Preface xi
Acknowledgements xiii
Some Help That You May Need xv
What Do You Need to Know Before You Start? xvii
Introduction xix
1 Nucleophilic Addition to the Carbonyl Group 1
Nucleophilic addition: what it is and how it happens 3
Alcohols as nucleophiles: acetal formation 6
Some carbon-carbon bond-forming reactions with carbon nucleophiles: cyanide ion, acetylide ion and Grignard reagents 10
Hydride ion and its derivatives LiAlH4 and NaBH4 Reduction of aldehydes and ketones 17
Meerwein-Ponndorf reduction and Oppenauer oxidation, with a branch program on how to draw transition states 19
Two general revision problems 25
2 Nucleophilic Substitution 29
Substitution: how it happens 31
LiAlH4 reduction of esters 33
Reaction of Grignard reagents with esters 34
Alkaline hydrolysis of esters 38
Acid hydrolysis of amides 39
Summary of acid and base catalysis 41
Reaction between carboxylic acids and thionyl chloride 41
Synthesis of esters and anhydrides from carboxylic acids 43
Review questions 45
3 Nucleophilic Subsitution at the Carbonyl Group with Complete Removal of Carbonyl Oxygen 49
Imine formation from aldehydes and ketones 51
Oxime formation and the structure of oximes 53
Hydrazone and semicarbazone formation 54
Reduction of C=O to CH2 56
Conversion of C=O to CCl2 60
DDT synthesis 64
Chloromethylation of aromatic compounds 65
Review questions 66
4 Carbanions and Enolisation 69
Carbanions 71
Tautomerism 72
Equilibration and racemisation of ketones by enolisation 73
Halogenation of ketones 78
Formation of bromo-acid derivatives 83
Organo-zinc derivatives and their use in synthesis 85
Review questions 87
5 Building Organic Molecules from Carbonyl Compounds 89
Using enols as nucleophiles to attack other carbonyl groups 92
The aldol reaction 92
The Claisen ester condensation 93
Acid catalysed condensation of acetone 94
Self-condensation reactions 96
Elaboration of a skeleton in synthesis 97
Cross-condensations with molecules which cannot enolise 98
Mannich reaction 103
Perkin reaction 105
Stable enols from beta-dicarbonyl compounds 108
Knoevenagel reaction 110
Alkylation of beta-dicarbonyl compounds 113
Michael reaction 116
Decarboxylation 125
Base cleavage of beta-dicarbonyl compounds 131
Cyclisation reactions: the Dieckmann condensation 134
Cyclisation of diketones 136
The dimedone synthesis 137
Ring opening by base cleavage of beta-dicarbonyl compounds 141
Revision questions 142
Examples of syntheses: two steroid syntheses 145
Stork's cedrene synthesis 150
Index 155
Chapter 1
Nucleophilic Addition to the Carbonyl Group
Concepts assumed:
- ? - and -bonds.
- ? Polarisable bonds.
- ? Electrophile and nucleophile.
- ? Conjugation with -bonds and lone pairs.
- ? Inductive effects.
- ? values.
- ? Periodic table.
- ? Transition states.
Concepts introduced:
- ? Acid catalysis.
- ? Instability of R2C(OR)2 in acid solution. Driving equilibria in a chosen direction by the use of acid, solvent, etc.
- ? Stability of different carbonyl compounds. Stability and reactivity as two sides of the same coin.
- ? Effect of substituents on equilibria. Relationship between basicity and nucleophilicity.
- ? Organo-magnesium compounds as nucleophiles.
- ? Use of Grignard reagents in syntheses.
- ? Ease of dehydration of tertiary alcohols in acid solution.
- ? Sources of nucleophilic H-.
- ? Use of Al and B compounds and as anion transferring reagents.
- ? Drawing transition states.
- ? Stability of the six-membered ring.
- ? Use of protecting groups.
- ? Use of reaction mechanisms in syntheses.
Have you read the introductions explaining what help you need, what you need to know and how to use the program? It's a good idea to do this before you start.
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- 1. The carbonyl group (1a) has an easily polarisable -bond with an electrophilic carbon atom at one end easily attacked by nucleophiles:
Write down the reaction (with curly arrows) between acetone and hydroxide ion.
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- 2. Have you actually written down the formulae of the reagents and drawn the arrows? The program won't be of much help to you unless you do.
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- 3.
A nucleophile such as water uses its lone pair electrons (:) to attack and forms a neutral addition compound by proton transfer:
Note that only one proton is needed.
Write down the reaction between the carbonyl compound acetaldehyde and the proton-bearing nucleophile ethanol.
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- 4. If you find this difficult, use the lone pair electrons on the ethanol oxygen atom to attack the carbonyl group of acetone.
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- 5. Answer to frame 3:
Another approach is to add the proton first, in acid solution, and to add the nucleophile afterwards:
In this case, the proton is regenerated and this is an example of acid catalysis. Show how water can be added to acetone with acid catalysis.
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- 6. If you are having difficulty with this, look back at the last reaction in frame 5. Carry out these same steps using acetone as the carbonyl compound and water as HX.
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- 7.
Notice that Me2C=O+H is much more reactive than acetone, but is still attacked at carbon although the positive charge is in fact on the oxygen atom. What would happen to R2C=O+H with water, ethanol, PhCH2SH and cyanide ion?
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- 8. The compounds:
would be formed by a mechanism exactly like the one in frame 7. When you combined R2C=O+H with ethanol you formed an adduct (8b), which is the product of ethanol addition to a ketone. The steps you drew are therefore part of the acid catalysed addition of ethanol to a ketone. Draw out the whole of this reaction.
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- 9.
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- 10. Look at the reactions in frames 7 and 9 again. Note that all the steps are reversible and that therefore R2C=O+H may be formed from R2C=O, R2C(OH)2 or R2C(OH)OR:
It is in fact a general rule that compounds of the type R2C(OR)2, having two oxygen atoms singly bonded to the same carbon atom, are unstable in acid solution. A reason for this is that both oxygens have lone pairs of electrons, and so, when one pair is protonated, the lone pair on the other can form a C=O double bond and expel the protonated atom. Draw this in detail.
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- 11.
Look at the reactions in frame 10 again. In the reverse reaction, we protonated and removed the EtO- group from 10c. What happens if we protonate and remove the HO- group?
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- 12.
This new cation, R2C=O+Et, is just as reactive as R2C=O+H and can add nucleophiles in the same way. What happens if we add EtOH to it?
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- 13.
This reaction sequence, added to the ones in frames 9 and 12, gives us the addition of two molecules of ethanol to a ketone to give R2C(OEt)2. Draw this sequence out in full without referring back.
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- 14. If you have difficulty doing this, look at frames 9, 12 and 13 without writing anything down and then try again.
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- 15.
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- 16. Does your reaction sequence exactly follow that in frame 15? If not, try to assess if the differences are trivial. If you are still in doubt, consult your adviser. It is important that you understand this reaction well.
This is a good place to stop if you want a break.
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- 17. Since this whole sequence is reversible, it will go forwards in ethanol and backwards in water. What do you think would happen if acetaldhyde and n-butanol were dissolved together in a 1 : 3 molar ratio, and the solution refluxed for 12 hours with a catalytic quantity of toluene sulphonic acid, and the product dried and distilled?
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- 18. This is a literature preparation of CH3CH(OBun)2. Acetaldehyde is the carbonyl component, butanol is the nucleophile and toluene sulphonic acid is the catalyst. How would you hydrolyse PhCH(OEt)2, and what would you get?
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- 19. Reflux PhCH(OEt)2 in water with a catalytic quantity of an acid. The products would be PhCHO and EtOH. How would you make EtCH(OMe)2?
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- 20. Treat EtCHO and MeOH as in frame 17. A glance at the reactions in frame 15 should convince you that the mono adducts of carbonyl compounds and nucleophiles with lone pairs are unstable. An example is R2C(OH)OEt, which is unstable even under the conditions of its formation. What happens to it?
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- 21. In ethanol it gives the acetal R2C(OEt)2, in water the carbonyl compound R2C=O.
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- 22. If we look instead at nucleophiles without lone pairs, we should find some stable mono adducts. Which of the adducts in frame 8 should be stable?
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- 23. The cyanide substituent has no lone pair and so its adduct, R2C(OH)(CN), should be stable. These compounds, cyanohydrins, are made by adding excess NaCN and one equivalent of acid to the carbonyl compound. The reaction is an equilibrium. What is the role of the acid?
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- 24. To drive over the equilibrium by protonating the intermediate:
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- 25. Since this reaction is an equilibrium, the amount of cyanohydrin formed from any given carbonyl compound will depend on the relative stabilities of the carbonyl compound itself and the product. There can be many substituents 'X' on a carbonyl compound RCOX, such as Cl, Me, NH2, Ph, OEt, H. Some have inductive effects, some are conjugated with the carbonyl group. Some stabilise RCOX making it less reactive. Others activate it towards nucleophilic attack. Arrange the compounds RCOX, where 'X' can be the substituents listed above, into an order of reactivity towards a nucleophile.
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- 26. Before you look at the answer in the next frame, just check that you have considered each of these factors: some substituents stabilise RCOX by -conjugation:
some by lone pair conjugation:
some destabilise RCOX by inductive electron withdrawal:
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- 27. Taking RCHO as standard, we can say that Cl destabilises by inductive withdrawal, Me stabilises more by -delocalisation and NH2 and OEt by lone pair donation. (NH2 is more effective at this: compare ammonia and water as bases). Our order...
