxide ions nucleophillic substitution takes place by the SN1 or SN2 mechanism. SN1 takes place mainly with tertiary halogenoalkanes (see module 2 notes). RX + OH- ROH + XWith a hot concentrated ethanolic solution of hydroxide ions elimination of HX takes place to give an alkene. RCH2CHXR + OH- RCH=CHR + H2O +X-

Obviously, the reaction is not as clear-cut as this. Some substitution takes place in the ethanolic solution and some elimination in the aqueous case. The more extreme the conditions the greater the yield of the required product will be.

Cyanide ions
With cyanide ions in ethanolic solution, nucleoplillic substitution takes place. It is necessary to use the organic solvent as water reacts with the cyanide ions to form HCN and OH ions, which then substitute instead. The mechanism is as follows:

If the halogenoalkane was optically active then the resulting compound will also be optically active. If the CN increases the chain length then the compound is named as a nitrile. If not it is named as a compound with a cyano group substituted.

With ammonia
With ammonia nucleophillic substitution takes place. Ammonia gas must be used under pressure and heated in a sealed container. The equation is RX + NH3 RNH2 + HX This process has many problems, not least that the primary amine produced is a stronger base than the ammonia itself, and therefore will react with the halogenoalkane itself. This is avoided by using a great excess of ammonia. This is necessary also because the HX produced will react with ammonia, but causes problems with the removal of the excess ammonia afterwards.

Grignard reagents
If a halogenoalkane is dissolved in dry ethoxyethane, it can be reacted with magnesium to produce a Grignard reagent. It is essential for the conditions to be anhydrous, otherwise the Grignard reagents will react with the water. RX + Mg R Mg X

The distribution of the charge on the atoms should be noted:

This is a carboanion, a very unusual species in organic chemistry, which can act as an electrophile. The reaction with water is: R-Mg-X + H2O RH + Mg(OH)X As can be seen, this uses up the reagent to form an alkane, which is virtually useless, and a magnesium salt.

Reacting this complex with an aldehyde or a ketone gives a secondary or tertiary alcohol respectively. The reaction mechanism for a general carbonyl compound is shown:

The reaction is also possible with carbon dioxide, in which case a carboxylic acid is formed. This produces a carboxylic acid with an extra carbon atom, which could be useful to produce carboxylic acids that are not found in nature. The mechanism is basically the same: In both cases, MgXCl is also produced. The hydrolysis could be carried out by water alone, but the suspension produced is difficult to handle.

Reduction of nitrobenzene

Nitrobenzene is easily produced by the nitration of benzene. It can then be converted to phenylamine by reduction. This is easier than trying to substitute ammonia into the benzene ring. In the lab, the reaction is accomplished using tin metal and concentrated hydrochloric acid. In industry, this route is too expensive, and iron is used with the most dilute hydrochloric acid that will carry out the reduction. The reaction with tin is:

The reaction with iron is very similar, except that iron(III) oxide is formed instead of tin(IV) chloride.

The production of azo dyes

Diazonium compounds are produced by reacting aromatic amines, particularly phenylamine, with nitrous acid, also known as nitric(III) acid. This is produced by dissolving sodium nitrate (III) (sodium nitrite) in dilute hydrochloric acid. This gives the reaction NaNO2 + HCl NaCl + HNO2, where HNO2 is nitrous acid. This is pale blue in colour and not very stable. It reacts with phenylamine in the presence of excess acid to produce benzene diazonium chloride:

It is necessary to keep this reaction cold below 5C otherwise the diazonium salt decomposes to give nitrogen gas and a poor yield of phenol. This is achieved by adding ice to the reaction mixture. This reaction, as it produces diazonium salts, is called diazotisation.

Coupling

Coupling is the reaction of a diazonium salt with an activated aromatic compound. Possibilities are aromatic amines and alcohols. This links the two aromatic groups with an N=N group, resulting in highly coloured compounds used as dyes and acid base indicators. For example, benzene diazonium chloride with phenol and 2-napthol: The reaction with 2-napthol can be used to distinguish between aliphatic and aromatic amines. With aliphatic amines, stable diazonium ions do not form, and therefore no coloured precipitate is formed.

Carbonyl compounds

Hydrogen cyanide

To provide this addition, an aqueous solution of potassium or sodium cyanide is used, but the overall reaction is the addition of HCN. The reaction is inhibited by acids. This is a nucleophillic addition reaction; the mechanism is as follows: The compound produced is usually referred to as the cyanohydrin of the carbonyl compound it can also be named systematically. The reaction adds a carbon atom to the chain, and also allows acid hydrolysis to -hydroxycarboxylic acids.

2,4-dinitrophenylhydrazine (Bradys reagent)

This is addition followed by elimination, also called a condensation reaction. The product formed is a yellow precipitate, giving a qualitative diagnosis of a carbonyl compound, which can be recrystalised and the melting point determined to give a precise diagnosis of which carbonyl was present. The mechanism for the reaction is: As shown, the initial product rapidly looses water to form a hydrazone. This is the substance that is analysed.

Tollens Reagent (ammonacial silver nitrate solution)

Tollens reagent contains Ag+ ions, which can be reduced to silver metal. This reaction is possible with an alcohol or an aldehyde, but not with a ketone, as a ketone cannot be oxidised. It can thus be used to distinguish between an aldehyde and a ketone. With a positive test (aldehyde) a silver mirror forms on the inside of the test tube used.

The iodoform test

The iodoform test is a test for compounds that contain either of the following groups: This includes ethanal and ethanol. If a methyl secondary alcohol is used it will be oxidised to the methyl ketone before the main part of the process takes place. The compound being tested is reacted with iodine in sodium hydroxide solution or sodium chlorate (I) and potassium iodate solution. A bright yellow precipitate of iodoform indicates a positive test. The reaction starts with the substitution of the hydrogens in the methyl group for iodine atoms. This causes a great withdrawing of electrons from the C-C bond joining the methyl group to the ketone group, allowing nucleophillic attack and fission of the bond:

The products are iodoform and a degraded carboxylic acid. This reaction is of more value for diagnostic purposes than for synthesis.

Sodium tetrahydridoborate (III) sodium borohydride NaBH4

This is a milder reducing agent than LiAlH4, and will not reduce carboxylic acids and their derivatives. However, it is easier to use because it can be used in aqueous solution, and is cheaper. It reduces aldehydes to primary alcohols and ketones to secondary alcohols.

Ethanoyl chloride CH3COCl

Acid chlorides, or acyl chlorides, fume in air (HCl). The presence of the Cl group makes them more susceptible to nucleophillic attack than the corresponding carboxylic acids, and thus they react vigorously at room temperature. Ethanoyl chloride can be manufactured by treating ethanoic acid with phosphorus pentachloride.

Water
The acid is reformed with the production of hydrochloric acid. This is a vigorous reaction, and therefore acid chlorides must be used in anhydrous conditions. CH3COCl + H2O CH3COOH + HCl

Ethanol
Esterification takes place, at a faster rate than with the acid and alcohol mixture. CH3COCl + CH3CH2OH CH3COOCH2CH3 + HCl

Ammonia

Again, the ammonia substitutes for the chloride group to produce a primary amide. The HCl eliminated then reacts with excess ammonia. CH3COCl + 2NH3 CH3CONH2 + NH4Cl

Primary amines
The reaction with primary amines is basically the same, except that a secondary amide is produced. Again, the HCl will react with excess amine, although this is not shown.

Ethylamine
CH3COCl + C2H5NH2 CH3CONHC2H5 + HCl

Phenylamine:

Nitriles

Nitriles are organic compounds where the chain is terminated by a CN group. The naming of the nitrile includes the carbon that the nitrogen is bonded to, e.g. CH3 CH2CN, propannitrile. Reduction of nitriles is with hydrogen in the presence of a nickel catalyst. This gives a primary amine. Other reduction mechanisms are possible, for example, lithium aluminium hydride Hydrolysis of nitriles is carried out by refluxing with acid or akali. This proceeds through an amide to the ammonium salt of the acid. RCN RCONH2 RCO2-NH4+ In practice, stopping at the amide is not easy. The ammonium salt is not actually produced, but in the case of acid hydrolysis, the ammonium salt of the mineral acid and the carboxylic acid. If alkaline hydrolysis is carried out then ammonia is produced and the sodium salt of the acid formed.

Amides
Amides can be used in synthesis to add the amino group onto a molecule. This can be done via a degradation (the Hofmann degradation), leading to a compound with one less carbon atom, or via dehydration to give an amine with the same number of carbon atoms. Dehydration is carried out by heating with phosphorus(V) oxide (P4O10). This gives the following reaction:

The product, a nitrile, can be reduced (e.g. with hydrogen and a nickel catalyst) to give an amine. The Hoffman degradation is carried out using bromine and aqueous alkali: RCONH2 + Br2 + 2NaOH RNH2 + CO2 + 2NaBr

Targeting Pharmaceuticals
This is to do with a balance between solubility in water / watery tissue and solubility in fat / fatty tissue. Hydrophilic - water loving Hydrophobic - water hating Lipophilc - fat loving To adjust the behaviour of a substance we adjust the functional groups attached.

Hydrophilic functional groups

-OH, -CO2H, -NH2, -NH, -CONH These groups can hydrogen bond with water.

Lipophilic / hydrophobic functional groups

Alkyl groups and benzene rings - hydrocarbon groups

Solubility and retention time

If the substance is too lipophilic (insoluble): 1. It may not be sufficiently absorbed. 2. Concentration in the bloodstream remains too low. If the substance is too hydrophilic (soluble):

Retention time is too low - the substance is quickly transported to the liver and broken down into soluble products, which are excreted via the urine. Both aspirin and oil of wintergreen have analgesic properties, but the different groups attached to the benzene group give them different solubility properties. Aspirin is very soluble and dissolves easily in the bloodstream. To make it more soluble and therefore easier to take the sodium salt can be prepared - this converts back into the usual form in the acidic conditions in the stomach. Oil of wintergreen is insoluble and is applied to the skin to relieve the pain of arthritis.

Penicillin is an important drug that acts by preventing bacteria forming cell walls and thus reproducing. Its original form, penicillin G, was very soluble and rapidly excreted - lipophilic side chains are added to make it less soluble. An even more soluble derivative, penicillamine, can be formed, which complexes with heavy metals and is then excreted very rapidly, removing the poisonous metals from the body. Co-ordination takes place with the marked lone pairs, using 2 molecules to surround a metal ion.

Organic Preparations
Step 1 - Getting a reaction to occur

Unless other information is given, assume a 60% yield at this stage. The most expensive reagent should be used as the limiting factor - the other reagents should be in excess. If the reaction is an equilibrium then an excess of one reagent should be considered - it is also helpful to remove the product(s) as they are produced. Heating under reflux gives the highest possible temperature for that mixture in the liquid phase (the boiling point) without loss of product or reagent. Heating methods:

1. Direct heating with a bunsan burner

This is relatively rarely used in organic preparations as organic chemicals tend to be highly flammable and the heat produced is not smooth.

2. Waterbath
This is used for low temperatures (<100C).

3. Oilbath
This is used for higher temperatures (<300C). Different oils are used for different temperatures.

Step 2 - Separating

Simple distillation can be used if the boiling point is less than 250C and no other volatile product or reagent is present. If the boiling point is above 180C then an air condenser is used, otherwise a Leibig water-cooled condenser. Distillation under reduced pressure is used if the product is likely to decompose at its usual boiling point. Fractional distillation is used for mixtures of liquids. The closer the boiling points are, the larger a column needs to be used. If the boiling points are too close, a pure product cannot be obtained. Steam distillation can be used for a product that has a high boiling point and is insoluble in water. The product dissolves in the steam and distils over with it, and then separates out in the cooled water. Solvent extraction is used where there is a solvent that the product dissolves in but the impurities and remaining reagents do not. The solvent is added and the product dissolved, the liquid is separated off by filtration and the product separated from the solvent by fractional distillation. Ethoxyethane is often used. It is more efficient to use the solvent in several smaller portions (usually 3) than all together in one portion. Buchner filtration is used as it is faster, dries the product as well as filtering it and allows the product to be washed easily.

Step 3 - Purification

Solids are purified by recrystallisation 1. The solid is dissolved in the minimum quantity of hot solvent (minimum quantity to increase yield). The solvent should be chosen so that the substance is as soluble as possible at high temperatures and as insoluble as possible at low temperatures. 2. Insoluble impurities are removed by hot filtration (running a little hot solvent through the funnel first or heating the funnel during filtration) or fast filtration (using a fluted filter paper and a funnel with a broken arm). 3. Allow the solution to cool to recrystallise the product. It may be necessary to induce crystallisation by the use of ice or scratching the side of the beaker with a glass rod. Too low a temperature should not be used or the impurities will recrystallise as well. 4. The solids produced are filtered with a Buchner funnel and washed with a little cold solvent. The filtration apparatus is then reconnected and the product dried.

Liquids are purified as follows: 1. Wash to remove impurities using a separating funnel. Release the pressure regularly when shaking with a substance. Soluble impurities should be removed with water, acid impurities with sodium carbonate and ethanol with calcium chloride. 2. Dry the liquid by standing it on anhydrous drying agent (may take up to 48 hours). Drying agents commonly used are calcium chloride (not with alcohols), calcium oxide (often used with alcohols) and sodium sulphate. 3. Distillation completes the process, collecting the fraction that distils within 1C of the boiling point of the liquid