These pages are designed to assist you with the learning of organic synthesis; like all other problem-solving, practice is essential, so you should obtain as many of the flow-type problems to do as you can.

Synthetic organic chemistry.

Reactions are of several types:

• those which make things; carbonyl compounds with HCN give useful products;
• those which test for things; carbonyl compounds with 2,4-dinitrophenylhydrazine give a yellow precipitate;
• some reactions do both; the haloform reaction is used to test for CH₃CO- of CH₃CHOH, and it is also used to make chloroform CHCl₃ commercially; bromine is used to test for alkenes but the same reaction is used as a route to diols.

Uses of organic synthesis:

• commercial production of necessary compounds on a large scale;
• the small-scale production of compounds needed in research, perhaps a range of slightly different compounds which are not commercially available;
• confirmation by synthesis of the structure of naturally occurring molecules.

Industry:

• ‘Heavy' organic: this involves the production of large quantities of relatively simple molecules;
• Small-scale organic: the production of perhaps only a few tons of substance, which might be relatively simple;
• Natural products: the extraction and use in synthesis of complex compounds from plants or animals, usually on a small scale;
• Pharmaceuticals: production of these could use all the above sources to give moderate quantities of quite complex compounds.

Synthetic routes.

Synthetic routes available include the following, which need careful selection:

• interconversion of functional groups, e.g. conversion of a halogenoalkane RCH₂Cl to an alcohol RCH₂OH.
• making C-C bonds, e.g. reaction of halogenoalkane with CN ^- ion
• breaking C-C bonds, e.g. the conversion of CH₃COCH₃ to CHI₃ and CH₃COOH
• some routes which look good on paper may not be useful in practice.

 

Selecting a particular route:

There may be several routes to a compound. Some routes may not be possible or desirable because of

• too many steps - the more steps there are the higher the yield has to be at each step. A yield of 80% is good per step: a four step reaction would give an overall yield of 41%, which would be made poorer by handling losses. Many reactions have much lower yields than 80%.
• poor yield may come from competing reactions, or the reaction may be an equilibrium.
• yields from equilibrium reactions can sometimes be improved by changing the conditions
• the products from competing reactions may or may not be useful
• competing reactions, giving other products which might be difficult or expensive to separate from the main product.
• stereochemical problems: chiral starting materials may have their configuration inverted or the product mixture may be racemic;
• non-availability of starting materials, or the expense of their synthesis.

Starting materials available in large quantities include: alkanes, alkenes, lower alcohols, lower halogenoalkanes, lower aldehydes and ketones, benzene and various mono-substituted benzenes.

The choice of reagents and conditions:

The reagents and conditions to produce a given material in industry are often different from those used in the lab

• lab processes may be too expensive for industrial use: some laboratory reagents are very expensive
• many laboratory reactions give useless by-products which may be difficult or hazardous to dispose of in quantity. Thus oxidation reactions in the laboratory would probably use acidified potassium dichromate producing chromium(III) salts or potassium manganate(VII) giving manganese(II) salts; industry would prefer to use air or oxygen and not have the salts to dispose of. Thus ethane-1 ,2-diol, used as anti-freeze and hydraulic fluid, can be made by the action of potassium manganate(VII) in alkaline solution on ethene. A sludge of manganese(IV) oxide also results. Industrially, ethene is oxidised to epoxyethane with air at 300^oC and a silver catalyst, the epoxy compound then being hydrolysed. There are no products other than the diol. The manganese-containing product is waste; epoxyethane can be used for other things as well as conversion to ethan-1,2-diol.

Techniques:

The practical techniques are not peripheral to a synthetic process; careful choice of technique can make or break a synthetic pathway. Techniques used in reaction and separation include:

• heating under reflux (NOT just ‘reflux')
• distillation and fractional distillation
• recrystallisation and filtration
• solvent extraction
• chromatography

Techniques used in analysis:

• melting temperature and mixed melting temperature
• elemental analysis (empirical formula)
• relative molecular mass determination and mass spectra
• other spectra: ultraviolet, infrared, nuclear magnetic resonance
• chromatography

Safety will need to be considered: this must be with regard to specific hazards, not in vague terms like 'wear goggles and lab coat':

• volatility and flammability
• volatility and toxicity by inhalation
• toxicity by skin absorbtion
• the scale of the preparation is significant - small quantities of a toxic material may present less of a hazard than large quantities of a merely harmful one.

Problem-solving in synthetic chemistry.

Problems in synthesis may be

• free-response; you have to obtain a given material but the choice of reactions is left to you;
• flow-type problems, where some data on the intermediates is given.  Usually you will know the starting material, or at least the class of compound to which it belongs, and you will know the substance required.
• Write all the information given on a flowchart
• Start at the end: often information about possible isomers is given last; if you commit yourself too early to a number of structures you will be reluctant to change them no matter how strong the later evidence is that you should!
• Synthetic pathways could well include compounds you have never met before; it's the principles of the interconversions that are being addressed.
• Do not include mechanisms unless they are asked.

Scheme 1 summarises the relationships between some classes of organic substance.

• Make a large copy of this, then
• fill in the reagents and conditions that are used at each step
• choose the simplest example that will work and write the equation for a typical reaction.

Scheme 2 summarises the relationships between some aromatic compounds.

The reactions fall into two classes;

• Reactions on the ring;
• Reactions of the side-chains; these on the whole resemble similar reactions in aliphatic chemistry.

The first illustrates the point about not deciding on structures too early; the second gives both ring and side-chain reactions of aromatic compounds, and shows that several ways of doing things are often possible.

Problem 1.

Compound A, C₃H₈0, gives steamy fumes when reacted with phosphorus pentachloride. On oxidation with acidified potassium dichromate solution A gives B, C₃H₆0. This, with methylmagnesium bromide under suitable conditions, gives C, C₄H₁₀O. C does not react with acidified potassium dichromate solution. Treatment of C with excess hot concentrated sulphuric acid gives D, C₄H₈, which on reaction with hydrogen bromide gives mainly 2-bromo-2-methylpropane. Find the structures of A to D, giving reasons and equations for the reactions which occur.

Problem 2.

Benzene C₆H₆ and chloromethane CH₃Cl react in the presence of aluminium chloride to give A, C₇H₈. A reacts with chlorine in sunlight to give B, C₇H₇Cl, which reacts with aqueous sodium hydroxide to give C, C₇H₈O. Mild oxidation of C gives D, C₇H₆O, which with 2,4-dinitrophenylhydrazine gives an orange precipitate. Further oxidation of D gives E, C₇H₆O₂, which can also be produced from A by vigorous oxidation with alkaline potassium manganate(VII) solution.

The reaction of B with potassium cyanide under suitable conditions gives F, C₈H₇N, which in turn can be reduced to G, C₈H₁₁N.

Identify the substances A to G, giving reasons for your choice and writing equations for the reactions that occur.

Write the mechanism for the reaction between benzene and chloromethane. Suggest another series of reactions by means of which you could convert F to G.